CA1294289C - Catecholamine derivatives - Google Patents
Catecholamine derivativesInfo
- Publication number
- CA1294289C CA1294289C CA000567118A CA567118A CA1294289C CA 1294289 C CA1294289 C CA 1294289C CA 000567118 A CA000567118 A CA 000567118A CA 567118 A CA567118 A CA 567118A CA 1294289 C CA1294289 C CA 1294289C
- Authority
- CA
- Canada
- Prior art keywords
- ethyl
- benzenediol
- solution
- alkyl
- aminoethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
- C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
Abstract
Abstract Compounds There are described compounds of formula I, in which one of R30 and R40 represents a group Ra, Ra and the other of R30 and R40 represents hydrogen or halogen, R50 and R60, which may be the same or different, each independently represent hydrogen or alkyl C 1 to C6;
in addition R60 may represent a group Rb, Rb wherein X represents a C2 to C8 alkylene chain optionally interrupted by a double bond or by S(0)n, wherein n is 0, 1 or 2, Z represents a C 1 to C3 alkylene chain, each of X and Z being optionally substituted by OH
or one or more alkyl C 1 to C6, R70 represents hydrogen, alkyl C 1 to C6 or (CH2)qR11, R10 and R11 independently represent phenyl substituted by one or more substituents R23, which may be the same or different; or R10 represents a saturated carbocyclic group, R15 represents hydrogen, alkyl C 1 to C6, or together with R23 forms a (CH2)p chain, wherein p represents 0, 1 or 2, R20, R21, R22 and R23 independently represent hydrogen, alkyl C 1 to C6, NHR25, SH, NO2, halogen, CF3, SO2R26, CH20H or O~, wherein R25 represents hydrogen, alkyl C 1 to C6 or alkanoyl C 1 to C6 and R26 represents alkyl C 1 to C6 or NH2 1 represents 2, 3 or 4, q represents an integer from 1 to 6 inclusive, provided that when R40, R50 and R70 each represent hydrogen and R60 represents Rb, then Ra represents 2(3-hydroxyphenyl)ethyl, R15 represents hydrogen and either a) X represents (CH2)p, in which p is 3, 5, 7 or 8 or b) at least one of X and Z is substituted by either OH or one or more alkyl C 1 to C6, and pharmaceutically acceptable salts and solvates thereof.
There are also described processes for the preparation of the compounds of formula I and pharmaceutical compositions containing them. The compounds of the invention may be used in the treatment or prophylaxis of renal failure or cardiovascular disorders.
2038L(ir)/ac
in addition R60 may represent a group Rb, Rb wherein X represents a C2 to C8 alkylene chain optionally interrupted by a double bond or by S(0)n, wherein n is 0, 1 or 2, Z represents a C 1 to C3 alkylene chain, each of X and Z being optionally substituted by OH
or one or more alkyl C 1 to C6, R70 represents hydrogen, alkyl C 1 to C6 or (CH2)qR11, R10 and R11 independently represent phenyl substituted by one or more substituents R23, which may be the same or different; or R10 represents a saturated carbocyclic group, R15 represents hydrogen, alkyl C 1 to C6, or together with R23 forms a (CH2)p chain, wherein p represents 0, 1 or 2, R20, R21, R22 and R23 independently represent hydrogen, alkyl C 1 to C6, NHR25, SH, NO2, halogen, CF3, SO2R26, CH20H or O~, wherein R25 represents hydrogen, alkyl C 1 to C6 or alkanoyl C 1 to C6 and R26 represents alkyl C 1 to C6 or NH2 1 represents 2, 3 or 4, q represents an integer from 1 to 6 inclusive, provided that when R40, R50 and R70 each represent hydrogen and R60 represents Rb, then Ra represents 2(3-hydroxyphenyl)ethyl, R15 represents hydrogen and either a) X represents (CH2)p, in which p is 3, 5, 7 or 8 or b) at least one of X and Z is substituted by either OH or one or more alkyl C 1 to C6, and pharmaceutically acceptable salts and solvates thereof.
There are also described processes for the preparation of the compounds of formula I and pharmaceutical compositions containing them. The compounds of the invention may be used in the treatment or prophylaxis of renal failure or cardiovascular disorders.
2038L(ir)/ac
Description
~ ~d ~3 ~ 9 Catecholamine Derivatives This invention relates to novel compounds, compositions thereof and processes for their preparation.
Catecholamine derivatives which may be used in the 5 treatment or prophylaxis of renal failure or cardiovascular disorders are described in New Zealand Patent Application No 218333.
We have now found a novel group of catecholamine derivatives which may also be used in the treatment or lO prophylaxis of renal failure or cardiovascular disorders.
According to the invention there are provided compounds of formula I, 11 0 ~ ~C ~15~ 50 ~ 0 t40 R
~o in which one f R30 and R40 represents a group Ra, ~ Ra 2S R~
and the other of R30 and R40 represents hydrogen or halogen, R50 and R60, which may be the same or different, each independently represent hydrogen or alkyl Cl to C6;
R20' R21 and R22 independently represent :
:
: ~: 25 : ~ ~
: ~ :
~2~8g hydrogen, alkyl Cl to C6, NHR25, SH, NO2~ halogen, CF3, CH20H or OH, wherein R25 represents hydrogen, alkyl Cl to C6, SO2R26, or alkanoyl Cl to C6 and R26 represents alkyl Cl to C6 or NH2, 5m represents 2, 3 or 4, and pharmaceutically acceptable salts and solvates thereof.
According to the invention, there is also provided a process for the preparation of compounds of formula I or 10 pharmaceutically acceptable salts or solvates thereof, which includes removing a protecting group from a corresponding compound of formula II, 15R3~
O~/ ~C~a~a NQ~sc~ R~O II
R LO~
Q 4~a :
:
12~ 9 in which R~Oa and R40a have the same ~ignificance, respectively, as R~o and R40 above, save that in addition one of R~Oa and R40a may represent a group R~l, ~ R 1 Q;,~
R~Oa has the same significance as R~o above, save that in addition it may represent R3a, : ~ :
~ ~ ' R1a, R2a and R3a~ which may be the same ordifferent, represent hydrogen or a protecting group, R20a, R21a and R22a respectively, have the same significance as R20, R21 and R22 above, save that in 5 addition th~y may represent NR25R27a, SR28a~
CH2OR29a or OR31a, wherein R27a~ R28a, R29a and R31a which may be the same or diffsrent, each represent a protecting group, and R25 and m are as defined above, provided that the compound of formula II bears at least one 10 protecting group, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable salt or solvate thereof, or vice versa.
Protecting groups that R1a, R2a, R3a~ R27a, 15 R28a' R29a~ and R31a may represent include, for example, alkyl Cl to 6, especially methyl; phenylalkyl C7 to 12, especially benzyl; alkanoyl C2 to 6, such as acetyl and haloalkanoyl C2 to 6, especially trifluoroacetyl. In addition, the protecting group may protect two functional 20 groups, for example R2a and R3a may together represent (CH3)2C~. Other protecting : : 25 : ~ :
:
z~
groups are well known and include those described in Protective Groups in Organic Chemistry, ed: J W F McOmie, Plenum Press (1973), and Protective Groups in Organic Synthesis, T W Greene, Wiley-Interscience (1981).
Removal of the protecting group depends on the nature of the protecting group, conventional techniques may generally be employed, including acidic or basic cleavage or hydrogenolysis. For example, protecting alkyl or phenylalkyl groups may be removed by cleavage using a 10 protic acid, eg hydrochloric acid or a hydrobromic acid at a temperature of from about 0 to 150C, or a Lewis acid, eg by reacting with boron trihalide in a halocarbon solvent.
1-Phenylalkyl groups, eg benzyl, may be removed by catalytic hydrogenation using a suitable catalyst, eg 15 palladium, in a suitable solvent, eg methanol or acetic acid. Further methods for the removal of protecting groups are described in both McOmie and Greene, loc~ cit. Both McOmie and Greene also describe numerous methods for the application of protecting groups.
: ~ :
~;~9~289 Compounds of formula II, in which one or both of s : :
:
.
: :
:
~ ~ ~: :2~
:
:
';
R50a and R60 represent alkyl C1 to 6 may be prepared by conventional alkylation of a compound of formula VI, ~0~
R la( ~ ) 2 N~
Ra~ VI
in which R1a, R2a, R30a and R40a are as defined above and R50a represents hydrogen or a protecting group.
Compounds of formula VI in which R50a represents H
may be produced from compounds of formula X as follows:
~,~.0~ R,0.0~?
5 Q~ RO. ~13 Br ~ 0~
~r ~ R~ Q Q~
Catecholamine derivatives which may be used in the 5 treatment or prophylaxis of renal failure or cardiovascular disorders are described in New Zealand Patent Application No 218333.
We have now found a novel group of catecholamine derivatives which may also be used in the treatment or lO prophylaxis of renal failure or cardiovascular disorders.
According to the invention there are provided compounds of formula I, 11 0 ~ ~C ~15~ 50 ~ 0 t40 R
~o in which one f R30 and R40 represents a group Ra, ~ Ra 2S R~
and the other of R30 and R40 represents hydrogen or halogen, R50 and R60, which may be the same or different, each independently represent hydrogen or alkyl Cl to C6;
R20' R21 and R22 independently represent :
:
: ~: 25 : ~ ~
: ~ :
~2~8g hydrogen, alkyl Cl to C6, NHR25, SH, NO2~ halogen, CF3, CH20H or OH, wherein R25 represents hydrogen, alkyl Cl to C6, SO2R26, or alkanoyl Cl to C6 and R26 represents alkyl Cl to C6 or NH2, 5m represents 2, 3 or 4, and pharmaceutically acceptable salts and solvates thereof.
According to the invention, there is also provided a process for the preparation of compounds of formula I or 10 pharmaceutically acceptable salts or solvates thereof, which includes removing a protecting group from a corresponding compound of formula II, 15R3~
O~/ ~C~a~a NQ~sc~ R~O II
R LO~
Q 4~a :
:
12~ 9 in which R~Oa and R40a have the same ~ignificance, respectively, as R~o and R40 above, save that in addition one of R~Oa and R40a may represent a group R~l, ~ R 1 Q;,~
R~Oa has the same significance as R~o above, save that in addition it may represent R3a, : ~ :
~ ~ ' R1a, R2a and R3a~ which may be the same ordifferent, represent hydrogen or a protecting group, R20a, R21a and R22a respectively, have the same significance as R20, R21 and R22 above, save that in 5 addition th~y may represent NR25R27a, SR28a~
CH2OR29a or OR31a, wherein R27a~ R28a, R29a and R31a which may be the same or diffsrent, each represent a protecting group, and R25 and m are as defined above, provided that the compound of formula II bears at least one 10 protecting group, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable salt or solvate thereof, or vice versa.
Protecting groups that R1a, R2a, R3a~ R27a, 15 R28a' R29a~ and R31a may represent include, for example, alkyl Cl to 6, especially methyl; phenylalkyl C7 to 12, especially benzyl; alkanoyl C2 to 6, such as acetyl and haloalkanoyl C2 to 6, especially trifluoroacetyl. In addition, the protecting group may protect two functional 20 groups, for example R2a and R3a may together represent (CH3)2C~. Other protecting : : 25 : ~ :
:
z~
groups are well known and include those described in Protective Groups in Organic Chemistry, ed: J W F McOmie, Plenum Press (1973), and Protective Groups in Organic Synthesis, T W Greene, Wiley-Interscience (1981).
Removal of the protecting group depends on the nature of the protecting group, conventional techniques may generally be employed, including acidic or basic cleavage or hydrogenolysis. For example, protecting alkyl or phenylalkyl groups may be removed by cleavage using a 10 protic acid, eg hydrochloric acid or a hydrobromic acid at a temperature of from about 0 to 150C, or a Lewis acid, eg by reacting with boron trihalide in a halocarbon solvent.
1-Phenylalkyl groups, eg benzyl, may be removed by catalytic hydrogenation using a suitable catalyst, eg 15 palladium, in a suitable solvent, eg methanol or acetic acid. Further methods for the removal of protecting groups are described in both McOmie and Greene, loc~ cit. Both McOmie and Greene also describe numerous methods for the application of protecting groups.
: ~ :
~;~9~289 Compounds of formula II, in which one or both of s : :
:
.
: :
:
~ ~ ~: :2~
:
:
';
R50a and R60 represent alkyl C1 to 6 may be prepared by conventional alkylation of a compound of formula VI, ~0~
R la( ~ ) 2 N~
Ra~ VI
in which R1a, R2a, R30a and R40a are as defined above and R50a represents hydrogen or a protecting group.
Compounds of formula VI in which R50a represents H
may be produced from compounds of formula X as follows:
~,~.0~ R,0.0~?
5 Q~ RO. ~13 Br ~ 0~
~r ~ R~ Q Q~
2 ~1C~30~ 1 ~ ~ CP~ ~ ~ C~
I Q ~ ;- Vl ~
t~ ~ .~ ~ ~ \~ , r~d~
RL~ O~ ~< ~ R ~ SOCIa ~ ~ ~ `
in which R represents hydrogen or haologen and R1a, R2a and Ra are as defined above.
: : ~Esters of the benzoic acid IX may also be prepared by 25 processes analogous to the following route:
~ ::::
: :
lZ~Z~
g CH2Br r PPh3 Rla~ ~ R21a G~ a~ ~ ~O~Et XII
1 ) base .
RzOa~} CHO X~ 2 reduc~
21a R22a in which Rla, R2a, R, R20a, R21a and R22a are as defined above.
Other routes ~or the preparation of compounds of 15 formula VI, in which R50a represents hydrogen, are described in the Examples.
The compounds of formulae X, XI and XII are either known or may be made from known compounds using conventional techniques known ~ se.
20Acid addition salts of compounds of formula I may be converted to the corresponding free-base by the action of a stronger base. ; The acid addition salts of the compound of ; ~ formula I may be prepared by reac~ion~of the ~ree base with ~an appropriate acid. ~ ~
25~ Pharmaceutically acceptable acid addition salts of :
4Z~9 the compounds of formula I include salts of mineral acids, for example, hydrohalic acids, eg hydrochloric or hydrobromic acid; or organic acids, eg formic, acetic or lactic acids. The acid may be polybasic, for example 5 sulphuric, fumaric or citric acid.
Solvates of the compounds of formula I and their salts include hydxates, in particular hydrates of the salts of formula I, eg hemihydrates, monohydrates and sesquihydrates.
We prefer compounds of formula I in which R30 represents Ra.
We prefer compounds of formula I in which R40 represents hydrogen.
We prefex comp~unds of formula I in which R50 15 represents hydrogen and more preferably compounds in which both R50 and R60 are hydrogen.
Z~91 We prefer compounds of formula I in which R20, R
and R22 independently represent hydrogen, hydroxy, alkyl Cl to 6, eg methyl or ethyl, halogen, eg chlorine or fluorine, or trifluoromethyl.
Compounds of formula I that may particularly be mentioned include those in which at least one of R20~
R21 and R22 r~presents hydroxy. We particularly prefer compounds in which one of R20~ R21 and R22 P
I Q ~ ;- Vl ~
t~ ~ .~ ~ ~ \~ , r~d~
RL~ O~ ~< ~ R ~ SOCIa ~ ~ ~ `
in which R represents hydrogen or haologen and R1a, R2a and Ra are as defined above.
: : ~Esters of the benzoic acid IX may also be prepared by 25 processes analogous to the following route:
~ ::::
: :
lZ~Z~
g CH2Br r PPh3 Rla~ ~ R21a G~ a~ ~ ~O~Et XII
1 ) base .
RzOa~} CHO X~ 2 reduc~
21a R22a in which Rla, R2a, R, R20a, R21a and R22a are as defined above.
Other routes ~or the preparation of compounds of 15 formula VI, in which R50a represents hydrogen, are described in the Examples.
The compounds of formulae X, XI and XII are either known or may be made from known compounds using conventional techniques known ~ se.
20Acid addition salts of compounds of formula I may be converted to the corresponding free-base by the action of a stronger base. ; The acid addition salts of the compound of ; ~ formula I may be prepared by reac~ion~of the ~ree base with ~an appropriate acid. ~ ~
25~ Pharmaceutically acceptable acid addition salts of :
4Z~9 the compounds of formula I include salts of mineral acids, for example, hydrohalic acids, eg hydrochloric or hydrobromic acid; or organic acids, eg formic, acetic or lactic acids. The acid may be polybasic, for example 5 sulphuric, fumaric or citric acid.
Solvates of the compounds of formula I and their salts include hydxates, in particular hydrates of the salts of formula I, eg hemihydrates, monohydrates and sesquihydrates.
We prefer compounds of formula I in which R30 represents Ra.
We prefer compounds of formula I in which R40 represents hydrogen.
We prefex comp~unds of formula I in which R50 15 represents hydrogen and more preferably compounds in which both R50 and R60 are hydrogen.
Z~91 We prefer compounds of formula I in which R20, R
and R22 independently represent hydrogen, hydroxy, alkyl Cl to 6, eg methyl or ethyl, halogen, eg chlorine or fluorine, or trifluoromethyl.
Compounds of formula I that may particularly be mentioned include those in which at least one of R20~
R21 and R22 r~presents hydroxy. We particularly prefer compounds in which one of R20~ R21 and R22 P
3-hydroxy. Compounds that may also be specifically 10 mentioned include those in which two of ~5 ~4~89 12 ~
R20, R21 and R~2 represent hydroxy.
We prefer compounds of formula I in which m represents 2 or 3, especially 2.
The compounds of formula I, and pharmaceutically 5 acceptable acid addition salts thereof, are useful because they possess pharmacological activity in animals. Thus the compounds act on peripheral and/or central dopamine receptors. As such, they lower blood pressure and increase blood flow to certain vascular beds, eg renal beds.
10 Activity of the compounds has been investigated in the following assay systems:
(a) canine renal blood flow, McNay and Goldberg, J. Pharmac Exp Ther, 151, 23-31, 1966:
(b) rabbit isolated ear artery, McCullogh, Rand and Story, Br J Pharmac, 49, 141-142, 1973;
(c) guinea pig tracheal chains, Akcasu, Arch Int Pharmacodyn Ther, 122, 201-207, 1959;
(d) guinea pig atria, O'Donnell and Wanstall, J
Pharm Pharmacol, 31, 686-690, 1979.
The oompounds of the invention are indicated for use , ~;29~2~
in the treatment of congestive heart failure, renal failure, angina pectoris, ischaemic heart disease and hypertension. The compounds of the invention are also indicated for use in the treatment of shock and other low cardiac output states of varying aetiology, acute cerebrovascular disease and improvement of the blood supply to and healing of intestinal anastomoses and stomata.
The dosage administered will naturally depend on the compound employea, the mode of administration and the desired effect. However, in general, satisfactory results are obtained when the compound is administered at a dosage of from 0.05 ~ug to 50mg per kilogram of body weight per day. For man, the indicated total daily dosage is in the range 2.5 ~g to 3.5g, which may be administered in divided doses of, for example 1 yg to 750mg.
The compounds of formula I, and pharmaceutically acceptable derivatives thereof, have the advantage that they are more efficacious or produce less undesirable side effects in certain pharmacological models than compounds of similar structure to the~compound of formula I.
The compound of the invention may be administered by a wide variety of routes and may act systemically or locally. Thus the compound may be administered by oral or 25~ n=Fal inhalation to the lung, to the buccal cavity, ' oesophageally, rectally, topically to the skin or to other available surfaces of the body, eg the eye, by injection, eg intravenously, intramuscularly, intraperitoneally, by instillation or by surgical implant~
According to our invention we also provide a pharmaceutical composition comprising preferably less than 80%, and more preferably less than 50~, by weight of a compound of formula I, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or carriers are: for tablets, capsules and dragees; microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin;
for suppositories natural or hardened oil or waxes;
and for inhalation compositions, coarse lactose.
When the compound is to be used in aqueous solution it may be necessary to incorporate a chelating or sequestering agent, eg sodium edetate, an antioxidant, eg sodium metabisolphite or buffering agents, eg sodium hydrogen phosphate and sodium phosphate. Aqueous solutions typically contain up to about 10~ w/w of the new compound and may be used for intravenous injections.
_ According to the invention, we further provide a method of treatment of acute renal failure in an animal, either human or non-human, which method comprises administering to the animal an effective amount of the compound of the invention or a pharmaceutically acceptable acid addition salt thereof.
The invention is illustrated, but in no way limited, by the following Examples in which temperatures are in degrees Centigrade.
A- Preparation of Intermediates 1. Preparation of 4,4-dimethyloxazoles a) 2-~3,4-Dimethoxy-2-(2-13-methoxyphenyl~ethyl)phenyl]-4,5-dihydro-4,4-dimethyloxazole A solution of 2 t3-methoxyphenyl]ethylbromide (12.2g) in dry tetrahydrofuran (20ml) was added dropwise to a suspension of magnesium (1.46g) in dry tetrahydrofuran (20ml), under an atmosphere of nitrogen, at a rate sufficient to maintain a state of reflux. After 1 hour the cooled solution was added to a stirred solution 20 of 4,5-dihydro-4,4-dimethyl-2-t2,3,4-trimethoxyphenyl]
oxazole (7.95g) ln dry tetrahydrofuran (50ml) under an atmosphere of nitrogen. The mixture was stirred at 20 for 16 hours. Water (400ml) was added and~ the aqueous phase thoroughly extracted with ethyl acetate (2 x 25 250ml). The organic phas~ was dried over magnesium .` ~
sulphate, filtered and the solvent removed ln vacuo to yield a yellow oil which was purified by flash column chromatography on silica gel, using 10% ethyl acetate/90%
petroleum ether as eluent, and by Kugelruhr distillation (air bath temperature 200/lmm Hg) 9.7g of the sub-title compound were obtained, ms m/e 369.
Similarly prepared ~ere:
b) 2-[3,4-Dimethoxy-2-~2-[4-methoxyphenyl3ethyl]phenyl]-4,5-dihydro 4,4-dimethyloxazole, ms m/e 369;
c) 2-[3,4-Dimethoxy-2-r2-phenylethyl]phenyl]-4,5-dihydro-4,4-dimethyloxazole, ms m/e 339;
d) 2--13,4-Dimethoxy-2 [2-[3,4-dimethoxyphenyl]ethyl]
phenyl]-4,5-dihydro-4,4-dimethyloxaæole, ms m/e 399;
e) 2-[5-Chloro 3,4-dimethoxy-2-[2-[3-methoxyphenyl3ethyl]
phenyl]-4,5-dihydro-4,4-dimethyloxazole, mp 95-98;
f) 2-[5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl~
phenyl~-4,5-dihydro-4,4-dimethyloxazole, m/e 403/405;
g) 2-[4,5-Dimethoxy-2-~2-[3-methoxyphenyl]ethyl]phenyl]-4,5-dihydro-4,4-dimethyloxazole, m/e 369.
2. Preparation of benzoic acids a) 3,4-Dimethoxy-2-[2-[3~methoxyphenyl]ethyl]benzoic acid A solutlon of the product from Intermediate 1 a) (9.7g) in excess methyl iodide (lOml) was heated at reflux temperature for 4 hours. Dry ether tlOOml) was added and .
~? 1 1 3LZ9~9L;Z89 ~he resulting precipitate filtered to yield 119 of the oxazolinium salt which was used without further purification.
A solution of this oxa201inium salt (llg) in 20~
aqueous sodium hydroxide (200ml) and methanol (200ml) was heated at reflux temperature for 6 hours. The cooled solution was acidified and the solid filtered, dried and crystallised from isopropanol to yield the sub-title compound (6.2g) as colourless prisms, mp 156-158.
Similarly prepared were:
b) 3,4-Dimethoxy-2-[2-[4-methoxyphenyl]ethyl]benzoic acid, mp 148-150;
c) 3,4-Dimethoxy-2-~2-phenylethyl]benzoic acid, mp 142-144;
15 d) 2-[2-~3,4-Dimethoxyphenyl]ethyl]-3,4~dimethoxy benzoic acid, mp 148~149.
e) 5-Chloro-3,4-dimethoxy-2-t2-[3-methoxyphenyl]ethyl]
benzoic acid, mp 123-125;
f) 5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl]
benzoic acid, mp 96-98;
g) 4,5-Dimethoxy-2-[2-[3-methoxyphenyl~ethyl3benzoic acid, mp 152-155.
3 Preparation of benzenemethanols Method A
.
~ 25 a) 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl~benzene .
methanol A solution of the product from Intermediate 2 a) (6.2g) in dry tetrahydrofuran (50ml) was stirred under an atmosphere of nitrogen during the addition of 40ml of a lM
solution of borane in tetrahydrofuran complex. The mixture was heated under reflux for 3 hours, cooled and methanol (80ml) added. The solution was evaporated to dryness, dissoIved in ethyl acetate and washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulphate, filtered and the solvent removed in vacuo to leave a solid which was crystallised from isopropanol to yield 5.29 of the sub-title compound as colourless flakes, mp 108 109.
Similarly prepared were:
b) 3,4-Dimethoxy-2-12-[4-methoxyphenyl]ethyl]
benzenemethanol, mp 83-85;
c) 3,4-Dimethoxy-2-12-phenylethyl]benzenemethanol, mp 99-100;
d) 2-t2-t3,4-Dimethoxyphenyl]eth~I]3,4-dimethoxy benzenemethanol, mp 103.5-105.5;
e) N-t3-[2-t2,3,-Dimethoxy~6 hydroxymethylphenyl]ethyl]
; phenyl]methanesulphonamide, mp 113-115;
f) 5-Chloro-3,4-dimethoxy-2-12-[3-methoxyphenyl]ethyl~
benzeneme~hanOl, p 54-56 :
. . .
-- 19 ~
g) 5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl]
benzenemethanol, m/e 408;
h) 4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]
benæenemethanol, m/e 302.
R20, R21 and R~2 represent hydroxy.
We prefer compounds of formula I in which m represents 2 or 3, especially 2.
The compounds of formula I, and pharmaceutically 5 acceptable acid addition salts thereof, are useful because they possess pharmacological activity in animals. Thus the compounds act on peripheral and/or central dopamine receptors. As such, they lower blood pressure and increase blood flow to certain vascular beds, eg renal beds.
10 Activity of the compounds has been investigated in the following assay systems:
(a) canine renal blood flow, McNay and Goldberg, J. Pharmac Exp Ther, 151, 23-31, 1966:
(b) rabbit isolated ear artery, McCullogh, Rand and Story, Br J Pharmac, 49, 141-142, 1973;
(c) guinea pig tracheal chains, Akcasu, Arch Int Pharmacodyn Ther, 122, 201-207, 1959;
(d) guinea pig atria, O'Donnell and Wanstall, J
Pharm Pharmacol, 31, 686-690, 1979.
The oompounds of the invention are indicated for use , ~;29~2~
in the treatment of congestive heart failure, renal failure, angina pectoris, ischaemic heart disease and hypertension. The compounds of the invention are also indicated for use in the treatment of shock and other low cardiac output states of varying aetiology, acute cerebrovascular disease and improvement of the blood supply to and healing of intestinal anastomoses and stomata.
The dosage administered will naturally depend on the compound employea, the mode of administration and the desired effect. However, in general, satisfactory results are obtained when the compound is administered at a dosage of from 0.05 ~ug to 50mg per kilogram of body weight per day. For man, the indicated total daily dosage is in the range 2.5 ~g to 3.5g, which may be administered in divided doses of, for example 1 yg to 750mg.
The compounds of formula I, and pharmaceutically acceptable derivatives thereof, have the advantage that they are more efficacious or produce less undesirable side effects in certain pharmacological models than compounds of similar structure to the~compound of formula I.
The compound of the invention may be administered by a wide variety of routes and may act systemically or locally. Thus the compound may be administered by oral or 25~ n=Fal inhalation to the lung, to the buccal cavity, ' oesophageally, rectally, topically to the skin or to other available surfaces of the body, eg the eye, by injection, eg intravenously, intramuscularly, intraperitoneally, by instillation or by surgical implant~
According to our invention we also provide a pharmaceutical composition comprising preferably less than 80%, and more preferably less than 50~, by weight of a compound of formula I, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or carriers are: for tablets, capsules and dragees; microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin;
for suppositories natural or hardened oil or waxes;
and for inhalation compositions, coarse lactose.
When the compound is to be used in aqueous solution it may be necessary to incorporate a chelating or sequestering agent, eg sodium edetate, an antioxidant, eg sodium metabisolphite or buffering agents, eg sodium hydrogen phosphate and sodium phosphate. Aqueous solutions typically contain up to about 10~ w/w of the new compound and may be used for intravenous injections.
_ According to the invention, we further provide a method of treatment of acute renal failure in an animal, either human or non-human, which method comprises administering to the animal an effective amount of the compound of the invention or a pharmaceutically acceptable acid addition salt thereof.
The invention is illustrated, but in no way limited, by the following Examples in which temperatures are in degrees Centigrade.
A- Preparation of Intermediates 1. Preparation of 4,4-dimethyloxazoles a) 2-~3,4-Dimethoxy-2-(2-13-methoxyphenyl~ethyl)phenyl]-4,5-dihydro-4,4-dimethyloxazole A solution of 2 t3-methoxyphenyl]ethylbromide (12.2g) in dry tetrahydrofuran (20ml) was added dropwise to a suspension of magnesium (1.46g) in dry tetrahydrofuran (20ml), under an atmosphere of nitrogen, at a rate sufficient to maintain a state of reflux. After 1 hour the cooled solution was added to a stirred solution 20 of 4,5-dihydro-4,4-dimethyl-2-t2,3,4-trimethoxyphenyl]
oxazole (7.95g) ln dry tetrahydrofuran (50ml) under an atmosphere of nitrogen. The mixture was stirred at 20 for 16 hours. Water (400ml) was added and~ the aqueous phase thoroughly extracted with ethyl acetate (2 x 25 250ml). The organic phas~ was dried over magnesium .` ~
sulphate, filtered and the solvent removed ln vacuo to yield a yellow oil which was purified by flash column chromatography on silica gel, using 10% ethyl acetate/90%
petroleum ether as eluent, and by Kugelruhr distillation (air bath temperature 200/lmm Hg) 9.7g of the sub-title compound were obtained, ms m/e 369.
Similarly prepared ~ere:
b) 2-[3,4-Dimethoxy-2-~2-[4-methoxyphenyl3ethyl]phenyl]-4,5-dihydro 4,4-dimethyloxazole, ms m/e 369;
c) 2-[3,4-Dimethoxy-2-r2-phenylethyl]phenyl]-4,5-dihydro-4,4-dimethyloxazole, ms m/e 339;
d) 2--13,4-Dimethoxy-2 [2-[3,4-dimethoxyphenyl]ethyl]
phenyl]-4,5-dihydro-4,4-dimethyloxaæole, ms m/e 399;
e) 2-[5-Chloro 3,4-dimethoxy-2-[2-[3-methoxyphenyl3ethyl]
phenyl]-4,5-dihydro-4,4-dimethyloxazole, mp 95-98;
f) 2-[5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl~
phenyl~-4,5-dihydro-4,4-dimethyloxazole, m/e 403/405;
g) 2-[4,5-Dimethoxy-2-~2-[3-methoxyphenyl]ethyl]phenyl]-4,5-dihydro-4,4-dimethyloxazole, m/e 369.
2. Preparation of benzoic acids a) 3,4-Dimethoxy-2-[2-[3~methoxyphenyl]ethyl]benzoic acid A solutlon of the product from Intermediate 1 a) (9.7g) in excess methyl iodide (lOml) was heated at reflux temperature for 4 hours. Dry ether tlOOml) was added and .
~? 1 1 3LZ9~9L;Z89 ~he resulting precipitate filtered to yield 119 of the oxazolinium salt which was used without further purification.
A solution of this oxa201inium salt (llg) in 20~
aqueous sodium hydroxide (200ml) and methanol (200ml) was heated at reflux temperature for 6 hours. The cooled solution was acidified and the solid filtered, dried and crystallised from isopropanol to yield the sub-title compound (6.2g) as colourless prisms, mp 156-158.
Similarly prepared were:
b) 3,4-Dimethoxy-2-[2-[4-methoxyphenyl]ethyl]benzoic acid, mp 148-150;
c) 3,4-Dimethoxy-2-~2-phenylethyl]benzoic acid, mp 142-144;
15 d) 2-[2-~3,4-Dimethoxyphenyl]ethyl]-3,4~dimethoxy benzoic acid, mp 148~149.
e) 5-Chloro-3,4-dimethoxy-2-t2-[3-methoxyphenyl]ethyl]
benzoic acid, mp 123-125;
f) 5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl]
benzoic acid, mp 96-98;
g) 4,5-Dimethoxy-2-[2-[3-methoxyphenyl~ethyl3benzoic acid, mp 152-155.
3 Preparation of benzenemethanols Method A
.
~ 25 a) 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl~benzene .
methanol A solution of the product from Intermediate 2 a) (6.2g) in dry tetrahydrofuran (50ml) was stirred under an atmosphere of nitrogen during the addition of 40ml of a lM
solution of borane in tetrahydrofuran complex. The mixture was heated under reflux for 3 hours, cooled and methanol (80ml) added. The solution was evaporated to dryness, dissoIved in ethyl acetate and washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulphate, filtered and the solvent removed in vacuo to leave a solid which was crystallised from isopropanol to yield 5.29 of the sub-title compound as colourless flakes, mp 108 109.
Similarly prepared were:
b) 3,4-Dimethoxy-2-12-[4-methoxyphenyl]ethyl]
benzenemethanol, mp 83-85;
c) 3,4-Dimethoxy-2-12-phenylethyl]benzenemethanol, mp 99-100;
d) 2-t2-t3,4-Dimethoxyphenyl]eth~I]3,4-dimethoxy benzenemethanol, mp 103.5-105.5;
e) N-t3-[2-t2,3,-Dimethoxy~6 hydroxymethylphenyl]ethyl]
; phenyl]methanesulphonamide, mp 113-115;
f) 5-Chloro-3,4-dimethoxy-2-12-[3-methoxyphenyl]ethyl~
benzeneme~hanOl, p 54-56 :
. . .
-- 19 ~
g) 5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl]
benzenemethanol, m/e 408;
h) 4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]
benæenemethanol, m/e 302.
5 MQ~hod B
a) 2-[2-~3,5-Dimethoxyphenyl~ethylL3~4-dimethoxvbenzene methanol A lM solution of lithium aluminium hydride in tetrahydrofuran ~80ml) was added dropwise to a stirred 10 solution of the intermediate ester from step 6Bb (20g) in dry tetrahydrofuran under a nitrogen atmosphere at -78.
The solution was stirred at 20 for 2 hours. The mixture was quenched with brine ~lOml) and evaporated to dryness.
The residue was partitioned between ether and 2N
15 hydrochloric acid and separated. The organic solution was washed with brine, dried (MgS0~), filtered and evaporated to give a solid. Crystallisation from isopropanol gave 15g o~ the intermediate alcohol as colourless flakes, mp 126-128.
Similarly prepared were:
b) 3,4-Dimethoxy-2-[2-[3,4,5-trimethoxyphenyl~ethylJ
benzenemethanol, mp 132.5-134-;
c) 3,4-Dimethoxy-5-[2-[3-methoxyphenyl]ethyl~
benzenemethanol, m/e 302.
25 Yit~ 5 ~1~
a) E-3.4-Dimethoxy-2-~2-~3,4,5-trimethoxyphenvlletheny benzenemethanol A 1.5M solution of diisobutylaluminium hydride in toluene (50ml) was added dropwise to a stirred solution of 5 the ethenyl ester from step 6Bal (14.6g) in dry tetrahydro~uran (120ml). The solution was stirred at 20O
for 1 1/2 hours. The solution was evaporated and the residue ~uenched slowly with 2N hydrochloric acid and extracted with ethyl acetate. The organic solution was 10 washed with brine, dried (MgSO4), filtered and evaporated to give a solid which crystalIised ~rom isopropanol to give 9.64g of the alcohol as colourless flakes, mp 119.5-121.
Method D
a) 3.4-Dime~hoxy-2-~2-C3-nitrophen~llethyllbenzenemethanol A 0.5M solution of aluminium hydride in t~trahydro~uran (56ml) was added dropwise to a solution of the inte~nediate 6Bc (5.06g) in dry tetrahydrofuran (50ml). The solution was stirred at 20 for 16 hours. The solution was quenched with water and extracted with ethyl 20 acetate. The organic phase was dried (MgSO4), filtered - and evaporated. The residue was purified by flash ~chromatography (Merck 9385 silioa gel) eluting with e~hyl acetate/60-80 petrol e~her (1:1) to give the alcohol ~2~Z~9 as a colourless solid (3.21g).
4. Preparation of benzeneacetonitriles .
a) 3,4-Dimethoxy-2-12-[3-methoxyphenyl]ethyl~
benzeneacetonitrile A solution of the alcohol from Intermediate 3 a) (5g) and thionyl chloride (1.5ml) in dry dichloromethane (50ml) was heated at reflux temperature for 3 hours. The solution was evaporated to dryness.
The cooled crude chloride was dissolved in dry dimethylsulphoxide (25ml). Powdered sodium cyanide (1.5g) was added to the solution and the mixture was stirred at 20 for 16 hours. Brine (150ml) was added and the mixture extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate, filtered and evaporated on a steam bath until HCN had ceased to be evolved. Further evaporation gave a yellow solid which was crystallised from isopropanol to yield 4.0g of the sub~title compound as prisms, mp 98-100.
Similarly prepared were:
b) 3,4-Dimethoxy-2-~2-[4-methoxyphenyl]ethyl]
benzeneacetonitrile, mp 91-93;
c) 3,4-Dimethoxy-2-[2-phenylethyl]benzeneacetonitrile, ms m/e 287;
d) E-3J4-Dimethoxy-2~~2-[3,4,5~trimethoxyphenylJethenyl]
25 benzeneacetonitrile, mp 134-136;
~;2g~;28~
e) 3,4-Dimethoxy-2-[2-~3-nitrophenyl]ethyl]
benzeneacetonitrile, mp 112-115, f) N-C3-[2-[2,3-Dimethoxy-6-cyanomethylphenyl]ethyl]
phenyl]methane sulphonamide, mp 111-112;
g) 5-Chloro-3,4-dimethoxy-2-[2-13-methoxyphenyl~ethyl]
benzeneacetonitrile, mp 70-72;
h) 5-Chloro-3,4-dimethoxy-2-[2-~4-methoxyphenyl]ethyl]
benzeneacetonitrile, mp 95-96;
i) 4,5-Dimethoxy-2-[2-13-methoxyphenyl]ethyl]
benzeneacetonitrile, mp 71-73;
j) 3,4-Dimethoxy-5-[2-[3-methoxyphenyl]ethyl]
benzeneacetonitrile, m/e 311.
Preparation of intermediates of formula VI in which R50a is hydrogen ._ a) 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]
enzeneethanamine hydrochloride A solution of the nitrile from Intermediate 4 a) (4g) in dry tetrahydrofuran (50ml) was stirred under an atmosphere of nitrogen during the addition of a lM
solution of borane in tetrahydrofuran (25O7ml). The mixture was heated at reflux temperature for 2 hours.
Methanol (40ml) was added to the cooled reaction mixture and the solution evaporated to dryness. The residue was dissolved in methanol~(50ml) and conc. hydrochloric acid (.Sml) added. The mixture was heated at reflux temperature for 1 hour and then the solution was evaporated to drynessto yield a beige solid. This was treated with dilute sodium hydroxide solution to yield 2-[2-(3-methoxyphenyl) ethyl]-3,4-dimethoxybenzeneethanamine which was purified by 5 flash column chromatography on silica gel using 90%
chloroform/10% methanol as eluant. The resulting oil was treated with ethereal HCl to give 1.2g of the sub-title compound as colourless prisms aft~r crystallisation from : isopropanol, mp 164-166.
Similarly prepared were:
b) 3,4-Dimethoxy 2-~2-[4-methoxyphenyl]ethyl]
benzeneethanamine hydrochloride, mp 135-137;
c) 3,4-Dimethoxy-2 [2 phenylethyl]benzeneethanamine hydrochloride, mp 201-203;
15 d) 3,4-Dimethoxy 2-[2-[3,4,5-trimethoxyphenyl]ethyl]
benzeneethanamine hydrochloride, softens 105-110, mp 158.5-159.5;
: e) 3,4-Dimethoxy-2 [2-t3-nitrophenyl]ethyl]
benzeneethanamine hydrochloride, mp 228-230;
20 f) N-[3-[2-[2,3-Dimethoxy-6-[2-aminoethyl]phenyl]ethyl]
phenyl]methanesulphonamide hydrochloride, mp 181-183.
g) 5-Chloro-3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]
benzen~ethanamine hydrochloride, mp 147-149O;
~ h) 5-Chloro-3,4-dimethoxy-2-[~t4-methoxyphenyl]ethyl]
:~ 25 benzeneethanamine hydrochloride, mp 197-199:
.
3'~Z~
i) 4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]
benzeneethanamine hydrochloride, mp 178-179;
j) 3,4-Dimethoxy-5-[2-[3-methoxyphenyl]ethyl]benzeneethana mine hydrochloride, m/e 315.
.
I
~ 1~
Z8~
a) 2-[2-~3,5-Dimethoxyphenyl~ethylL3~4-dimethoxvbenzene methanol A lM solution of lithium aluminium hydride in tetrahydrofuran ~80ml) was added dropwise to a stirred 10 solution of the intermediate ester from step 6Bb (20g) in dry tetrahydrofuran under a nitrogen atmosphere at -78.
The solution was stirred at 20 for 2 hours. The mixture was quenched with brine ~lOml) and evaporated to dryness.
The residue was partitioned between ether and 2N
15 hydrochloric acid and separated. The organic solution was washed with brine, dried (MgS0~), filtered and evaporated to give a solid. Crystallisation from isopropanol gave 15g o~ the intermediate alcohol as colourless flakes, mp 126-128.
Similarly prepared were:
b) 3,4-Dimethoxy-2-[2-[3,4,5-trimethoxyphenyl~ethylJ
benzenemethanol, mp 132.5-134-;
c) 3,4-Dimethoxy-5-[2-[3-methoxyphenyl]ethyl~
benzenemethanol, m/e 302.
25 Yit~ 5 ~1~
a) E-3.4-Dimethoxy-2-~2-~3,4,5-trimethoxyphenvlletheny benzenemethanol A 1.5M solution of diisobutylaluminium hydride in toluene (50ml) was added dropwise to a stirred solution of 5 the ethenyl ester from step 6Bal (14.6g) in dry tetrahydro~uran (120ml). The solution was stirred at 20O
for 1 1/2 hours. The solution was evaporated and the residue ~uenched slowly with 2N hydrochloric acid and extracted with ethyl acetate. The organic solution was 10 washed with brine, dried (MgSO4), filtered and evaporated to give a solid which crystalIised ~rom isopropanol to give 9.64g of the alcohol as colourless flakes, mp 119.5-121.
Method D
a) 3.4-Dime~hoxy-2-~2-C3-nitrophen~llethyllbenzenemethanol A 0.5M solution of aluminium hydride in t~trahydro~uran (56ml) was added dropwise to a solution of the inte~nediate 6Bc (5.06g) in dry tetrahydrofuran (50ml). The solution was stirred at 20 for 16 hours. The solution was quenched with water and extracted with ethyl 20 acetate. The organic phase was dried (MgSO4), filtered - and evaporated. The residue was purified by flash ~chromatography (Merck 9385 silioa gel) eluting with e~hyl acetate/60-80 petrol e~her (1:1) to give the alcohol ~2~Z~9 as a colourless solid (3.21g).
4. Preparation of benzeneacetonitriles .
a) 3,4-Dimethoxy-2-12-[3-methoxyphenyl]ethyl~
benzeneacetonitrile A solution of the alcohol from Intermediate 3 a) (5g) and thionyl chloride (1.5ml) in dry dichloromethane (50ml) was heated at reflux temperature for 3 hours. The solution was evaporated to dryness.
The cooled crude chloride was dissolved in dry dimethylsulphoxide (25ml). Powdered sodium cyanide (1.5g) was added to the solution and the mixture was stirred at 20 for 16 hours. Brine (150ml) was added and the mixture extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate, filtered and evaporated on a steam bath until HCN had ceased to be evolved. Further evaporation gave a yellow solid which was crystallised from isopropanol to yield 4.0g of the sub~title compound as prisms, mp 98-100.
Similarly prepared were:
b) 3,4-Dimethoxy-2-~2-[4-methoxyphenyl]ethyl]
benzeneacetonitrile, mp 91-93;
c) 3,4-Dimethoxy-2-[2-phenylethyl]benzeneacetonitrile, ms m/e 287;
d) E-3J4-Dimethoxy-2~~2-[3,4,5~trimethoxyphenylJethenyl]
25 benzeneacetonitrile, mp 134-136;
~;2g~;28~
e) 3,4-Dimethoxy-2-[2-~3-nitrophenyl]ethyl]
benzeneacetonitrile, mp 112-115, f) N-C3-[2-[2,3-Dimethoxy-6-cyanomethylphenyl]ethyl]
phenyl]methane sulphonamide, mp 111-112;
g) 5-Chloro-3,4-dimethoxy-2-[2-13-methoxyphenyl~ethyl]
benzeneacetonitrile, mp 70-72;
h) 5-Chloro-3,4-dimethoxy-2-[2-~4-methoxyphenyl]ethyl]
benzeneacetonitrile, mp 95-96;
i) 4,5-Dimethoxy-2-[2-13-methoxyphenyl]ethyl]
benzeneacetonitrile, mp 71-73;
j) 3,4-Dimethoxy-5-[2-[3-methoxyphenyl]ethyl]
benzeneacetonitrile, m/e 311.
Preparation of intermediates of formula VI in which R50a is hydrogen ._ a) 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]
enzeneethanamine hydrochloride A solution of the nitrile from Intermediate 4 a) (4g) in dry tetrahydrofuran (50ml) was stirred under an atmosphere of nitrogen during the addition of a lM
solution of borane in tetrahydrofuran (25O7ml). The mixture was heated at reflux temperature for 2 hours.
Methanol (40ml) was added to the cooled reaction mixture and the solution evaporated to dryness. The residue was dissolved in methanol~(50ml) and conc. hydrochloric acid (.Sml) added. The mixture was heated at reflux temperature for 1 hour and then the solution was evaporated to drynessto yield a beige solid. This was treated with dilute sodium hydroxide solution to yield 2-[2-(3-methoxyphenyl) ethyl]-3,4-dimethoxybenzeneethanamine which was purified by 5 flash column chromatography on silica gel using 90%
chloroform/10% methanol as eluant. The resulting oil was treated with ethereal HCl to give 1.2g of the sub-title compound as colourless prisms aft~r crystallisation from : isopropanol, mp 164-166.
Similarly prepared were:
b) 3,4-Dimethoxy 2-~2-[4-methoxyphenyl]ethyl]
benzeneethanamine hydrochloride, mp 135-137;
c) 3,4-Dimethoxy-2 [2 phenylethyl]benzeneethanamine hydrochloride, mp 201-203;
15 d) 3,4-Dimethoxy 2-[2-[3,4,5-trimethoxyphenyl]ethyl]
benzeneethanamine hydrochloride, softens 105-110, mp 158.5-159.5;
: e) 3,4-Dimethoxy-2 [2-t3-nitrophenyl]ethyl]
benzeneethanamine hydrochloride, mp 228-230;
20 f) N-[3-[2-[2,3-Dimethoxy-6-[2-aminoethyl]phenyl]ethyl]
phenyl]methanesulphonamide hydrochloride, mp 181-183.
g) 5-Chloro-3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]
benzen~ethanamine hydrochloride, mp 147-149O;
~ h) 5-Chloro-3,4-dimethoxy-2-[~t4-methoxyphenyl]ethyl]
:~ 25 benzeneethanamine hydrochloride, mp 197-199:
.
3'~Z~
i) 4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]
benzeneethanamine hydrochloride, mp 178-179;
j) 3,4-Dimethoxy-5-[2-[3-methoxyphenyl]ethyl]benzeneethana mine hydrochloride, m/e 315.
.
I
~ 1~
Z8~
6. Alternative route for the preparation of benzene methanols, via Wittiq reaction Phosphonium salt formation a) Ethyl 3,4-dimethoxy-2-methyl benzoate A solution of 3,4-dimethoxy-2-methylbenzoic acid (5-9g) in ethanol (200ml) containing concentrated hydrochloric acid (lOml) was heated at reflux temperature for 16 hours. The cool solution was evaporated down to an oil then dissolved in ether. The organic solution was washed with lN sodium hydroxide solution (lOOml), brine (lOOml), dried (MgS04), filtered and evaporated to leave a solid.
The solid was purified by flash chromatography eluting with 60-80 petrol ether/ethyl acetate (10:1) to give the sub-title ester as colourless needles (6.58g), mp 46-49.
15 b) Ethyl 2-bromomethyl-3.~-dimethoxvbenzoate 2~
:
A solution o the ester (stage a) (67.2g), N-bromosuccinimide (57g) and azobisisobutyronitrile (catalytic) in carbontetrachloride (700ml) was heated under reflux under irradiation (60w bulb) for 2 l/2 S hours. The cooled reaction was washed with water.
The organic solution was dried (MgSO4), filtered and evaporated to leave a solid. The solid was purified by flash chromatography (Merck 9385 silica gel) eluting with dichloromethane /60/80 petrol ether (l:l). Evaporation of the required fractions gave a yellow solid (84.1g), ms m/e 302/304.
Similarly prepared was:
b.l) 2-[2-Bromomethyl 3,4-dimethoxyphenyl]-4t5-dihydro-4,4-dimethyloxazole, ms m/e 327/329.
lS c) 6-Ethoxycarbonyl 2,3~dimethoxyphenyl]methyltriphenyl phosphonium bromide A solution of the product of step b) (83.9g) and triphenylphosphine (72.55g) in toluene (500ml) was heated under reflux in a nitrogen atmosphere for 24 hours. The precipitate from the cooled solution was filtered, slurried with ether and stirred for 2 hours. The solid ; was Eiltered and dried (129g), mp 198-200.
Similarly prepared was:
c.l) [6-~4,5-Dihydro-4,4-dimethyloxazole 2-yl~-2,3-~25 dimethoxyphenyl]methyltriphenylphosphonium bromide, ms m/e -~4;28~
510 (cation) Variation A ~ oxazole route Wittia reaction Aa) E-2-[3,4-Dimethoxy-2- r 2~[3-nitrophenyllethenyllphenyl~
4,5-dihydro-4 ~4-dimethyloxazole A solution of the phosphonium bromide from step c.l) (69g) in dry dimethylformamide (300ml) was added dopwise to a suspension of 80% sodium hydride ~3.51g) stirred in dry dimethylformamide (lOOml) at 0 under a nitrogen atmosphere. The mixture was stirred for 30 minutes at 60 lO and a solution of 3-nitrobenzaldehyde (17.7g) in dry dimethylformamide (lOOml) was then added.
The mixture was stirred at 20 for 1 hour then quenched with ice/water.
The solid mass was extracted into ethyl acetate and lS separated. The organic solution was washed with water, dried (MgS04), filtared and evaporated to give a yellow oil which was purified by flash chromatogarphy (Merck 9385 silica gel) eluting with dichloromethane/ethyl acetate (95:5)0 Evaporation of the relevant fractions gave the 20 sub-title compound as pure E isomer (35g), mp 78-80~.
Reduction of nitro qroup Ab) E-3- r 2-~6- r 4.5-Dihydro-4 ~4-dimethyloxazole-2-yll-2,3-dimethoxvPhenyllethenyl]benzeneamine A solution of the nitro intermediate Aa) (32g) in :
~9L28g O ethanol (250ml) was hydrogenated over a platinum oxide catalyst (0.3g) at 2 atmospheres for 2 hours. The catalyst was removed by filtration and the filtrate evaporated to leave a colourless solid (26.5g), ms m/e 352.
Sulphonamide ~ormation and_cleavaqQ of oxazole Ac) E-3,4-Dimethoxy-2- r 2-r3- r methanesulphonyllaminophenyl~
ethenyl~-benzoic acid Methanesulphonylchloride (12.4ml) was added dropwise to a stirred solution of the benzenamine Ab) (26.5g) and lO triethylamine (24ml) in dry dichloromethane (200ml). The solution was stirred at 20 for 1 hour. The solution was washed with water, dried (MgS04), filtered and evaporated to leave 29g of the dimethanesulphonamide intermediate.
A solution of this intermediate in methyliodide (50ml) 15 and dichloromethane (200ml) was heated at reflux temperatura for 2 days. The solution was evaporated and the residue triturated with ether to give 41g of the quaternary salt as a yellow solid, mp 193.
A solution of the quaternary salt in methanol (800ml) 20 and 10% sodium hydroxide solution (160ml) was heated to reflux temperature for 3 hours. The solution was evaporated and acidified~ with 2N hydrochloric acid. The solid precipitate was filtered, washed with water and dried. The solid crystallised from ethanol to give 20.5g .
of the acid as a colourless solid, mp 221-223.
Reduction of double bond Ad) 3,4-Dimethoxy-2- r 2-[3-~methanesulphonyllamino Phenyl~ethyl~benzoic acid 5 A solution of the acid Ac) (8.15g) in lM sodium hydroxide solution (200ml) was hydrogenated over a 10% palladium on charcoal catalyst (2g) at 3 atmospheres and 45 for 18 hours. The catalyst was removed by filtration and the cooled solution acidified with 2N hydrochloric acid. The 10 solid was dissolved in ethyl acetate and separated. The organic solution was washed with water, dried (MgS04), filtered and evaporated to leave a solid. Crystallisation from ethyl acetate/petrol gavP 6.26g of the acid as a colourless powder, mp 187.5-188.5.
15 Variation B - benzoate ester route Wltt.iq reaction Ba) E~Z-~thYl-2- r 2- r 3 5-Dimethoxv~henYllethenyll 3.4-dimethoxY benzoate A l.~M solution of butyl lithium in hexane (55ml) was added 20 dropwise to a stirred suspension of the phosphonium salt (45.2g) from step 6c) in dry tetrahydrofuran (200ml) under a nitrogen atmosphere at 0. The mixture was stirred at 0 for 1 hour and a solution of 3,5-dimethoxybenzaldehyde ; added. The ~ 25 ~ ' .
~9~9 resulting mixture was stirred at 20 for 16 hours.
The mixture was quenched with brine (50ml) and evaporated to dryness. The solid was dissolved in ethyl acetate washed with brine, dried (MgSO4), filtered and evaporated to give a dark oil. The oil was purified by flash chromatography (Merck 9385 silica gel) eluting with dichloromethane/petrol 60/80 (1:1) to give 24g of the intermediate ester as a colourless oil, ms m/e 372.
Similarly prepared were:
Ba.l) E-Ethyl 3,4-Dimethoxy-2-t2-~3,4,5-trimethoxyphenyl]
ethenyl]benzoate, mp 103-104 Ba.2) E/Z-Ethyl 3,4-Dimethoxy-2-[2-t3-nitrophenyl]ethenyl]
benzoate, mp 80-82.
Ba.3) Ethyl 3,4-dimethoxy-5-~2-[3-methoxyphenyl]ethenyl]
lS benzoate, m/e 342.
Reduction of double bond Bb) Ethyl-2-12-[3,5-Dimethoxyphenyl]ethyl]3,4-dimethoxy benzoate A solution of the intermediate ethenyl ester Ba) ~24g) in ethanol (150ml) was hydrogenated over a lQ%
palladium on charcoal catalyst (lg) at atmospheric pressure for 24 hours. The catalyst was removed by filtration and the filtrate evaporated to leave a yellow oil The oil was purified by flash chromotography (Merck 9385 silica gel) eluting with 60/80 petrol ether/10% ethyl ~LZ~4~
~ 31 -acetate to give 20g of the intermediate ester as acolourless oil, ms m/e 374.
Similarly prepared were:
Bb.1) Ethyl 3,4-dimethoxy-2-[2-[3,4,5-trimethoxyphenyl]
5 ethyl]benzoate, ms m/e 440;
Bb.2) 3,4-Dimethoxy-2-[2-[3,4,5-trimethoxyphenyl]ethyl]
benzeneacetonitrile, mp 119.5-120.5;
Bb.3) Ethyl 3,4-dimethoxy-5-[2-[3-methoxyphenyl]ethyl~
benzoate, ms m/e 344.
10 Selective reduction of the double bond of the intermediate Ba.2 Bc) Ethyl-3 4-dimethoxY-2- r 2-~3-nitrophen~llethyllbenzoate A solution of the ethenyl ester Ba.2) (5g) in benzene (lOOml) was hydrogenated over Wilkinson's catalyst 15 at 65 atmospheres for 4$ hours.
The mixture was ~vaporated to dryness and purified by ~lash chromatography (Merck 9385 silical gel) eluting with ethyl acetate/60-80 petrol ether (1:3) to give the ester as a colourless powder (4.83g).
20 7. Alternative routes to benzeneethanamines a) 2-~2-l3~-Dimethoxyphenyl1ethyll-3.4-dimethoxy benzaldehyde A solution of the intermediate alcohol 3Ba) (13.3g) in dry dichloromethane containing activated manganese dioxide : 25 (60g): was vigorously stirred at 20 for 2 -`` 12~
hours. The suspension was filtered and the filtrate evaporated to give 13.2g of the aldehyde as a white solid, ~p 88-89O.
Similarly prepared was:
2-[2-[3,4-dimethoxyphenyl]ethyl]-3,4-dimethoxy-benzaldehyde, ms m/e 330.
3-[2- r 3.5-Dimethoxy~henyl]ethyll-1 2-dimethoxy-4-r E~2-nitroethenyllbenzene A solution of the aldehyde 7a) (10.8g) in n-butylamine 10 (15ml) was heated at 110 for 2 hours. The solution was evaporated, dissolved in ether, dried (MgSO4), filtered and evaporated to give 12.lg of the butylimine as a solid, mp 67-68.
A solution of the imine (12.1g) and nitromethane (4ml) 15 in glacial acetic acid was heated at 100 for 4 hours. The solution was evaporated and the residue dissolved in ethyl acetate. The organic solution was washed with brine, dried (MgSO4), filtered and evaporated. Crytallisation from isopropanol gave 10.8g of the nitrostyrene as yellow 20 priSmS, mp 110~112O
Similarly prepared was:
b.1) 3-[2-[3,4-Dimethoxyphenyl~ethyl]-1,2-dimethoxy-4-tE-2-nitroethenyl]benzene, mp 95-96.
Reduction ~ Mathod A:
25 c)~ 2-r2-[3.5-Dimethoxyphenyllethyll-3.4-'~
dimethoxybenzeneethanamine A lM solution of lithium aluminium hydride in tetrahydrofuran (60ml) was added dropwise to a stirred solution of the nitro compound b) (3.7g) in dry tetrahydrofuran under a nitrogen atmosphere. The solution was stirred at 20 for 24 hours. The cooled solution was treated with 2N sodium hydroxide solution until precipitation was complete. The solid mass was extracted with warm ethyl acetate. The organic solution was dried (MsS04), filtered and evaporated to leave a yellow oil.
Trituration with ethereal hydrogen chloride gave a pink solid (2.6g).
This was ~purified by reverse phase semi preparitive ~y~lRMAY~
HPLC (~ 60A SiO2 column) eluting with water with 15 0.1% trifluoroacetic acid/methanol (50:50). Evaporation of the relevant fractions gave an oil which was basified with 10~ sodium hydroxide solution and extracted into ethyl acetate. The organic solution was dried (MgS04), eiltered and evaporated to leave a colourless oil.
20 Tritu~ation with ethereal hydrogen chloride gave a solid which crystallised from isopropanol to give 1.35g of the sub-title compound as the hydrochloride salt, mp 179-180.
Reduction - Method B:
_. .
25 d) 2-~2-~3,4 Dimethoxyphenyl]ethyl]-3,4-k:
, -` ~2~2i~39 dimethoxyben2eneethanamine Sodium borohydride (2.8g) was added portionwise over10 minutes to a stirred suspension of the nitrostyrene b.l) (5.6g) and silica gel (Fluka* 60) (28g) in chloroform (200ml) and isopropanol (50ml). The suspension was stirred at 20 for 16 hours. The silica gel was removed by filtration and the solvent evaporated to dryness to give the intermediate nitroethane as a pale yellow oil.
A sQlution of the oil in ethanol (lOOml) was 10 hydrogenated over a platinum oxide catalyst (2Omg) at 3 atmospheres and 45 for 7 days.
The aatalyst was removed by filtration and the filtrate evaporated. Trituration with ethereal hydrogen chloride gave a grey solid. This was purified by reverse 15 phase HPLC (Dynamax 60A SiO2 column) eluting with water with 0.1~ trifluoroacetic acid/methanol (55:45).
Evaporation of the relevant fractions gave an oil which was basi~ied with 10% sodium hydroxide solution and extracted into ethyl acetate. The organic solution was dried 20 (MgS04), filtered and evaporated to leave a colourless oil. Tri~uration with ethereal hydrogen chlori~e gave a solid which crystallised from isopropanol to give 1.3g of the sub-title compound as the hydrochloride salt, mp 152-153.
*Trade-mark _ 35 ~ 2 8. Preparation of 3.4-Dimethoxy-2- r 2-L3-methoxyphenyl~
ethyl]-N,N-Di-propylbenzeneethanamine hvdrochloride A mixture of 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]
ethyl]benzeneethanamine hydrochloride (3.5g), potassium 5 carbonate (6.9g), n-propyliodide (3~9ml) in acetonitrile (120ml) was heated at reflux temperatuxe for 4 hours.
The solution was ~ilt~red whilst hot and evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water. The organic solution was dried 10 (MgS04), filtered and evaporated to give an oil which was purified by flash chromatography (Merck 9385 silica gel) eluting with dichloromethane/5% methanol. The relevant fractions were evaporated to give a colourless oil (2.0g).
The oil in ether (20ml) was treated with etAereal hydrogen 15 Chloride. The precipitate was filtered and crystallised from isopropanol (1.9g), mp 159-160.
9. Preparation of 3,4-Dimethoxy-2-[2- r 3-methoxyPhenyl 1 ethyl]-N- r l-methylethYl~benzeneethanamine hydrochloride a~ 3.4-Dimethoxy-2- r 2-~3-methox~henvllethvll 20 benzeneacetlc acid A ~olution of 3,4-Dimethoxy~2-[2-[3-methoxyphenyl]
ethyl]benzeneacetonitr1le (4.9g~ and potassium hydroxide (4.41g) in ethanol (150ml) and water (50ml) was heated under reflux for 18 hours. The mixture was evaporated to b 3 Z9/~ 9 dryness and the residue dissolved in water and extracted with ethyl acetate. The organic solution was washed with brine, dried (MgSO4), filtered and evaporated to leave the sub-title compound as an oil which solidified on trituration with petrol ether (1.72g), mp 77-79.
b) 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethylJ-N-[l-methylethyl]benzeneacetamide _ A solution of the acid from step a) (2.18g) and thionyl chloride (0.96ml) in dry dichloromethane (20ml) was heated at reflux temperature for 5 hours. The solution was evaporated to dryness. A solution of the acid chloride in dry dichloromethane (20ml) was added dropwise to an ice-cold solution of isopropylamine (1.12ml) in dry dichloromethane. The solution was stirred at 20 or 16 hours. The reaction mixture was washed with 2N hydrochloric acid, sodium bicarbonate solution and brine, dried (MgSO4), filtered and evaporated to leave a solid which crystallised from isopropanol to give the sub-title compound as prisms (1.98g), mp 138.5-140.
20 c) 3,4-Dimethoxy-2-[2-~3-methoxyphenyl]ethyl]-N-[l-methylethyl]benzeneathanamine hydrochloride 1 M Borane THF complex (25ml) was added dropwise to a stirred solution of the amide of step b) (1.85g) in dry tetrahydrofuran (50ml) under a nitrogen atmosphere. The 25 solution was heated at reflux temperature ~or 16 hours.
The cooled solution was quenched with methanol (50ml) and evaporated to dryness. The residue was dissolved in methanol (SOml) containing concentrated hydrochloric acid (5ml) and the solution heated under reflux for 3 hours.
Evaporation gave a solid which crystallised from isopropanol to give the title product as prisms (1.77g), mp 185-18~.
B. Examples .
Example _ 4-[2-Aminoethyl]-3-12-[3-hydroxyphenyl]ethyl]-1,2-benzenediol A solution of the product Erom Intermediate 5 (l.lg) in 48% aqueous hydrobromic acid ~15ml) containing hypophosphorous acid (O.lml) under a nitrogen atmosphere lS was heated under reflux for 2.5 hours. Evaporation gave the hydrobromide salt o the title compound as a solid which crystallised from isopropanol/ether as prisms (0.8g), mp 154-1S6.
Example 2 4-[2-Aminoethyl]-3-[2-[3,5-dihydroxyphenyl]ethyl]
1,2-benzenediol A lM solution o boron tribromide in dichloromethane (lSml) was added dropwise to a stirred solution of the benzeneethanamine (lg) in dry dichloromethane (50ml) at 25 -78 under a nitrogen atmosphere. The solution was _ 38 -stirred at 20 for 24 hours. The solution was quenchedwith methanol (50ml) and evaporated to dryness. The residue was triturated with ether to give 0.8g of the title compound as the hydrobromide salt, mp 222-224.
5 Example 3 The following compounds of formula I were prepared by the method o~ Example 1 from the corresponding intermediates:
3.1) 4-~2-Aminoethyl~-3-C2-[4-hvdroxYphenYl~ethyll-1 2-10 benzenediol, as the hydrobromide salt, mp 214-216;
3.2) 4-r2-~minoethyll-3- r 2-Phenxlethvll-1.2-benzenediol, as the hydrobromide salt, mp 176-177;
3.3) 4-[2-Aminoethyll-6-chloro-3- r 2- r 3-hydroxyphenvl1ethvl1-1.2-benzenediol, as the hydrobromide salt, mp 141-143;
15 3-4) 3-r2- r 3-HYdroxyphenyllethyll-4- r 2-~N.N-Di-n-proPYl amino)ethyll-1,2 benzenediol, as the hydrobromide salt, mp 143-144;
3.5) 3-~2-L3-Hydroxyphenvlleth~1]-4- r 2-~N-(l-methylethyl~
amino)ethyl~-1,2-benzenediol, as the hydrohromide salt, mp 20 2l7.5-2190;
3~6) 4- r 2--AminoethYll-5- r 2-[3-hydroxye_enyllethvll-lL2-benzenedio~, as the hydrobromide salt, mp 182 (decomposes);
3.7j 5- r 2-~minoethvl1-3-~2- r 3-hydroxyphenyllethyll-1.2-25 benzenediol, as the hydrobromide salt, mp 146-148~-~' Example 4 The following compounds of formula I were prepared bythe method of Example 2 from the corresponding Intermediates:
5 4.1~ 5-~2-~6- r 2-Aminoethyll-2.3-dihydroxYphenYlleth 1,2 ! 3-benzenetriol, as a hydrobromide, mp 225-227;
4.2) 4-~2-AminoethYl]-3- r 2- r 3~4-dihYdroxyp~Lenyllethvl]-l~2-benzenediol, as a hydrobromide, mp 118-120 (decomposes);
4.3) 4-l2-~minoethyll-3~ 2- r 3-nitrophenyl]ethyll-1 2-10 benzenedioL, as a hydrobromide, mp 217-218;
4.4) N-[3- r 2- r 6-~2-Aminoethyll-2.3-dihydroxyl~henYll ethvllphenYl]methanesulphonamide, as a hydrobromide, mp 189-191;
- ~o -4.5) 4-t2-~minoethyll-6-chloro-3-[2-[4-hYdroxyPhenyl~
ethyll~l,2-benzenediol, as th~ hydrobromide salt, softens 128-130, mp 162-164~ -~ .
The solid was purified by flash chromatography eluting with 60-80 petrol ether/ethyl acetate (10:1) to give the sub-title ester as colourless needles (6.58g), mp 46-49.
15 b) Ethyl 2-bromomethyl-3.~-dimethoxvbenzoate 2~
:
A solution o the ester (stage a) (67.2g), N-bromosuccinimide (57g) and azobisisobutyronitrile (catalytic) in carbontetrachloride (700ml) was heated under reflux under irradiation (60w bulb) for 2 l/2 S hours. The cooled reaction was washed with water.
The organic solution was dried (MgSO4), filtered and evaporated to leave a solid. The solid was purified by flash chromatography (Merck 9385 silica gel) eluting with dichloromethane /60/80 petrol ether (l:l). Evaporation of the required fractions gave a yellow solid (84.1g), ms m/e 302/304.
Similarly prepared was:
b.l) 2-[2-Bromomethyl 3,4-dimethoxyphenyl]-4t5-dihydro-4,4-dimethyloxazole, ms m/e 327/329.
lS c) 6-Ethoxycarbonyl 2,3~dimethoxyphenyl]methyltriphenyl phosphonium bromide A solution of the product of step b) (83.9g) and triphenylphosphine (72.55g) in toluene (500ml) was heated under reflux in a nitrogen atmosphere for 24 hours. The precipitate from the cooled solution was filtered, slurried with ether and stirred for 2 hours. The solid ; was Eiltered and dried (129g), mp 198-200.
Similarly prepared was:
c.l) [6-~4,5-Dihydro-4,4-dimethyloxazole 2-yl~-2,3-~25 dimethoxyphenyl]methyltriphenylphosphonium bromide, ms m/e -~4;28~
510 (cation) Variation A ~ oxazole route Wittia reaction Aa) E-2-[3,4-Dimethoxy-2- r 2~[3-nitrophenyllethenyllphenyl~
4,5-dihydro-4 ~4-dimethyloxazole A solution of the phosphonium bromide from step c.l) (69g) in dry dimethylformamide (300ml) was added dopwise to a suspension of 80% sodium hydride ~3.51g) stirred in dry dimethylformamide (lOOml) at 0 under a nitrogen atmosphere. The mixture was stirred for 30 minutes at 60 lO and a solution of 3-nitrobenzaldehyde (17.7g) in dry dimethylformamide (lOOml) was then added.
The mixture was stirred at 20 for 1 hour then quenched with ice/water.
The solid mass was extracted into ethyl acetate and lS separated. The organic solution was washed with water, dried (MgS04), filtared and evaporated to give a yellow oil which was purified by flash chromatogarphy (Merck 9385 silica gel) eluting with dichloromethane/ethyl acetate (95:5)0 Evaporation of the relevant fractions gave the 20 sub-title compound as pure E isomer (35g), mp 78-80~.
Reduction of nitro qroup Ab) E-3- r 2-~6- r 4.5-Dihydro-4 ~4-dimethyloxazole-2-yll-2,3-dimethoxvPhenyllethenyl]benzeneamine A solution of the nitro intermediate Aa) (32g) in :
~9L28g O ethanol (250ml) was hydrogenated over a platinum oxide catalyst (0.3g) at 2 atmospheres for 2 hours. The catalyst was removed by filtration and the filtrate evaporated to leave a colourless solid (26.5g), ms m/e 352.
Sulphonamide ~ormation and_cleavaqQ of oxazole Ac) E-3,4-Dimethoxy-2- r 2-r3- r methanesulphonyllaminophenyl~
ethenyl~-benzoic acid Methanesulphonylchloride (12.4ml) was added dropwise to a stirred solution of the benzenamine Ab) (26.5g) and lO triethylamine (24ml) in dry dichloromethane (200ml). The solution was stirred at 20 for 1 hour. The solution was washed with water, dried (MgS04), filtered and evaporated to leave 29g of the dimethanesulphonamide intermediate.
A solution of this intermediate in methyliodide (50ml) 15 and dichloromethane (200ml) was heated at reflux temperatura for 2 days. The solution was evaporated and the residue triturated with ether to give 41g of the quaternary salt as a yellow solid, mp 193.
A solution of the quaternary salt in methanol (800ml) 20 and 10% sodium hydroxide solution (160ml) was heated to reflux temperature for 3 hours. The solution was evaporated and acidified~ with 2N hydrochloric acid. The solid precipitate was filtered, washed with water and dried. The solid crystallised from ethanol to give 20.5g .
of the acid as a colourless solid, mp 221-223.
Reduction of double bond Ad) 3,4-Dimethoxy-2- r 2-[3-~methanesulphonyllamino Phenyl~ethyl~benzoic acid 5 A solution of the acid Ac) (8.15g) in lM sodium hydroxide solution (200ml) was hydrogenated over a 10% palladium on charcoal catalyst (2g) at 3 atmospheres and 45 for 18 hours. The catalyst was removed by filtration and the cooled solution acidified with 2N hydrochloric acid. The 10 solid was dissolved in ethyl acetate and separated. The organic solution was washed with water, dried (MgS04), filtered and evaporated to leave a solid. Crystallisation from ethyl acetate/petrol gavP 6.26g of the acid as a colourless powder, mp 187.5-188.5.
15 Variation B - benzoate ester route Wltt.iq reaction Ba) E~Z-~thYl-2- r 2- r 3 5-Dimethoxv~henYllethenyll 3.4-dimethoxY benzoate A l.~M solution of butyl lithium in hexane (55ml) was added 20 dropwise to a stirred suspension of the phosphonium salt (45.2g) from step 6c) in dry tetrahydrofuran (200ml) under a nitrogen atmosphere at 0. The mixture was stirred at 0 for 1 hour and a solution of 3,5-dimethoxybenzaldehyde ; added. The ~ 25 ~ ' .
~9~9 resulting mixture was stirred at 20 for 16 hours.
The mixture was quenched with brine (50ml) and evaporated to dryness. The solid was dissolved in ethyl acetate washed with brine, dried (MgSO4), filtered and evaporated to give a dark oil. The oil was purified by flash chromatography (Merck 9385 silica gel) eluting with dichloromethane/petrol 60/80 (1:1) to give 24g of the intermediate ester as a colourless oil, ms m/e 372.
Similarly prepared were:
Ba.l) E-Ethyl 3,4-Dimethoxy-2-t2-~3,4,5-trimethoxyphenyl]
ethenyl]benzoate, mp 103-104 Ba.2) E/Z-Ethyl 3,4-Dimethoxy-2-[2-t3-nitrophenyl]ethenyl]
benzoate, mp 80-82.
Ba.3) Ethyl 3,4-dimethoxy-5-~2-[3-methoxyphenyl]ethenyl]
lS benzoate, m/e 342.
Reduction of double bond Bb) Ethyl-2-12-[3,5-Dimethoxyphenyl]ethyl]3,4-dimethoxy benzoate A solution of the intermediate ethenyl ester Ba) ~24g) in ethanol (150ml) was hydrogenated over a lQ%
palladium on charcoal catalyst (lg) at atmospheric pressure for 24 hours. The catalyst was removed by filtration and the filtrate evaporated to leave a yellow oil The oil was purified by flash chromotography (Merck 9385 silica gel) eluting with 60/80 petrol ether/10% ethyl ~LZ~4~
~ 31 -acetate to give 20g of the intermediate ester as acolourless oil, ms m/e 374.
Similarly prepared were:
Bb.1) Ethyl 3,4-dimethoxy-2-[2-[3,4,5-trimethoxyphenyl]
5 ethyl]benzoate, ms m/e 440;
Bb.2) 3,4-Dimethoxy-2-[2-[3,4,5-trimethoxyphenyl]ethyl]
benzeneacetonitrile, mp 119.5-120.5;
Bb.3) Ethyl 3,4-dimethoxy-5-[2-[3-methoxyphenyl]ethyl~
benzoate, ms m/e 344.
10 Selective reduction of the double bond of the intermediate Ba.2 Bc) Ethyl-3 4-dimethoxY-2- r 2-~3-nitrophen~llethyllbenzoate A solution of the ethenyl ester Ba.2) (5g) in benzene (lOOml) was hydrogenated over Wilkinson's catalyst 15 at 65 atmospheres for 4$ hours.
The mixture was ~vaporated to dryness and purified by ~lash chromatography (Merck 9385 silical gel) eluting with ethyl acetate/60-80 petrol ether (1:3) to give the ester as a colourless powder (4.83g).
20 7. Alternative routes to benzeneethanamines a) 2-~2-l3~-Dimethoxyphenyl1ethyll-3.4-dimethoxy benzaldehyde A solution of the intermediate alcohol 3Ba) (13.3g) in dry dichloromethane containing activated manganese dioxide : 25 (60g): was vigorously stirred at 20 for 2 -`` 12~
hours. The suspension was filtered and the filtrate evaporated to give 13.2g of the aldehyde as a white solid, ~p 88-89O.
Similarly prepared was:
2-[2-[3,4-dimethoxyphenyl]ethyl]-3,4-dimethoxy-benzaldehyde, ms m/e 330.
3-[2- r 3.5-Dimethoxy~henyl]ethyll-1 2-dimethoxy-4-r E~2-nitroethenyllbenzene A solution of the aldehyde 7a) (10.8g) in n-butylamine 10 (15ml) was heated at 110 for 2 hours. The solution was evaporated, dissolved in ether, dried (MgSO4), filtered and evaporated to give 12.lg of the butylimine as a solid, mp 67-68.
A solution of the imine (12.1g) and nitromethane (4ml) 15 in glacial acetic acid was heated at 100 for 4 hours. The solution was evaporated and the residue dissolved in ethyl acetate. The organic solution was washed with brine, dried (MgSO4), filtered and evaporated. Crytallisation from isopropanol gave 10.8g of the nitrostyrene as yellow 20 priSmS, mp 110~112O
Similarly prepared was:
b.1) 3-[2-[3,4-Dimethoxyphenyl~ethyl]-1,2-dimethoxy-4-tE-2-nitroethenyl]benzene, mp 95-96.
Reduction ~ Mathod A:
25 c)~ 2-r2-[3.5-Dimethoxyphenyllethyll-3.4-'~
dimethoxybenzeneethanamine A lM solution of lithium aluminium hydride in tetrahydrofuran (60ml) was added dropwise to a stirred solution of the nitro compound b) (3.7g) in dry tetrahydrofuran under a nitrogen atmosphere. The solution was stirred at 20 for 24 hours. The cooled solution was treated with 2N sodium hydroxide solution until precipitation was complete. The solid mass was extracted with warm ethyl acetate. The organic solution was dried (MsS04), filtered and evaporated to leave a yellow oil.
Trituration with ethereal hydrogen chloride gave a pink solid (2.6g).
This was ~purified by reverse phase semi preparitive ~y~lRMAY~
HPLC (~ 60A SiO2 column) eluting with water with 15 0.1% trifluoroacetic acid/methanol (50:50). Evaporation of the relevant fractions gave an oil which was basified with 10~ sodium hydroxide solution and extracted into ethyl acetate. The organic solution was dried (MgS04), eiltered and evaporated to leave a colourless oil.
20 Tritu~ation with ethereal hydrogen chloride gave a solid which crystallised from isopropanol to give 1.35g of the sub-title compound as the hydrochloride salt, mp 179-180.
Reduction - Method B:
_. .
25 d) 2-~2-~3,4 Dimethoxyphenyl]ethyl]-3,4-k:
, -` ~2~2i~39 dimethoxyben2eneethanamine Sodium borohydride (2.8g) was added portionwise over10 minutes to a stirred suspension of the nitrostyrene b.l) (5.6g) and silica gel (Fluka* 60) (28g) in chloroform (200ml) and isopropanol (50ml). The suspension was stirred at 20 for 16 hours. The silica gel was removed by filtration and the solvent evaporated to dryness to give the intermediate nitroethane as a pale yellow oil.
A sQlution of the oil in ethanol (lOOml) was 10 hydrogenated over a platinum oxide catalyst (2Omg) at 3 atmospheres and 45 for 7 days.
The aatalyst was removed by filtration and the filtrate evaporated. Trituration with ethereal hydrogen chloride gave a grey solid. This was purified by reverse 15 phase HPLC (Dynamax 60A SiO2 column) eluting with water with 0.1~ trifluoroacetic acid/methanol (55:45).
Evaporation of the relevant fractions gave an oil which was basi~ied with 10% sodium hydroxide solution and extracted into ethyl acetate. The organic solution was dried 20 (MgS04), filtered and evaporated to leave a colourless oil. Tri~uration with ethereal hydrogen chlori~e gave a solid which crystallised from isopropanol to give 1.3g of the sub-title compound as the hydrochloride salt, mp 152-153.
*Trade-mark _ 35 ~ 2 8. Preparation of 3.4-Dimethoxy-2- r 2-L3-methoxyphenyl~
ethyl]-N,N-Di-propylbenzeneethanamine hvdrochloride A mixture of 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]
ethyl]benzeneethanamine hydrochloride (3.5g), potassium 5 carbonate (6.9g), n-propyliodide (3~9ml) in acetonitrile (120ml) was heated at reflux temperatuxe for 4 hours.
The solution was ~ilt~red whilst hot and evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water. The organic solution was dried 10 (MgS04), filtered and evaporated to give an oil which was purified by flash chromatography (Merck 9385 silica gel) eluting with dichloromethane/5% methanol. The relevant fractions were evaporated to give a colourless oil (2.0g).
The oil in ether (20ml) was treated with etAereal hydrogen 15 Chloride. The precipitate was filtered and crystallised from isopropanol (1.9g), mp 159-160.
9. Preparation of 3,4-Dimethoxy-2-[2- r 3-methoxyPhenyl 1 ethyl]-N- r l-methylethYl~benzeneethanamine hydrochloride a~ 3.4-Dimethoxy-2- r 2-~3-methox~henvllethvll 20 benzeneacetlc acid A ~olution of 3,4-Dimethoxy~2-[2-[3-methoxyphenyl]
ethyl]benzeneacetonitr1le (4.9g~ and potassium hydroxide (4.41g) in ethanol (150ml) and water (50ml) was heated under reflux for 18 hours. The mixture was evaporated to b 3 Z9/~ 9 dryness and the residue dissolved in water and extracted with ethyl acetate. The organic solution was washed with brine, dried (MgSO4), filtered and evaporated to leave the sub-title compound as an oil which solidified on trituration with petrol ether (1.72g), mp 77-79.
b) 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethylJ-N-[l-methylethyl]benzeneacetamide _ A solution of the acid from step a) (2.18g) and thionyl chloride (0.96ml) in dry dichloromethane (20ml) was heated at reflux temperature for 5 hours. The solution was evaporated to dryness. A solution of the acid chloride in dry dichloromethane (20ml) was added dropwise to an ice-cold solution of isopropylamine (1.12ml) in dry dichloromethane. The solution was stirred at 20 or 16 hours. The reaction mixture was washed with 2N hydrochloric acid, sodium bicarbonate solution and brine, dried (MgSO4), filtered and evaporated to leave a solid which crystallised from isopropanol to give the sub-title compound as prisms (1.98g), mp 138.5-140.
20 c) 3,4-Dimethoxy-2-[2-~3-methoxyphenyl]ethyl]-N-[l-methylethyl]benzeneathanamine hydrochloride 1 M Borane THF complex (25ml) was added dropwise to a stirred solution of the amide of step b) (1.85g) in dry tetrahydrofuran (50ml) under a nitrogen atmosphere. The 25 solution was heated at reflux temperature ~or 16 hours.
The cooled solution was quenched with methanol (50ml) and evaporated to dryness. The residue was dissolved in methanol (SOml) containing concentrated hydrochloric acid (5ml) and the solution heated under reflux for 3 hours.
Evaporation gave a solid which crystallised from isopropanol to give the title product as prisms (1.77g), mp 185-18~.
B. Examples .
Example _ 4-[2-Aminoethyl]-3-12-[3-hydroxyphenyl]ethyl]-1,2-benzenediol A solution of the product Erom Intermediate 5 (l.lg) in 48% aqueous hydrobromic acid ~15ml) containing hypophosphorous acid (O.lml) under a nitrogen atmosphere lS was heated under reflux for 2.5 hours. Evaporation gave the hydrobromide salt o the title compound as a solid which crystallised from isopropanol/ether as prisms (0.8g), mp 154-1S6.
Example 2 4-[2-Aminoethyl]-3-[2-[3,5-dihydroxyphenyl]ethyl]
1,2-benzenediol A lM solution o boron tribromide in dichloromethane (lSml) was added dropwise to a stirred solution of the benzeneethanamine (lg) in dry dichloromethane (50ml) at 25 -78 under a nitrogen atmosphere. The solution was _ 38 -stirred at 20 for 24 hours. The solution was quenchedwith methanol (50ml) and evaporated to dryness. The residue was triturated with ether to give 0.8g of the title compound as the hydrobromide salt, mp 222-224.
5 Example 3 The following compounds of formula I were prepared by the method o~ Example 1 from the corresponding intermediates:
3.1) 4-~2-Aminoethyl~-3-C2-[4-hvdroxYphenYl~ethyll-1 2-10 benzenediol, as the hydrobromide salt, mp 214-216;
3.2) 4-r2-~minoethyll-3- r 2-Phenxlethvll-1.2-benzenediol, as the hydrobromide salt, mp 176-177;
3.3) 4-[2-Aminoethyll-6-chloro-3- r 2- r 3-hydroxyphenvl1ethvl1-1.2-benzenediol, as the hydrobromide salt, mp 141-143;
15 3-4) 3-r2- r 3-HYdroxyphenyllethyll-4- r 2-~N.N-Di-n-proPYl amino)ethyll-1,2 benzenediol, as the hydrobromide salt, mp 143-144;
3.5) 3-~2-L3-Hydroxyphenvlleth~1]-4- r 2-~N-(l-methylethyl~
amino)ethyl~-1,2-benzenediol, as the hydrohromide salt, mp 20 2l7.5-2190;
3~6) 4- r 2--AminoethYll-5- r 2-[3-hydroxye_enyllethvll-lL2-benzenedio~, as the hydrobromide salt, mp 182 (decomposes);
3.7j 5- r 2-~minoethvl1-3-~2- r 3-hydroxyphenyllethyll-1.2-25 benzenediol, as the hydrobromide salt, mp 146-148~-~' Example 4 The following compounds of formula I were prepared bythe method of Example 2 from the corresponding Intermediates:
5 4.1~ 5-~2-~6- r 2-Aminoethyll-2.3-dihydroxYphenYlleth 1,2 ! 3-benzenetriol, as a hydrobromide, mp 225-227;
4.2) 4-~2-AminoethYl]-3- r 2- r 3~4-dihYdroxyp~Lenyllethvl]-l~2-benzenediol, as a hydrobromide, mp 118-120 (decomposes);
4.3) 4-l2-~minoethyll-3~ 2- r 3-nitrophenyl]ethyll-1 2-10 benzenedioL, as a hydrobromide, mp 217-218;
4.4) N-[3- r 2- r 6-~2-Aminoethyll-2.3-dihydroxyl~henYll ethvllphenYl]methanesulphonamide, as a hydrobromide, mp 189-191;
- ~o -4.5) 4-t2-~minoethyll-6-chloro-3-[2-[4-hYdroxyPhenyl~
ethyll~l,2-benzenediol, as th~ hydrobromide salt, softens 128-130, mp 162-164~ -~ .
Claims (10)
1. Compounds of formula I, I
in which one of R30 and R40 represents a group Ra, Ra and the other of R30 and R40 represents hydrogen or halogen, R50 and R60, which may be the same or different, each independently represent hydrogen or alkyl C1 to C6;
R20, R21 and R22 independently represent hydrogen, alkyl C1 to C6, NHR25, SH, NO2, halogen, CF3, CH2OH or OH, wherein R25 represents hydrogen, alkyl C1 to C6, SO2R26, or alkanoyl C1 to C6 and R26 represents alkyl C1 to C6 or NH2, m represents 2, 3 or 4, and pharmaceutically acceptable slats and solvates thereof.
in which one of R30 and R40 represents a group Ra, Ra and the other of R30 and R40 represents hydrogen or halogen, R50 and R60, which may be the same or different, each independently represent hydrogen or alkyl C1 to C6;
R20, R21 and R22 independently represent hydrogen, alkyl C1 to C6, NHR25, SH, NO2, halogen, CF3, CH2OH or OH, wherein R25 represents hydrogen, alkyl C1 to C6, SO2R26, or alkanoyl C1 to C6 and R26 represents alkyl C1 to C6 or NH2, m represents 2, 3 or 4, and pharmaceutically acceptable slats and solvates thereof.
2. A compound according to claim 1, wherein R30 represents Ra.
3. A compound according to claim 1 or claim 2, wherein R40 represents hydrogen.
4. A compound according to claim 1 or claim 2, wherein R50 represents hydrogen.
5. A compound according to claim 1 or claim 2, wherein R60 represents hydrogen.
6. A compound according to claim 1 or claim 2, wherein at least one of R20, R21 and R22 represents hydroxy.
7. A compound according to claim 1 or claim 2, wherein one of R20, R21 or R22 represents 3-hydroxy.
8. A compound of formula I according to claim 1, which is 4-[2-Aminoethyl]-3-[2-[3-hydroxyphenyl]ethyl]-l,2-benzenediol;
4-[2-Aminoethyl]-3-[2-[3,5-dihydroxyphenyl]ethyl]-1,2-benzenediol;
4-[2-Aminoethyl]-3-[2-[4-hydroxyphenyl]ethyl]-1,2-benzenediol;
4-[2-Aminoethyl]-3-[2-phenylethyl]-1,2-benzenediol;
4-[2-Aminoethyl]-6-chloro-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol;
3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-(N,N-Di-n-propylamino)ethyl]-1,2-benzenediol;
3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[N-(1-methylethyl) amino]ethyl]-1,2-benzenediol;
4-[2-Aminoethyl]-5-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol;
5-[2-Aminoethyl]-3-[3-hydroxyphenyl]ethyl]-1,2-benzenediol;
5-[2-[6-[2-Aminoethyl]-2,3-dihydroxyphenyl]ethyl]-1,2,3-benzenetriol;
4-[2-Aminoethyl]-3-[2-[3,4-dihydroxyphenyl]ethyl]-1,2-benzenediol;
4-[2-Aminoethyl]-3-[2-[3-nitrophenyl]ethyl]-1,2-benzenediol;
N-[3-[2-[6-[2-Aminoethyl]-2,3-dihydroxy]phenyl]ethyl]
phenyl]methanesulphonamide; and 4-[2-Aminoethyl]-6-chloro-3-[2-[4-hydroxyphenyl]ethyl]-1,2-benzenediol;
or a pharmaceutically acceptable salt or solvate thereof.
4-[2-Aminoethyl]-3-[2-[3,5-dihydroxyphenyl]ethyl]-1,2-benzenediol;
4-[2-Aminoethyl]-3-[2-[4-hydroxyphenyl]ethyl]-1,2-benzenediol;
4-[2-Aminoethyl]-3-[2-phenylethyl]-1,2-benzenediol;
4-[2-Aminoethyl]-6-chloro-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol;
3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-(N,N-Di-n-propylamino)ethyl]-1,2-benzenediol;
3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[N-(1-methylethyl) amino]ethyl]-1,2-benzenediol;
4-[2-Aminoethyl]-5-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol;
5-[2-Aminoethyl]-3-[3-hydroxyphenyl]ethyl]-1,2-benzenediol;
5-[2-[6-[2-Aminoethyl]-2,3-dihydroxyphenyl]ethyl]-1,2,3-benzenetriol;
4-[2-Aminoethyl]-3-[2-[3,4-dihydroxyphenyl]ethyl]-1,2-benzenediol;
4-[2-Aminoethyl]-3-[2-[3-nitrophenyl]ethyl]-1,2-benzenediol;
N-[3-[2-[6-[2-Aminoethyl]-2,3-dihydroxy]phenyl]ethyl]
phenyl]methanesulphonamide; and 4-[2-Aminoethyl]-6-chloro-3-[2-[4-hydroxyphenyl]ethyl]-1,2-benzenediol;
or a pharmaceutically acceptable salt or solvate thereof.
9. A pharmaceutical composition comprising a compound according to claim 1, 2 or 8 in admixture with pharmaceutically acceptable adjuvant, diluent or carrier.
10. A process for the preparation of a compound as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof, which includes removing a protecting group from a corresponding compound of formula II, II
in which R30a and R40a have the same significance, respectively, as R30 and R40 as defined in claim 1, save that in addition one of R30a and R40a may represent a group R?1, Ra1 R50a has the same significance as R50 in claim 1, save that in addition it may represent R3a, R60 is as defined in claim 1, R1a, R2a and R3a, which may be the same or different, represent hydrogen or a protecting group, R20a, R21a and R22a respectively, have the same significance as R20, R21 and R22 in claim 1, save that in addition they may represent NR25R27a, SR28a, CH2OR29a or OR31a, wherein R27a, R28a, R29a and R31a which may be the same or different, each represent a protecting group, and R25 and m are as defined above, provided that the compound of formula II bears at least one protecting group, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable salt or solvate thereof, or vice versa.
in which R30a and R40a have the same significance, respectively, as R30 and R40 as defined in claim 1, save that in addition one of R30a and R40a may represent a group R?1, Ra1 R50a has the same significance as R50 in claim 1, save that in addition it may represent R3a, R60 is as defined in claim 1, R1a, R2a and R3a, which may be the same or different, represent hydrogen or a protecting group, R20a, R21a and R22a respectively, have the same significance as R20, R21 and R22 in claim 1, save that in addition they may represent NR25R27a, SR28a, CH2OR29a or OR31a, wherein R27a, R28a, R29a and R31a which may be the same or different, each represent a protecting group, and R25 and m are as defined above, provided that the compound of formula II bears at least one protecting group, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable salt or solvate thereof, or vice versa.
Applications Claiming Priority (16)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB87/11779 | 1987-05-19 | ||
| GB87/11781 | 1987-05-19 | ||
| GB87/11780 | 1987-05-19 | ||
| GB878711779A GB8711779D0 (en) | 1987-05-19 | 1987-05-19 | Compounds |
| GB87/11784 | 1987-05-19 | ||
| GB87/11785 | 1987-05-19 | ||
| GB878711781A GB8711781D0 (en) | 1987-05-19 | 1987-05-19 | Compounds |
| GB878711780A GB8711780D0 (en) | 1987-05-19 | 1987-05-19 | Compounds |
| GB878711785A GB8711785D0 (en) | 1987-05-19 | 1987-05-19 | Compounds |
| GB878711784A GB8711784D0 (en) | 1987-05-19 | 1987-05-19 | Compounds |
| GB878730256A GB8730256D0 (en) | 1987-12-29 | 1987-12-29 | Compounds |
| GB87/30255 | 1987-12-29 | ||
| GB87/30256 | 1987-12-29 | ||
| GB878730255A GB8730255D0 (en) | 1987-12-29 | 1987-12-29 | Compounds |
| GB878730254A GB8730254D0 (en) | 1987-12-29 | 1987-12-29 | Compounds |
| GB87/30254 | 1987-12-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1294289C true CA1294289C (en) | 1992-01-14 |
Family
ID=27571251
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000567118A Expired - Fee Related CA1294289C (en) | 1987-05-19 | 1988-05-18 | Catecholamine derivatives |
Country Status (12)
| Country | Link |
|---|---|
| US (2) | US4922022A (en) |
| EP (2) | EP0292202B1 (en) |
| JP (1) | JPH01503303A (en) |
| AU (1) | AU614749B2 (en) |
| CA (1) | CA1294289C (en) |
| DE (1) | DE3874206D1 (en) |
| FI (1) | FI890207A (en) |
| IL (1) | IL86411A (en) |
| NO (1) | NO890187L (en) |
| NZ (1) | NZ224676A (en) |
| PT (1) | PT87503B (en) |
| WO (1) | WO1988009326A1 (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8811056D0 (en) * | 1988-05-10 | 1988-06-15 | Ici Plc | Antibiotic compounds |
| EP0576567A1 (en) * | 1991-03-20 | 1994-01-05 | North Dakota State University | Compounds with liquid crystalline properties and coating binders based thereon |
| GB2270914A (en) * | 1992-09-14 | 1994-03-30 | Merck & Co Inc | HIV protease inhibitor compounds |
| US5817722A (en) * | 1995-10-10 | 1998-10-06 | Exxon Chemical Patents Inc. | Low viscosity, high solids polyesterdiols and compositions containing same |
| US6211197B1 (en) * | 1998-10-07 | 2001-04-03 | Merck Frosst Canada & Co. | Prostaglandin receptor ligands |
| US20030140920A1 (en) * | 2001-10-26 | 2003-07-31 | Dey L.P. | Albuterol inhalation soultion, system, kit and method for relieving symptoms of pediatric asthma |
| JP2003221335A (en) | 2001-10-26 | 2003-08-05 | Dey Lp | Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptom of chronic obstructive pulmonary disease |
| US20030203930A1 (en) * | 2001-10-26 | 2003-10-30 | Imtiaz Chaudry | Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease |
| US6702997B2 (en) | 2001-10-26 | 2004-03-09 | Dey, L.P. | Albuterol inhalation solution, system, kit and method for relieving symptoms of pediatric asthma |
| FR2872159B1 (en) | 2004-06-28 | 2007-10-05 | Merck Sante Soc Par Actions Si | NOVEL PHENYL CARBOXYLIC ACID DERIVATIVES AND THEIR USE IN THE TREATMENT OF DIABETES |
| WO2012003476A2 (en) * | 2010-07-02 | 2012-01-05 | Ventana Medical Systems, Inc. | Hapten conjugates for target detection |
| EP3558293A4 (en) * | 2016-12-23 | 2020-10-28 | The University of Queensland | Inhibitors of sox18 protein activity for treating angiogenesis- and/or lymphangiogenesis-related diseases |
| CN107382796B (en) * | 2017-08-11 | 2020-10-09 | 浙江华理生物制药有限公司 | CA-4 antineoplastic medicine, synthetic method and application thereof |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3408396A (en) * | 1965-10-22 | 1968-10-29 | Colgate Palmolive Co | alpha-cyclohexyl-3, 4-disubstituted-phenyl acetamides |
| US3789072A (en) * | 1970-04-22 | 1974-01-29 | Squibb & Sons Inc | Carboxamides |
| JPS5059339A (en) * | 1973-09-28 | 1975-05-22 | ||
| DE3263531D1 (en) * | 1981-08-05 | 1985-06-20 | Fisons Plc | Amine derivatives, processes for their production and pharmaceutical compositions containing them |
| EP0142283B1 (en) * | 1983-10-25 | 1991-01-30 | FISONS plc | Phenylethylamines, process for their preparation and compositions containing them |
| US4720586A (en) * | 1983-12-06 | 1988-01-19 | Fisons, Plc | Substituted 3,4-dihydroxy-phenylethylamino compounds |
| DE3428526A1 (en) * | 1984-08-02 | 1986-02-13 | Boehringer Mannheim Gmbh, 6800 Mannheim | NEW AMINO ALCOHOLS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THIS COMPOUND |
| DK17386A (en) * | 1985-01-15 | 1986-07-16 | Glaxo Group Ltd | AMIN DERIVATIVES |
| FI864680A (en) * | 1985-11-20 | 1987-05-21 | Fisons Plc | AROMATIC FOERENINGAR. |
-
1988
- 1988-05-12 JP JP63503852A patent/JPH01503303A/en active Pending
- 1988-05-12 EP EP88304319A patent/EP0292202B1/en not_active Expired - Lifetime
- 1988-05-12 WO PCT/GB1988/000366 patent/WO1988009326A1/en not_active Application Discontinuation
- 1988-05-12 DE DE8888304319T patent/DE3874206D1/en not_active Expired - Lifetime
- 1988-05-12 AU AU17067/88A patent/AU614749B2/en not_active Ceased
- 1988-05-12 EP EP88903910A patent/EP0314725A1/en active Pending
- 1988-05-17 IL IL86411A patent/IL86411A/en unknown
- 1988-05-18 US US07/195,722 patent/US4922022A/en not_active Expired - Fee Related
- 1988-05-18 NZ NZ224676A patent/NZ224676A/en unknown
- 1988-05-18 PT PT87503A patent/PT87503B/en not_active IP Right Cessation
- 1988-05-18 CA CA000567118A patent/CA1294289C/en not_active Expired - Fee Related
-
1989
- 1989-01-16 FI FI890207A patent/FI890207A/en not_active Application Discontinuation
- 1989-01-16 NO NO89890187A patent/NO890187L/en unknown
- 1989-08-02 US US07/388,383 patent/US4939147A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| NO890187D0 (en) | 1989-01-16 |
| US4939147A (en) | 1990-07-03 |
| PT87503A (en) | 1989-05-31 |
| WO1988009326A1 (en) | 1988-12-01 |
| IL86411A (en) | 1992-03-29 |
| AU1706788A (en) | 1988-12-21 |
| US4922022A (en) | 1990-05-01 |
| FI890207A0 (en) | 1989-01-16 |
| FI890207A (en) | 1989-01-16 |
| JPH01503303A (en) | 1989-11-09 |
| NZ224676A (en) | 1991-05-28 |
| AU614749B2 (en) | 1991-09-12 |
| EP0292202B1 (en) | 1992-09-02 |
| NO890187L (en) | 1989-01-16 |
| EP0292202A1 (en) | 1988-11-23 |
| EP0314725A1 (en) | 1989-05-10 |
| IL86411A0 (en) | 1988-11-15 |
| DE3874206D1 (en) | 1992-10-08 |
| PT87503B (en) | 1992-09-30 |
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