CA2134067A1 - Adenosine derivatives having a2 agonist activity - Google Patents

Adenosine derivatives having a2 agonist activity

Info

Publication number
CA2134067A1
CA2134067A1 CA002134067A CA2134067A CA2134067A1 CA 2134067 A1 CA2134067 A1 CA 2134067A1 CA 002134067 A CA002134067 A CA 002134067A CA 2134067 A CA2134067 A CA 2134067A CA 2134067 A1 CA2134067 A1 CA 2134067A1
Authority
CA
Canada
Prior art keywords
compounds
formula
hydrogen
phenyl
compound
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.)
Abandoned
Application number
CA002134067A
Other languages
French (fr)
Inventor
Gloria Cristalli
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme Corp
Original Assignee
Individual
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2134067A1 publication Critical patent/CA2134067A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16Purine radicals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/08Antiepileptics; Anticonvulsants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/20Hypnotics; Sedatives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/08Vasodilators for multiple indications
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives

Abstract

Adenosine derivatives having A2 agonist activity of formula (I), a process for the preparation thereof and pharmaceutical compositions containing them. The compounds of the invention are useful for the treatment of cardiovascular pathologies and nervous system diseases.

Description

213 ~067 WO 93/2~328 PCllEP93/00972 ADENOSINE DERIVATIVES E~VING A AGONIST ACTIVITY

The present invention relates to adenosine deriva-tives having A2 agonist activity and the use thereof in therapy.
P~denosine is known to modulate a number of physio-5 logical functions. At the cardiovascular system level,adenosine is a strong vasodilator and a cardiac depres-sor. On central nerve~us system, adenosine incluces seda-tive, anxiolytic and antiepileptic effects. At the kidney level, it exerts a diphasic action, inducing va-- 10 soconstriction at low concentrations and vasodilatation at high doses. Adenosine acts as a lipolysis inhibitor on fat cells and as an antiaggregant on platelets (Stone ToW~ Purine recep_ors and their pharmacologi~al roles. In: AdYances in drug research. Academic Press Limited, 1989, 18, 291-429; Pro~ress Cardiovasc. Dis.
1989, 32, 73-9~
A number of studies showed adenosine actions are mediated by two subtypes of receptors which are located - - on the cell membrane: an high-affinity one, inhibiting the ac~ivity of the enzyme adenylate cyclase tAl receptor), and a low affinity one, stimulating the - activity of the same enzyme ~A2 receptor). (J. Med.
Chem. 1982, 25, 197-207. Physiol. Rev. 1990, 70(3), ~ 761-845. J. Med. Chem. l9g2, 35, 407-422). Both recep-tors are widely spread in the different systems of the organism. In some tissues, however, only one of said receptors is mainly present. For example, Al receptor is prevailing at the cardiac level, whereas the A2 receptor is present mainly at the vascular level and 213~067 WO 93/22328 P~/EP93/00~,_ on platelets.
Therefore, it is clear that c:ompounds c:apable of , ;
interacting selectively with the A2 recep~or could have an interesting pharmacological pattern. In fact, the vasodilating activity, together with the antiaggre~a-ting action, can lead to useful therapeutical applica-tions in the treatment of severe cardiovascular patho-logies , such as ischemic cardiopathy, hypertension and i atherosclerosis. ~:
Moreover, due to the actions on centra:L nervous system, the use of A2 selective medicaments can be en-visaged in the treatment of cerebrovascular ischemia, epilepsy and various emotional disorders, such as anxiety and psychosis.
The prototypical compound havLng activity on the A2 receptor is adenosine-5'-N-ethylursnamide or NECA
(Mol. Pharmacol., 1986, 25, 331-336~. On the other hand, NECA is also active on the Al receptox and there-fore it lacks selectivity-for the adenosine receptors.
Being the only available compound ha~ing A2 affinity, NECA was used for pharmacological tests for ~he~.~
re~eptor binding. Only recently, the use of NECA as a prototypical A2 agonist has been gradually quit since compounds were found having a certain A2 receptor ~
selectivity. Said compounds are NECA derivatives which .
are substituted at the C2-position with phenyla~n~--~~
groups . For example / compound 2- (p- ( carboxye-thyl)phenylethylamino)-5l -N-ethyluronamide, named CGS
21680 (J. Pharmacol Exp. Ther., 1989, 251, 888-893) has become the reference compound for the pharmacological studies on A2 receptor.

WO 93t22328 2 1 3 1 0 6 7 PCl ~EP93/00972 Purlne derivatives having a selective A2 agonist .
activity are disclosed, for example, in GB-A-2203i49, EP-A-0309112, EP-A-0267878, EP-A-0277917, EP-A-0323807.
Particularly, substitution at the 2-position of 5the purine group has been considered promising to give -~
the desired selectivity ( J . Med. Chem. lg92, 3 5, 4û7-4 ~ 2 ) .
2-Alkynylpurine derivati~res have been disclosed in -EP--A-0219876 .
10Now it has been found that 2-alkynylade!nosine de- -rivati~es substituted at the e~hyne position with aryl, ~-heterocyclic or hydrs:~xyalkyl groups and in which the j .
riboside residue is substituted by the Nalkyl- (or cy-cloalkyl)-uronamido, have s~lrprisingly advantageous 15properties compared with the known compounds. i ~
The compounds of the invention have the following ..
general formula:

N~N

~l--C_C f~N~N~
-:

where in 30 R is hydrogen, Cl-C6 alkyl, C3-C7 cSrcloalkyl, phenyl C1-C3 alkyl;

213 ~05~
W093~2232~ PCT/EP93/00~,~

Rl has one of the following meanings:
a~ phenyl or naphthyl optionally substituted with one t to three halogen atoms (chlorine, fluorine and . bromine), Cl-C~ alkyl, Cl-C6 haloalkyl, Cl-C6 alkoxy, Cl-C6 haloalkoxy, C2-C6 alkoxy~arbonyl, C2-C6 alkoxyalkyl, Cl-C6 alkylthio, thio, CHO, cyanomethyl, nitro, cyano, hydroxy, carboxy, C2-C6 acyl, amino, Cl-C3 monoalkylamino, C2-C~ dialkyla-mino, me ~hylenedioxy; aminocarbonyl;
10 b) a group of formula -(CH2)m-Het wherein m is O or an integer f rom 1 to 3 and Het is S or 6 membered heterocyclic aromatic or non aromatic ring, optionally benzocondensed, containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, linked through a carbon atom or through a nitrogen atom;
C! ) C3-C7 cycloalkyl optionally containing insatura-tions or C2-C4 al~enyl;

d) -(C~2) -C-R2 -I

R2 is hydrogen, methyl or phenyl;
R5 is hydrogen, Cl-C6 linear or branched. alkyl, C5-C6 cycloalXyl or C3-C7 cycloalkenyl, phenyl-Cl-C2-alkyl or _-R2 and R5, taken together, form a 5 or 6-membered -~
carbocyclic ring or R3 is hydrogen and R2 and R4, taken together, form an oxo group or a corresponding acetalic derivative;
when R is different from hydrogen and/or R3 is differe~t from ethyl, Rl can also be Cl-C6 linear or W093/22328 2 13 ~ ~ 6 7 PCT/EW3/00972 - branched alkyl; .
R4 is OH, NH2, dialkylamino, halogen, cyano; -.
n is 0 or 1 to 4;
Within the scope of the definitions ~iven for S formula I, the following meanings are preferred:
- for Cl-C~ alkyl: methyl or ethyl;
- for C3-C7 cycloalkyl: cyclopropyl, cyclopentyl, cyclohexyl or cyclohexenyl;
- for phenyl-Cl-C2 alkyl: benzyl or phenylethyl;
- for C~-C6 haloalkyl: trifluoromethyl;
- for halogen: chlorine;
- for Cl-C6 alkoxy: methoxy or ethoxy; ¦ .
- for Cl-C6 haloalkoxy: trifluoromethoxy or difluo- ! :
romethoxy; ¦ ~
_ for C2-C6 alkoxycarbonyl: methoxycarbonyl or I .
ethoxycar~onyl;
- for C2-C6 alkoxyalkyl: methoxymethyl, methoxyethyl ~ or ethoxymethyl; .
- for Cl-C6 alkylthio: methylthio; :~
- for C2-C6 acyl: acetyl;
- for Cl-C3 monoalkylamino: methylamino, ethylamino, isopropylamino;
- for C2-C~ dialkylamino: dimethylamino, diethyla-~ ~ mino, methylethylamino, methylisopropylamino, dii-sopropylamino;
- _ ~---~~~~-~ - for heterocyclic aromatic or non aromatic ring .
. containing 1 to 3 N, S, O atoms: pyridyl, thienyl, .
- furyl, imidazolyl, ~hiazolyl, pyrazolyl, ~ria-zo lyl O
- for acetalic deri~ative: diethylacetal.
Preferred compounds of formula I are:

2134nG7 i ,. .

1. Compounds in which R is hydrogen;
2. Compounds in which R is C3-C7 cycloalkyl; (R) or (S)-phenylisopropyl;
3. Compounds in which Rl is phenyl or naphthyl optio-nally monosubstituted with one of the substituents in point a3;
4. Compounds in which Rl is phenyl optionally substi-tuted with one of the substituents in point a);
5. Compounds in which Rl is phenyl, 2-, 3- or 4-ni-trophenyl, 2-, 3- or 4-aminophenyl, 2-, 3- or 4-methyl-phenyl, 2-, 3- or 4-acetylphenyl, 4-cyanomethylphenyl, 4-formylphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2 ~
3- or 4-fluorophenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3-or 4-carbomethoxyphenyl, 2-, 3- or 4-carbethoxyphenyl;
6. Compounds in which Rl is cyclohexyl or l-cy-clohexenyl;
7. Compounds in which Rl is 2-thienyl, 2-pyridyl, 4-pyridyl, 4-pyrazolyl,_2-furyl, 3-furyl, 2-thiazolyl, 1-imidazolyl-methyl, l-triazolylmethyl.
Rs 8. Compounds in which Rl is -(CH2)n-C-R2 group wherein R2 is hydrogen or methyl, R5 i5 hydrogen or Cl-C6 alkyl, R4 is hydroxy or amino.
9. Compounds in which R is hydrogen and Rl has the meanings according to points 2-7 above.
The claimed compounds can be used as anhydrous bases, solvates or pharmaceutically acceptable acid salts.
Compounds I can be prepared according to the 213 1057 ` ' ~
WO 93/22328 P~EP93/00972 ; ~:

following general schemes ~
Scheme ~R' . ~:
,1~ ::
N ~ ~ N ~ ~

y~ ~J~ ' .''.
+ Ri-C--C-H . ~. I
III ~:
R3NHCO II ~.

~ i ,~:

Scheme II i ~::

~' - I

N~,N
~i--X + i 11 11 ' ~ . ., IY~C _ C~Nf~lN~

R3N~ - -- ~ ~ V' ' .

~ .- i -' In schemes I and II, R' and~-R'i`~have the same meanings as R ~nd Rl or they are groups whi~h can be converted into R and Rl, respecti-~rely, for example by removing any protecting groups which can be present in 30 R' and R'1 compatible with the reaction conditions; Y
is Br or I and X is chlorine, bromine or iodine.

213~0~7 ``
WO 93/223~8 PCl/EP93/009,_ Preferably Y is iodine and X is bromine or iodine.
The reactions reported in schemes I and II are carried out in the presence of -atalysts (for example:
bis (triphenylphosphine) palladium dichloride and a 5 cupro~s halide) and of a suitable acid-binding agent, such as an organic base ( for example: triethylamine, diisopropylethylamine or pyridine ) ~
As the solvent, a substituted amide (such as di-methylfonnamide), an ether (such as dioxane or tetrahy-10 drofuran), acetonitrile or optionally a mixture of twoor more of said solvents, are preferably used.
The compounds of formula II, in which Y is iodine and R ' is hydrogen, can be prepared from 2-iodioadeno-sine t Synthesis, 1982, 670-672 ~ according to the following scheme III

.
.
. .

2~3 S067 WO 93/22328 PCI /EP93/0û972 ~Z E~ z ~z o~O

-- S . , j T ¦

Z~ Z~ :
Z~z ~oX Z~Zo~S

1 ~ --- Z

a ¦

Z~ X

-- S

o,~ .

U ~ - _ Z~ _ E ~ .
-kZ /`r-= 'q z~ L~
_ S

2134067` ` `
WO 93/22328 PCI`/EP93/009,_ The compounds of formula II, in which Y is iodine and R ' is different from hydrogen can be prepared ac: cording to the fol lowing Scheme IV
Sche~e nir I J~Ji C2R3NHC~ C2R3NHC~
H 0~ H H
¦H2 11 HN--R ~N_R

R1--C_C N N ( ) 7 C2R3NHC~ ~ J C2R3NHC~

H9 OH ` -- H Oll lo) ' lPh3~)P~U2; ~ul; Et3~

,. . .

213~067'''"' '` , ;:~
W093/22328 PCT/~P93/00972 In the abo~e scheme IV, R, ~1 and R3 are as above defined.
The compounds of formula VI are novel and they are a further object of the inventiont as intermediates.
The compounds of formula V are prepared by reaction of compounds II with an acetylene deriva~ive, for example l-trimethylsilylethynyle, under the condi-tions reported for the reaction between compounds II
and III. Compounds V æ e novel and they are a ~urther objezt of the invention, as inte~-.~diates.
Compounds III and IV are known or they can be prepared according to well~known methods.
Compounds I ha~e a strong A2 agonist seleeti~ity and therefore they are useful for ~he trea~ment of car-diovascular pathologies such as cardiac ischemia, hy-pertension and atherosclerosis and of diseases of cen-tral nervous system such as cerebrovascular ischemia, - epilepsy and emotional disorders ~~anxlety and psychosis).
Pharmacological activ~y - The pharmacological properties of -~the disclosed compounds can be shown in the most suitable experimen-tal models both in vitro and ln ivo.
Adenosine A2 receptor affinity was tested by means of receptor binding techniques on rat (Wistar strain) brain striatum, which is a tissue rich--rn~-A2~receptors.
- Compound 3R-CGS 21680 (J. Pharm~ Exp. Ther. 1 989, 251, 888-893 ) was used as the radioligand.-The Al receptor affini~y was tested with receptor 30 binding techniques on rat (Wistar strain) cerebellar cort ex membranes, which are tis sues rich in Al recep-213~0~7 - `
.. . .
W093/2~28 PCT~EP93/OOg,, tors. 3H-Cyclohexyl-adenosine, 3H-CHA (Proc. Natl.
Acad. Sci. - USA - 1980, 77, t;547-5551) was used as the radioligand. The affinity for the Al or A2 receptor shown by each compound was compared to evaluate selec-5 tiv ity for the A2 receptor. A number of experimentalproofs evidence a marked relationship between the affinity found with binding technic~es in brain tissues and the physiological effects moclulated by adenosine receptors.
10In order to ~aluate the functional response of specific tissues to the disclosed compounds, the isolated organs models were used. Particularly, the va-sodilatation response, which is modulated by A2 receptors~ was studied to the tested compounds (Eur. J.
15Pharmacol 1990, 176, 207-212) on rat aorta in which a contraction had been induced by a prostaglandin compound ~PGF2~)o Any chronotropic negative effects of the various compounds (Br. J. Pharmacol 1983, 78, 207-212) were tested on ra~ isolated heart atria, whose rate is known to be modulated by Al receptors. From the compariso~ of the~activities shown by each compound for the functional responses of the A2 type (vasodilata-tion) or the Al type (reduction in the heart rate), the potential anti-ischemic and antihypertensive activities of the tested compounds can be evaluated, as well as the absence o~f~ undesired effects on the heart rate.
-In order to e~aluate the potential anti-athero-sclerosis and anti-ischemic activities, the inhibiting effect of various compounds on platelet aggregation induced by aggregation agents such as adenosine dipho-sphate ~A~P) (J. Physiol. 1963, 168, 178-195) was 21~4067 W093/2~28 PCT/EP93/00972 studied. The test is particularl~ important as only the A2 receptor is present on the platelet cell mem~rane.
The in vivo activity was evaluated in Swiss mice and spontaneously hypertensive rats (SHR). The behaviour response to a treatment with various doses of the tested compounds administered parenterally was eva-luated. To test the antiepileptic action, the property of the no~el compounds ~o antagonize the convulsions ¦
induced by pentylenetetrazole was evaluated in the mouse.
The antihypertensive activity was tested measuring the systolic arterial pressure by means of the "tail~
cuff" techni~ue (Arch. Int. Pharmacodyn., 1987, 286, 546-2~4~ in SHR rats conditioned to the experimental environment.
The tested compounds were administered parente-rally at incraasing doses and arterial pressure and heart ~at-e were measured at various times from the tre- j atment.
The compounds of formula I showed a marked A2 affinity with ~i ranging from 7 to 200 nM. The A2=-se-lecti~ity fo~ some compounds is higher th~n lO0 and anyhow it turned out to be markedly higher than that of the prototypical compound NECA. In the platelet aggre-gation test, said compounds proved to be effective anti-platelet aggregation agents, with IC50s of 0-,1-10 pM. The vasodilatation activity is clear, as evidenced by ED50s of 0,1-10 ~M, whereas the same concentrations did not change the he æt rate of isolated atria. In the ln vivo models, the tested compounds showed a depres-sing activity on central nervous system, they antagoni-213~0S7 W093t2~28 ~ PCTJEP93/009,_ zed the convulsions induced by pentylenetetrazole and reduced the ar erial pressure without changing signifi-cantly the heart rate. The colnpounds turned out to be active at doses from 0.001 to 3 mg/kg intraperîtoneally.
For the envisaged therapeuti~al uses, compounds I
will be formulated as suitable pharmaceu~ical compositions, which can ~e admini2itered, for example, by the oral or parenteral routes, using known techni-ques and excipients, as described for çxample in Remington's Pharmaceutical Sciences Handbook, Mack Pub.
Co., NY, USA, XVII ed. The daily dosage will depend, of - course, on many factors (severity of the pathology to treat, patient conditions, toxicology and pharmacokine-tic of the selected compound) but generally it will range from 0,01 to 10 ~g/kg of body weight, preferably from 0,1 to 1 mg/kg, optionally subdivided in more ad-ministrations. Examples of pharmaceutical compositions ~omprise capsules, tablets, solutions, syrups, vials, controlled-release forms and the like.
- The following example--s illustrate the invention.
- . EXAMP~E_1 N-e~hyl-l'-deoxy-l'-(6-amino-2-iodo-9H-purin-9-yl)-B-D-ribofuranuronamide.
a) A solution of 2 g (5.08 mmoles) of 2-iodoadenosine in 100 ml of acetone:-was~-added with 9.6 g of p-tolue-nesulfonic a~id. The reaction mixture was stirred at room temperature for 1 h, then, after addition of 15 g of NaHC03, it was stirred again for 3 h. The solid was removed and washed 2 times with ethyl acetate and the filtrate was concentrated to dryness. The residue was I

213~067 WO 93/22328 PC~/EP93tO0972 flash chromatographed on a siiica gel column eluting with CHC13-MeOH (99:1) to give. 1.62 g (74%) of 6-amino-2-iodo-9- ( 2 ', 3 ' -O-isopropylidelle-B-D-ribofuranosyl 3 9H-purine as a solid:
m.p. ~ 85-187C;
H NMR (Me2SO-d6) ~i 1.33 and 1.54 (s, 3EI each, CtCH3)2, 3.53 (m, 2H, CH2-5'), 4.19 (m, 1~l, H-4'), 5.07 (t, lH, OH), 4.93 (m, lH, H-3'), 5.27 (r.t, lH, EI-2'~, 6.05 (d, J=2.5 Hz, lH, H-l' ), 7.76 (s, 2H, NH2), 8.28 (s, lH, 8 ) . Anal . (cl3Hl6INso4 ) C~
b ) A stirred solution of 1. 6 g ( 3 . 7 mmoles ) of the product obtained in a) in 200 ml of H20 was added with I;
O . 60 g of E~OH and, dropwise, with a solution of 1. 70 g ( 10 . 8 ~oles ) of K~nO4 in 50 ml of H20. The mixture was lef~ aside in the dark at room temperature for 20 h. j The reaction mixture was cooled ~o 5-10 C and then de-colorized with a solution of 4 ml of 30% H202 in 16 ml of w~ter, keepi~g the temperattLre under 10C with an ice-salt ba h. The mixture was filtered through Celite and the filtrate was concentrated under vacuum to about 15 ml and then acidified to p~ 4 con 2N ~Cl. T~e~-~esul- ~;
ting precipitate was filtered, and subsequently washed with water, acetone and ether to give 1.25 g (76%) of l'-deoxy~ (6-amino-2-iodo-9H-purin-9-yl)-2',3'-0-iso-propylidene-~-D-ribofuranuronic acid as a white solid: ¦
m.p. 187-190C; ~-~~
IR ~ max 1590, 1640 cm 1 (C~OR); 1~ NMR (Me2SO-d6) 1.33 and 1.49 (s, 3H each, C(CII3~2, 4.64 (s-, lH, H-4'), 5.35 (d, J3, 2,-5.6 Hz, lH, Ho31 ), 5.41 (d~ 32' 3,.5"6 Hz, lH, H-2' ), 6.23 (s, lH, H-l' ), 7.53 (s, lH, COO~I), 7.67 (s, 2H, NH2), 8.17 (s, lH, H-8). Anal.

2 1 3 ~ o 6 7 W093/2~2~ PCT/EP93/009,~

; ~. I .

( 13H14IN505) C, H, ~
c) A solution of 1.72 g (3.85 mmoles) of the product obtained in b) in 80 ml of 50% formic acid was stirr~d at 80C for 1.5 h. The reaction mixture was evaporated under vacuum and the residue was dissolved in water, and the solution was evaporated. This process was repeated several times, until there was no more odor of formic acid in the re si due . Re~rystallization f rom water yielded 1.33 g (85%) of 1'-deoxy-1'-(6-amino-2-iodo-9H-purin-9-yl)-B-D-ribofuranuronic acid as a white solid:
m.p. 217-220C (dec.) NMR (Me2SO_d6) ~ 4.28 (m, lH, H-3'), 4.41 td, J-2-1 ~z, lH, H-4'), 4.81 (m, lH, H-2'), 5.95 (d, J=6.7 ~z, 1~, H-l'), 7.78 (s, 2H, N~2), 8.38 (s, lH, H-8), 12.98 (br s, 1~, COOH). Anal. (CloHloIN505) C, ~, N-d) A cooled (5~C) and stirred solution of 1.29 g (3.17 - mmoles) of the product obtained in c) in 150 ml of absolute ethanol was added dropwise with 1.15 ml of ice cooled SOC12. The mixture was stirred at room tem-- perature overnight and ~hen~- brought to pH 8 with saturated aqueous sodium bicarbonate. The mixture was filtered and the filtrate was concentrated under ~acuum. The recrystallization ~f the residue from water-ethanol (1:1) gave 900 mg (65%) of ethyl 1' -de-oxy~ ( 6-amino-2-iodo-9~-purin-g-yl ) -B-D-ribofuranu-ronate as a white solid:
m.p. 221-223C (dec. ) -IR ~ max 1728 cm 1 ~COOEt ), H NMR ~Me2St)-D6 ) S 1 . 21 (t, 3H, -C~2CH,), 4.18 (q, 2H, -CH2CR3), 4.34 (m, 1~, H-3'), 4.47 (s, lH, H-4'), 4.58 (m, lR, H-2~), 5.g6 (d, W093/2~28 213 I ~ fi 7 PCT/EP93/00972 J=6.7 Hz, lH, H-l'), 7~74 (s, 2H, NH2), 8.33 (s, lH, H-8). Anal. (C12H14IN505) C, H, ~
e) A mixtur~ of 620 mg of th.e product obtained in the ~:.
step d) and 18 ml of dry ethylamine was stirred at -20C for 3 h and then at room temperature overnight.
The reaction mixture was diluted with absolute ethanol and the precipitated product wa~; filtered and washed wi~h dry ether to give 530 mg (85~) of N-ethyl~
deoxy~ ( 6-amino-2-iodo-9E~-puri~l-9-yl ) -B-D-ri~ofura-nuronamide as a pure solid: .
m~p . 232-234 C
IR ~ max 1637 , 1560 cm 1 (C=O, amide); lH NMR (Me;~S0-d~) ~ 1.06 (t, 3H, -CH2CH3), 3.28 (m, 2EI, -CH2CH3), 4.16 (m, lH, H-3'), 4.31 (d, J=2,1 ~z, lH, H-4~), 4.58 (m, lH, H-2' ), 5.91 (d, lH, J=7.3 ~z, EE-l' ), 7.79 (s, 2H, NH2), 8.15 (t, l~I, NH), 8.40 (s, lH, H-8). Anal.
t C12H15IN64 ) C, H, r - X2~L15 2 A solution of 2 50 mg ( Q .~ 8 mmole ) of the product of 20 Example 1 .in 10 ml of dry acetonitrile, 5 ml of DMF and 2.5 ml of triethylamine under nitrogen was added with ~ -8.1 mg (0.0115 mmole) of bis(triphenylphosphi-ne) palladium dichloride and O.58 mg (O~003 mmole) of cuprous iodide. The mixture was added with 2.9 mmoles -of phenylacetylene and the reaction mixture was stirred iunder nitrog~n atmosphere at room temperature for 2 h.~
- The sol~ent was evaporated off under ~acuum and the residue was chromatographed on a sili~a gel colum~, eluting with a chloroform-benzene-methanol 78:10 :12 30 mixture, to give N-ethyl-l~-deoxy-1~-(6-amino-2-phenylethynyl-9H-purin-9-yl)-B-D-ribofuranuronamide 213 ilOS7 W093/22328 PCT/EP93/00~, J

~ 18 ( yield: 60%):
m.p. 175-178C (dec) H NMR (Me2SO-d6~ 02 (t, 3H, -CH2CH3), 3.2~ (m, 2H, -CH CH ), 4.15 (m, lH, H-3~ ), 4.31 (d, J=1~2 Hz, lH, H-4 ' ), 4.62 (m, lH, H-2 ' ), 5.97 ~ , J=7.5 HZ, H-l ' ), 7.58 td, J=7.8 Hz, 2H, H-Ph), 7.46 (m, 2H, H-Ph), 7.66 (s, 2H, NH2), 8.49 (s, lH, H - 8), 8.60 (t, lH, N~
Anal. (C20H20N604 H20) EXAMPL~S 3 - 35 .
By the same method of Example 2, the following compounds I, wherein R3 is ethyl and R is hydrogen, were prepared.
___ _ _ __ __ _____________ _____ ____ __________ _ _______ _____ Ex. Rl m.p. ( C) Yield Reaction lS (%) time (h) _______ ________ ____ _ ____ _______________ ___ ___ __________ , 3 4-NO2-Ph 180-183 ( dec) 80 4 - 4 4-NH2-Ph 225-~228 (dec) 60 4 4-NH2-CO-Ph 240-243 (dec) 55 16 6 4-CH3-~h 210-213 (dec) 50 3 7 4-CHO-Ph 210-213 ( dec ) - - 80 6 8 4-CH3-CO-Ph 185-188 (de~) 60 20 9 4-CNC~2~ 230-232 (dec) 55 20 ~ 225-228 (dec) 45 20 ~ . _ I
11 -C-Ph 203-205 (dec) 75 20 O~
12 HO(CH2)4 245-247 69 24 ___ ___ _ _ __ _ _____ _ _______ ___ _ __ __ ____ ___ _ _ ____ __ ___ __ ___ 213~067 W093~22328 PCT/EP93/00g72 _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ , _ _ _ _ _ _ _ _ _ _ _ _ . _ _ _ _ _ _ _ _ _ Ex. Rlm.p. (C) Yield Reaction `-(%) time (h) _________________ _____~_____________________________ 13 ~ 200-203 (~ec) t8 6 ~4 ~ 210-213 ~dec) 75 3 (CH3)3Si 208-211 ~d~c) 95 16 16 (~H2)3C 156-lS~ 52 20 17 (C~2)3CN 131~134 65 48 18 CH2H 173-175 (dec) 52 3 19 -CH ~ 150-152 (dec) 67 20 O~I
CH2CH2OH 245-248 (dec3 79 20 21 -CH-CH3 211-214 (dec) 52 20 OH
22 (CH2~3OH 230-232 57 20 23 CH2~CH-C~3 232-234 (dec) 39 5 .
OH
24 -CH-CH2-CH3 148-150 (dec) 37 5 OH
C 3 IH3 ~
-CH-CH2-CH-CH3 135-137 41 S -- ~:-OH

-----------_______~____________________~_______________ 213~0S7 W093/22328 PCT/EP93/00~,~

__________.____________________.______________ _________ Ex. Rl m.p. (~C) Yield Reaction (%) time (h) _______________________________.________________________ .

29 CH2CH2N 227-230 (d,ec) 61 20 -C=CH~ 175-177 ~dec) 65 20 1 ,~
C~3 C~O
31 ~ 164-165 tdec) 50 36 !-32 -C~ 184-187 56 ~8 C2~5 33 ~ -C~2- 124~126 53 4 34 ~ -C~2-CH2- 143-145 ~~ 53 16 ~ -(CH2)3- 128-130 .~ ~3 16 Anal. (CHN) and lH-NMR in agreement with the gi~en formulas. - - -EXAMPL~ 36 a) N-ethyl-l'-deoxy~ 6-amino-2-~hynyl-9$-purin-9-yl ~-B-D-ribofuranuronamide . ~ ~
1.6 mg (3.96 mmoles) of the product obtained in ~
Example 15 in 30 ml of methanol were added with ~:
0 . 32 g of ROH in 10 ml of methanol. The reaction ;
mixture was stirred at room temperature for 1 h W093/2~28 PCT/EP93/00972 -and then the solvent was r~moved under vacuum. The residue was partitioned between ethyl acetate and water and the com~ined organic layers were dried (Na2S04) and e~aporated to give 1.0 g ~81%) of the title compound as a chromatographically pure solid:
m.p.: 245-248C (dec) H NMR ~Me~S0-d6) ~ 1.04 '~t, 3~, -CH2CH3), 3.26 (m, 2H, -CH2CH3), 4.10 (s, lH, -C=C~), 4.12 (m, lH, H-3'), 4.29 (d, J=1.5, lH, H-4'~, 4.55 (m, lH, ~-2'), 5.92 (d, lH, J=7.5 Hz, H-l'), 7.S2 (s, 2H, ~1 NH2), 8.46 (s, lH, H-8), 8.63 (t, lH, NH). Anal.
(Cl4Hl6N604 ~2~ C, H, N.
b) N-ethyl~ deoxy-1'-{6-amino-2-(4-trifl~orome-thyl)phenylJethynyl-9h-purin-9-yl}-B-D-ribofura~
nuronæmide.
A solution of 200 mg (O.66 mmole) of the compound of step a) in ~0 ml of dry acetonitrile, 5 ml of DMF and 2.6 ml of triethylamine under nitrogen a'cmosphere, was added with 9 . 24 Tn~ ( O . 013 mmole) :1 of bis(triphenylphosphine~palladium dichloride and 0.66 mg (0.0035 mmole) of cuprous iodide. The mixture was added with 3.3 mmoles of 4-trifluoromethyl-iodobenzene and the reaction mixture was stirred under nitrogen atmosphere for 1 h at 50C. The sol~ent was evaporated under vacuum and the residue was chromat~graphed on a silica gel column, eluting with chloroform-ben -zene-methanol (80:10:10). The title product was obtained in a 65% yield.
m.p.: 224-227C (dec) ... ... . , ., , . . . -- -213 iO67 ` `
WO 93/22328 PCI'~EP93/004, H NMR (Me2SO-d6) c~ 1.01 ~t, 3H, -CH2CH3), 3.26 ~m, 2H, -CH2CH3), 4.14 (r.t, lH, H-3' ), 4.31 (s, lH, H-4'), 4.61 (m, lH, H-2')1 5.97 (d, lH, J_7.5 Hz, H-l'), 7.71 (s, 2H, NH2), 7.81 (s, 4H, H-Ph), 8.52 S (s, lH, N-8), 8.58 (t, lEI~ NH). Anal.
(C2lHl9F3N6O4 X20) C, ~I, N-EXA~PLES 37- 4 3 , By the same me~hod of Example 3 6 t the following compounds I, wherein R is hyd.~ogen and R3 is ethyl, 10 were prepared.
____________________ _____________________________ ___. , Ex. Rl m.p. ( C) Yield Reaction (~) time ~h) ___________________________ __________________________ 37 _~ 213-215 ( dec: ) 88 20 N
38 ~ 245 248 (dec) 82 16 39 ~3 210-213 (dec) 67 5 ~O~I 200-202 63 ~ - - 16 41 ~F 184-185 ~ dec ) 55 16 42 ~OCH3 151-154 (dec) 49 3 ~ - , ::
- 43 ~> 189-191 23 5 CHO
___________________ __________________________________-- :

213~067 `

~XAMPL~S 4~-46 By reacting the compound of Example ld with an amine selected from:
- cyclopentylamine;
- benzylamine;
- aniline;
at room temperature for 20 ~lours, the following compounds as chromatogra~hically pure o.ils were obtained after the usual work-u~ (solution concentrated to dryness and the residue chromatographed on a silica ~.
ge~ column elu~ing with a suitable mixture of so lvents ): ¦
N-cyclopentyl~ deoxy~ ( 6-~mino-2-iodo-9H-purin-9- ¦
yl ) -B-D-ribo~uranuronamide ( IIa) :-lH NMR (Me2SO-d6 ) ~ 1. 33-1;98 (m, 8H, R-cyclopentyl ), ~-4.06 tm, lEI, ~-cyclopentyl), 4.19 (m, l~i, H-3'), 4.35 ~
(d, lH, J = 2.4 ~z, H--4'), 4.58 ~m, lH, EI--2'), 5.93 (d, rS
lH, J = 6.4 Hz, ~ ), 7.77 (s, 2~, NH2), 8.08 (d, lH, J - 7.5 Hz, N~), 8.50 (5, lH, H-8). Anal. (C15HlgI~6O4) C, H, N.
-- N-benzyl-l'-deoxy~ (6-amino-2-iodo-9H-purin-9-yl)-3-D-ribofuranuronamide t IIb ) H NMR (Me2SO-d6) S 4.22 (m, lH, H-3'), 4.42 (d, lH, J
z 1.5 Hz, H--4'), 4.46 (m, 2~, C~2), 4.59 (sn, l}I, H-2'), 5.94 (d, lH, J = 7.2 Hz, R-l'), 7.28 (m, 5H, H-Ph), 7.81 ~s, 2~, N~2), 8.40 (s, lH, ~-8), 8.74 (t, lH, ~N).
Anal . ( C17H17I~64 ) ' N-phenyl~ deoxy-l ' - ( 6-amino-2-iodo-9H-purin-9-yl ) -~-D-ribof uranuronamide ( IIc ) lH N.~R (Me2SO-d6) ~ 4.35 (m, lH, ~-3'), 4.58 (d, J =
1.5 Hz, lH, H-4'), 4.66 (m, lH, ~-2'), 6.01 (d, lH, J =

21~4057 WO 93/22328 PCT/~P93/OOg, ~

6.6 Hz, H-l~ ), 7.71 (t, 1~, H-PhJ, I.34 (t, 2H, H-Ph), 7.65 (d, 2H, H-Rh), 7.78 ~s, 2~, N~2), 8.52 (s, lH, H-8), 10.16 (s, lH, NH3. Anal. (`'`16H15IN60~) C, H, N-Said compounds were rea::ted with l-hexyne S according to the procedure of Example 2 to give the compounds of formula I reported in the following Table.
_________________________________._____________________ , Ex. R Rl R3 m.p. Yield Reaction ( C) (%) time (h) 1 0~~~~~~_________ ____________~___ r 44 H -(C~233-CEI3 ~ 145-147 48 40 4 5 H - ( CH~ ) 3--CH3 -CH2~ 128 -13 0 3 7 4 0 1546 ~ -tCH ) 3 CH3 --OE) ~ 35 40 _________________________ ___ Anal. -tCHN1 and lH-NMR in agreement with the given formulas. ¦
J3XA~LE J,7 a)- N-ethyl~ deoxy-1'-(2,6-diiodo-9~-purin-9-yl)-B- ~
D-ribofura~uronamide (VI) To 0.5 g (l.16 mmol ) in 10 ml of DMF was added 1.1 ml of isopentyl nitrite and 5 . 6 ml of diiodometane and the mixture was hea~ed at 85C under a N~ L
atmosphere for 2 h. The solvent was removed~under ' pressure (oil pomp) and the residue was chromatographed on a flash silica gel column eluting with a gradient from CRCl3 to C~Cl3-MeO~
(98:2) to give 28S mg (45~) of the title compound as a chromatographically pure oil.

213~0~7 WO 93/2?32X PCT/EP93~00972 H NMR (Me2SO-d6) S 1.04 (t, ~v, CH2CH3), 3.19 (m, 2H, CH2C~I3), 4.28 (m, lH, H-3' ), 4.36 (s, lH, H-4'), 4.70 (m, lH, H-2'), 6.03 ~d, lH, J = 6.4 Hz, H-l' ), 8.15 (t, lH, N}~), 8.98 (s, lH, H-8) . Anal.
(C12H13I2NS4 ) C, H, N.
b ) N-ethyl~ deoxy-1 ' - ( 6-~ycl~?entylamino-2-iodo-9H-purin-9-yl ) B-D-ribofuranuronamide (VII ) To 240 m~ ( O . 44 Imnol ) of N-e!thyl-l ' -deoxy-1 ' - ( 2, 6-diiodo-9H-purin-9-yl ) -B-D-ribofuranuronamide was added 10 ml of cyclope. tylamirle and thle mixture was stirred at rc~om temperature for 4 h. The solution was concentrated to dryness and the residue was ~hromatographed on a sili~a gel column eluting with CHC13-MeOH (96:4) to gIve 160 mg lS (72~) of the title compound as a chromatographically pure oil.
lR NMR (Me2SO-d6) ~ 1.07 (~, 3E~, CH2C~I3), 1.48-2.08 (m, 8H, H-cyclopent~l), 3.23 ~m, 2~, C~2CH3), 4.18 (m, lH, ~-3'~, 4.32 (d, 1~, J = 1.7 Hz, H-4'), 4.44 (m, 1~, H-cyclopentyl), 4.60 (m, 1~, H- i -- 2'), 5.92 (d, lH, J =-7.2 Hz, H-l~), 8.16 (t, lH, NHCH2), 8,29 (d, lH, J ~ 7.7 Hz, N~), 8.41 (s, lH, H-8). Anal. (C17H~3IN6O4) , c) N-ethyl-l'-deoxy-1'-[6-cyclopentylamino-2-(1-hexyn-1-yl)-9H-purin-9-yl~-~-D-ribofuranuronamide (VIII) The title compound was prepared according to Example 2.
Rea~tion time: 15 h.
Chromatographical system: chloroform-methanol (g5:5) 2l3ln67 WO 93/22328 PCI`/EP~3/00~,_ Yiel d: 5 7~, m.p.: 120-122 C.
H NMR (Me2SO-d6) ~ 0.92 (t, 3EI, CH2CH3), 1.08 (t, 3H, NCH2CR3), 1.35-2.07 (m, 12EI, H-cyclopentyl and C~2CH2), 2.44 (m, 2H, CH2C = C), 3~31 (m, 2~, NCH2CH3~, 4.12 (m, lH, H-3'), 4.31 (s, lH, H-4'), 4.60 (m, 2H, H-2t and H-cyclopentylj, 5.94 (d, l~I, J ~ 7.7 ~z, H-l' ), 8.03 (d, lH, NH), 8.43 (s, lH, H 8), 8.75 (t, lH, NHCH2). Anal. (C23'~32N604 ~2O) ~ N-

Claims (12)

1. Compounds of formula I

I

wherein R is hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl C1-C3 alkyl;
R1 has one of the following meanings:
a) phenyl or naphthyl optionally substituted with one to three halogen atoms (chlorine, fluorine and bromine), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkoxycarbonyl, C2-C6 alkoxyalkyl, C1-C6 alkylthio, thio, CHO, cyanomethyl, nitro, cyano, hydroxy, carboxy, C2-C6 acyl, amino, C1-C3 monoalkylamino, C2-C6 dialkyla-mino, methylenedioxy; aminocarbonyl;
b) a group of formula -(CH2)m-Het wherein m is O or an integer from 1 to 3 and Het is 5 or 6 membered heterocyclic aromatic or non aromatic ring, optionally benzocondensed, containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, linked through a carbon atom or through a WO 93/22328 PCT/EP93/009??

nitrogen atom;
c) C3-C7 cycloalkyl optionally containing insatura-tions or C2-C4 alkenyl;

d) R2 is hydrogen, methyl or phenyl;
R5 is hydrogen, C1-C6 linear or branched alkyl, C5-C6 cycloalkyl or C3-C7 cycloalkenyl, phenyl-C1-C2-alkyl or R2 and R5, taken together, form a 5 or 6-membered carbocyclic ring or R5 is hydrogen and R2 and R4, taken together, form an oxo group or a corresponding acetalic derivative;
when R is different from hydrogen and/or R3 is different from ethyl, R1 can also be C1-C6 linear or branched alkyl;
R4 is OH, NH2, dialkylamino halogen, cyano;
n is 0 or 1 to 4.
2. Compounds according to claim 1 in which R is hydrogen or cyclepentyl.
3. Compounds according to claim 1 or 2 in which R1 is phenyl, 2-, 3- or 4-nitrophenyl, 2-, 3- or 4-ami-nophenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4-acetyl-phenyl, 4-cyanomethylphenyl, 4-formylphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-fluorophenyl, 3- or 4-methoxyphenyl, 2-, 3- or 4-carbomethoxyphenyl, 2-, 3- or 4-carbethoxyphenyl, cyclohexyl or 1-cy-clohexenyl, hydroxyphenyl.
4. Compounds according to claim 1 or 2 in which R1 is 2-thienyl, 2-pyridyl, 4-pyridyl, 4-pyrazolyl, 2-furyl, 3-furyl, 2-thiazolyl.
5. Compounds according to claim 1 or 2 in which R1 is a group wherein R2 and R5 are hydrogen and n is an integer 1 to 4 or R2 is phenyl, R5 is hydrogen and n is zero.
6. A compound according to anyone of the preceding claims, wherein R3 is cyclopentyl, benzyl or phenyl.
7. A compound according to claim 6, wherein R1 is n-butyl.
8. A process for the preparation of compounds of formula I which comprises the reaction of a compound of formula II
II

wherein Y is Br or I and R' has the same meanings as or is a group which can be converted into R, with a compound of formula III

WO 93/22328 PCT/EP93/009??

R'1-C??-H III

wherein R'1 has the same meanings as R1 or is a group which can be converted into R1.
9. A process for the preparation of compounds of formula I which comprises the reaction of a compound of formula IV
R'1--X IV
wherein R'1 is as defined in claim 8, with a compound of formula V

V

wherein R' is as defined in the claim 8.
10. Compounds of formula V

V

wherein R' is as defined in claims 8 and 9, as interme-diate compounds.
11. Compounds of formula VI

VI
wherein R3 is as defined in claim 1, as intermediate compound.
12. Pharmaceutical compositions containing a compound of claims 1-7 in admixture with a suitable carrier.
CA002134067A 1992-04-24 1993-04-21 Adenosine derivatives having a2 agonist activity Abandoned CA2134067A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI920973A IT1254915B (en) 1992-04-24 1992-04-24 ADENOSINE DERIVATIVES FOR ACTIVITY A2 AGONIST
ITMI92A000973 1992-04-24

Publications (1)

Publication Number Publication Date
CA2134067A1 true CA2134067A1 (en) 1993-11-11

Family

ID=11363039

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002134067A Abandoned CA2134067A1 (en) 1992-04-24 1993-04-21 Adenosine derivatives having a2 agonist activity

Country Status (9)

Country Link
US (1) US5593975A (en)
EP (1) EP0637315B1 (en)
JP (1) JPH07508718A (en)
AT (1) ATE193299T1 (en)
CA (1) CA2134067A1 (en)
DE (1) DE69328722T2 (en)
ES (1) ES2145774T3 (en)
IT (1) IT1254915B (en)
WO (1) WO1993022328A1 (en)

Families Citing this family (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5646156A (en) * 1994-04-25 1997-07-08 Merck & Co., Inc. Inhibition of eosinophil activation through A3 adenosine receptor antagonism
US6514949B1 (en) 1994-07-11 2003-02-04 University Of Virginia Patent Foundation Method compositions for treating the inflammatory response
US6448235B1 (en) 1994-07-11 2002-09-10 University Of Virginia Patent Foundation Method for treating restenosis with A2A adenosine receptor agonists
YU44900A (en) 1998-01-31 2003-01-31 Glaxo Group Limited 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
US6117878A (en) * 1998-02-24 2000-09-12 University Of Virginia 8-phenyl- or 8-cycloalkyl xanthine antagonists of A2B human adenosine receptors
GB9813540D0 (en) * 1998-06-23 1998-08-19 Glaxo Group Ltd Chemical compounds
JP2002173427A (en) * 1998-09-01 2002-06-21 Yamasa Shoyu Co Ltd Medicine composition for treating eye disease
JP4837831B2 (en) * 1999-02-01 2011-12-14 ユニバーシティ オブ バージニア パテント ファウンデーション Composition for treating inflammatory response
US7427606B2 (en) * 1999-02-01 2008-09-23 University Of Virginia Patent Foundation Method to reduce inflammatory response in transplanted tissue
US6232297B1 (en) 1999-02-01 2001-05-15 University Of Virginia Patent Foundation Methods and compositions for treating inflammatory response
US7378400B2 (en) * 1999-02-01 2008-05-27 University Of Virginia Patent Foundation Method to reduce an inflammatory response from arthritis
US6322771B1 (en) * 1999-06-18 2001-11-27 University Of Virginia Patent Foundation Induction of pharmacological stress with adenosine receptor agonists
US6214807B1 (en) 1999-06-22 2001-04-10 Cv Therapeutics, Inc. C-pyrazole 2A A receptor agonists
USRE47351E1 (en) 1999-06-22 2019-04-16 Gilead Sciences, Inc. 2-(N-pyrazolo)adenosines with application as adenosine A2A receptor agonists
US6403567B1 (en) 1999-06-22 2002-06-11 Cv Therapeutics, Inc. N-pyrazole A2A adenosine receptor agonists
US6180615B1 (en) 1999-06-22 2001-01-30 Cv Therapeutics, Inc. Propargyl phenyl ether A2A receptor agonists
GB0003960D0 (en) * 2000-02-18 2000-04-12 Pfizer Ltd Purine derivatives
CA2439222C (en) * 2000-02-23 2009-07-14 Cv Therapeutics, Inc. Identification of partial agonists of the a2a adenosine receptor
WO2002020539A1 (en) * 2000-09-08 2002-03-14 Toa Eiyo Ltd. Adenosine derivatives and use thereof
US6670334B2 (en) 2001-01-05 2003-12-30 University Of Virginia Patent Foundation Method and compositions for treating the inflammatory response
ES2621652T3 (en) * 2001-01-16 2017-07-04 Vascular Therapies, Inc. Implantable device containing resorbable matrix material and rapamycin to prevent or treat vasculoproliferative diseases
CA2460911C (en) * 2001-10-01 2011-08-30 University Of Virginia Patent Foundation 2-propynyl adenosine analogs having a2a agonist activity and compositions thereof
GB0129273D0 (en) * 2001-12-06 2002-01-23 Pfizer Ltd Crystalline drug form
EP1524984A1 (en) * 2002-07-29 2005-04-27 Cv Therapeutics, Inc. Myocardial perfusion imaging using a2a receptor agonists
US8470801B2 (en) 2002-07-29 2013-06-25 Gilead Sciences, Inc. Myocardial perfusion imaging methods and compositions
US20050020915A1 (en) * 2002-07-29 2005-01-27 Cv Therapeutics, Inc. Myocardial perfusion imaging methods and compositions
US20050033044A1 (en) * 2003-05-19 2005-02-10 Bristol-Myers Squibb Pharma Company Methods for preparing 2-alkynyladenosine derivatives
BRPI0415888A (en) * 2003-10-31 2007-01-09 Cv Therapeutics Inc a2b adenosine receptor antagonists
TWI346109B (en) 2004-04-30 2011-08-01 Otsuka Pharma Co Ltd 4-amino-5-cyanopyrimidine derivatives
WO2006028618A1 (en) 2004-08-02 2006-03-16 University Of Virginia Patent Foundation 2-polycyclic propynyl adenosine analogs with modified 5'-ribose groups having a2a agonist activity
NZ585697A (en) 2004-08-02 2011-12-22 Univ Virginia Patent Found 2-propynyl adenosine analogs with modified 5'-ribose groups having A2A agonist activity
US7442687B2 (en) 2004-08-02 2008-10-28 The University Of Virginia Patent Foundation 2-polycyclic propynyl adenosine analogs having A2A agonist activity
CN101076343A (en) * 2004-10-20 2007-11-21 Cv医药有限公司 Use of A2A adenosine receptor agonists
GT200500281A (en) 2004-10-22 2006-04-24 Novartis Ag ORGANIC COMPOUNDS.
GB0500785D0 (en) 2005-01-14 2005-02-23 Novartis Ag Organic compounds
EP1989214B8 (en) 2006-02-03 2016-12-21 Gilead Sciences, Inc. Process for preparing an a2a-adenosine receptor agonist and its polymorphs
WO2007092936A2 (en) * 2006-02-08 2007-08-16 University Of Virginia Patent Foundation Method to treat gastric lesions
WO2007120972A2 (en) 2006-02-10 2007-10-25 University Of Virginia Patent Foundation Method to treat sickle cell disease
NZ571429A (en) 2006-04-21 2011-09-30 Novartis Ag Purine derivatives for use as adenosine A2A receptor agonists
GB0607950D0 (en) 2006-04-21 2006-05-31 Novartis Ag Organic compounds
US8188063B2 (en) * 2006-06-19 2012-05-29 University Of Virginia Patent Foundation Use of adenosine A2A modulators to treat spinal cord injury
WO2008063712A1 (en) * 2006-06-22 2008-05-29 Cv Therapeutics, Inc. Use of a2a adenosine receptor agonists in the treatment of ischemia
EP1889846A1 (en) 2006-07-13 2008-02-20 Novartis AG Purine derivatives as A2a agonists
US20090081120A1 (en) * 2006-09-01 2009-03-26 Cv Therapeutics, Inc. Methods and Compositions for Increasing Patient Tolerability During Myocardial Imaging Methods
KR20090047499A (en) * 2006-09-01 2009-05-12 씨브이 쎄러퓨틱스, 인코포레이티드 Methods and compositions for increasing patient tolerability during myocardial imaging methods
EP1903044A1 (en) 2006-09-14 2008-03-26 Novartis AG Adenosine Derivatives as A2A Receptor Agonists
CA2663361A1 (en) * 2006-09-29 2008-04-10 Cv Therapeutics, Inc. Methods for myocardial imaging in patients having a history of pulmonary disease
JP2010515081A (en) * 2007-01-03 2010-05-06 ギリアード・パロ・アルト・インコーポレイテッド Myocardial perfusion imaging
US8058259B2 (en) * 2007-12-20 2011-11-15 University Of Virginia Patent Foundation Substituted 4-{3-[6-amino-9-(3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid esters as A2AR agonists
WO2009114533A2 (en) 2008-03-10 2009-09-17 Cornell University Modulation of blood brain barrier permeability
BRPI0918962A2 (en) * 2008-09-29 2015-12-01 Gilead Sciences Inc combinations of a rate control agent and an α-2-alpha receptor antagonist for use in multidetector computed tomography methods
WO2011002917A1 (en) 2009-06-30 2011-01-06 Pgxhealth, Llc Alkoxy-carbonyl-amino-alkynyl-adenosine compounds and derivatives thereof as a2a r agonists
WO2014022577A1 (en) 2012-08-01 2014-02-06 Lewis And Clark Pharmaceuticals, Inc. N-alkyl 2-(disubstituted)alkynyladenosine-5-uronamides as a2a agonists
US9822141B2 (en) 2012-08-01 2017-11-21 Lewis And Clark Pharmaceuticals, Inc. N-alkyl 2-(disubstituted)alkynyladenosine-5-uronamides as A2A agonists

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6299395A (en) * 1985-10-25 1987-05-08 Yamasa Shoyu Co Ltd 2-alkinyladenosine and antihypertensive
IL84414A0 (en) * 1986-11-14 1988-04-29 Ciba Geigy Ag N9-cyclopentyl-substituted adenine derivatives
FI880405A (en) * 1987-02-04 1988-08-05 Ciba Geigy Ag Adenosine-5'-KARBOXAMIDDERIVAT.
LU87181A1 (en) * 1987-04-06 1988-11-17 Sandoz Sa NOVEL DERIVATIVES OF FURANNURONIC ACID, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS
US5034381A (en) * 1988-01-07 1991-07-23 Ciba-Geigy Corporation 2-(substituted amino) adenosines as antihypertensives
ZA902280B (en) * 1989-03-29 1990-12-28 Merrell Dow Pharma Selective adenosine receptor agents

Also Published As

Publication number Publication date
ITMI920973A1 (en) 1993-10-24
US5593975A (en) 1997-01-14
WO1993022328A1 (en) 1993-11-11
ES2145774T3 (en) 2000-07-16
EP0637315A1 (en) 1995-02-08
EP0637315B1 (en) 2000-05-24
DE69328722D1 (en) 2000-06-29
ITMI920973A0 (en) 1992-04-24
ATE193299T1 (en) 2000-06-15
IT1254915B (en) 1995-10-11
DE69328722T2 (en) 2000-12-14
JPH07508718A (en) 1995-09-28

Similar Documents

Publication Publication Date Title
CA2134067A1 (en) Adenosine derivatives having a2 agonist activity
CA2093502C (en) Hydrazoadenosines
US6639059B1 (en) Synthesis of [2.2.1]bicyclo nucleosides
CA1285557C (en) N-6 and 5'-n substituted carboxamidoadenosine derivatives as cardiac vasodilators and antihypertensive agents and process for making said compounds
EP0992510B1 (en) N6 heterocyclic substituted adenosine derivatives
US6734291B2 (en) Synthesis of [2.2.1]bicyclo nucleosides
EP0342203B1 (en) 2',3' dideoxyribofuranoxide derivatives
KR101267202B1 (en) Purine derivatives as adenosine a1 receptor agonists and methods of use thereof
US20040214844A1 (en) N4-acylcytosine nucleosides for treatment of viral infections
WO2012082436A2 (en) Modulators of histone methyltransferase, and methods of use thereof
EP0708781A1 (en) A 3 adenosine receptor agonists
AU2002365234A1 (en) N4-acylcytosine nucleosides for treatment of viral infections
KR100210179B1 (en) A pharmaceutical composition comprising n-heteroaryl-purin-6-amines
Webb et al. Synthesis of 2′, 3′-dideoxyinosine
KR20190029729A (en) S1P1 agonists and their applications
US5013829A (en) Stable congener of 2',3'-dideoxyadenosine
JP3202234B2 (en) New process for producing 2-fluoropurine derivatives
CA2728681A1 (en) Adenine receptor ligands
US5886162A (en) Lipophilic diakylaminomethylene prodrug derivatives for the inhibition of replication of viruses
Dai et al. Synthesis of c-di-GMP analogs modified by ganciclovir and biological activity to induce type I interferon.
CA2145682C (en) 2-substituted adenosines with a-2 receptor affinity
Bhattacharya et al. Studies on the synthesis of furo [3, 2-d] pyrimidine C-nucleosides: new inosine analogues with antiprotozoan activity
CN113024573B (en) Epodophyllotoxin derivative, preparation method and application thereof in preparation of antitumor drugs
Camara et al. Synthesis of L‐Analogues of 1‐(2′, 3′‐Dideoxy‐β‐D‐glycero‐pent‐2‐enofuranosyl) thymine
US5231174A (en) 2'isodideoxy-β-D-nucleosides as stable antiviral agents

Legal Events

Date Code Title Description
EEER Examination request
FZDE Discontinued