SK140099A3 - 5,6,7-trisubstituted-4-aminopyridol[2,3-d]pyrimidine compounds - Google Patents

Abstract

A compound having formula (II) wherein R<1>, R<2>, R<3>, R<4> and R<5> are defined, 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, pain, nociperception, 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 for preparation thereof.

Description

The present invention relates to a method of inhibiting adenosine kinase by administering pharmaceutical compositions comprising 5,6,7-trisubstituted-4-aminopyrido [2,3-d] pyrimidine compounds as well as novel 5,6,7-trisubstituted-4-aminopyrido [2,3-d] compounds pyrimidine.

BACKGROUND OF THE INVENTION

Adenosine kinase (ATP: adenosine-5'-phosphotransferase EC 2.7.1.20) is a ubiquitous enzyme that catalyzes the phosphorylation of adenosine to AMP, using preferably ATP as a source of phosphate. Adenosine kinase is widespread in tissue and species distribution and has been isolated from yeast, various mammalian sources and certain microorganisms. It has been found to be potentially present in every human tissue tested including kidney, liver, brain, spleen, placenta and pancreas. Adenosine kinase is a key enzyme for regulating the cellular concentration of adenosine.

Adenosine is a purine nucleoside, an intermediate in the purine nucleotide degradation and replacement cycle. Adenosine also has many important physiological effects, many of which are mediated in the activation of specific ectocellular receptors, designated Pi receptors (Burnstock, Cell Membrane Receptors for Drugs and Hormones, 1978, (Bolis and Straub, eds.) Raven, New York, p. 107-118; Fredholm, et al., Pharmacol. Rev. 1994, 46: 143-156).

In the central nervous system, adenosine inhibits the release of certain neurotransmitters (Corradetti, et al., Eur. J. Pharmacol. 1984, 104: 19-26), stabilizes the membrane potential (Rudolphi, et al., Cerebrovasc. Brain Metab. Rev.

1992, 4: 346-360), acts as an endogenous anticonvulsant (Dragunow, Trends

Pharmacol. Sci. 1986, 7: 128-130) and may play a role as an endogenous neuroprotective agent (Rudolphi, et al., Trends Pharmacol. Sci., 1992, 13: 439-445). Adenosine can play a role in various central nervous system disorders 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, 643-655).

Adenosine has also been implicated in modulating transmission in spinal cord pain. (Sawynok, et al., Br. J. Pharmacol., 1986, 88: 923-930) and in mediating the analgesic effects of morphine (Sweeney, et al., J. Pharmacol. Exp. Ter. 1987, 243: 657-665). ).

In the immune system, adenosine inhibits certain neutrophil functions and exerts anti-inflammatory effects (Cronstein, J. Appl. Physiol. 1994, 76: 5-13). The AK inhibitor has been reported to diminish paw swelling in an adjuvant arthritis model in rats (Firestein, et al., Arthritis and Rheumatism, 1993, 36, S48).

Adenosine also exhibits various effects on the cardiovascular system, including vasodilation, atrioventricular conduction damage, and endogenous cardio-protection in myocardial ischemia and reperfusion (Mullane and Williams, Adenosine and Adenosine Receptors, 1990 (Williams, ed.) Humana Press, New Jersey, 289334). The widespread effects of adenosine also include effects on the renal, respiratory, gastrointestinal and reproductive systems, as well as on blood cells and adipocytes. Adenosine, through activation of its A1 receptor to adipocytes, plays a role in diabetes by inhibiting lipolysis (Londos, et al., Proc. Natl. Acad. Sci. USA, 1980, 77, 2551).

It appears that secreted endogenous adenosine plays a role as a natural defense mechanism in a variety of pathophysiological 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 exertion. In the extracellular space, adenosine activates specific extracellular receptors to elicit various responses that tend to restore cellular functions to normal (Bruns, Nucle3 osides 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 effects are therefore highly localized.

Inhibition of adenosine kinase may result in an increase in local concentrations of adenosine in the focus of the damaged tissue, further enhancing cyto-protection. This effect is probably most noticeable at tissue sites where trauma results in an increase in adenosine production, thereby minimizing systemic toxicity.

Pharmacological compounds directed to the inhibition of adenosine kinase potentially provide effective new effective therapies for diseases that utilize local and specific adenosine potentiation. Disorders where such compounds may be useful include ischemic conditions such as cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft (CABG) surgery, conditions following percutaneous transluminal angioplasty (PTCA), stroke, other thrombotic and neurological conditions disorders such as epilepsy, anxiety, schizophrenia, nociperception, including pain perception, neuropathic pain, visceral pain and inflammation, arthritis, immunosuppression, sepsis, diabetes and gastrointestinal dysfunction such as abnormal gastrointestinal motility.

A number of compounds have been reported to inhibit adenosine kinase. The most effective of these include 5'-amino-5'-deoxyadenosine (Miller, et al., J. Biol. Chem. 1979, 254: 2339-2345), 5-iodotubercidine (Wotring and Townsend, Cancer Res. 1979, 39: 3018-3023) and 5'-deoxy-5-iodotubercidine (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 tubercidine, formycin, ribavirin, pyrazofurine and 6- (methylmercapto) purinriboside. These purine nucleoside analogs represent an important class of antimetabolites having cytotoxic, antitumor and antiviral properties. They are suitable as substrates for adenosine kinase and are phosphorylated by the enzyme to form the active form. Loss of adenosine kinase activity has been implicated as a mechanism of cellular resistance to the pharmacological effects of these nucleoside analogues (e.g., Bennett, et al., Mol. Pharmacol., 1966, 2: 432443; Caldwell, et al., Can. J. Biochem., 1967, 45). Suttle, et al., European J. Cancer, 1981, 17: 43-51). Loss of cellular levels of adenosine kinase has 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 2'-deoxyadenosine phosphorylation has been suggested as a toxic mechanism in immune deficiency associated with hereditary adenosine deaminase deficiency (Kredich and Hershfield, The Metabolic Basis of Inherited Diseases, 1989 (Scriver, et al., Eds.). , New York, 1045-1075).

BS Hurlbert et al. (J. Med. Chem., 11: 711-717 (1968)) disclose various diaminopyrido [2,3-d] pyrimidine compounds having use as an antibacterial agent. RK Robins et al. (J. Amer. Chem. Soc., 80: 3449-3457 (1958)) disclose processes for the preparation of many 2,4-dihydroxy-, 2,4-diamino-, 2-amino-4-hydroxy- and 2- mercapto-4-hydroxypyrido [2,3-d] pyrimidines with folic acid activity. R. Sharma et al. (Indian J. Chem., 3IB: 719-720 (1992)) disclose 4-amino-5- (4-chlorophenyl) -7- (4-nitrophenyl) pyrido [2,3-d] compounds. ] pyrimidine and 4-amino-5- (4-methoxyphenyl) -7- (4-nitrophenyl) pyrido [2,3-d] pyrimidine, which have antibacterial effects. A. Gupta et al., J. Indian Chem. Soc., 71: 635 636 (1994)) disclose the compound 4-amino-5- (4-fluorophenyl) -7- ^(4-n fluorofe yl) -pyrido [2,3-d] pyrimidine and 4-amino-5- ( 4-chlorophenyl) -7- (4-fluorophenyl) pyrido [2,3-d] pyrimidine 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 having fungicidal activity. P. Victory et al., Tetrahedron, 51: 10253-10258 (1995) disclose the synthesis of 4-amino-5,7-diphenylpyrido [2,3-d] pyrimidine compounds from acyclic precursors. Bridges et al. (PCT Patent Application No. WO

95/19774 published on July 27, 1995) disclose various bicyclic heteroaromatic compounds useful for inhibiting epidermal growth factor tyrosine kinase.

SUMMARY OF THE INVENTION

The present invention provides compounds of 5,6,7-trisubstituted-4-aminopyrido [2,3-d] pyrimidine, which are useful as adenosine kinase inhibitors.

In this regard, the present invention provides compounds having the general formula (I)

wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be attached to the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur atoms;

R ³ , R ⁴ and R ⁵ are independently selected from lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group, and the dotted line indicates an optional double bond.

The present invention also relates to a compound of formula (II)

wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be linked to the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur atoms; and R ³ , R ⁴ and R ⁵ are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group.

In another aspect, the present invention provides a method of inhibiting adenosine kinase by administering a compound of formula (I) or (II).

Further, the method of inhibiting adenosine kinase comprises exposing the adenosine kinase to an effective inhibitory amount of a compound of formula (I) or (II) of the present invention. Where adenosine kinase is detected in vivo, the compound is administered to the body.

Still further, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or (II) above in combination with a pharmaceutically acceptable carrier.

Still further, the present invention provides a method of treating ischemia, neurological disorders, nociperception, inflammation, immunosuppression, gastrointestinal dysfunction, 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) or (II) of the present invention.

Preferably, in this regard, the present invention provides a method of treating cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery conditions, percutaneous transluminal angioplasty conditions, stroke, thrombotic and embolic states, epilepsy, anxiety, pain perception, perception perception , visceral pain, arthritis, sepsis, diabetes and abnormal gastrointestinal motility in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or (II) of the present invention.

Pharmaceutically acceptable salts and amides of the compounds of formula (I) or (II) are also contemplated in the present invention.

In another aspect, the present invention provides a process for preparing a compound having the general formula

wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be linked to the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur atoms and R ³ and R ⁴ are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group, and R ⁵ is selected from the group consisting of aryl, heteroaryl or heterocyclic;

the method comprising (a) reacting an aryl, or a heterocyclic bromide having the formula ^R Br in which R ⁵ is as defined above, with a carboxylic acid derivative having the formula ^R4-CH2-CO-Y, wherein Y Part is OH or Cl, and R ⁴ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group, with N, O-dimethylhydroxylamine hydrochloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, or 1-hydroxybenzotriazole hydrate and triethylamine, whereby a first intermediate having the formula R ⁵ -CO-CH ₂ -R ⁴ is obtained and isolated;

(b) reacting a first intermediate having the formula R ⁵ -CO-CH ₂ -R ⁴ with an aldehyde having the formula R ³ -CHO, wherein R ³ is as defined above, and malononitrile in the presence of an ammonium salt under anhydrous conditions, recovering and isolating a second intermediate having the general formula

R4

R ⁵ (c) reacting the second intermediate with formamide at reflux for about 1 to about 24 hours to obtain and isolate the compound of formula (II).

In another aspect, the present invention provides a process for the preparation of compounds having the general formula

wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be linked to the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing one to three additional heteroatoms selected and the substituents R ³ and R ⁴ are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group; and R ^p is selected from aryl, heteroaryl or heterocyclic group;

with the proviso that both substituents R ¹ and R ² are H, the method comprising (a) reacting an aryl, or a heterocyclic bromide having the formula ^R-Br with a carboxylic acid derivative having the formula R ⁴ -CH 2 CO-Y wherein Y is OH or Cl, and R ⁴ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group, with N, O-dimethylhydroxylamine hydrochloride, 1- (3) -dimethylaminopropyl) -3-ethylcarbodiimide or 1-hydroxybenzotriazole hydrate and triethylamine, thereby obtaining and isolating a first intermediate having the formula R ⁵ -CO-R ⁴ ;

(b) reacting a first intermediate having the formula R ⁵ -CO-R ⁴ with an aldehyde having the formula R ³ -CHO, wherein R ³ is as defined above, and malononitrile in the presence of an ammonium salt under anhydrous conditions, to obtain and isolate the second an intermediate having the general structure

c) reacting the second intermediate with sulfuric acid and heating, followed by reaction with triethyl orthoformate at reflux for from about 1 to about 24 hours, thereby obtaining and isolating a third intermediate having the general structure

(d) reacting the third intermediate with a chlorinating agent to obtain and isolate a fourth intermediate having the general formula

amine with a compound having formula RZ-NH-R ^2, wherein each of R ¹ and R ² are as described above, and isolating a compound of formula (II).

In yet another aspect, the present invention provides a process for the preparation of compounds having the general formula

wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be linked to the nitrogen atom to which they are attached, resulting in a five to seven membered ring optionally containing one to three additional heteroatoms selected from nitrogen, oxygen or sulfur; and R ³ and R ⁴ are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group; and R ⁵ is selected from the group consisting of aryl, heteroaryl or heterocyclic;

the method comprising (a) reacting an aryl, or a heterocyclic bromide having the formula ^R-Br with a carboxylic acid derivative having the formula ^R4-CH2-CO-Y, wherein Y is OH or Cl, and R ⁴ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group, with N, O-dimethylhydroxylamine hydrochloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or 1-hydroxybenzotriazole hydrate and triethylamine, to give and isolating a first intermediate having the formula R ⁵ -CO-CH ₂ -R ⁴ ;

(b) reacting a first intermediate having the formula R ⁵ -CO-CH 2 -R ⁴ with a compound having the formula

NC CN in which

R ³ is as described above, in an alcoholic solvent at reflux, whereby a second intermediate having the general formula is obtained and isolated

R ⁴

R ⁵ (c) reacting the second intermediate with formamide at reflux for about 1 to about 24 hours to obtain and isolate the desired product.

In yet another aspect, the present invention provides a process for preparing compounds having the general formula

R ¹ R ²

wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be linked to the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing one to three additional heteroatoms selected nitrogen, oxygen or sulfur; and R ³ and R ⁴ are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group; and R ^p is selected from aryl, heteroaryl, or heterocyclic group with the proviso that both R

R ¹ and R ² are not hydrogen.

the method comprising (a) reacting an aryl, or a heterocyclic bromide having the formula ^R-Br with a carboxylic acid derivative having the formula R ⁴ CH ₂ CO-Y, wherein Y is OH or Cl, and R ⁴ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group, with N, O-dimethylhydroxylamine hydrochloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or 1-hydroxybenzotriazole hydrate and triethylamine to give and isolating the first intermediate having the formula R ⁵ CO-CH 2 -R ⁴ ;

(b) reacting a first intermediate having the formula R ⁵ -CO-CH ₂ -R ⁴ with a compound having the formula R ³

NC CN í

wherein R ³ is as described above, in an alcoholic solvent at reflux, thereby obtaining and isolating a second intermediate having the general formula

R ⁴ a;

c) reacting the second intermediate with sulfuric acid and heating, followed by treatment with triethyl orthoformate at reflux for about 1 to 24 hours to obtain and isolate a third intermediate having the general structure V • R ⁴

'N N

H (d) reacting the third intermediate with a chlorinating agent to obtain and isolate the fourth intermediate having the general formula

(e) reacting a fourth intermediate with an amine compound having the general formula R 1 -NH-R ² , wherein R ¹ and R ² are as defined above, to obtain and isolate the compound of formula (II).

The present invention also relates to the above processes and to a further step of the process that reduces or partially reduces the right side of the double bond (s) to a partially saturated or fully saturated compound as shown in Formula (I). The preferred reduction method is via catalytic hydrogenation.

The present invention relates to novel 5,6,7-trisubstituted-4-aminopyrido [2,3-d] pyrimidine compounds of formula (I) above useful for inhibiting adenosine kinase, to a method for inhibiting adenosine kinase by such compounds, to pharmaceutical compositions containing such compounds, for methods of using such compounds for inhibiting adenosine kinase, and for the novel 5,6,7-trisubstituted-4-aminopyrido [2,3-d] pyrimidine compounds of formula (I) and (II) described above, wherein:

R ¹ and R ² are independently selected from the group consisting of hydrogen, lower alkyl, arylC 1 -C ₆ alkyl, -C (O) C 1 -C ₆ alkyl, -C (O) aryl, -C (O) heterocyclic group, or may be combined with the nitrogen atom to which they are attached to form a five to seven membered ring, optionally containing one to two additional heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur;

R ³ , R ⁴ and R ⁵ are independently selected from the group consisting of:

C Cealkylu,

C ₂ -C ₆ alkenyl,

C 2 Ceatkinylu,

C ₃ -C ₈ cycloalkyl, heteroarylC ₀ -C ₆ alkyl or substituted heteroaryl C ₀ -C ₆ alkyl, arylC ₀ -C ₆ alkyl or substituted arylC ₀ -C ₆ alkyl, heteroaryl C ₂ -C ₆ alkenyl or substituted heteroaryl C ₂ -C ₆ alkenyl, heteroaryl C ₂ -C ₆ alkenyl or substituted arylC 2, Cealkinyl, arylC 2 -C 6 alkynyl or substituted arylC 2 -C 6 alkynyl wherein the substituents 1-4 of heteroaryl or aryl are independently selected from the group consisting of halogen, oxo, cyanoC 1 -C ₆ alkyl, heteroarylC 0 -C ₆ alkyl, heterocyclic C ₁ -C ₆ alkyl, C 1 -C ₆ alkyloxy C CealkyloxyCiCealkylu, aryl-Co-Cíalkylu, arylC Cealkyloxy, R ^J R ⁶ NC (O), cyano, C 2 C 2 Cealkenylu Cealkinylu, C Cealkylu, C2Cealkenyldialkylmalonylu, CF 3, -OH, C CealkyloxyCiCgalkyloxy, C Wherein n is 1-2, C 1 -C 6 alkylthio, C 1 -C 6 alkylacryl, CF 3 O, CF 3, C 1 -C 4 alkylenedioxy, C 1 -C 6 alkylacryl, R ⁵ R ⁶ N (CO) NR ⁵ , N-formyl (heterocyclic), NO 2, NR ^{6 with} R ⁶ C ₀ -C ₆ alkyl, wherein R ⁵ and R ⁶ are independently selected from hydrogen, C 1 -C 6 alkyl, HC (O), C 1 -C ₆ alkyloxyC 1 -C ₆ alkyl, C 1 -C ₆ alkyloxy, C 1 -C 6 alkylC (O), CF ₃ C (O), NR'R '(C 1 -C 6 alkylCO), phthalimidoC 1 -C ₆ C (O), C 1 -C ₆ alkylSO ₄ , wherein n is 1-2, CNC 1 -C 6 alkyl,

R ⁷ R ⁸ NC (O) NR ⁷ -, heteroaryl, NR'R '(C 1 -C 6 alkylCCO), C 1 -C 6 alkyloxycarbamidoC 1 -C 6 alkyl, wherein R ⁸ and R ⁹ are independently selected from those variable substituents for R ⁶ and R ⁷ or R ⁶ and R ⁷ or R ⁸ and R ⁹ may be taken together with the nitrogen atom to which they are attached to form a five to seven membered unsubstituted or substituted ring optionally containing one to three additional heteroatoms selected from oxygen, nitrogen or sulfur atoms wherein the substituents are selected from C 1 -C 6 alkyl, wherein when the line in formula (I) is a dotted line, this indicates an optional double bond.

In a preferred embodiment of the present invention, the aforementioned compound of formula (I) or (II), wherein R ⁵ is aryl, arylalkyl, heteroaryl or heterocyclic group, or in each of these classes more specific groups, is mentioned.

In a more preferred embodiment of the present invention, the above compound is of formula (I) or (II) wherein R ^{5 is} selected from the group consisting of: 4- (dimethylamino) phenyl; 5-dimethylamino-2-pyridinyl; 5-methoxy-2-pyridinyl; 4-methoxyphenyl; 5-methyl-thiophen-2-yl; 4- (N-methyl-N- (2-methoxyethyl) amino) phenyl; and thiophen-2-yl.

In a preferred embodiment of the present invention, the aforementioned compound of formula (I) or (II) wherein R ^{4 is} aryl, arylalkyl, heteroaryl or a heterocyclic group or in each of these classes the more specific groups mentioned above.

In a more preferred embodiment of the present invention, the compound of formula (I) or (II) above is wherein R ⁴ is selected from the group consisting of: ethoxycarbonylmethyl; ethyl; 3-fluorophenyl; 3-fluoro-4-methylphenyl;

3,4-dimethoxyphenyl; 3-methoxyphenyl; 4-methoxyphenyl; pentyl; phenyl; 3- (2-propyl) phenyl; and 4- (2-propyl) phenyl.

In another more preferred embodiment of the present invention, the aforementioned compound of formula (I) or (II) is wherein R ³ is aryl, arylalkyl, heteroaryl or heterocyclic, or in each of these classes the more specific groups mentioned above.

In another more preferred embodiment of the present invention, the above compound of formula (I) or (II) is wherein R ³ is selected from the group consisting of: 3-bromophenyl; 3-bromo-4-fluorofenyI; 4-bromothiophen-2-yl; 3-chlorophenyl; 3,4-dimethoxyphenyl; 3-fluorophenyl; 3-fluoro-4-methylphenyl; 4- (2-propyl) phenyl; and 3-trifluoromethyl-4-fluorophenyl.

Exemplary and preferred compounds of the invention include:

4-amino-5- (3-bromo-4-fluorophenyl) -6-pentyl-7- (4- (dimethylamino) pyrido [2,3djpyrimidín;

4-amino-5- (3-bromo-4-fluorophenyl) -6-pentyl-7- (thiophen-2-yl) -pyrido [2,3djpyrimidín;

4-amino-5- (3-bromophenyl) -6- (4-methoxyphenyl) -7- (4-methoxyphenyl) -pyrido [2,3djpyrimidín;

4-amino-5- (3-bromophenyl) -6-ethyl-7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-5- (3-bromophenyl) -6-pentyl-7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-5- (3-bromophenyl) -6- (3,4-dimethoxyphenyl) -7- (thiophen-2-yl) -pyrido [2,3djpyrimidín;

4-amino-5- (3-bromophenyl) -6- (4- (2-propyl) phenyl) -7- (4- (dimethylamino) phenyl ^{N-yl) pyridinium} ° id [2,3-d] pyrimidine;

4-amino-5- (3-bromophenyl) -6-ethoxycarbonylmethyl-7- (thiophen-2-yl) -pyrido [2,3djpyrimidín;

4-amino-5- (3-bromophenyl) -6- (3-methoxyphenylmethyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

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

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

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

4-amino-5- (3-trifluoromethyl-4-fluorophenyl) -6- (3,4-dimethoxyphenyl) -7- (thiophen-2-yl) -pyrido [2,3-pyrimidine;

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

4-amino-5- (3-trifluoromethyl-4-fluorophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-pyrimidine;

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

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

4-amino-5- (4-bromo-thiophen-2-yl) -6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine;

4-amino-5- (4-bromothiophen-2-yl) -6- (3,4-dimethoxyphenyl) -7- (4- (N-methyl-N- (2-methoxyethyl) amino) phenyl) pyrido [2, 3-pyrimidine;

4-amino-5-phenyl-6- (3,4-dimethoxyphenyl) -7- (4- (N-methyl-N- (2-methoxyethyl) amino) phenyl) -5-phenyl-pyrido [2,3-pyrimidine;

4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (N-methyl-N- (2-methoxyethyl) amino) phenyl) pyrido [2,3-pyrimidine;

4-amino-5-phenyl-6- (3,4-dimethoxyphenyl) -7- (5-methoxy-2-pyridinyl) -pyrido [2,3-pyrimidine;

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

4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -5- (5-dimethylamino-2-pyridinyl) -pyrido [2,3-d] pyrimidine;

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

4-amino-5,6-diphenyl-7- (4- (N-methyl-N- (2-methoxyethyl) amino) phenyl) -pyrido [2,3-d] pyrimidine;

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

4-amino-5,6-bis (3-fluorophenyl) -7- (4-dimethylaminophenyl) -pyrido [2,3djpyrimidín;

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

4-amino-5,6-bis (3-fluoro-4-methylphenyl) -7- (4-dimethylaminophenyl) -pyrido [2,3 ·

d] pyrimidine;

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

4-Amino-5,6-diphenyl-7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine;

4-amino-5,6-diphenyl-7- (5-dimethylamino-2-pyridinyl) pyrido [2,3-d] pyrimidine;

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

4-Amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (5-N- (2-methoxyethyl) -N-methylamino) -2-pyridinyl) pyrido [2,3-d] ] pyrimidine;

4-amino-5- (3-chlorophenyl) -6-phenyl-7- (5-dimethylamino-2-pyridinyl) -pyrido [2,3-d] pyrimidine;

4-amino-5- (4-bromo-thiophen-2-yl) -6-phenyl-7- (5-dimethylamino-2-pyridinyl) -pyrido [2,3-d] pyrimidine;

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

4-amino-5- (3-bromophenyl) -6- (4-fluorophenyl) -7- (6-morpholinyl-3-pyridinyl) -pyrido [2,3-d] pyrimidine;

4-amino-5-phenyl-6-phenyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3djpyrimidín;

4-amino-5- (3-bromophenyl) -6-phenyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3djpyrimidín;

4-amino-5-phenyl-6-phenyl-7- (6- (N-methyl-N- (2-methoxyethyl) amino) -3-pyridinyl) pyrido [2,3-d] pyrimidine;

4-amino-5- (4-bromothienyl) -6-phenyl-7- (6- (N-methyl-N- (2-methoxyethyl) amino) 3-pyridinyl) pyrido [2,3-d] pyrimidine;

4-amino-5- (4-bromothienyl) -6-cyclopropyl-7- (6-dimethylamino-3-pyridinyl) -pyrido [2,3-d] pyrimidine;

4-amino-5- (4-bromothienyl) -6- (4-F-phenyl) -7- (6-morpholinyl-3-pyridinyl) -pyrido [2,3-pyrimidine;

4-amino-5- (3-bromophenyl) -6-phenyl-7- (6-cyclopropylmethylamino-3-pyridinyl) -pyrido [2,3-d] pyrimidine;

4-amino-5-phenyl-6-phenyl-7- (6-cyklopropyImetylamino-3-pyridinyl) -pyrido [2,3-pyrimidine;

4-amino-5- (3-bromophenyl) -6- (4-fluorophenyl) -7- (6-morpholinyl-3-pyridinyl) -pyrido [2,3-pyrimidine;

4-amino-5- (3-chlorophenyl) -6-heptyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d] pyrimidine;

4-amino-5-phenyl-6-phenylmethyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3djpyrimidín;

4-amino-5- (4-bromothienyl) -6-heptyl-7- (6-morpholinyl-3-pyridinyl) -pyrido [2,3-pyrimidine;

4-amino-5- (4-bromothienyl) -6- (methylethyl) -7- (6-morpholinyl-3-pyridinyl) -pyrido [2,3-d] pyrimidine;

4-amino-5- (4-bromothienyl) -6-phenylmethyl-7- (6-morpholinyl-3-pyridinyl) -pyrido [2,3-pyrimidine;

4-amino-5- (3-bromophenyl) -6-cyclohexyl-7- (6-dimethylamino-3-pyridinyl) -pyrido [2,3-pyrimidine;

and

4-amino-5- (3-bromophenyl) -6-pentyl-7- (6-dimethylamino-3-pyridinyl) pyrido [2,3-d] pyrimidine; and pharmaceutically acceptable salts and amides thereof. Partially saturated and fully saturated forms of the above compounds are also included in the method of inhibiting adenosine kinase in the treatment of a patient in need thereof. The above compounds may be treated with hydrogen and a catalyst to form a compound of formula (I) wherein the double bonds on the right side are absent or there is a double bond between carbon atoms 5,6; carbon atoms 6,7 or carbon atom 7 and nitrogen atom 8.

The groups R ³ , R ⁴ and R ⁵ may independently be selected from the group consisting of phenyl; thiophen-2-yl; l-methyl-2-oxobenzoxazolin-5-yl; 2- (dimethylamino) -5pyridimidinyl; 2- (N-formyl-N-methylamino) -3-pyrimidinyl; 2- (N- (2-methoxyethyl) N-methylamino) -5-pyrimidinyl; 5-dimethylamino-2-pyridinyl; 5- (N- (2-methoxyethyl) N-methylamino) -2-pyridinyl; 2- (N-methylamino) -5-pyrimidinyl; 2- (l-morpholinyl) -5-pyrimidinyl; 2- (1-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-422 (N-methyl-N- (trifluoroacetyl) amino) phenyl; 3-methyl-4- (N-methylamino) phenyl; 3-methyl-4pyrrolidinylphenyl; 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) 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-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-Ntrifluóracetylamino) phenyl; 4- (N-morpholinyl) phenyl; 4- (thiophen-2-yl) phenyl; 4 (ureido) phenyl; 4- (2- (dimethylamino) acetylamino) phenyl; 4- (2- (2-methoxy) acetylamino) ethyl) amino) phenyl; 4- (2-methoxy) ethoxyphenyl; 4- (2-oxo-oxazolidinyl) phenyl; 4 (4-methoxy-2-butyl) phenyl; 4- (4-methylpiperidinyl) phenyl; 4- (5-pyrimidinyl) phenyl; 4-aminophenyl; 4-bromophenyl; 4-butoxy-phenyl; 4-carboxamidophenyl; 4-chlorophenyl; 4-cyano; 4diethylaminophenyl; 4-diethylmalonylallylphenyl); 4-dimethylaminophenyl;

4-ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4-iodophenyl; 4-isopropyl-phenyl; 4-methoxyphenyl) 4-methylaminophenyl; 4-methylsulfonylphenyl; 4morpholinylphenyl; 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; 4piperidinylphenyl; 4pyridylfenyl; 4pyrrolidinylphenyl; 4-t-butylacrylphenyl; 5- (dimethylamino) thiophen-2-yl;

5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 3-dimetylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 6-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-morpholinyl-3-pyridinyl; 6-pyrrolidinyl-3-pyridinyl; (2-propyl) -3-pyridinyl; and (4formylamino) 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 3-bromo-5-iodophenyl, 3-bromo-5-methoxyphenyl;

3-bromophenyl; 3-Bromophenyl-methyl; 3carboxamidophenyl; 3-chlorophenyl; 3-cyanophenyl; 3-diethylmalonylallylphenyl; 3-dimethylamino-phenyl; 3-ethoxyphenyl; 3-fluoro-5trifluórmetylfenyl; 3-fluorophenyl; 3-hydroxyphenyl; 3-iodophenyl; 3-methoxyethyoxyphenyl; 3-methoxyphenyl; 3-methylphenyl; 3-methylsulfonylphenyl; 3-methylthiophenyl; 3-tbutylakrylfenyl; 3-trifluórmetyloxyfenyl; 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-dimethyl-phenyl; 4- (2-propyl) phenyl; 4- (2-propyl) oxyphenyl; 4-benzyloxyphenyl; 4-bromophenyl; 4-bromo-thiophen-2-yl; 4-butoxy-phenyl; 4-dimethylaminophenyl; 4-fluoro-3-trifluoromethylphenyl; 4-methoxyphenyl; 4-neopentylphenyl; 4-phenoxyphenyl; 5-bromo-thiophen-2-yl; cyclohexyl; cyclopropyl; hexyl; methyl; phenyl; (2-bromo-5-chlorophenyl) methyl; (2-bromophenyl) methyl; 6-cykIopropylmetylamino-3-pyridinyl; and (5-chloro-2- (3-methoxyphenyl) phenyl) methyl.

The term acyl, as used herein, means a moiety attached by a carbonyl bond such as lower alkylcarbonyl or arylcarbonyl, in which lower alkyl and aryl are 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-naphthyl or 2-naphthyl, which may be unsubstituted or substituted, by substituting independently one, two or three hydrogen atoms with Cl Br, F, I , cyano, carboxamido, hydroxy, lower alkoxy, lower alkyl, lower alkenyl, lower alkynyl, amino, lower alkylamino, di (lower alkylamino), N-lower alkyl-N-lower alkoxyamino, trifluoromethyl or methoxymethyl. In addition, the term aryl refers to a phenyl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, morpholinyl, phenyl-lower alkoxy, phenyl-lower alkenyl or cycloalkyl-lower alkyl 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-methoxy) 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 mentioned herein.

The term arylalkyl refers to a lower alkyl radical having the ability to attach to an aryl group as defined above, such as benzyl and phenylethyl.

The term aryloxy refers to an aryl radical that is attached to the molecule by an ether bond (i.e., oxygen atoms), such 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 three to seven ring atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl is also described as C 3 -C 8 cycloalkyl.

The term cycloalkyl-lower alkyl refers to a lower alkyl radical, as defined below, substituted with a cycloalkyl group, as defined above, by replacing one hydrogen atom. Examples of cycloalkyl-lower alkyl include cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylbutyl, and the like.

The term heteroaryl or substituted heteroaryl refers to a monocyclic aromatic radical having from five to seven ring atoms of which one is nitrogen, oxygen or sulfur; none, one or two atoms are other heteroatoms independently selected from S, O and N; and the remaining atoms are a carbon atom, a radical attached to the rest of the molecule through any atom in the ring. The heteroaryl group may be unsubstituted or substituted by the independent exchange of one, two or three hydrogen atoms with Cl, Br, F, I, cyano, carboxamido, hydroxy, lower alkoxy, lower alkyl, lower alkenyl, lower alkynyl, amino, lower alkylamino, di ( lower alkylamino), N-lower alkyl-N-lower alkoxyamino, trifluoromethyl or methoxymethyl. In addition, the term heteroaryl refers to a heteroaryl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, morpholinyl, phenyl-lower alkoxy, phenyl-lower alkenyl or cycloalkyl-lower alkyl group. In addition, a heteroaryl group may be substituted by exchanging any two adjacent hydrogen atoms with a grouping of atoms that leads to 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, benzofuranyl , benzothiophenyl, and the like. and others described herein.

The term heterocyclic refers to a saturated or unsaturated monocyclic hydrocarbon radical of the ring system having from four to seven ring atoms, of which one is nitrogen or oxygen; none, one or two atoms are other heteroatoms independently selected from S, O and N; and the remaining are carbon atoms, the radical is attached to the remainder of the molecule through any ring atoms and is optionally substituted on either the nitrogen or carbon atom with another radical selected from aryl (lower alkyl), alkoxycarbonyl, lower alkyl, halo (lower alkyl), amino ( lower alkyl), hydroxy-substituted lower alkyl, hydroxy, lower alkoxy, halogen, amino, lower alkylamino, and amino, (lower alkyl) 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 carbon atoms, α-amino acid or polypeptide. Examples of the term heterocyclic include pyrrolidine, tetrahydrofuran, dihydropyrole, isoxazolidine, oxazolidine, tetrahydropyridine, piperidine, piperazine, morpholine, thiomorpholine, aziridine and azetidine and others described herein.

The term heterocyclic-lower alkyl refers to a lower alkyl radical, as defined below, substituted with a heterocyclic group, as defined above, by replacing one hydrogen atom. Examples of cycloalkyl-lower alkyl include pyrrolidinylmethyl, piperidinylethyl, and the like.

The term lower alkyl as used herein refers to a saturated, straight or branched chain hydrocarbon radical containing from one to six carbon atoms inclusive, which may be unsubstituted or substituted independently by the exchange of one, two or three carbon atoms with Cl, Br, F, I , cyano, carboxamido, hydroxy, lower alkoxy, amino, lower alkylamino, di (lower alkylamino) or N-lower alkyl-N-lower alkyloxyamino. Examples of lower alkyl 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 instances, a C 1 -C 6 alkyl group is mentioned which has a similar meaning to the aforementioned lower alkyl but is more specific. Also, the term C 0 -C 6 alkyl means carbon atoms that may be present in the alkyl chain, including the carbon-free variant. These terms also apply to an aryl or heteroaryl or other generic group and represent or have the same meaning as, for example, arylalkyl or heteroarylalkyl.

The term lower alkenyl as used herein refers to a mono-unsaturated straight or branched chain hydrocarbon radical containing from two to six carbon atoms including, but not limited to, vinyl, propenyl, n-butenyl, i-butenyl, n- pentenyl and n-hexenyl. These options are also mentioned, such as C 2 -C 6 alkenyl.

The term lower alkoxy refers to a lower alkyl radical that is attached to the molecule via an ether bond (namely, through an oxygen atom), such as methoxy, ethoxy, propoxy, 2-propoxy, 2-methyl-2-propoxy, tert-butoxy, pentyloxy, hexyloxy, their isomeric forms and the like. This term is also referred to as C _1-6 alkyloxy.

The term lower alkynyl, as used herein, refers to a straight or branched chain single-bonded hydrocarbon radical containing from two to six carbon atoms including, but not limited to, ethynyl, propynyl, n -butinyl, n -pentinyl, and n -hexinyl. This term is also referred to as C 2 -C 6 alkynyl.

The term mammal has its usual meaning and includes man.

In another aspect of the present invention, pharmaceutical compositions comprising a compound of the invention in combination with a pharmaceutically acceptable carrier are provided.

The present invention encompasses one or more of the above compounds that are formulated into formulations with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or carriers, collectively referred to herein as diluents for parenteral injection, for oral administration in solid form. or liquid form, for rectal or topical administration, and the like. As is well known in the art, a compound of the present invention may exist in various forms including pharmaceutically acceptable salts, amides, and the like.

The formulations may be prepared by administering the exact amount of the compound or compounds of the invention. The following dosages are intended to provide optimal therapy: iv infusion: 0.1-250 nmol / kg / minute, preferably from 150 nmol / kg / minute; orally: 0.01-250 μΜοΙ / kg / day, preferably from about 0.1-50 μΜοΙ / kg / day; these oral molar dosage ranges correspond to 0.005-125 mg / kg / day, preferably 0.05-25 mg / kg / day. For the treatment of acute disorders, intravenous administration is more preferred; a preferred method for treating chronic disorders is oral administration by tablet or sustained release formulation.

Pharmaceutically acceptable amide refers to pharmaceutically acceptable non-toxic amides of the compounds of the present invention which include amides formed with suitable organic acids or amino acids, including short peptides consisting of one to six amino acids linked by amide bonds that may be branched or linear, the amino acids being selected independently naturally occurring amino acids such as glycine, alanine, leucine, valine, phenylalanine, proline, methionine, tryptophan, asparagine, aspartic acid, glutamic acid, glutamine, serine, threonine, lysine, arginine, tyrosine, histidine, ornithine, and so on.

The term pharmaceutically acceptable salts refers to the pharmaceutically acceptable, nontoxic compounds of the inorganic or organic acid addition salts of the present invention, as described in more detail below.

The compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. These compounds include, but are not limited to, the following salts: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecylsulfate, ethanesulfonate, flavianate, fianate, fianate, fianate glycerophosphate, hemisulfate, heptonate, hexonoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmate, pectinate, persulfate, p-phenylpropionate, p-phenylpropionate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.

Suitable cationic salts are also readily prepared by conventional procedures such as e.g. reacting an acid of formula (I) or (II) with a suitable amount of a base such as an alkaline or alkaline earth metal hydroxide, for example sodium, potassium, lithium, calcium or magnesium, or with an organic base such as an amine, for example dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine , triethylamine, piperidine, pyrrolidine, benzylamine, and the like, or with a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, iodides; dialkyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; arylalkyl halides such as benzyl and phenylethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.

Salts of the present invention can be synthesized from compounds of formula (I) or (II) which contain basic or acidic moieties by conventional methods such as reacting the free base or free acid with a stoichiometric amount or excess of the desired inorganic acid-forming salt or base in a suitable solvent or a different combination of solvents.

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

Formulations suitable for parenteral injection may contain pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents, or carriers 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 . Self-adaptability can 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 dispersion, and by the use of surfactants.

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

If desired, and for more efficient distribution, the compounds may be incorporated into slow release or delivery systems, such as e.g. polymer matrices, liposomes, microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating the sterilizing agent into sterile solid compositions which can be dissolved in sterile water or any other sterile injectable medium immediately prior to use.

Dosages in solid form for oral administration may include capsules, tablets, pills, powders, and granules. In these solid form doses, the active compound is admixed with at least one inert conventional vehicle (or carrier) such as sodium citrate, dicalcium phosphate, and auxiliary (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and acid. silicic; (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia gelatin; (c) humectants such as glycerol; (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, a certain complex of silicates, and calcium carbonate; (e) solution inhibitors such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin, bentonite; and (i) lubricants such as talc, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents.

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

Dosages in solid form such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and others well known in the art. They may contain a pacifying agent and may also be of a composition such that they release the active compound or compounds in some part of the intestinal tract to some extent delayed. Examples of incorporation formulations that can be used are polymeric substances and waxes.

The active compounds may also be in microencapsulated 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, dosages in liquid form may contain inert diluents used in the art such as water or other solvents, solubilizable agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfurylalcobol, polyethylene glycols and sorbitan fatty acid esters or mixtures thereof, and the like.

In addition to such inert diluents, such liquid dosage forms may also include wetting agents, emulsifying and suspending agents, neutralizing agents, sweetening, flavoring, flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures thereof, and the like.

Formulations for rectal and vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating vehicles or carriers such as cocoa butter, polyethylene glycol or a wax suppository, which are solids at ordinary temperature but liquid at body temperature, and therefore, they soften in the rectal or vaginal cavity and release the active components.

Dosage forms for topical and transdermal administration of a compound of this invention further include ointments, pastes, creams, liquid forms for external use, gels, powders, solutions, sprays, inhalants or transdermal patches. Transdermal administration through a transdermal patch is particularly effective and is the preferred dosage form of the present invention. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants as desired. It is known that some agents may require special maneuver to prepare the formation of transdermal patches. For example, compounds that are volatile in natural form may require mixing with specially formulated agents or special fillers to ensure delivery of the correct dose. In addition, compounds that are rapidly absorbed by the skin may require formulations with absorption retardants or barriers. Ophthalmic formulations, eye ointments, powders and solutions are also included 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 monolamellar or multilamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizing agents, preservatives, vehicles, and the like. Preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y., (1976), p. 33rd

Synthetic methods

The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes, illustrating the methods by which the compounds of the present invention can be prepared. The substituent groups R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above, unless otherwise stated below.

The compounds of the present invention can be synthesized by the methods illustrated in Schemes 1-3.

Scheme 1 R ₂ -ch ₂ -co-y + ch ₃ -nh-o-ch ₃ 1 2

R ⁴ -CH ₂ -CO-N (CK ₃ ) -O-C ₃ + R ⁵ -Br ₂ -r ⁴

R ⁵ ₊ ° γ

DR I

R ⁵

R ³ + NC CN

R ³

H NH,

R ⁵ and R ³ are aryl, heteroaryl or heterocyclic, and R ⁴ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or heterocyclic, are prepared by a modification of the method of Kambe et al., Synthesis, 1980, 366-368.

The N-methoxy-N-methylamide compounds (3) can be prepared from acceptable carboxylic acid derivatives (1, reagent R ⁴ ) wherein Y is OH or Cl, and R ⁴ is lower alkyl, lower alkenyl, lower alkynyl, aryl , arylalkyl, heteroaryl or heterocyclic group, by reaction with N, Odimethylhydroxylamine (2) hydrochloride and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI), t-butanol, and triethylamine. The reaction may be carried out in methylene chloride or a similar suitable solvent such as toluene or THF at room temperature for from about 8 hours to about 24 hours.

I

Compound (3) is then reacted with compounds (4, R ³ reagent) wherein R ³ is substituted aryl, heteroaryl or heterocyclic compounds to prepare compound (5) according to literature procedure, Nahm and

Weinreb (Tetrahedron Lett. 1981, 22: 3815). Compounds (4) are obtained commercially or can be readily prepared by standard methods known in the art. Compound (5) is then reacted with an appropriately substituted aldehyde (6, R ³ reagent) in which R ³ is aryl, heteroaryl or heterocyclic group, and with malononitrile (7) by heating in the presence of ammonium acetate or another suitable ammonium salt such as ammonium propionate, ammonium iodide, and the like, in a suitable solvent, resulting in compound (8). Suitable solvents include ethanol, benzene, toluene, methylene chloride, DMF, THF, dioxane, and the like. Water from the reaction can be removed using a Dean Stork apparatus or other suitable means such as 4 A * molecular sieves. The reaction may be carried out at a temperature of from about 40 ° C to about 200 ° C and preferably at the reflux temperature of the solvent for from about 1 hour to about 24 hours, preferably from about 4 hours to about 8 hours. After isolation from the reaction mixture, the product (8) is preferably purified by chromatography.

Suitable starting aldehyde compounds (6) can be obtained commercially or can be readily prepared, for example, by reduction of esters or acids with DIBAL or another suitable hydride reducing agent, or by oxidation of alcohols under, for example, Swern conditions. Aliphatic aldehydes cannot be effectively prepared by this route. However, the ketone (5) may include the substituent R ⁵ as alkyl groups.

Compound (8) is then reacted with excess formamide by heating at reflux. Product formation is monitored by TLC and when the reaction is complete (after about 1 to 8 hours), the reaction mixture is cooled to room temperature. The desired product 5,6,7-trisubstituted pyrido [2,3-d] pyrimidine (I) is then removed by filtration and purified by column chromatography. This compound can then be partially or completely reduced by catalytic hydrogenation to the version (s) of partially saturated or fully saturated (on the right side of the molecule) compounds as shown in Scheme 1 or in compounds of formula (I). Stereoisomers resulting from the reduction process or reduction step (s) are included within the scope of the invention. The invention also encompasses those compounds wherein the single bond is between positions 5,6 and positions 7,8 and the double bond is present between carbon 6,7. Stereoisomers may be isolated and purified by conventional means.

In an alternative procedure, compound (8) is treated by heating with formamide acetate in ethoxyethanol or bis (2-methoxyethyl) ether, followed by purification by flash chromatography. In another alternative method, compound (8) and ammonium sulfate are heated at reflux in triethyl orthoformate for from about 1 hour to about 8 hours, but preferably about 2 hours. The reaction mixture was cooled and added to a mixture of ammonia in ethanol. The mixture is stirred for from about 12 to about 24 hours at 25 ° C, then at reflux for 1 to 4 hours and the solvent is removed in vacuo. The distillation residue is purified by trituration with chloroform / ethyl acetate, and the product can be converted to the hydrochloride salt with a suspension of 3M HCl, followed by lyophilization.

From the compound of formula (I) wherein both substituents R ¹ and R ² are hydrogen atoms, it is possible to prepare the desired compound of formula (I) wherein substituents R ¹ and R ² are not both hydrogen atoms. When R ¹ or R ² is lower alkyl, a compound of formula (I) may be obtained by reacting the free amino group with a suitable alkylating agent such as an alkyl halide, alkyl mesylate, alkyl tosylate in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent, such as methylene chloride or THF. When R ¹ or R ² is arylalkyl, a compound of formula (I) can be obtained by reacting the free amino group with a suitable arylalkyl halide, alkyl mesylate, or alkyl tosylate, for example in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent such as methylene chloride or THF . When R ¹ or R ² is acyl, the compound of formula (I) may be obtained by reacting the free amino group with a suitable acid anhydride, acyl chloride or activated acyl group in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent such as methylene chloride or THF. When R ¹ and R ² combine with the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing an additional oxygen or nitrogen atom, the compound may be prepared by reacting a precursor compound having a halogen atom instead of an amino group in position

4, with a compound of five to seven membered ring optionally containing an additional oxygen atom or a nitrogen atom. The precursor compound having a halogen atom instead of the amino group at the 4-position can be prepared by substitution by reaction with sulfuric acid with heating, followed by treatment with triethyl orthoformate / formamide (cf. Scheme 1, wherein compound (8) is converted to compound (I)). followed by chlorination at the 4-position of the ring with phosphorus oxychloride or thionyl chloride.

Also, this alternative process can be used to prepare alkyl substituted amino compounds, for example by reacting a chlorinated compound with a monosubstituted or disubstituted amine, such as diethylamine, allylamine, dibutylamine. This reaction proceeds readily in a solvent such as methylene chloride in the presence of a tertiary amine. Examples of possible rings in which R ¹ and R ² combine with the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing an additional oxygen or nitrogen atom include, but are not limited to, morpholine , piperidine, pyrrolidine, piperazine, thiomorpholine, and the like.

Scheme 2

R3

^NC \ / \ XR ⁴

Scheme 2 illustrates an alternative method for preparing compounds (8) in Scheme 1. Compounds (5), prepared as described above, are reacted with a dicyanoalkene compound (10) by heating at reflux in an alcoholic solvent such as ethanol or n-butanol to form compound ( 8). The dicyano compounds (10) can be prepared from the aldehyde precursor (6) by treatment with 1: 1 H 2 O: EtOH malononitrile in the presence of a catalytic amount of glycine according to the method of Bastus (Tetrahedron Lett., 1963: 955).

Scheme 3

R ³ = R ⁴ +

- (I)

Scheme 3 illustrates an alternative method for preparing compounds of formula (I) wherein R ⁴ and R ^{3 are} identical. The bis-substituted acetylene derivative (11) is treated with catecholborane in THF at reflux for about 8 to about 48 hours, then 4,6-diamino-5-iodo-pyrimidine (12), saturated aqueous sodium bicarbonate, aqueous hydroxide are added. sodium 3N and tetrakis (triphenylphosphine) palladium (0). The mixture is then heated at reflux for about 8 to about 48 hours to give the substituted pyrimidine compound (13). Compound (13) is then treated with a suitably substituted aldehyde compound (14) to give the desired compound of formula (I).

Scheme 4

5, cf Scheme 2

An alternative process for the preparation of compounds of formula (5) is shown in Scheme 4. This process is particularly useful when it is desired to have a substituted aryl moiety or a substituted heteroaryl moiety in the R ^s position.

Compound (15) containing the desired R ⁴ moiety can be reacted with an acyl halide of halogen-substituted compound (16), wherein the ring, which is for illustrative purposes only, is shown as a pyridyl ring (for example, 2-halo-5-pyridinecarboxylic acid halide) resulting in compound (17). Compound (17) is decarboxylated by heating to give compound (18).

Alternatively, compound (16) can be treated in a two step procedure, first step with N-methoxymethylamine HCl, then reacting the me39 intermediate with compound (19) under Grignard conditions to prepare compound (18).

Compound (18) may then be reacted with a suitable amine compound (20), wherein compound (20) may be a heterocyclic compound such as piperidine, pyrrolidine or morpholine, or may be protected or substituted with an amine in which R 1 and R 2 are either substituents or amine protecting groups, or R 1 and R 2, combine with the nitrogen atom to which they are attached to form a heterocyclic ring to prepare compound (5).

Methods of inhibiting kinase

In yet another aspect of the present invention, there is provided a method of inhibiting adenosine kinase. According to this procedure, the adenosine kinase enzyme is exposed to an effective inhibitory amount of an adenosine kinase inhibitor compound of the present invention. Preferred compounds for use in this method are the same as above. Means for determining an effective inhibitory amount are well known in the art.

The adenosine kinase can be localized in vitro, in situ or in vivo to be inhibited. Where adenosine kinase is localized in vitro, adenosine kinase is contacted with the inhibitor compound typically by adding the compound to an aqueous solution containing the enzyme, radioisotope-labeled adenosine substrate, magnesium chloride, and ATP. ₍ The enzyme may exist in intact cells or in isolated subcellular portions containing the enzyme. The enzyme is then maintained in the presence of the inhibitor for a certain period of time under appropriate physiological conditions. The means to maintain a given time are well known in the art and depend on enzyme concentrations and physiological conditions. Suitable physiological conditions are those necessary to maintain viable adenosine kinase and include temperature, acidity, tonicity, etc. Inhibition of adenosine kinase can be performed, for example, according to standard procedures well known in the art (Yamada et al. Comp. Biochem. Physiol. 1982, 71B: 367). -372).

Where adenosine kinase is localized in situ or in vivo, the compound of the invention is typically administered by spraying tissue containing the enzyme. The fluid may be a naturally occurring fluid such as blood or plasma or an artificial fluid such as saline, Ringer's solution, and the like. The method of inhibiting adenosine kinase in vivo is particularly useful in mammals such as humans. Administration of the inhibitor compound is typically accomplished in particular by parenteral (e.g., intravenous injection or oral administration) administration of the compound. By amount of application is meant an effective inhibitory amount or an effective therapeutic amount.

By a therapeutically effective amount of a compound of the invention is meant a sufficient amount of the compound to modulate the effect or alleviate related adenosine kinase disorders that broadly include those diseases, disorders or conditions, inhibitions useful for adenosine kinase in a reasonable benefit / risk ratio useful in any medical treatment. . However, it is clear that the overall daily use of the compounds and compositions of the present invention will be decided by the attending physician based on reasonable medical judgment. The specific therapeutically effective dose level for any particular patient will depend on various factors including the disorder to be treated and the severity of the disorder; the effect of the specific composition used; use of a specific preparation; the age, body weight, general health, gender and lifestyle of the patient; the time of administration, the method of administration and the rate of excretion of the specific compound used; duration of treatment; in combination with the drug administration or the specific compound used; and similar factors well known in the medical art and the ability of the attending physician.

The compounds of the present invention inhibit activity in vitro and in vivo. In vitro adenosine kinase activity can be measured using any standard procedure 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 inhibitor. In these cells, inhibition is measured as the ability to inhibit the phosphorylation of endogenous or externally administered ¹⁴ Cadenosine. Cells may be intact or disrupted. The specificity of the inhibitory actinic adenosine kinase is determined by studying the effects of inhibitors on the adenosine A1 and A2a binding receptor, adenosine deaminase activity, and adenosine transport.

The compounds of the present invention are effective in inhibiting adenosine kinase activity in vivo. A number of animal models for studying adenosine kinase activity and affects for inhibiting such activity are well known in the art. Examples are adenosine kinase inhibitors that have been reported to protect rodents (e.g., mice and rats) from seizures induced by subcutaneous administration of pentylenetetrazole (PTZ). Usually, different doses of the administered inhibitor are injected into the rodent, followed, at different times, by subcutaneous administration of from about 10 to about 500 milligrams per kilogram of PTZ. The injected animals are then observed from the onset of the seizures.

The compounds of the invention are tested in vivo for mammalian analgesia such as e.g. mice in a hot plate test. For example, the compounds of Examples 19 and 27 in the procedure described below are tested for 30 minutes after pre-administration of the drug (30 gmol / kg i.p.) for tenth jump latency (in seconds). The more seconds, the more effective the administration of the drug is to mask the pain felt by the hot plate. A time of 142.13 seconds was measured with compound 19, with the time related to the vehicle alone being 72.76 ± 10.51 seconds. A time of 154.86 seconds was measured with compound 27. The compounds of the invention are therefore very effective in relieving pain, as demonstrated in this animal model.

Hot plate test performed on mice

Male CF1 mice (Charles River) with approximately 25-30 g body weight are pre-administered with 10 ml / kg test compound, i.p. or p.o., in groups of 8 animals per dose. At the end of the test compound pre-treatment period, mice are transferred to the Omnitech Electronics Automated 16 Animal Hot Plate Analgesia Monitor (Columbus, OH; Model AHP16AN) individually, 9.8 x 7.2 x 15.3 cm (length x width x height) ) of plastic enclosure on top of copper plate heated to 55 ° C. Infrared sensors, located near the top of each enclosure, detect the intersection of rays appearing behind the heated surface when the mice do not jump. The latency times for each jump are automatically recorded and the latency times of the first and tenth leaps are used to analyze the data. Mice that do not meet the 10 jumps criterion in 180 seconds are immediately moved from the hot plate to avoid tissue damage and are assigned a maximum value of 180 seconds as their latency to the tenth jump.

A number of other animal models of adenosine kinase activity have been described [See, for example, Davies et al., Biochem. Pharmaeol., 33: 347-355 (1984); Keil et al., Eur. J. Pharmaeol., 271: 37-46 (1994); Murray, et al., Drug Development Res., 28: 410-415 (1993)].

A number of inhibitor compounds of the present invention were tested in vitro and inhibition of adenosine kinase activity was found. The results of some representative studies are shown in Table 1 below. The data show that the compounds inhibit adenosine kinase.

Table 1

Inhibition of adenosine kinase by representative compounds of the invention.

Example number of the compound ICjo (nM) 1 80 4 3 6 1 8 3 9 23 11 0.3 12 1 19 0.1 25 4 26 5 27 9 39 5 40 3 41 2

A method of treating cerebral ischemia, epilepsy, nociperception (nociception) (pain), inflammation involving conditions such as septic shock due to sepsis.

In yet another aspect of the present invention, there is provided a method of treating cerebral ischemia, epilepsy, nociperception or nociception, inflammation comprising conditions such as septic shock caused by sepsis infection in humans or lower mammals, comprising administering to the mammal a therapeutically effective amount of the compound.

Changes in cellular adenosine kinase activity have been observed in certain disorders. Adenosine kinase activity has been found to be reduced, relative to normal liver, in various rat hepatomases: enzyme activity providing a negative correlation with tumor growth rate (Jackson, et al., Br. J. Cancer, 1978, 37: 701-713) . Adenosine kinase activity was also reduced in experimental animals in liver regeneration after partial hepatectomy (Jackson, et al., Br. J. Cancer, 1978, 37: 701-713). It has been found that erythrocyte adenosine kinase activity is reduced in gout patients. (Nishizawa, et al., Clin. Chim. Acta 1976, 67: 15-20). Lymphocyte adenosine kinase activity was decreased in patients infected with human immunodeficiency virus (HIV) presenting with symptoms of AIDS, and was increased in asymptomatic HIV seropositive and HIV seronegative high-risk subjects compared to normal healthy subjects (Renouf, et al., Clin. Chem., 1989, 35: 1478-1481). It has been suggested that measurement of adenosine kinase activity is useful in monitoring the clinical development of patients with HIV infection (Renouf, et al., Clin. Chem. 1989, 35: 1478-1481). Infection with sepsis can lead to systemic inflammatory syndrome (SIRS), characterized by an increase in cytokine production, neutrophil accumulation, hemodynamic effects, and tissue damage or death. The ability of an adenosine kinase inhibitor to increase adenosine levels in tissues has been demonstrated by the improving symptoms of the syndrome due to the known anti-inflammatory effects of adenosine (Firestein, et al., J. of immunology, 1994, 5853-5859). The ability of adenosine kinase inhibitors is expected to increase pain relieving levels as it has been demonstrated that the administration of adenosine or its analogs results in antinociception or antinociperception (Swaynok, et al., Neuroscience, 1989, 32: No.3, 557-569). .

The following examples illustrate preferred embodiments of the present invention and do not limit the scope of the invention, which is fully defined by the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

4-amino-5- (3-bromo-4-fluorophenyl) -6-pentyl-7- (4- (dimethylamino) phenyl) pyrido [2,3djpyrimidín

4- (3-bromo-4-fluorophenyl) -3-cyano-6- (dimethylaminophenyl) -5-pentyl-2-pyridinamine (951 mg, 1.98 mmol) was suspended in 2-ethoxyethanol followed by the addition of formamidine acetate ( 411 mg, 3.95 mmol). The reaction was heated to 130 ° C for two days during which additional formamidine acetate (2-3 eq each) was added at several hour intervals. After this time, the reaction was cooled, concentrated in vacuo and the residue triturated with CH ₂ Cl ₂ and filtered. The filtrate was purified by flash chromatography (9% MeOH / CH ₂ Cl ₂ ) to give a red oil which was triturated with ethyl ether to give the title compound as a yellow solid (174 mg, 17%). MS 508/510 (M + H) ^&lt; ^{+ &gt};; IR (cm ^-1 ) 3480, 2920, 1610, 1550, 820.

4- (3-Bromo-4-fluorophenyl) -3-cyano-6- (dimethylaminophenyl) -5-pentyl-2-pyridinamine is prepared as follows:

and 1- (4-Dimethylaminophenyl) heptan-1-one

Triethylamine (19.6 g, 194 mmol) was added dropwise to a suspension of N, Odimethylhydroxyamine hydrochloride (6.93 g, 71 mmol) in anhydrous CH ₂ Cl ₂ at 0 ° C. Heptanoyl chloride (9.60 g, 65 mmol) is then added dropwise and the reaction is stirred for one hour. The crude product mixture was poured into water and the separated aqueous phase was extracted with CH 2 Cl 2. The combined organic layers were washed with aqueous HCl, saturated NaHCO 3, brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 10 g (89%) of N-methyl-N-methoxyheptanamide as a yellow oil.

n-Butyllithium (2.5 M in hexanes, 51 mL, 127 mmol) was added dropwise to 4-bromo-,, γ-dimethylaniline (23.1 g, 115 mmol, Aldrich Chemical Co.) in anhydrous THF at temperature 78 ° C. After ten minutes, a solution of Ύ-methyl-N-methoxyheptanamide (10.0 g, 57.7 mmol) in 20 mL THF was added dropwise via cannula. The reaction was allowed to proceed for one hour, then quenched with 1 N aqueous HCl and carefully poured into saturated NaHCO 3. The aqueous layer was extracted with ethyl ether and the combined organic fractions were washed with water, brine, dried (MgSO ₄ ) and concentrated in vacuo. Flash chromatography (15% EtOAc / hexanes) gave 1- (4-dimethylaminophenyl) heptan-1-one as a yellow solid (6.49 g, 48%). MS 234 (M + H) &lt; ⁺ &gt; 4- (3-Bromo-4-fluorophenyl) -3-cyano-6- (dimethylaminophenyl) -5-pentyl-2-pyridinamine 1- (4-Dimethylaminophenyl) heptan-1-one (2.15 g, 9.21 mmol) , 3-bromo-4-fluorobenzaldehyde (1.87 g, 9.21 mmol, R ³ reagent), malononitrile (0.91 g, 13.8 mmol) and NH ₄ OAc (1.42 g, 18.4 mmol) are dissolved in benzene ( 75mL) and heated to reflux. After three days, the crude reaction mixture was partitioned between EtOAc and H 2 O. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was triturated with Et 2 O and the resulting solid collected by filtration to give 1.25 g of the desired product as a yellow solid (28%): MS 444/446 (M + H) ⁺ .

Examples 2-10

Following the procedure of Example 1, except substituting the appropriate reagents required for the substituents R ^p, R ⁴ and R ^3, as shown in ta46 buľlce 2 below, optionally omitting the step of preparing the salt of HC1, the compounds of Examples 2-10 were prepared as described in Table 3 below.

Table 2

Examples 2-10

č.pr. R ⁵ reagent (for position 7) R ⁴ reagent (for position 6) R ³ reagent (for position S) 2 2-bromothiophene heptanoyl 3-bromo-4- fluorobenzaldehyde 3 l-bromo-4-methoxy-benzene 4-metoxyfenylacetylchloric 3-bromobenzaldehyde 4 2-bromothiophene butanoyl 3-bromobenzaldehyde 5 2-bromothiophene heptanoyl 3-bromobenzaldehyde 6 2-bromothiophene 3,4-dimethoxyphenylacetic acid 3-bromobenzaldehyde 7 l-bromo-4- (Dimethylamino) benzene 4- (2-propyl) -phenyl acid 3-bromobenzaldehyde 8 2-bromothiophene succinyl chloride 3-bromobenzaldehyde 9 2-bromothiophene 3- (3-Methoxyphenyl) propionic acid 3-Bromobenzaldehyde 10 l-bromo-4- (Dimethylamino) benzene 3,4-dimethoxyphenylacetic acid 3-bromobenzaldehyde

Table 3

Examples 2-10

č.pr. Title Analytical data 2 4-Amino-5- (3-bromo-4-fluorophenyl) -6-pentyl-7 (thiophen-2-yl) pyrido [2,3-d] pyrimidine IR: 3480, 2920, 1610, 1550, 820; MS m / z 508/510 (M + H) &lt; ^{+ &gt};. 3 4-Amino-5- (3-bromophenyl) -6- (4-methoxyphenyl) 7- (4-methoxyphenyl) pyrido [2,3-d] pyrimidine IR: 3480.3400.3070, 1610, 1550; MS m / z 513 & 515 (M + H) ⁺ . 4 4-amino-5- (3-bromophenyl) -6-ethyl-7- (thiophen-2- yl) pyrido [2,3-d] pyrimidine IR: 3470.3390.3060, 1550.1425; MS m / z 411 & 413 (M + H) ⁺ .

5 4-amino-5- (3-bromophenyl) -6-pentyl-7- (thiophen-2- yl) pyrido [2,3-d] pyrimidine IR: 3480, 30030, 3040, 1550, 1420; MS m / z 453-455 (M + H) ⁺ . 6 4-Amino-5- (3-bromophenyl) -6- (3,4-dimethoxyphenyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine IR: 3480.3390.3060, 1545, 1510; MS m / z 519 & 521 (M + H) ⁺ . 7 4-amino-5- (3-bromophenyl) -6- (4- (2-propyl) phenyl) -7- (4- (Dimethylamino) phenyl) pyrido [2,3-d] pyrimidine [R: 3470, 3280, 3060, 1605, 1540; MS m / z 538 & 540 (M + H) ⁺ . 8 4-Amino-5- (3-bromophenyl) -6-ethoxycarbonylmethyl-7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine hydrochloride IR: 3420.3060, 1725, 1600, 1585; MS m / z 469 & 471 (M + H) ⁺ . 9 4-Amino-5- (3-bromophenyl) -6- (3-methoxyphenylmethyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine hydrochloride [R: 3440.3040, 1635, 1600.1580; MS m / z 503 & 505 (M + H) ⁺ . 10 4-Amino-5- (3-bromophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine dihydrochloride [R: 3430.3020, 1635, 1600.1580; MS m / z 556-558 (M + H) ⁺ .

Example 11

4-amino-5- (4-bromo-thiophen-2-yl) -6- (3,4-dimethoxyphenyl) -7- (thiophen-2-yl) -pyrido [2,3djpyrimidínhydrochlorid

3-Cyano-4- (4-bromothiophen-2-yl) -5-pentyl-6- (thiophen-2-yl) pyridinamine (750 mg, 1.50 mmol) and formamidine acetate (312 mg, 3.00 mmol) are added to 10 mL of bis (2-methoxyethyl) ether and heated to 155 ° C. Additional formamidine acetate (1 eq.) Is added at 90 minute intervals for a total of 6 hours, then heating is continued overnight. The cooled reaction mixture was then partitioned between EtOAc and H 2 O. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. Flash chromatography (3.5% MeOH / CH 2 Cl 2) gave a brown residue which was dissolved in a small amount of CH 2 Cl 2 followed by addition of Et 2 O to the precipitated product (209 mg, 26%). This material was converted to the hydrochloride salt using 7M ethanolic HCl followed by precipitation with Et2O and filtration of the product. IR: 525/527; 3420, 2930, 1580, 1510, 820 cm ^-1 ; MS m / z 498 (M + H) &lt; ^{+ &gt};.

3-Cyano-4- (4-bromothiophen-2-yl) -5- (3,4-dimethoxyphenyl) -6- (thiophen-2-yl) pyridinamine is prepared as follows:

11a. 2- (3,4-Dimethoxyphenyl) -1- (thien-2-yl) ethanone (3,4-Dimethoxyphenyl) acetic acid (13.0 g, 66.4 mmol) was suspended in anhydrous CH 2 Cl 2 followed by addition of EDCI (15.3 g, 79.7 mmol), HOBt (20.6 g, 152 mmol), triethylamine (8.06 g, 79.7 mmol), and N, N -dimethylhydroxylamine hydrochloride (6.48 g, 66.4 mmol) ). The reaction was stirred at room temperature for 3 days after which the solvent was evaporated under reduced pressure. The residue was partitioned between EtOAc and H 2 O. The organic layer was washed with aqueous HCl, saturated NaHCO 3, brine, dried (Na 2 SO 4) and concentrated in vacuo to give

10.5 g (66%) of N-methyl-N-methoxy- (3,4-dimethoxyphenyl) acetamide as a light brown oil.

2-Lithiothiophene (1.0 M in THF, 33.0 mL, 33.0 mmol, Aldrich Chemical Co.) was added dropwise to N-methyl-N-methoxy- (3,4-dimethoxyphenyl) acetamide (5 mL). (26 g, 22.0 mmol) in anhydrous THF at -78 ° C. The reaction was allowed to proceed for 90 minutes, then the mixture was diluted with 100 mL Et ₂ O and poured into 1 N aqueous HCl. The aqueous phase is extracted with Et 2 O and the combined organic fraction is washed with brine, dried (Na 2 SO 4) and concentrated in vacuo. Flash chromatography (25% EtOAc / hexanes) afforded 2.91 g (50%) of 2- (3,4-dimethoxyphenyl) -1- (thien-2-yl) ethanone as a brown oil. MS 263 (M + H) +, 280 (M + NH ₄₎ +.

11b. 4-bromo-2- (2,2-dicyanoethenyl) thiophene

4-bromo-2-thiophenecarboxaldehyde (6.92 g, 36.2 mmol) and malononitrile (2.39 g,

36.2 mmol) is dissolved in 100 mL of 1: 1 EtOH: H ₂ O. A small teaspoon of glycine is added and the reaction is stirred at room temperature for 30 minutes. The precipitated product was collected by vacuum filtration, washed with water, and dried under vacuum overnight. This resulted in 8.38 g (97%) of 4-bromo-2- (2,2-dicyanoethenyl) thiophene as a light green solid. MS 238/240 (M + H) &lt; + &gt;.

llc. 3-Cyano-4- (4-bromo-thiophen-2-yl) -5- (3,4-dimethoxyphenyl) -6- (thiophen-2-yl) -2pyridínamín

2- (3,4-dimethoxyphenyl) -1- (thien-2-yl) ethanone (1.56 g, 5.95 mmol), 4-bromo-2- (2,2-dicyanoethenyl) thiophene (1.71 g) , 7.13 mmol) and NH ₄ OAc (1.15 g, 14.9 mmol) were combined in n-BuOH (10 mL) and heated to reflux. After 24 h, the reaction mixture was cooled, diluted with EtOAc and washed with water, brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Flash chromatography (40% EtOAc / hexanes) gave the desired product (0.76 g, 26%) as a dark yellow solid.

Examples 12-24

Using the procedures of Example 11, except for substituting the appropriate reagents required for R ⁵ , R ^4, and R ³ as shown in Table 4 below, the compounds of Examples 12-24 were prepared as described in Table 5.

Table 4

Examples 12-24

č.pr. R ^s reagent (for position 7) R ⁴ reagent (for position 6) R ³ reagent (for position 5) 12 2-bromothiophene 3,4-dimethoxyphenylacetic acid 3-chlórbenzalde- hyd 13 2-bromothiophene 3,4-dimethoxyphenylacetic acid 3- trifluoromethyl- 4-fluorobenzaldehyde 14 l-bromo-4- (Dimethylamino) benzene 3,4-dimethoxyphenylacetic acid 3-chlórbenzalde- hyd

15 l-bromo-4- (Dimethylamino) benzene 3,4-dimethoxyphenylacetic acid 4-fluoromethyl-3- trifluórbenzalde- hyd 16 2-bromo-5-methylthiophene 3,4-dimethoxyphenylacetic acid 3-chlórbenzalde- hyd 17 2-bromo-5-methylthiophene 3,4-dimethoxyphenylacetic acid 4-bromo-2- tiofénkarboxalde- hyd 18 l-bromo-4- (Dimethylamino) benzene 3,4-dimethoxyphenylacetic acid 4-bromo-2- tiofénkarboxalde- hyd 19 1-Bromo-4- (N-methyl-N- (2-methoxyethyl) amino no) benzene 3,4-dimethoxyphenylacetic acid 4-bromo-2-thiophene carboxaldehyde 20 l-bromo-4- (N-methyl-N- (2-methoxyethyl) amino no) benzene 3,4-dimethoxyphenylacetic acid benzaldehyde 21 1-Bromo-4- (N-methyl-N- (2-methoxyethyl) amino no) benzene 3,4-dimethoxyphenylacetic acid 3-chlórbenzalde- hyd 22 5-bromo-2-methoxypyridine 3,4-dimethoxyphenylacetic acid benzaldehyde 23 5-bromo-2-methoxypyridine 3,4-dimethoxyphenylacetic acid 3-chlórbenzalde- hyd 24 5-bromo-2-dimethylamino pyridine 3,4-dimethoxyphenylacetic acid 3-chlórbenzalde- hyd

Table 5

Examples 12-24

č.pr. Title Analytical data 12 4-Amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) 7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine hydrochloride IR: 3440, 2940, 1540, 1420, 1020 cm MS m / z 475 (M + H) &lt; ^{+ &gt};. 13 4-amino-5- (3-trifluoromethyl-4-fluorophenyl) -6- (3,4- dimethoxyphenyl) -7- (thiophen-2-yl) pyrido [2,3- d] pyrimidine hydrochloride IR: 3460, 3060, 1600, 1510, 1410, 1140; MS m / z 527 (M + H) &lt; ^{+ &gt};. 14 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3- d] pyrimidíndihydrochlorid IR: 3440, 2940, 1600, 1570, 1360, 1170; MS m / z 512 (M + H) &lt; ^{+ &gt};.

15 4-Amino-5- (3-trifluoromethyl-4-fluorophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine dihydrochloride IR: 3450, 3020, 1605, 1510, 1320, 1140; MS m / z 564 (M + H) &lt; + &gt;. 16 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (5-methyl-thiophen-2-yl) pyrido [2,3- d] pyrimidine hydrochloride IR: 3440, 2920, 1600, 1570, 1440, 1360; MS m / z 489 (M + H) &lt; + &gt;. 17 4-amino-5- (4-bromo-thiophen-2-yl) -6- (3,4- dimethoxyphenyl) -7- (5-methyl-thiophen-2-yl) pyrido [2,3- d] -pyrimidine IR: 3420, 2960, 1580, 1440, 820; MS m / z 539/541 (M + H) &lt; + &gt;. 18 4-amino-5- (4-bromo-thiophen-2-yl) -6- (3,4- dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrimido [2,3-d] pyrimidíndihydrochlorid IR: 3420, 2920, 1600, 1380, 820; MS m / z 562/564 (M + H) &lt; + &gt;. 19 4-amino-5- (4-bromo-thiophen-2-yl) -6- (3,4- dimethoxyphenyl) -7- (4- (N-methyl-R / - (2- methoxyethyl) amino) phenyl) pyrido [2,3- d] pyrimidine hydrochloride IR: 3420, 2920, 1600, 1380, 820; MS m / z 606/608 (M + H) &lt; + &gt;. 20 4-amino-5-phenyl-6- (3,4-dimethoxyphenyl) -7- (4- (N- methyl-N- (2-methoxyethyl) amino) phenyl) -5- phenyl-pyrido [2,3-d] pyrimidine hydrochloride IR: 3420, 2930, 1630, 1600, 1570, 1360; MS m / z 522 (M + H) &lt; + &gt;. 21 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (N-methyl-N- (2- methoxyethyl) amino) phenyl) pyrido [2,3- d] pyrimidine hydrochloride IR: 3440, 2930, 1605, 1570, 1355, 1025; MS m / z 556 (M + H) &lt; + &gt;. 22 4-amino-5-phenyl-6- (3,4-dimethoxyphenyl) -7- (5- methoxy-2-pyridinyl) pyrido [2,3- djpyrimidínhydrochlorid IR: 3420, 3000, 1600, 1320, 1030; MS m / z 466 (M + H) &lt; + &gt;. 23 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (5-methoxy-2-pyridinyl) pyrido [2,3- d] pyrimidine hydrochloride IR: 3440, 3000, 1635, 1600, 1365; MS m / z 500 (M + H) &lt; + &gt;. 24 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -5- (5-dimethylamino-2-pyridinyl) pyrido [2,3- d] pyrimidíndihydrochlorid IR: 3435, 2950, 1645, 1600, 1260; MS m / z 513 (M + H) &lt; + &gt;.

Example 25

4-amino-5,6-bis (4- (2-propyl) phenyl) -7- (4-dimethylaminophenyl) -pyrido [2,3djpyrimidín

A sample of 4,6-diamino-5- (1,2-bis (4- (2-propyl) phenyl) ethenyl) pyrimidine (745 mg, 2mmol) was dissolved in 20 mL of 1,2,4-trichlorobenzene containing 4-dimethylaminobenzaldehyde (0 , 89 g, 6 mmol) and about 1 g of a 4 A * molecular sieve filter are added to the reaction mixture. The mixture was heated to reflux for 20 hours, cooled and filtered through a pad of celite. The filtrate is immediately chromatographed on a silica gel column using an elution system (19: 1 ammonium ethane hydroxide) which elutes with a 2.5% solution in ethyl acetate to give the desired product (186 mg, 18.5% yield): IR 3460, 2960 , 1605, 1555, 1540, 1525, 1350, 820; MS m / z 502 (M + H) &lt; ^{+ &gt};.

4,6-Diamino-5- (1,2bis (4-isopropylphenyl) ethenyl) pyrimidine was prepared as follows:

25. and 1,2-Bis (4- (2-propyl) phenyl) acetylene

To a solution of 4-iodoisopropylbenzene (12.3 g, mmol, Lancaster Chemical Co.) in triethylamine (150 mL) was added trimethylsilylacetylene (5.89 g, 60 mmol), palladium dichlorobis (triphenylphosphine) (0.70 g, 1 mmol). , Aldrich) and copper (I) iodide (1.5 g). The reaction was stirred at room temperature for 18 hours, diluted with hexanes and filtered. The filtrate was evaporated under reduced pressure to give crude 1- (4- (2-propyl) phenyl) -2-trimethylsilylacetylene.

The crude 1- (4- (2-propyl) phenyl) -2-trimethylsilylacetylene was dissolved in methanol (100mL). Aqueous 1M potassium carbonate solution was added and the reaction was stirred at room temperature for 2 hours. The reaction mixture was then diluted with water and extracted with pentane. The organic layers were combined, dried with magnesium sulfate and evaporated under reduced pressure without heating to give crude 4- (2-propyl) phenylacetylene.

The crude 4-isopropylphenylacetylene was dissolved in triethylamine (100 mL). 4-Iodoisopropylbenzene (12.3 g, 50 mmol), palladium dichlorobis (triphenylphosphine) (0.70 g, 1 mmol) and copper (I) iodide (1.5 g) were added. The reaction was stirred at room temperature for 2 days, heated to reflux for 1 hour, cooled, diluted with hexanes and filtered. The filtrate was evaporated under reduced pressure. The residue was filtered through silica gel with hexanes and the solvent was evaporated, yielding 11.40 g (87%) of 1,2-bis (4- (2-propyl) phenyl) acetylene.

25b. Dissolve 4,6-diamino-5- (1,2-bis (4-isopropylphenyl) ethenyl) pyrimidine 1,2-Bis (4- (2-propyl) phenyl) acetylene (11.40 g, 43 mmol) in 50 mL THF, catecholborane (1 M, 50 mL) in THF is added and the mixture is heated at reflux for 30 hours. The mixture was cooled and then 4,6-diamino-5-iodopyrimidine, 30 mL of saturated aqueous sodium bicarbonate, 20 mL of 3N aqueous sodium hydroxide, and 1.00 g (0.87 mmol of tetrakis (triphenylphosphine) palladium) were added. The organic layers were combined, dried (MgSO4), and the solvent was evaporated. with 2.5% to 5% in ethyl acetate to give the desired product (4.53 g, 28% yield).

Examples 26-32

Following the procedures of Example 25, except substituting the appropriate reagents required for the substituents R ^p, R ⁴ and R ³ as shown in Table 6 below, compounds of Examples 26-32 are prepared as described in Table 7 below.

Table 6

Examples 26-32

č.pr. R ⁵ reagent (for position 7) R ⁴ - R ³ reagent (for positions 6 and 7) 26 4- (N- (2-methoxyethyl) -N-methylamino) benz aldehyde 1,2-diphenyl acetylenes 27 4-dimethylaminobenzaldehyde 1,2-diphenyl acetylenes

28 4-dimethylaminobenzaldehyde l, 2-bis (3-fluorophenyl) acetylene 29 4-dimethylaminobenzaldehyde l, 2-bis (3,4-dimetoxyfe- phenyl) acetylene 30 4-dimethylaminobenzaldehyde l, 2-bis- (3-fluoro-4-metylfe- phenyl) acetylene 31 thiophene-2-carboxaldehyde l, 2-bis- (3-fluoro-4-metylfe- phenyl) acetylene 32 thiophene-2-carboxaldehyde 1,2-diphenyl acetylenes

Table 7

Examples 27-32

č.pr. Title Analytical data 26 4-amino-5-phenyl-6-phenyl-7- (4- (N -methyl- N (2-methoxyethyl) amino) phenyl) pyrido [2,3- djpyrimidínhydrochlorid IR: 3420, 3020, 1600, 1580, 1365; MS m / z 462 (M + H) &lt; ^{+ &gt};. 27 4-amino-5,6-diphenyl-7- (4- dimethylaminophenyl) -pyrido [2,3- d] pyrimidíndihydrochlorid IR: 3410, 1635, 1600, 1580, 1360, 705 cm **; MS m / z 418 (M + H) &lt; ^{+ &gt};. 28 4-amino-5,6-bis (3-fluorophenyl) -7- (4- dimethylaminophenyl) -pyrido [2,3- d] pyrimidíndihydrochlorid IR: 3450, 3060, 1605, 1540, 1345, 1200 cm MS. M / z 454 (M + H) ⁺ . 29 4-Amino-5,6-bis (3,4-dimethoxyphenyl) -7- (4-dimethylaminophenyl) pyrido [2,3d] pyrimidine trihydrochloride IR: 3400, 3100-2800, 1630, 1600, 1575, 1510, 1360, 1250, 1140, 1020 cm **; MS m / z 538 (M + H) &lt; ^{+ &gt};. 30 4-amino-5,6-bis (3-fluoro-4-methylphenyl) -7- (4-dimethylaminophenyl) -pyrido [2,3- d] pyrimidíndihydrochlorid IR: 3330, 3100-2800, 1635, 1600, 1575, 1535, 1505, 1360, 1200 cm ^-1 ; MS m / z 482 (M + H) &lt; ^{+ &gt};. 31 4-amino-5,6-bis (3-fluoro-4-methylphenyl) -7- (Thiophen-2-yl) pyrido [2,3- d] pyrimidine hydrochloride IR: 333 O, 3100-2800, 1635, 1580, 1540, 1505, 1415, 1365, 1235 cm ^@ -1; MS m / z 445 (M + H) &lt; ^{+ &gt};. 32 4-amino-5,6-diphenyl-7- (thiophen-2- yl) pyrido [2,3-d] pyrimidine IR: 3470, 3390, 3050, 1540, 1420 cm

Examples 33-38

Using the procedures of Example 11, except for substituting the appropriate reagents required for R ⁵ , R ^4, and R ³ as shown in Table 8 below, the compounds of Examples 33-38 were prepared as described in Table 9 below.

Table 8

Examples 33-38

č.pr. R ⁵ reagent (for position 7) R ⁴ reagent (for position 6) R ³ reagent (for position 5) 33 5-bromo-2- (Dimethylamino) pyridine phenylacetic acid benzaldehyde 34 5-bromo-2- (Dimethylamino) pyridine 3,4-dimethoxyphenylacetic acid benzaldehyde 35 5-bromo-2- (N-methyl-N- (Methoxyethyl) amino) pyrimido deen 3,4-dimethoxyphenylacetic acid 3-chlorobenzaldehyde 36 5-bromo-2- (Dimethylamino) pyridine phenylacetic acid 3-chlorobenzaldehyde 37 5-bromo-2- (Dimethylamino) pyridine phenylacetic acid 4-bromothiophene-2 carboxaldehyde 38 5-bromo-2- (Dimethylamino) pyridine phenylacetic acid 3-bromobenzaldehyde

Table 9

Examples 33-38

č.pr. Title Analytical data 33 4-amino-5,6-diphenyl-7- (5-dimethylamino-2- pyridinyl) pyrido [2,3-d] pyrimidine hydrochloride [R: 3400.3040, 1640, 1565, 1365 cm @ ^-1 ; MS m / z 419 (M + H) &lt; ^{+ &gt};. 34 4-Amino-5-phenyl-6- (3,4-dimethoxyphenyl) -7- (5 (dimethylamino) piridin-2-yl) pyrido [2,3-d] pyrimidine hydrochloride IR: 3420, 2930, 1645, 1600, 1255; MS m / z 479 (M + H) &lt; ^{+ &gt};. 35 4-amino-5- (3-chlorophenyl) -6- (3,4- dimethoxyphenyl) -7- (5- (N- (2-methoxyethyl) -N- amino) -2-pyridinyl) pyrido [2,3- djpyrimidíndihydrochlorid IR: 3040, 2930, 1640, 1600, 1370; MS m / z 557 (M + H) &lt; ^{+ &gt};.

36 4-amino-5- (3-chlorophenyl) -6-phenyl-7- (5- dimethylamino-2-pyridinyl) pyrido [2,3- djpyrimidíndihydrochlorid IR: 3420, 3040, 1650, 1575, 1260; MS m / z 453 (M + H) &lt; ^{+ &gt};. 37 4-amino-5- (4-bromo-thiophen-2-yl) -6-phenyl-7- (5- dimethylamino-2-pyridinyl) pyrido [2,3- djpyrimidínhydrochlorid IR: 3400, 3100, 1650, 1355; MS m / z 503/505 (M + H) &lt; ^{+ &gt};. 38 4-amino-5- (3-bromophenyl) -6-phenyl-7- (5- dimethylamino-2-pyridinyl) pyrido [2,3- djpyrimidínhydrochlorid IR: 3450, 3050, 1650, 1575; MS m / z 497/499 (M + H) &lt; ^{+ &gt};.

Example 39

4-amino-5- (3-bromophenyl) -6- (4-fluorophenyl) -7- (6-morpholinyl-3-pyridinyl) -pyrido [2,3-d] pyrimidine hydrochloride

Step 39a. l- (6-chloro-3-pyridyl) -2- (4-fluorophenyl) ethanone

A solution of ethyl (p-fluorophenyl) acetate (12.1 g, 68.8 mmol, R ⁴ reagent) in 10 mL THF was added dropwise to a solution of lithium bis (trimethylsilyl) amide (138 mmol) in 150 mL THF at temperature -78 ° C. The reaction was stirred for 60 minutes followed by the addition of 6-chloronicotinyl chloride (solid, R ^s reagent) as one portion. The reaction was stirred for an additional 60 minutes, then quenched with saturated ammonium chloride solution. The mixture is diluted with Et ₂ O, poured into water and the aqueous phase extracted with Et ₂ O. The combined organic layers are washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to 27.1 g of crude product, which is obtained as a yellow solid. This material was dissolved in DMSO (200mL) and H ₂ O (10mL) and the solution was heated at 155 ° C for 3 hours. The reaction was cooled, poured into water and the product extracted with Et ₂ O. The combined Et ₂ O layers were washed with water, brine, dried (MgSO ₄ ) and concentrated in vacuo. The product was purified by flash chromatography eluting with 30% EtOAc / hexanes to give 3.02 g (19%) of the title compound as a yellow solid: MS 250 (M + H) ⁺ .

Step 39b. 2- (4-fluorophenyl) -l- (2-morpholinyl-5-pyridyl) ethanone

The ketone compound from step 39a (3.02 g, 12.1 mmol) and morpholine (4.30 mL, 48.4 mmol) were dissolved in 30 mL anhydrous ethanol and the mixture was heated to reflux for 18 hours. The volatiles were removed in vacuo and the residue partitioned between Et ₂ O and saturated NaHCO 3. The Et ₂ O layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound (3.42 g, 94%) as a yellow solid. MS: 301 (M + H) &lt; ^{+ &gt};.

Step 39c. 4-Amino-5- (3-bromophenyl) -6- (4-fluorophenyl) -7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d] pyrimidine hydrochloride

The procedure of Example 11, step c was followed, except that the compound of Example 11a was replaced with the compound of step 39b and the 4-bromo-2-thiophenecarboxyaldehyde of Example 11, step b was replaced with 3-bromobenzaldehyde, followed by the reaction product as in Example 1 to prepare the desired compound. MS m / z (M + H) &lt; ^{+ &gt};557; IR (cm -1) 3433, 3040, 1641, 1602, 1367.

Examples 40-47

Following the procedure of Example 39 and Example 11, except substituting the reagents listed below for reagents R ³ and R ⁴ and substituting the reagent shown for the 7-position portion with the morpholine of Example 39b, the compounds listed in Table 10 below were prepared.

Table 10

Examples 40-47

č.pr. position 5 position 6 step 39b reagent / part position 7 40 benzaldehyde etylfenylacetát morpholine / 6-morpholinyl-3-pyridine 41 3-bromobenzaldehyde etylfenylacetát morpholine / 6-morpholinyl-3-pyridine

42 benzaldehyde etylfenylacetát N-methyl-N- (2-methoxyethyl) amine / 6- (N-methyl-N- (2-methoxyethyl) amino) 3-pyridine 43 4-bromo-2- thiophenecarboxaldehyde etylfenylacetát N-methyl-N- (2-methoxyethyl) amine / 6- (N-methyl-N- (2-methoxyethyl) amino) 3-pyridine 44 4-bromo-2- thiophenecarboxaldehyde ethyl (2 Pr) acetyl melt dimethylamine / 6-dimethylamino-3-pyridine 45 4-bromo-2- thiophenecarboxaldehyde ethyl (4- phenyl) acetate morpholine / 6-morpholinyl-3-pyridine 46 3-Bromobenzaldehyde d etylfenylacetát cyclopropylmethylamine / 6-cyclopropylmethylamino-3-pyridine 47 benzaldehyde etylfenylacetát cyclopropylmethylamine / 6-cyclopropylmethylamino-3-pyridine

Analytical Data, Examples 40-47

č.pr. Title Analytical data 40 4-amino-5-phenyl-6-phenyl-7- (6-morpholinyl-3 pyridinyl) pyrido [2,3- d] pyrimidine hydrochloride MS m / z (M + H) &lt; ^{+ &gt};461; IR (cm -1) 3431, 3050, 1600, 1576, 1245 41 4-amino-5- (3-bromophenyl) -6-phenyl-7- (6- morpholinyl-3-pyridinyl) pyrido [2,3- d] pyrimidine hydrochloride MS m / z (M + H) &lt; ^{+ &gt};539; IR ^ m ¹⁾ 3423, 2855, 1639, 1600, 1367 42 4-amino-5-phenyl-6-phenyl-7- (6- (N-methyl-N- (2-methoxyethyl) amino) -3-pyridinyl) -pyrido [2,3-d] pyrimidíndihydrochlorid MS m / z (M + H) &lt; ^{+ &gt};463; IR (cm ^-1 ) 3419, 2932, 1644, 1580, 1367 43 4-amino-5- (4-bromothienyl) -6-phenyl-7- (6- (N- methyl-N- (2-methoxyethyl) amino) -3- pyridinyl) pyrido [2,3- d] pyrimidine hydrochloride MS m / z (M + H) &lt; ^{+ &gt};547; IR ⁽ cm ^-1 ) 3417, 3053, 2928, 1643, 1367 44 4-amino-5- (4-bromothienyl) -6-cyclopropyl-7- (6-dimethylamino-3-pyridinyl) pyrido [2,3- djpyrimidínhydrochlorid MS m / z (M + H) &lt; ^{+ &gt};467; IR (cm ^-1 ) 3426, 3001, 1649, 1600, 1373 45 4-amino-5- (4-bromothienyl) -6- (4-fluorophenyl) - 7- (6-morpholinyl-3-pyridinyl) pyrido [2,3- d] pyrimidine hydrochloride MS m / z (M + H) &lt; ^{+ &gt};563; IR ^ m ^-1) 3417, 2969, 1602, 1571, 1367

46 4-amino-5- (3-bromophenyl) -6-phenyl-7- (6- cyclopropylmethyl-3-pyridinyl) -pyrido [2,3-d] pyrimidine hydrochloride MS m / z (M + H) &lt; ^{+ &gt};523; ¹ ) 3430, 3000, 1650, 1630, 1600 47 4-amino-5-phenyl-6-phenyl-7- (6-cyclopropyl- methylamino-3-pyridinyl) pyrido [2,3- d] pyrimidine hydrochloride MS m / z (M + H) &lt; ^{+ &gt};445; IR (cm ^-1 ) 3410, 3000, 1655, 1600, 1375

Example 48

252029.3

4-amino-5- (3-bromophenyl) -6-phenylmethyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3djpyrimidínhydrochlorid

Step 48a. l- (6-chloro-3-pyridyl) -3-phenylpropanone

A sample of 6-chloronicotinyl chloride (15.4 g, 87.4 mmol) was added to a mixture of Ν, Ο-dimethylhydroxylamine hydrochloride (9.38 g, 96.2 mmol) and triethylamine (36.6 mL, 262 mmol) in 200 mL CH 2 Cl 2. cooled to 0 ° C. The reaction was stirred for 2 hours, then poured into water. The separated organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 14.6 g of the intermediate Weinreb amide as a light brown oil. A sample of the intermediate amide (4.09g, 20.4 mmol) in 100 mL of THF was cooled to -78 ° C followed by the addition of phenethylmagnesium chloride (30.6 mL, 30.6 mmol, 1 M in THF). The reaction was allowed to warm to room temperature and stirred for 3 hours, after which it was quenched with 1N aqueous HCl. The mixture was partitioned between Et 2 O and saturated NaHCO 3. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product is purified by flash chromatography eluting with 30% EtOAc / hexanes to give 3.77 g (75%) of the desired product as a white solid. MS: 246 (M + H) &lt; ^{+ &gt};.

Step 48b. l- (6-morpholinyl-3-pyridyl) -3-phenylpropanone

Following the procedure of Example 39b, the compound of step 48a was converted to the title compound.

Step 48c. 4-amino-5- (3-bromophenyl) -6-phenylmethyl-7- (6-morpholinyl-3-pyridinyl) -pyrido [2,3-d] pyrimidine hydrochloride

By the method of Example 11, step c, except that the compound of Example 11, step a was replaced with the compound of step 48b, and the 4-bromo-2-thiophenecarboxaldehyde of Example 11, step b was replaced with 3-bromobenzaldehyde, followed by the reaction product. of Example 11 to prepare the title compound. MS m / z (M + H) &lt; ^{+ &gt};553; IR (cm ^-1 ) 3430, 3050, 1640, 1600, 1360.

Examples 49-55

Following the procedures of Example 48 and Example 11, substituting excluding an agent below the reagents R ³ and R ⁴ and substitution of reagents for the position of the part 7 for morpholine in Example 48 Step b, the compounds shown below in Table eleventh

Table 11

Examples 49-55

č.pr. position 5 position 6 step 48b reagent / part position 7 49 3-chlorobenzaldehyde n-octyl magnesium chloride morpholine / 6-morpholinyl 3-pyridine 50 benzaldehyde phenethyl morpholine / 6-morpholinyl 3-pyridine 51 4-bromo-2- thiophenecarboxaldehyde n-octyl magnesium chloride morpholine / 6-morpholinyl 3-pyridine 52 4-bromo-2- thiophenecarboxaldehyde isobutylmagnesium chloride morpholine / 6-morpholinyl 3-pyridine 53 4-bromo-2- thiophenecarboxaldehyde phenethyl morpholine / 6-morpholinyl 3-pyridine 54 3-bromobenzaldehyde cyclohexylmethyl magnesium chloride dimethylamine / 6dimetylamino-3-pyridine 55 3-bromobenzaldehyde n-hexyl magnesium chloride dimethylamine / 6- dimethylamino-3-pyridine

Analytical Data, Examples 49-55

č.pr. Title Analytical data 49 4-amino-5- (3-chlorophenyl) -6-heptyl-7- (6- morpholinyl-3-pyridinyl) pyrido [2,3- d] pyrimidine hydrochloride MS m / z (M + H) &lt; ^{+ &gt};517; IR (cm -1) 3430, 2940, 1650, 1600, 1380 50 4-amino-5-phenyl-6-phenylmethyl-7- (6- morpholinyl-3-pyridinyl) pyrido [2,3- d] pyrimidine hydrochloride MS m / z (M + H) &lt; ^{+ &gt};475; IR ^ m ^-1) 3430, 2850, 1640, 1600, 1385 51 4-amino-5- (4-bromothienyl) -6-heptyl-7- (6- morpholinyl-3-pyridinyl) pyrido [2,3- d] pyrimidine hydrochloride MS m / z (M + H) &lt; ^{+ &gt};567; IR (cm -1) 3420, 2940, 1625, 1600, 1380 52 4-amino-5- (4-bromothienyl) -6- (l-methylethyl) -7- (6-morpholinyl-3-pyridinyl) pyrido [2,3- d] pyrimidine hydrochloride MS m / z (M + H) &lt; ^{+ &gt};511; IRCcrn ^-1) 3410, 3000, 1650, 1600, 1250 53 4-amino-5- (4-bromothienyl) -6-phenylmethyl-7- (6- morpholinyl-3-pyridinyl) pyrido [2,3- d] pyrimidine hydrochloride MS m / z (M + H) &lt; ^{+ &gt};559; IR (cm -1) 3410, 2890, 1650, 1600, 1380 54 4-amino-5- (3-bromophenyl) -6-cyclohexyl-7- (6- dimethylamino-3-pyridinyl) pyrido [2,3- d] pyrimidine hydrochloride MS m / z (M + H) &lt; ⁺ &gt; 503.505; IR (cm ^-1 ) 3432, 3047, 2945, 1560, 1465, 1340 55 4-amino-5- (3-bromophenyl) -6-pentyl-7- (6- dimethylamino-3-pyridinyl) pyrido [2,3- d] pyrimidine hydrochloride MS m / z (M + H) &lt; ^{+ &gt};491; IR (cm -1) 3437, 3025, 2925, 2952, 1550, 1460, 1320

Claims (19)

PATENT CLAIMS A compound or a pharmaceutically acceptable salt thereof or an amide thereof having the general formula (I) wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be associated with the nitrogen atom to which they are attached, to form a five to seven membered ring optionally containing one to three additional heteroatoms selected from nitrogen, oxygen or sulfur; R ³ , R ⁴ and R ⁵ are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group, and the dotted line indicates an optional double bond. A compound according to claim 1, wherein: R ¹ and R ² are independently selected from the group consisting of hydrogen, lower alkyl, arylC 1 -C 6 alkyl, -C (O) C 1 -C 6 alkyl, -C (O) aryl, -C (O) heterocyclic or may be joined together with the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing one to two additional heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur; R ³ , R ⁴ and R ⁵ are independently selected from the group consisting of: Ci-Cealkyl, C2-Cealkenyl, C ₂ -C ₆ alkynyl, C3-cycloalkyl, heteroaryl-Cealkyl or substituted heteroaryl-Cealkyl, aryl-Co-Cealkyl, or substituted aryl-Cealkyl, heteroaryl or substituted ₂ -C6alkenyl ₂ -Cealkenyl heteroaryl, _aryl-2 -Cealkenyl or substituted aryl-C ₂ 'alkenyl, heteroaryl ₂ -Cfialkinyl or substituted heteroarylC ₂ -C ₆ alkynyl, arylC ₂ -C ₆ alkynyl or substituted arylC ₂ -C ₆ alkynyl, wherein the substituents 1-4 heteroaryl or aryl are independently selected from the group consisting of halogen, oxo, cyanoC 1 -C 6 alkyl, heteroarylC ₀ -C ₆ alkyl, heterocyclic C ₁ -C ₆ alkyl, C 1 -C ₆ alkyloxy, C 1 -C ₆ alkyloxyC 1 -C ₆ alkyl, arylCo-C ₆ alkyl , arylC 1 -C 6 alkyloxy, R ⁵ R ⁶ NC (O), cyano, C ₂ -C ₆ alkenyl, C ₂ -C 6 alkynyl, C 1 -C 6 alkyl, C ₂ -C 6 alkenyldialkylmalonyl, CF ₃ , -OH, C 1 -C 6 alkyloxyC 1 -C 6 alkyloxy, C 1 -C 6 alkylSO _n wherein n is 1-2, C 1 -C 6 alkylthio, C 1 -C 6 alkylacryl, CF ₃ O, CF ₃ , C 4 -C ₄ alkylenedioxy, C 1 -C 6 alkylacryl, R ⁵ R ⁶ N (CO ) NR ^Í, N- (heterocyclic) formyl, NO _2, NR ^J R ⁶ Co-Cealkyl, wherein the substituents ^R and R ⁶ are independently selected from H, Ci-6 alkyl, HC (O), C CealkyloxyCi -C 6 alkyl, C 1 -C 6 alkyloxy, C 1 -C 6 alkylC (O), CF 3 C (O), NR ⁷ R ⁸ C 1 -C 6 alkyl, phthalimidoC 1 -C ₆ C (O), C 1 -C 6 alkylSO 2, wherein n is 1-2, Cealkyl. R ⁷ R ⁸ NC (O) NR ⁷ -, heteroaryl, NR ⁷ R ⁸ C 1 -C ₆ alkylC (O), C 1 -C 6 alkyloxycarbamidoC 1 -C 6 alkyl, wherein R ⁸ and R ⁹ are independently selected from the meanings indicated for R ⁶ and R ⁷ or R ⁶ and R ⁷ or R ⁸ and R ⁹ may be taken together with the nitrogen atom to which they are attached to form a five to seven membered unsubstituted or substituted ring, optionally containing one to three additional heteroatoms selected from oxygen, nitrogen or sulfur, wherein the substituents are selected from C 1 -C 6 alkyl. A compound of formula (II) (Π), wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be linked to the nitrogen atom to which they are attached to form five to a seven membered ring optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur atoms; and R ^3, R ⁴ and R ^J are independently selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl, or heterocyclic group. The compound of claim 3, wherein: R ¹ and R ² are independently selected from the group consisting of hydrogen, lower alkyl, arylC 1 -C 6 alkyl, -C (O) C 1 -C 6 alkyl, -C (O) aryl, -C (O) heterocyclic, or may be joined together with the nitrogen atom to which they are attached to form a five to seven membered ring, optionally containing one to two additional heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur atoms; R ³ , R ⁴ and R ³ are independently selected from the group consisting of: C Cealkylu, C 2 Cíalkenylu, C ₂ -C ₆ alkynyl, C ₃ -Cgcykloalkylu, heteroaryl-C ₆ alkyl, or substituted heteroaryl-Cealkylu, aryl-Co-Cealkylu or substituted aryl-Cealkylu, heteroaryl, and substituted ₂ heteroaryl -Cealkenylu -C6alkenylu _2, arylC ₂ -C ₆ alkenyl, or substituted aryl-C ₂ <5 alkenyl , heteroarylC 2 -C 6 alkynyl or substituted heteroarylC ₂ -C ₆ alkynyl, arylC ₂ -C ₆ alkynyl or substituted arylC ₂ -C ₆ alkynyl, wherein the substituents 1-4 heteroaryl or aryl are independently selected from the group consisting of halogen, cyanoC 1 -C 6 alkyl, heteroaryl, heterocyclic, C ₁ -C ₆ alkyloxy , _Ci-6 alkyloxy-C ₆ alkyl, aryl, -C ₆ alkyl, H ₂ NC ₁ -C ₆ alkyl, _arylC-C6 alkoxy, H ₂ NC (O), cyano group, a C ₂ -C6alkenyl, _C2 -C6alkinyl. C 1 -C 6 alkyl, C ₂ -C 6 alkenyldialkylmalonyl, CF ₃ , -OH, C 1 -C 6 alkyl66 oxyC 1 -C ₆ alkyloxy, SO 4 C 1 -C ₆ alkyl, wherein n is 1-3, C 1 -C ₆ alkylthio, C ₁ -C ₆ alkylacryl, CF ₃ O, CF ₃ , C 1 -C ₄ alkylenedioxy, C 1 -C ₆ alkylacryl, H ₂ N (CO) NH, N- (heterocyclic) formyl, NO ₂ , NR ⁶ R ⁷ C 0 -C 6 alkyl, wherein the substituents R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, HC (O), C 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 1 -C 6 alkylC (O), CF ³ C (O), NR ⁸ R ⁹ C ! 6 alkyl, C ₆ ftalimidoCi-C (O), CNCi -C ₆ alkyl, H ₃ NC (O) NH-, heteroaryl, NR ⁸ R ⁹ _R CealkylC C (O), C CealkyloxykarbamidoCi-Cealkyl, wherein the substituents R R ⁸ and R ⁹ are independently selected from the meanings indicated for R ⁶ and R ⁷ or R ⁷ ; R ⁶ and R ⁷ or R ⁸ and R ⁹ may combine with the nitrogen atom to which they are attached to form a five to seven membered unsubstituted or substituted ring, optionally containing one to three additional heteroatoms selected from oxygen, nitrogen or sulfur wherein the substituents are selected from C 1 -C 6 alkyl. The compound of claim 4, wherein R ³ , R ⁴ and R ⁵ are independently selected from the group consisting of phenyl; thiophen-2-yl; l-methyl-2oxobenzoxazolin-5-yl; 2- (dimethylamino) -5-pyridimidinyl; 2- (N-formyl-N-methylamino) -3-pyrimidinyl; 2- (N- (2-methoxyethyl) -N-methylamino) -5-pyrimidinyl; 5-dimethylamino-2-pyridinyl; 5- (N- (2-methoxyethyl) -N-methylamino) -2-pyridinyl; 2- (N-methylamino) -5-pyrimidinyl; 2- (l-morpholinyl) -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-4pyrrolidinylphenyl; 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-l (morpholinyl) 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 - ((2dimetylamino) 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-amino) -phenyl; 4- (N-morpholinyl) phenyl; 4- (thiophen-2-yl) phenyl; 4 (ureido) phenyl; 4- (2- (dimethylamino) acetylamino) phenyl; 4- (2- (2-methoxy) acetylamino) ethyl) amino) phenyl; 4- (2-methoxy) ethoxyphenyl; 4- (2-oxo-oxazolidinyl) phenyl; 4- (4-methoxy-2-butyl) phenyl; 4- (4-metyIpiperidinyI) phenyl; 4- (5pyrimidinyl) phenyl; 4-aminophenyl; 4-bromophenyl; 4-butoxy-phenyl; 4-carboxamidophenyl; 4-chlorophenyl; 4-cyanophenyl; 4diethylaminophenyl; 4dietylmalonylalylfenyl); 4-dimethylaminophenyl; 4-ethoxyphenyl; 4-ethylphenyl; 4-Fluoro-; 4-hydroxyphenyl; 4-imidazolylphenyl; 4-iodophenyl; 4-isopropylphenyl; 4-methoxyphenyl, 4-methylaminophenyl; 4-methylsulfonylphenyl; 4morpholinylphenyl; 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; 4piperidinylphenyl; 4-pyridylphenyl; 4-pyridylphenyl; 4pyrrolidinylphenyl; 4-tbutylakrylfenyl; 5- (dimethylamino) thiophen-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 3-dimetylaminopyridazin-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-morfolinyl3-pyridinyl; 6-pyrrolidinyl-3-pyridinyl; (2-propyl) -3-pyridinyl; and (4formylamino) 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; 3brómfenylmetyl; 3carboxamidophenyl; 3-chlorophenyl; 3-cyanophenyl; 3-diethylmalonylallylphenyl; 3-dimethylamino-phenyl; 3-ethoxyphenyl; 3-fluoro-5-trifluoromethylphenyl; 3-fluorophenyl; 3-hydroxyphenyl; 3-iodophenyl; 3-methoxyethyoxyphenyl; 3-methoxyphenyl; 3-methylphenyl; 3-methylsulfonylphenyl; 3-methylthiophenyl; 3-tbutylakrylfenyl; 3-trifluórmetyoxyfenyl; 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-dimethyl-phenyl; 4- (2-propyl) phenyl; 4- (2-propyl) oxyphenyl; 4-benzyloxyphenyl; 4-bromophenyl; 4-bromo-thiophen-2-yl; 4butoxyfenyl; 4-dimethylaminophenyl; 4-fluoro-3-trifluoromethylphenyl; 4-methoxyphenyl; 4-neopentylphenyl; 4-phenoxyphenyl; 5-bromo-thiophen-2-yl; cyclohexyl; cyclopropyl; hexyl; methyl; phenyl; (2-bromo-5-chlorophenyl) methyl; (2-bromophenyl) methyl; 6-cyclopropylmethyl-3-pyridinyl; and (5-chloro-2- (3-methoxyphenyl) phenyl) methyl. The compound of claim 5, wherein R ^{5 is} selected from the group consisting of: 4- (dimethylamino) phenyl; 5-dimethylamino-2-pyridinyl; 5-methoxy-2-pyridinyl; 4-methoxyphenyl; 5-methyl-thiophen-2-yl; 4- (N-methyl-N- (2-methoxyethyl) amino) phenyl; and thiophen-2-yl. The compound of claim 5, wherein R ^{4 is} selected from the group consisting of: ethoxycarbonylmethyl; ethyl; 3-fluorophenyl; 3-fluoro-4-methylphenyl; 3,4-dimethoxyphenyl; 3-methoxyphenyl; 4-methoxyphenyl; pentyl; phenyl; 3- (2-propyl) phenyl; and 4- (2-propyl) phenyl. The compound of claim 5, wherein R ^{3 is} selected from the group consisting of: 3-bromophenyl; 3-bromo-4-fluorophenyl; 4-bromo-thiophen-2-yl; 3-Chloro; 3,4-dimethoxyphenyl; 3-fluorophenyl; 3-fluoro-4-methylphenyl; 4- (2-propyl) phenyl; and 3-trifluoromethyl-4-fluorophenyl. The compound of claim 1 which is 4-amino-5- (3-bromo-4-fluorophenyl) -6-pentyl-7- (4- (dimethylamino) pyrido [2,3djpyrimidín; 4-amino-5- (3-bromo-4-fluorophenyl) -6-pentyl-7- (thiophen-2-yl) -pyrido [2,3djpyrimidín; 4-amino-5- (3-bromophenyl) -6- (4-methoxyphenyl) -7- (4-methoxyphenyl) -pyrido [2,3djpyrimidín; 4-amino-5- (3-bromophenyl) -6-ethyl-7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-Amino-5- (3-bromophenyl) - _? 6-pentyl-7- (thiophen-2-yl) -pyrido [2,3-pyrimidine; 4-amino-5- (3-bromophenyl) -6- (3,4-dimethoxyphenyl) -7- (thiophen-2-yl) -pyrido [2,3djpyrimidín; 4-amino-5- (3-bromophenyl) -6- (4- (2-propyl) phenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6-ethoxycarbonylmethyl-7- (thiophen-2-yl) -pyrido [2,3djpyrimidín; 4-amino-5- (3-bromophenyl) -6- (3-methoxyphenylmethyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-pyrimidine; 4-amino-5- (4-bromo-thiophen-2-yl) -6- (3,4-dimethoxyphenyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (thiophen-2-yl) pyrido [2,3- d] pyrimidine; 4-amino-5- (3-trifluoromethyl-4-fluorophenyl) -6- (3,4-dimethoxyphenyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; Of 4-amino-5- (3-trifluoromethyl-4-fluorophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (5-methylthiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromo-thiophen-2-yl) -6- (3,4-dimethoxyphenyl) -7- (5-methyl-thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromo-thiophen-2-yl) -6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothiophen-2-yl) -6- (3,4-dimethoxyphenyl) -7- (4- (N-methyl-N- (2-methoxyethyl) amino) phenyl) pyrido [2, 3-d] pyrimidine; 4-amino-5-phenyl-6- (3,4-dimethoxyphenyl) -7- (4- (N-methyl-N- (2-methoxyethyl) amino) phenyl) -5-phenyl-pyrido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (N-methyl-N- (2-methoxyethyl) amino) phenyl) pyrido [2,3-d] pyrimidine ; 4-amino-5-phenyl-6- (3,4-dimethoxyphenyl) -7- (5-methoxy-2-pyridinyl) -pyrido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (5-methoxy-2-pyridinyl) -pyrido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -5- (5-dimethylamino-2-pyridinyl) -pyrido [2,3-d] pyrimidine; 4-amino-5,6-bis (4- (2-propyl) phenyl) -7- (4-dimethylaminophenyl) -pyrido [2,3-d] pyrimidine; 4-amino-5,6-diphenyl-7- (4- (N-methyl-N- (2-methoxyethyl) amino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-5,6-diphenyl-7- (4-dimethylaminophenyl) -pyrido [2,3-d] pyrimidine; 4-amino-5,6-bis (3-fluorophenyl) -7- (4-dimethylaminophenyl) -pyrido [2,3djpyrimidín; 4-amino-5,6-bis (3,4-dimethoxyphenyl) -7- (4-dimethylaminophenyl) -pyrido [2,3djpyrimidín; 4-amino-5,6-bis (3-fluoro-4-methylphenyl) -7- (4-dimethylaminophenyl) pyrido [2,3-d] pyrimidine; 4-amino-5,6-bis (3-fluoro-4-methylphenyl) -7- (thiophen-2-yl) -pyrido [2,3djpyrimidín, 4-Amino-5,6-diphenyl-7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5,6-diphenyl-7- (5-dimethylamino-2-pyridinyl) -pyrido [2,3djpyrimidín; 4-amino-5-phenyl-6- (3,4-dimethoxyphenyl) -7- (5- (dimethylamino) pyridin-2-yl) pyrido [2,3-d] pyrimidine; 4-Amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (5-N- (2-methoxyethyl) -N-methylamino) -2-pyridinyl) pyrido [2,3-d] ] pyrimidine; 4-amino-5- (3-chlorophenyl) -6-phenyl-7- (5-dimethylamino-2-pyridinyl) -pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromo-thiophen-2-yl) -6-phenyl-7- (5-dimethylamino-2-pyridinyl) -pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6-phenyl-7- (6-dimethylamino-3-pyridinyl) -pyrido [2,3-d] pyrimidine 4-amino-5- (3-bromophenyl) -6- (4-fluorophenyl) -7- (6-morpholinyl-3-pyridinyl) -pyrido [2,3-d] pyrimidine; 4-amino-5-phenyl-6-phenyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3djpyrimidín; 4-amino-5- (3-bromophenyl) -6-phenyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3djpyrimidín; 4-amino-5-phenyl-6-phenyl-7- (6- (N-methyl-N- (2-methoxyethyl) amino) -3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6-phenyl-7- (6- (N-methyl-N- (2-methoxyethyl) amino) 3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6-cyclopropyl-7- (6-dimethylamino-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6- (4-fluorophenyl) -7- (6-morpholinyl-3-pyridinyl) -pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6-phenyl-7- (6-cyclopropylmethylamino-3-pyridinyl) -pyrido [2,3-pyrimidine; 4-amino-5-phenyl-6-phenyl-7- (6-cyclopropylmethylamino-3-pyridinyl) -pyrido [2,3-pyrimidine; 4-amino-5- (3-bromophenyl) -6- (4-fluorophenyl) -7- (6-morpholinyl-3-pyridinyl) -pyrido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6-heptyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3djpyrimidín; 4-amino-5-phenyl-6-phenylmethyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3djpyrimidín; 4-amino-5- (4-bromothienyl) -6-heptyl-7- (6-morpholinyl-3-pyridinyl) -pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6- (methylethyl) -7- (6-morpholinyl-3-pyridinyl) -pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6-phenylmethyl-7- (6-morpholinyl-3-pyridinyl) -pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6-cyclohexyl-7- (6-dimethylamino-3-pyridinyl) -pyrido [2,3-d] pyrimidine; or 4-amino-5- (3-bromophenyl) -6-pentyl-7- (6-dimethylamino-3-pyridinyl) -pyrido [2,3-d] pyrimidine A method of inhibiting adenosine kinase by administering a compound according to claim 1 or 3. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or 3 in combination with a pharmaceutically acceptable carrier. A method of treating ischemia, neurological disorders, nociperception, inflammation, immunosuppression, gastrointestinal dysfunction, diabetes and sepsis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 or 3. The method of claim 12, wherein the method comprises treating cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery, percutaneous transluminal angioplasty, stroke, thrombotic and embolic states, epilepsy, anxiety, schizophrenia , pain perception, neuropathic pain, visceral pain, arthritis, sepsis, diabetes and abnormal gastrointestinal motility. A process for the preparation of a compound having the general formula (Π), wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be linked to the nitrogen atom to which they are attached, resulting in the formation of a five to seven membered ring optionally having one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur atoms; and R ³ and R ⁴ are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, arylalkyl, heteroaryl or heterocyclic; and R ^p is selected from aryl, heteroaryl or heterocyclic group; characterized in that it comprises (a) reacting an aryl, heteroaryl or heterocyclic bromide having the formula R ⁵ -Br, wherein R ⁵ is as defined above, with a carboxylic acid derivative having the formula R ⁴ -CH 2 -COY, wherein Y is OH or Cl, and R ⁴ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or heterocyclic, with N, O-dimethylhydroxylamine hydrochloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or hydrate 1-hydroxybenzotriazole and triethylamine, thereby obtaining and isolating a first intermediate having the formula R ⁵ -CO-CH 2 -R ⁴ ; (b) reacting a first intermediate having the formula R ⁵ -COCH ₂ -R ⁴ with an aldehyde having the formula R ³ -CHO, wherein R ³ is as defined above, and malononitrile in the presence of an ammonium salt under anhydrous conditions to obtain a; isolating a second intermediate having the general formula R ³ (c) reacting the second intermediate compound with formamide at reflux for from about 1 to about 24 hours, and isolating a compound of formula (II). 15th A process for the preparation of compounds having the general formula R ¹ R ² N ^ N ^ R ⁵ (II) in which • 19 R and R are independently H, loweralkyl, arylalkyl or acyl, or may be the nitrogen atom to which they are attached, resulting in to from a seven membered ring optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur atoms; and R ³ and R ⁴ are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group; and R ^p is selected from aryl, heteroaryl or heterocyclic group; with the proviso that both substituents R ¹ and R ² are hydrogen, characterized in that it comprises (a) reacting an aryl, or a heterocyclic bromide having the formula ^R-Br with a carboxylic acid derivative having the formula R ⁴ CH ₂ -CO-Y wherein Y is OH or Cl and R ⁴ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or heterocyclic, with N, N-dimethylhydroxylamine hydrochloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or 1-hydroxybenzotriazole hydrate and triethylamine, thereby obtaining and isolating a first intermediate having the formula R ⁵ -CO-R ⁴ ; (b) reacting a first intermediate having the formula R ⁵ -CO-R ⁴ with an aldehyde having the formula R ³ -CHO, wherein R ³ is as defined above and malononitrile in the presence of an ammonium salt under anhydrous conditions to obtain and isolate the second an intermediate having the general structure R ⁴ R ⁵ . > (c) reacting the second intermediate with sulfuric acid and heating, followed by reaction with triethyl orthoformate at reflux for from about 1 to about 24 hours, thereby obtaining and isolating the third intermediate having the general structure (d) reacting the third intermediate with a chlorinating agent; to obtain and isolate a fourth intermediate having the formula R 1 -R 1 -R ⁵ R ⁵ with an amine compound having the formula R 1 -NH-R ² , wherein the substituents R ¹ and R ² are as described above, to obtain and isolate the compound of the formula ( II). A process for the preparation of compounds having the general formula (Π), wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be linked to the nitrogen atom to which they are attached, resulting in five up to seven membered rings optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur atoms; and R ³ and R ⁴ are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or heterocyclic; and R ⁵ is selected from the group consisting of aryl, heteroaryl or heterocyclic; characterized in that it comprises (a) reacting an aryl, heteroaryl or heterocyclic bromide having the formula R ⁵ -Br with a carboxylic acid derivative having the formula R ⁴ -CH 2 -CO-Y, wherein Y is OH or Cl, and a substituent R ⁴ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or heterocyclic, with N, N -dimethylhydroxylamine hydrochloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or 1-hydroxybenzotriazole hydrate and triethylamine to give and isolating a first intermediate having the formula R ⁵ -CO-CH 2 -R ⁴ ; (b) reacting a first intermediate having the formula R ⁵ -COCH ₂ -R ⁴ with a compound having the formula R3 NC CN wherein R ³ is as described above, at reflux in an alcoholic solvent, thereby obtaining and isolating a second intermediate having the general formula R < R ⁵ . (c) reacting the second intermediate with formamide at reflux for about 1 to about 24 hours to obtain and isolate the compound of formula (II). A process for the preparation of compounds having the general formula (Π), wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl or may be linked to the nitrogen atom to which they are attached, resulting in five to five a seven membered ring optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur atoms; and R ³ and R ⁴ are independently selected from the group consisting of, lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a heterocyclic group; and R ⁵ is selected from the group consisting of aryl, heteroaryl or heterocyclic, with the proviso that both R 1 and R ² are not hydrogen, comprising (a) a reaction of an aryl, heteroaryl or heterocyclic bromide having the general formula ^R-Br with a carboxylic acid derivative having the formula ^R4-CH2-CO-Y, wherein Y is OH or Cl, and R ⁴ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl, or heterocyclic with N, N-dimethylhydroxylamine hydrochloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or 1-hydroxybenzotriazole hydrate and triethylamine, thereby obtaining and isolating a first intermediate having the formula R ⁵ -CO-CH 2 -R ⁴ ; (b) reacting a first intermediate having the formula R ⁵ -COCH 2 -R ⁴ with a compound having the formula R ³ wherein R ³ is as described above, at reflux in an alcoholic solvent, whereby a second intermediate having the general formula is obtained and isolated R4 R ⁵ . and (c) reacting the second intermediate with sulfuric acid and heating, followed by reaction with triethyl orthoformate, at reflux for from about 1 to about 24 hours, thereby obtaining and isolating a third intermediate having the general structure R ³ R ⁴ (d) reacting a third intermediate with a chlorinating agent to obtain and isolate a fourth intermediate having the general formula (e) reacting a fourth intermediate with an amine compound having the general formula R 2 -NH-R ² wherein R ¹ and R ² are as defined above to obtain and isolate a compound of formula (II). 18. A compound of formula It wherein the substituents R ³ -R ^p are as defined in Claim 1 and code X is selected from OH or halogen. and A method of using a compound of formula (U1) according to claim 17 as an intermediate for the preparation of a compound of formula (II) according to claim 2, comprising (a) reacting said compound of formula (III) with an amine or substituted amine of formula of formula NR ¹ R ² , wherein R ¹ and R ² are as defined above, under suitable conditions, to form a compound of formula (II) according to claim 2.