EP0979230A1 - 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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EP0979230A1
EP0979230A1 EP98917950A EP98917950A EP0979230A1 EP 0979230 A1 EP0979230 A1 EP 0979230A1 EP 98917950 A EP98917950 A EP 98917950A EP 98917950 A EP98917950 A EP 98917950A EP 0979230 A1 EP0979230 A1 EP 0979230A1
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phenyl
pyrido
amino
methyl
pyrimidine
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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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Abbott Laboratories
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Abstract

A compound having formula (I), wherein R?1, R2, R3 and R4¿ are defined variables selected from the groups as specified herein which include alkyl, aryl, heteroaryl and heterocyclic and substituted versions thereof, a method for inhibiting adenosine kinase by administering a compound thereof, a pharmaceutical composition comprising a therapeutically effective amount of a compound thereof above in combination with a pharmaceutically acceptable carrier, a method of treating cerebral ischemia, epilepsy, nociperception, pain, inflammation and sepsis in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound thereof, and methods of preparation thereof.

Description

6.7-DISUBSΗTUTED-4-AMINOPYRIDOΓ2.3-D1PYRIMIDINE COMPOUNDS
Technical Field
The present invention relates a method for inhibiting adenosine kinase by adrninistering 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]pyrirrύdine 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. 107-1 18; 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 neuro protective 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, ./. 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. Na . 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 neurological disorders such as epilepsy, anxiety, schizophrenia, nociperception including pain perception, neuropathic pain, visceral pain, as well as inflammation, arthritis, immunosuppression, sepsis, diabetes and 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 2'- 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 ai, 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., 3JB: 719-720 (1992)) disclose 4-amino-5-(4-chlorophenyl)-7-(4- nirrophenyl)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, 71: 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- d]pyrimidine, 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, : 10253-10258 (1995)) discloses the synthesis of 4-amino-5,7-diphenylpyrido[2,3-d]pyrimidine compounds from acyclic precursors. Bridges et α/.(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 kinase inhibitors.
In one aspect, the present invention provides novel compounds having the formula
wherein
R1 and R2 are independently H, loweralkyl, arylalkyl or acyl, or may be taken together with the nitrogen atom to which they are attached to form a 5-to-7 membered ring optionally containing 1-3 additional heteroatoms selected from O, N or S;
R3 and R^ are independently selected from loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group and the dashed lines indicate a double bond is optionally present.
The present invention also contemplates the pharmaceutically acceptable salts and amides of the compounds of Formula I, and the use thereof as provided below.
In another aspect, the present invention provides a method for inhibiting adenosine kinase by administering a compound of Formula (I).
In particular, the method of inhibiting adenosine kinase comprises exposing an adenosine kinase to an effective inhibiting amount of a compound of Formula I of the present invention. Where the adenosine kinase is located in vivo, the compound is administered to the organism. In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I above in combination with a pharmaceutically acceptable carrier.
In still another aspect, the present invention provides a method of treating ischemia, neurological disorders, nociperception , inflammation, immunosuppression, gastrointestinal disfunctions, diabetes and sepsis in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of Formula I of the present invention. In a preferred aspect, the present invention provides a method of treating cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery, percutaneous transluminal angioplasty, stroke, thrombotic and embolic conditions, epilepsy, anxiety, schizophrenia, pain perception, neuropathic pain, visceral pain, arthritis, sepsis, diabetes and abnormal gastrointestinal motility in a mammal in need of such treatment, comprising adrriinistering to the mammal a therapeutically effective amount of a compound of Formula I of the present invention.
The present invention also contemplates the pharmaceutically acceptable salts and amides of compounds having Formula I, and their use for inhibiting adenosine kinase, in pharmaceutical compositions and for administration to a mammal.
In addition, the present invention relates to a compound of formula (II)
wherein
R1 and R2 are independently H, loweralkyl, arylalkyl or acyl, or may be taken together with the nitrogen atom to which they are attached to form a 5-to-7 membered ring optionally containing an additional oxygen or nitrogen atom;
R3 and R^ are independently selected from loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group.
In another aspect, the present invention provides a process for the preparation of compounds of formula II
wherein
R1 and R2 are hydrogen;
R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group;
R4 is aryl, heteroaryl, or a heterocyclic group; the method comprising
(a) reacting 4,6-diamino-5-iodopyrimidine with an ethenylboronic acid derivative having the formula wherein R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heterocyclic or heteroaryl or substituted versions thereof, in the presence of tetrakistriphenylphosphinepalladium(O) and an aqueous alkali metal base, and isolating a first intermediate compound having the formula
(b) reacting the first intermediate compound with an aldehyde compound having the formula R -CHO, wherein R4 is aryl, heteroaryl, or a heterocyclic group, under anhydrous conditions and with the removal of the water of reaction, and isolating the compound of formula II.
In another aspect, the present invention provides a process for the preparation of compounds of formula (II)
wherein R1 and R2 are independently H, loweralkyl, arylalkyl or acyl, or may be taken together with the nitrogen atom to which they are attached to form a 5-to-7 membered ring optionally containing an additional oxygen or nitrogen atom, with the requirement that not both R1 and R2 may be hydrogen,
R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group;
R4 is aryl, heteroaryl, or a heterocyclic group;
the method comprising
(a) reacting a compound having the formula (II)
wherein R1 and R2 are hydrogen;
R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group;
R4 is aryl, heteroaryl, or a heterocyclic group;
with a compound selected from the group consisting of
(i) an alkylating agent R -Y, wherein R1 is loweralkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (ii) an arylalkylating agent RMoweralkyl-Y, wherein R1 is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate;
(iii) an acyl compound R*-Z, wherein R1 is an acyl 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 loweralkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (ii) an arylalkylating agent R2-loweralkyl-Y, wherein R2 is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (iii) an acyl compound R2-Z, wherein R2 is an acyl 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 product. In another aspect, the present invention provides a process for the preparation of compounds of formula II
wherein
R1 and R2 are independently H, loweralkyl, arylalkyl or acyl, or may be taken together with the nitrogen atom to which they are attached to form a 5-to-7 membered ring optionally containing an additional oxygen or nitrogen atom, with the proviso that not both R4 and R5 are hydrogen;
R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group;
R4 is aryl, heteroaryl, or a heterocyclic group; the method comprising
(a) reacting 6-arnino-4-chloro-5-iodopyrimidine with an ethenylboronic acid derivative having the formula
(HO)2B^^ R3 wherein R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heterocyclic or heteroaryl, in the presence of tetrakistriphenylphosphinepalladium(O) and an aqueous alkali metal base, and isolating a first intermediate compound having the formula
(b) reacting the first intermediate compound with an aldehyde compound having the formula R -CHO, wherein R4 is aryl, heteroaryl, or a heterocyclic group, under anhydrous conditions and with the removal of the water of reaction, and isolating the second intermediate compound having the formula Cl
and (c) treating the fourth intermediate compound with an arnine compound having the formula Rl-NH-R2, wherein R1 and R2 are as described above, and isolating the desired product.
Detailed Description of the Invention
The present invention relates to 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine 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 aspect, the present invention provides 6,7-disubstituted-4-aminopyrido[2,3- d]pyrimidine compounds that are adenosine kinase inhibitors. An adenosine kinase inhibitor of the present invention is a compound of the Formula I or D, shown above.
In a preferred embodiment, an adenosine kinase inhibitor of the present invention is a compound of Formula (I) or (II) above, wherein R4 is aryl or heteroaryl and substituted versions thereof.
In a more preferred embodiment, an adenosine kinase inhibitor of the present invention is a compound of Formula (I) or (II) above, wherein R4 is aryl or heteroaryl or substituted versions thereof and R3 is loweralkyl, aryl, arylalkyl or heteroaryl or substituted versions thereof.
In an additional embodiment, the present invention relates to compounds of formula I and II as shown above wherein
Rl and R^ are independently selected from H, loweralkyl, arylCι-C6alkyl, -C(O)Cl-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to from a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S; R and R^ are independently selected from the group consisting of:
Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heteroarylCθ-C6alkyl or substituted heteroarylCθ-C6alkyl, aryl )-C6alkyl or substituted arylC()-C6alkyl, heteroarylC2-C6alkenyl or substituted heteroarylC2-C6alkenyl, arylC2-C6alkenyl or substituted arylC2-C6alkenyl, heteroarylC2-C6alkynyl or substituted heteroarylC2-C6alkynyl, arylC2-C6alkynyl or substituted arylC2-C6alkynyl wherein the 1-4 heteroaryl or aryl substituents are independently selected from halogen, oxo, cyanoCι-C6alkyl, heteroarylCo-C6alkyl, heterocyclic )- C6alkyl, Cl-C6alkyloxy, Ci-C6alkyloxyCi-C6alkyl, arylCθ-C6alkyl, arylCl-C6alkyloxy, R5R6NC(O), cyano, C2-C6alkenyl, C2-C6alkynyl, Cl-C6alkyl, C2-C6alkenyldialkylmalonyl, CF3, HO-, Cι-C6alkyloxyCi-
Cόalkyloxy, Cl-C6alkylSOn wherein n is 1-2, Ci-C6alkylthio, Cl- Cόalkylacryl, CF3O, CF3, Cl-C4alkylenedioxy, Cl-C6alkylacryl, R5R6N(CO)NR5, N-formyl(heterocyclic), NO2, NR5R6Q)-C6alkyl, wherein R^ and R" are independently selected from H, Ci-C6alkyl, HC(O), Cl-C6alkyloxyCi-C6alkyl, Ci-C6alkyloxy, -
C6alkylC(O), CF3C(O), NR7R8C i -C6 lkyl, phthalimidoCi - C6C(O), C i-C6alkylSOn where n is 1-2, CNCi-Cόalkyl, R7R8NC(O)NR7-, heteroaryl, NR7R8Ci-C6alkylC(O), C\- C6alkyloxycarbamidoC 1 -C6alkyl, wherein R7 and R8 are independently selected from those variables identified for R^ and R^ or R5 and R^ or R7 and R8 may join together with the nitrogen atom to which they are attached to form a 5-7 membered unsubstituted or substituted ring optionally containing 1-3 additional heteroatoms selected from O, N or S wherein the substituents are selected from Cl-C6alkyl and wherein, in the case of formula I, a dashed line — indicates a double bond is optionally present. The present invention also includes those compounds having R^ and R^ independently selected from those groups shown below as 6-substituted groups and as 7-substituted groups.
Exemplary and preferred compounds of the invention include: 4-annno-6-phenyl-7-(p-dimethylan inophenyl)pyrido[2,3-d]pyrimidine;
4-arnino-6-(4-methylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrirrtidine; 4-amirιo-6-(4-(dimethylamino)phenyl)-7-(4-(dimelhylarnino)phenyl)pyrido[2,3- d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-phenylpyrido[2,3-d]pyrimidine; 4-arnino-6-(4-methylphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-an ino-6-(4-(dimethylarrύno)phenyl)-7-(4-pyridinyl)pyrido[2,3-d]pyrirnidine; 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- d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(3-pyridinyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(thiophen-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- d]pyrimidine;
4-anτino-6-butyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-an ino-6-butyl-7-(thiophen-3-yl)pyrido[2,3-d]pyrirnidine; 4-an ino-6-(4-meώylphenyl)-7-(5-bromothiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(5-methylthiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-(trifluoromethoxy)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-6-(4-methylphenyl)-7-(3-phenoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(5-nitrothiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-ar no-6-(4-methylphenyl)-7-(4-bromotr ophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(3-methylthiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(furan-2-yl)pyrido[2,3-d]pyrimidine; 4-amrno-6-(4-methylphenyl)-7-(furan-3-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(5-methyl-furan-2-yl)pyrido[2,3-d]pyrimidine; 4-arm^o-6-(4-(2-propyl)phenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-arm^o-6-(4-(2-propyl)phenyl)-7-(5-nitrothiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(5-nitrothiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-aπrino-6-(4-(dimethylarrύno)phenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrirm^ine; 4-amino-6-(3,4-dimethoxyphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-aπύno-6-(3,4-dimethoxyphenyl)-7-(5-nitrothiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-arrιino-6-hexyl-7-(4-(dimethylami ιo)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-hexyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-armϊιo-6-(2-methyl-2-propyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-aπώo-6-(4-(2-propyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-an ino-6-(4-propylphenyl)-7-(4-(dimethylanτino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(3,4-dimethoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-anτino-6-(3-methoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine;
4-anrino-6-(3-bromophenyl)-7-(4-(dimethylar no)phenyl)pyrido[2,3-d]pyrirnidine; 4-anτko-6-(3-fluorophenyl)-7-(4-(dimethylanτino)phenyl)pyrido[2,3-d]pyrirnidine;
4-an ino-6-(3-trifluoromethylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine;
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-aπ o-6-(3,4-methylenedioxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-aιτuno-6-(3,4-methylenedioxyphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-arnino-6-(3-methoxycarbonylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine;
4-amino-6-(3-(2-propyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6-(4-(2-methyl-2-propyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine; 4-amino-6-(4-fluorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrirnidine;
4-amino-6-(4-methoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine; 4-aπu^o-6-(3-(phenylmethoxy)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- d]pyrirnidine;
4-arm^o-6-(4-chlorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(3-fluoro-4-methylphenyl)-7-(4-(dimethylarnino)phenyl)pyrido[2,3- d]pyrirnidine;
4-an no-6-(3-fluoro-4-methylphenyl)-7-(tMophen-2-yl)pyrido[2,3-d]pyrimidine;
4-arm^o-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-aπτino-6-(2-phenylethyl)-7-(4-(dimethylanrino)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-aπιino-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-aπvino-6-(2-methylpropyl)-7-(4-(dimethylarrύno)phenyl)pyrido[2,3-d]pyrimidine;
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-(dimethylaιτιino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-pentyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6 3-carboxamidopropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6- (4-methoxyphenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6- (3-bromophenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6- (4-(2-propyl)phenyl)methyl)-7-(thiophen-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-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6- (3-fluorophenyl)memyl)-7-(tlu^phen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6- (4-bromophenyl)memyl)-7-(thiazole-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6- (3-methoxyphenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6- phenylmethyl)-7-(thiophen-2-yl)pyrido[2,3-dlpyrimidine; 4-amino-6- (3-methoxyphenyl)methyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine;
4-amino-6- 4-methylphenyl)-7-(4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- 4-methylphenyl)-7-(4-methylphenyl)pyrido[2,3-d]pyrimidine; 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-arrιino-6-(4-methylphenyl)-7-(4-cyanophenyl)pyrido[2,3-d]pyrimidine; 4-arrύno-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-arm^o-6-(4-methylphenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4 Uorophenyl)pyrido[2,3-d]pyrimidine; 4-arrιino-6-(4-methylphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine; 4-arr no-6-(4-methylphenyl)-7-(4-methylthiophenyl)pyrido[2,3-d]pyrimidine; 4-aπvino-6-(4-methylphenyl)-7-((4-phenyl)phenyl)pyrido[2,3-d]pyrimidine; 4-arru ιo-6-(4-methylphenyl)-7-((4-phenylmethoxy)phenyl)pyrido[2,3-d]pyrirnidine;
4-amino-6-(4-methylphenyl)-7-((4-N,N-diethylamino)phenyl)pyrido[2,3- d]pyrirnidine;
4-amino-6-(4-methylphenyl)-7-((4-2-phenylethenyl)phenyl)pyrido[2,3- djpyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-(2-methyl-2-propoxy)phenyl)pyrido[2,3- djpyrimidine;
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-(thiophen-2-yl)-7-(4-N,N-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-6-(4-methylphenyl)-7-(benzofuran-2-yl)pyrido[2,3-d]pyrimidine; 4-arnino-6-(thiophen-2-yl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(thiophen-2-yl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-bromophenyl)-7-(4-N,N-dimethylaminophenyl)pyrido[2,3- d]pyrirnidine;
4-amino-6-(3-bromo-4-methoxyphenyl)-7-(4-N,N-dimethylaminophenyl)- pyrido[2,3-d]pyrimidine;
4-anτino-6-(3-bromo-4-methoxyphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 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. The present invention also includes those reduced versions of the compounds described above wherein the right side of the bicyclic ring may be reduced or partially reduced as shown in formula I via catalytic hydrogenation or other known reduction process to form compounds as above wherein the 5,6 and/or the 7,8 double bond is absent or where there is a double bond between the 6 and 7 carbons. It is contemplated that the final compounds shown above may be readily reduced and thus these compounds are within the scope of the invention.
In addition, R^ and R^ may independently be selected fromphenyl; thiophen-2-yl; 1- methyl-2-oxobenzoxazolin-5-yl; 2-(dimethylamino)-5-pyrimidinyl; 2-(N-formyl-N-methyl anιino)-3-pyrimidinyl; 2-(N-(2-mεthoxyethyl)-N-methyl amino)-5-pyrimidinyl; 2-(N- methylamino)5-pyrimidinyl; 2-(l-mo hoUnyl)-5-pyrimidinyl; 2-(l-pyrrolidinyl)-5- pyrimidinyl; 2-dimethylarnino-5-pyrimidinyl; 2-furanyl; 2-oxobenzoxazolin-5-yl; 2-pyridyl; 3-(dimethylamino)phenyl; 3-amino-4-methoxyphenyl; 3-bromo-4-(dimethylamino)phenyl; 3-methoxyphenyl; 3-methyl-4-(N-acetyl-N-methylamino)phenyl; 3-methyl-4-(N-formyl-N- methylamino)phenyl; 3-methyl-4-(N-methyl-N-(txffluoroacetyl)amino)phenyl; 3-methyl-4- (N-methylamino)phenyl; 3-methyl-4-pyrrolidinylphenyl; 3-pyridyl; 3,4-dichlorophenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 4-(acetylamino)phenyl; 4- (dimethylamino)-3-fluorophenyl; 4-(dimethylamino)phenyl; 4-(imidazol-l-yl)phenyl; 4- (methylthio)phenyl; 4-(morpholinyl)phenyl; 4-(N-(2-(dimethylanτino)ethyl)amino)phenyl; 4-(N-(2-methoxyethyl)amino)phenyl; 4-(N-acetyl-N-methylamino)phenyl; 4-(N-ethyl-N- formylamino)phenyl; 4-(N-ethylamino)phenyl; 4-(N-formyl-N-(2- methoxyethyl)amino)phenyl; 4-(N-isopropylamino)phenyl; 4-(N-methyl-N-((2- dimethylamino)ethyl)amino)phenyl; 4-(N-methyl-N-(2-(N- phthaUmidyl)acetyl)amino)phenyl; 4-(N-methyl-N-(2-cyano)ethylamino)phenyl; 4-(N- methyl-N-(2-methoxyethyl)amino)phenyl; 4-(N-methyl-N-(3- methoxy)propionylamino)phenyl; 4-(N-methyl-N-acetylamino)phenyl; 4-(N-methyl-N- formylamino)phenyl; 4-(N-methyl-N-trifluoroacetylamino)phenyl; 4-(N- morpholinyl)phenyl; 4-(thiophen-2-yl)phenyl; 4-(ureido)phenyl; 4-(2- (dimemylamino)acetylarr no)phenyl; 4-(2-(2-methoxy)acetylarnino)ethyl)amino)phenyl; 4- (2-methoxy)ethoxyphenyl; 4-(2-oxo- l-oxazolidinyl)phenyl; 4-(4-methoxy-2-butyl)pheny); 4-(4-methylpiperidinyl)phenyl; 4-(5-pyrimidinyl)phenyl; 4-aminophenyl; 4-bromophenyl; 4-butoxyphenyl; 4-carboxamidophenyl; 4-chlorophenyl; 4-cyanophenyl; 4- diethylaminophenyl; 4-diethylmalonylallylphenyl); 4-dimethylaminophenyl; 4- ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4- iodophenyl; 4-isopropylphenyl; 4-methoxyphenyl) 4-methylaminophenyl; 4- methylsulfonylphenyl; 4-moφholinylphenyl; 4-N-(2-(dimethylamino)ethyl)-N- formylamino)phenyl; 4-N-(3-methoxypropionyl)-N-isopropyl-amino)phenyl; 4-N-ethyl-N- (2-methoxyethyl)amino)phenyl; 4-N-formylpiperidinylphenyl; 4-nitrophenyl; 4- piperidinylphenyl; 4-pyridylphenyl; 4-pyrrolidinylphenyl; 4-t-butylacrylphenyl; 5- (dimethylamino)thiophen-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 3- dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6-(N- methyl-N-formylamino)-3-pyridinyl; 6-(N-methyl-N-(2-methoxyethyl)amino)-3-pyridinyl; 6-(2-oxo-oxazolidinyl)-3-pyridinyl; 6-dimethylamino-3-pyridinyl; 6-imidazolyl-3-pyridinyl; 6-morphoUnyl-3-pyridinyl; 6-pyrrolidinyl-3-pyridinyl; (2-propyl)-3-pyridinyl; and (4- formylarnino)phenyl; (thiophen-2-yl)methyl; (thiophen-3-yl)methyl; butyl; cycloheptyl; pentyl; thiophen-2-yl; l-(3-bromophenyl)ethyl; 2-(N-phenylmethoxycarbonyl)aminophenyl; 2-(3-bromophenyl)ethyl; 2-(3-cyanophenyl)methyl; 2-(4-bromophenyl)ethyl; 2-(5-chloro-2- (thiophen-3-yl)phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl; phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3-(furan-2-yl)phenyl; 3- (thiophen-2-yl)phenyl; 3-(2-pyridyl)phenyl; 3-(3-methoxybenzyl)phenyl; 3- (amino)propynyl; 3-benzyloxyphenyl; 3-bromo-4-fluorophenyl; 3-bromo-5-iodophenyl; 3- bromo-5-methoxyphenyl; 3-bromophenyl; 3-bromophenylmethyl; 3-carboxamidophenyl; 3- chlorophenyl; 3-cyanophenyl; 3-diethylmalonylallylphenyl; 3-dimethylaminophenyl; 3- ethoxyphenyl; 3-fluoro-5-rrifluoromethylphenyl; 3-fluorophenyl; 3-hydroxyphenyl; 3- iodophenyl; 3-methoxyethyoxyphenyl; 3-methoxyphenyl; 3-methylphenyl; 3- methylsulfonylphenyl; 3-methylthiophenyl; 3-t-butylacrylphenyl; 3-trifloromethyoxyphenyl; 3-trifluoromethylphenyl; 3-vinylpyridinylphenyl; 3,4-dichlorophenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 3,5-di(trifluoromethyl)phenyl; 3,5- dibromophenyl; 3,5-dichlorophenyl; 3,5-dimethoxyphenyl; 3,5-dimethylphenyl; 4-(2- propyl)phenyl; 4-(2-propyl)oxyphenyl; 4-benzyloxyphenyl; 4-bromophenyl; 4- bromothiophen-2-yl; 4-butoxyphenyl; 4-dimethylaminophenyl; 4-fluoro-3- trifluoromethylphenyl; 4-methoxyphenyl; 4-neopentylphenyl; 4-phenoxyphenyl; 5- bromothiophen-2-yl; 5-cyclohexyl; 5-cyclopropyl; 5-hexyl; 5-methyl; 5-phenyl; (2-bromo- 5-chlorophenyl)methyl; (2-bromophenyl)methyl; and (5-chloro-2-(3- methoxyphenyl)phenyl)methyl or other groups as specified herein.
The term "acyl", as used herein, refers to a moiety attached by a carbonyl linkage, as for example, loweralkyl-carbonyl or aryl-carbonyl, wherein loweralkyl and aryl are as defined herein. Examples of acyl include, for example, acetyl, propionyl, hexanoyl, trifluoroacetyl, benzoyl, 4-methylbenzoyl, methoxyacetyl, pentanoyl, N- Bocglycylimidazoyl, N-phthalimidylglycyl and the like or others as specified herein. The term "aryl" or "substituted aryl", as used herein, refers to a carbocyclic aromatic radical, including, for example, phenyl and 1 - or 2-naphthyl, which may be unsubstituted or substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, cyano, carboxamido, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkylamino), N-loweralkyl- N-loweralkoxyamino, trifluoromethyl or methoxymethyl groups. In addition, the term "aryl" refers to a phenyl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, morpholinyl, phenyl-lowerlalkoxy, phenyl-loweral enyl or cycloalkyl-loweralkyl group. Examples of aryl radicals include, but are not limited to, 3- bromophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 3-(2-propyl)phenyl, 3,4-dimethoxyphenyl, 3-trifluoromethylphenyl, 3-trifluoro-4-fluorophenyl, 4-(N-methyl- N-methoxyl)ethylaminophenyl, 4-dimethylaminophenyl, 3-fluoro-4-methylphenyl, 4- methylphenyl, 4-cyanophenyl, 4-propylmethyl, 3,5-dichlorophenyl, 3,4- methylenedioxyphenyl, 3-cyanopropylphenyl, 4-ureidophenyl, 3-methylsulfonylphenyl, 3- carboxamidopropylphenyl or others as shown herein.
The term "arylalkyl" refers to a loweralkyl radical having appended thereto an aryl group, as defined above, as for example benzyl and phenylethyl. The term "aryloxy" refers to a aryl radical which is appended to the molecule via an ether linkage (i.e., through an oxygen atom), as for example phenoxy, naphthyloxy, 4- chlorophenoxy, 4-methylphenoxy, 3,5-dimethoxyphenoxy, and the like.
The term "cycloalkyl" refers to a cyclic saturated hydrocarbon radical having from 3 to 7 ring atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl is also described as C3-C8cycloalkyl.
The term "cycloalkyl-loweralkyl" refers to a loweralkyl radical as defined below substituted with a cycloalkyl group as defined above by replacement of one hydrogen atom. Examples of cycloalkyl-loweralkyl include cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylbutyl, and the like. The term "heteroaryl" refers to a monocyclic aromatic radical having from five to seven ring atoms of which one ring atom is nitrogen, oxygen or sulfur; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms. A heteroaryl group may be unsubstituted or substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, cyano, carboxamido, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkylamino), N-loweralkyl-N-loweralkoxyamino, trifluoromethyl or methoxymethyl groups. In addition, the term "heteroaryl " refers to a heteroaryl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, moφholinyl, phenyl-lowerlalkoxy, phenyl-loweralkenyl or cycloalkyl-loweralkyl group. In addition a heteroaryl group may be substituted by replacement of any two adjacent hydrogen atoms with a grouping of atoms to form a fused benzene ring. Examples of heteroaryl include pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, furanyl, thiophenyl, 5- methylthiophen-2-yl, 5-nitrothiophen-2-yl, 5-methylfuranyl, benzofuranyl, benzothiophenyl, and the like and others as shown herein. The term "heterocyclic" refers to a saturated or unsaturated monocyclic ring system radical having from four to seven ring atoms of which one is nitrogen or oxygen; one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remainder are carbon, the radical being joined to the rest of the molecule via any of the ring atoms and being optionally substituted, either on a nitrogen or a carbon atom, by an additional radical selected from among aryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl), amino (loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy, halogen, amino, loweralkylamino, and amino, (loweralkyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further substituted with alkanoyl of from one to eight carbons, an alpha-amino acid or a polypeptide. Examples of heterocyclic include pyrrolidine, tetrahydrofuran, dihydropyrrole, isoxazolidine, oxazolidine, tetrahydropyridine, piperidine, piperazine, moφholine, thiomoφholine, aziridine and azetidine and those additionally described herein. The term "heterocyclic-loweralkyl" refers to a loweralkyl radical as defined below substituted with a heterocyclic-group as defined above by replacement of one hydrogen atom. Examples of cycloalkyl-loweralkyl include pyrrolidinylmethyl, piperidinylethyl, and the like.
The term "loweralkyl", as used herein, refers to saturated, straight- or branched- chain hydrocarbon radicals containing from one to six carbon atoms including, which may be unsubstituted or substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, cyano, carboxamido, hydroxy, loweralkoxy, amino, loweralkylamino, di(loweralkylamino) or N-loweralkyl-N-loweralkoxyamino groups. Examples of loweralkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, hydroxyethyl, methoxymethyl, trifluoromethyl, 3-cyanopropyl, 3-carboxamidopropyl, and the like. In certain cases, the group "Ci-Cβalkyl" is described and has a similar meaning as above for loweralkyl but is more specifically recited. Likewise, the term "Co-Cβalkyl" indicates the carbon atoms which may be present in the alkyl chain including zero. These terms are also provided adjacent to aryl or heteroaryl or other generic group and represent or have the same meaning as, for example, "arylalkyl" or "heteroarylalkyl".
The term "loweralkenyl", as used herein, refers to mono-unsaturated straight- or branched-chain hydrocarbon radicals containing from two to six carbon atoms including, but not limited to, vinyl, propenyl, rc-butenyl, /-butenyl, n-pentenyl, and n-hexenyl. These variables are also recited as, for example, C2-C6alkenyl. The term "loweralkoxy" refers to a loweralkyl radical which is appended to the molecule via an ether linkage (i.e., through an oxygen atom), as for example methoxy, ethoxy, propoxy, 2-propoxy, 2-methyl-2-propoxy, tert-butoxy, pentyloxy, hexyloxy, isomeric forms thereof and the like. This term is also described as Ci-Cβalkyloxy.
The term "loweralkynyl", as used herein, refers to straight- or branched-chain hydrocarbon radicals possessing a single triple bond and containing from two to six carbon atoms including, but not limited to, ethynyl, propynyl, n-butynyl, Λ-pentynyl, and n- hexynyl. This term is also described as C2-C6alkynyl.
The term "mammal" has its ordinary meaning and includes human beings. 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/Tcg/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 heterocychc 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 Formula I 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, triethylamine, piperidine, pyrrolidine, benzylamine, and the like, or a quantemary 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 Formula I or π 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 (I) 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 absoφtion of the injectable pharmaceutical form may be brought about by the use of agents delaying absoφtion, for example, aluminum monostearate and gelatin.
If desired, and for more effective distribution, the compounds may be incoφorated 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 incoφorating 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) absoφtion 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 absoφtion-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 XIN, 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 R1, R2, R3 and R+ are as defined above unless otherwise noted.
Scheme 1
In accordance with Scheme 1 are prepared compounds of Formula (II) wherein R1 and R2 are hydrogen. A starting material, 4,6-diamino-5-iodopyrimidine (1), is reacted with ethenylboronic acid derivatives (2), wherein R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heterocyclic or heteroaryl or substituted versions thereof, 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. Compounds of formula (2) may be prepared by reaction of an R3-substituted acetylene with catecholborane in a solvent such as THF. R3-substituted acetylenes may be prepared according to various literature procedures, such as, for example, Van Hijfte et al, Tetrahedron Letters, 1989, 30: 3655; Tao et al, J. Org.Chem., 1990, 55: 63; and Rossi et al., Gazz. Chim. Ital, 1990, 120: 783-791.
Compound (3) is then reacted with the aldehyde compound (4), wherein R4 is aryl, heteroaryl, or a heterocyclic group, 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 Formula (II) wherein R1 and R2 are hydrogen. The compounds prepared according to Scheme 1 may be further treated with a suitable reducing agent such as hydrogen in the presence of a catalyst or other reducing agent to form the 5,6 and/or 7,8 reduced versions of a compound of formula II. In addition, reduction can proceed to form single bonds at the 5,6 and 7,8 positions and a double bond between the 6, 7 carbons. In the former case(s), stereoisomers are formed and are included within the scope of the invention. These isomers may be isolated by conventional means.
Scheme 2
In accordance with Scheme 2, compounds of Formula (II) wherein one or both of R1 and R2 are loweralkyl, arylalkyl or acyl, may be prepared by treatment of compound (5) with the appropriate reagent. To prepare compounds of formula (I) or (II) wherein R1 and R2 are not both hydrogen atoms, it is possible to prepared the desired derivative from the compound of Formula (I) wherein R1 and R2 are both hydrogen atoms. When R1 or R2 is loweralkyl 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 R1 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 R1 or R2 is acyl 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 R1 and R2 are taken together with the nitrogen atom to which they are attached to form a 5-to-7 membered ring optionally containing an additional oxygen or nitrogen atom, 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 a 5-7 membered ring compound optionally containing an additional oxygen or nitrogen atom. Examples of such compounds include, but are not limited to, morpholine, piperidine, pyrrolidine, piperazine, thiomoφholine, and the like. 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.
By a "therapeutically-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 ^C-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 adrriinistration 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 Omni tech 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
Method of Treating Cerebral Ischemia, Epilepsy,
Nociperception (Nociception) (Pain), Inflammation including conditions such as Septic Shock due to Sepsis Infection
In yet another aspect of the present invention a method of treating cerebral ischemia, epilepsy, nociperception or nociception, pain, inflammation including conditions such as septic shock due to sepsis infection in a human or lower mammal is disclosed, comprising adrninistering to the mammal a therapeutically effective amount of a compound.
Alterations in cellular adenosine kinase activity have been observed in certain 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. Acta 1976, 67: 15-20). Lymphocyte adenosine kinase activity was decreased in patients infected with the human immunodeficiency virus (HTV) exhibiting symptoms of AIDS, and increased in asymptomatic HIV-seropositive and HJV-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 a , 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 abihty 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., /. 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 antinociperception. (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-(p-dimethylaminophenyl)pyridor2.3-dlpyrimidine
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" 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
The 4,6-diamino-5-(2-phenylethenyl)pyrimidine was prepared as follows: la. 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 "R3" Reagent)
Phenylacetylene (5 mmol, Aldrich) was dissolved in 5 mL of dry THF and catecholborane (5 mL, 1M 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 1M HCl (10 mL), and this solution is taken directly to the next step. lc. 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 1M 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/CH2Cl2 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 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, and pharmaceutically acceptable salts and amides thereof, having the formula
wherein
R1 and R2 are independently H, loweralkyl, arylalkyl or acyl, or may be taken together with the nitrogen atom to which they are attached to form a 5-to-7 membered ring optionally containing an additional oxygen or nitrogen atom; R. and R are independently selected from loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group and the dashed lines indicate a double bond is optionally present.
2. A compound according to Claim 1 wherein
R3 is selected from loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group; and
R is selected from aryl, arylalkyl, heteroaryl, or a heterocyclic group.
3. A compound according to Claim 1 wherein
Rl and R^ are independently selected from H, loweralkyl, arylCi-C6alkyl, -C(O)Ci-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to from a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
R3 and R^ are independently selected from the group consisting of:
Ci-Cόalkyl,
C2-C6alkenyl,
C2-C6alkynyl, C3-C8cycloalkyl, heteroarylCθ-C6alkyl or substituted heteroarylCθ-C6alkyl, arylCo-C6alkyl or substituted arylCo-Cόalkyl, heteroarylC2-C6alkenyl or substituted heteroarylC2-C6alkenyl, arylC2-C6alkenyl or substituted arylC2-C6alkenyl, heteroarylC2-C6alkynyl or substituted heteroarylC2-C6alkynyl, arylC2-C6alkynyl or substituted arylC2-C6alkynyl wherein the 1-4 heteroaryl or aryl substituents are independentiy selected from halogen, cyanoCi-C6alkyl, heteroaryl, heterocyclic, Cι-C6alkyloxy, Ci- C6alkyloxyCι-C6alkyl, arylCi -Cόalkyl, H2NCι-C6alkyl, arylCi - Cόalkyloxy, H2NC(O), cyano, C2-C6alkenyl, C2-C6alkynyl, Cι-C6alkyl,
C2-C6alkenyldialkylmalonyl, CF3, HO-, Ci-CβalkyloxyCi-Cόalkyloxy, SOnCi-C6alkyl wherein n is 1-3, Cι-C6alkylthio, Cι-C6alkylacryl, CF3O, CF3, Cι-C4alkylenedioxy, Ci-Cβalkylacryl, H2N(CO)NH, N- formyl(heterocyclic), NO2, NR5R6C()-C6alkyl, wherein R^ and R^ are independently selected from H, Ci-C alkyl,
HC(O), Cι-C6alkyloxyCι-C6alkyl, Cι-C6alkyloxy, Ci- C6alkylC(O), CF3C(O), NR7R8Cι-C6alkyl, phthalimidoCi- C6C(O), CNCi-Cβalkyl, H3NC(O)NH-, heteroaryl, NR7R8Ci- C6alkylC(O), Cι-C6alkyloxycarbamidoCi-C6alkyl, wherein R ' and R° are independently selected from those variables identified for R^ and R^ or R^ and R6 or R7 and R8 may join together with the nitrogen atom to which they are attached to form a 5-7 membered unsubstituted or substituted ring optionally containing 1-3 additional heteroatoms selected from O, N or S wherein the substituents are selected from Ci-C6alkyl.
4. A compound according to Claim 1 wherein R3 and R^ are independently selected from phenyl; thiophen-2-yl; l-methyl-2- oxobenzoxazolin-5-yl; 2-(dimethylamino)-5-pyrimidinyl; 2-(N-formyl-N-methyl amino)-3- pyrimidinyl; 2-(N-(2-methoxyethyl)-N-methyl amino)-5-pyrimidinyl; 2-(N-methylamino)5- pyrimidinyl; 2-(l-morpholinyl)-5-pyrimidinyl; 2-(l-pyrroUdinyl)-5-pyrimidinyl; 2- dimethylamino-5-pyrimidinyl; 2-furanyl; 2-oxobenzoxazolin-5-yl; 2-pyridyl; 3- (dimethylarnino)phenyl; 3-amino-4-methoxyphenyl; 3-bromo-4-(dimethylamino)phenyl; 3- methoxyphenyl; 3-methyl-4-(N-acetyl-N-methylamino)phenyl; 3-methyl-4-(N-formyl-N- methylamino)phenyl; 3-methyl-4-(N-methyl-N-(trifluoroacetyl)amino)phenyl; 3-methyl-4- (N-methylamino)phenyl; 3-methyl-4-pyrrolidinylphenyl; 3-pyridyl; 3,4-dichlorophenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 4-(acetylamino)phenyl; 4- (dimethylamino)-3-fluorophenyl; 4-(dimethylamino)phenyl; 4-(imidazol-l-yl)phenyl; 4- (methylthio)phenyl; 4-(mo holinyl)phenyl; 4-(N-(2-(dimethylamino)ethyl)amino)phenyl; 4-(N-(2-methoxyethyl)amino)phenyl; 4-(N-acetyl-N-methylamino)phenyl; 4-(N-ethyl-N- formylamino)phenyl; 4-(N-ethylamino)phenyl; 4-(N-formyl-N-(2- methoxyethyl)amino)phenyl; 4-(N-isopropylamino)phenyl; 4-(N-methyl-N-((2- dimethylarriino)ethyl)amino)phenyl; 4-(N-methyl-N-(2-(N- phthaUππdyl)acetyl)ar no)phenyl; 4-(N-methyl-N-(2-cyano)ethylamino)phenyl; 4-(N- methyl-N-(2-methoxyethyl)amino)phenyl; 4-(N-methyl-N- (3- methoxy)propionylamino)phenyl; 4-(N-methyl-N-acetylamino)phenyl; 4-(N-methyl-N- formylamino)phenyl; 4-(N-methyl-N-trifluoroacetylamino)phenyl; 4-(N- morpholinyl)phenyl; 4-(thiophen-2-yl)phenyl; 4-(ureido)phenyl; 4-(2- (dimethylarruno)acetylamino)phenyl; 4-(2-(2-methoxy)acetylamino)ethyl)amino)phenyl; 4- (2-methoxy)ethoxyphenyl; 4-(2-oxo- l-oxazolidinyl)phenyl; 4-(4-methoxy-2-butyl)phenyl; 4-(4-methylpiperidinyl)phenyl; 4-(5-pyrimidinyl)phenyl; 4-aminophenyl; 4-bromophenyl; 4-butoxyphenyl; 4-carboxamidophenyl; 4-chlorophenyl; 4-cyanophenyl; 4- diethylaminophenyl; 4-diethylmalonylallylphenyl); 4-dimethylaminophenyl; 4- ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4- iodophenyl; 4-isopropylphenyl; 4-methoxyphenyl) 4-methylaminophenyl; 4- methylsulfonylphenyl; 4-morpholinylphenyl; 4-N-(2-(dimethylamino)ethyl)-N- formylamino)phenyl; 4-N-(3-methoxypropionyl)-N-isopropyl-amino)phenyl; 4-N-ethyl-N- (2-methoxyethyl)amino)phenyl; 4-N-formylpiperidinylphenyl; 4-nitrophenyl; 4- piperidinylphenyl; 4-pyridylphenyl; 4-pyrrolidinylphenyl; 4-t-butylacrylphenyl; 5- (dimethylamino)thiophen-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 3- dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6-(N- methyl-N-formylamino)-3-pyridinyl; 6-(N-methyl-N-(2-methoxyethyl)amino)-3-pyridinyl; 6-(2-oxo-oxazolidinyl)-3-pyridinyl; 6-dimethylarnino-3-pyridinyl; 6-imidazolyl-3-pyridinyl; 6-morpholinyl-3-pyridinyl; 6-pyrrolidinyl-3-pyridinyl; (2-propyl)-3-pyridinyl; and (4- formylamino)phenyl; (thiophen-2-yl)methyl; (thiophen-3-yl)methyl; butyl; cycloheptyl; pentyl; thiophen-2-yl; l-(3-bromophenyl)ethyl; 2-(N-phenylmethoxycarbonyl)aminophenyl; 2-(3-bromophenyl)ethyl; 2-(3-cyanophenyl)methyl; 2-(4-bromophenyl)ethyl; 2-(5-chloro-2- (thiophen-3-yl)phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl; phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3-(furan-2-yl)phenyl; 3- (thiophen-2-yl)phenyl; 3-(2-pyridyl)phenyl; 3-(3-methoxybenzyl)phenyl; 3- (amino)propynyl; 3-benzyloxyphenyl; 3-bromo-4-fluorophenyl; 3-bromo-5-iodophenyl; 3- bromo-5-methoxyphenyl; 3-bromophenyl; 3-bromophenylmethyl; 3-carboxamidophenyl; 3- chlorophenyl; 3-cyanophenyl; 3-diethylmalonylallylphenyl; 3-dimethylaminophenyl; 3- ethoxyphenyl; 3-fluoro-5-trifluoromethylphenyl; 3-fluorophenyl; 3-hydroxyphenyl; 3- iodophenyl; 3-methoxyethyoxyphenyl; 3-methoxyphenyl; 3-methylphenyl; 3- methylsulfonylphenyl; 3-methylthiophenyl; 3-t-butylacrylphenyl; 3-trifloromethyoxyphenyl; 3-trifluoromethylphenyl; 3-vinylpyridinylphenyl: 3,4-dichlorophenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 3,5-di(trifluoromethyl)phenyl; 3,5- dibromophenyl; 3,5-dichlorophenyl; 3,5-dimethoxyphenyl; 3,5-dimethylphenyl; 4-(2- propyl)phenyl; 4-(2-propyl)oxyphenyl; 4-benzy oxyphenyl; 4-bromophenyl; 4- bromothiophen-2-yl; 4-butoxyphenyl; 4-dimethylarninophenyl; 4-fluoro-3- trifluoromethylphenyl; 4-methoxyphenyl; 4-neopentylphenyl; 4-phenoxyphenyl; 5- bromothiophen-2-yl; 5-cyclohexyl; 5-cyclopropyl; 5-hexyl; 5-methyl; 5-phenyl; (2-bromo- 5-chlorophenyl)methyl; (2-bromophenyl)methyl; and (5-chioro-2-(3- methoxyphenyl)phenyl)methyl.
5. A compound according to Claim 1 of the formula:
wherein
R1 and R2 are independently H, loweralkyl, arylalkyl or acyl, or may be taken together with the nitrogen atom to which they are attached to form a 5-to-7 membered ring optionally containing an additional oxygen or nitrogen atom;
R3 and R^ are independently selected from loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group.
6. A compound according to Claim 5 wherein
R3 is selected from loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group; and
R4 is selected from aryl, arylalkyl, heteroaryl, or a heterocyclic group.
7. A compound according to Claim 5 wherein
Rl and R^ are independently selected from H, loweralkyl, arylCi-C6alkyl, -C(O)Cι-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to from a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
R3 and R^ are independently selected from the group consisting of:
Cl-C6alkyl,
C2-C6alkenyl,
C2-C6alkynyl, C3-C8cycloalkyl, heteroarylCo-Cόalkyl or substituted heteroarylCo-Cόalkyl, arylC()-C6alkyl or substituted arylCo-Coalkyl, heteroarylC2-C6alkenyl or substituted heteroarylC2-C6alkenyl, arylC2-C6alkenyl or substituted arylC2-C6alkenyl, heteroarylC2-C6alkynyl or substituted heteroarylC2-C6alkynyl, arylC2-C6alkynyl or substituted arylC2-C6alkynyl wherein the 1-4 heteroaryl or aryl substituents are independently selected from halogen, oxo, cyanoCi-Cόalkyl, heteroarylCo-Cόalkyl, heterocyclic )- Cόalkyl, Cι-C6alkyloxy, Cι-C6alkyloxyCi-C6alkyl, arylCo-C6alkyl, arylCi-C6alkyloxy, R5R6NC(O), cyano, C2-C6alkenyl, C2-C6alkynyl,
Cι-C6alkyl, C2-C6alkenyldialkylmalonyl, CF3, HO-, Cι-C6alkyloxyCi- Cόalkyloxy, Ci-CgalkylSOn wherein n is 1-2, Cι-C6alkylthio, Ci- Cόalkylacryl, CF3O, CF3, Cι-C4alkylenedioxy, Cι-C6alkylacryl, R5R6N(CO)NR5, N-formyl(heterocyclic), NO2, NR5R6Cθ-C6alkyl, wherein R^ and R^ are independendy selected from H, Ci-Cβalkyl,
HC(O), Cι-C6alkyloxyCι-C6alkyl, Cι-C6alkyloxy, C{- C6alkylC(O), CF3C(O), NR7R8Cι-C6alkyl, phthalimidoCi- C6C(O), Cι-C6alkylSOn where n is 1-2, CNCi-Cβalkyl, R7R8NC(O)NR7-, heteroaryl, NR7R8cι-C6alkylC(O), C\- C6alkyloxycarbamidoCi-C6alkyl, wherein R7 and R8 are independently selected from those variables identified for R^ and R^ or R5 and R^ or R7 and R° may join together with the nitrogen atom to which they are attached to form a 5-7 membered unsubstituted or substituted ring optionally containing 1-3 additional heteroatoms selected from O, N or S wherein the substituents are selected from Ci-C6alkyl.
8. A compound according to Claim 5 wherein R- and R^ are independently selected from phenyl; thiophen-2-yl; l-methyl-2- oxobenzoxazolin-5-yl; 2-(dimethylamino)-5-pyrimidinyl; 2-(N-formyl-N-methyl amino)-3- pyrimidinyl; 2-(N-(2-methoxyethyl)-N-methyl amino)-5-pyrimidinyl; 2-(N-methylamino)5- pyrimidinyl; 2-(l-moφholinyl)-5-pyrimidinyl; 2-(l-pyrrolidinyl)-5-pyrimidinyl; 2- dimethylamino-5-pyrimidinyl; 2-furanyl; 2-oxobenzoxazolin-5-yl; 2-pyridyl; 3- (dimethylamino)phenyl; 3-amino-4-methoxyphenyl; 3-bromo-4-(dimethylamino)phenyl; 3- methoxyphenyl; 3-methyl-4-(N-acetyl-N-methylamino)phenyl; 3-methyl-4-(N-formyl-N- methylamino)phenyl; 3-methyl-4-(N-methyl-N-(trifluoroacetyl)amino)phenyl; 3-methyl-4- (N-methylamino)phenyl; 3-methyl-4-pyrrolidinylphenyl; 3-pyridyl; 3,4-dichlorophenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 4-(acetylamino)phenyl; 4- (dimethylamino)-3-fluorophenyl; 4-(dimethylamino)phenyl; 4-(imidazol-l-yl)phenyl; 4- (methylthio)phenyl; 4-(morpholinyl)phenyl; 4-(N-(2-(dimethylamino)e yl)amino)phenyl; 4-(N-(2-methoxyethyl)amino)phenyl; 4-(N-acetyl-N-methylamino)phenyl; 4-(N-ethyl-N- formylamino)phenyl; 4-(N-ethylamino)phenyl; 4-(N-formyl-N-(2- methoxyethyl)amino)phenyl; 4-(N-isopropylamino)phenyl; 4-(N-methyl-N-((2- dimethylamino)ethyl)amino)phenyl; 4-(N-methyl-N-(2-(N- phthalimidyl)acetyl)amino)phenyl; 4-(N-methyl-N-(2-cyano)ethylamino)phenyl; 4-(N- methyl-N-(2-methoxyethyl)amino)phenyl; 4-(N-methyl-N-(3- methoxy)propionylamino)phenyl; 4-(N-methyl-N-acetylamino)phenyl; 4-(N-methyl-N- formylamino)phenyl; 4-(N-methyl-N-trifluoroacetylamino)phenyl; 4-(N- morpholinyl)phenyl; 4-(thiophen-2-yl)phenyl; 4-(ureido)phenyl; 4-(2- (dimemylamino)acetylamino)phenyl; 4-(2-(2-methoxy)acetylarrιino)ethyl)arnino)phenyl; 4- (2-methoxy)ethoxyphenyl; 4-(2-oxo- l-oxazolidinyl)phenyl; 4-(4-methoxy-2-butyl)phenyl; 4-(4-methylpiperidinyl)phenyl; 4-(5-pyrimidinyl)phenyl; 4-aminophenyl; 4-bromophenyl; 4-butoxyphenyl; 4-carboxamidophenyl; 4-chlorophenyl; 4-cyanophenyl; 4- diethylaminophenyl; 4-diethylmalonylallylphenyl); 4-dimethylaminophenyl; 4- ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4- iodophenyl; 4-isopropylphenyl; 4-methoxyphenyl) 4-methylaminophenyl; 4- methylsulfonylphenyl; 4-morpholinylphenyl; 4-N-(2-(dimethylammo)ethyl)-N- formylamino)phenyl; 4-N-(3-methoxypropionyl)-N-isopropyl-amino)phenyl; 4-N-ethyl-N- (2-methoxyethyl)amino)phenyl; 4-N-formylpiperidinylphenyl; 4-nitrophenyl; 4- piperidinylphenyl; 4-pyridylphenyl; 4-pyrrolidinylphenyl; 4-t-butylacrylphenyl; 5- (dimethylamino)thiophen-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 3- dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6-(N- methyl-N-formylamino)-3-pyridinyl; 6-(N-methyl-N-(2-methoxyethyl)amino)-3-pyridinyl; 6-(2-oxo-oxazolidinyl)-3-pyridinyl; 6-dimethylamino-3-pyridinyl; 6-imidazolyl-3-pyridinyi; 6-morpholinyl-3-pyridinyl; 6-pyrrolidinyl-3-pyridinyl; (2-propyl)-3-pyridinyl; and (4- formylarnino)phenyl; (thiophen-2-yl)methyl; (thiophen-3-yl)methyl; butyl; cycloheptyl; pentyl; thiophen-2-yl; l-(3-bromophenyl)ethyl; 2-(N-phenylmethoxycarbonyl)aminophenyl; 2-(3-bromophenyl)ethyl; 2-(3-cyanophenyl)methyl; 2-(4-bromophenyl)ethyl; 2-(5-chloro-2- (thiophen-3-yl)phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl; phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3-(furan-2-yl)phenyl; 3- (thiophen-2-yl)phenyl; 3-(2-pyridyl)phenyl; 3-(3-methoxybenzyl)phenyl; 3- (amino)propynyl; 3-benzyloxyphenyl; 3-bromo-4-fluorophenyl; 3-bromo-5-iodophenyl; 3- bromo-5-methoxyphenyl; 3-bromophenyl; 3-bromophenylmethyl; 3-carboxamidophenyl; 3- chlorophenyl; 3-cyanophenyl; 3-diethylmalonylallylphenyl; 3-dimethylaminophenyl; 3- ethoxyphenyl; 3-fluoro-5-trifluoromethylphenyl; 3-fluorophenyl; 3-hydroxyphenyl; 3- iodophenyl; 3-methoxyethyoxyphenyl; 3-methoxyphenyl; 3-methylphenyl; 3- methylsulfonylphenyl; 3-methylthiophenyl; 3-t-butylacrylphenyl; 3-trifloromethyoxyphenyl; 3-trifluoromethylphenyl; 3-vinylpyridinylphenyl; 3,4-dichlorophenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 3,5-di(trifluoromethyl)phenyl; 3,5- dibromophenyl; 3,5-dichlorophenyl; 3,5-dimethoxyphenyl; 3,5-dimethylphenyl; 4-(2- propyl)phenyl; 4-(2-propyl)oxyphenyl; 4-benzyloxyphenyl; 4-bromophenyl; 4- bromothiophen-2-yl; 4-butoxyphenyl; 4-dimethylaminophenyl; 4-fluoro-3- trifluoromethylphenyl; 4-methoxyphenyl; 4-neopentylphenyl; 4-phenoxyphenyl; 5- bromothiophen-2-yl; 5-cyclohexyl; 5-cyclopropyl; 5-hexyl; 5-methyl; 5-phenyl; (2-bromo- 5-chlorophenyl)methyl; (2-bromophenyl)methyl; and (5-chloro-2-(3- methoxyphenyl)phenyl)methyl.
9. A compound according to Claim 5 wherein R3 and R^ are independently selected from: phenyl; 4-dimethylaminophenyl; 4-methylphenyl; 4-bromophenyl; 4- pyridinyl; (5-pyrimidinyl)phenyl; 2-(2-pyridinyl)ethenyl)phenyl; 3-pyridinyl; thiophen-3-yl; 2-pyridinyl; 3,4-methylenedioxyphenyl; butyl; 5-bromothiophen-2-yl; 5-methylthiophen-2- yl; 4-(trifluoromethoxy)phenyl; 3-phenoxyphenyl; 5-nitrothiophen-2-yl; 4-bromothiophen- 2-yl; 3-methylthiophen-2-yl; furan-2-yl; furan-3-yl; 5-methyl-furan-2-yl; 4-(2- propyl)phenyl; 3,4-dimethoxyphenyl; hexyl; 2-methyl-2-propyl; 4-(2-propyl)phenyl; 4- propylphenyl; 3-methoxyphenyl; 3-bromophenyl; 3-fluorophenyl; 3-trifluoromethylphenyl; 3-chlorophenyl; 3,5-dichlorophenyl; 3-methoxycarbonylphenyl; 3-(2-propyl)phenyl; 4-(2- methyl-2-propyl)phenyl; 4-fluorophenyl; 4-methoxyphenyl; 3-(phenylmethoxy)phenyl; 4- chlorophenyl; 3-fluoro-4-methylphenyl; 3-phenylpropyl; 4-methoxyphenyl; 3-phenylpropyl; 2-phenylethyl; phenylmethyl; cyclohexylmethyl; pentyl; 2-methylpropyl; propyl; 3- cyanopropyl; 3-nitrophenyl; 3-carboxamidopropyl; (4-methoxyphenyl)methyl; (3- bromophenyl)methyl; (4-(2-propyl)phenyl)methyl); (4-methoxyphenyl)methyl); (4- bromophenyl)methyl); (3-fluorophenyl)methyl; (4-bromophenyl)methyl; thiazole-2-yl; (3- methoxyphenyl)methyl; phenylmethyl; (3-methoxyphenyl)methyl; 4-methylphenyl; 4- (trifluoromethyl)phenyl; 4-ethylphenyl; 4-acetamidophenyl; 4-phenoxyphenyl; 4- nitrophenyl; 4-fluorophenyl; 4-chlorophenyl; 4-aminophenyl; 4-methylthiophenyl; (4- phenyl)phenyl; (4-phenylmethoxy)phenyl; (4-N,N-diethylamino)phenyl; (4-2- phenylethenyl)phenyl; (2-methyl-2-propoxy)phenyl; 3-chlorophenyl; 3,5-dimethoxyphenyl; 4-N,N-dimethylphenyl; benzofuran-2-yl; 3-bromo-4-methoxyphenyl; 4-butoxyphenyl; 3- methoxyphenyl and 3,5-dichlorophenyl.
10. A compound according to Claim 5 which is: 4-amino-6-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-meώylphenyl)-7-(4-(dimethylarrvino)phenyl)pyrido[2,3-d]pyrirnidm
4-arru^o-6-(4-(dimethylamino)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine;
4-arnino-6-(4-methylphenyl)-7-phenylpyrido[2,3-d]pyrimidine;
4-arrιino-6-(4-met ylphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-(dimethylamino)phenyl)-7-(4-pyridinyl)pyrido[^^
4-amino-6-(4-(dimethylaπύno)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- d]pyrimidine;
4-arrvino-6-(4-methylphenyl)-7-(3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-arnino-6-(4-methylphenyl)-7-(thiophen-3-yl)pyrido[2,3-d]pyrimidine; 4-arrιho-6-(4-methylphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-ammo-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-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-butyl-7-(thiophen-3-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(5-bromothiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(5-methylthiophen-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-arruno-6-(4-methylphenyl)-7-(5-nitrothiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-bromothiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(3-methylthiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(furan-2-yl)pyrido[2,3-d]pyrirnidine; 4-arrιino-6-(4-methylphenyl)-7-(furan-3-yl)pyrido[2,3-d]pyrimidine;
4-arr no-6-(4-methylphenyl)-7-(5-methyl-furan-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-(2-propyl)phenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-(2-propyl)phenyl)-7-(5-nitrothiophen-2-yl)pyridof2,3-dlpyrimidine;
4-amino-6-(4-methylphenyl)-7-(5-nitrothiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-(dimethylamino)phenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(3,4-dimethoxyphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(3,4-dimethoxyphenyl)-7-(5-nitrothiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-arnino-6-hexyl-7-(4-(dimethylarrιino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-hexyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(2-methyl-2-propyl)-7-(miophen-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-(dimethylarrιino)phenyl)pyrido[2,3-d]pyrirnidine; 4-arrύno-6-(3,4-dimethox>φhenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine;
4-amino-6-(3-methoxyphenyl)-7- (4-(dimethylamino)phenyl)pyrido [2,3- djpyrimidine;
4-arrιino-6-(3-bromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrirnidine; 4-amino-6-(3-fluorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-arriino-6-(3-trifluoromethylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrirnidine;
4-amino-6-(3-cUorophenyl)-7-(4-(dimethylarr no)phenyl)pyrido[2,3-d]pyrirnidine; 4-amino-6-(3,5-dichlorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine; 4-arrύ ιo-6-(3,4-methylenedioxyphenyl)-7-(4-(dimethylaπvino)phenyl)pyrido[2,3-- djpyrimidine;
4-amino-6-(3,4-methylenedioxyphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-arnino-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-arrιino-6-(4-(2-methyl-2-propyl)phenyl)-7-(4-(dimethylarnino)phenyl)pyrido[2,3- djpyrimidine;
4-arnino-6-(4-fluorophenyl)-7-(4-(dimethylaπ no)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-(dimemylarrύno)phenyl)pyrido[2,3-d]pyrirnidine; 4-amino-6-(3-fluoro-4-methylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6-(3-fluoro-4-methylphenyl)-7-(tWophen-2-yl)pyrido[2,3-d]pyrimidine; 4-anήno-6-(3-phenylpropyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrirnidine; 4-amino-6-(3-phenylpropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-arrύno-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-arnino-6-(cyclohexylmethyl)-7-(4-(dimethylarnino)phenyl)pyrido[2,3- d]pyrimidine;
4-arnijιo-6-butyl-7-(4-(ώmethylamino)phenyl)pyrido[2,3-d]pyrirnidine; 80 4-amino-6-pentyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrirrύdine;
4-amino-6-(2-methylpropyl)-7-(4-(dimethylarnino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-propyl-7-(4-(o methylarrιino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(3-cyanopropyl)-7-(4-(dimethylarrύno)phenyl)pyrido[2,3-d]pyrimidine;
4-arrrøo-6-(3-rdtrophenyl)-7-(4-(dimethylarnino)phenyl)pyrido[2,3-d]pyrimidine; 85 4-arriino-6-pentyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-arnino-6-(3-carboxamidopropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-arruno-6-((4-methoxyphenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-arrιino-6-((3-bromophenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 90 4-arrιino-6-((4-(2-propyl)phenyl)methyl)-7-(tMophen-2-yl)pyrido[2,3-d]pyrirrύdinc;
4-amino-6-((4-methoxyphenyl)methyl)-7-(4-(2-propyl)phenyl)pyrido[2,3- djpyrirnidine;
4-arrιino-6-((4-bromophenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-((3-fluorophenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-dlpyrimidine; 95 4-annιιo-6-((4-bromophenyl)methyl)-7-(thiazole-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-((3-methoxyphenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-anτino-6-(phenylmethyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-arriino-6-((3-methoxyphenyl)methyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine; 100 4-amino-6-(4-methylphenyl)-7-(4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyrimidine;
4-arnino-6-(4-methylphenyl)-7-(4-methylphenyl)pyrido[2,3-d]pyrimidine;
4-arruno-6-(4-methylphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-arm ιo-6-(4-methylphenyl)-7-(4-ethylphenyl)pyrido[2,3-d]pyrirnidine;
4-amino-6-(4-methylphenyl)-7-(4-cyanophenyl)pyrido[2,3-d]pyrimidine; 105 4-arr no-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-dlpyrimidine;
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; 110 4-amino-6-(4-methylphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-methylthiophenyl)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-d]pyrirnidine; 4-anτino-6-(4-methylphenyl)-7-((4-N,N-diethylamino)phenyl)pyrido[2,3- 115 dlpyrimidine;
4-amino-6-(4-methylphenyl)-7-((4-2-phenylethenyl)phenyl)pyrido[2,3- djpyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-(2-methyl-2-propoxy)phenyl)pyrido[2,3- dlpyrimidine; 120 4-amino-6-(4-methylphenyl)-7-(3-cWorophenyl)pyrido[2,3-dlpyrirnidine;
4-amino-6-(4-methylphenyl)-7-(3,5-dimethoxyphenyl)pyrido[2,3-dlpyrimidine;
4-arnino-6-(thiophen-2-yl)-7-(4-N,N-dimethylphenyl)pyrido[2,3-d]pyrimidine;
4-arnino-6-(4-methylphenyl)-7-(benzofuran-2-yl)pyrido[2,3-dlpyrimidine;
4-amino-6-(thiophen-2-yl)-7-(ώiophen-2-yl)pyrido[2,3-d]pyrimidine; 125 4-amino-6-(thiophen-2-yl)-7-(4-memoxyphenyl)pyrido[2,3-dlpyrimidine;
4-arrύno-6-(4-bromophenyl)-7-(4-N,N-dimethylphenyl)pyrido[2,3-d]pyrimidine;
4-amino6-(3-bromo-4-methoxyphenyl)-7-(4-N,N-dimethylphenyl)-pyrido[2,3- dlpyrimidine;
4-amino-6-(3-bromo-4-methoxyphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 130 4-arruιιo-6-(4-methylphenyl)-7-(4-butoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(3-methoxyphenyl)pyrido[2,3-dlpyrimidine; or
4-arnino-6-(4-methylphenyl)-7-(3,5-dichlorophenyl)pyrido[2,3-dlpyrimidine.
1 1. A method of inhibiting adenosine kinase comprising exposing an adenosine kinase to an effective inhibiting amount of a compound according to Claim 1 or 5.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to Claim 1 or 5 in combination with a pharmaceutically acceptable carrier.
13. A method of treating ischemia, neurological disorders, nociperception , inflammation, immunosuppression, gastrointestinal disfunctions, diabetes and sepsis in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound according to Claim 1 or 3.
5
14. A method according to Claim 12 wherein the method consists of treating cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery, percutaneous transluminal angioplasty, stroke, thrombotic and embolic conditions, epilepsy, anxiety, schizophrenia, pain perception, neuropathic pain, visceral pain, arthritis, sepsis, diabetes and abnormal gastrointestinal motility.
15. A process for the preparation of a compound having the formula
wherein
R1 and R2 are hydrogen, R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group or substituted versions thereof;
R4 is aryl, heteroaryl, or a heterocyclic group or substituted versions thereof;
the method comprising (a) reacting 4,6-diamino-5-iodopyrimidine with an ethenylboronic acid derivative having the formula
(HO)2B^^ R3
wherein R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl or heteroaryl or heterocyclic or substituted versions thereof, in the presence of tetrakistriphenylphosphinepalladium(O) and an aqueous alkali metal base, and isolating a first intermediate compound having the formula
(b) reacting the first intermediate compound with an aldehyde compound having the formula R4-CHO, wherein R4 is aryl, heteroaryl, or a heterocyclic group or substituted versions thereof, under anhydrous conditions and with the removal of the water of reaction, and isolating the compound of formula II.
16. A process for the preparation of a compound having the formula
wherein
R1 and R2 are independently H, loweralkyl, arylalkyl or acyl, or may be taken together with the nitrogen atom to which they are attached to form a 5-to-7 membered ring optionally containing an additional oxygen or nitrogen atom, with the requirement that not both R1 and R2 may be hydrogen;
R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group or substituted versions thereof; R4 is aryl, heteroaryl, or a heterocyclic group or substituted versions thereof; the method comprising (a) reacting a compound having the formula
wherein R1 and R2 are hydrogen;
R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group or substituted versions thereof; R4 is aryl, heteroaryl, or a heterocyclic group or substituted versions thereof;
with a compound selected from the group consisting of
(i) an alkylating agent R*-Y, wherein R1 is loweralkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (ii) an arylalkylating agent R1 -loweralkyl- Y, wherein R1 is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (iii) an acyl compound R!-Z, wherein R1 is an acyl 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 loweralkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (ii) an arylalkylating agent R2-loweralkyl-Y, wherein R2 is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (iii) an acyl compound R2-Z, wherein R2 is an acyl group and Z is selected from the group consisting of an acid anhydride moiety, a halide or an acyl activating group; and isolating the compound of formula II.
17. A process for the preparation of a compound having the formula
wherein
R1 and R2 are independently H, loweralkyl, arylalkyl or acyl, or may be taken together with the nitrogen atom to which they are attached to form a 5-to-7 membered ring optionally containing an additional oxygen or nitrogen atom, with the proviso that not both R1 and R2 are hydrogen;
R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group or substituted versions thereof; R4 is aryl, heteroaryl, or a heterocyclic group or substituted versions thereof; the method comprising
(a) reacting 6-amino-4-chloro-5-iodopyrimidine with an ethenylboronic acid derivative having the formula
wherein R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl or heteroaryl, or heterocyclic or substituted versions thereof in the presence of tetrakistriphenylphosphinepalladium(O) and an aqueous alkali metal base, and isolating a first intermediate compound having the formula
(b) reacting the first intermediate compound with an aldehyde compound having the formula R -CHO, wherein R4 is aryl, heteroaryl, or a heterocyclic group or substituted versions thereof, under anhydrous conditions and with the removal of the water of reaction, and isolating the second intermediate compound having the formula
(c) treating the fourth intermediate compound with an amine compound having the formula Rϊ-NH-R2, wherein R1 and R2 are as described above, and isolating the compound of formula II.
18. A compound of the formula:
wherein X is selected from halogen or OH and R3 and R^ are as defined above.
EP98917950A 1997-04-16 1998-04-16 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds Withdrawn EP0979230A1 (en)

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HU229604B1 (en) * 2001-02-12 2014-02-28 Hoffmann La Roche 6-substituted pyrido-pyrimidines, process for their preparation and pharmaceutical compositions containing them
WO2006053250A2 (en) 2004-11-12 2006-05-18 Trustees Of Tufts College Lipase inhibitors
US20100063032A1 (en) * 2007-03-28 2010-03-11 Debenham John S Substituted pyrido[2,3-d]pyrimidine derivatives as cannabinoid-1 receptor modulators
EA201590693A1 (en) * 2012-10-05 2015-08-31 Ригель Фармасьютикалс, Инк. INHIBITORS GDF-8
US10016432B2 (en) 2016-05-27 2018-07-10 Legacy Emanuel Hospital & Health Center Methanocarba derivatives of pseudoribose that inhibit adenosine kinase

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IL112249A (en) * 1994-01-25 2001-11-25 Warner Lambert Co Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds

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