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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
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Definitions

• 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]pyrirr ⁇ dine compounds.
• 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).
• 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).
• 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.
• adenosine kinase inhibition 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.
• 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.
• CABG coronary artery bypass graft surgery
• PTCA percutaneous transluminal angioplasty
• stroke other thrombotic and embolic conditions
• 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.
• 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.
• 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.
• 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.
• 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.
• the present invention provides for 6,7-disubstituted-4-aminopyrido[2,3- d]pyrimidine compounds having utility as adenosine kinase inhibitors.
• the present invention provides novel compounds having the formula
• R 1 and R 2 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.
• the present invention provides a method for inhibiting adenosine kinase by administering a compound of Formula (I).
• 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.
• the adenosine kinase is located in vivo, the compound is administered to the organism.
• 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.
• 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.
• 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.
• R 1 and R 2 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.
• the present invention provides a process for the preparation of compounds of formula II
• R 1 and R 2 are hydrogen
• R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group;
• R 4 is aryl, heteroaryl, or a heterocyclic group; the method comprising
• the present invention provides a process for the preparation of compounds of formula (II)
• R 1 and R 2 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 R 1 and R 2 may be hydrogen,
• R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group;
• R 4 is aryl, heteroaryl, or a heterocyclic group
• R 1 and R 2 are hydrogen
• R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group;
• R 4 is aryl, heteroaryl, or a heterocyclic group
• an alkylating agent R -Y wherein R 1 is loweralkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate
• an arylalkylating agent RMoweralkyl-Y wherein R 1 is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate
• an acyl compound R*-Z wherein R 1 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 R 2 should not be hydrogen, treating the compound from step (a) with a compound selected from the group consisting of
• an alkylating agent R 2 -Y wherein R 2 is loweralkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate;
• an arylalkylating agent R 2 -loweralkyl-Y wherein R 2 is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate;
• an acyl compound R 2 -Z wherein R 2 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.
• the present invention provides a process for the preparation of compounds of formula II
• R 1 and R 2 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 R 4 and R 5 are hydrogen;
• R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group;
• R 4 is aryl, heteroaryl, or a heterocyclic group; the method comprising
• R 3 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
• 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.
• 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.
• an adenosine kinase inhibitor of the present invention is a compound of Formula (I) or (II) above, wherein R 4 is aryl or heteroaryl and substituted versions thereof.
• an adenosine kinase inhibitor of the present invention is a compound of Formula (I) or (II) above, wherein R 4 is aryl or heteroaryl or substituted versions thereof and R 3 is loweralkyl, aryl, arylalkyl or heteroaryl or substituted versions thereof.
• the present invention relates to compounds of formula I and II as shown above wherein
• Rl and R ⁇ are independently selected from H, loweralkyl, arylC ⁇ -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, heteroarylC ⁇ -C6alkyl or substituted heteroarylC ⁇ -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, cyanoC ⁇ -C6alkyl, heteroarylCo-C6alkyl, heterocyclic )- C
• Exemplary and preferred compounds of the invention include: 4-annno-6-phenyl-7-(p-dimethylan inophenyl)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.
• 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 an ⁇ ino)-3-pyrimidinyl; 2-(N-(2-m ⁇ thoxyethyl)-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
• acyl 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.
• 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.
• 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.
• aryl refers to a phenyl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, morpholinyl, phenyl-lowerlalkoxy, phenyl-loweral enyl or cycloalkyl-loweralkyl group.
• 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.
• arylalkyl refers to a loweralkyl radical having appended thereto an aryl group, as defined above, as for example benzyl and phenylethyl.
• 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.
• 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.
• 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.
• 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.
• heteroaryl refers to a heteroaryl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, mo ⁇ holinyl, phenyl-lowerlalkoxy, phenyl-loweralkenyl or cycloalkyl-loweralkyl group.
• 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.
• heteroaryl examples 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.
• 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
• heterocyclic examples include pyrrolidine, tetrahydrofuran, dihydropyrrole, isoxazolidine, oxazolidine, tetrahydropyridine, piperidine, piperazine, mo ⁇ holine, thiomo ⁇ holine, aziridine and azetidine and those additionally described herein.
• 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.
• loweralkyl 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.
• loweralkyl examples 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.
• group "Ci-C ⁇ alkyl” is described and has a similar meaning as above for loweralkyl but is more specifically recited.
• the term “Co-C ⁇ alkyl” 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”.
• loweralkenyl 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.
• 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-C ⁇ alkyloxy.
• loweralkynyl 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, ⁇ -pentynyl, and n- hexynyl. This term is also described as C2-C6alkynyl.
• compositions 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.
• diluents for parenteral injection, for oral administration in solid or liquid form, for rectal or topical administration, or the like.
• 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 ⁇ Mol/kg day, preferably from about 0.1-50 ⁇ Mol/kg/day; these oral molar dosage ranges correspond to 0.005-125 mg/kg/day, preferably 0.05-25 mg/kg/day.
• 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.
• 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.
• 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,
• 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.
• base such as an alkali or alkaline earth metal hydroxide, e.g., sodium, potassium, lithium, calcium, or magnesium
• an organic base such as an amine, e.g., dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, triethylamine, piperidine,
• 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.
• 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 benzy
• the salts of the present invention can be synthesized from the compounds of Formula I or ⁇ 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.
• 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.
• 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.
• 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 abso ⁇ tion of the injectable pharmaceutical form may be brought about by the use of agents delaying abso ⁇ tion, for example, aluminum monostearate and gelatin.
• the compounds may be inco ⁇ orated 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 inco ⁇ orating 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.
• 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) abso ⁇ tion accelerators, as for example, quaternary ammonium compounds; (g) fillers
• 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.
• 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.
• inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and e
• these liquid dosage forms may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
• 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.
• 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.
• 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 abso ⁇ tion-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.
• 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.
• 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 R 3 -substituted acetylene with catecholborane in a solvent such as THF.
• R 3 -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 R 4 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 R 1 and R 2 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.
• a suitable reducing agent such as hydrogen
• reduction can proceed to form single bonds at the 5,6 and 7,8 positions and a double bond between the 6, 7 carbons.
• stereoisomers are formed and are included within the scope of the invention. These isomers may be isolated by conventional means.
• compounds of Formula (II) wherein one or both of R 1 and R 2 are loweralkyl, arylalkyl or acyl may be prepared by treatment of compound (5) with the appropriate reagent.
• R 1 or R 2 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.
• 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.
• R 1 or R 2 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.
• a base such as triethylamine or potassium carbonate
• a suitable solvent such as for example, methylene chloride or THF.
• R 1 or R 2 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.
• a base such as triethylamine or potassium carbonate
• a suitable solvent such as for example, methylene chloride or THF.
• 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.
• 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, thiomo ⁇ holine, and the like.
• 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.
• a method of inhibiting adenosine kinase is disclosed.
• 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.
• 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.
• 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.
• adenosine kinase activity can be measured using any of the standard procedures well known in the art.
• 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.
• adenosine kinase inhibitory activity is determined by studying the effects of inhibitors on adenosine Al and A2 ⁇ receptor binding, adenosine deaminase activity and adenosine transport.
• adenosine kinase inhibitors have been reported to protect rodents (e.g., mice and rats) from seizures induced by the subcutaneous adrriinistration of pentylenetetrazol (PTZ).
• rodents e.g., mice and rats
• PTZ pentylenetetrazol
• 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.
• the compounds of examples 55, 103 and 104 in the procedure described directly below were tested thirty minutes after pretreatment with the drugs (30 ⁇ mol/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.
• mice 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.
• Omni tech Electronics Automated 16 Animal Hot Plate Analgesia Monitor Coldbus, OH; Model AHP16AN
• 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
• Nociperception Nociperception (Nociception) (Pain)
• Inflammation including conditions such as Septic Shock due to Sepsis Infection
• 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 comprising adrninistering to the mammal a therapeutically effective amount of a compound.
• 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.
• 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.
• SIRS systemic inflammatory syndrome
• 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).
• 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 4,6-diamino-5-(2-phenylethenyl)pyrimidine was prepared as follows: la. 5-iodo-4,6-diaminopyrimidine
• 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
• Example 2 Following the procedures of Example 1, except substituting the reagents given in Table 1 below for the R 4 and R 3 Reagents of Example 1, the compounds of Examples 2-107 were prepared.

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