WO2001057040A1 - 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds - Google Patents

6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds

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WO2001057040A1
WO2001057040A1 PCT/US2001/003469 US0103469W WO2001057040A1 WO 2001057040 A1 WO2001057040 A1 WO 2001057040A1 US 0103469 W US0103469 W US 0103469W WO 2001057040 A1 WO2001057040 A1 WO 2001057040A1
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amino
pyrido
group
pyrimidine
phenyl
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PCT/US2001/003469
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French (fr)
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Shripad S. Bhagwat
Chih-Hung Lee
Richard J. Perner
Yu-Gui Gu
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Abbott Laboratories
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

Abstract

A compound of formula (I): wherein R?1, R2, R3, R4, and R5¿ are defined, a pharmaceutical composition comprising a therapeutically effective amount of a compound thereof above in combination with a pharmaceutically acceptable carrier, and a method of treating cerebral ischemia, epilepsy, nociception, inflammation and sepsis in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound thereof, a process for preparing said compounds, and compounds having the above formula wherein R?1, R2, R3, R4, and R5¿ are separately defined.

Description

6 -DISUBSTITUTED-4-AMINOPYRIDOr2.3-D1PYRIMIDINE COMPOUNDS

Technical Field

The present invention relates a method for inhibiting adenosine kinase by administering 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds, to pharmaceutical compositions containing such compounds, as well as novel 6,7- disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds.

Background Of The Invention

Adenosine kinase (ATP: adenosine 5'-phosphotransferase, EC 2.7.1.20) is a ubiquitous enzyme which catalyzes the phosphorylation of adenosine to AMP, using ATP, preferentially, as the phosphate source. Adenosine kinase has broad tissue and species distribution, and has been isolated from yeast, a variety of mammalian sources and certain microorganisms. It has been found to be present in virtually every human tissue assayed including kidney, liver, brain, spleen, placenta and pancreas. Adenosine kinase is a key enzyme in the control of the cellular concentrations of adenosine. Adenosine is a purine nucleoside that is an intermediate in the pathways of purine nucleotide degradation and salvage. Adenosine also has many important physiologic effects, many of which are mediated through the activation of specific ectocellular receptors, termed Pi receptors (Burnstock, in Cell Membrane Receptors for Drugs and Hormones, 1978, (Bolis and Straub, eds.) Raven, New York, pp. 107-118; Fredholm, et al., Pharmacol. Rev. 1994, 46: 143-156).

In the central nervous system, adenosine inhibits the release of certain neurotransmitters (Corradetti, et al., Eur. J. Pharmacol. 1984, 104: 19-26), stabilizes membrane potential (Rudolphi, et al., Cerebrovasc. Brain Metab. Rev. 1992, 4: 346-360), functions as an endogenous anticonvulsant (Dragunow, Trends Pharmacol. Sci. 1986, 7: 128-130) and may have a role as an endogenous neuroprotective agent (Rudolphi, et al., Trends Pharmacol. Sci., 1992, 13: 439-445). Adenosine may play a role in several disorders of the central nervous system such as schizophrenia, anxiety, depression and Parkinson's disease. (Williams, M., in Psychopharmacology: The Fourth Generation of Progress; Bloom, Kupfer (eds.), Raven Press, New York, 1995, pp 643-655. Adenosine has also been implicated in modulating transmission in pain pathways in the spinal cord (Sawynok, et al., Br. J. Pharmacol., 1986, 88: 923-930), and in mediating the analgesic effects of morphine (Sweeney, et al., J. Pharmacol. Exp. Ther. 1987, 243: 657-665). In the immune system, adenosine inhibits certain neutrophil functions and exhibits anti-inflammatory effects (Cronstein, J. Appl. Physiol. 1994, 76: 5- 13). An AK inhibitor has been reported to decrease paw swelling in a model of adjuvant arthritis in rats (Firestein, et.al., Arthritis and Rheumatism, 1993, 36, S48.

Adenosine also exerts a variety of effects on the cardiovascular system, including vasodilation, impairment of atrioventricular conduction and endogenous cardioprotection in myocardial ischemia and reperfusion (Mullane and Williams, in Adenosine and

Adenosine Receptors, 1990 (Williams, ed.) Humana Press, New Jersey, pp. 289-334). The widespread actions of adenosine also include effects on the renal, respiratory, gastrointestinal and reproductive systems, as well as on blood cells and adipocytes. Adenosine, via its Al receptor activation on adipocytes, plays a role in diabetes by inhibiting lipolysis [Londos, et al., Proc. Natl. Acad. Sci. USA, 1980, 77, 2551. Endogenous adenosine release appears to have a role as a natural defense mechanism in various pathophysiologic conditions, including cerebral and myocardial ischemia, seizures, pain, inflammation and sepsis. While adenosine is normally present at low levels in the extracellular space, its release is locally enhanced at the site(s) of excessive cellular activity, trauma or metabolic stress. Once in the extracellular space, adenosine activates specific extracellular receptors to elicit a variety of responses which tend to restore cellular function towards normal (Bruns, Nucleosides Nucleotides, 1991, 10: 931-943; Miller and Hsu, J. Neurotrauma, 1992, 9: S563-S577). Adenosine has a half- life measured in seconds in extracellular fluids (Moser, et al., Am. J. Physiol. 1989, 25: C799-C806), and its endogenous actions are therefore highly localized.

The inhibition of adenosine kinase can result in augmentation of the local adenosine concentrations at foci of tissue injury, further enhancing cytoprotection. This effect is likely to be most pronounced at tissue sites where trauma results in increased adenosine production, thereby minimizing systemic toxicities. Pharmacologic compounds directed towards adenosine kinase inhibition provide potentially effective new therapies for disorders benefited by the site- and event-specific potentiation of adenosine. Disorders where such compounds may be useful include ischemic conditions such as cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery (CABG), percutaneous transluminal angioplasty (PTCA), stroke, other thrombotic and embolic conditions, and certain neurological disorders such as epilepsy, anxiety, schizophrenia, nociception including pain perception, neuropathic pain, visceral pain, as well as inflammation, arthritis, sepsis, and certain gastrointestinal disfunctions such as abnormal gastrointestinal motility.

A number of compounds have been reported to inhibit adenosine kinase. The most potent of these include 5'-amino-5'-deoxyadenosine (Miller, et al., J. Biol. Chem. 1979, 254: 2339-2345), 5-iodotubercidin (Wotring and Townsend, Cancer Res. 1979, 39: 3018- 3023) and 5'-deoxy-5-iodotubercidin (Davies, et al., Biochem. Pharmacol. 1984, 33: 347- 355).

Adenosine kinase is also responsible for the activation of many pharmacologically active nucleosides (Miller, et al., J. Biol. Chem. 1979, 254: 2339-2345), including tubercidin, formycin, ribavirin, pyrazofurin and 6-(methylmercapto)purine riboside. These purine nucleoside analogs represent an important group of antimetabolites which possess cytotoxic, anticancer and antiviral properties. They serve as substrates for adenosine kinase and are phosphorylated by the enzyme to generate the active form. The loss of adenosine kinase activity has been implicated as a mechanism of cellular resistance to the pharmacological effects of these nucleoside analogs (e.g. Bennett, et al., Mol. Pharmacol., 1966, 2: 432-443; Caldwell, et al., Can. J. Biochem., 1967, 45: 735-744; Suttle, et al., Europ. J. Cancer, 1981, 17: 43-51). Decreased cellular levels of adenosine kinase have also been associated with resistance to the toxic effects of 2'-deoxyadenosine (Hershfield and Kredich, Proc. Natl. Acad. Sci. USA, 1980, 77: 4292-4296). The accumulation of deoxyadenosine triphosphate (dATP), derived from the phosphorylation of - deoxyadenosine, has been suggested as a toxic mechanism in the immune defect associated with inheritable adenosine deaminase deficiency (Kredich and Hershfield, in The Metabolic Basis of Inherited Diseases, 1989 (Scriver, et al., eds.), McGraw-Hill, New York, pp. 1045-1075). B.S. Hurlbert et al. (J. Med. Chem., U : 711-717 (1968)) disclose various 2,4- diaminopyrido[2,3-d]pyrimidine compounds having use as antibacterial agents. R. K. Robins et al. (J. Amer. Chem. Soc, 80:3449-3457 (1958)) disclose methods for preparing a number of 2,4-dihydroxy-, 2,4-diamino-, 2-amino-4-hydroxy- and 2-mercapto-4- hydroxypyrido[2,3-d]pyrimidines having antifolic acid activity. R. Sharma et al., (Indian J. Chem., 31B: 719-720 (1992)) disclose 4-amino-5-(4-chlorophenyl)-7-(4- nitrophenyl)pyrido[2,3-d]pyrimidine and 4-amino-5-(4-methoxyphenyl)-7-(4- nitrophenyl)pyrido[2,3-d]pyrimidine compounds having antibacterial activity. A. Gupta et al., (J. Indian Chem. Soc, l±: 635-636 (1994)) disclose 4-amino-5-(4-fluorophenyl)-7-(4- fluorophenyl)pyrido[2,3-d]pyrimidine and 4-amino-5-(4-chlorophenyl)-7-(4- fluorophenyl)pyrido[2,3-d]pyrimidine compounds having antibacterial activity. L. Prakash et al., Pharmazie, 48: 221-222 (1993)) disclose 4-amino-5-phenyl-7-(4- aminophenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-phenyl-7-(4-bromophenyl)pyrido[2,3- djpyrimidine, 4-amino-5-(4-methoxyphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine, and 4-amino-5-(4-methoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine compounds having antifungal activity. P. Victory et al., Tetrahedron, 5_1 : 10253-10258 (1995)) discloses the synthesis of 4-amino-5,7-diphenylpyrido[2,3-d]pyrimidine compounds from acyclic precursors. Bridges et al.(PCT application WO 95/19774, published July 27, 1995) disclose various bicyclic heteroaromatic compounds as having utility for inhibiting tyrosine kinase of epidermal growth factors.

Summary Of The Invention

The present invention provides for 6,7-disubstituted-4-aminopyrido[2,3- d]pyrimidine compounds having utility as adenosine inhibitors.

The present invention provides novel compounds having formula I:

I, or a pharmaceutically acceptable salt thereof, wherein

R, and R2 are independently selected from hydrogen, lower alkyl, alkylcarbonyl, and arylalkyl or R, and R2 may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from the group consisting of morpholine, piperazine, piperdine, pyrrolidine, thiomorpholine, and thiomorpholine sulfone. Preferably, R, and R2 are hydrogen.

R3 is selected from alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl. Preferably R3 is selected from alkyl, aryl, arylalkyl, aminocarbonylalkyl, cyanoalkyl, cycloalkylalkyl, and heterocycle.

R4 is selected from aryl and heterocycle.

R5 is selected from hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, and heterocycleoxy. Preferably R5 is selected from hydrogen, aryl, arylalkenyl, arylalkoxy, aryloxy, heterocycle, and heterocyclealkenyl.

Detailed Description Of The Invention The present invention relates to 6,7-disubstituted-4-aminopyrido [2,3 -d]pyrimi dine compounds that are useful in inhibiting adenosine kinase, to pharmaceutical compositions containing such compounds, to a method of using such compounds for inhibiting adenosine kinase, and to novel 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds. In one embodiment the present invention discloses compounds of formula I:

I, R, and R2 are hydrogen.

R3 is selected from alkyl, aryl, arylalkyl, aminocarbonylalkyl, cyanoalkyl, cycloalkylalkyl, and heterocycle. The preferred aryl group is phenyl optionally substituted with 1, 2, or 3 substituents. Preferably, phenyl groups are substituted with 1 or 2 substituents selected from alkoxy, alkoxycarbonyl, alkyl, alkylthio, amino, aminoalkyl, benzyloxy, cyano, halogen, haloalkoxy, haloalkyl, methylenedioxy, and nitro. A preferred heterocycle is an optionally substituted thienyl group. R4 is selected from furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, indolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, quinolinyl, and phenyl. Preferably, R4 is an optionally substituted furyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, benzofuranyl, or phenyl group.

R5 is selected from hydrogen, aryl, arylalkenyl, arylalkoxy, aryloxy, heterocycle, and heterocyclealkenyl.

Exemplary and preferred compounds of the present invention include, but are not limited to:

4-amino-6-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;

4-amino-6- (4-methylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine;

4-amino-6-ι (4-(dimethylamino)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine;

4-amino-6- 4-methylphenyl)-7-phenylpyrido[2,3-d]pyrimidine;

4-amino-6- 4-methylphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;

4-amino-6- 4-(dimethylamino)phenyl)-7-(4-pyridinyl)pyrido[2,3-d]pyrimidine;

4-amino-6- 4-(dimethylamino)phenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl)-7-(4-(5-pyrimidinyl)phenyl)pyrido[2,3-d]pyrimidine;

4-amino-6- 4-methylphenyl)-7-(4-(2-(2-pyridinyl)ethenyl)phenyl)pyrido[2,3- djpyrimidine;

4-amino-6- (4-methylphenyl)-7-(3 -pyridinyl)pyrido [2,3 -djpyrimidine;

4-amino-6-( (4-methylphenyl)-7-(thien-3-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-( (4-methylphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;

4-amino-6-( (4-methylphenyl)-7-(2-pyridinyl)pyrido[2,3-d]pyrimidine;

4-amino-6-( (4-methylphenyl)-7-(3,4-methylenedioxyphenyl)pyrido[2,3- djpyrimidine;

4-amino-6-butyl-7-(thien-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-butyl-7-(thien-3-yl)pyrido[2,3-d]pyrimidine;

4-amino-6-(4-methylphenyl)-7-(5-bromothien-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(5-methylthien-2-yl)pyrido[2,3-d]pyrimidine;

4-amino-6-(4-methylphenyl)-7-(4-(trifluoromethoxy)phenyl)pyrido[2,3- d]pyrimidine;

4-amino-6-(4-methylphenyl)-7-(3-phenoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(5-nitrothien-2-yl)pyrido[2,3-d]pyrimidine;

4-amino-6-(4-methylphenyl)-7-(4-bromothien-2-yl)pyrido[2,3-d]pyrimidine;

4-amino-6-(4-methylphenyl)-7-(3-methylthien-2-yl)pyrido[2,3-d]pyrimidine;

4-amino-6-(4-methylphenyl)-7-(2-furyl)pyrido[2,3-d]pyrimidine;

4-amino-6-(4-methylphenyl)-7-(3-furyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(5-methyl-2-furyl)pyrido[2,3-d]pyrimidine;

4-amino-6-(4-(2-propyl)phenyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine;

4-amino-6-(4-(2-propyl)phenyl)-7-(5-nitrothien-2-yl)pyrido[2,3-d]pyrimidine;

4-amino-6-(4-methylphenyl)-7-(5-nitrothien-2-yl)pyrido[2,3-d]pyrimidine;

4-amino-6-(4-(dimethylamino)phenyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(3,4-dimethoxyphenyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine;

4-amino-6-(3,4-dimethoxyphenyl)-7-(5-nitrothien-2-yl)pyrido[2,3-d]pyrimidine;

4-amino-6-hexyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;

4-amino-6-hexyl-7-(thien-2-yl)pyrido [2,3 -d]pyrimidine;

4-amino-6-(2-methyl-2-propyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-(2-propyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine;

4-amino-6-(4-propylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;

4-amino-6-(3,4-dimethoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine; 4-amino-6-(3-methoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine;

4-amino-6-(3-bromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;

4-amino-6-(3-fluorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;

4-amino-6-(3 -trifluoromethylphenyl)-7-(4-(dimethylamino)phenyl)pyrido [2,3 - djpyrimidine;

4-amino-6-(3-chlorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 3,5 -dichloropheny l)-7-(4-(dimethy lamino)pheny l)pyrido [2,3- djpyrimidine;

4-amino-6- 3,4-methylenedioxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;

4-amino-6- 3,4-methylenedioxyphenyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6- 3-methoxycarbonylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;

4-amino-6- 3-(2-propyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;

4-amino-6- 4-( 1 , 1 -dimethy lethyl)pheny l)-7-(4-(dimethylamino)phenyl)pyrido [2,3 - djpyrimidine;

4-amino-6- 4-fluorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;

4-amino-6- 3-(phenylmethoxy)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;

4-amino-6- 4-chlorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 3-fluoro-4-methylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;

4-amino-6- 3-fluoro-4-methylphenyl)-7-(thien-2-yl)pyrido[2,3-djpyrimidine; 4-amino-6- 3 -pheny lpropy l)-7-(4-methoxypheny l)pyrido [2, 3 -d] pyrimidine ; 4-amino-6- 3-phenylpropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 2-phenylethyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- (phenylmethyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- (cyclohexylmethyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;

4-amino-6- -butyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-djpyrimidine; 4-amino-6- -pentyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- -(2-methylpropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;

4-amino-6-propyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 3-cyanopropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-djpyrimidine; 4-amino-6- 3-nitrophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- pentyl-7-(thien-2-yl)pyrido [2,3 -djpyrimidine; 4-amino-6- 3 -carboxamidopropy l)-7-(4-(dimethy lamino)pheny l)pyrido [2,3- djpyrimidine;

4-amino-6- (4-methoxyphenyl)methyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6- (3 -bromophenyl)methyl)-7-(thien-2-yl)pyrido [2,3 -djpyrimidine; 4-amino-6- (4-(2-propyl)phenyl)methyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6- (4-methoxyphenyl)methy l)-7-(4-(2-propy l)phenyl)pyrido [2,3 - djpyrimidine;

4-amino-6- (4-bromophenyl)methyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6- (3-fluorophenyl)methyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6- (4-bromophenyl)methyl)-7-(thiazol-2-yl)pyrido[2,3-djpyrimidine; 4-amino-6- (3-methoxyphenyl)methyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6- phenylmethyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine;

4-amino-6- (3-methoxyphenyl)methyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;

4-amino-6- 4-methylpheny l)-7-(4-(trifluoromethyl)phenyl)pyrido [2,3 - djpyrimidine; 4-amino-6- 4-methylphenyl) 7-(4-methylphenyl)pyrido[2,3-djpyrimidine;

4-amino-6- 4-methylphenyl) 7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl) 7-(4-ethylphenyl)pyrido [2,3 -djpyrimidine; 4-amino-6- 4-methylphenyl) 7-(4-cyanophenyl)pyrido[2,3-djpyrimidine; 4-amino-6- 4-methylphenyl) 7-(4-acetamidopheny l)pyrido [2 ,3 -djpyrimidine ; 4-amino-6- 4-methylphenyl) 7-(4-phenoxyphenyl)pyrido[2,3-d]pyrimidine;

4-amino-6- 4-methylphenyl) 7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl) 7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl) 7-(4-chloropheny l)pyrido [2,3 -djpyrimidine; 4-amino-6- 4-methylphenyl) 7-(4-aminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl) 7-(4-methylsulfanyl)pyrido[2,3-d]pyrimidine;

4-amino-6- 4-methylphenyl) 7-((4-phenyl)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-((4-phenylmethoxy)phenyl)pyrido[2,3- djpyrimidine;

4-amino-6-(4-methylphenyl)-7-(4-(diethylamino)phenyl)pyrido[2,3-d]pyrimidine;

4-amino-6-(4-methylphenyl)-7-(4-(2-phenylethenyl)phenyl)pyrido[2,3- djpyrimidine;

4-amino-6-(4-methylphenyl)-7-(4-(tert-butoxy)phenyl)pyrido[2,3-d]pyrimidine;

4-amino-6-(4-methylphenyl)-7-(3-chlorophenyl)pyrido[2,3-djpyrimidine;

4-amino-6-(4-methylphenyl)-7-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

4-amino-6-(thien-2-yl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(benzofuran-2-yl)pyrido [2,3 -djpyrimidine;

4-amino-6-(thien-2-yl)-7-(thien-2-y l)pyrido [2 ,3 -djpyrimidine;

4-amino-6-(thien-2-yl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;

4-amino-6-(4-bromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;

4-amino6-(3-bromo-4-methoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;

4-amino-6-(3-bromo-4-methoxyphenyl)-7-(thien-2-yl)pyrido[2,3-djpyrimidine;

4-amino-6-(4-methylphenyl)-7-(4-butoxyphenyl)pyrido[2,3-d]pyrimidine;

4-amino-6-(4-methylphenyl)-7-(3-methoxyphenyl)pyrido[2,3-d]pyrimidine; and

4-amino-6-(4-methylphenyl)-7-(3,5-dichlorophenyl)pyrido[2,3-d]pyrimidine. In another embodiment, the present invention discloses a method of inhibiting adenosine kinase comprising exposing an adenosine kinase to an effective inhibiting amount of a compound of formula I.

In another embodiment, the present invention discloses a pharmaceutical composition comprising a therapeutic amount of a compound of formula I in combination with a pharmaceutically acceptable carrier.

In another embodiment, the present invention discloses a method of treating ischemia, certain neurological disorders, nociception , inflammation, and sepsis in a mammal in need of such treatment, comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I. In another embodiment, the present invention discloses a method of treating cerebral ischemia, myocardial ischemia, angina, stroke, thrombotic and embolic conditions, epilepsy, anxiety, schizophrenia, pain perception, neuropathic pain, visceral pain, arthritis, sepsis, and abnormal gastrointestinal motility which comprises adminstering to a mammal in need of such treatment, an effective amount of a compound of formula I.

In another embodiment, the present invention discloses a process for the preparation of a compound of formula I:

I, wherein R, and R2 are hydrogen;

R3 is selected from alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl; R4 is selected from aryl and heterocycle; and

R5 is selected from hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, and heterocycleoxy; the method comprising

(a) reacting 4,6-diamino-5-iodopyrimidine with an ethenylboronic acid derivative having the formula

(HO)2B^^

K3 wherein R3 is selected from alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl, in the presence of tetrakistriphenylphosphinepalladium(O) and an aqueous alkali metal base, and isolating an intermediate compound having the formula (b) reacting said intermediate compound of formula

with an aldehyde compound having the formula R5-R4-CHO, wherein R4 is aryl or heterocycle and R5 is selected from hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, and heterocycleoxy, under anhydrous conditions and with the removal of the water of reaction, and isolating said compound of formula I.

In another embodiment, the present invention discloses a process for the preparation of a compound of formula I

I, wherein

R, and R2 are independently hydrogen, lower alkyl, alkylcarbonyl, and arylalkyl or R, and R2 may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from the group consisting of morpholine, piperazine, piperdine, pyrrolidine, thiomorpholine, and thiomorpholine sulfone, with the requirement that not both R, and R2 may be hydrogen;

R3 is selected from the group consisting of alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl;

R4 is selected from the group consisting of aryl and heterocycle; and R5 is selected from the group consisting of hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, and heterocycleoxy; the method comprising (a) reacting a compound of formula I

I, wherein

R, and R2 are hydrogen; R3 is selected from the group consisting of alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl;

R4 is selected from the group consisting of aryl and heterocycle; and R5 is selected from the group consisting of hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, and heterocycleoxy; with a compound selected from the group consisting of

(i) an alkylating agent R,-Y, wherein R, is lower alkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate;

(ii) an arylalkylating agent R,-Y, wherein R, is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate;

(iii) an alkylcarbonyl compound R,-Z, wherein R, is an alkylcarbonyl group and Z is selected from the group consisting of an acid anhydride moiety, a halide or an acyl activating group; and isolating the desired compound; and

(b) optionally, when it is desired that R2 should not be hydrogen, treating the compound from step (a) with a compound selected from the group consisting of

(i) an alkylating agent R -Y, wherein R2 is lower alkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (ii) an arylalkylating agent R2-Y, wherein R2 is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate;

(iii) an alkylcarbonyl compound R2-Z, wherein R2 is an alkylcarbonyl group and Z is selected from the group consisting of an acid anhydride moiety, a halide or an acyl activating group; and isolating said compound of formula I.

In another embodiment, the present invention discloses a process for the preparation of a compound of formula I

I, wherein

R, and R2 are independently hydrogen, lower alkyl, alkylcarbonyl, and arylalkyl or R, and R2 may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from the group consisting of morpholine, piperazine, piperdine, pyrrolidine, thiomorpholine, and thiomorpholine sulfone, with the requirement that not both R, and R2 may be hydrogen;

R3 is selected from the group consisting of alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl; R4 is selected from the group consisting of aryl and heterocycle; and

R5 is selected from the group consisting of hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, and heterocycleoxy; the method comprising (a) reacting 6-amino-4-chloro-5-iodopyrimidine with an ethenylboronic acid derivative having the formula (HO)2B^^ wherein R3 is selected from alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl, in the presence of tetrakistriphenylphosphinepalladium(O) and an aqueous alkali metal base, and isolating an intermediate compound having the formula

(b) reacting said intermediate compound of formula

with an aldehyde compound having the formula R5-R4-CHO, wherein R4 is selected from the group consisting of aryl and heterocycle and R5 is selected from the group consisting of hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, and heterocycleoxy, under anhydrous conditions and with the removal of the water of reaction, and isolating the intermediate compound having the formula

(c) treating said intermediate compound of formula

with an amine compound having formula R,NHR2, wherein R, and R2 are as described above, and isolating the compound of the invention.

In another embodiment, the present invention discloses a compound having formula II π, wherein

X is selected from halogen or hydroxy; R3 is selected from alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl;

R4 is selected from the group consisting of aryl and heterocycle; and R5 is selected from the group consisting of hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, and heterocycleoxy.

Definition of Terms As used throughout this specification and the appended claims, the following terms have the following meanings:

The term "alkenyl," as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 8 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3- butenyl, 4-pentenyl, and 5-hexenyl.

The term "alkoxy," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. The term "alkoxyalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl. The term "alkoxycarbonyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxy carbonyl, and tert-butoxy carbonyl. The term "alkoxycarbonylalkyl," as used herein, refers to an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxycarbonylalkyl include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and 2-tert- butoxycarbony lethyl . The term "alkyl," as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 8 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, and n-octyl. The term "alkylcarbonyl," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1 - oxopropyl, 2,2-dimethyl-l-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term "alkylcarbonylalkyl," as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.

The term "alkylcarbonyloxy," as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.

The term "alkylsulfinyl," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein. Representative examples of alkylsulfinyl include, but are not limited, methylsulfinyl and ethylsulfinyl. The term "alkylsulfinylalkyl," as used herein, refers to an alkylsulfinyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylsulfinylalkyl include, but are not limited to, methylsulfinylmethyl and ethylsulfinylmethyl. The term "alkylsulfonyl," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited, methylsulfonyl and ethylsulfonyl.

The term "alkylsulfonylalkyl," as used herein, refers to an alkylsulfonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylsulfonylalkyl include, but are not limited to, methylsulfonylmethyl and ethylsulfonylmethyl.

The term "alkylthio," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, and hexylsulfanyl.

The term "alkylthioalkyl," as used herein, refers to an alkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylthioalkyl include, but are not limited, methylsulfanylmethyl and 2-(ethylsulfanyl)ethyl.

The term "alkynyl," as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 8 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl. The term "amino," as used herein, refers to a -NRARB group wherein RA and RB are independently selected from hydrogen, alkyl, alkylcarbonyl, arylalkyl, and formyl, as defined herein.

The term "aminoalkyl," as used herein, refers to an amino group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aminoalkyl include, but are not limited, aminomethyl, 2- (amino)ethyl, benzyl(methyl)aminomethyl, and dimethylaminomethyl. The term "aminocarbonyl," as used herein, refers to an amino group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of aminocarbonyl include, but are not limited, aminocarbonyl, dimethylaminocarbonyl, benzylaminocarbonyl, and ethylaminocarbonyl. The term "aminocarbonylalkyl," as used herein, refers to an aminocarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aminocarbonylalkyl include, but are not limited to, 2-amino-2-oxoethyl, 2-(benzylamino)-2-oxoethyl, 2-(methylamino)-2-oxoethyl 4-amino-4-oxobutyl, and 4-(dimethylamino)-4-oxobutyl. The term "aryl," as used herein, refers to a naphthyl or phenyl group.

The aryl groups of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, benzyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, methylenedioxy, mercapto, nitro, and phenoxy.

The term "arylalkenyl," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein.

Representative examples of arylalkenyl include, but are not limited to, 2-phenylethenyl, 3- phenylpropen-2-yl, and 2-naphth-2-ylethenyl.

The term "arylalkoxy," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3- naphth-2-ylpropoxy, and 5-phenylpentyloxy.

The term "arylalkyl," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl. The term "aryloxy," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy, 3,4-dimethoxyphenoxy, and 3,5- dimethoxyphenoxy.

The term "carbonyl," as used herein, refers to a -C(O)- group.

The term "carboxy," as used herein, refers to a -CO2H group.

The term "carboxyalkyl," as used herein, refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2- carboxyethyl, and 3-carboxypropyl.

The term "cyano," as used herein, refers to a -CN group.

The term "cyanoalkyl," as used herein, refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2- cyanoethyl, and 3-cyanopropyl.

The term "cycloalkyl," as used herein, refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbons. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl . The term "cycloalkylalkyl," as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl . The term "formyl," as used herein, refers to a -C(O)H group.

The term "formylalkyl," as used herein, refers to a formyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of formylalkyl include, but are not limited to, formylmethyl and 2-formylethyl. The term "halo" or "halogen," as used herein, refers to -Cl, -Br, -I or -F. The term "haloalkoxy," as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy. The term "haloalkyl," as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2- fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term "heterocycle" as used herein, refers to a monocyclic or bicyclic ring system. Monocyclic ring systems are exemplified by any 5- or 6-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from nitrogen, oxygen and sulfur. The 5-membered ring has from 0-2 double bonds and the 6-membered ring has from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomorpholinyl, and 1,1- dioxidothiomorpholinyl (thiomorpholine sulfone). Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to a phenyl group. Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, indolyl, indolinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoindolinyl, isoquinolinyl, and quinolinyl. The heterocycles of this invention can be substituted with 1, 2,or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, methylenedioxy, mercapto, and nitro. The term "heterocyclealkenyl," as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein. Representative examples of heterocyclealkenyl include, but are not limited to, 2-pyrid-3-ylethenyl, 3-quinolin-3-ylpropen-2-yl, and 5-pyrid-4-ylpentylen-4-yl. The term "heterocyclealkoxy," as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of heterocyclealkoxy include, but are not limited to, 2-pyrid-3-ylethoxy, 3-quinolin-3-ylpropoxy, and 5-pyrid-4-ylpentyloxy.

The term "heterocyclealkyl," as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkyl include, but are not limited to, pyrid-3- ylmethyl and 2-pyrimidin-2-ylpropyl.

The term "heterocycleoxy," as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of heterocycleoxy include, but are not limited to, pyrid-3-yloxy and quinolin-3-yloxy.

The term "hydroxy," as used herein, refers to an -OH group.

The term "hydroxyalkyl," as used herein, refers to a hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and 2-ethyl-4-hydroxyheptyl.

The term "lower alkyl," as used herein, is a subset of alkyl as defined herein and refers to a straight or branched chain hydrocarbon group containing from 1 to 4 carbon atoms. Examples of lower alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.

The term "mercapto," as used herein, refers to a -SH group.

The term "methylenedioxy," as used herein, refers to a -OCH2O- group wherein the oxygen atoms of the methylenedioxy are attached to the parent molecular moiety through two adjacent carbon atoms. The term "nitro," as used herein, refers to a -NO2 group.

The term "oxo," as used herein, refers to a =O moiety. The term "oxy," as used herein, refers to a -O- moiety.

The term "sulfinyl," as used herein, refers to a -S(O)- group.

The term "sulfonyl," as used herein, refers to a -SO2- group.

The term "thio," as used herein, refers to a -S- moiety. • In a further aspect of the present invention pharmaceutical compositions are disclosed which comprise a compound of the present invention in combination with a pharmaceutically acceptable carrier.

The present invention includes one or more compounds, as set forth above, formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for oral administration in solid or liquid form, for rectal or topical administration, or the like. As is well known in the art, a compound of the present invention can exist in a variety of forms including pharmaceutically-acceptable salts, amides and the like. Compositions may be prepared that will deliver the correct amount of a compound or compounds of the invention. The following dosages are thought to provide the optimal therapy: iv infusions: 0.1- 250 nmol/kg/minute, preferably from 1-50 nmol/kg/minute; oral: 0.01-250 μMol/kg/day, preferably from about 0.1-50 μMol/kg/day; these oral molar dosage ranges correspond to 0.005-125 mg/kg/day, preferably 0.05-25 mg/kg/day. For treatment of acute disorders the preferred route of administration is intravenous; the preferred method of treating chronic disorders is orally by means of a tablet or sustained release formulation.

"Pharmaceutically-acceptable amide" refers to the pharmaceutically-acceptable, nontoxic amides of the compounds of the present invention which include amides formed with suitable organic acids or with amino acids, including short peptides consisting of from l-to-6 amino acids joined by amide linkages which may be branched or linear, wherein the amino acids are selected independently from naturally-occurring amino acids, such as for example, glycine, alanine, leucine, valine, phenylalanine, proline, methionine, tryptophan, asparagine, aspartic acid, glutamic acid, glutamine, serine, threonine, lysine, arginine, tyrosine, histidine, ornithine, and the like. "Pharmaceutically-acceptable salts" refers to the pharmaceutically-acceptable, nontoxic, inorganic or organic acid addition salts of the compounds of the present invention, as described in greater detail below.

The term "substituted versions thereof refers to those generic groups such as aryl or heteroaryl or heterocyclic which have substituents around the aryl, heteroaryl, heterocyclic or other genera variable at chemically appropriate positions and as designated or exemplified herein.

The compounds of the present invention can be used in the form of pharmaceutically-acceptable salts derived from inorganic or organic acids. These salts include, but are not limited to, the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, flavianate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexonoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.

Appropriate cationic salts are also readily prepared by conventional procedures such as treating an acid of the compound of the above formula with an appropriate amount of base, such as an alkali or alkaline earth metal hydroxide, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, ttiethylamine, piperidine, pyrrolidine, benzylamine, and the like, or a quanternary ammonium hydroxide such as tetramethylammonium hydroxide and the like. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained. The salts of the present invention can be synthesized from the compounds of having the above formula which contain a basic or acidic moiety by conventional methods, such as by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt forming inorganic acid or base in a suitable solvent or various combinations of solvents.

Further included within the scope of the present invention are pharmaceutical compositions comprising one or more of the compounds of formula prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable carriers compositions, in the manner described below.

Compositions suitable for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

If desired, and for more effective distribution, the compounds may be incorporated into slow-release or targeted-delivery systems, such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water, or some other sterile injectable medium immediately before use. Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier), such as sodium citrate or dicalcium phosphate, and additionally (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retarders, as for example paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules, using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings and others well known in this art. They may contain pacifying agents, and may also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which may be used are polymeric substances and waxes.

The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.

Besides such inert diluents, these liquid dosage forms may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like. Compositions for rectal or vaginal administrations are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component. Dosage forms for topical or transdermal administration of a compound of this invention further include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or transdermal patches. Transdermal administration via a transdermal patch is a particularly effective and preferred dosage form of the present invention. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservative, buffers or propellants as may be required. It is known that some agents may require special handling in the preparation of transdermal patch formulations. For example, compounds that are volatile in nature may require admixture with special formulating agents or with special packaging materials to assure proper dosage delivery. In addition, compounds which are very rapidly absorbed through the skin may require formulation with absorption-retarding agents or barriers. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

The present compounds may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology. Volume XIV, Academic Press, New York, N. Y., (1976), p 33 et seq.

Synthetic Methods

The compounds and processes of the present invention will be better understood in connection with the following synthetic Schemes 1 and 2 which illustrate the methods by which the compounds of the invention may be prepared. The groups R,, R2, R3, R4, and R5 are as defined in formula I unless otherwise noted.

Scheme 1

In accordance with Scheme 1 are prepared compounds of the invention wherein R, and R2 are hydrogen. A starting material, 4,6-diamino-5-iodopyrimidine (1), is reacted with ethenylboronic acid derivatives (2), wherein R3 is alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, or hydroxyalkyl, to prepare compound (3) in the presence of tetrakistriphenylphosphinepalladium(O) or other suitable palladium(O) complexes, and aqueous alkali metal base, such as sodium or potassium hydroxide, for example, preferably buffered with an aqueous sodium or potassium bicarbonate at reflux for about 8 to about 24 hours. Compound (1) may be prepared from 4,6-diaminopyridine by treatment with iodine in DMF at about 40 °C to about 50 °C for about 24 hours in the presence of potassium carbonate.

Compound (3) is then reacted with the aldehyde compound (4), wherein R4 is aryl or heterocycle and R5 is hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, or heterocycleoxy, to prepare compound (5) in a suitable anhydrous solvent, under Suzuki reaction conditions, such as diphenyl ether, 1 ,2,4-trichlorobenzene, toluene, or the like, in the presence of 4A molecular sieves to adsorb the water of reaction, at reflux for from about 2 to about 24 hours. Compounds (5) are compounds of of the invention wherein R, and R2 are hydrogen.

Scheme 2

5 6

In accordance with Scheme 2, compounds exemplified by the above formula wherein one or both of R, and R2 are lower alkyl, arylalkyl or alkylcarbonyl, may be prepared by treatment of compound (5) with the appropriate reagent. To prepare compounds of the invention wherein R, and R2 are not both hydrogen atoms, it is possible to prepare the desired derivative from the compound of the above formula wherein R, and R2 are both hydrogen atoms. When R, or R2 is lower alkyl this may be accomplished by reaction of the free amino group with the appropriate alkylating reagent, such as an alkyl halide, an alkyl mesylate or an alkyl tosylate, for example, in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF. When R, or R2 is arylalkyl this may be accomplished by reaction of the free amino group with the appropriate arylalkyl halide, an alkyl mesylate or an alkyl tosylate, for example, in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF. When R, or R2 is alkylcarbonyl this may be accomplished by reaction of the free amino group with the appropriate acid anhydride, an acyl halide such as acyl chloride, or an activated acyl group, such as an acyl cyanide, an acyl azide or a thiolester, in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF. When R, and R2 are taken together with the nitrogen atom to which they are attached to form morpholine, piperazine, piperdine, pyrrolidine, thiomorpholine, or thiomorpholine sulfone, the compound may be prepared by reacting a precursor compound having a halogen atom in place of the amino group at the 4-position with morpholine, piperazine, piperdine, pyrrolidine, thiomorpholine, or thiomorpholine sulfone. Also, this alternate procedure may be used to prepare alkyl substituted amino compounds, for example by reacting the chloro compound with a mono- or disubstituted amine, such as for example, diethylamine, allyl amine, dibutylamine. This reaction takes place readily in a solvent such as methylene chloride, for example, in the presence of a tertiary amine. The precursor compound having a halogen atom in place of the amino group at the 4-position may be prepared by substitution of 6-amino-4-chloro-5- iodopyrimidine for the 4,6-diamino-5-iodopyrimidine (compound (1) of Scheme 1) and carrying the product forward.

Method of Inhibiting Kinase

In yet another aspect of the present invention a method of inhibiting adenosine kinase is disclosed. In accordance with this method, an adenosine kinase enzyme is exposed to an effective inhibiting amount of an adenosine kinase inhibitor compound of the present invention. Preferred such compounds for use in the method are the same as set forth above. Means for determining an effective inhibiting amount are well known in the art.

The adenosine kinase to be inhibited can be located in vitro, in situ or in vivo. Where the adenosine kinase is located in vitro, adenosine kinase is contacted with the inhibitor compound, typically by adding the compound to an aqueous solution containing the enzyme, radiolabeled substrate adenosine, magnesium chloride and ATP. The enzyme can exist in intact cells or in isolated subcellular fractions containing the enzyme. The enzyme is then maintained in the presence of the inhibitor for a period of time and under suitable physiological conditions. Means for determining maintenance times are well known in the art and depend inter alia on the concentrations of enzyme and the physiological conditions. Suitable physiological conditions are those necessary to maintain adenosine kinase viability and include temperature, acidity, tonicity and the like. Inhibition of adenosine kinase can be performed, by example, according to standard procedures well known in the art (Yamada, et al, Comp. Biochem. Physiol. 1982, 71B: 367-372). Where the adenosine kinase is located in situ or in vivo, is typically administered to a fluid perfusing the tissue containing the enzyme. That fluid can be a naturally occuring fluid such as blood or plasma or an artificial fluid such as saline, Ringer's solution and the like. A process of inhibiting adenosine kinase in vivo is particularly useful in mammals such as humans. Administering an inhibitor compound is typically accomplished by the parenteral (e.g., intravenous injection or oral) administration of the compound. The amount administered is an effective inhibiting or therapeutic amount.

The compounds of the invention are believed to be primarily useful in the treatment of pain and inflammation in a mammal. Such treatment is accomplished by inhibiting adenosine kinase in a mammal through the administration to the mammal in need of such treatment of an effective adenosine kinase inhibiting amount of a compound according to this invention.

Among the pain/inflammation or other indications which have been shown to be treatable using an adenosine kinase inhibitor are conditions including cerebral or myocardial ischemia, nociception , inflammation, pain and sepsis. The compounds of the invention may show particular utility in the treatment of cerebral ischemia, myocardial ischemia, angina, stroke, thrombotic and embolic conditions, neurological disorders such as epilepsy, anxiety, and schizophrenia, pain perception, neuropathic pain, visceral pain, arthritis, sepsis, and abnormal gastrointestinal motility. As will be seen by one skilled in the art, the adenosine kinase inhibitors of the invention may operate to reduce pain and inflammation that occurs through any number of reasons including surgery, trauma, disease (including inflamatory auto-immune disease such as arthritis), and the like. The compounds of the invention may find particular use in the treatment of the side effects experienced by patients who have undergone coronary bypass surgery, angioplasty, or the like. By a "therapeutically-effective amount" or "effective amount" of the compound of the invention is meant a sufficient amount of the compound to treat or mitigate adenosine kinase related disorders or those diseases or conditions which are ameliorated by adenosine kinase inhibition and elevated levels of adenosine, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention is to be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with specific compound employed; and the like factors well known in the medical arts and well within the capabilities of attending physicians.

Compounds of the present invention inhibit adenosine kinase activity in vitro and in vivo. In vitro adenosine kinase activity can be measured using any of the standard procedures well known in the art. By way of example, cells containing adenosine kinase, such as IMR-32 human neuroblastoma cells, are cultured in the presence and absence of an inhibitor. Inhibition is measured as the ability to inhibit phosphorylation of endogenous or externally applied 14C-adenosine by these cells. The cells can be intact or broken. The specificity of adenosine kinase inhibitory activity is determined by studying the effects of inhibitors on adenosine Al and A2α receptor binding, adenosine deaminase activity and adenosine transport.

Compounds of the present invention are effective in inhibiting adenosine kinase activity in vivo. Numerous animal models for studying adenosine kinase activity and the affects of inhibiting such activity are well known in the art. By way of example, adenosine kinase inhibitors have been reported to protect rodents (e.g., mice and rats) from seizures induced by the subcutaneous administration of pentylenetetrazol (PTZ). Typically the rodents are injected with various doses of a given inhibitor followed at various times by the subcutaneous administration of from about 10 to about 500 milligrams per kilogram of PTZ. The injected animals are then observed for the onset of seizures. The compounds of the invention were tested in vivo in the hot plate test of analgesia in mammals such as mice. For example, the compounds of examples 55, 103 and 104 in the procedure described directly below were tested thirty minutes after pretreatment with the drugs (30 μmol/kg i.p.) for latency to 10th jump (in seconds). The longer the number of seconds, the more effective the drug at masking the pain felt from the hot plate. Compound 55 resulted in 132.86 seconds relative to the vehicle alone of 72.76±10.51 seconds. Compound 103 resulted in 103.29 seconds. Compound 104, when tested, resulted in an insignificant score of 62.44 seconds and will be retested in additional models of pain. Compounds of the invention are therefore potent pain relievers as well as adenosine kinase inhibitors as demonstrated in this animal model and the additional assays described below.

Mouse Hot Plate Assay

Male CF1 mice (Charles River) of approximately 25-30 g body weight are pretreated with 10 ml/kg of the test compounds, i.p. or p.o, in groups of 8 animals per dose. At the end of the pretreatment period, the mice are placed in an Omnitech Electronics Automated 16 Animal Hot Plate Analgesia Monitor (Columbus, OH; Model AHP16AN) in individual, 9.8 x 7.2 x 15.3 cm (1 x w x h) plastic enclosures on top of a copper plate warmed to 55 °C. Infared sensors located near the top of each enclosure record beam crossings that occur as the mice jump off of the heated surface. Latency times for each jump are automatically recorded, and latency to both the first and tenth jumps are used for data analysis. Mice that do not reach the criteria of 10 jumps by 180 seconds are immediately removed from the hotplate to avoid tissue damage, and they are assigned the maximum value of 180 seconds as their latency to tenth jump. Numerous other animal models of adenosine kinase activity have been described

[See, e.g., Davies,, et al, Biochem. Pharmacol, 33:347-355 (1984); Keil, et al, Eur. J. Pharmacol, 271:37-46 (1994); Murray, et al, Drug Development Res., 28:410-415 (1993)].

Numerous inhibitor compounds of the present invention were tested in vitro and found to inhibit adenosine kinase activity. The results of some representative studies are shown below in Table 1 below. The data indicate that the compounds inhibit adenosine kinase.

Table 1 Inhibition of Adenosine Kinase by Representative Compounds of the Invention

disorders. Adenosine kinase activity was found to be decreased, relative to normal liver, in a variety of rat hepatomas: activity of the enzyme giving a negative correlation with tumor growth rate (Jackson, et al, Br. J. Cancer, 1978, 37: 701-713). Adenosine kinase activity was also diminished in regenerating liver after partial hepatectomy in experimental animals (Jackson, et al, Br. J. Cancer, 1978, 37: 701-713). Erythrocyte Adenosine kinase activity was found to be diminished in patients with gout (Nishizawa, et al. , Clin. Chim. Ada 1976, 67: 15-20). Lymphocyte adenosine kinase activity was decreased in patients infected with the human immunodeficiency virus (HIV) exhibiting symptoms of AIDS, and increased in asymptomatic HIV-seropositive and HIV-seronegative high-risk subjects, compared to normal healthy controls (Renouf, et al, Clin. Chem. 1989, 35: 1478-1481). It has been suggested that measurement of adenosine kinase activity may prove useful in monitoring the clinical progress of patients with HIV infection (Renouf, et al, Clin. Chem. 1989, 35: 1478-1481). Sepsis infection may lead to a systemic inflammatory syndrome (SIRS), characterized by an increase in cytokine production, neutrophil accumulation, hemodynamic effects, and tissue damage or death. The ability of adenosine kinase inhibitor to elevate adenosine levels in tissues has been demonstrated to ameliorate syndrome symptoms, due to the know anti-inflammatory effects of adenosine. (Firestein, et al., J. of Immunology, 1994, pp. 5853-5859). The ability of adenosine kinase inhibitors to elevate adenosine levels is expected to alleviate pain states, since it has been demonstrated that administration of adenosine or its analogs results in antinociception or antinociception. (Swaynok, et al., Neuroscience, 1989, 32: No. 3, pp. 557-569). The compounds and processes of the present invention will be better understood in connection with the following Examples, which are intended as an illustration of and not a limitation upon the scope of the invention.

Example 1

4-amino-6-phenyl-7-(4-(dimethylamino)phenyl)pyrido[2.3-d1pyrimidine

A sample of 4,6-diamino-5-(2-phenylethenyl)pyrimidine (150 mg) was suspended in 10 mL of phenylether with 1.2 eq of 4-(dimethylamino)benzaldehyde (the "R4-R5" Reagent) and 1.5 g of 4A molecular sieves. The solution was heated to 170 °C for 4 hours, then cooled, and the solvent was removed. The residue was purified by column chromatography to give the title compound. IR (KBr) 3325, 1589, 1555, 1400, 1340,

1196, 819 cm"1 ; MS m/z 342 [M+H]+.

The 4,6-diamino-5-(2-phenylethenyl)pyrimidine was prepared as follows: 1 a. 5 -iodo-4,6-diaminopyrimidine 4,6-Diaminopyrimidine hemisulfate monohydrate (26.13 g, 147.5 mmol, Aldrich) and K2CO3 (30.58 g, 221.3 mmol) were suspended in water (400 mL). To this suspension was added a solution of iodine (41.19g, 162.3 mmol) in DMF (100 mL). The mixture was heated at 45 °C for 23 hours. After cooling, a 2 M solution of Na2S2θ3 (15 mL) was added to quench the excess iodine. The white product was then collected, washed with water (3 x 20 mL) and dried under high vacuum to yield 33.1 g of the title compound (90%). lb. 2-phenylethenylboronic acid (the "R^" Reagent)

Phenylacetylene (5 mmol, Aldrich) was dissolved in 5 mL of dry THF and catecholborane (5 mL, IM in THF, Aldrich) was added dropwise at 0 °C. The solution was heated to reflux for 1.5 hours, and the solvent was removed under vacuum. The solution was quenched with IM HCl (10 mL), and this solution is taken directly to the next step. 1 c. 4.6-diamino-5-(2-phenylethenyl)pyrimidine

To a solution of 5-iodo-4,6-diaminopyrimidine (1 mmol, from step la above) in 50 mL of dioxane , 2-phenylethenylboronic acid (5 mmol), 5% of Pd(PPh3)4, and IM Na2CO3 (10 mL) were added. The reaction mixture was heated for 12 hours. The solvent was removed under vacuum, and the residue was diluted with water and extracted with CH2CI2 (3 x 30 mL). The organic layer was concentrated under reduced pressure, and the residue was dried under high vacuum. The crude mixture was subjected to column chromatography (using 5% MeOH/CH2θ2 as eluant) to give the title compound. MS m/z: 213 (M+H)+.

Examples 2-107

Following the procedures of Example 1 , except substituting the reagents given in Table 1 below for the R4-R5 and R3 Reagents of Example 1, the compounds of Examples 2-107 were prepared. Table 1 Examples 2-107

Claims

WHAT IS CLAIMED IS:
1. A compound of formula I :
I, or a pharmaceutically acceptable salt thereof, wherein
R, and R2 are independently selected from the group consisting of hydrogen, lower alkyl, alkylcarbonyl, and arylalkyl or R, and R2 may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from the group consisting of morpholine, piperazine, piperdine, pyrrolidine, thiomorpholine, and thiomorpholine sulfone;
R3 is selected from the group consisting of alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl; R is selected from the group consisting of aryl and heterocycle; and
R5 is selected from the group consisting of hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, and heterocycleoxy.
2. A compound according to claim 1 wherein
R, and R2 are independently selected from the group consisting of hydrogen, lower alkyl, alkylcarbonyl, and arylalkyl;
R3 is selected from the group consisting of alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl;
R4 is selected from the group consisting of aryl and heterocycle; and R5 is selected from the group consisting of hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, heterocycleoxy.
3. A compound according to claim 1 wherein
R, and R2 are independently selected from the group consisting of hydrogen, lower alkyl, alkylcarbonyl, and arylalkyl wherein arylalkyl is benzyl;
R3 is selected from the group consisting of alkyl, aryl, arylalkyl, aminocarbonylalkyl, cyanoalkyl, cycloalkylalkyl, and heterocycle; R4 is selected from the group consisting of aryl and heterocycle; and
R5 is selected from the group consisting of hydrogen, aryl, arylalkenyl, arylalkoxy, aryloxy, heterocycle, and heterocyclealkenyl.
4. A compound according to claim 1 wherein R, and R2 are independently selected from the group consisting of hydrogen, lower alkyl, alkylcarbonyl, and arylalkyl wherein arylalkyl is benzyl;
R3 is selected from the group consisting of alkyl, aryl, arylalkyl, aminocarbonylalkyl, cyanoalkyl, cycloalkylalkyl, and heterocycle wherein heterocycle is selected from the group consisting of furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, thiadiazolyl, thiazolyl, and thienyl;
R4 is selected from the group consisting of aryl wherein aryl is phenyl and heterocycle wherein heterocycle is selected from the group consisting of furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, indolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, and quinolinyl; and
R5 is selected from the group consisting of hydrogen, aryl, arylalkenyl, arylalkoxy, aryloxy, heterocycle, and heterocyclealkenyl.
A compound according to claim 1 wherein R, and R2 are hydrogen;
R3 is selected from the group consisting of alkyl, aminocarbonylalkyl wherein aminocarbonylalkyl is 4-amino-4-oxobutyl, arylalkyl wherein arylalkyl is benzyl, cyanoalkyl wherein cyanoalkyl is 3-cyanopropyl, cycloalkylalkyl wherein cycloalkylalkyl is cyclohexylmethyl, aryl wherein aryl is phenyl, arylalkyl wherein arylalkyl is selected from the group consisting of 2-phenylethyl and 3-phenylpropyl, and heterocycle wherein heterocycle is thienyl;
R4 is selected from the group consisting of aryl wherein aryl is phenyl and heterocycle wherein heterocycle is selected from the group consisting of benzofuranyl, furyl, pyridyl, pyrimidinyl, thiazolyl, and thienyl; and
R5 is selected from the group consisting of hydrogen, arylalkoxy wherein arylalkoxy is benzyloxy, aryl wherein aryl is phenyl, arylalkenyl wherein arylalkenyl is 2- phenylethenyl, aryloxy wherein aryloxy is phenoxy, heterocyclealkenyl wherein heterocyclealkenyl is 2-pyridylethenyl, and heterocycle wherein heterocycle is pyrimidinyl.
6. A compound according to claim 5 selected from the group consisting of:
4-amino-6-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6-(4-(dimethylamino)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6-(4-methylphenyl)-7-phenylpyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-(dimethylamino)phenyl)-7-(4-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-(dimethylamino)phenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-(5-pyrimidinyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-(2-(2-pyridinyl)ethenyl)phenyl)pyrido[2,3- djpyrimidine; 4-amino-6-(4-methy Ipheny l)-7-(3 -pyridinyl)pyrido [2,3 -djpyrimidine;
4-amino-6-(4-methylphenyl)-7-(thien-3-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(2-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(3,4-methylenedioxyphenyl)pyrido[2,3- djpyrimidine; 4-amino-6-butyl-7-(thien-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-butyl-7-(thien-3-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(5-bromothien-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(5-methylthien-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-(trifluoromethoxy)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6-(4-methylphenyl)-7-(3-phenoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(5-nitrothien-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-bromothien-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(3-methylthien-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(2-furyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(3-furyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(5-methyl-2-furyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-(2-propyl)phenyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-(2-propyl)phenyl)-7-(5-nitrothien-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(5-nitrothien-2-yl)pyrido[2,3-djpyrimidine;
4-amino-6-(4-(dimethylamino)phenyl)-7-(thien-2-yl)pyrido[2,3-djpyrimidine;
4-amino-6-(3,4-dimethoxyphenyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(3,4-dimethoxyphenyl)-7-(5-nitrothien-2-yl)pyrido[2,3-djpyrimidine;
4-amino-6-hexyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-hexyl-7-(thien-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(2-methyl-2-propyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-(2-propyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6-(4-propylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-djpyrimidine; 4-amino-6-(3,4-dimethoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine; 4-amino ■6-(3 -methoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido [2,3 - djpyrimidine;
4-amino-6- 3-bromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6- 3-fluorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 3-trifluoromethylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6- 3-chlorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 3,5-dichlorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine; 4-amino-6- 3,4-methylenedioxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6- 3,4-methylenedioxyphenyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6- 3-methoxycarbonylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine; 4-amino-6- 3-(2-propyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6- 4-(l,l-dimethylethyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6- 4-fluorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6- 3-(phenylmethoxy)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6- 4-chlorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 3-fluoro-4-methylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6- 3-fluoro-4-methylphenyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6- 3-phenylpropyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 3-phenylpropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 2-phenylethyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-djpyrimidine;
4-amino-6- phenylmethyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(cyclohexylmethyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6- butyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- pentyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- (2-methylpropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6- propyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 3-cyanopropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 3-nitrophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- pentyl-7-(thien-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6- 3 -carboxamidopropyl)-7-(4-(dimethy lamino)phenyl)pyrido [2,3 - djpyrimidine;
4-amino-6- (4-methoxyphenyl)methyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6- (3-bromophenyl)methyl)-7-(thien-2-yl)pyrido[2,3-djpyrimidine; 4-amino-6- (4-(2-propyl)phenyl)methyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6- (4-methoxyphenyl)methyl)-7-(4-(2-propyl)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6- (4-bromophenyl)methyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6- (3 -fluorophenyl)methyl)-7-(thien-2-yl)pyrido [2,3 -djpyrimidine; 4-amino-6- (4-bromophenyl)methyl)-7-(thiazol-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6- (3-methoxyphenyl)methyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6- phenylmethyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6- (3 -methoxyphenyl)methyl)-7-(4-(dimethylamino)phenyl)pyrido [2,3 - djpyrimidine; 4-amino-6- 4-methylphenyl)-7-(4-(trifluoromethyl)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6- 4-methy Ipheny l)-7-(4-methy Ipheny l)pyrido [2 , 3 -djpyrimidine ; 4-amino-6- 4-methylphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl)-7-(4-ethylphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl)-7-(4-cyanophenyl)pyrido[2,3-d]pyrimidine;
4-amino-6- 4-methylphenyl)-7-(4-acetamidophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl)- 7-(4-phenoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl)- 7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl)- 7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl)- 7-(4-chlorophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl)- 7-(4-aminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-6- 4-methylphenyl)- 7-(4-methylsulfanyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl)- 7-((4-phenyl)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl)- 7-((4-phenylmethoxy)phenyl)pyrido[2,3- djpyrimidine; 4-amino-6- 4-methylphenyl)-7-(4-(diethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6- 4-methylphenyl)-7-(4-(2-phenylethenyl)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6- 4-methylphenyl)-7-(4-(tert-butoxy)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl)-7-(3-chlorophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl)-7-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-6- thien-2-yl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl)-7-(benzofuran-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6- fhien-2-yl)-7-(thien-2-yl)pyrido[2,3-djpyrimidine; 4-amino-6- thien-2-yl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-bromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino6-ι (3-bromo-4-methoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6 3-bromo-4-methoxyphenyl)-7-(thien-2-yl)pyrido[2,3-djpyrimidine; 4-amino-6 4-methylphenyl)-7-(4-butoxyphenyl)pyrido[2,3-djpyrimidine; 4-amino-6 4-methylphenyl)-7-(3-methoxyphenyl)pyrido[2,3-d]pyrimidine; and
4-amino-6 4-methylphenyl)-7-(3,5-dichlorophenyl)pyrido[2,3-d]pyrimidine.
7. A method of inhibiting adenosine kinase in a mammal which comprises administering to a mammal in need such treatment an effective adenosine kinase inhibiting amount of a compound according to Claim 1.
8. A method of inhibiting adenosine kinase in a mammal which comprises administering to a mammal in need of such treatment an effective adenosine kinase inhibiting amount of a compound according to Claim 5.
9. A pharmaceutical composition comprising a therapeutic amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.
10. A pharmaceutical composition comprising a therapeutic amount of a compound according to claim 5 in combination with a pharmaceutically acceptable carrier.
11. A method of treating cerebral or myocardial ischemia, nociception , inflammation, and sepsis in a mammal in need of such treatment, comprising administering to a mammal in need of such treatment an effective amount of a compound according to claim 1.
12. A method of treating cerebral or myocardial ischemia, nociception, inflammation, and sepsis in a mammal in need of such treatment, comprising administering to a mammal in need of such treatment an effective amount of a compound according to claim 5.
13. A method of treating one or more conditions in a mammal selected from the group consisting of: cerebral ischemia; myocardial ischemia, angina, stroke, thrombotic and embolic conditions; neurological disorders consisting of stroke, epilepsy, anxiety, and schizophrenia; pain perception; neuropathic pain; visceral pain; arthritis; sepsis; and abnormal gastrointestinal motility which comprises adminstering to a mammal in need of such treatment, an effective amount of a compound according to claim 5.
14. A method of treating inflammation in a mammal which comprises administering to a mammal in need of such treatment an effective amount of the compound of claim 5.
15 A method of treating pain in a mammal which comprises administering to a mammal in need of such treatment an effective amount of the compound of claim 5.
16. A process for the preparation of a compound of formula I :
I, wherein
R, and R2 are hydrogen;
R3 is selected from alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl;
R4 is selected from aryl and heterocycle; and
R5 is selected from hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, and heterocycleoxy;
the method comprising
(a) reacting 4,6-diamino-5-iodopyrimidine with an ethenylboronic acid derivative having the formula
wherein R3 is selected from alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl, in the presence of tetrakistriphenylphosphinepalladium(O) and an aqueous alkali metal base, and isolating an intermediate compound having the formula
(b) reacting said intermediate compound of formula
with an aldehyde compound having the formula R5-R4-CHO, wherein R4 is aryl or heterocycle and R5 is selected from hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, and heterocycleoxy, under anhydrous conditions and with the removal of the water of reaction, and isolating said compound of formula I.
17. A process for the preparation of a compound of formula I
I, wherein
R, and R2 are independently hydrogen, lower alkyl, alkylcarbonyl, and arylalkyl or R, and R2 may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from the group consisting of morpholine, piperazine, piperdine, pyrrolidine, thiomorpholine, and thiomorpholine sulfone, with the requirement that not both R, and R2 may be hydrogen;
R3 is selected from the group consisting of alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl; R4 is selected from the group consisting of aryl and heterocycle; and R5 is selected from the group consisting of hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, and heterocycleoxy; the method comprising (a) reacting a compound of formula I
I, wherein
R, and R2 are hydrogen; R3 is selected from the group consisting of alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl;
R4 is selected from the group consisting of aryl and heterocycle; and R5 is selected from the group consisting of hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, and heterocycleoxy; with a compound selected from the group consisting of
(i) an alkylating agent R,-Y, wherein R, is lower alkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate;
(ii) an arylalkylating agent R,-Y, wherein R, is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate;
(iii) an alkylcarbonyl compound R,-Z, wherein R, is an alkylcarbonyl group and Z is selected from the group consisting of an acid anhydride moiety, a halide or an acyl activating group; and isolating the desired compound; and
(b) optionally, when it is desired that R2 should not be hydrogen, treating the compound from step (a) with a compound selected from the group consisting of
(i) an alkylating agent R2-Y, wherein R2 is lower alkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (ii) an arylalkylating agent R2-Y, wherein R2 is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate;
(iii) an alkylcarbonyl compound R2-Z, wherein R2 is an alkylcarbonyl group and Z is selected from the group consisting of an acid anhydride moiety, a halide or an acyl activating group; and isolating said compound of formula I.
18. A process for the preparation of a compound of formula I
I, wherein
R, and R2 are independently hydrogen, lower alkyl, alkylcarbonyl, and arylalkyl or R, and R2 may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from the group consisting of morpholine, piperazine, piperdine, pyrrolidine, thiomorpholine, and thiomorpholine sulfone, with the requirement that not both R, and R2 may be hydrogen;
R3 is selected from the group consisting of alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl; R4 is selected from the group consisting of aryl and heterocycle; and
R5 is selected from the group consisting of hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, and heterocycleoxy; the method comprising (a) reacting 6-amino-4-chloro-5-iodopyrimidine with an ethenylboronic acid derivative having the formula
wherein R3 is selected from alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl, in the presence of tetrakistriphenylphosphihepalladium(O) and an aqueous alkali metal base, and isolating an intermediate compound having the formula
(b) reacting said intermediate compound of formula
with an aldehyde compound having the formula R5-R4-CHO, wherein R4 is selected from the group consisting of aryl and heterocycle and R5 is selected from the group consisting of hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, and heterocycleoxy, under anhydrous conditions and with the removal of the water of reaction, and isolating the intermediate compound having the formula
(c) treating said intermediate compound of formula
with an amine compound having formula R,NHR2, wherein R, and R2 are as described above, and isolating the compound of the invention.
19. A compound having formula II
II, wherein
X is selected from halogen or hydroxy; R3 is selected from alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkynyl, aminoalkyl, aryl, arylalkyl, aminocarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl;
R4 is selected from the group consisting of aryl and heterocycle; and R5 is selected from the group consisting of hydrogen, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkenyl, heterocyclealkoxy, heterocyclealkyl, and heterocycleoxy.
PCT/US2001/003469 2000-02-03 2001-02-02 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds WO2001057040A1 (en)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051366A2 (en) 2001-12-13 2003-06-26 Abbott Laboratories 3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancer
WO2007081517A2 (en) 2005-12-21 2007-07-19 Abbott Laboratories Anti-viral compounds
US7547782B2 (en) 2005-09-30 2009-06-16 Bristol-Myers Squibb Company Met kinase inhibitors
US20100063032A1 (en) * 2007-03-28 2010-03-11 Debenham John S Substituted pyrido[2,3-d]pyrimidine derivatives as cannabinoid-1 receptor modulators
US7763731B2 (en) 2005-12-21 2010-07-27 Abbott Laboratories Anti-viral compounds
US7910595B2 (en) 2005-12-21 2011-03-22 Abbott Laboratories Anti-viral compounds
EP2345652A1 (en) 2005-12-21 2011-07-20 Abbott Laboratories Antiviral compounds
US8236950B2 (en) 2006-12-20 2012-08-07 Abbott Laboratories Anti-viral compounds
WO2014055955A1 (en) * 2012-10-05 2014-04-10 Rigel Pharmaceuticals, Inc. Gdf-8 inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5665721A (en) * 1995-06-07 1997-09-09 Abbott Laboratories Heterocyclic substituted cyclopentane compounds
WO1998046603A1 (en) * 1997-04-16 1998-10-22 Abbott Laboratories 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds
WO1998046604A1 (en) * 1997-04-16 1998-10-22 Abbott Laboratories 5,6,7-trisubstituted-4-aminopyridol[2,3-d]pyrimidine compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5665721A (en) * 1995-06-07 1997-09-09 Abbott Laboratories Heterocyclic substituted cyclopentane compounds
WO1998046603A1 (en) * 1997-04-16 1998-10-22 Abbott Laboratories 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds
WO1998046604A1 (en) * 1997-04-16 1998-10-22 Abbott Laboratories 5,6,7-trisubstituted-4-aminopyridol[2,3-d]pyrimidine compounds

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051366A3 (en) * 2001-12-13 2004-03-25 Abbott Lab 3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancer
US6831175B2 (en) 2001-12-13 2004-12-14 Abbott Laboratories Kinase inhibitors
WO2003051366A2 (en) 2001-12-13 2003-06-26 Abbott Laboratories 3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancer
US7547782B2 (en) 2005-09-30 2009-06-16 Bristol-Myers Squibb Company Met kinase inhibitors
EP2345652A1 (en) 2005-12-21 2011-07-20 Abbott Laboratories Antiviral compounds
WO2007081517A2 (en) 2005-12-21 2007-07-19 Abbott Laboratories Anti-viral compounds
US8338605B2 (en) 2005-12-21 2012-12-25 Abbott Laboratories Anti-viral compounds
US7763731B2 (en) 2005-12-21 2010-07-27 Abbott Laboratories Anti-viral compounds
US7910595B2 (en) 2005-12-21 2011-03-22 Abbott Laboratories Anti-viral compounds
US7915411B2 (en) 2005-12-21 2011-03-29 Abbott Laboratories Anti-viral compounds
US8236950B2 (en) 2006-12-20 2012-08-07 Abbott Laboratories Anti-viral compounds
US20100063032A1 (en) * 2007-03-28 2010-03-11 Debenham John S Substituted pyrido[2,3-d]pyrimidine derivatives as cannabinoid-1 receptor modulators
WO2014055955A1 (en) * 2012-10-05 2014-04-10 Rigel Pharmaceuticals, Inc. Gdf-8 inhibitors
US9145433B2 (en) 2012-10-05 2015-09-29 Rigel Pharmaceuticals, Inc. GDF-8 inhibitors
JP2016500671A (en) * 2012-10-05 2016-01-14 ライジェル ファーマシューティカルズ, インコーポレイテッド Gdf-8 inhibitor
US9518040B2 (en) 2012-10-05 2016-12-13 Rigel Pharmaceuticals, Inc. GDF-8 inhibitors
US9878992B2 (en) 2012-10-05 2018-01-30 Rigel Pharmaceuticals, Inc. GDF-8 inhibitors

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