WO1997014685A1 - Pyrimidine derivatives - Google Patents

Pyrimidine derivatives Download PDF

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Publication number
WO1997014685A1
WO1997014685A1 PCT/HU1996/000058 HU9600058W WO9714685A1 WO 1997014685 A1 WO1997014685 A1 WO 1997014685A1 HU 9600058 W HU9600058 W HU 9600058W WO 9714685 A1 WO9714685 A1 WO 9714685A1
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WIPO (PCT)
Prior art keywords
formula
hydroxy
optionally substituted
group
defined above
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Application number
PCT/HU1996/000058
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French (fr)
Inventor
Zoltán ZUBOVICS
Katalin SZILÁGYI
Franciska Vida
Ferenc ANDRÁSI
Klára SUTKA
Eszter Hodula
Tibor Szekeres
Gábor FEHÉR
Imre Moravcsik
Péter MÁTYUS
László Sebestyén
Hilda SZABÓ
Erzsébet ZÁRA
Edit HORVÁTH
Lajos Toldy
Original Assignee
Gyógyszerkutató Intézet Kft
TOLDY, Rózsa
TOLDY, Márta
TOLDY, András
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Application filed by Gyógyszerkutató Intézet Kft, TOLDY, Rózsa, TOLDY, Márta, TOLDY, András filed Critical Gyógyszerkutató Intézet Kft
Priority to AU73259/96A priority Critical patent/AU7325996A/en
Priority to HU9900088A priority patent/HUP9900088A2/en
Publication of WO1997014685A1 publication Critical patent/WO1997014685A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/50—Three nitrogen atoms

Definitions

  • This invention relates to novel pyrimidme deriva ⁇ tives capable to effectively inhibit the peroxidation of lipids. More particularly, the invention refers to novel pyrimidine derivatives of formula (I),
  • R stands for a moiety of formula (a)
  • Ar means a C 6 - ⁇ o aromatic homocyclic group
  • R 4 and R 3 independently from each other, represent hydrogen, halogen, hydroxy, C:- ⁇ al yl, C ⁇ - 4 alkoxy optionally substituted by phenyl, C ⁇ _ 4 alkylthio,
  • R" and R ⁇ independently from each other, stand for ammo; or a moiety derived from a 5-8-membered saturated heterocycle containing at least one nitrogen atom;
  • X means a single bcr. ⁇ ; a sulfur atom optionally substi ⁇ tuted one or two oxygen atcmls, or an optionally substituted nitrogen atom;
  • A stands for a straight or branched chain C ; - alkylene group optionally substituted by halogen, hydroxy, C;- alkoxy optionally substituted by phenyl, c 4 al- kanoyloxy, optionally substituted ammo and/or oxo; and n is 1 or 2, with the proviso that when
  • R" means a moiety cf formula (a) , wherein Ar means phenyl; and at least one of R J and R ; ⁇ .ands for halogen, hy ⁇ droxy, C.-3 al yl, C;. alkoxy, C .., alkanoyloxy or ethanesulfor.yloxy;
  • A may not be unsubstituted C alkylene; and with the further proviso that when R" is 2, 5-dihydroxybenzoyl; A may not be alkylene substituted by oxo; as well as their salts and pharmaceutical compositions containing these compounds.
  • the invention refers also to a process for the prepa ⁇ ration of the above pyri idine derivatives.
  • the novel in ⁇ termediates of formula (II) are also to a process for the prepa ⁇ ration of the above pyri idine derivatives.
  • the objective of the present invention was to find novel synthetic pyrimidme derivatives, which effectively inmbit the lipid peroxidation and are consequently use ⁇ ful to treat certain diseases and conditions in mammals, including man, where the inhibition of lipid peroxidation is desired.
  • One important class of these known compounds is rep ⁇ resented by substances wherein the group derived from the above-mentioned heterocycle containing one or more nitro- gen(s) is e.g. a pyridinyl, pyrimidinyl or triazinyl group bearing optionally substituted amino group (s) [such as the 2, 6-d ⁇ (substituted ammo) -4-pyr ⁇ midinyl moiety oc ⁇ curring also in the compounds of the present invention) .
  • said hydrocarbon group of these compounds may be varied within a wide range: it may be e.g. a group with a steroidal skeleton (see the PCT patent applica ⁇ tions published under Nos.
  • character- istic compounds contain, besides nitrogen heterocycles which are nearly the same as those mentioned in the pre- ceding paragraph, hydrocarbon groups that are either similar to or different from those mentioned above.
  • the characteristic hydrocarbon based moiety is e.g. phenyl, benzyl or benzhydryl group [French patent specification No. 1,507,062; published German patent ap ⁇ plications Nos. 1,947,332 and 2,211,738; Belgian patent specification No. 739,283; Canadian patent specification No. 983,497; as well as published Japanese patent appli ⁇ cation (Kokai) No. 74/76887]; benzodioxolyl or benzodi- oxanyl group [Canadian patent specifications Nos. 979,894, 983,493, 983,494 and 983,495 as well as pub ⁇ lished Japanese patent applications Nos.
  • ether compound types are also reported m the literature to possess a lipid peroxidation inhibitory effecr. This s exemplified by some compound classes as follows:
  • Cyclic hydroxamic acids [Y. Teshima et al . : J. Anti- blot. 44, 685 (1991)]; dehydroalanme derivatives [P. Buc-Calceron et al.: Arch. Biochem. Biophys. 273, 339 (1989)]; acylated polyamines [J. M. Braughler et al.: Biochem. Pharmacol. 37, 3853 (1938)]; glutathione analogues [Drug Data Reports 12, 339 (1990)]; amino analogues of vitamin C (published European pat ⁇ ent applications Nos. 446,539 and 447,325); monocyclic analogues of vitamin E (Japanese patent specification No. 01,226,843); other derivatives of vitamin E [R. Nikolov: Drug News & Perspectives 5, 507 (1992)];
  • methylprednisolone e.g. H. ⁇ . Demopoulos et al . : J. Physiol. Pharm. 60, 1415 (1982)]; flavonoids [e.g. R. Campos et al. : Planta Med. 55, 417 (1989)]; pyrazolmo ⁇ e derivatives [K. Abe et al.: Stroke 19, 480 (1988)]; pyrazolone ⁇ erivatives (published Japanese patent ap ⁇ plication No. 62-149,617); thiazolidinediones [T. Yoshicka et al . : J. Med. Chem.
  • Example 35 of the Hungarian patent application No. P 92 02172 a compound, namely l-[6- (2, 5-d ⁇ hydroxyben- zoylammo) -caproyl]-4-[2, 6-d ⁇ (1-pyrrol ⁇ dmyl) -4-pyr ⁇ m ⁇ d ⁇ - nyl]p ⁇ perazme is described, which is to some degree structurally similar to a variant, containing a benzoyl group, of compounds cf formula (I) of the present inven ⁇ tion, and exerts a remarkable lipid peroxidation mhibi- tory effect.
  • tnere are known compounds showing cer ⁇ tain structural relations to the compounds of formula (I) of the present invention, namely substances of formula (A)
  • Lip means inter alia 1- or 2-naphthyloxy; or 1,2,3,4- -tetrahydro-6-napnthyloxy substituted Dy oxo;
  • a : and A * represent single bond(s) or C ; . alkylene op ⁇ tionally substituted by hydroxy or oxo; n is 1 or 2; and Ke :an ⁇ s i r. ter al ⁇ ⁇ group cr tor: ,3)
  • R means ammo or 1-pyrrol ⁇ dmyl group.
  • the compounds of formula (A) mentioned aoove showed a remarkable lipid peroxidation inhibitory effect under in vi tro conditions.
  • e value of lower than 30 ⁇ M (the test method will be discussed hereinafter) .
  • n mice Under i n vi vo conditions m a head injury model n mice a dose of 20 mg/ g of the most active compound among the napnth ⁇ yloxy derivatives, .e. the l-[2, 6-d ⁇ (1-pyrrol ⁇ dmyl) -4- -pyr ⁇ m ⁇ dmyl]-4-[2-hydrcxy-3- (2-naphthyloxy)propyl]homop ⁇ - perazme of Example 27, induced a 82 . increase in the total score characterizing the neurologic state of the O 97/14685 "" - ,_ _ -_,. PCT/HU96/00058
  • Example 31 the IC value of l-[2, 6-d ⁇ (1-pyrrol ⁇ d ⁇ nyl) - -4-pyr ⁇ m ⁇ dmyl]-4-[2-hydroxy-3- (2-naphthylam ⁇ no)propyl]- piperazme of Example 31 was 2 ⁇ M; that of l-[2,6-d ⁇ (l- -pyrrolicmyl) -4-pyr ⁇ m ⁇ dmyl]-4-[2-hydroxy-3- (2-naphthyl- ammo) propyl]homop ⁇ perazme according to Example 34 was 4 ⁇ M; that cf l-[2, 6-d ⁇ ( 1-pyrrol ⁇ dmyl) -4-pyr ⁇ m ⁇ dmyl]-4-[2- -hyoroxy-3- (2-naphthylth ⁇ o)propyl]homop ⁇ perazme accord ⁇ ing to Example 37 was 10 ⁇ M; and that of l-[6-(2,5- -o ydroxy
  • these compounds exerted a much stronger protective action under in vi vo conditions, and this action can oe explained by their lipid peroxidation nibitory effect detectable under in vi tro conditions.
  • these substances showed a surprising sur ⁇ plus effect when they were compared either to known com ⁇ pounds remote from those of formula (I), or to known com ⁇ pounds m some structural relation to those of formula (I), e.g. compounds of formula (A) containing a naphthy- loxy group.
  • a 2.5 mg/kg dose of l-[2,6- -di (1-pyrrol ⁇ d ⁇ nyl) -4-pyr ⁇ m ⁇ dmyl]-4-[2-hydroxy-3- (2-naph- thylammo) propyl]homop ⁇ perazme according to the present invention (compound of Example 34) augmented the total score by 119 * in the same test; and a 2.5 mg/kg dose of l-[6- (2, 5-d ⁇ hyoroxybenzoylam ⁇ no) hexyl]-4-[2, 6-d ⁇ (1-pyrro- lidinyl) -4-pynm ⁇ dmyi]p ⁇ peraz ⁇ ne (compound of Example 1) of the present invention resulted in a total score in ⁇ crease of 125 _.
  • the present invention relates to novel pyrimidine derivatives of formula (I) and their salts, wherein R', R : , R " , X, A and n are as defined above.
  • Some representative compounds of formula (I) accord ⁇ ing to the present invention contain one or more asymmet ⁇ ric carbon atom(s); therefore, they can exist either in the form of stereoisomers (e.g. enantiomers or diastereo- mers) or their mixtures (e.g. racemates of enantiomers) .
  • the scope of the present invention includes also the pure stereoisomers, the racem c and other mixtures of compounds of formula (I) as well as the salts, especially pharmaceutically acceptable salts, of all these co - pounds.
  • R" or R ; in formula (a) being present as R" means an optionally substituted amino group
  • the said substitu- ent of the amino group may be e.g. one or two C ; - 4 alkyl,
  • C-.-4 alkanoyl C.- 4 alkoxycarbonyl optionally substituted by phenyl, C . - ⁇ alkylsulfonyl or arylsulfonyl group.
  • R may be (but not limited to) 1-naphthyi, 2- -naphthyl, l-chloro-2-naphthyl, 4-chloro-l-naphthyl, 5- -chIoro-2-naphthyl, l-bromo-2-naphthyi, 5-brcmo-2- -naphthyl, 6-bromo-2-naphthyl, 1, 6-d ⁇ bromo-2-naphthyl, 5, 8-dibromo-2-naphthyl, 2-hydroxy-l-naphthyl, 4-hydroxy- -1-naphthyl, 3-hydroxy-2-naphthyi, l-hydroxy-2-naphthyl, 4-methoxy-l-naphthyl, 6-methoxy-i-naphthyl, 6- ⁇ r.ethoxy-2--
  • R" preferably represents e.g. 3- -hydroxy-2-naphthyl or l-hydroxy-2-naphthyl group; whereas in the case, when the meaning of X is different from a single bond, R" preferably stands for 1-naphthyl, 2-naphthyI, 2-naphthylmethyl, 2- (2-naphthyl) acetyl group or 2, 5-d ⁇ hydroxybenzoyl .
  • a substituent optionally being present on the naphthyi group may be at- tached to any carbon atom of any ring of tne naphthyi moiety; but preferably, it is attached to a carbon atom of the same ring, which bears the X group.
  • R 4 and R substituents within the groups of formula (a) being present as R 1 (e.g. hydroxyl, amino and/or carboxyl group) may be protected, if desired.
  • R 1 e.g. hydroxyl, amino and/or carboxyl group
  • substituents within the groups of formula (a) being present as R 1 may be protected, if desired.
  • R 1 e.g. hydroxyl, amino and/or carboxyl group
  • R 1 e.g. hydroxyl, amino and/or carboxyl group
  • R and R " may be (but not limited thereto) , independ ⁇ ently from eacn other, amino, 1-pyrrolidmyl, 1-p ⁇ per ⁇ - dinyl, hexahydro-lH-azepm-1-yi or cctahydroazccm-I-yi group and preferably amino and/or pyrrolidinyl group.
  • X may stand (but not limited thereto) e.g.
  • sulfur optionally substituted by one or more oxygen atom(s), an unsubstituted nitrogen or nitrogen op ⁇ tionally substituted by methyl, ethyl, formyl, acetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, methanesulfonyl or p-toluenesulfonyl group and preferably a simple chemical bond, sulfur or unsubstituted nitrogen.
  • A may be e.g.
  • a C - posture alkoxy group optionally substituted by a phenyl group can be considered as a pro- tected hydroxyl group; whereas e.g. an amino group sub ⁇ stituted by a C - alkanoyl group or a C _ ⁇ alkoxycarbonyl group optionally substituted by a phenyl group or C . - 4 al- kylsulfonyl group may be considered to be a protected amino group.
  • the value of n is 1 or 2, and preferably 1.
  • Suitable salts of the compounds cf formula (I! con ⁇ taining basic groups are e.g. the salts formed with inor ⁇ ganic acids (e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acid and the like) or with organic acids (e.g. acetic, tartar c, citric, fuir.aric, succmic, maleic, methanesulfonic, ethanesulfonic or p-toluenesulfonic acid and the like) .
  • compounds of formula (I) con ⁇ taining a phenyl or naphthyi group substituted by hydroxy and/or carboxy can form salts with bases in addition to the acid-addition salts.
  • Suitable salts formed with bases are e.g. the alkali metal salts (such as sodium or potas- O 97/14685 - I S - PCT/HU96/00O58
  • sium salts alkaline earth metal salts , e.g. calcium or magnesium, salts) and the like; as well as salts formed with some organic bases such as ethanolamme, diethanoia- mine, ethylenedia ine and the like.
  • R " and R" are as defined above and Z means a leaving group; or b) in order to obtain compounds cf formula (I), wherein R', ?.-, R 3 and n are as defined above; A is as defined above, with the proviso that it may not be alkylene substituted by halogen, ammo cr C;-,, alkylaminc; and
  • X is as defined for the formula (I), with the pro ⁇ viso that it may not be a single bond or a sulfur atom substituted by one or two oxygen atom(s), a compound of formula (IV),
  • R : , R 3 , A and n are as defined above and Z means a leaving group; cr c) in order to obtain compounds of formula (I), wherein R", R", R- ' and n are as defined above;
  • A is as defined above, with the proviso that it may not be alkylene substituted by halogen, amino or C;.j alkylaminc; and
  • X is as defined above, with the proviso that it may- net be a single bond, a compound of formula (VI),
  • R -X-A-Z (VI) wr.e em R , X and A are as defined above and 2 ⁇ *ea ⁇ 3 ⁇ leaving group, s reacted with a compound of formula
  • R", R", R 3 and n are as defined above; and X s as defined above, with the proviso that it may not be a single bond, a compound of ormula (VIII) ,
  • R', R", R J and n are as defined above; and X is as defined for formula (I), with the proviso that it may not be a single bono or a sulfur atom substituted by one or two oxygen atom(s), a compound of formula (IV), wherein R and X are as de ⁇ fined above, s reacted with a compound of formula (IX),
  • R', R", R", X and r. are as defined above; and B * means a single bond or a straight or branched chain C -- alkylene group optionally substituted by halogen, C... alkoxy, C - alkanoyloxy and/or an optionally substituted ammo group, a carboxylic acid of formula (X) , R - -X -3 ' -C0CH ( X !
  • R", R", R J and n are as defined above;
  • X stands for a nitrogen atom optionally substituted by a C alky group; and B" means a straight or branched chain C.. 3 alkylene group optionally substituted by hydroxy, C 4 alk ⁇ oxy and/or di;C- . - 4 alkyl) ammo group, a compound of formula ,XI),
  • Z means a leaving or hydroxyl group and R : is as defined above, with the proviso that p, q and r are 0 when Z means a nydrcxyl group, is reacted with a compound of formula (XII) ,
  • R", R 3 , B : , X and n are as defined above, and, if desired, a compound of formula (I) obtained by using any of the process variants a) to g) is transformed to an other compound of formula (I) m a manner known per se; and/or a protective group optionally being present is removed; and/or, if desired, a base is prepared from an obtained salt of the compound cf formula (I); or the ob ⁇ tained base is transformed to one of its salts, e.g. to its acid-addition salt.
  • Pure enantiomers of a compound of formula (I) con ⁇ taining one single centre of asymmetry can be obtained e.g. by resolution cf a racemic compound cf formula (I) prepared by means of racemic reagents by using methods known par se (e.g. by formation and separation of diastereomeric salts or other derivatives) ; or, by carry ⁇ ing out the above process variants with the pure enanti- o eric forms of the required reagents.
  • the diasterecmers of a substance of formula (I) m- eluding more centres of asymmetry can be separated by us ⁇ ing methods known per se, e.g. chromatography, fractional crystallization cr ether similar methods.
  • the protective group (s) is (are) removed without any undesired change in other parts of the molecule.
  • usual protective groups known per se may be employed, e.g. C -4 alkyl groups optionally substituted by an aryl group (such as tert-butyl or benzyl group) for protecting hydroxyl groups; C - 4 alkoxycarbonyl groups optionally substituted by an aryl, e.g. phenyl group (e.g. tert- -butoxycarbonyl or benzyloxycarbonyl group) , C - 4 alkanoyl groups (e.g.
  • C -4 alkanesulfonyl groups e.g. methanesulfonyl group
  • p-toluenesulfonyl group for protecting ammo groups
  • C _ 4 alkyl e.g. ethyl ester groups for protecting carboxyl groups.
  • any other protective group Known per se [such as the ones discussed by T. W. Greene and P. Wuts m: "Protective Groups in Organic Synthesis", John Wiley _ Sons, New York, N.Y. (1991)] may be employed. Suitable methods of cleaving protective groups are discussed the same work cited above.
  • reaction steps of the proc ⁇ ess according tc the present invention can be performed also without t e transient protection of reactive groups not participating in the desired reaction.
  • Process variant a) (Reaction scheme A) A compound of formula (II) is reacted with a compound of formula (III) in a suitable solvent such as chlcroben- zene, dimethylfor amide, dimethylacetamide, N-methylpyr- rolidone or the like; or optionally without any solvent, at a temperature between 100 ⁇ C and 200 °C and, if neces ⁇ sary, in the presence of a base, e.g. inorganic base such as potassium carbonate or sodium hydroxide, or an organic base, e.g. triethyiamine or pyridine as acid-binding agent. When carrying out the reaction in the absence of any base, the liberated acid of formula H-Z may be bound by the product of formula (I) .
  • a suitable solvent such as chlcroben- zene, dimethylfor amide, dimethylacetamide, N-methylpyr- rolidone or the like; or optionally without any solvent, at a temperature
  • n is the same as defined for formula ( I ) ;
  • R" means an amine-protecting group, which i s t rans f ormed to a compound cf formula (XIV) ,
  • R : , X, A and n are as defined for formula (I);
  • R stands for an amine-protect g group, by using any of methods A) to E) to be discussed herein ⁇ after; then, after cleaving the protective group, a com ⁇ pound of formula (II) is obtained.
  • the difference between the methods starting from compounds cf formula (XIII) is that they provide the intermediate of formula (XIV) by means of various reagents.
  • the variants of preparing the intermediates of formula (XIV) are described hereinafter in detail [methods A) to C) are illustrated by reaction scheme H, whereas methods D) and ⁇ ) are shown by reaction scheme I] .
  • R " and n are as defined for formula (I);
  • X means a sulfur atom optionally substituted by one cr two oxygen atom(s) or an optionally substituted ni ⁇ trogen atom; and A stands for C-.- 9 alkylene substituted by hydroxy, C : alkoxy or C-..
  • a compound of formula (XIII), wherein R 4 means an amine- protecting group and n is as defined above, may be re ⁇ acted with a compound of formula (VI), wherein R 1 , X and A are as defined above, and Z is a leaving group, to give a compound of formula (XIV) , wherein R , R , X, A and n are as defined above.
  • This reaction is suitably carried out m a solvent, e.g. ethanol, propanol, acetonitrile or the like, in the presence e.g. of an inorganic base such as potassium car ⁇ bonate or sodium hydroxide, in a temperature range be ⁇ tween 20 °C and 100 ⁇ C.
  • a solvent e.g. ethanol, propanol, acetonitrile or the like
  • an inorganic base such as potassium car ⁇ bonate or sodium hydroxide
  • R 4 means an amme-protective group, e.g. alkanoyl group such as for yl group or preferably a C - 4 alkoxycarbonyl group op ⁇ tionally substituted oy aryl group such as tert-butoxy- carbonyl or benzyloxycarbonyl group.
  • alkanoyl group such as for yl group or preferably a C - 4 alkoxycarbonyl group op ⁇ tionally substituted oy aryl group such as tert-butoxy- carbonyl or benzyloxycarbonyl group.
  • a part of the pro ⁇ tected piperazme and homopiperazine derivatives of for- mula (XIII) is known [see e.g. T. R. Herrm et al.: J. Med. Chem. 18, 1216 (1975)] or can be prepared by methods analogous to known ones.
  • Z means a leaving group, suitably e.g. halogen such as chlorine, bromine or iodine; or an aliphatic or aromatic sulfonyloxy group sucn as methane- sulfonyloxy or p-toluenesulfonyloxy group.
  • a part of the compounds of formula (VI) is known [see e.g. E.K. Harwill et al.: J. Org. Chem. 17, 1957 (1952); and L.M. Schemel : J. Med. Chen. 6, 637 '1963)] or they can be prepared by using simple methods Known per se .
  • compounds of formula (VI) containing C . .- alkylene group as A may be prepared e.g. as illustrated in reaction scne e J start ⁇ ing with alcohols of formula (XIX) ,
  • R' and X are as defined above; and B stands for a C;-. alkylene group by using methods known per se .
  • compounds of formula (VI), con ⁇ taining an alkylene group substituted by oxo at the car ⁇ bon atom attached to X are suitably prepared by reacting an appropriate compound of formula (IV), wherein R * and X are as defined above, with a carboxylic acid of formula (XX) ,
  • B 3 means a C.-- alkylene group
  • Z is a leaving group, or with a reactive derivative thereof activated at the carboxyl group (see reaction scheme J) .
  • X means a sulfur atom optionally substituted by one or two oxygen atom(s) or an optionally substituted ni ⁇ trogen atom; and A stands for 2-hydroxy-l, 3-propylene group, a protected compound of formula (XIII), wherein R' 1 stands for an amme-protective group; and n is as defined above, is reacted with an epoxide of formula (VIII), wherein R' and X are as defined above, to obtain a compound of for- mula (XIV), wherein R', R ⁇ X, A and n are as defined above.
  • This reaction is conveniently performed in a solvent such as an alcohol, e.g. ethanol, at a temperature be ⁇ tween 20 °C and 100 ⁇ C, preferably at the boiling point of the solvent.
  • a solvent such as an alcohol, e.g. ethanol
  • R", X and n are as defined for formula (I); and A stands for C _- alkylene substituted by oxo at the carbon atom attached to the nitrogen-containing het ⁇ erocycle, a protected compound of formula (XIII), wherein R "1 means an amme-protecting group; and n is as defined above, is reacted with a carboxylic acid of formula (X) , wherein R * and X are as defined above; and B- means a single bond or C 1 --1 alkylene, cr a reactive derivative thereof activated at the car ⁇ boxyl group to obtain a compound cf formula (XIV) , wherein R", R ⁇ X, A and n are as defined above.
  • Such reactive forms are e.g.: acyl halides, e.g. an acyl chloride or acyl bromide; active esters, e.g. an aryl ester such as a phenyl ester; sym ⁇ metric or mixed anhydrides, e.g. a mixed anhydride pre ⁇ pared by means of a chloroformate ester and the like.
  • X and B are as defined for formula (X ) ; and Ar, R" and R are as defined for Ar, R" and R , respec ⁇ tively, forming a part of the group of formula (a) , with the proviso that R 4 and R 5 may not mean unsub ⁇ stituted ammo or am o substituted by a C,- 4 alkyl group.
  • lactons are the intramolecular aryl esters of the respective acids.
  • Some compounds of formula (X) such as 1-naphtho ⁇ c acid, 2-naphtho ⁇ c acid, 1-naphthylacet ⁇ c acid, 1-hydroxy- -2-naphtho ⁇ c acid, 3-hydroxy-2-naphtho ⁇ c acid are commer ⁇ cially available; whereas other ones, e.g. 2- (2-hydroxy- -1-naphthyl) acetic acid, 2- (3-hydroxy-2-naphthyl) acetic acid or 3- (2-hydroxy-l-naphthyl) propionic acid and their lactones of formula (XXI) [see e.g. Y. Ogata et al.: J. Org. Chem.
  • R ano n are as defined for formula (I);
  • X is as defined for formula (I), with the proviso that it may not be a single bond or a sulfur atom substi ⁇ tuted by one or two oxygen atom(s); and A stands for C . ._ alkylene substituted by hydroxy, C -; alkoxy, C ;-4 alkancyloxy cr optionally substituted by oxo at the carbon atom attached to X, a compound of formula (XIII), wherein R' means an amme-protective group; and n is as defined above, is first reacted with a compound of formula Z'-A-Z : , wherein
  • A is as defined above; and Z ' as well as Z ⁇ mean, independently from each other, leaving groups, to give a compound of formula (XV) ,
  • Both reactions may be carried out similarly as de- scribed in method A) .
  • the starting compounds cf formula Z"-A-Z " are commer ⁇ cially available cr may be prepared by using simple meth ⁇ ods known per se .
  • R ⁇ A and n are as defined above;
  • X represents a nitrogen atom optionally substituted by a C - 4 alkyl group, is obtained.
  • This suostitution reaction can be performed e.g. by reacting the compound of formula (XV) with ammo ⁇ nia, a C ., alkylamme cr potassium phthalimide in a man ⁇ ner known per se an inert solvent, such as an aii- phatic alcohol, dimethylformamide or the like.
  • an inert solvent such as an aii- phatic alcohol, dimethylformamide or the like.
  • potassium nthalimi ⁇ e the phthalimido compound obtained is treated e.g. with hydrazine an aliphatic alcohol in a manner known per se to provide the required substance of formula (XVI) .
  • R , ?.', A ano n are as defined abcve;
  • R * and n are as defined for formula (I);
  • X is as defined for formula (I), with the proviso that it may not be a single bond or a sulfur atom substi ⁇ tuted by one or two oxygen atoms; and
  • A stands for 2-hydrcxy-l, 3-propylene group, a protected compound cf formula (XIII), wherein R" means an amine-protective group; and n is as defined above, is first reacted with epichlorohyd ⁇ n and then the ob ⁇ tained epoxide of formula (XVII),
  • a compound of formula (XIII I can be reacted with epichiorohydrin e.g. by using methods described above for the preparation of the compounds of formula (VIII) .
  • compounds of formula (XVII; obtained as intermediates can be reacted with compounds of formula .IV) under conditions discussed in method 3) above.
  • an epox ⁇ ide of formula (XVII) prepared as described above is re ⁇ acted with ammonia or a C ; . 4 alkylamine in a suitable sol- vent, e.g. water cr an aliphatic alcohol or a mixture thereof, to give a compound of formula ,
  • R" and n are as defined above;
  • X means a nitrogen atom optionally substituted by a C : . 4 alkyl group, then the obtained compound is reacted with a compound of formula (XI), wherein R- is as defined above;
  • Z stands for a leaving group, under the conditions discussed in method D) , again to ob ⁇ tain a compound of formula (XIV) , wherein R-, R ⁇ A and n are as defined above; and X stands for a nitrogen atom optionally substituted by a C;- 4 alkyl group.
  • the protective group R 4 can be removed from compounds of formula (XIV) prepared by the above methods A) to E) to afford compounds cf formula (II) .
  • alkanoyl type protective groups can be removed by acidic or alkaline treatment; C : - 4 alkoxycarbonyl groups can be removed e.g. by treatment with an acid; whereas C.- 4 alkoxycarbonyl groups substituted by an aryl group can be split off e.g. by catalytic hydrogenation.
  • a part of the starting compounds of formula (III; used in process variant a) is known [see e.g. B. Roth et al.: J. Am. Chem. Soc. 72, 1914 (1950); and published PCT patent application No. WO 87/01706], whereas an ether part thereof can be obtained from starting compounds of formula (XXII! ,
  • R " and R 3 are as defined for formula (I) , by us ⁇ ing methods known per se in a route illustrated by the reaction scne e K.
  • reaction scheme B A compound of formula (IV) is reacted with a compound of formula (V) a suitable solvent, e.g. ethanol, ace ⁇ tone or dimethylformamide, conveniently in the presence of a base such as an inorganic base, e.g. potassium car ⁇ bonate or sodium hydroxide, or an organic base, e.g. pyridme or triethylamine, at a temperature between room temperature and the boiling point of the solvent used.
  • a suitable solvent e.g. ethanol, ace ⁇ tone or dimethylformamide
  • the starting compounds of formula (IV) are commer ⁇ cially available wnereas the compounds of formula (V) are partly known (see e.g. the published European patent ap- plication No. 0,574,906A); or they can be prepared simi ⁇ larly to known substances by using known methods.
  • reaction scheme C A compound of formula (VI) is reacted with a compound of formula (VII) in an inert solvent, e.g. acetone, ace ⁇ tonitrile, or dimethylformamide, suitably in the presence of a base, e.g. potassium carbonate or the like, at a temperature between room temperature and the boiling point of the solvent used.
  • an inert solvent e.g. acetone, ace ⁇ tonitrile, or dimethylformamide
  • a compound of formula (VIII) is reacted with a com ⁇ pound of formula (VII) in an inert solvent, e.g. a halo- genated hydrocarbon such as methylene chloride or in an alcohol, e.g. ethanol or the like, at a temperature be- tween room temperature and the boiling point of the sol ⁇ vent used.
  • an inert solvent e.g. a halo- genated hydrocarbon such as methylene chloride or in an alcohol, e.g. ethanol or the like
  • reaction scheme E A compound of formula (IV) is reacted with a compound of formula (IX) under conditions described for process variant d) .
  • the starting compounds of formula (IX) can simply be prepared by reacting the compounds of formula (VII) with epichlorohydrm in a manner described e.g. for the prepa ⁇ ration of compounds cf formula (VIII) as illustrated by reaction scheme L.
  • reaction scheme F The free acid form of a compound of formula (X) or a reactive form thereof activated at the carboxyl group is reacted with a compound of formula (VII) .
  • This reaction can be carried out under similar conditions as the start ⁇ ing compounds of formula (II) of process variant a) are obtained according to the above-described method C) .
  • the present process variant f) e.g. the following characteristic compounds according to the present invention can be prepared: 1 [2, 6-di (1-pyrrolidinyl) -4-pyr ⁇ m ⁇ d ⁇ nyl]-4- (1-
  • a compound of formula (XI) containing a hydroxyl group as Z is reacted with a compound of formula (XII) suitably m an appropriate solvent, e.g. water, an alco ⁇ hol such as ethanol or in a polar, aprotic solvent such as dimethylformamide, dimethylacetamide and the like, or m the mixture thereof, at the boiling point of the sol ⁇ vent or without any solvent, at a temperature between 120 °C and 250 ⁇ C, optionally in the presence of a suitable catalyst, e.g. sodium hydrogen sulfite or the like, op ⁇ tionally m a closed vessel under pressure.
  • a suitable catalyst e.g. sodium hydrogen sulfite or the like, op ⁇ tionally m a closed vessel under pressure.
  • a compound of formula (XI) containing a leaving group as Z can be reacted with a compound of formula (XII) e.g. under conditions discussed under process variant c) .
  • C . alkylene group optionally substituted by hydroxy, C;- 4 alkoxy and/or di (C.. alkyl) amino; Z means a leaving group; ?" is an amine-protective group; and
  • X means a nitrogen atom optionally substituted by a d- alkyl group; or 5 and X together stand for a nitrogen atom protected by a bivalent amme-protective group, e.g. phthali ido group; e.g. under conditions similar to those described m proc ⁇ ess variant c , then the amine-protective group is re- moved from the obtained compound of formula (XXIV)
  • a compound of formula (I) prepared by employing one of the process variants a) to g) described above can be transformed to other compounds of formula (I) by using methods known per se .
  • an aromatic ring being present in group R " can be halogenated by a suitable halogenatmg agent, e.g. elementary halogen (such as chlorine or bromine) or an other convenient rea- gent (such as an N-halosuccinimide or sulfuryl halide); or nitrated by an appropriate nitrating agent, e.g.
  • Any nitro group occurring as a substituent of the group R" may be reduced to an amino group by means of a suitable reducing agent, e.g. elementary hydrogen in the presence of a noble metal catalyst or by using a complex • hydride, e.g. sodium borohydride.
  • a y carbonyl group optionally being present in the aliphatic moiety of the group R' may be reduced to meth ⁇ ylene group by means of a suitable reducing agent, such as a complex metal hydride, e.g. lithium aluminum hydride optionally in the presence of a Lewis acid, e.g. aluminum trichloride.
  • Any sulfur atom m the alkylthio group being present as a substituent of the group R' cr occurring as X can be oxidized by suitably choosing the amount of an appropri ⁇ ate oxidizing agent, e.g. m-chloroperbenzoic acid, to transform the sulfur atom being present at said site to a sulfur atom substituted by one or two oxygen atom(s) .
  • an appropri ⁇ ate oxidizing agent e.g. m-chloroperbenzoic acid
  • Any carboxyl group occurring as a substituent of the group R " ' may be esterified with an alcohol, e.g.
  • an ali ⁇ phatic alcohol suitably in the presence of an inorganic or organic acid (such as hydrochloric, sulfu ⁇ c, p- -toluenesulfomc acio and the like) as catalyst.
  • an esterified carboxyl group being present as a substituent of the group R' can be hydrolyzed to the free acid by using an aqueous solution of a base (e.g. an al ⁇ kali metal hydrcxide or carbonate) ; or it can be reacted with ammonia or an aliphatic amine to obtain the respec- tive carboxamide.
  • a base e.g. an al ⁇ kali metal hydrcxide or carbonate
  • a nitrogen-unsubstituted carboxamide can be transformed to the corresponding cyano compound by treatment with a suitable dehydrating agent (e.g. sulfu- ric acid, pncs r.crus pentoxide, polyphosphoric acid or the like) .
  • a cyano group can be hydrolyzed with a strong acid (such as hydrochloric, sulfuric or phosphoric acid and the like) or a base (such as sodium hydrcxide, potassium carbonate and the like) to a carbox- amido or carboxyl group depending on the reaction condi ⁇ tions .
  • Any NH or OH group occurring as a substituent of the R' and/or A group can be acylated to an N-acyl or O-acyl derivative, respectively, by means of an appropriate acy- lating agent (e.g. acyl chloride, acid anhydride, active ester, mixed anhydride or the like) ; or can be trans ⁇ formed to an N-alkyl cr O-alkyl derivative, respectively, by means of a usual alkylat g agent (such as an alkyl halide, alkyl sulfate, aromatic sulfonate ester or the like) .
  • an appropriate acy- lating agent e.g. acyl chloride, acid anhydride, active ester, mixed anhydride or the like
  • a usual alkylat g agent such as an alkyl halide, alkyl sulfate, aromatic sulfonate ester or the like
  • a hydroxyl group can be replaced by a halo ⁇ gen atom by means of a convenient halogenating agent (such as thionyl chloride, phosphorus pentachloride, phosphorus pentabromide or the like) and subsequently, this halogen can be replaced by an ammo or alkoxy group by using the respective am e or alkoxide.
  • a convenient halogenating agent such as thionyl chloride, phosphorus pentachloride, phosphorus pentabromide or the like
  • the compounds of formula (I) according to the present invention and their pharmaceutically acceptable salts possess valuable biological effects. More particularly, these compounds inhibit the peroxidation cf lipids and therefore, they are useful to treat diseases and patho ⁇ logical conditions where the inhibition of lipid peroxi- dation is desirable.
  • the lipid peroxidation inhibiting effect of the com ⁇ pounds according to the present invention and their phar- maceutically acceptable salts can be detected or meas ⁇ ured, respectively, by means of biochemical and pharma ⁇ cological investigations.
  • some of these in ⁇ vestigations as well as the results obtained in these m- vestigations with characteristic compounds according to the present invention are given.
  • the following known lipid peroxidation inhibiting compounds were used as ref ⁇ erence substances in these biological tests: 3,5-d ⁇ (tert- -butyll -4-hydroxytoluene ["butylated hydroxytoluene", BHT; see e.g. W.
  • the inhibition of iron (II) ion dependent lipid per ⁇ oxidation was measured in rat brain nomogenate as de ⁇ scribed by J.M. Braughler et al. [J. Biol. Chem. 262, 10438 (1987)] as well as by J. A. Buege and S. D. Aust [Metnocs m Enzy ology 52, 302 (1978)].
  • the IC_- values measured m this experiment and expressed in micromoles of several representatives of compounds according to the invention and reference compounds are shown in Table 1.
  • the IC. value is the concentration of a compound tested, which decreases by 50 % the amount of thiobarbituric acid reactive substances (first of all malondialdehyde) con- sidered to be characteristic for the degree of lipid per ⁇ oxidation.
  • the acute toxicity of compounds of the present inven ⁇ tion was determined in rats.
  • the tcxicity of these com ⁇ pounds was found to be in general favourable, e.g. an in- traperitoneal dose of 500 mg/kg cf the compounds of Exam ⁇ ples 31, 34 or 44, respectively, did not provoke death of any of the treated animals (LD 5 r 500 mg/kg), similarly to tne above-mentioned compound U74006F used as reference compound.
  • the results shown above demonstrate that several rep ⁇ resentatives of the compounds of formula (I) according to the present invention inhibit the lipid peroxidation to a significant degree under in vi tro conditions.
  • these compounds are capable to suppress various pathological processes related to an enhanced peroxida ⁇ tion of lipids in the living organism.
  • these advantageous effects are accompanied by a favourable tox- lcity.
  • the compounds according to the present invention and their pharmaceutically ac ⁇ ceptable salts can be used alone or suitably m the form of pharmaceutical compositions. These compositions also fall within the scope of the present invention.
  • compositions contain an amount required to exert the therapeutical effect of a compound of formula (I) or its pharmaceutically acceptable salt, in admixture with known carriers, excipients, diluents and/or other additives commonly used m the pharmaceuti ⁇ cal practice.
  • the doses required to exert the therapeutical effect of tne compounds according to the invention may be varied depending on the individual condition and age of the pa- tient to be treated and finally these doses are deter ⁇ mined by the attending physician.
  • daily doses of these compounds falling between about 0.1 mg/kg of body weight and about 100 mg/kg of body weight and preferably between about 1 mg/kg of body weight and about 20 mg/kg of body weight are used by the oral or parenteral, e.g. intravenous, route.
  • the compounds according to the invention and the process for the preparation thereof are illustrated in detail by the following non limiting Examples.
  • the reac ⁇ tion mixture is then diluted with 120 ml of ice-water and after addition of 2 g of sodium, chloride, it is extracted with ethyl acetate. The organic layer is washed with wa- ter, drieo and tne ethyl acetate is evaporated under re ⁇ quiz hand. After washing the residue with ethyl ether, 2.4 " g (72 . yield) of title compound are ob ⁇ tained, m.p. 131-132 °C.
  • Step b) l - ⁇ 6-[N- (2 , 5-D ⁇ hydroxybenzoyl) am no]hexyl)-4 -[2 , 6-di (1- -pyrrol idinyl ) -4 -pyr ⁇ m d ⁇ nyl]p ⁇ peraz ⁇ ne
  • the pH value of the solution ob ⁇ tained is adjusted to 5 by using concentrated ammonium hydroxide, then the solvent is evaporated under reduced pressure.
  • the residue is dissolved in 30 ml of water, the pH of the solution is adjusted to 8.5 with concentrated ammonium hydroxide and the mixture is extracted with chloroform.
  • the residue is subjected to chromatography on a silica gel column by us ⁇ ing ethyl acetate as eluent, the title compound is ob ⁇ tained in a yield of 0.76 g (43%), m.p. 182-183 °C.
  • the title compound is prepared as described in Exam ⁇ ple 14, except that 2-thionaphthol is reacted with 1- -[2, 6-di (1-pyrrolidinyl) -4-pyrimidinyl]-4- (2-chloroace- tyl) homopiperazine instead of l-[2, 6-di (1-pyrrolidinyl) - -4-pyrimidinyl]-4- (2-chloroacetyl)piperazine and the crude product is stirred with 50 ml of water until it is disintegrated tc a filtrable powder to give 1.77 g (86 ) of title product, m.p. 56-63 °C.
  • aqueous phase is separated, extracted twice more with 40 ml of methylene cnloride each, the combined organic layers are wasned with water until neutral, dried over anhydrous magnesium sulfate, and the solvent is evapo ⁇ rated under reduced pressure to give 1.82 g (94.7.) of title product, m.p. 212-214 °C (after recrystallization from ethyl acetate) .
  • A represents a -C(0)-CH 2 - group
  • R has the meaning given in the following Table.
  • This intermediate is dissolved in 10 ml of aceto ⁇ nitrile, this solution is added to a suspension contain ⁇ ing 0.6 g (2 mmol) of l-[2, 6-di (l-pyrrolidmyl) -4-pyr ⁇ - m ⁇ d ⁇ nyl]p ⁇ perazme, 0.31 g (2.2 mmol) of potassium car ⁇ bonate and 0.01 g of sodium iodide m 10 ml of acetoni ⁇ trile, and the reaction mixture is stirred under reflux for 5 hours.
  • a suspension containing 2.11 g (5 mmol) of l-(2,6- -diammo- -pyri idinyl(piperazme bisz-t ⁇ fluoroacetate and 2.07 g (15 mmol) of potassium carbonate m 100 ml of ethanol is heated under reflux while vigorously stirring for 30 minutes. After filtering off the msolubles from the hot mixture, 1.0 g (5 mmol) of N- (2, 3-epoxypropyl) -1- -naphthylamme dissolved in 20 ml of ethanol is added to the filtrate.
  • Ms means methanesulfonyl group.
  • Example 1 The title compound is similarly prepared as described in Example 39, except that 2-naphthylamme is used in ⁇ stead of 2-th ⁇ onaphthol and the reaction mixture is heated under reflux for 24 hours.
  • the thus-prepared title compound is identical to the compound of Example 31.
  • the title product is obtained in a yield of 28.7%, m.p. 198- -201 °C.
  • the title compound is obtained m a yield of 39.0t if about 0.05 ml of concentrated aqueous hydrochloric acid is used as catalyst instead of tri ⁇ ethylamine.
  • Example 1 Example 1
  • All 1-naphthyl compounds occurring in the present Example contain the respective 2-naphthyl isomer as a contamination in an amount of about 15 to 20% (see also Example 117) .
  • Tne crude product obtained is purified by chromatograpny en a silica gel column by using a 1:2 mix ⁇ ture of n-hexane and ethyl acetate to obtain 0.51 g (54.4 %) of title compound, m.p. 211-214 °C.
  • R 1 , n, R 2 and R are as shown in the following Table.
  • R 1 means 6-methoxy-2-naphthyl group
  • X represents a single bond
  • A stands for -CH (CH 3 ) -C (0) - group
  • R , R 3 and n are as shown in the following Table.
  • both R and R 3 mean l-pyrrolidinyl group; and R' is as shown m the following Table.
  • X represents a single bond
  • B 1 means -CH -CH[NH-C0-0C (CH 3 ) 3 ] ⁇ group
  • n is 1
  • both R and R J mean l-pyrrolidmyl group
  • R 1 is as shown in the following Table.
  • X represents a single bond
  • B ! means -CH -CH (NH ; ) - group
  • n is 1
  • both R 2 and R 3 mean l -pyrrol idinyl group
  • R 1 is as shown in the following Table .
  • R 1 means 2-hydroxy-l-naphthyl group
  • X represents a single bond
  • n is 1
  • Method B A mixture containing 0.29 g (2 mmol) of 2-naphthol, 0.76 g (2.2 mmolj of 1- (2-ammoethyl) -4-[2, 6-di (l-pyrro ⁇ lidmyl) -4-pyr ⁇ m ⁇ d ⁇ nyl]piperaz ⁇ ne and 0.35 g (2 mmol) of sodium dithionite in 10 ml of water is heated in a steel bomb in an oil bath at 150-155 °C for 7 hours. After cooling down, the reaction mixture is extracted with ben ⁇ zene, the organic phase is washed first with 1 M aqueous sodium hydroxide solution, then with water and dried over anhydrous magnesium sulfate.
  • a solution of 0.6 g (3.2 mmol) of naphthalene-2- -carboxylic acid chloride in 6 ml of methylene chloride is added dropwise to a solution containing 1.0 g (2.9 mmol) of 1- (2-ammoethyl) -4-[2, 6-di (l-pyrrolidinyl) -4- -pyr ⁇ midmyl]piperazme and 0.5 ml (3.5 mmol) of triethy ⁇ lamine in 20 ml of methylene chloride, and the mixture is stirred without cooling for one hour.
  • Example 81 The title compound is prepared by using l-[2,6-di(l- -pyrrolidinyl) -4-pyrimidinyl]-4- ⁇ 2-[2- (2-naphthyl) acetyl- amino]ethyl ⁇ -piperazine as starting substance and follow ⁇ ing a procedure similar to that described m Example 79.
  • the title compound is obtained in a yield of 55.2 %, the L- (+) -tartrate salt melts at 105-115 °C (after crystalli ⁇ zation from ethanol) .
  • Example 81 The title compound is obtained in a yield of 55.2 %, the L- (+) -tartrate salt melts at 105-115 °C (after crystalli ⁇ zation from ethanol) .
  • a solution of 0.20 g (3.56 mmol) of potassium hydrox ⁇ ide in 2 ml of ethanol is added to a suspension contain ⁇ ing 0.4 g (0.7 mmol) of l-[2, 6-di (l-pyrrolidmyl) -4-pyr ⁇ - m ⁇ dmyl]-4-[N- (7-ethoxycarbonyl-l-naphthyl) carbamoyl- methyl]p ⁇ perazme in 10 ml of ethanol and the reaction mixture is heated under reflux for one hour while stir ⁇ ring.
  • the residue is subjected to chromatography on a silica gel column by using an 1:1 mixture of benzene and methanol as eluent to give the potassium salt of the ti ⁇ tle product in a yield of 0.16 g (41.0 %), m.p. above 360 °C.
  • aque ⁇ ous solution is rendered alkaline by adding 5 N sodium hydroxide solution, the precipitate is filtered, washed with water and then with acetonitrile to obtain 0.09 g (90%) of title product, m.p. 280 °C (with decomposition) .
  • Example 88
  • the mixture is ex ⁇ tracted three times with 40 ml of chloroform each, the combined organic solution is washed with 30 ml of satu ⁇ rated aqueous sodium chloride solution, dried over anhy ⁇ drous magnesium sulfate and the solvent is evaporated un ⁇ der reduced pressure.
  • the residue is subjected to chroma ⁇ tography on a silica gel column by using a 4:1 mixture of ethyl acetate and methanol as eluent to give 0.12 g (20.0%) of title compound, m.p. 184-186 ⁇ C.
  • a suspension containing the above chlorohydrm, 2.1 g (7 mmol) of l-[2, 6-di (1-pyrrol ⁇ d ⁇ nyl) -4-pyr ⁇ m ⁇ dmyl]p ⁇ per- azme and 1.8 g (13 mmol) of potassium carbonate in 40 ml of acetonitrile is heated under reflux under vigorous stirring for 5 hours. After evaporating the solvent under reduced pressure and triturating the residue with the mixture of 50 ml of water and 100 ml of ethanol while boiling, the suspension obtained is cooled to room tem ⁇ perature, tne precipitate is filtered off, washed with water until neutral and dried on air.
  • R 4 stands for a tert-butoxycarbonyl group
  • R 1 and X are as shown in the following Table, are prepared similarly to the procedures described in the above methods A) or B) , respectively.
  • the crystal ⁇ line product obtained is dissolved in 30 ml of water, the solution is rendered alkaline by adding 10 M aqueous so ⁇ dium hydroxide solution under stirring and cooling, then the mixture is extracted 4 times with 30 ml of ethyl ace ⁇ tate each. After washing the combined ethyl acetate lay ⁇ ers with 40 ml of water and drying over anhydrous magne ⁇ sium sulfate, the solvent is evaporated to obtain 0.67 g (45.9%) of crystalline title compound, m.p. 142-144 °C.
  • compounds of formula (II) are prepared, wherein A means 2-hydroxy-l, 3-propylene group; n is 1; and R' and X are as shown m the following Table.
  • Thin layer chromatography R f value is 0.58 on a Kiesel- gel 60 silica gel plate, by elut g with a 75:20:5 mixture of etnyl acetate, methanol and concentrated aqueous ammonium hydroxide solution.
  • a solution of 0.45 mi (0.66 g, 5.7 mmol) of mesyl chloride m 5 mi cf methylene chloride is added dropwise to a solution containing 1.7 g (4.2 mmol) of l-[2- -hydroxy-3- (2-napnthylth ⁇ o)propyl]-4- (tert-butoxycarbo ⁇ nyl)piperazme ana 0.87 ml (0.64 g, 63 mmol) of triethy ⁇ lamine m 30 ml of methylene chloride at a temperature between 20 and 25 ⁇ C.
  • the aqueous layer is separated and extracted twice with 15 ml of ethyl acetate each.
  • the combined organic solution is ex ⁇ tracted three times with 15 ml of 1 N hydrochloric acid each, then the pH of the combined aqueous-acidic solution is adjusted to 10 by adding a 5 N sodium hydroxide solu ⁇ tion and extracted three times with 20 ml of ethyl ace ⁇ tate each.
  • the organic layers obtained in the latter ex ⁇ traction are combined, washed with water until neutral, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure.
  • the base form of the product precipitates from the solution in the form of a white solid within a short time. After stirring the mixture for additional 10 min ⁇ utes, the precipitate is filtered off, washed with a small volume of cold water and dried on air to give 0.31 g (99%) of title product, m.p. 107-109 °C.
  • a suspension containing 0 . 78 g ( 3 mmol ) of 1- ( 2- -chloroacetyl ) -4- ( tert-butoxycarbonyl ) piperazine, 0.43 g ( 3 mmol ) of 2-naphthylamme and 0. 42 g ( 3 mmol ) of potas ⁇ sium carbonate in 30 ml of acetonitrile is heated under reflux for 8 hours under vigorous stirring. Then, the solvent is distilled off and the residue is partitioned between 30 ml of methylene chloride and 30 ml of water.
  • the title compound is prepared by starting from the compound prepared as described in the preceding step b) and following the procedure described m step c) of Exam ⁇ ple 93.
  • the t ⁇ fluoroacetate salt melts at 102-108 °C; a yield of 85.3* is achieved.
  • Step b) l-[2-(2-Naphthyith o)ac tyl]p ⁇ peraz ne
  • the title compound is prepared by starting from the compound prepared as described m the preceding step a) and following the procedure described under step c) of Example 93.
  • the product is obtained as an oil with a thin layer chromatography R f value of 0.64 (on a Kieselgel 60 silica gel plate, by elutmg with a 75:20:5 mixture of ethyl acetate, methanol and concentrated aqueous ammonium hydroxide solution) in a yield of 96.8%.
  • the title compound is prepared by starting from the compound prepared as described in the preceding step a) by following the procedure described in step c) of Exam ⁇ ple 93.
  • the product is identified in the form of its bis- -trifluoroacetate salt, m.p. 169-175 °C. A yield of 80.6% is achieved.
  • 6-Am no-4-hydroxy-2-(1-pyrrolidinyl)pyrimidine After dissolving 8.1 g (0.35 mol) of sodium metal in 240 ml of anhydrous methanol under stirring, 72.3 g (0.3 mol) of 1-am ⁇ d ⁇ nopyrrol ⁇ dme hydroiodide are added to the obtained solution. In an other flask 8.1 g of sodium metal are dissolved in 240 ml of anhydrous methanol and 34.2 g (0.3 mol) of ethyl cyanoacetate are dissolved in this latter solution. The mixture obtained is added to the solution prepared above. The reaction mixture is stirred under reflux for 3 hours and then cooled down.
  • 6-Am no-2- (1-pyrrolidinyl) -4-tosyloxypyr ⁇ m ⁇ d-.ne To a suspension containing 3.6 g '20 mmol) of 6- -ammo-4-hydroxy-2- (1-pyrrol ⁇ d ⁇ nyl) pyrimid e in 20 ml of pyridme, 5.0 g (25 mmol) of tosyl chloride are added at room temperature. The reaction mixture is stirred at room temperature for 30 minutes, during this time the starting compounds are dissolved. Then, the reaction mixture is poured onto 100 ml of water whereupon the product is pre ⁇ cipitated m solid form. The precipitate is filtered off, washed with a large volume of water and dried on air to yield 3.0 g (45 c ) of title product, m.p. 155-168 ⁇ C (with decomposition) .
  • the residue is dissolved in 15 ml of methanol and the solu ⁇ tion is acidified to pH 6 by adding ethyl acetate con ⁇ taining hydrogen chloride.
  • the crystalline precipitate is filtered, washed with ethyl acetate and dried.
  • the hydro- chloride obtained (m.p. above 280 °C) is dissolved m a small volume of water, made alkaline to pH 10 by adding 1 M sodium hydroxide solution and the product is extracted into methylene chloride (3 x 100 ml) . After combining the organic phases, the solution is dried over anhydrous mag ⁇ nesium sulfate and the solvent is distilled off to give 3.7 g (30%) of title product as a light yellow oil, which solidifies upon standing.
  • Step d) l-[6-Amino-2- (1-piperidinyl) -4-pyrimidinyl]piperazine
  • the tile compound is prepared starting with the com ⁇ pound prepared as described in the preceding step c) and by following the procedure described in step d) of Exam ⁇ ple 102 to give a yield of 66.7%.
  • the product is a yellow oil having a thin layer chromatography R ; value of 0.3 (on a Kieselgel 60 silica gel plate, by eluting with a 10:5:0.3 mixture of ethyl acetate, methanol and concen ⁇ trated aqueous ammonium hydroxide solution) .
  • Step c) l-[6-Am ⁇ no-2- (hexahydro-lH-azepm-1-yl) -4-pyr m ⁇ d - nyl]p ⁇ peraz ne
  • a solution containing 1.5 g (5 mmol) of l-[2,6-di(l- -pyrrolidinyl) -4-pyrimidinyl]piperazine and 0.5 ml (0.59 g, 6.4 mmol) of epichlorohydrm in 10 ml of ethanol is stirred at ambient temperature for 24 hours.
  • the precipi- tate is filtered off and washed with 2 ml of ethanol.
  • the wet material is dissolved in the mixture of 50 mi of ethyl ether and 5 ml of ethanol and stirred with 10 ml of a 10 M aqueous sodium hydroxide solution for 2 hours.
  • Example 107 Preparation of 1- (2-am ⁇ noethyl) -4-[2, 6-di (1-pyrrol ⁇ - d yl) -4-pyr ⁇ m ⁇ d ⁇ nyl]p ⁇ peraz ⁇ ne
  • Step a) l-[2 , 6-D ⁇ (1-pyrrolidinyl) -4-pyr m ⁇ d ⁇ nyl]-4-(2-phthal- lmidoethyl)piperazine
  • A represents -C(0)-CH 2 - group
  • R' is as shown in the following Table.
  • the precipitated salt is filtered off and washed with anhy- drous tetrahydrofuran.
  • the combined filtrate and washings are added portionwise to the solution of 3.1 g (82 mmol) of sodium borohydride in 78 ml of water at a temperature of 15 °C under stirring during 30 minutes, then the reac ⁇ tion mixture is stirred at ambient temperature for 4 hours.
  • the pH of the solution is again adjusted to 4 as men ⁇ tioned above.
  • the organic solution is briefly dried over an ⁇ hydrous magnesium sulfate, the solvent is evaporated un ⁇ der reduced pressure and the residue is stirred under re ⁇ flux in 25 ml of acetone saturated with sodium iodide, in the presence of 0.09 g (0.7 mmol) of diisopropylethy- lamine under nitrogen for 30 minutes.
  • the ethereal solution is dried over anhy ⁇ drous magnesium sulfate, the solvent is evaporated under reduced pressure and the residue obtained is washed with petroleum ether (b.p. 40-70 °C) to yield 3.83 g (89%) of title compound, m.p. 80-82 ⁇ C.
  • Intravenous pharmaceutical formulation Ingredients l- ⁇ 6-[N- (2, 5-D ⁇ hydroxybenzoyl) -amino]- hexyl ⁇ -4-[2, 6-di ( l-pyrrolidmylj -4-
  • the solution is filtered germ-free through a cellulose membrane of 0.2 ⁇ m pore diameter, filled into glass ampoules under aseptic conditions and the ampoules are sealed in an inert gas atmosphere.

Abstract

The invention refers to novel pyrimidine derivatives of formula (I), wherein R1 stands for a group of formula (a), wherein Ar means an aromatic homocyclic group, R?4 and R5¿ represent hydrogen, halogen, hydroxy, alkyl, optionally substituted alkoxy, alkylthio group and oxidized derivatives thereof, optionally substituted amino, carboxy and derivatives thereof, sulfo and/or sulfonamido; and p, q and r are 0 or 1; R?2 and R3¿ stand for amino; or a moiety derived from a nitrogen-containing heterocycle; X means a single bond; an optionally oxidized sulfur atom; or an optionally substituted nitrogen atom; A stands for an optionally substituted alkylene group; and n is 1 or 2. The invention relates also to a process and the intermediates for the preparation of the compounds of formula (I). The compounds according to the invention possess a remarkable lipid peroxidation inhibiting effect which is detectable both under in vitro and in vivo conditions. Thus, these compounds are useful for the prevention and/or treatment e.g. of injuries of the head, brain and spinal cord; as well as tissue damages arising from ischemia (including e.g. reperfusion injuries), myocardial infarction or coronary heart disease.

Description

PYRIMIDINE DERIVATIVES
This invention relates to novel pyrimidme deriva¬ tives capable to effectively inhibit the peroxidation of lipids. More particularly, the invention refers to novel pyrimidine derivatives of formula (I),
Figure imgf000003_0002
wherein
R: stands for a moiety of formula (a)
Figure imgf000003_0001
wherein
Ar means a C6-ιo aromatic homocyclic group, R4 and R3, independently from each other, represent hydrogen, halogen, hydroxy, C:-< al yl, Cι-4 alkoxy optionally substituted by phenyl, Cι_4 alkylthio,
Ci-4 alkylsulfinyl, C^., alkylsulfonyl, nitro, d-., alkanoyl, optionally substituted amino, carboxy, C:- alkoxycarbonyl, carboxamido, cyano, sulfo and/or sulfonamido; and p, q, and r are, independently from each other, 0 or
— t
R" and R~, independently from each other, stand for ammo; or a moiety derived from a 5-8-membered saturated heterocycle containing at least one nitrogen atom; X means a single bcr.ά; a sulfur atom optionally substi¬ tuted one or two oxygen atcmls, or an optionally substituted nitrogen atom; A stands for a straight or branched chain C;- alkylene group optionally substituted by halogen, hydroxy, C;- alkoxy optionally substituted by phenyl, c 4 al- kanoyloxy, optionally substituted ammo and/or oxo; and n is 1 or 2, with the proviso that when
R" means a moiety cf formula (a) , wherein Ar means phenyl; and at least one of RJ and R; ≤.ands for halogen, hy¬ droxy, C.-3 al yl, C;. alkoxy, C .., alkanoyloxy or ethanesulfor.yloxy;
A may not be unsubstituted C alkylene; and with the further proviso that when R" is 2, 5-dihydroxybenzoyl; A may not be alkylene substituted by oxo; as well as their salts and pharmaceutical compositions containing these compounds.
The invention refers also to a process for the prepa¬ ration of the above pyri idine derivatives. The novel in¬ termediates of formula (II)
R-X-A-N NH
used in the synthesis of the compounds of formula (I) also fall within the scope of the invention.
It is known that the peroxidation of lipids of the living organism is a metal ion-catalyzed radical process, which oxygen-containing radicals (e.g. hydroxyl raαi- cal, superoxide anion being radical in character and the like) also participate. This process alters the cellular membranes, interferes with the membrane transport proc- esses and finally, it may lead to the death of cells. Lipid peroxidation plays an important role in a number of pathological conditions and diseases and even in ageing. Such diseases and conditions are e.g. the in uries of the brain and spinal cord, acute cerebral stroke, some types of cerebrovascular spasms, tissue damages arising from ischemia (especially the so-called reperfusion injuries occurring during and after restoration cf blood circula¬ tion] , myocardial infarction, coronary heart disease, atherosclerosis, inflammatory diseases such as rheumatic arthritis or some inflammatory diseases of the gastroin¬ testinal system, e.g. pancreatitis or ulcerative colitis; furtnermore autoimmune diseases, certain side-effects of drugs, asthma; as well as several chronic diseases of the nervous system, e.g. parkinsonism, Alzheimer's disease and the like [see e.g. B. Halliwell: FASEB J. 1, 358 (1987); J.M. Gutteridge and B. Halliwell: Methods m En- zy oiogy 186, p. 1-84 (1990); D. Salvem i and R. Bot- ting: Drug News & Perspectives 6, 274 (1993)].
An intensive research is oe g carried out worldwide to find, on the one hand, substances wnicn moderate or inhibit oxidative processes the living organism in general (antioxidants) and, on the other hand, active agents specifically preventing the peroxidation of lip¬ ids. This latter type of active agents can be used in mammals, including man, for the prevention or treatment of diseases and conditions such as those mentioned above as being related to lipid peroxidation processes. These drugs may have an outstanding therapeutical importance: active agents with lipid peroxidation inhibitory activity that are suitable to treat e.g. injuries of the central nervous system can be considered as life-saving drugs [see e.g. J. Lehman: Drug News & Perspectives 5, 252 (1992)].
Several endogenous substances inhibiting lipid per¬ oxidation, e.g. alpha-tocopherol (alternatively named vi¬ tamin E) are present in the internal regulatory system of the mammalian body [see, e.g. M. J. Kelly in: "Progress in Medicinal Chemistry", vol. 25, p. 250, eds. G.P. Ellis and G. B. West, Elsevier Science Publisher (1988)]. The importance of substances inhibiting lipid peroxidation is illustrated e.g. also by two studies involving more than one hundred thousand people, according to which the risk of some diseases such as coronary neart disease can be reduced by the regular intake of vitamin E [M.J. Stampfer et al.: The New England Journal of Medicine 328, 1444 (1993); and E. B. Ri m et al.: The New England Journal of Medicine 328, 1450 (1993)].
The objective of the present invention was to find novel synthetic pyrimidme derivatives, which effectively inmbit the lipid peroxidation and are consequently use¬ ful to treat certain diseases and conditions in mammals, including man, where the inhibition of lipid peroxidation is desired.
Now, it has been found that this requirement is met m an outstanding manner by certain pyrimidme deriva¬ tives bearing two optionally substituted am o groups, wnere the pyrimidme ring is attached to a nitrogen atom of a piperaz e or homopiperazine cycle and the other ni¬ trogen of said piperazme or homopiperazine cycle bears a moiety, which comprises a naphthyi or phenyl group in a bond system defined hereinafter in detail.
A number of compounds with structures resembling to some degree the structure of the compounds of the present invention are described in the literature. For instance, some compounds are known, wherein one of the nitrogen at¬ oms of a piperazme ring is attached to an open-chain or cyclic hydrocarbon group whereas the other nitrogen atom thereof bears a 6-membered nitrogen-containing heterocy- cle such as a substituted pyridine, pyrimidine or triaz- ine ring. These known compounds show a variety of bio¬ logical effects .
One important class of these known compounds is rep¬ resented by substances wherein the group derived from the above-mentioned heterocycle containing one or more nitro- gen(s) is e.g. a pyridinyl, pyrimidinyl or triazinyl group bearing optionally substituted amino group (s) [such as the 2, 6-dι (substituted ammo) -4-pyrιmidinyl moiety oc¬ curring also in the compounds of the present invention) . Simultaneously, said hydrocarbon group of these compounds may be varied within a wide range: it may be e.g. a group with a steroidal skeleton (see the PCT patent applica¬ tions published under Nos. WO 87/01706 and WO 87/07895); a group with a secosteroidal skeleton (PCT patent appli- cation published under No. WO 88/07527); various substi¬ tuted alkyl groups of medium chain length; as well as various mono- and bicycles, e.g. substituted phenyl, phe- noxyalkyl or benzopyranyl groups and the like (PCT patent applications published under Ncs. WO 38/08424 and WO 91/06542) . These classes of compounds were reported to have lipid peroxidation inhibitory effect. It should be noted here that no molecules containing a naphthyi or nenzyl group or a benzcyl group attached through a nitro¬ gen or sulfur atom occur among these known compounds. The said PCT patent application published under No. WO 88/08424 disclosed some compounds resembling to one type of the compounds of the present invention, these known compounds contain a nitrogen heterocycle attached to a piperazme ring nitrogen while the claimed scope of the groups attached to the other nitrogen atom of the same piperazme ring include among others 2, 5-dιhydroxybenzyl or substituted benzoylamino both being connected to the piperazme ring via a C_-^ alkylene chain. In the specific compounds mentioned in the examples coth the dihydroxy- benzyl and the substituted benzoylamino group mentioned above are, however, attached directly to the piperazme ring nitrogen. No 2, 5-dιhydroxybenzoylammo compounds, wherein this group would be connected to tne piperazme ring through an alkylene chain longer than four carbon atoms, are mentioned specifically in the examples or claims of the published patent application mentioned above.
Antiiscnaemic 2-pyrιmιdmylpιperazme derivatives analogous to those described above are disclosed m the published European patent application No. EP 400661A among which derivatives, however, no 2, 6-dιammo-4- -pyrimidinyl compounds are mentioned.
In an other broad class of known compounds containing the above-mentioned three characteristic structural moie¬ ties (namely, a hydrocarbon group, a piperazme ring and a 6-membered nitrogen-containing heterocycle) character- istic compounds contain, besides nitrogen heterocycles which are nearly the same as those mentioned in the pre- ceding paragraph, hydrocarbon groups that are either similar to or different from those mentioned above.
Thus, the characteristic hydrocarbon based moiety is e.g. phenyl, benzyl or benzhydryl group [French patent specification No. 1,507,062; published German patent ap¬ plications Nos. 1,947,332 and 2,211,738; Belgian patent specification No. 739,283; Canadian patent specification No. 983,497; as well as published Japanese patent appli¬ cation (Kokai) No. 74/76887]; benzodioxolyl or benzodi- oxanyl group [Canadian patent specifications Nos. 979,894, 983,493, 983,494 and 983,495 as well as pub¬ lished Japanese patent applications Nos. 74/72270, 74/72271, 74/72272 and 74/72273 (Kokai)] as well as 3- -tπtyl-n-propyl group [G.R. Regnier et al.: J. Med. Chem. 15, 295 (1972)] directly connected to one nitrogen of tne piperazme r ng. (It is noted that derivatives containing naphthyi group do not occur among these com¬ pounds. ) A very wide variety of biological effects of a hign number of these latter compounds are described, e.g. the vasodilatory, tranquilizmg, analgetic, respiration- -stimulatmg effects are discussed. No mention is maoe about their lipid peroxidation inhibiting action.
In addition to tne classes cf compounds mentioned above which contain a piperazme ring and otner nitrogen- -heterocycle (s) , e.g. a pyrimidme ring, ether compound types are also reported m the literature to possess a lipid peroxidation inhibitory effecr. This s exemplified by some compound classes as follows:
Cyclic hydroxamic acids [Y. Teshima et al . : J. Anti- blot. 44, 685 (1991)]; dehydroalanme derivatives [P. Buc-Calceron et al.: Arch. Biochem. Biophys. 273, 339 (1989)]; acylated polyamines [J. M. Braughler et al.: Biochem. Pharmacol. 37, 3853 (1938)]; glutathione analogues [Drug Data Reports 12, 339 (1990)]; amino analogues of vitamin C (published European pat¬ ent applications Nos. 446,539 and 447,325); monocyclic analogues of vitamin E (Japanese patent specification No. 01,226,843); other derivatives of vitamin E [R. Nikolov: Drug News & Perspectives 5, 507 (1992)];
1, 4-benzoqumones [e.g. G. Goto: Chem. Pharm. Bull. 33, 4422 (1985)]; or napthoqumones [Drugs of the Future 14, 692 (1989)]; carboxyalkyi- and hydroxyalkyl-naphthoquinones [K. Oka oto et al. : Chem. Pharm. Bull. 30, 2797 (1982)]; salicylideneamine derivatives [ . Musleh et al.: Neu- ropharmacology 33, 929 (1994)]; acylammo-7-hydroxymdane derivatives [Y. Oshiro et al.: J. Med. Chem. 34, 2014 (1991)]; methylprednisolone [e.g. H. Ξ. Demopoulos et al . : J. Physiol. Pharm. 60, 1415 (1982)]; flavonoids [e.g. R. Campos et al. : Planta Med. 55, 417 (1989)]; pyrazolmoπe derivatives [K. Abe et al.: Stroke 19, 480 (1988)]; pyrazolone αerivatives (published Japanese patent ap¬ plication No. 62-149,617); thiazolidinediones [T. Yoshicka et al . : J. Med. Chem. 32, 421 (1989)]; piperidine derivatives [T. Kaneko et al.: Arzneimit- telforschung 39, 445 (1989)]; 4-arylthιopιperidme derivatives (published European patent application No. 433,167); dihydropyridmethiones [A.G. Odynets et al.: Eksp. Med. (Riga) 21, 127 (1986); Chem. Abstr. 106, 148956]; tetrahydropyridine derivatives [T. Gizur et al. : Eur. J. Med. Chem. 29, 349 (1994)]; pyrimidinediones (published European patent applica¬ tion No. 447, 324) ; bis (nicotmoyl-alkylene) -dia es [Drugs of the Fu- ture 61, 586 (1992)]; dihydroqumoline derivatives [A. Blazovics et al.: Free Radical Res. Commun. 4, 409 (1988)]; quinazolme derivatives (published European patent application No. 302,967); pyridylqumol es (published European patent applica¬ tion No. 289, 365) ; pyrimido-pyπmidines [T. Bellido et al.: Meth. Find. Exp. Clin. Pharmacol. 13, 371 (1991)]; benzothiaz es (Japanese patent specification No. 01,287,077) ; carbazole derivatives [R. Feuerste : Pharmacology 48, 385 (1994)]; anthrone ana acridine derivatives [P. Frank: Biochem. Biophys. Res. Commun. 140, 797 (1986)]; methylated uric acid analogues [Y. Nishida: J. Phar¬ macol. 43, 385 (1991)]; selenium compounds [A. Muller et al . : Biochem. Phar¬ macol. 33, 3235 (1984) and A. L. Tappel: Fed. Proc. 24, 73 (1965)]; and curcuminoids [S. Toda et al.: J. Ethnopharmacology 23, 105 (1988)]. The literature data discussed above illustrate, on tne one part, that compounds containing a piperazme ring and a mono- or diammo- (N-heterocycle* attached thereto do not necessarily show lipid peroxidation inhibitory ac- tivity; and, on the ether part, that the presence of the above nitrogen-heterccycies is not inevitable for this activity.
In Example 35 of the Hungarian patent application No. P 92 02172 a compound, namely l-[6- (2, 5-dιhydroxyben- zoylammo) -caproyl]-4-[2, 6-dι (1-pyrrolιdmyl) -4-pyrιmιdι- nyl]pιperazme is described, which is to some degree structurally similar to a variant, containing a benzoyl group, of compounds cf formula (I) of the present inven¬ tion, and exerts a remarkable lipid peroxidation mhibi- tory effect.
Furthermore, tnere are known compounds showing cer¬ tain structural relations to the compounds of formula (I) of the present invention, namely substances of formula (A)
Figure imgf000012_0001
with lipid peroxidation inhibitory effect, which had been disclosed the published European patent application
No. 057 906A, where formula (A)
Lip means inter alia 1- or 2-naphthyloxy; or 1,2,3,4- -tetrahydro-6-napnthyloxy substituted Dy oxo;
A: and A* represent single bond(s) or C;. alkylene op¬ tionally substituted by hydroxy or oxo; n is 1 or 2; and Ke :anαs i r. ter alι < group cr tor: ,3)
Figure imgf000013_0001
wherein
R means ammo or 1-pyrrolιdmyl group.
However, no compounds containing naphthylam o, naphthylthio group or the naphthyi group as a part of an acyi moiety are found among these substances.
The compounds of formula (A) mentioned aoove showed a remarkable lipid peroxidation inhibitory effect under in vi tro conditions. Thus, e.g. the compounds containing napnthyloxy or oxo-tetrahydronaphtnyloxy group according to Examples 22, 23, 26, 27, 30, 33 and 36 of the pub¬ lished European patent application No. 0574906A inhioiteα the iron ion-induced lipid peroxidation n rat brain ho¬ mogenate with an IC.e value of lower than 30 μM (the test method will be discussed hereinafter) . Unoer in vi tro ccnait ons, i-[2, 6-dι ,1-pyrrolιdmyl) -4-pyrιmιdmyl]-4-[2- -nydroxy-3- (i-napnthyloxy)propyl]hcmopιperazme of Exam¬ ple 23 with an IC_- value of 9 μM ano l-[2,6-dι(l- -pyrrolidmyl) -4-pyr mιdιnyl]-4-[2-hydroxy-3- '2-naphthyi- cxy, propyi]homopιperazιne of Example 27 with an IC33 value of S μM were found to be the most active compounds. Under i n vi vo conditions m a head injury model n mice a dose of 20 mg/ g of the most active compound among the napnth¬ yloxy derivatives, .e. the l-[2, 6-dι (1-pyrrolιdmyl) -4- -pyrιmιdmyl]-4-[2-hydrcxy-3- (2-naphthyloxy)propyl]homopι- perazme of Example 27, induced a 82 . increase in the total score characterizing the neurologic state of the O 97/14685 "" - ,_ _ -_,. PCT/HU96/00058
animals (the test method will be discussed hereinafter) . At the same t me, a 30 mg/kg dose of 21-{4-[2, 6-dι (1- -pyrrolidmyl) -4-pynmιdmyl]-l-pιperazιnyl}-16α-methyi- pregna-1, 4, 9 (11) -trιene-3, 20-dιone [U74006F, see e.g. in: Drugs of the Future 20, 218 (1995)] resulted in an im¬ provement of ~< 1 . in the same test.
On the other hand it has been found that, in compari¬ son with compounds according to the published European patent application No. 0574906A, some representatives of formula (I) of the present invention showed the same or somewhat stronger in vi tro lipid peroxidation inhibiting effect, e.g. the IC value of l-[2, 6-dι (1-pyrrolιdιnyl) - -4-pyrιmιdmyl]-4-[2-hydroxy-3- (2-naphthylamιno)propyl]- piperazme of Example 31 was 2 μM; that of l-[2,6-dι(l- -pyrrolicmyl) -4-pyrιmιdmyl]-4-[2-hydroxy-3- (2-naphthyl- ammo) propyl]homopιperazme according to Example 34 was 4 μM; that cf l-[2, 6-dι ( 1-pyrrolιdmyl) -4-pyrιmιdmyl]-4-[2- -hyoroxy-3- (2-naphthylthιo)propyl]homopιperazme accord¬ ing to Example 37 was 10 μM; and that of l-[6-(2,5- -o ydroxybenzoyiamino) hexyl]-4-[2, 6-dι (1-pyrrolιdιnyl) -4- -pyrιmιdιnyι]pιperazme according to Example 1 was 4 μM. In addition, surorisingly, these compounds exerted a much stronger protective action under in vi vo conditions, and this action can oe explained by their lipid peroxidation nibitory effect detectable under in vi tro conditions. In other woros, these substances showed a surprising sur¬ plus effect when they were compared either to known com¬ pounds remote from those of formula (I), or to known com¬ pounds m some structural relation to those of formula (I), e.g. compounds of formula (A) containing a naphthy- loxy group. Thus, e.g. l-[ό-ammo-2- ( 1-pyrrolιdmyl) -4-pynmι- dmyl]-4- ( l-hydroxy-2-naphthoyl)piperazme (compound of Example 46), in a dose of 1.25 mg/kg which is by an order of magnitude lower than that of the compounds of formula (A) or that of the above-mentioned compound U74006F used as reference substance, resulted m a higher improvement (132 .) of the total score in the above-mentioned m vivo head injury test. Similarly, a 2.5 mg/kg dose of l-[2,6- -di (1-pyrrolιdιnyl) -4-pyrιmιdmyl]-4-[2-hydroxy-3- (2-naph- thylammo) propyl]homopιperazme according to the present invention (compound of Example 34) augmented the total score by 119 * in the same test; and a 2.5 mg/kg dose of l-[6- (2, 5-dιhyoroxybenzoylamιno) hexyl]-4-[2, 6-dι (1-pyrro- lidinyl) -4-pynmιdmyi]pιperazιne (compound of Example 1) of the present invention resulted in a total score in¬ crease of 125 _. In addition, l-[2, 6-dι (1-pyrrolιdιnyl) - -4-pyrιmιdιnyl]-4-[2-hydroxy-3- (2-naphthylammo) propyl]- piperazme (compound of example 31) according to the pre¬ sent invention proved to be even more active since it augmented the total score Dy 151 a 0.31 mg/kg dose, which is by two orders of magnitude lower than those of the above kncwn compounds.
Summing up, it can be stated that especially high lipid peroxidation mnibitory activity was exerted by those novel synthetic pyrimidme derivatives, wherein said pyrimidme ring oears two identical or different, optionally substituted, amino groups and the carbon atom n position 4 of the pyrimidme ring is attached to one of the nitrogen atoms of a piperazme or homopiperazine ring. Simultaneously, the other nitrogen atom of said piperazme or homopiperazine ring bears a structural subunit containing an optionally substituted naphthyi or substituted phenyl group as defined in detail hereinbe¬ low.
Thus, the present invention relates to novel pyrimidine derivatives of formula (I) and their salts, wherein R', R:, R", X, A and n are as defined above.
Some representative compounds of formula (I) accord¬ ing to the present invention contain one or more asymmet¬ ric carbon atom(s); therefore, they can exist either in the form of stereoisomers (e.g. enantiomers or diastereo- mers) or their mixtures (e.g. racemates of enantiomers) . Thus, the scope of the present invention includes also the pure stereoisomers, the racem c and other mixtures of compounds of formula (I) as well as the salts, especially pharmaceutically acceptable salts, of all these co - pounds.
Hereinbelow, characteristic groups represented by the symbols in formula (I) will be explained.
When R" or R; in formula (a) being present as R" means an optionally substituted amino group, the said substitu- ent of the amino group may be e.g. one or two C;-4 alkyl,
C-.-4 alkanoyl, C.-4 alkoxycarbonyl optionally substituted by phenyl, C .-< alkylsulfonyl or arylsulfonyl group.
R: may be (but not limited to) 1-naphthyi, 2- -naphthyl, l-chloro-2-naphthyl, 4-chloro-l-naphthyl, 5- -chIoro-2-naphthyl, l-bromo-2-naphthyi, 5-brcmo-2- -naphthyl, 6-bromo-2-naphthyl, 1, 6-dιbromo-2-naphthyl, 5, 8-dibromo-2-naphthyl, 2-hydroxy-l-naphthyl, 4-hydroxy- -1-naphthyl, 3-hydroxy-2-naphthyi, l-hydroxy-2-naphthyl, 4-methoxy-l-naphthyl, 6-methoxy-i-naphthyl, 6-ιr.ethoxy-2- -naphthyi, 7-methoxy-2-naphthyl, 4-benzyloxy-l-naphthyl, l-methylthio-2-naphthyl, 1-methyisulfinyl-2-naphthyl, 1- -methylsulfonyl-2-naphthyl, 4-methylthio-l-naphthyl, 4- -m thy lsulf nyl-1 -naphthyi, 4-methylsulf onyi-1-naphthyi , 4-acetyl-l-naphthyl, 7-acetyl-2-naphthyl , 4-nιtro-l-
-naphthyl, 6-nιtro-2-naphthyl, 4-ammo-l-naphthyl, 3- -amιno-2-naphthyl, 6-amιno-2-naphthyl, 3-methylammo-l- -naphthyi, 3-dιmethylammo-l-naphthyl, 3-dιmethylammo-2- -naphthyl, 3-acetylammo-l-naphthyl, 4-methylammo-l- -naphthyl, 4-dιmethylammo-l-naphthyl, 6-dιmethylammo-2- -naphthyl, 4-acetylammo-l-naphthyl, 4-ethoxycarbonyl- ammo-1-naphthyl, 4-benzyloxycarbonylamιno-l-naphthyl, 4- -methanesulfonylamιno-1-naphthyl, 4- (p-toluenesulf onyl- ammo) -1-naphthyl, 3-carboxy-2-naphthyl , 3-methoxy- caroonyl-2-naphthyl, 5-carboxamιdo-2-napnthyl, 7-carboxy- -2-naphthyl, 7-methoxycarbonyl-2-naphthyl, 7-carboxamιdo- -2-naphthyl, 3-cyano-2-naphthyl, 5-cyano-2-naphthyl, 6- -cyano-2-naphthyl, 1-sulf o-2-naphthyl , 4-sulfo-l-naph- thyl, 5, 8-dιsulfo-2-naphthyl, 4-sulf onamιoo-1-naphthyl, 4- (N,N-dιethyl) sulf onamιdo-1-napnthyl, 4- ^N, N-dimethyl ) - sulfonamιdo-1-naphthyl, 1-naphthylmethyl, 2-naphthyl- methyl, 2- (2-naphthyl ) ethyl, l-naphthoyl, 2-naphthoyl, 2- -naphthoyimethyl, l-hydroxy-2-naphthoyI, 3-hydroxy-2-
-naphthoyl, 2-hydroxybenzoyl, 2-benzyloxybenzoyl, 2-ben- zylcxybenzyl, 2 , -dιhydroxybenzoyl, 2, 5-dιhydroxybenzoyl, 2, 5-dιbenzyloxybenzcyl, 2- ( 1-naphthyl j acetyl, 2- (2-
-naphthyl) acetyl group and the like. Within this, when X means a single bond, R" preferably represents e.g. 3- -hydroxy-2-naphthyl or l-hydroxy-2-naphthyl group; whereas in the case, when the meaning of X is different from a single bond, R" preferably stands for 1-naphthyl, 2-naphthyI, 2-naphthylmethyl, 2- (2-naphthyl) acetyl group or 2, 5-dιhydroxybenzoyl .
It can be seen from the above list that a substituent optionally being present on the naphthyi group may be at- tached to any carbon atom of any ring of tne naphthyi moiety; but preferably, it is attached to a carbon atom of the same ring, which bears the X group.
Certain R4 and R= substituents within the groups of formula (a) being present as R1 (e.g. hydroxyl, amino and/or carboxyl group) may be protected, if desired. Thus, in the above definitions, e.g. a Cι-4 alkoxy group or a C.-4 alkoxy group substituted by a phenyl group can be considered as a protected hydroxyl group. Similarly, an amino group substituted by a C-,- alkanoyl or C j alk- oxycarbonyl group optionally substituted by a phenyl group, or C -j alkylsulfonyl or arylsulfonyl group may be considered to be a protected am o group. Furthermore, a C;-4 alkoxycarbonyl moiety may represent a protected car- boxyl group, too.
R and R" may be (but not limited thereto) , independ¬ ently from eacn other, amino, 1-pyrrolidmyl, 1-pιperι- dinyl, hexahydro-lH-azepm-1-yi or cctahydroazccm-I-yi group and preferably amino and/or pyrrolidinyl group. X may stand (but not limited thereto) e.g. for a sin¬ gle bond, sulfur optionally substituted by one or more oxygen atom(s), an unsubstituted nitrogen or nitrogen op¬ tionally substituted by methyl, ethyl, formyl, acetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, methanesulfonyl or p-toluenesulfonyl group and preferably a simple chemical bond, sulfur or unsubstituted nitrogen. The meaning of A may be e.g. (but not limited thereto) methylene, 1, 2-ethylene, 1, 3-propylene, 1,4- -butylene, 1, 5-pentylene, 1, €-hexylene, 1, 7-heptylene, 1, 8-octylene; carbonyl; 1-oxo-l, 2-ethylene, l-oxo-2-me- thyl-1, 2-ethylene, 1-oxo-l, 3-propylene, 2-oxo-l, 3-propy- lene, l-oxo-2-amino-l, 3-propylene; l-oxo-2- (tert-butoxy- carbonylammo) -1, 3-propylene; 2-hydroxy-l, 3-propyl ene, 2- -acetoxy-1, 3-propylene, 2-methoxy-1, 3-propylene, 2-ben- zyloxy-1, 3-propylene; l-oxo-2-bromo-l, 3-propylene, 2- -chloro-1, 3-propylene, 2-ammo-l, 3-propylene, 2-methyi- amino-1, 3-propylene, 2-dιmethylammo-l, 3-propylene; 2- -acetylamιno-1, 3-propylene, 2- (benzyloxycarbonylamino) - -1, 3-propylene or 2-methanesulfonylamιno-l, 3-propylene group and the like; and preferably, e.g. 1, 2-ethylene, 1, 3-propylene, 1, 6-hexylene, carbonyl, 1-oxo-l, 2-ethylene or 2-hydroxy-l, 3-propylene group.
Similarly to what was described for the substituents of the group R , among the substituents of the alkylene chain being present as A, a C -„ alkoxy group optionally substituted by a phenyl group can be considered as a pro- tected hydroxyl group; whereas e.g. an amino group sub¬ stituted by a C - alkanoyl group or a C _< alkoxycarbonyl group optionally substituted by a phenyl group or C.-4 al- kylsulfonyl group may be considered to be a protected amino group. In the formula (I) the value of n is 1 or 2, and preferably 1.
Suitable salts of the compounds cf formula (I! con¬ taining basic groups are e.g. the salts formed with inor¬ ganic acids (e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acid and the like) or with organic acids (e.g. acetic, tartar c, citric, fuir.aric, succmic, maleic, methanesulfonic, ethanesulfonic or p-toluenesulfonic acid and the like) . Furthermore, compounds of formula (I) con¬ taining a phenyl or naphthyi group substituted by hydroxy and/or carboxy can form salts with bases in addition to the acid-addition salts. Suitable salts formed with bases are e.g. the alkali metal salts (such as sodium or potas- O 97/14685 - I S - PCT/HU96/00O58
sium salts) , alkaline earth metal salts ,e.g. calcium or magnesium, salts) and the like; as well as salts formed with some organic bases such as ethanolamme, diethanoia- mine, ethylenedia ine and the like.
As an ether aspect of the invention, there is pro¬ vided a process for the preparation of the compounds of formula (I) and their salts, the variants a) to g) of which are illustrated in the reaction schemes A to G. Thus, according to the process of the invention a) in order to obtain compounds cf formula (I), wherein R', R", RJ, X and n are as defined above; and A is as defined above, with the proviso that it may not be alkylene substituted by halogen, amino or C.-j alkylamino, a compound of formula .'II),
Figure imgf000020_0001
wherein R1, X, A and n are as defined above, is re¬ acted with a compound of formula (III) ,
Figure imgf000020_0002
wherein R" and R" are as defined above and Z means a leaving group; or b) in order to obtain compounds cf formula (I), wherein R', ?.-, R3 and n are as defined above; A is as defined above, with the proviso that it may not be alkylene substituted by halogen, ammo cr C;-,, alkylaminc; and
X is as defined for the formula (I), with the pro¬ viso that it may not be a single bond or a sulfur atom substituted by one or two oxygen atom(s), a compound of formula (IV),
R^XH (IV)
wherein R: and X are as defined above, s reacted with a compound of formula (V) ,
wherein R:, R3, A and n are as defined above and Z means a leaving group; cr c) in order to obtain compounds of formula (I), wherein R", R", R-' and n are as defined above;
A is as defined above, with the proviso that it may not be alkylene substituted by halogen, amino or C;.j alkylaminc; and
X is as defined above, with the proviso that it may- net be a single bond, a compound of formula (VI),
R:-X-A-Z (VI) wr.e em R , X and A are as defined above and 2 ι*ea~3 ~ leaving group, s reacted with a compound of formula
Figure imgf000022_0001
wnerein R", R' and n are as defined above; or d) in order to obtain compounds of formula (la)
Figure imgf000022_0002
representing a narrower scope of compounds of formula
( I ) , wherein
R", R", R3 and n are as defined above; and X s as defined above, with the proviso that it may not be a single bond, a compound of ormula (VIII) ,
Figure imgf000022_0003
wherein R" and X are as defined above, is reacted with a compound cf formula (VII), wherein R", R3 and n are as defined above; or e) in order to obtain compounds cf ormula (la) repre¬ senting a narrower scope of the compounds cf formula (I) , wherein
R', R", RJ and n are as defined above; and X is as defined for formula (I), with the proviso that it may not be a single bono or a sulfur atom substituted by one or two oxygen atom(s), a compound of formula (IV), wherein R and X are as de¬ fined above, s reacted with a compound of formula (IX),
Figure imgf000023_0001
wherein R-, P" and n are as defined above; or f) in oroer to obtain compounds cf formula (lb)
Figure imgf000023_0002
representing a narrower scope c r ccnrocun s o r :ormuιa (I) , wherein
R', R", R", X and r. are as defined above; and B* means a single bond or a straight or branched chain C -- alkylene group optionally substituted by halogen, C... alkoxy, C - alkanoyloxy and/or an optionally substituted ammo group, a carboxylic acid of formula (X) , R - -X -3 ' -C0CH ( X !
wherein R;, X and B- are as defined above, or a reactive derivative thereof activated at the carboxyl group is re¬ acted with a compound cf formula (VII), wherein R:, R;' and n are as defined above; or g) in order to obtain compounds cf formula (Ic)
Figure imgf000024_0001
representing a narrower scope of the compounds of formula (I) , wherein
R", R", RJ and n are as defined above;
X stands for a nitrogen atom optionally substituted by a C alky group; and B" means a straight or branched chain C..3 alkylene group optionally substituted by hydroxy, C 4 alk¬ oxy and/or di;C-.-4 alkyl) ammo group, a compound of formula ,XI),
R:-Z (XI)
wherein Z means a leaving or hydroxyl group and R: is as defined above, with the proviso that p, q and r are 0 when Z means a nydrcxyl group, is reacted with a compound of formula (XII) ,
Figure imgf000025_0001
wherein R", R3, B:, X and n are as defined above, and, if desired, a compound of formula (I) obtained by using any of the process variants a) to g) is transformed to an other compound of formula (I) m a manner known per se; and/or a protective group optionally being present is removed; and/or, if desired, a base is prepared from an obtained salt of the compound cf formula (I); or the ob¬ tained base is transformed to one of its salts, e.g. to its acid-addition salt.
Pure enantiomers of a compound of formula (I) con¬ taining one single centre of asymmetry can be obtained e.g. by resolution cf a racemic compound cf formula (I) prepared by means of racemic reagents by using methods known par se (e.g. by formation and separation of diastereomeric salts or other derivatives) ; or, by carry¬ ing out the above process variants with the pure enanti- o eric forms of the required reagents.
The diasterecmers of a substance of formula (I) m- eluding more centres of asymmetry can be separated by us¬ ing methods known per se, e.g. chromatography, fractional crystallization cr ether similar methods.
It is obvious to those skilled in the art that when some substituents cf the starting compounds, e.g. the R" and/or A group contain reactive groups (e.g. hydroxy, amino, carboxy cr the like) net to be transformed in the respective reaction, these groups can be protected by - _4 -
methods generally known in organic chemistry. Then, _fter the desired transformation, the protective group (s) is (are) removed without any undesired change in other parts of the molecule. For protection of the groups mentioned, usual protective groups known per se may be employed, e.g. C -4 alkyl groups optionally substituted by an aryl group (such as tert-butyl or benzyl group) for protecting hydroxyl groups; C -4 alkoxycarbonyl groups optionally substituted by an aryl, e.g. phenyl group (e.g. tert- -butoxycarbonyl or benzyloxycarbonyl group) , C -4 alkanoyl groups (e.g. formyl or acetyl group), C -4 alkanesulfonyl groups (e.g. methanesulfonyl group) or p-toluenesulfonyl group for protecting ammo groups; and e.g. C _4 alkyl (e.g. ethyl) ester groups for protecting carboxyl groups. In addition to the protective groups exemplified above any other protective group Known per se [such as the ones discussed by T. W. Greene and P. Wuts m: "Protective Groups in Organic Synthesis", John Wiley _ Sons, New York, N.Y. (1991)] may be employed. Suitable methods of cleaving protective groups are discussed the same work cited above.
It is noted that certain reaction steps of the proc¬ ess according tc the present invention can be performed also without t e transient protection of reactive groups not participating in the desired reaction.
The preferred embodiments of variants cf the process according to the invention are hereinbelow discussed in detail .
Process variant a) (Reaction scheme A) A compound of formula (II) is reacted with a compound of formula (III) in a suitable solvent such as chlcroben- zene, dimethylfor amide, dimethylacetamide, N-methylpyr- rolidone or the like; or optionally without any solvent, at a temperature between 100 βC and 200 °C and, if neces¬ sary, in the presence of a base, e.g. inorganic base such as potassium carbonate or sodium hydroxide, or an organic base, e.g. triethyiamine or pyridine as acid-binding agent. When carrying out the reaction in the absence of any base, the liberated acid of formula H-Z may be bound by the product of formula (I) .
The intermediates of formula (II) used in the present process variant are new and as such they also fall within the scope of the present invention. These compounds can be prepared in various routes depending on the meaning of
X and A as illustrated in reaction schemes H and I.
A common characteristic feature of these methods con¬ sists in a common starting compound of formula (XIII),
Figure imgf000027_0001
wherein n is the same as defined for formula ( I ) ; and
R" means an amine-protecting group, which i s t rans f ormed to a compound cf formula (XIV) ,
Figure imgf000028_0001
wherein
R:, X, A and n are as defined for formula (I); and
R stands for an amine-protect g group, by using any of methods A) to E) to be discussed herein¬ after; then, after cleaving the protective group, a com¬ pound of formula (II) is obtained. The difference between the methods starting from compounds cf formula (XIII) is that they provide the intermediate of formula (XIV) by means of various reagents. The variants of preparing the intermediates of formula (XIV) are described hereinafter in detail [methods A) to C) are illustrated by reaction scheme H, whereas methods D) and Ξ) are shown by reaction scheme I] .
Method A)
In order to obtain a compound of formula (II), wherein
R" and n are as defined for formula (I);
X means a sulfur atom optionally substituted by one cr two oxygen atom(s) or an optionally substituted ni¬ trogen atom; and A stands for C-.-9 alkylene substituted by hydroxy, C : alkoxy or C-..4 alkanoyloxy cr optionally substituted by oxo at the carbon atom attached to X; a compound of formula (XIII), wherein R4 means an amine- protecting group and n is as defined above, may be re¬ acted with a compound of formula (VI), wherein R1, X and A are as defined above, and Z is a leaving group, to give a compound of formula (XIV) , wherein R , R , X, A and n are as defined above.
This reaction is suitably carried out m a solvent, e.g. ethanol, propanol, acetonitrile or the like, in the presence e.g. of an inorganic base such as potassium car¬ bonate or sodium hydroxide, in a temperature range be¬ tween 20 °C and 100 βC.
In the starting compounds of formula (XIII), R4 means an amme-protective group, e.g. alkanoyl group such as for yl group or preferably a C -4 alkoxycarbonyl group op¬ tionally substituted oy aryl group such as tert-butoxy- carbonyl or benzyloxycarbonyl group. A part of the pro¬ tected piperazme and homopiperazine derivatives of for- mula (XIII) is known [see e.g. T. R. Herrm et al.: J. Med. Chem. 18, 1216 (1975)] or can be prepared by methods analogous to known ones.
In the compounds cf formula (VI) used as starting ma¬ terials m method A) , Z means a leaving group, suitably e.g. halogen such as chlorine, bromine or iodine; or an aliphatic or aromatic sulfonyloxy group sucn as methane- sulfonyloxy or p-toluenesulfonyloxy group. A part of the compounds of formula (VI) is known [see e.g. E.K. Harwill et al.: J. Org. Chem. 17, 1957 (1952); and L.M. Werbel : J. Med. Chen. 6, 637 '1963)] or they can be prepared by using simple methods Known per se . Thus, compounds of formula (VI) containing C..- alkylene group as A may be prepared e.g. as illustrated in reaction scne e J start¬ ing with alcohols of formula (XIX) ,
R'-X-B^OH (XIX) wherein
R' and X are as defined above; and B stands for a C;-. alkylene group by using methods known per se . On the other hand, compounds of formula (VI), con¬ taining an alkylene group substituted by oxo at the car¬ bon atom attached to X, are suitably prepared by reacting an appropriate compound of formula (IV), wherein R* and X are as defined above, with a carboxylic acid of formula (XX) ,
HOOC-B -Z (XX)
wherein B3 means a C.-- alkylene group and
Z is a leaving group, or with a reactive derivative thereof activated at the carboxyl group (see reaction scheme J) .
The compounds of formulae (XIX) and (XX) are known from the literature [see e.g. J.S. Pierce and R. Adams:
J. Am. Chem. Soc. 45, 790 (1923); and R. E. Foster et al.: J. Am. Chem. Soc. 68, 1328 (1946)] or partly they are commercially available.
Method B) In order to obtain compounds of formula (II), wherein R" and n are as defined for formula (I);
X means a sulfur atom optionally substituted by one or two oxygen atom(s) or an optionally substituted ni¬ trogen atom; and A stands for 2-hydroxy-l, 3-propylene group, a protected compound of formula (XIII), wherein R'1 stands for an amme-protective group; and n is as defined above, is reacted with an epoxide of formula (VIII), wherein R' and X are as defined above, to obtain a compound of for- mula (XIV), wherein R', R\ X, A and n are as defined above.
This reaction is conveniently performed in a solvent such as an alcohol, e.g. ethanol, at a temperature be¬ tween 20 °C and 100 βC, preferably at the boiling point of the solvent.
A part of the starting compounds of formula (VIII) is known [see e.g. British patent specification No. 1,592,524; Soviet patent specification No. 1,286,596; as well as the published Japanese patent application No. 79- 01300] or can be prepared by using methods analogous to known ones such as methods illustrated hereinafter by ex¬ amples.
Method C)
Alternatively, m order to obtain compounds of for- mula (II), wherein
R", X and n are as defined for formula (I); and A stands for C _- alkylene substituted by oxo at the carbon atom attached to the nitrogen-containing het¬ erocycle, a protected compound of formula (XIII), wherein R"1 means an amme-protecting group; and n is as defined above, is reacted with a carboxylic acid of formula (X) , wherein R* and X are as defined above; and B- means a single bond or C1--1 alkylene, cr a reactive derivative thereof activated at the car¬ boxyl group to obtain a compound cf formula (XIV) , wherein R", R\ X, A and n are as defined above.
Compounds of formula (XIII) can be reacted with the free acid form of compounds of formula (X) . In such cases, the reaction can be carried out an inert sol¬ vent, e.g. dimethylformamide, methvlene chloride, ethanol or the like, in the presence of a condensing agent, e.g. N,N' -dicyclohexylcarbcdiimide or carbonyldiimidazole, op- tionally by using an additive agent, e.g. 1- -hydroxybenzctriazole. However, it is suitable to use the compounds of formula (X) the form of their reactive derivatives activated at the carboxyl group and not in their free acid form. Such reactive forms are e.g.: acyl halides, e.g. an acyl chloride or acyl bromide; active esters, e.g. an aryl ester such as a phenyl ester; sym¬ metric or mixed anhydrides, e.g. a mixed anhydride pre¬ pared by means of a chloroformate ester and the like. Carboxylic acids of formula (X) , wherein R- is as defined for formula (I) , with the proviso that in formula (a) at least one cf R" and R= stands for hydroxy, and each of p, q and r are C. can be used also in their lactcne forms cf formula (XXI),
Figure imgf000032_0001
wnerein
X and B; are as defined for formula (X ) ; and Ar, R" and R are as defined for Ar, R" and R , respec¬ tively, forming a part of the group of formula (a) , with the proviso that R4 and R5 may not mean unsub¬ stituted ammo or am o substituted by a C,-4 alkyl group.
These lactons are the intramolecular aryl esters of the respective acids.
Some compounds of formula (X) such as 1-naphthoιc acid, 2-naphthoιc acid, 1-naphthylacetιc acid, 1-hydroxy- -2-naphthoιc acid, 3-hydroxy-2-naphthoιc acid are commer¬ cially available; whereas other ones, e.g. 2- (2-hydroxy- -1-naphthyl) acetic acid, 2- (3-hydroxy-2-naphthyl) acetic acid or 3- (2-hydroxy-l-naphthyl) propionic acid and their lactones of formula (XXI) [see e.g. Y. Ogata et al.: J. Org. Chem. 16, 1588 (1951); A.F. Hardman: J. Am. Chem. Soc. 70, 2119 (1948); as well as H. Krzikalla and B. Eis- tert: J. prakt. Chem. 143, 50 (1935)], furtnermore 2- (2- -naphthylthio) acetic acid and 2- (2-naphthylamιno) acetic acid [see e.g. T. M. Furman et al . : J. Am. Chem. Soc. 82, 1450 1960); and C. A. Bischoff and A. Hausdorfer: Chem. Ber. 23, 2005 (1980^] are known compounds. Other sub¬ stances of formula (X) may be prepared Dy using methods analogous to the above ones.
Method D) In order to obtain compounds of formula (II), wherein
R ano n are as defined for formula (I);
X is as defined for formula (I), with the proviso that it may not be a single bond or a sulfur atom substi¬ tuted by one or two oxygen atom(s); and A stands for C.._ alkylene substituted by hydroxy, C -; alkoxy, C;-4 alkancyloxy cr optionally substituted by oxo at the carbon atom attached to X, a compound of formula (XIII), wherein R' means an amme-protective group; and n is as defined above, is first reacted with a compound of formula Z'-A-Z:, wherein
A is as defined above; and Z ' as well as Z~ mean, independently from each other, leaving groups, to give a compound of formula (XV) ,
Figure imgf000034_0001
wnerein
R\ A, Z" and n are as defined above. When this latter substance is reacted with a compound cf formula (IV), wherein R- and X are as defined above, a compound of formula (XIV) is obtained, wherein R-, R\ X, A and n are as defined above.
Both reactions may be carried out similarly as de- scribed in method A) .
The starting compounds cf formula Z"-A-Z" are commer¬ cially available cr may be prepared by using simple meth¬ ods known per se .
On the other hand, on substituting amino or C-.-4 alky- lamino for the leaving group Z: in a compound of formula (XV) in a way known per se, a substance of formula (XVI),
Figure imgf000035_0001
wherein
R\ A and n are as defined above; and
X represents a nitrogen atom optionally substituted by a C -4 alkyl group, is obtained. This suostitution reaction can be performed e.g. by reacting the compound of formula (XV) with ammo¬ nia, a C ., alkylamme cr potassium phthalimide in a man¬ ner known per se an inert solvent, such as an aii- phatic alcohol, dimethylformamide or the like. On using potassium nthalimiαe, the phthalimido compound obtained is treated e.g. with hydrazine an aliphatic alcohol in a manner known per se to provide the required substance of formula (XVI) . By reacting a compound of formula (XVI) with a com¬ pound cf formula (XI) , wherein R1 is as defined above; and Z means nycrcxy or a leaving group, similarly as discussed e.g. process variant g) to be described hereinafter, again a compound of formula (XVI), wherein
R , ?.', A ano n are as defined abcve; and
X stands for a nitrogen atom optionally substituted by a C;-4 alkyl group, is obtained. Method E )
Alternatively, m order to prepare compounds cf for¬ mula (II) , wherein
R* and n are as defined for formula (I); X is as defined for formula (I), with the proviso that it may not be a single bond or a sulfur atom substi¬ tuted by one or two oxygen atoms; and A stands for 2-hydrcxy-l, 3-propylene group, a protected compound cf formula (XIII), wherein R" means an amine-protective group; and n is as defined above, is first reacted with epichlorohydπn and then the ob¬ tained epoxide of formula (XVII),
Figure imgf000036_0001
wherein R* and n are as defined above, is reacted with a compound of formula (IV) , wherein R' and X are as defined above to give a compound of formula (XIV) , wherein R;, R , X, A and n are as defined above.
A compound of formula (XIII I can be reacted with epichiorohydrin e.g. by using methods described above for the preparation of the compounds of formula (VIII) . On the other hand, compounds of formula (XVII; obtained as intermediates can be reacted with compounds of formula .IV) under conditions discussed in method 3) above. According to an other variant of process E) an epox¬ ide of formula (XVII) prepared as described above is re¬ acted with ammonia or a C;.4 alkylamine in a suitable sol- vent, e.g. water cr an aliphatic alcohol or a mixture thereof, to give a compound of formula
Figure imgf000037_0001
,
IXVTI:
wherein R" and n are as defined above; and
X means a nitrogen atom optionally substituted by a C:.4 alkyl group, then the obtained compound is reacted with a compound of formula (XI), wherein R- is as defined above; and
Z stands for a leaving group, under the conditions discussed in method D) , again to ob¬ tain a compound of formula (XIV) , wherein R-, R\ A and n are as defined above; and X stands for a nitrogen atom optionally substituted by a C;-4 alkyl group.
The protective group R4 can be removed from compounds of formula (XIV) prepared by the above methods A) to E) to afford compounds cf formula (II) . Thus, alkanoyl type protective groups can be removed by acidic or alkaline treatment; C:-4 alkoxycarbonyl groups can be removed e.g. by treatment with an acid; whereas C.-4 alkoxycarbonyl groups substituted by an aryl group can be split off e.g. by catalytic hydrogenation. A part of the starting compounds of formula (III; used in process variant a) is known [see e.g. B. Roth et al.: J. Am. Chem. Soc. 72, 1914 (1950); and published PCT patent application No. WO 87/01706], whereas an ether part thereof can be obtained from starting compounds of formula (XXII! ,
Figure imgf000038_0001
wherein R" and R3 are as defined for formula (I) , by us¬ ing methods known per se in a route illustrated by the reaction scne e K.
By using process variant a) , e.g. the following char¬ acteristic compounds according to the present invention can be prepared:
1- (2, 6-dιamιno-4-pyrimidinyl) -4-[2-hydroxy-3- (2-
-naphthylthio) propyljpiperazme, 1- (2, 6-dιamιno-4-pyrιmidinyl) -4-[2-dimethylammo-3- - (2-naphthyithio) propyl]piperazine, l-[2, 6-di ( 1-pyrrolidinyl) -4-pyrimιdmyl]-4-[2-hydrcxy- -3- (2-naphthyithio)propyi]pιperazine, l-[2, 6-di ( i-pyrrolidinyl) -4-pyrιmιdιnyl]-4-[2-hydrcxy-
-3- (2-naphthylamino) propyl]pιperazine, 1- (2, 6-dιamιno-4-pyrimidinyl) -4-[2-hydroxy-3- (2- -naphtnylammo) propyljpiperazme,
1- (2, 6-dιammo-4-pyrιmidinyI) -4-{2-hydroxy-3-[N-
-methyl-N- (2-naphthyl) ammo]propyl}piperazine, 1- (2, 6-dιamιno-4-pyrimidinyl) -4-[N- (2-naphthyl) - carbamoylmeth l]piperazine, 1- (2, 6-diamino-4-pyrimidinyl) -4-[2- (2-naphthylthio) - acetyl]piperazme and l-[6-amι o-2- ( 1-pyrrolld yl) -4-pyrιmιdmyl]-4-[3- '2- -hydroxy-1-naphthyi) propιonyl]pιperazme.
Process variant b)
(Reaction scheme B) A compound of formula (IV) is reacted with a compound of formula (V) a suitable solvent, e.g. ethanol, ace¬ tone or dimethylformamide, conveniently in the presence of a base such as an inorganic base, e.g. potassium car¬ bonate or sodium hydroxide, or an organic base, e.g. pyridme or triethylamine, at a temperature between room temperature and the boiling point of the solvent used.
The starting compounds of formula (IV) are commer¬ cially available wnereas the compounds of formula (V) are partly known (see e.g. the published European patent ap- plication No. 0,574,906A); or they can be prepared simi¬ larly to known substances by using known methods.
By using process variant b) , e.g. the following char¬ acteristic compounds according to the present invention can be prepared: l-[2, 6-di ( l-pyrrc_ιdmyl) -4-pynmιdmyι]-4-[2- (2- -naphthylammo) acetyl]pιperazme, l-[2, 6-di ( 1-pyrrolιdmyl) -4-pyrιmιdιnyl]-4-[2- (4-
-nitro-1-naphthyiamino) acetyl]pιperazme, l-[2, 6-di ( 1-pyrrolld yl) -4-pyrιmιdmyl]-4-[2- (2- -napnthylthic) acetyl]pιperazme, and
1-[2, 6-01 (1-pyrrolldmyl) -4-pyrιmιdmy_]-4-[2- (2- -naphthylthio) acetyl]homopιperazιne .
Process variant c)
(Reaction scheme C) A compound of formula (VI) is reacted with a compound of formula (VII) in an inert solvent, e.g. acetone, ace¬ tonitrile, or dimethylformamide, suitably in the presence of a base, e.g. potassium carbonate or the like, at a temperature between room temperature and the boiling point of the solvent used.
The preparation of compounds of formula (VI) has been described above; see method A) for the preparation of the intermediates of formula (II) used in process variant a) . A part of compounds of formula (VII) is known (see e.g. the published PCT patent application No. 87/01706) whereas an other part thereof can be prepared analogously to known compounds by using methods known per se .
By using process variant c) , e.g. the following char- acteristic compounds according to the present invention can be prepared: l-{6-[N- (2, 5-dibenzyloxybenzoyl) ammo]hexyl}-4-[2, 6- -di (1-pyrrolidinyl) -4-pyrimidinyl]-piperazine, l-[2, 6-di (1-pyrrolidinyl) -4-pyrimιdmyl]-4-[N- (2- -naphthyi) carbamoylmethyl]piperazine, l-[2, 6-di (1-pyrrolidinyl) -4-pyrιmidinyl]-4-[N- (1- -sulfo-2-naphthyl) carbamoylmethyl]piperazine, l-[2, 6-di (1-pyrrolidinyl) -4-pyrimidinyl]-4-[N- (2- -methyl-1-naphthyl) carbamoylmethyl]piperazine, l-[2, 6-di (1-pyrrolidinyl) -4-pyrimidmyl]-4-[N- (7- -ethoxycarbonyl-i-naphthyl) carbamoylmethyl]- piperazine, l-[2, 6-di (1-pyrrolidinyl) -4-pyrimidinyl]-4-[N- (7- -acetyl-2-naphthyi) carbamoylmethyl]piperazine, l-[2, 6-di (1-pyrrolidinyl) -4-pyrimidinyl]-4-[N- (4- -dimethylaminosulfonyl-1-naphthyl) carbamoyl- methyl]piperazine, l-[2, 6-di (1-pyrrolidinyl) -4-pyrιmιdιnyl]-4-[N- (J-
-methylthιo-1-naphthyi) carbamoylmethyl]pι- perazme, l-[2, 6-di (1-pyrrolld yl) -4-pyrιmιdιnyl]-4-[N- (4- -methylsulfonyl-1-naphthyl) carbamoylmethyl]- piperazine and l-[2, 6-di (1-pyrrolidinyl) -4-pyrιmιdιnyl]-4-[3- (2-
-naphthylam o)propyl]pιperazιne.
Process variant d) (Reaction scheme D)
A compound of formula (VIII) is reacted with a com¬ pound of formula (VII) in an inert solvent, e.g. a halo- genated hydrocarbon such as methylene chloride or in an alcohol, e.g. ethanol or the like, at a temperature be- tween room temperature and the boiling point of the sol¬ vent used.
Concerning the preparation of compounds of formula (VIII) see the above description for the preparation of the starting compounds for process variant a) . By using process variant d) , e.g. the following char¬ acteristic compounds according to the present invention can be prepared:
1- (2, 6-dιamιno-4-pyrιmιdmyl) -4-[2-hydroxy-3- (1- -naphthylam o)propyl]pιperazιne, 1- (2, 6-dιammo-4-pyπmιdmyl) -4-[2-hydroxy-3- (2- -naphthylamino)propyl]pιperazme, l-[2, 6-di (1-pyrrolιdmyl) -4-pyrιmιdmyl]-4-[2-hydroxy-
-3- (l-naphthylamιno)propyl]pιperazιne, (±) -l-[2, 6-di (1-pyrrolidinyl) -4-pyrιmιdιnyl]-4-[2- -hydroxy-3- (2-naphthylamιno)propyl]pιperazme, '-) -l-[2, 6-di ( 1-pyrrolidinyl) -4-pynmidιnyl]-4-[2- -hydroxy-3- (2-naphthylamino)propyl]pιperazιne, (+) -l-[2, 6-di (1-pyrrolidinyl) -4-pyrimidinyl]-4-[2- -hydroxy-3- (2-naphthylamino)propyl]piperazine, 1"[2, 6-di (1-pyrrolidinyl) -4-pyrimidinyl]-4-{2-hydroxy- -3-[N-methanesulfonyl-N- (2-naphthyl) amino]propyl}- -piperazine, l-[2, 6-di ( 1-pyrrolidinyl) -4-pyrimidinyl]-4-{2-hydroxy- -3-[N-methyl-N- (2-naphthyl) aminojpropyl}- -piperazine, l-[2, 6-di (1-pyrrolidinyl) -4-pynmidinyl]-4-[2-hydroxy-
-3- ( 1-naphthylamino) propyl]homopiperazine, (±) -l-[2, 6-di (1-pyrrolidinyl) -4-pyrimidinyl]-4-[2- -hydroxy-3- (2-naphthyiamino)propyl]homo- piperazine,
(-) -l-[2, 6-di (1-pyrrolidinyl) -4-pyrimidinyl]-4-[2- -hydroxy-3- (2-naphthylamino)propyljhomo- piperazine, (+) -l-[2, 6-di (1-pyrrolidinyl) -4-pyrimidinyl]-4-[2- -hydroxy-3- (2-naphthylamino)propyl]homo- piperazine, 1-[6-amino-2- (1-pyrrolidinyl) -4-pyrimidinyl]-4-[2- -hydroxy-3- (2-naphthylamino)propyl]piperazine, l-[6-ammo-2- (1-piperidir.yl) -4-pyrimidinyl]-4-[2- -hydroxy-3- (2-naphthyla_nino)propyl]piperazine,
1- (2, 6-diamino-4-pyrimidinyl) -4-[2-hydroxy-3- (2-
-naphthylthio)propyi]piperazine, l-[2, 6-di (1-pyrrolidinyl) -4-pyrimidinyl]-4-[2-hydroxy- -3- (2-naphthylthio)propyl]piperazine and l-[2, 6-di ( 1-pyrrolidιnyl) -4-pynmιdmyl]-4-[2-hydroxy- -3- (2-naphthyithio)propyl]homopιperazme.
Process variant e)
(Reaction scheme E) A compound of formula (IV) is reacted with a compound of formula (IX) under conditions described for process variant d) .
The starting compounds of formula (IX) can simply be prepared by reacting the compounds of formula (VII) with epichlorohydrm in a manner described e.g. for the prepa¬ ration of compounds cf formula (VIII) as illustrated by reaction scheme L.
By using the present process variant e) , e.g. the following cnaracteristic compounds according to the m- vention can be prepared: l-[2, 6-di (1-pyrrolidinyl) -4-pyrιmιdιnyl]-4-[2-hydroxy-
-3- (2-naphthyithio)propyljpiperazme, l-[2, 6-di (1-pyrrolidinyl) -4-pyrιmιdmyl]-4-[2-hydroxy- -3- (2-naphthyIammo)propyljpiperazme, and l-[2, 6-di (1-pyrrolidinyl) -4-pyrιmιdmyl]-4-[2-hydroxy- -3- (2-naphthoylmethylammo)propyl]pιpera∑ine.
Process variant f)
(Reaction scheme F) The free acid form of a compound of formula (X) or a reactive form thereof activated at the carboxyl group is reacted with a compound of formula (VII) . This reaction can be carried out under similar conditions as the start¬ ing compounds of formula (II) of process variant a) are obtained according to the above-described method C) . By using the present process variant f) , e.g. the following characteristic compounds according to the present invention can be prepared: 1 [2, 6-di (1-pyrrolidinyl) -4-pyrιmιdιnyl]-4- (1-
-naphthoyl)piperazine, [2, 6-di (1-pyrrolldmyl) -4-pyrιmιdmyl]-4- (1-
-naphthoyl) homopiperazine,
1-[2, 6-di (1-pyrrolidinyl) -4-pyrιmιdιnyl]-4- (1-hydroxy-
-2-naphthoyl) piperazme,
1-[2, 6-di (l-pyrrolidmyl) -4-pyrιmιdmyl]-4- (1-hydroxy-
-2-naphthoyl) homopiperazine, [6-amιno-2- (1-pyrrolldmyl) -4-pyrιmιdmyl]-4- (1-
-hydroxy-2-naphthoyl) piperazme,
1-[6-amιno-2- (1-pιperιdmyl) -4-pyrιmιomyl]-4- (1-
-hydroxy-2-napnthoyl(piperazine, [2, 6-di (1-pyrrolιdιnyl) -4-pyrιmιdmyl]-4- (3-hydroxy-
-2-naphthoyl) piperazme,
1-[2, 6-di (l-pyrrolidmyl) -4-pynmιdmyl]-4- (3-hydroxy-
-2-naphthoyl) homopiperazine,
1-[6-ammo-2- (1-pyrrolldmyl) -4-pyrιmιdιnyl]-4- ι3-
-hydroxy-2-naphthoyl)piperaz e,
1-[6-ammo-2- (1-pιperιdmyl) -4-pyrιmιdιnyl]-4- (3-
-hydroxy-2-naphthoyl)piperazine,
1-[6-amιno-2- (hexanydro-IH-azepm-1-yl) -4-pyπmιαι- nyl]-4- (l-hyoroxy-2-naphtnoyl)piperazme, ) -1- (2, 6-dιammo-4-pyrιmιomyl) -4-[2- (6-methoxy-2-
-naphthyl) prcpιonyl]pιperazme,
(-) -l-[2, 6-di (1-pyrrolιdιnyl -4-pyπmιdmyl]-4-[2- (6-
-methoxy-2-naphthyl)propιonyl]pιperazιne,
( -) -l-[2, 6-di (l-pyrrolidmyl) -4-pyrιmιdmyl]-4-[2- (6-
-methoxy-2-naphthyl)propιonyl]homopιperazιne, (±) -l-[2, 6-di (1-pyrrolιdιnyl) -4-pynmιdmyl]-4-[N- - (tert-butoxycarbonyl) -3- (1-naphthyi) ala- nyl]pιperazme, (±) -l-[2, 6-di (1-pyrrolιdιnyl) -4-pyrιmιdmyl]-4-[N- - (tert-butoxycarbonyl) -3- (2-naphthyi) ala- nyl]pιperazme, (-) -l-[2, 6-di (l-pyrrolidmyl) -4-pyrιmιdmyl]-4-[N-
- (tert-butoxycarbonyl) tyrosyl]pιperazme, (+) -l-[2, 6-di (1-pyrrolldmyl) -4-pyrιmιdmyl]-4-[N- - (tert-butoxycarbonyl)phenylalanyl]pιperazιne,
1- (5-bromo-2-naphthoyl) -4-[2, 6-di (1-pyrrolιdιnyl) -4-
-pyrιmιdmyl]pιperazme, 1- (5, 8-dιbromo-2-naphthoyl) - -[2, 6-di ( 1 -pyrrol idi¬ nyl) -4-pyrιmιomyl]pιperazme, l-[2, 6-di (l-pyrrolidmyl) -4-pyrιmιdιnyl]-4-[3- (2-
-hydr ox y-1 -naphthyi) propιonyl]pιperazme, l-[2, 6-di (l-pyrrolidmyl) -4-pyrιmιdιnyl]-4-[2- (2-
-hydroxy-1 -naphthyi) acetyl]pιperazme, l-[6-ammo-2- ( 1-pιperιdιnyl ) -4-pyrιmιdmyl]-4-[3- (2- -hydroxy-1-naphthyl ) propionyljpiperazme, l-[2, 6-di ( 1 -pyrrol ldmyl) -4-pyπmιdιnyl]-4- (3-
-methylammo-2-naphthoyl ) piperazine, l-[2, 6-di (l-pyrrolidmyl) -4-pyrιmιdιnyl]-4- (3- -dime thylammo- 2 -naphthoyl) piperazme, 1_[2, 6-di (l-pyrrolidmyl) -4-pyπmιdmyl]-4- (3-
-acetylamιno-2 -naphthoyl) piperazine, l-[2, 6-di (l-pyrrolidmyl) -4-pyrιmιdmyl]-4- (3-
-trif luoroacetylammo-2 -naphthoyl) piperazme, 1- (5-cyano-2-naphthoyl) -4-[2, 6-di (1-pyrrclιdmyl) -4- -pyrιmιdmyl]pιperazιne, l-[<. -ammc-2- (l-pyrrolιdιnyl)-4-pynmιdιnyl]-4-[3-t2-
-hyαroκy-1-naphthyl) propionyljpiperaz e, and l-[2, 6-di (1-pyrrolidinyl) -4-pyrιmιdιnyl]-4-[2- ( 3- -hydroxy-2-naphthyl) acetyl]pιperazine.
Process variant g)
(Reaction scheme G)
A compound of formula (XI) containing a hydroxyl group as Z is reacted with a compound of formula (XII) suitably m an appropriate solvent, e.g. water, an alco¬ hol such as ethanol or in a polar, aprotic solvent such as dimethylformamide, dimethylacetamide and the like, or m the mixture thereof, at the boiling point of the sol¬ vent or without any solvent, at a temperature between 120 °C and 250 βC, optionally in the presence of a suitable catalyst, e.g. sodium hydrogen sulfite or the like, op¬ tionally m a closed vessel under pressure.
A compound of formula (XI) containing a leaving group as Z can be reacted with a compound of formula (XII) e.g. under conditions discussed under process variant c) .
A part cf the starting compounds of formula (XI) is commercially available; others can be prepared by using methods known from the literature [see e.g. K. Fries: Ber. 58, 2848 (1925)]. The compounds of formula (XII, can be prepared e.g. by using methods illustrated in the reaction scheme M. Thus, a compound of formula (VII), wherein R2, R3 and n are as defined for formula (I), can be reacted with a compound of formula (XXIII),
Rε-X-B2-Z (XXIII) «nerem
3 stands for a straight or branched chain C . alkylene group optionally substituted by hydroxy, C;-4 alkoxy and/or di (C.. alkyl) amino; Z means a leaving group; ?" is an amine-protective group; and
X means a nitrogen atom optionally substituted by a d- alkyl group; or 5 and X together stand for a nitrogen atom protected by a bivalent amme-protective group, e.g. phthali ido group; e.g. under conditions similar to those described m proc¬ ess variant c , then the amine-protective group is re- moved from the obtained compound of formula (XXIV)
Figure imgf000047_0001
a known manner, e.g. by hydrogenolysis, hydrolysis or hydrazmoiysis .
Alternatively, for preparing compounds of general formula ;XII) containing a 2-hydroxy-l, 3-prcpylene group as 3", a compound of formula (VII) mentioned above, wherein R-, R- and r. are as defined for formula (I), is reacted with epichlorohydrm as described above under process variant e) and illustrated by reaction scheme L, to give an epoxide of formula (IX), wherein R", R3 and n are as defined for formula (I), then the obtained com¬ pound of formula (IX) is reacted with ammonia or with a reagent capable to introduce an amino group (such as hex- amethylenetetra ine or the like) or with a C1-4 alky- lamine.
By using the present process variant g) , e.g. the following characteristic compounds according to the pres¬ ent invention can be prepared: l-[2, 6-di (1-pyrrolidinyl) -4-pyrιmidιnyl]-4-[2- (2-
-naphthylamino) ethyl]piperazine, l-[2, 6-di ( 1-pyrrolidinyl) -4-pyrimidmyl]-[2- (2- -naphthoylamino) ethyljpiperazme and l-[2, 6-di ( 1-pyrrolidinyl) -4-pyrimιdιnyl]-4-{2-[2- (2-
-naphthyl) acetylamino]ethyl}pιperazιne. When desired, a compound of formula (I) prepared by employing one of the process variants a) to g) described above can be transformed to other compounds of formula (I) by using methods known per se . Thus, e.g. an aromatic ring being present in group R" can be halogenated by a suitable halogenatmg agent, e.g. elementary halogen (such as chlorine or bromine) or an other convenient rea- gent (such as an N-halosuccinimide or sulfuryl halide); or nitrated by an appropriate nitrating agent, e.g. con¬ centrated nitric acid or a mixture of an alkali metal ni¬ trate and a strong acid (e.g. sulfuric or trifluoroacetic acid) . Any nitro group occurring as a substituent of the group R" may be reduced to an amino group by means of a suitable reducing agent, e.g. elementary hydrogen in the presence of a noble metal catalyst or by using a complex • hydride, e.g. sodium borohydride. A y carbonyl group optionally being present in the aliphatic moiety of the group R' may be reduced to meth¬ ylene group by means of a suitable reducing agent, such as a complex metal hydride, e.g. lithium aluminum hydride optionally in the presence of a Lewis acid, e.g. aluminum trichloride.
Any sulfur atom m the alkylthio group being present as a substituent of the group R' cr occurring as X can be oxidized by suitably choosing the amount of an appropri¬ ate oxidizing agent, e.g. m-chloroperbenzoic acid, to transform the sulfur atom being present at said site to a sulfur atom substituted by one or two oxygen atom(s) . Any carboxyl group occurring as a substituent of the group R"' may be esterified with an alcohol, e.g. an ali¬ phatic alcohol, suitably in the presence of an inorganic or organic acid (such as hydrochloric, sulfuπc, p- -toluenesulfomc acio and the like) as catalyst. Con- versely, an esterified carboxyl group being present as a substituent of the group R' can be hydrolyzed to the free acid by using an aqueous solution of a base (e.g. an al¬ kali metal hydrcxide or carbonate) ; or it can be reacted with ammonia or an aliphatic amine to obtain the respec- tive carboxamide. A nitrogen-unsubstituted carboxamide can be transformed to the corresponding cyano compound by treatment with a suitable dehydrating agent (e.g. sulfu- ric acid, pncs r.crus pentoxide, polyphosphoric acid or the like) . Furthermore, a cyano group can be hydrolyzed with a strong acid (such as hydrochloric, sulfuric or phosphoric acid and the like) or a base (such as sodium hydrcxide, potassium carbonate and the like) to a carbox- amido or carboxyl group depending on the reaction condi¬ tions . Any NH or OH group occurring as a substituent of the R' and/or A group can be acylated to an N-acyl or O-acyl derivative, respectively, by means of an appropriate acy- lating agent (e.g. acyl chloride, acid anhydride, active ester, mixed anhydride or the like) ; or can be trans¬ formed to an N-alkyl cr O-alkyl derivative, respectively, by means of a usual alkylat g agent (such as an alkyl halide, alkyl sulfate, aromatic sulfonate ester or the like) .
Finally, a hydroxyl group can be replaced by a halo¬ gen atom by means of a convenient halogenating agent (such as thionyl chloride, phosphorus pentachloride, phosphorus pentabromide or the like) and subsequently, this halogen can be replaced by an ammo or alkoxy group by using the respective am e or alkoxide.
The following characteristic compounds according to the present invention can be obtained by methods given as examples for the above additional transformations:
(±) -l-[2, 6-di (l-pyrrolidmyl) -4-pyrιmιdmyl]-4-[3- (1-
-naphthyl) alanyl]piperazine, l-[2, 6-di (1-pyrrolidinyl) -4-pyrimidmyl]-4-[2- (2- -naphthylmethylammo) ethyl]piperazιne, l-[2, 6-di (1-pyrrolidinyl) -4-pyrimidinyl]-4-{2-[2- (2- -naphthyl) ethylammo]ethyl}piperazme and l-[2-acetoxy-3- (N-acetyi-2-naphthylamιno) propyl]-4-
-[2, 6-di (1-pyrrolidinyl) -4-pyrimιdinyl]piperazme. The compounds of formula (I) according to the present invention and their pharmaceutically acceptable salts possess valuable biological effects. More particularly, these compounds inhibit the peroxidation cf lipids and therefore, they are useful to treat diseases and patho¬ logical conditions where the inhibition of lipid peroxi- dation is desirable.
The lipid peroxidation inhibiting effect of the com¬ pounds according to the present invention and their phar- maceutically acceptable salts can be detected or meas¬ ured, respectively, by means of biochemical and pharma¬ cological investigations. Hereinafter, some of these in¬ vestigations as well as the results obtained in these m- vestigations with characteristic compounds according to the present invention are given. The following known lipid peroxidation inhibiting compounds were used as ref¬ erence substances in these biological tests: 3,5-dι(tert- -butyll -4-hydroxytoluene ["butylated hydroxytoluene", BHT; see e.g. W. Snipes et al.: Science 188, 64 (1975)]; alpha-tocopherol (Vitamin E, see e.g. the above-cited ar¬ ticle of M. J. Kelly); 21-{4-[2, 6-di (1-pyrrolιdιnyl) -4- -pyrιmιdιnyl]-l-pιperazmyl}-16α-methylpregna-l, 4,9(11)- -tπene-3, 20-dιone [U74006F, see e.g. E. J. Jacobsen et al. : J. Med. Chem. 33, 1145 (1990)]; as well as 2-{[4-[2,6- -di (1-pyrrolldmyl) -4-pyrιmιdιnyl]-l-pιperazιnyl]methyl}- -6-hydroxy-2, 5, 7, 8-tetramethyl-3, 4-dιhydro-2H-l-ben- zopyran [U78517F, see e.g. E. J. Jacobsen et al . : J. Med. Chem. 35, 4464 (1992)].
Biochemical investigation
The inhibition of iron (II) ion dependent lipid per¬ oxidation was measured in rat brain nomogenate as de¬ scribed by J.M. Braughler et al. [J. Biol. Chem. 262, 10438 (1987)] as well as by J. A. Buege and S. D. Aust [Metnocs m Enzy ology 52, 302 (1978)]. The IC_- values measured m this experiment and expressed in micromoles of several representatives of compounds according to the invention and reference compounds are shown in Table 1. The IC. value is the concentration of a compound tested, which decreases by 50 % the amount of thiobarbituric acid reactive substances (first of all malondialdehyde) con- sidered to be characteristic for the degree of lipid per¬ oxidation.
Table 1
Figure imgf000052_0001
Table 1 ( contd . )
Figure imgf000053_0001
Pharmacological investigation
In the acute head injury test in mice described by E. D. Hall et al. [J. Neurosurg. 68_, 456 (1988)], intravenous doses (given below) cf representative compounds according to the invention and reference substances inhibited the brain damage ( improved the neurological state of the ani¬ mals) to the degree shown. The percentage cf improvement is given by the change of sum of the scores characteris¬ tic for the neurological state of the animals.
Table 2
Figure imgf000053_0002
Table 2 (contd.)
Figure imgf000054_0001
Toxicolog cal study
The acute toxicity of compounds of the present inven¬ tion was determined in rats. The tcxicity of these com¬ pounds was found to be in general favourable, e.g. an in- traperitoneal dose of 500 mg/kg cf the compounds of Exam¬ ples 31, 34 or 44, respectively, did not provoke death of any of the treated animals (LD5r 500 mg/kg), similarly to tne above-mentioned compound U74006F used as reference compound. The results shown above demonstrate that several rep¬ resentatives of the compounds of formula (I) according to the present invention inhibit the lipid peroxidation to a significant degree under in vi tro conditions. Conse- quently, as confirmed also by the above m vi vo test re¬ sults, these compounds are capable to suppress various pathological processes related to an enhanced peroxida¬ tion of lipids in the living organism. In addition, these advantageous effects are accompanied by a favourable tox- lcity.
For therapeutical purposes, the compounds according to the present invention and their pharmaceutically ac¬ ceptable salts can be used alone or suitably m the form of pharmaceutical compositions. These compositions also fall within the scope of the present invention.
These pharmaceutical compositions contain an amount required to exert the therapeutical effect of a compound of formula (I) or its pharmaceutically acceptable salt, in admixture with known carriers, excipients, diluents and/or other additives commonly used m the pharmaceuti¬ cal practice.
The doses required to exert the therapeutical effect of tne compounds according to the invention may be varied depending on the individual condition and age of the pa- tient to be treated and finally these doses are deter¬ mined by the attending physician. However, for the pre¬ vention and/or treatment of diseases, where the inhibi¬ tion of lipid peroxidation is desirable, daily doses of these compounds falling between about 0.1 mg/kg of body weight and about 100 mg/kg of body weight and preferably between about 1 mg/kg of body weight and about 20 mg/kg of body weight are used by the oral or parenteral, e.g. intravenous, route. The compounds according to the invention and the process for the preparation thereof are illustrated in detail by the following non limiting Examples.
Example 1 Preparation of l-{6-[N- (2,5-dιhydroxybenzoyl)aroιno]- hexyl)-4-[2 , 6-di (1-pyrrol dinyl) -4-pyr mιd nyl]pιpe- raz ne
Step a) l-{6-[N- (2 ,5-D benzyloxybenzoyl)amιno]hexyl}-4-[2,6-dι- (1-pyrrolidinyl) - -pyr m dιnyl]pιperazιne
A mixture of 1.45 g (4.8 mmol) of l-[2,6-dι(l- -pyrrolidinyl) -4-pyrιmιdmyl]pιperazme, 3.1 g (5.7 mmol) of 6-[N- (2, 5-dιbenzyloxybenzoyl) amιno]hexyl iodide and 0.96 g (6.9 mmol) of anhydrous potassium carbonate in 36 ml of anhydrous dimethylformamide is stirred at a tem¬ perature of 55 °C under nitrogen for 5 hours. The reac¬ tion mixture is then diluted with 120 ml of ice-water and after addition of 2 g of sodium, chloride, it is extracted with ethyl acetate. The organic layer is washed with wa- ter, drieo and tne ethyl acetate is evaporated under re¬ duced pressure. After washing the residue with ethyl ether, 2.4" g (72 . yield) of title compound are ob¬ tained, m.p. 131-132 °C.
Step b) l -{6-[N- (2 , 5-Dιhydroxybenzoyl) am no]hexyl)-4 -[2 , 6-di (1- -pyrrol idinyl ) -4 -pyrιm dιnyl]pιperazιne
A solut ion containing 2 . 4 g ( 3 . 3 mmol ) of l -{6-[N- - ( 2 , 5-dιbenzyloxybenzoyl ) ammo]hexyl}-4-[2 , 6-di ( 1 -pyrrol l- dinyl ) -4-pyrιmιdιnyl]pιperazme in 120 ml o f 80% aqueous ethanol is adjusted to pH 3 by adding concentrated hydro¬ chloric acid and then hydrogenated m the presence of 1 . 1 q of 10 of palladium on charcoal as catalyst. After fil¬ tering off the catalyst, the pH value of the solution ob¬ tained is adjusted to 5 by using concentrated ammonium hydroxide, then the solvent is evaporated under reduced pressure. The residue is dissolved in 30 ml of water, the pH of the solution is adjusted to 8.5 with concentrated ammonium hydroxide and the mixture is extracted with chloroform. After drying the organic layer and evaporat¬ ing the chloroform under reduced pressure, the residue is subjected to chromatography on a silica gel column by us¬ ing ethyl acetate as eluent, the title compound is ob¬ tained in a yield of 0.76 g (43%), m.p. 182-183 °C.
Example 2 Preparation of 1- (2,6-d am no-4-pyr m dιnyl) -4-[2- -hydroxy-3- (2-naphthylthιo)propyl]pιperazιne
A solution containing 2.41 g (8 mmol) of l-[2- -hydroxy-3- (2-naphthyιthιo)propyl]pιperazme and 1.13 g (7.85 mmol) of 2, 6-dιammo-4-chloropyrιmιdιne in 20 ml of chlorobenzene is stirred under reflux under nitrogen for 4 hours. After cooling, the chlorobenzene is distilled off from the precipitated, somewhat sticky material under reduced pressure. The residue is stirred with 60 ml of 2 M aqueous sodium hydroxide solution until it is dismte- grated to a filtrable powder. After filtering, the solid product is wasned with water until neutral and then re- crystallized from etnyl acetate to oota 1.95 g (59.5%) of title product, m.p. 165-168 °C.
Examples 3 to 10 By using appropriately substituted starting compounds and following a process similar to that described in Ex¬ ample 2, compounds of formula (I) are prepared, wherein R means 2-naphthyl group; and
X, A, n, R^ and R* are as shown in the following Table.
Figure imgf000058_0001
Notes
' After chromatography on a silica gel column by using ethyl acetate as eluent; the product is identical to the compound of Examples 36 or 39, respectively.
"' The reaction is carried out m the presence of 1 equivalent of sodium iodide; the product is identical to the compound of Examples 31 or 40, respectively.
31 After recrystallization from methanol; the product is identical to the compound of Example 28.
Example 11
Preparation of l-[6-amιno-2- (1-pyrrolidinyl) -4-pyrι- m d yl]-4-[3- (2-hydroxy-l-naphthyl)prop onyl]pιper- az ne
A mixture containing 0.33 g (1.0 mmol) of 6-ammo-2- - (l-pyrrolidmyl) -4-tosyloxypyrιmιdme and 0.3 g (1.05 mmol) of l-[3- (2-hydroxy-l-naphthyl)propιonyl]pιperazme in 20 ml of chlorobenzene is heated in a steel bomb in an oil bath at 200 - 210 °C for 10 hours, then cooled down. After evaporating the solvent, the oily residue is dis¬ solved in 30 ml of hot methanol and after cooling down, the brown precipitate is filtered off. After evaporating the solvent from the methanolic filtrate, the residue is subjected to chromatography on a silica gel column by us¬ ing a 10:3 mixture of ethyl acetate and methanol as elu- ent to obtain 15 mg (3.8%) of the title compound the form of a light brown powder, which is identical to the compound of Example 72.
Example 12
Preparation of l-[2,6-di (1-pyrrol d nyl) -4-pyπm_.dι- nyl]-4-[2- (2-naphthylammo)acetyljp perazme A suspension of 0.70 g (4.88 mmol) of 2-naphthylamme and 1.90 g (5 mmol) of l-[2, 6-di (1-pyrrolιdιnyl) -4-pyrι- mιdιnyl]-4- (2-chloroacetyl) piperazme in 70 ml of ethanol is heated under reflux for 6 hours. After distilling off the solvent under reduced pressure, the residue is stirred with a mixture of 50 ml of saturated aqueous so¬ dium hydrogen carbonate solution and 50 ml of methylene chloride for 30 minutes. After separation the aqueous layer is extracted twice more with 50 ml of methylene chloride each, the combined organic layer is washed with 50 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. After triturating the obtained crude product with 25 ml of acetonitrile under mild heating, the solids are filtered off and washed with acetonitrile to give 1.31 g (55 ) of title product, m.p. 200-220 βC.
Example 13
Preparation of l-[2 , 6-di (1 -pyrrol dinyl ) -4-pyrιmιdι- nyl]-4 -[2- (4-nιtro-l-naph thylammo) acetyl]piperazιne A suspension containing 0.38 g ( 1 . 0 mmol ) of l-[2 , 6-
-di ( 1-pyrrolidιnyl ) -4-pyrιmιdinyl]-4- (2-chloroacetyl ) - piperazine , 0 . 19 g ( 1 . 0 mmol ) of 4-nιtro- l-naphthylamme and 0.2 g (1.45 mmol) of potassium carbonate m 40 ml of acetonitrile is heated under reflux for 30 hours. After filtering off the msolubles, the solvent is evaporated from the filtrate under reduced pressure. By purification of the residue by chromatography on a silica gel column using a 20:1 mixture of methylene dichloride and methanol as eluent, 90 mg (17.0 %) of title product are obtained, m.p. 192-201 °C.
Example 14 Preparation of l-[2,6-di (1-pyrrolidinyl)-4-pyrimidi- nyl]-4-[2- (2-naphthylthio)acetyl]pιperazιne
To a solution containing 0.64 g (4 mmol) of 2- -thionaphthol in a mixture of 80 ml of ethanol and 4 ml of 1 M aqueous sodium hydroxide solution, 1.51 g (4 mmol) of l-[2, 6-di (1-pyrrolidinyl) -4-pyπmιdmyl]-4- (2-chloro- acetyl)piperazine are added at room temperature. After stirring the reaction mixture at the same temperature for 2 hours and then evaporating the solvent under reduced pressure, the residue is worked up as described in Exa - pie 12. After recrystallizing the obtained crude product (2.19 g) from ethanol, 1.57 g (78.2 I ) of pure title com¬ pound are obtained, m.p. 135-138 °C.
Example 15
Preparation of l-[2,6-di (1-pyrrol dinyl) -4-pyrιmidi- nyl]-4-[2- (2-naphthylthio)acetyl]homopiperazine
The title compound is prepared as described in Exam¬ ple 14, except that 2-thionaphthol is reacted with 1- -[2, 6-di (1-pyrrolidinyl) -4-pyrimidinyl]-4- (2-chloroace- tyl) homopiperazine instead of l-[2, 6-di (1-pyrrolidinyl) - -4-pyrimidinyl]-4- (2-chloroacetyl)piperazine and the crude product is stirred with 50 ml of water until it is disintegrated tc a filtrable powder to give 1.77 g (86 ) of title product, m.p. 56-63 °C.
Example 16
Preparation of 1-[2,6-di (l-pyrrolidmyl) -4-pyrimid - nyl]-4-[N- (2-naphthyl)carbamoylmethyl]pιperaz ne
To a boiling suspension containing 1.2 g (4 mmol) of l-[2, 6-di (1-pyrrolidinyl) -4-pyrιmιdmyl]pιperazme and 0.68 g (5 mmol) of anhydrous potassium carbonate in 120 ml of acetonitrile, 0.86 g (4.9 mmol) of N-(2-chloro- acetyl) -2-naphthylamιne are added and the reaction mix¬ ture is vigorously stirred under reflux for 2 hours. Af¬ ter evaporating the solvent the residue is partitioned between 100 ml of water and 100 ml of methylene chloride. The aqueous phase is separated, extracted twice more with 40 ml of methylene cnloride each, the combined organic layers are wasned with water until neutral, dried over anhydrous magnesium sulfate, and the solvent is evapo¬ rated under reduced pressure to give 1.82 g (94.7.) of title product, m.p. 212-214 °C (after recrystallization from ethyl acetate) .
Examples 17 to 23
By using appropriately substituted starting compounds and following a process similar to that described m Ex¬ ample 16, compounds of formula (I, are prepared, wherein X means an NH group;
A represents a -C(0)-CH2- group;
ooth R2 and R mean 1-pyrrolιdιnyl group; and
R" has the meaning given in the following Table.
Figure imgf000062_0001
Notes
Contains about 30% of 6-acetyl isomer. "Thin layer chromatography Rt value is 0.70 on a Kiesel- gel 60 silica gel plate, eluting with a 10:3 mixture of ethyl acetate and methanol.
Example 24
Preparation of l-[2,6-di (1-pyrrolidinyl)-4-pyrιmid - nyl]-4-[3- (2-naphthylamino)propyl]p perazιne
To a solution containing 0.45 g (2.25 mmol) of N-(3- -hydroxypropyl) -2-naphthylamme and 0.37 ml (0.27 g, 2.7 mmol) of triethylamine in 10 ml of anhydrous toluene a solution of 0.17 ml (0.27 g, 2.3 mmol) of methanesulfonyl chloride in 2.5 ml of anhydrous toluene is added dropwise at 0 °C over 10 minutes and the mixture is stirred at the same temperature for one hour. Subsequently, the mixture is washed with water until neutral (2 x 5 ml), dried over anhydrous magnesium sulfate, and the solvent is evapo¬ rated under reduced pressure. Thus, 0.55 g (2 mmol) of N- - (3-methanesulfonyloxypropyl) -2-naphthylamme are ob- tamed. This intermediate is dissolved in 10 ml of aceto¬ nitrile, this solution is added to a suspension contain¬ ing 0.6 g (2 mmol) of l-[2, 6-di (l-pyrrolidmyl) -4-pyrι- mιdιnyl]pιperazme, 0.31 g (2.2 mmol) of potassium car¬ bonate and 0.01 g of sodium iodide m 10 ml of acetoni¬ trile, and the reaction mixture is stirred under reflux for 5 hours. After working up the reaction mixture as de- scribed in Example 13, the crude product (0.87 g) is sub¬ jected to chromatography on a silica gel column by using a 9:1 mixture of benzene and methanol as eluent to give 0.55 g (56.7%) of title product, m.p. 70-71 βC.
Example 25 Preparation of l-[2, 6-d amιno-4-pyr mιdιnyl]-4-[2- -hydroxy-3- (l-naphthylam no)propyl]p perazine
A suspension containing 2.11 g (5 mmol) of l-(2,6- -diammo- -pyri idinyl(piperazme bisz-tπfluoroacetate and 2.07 g (15 mmol) of potassium carbonate m 100 ml of ethanol is heated under reflux while vigorously stirring for 30 minutes. After filtering off the msolubles from the hot mixture, 1.0 g (5 mmol) of N- (2, 3-epoxypropyl) -1- -naphthylamme dissolved in 20 ml of ethanol is added to the filtrate. After heating the reaction mixture under reflux for 3 hours and evaporating the solvent, tne resi¬ due is partitioned between 100 ml of ethy_ acetate and 100 ml of water. The aqueous layer is extracted with 50 ml of ethyl acetate, the combined organic solution is washed with 50 ml of saturated saline, dried over anhy- drous magnesium sulfate and the solvent is distilled off. The residue is subjected to chromatography on a silica gel column by using a 2:8 mixture of benzene and methanol as eluent to obtain 0.95 g (48.4%) of title product, m.p. 105-109 °C (after tπturation with ethyl ether) . Examples 26 to 37
By using appropriately substituted starting compounds and following a procedure similar to that described in Example 25, compounds of formula (la) are obtained, wherein R1, X, n, R2 and R3 are as shown in the following Table.
Figure imgf000064_0001
Notes:
11 Instead of ethanol, methylene chloride is used as sol¬ vent. 2! Ms means methanesulfonyl group.
Example 38
Preparation of salts of l-[2 , 6-di (l-pyrrolidinyl) -4- -pyrimidinyl]-4-[2-hydroxy-3- (2-naphthylamino)propyl]- piperazine a) Salt formed with salicylic acid (salicylate)
To a solution containing 0.25 g (0.5 mmol) of l-[2, 6-
-di (l-pyrrolidinyl) -4-pyrimidinyl]-4-[2-hydroxy-3- (2-naph- thylamino) -propyljpiperazine base prepared according to
Example 31 in 7 ml of benzene, 10 ml of 0.1 M salicylic acid solution etanci are added while boiling. The mix¬ ture is allowed to cool down to room temperature, the precipitated crystalline substance is filtered off, washed with ice-cold ethanol and air-dried to give the 5 monosalicylate of the above base, m.p. 200-206 °C; the yield of the salt formation is 77.4%.
b) Salt formed w th p-toluenesulfomc acid
By following the procedure described under a) above, 10 mono-p-toluenesulfonate of the above base is obtained with a yield of 74.7%, m.p. 173-176 "C.
c) Salt formed with phosphoric acid
By following the procedure described under a) above, 15 diphosphate of the above base is obtained with a yield of 98.2%, which crystallizes with 2 moles of water, m.p. 260-265 °C (with decomposition) .
d) Salt formed with sulfur c acid
20 0.25 g (0.5 mmol) of l-[2, 6-di ( l-pyrrolidinyl) -4- -pynmιdιnyl]-4-[2-hydroxy-3- (2-naphthylammo) propyl]pιpe- razme base prepared according to Example 31 are dis¬ solved in a mixture of 10 ml of 0.1 M aqueous sulfuric acid solution and 13 ml of ethanol under heating, then z> - allowed to cool down. The precipitated crystals are fil¬ tered off, washed with ice-cold ethanol and air-dried to give the disulfate dihydrate of the above base, m.p. 228- -230 βC (with decomposition) ; the yield of salt formation is 75.7%. Example 39
Preparation of l-[2,6-d (l-pyrrolid yl) -4-pyrιm d - nyl]-4-[2-hydroxy-3- (2-naphthylthιo)propyl]pιperazιne
A solution containing 0.53 g (1.5 mmol) of l-[2,6- -di (l-pyrrolidinyl) -4-pyrιmιdmyl]-4- (2, 3-epoxypropyl) - piperaz e and 0.24 g (1.5 mmol) of 2-thιonaphthol m 10 ml of ethanol is heated under reflux with a catalytic amount (about 0.03 ml) of triethylamine under stirring for one hour. After cooling down, the crystalline product is filtered and washed with 2 ml of cold ethyl acetate to give 0.64 g (83.1%) of title compound, which is identical to the compound of Example 3 or Example 36, m.p. 136- -143 °C.
Example 40 Preparation of l-[2,6-d (1-pyrrol dιnyl) -4-pyrιmιd - nyl]-4-[2-hydroxy-3- (2-naphthyiamino)propyljpiperazme
The title compound is similarly prepared as described in Example 39, except that 2-naphthylamme is used in¬ stead of 2-thιonaphthol and the reaction mixture is heated under reflux for 24 hours. The thus-prepared title compound is identical to the compound of Example 31. The title product is obtained in a yield of 28.7%, m.p. 198- -201 °C. Alternatively, the title compound is obtained m a yield of 39.0t if about 0.05 ml of concentrated aqueous hydrochloric acid is used as catalyst instead of tri¬ ethylamine. Example 1
Preparation of l-[2 , 6-d (l-pyrrolid yl) -4-pyrιmidi- nyl]-4 - (2-hydroxy-3- (l-naphthoylmethylamino) propyl]- pipβrazine Step a)
2-{3-[4 -[2 , 6-Di ( l-pyrrolidinyl ) -4 -pyrim dιnyl]-l-pipe- raz nyl]-2-hydroxypropyl)-2- ( 1 -naphthyi ) -1 , 3-dioxo- lane
A solution containing 0.18 g (0.5 mmol) of l-[2, 6- -di (1-pyrrolidinyl) -4-pyrιmidιnyl]-4- (2, 3-epoxypropyl)pi¬ peraz e, 0.11 g (0.5 mmol) of 2-ammomethyl-2- ( 1- -naphthyl) -1, 3-dιoxolane and 0.1 ml (0.7 mmol) of trieth¬ ylamine 5 ml of ethanol is heated under reflux for 2 hours. The solvent is distilled off under reduced pres- sure and the residue is dissolved in 10 ml of ethyl ace¬ tate. After washing the solution with water and drying over anhydrous magnesium sulfate, the solvent is evapo¬ rated under reduced pressure. The residue is subjected to chromatography on a silica gel column by using a 80:20 mixture of chloroform and methanol as eluent to give 0.16 g (55%) of title product, m.p. 55-60 °C.
Step b) l-[2,6-Dι (1-pyrrolidxnyl) -4-pyrιmid nyl]-4-[2-hydroxy-
-3- (1-naphthoylme thylamino) propyl]piperazine The mixture containing 0 . 1 g ( 0 . 17 mmol ) of the in¬ termediate [prepared as described under step a ) above ] and 2 ml of formic acid is al lowed to stand for 10 days at ambient temperature . After pouring onto 20 ml of wa¬ ter, the mixture is rendered alkaline to pH 10 by adding 5 N aqueous sodium hydroxide solution, the separated crystals are collected, washed with water and dried on air. In this manner 0.06 g (65.) of title compound are obtained as a tan solid, m.p. 72-75 °C.
All 1-naphthyl compounds occurring in the present Example contain the respective 2-naphthyl isomer as a contamination in an amount of about 15 to 20% (see also Example 117) .
Example 42
Preparation of l-[2,6-di (1-pyrrol dmyl) -4-pyrimid - nyl]-4- (1-naphtoyl)piperazine To a solution containing 0.60 g (2 mmol) of l-[2,6-
-di (l-pyrrolidmyl) -4-pyrιmιdmyl]pιperazme and 0.30 ml
(0.22 g, 2.2 mmol) of triethylamine in 20 ml of anhydrous methylene chloride, a solution of 0.45 g (2.2 mmol) of naphthalene-1-carboxylιc acid chloride in 5 ml of anhy- drous methylene chloride is added dropwise at 0 °C under stirring. After stirring at room temperature for 2 hours the reaction mixture is diluted to the twofold volume with methylene chloride. The solution is washed with wa¬ ter (2 x 20 ml) until neutral, dried over anhydrous mag- nesium sulfate, and the solvent is evaporated under re¬ duced pressure. Tne crude product obtained is purified by chromatograpny en a silica gel column by using a 1:2 mix¬ ture of n-hexane and ethyl acetate to obtain 0.51 g (54.4 %) of title compound, m.p. 211-214 °C.
Examples 43 to 51
By using appropriately substituted starting compounds and following a procedure similar to that described in Example 42, compounds of formula (lb) are prepared, wherein X and B1 together form a single bond; and
R1, n, R2 and R; are as shown in the following Table.
Figure imgf000069_0001
Note:
'*' The reaction is performed in boiling acetonitrile.
Example 52
Preparation of l-[6-amino-2- (hexahydro-lH-azepin-1-
-yl ) -4 -pyrιmιdinyl]-4- ( l-hydroxy-2 -naphthoyl ) pipera- zme
Method A)
By using appropriately substituted starting compounds and following a procedure similar to that described in Example 42, the title compound is obtained as an oil in a yield of 18%, the thin layer chromatography Rf value of which is 0.73 by developing in a 2:1 mixture of ethyl acetate and methanol on a Kieselgel 60 silica gel plate. Method B)
After dissolving 0.19 g (1.0 mmol) of l-hydroxy-2- -naphthoic acid and 0.16 g (1.0 mmol) of carbonyldii ida- zole in 20 ml of anhydrous tetrahydrofuran and stirring the reaction mixture at room temperature for one hour, 0.28 g (1.0 mmol) of l-[6-ammo-2- (hexahydro-lH-azepin-1- -yl) -4-pyrιmidιnyl]piperazme are added, then the reac¬ tion mixture is stirred at room temperature for addi¬ tional 5 hours. After evaporating the solvent, the oily residue is purified by chromatography on a silica gel column. By using a 10:2 mixture of ethyl acetate and methanol as eluent, 0.19 g (42.5~_) of title product are obtained in the form of a colourless oil.
Example 53 Preparation of (-) -l-[2,6-di (1-pyrrolidinyl) -4-pyr - midιnyl]-4-[2- (6-methoxy-2-naphthyl)propιonyl]piper- azine
To a suspension containing 2.0 g (6.61 mmol) of 1- -[2, 6-di (l-pyrrolidmyl) -4-pyrιmιdιnyl]pιperazιne and 1.24 g (9 mmol) of potassium carbonate in 160 ml of dimethyl¬ formamide, an acyl chloride solution [prepared from 1.64 g (6.60 mmol) of [S- (+) -2- (6-methoxy-2-naphthyl) -propio¬ nic acid with thionyl chloride in benzene, in the pres¬ ence of pyridme at room temperature] is added at 60 βC temperature during 15 minutes while stirring, then the reaction mixture is stirred at 60 °C for 4 hours. After cooling down, the reaction mixture is poured onto 750 ml of saturated aqueous sodium chloride solution. The pre¬ cipitated crystals are filtered, washed with water, dried on air and subjected to chromatography on a silica gel column. By using a 9:1 mixture of chloroform and acetone as eluent 1.5 g (44.9%) of crystalline title compound are obtained, m.p. 151-154 °C; [α]. = -38.4° (c = 1, chloro¬ form) .
Examples 54 and 55
By using appropriately substituted starting compounds and following a procedure similar to that described in Example 53, compounds of formula (I) are prepared, wherein
R1 means 6-methoxy-2-naphthyl group; X represents a single bond; A stands for -CH (CH3) -C (0) - group; and R , R3 and n are as shown in the following Table.
Figure imgf000071_0001
Note:
(c = 1, chloroform)
Example 56
Preparation of (±) -l-[2 , 6-di (l-pyrrolidinyl) -4-pyri- midinyl_-4-[N- (tert-butoxycarbonyl) -3- (1 -naphthyi) - alanyl]piperazine
To a solution containing 0.90 g (2.9 mmol) of (±) -N- - (tert-butoxycarbonyl) -3- (1-naphthyl) -alanine in 15 ml of anhydrous dimethylformamide, first 0.62 g (3 mmol) of N, N' -dicyclohexylcarbodiimide, then 0.45 g (3 mmol) of 1- -hydroxybenzotriazole are added under nitrogen. After stirring for 30 minutes, a solution of 0.91 g (3 mmol) of l-[2, 6-di (l-pyrrolidinyl) -4-pyrimidinyl]piperazine in 5 ml of anhydrous dimethylformamide is added. The reaction mixture is stirred at room temperature for 24 hours, then the precipitated dicyclohexylurea is filtered off and the filtrate is poured onto 100 ml of 20' aqueous sodium chloride solution. The precipitate is filtered, washed with water, dried, washed with hexane and dried on air. After recrystallizing the crude product obtained (1.20 g, 66.7%) twice from ethanol, 0,72 g (40.0 ) of pure title compound are obtained, m.p. 174-176 βC.
Examples 57 to 63 By using the appropriately substituted starting com¬ pounds and following a procedure similar to that de¬ scribed in Example 56, compounds of formula (lb) are pre¬ pared, wherein X and B1 together form a single bond;
both R and R3 mean l-pyrrolidinyl group; and R' is as shown m the following Table.
Figure imgf000072_0001
Note: *Thin layer chromatography R£ value is 0..0 on a Kiesel- gel 60 silica gel plate by eluting with a 10:3 mixture of ethyl acetate and methanol. Examples 64 to 66
By using appropriately substituted starting compounds and following a procedure similar to that described m Example 56, compounds of formula (lb) are prepared, wherein
X represents a single bond; B1 means -CH -CH[NH-C0-0C (CH3) 3]~ group; n is 1; both R and RJ mean l-pyrrolidmyl group; and R1 is as shown in the following Table.
Figure imgf000073_0001
Note: (c = 1, chloroform)
Example 67 Preparation of (±) -l-[2,6-d (1-pyrrolidinyl) -4-pyrι- m d nyl]-4-[3- (1-naphthyi)alanyljpιperazιne
A mixture containing 0.24 g (0.4 mmol) of (±)-l-[2,6- -di (1-pyrrolldmyl) -4-pyrιmidinyl]-4-[N- ( ert-butoxycaroo- nyl) -3- (1-naphthyl) alanyl]pιperazme and 2 ml of 97% for- mic acid is stirred at room temperature for 24 hours. Af¬ ter pouring onto 5 ml of water under cooling by ice, the pH of the mixture is adjusted to 10 by adding 10 M sodium hydroxide solution. The formed precipitate is filtered off, washed with water, dried and then triturated with ethyl ether to obtain 0.15 g (75%) of title compound, m.p. 142-143 °C. Examples 68 to 70
By using appropriately substituted starting compounds and following a procedure similar to that described in Example 67 , compounds of formula ( lb ) are prepared, wherein
X represents a single bond; B! means -CH -CH (NH; ) - group; n is 1 ; both R2 and R3 mean l -pyrrol idinyl group; and R1 is as shown in the following Table .
Figure imgf000074_0001
Note:
(c = 1, chloroform)
Example 71 Preparation of l-_2 , 6-di (l-pyrrolidinyl) -4-pyrimidi- nyl]-4-[3- (2-hydroxy-l-naphthyl)propιonyl]piperazine
After dissolving 3.0 g (9.9 mmoii of l-[2,6-di(l- -pyrrolidinyl) -4-pyrimidinyl]piperazine in 300 ml of an¬ hydrous acetonitrile, 2.0 g (10.1 mmol) of 3- (2-hydroxy- -1-naphthyl) propionic acid lactone are added under stir¬ ring. After heating under reflux for 22 hours the mixture is cooled down, the precipitate is filtered off, washed with ice-cold acetonitrile and dried on air to obtain 4.36 g (95.7%) of title compound, m.p. 274-275 °C.
Examples 72 to 74
By using appropriately substituted starting compounds and following a procedure similar to that described in Example 71, compounds of formula (lb) are prepared, wherein
R1 means 2-hydroxy-l-naphthyl group;
X represents a single bond; n is 1; and
B1, R2 and R3 are as shown in the following Table.
Figure imgf000075_0001
Note:
Identical to the compound of Example 11
Example 75 Preparation of l-[2 , 6-di (l-pyrrolidmyl) -4-pyrimidi- nyl]-4-[2- (3-hydroxy-2-naphthyi)acetyljp perazine
A solution containing 0.45 g (1.5 mmol) of l-[2,6- -di (l-pyrrolidmyl) -4-pyrimidinyl]piperazme and 0.32 g (1.74 mmol) of 2- (3-hydroxy-2-naphthyl) acetic acid lac- tone in 50 ml of anhydrous acetonitrile is stirred at 40 °C for one hour, during this time a white precipitate ap¬ pears. The mixture is cooled down, the precipitate is filtered off, washed with acetonitrile and dried on air to obtain 0.52 g (77.3%) of title compound as an off- -white powder, m.p. 210-221 °C. Example 76
Preparation of l -[2 , 6-di ( 1 -pyrrol ldmyl ) -4 -pyrιm dι - nyl]-4 -[2- (2 -naph hylammo) ethyl]pιperaz ne
Method A) The mixture of 0.14 g (1 mmol) of 2-naphthol and 0.35 g (1 mmol) of 1- (2-ammoethyl) -4-[2, 6-di (l-pyrrolidmyl) - -4-pyrιmιdmyl]pιperazine is heated in a steel bomb in an oil bath at 220-225 °C for 3 hours. After cooling down, the mixture is dissolved in 20 ml of chloroform, ex- tracted with 1 M sodium hydroxide solution, washed with saturated sodium chloride solution until neutral and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue is sub¬ jected to chromatography on a silica gel column. By using a 9:1 mixture of benzene and methanol as eluent, 0.08 g of title product are obtained, which is recrystallized from isopropanol to give the title product in a yield of 17%, m.p. 109-110 °C.
Method B) A mixture containing 0.29 g (2 mmol) of 2-naphthol, 0.76 g (2.2 mmolj of 1- (2-ammoethyl) -4-[2, 6-di (l-pyrro¬ lidmyl) -4-pyrιmιdιnyl]piperazιne and 0.35 g (2 mmol) of sodium dithionite in 10 ml of water is heated in a steel bomb in an oil bath at 150-155 °C for 7 hours. After cooling down, the reaction mixture is extracted with ben¬ zene, the organic phase is washed first with 1 M aqueous sodium hydroxide solution, then with water and dried over anhydrous magnesium sulfate. After evaporating the sol¬ vent under reduced pressure, the residue is recrystal- lized from isopropanol to give 0.20 g (21.3 %) of title compound in the form of a colourless crystalline product, m.p. 110-112 °C. Method C)
By using appropriately substituted starting compounds and following a procedure similar to that described in Example 24, first the intermediary N- (2-methanesulfonyl- oxyethyl) -2-naphthylamine is obtained m a yield of 50.0%, which is then reacted with l-[2, 6-di (l-pyrrolidi¬ nyl) -4-pyπmιdmyl]piperazine similarly to the procedure described m Example 24 to give the title compound in a yield of 34.1* (calculated upon the esyloxy derivative) .
Example 77
Preparation of l-[2,6-di (1-pyrrol dinyl) -4-pyr mid - nyl]-4-[2- (2-naphthoylam o)ethyl]p perazιne
A solution of 0.6 g (3.2 mmol) of naphthalene-2- -carboxylic acid chloride in 6 ml of methylene chloride is added dropwise to a solution containing 1.0 g (2.9 mmol) of 1- (2-ammoethyl) -4-[2, 6-di (l-pyrrolidinyl) -4- -pyrιmidmyl]piperazme and 0.5 ml (3.5 mmol) of triethy¬ lamine in 20 ml of methylene chloride, and the mixture is stirred without cooling for one hour. After washing the reaction mixture successively twice with 20 ml of water each, twice with 20 ml of 5% aqueous sodium hydrogen car¬ bonate solution each and finally, twice with 20 ml of wa¬ ter each and drying over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The solid residue is triturated with acetonitrile to obtain 1.4 g (96.6.) of title compound, m.p. 221-222 °C.
Example 78
Preparation of 1-[2,6-di (l-pyrrolidinyl) -4-pyrimidi- nyl]-4-{2-[2-(2-naphthyi)acetylamino]ethyl}piperazine The title compound is prepared similarly to the pro¬ cedure described in Example 77, except that 2- (2- -naphthyl) acetyl chloride is used instead of naphthalene- -2-carboxylιc acid chloride, yield: 91.3', m.p. 214-215 °C.
Example 79
Preparation of l-[2,6-di (l-pyrrolidinyl) -4-pyrimidi- nyl]-4-[2- (2-naphthylmethylamino)ethyl]pιperazine
To 20 ml of anhydrous tetrahydrofuran, 91 mg (2.4 mmol) of lithium aluminum hydride and then 80 mg (0.6 mmol) of aluminum chloride are added. The suspension ob¬ tained is cooled to -78 °C and 0.15 g (0.3 mmol) of 1- -[2, 6-di (l-pyrrolidinyl) -4-pyrimidmyl]-4-[2- (2-naphthoyl- amino) ethyl]piperazιne are added. The mixture is allowed to warm to 0 °C and stirred at the same temperature for 2 hours. Subsequently, 2 ml of water and 5 ml of a 5 M aqueous sodium hydroxide solution are adoed dropwise un- der cooling with ice. After extracting the resulting milky mixture with 20 ml of ethyl acetate, the organic phase is washed three times with 10 ml of water each un¬ til neutral, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure to ob- tain 0.14 g (96.6 %) of crude title product as a yellow oil. The - (+) -tartrate melts at 90-95 °C (after crystal¬ lization from ethanol) .
Example 80
Preparation of 1-[2,6-di (1-pyrrolidinyl) -4-pyrimidi- nyl]-4-{2-[2- (2-naphthyi)ethylam no]ethyl)piperazine
The title compound is prepared by using l-[2,6-di(l- -pyrrolidinyl) -4-pyrimidinyl]-4-{2-[2- (2-naphthyl) acetyl- amino]ethyl}-piperazine as starting substance and follow¬ ing a procedure similar to that described m Example 79. The title compound is obtained in a yield of 55.2 %, the L- (+) -tartrate salt melts at 105-115 °C (after crystalli¬ zation from ethanol) . Example 81
Preparation of l-[2-acetoxy-3- (N-acetyl-2-naphthyi- amino)propyl]- -[2,6-di (l-pyrrolidinyl) -4-pyrimidι- nyllpiperazine After dissolving 0.17 g (0.34 mmol) of l-[2,6-di(l- -pyrrolidinyl) -4-pyrιmidinyl]-4-[2-hydroxy-3- (2-naphthyl- amino) propyl]pιperazιne in 3 ml of acetic anhydride by heating to about 50 "C, the solution is allowed to stand at room temperature for 2 hours, then poured onto water. After dissolution of the excess acetic anhydride, the mixture is extracted three times with 10 ml of chloroform each. The combined organic solution is washed three times with water, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. After triturating the oily residue with water, 0.16 g of solids are obtained. This product is subjected to cnromatography on a silica gel column. By using a 9:1 mixture of methyl¬ ene chloride and methanol as eluent, the title product is obtained in a yield of 0.13 g (65.0%), m.p. 70-75 'C.
Example 82
Preparation of l-[2,6-di (1-pyrrolidinyl) -4-pyri di- nyl]-4-[2-methoxy-3- (2-naphthylamino)propyl]piperazine
To 10 ml of anhydrous dimethylsulfoxide, 33 mg (1.1 mmol) of 80% sodium hydride are added under nitrogen, and the mixture is stirred at room temperature for 30 min¬ utes. Then, 0.5 g (1 mmol) of l-[2, 6-di (l-pyrrolidmyl) - -4-pyrιmidιnyl]-4-[2-hydroxy-3- (2-naphthylammo)propyl]- piperazine are added and the mixture is stirred for addi¬ tional 30 minutes. After adding 0.1 ml (0.23 g, 1.6 mmol) of methyl iodide to the suspension and stirring the reac¬ tion mixture for an additional hour, a yellow solution is formed. The dimethylsulfoxide solution is extracted three times with 10 ml of ethyl ether each, the combined ethe¬ real solution is washed with water until neutral, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The oily residue (0.42 g) is subjected to chromatography on a silica gel column by using ethyl acetate as eluent to obtain 0.16 g (31.1%) of title product as a colourless gum, which solidifies upon standing, m.p. 33-38 °C. This compound has a thin layer chromatography Rf value of 0.5 on a Kieselgel 60 silica gel plate, by eluting with ethyl acetate.
Example 83
Preparation of l-[2,6-di (l-pyrrolidinyl) -4-pyrimidi- nyl]-4-[2-hydroxy-3- (N-ethoxycarbonyl-2-naphthyi- amino)propyl]piperazine A suspension containing 0.50 g (1 mmol) of l-[2, 6- -di (l-pyrrolidmyl) -4-pyrimidinyl]-4-[2-hydroxy-3- (2-naph- thyla ino) propyl]piperazine in 15 ml of anhydrous pyri- dine is cooled to -5 °C temperature and 0.15 ml (0.17 g, 1.56 mmol) of ethyl chloroformate are added. The mixture is stirred at 0 °C for one hour, during this time the suspension is transformed to a yellow solution. After pouring the reaction mixture onto 100 ml of water and ex¬ tracting three times with 50 ml of ethyl ether each, the combined organic layers are washed twice with 50 ml of water each, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure to give 0.47 g (82.8%) of title product, m.p. 70-77 °C. Example 84
Preparation of 1-[2,6-di (1-pyrrolidinyl) -4-pyrimidi- nyl]-4-[2-(ethoxycarbonyloxy) -3-(2-naphthylamino)- propyl]pιperazine To a suspension containing 0.50 g (1 mmol) of l-[2, 6- -di (l-pyrrolidinyl) -4-pyrimidinyl]-4-[2-hydroxy-3- (2-naph- thylamino)propyl]piperazine in 20 ml of anhydrous methyl¬ ene chloride, 0.27 ml (0.30 g, 1.85 mmol) of diethyl di- carbonate are added at 0 °C under stirring. The mixture is stirred at the same temperature for one hour and then at room temperature fcr 16 hours, whereupon the insoluble materials are dissolved. After evaporating the solvent, the residue is purified by chromatography on a silica gel column. By using an 1:4 mixture of hexane and ethyl ace- tate as eluent, 0.40 g (69.8%) cf title compound is ob¬ tained, m.p. 63-68 °C.
Example 85
Preparation of l-[2,6-di (l-pyrrolidinyl) -4-pyrimidi- nyl]-4-[2- (tert-butoxycarbonyloxy) -3- (2-naphthyl- amino)propyljpiperazine
To a suspension containing 0.95 g (1.9 mmol) of 1- -[2, 6-di (1-pyrrolιdιnyl) -4-pyrimidinyl]-4-[2-hydroxy-3- (2- -naphthylammo) propyl]piperazine in 20 ml of anhydrous methylene chloride, 0.36 ml (0.19 g, 1.9 mmol) of trieth- ylamine, 0.23 g (1.9 mmol) of 4-dιmethylamιnopyridine and 0.83 g (3.8 mmol) of di (tert-butyl) dicarbonate are added. After stirring the reaction mixture at room temperature for 8 hours and then allowed to stand overnight in the refrigerator, the insolubles are filtered off and the solvent is evaporated from the filtrate under reduced pressure. The residue is purified by chromatography on a silica gel column by using an 1:4 mixture of hexane and ethyl acetate as eluent to obtain 0.32 g (28.3%) of title product, m.p. 82-84 °C.
Example 86
Preparation of l-[2 ,6-di (1-pyrrolιdιnyl) -4-pyrιmιd - nyl]-4-[N- (7-carboxy-1-naphthyi)carbamoylmethyl]pιpQr- az ne
A solution of 0.20 g (3.56 mmol) of potassium hydrox¬ ide in 2 ml of ethanol is added to a suspension contain¬ ing 0.4 g (0.7 mmol) of l-[2, 6-di (l-pyrrolidmyl) -4-pyrι- mιdmyl]-4-[N- (7-ethoxycarbonyl-l-naphthyl) carbamoyl- methyl]pιperazme in 10 ml of ethanol and the reaction mixture is heated under reflux for one hour while stir¬ ring. After evaporating the solvent under reduced pres¬ sure, the residue is subjected to chromatography on a silica gel column by using an 1:1 mixture of benzene and methanol as eluent to give the potassium salt of the ti¬ tle product in a yield of 0.16 g (41.0 %), m.p. above 360 °C.
Example 87 Preparation of l-[2,6-di (1-pyrrol d nyl) -4-pyrιmιd - nyl]-4- (5-carboxamιdo-2-naphthoyl)piperazme
To 3 g of polyphospnoric acid stirred in an oil bath at 110-115 βC 0.1 g (0.2 mmol) of 1- (5-cyano-2-naph- thoyl) -4-[2, 6-di (1-pyrrelιdmyl) -4-pynmιomyl]pιperazme is added, and the reaction mixture is stirred at the same temperature for one hour. After cooling to about 60 °C, the mixture is poured onto 20 ml of ice-water. The aque¬ ous solution is rendered alkaline by adding 5 N sodium hydroxide solution, the precipitate is filtered, washed with water and then with acetonitrile to obtain 0.09 g (90%) of title product, m.p. 280 °C (with decomposition) . Example 88
Preparation of l -[2 , 6-d ( 1 -pyrrol dinyl ) -4 -pyrιmidι - nyl3-4 -f2-hydroxy-3- (2-naphthylsulfinyl ) propyl3piper- azine To a solution containing 0.58 g (1.12 mmol) of 1-
-[2, 6-di (l-pyrrolidmyl) -4-pyrimidinyl]-4-[2-hydroxy-3- (2- -naphthylthio)propyl]piperazine in 5 ml of acetic acid cooled an ice bath, 0.35 ml of a 30 % aqueous hydrogen peroxide solution are added, then the mixture is allowed to stand at room temperature for 60 hours. After diluting with 20 ml of water, the mixture is neutralized by adding a saturated sodium hydrogen carbonate solution while stirring in an ice bath. Subsequently, the mixture is ex¬ tracted three times with 40 ml of chloroform each, the combined organic solution is washed with 30 ml of satu¬ rated aqueous sodium chloride solution, dried over anhy¬ drous magnesium sulfate and the solvent is evaporated un¬ der reduced pressure. The residue is subjected to chroma¬ tography on a silica gel column by using a 4:1 mixture of ethyl acetate and methanol as eluent to give 0.12 g (20.0%) of title compound, m.p. 184-186 βC.
Example 89
Preparation of 1-[2,6-di (1-pyrrolidinyl) -4-pyr midi- nyl]-4-[2-hydroxy-3- (2-naphthylamino)propyl]pιperazine The solution of 0.5 g (0.86 mmol) of l-[2, 6-di (1-pyr- rolidmyl) -4-pyrιmιdmyl]-4-{2-hydroxy-3-[N-methanesulfo- nyl-N- (2-naphthyl) ammo]propyl}piperazine in 15 ml of an¬ hydrous tetrahydrofuran is added dropwise to a suspension containing 1.0 g (26.4 mmol) of lithium aluminum hydride in 50 ml of anhydrous tetrahydrofuran at room temperature during 20 minutes and the reaction mixture is stirred at the same temperature for 2 hours. Then, successively 10 — o 2 —
ml of ethyl acetate, 10 ml of water and finally, 20 ml of 10 N aqueous sodium hydroxide solution are added while cooling with ice. After separation, the aqueous phase is extracted three times with 20 ml of ethyl acetate each. The combined organic layers are washed with water until neutral (3 x 20 ml), dried over anhydrous magnesium sul¬ fate and the solvent is evaporated under reduced pres¬ sure. After triturating the solid residue with acetoni¬ trile, 0.27 g (62.8%) of title product are obtained as a tan powder, which is identical to the product of Example 31, m.p. 188-190 °C.
Example 90
Preparation of 1- (3-amino-2-naphthoyl) -4-[2 ,6-di (1-
-pyrrolidinyl) -4-pyrimidinyl]piperazine To a solution containing 0.29 g (0.51 mmol) of 1- -[2, 6-di (l-pyrrolidinyl) -4-pyrιmιdinyl]-4-[3-trifluoroace- tylamino-2-naphthoyl]pιperazine in 20 ml of anhydrous tetrahydrofuran, 2 ml of 4% aqueous sodium hydroxide so¬ lution are added and the mixture is heated under reflux for 8 hours under vigorous stirring, then allowed to stand at room temperature overnight. After evaporation of the solvent, the oily residue is triturated with water, the solidified product is filtered, washed with water and dried on air. Thus, the title compound is obtained in a yield of 0.21 g (77.8%) as a white powder, m.p. 223-224 °C. Example 91
Preparation of ( - ) -l -[2 , 6-di ( 1 -pyrrol dinyl ) -4 -pyr - mιdιnyl]-4 -[2-hydroxy-3- <2-naph thylamino) propyljpiper- azine
Method A)
A solution containing 1.02 g (7.1 mmol) of 2- -naphthylamme and 0.73 g (0.62 ml, 7.9 mmol) of S-(+)- -epichlorohydrin m the mixture of 10 ml of ethanol and 2.4 ml of water is stirred under reflux for 3 hours. Af- ter evaporating the solvent under reduced pressure, three times 10 ml of ethanol each are evaporated from the resi¬ due. Thus, 1.78 g (7 mmol) of the corresponding crude chlorohydrm, namely N- (2-hydroxy-3-chloropropyl) -2-naph- thylamme are obtained, which is used without further pu- rification in the next reaction step.
A suspension containing the above chlorohydrm, 2.1 g (7 mmol) of l-[2, 6-di (1-pyrrolιdιnyl) -4-pyrιmιdmyl]pιper- azme and 1.8 g (13 mmol) of potassium carbonate in 40 ml of acetonitrile is heated under reflux under vigorous stirring for 5 hours. After evaporating the solvent under reduced pressure and triturating the residue with the mixture of 50 ml of water and 100 ml of ethanol while boiling, the suspension obtained is cooled to room tem¬ perature, tne precipitate is filtered off, washed with water until neutral and dried on air. Thus, 1.4 g of ti¬ tle product are obtained, which is boiled with 140 ml of a 1:1:1 mixture of ethanol, ethyl acetate and acetoni¬ trile for a few minutes. After cooling down, the purified product is filtered, washed with the aoove solvent mix- ture and dried on air to obtain 2.1 g (59.0%) of title compound, m.p. 217-221 °C; [α]D = -4.4° (c = 2, in a 1 M aqueous hydrochloric acid solution) . Method B)
Step a)
(+) -N- (2,3-Epoxypropyl) -2-naphthylamine
A solution containing 1.02 g (7.1 mmol) of 2- -naphthylamine and 0.73 g (0.62 ml, 7.9 mmol) of S-(+)- -epichlorohydrin in the mixture of 10 ml of ethanol and 2.4 ml of water is stirred under reflux for 3 hours. Af¬ ter evaporating the solvent under reduced pressure, three times about 10 ml of ethanol each are evaporated from the residue. Thus, 1.78 g (7 mmol) of the corresponding chlorohydrm, namely N- (2-hydroxy-3-chloropropyl) -2-naph- thylamme are obtained which is used without further pu¬ rification in the next reaction step.
To the solution of the above crude chlorohydrin in the mixture of 3.5 ml of anhydrous methanol and 1.6 ml of anhydrous ethyl ether, 0.25 g (10.87 mmol) of sodium metal is added in three equal portions at a temperature between 0 °C and 5 °C during 15 minutes. After stirring the reaction mixture at 0 °C for one hour, the solvent is distilled off under reduced pressure, the residue is sub¬ jected to chromatography on a silica gel column by using a 96:4 mixture of benzene and methanol as eluent to give 0.52 g of crystalline title compound, which is washed with isopropyl ether, filtered and dried on air. Accord- ing to thin layer chromatography this product is not com¬ pletely pure. The yield is 0.53 g (37.4%), m.p. 119-121 °C; [α]- = +16.4° (c = 1, chloroform) .
Step b)
( -) -l-[2 , 6-Di (l-pyrrolidinyl ) -4 -pyrimidinyl]-4-[2- -hydroxy-3- (2 -naph thylamino) propyl]piperazine
A solution containing 0. 39 g ( 1 . 95 mmol ) of ( + ) -N- - ( 2 , 3-epoxypropyl ) -2-naphthylamine and 0 . 57 g ( 1 . 90 mmol ) of l-[2 , 6-di ( l-pyrrolidinyl ) -4-pyrimidinyl]piperazine in 30 ml of ethanol is stirred under reflux for 2 hours. Af¬ ter cooling down, the crystalline precipitate is filtered off, washed with ice-cold ethanol and dried on air to give 0.70 g (73.4%) of title product, m.p. 220-221 °C; [ ]D = -4.5° (c = 2, m a 1 M aqueous hydrochloric acid solution) .
Example 92
Preparation of ( + ) -l-[2 , 6-di ( 1 -pyrrol idinyl ) -4 -pyri- midιnyl]-4 -[2-hydroxy-3- (2-naphthylamino) propyl]piper- azine
Method A)
Method A) of Example 91 is followed, except that R- -(-) -epichlorohydrm is used instead of S-(+)- -epichlorohydr to give 1.9 g (53.4%) of title product, m.p. 216-219 °C; [α]D = +4.3° (c = 2, in a 1 M aqueous hy¬ drochloric acid solution) .
Method B)
Step a)
(-) -N- (2 ,3-Epoxypropyl) -2-naphthyiamine Step a) of method B) of Example 91 is followed, ex¬ cept that R- (-) -epichlorohydrm is used instead of S-(+)- -epichlorohydrin to obtain 0.50 g (35.3%) of title com¬ pound, m.p. 116-118 °C; [α]D = -22.8° (c = 1, chloroform) .
Step b) (+) -l-[2,6-dι (l-pyrrolidinyl) -4-pyrιmidιnyl]-4-[2- -hydroxy-3- (2-naphthylamino)propyl]p perazine
Step b) of method B) of Example 91 is followed, ex¬ cept that (-) -N- (2, 3-epoxypropyl) -2-naphthylamine de¬ scribed in step a) of method B) of the present Example is used instead of (+) -N- (2, 3-epoxypropyl) -2-naphthylamine to obtain 0.58 g (60.8%) of title compound, m.p. 218-220 °C; [α]n = +4,4° (c = 2, in a 1 M aqueous hydrochloric acid solution) .
The preparation of novel intermediates used in the above Examples 1 to 92 is illustrated in Examples 93 to 117 described hereinbelow.
Example 93
Preparation of 1 -[2 -hydroxy- 3- (2-naphthylammo) - propyl]pιperaz ne
Step a) N- (2,3-Epoxypropyl) -2-naphthylam ne
A solution containing 5.16 g (36 mmol) of 2- -naphthylamine and 4.4 g (3.7 ml, 47.5 mmol) of epichlorohydrm in the mixture of 12 ml of ethanol and 6 ml of water is heated under reflux for 3 hours while stirring. After cooling down, the mixture is diluted with water to a volume of 100 ml and extracted three times with 30 ml of ethyl acetate each. The combined organic phase is washed with water, dried over anhydrous magne¬ sium sulfate and the solvent is distilled off. After stirring the residue with 100 ml of ethyl ether and 20 ml of 10 M aqueous sodium hydroxide solution for 2 hours, the organic phase is separated, washed with water until neutral, dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is subjected to chromatography on a silica gel column by using a 95:5 mixture of benzene and methanol as eluent to obtain 4.33 g of product which is triturated with isopropyl ether to give the title compound in a yield of 60.3%, m.p. 101-102 βC. By using appropriately substituted starting compounds and following a procedure similar to that described in the above step a), the oily compounds of formula (VIII) are prepared, wherein R; and X are as shown in the following Table.
Figure imgf000089_0001
Note:
11 Thin layer chromatography Rf values on Kieselgel 60 silica gel plates by eluting with a 95:5 mixture of ben- zene and methanol.
Step b)
1-[2-Hydroxy-3- (2-naphthylamino)propyl]-4- (tert- -butoxycarbonyl)piperazine Method A) A solution containing 1.47 g (7.35 mmol) of N- (2, 3- -epoxypropyl) -2-naphthylamine [prepared as described in step a) above] and 1.38 g (7.4 mmol) of 1- (tert- -butoxycarbonyl)piperazine in 30 ml of ethanol is heated under reflux for 2 hours. After distilling off the alco- hoi, the crystalline residue obtained is washed with ethyl acetate to give 1.97 g (65.9%) of title compound, m.p. 131-132 °C.
Method B)
A mixture containing 1.21 g (5 mmol) of l-(2,3- -epoxypropyl) -4- (tert-butoxycarbonyl) piperazine, 0.59 g (4.2 mmol) of 2-naphthylamine and 20 ml of ethanol is heated under reflux for 15 hours. After distilling off the solvent, the crude product obtained is subjected to chromatography on a silica gel column by using ethyl ace¬ tate as eluent to obtain 0.89 g (55.3 %) of title com¬ pound.
Compounds of formula (XIV) , wherein A means 2-hydroxy-l, 3-propylene group; n is 1;
R4 stands for a tert-butoxycarbonyl group; and
R1 and X are as shown in the following Table, are prepared similarly to the procedures described in the above methods A) or B) , respectively.
Figure imgf000090_0001
Note:
" Thin layer chromatography R value on Kieselgel 60 sil¬ ica gel plates by eluting with a 95:5 mixture of benzene and methanol .
Step c) l-[2-Hydroxy-3- (2-naphthylamino)propyl]piperazine
To 1.85 g (4.79 mmol) of l-[2-hydroxy-3- (2-naphthyl- amino)propyl]-4- (tert-butoxycarbonyl)piperazine [prepared by using any of the methods of step b) above] 6 ml of trifluoroacetic acid cooled to 0 °C are added and the mixture is stirred for 90 minutes while maintaining the temperature at 0 °C. After distilling off the excess acid under reduced pressure, twice 10 ml of anhydrous ethyl ether each are evaporated from the residue. The crystal¬ line product obtained is dissolved in 30 ml of water, the solution is rendered alkaline by adding 10 M aqueous so¬ dium hydroxide solution under stirring and cooling, then the mixture is extracted 4 times with 30 ml of ethyl ace¬ tate each. After washing the combined ethyl acetate lay¬ ers with 40 ml of water and drying over anhydrous magne¬ sium sulfate, the solvent is evaporated to obtain 0.67 g (45.9%) of crystalline title compound, m.p. 142-144 °C. By following the procedure described in step c> above, compounds of formula (II) are prepared, wherein A means 2-hydroxy-l, 3-propylene group; n is 1; and R' and X are as shown m the following Table.
Figure imgf000091_0001
Notes :
" Bis-trifluoroacetate salts.
" Thin layer chromatography Rf value is 0.58 on a Kiesel- gel 60 silica gel plate, by elut g with a 75:20:5 mixture of etnyl acetate, methanol and concentrated aqueous ammonium hydroxide solution.
Example 97 Preparation of l-[2-d methylam no-3-(2-naphthyl hio) - propyl]pιperazιne
A solution of 0.45 mi (0.66 g, 5.7 mmol) of mesyl chloride m 5 mi cf methylene chloride is added dropwise to a solution containing 1.7 g (4.2 mmol) of l-[2- -hydroxy-3- (2-napnthylthιo)propyl]-4- (tert-butoxycarbo¬ nyl)piperazme ana 0.87 ml (0.64 g, 63 mmol) of triethy¬ lamine m 30 ml of methylene chloride at a temperature between 20 and 25 βC. After stirring the mixture for one hour, an additional 0.87 ml of triethylamine and 0.45 ml of mesyl chloride are added and the mixture is stirred for an additional hour. Subsequently, it is washed three times with 15 ml of water each, dried over anhydrous mag¬ nesium sulfate and the solvent is evaporated under re¬ duced pressure. Thus, 2.32 g of crude l-[2-methane- sulfonyloxy-3- (2-naphthyithio)propyl]-4- (tert-butoxycar¬ bonyl) piperazine are obtained (m a yield over 100 c) li¬ the form of a yellow oil, which is used without further purification in the next reaction step. A mixture containing the above crude methanesulfonyl- oxy derivative and 20 ml of 33% ethanolic dimethyla ine solution is allowed to stand at room temperature for 48 hours, then the volatile components are evaporated under reduced pressure. After partitioning the residue between 30 ml of water and 30 ml of ethyl acetate, the aqueous layer is separated and extracted twice with 15 ml of ethyl acetate each. The combined organic solution is ex¬ tracted three times with 15 ml of 1 N hydrochloric acid each, then the pH of the combined aqueous-acidic solution is adjusted to 10 by adding a 5 N sodium hydroxide solu¬ tion and extracted three times with 20 ml of ethyl ace¬ tate each. The organic layers obtained in the latter ex¬ traction are combined, washed with water until neutral, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. Thus, 1.46 g of crude l-[2-dimethylamino-3- (2-naphthyithio) propyl]-4- (tert-but¬ oxycarbonyl)piperazme are obtained m the form of a yel¬ low oil (m a yield of 81.1. calculated upon the starting hydroxy compound) , which is used without further punfi- cation in the next reaction step.
After dissolving tne above cruoe, protected dimethyl- ammo compound in 20 ml of 10% aqueous hydrochloric acid and stirring the solution at room temperature for one hour, the solution is washed three times with 10 ml of ethyl acetate each, then the aqueous-acidic phase is ad¬ justed to pH 10 by adding a 5 N sodium hydroxide solution and extracted three times with 20 ml of ethyl acetate each. The organic phases obtained m the latter extrac¬ tion are combined, washed with water until neutral, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. By purifying the ob¬ tained crude product (0.87 g) through its salt formed with L- (+) -tartaric acid [m.p. 40-45 "C (after crystalli- zation from ethanol)], 0.66 g of title product are ob¬ tained as a thick, light yellow oil having a thin layer chromatography Rf value of 0.30 (on a Kieselgel 60 silica gel plate, by elutmg with a 20:11:6:30 mixture of pyri¬ dme, water, acetic acid and ethyl acetate) . The overall yield of the three reaction steps is 47.8% calculated upon the starting hydroxy compound.
Example 98
Preparation of l-[3-(2-hydroxy-l-naphthyl)prop onyl]- piperaz e Step a) l-[3- (2-Hydroxy-l-naphthyl)propιonyl]-4- (tert-butoxy¬ carbonyl)piperazine
To the solution of 0.85 g (5.0 mmol) of l-(tert- -butoxycarbonyl) piperazme in 75 mi of anhydrous acetoni¬ trile 1.0 g (5.04 mmol) of 3- (2-hydroxy-l-naphthyl) - propionic acid lactone is added and the solution is heated under reflux for 4 hours. After evaporation of the solvent 1.85 g (97%) of title compound are obtained as a colourless oil, which is used without further purifica¬ tion in the next reaction step.
Step b) l-[3-(2-Hydroxy-1-naphthyi)propιonyl]pιperazιne
Upon dissolving 0.37 g (1.0 mmol) of l-[3- (2-hydroxy- -1-naphthyi)propιonyl]-4- (tert-butoxycarbonyl) piperazine under stirring at room temperature in 10 ml of a 16% so¬ lution of hydrogen chloride in ethyl acetate fine parti¬ cles of a white precipitate appear after a few minutes. After stirring for one hour the precipitate is filtered off, washed with a small amount of ethyl acetate and dried at room temperature. The dried product is dissolved m 5 ml of 5% sodium hydrogen carbonate solution while stirring. The base form of the product precipitates from the solution in the form of a white solid within a short time. After stirring the mixture for additional 10 min¬ utes, the precipitate is filtered off, washed with a small volume of cold water and dried on air to give 0.31 g (99%) of title product, m.p. 107-109 °C.
Example 99
Preparation of l-[2- (2-naphthylamιno) acetyl]p perazιne
Step a)
1- (2-Chloroacetyl) -4- (tert-butoxycarbonyl)piperazme The solution of 0.88 ml (1.24 g, 11 mmol) cf 2-
-chloroacetyl chloride in 10 ml of anhydrous chloroform is added dropwise to a solution containing 1.86 g (10 mmol) of 1- (tert-butoxycarbonyl)piperazme and 1.53 ml
(1.11 g, 11 mmol) of triethylamine m 50 mi of anhydrous chloroform at 0 °C temperature under stirring. The reac¬ tion mixture is stirred at room temperature for an addi¬ tional hour, washed with water until neutral, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure to give 1.91 g (72.9%) of title compound, m.p. 91-93 °C.
Step b) l-[2- (2 -Naph thylamino) acetyl]-4- ( tert-butoxycarbo¬ nyl ) piperazine
A suspension containing 0 . 78 g ( 3 mmol ) of 1- ( 2- -chloroacetyl ) -4- ( tert-butoxycarbonyl ) piperazine, 0.43 g ( 3 mmol ) of 2-naphthylamme and 0. 42 g ( 3 mmol ) of potas¬ sium carbonate in 30 ml of acetonitrile is heated under reflux for 8 hours under vigorous stirring. Then, the solvent is distilled off and the residue is partitioned between 30 ml of methylene chloride and 30 ml of water. The organic phase is washed three times with 10 ml of wa- ter each, dried over anhydrous magnesium sulfate and the solvent is distilled off to give 1.03 g of crude product which is subjected to chromatography on a silica gel col¬ umn by using an 1:1 mixture of n-hexane and ethyl acetate as eluent to yield 0.34 g (30.9%) of crystalline title product, m.p. 190-192 °C.
Step c) l-[2-(2-Naphthylam o)acetyl]pιperazιne
The title compound is prepared by starting from the compound prepared as described in the preceding step b) and following the procedure described m step c) of Exam¬ ple 93. The tπfluoroacetate salt melts at 102-108 °C; a yield of 85.3* is achieved.
Example 100
Preparation of l-[2- (2-naphthyith o)acetyl]p perazιne Step a) l-[2- (2-Naphthylth o)ac tyl]-4- (tert-butoxycarbonyl) - piperazine
A mixture containing 0.48 g (3 mmol) of 2- -thionaphthol, 70 ml of ethanol, 3 ml of 1 N aqueous so- dium hydroxide solution and 0.78 g (3 mmol) of l-(2- -chloroacetyl) -4- (tert-butoxycarbonyl)piperazine (prepa¬ red as described under step a) cf Example 100 above) is stirred at room temperature for 2 hours. After evaporat¬ ing the solvent under reduced pressure, the residue is partitioned between 30 ml of methylene chloride and 30 ml of water. The organic solution is washed with water until neutral, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure to give 0.66 g (58.6%) of title product, m.p. 80-S2 °C.
Step b) l-[2-(2-Naphthyith o)ac tyl]pιperaz ne The title compound is prepared by starting from the compound prepared as described m the preceding step a) and following the procedure described under step c) of Example 93. The product is obtained as an oil with a thin layer chromatography Rf value of 0.64 (on a Kieselgel 60 silica gel plate, by elutmg with a 75:20:5 mixture of ethyl acetate, methanol and concentrated aqueous ammonium hydroxide solution) in a yield of 96.8%.
Example 101
Preparation of 1-[N- (2-naphthyi)carbamoylmethyl]pιper- azme
Step a)
1-[N- (2-Naphthyi)carbamoylmethyl]-4-(tert-butoxycar¬ bonyl)piperazine
A mixture containing 1.48 g (8 mmol) of l-(tert- -butoxycarbonyl) piperazme, 1.36 g (9.8 mmol) of powdered potassium carbonate and 1.76 g (8 mmol) of N- (2- -chloroacetyl ) -2-naphthylamme in 60 ml cf acetonitrile is heated unoer reflux for 2 hours while stirring. After evaporating the solvent, the residue is partitioned be- tween 60 ml of methylene chloride and 60 ml of water. The organic phase is washed with water until neutral, dried over anhydrous magnesium sulfate and the solvent is dis¬ tilled off. The crude product is subjected to chromatog¬ raphy on a silica gel column by using an 1:2 mixture of n-hexane and ethyl acetate as eluent to yield 2.05 g (69.5%) of crystalline title product, m.p. 124-128 °C. WO 97/14685 _ „ _ PCT/HU96/00058
Step b)
1-fM- (2-Naphthyi)carbamoylmethyl]pιperaz ne
The title compound is prepared by starting from the compound prepared as described in the preceding step a) by following the procedure described in step c) of Exam¬ ple 93. The product is identified in the form of its bis- -trifluoroacetate salt, m.p. 169-175 °C. A yield of 80.6% is achieved.
Example 102
Preparation of l-[6-am no-2- (1-pyrrolldmyl)-4-pyrι- m d nyl]pιperaz ne Step a)
1-Am d nopyrrolιd ne hydroiodide To a solution of 174.32 g (0.8 mol) of S-methyliso- thiourea hydroiodide in 600 ml of methanol, 60.53 g (70.2 ml, 0.85 mol) of pyrrolidme are added while stirring. The reaction mixture is heated under reflux for 3 hours until ceasing of the gas evolution. After cooling down and evaporating the solvent, the residue is recrystal- lized from methanol to yield 169.3 g (87.9J) of title product, m.p. 192-193 °C.
Step b)
6-Am no-4-hydroxy-2-(1-pyrrolidinyl)pyrimidine After dissolving 8.1 g (0.35 mol) of sodium metal in 240 ml of anhydrous methanol under stirring, 72.3 g (0.3 mol) of 1-amιdιnopyrrolιdme hydroiodide are added to the obtained solution. In an other flask 8.1 g of sodium metal are dissolved in 240 ml of anhydrous methanol and 34.2 g (0.3 mol) of ethyl cyanoacetate are dissolved in this latter solution. The mixture obtained is added to the solution prepared above. The reaction mixture is stirred under reflux for 3 hours and then cooled down. After evaporating the solvent under reduced pressure, the residue is dissolved in 150 ml of water and the solution is acidified to pH 5 by adding acetic acid while stir¬ ring. The white precipitate is filtered off, washed sev- eral times with water and dried on air to obtain 39.0 g (71.0%) of title product, m.p. 264-266 °C.
Step c)
6-Am no-2- (1-pyrrolidinyl) -4-tosyloxypyrιmιd-.ne To a suspension containing 3.6 g '20 mmol) of 6- -ammo-4-hydroxy-2- (1-pyrrolιdιnyl) pyrimid e in 20 ml of pyridme, 5.0 g (25 mmol) of tosyl chloride are added at room temperature. The reaction mixture is stirred at room temperature for 30 minutes, during this time the starting compounds are dissolved. Then, the reaction mixture is poured onto 100 ml of water whereupon the product is pre¬ cipitated m solid form. The precipitate is filtered off, washed with a large volume of water and dried on air to yield 3.0 g (45c) of title product, m.p. 155-168 βC (with decomposition) .
Step d) l-[6-Ammo-2- (l-pyrrolidmyl) -4-pyrιm dιnyl]pιperaz ne
The mixture of 17.0 g (50.9 mmol) of 6-amιno-2- {1- -pyrrolidmyl) -4-tosyloxypyrιmιdme, 150 ml of chloroben- ze e and 15 g (175 mmol) of anhydrous piperazine is heated m a steel bomb in an oil oath at 140-145 βC for 4 hours. Next day, the crystalline precipitate (excess of piperazme) is filtered off, wasned with a small volume of chlorobenzene and the solvent is distilled off from the combined chlorobenzene filtrate and washings. The residue is dissolved in 15 ml of methanol and the solu¬ tion is acidified to pH 6 by adding ethyl acetate con¬ taining hydrogen chloride. The crystalline precipitate is filtered, washed with ethyl acetate and dried. The hydro- chloride obtained (m.p. above 280 °C) is dissolved m a small volume of water, made alkaline to pH 10 by adding 1 M sodium hydroxide solution and the product is extracted into methylene chloride (3 x 100 ml) . After combining the organic phases, the solution is dried over anhydrous mag¬ nesium sulfate and the solvent is distilled off to give 3.7 g (30%) of title product as a light yellow oil, which solidifies upon standing.
Example 103
Preparation of l-[6-am no-2- (1-pιper dιnyl) -4-pynmι- d nyljp perazme Step a)
1-Amιdιnop pendιne hydroiodide The title compound is prepared as described in step a) of Example 102, except that piperidme is used instead of pyrrolidme to give a yield of 72.3%, m.p. 118-120 βc.
Step b)
6-Amιno-4-hydroxy-2- (1-pιperιdιnyl)pyrimidine The title compound is prepared starting with the com¬ pound obtained as described in the preceding step a) and by following tne procedure described m step b) of Exam¬ ple 102 to give a yield of 97.3., m.p. 182-192 °C (with decomposition) .
Step c)
6-Am no-2- (1-p perιdιnyl) -4-chloropyr m dιne
A mixture containing 7.29 g (37.6 mmol) of 6-amιno-4- -hydroxy-2- (1-pιperιdmyl)pyrimidine and 37.5 ml of phos¬ phorus oxychloride is stirred at 100 °C for 2 hours, then the excess of phosphorus oxychloride is distilled off un¬ der reduced pressure. After mixing the residue with a twofold volume of water, the viscous yellow oil is dis¬ solved after a few minutes with violent warming and gas evolution. The solution is made alkaline by adding a 10% aqueous sodium carbonate solution up to pH 8 and cooling down. The crystalline precipitate is filtered off, washed with water until neutral and dried on air to give a yield of 73.3% of the title product, m.p..: 148-149 °C.
Step d) l-[6-Amino-2- (1-piperidinyl) -4-pyrimidinyl]piperazine The tile compound is prepared starting with the com¬ pound prepared as described in the preceding step c) and by following the procedure described in step d) of Exam¬ ple 102 to give a yield of 66.7%. The product is a yellow oil having a thin layer chromatography R; value of 0.3 (on a Kieselgel 60 silica gel plate, by eluting with a 10:5:0.3 mixture of ethyl acetate, methanol and concen¬ trated aqueous ammonium hydroxide solution) .
Example 104
Preparation of l-[6-amino-2-(hexahydro-lH-azepin-1- -yl) -4-pyrimidinyl]piperazine Step a)
6-Amino-2- (hexahydro-lH-azepin-1-yl) - -chloropyrimi¬ dine
After dissolving 6.56 g (40 mmol) of 6-amino-2, 4-di- chloropyrimidine in 200 ml of anhydrous dimethylformamide under stirring and adding 4.2 g (4.8 ml, 43 mmol) of hex- amethylene imine, the reaction mixture is stirred at room temperature for 24 hours, then 8 ml of anhydrous pyridine are added and the mixture is stirred at the same tempera- ture for additional 24 hours. After distilling off the solvent under reduced pressure, the white solid residue is extracted with a 10:2 hot mixture of chloroform and methanol (2 x 100 ml) . After evaporating the solvent from the extract under reduced pressure, the residue is sub¬ jected to chromatography on a silica gel column by using a 20:1 mixture of chloroform and methanol as eluent to obtain 1.97 g (21.7%) of title compound as a white pow¬ der, m.p. 152-154 °C.
Step b)
6-Am no-2- (hexahydro-lH-azepιn-1-yl) -4-[4-(tert-
-butoxycarbonyl) -l-pιperazιnyl]pyr mιdιne A solution containing 1.97 g (8.68 mmol) of 6-amιno- -2- (hexahydro-lH-azepm-1-yl) -4-chloropyrιmιdιne and 5.55 g (32.6 mmol) of 1- (tert-butoxycarbonyl)piperazme in 55 ml of anhydrous chlorobenzene is heated under reflux for 24 hours while stirring under dry nitrogen. Subsequently, a little amount of solid precipitate is filtered off and the solvent is evaporated from the filtrate under reduced pressure. The residue is subjected to chromatography on a silica gel column by using ethyl acetate as eluent to give 3.05 g (97.0%) of title product as a light yellow oil with a thin layer chromatography Rf value of 0.48 (on a Kieselgel 60 silica gel plate, cy elut g with a 10:2 mixture of ethyl acetate and methanol) .
Step c) l-[6-Amιno-2- (hexahydro-lH-azepm-1-yl) -4-pyr mιd - nyl]pιperaz ne
After dissolving 2.92 g (8.1 mmol) of the compound prepared as described in the preceding step b) in 20 ml of anhydrous ethyl acetate while stirring, 10.8 ml of a 16% m/v solution of hydrogen chloride in ethyl acetate are added under stirring. A white substance immediately begins to precipitate from the solution. The mixture is stirred at room temperature for one hour, then the pre- cipitate is filtered off, washed with ethyl acetate and dried on air. The dry intermediate is dissolved in 30 ml of distilled water and rendered alkaline to pH 9 by add¬ ing a 4% aqueous sodium hydroxide solution. After ex¬ tracting the oily precipitate into methylene chloride, the organic phase is dried over anhydrous magnesium sul¬ fate and the solvent is evaporated under reduced pressure to yield 1.13 g (50.5%) of title compound as a yellow powder, m.p. 122-124 °C.
Example 105
Preparation of N-(2,3-epoxypropyl) -N-methanesulfonyl-
-2-naphthyiamine
To the solution of 0.5 g (2.5 mmol) of N- (2, 3-epoxy- propyl) -2-naphthylamine in 5 ml of anhydrous pyridine, 0.24 ml (0.35 g, 3.0 mmol) of methanesulfonyl chloride is added dropwise while stirring and cooling in an ice bath, then the mixture is stirred in an ice bath for one hour. Subsequently, 0.24 ml of methanesulfonyl chloride is again added and the stirring is continued at the same temperature for 2 hours. After allowing to warm to ambi¬ ent temperature the mixture is poured onto water. The precipitate is filtered, washed with water and recrystal- lized from methanol to obtain 0.37 g (52.9%) of title compound as a pale yellow crystalline product, m.p. 114- -115 °C.
Example 106
Preparation of l-[2 ,6-di (l-pyrrolidinyl) -4-pyrimidi- nyl]-4-(2,3-epoxypropyl)piperazine
A solution containing 1.5 g (5 mmol) of l-[2,6-di(l- -pyrrolidinyl) -4-pyrimidinyl]piperazine and 0.5 ml (0.59 g, 6.4 mmol) of epichlorohydrm in 10 ml of ethanol is stirred at ambient temperature for 24 hours. The precipi- tate is filtered off and washed with 2 ml of ethanol. The wet material is dissolved in the mixture of 50 mi of ethyl ether and 5 ml of ethanol and stirred with 10 ml of a 10 M aqueous sodium hydroxide solution for 2 hours. Af- ter separation, the organic layer is washed with water until neutral, dried over anhydrous magnesium sulfate and the solvent is distilled off to yield 1.18 g (66.4%) of crystalline title substance, m.p. 107-112 °C.
Example 107 Preparation of 1- (2-amιnoethyl) -4-[2, 6-di (1-pyrrolι- d yl) -4-pyrιmιdιnyl]pιperazιne Step a) l-[2 , 6-Dι (1-pyrrolidinyl) -4-pyr mιdιnyl]-4-(2-phthal- lmidoethyl)piperazine A suspension containing 6.04 g (20 mmol) of l-[2,6- -di (1-pyrrolιdιnyl) -4-pyrιmιdmyl]pιperazιne, 6.35 g (25 mmol) of N- (2-bromoethyl)phthalimide, 3.45 g (25 mmol) of potassium carbonate and 3.0 g (20 mmol, of sodium iodide in 100 ml of acetonitrile is heated under reflux for 3 hours while stirring. After cooling oown the reaction mixture m ice bath, the solids are filtered off ano washed first with acetonitrile and then with a large vol¬ ume of water to give 6.03 g of crude product. The solvent is distilled off from the acetonitrile filtrate under re- duced pressure and the residue is subjected to chromato¬ graphy on a silica gel column by using etnyl acetate as eluent. Thus, 2.2 g of a not completely pure product are obtained, which is combined with the aoove crude product of 6.03 g (yield 86.2%) and recrystallized first from acetonitrile and then from isopropanol. Thus, 4.85 g (51.0%) of title product are obtained as yellow crystals, m.p. 153-154 °C. - 102 -
Step b)
1- (2-Ammoethyl) -4-[2 ,6-dι (l-pyrrolidmyl) -4-pyrιm - dinyl]pιperaz ne
4.25 g (8.9 mmol) of l-[2, 6-di (l-pyrrolidmyl) -4- -pyrιmιdmyl]-4- (2-phthalιmιdoethyl)piperazine are dis¬ solved in 100 ml of ethanol at 60-70 °C, 4.6 ml (90 mmol) of 98% hydrazine hydrate are added and the reaction mix¬ ture is heated under reflux for one hour. After cooling down, the precipitated phthaloylhydrazide is filtered off, washed with ethanol, then the solvent is evaporated from the filtrate unoer reduced pressure. To the residue 15 ml of methylene chloride are added ano a little amount of insoluble phthaloylhydrazide is filtered off. The fil¬ trate is washed with water, dried over anhydrous magne- siu sulfate and the solvent is evaporated under reduced pressure to yield 2.91 g (94.8.^ of title compound as a colourless powder, m.p. 99-100 βC.
Example 108 Preparation of N- (2-chloroacetyl) -2-methyl-l-naph- thylamine
To a solution of 0.5 g (3.18 mmol) of 2-methyl-l- -naphthylamme in 5 ml of N,N-dimethylacetamide, 0.3 ml (0.45 g, 4.0 mmol) of 2-chloroacetyl chloride are added at ambient temperature under stirring. After 30 minutes, the solvent is evaporated under reoucec pressure and the residue is recrystallized from 5 ml of isopropanol to give 78.0% of title product, m.p. 177-178 °C.
Examples 109 to 113 By using appropriately substituted starting compounds and following a procedure similar to that described in Example 108, compounds of fornula (VI) are prepared, wherein X means NH group;
A represents -C(0)-CH2- group;
Z means chlorine; and
R' is as shown in the following Table.
Figure imgf000105_0001
Note:
Contains about 30% of 6-acetyl isomer,
Example 114
Preparation of 4- (dimethylaminosulfonyl) -N- (2-chloro- acetyl) -1-naphthylamme
To the solution of 0.63 g (2 mmol) of N-(2-chloro- acetyl) -4-chlorosulfonyl-2-naphthylamme in 50 ml of tet¬ rahydrofuran, 0.5 ml (4 mmol) of 401 aqueous dimethy- lamme solution are added dropwise at ambient tempera¬ ture. The mixture is stirred for 30 minutes, then the solvent is evaporated under reduced pressure and an addi¬ tional 5 ml of ethanol are distilled off from the resi¬ due. The residue is triturated with hot ethyl acetate and kept m the refrigerator overnight. Next oay, the solid product is filtered off to obtain 0.58 g (89.2%) of title compound, m.p. 186-190 βC. Example 115
Preparation of 6-[N- (2 ,5-dιbenzyloxybenzoyl)aminol- hexyl iodide Step a) 6-[N- (2, 6-Dιbenzyloxybenzoyl)am o]hexylalcohol
To a solution containing 15.1 g (33.7 mmol) of 6-[N- - (2, 5-dιbenzyloxybenzoyl) amιno]hexanoιc acid in the mix¬ ture of 390 mi of anhydrous tetrahydrofuran and 3.4 g (33.7 mmol) of anhydrous triethylamine, the solution of 3.65 g (33.7 mmol) of distilled ethyl chloroformate in 17 ml of anhydrous tetrahydrofuran is added dropwise at -5 °C temperature while stirring, then the reaction mixture is stirred at the same temperature for 30 minutes. The precipitated salt is filtered off and washed with anhy- drous tetrahydrofuran. The combined filtrate and washings are added portionwise to the solution of 3.1 g (82 mmol) of sodium borohydride in 78 ml of water at a temperature of 15 °C under stirring during 30 minutes, then the reac¬ tion mixture is stirred at ambient temperature for 4 hours. After adjusting the pH of the solution to 4 by adding 5 M hydrochloric acid solution and stirring the mixture at amoient temperature for 3 hours, if required, the pH of the solution is again adjusted to 4 as men¬ tioned above. Tnen, 240 ml of water and 240 ml of ethyl ether are added to tne solution, the aqueous layer is separated and extracted with a 6:1 mixture of ethyl ether ano tetranydrofuran. The organic layers are combined, wasned with water and 5% sodium hydroxide solution and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue is washed with petroleum ether (b.p. 40-70 °C) to give 11.7 g (80%) of title com¬ pound, m.p. 90-92 °C. Step b)
6-[N- (2,5-Dibenzyloxybenzoyl)amino]hexyl iodide
To a solution containing 3.44 g (7.9 mmol) of 6-[N- - (2, 5-dibenzyloxybenzoyl) amino]hexylalcohol in the mix- ture of 24 ml of anhydrous methylene chloride and 1.2 g (12 mmol) of anhydrous triethylamine, 1.1 g (9.6 mmol) of methanesulfonyl chloride are added at 0 °C while stirring and the reaction mixture is stirred at 0 °C for 30 min¬ utes. Subsequently, 24 ml of water are added and after separation the aqueous layer is extracted with methylene chloride. The organic solution is briefly dried over an¬ hydrous magnesium sulfate, the solvent is evaporated un¬ der reduced pressure and the residue is stirred under re¬ flux in 25 ml of acetone saturated with sodium iodide, in the presence of 0.09 g (0.7 mmol) of diisopropylethy- lamine under nitrogen for 30 minutes. After diluting the reaction mixture with 25 ml of water and extraction with ethyl ether, the ethereal solution is dried over anhy¬ drous magnesium sulfate, the solvent is evaporated under reduced pressure and the residue obtained is washed with petroleum ether (b.p. 40-70 °C) to yield 3.83 g (89%) of title compound, m.p. 80-82 βC.
Example 116
Preparation of 3-trifluoroacetylamino-2-naphthoic acid
After boiling under reflux a mixture consisting of 1.37 g (10 mmol) of 3-amino-2-naphthoic acid and 10 ml of trifluoroacetic acid anhydride for 3 hours, the mixture is cooled down, the solid precipitate is filtered, washed with trifluoroacetic acid anhydride and ethyl ether and dried over phosphorus pentoxide under reduced pressure, Thus, 1.93 g (68.2%) of title compound are obtained as a white powder, m.p. 133-134 °C. Example 117
Preparation of 2-aminomethyl-2- (1-naphthyl) -1 ,3-di- oxolane
Step a) 2-Azidomethyl-2-( -naphthyl) -1,3-dioxolane
To a solution containing 2.04 g (10 mmol) of l-(2- -chloroacetyl) naphthalene in 20 ml of dimethylformamide, 1.3 g (20 mmol) of sodium azide are added under cooling by ice water and the mixture is stirred without cooling for one hour. The deep red suspension obtained is diluted with 60 ml of water and extracted three times with 40 ml of benzene each. The combined organic solution is washed with water, dried over anhydrous magnesium sulfate, de¬ colorized with about 5 g of silica gel and the solvent is distilled off under reduced pressure. Thus, 1.82 g (86.3%) of 1- (2-azidoacetyl) naphthalene are obtained as an orange yellow oil, which is used without further puri¬ fication in the next reaction step.
To the emulsion of the above azido compound in 22 ml of anhydrous ethylene glycol, 4.3 ml (2.84 g, 26.1 mmol) of chlorotrimethylsilane are added dropwise under nitro¬ gen at ambient temperature and the mixture is stirred for 2 hours. At this time, an additional amount of 2.15 ml of chlorotrimethylsilane is added and the stirring is con- tinued for one hour. After extracting the solution ob¬ tained three times with 40 ml of hexane each, the com¬ bined hexane solution is washed with 5% aqueous sodium hydrogen carbonate solution and water, dried over anhy¬ drous magnesium sulfate and the solvent is evaporated un- der reduced pressure. Thus, 1.36 g (61.8%) of title com¬ pound are obtained as a lemon yellow oil, which solidi¬ fies upon standing, m.p. 30-35 °C. Step b)
2-Amιnomethyl-2- (1-naphthyl) -1,3-d oxolane
To a solution containing 0.37 g (1.45 mmol) of the intermediate obtained as described in the preceding step a) in 10 ml of ethanol, 0.05 g (0.2 mmol) of nickel chlo¬ ride hexahydrate and subsequently 0.29 g (5.8 mmol) of sodium borohydride are added. After stirring for 10 min¬ utes, the pH of the mixture is adjusted to 7 by adding 1 N hydrochloric acid, the black precipitate is filtered off and the ethanol is removed from the filtrate under reduced pressure. After triturating the residue with wa¬ ter, a little amount of insoluble material is filtered off, and the filtrate is rendered alkaline by adding con¬ centrated aqueous ammonium hydroxide solution and ex- tracted three times with 10 ml of ethyl acetate each. The combined organic solution is washed with saturated aque¬ ous sodium chloride solution, dried over anhydrous magne¬ sium sulfate and the solvent is evaporated under reduced pressure. Thus, 0.17 g of title compound is obtained as a yellow oil, which solidifies upon standing, m.p. 94-95 °C (after triturating with isopropyl ether) . The yield is 51.5..
All 1-naphthyl compounds occurring in the present Ex¬ ample contain as contamination about 15-20% of the re- spective 2-naphthyl isomer. During preparation of chloroacetylnaphthalene used as starting substance m step a) , a mixture of 1- and 2-naphthyl isomer is namely formed, in agreement with the literature data [see Y. Mu¬ rakami: Chem. Pharm. Bull. 36, 2023 (1988)].
Example 118
Intravenous pharmaceutical formulation Ingredients l-{6-[N- (2, 5-Dιhydroxybenzoyl) -amino]- hexyl}-4-[2, 6-di ( l-pyrrolidmylj -4-
-pyrιmιdmyl]pιperazme dihydrochloride 5.00 g
Sodium chloride 4.00 g
Water for injection q.s. ad 1000.00 ml
Preparation:
After dissolving the pyrogen-free l-{6-[N- (2, 5-dι- hydroxybenzoyl) ammo]hexyl}-4-[2, 6-di (1-pyrrolιdιnyl) -4- -pyrιmidmyl]pιperazme dihydrochloride and the sodium chloride in 800 ml of distilled water for injection, the volume of the solution is supplemented with distilled wa¬ ter for injection up to 1000.00 ml.
Subsequently, the solution is filtered germ-free through a cellulose membrane of 0.2 μm pore diameter, filled into glass ampoules under aseptic conditions and the ampoules are sealed in an inert gas atmosphere.

Claims

Claims
1. Compounds of the formula (I)
Figure imgf000111_0001
wherein
R1 stands for a moiety of formula (a)
Figure imgf000111_0002
wherein
Ar means a C6-10 aromatic homocyclic group,
R4 and R5, independently from each other, represent hydrogen, halogen, hydroxy, C1-4 alkyl, C1-4 alkoxy optionally substituted by phenyl, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, nitro, C1-4 alkanoyl, optionally substituted amino, carboxy, C1-4 alkoxycarbonyl, carboxamido, cyano, sulfo and/or sulfonamido; and
p, q, and r are, independently from each other, 0 or 1;
R2 and R3, independently from each other, stand for amino; or a moiety derived from a 5-8-membered saturated heterocycle containing at least one nitrogen atom; X means a single bend; a sulfur atom optionally substituted by one or two oxygen atom(s) or an optionally substituted nitrogen atom;
A stands for a straight or branched chain C1-8 alkylene group optionally substituted by halogen, hydroxy, C1-4 alkoxy optionally substituted by phenyl, C1-4 al kanoyloxy, optionally substituted amino and/or oxo; and
n is 1 or 2,
with the proviso that when
R1 means a moiety of formula (a), wherein
Ar means phenyl; and
at least one of R4 and R5 stands for halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, C1-4 alkanoyloxy or methanesulfonyloxy;
A may not be unsubstituted C1-4 alkylene; and
with the further proviso that when
R1 is 2, 5-dihydroxybenzoyl;
A may not be alkylene substituted by oxo;
as well as their pure stereoisomers, mixtures of stereoisomers and addition salts, especially pharmaceutically acceptable salts formed with acids or oases of these compounds.
2. 1-[2,6-Di(1-pyrrolidinyl)-4-pyrimidinyl]-4-[2-hydroxy-3-(2-naphthylamino)propyl]piperazine and acid-addition salts thereof.
3. (+)-1-[2,6-Di(1-pyrrolidinyl)-4-pyrimidinyl]-4-[2-hydroxy-3-(2-naphthylamino)propyl]piperazine and acid-addition salts thereof.
4. (-)-1-[2,6-Di(1-pyrrolidinyl)-4-pyrimidinyl]-4-[2-hydroxy-3-(2-naphthylamino)propyl]piperazine and acid¬
-addition salts thereof.
5. 1-[2,6-Di(1-pyrrolidinyl)-4-pyrimidinyl]-4-[2-hydroxy-3-(2-naphthylamino)propyl]homopiperazine and acid-addition salts thereof.
6. (+)-1-[2,6-Di(1-pyrrolidinyl)-4-pyrimidinyl]-4-[2-hydroxy-3-(2-naphthylamino)propyl]homopiperazine and acid-addition salts thereof.
7. (-)-1-[2,6-Di(1-pyrrolidinyl)-4-pyrimidinyl]-4-[2-hydroxy-3-(2-naphthylamino)propyl]homopiperazine and acid-addition salts thereof.
8. 1-[6-Amino-2-(1-pyrrolidinyl)-4-pyrimidinyl]-4-(1-hydroxy-2-naphthoyl)piperazine and salts thereof.
9. 1-{6-[N-(2,5-Dinydroxybenzoyl)amino]hexyl}-4-[2,6-di(1-pyrrolidinyl)-4-pyrimidinyl]piperazine and salts thereof.
10. Pharmaceutical composition, which comprises as active ingredient a compound of formula (I), wherein R1, R2, R3, X, A and n are as defined in claim 1, or a pharmaceutically acceptable salt thereof in admixture with solvents, diluents, carriers, excipients and other additives commonly used in the pharmaceutical practice.
11. Process for tne preparation of pyrimidine derivatives of formula (I),
Figure imgf000113_0001
wherein
R1 s tands for a moiety o f formul a ( a )
Figure imgf000113_0002
wnerein
Ar means a C6-10 aromatic homocyclic group,
R4 and R5, independently from each other, represent hydrogen, halogen, hydroxy, C1-4 alkyl, C1-4 alkoxy optionally substituted by phenyl, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, nitro, C1-4 alkanoyl, optionally substituted amino, carboxy, C1-4 alkoxycarbonyl, carboxamido, cyano, sulfo and/or sulfonamido; and
p, q, and r are, independently from each other, 0 or 1;
R2 and R3, independently from each other, stand for amino; or a moiety derived from a 5-8-membered saturated heterocycle containing at least one nitrogen atom; X means a single bond; a sulfur atom optionally substituted by one or two oxygen atom(s) or an optionally substituted nitrogen atom;
A stands for a straight or branched chain C1-8 alkylene group optionally substituted by halogen, hydroxy, C1-4 alkoxy optionally substituted by phenyl, Cι-4 alkanoyloxy, optionally substituted amino and/or oxo; and
n is 1 or 2,
with the proviso that when
R1 means a moiety of formula (a), wherein
Ar means phenyl; and
at least one of R4 and R5 stands for halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, C1-4 alkanoyloxy or methanesulfonyloxy;
A may not be unsubstituted C1-4 alkylene; and
with the further proviso that when
R1 is 2, 5-dihydroxybenzoyl;
A may not be alkylene substituted by oxo;
which comprises that
a) in order to obtain compounds of formula (I), wherein R1, R2, R3, x and n are as defined above; and
A is as defined above, with the proviso that it may not be alkylene substituted by halogen, amino or C1-4 alkylamino. a compound o f f o rmul a ( I I ) ,
Figure imgf000115_0001
wherein R1, X, A and n are as defined above, is reacted with a compound of formula (III),
Figure imgf000115_0002
wherein R2 and R3 are as defined above and Z means a leaving group; or
b) in order to obtain compounds of formula (I), wherein R1, R2, R3 and n are as defined above;
A is as defined above, with the proviso that it may not be alkylene substituted by halogen, amino or C1-4 alkylamino; and
X is as defined for the formula (I), with the proviso that it may not be a single bond or a sulfur atom substituted by one or two oxygen atom(s), a compound of fermula (IV), R1-XH (IV) wherein R1 and X are as de fined above, is reacted with a compound o f formula (V) ,
Figure imgf000116_0001
wherein R2, R3, A and n are as defined above and Z means a leaving group; or
c) in order to obtain compounds of formula (I), wherein R1, R2, R3 and n are as defined above;
A is as defined above, with the proviso that it may not be alkylene substituted by halogen, amino or C1-4 alkylamino; and
X is as defined above, with the proviso that it may not be a single bond,
a compound of formula (VI), R1-X-A-Z (VI) wherein R1, X and A are as defined above and Z means a leaving group, is reacted with a compound of formula (VII),
Figure imgf000116_0002
wherein R2, R3 and n are as defined above; or
d) in order to obtain compounds of formula (la)
Figure imgf000117_0001
representing a narrower scope of compounds of formula
(I), wherein
R1, R2, R3 and n are as defined above; and
X is as defined above, with the proviso that it may not be a single bond,
a compound of formula (VIII),
Figure imgf000117_0002
wherein R1 and X are as defined above, is reacted with a compound of formula (VII), wherein
R2, R3 and n are as defined above; or
e) in order to obtain compounds of formula (la) representing a narrower scope of the compounds of formula (I), wherein
R1, R2, R3 and n are as defined above; and
X is as defined for formula (I), with the proviso that it may net be a single bond or a sulfur atom substituted by one or two oxygen atom(s), a compound of formula (IV), wherein R1 and X are as defined above, is reacted with a compound of formula (IX),
Figure imgf000118_0001
wherein R2, R3 and n are as defined above; or
f) in order to obtain compounds of formula (lb)
Figure imgf000118_0002
representing a narrower scope of compounds of formula (I), wherein
R1, R2, R3, X and n are as defined above; and
B; means a single bond or a straight or branched chain C1-8 alkylene group optionally substituted by halogen, C1-4 alkoxy, C1-4 alkanoyloxy and/or an optionally substituted amino group,
a carboxylic acid of formula (X), R1-X-B1-COOH wherein R1, X and B1 are as defined above, or a reactive derivative thereof activated at the carboxyl group is reacted with a compound of formula (VII), wherein R2, R3 and n are as defined above; or
g) in order to obtain compounds cf formula (Ic)
Figure imgf000119_0001
representing a narrower scope of the compounds of formula (I), wherein
R1, R2, R3 and n are as defined above;
X stands for a nitrogen atom optionally substituted by a C1-4 alkyl group; and
B2 means a straight or branched chain C2-3 alkylene group optionally substituted by hydroxy, C1-4 alkoxy and/or di (C1-4 alkyl) amino group,
a compound of formula (XI),
R1-Z (XI) wherein Z means a leaving or hydroxyl group and R1 is as defined above, with the proviso that p, q and r are 0 when Z means a hydroxyl group, is reacted with a compound of formula (XII),
Figure imgf000119_0002
wherein R2, R3, B2, X and n are as defined above,
and, if desired, a compound of formula (I) obtained by using any of the process variants a) to g) is transformed to an other compound of formula (I) in a manner known per se; and/or a protective group optionally being present is removed; and/or, if desired, a compound of formula (I) thus prepared is resolved; and/or transformed to the salt form, e.g. acid-addition salt thereof.
12. Compounds of the formula (II),
Figure imgf000120_0001
wherein
R1 stands for a moiety of formula (a),
Figure imgf000120_0002
wherein
Ar means a C6-10 aromatic homocyclic group;
R4 and R5, independently from each other, represent hydrogen, halogen, hydroxy, C1-4 alkyl, C1-4 alkoxy optionally substituted by phenyl, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, nitro, C1-4 alkanoyl, optionally substituted amino, carboxyl, C1-4 alkoxycarbonyl, carboxamido, cyano, sulfo and/or sulfonamido; and
p, q and r are, independently from each other, 0 or 1; R2 and R3, independently from each other, stand for amino; or a moiety derived from a 5 to 8-membered saturated heterocycle containing at least one nitrogen atom; X means a single bond; a sulfur atom optionally substituted by one or two oxygen atom(s); or an optionally substituted nitrogen atom;
A stands for a straight or branched chain C1-8 alkylene group optionally substituted by halogen, hydroxy, C1-4 alkoxy optionally substituted by phenyl, C1-4 alkanoyloxy, optionally substituted amino and/or oxo group; and
n is 1 or 2,
with the proviso that when
R1 means a moiety of formula (a), wherein
Ar means phenyl; and
at least one of R4 and R5 stands for halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, C1-4 alkanoyloxy or methanesulfonyloxy;
A may not be unsubstituted C1-4 alkylene; and
with the further proviso that when
R1 is 2, 5-dihydroxybenzoyl;
A may not be alkylene substituted by oxo.
PCT/HU1996/000058 1995-10-19 1996-10-14 Pyrimidine derivatives WO1997014685A1 (en)

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US6407099B1 (en) 1997-10-31 2002-06-18 Suntory Limited Arylpiperidinopropanol and arylpiperazinopropanol derivatives and pharmaceuticals containing the same
US6525199B1 (en) 1997-10-31 2003-02-25 Suntory Limited Arylpiperidinopropanol and arylpiperazinopropanol derivatives and pharmaceuticals containing the same
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US8536184B2 (en) 2000-11-01 2013-09-17 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
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WO2004050639A2 (en) * 2002-12-03 2004-06-17 Epcellon, Inc. 5-nitroso-6-piperazinyl-pyrimidine derivatives for treating ischemia
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JP2007532678A (en) * 2004-04-13 2007-11-15 セフアロン・インコーポレーテツド Bicyclic aromatic sulfinyl derivatives
US8314155B2 (en) 2004-04-13 2012-11-20 Cephalon, Inc Bicyclic aromatic sulfinyl derivatives
US8895717B2 (en) 2005-04-15 2014-11-25 The Board Of Regents Of The University Of Texas System Delivery of siRNA by neutral lipid compositions
WO2008016165A3 (en) * 2006-07-31 2008-04-03 Asubio Pharma Co Ltd Liquid preparation
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