RU2003105885A - CELLULAR ADHESION INHIBITORS ALPHA-MEDIATED 4-INTEGRINS - Google Patents

Claims (17)

1. The compound representing a phenylalanine derivative with the formula [I]

where X ¹ is a halogen atom; X ² is a halogen atom; Q is a —CH ₂ group or - (CH ₂ ) ₂ group; Y is a C _1-6 alkyl group; CO ₂ R is a carboxyl group that can be esterified, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, characterized in that its chemical structure corresponds to the following formula [I-1]:

in which the designations are the same as in claim 1. 3. The compound according to claim 2, characterized in that X ¹ is a chlorine atom or a fluorine atom, X ² is a chlorine atom or a fluorine atom, Y is a C _1-4 alkyl group and CO ₂ R is a carboxyl group or C _2-7 alkoxycarbonyl group. 4. The compound according to claim 3, characterized in that X ¹ is a chlorine atom or a fluorine atom, X ² is a chlorine atom or a fluorine atom, Q is a —CH ₂ group, Y is a methyl group, an ethyl group or an n-propyl group and CO ₂ R is a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group or a tert-butoxycarbonyl group. 5. The compound according to claim 3, characterized in that X ¹ is a fluorine atom, X ² is a chlorine atom or a fluorine atom, Q is a —CH ₂ group, Y is a methyl group or an ethyl group, and CO ₂ R is a carboxyl group or C _2-7 alkoxycarbonyl group. 6. N- (2,6-Difluorobenzoyl) -4- (2,6-dimethoxy-4-ethoxymethylphenyl) -L-phenylalanine, N- (2-chloro-6-fluorobenzoyl) -4- (2,6-dimethoxy -4-ethoxymethylphenyl) -L-phenylalanine, N- (2-chloro-6-fluorobenzoyl) -4- (2,6-dimethoxy-4-methoxymethylphenyl) -L-phenylalanine, N- (2,6-difluorobenzoyl) - 4- (2,6-dimethoxy-4-methoxymethylphenyl) -L-phenylalanine, or their C _1-6 alkyl esters, or their pharmaceutically acceptable salts. 7. A pharmaceutical composition comprising a therapeutically effective amount of a compound, as defined in any one of claims 1 to 6, in admixture with a pharmaceutically acceptable carrier or diluent. 8. The compound, as defined in any one of claims 1 to 6, for use as an active therapeutic substance. 9. The use of a compound as defined in any one of claims 1-6 for the manufacture of a medicament for use in the treatment of disorders mediated by cell adhesion mediated by α ₄ -integrins. 10. A method for treating or preventing a condition caused by cell adhesion mediated by α ₄ -integrins in a patient, which comprises administering to said patient an effective amount of a compound as defined in any one of claims 1 to 6. 11. The method according to claim 10, characterized in that the above condition is selected from the group consisting of rheumatoid arthritis, asthma, allergic conditions, adult respiratory distress syndrome, AIDS dementia, Alzheimer's disease, diseases of the cardiovascular system, thrombosis or pathological platelet aggregation, repeated occlusion after thrombosis, reperfusion lesions, psoriasis, inflammatory skin diseases, diabetes, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, diseases associated with leukocyte infiltration of the gastrointestinal tract, diseases associated with leukocyte infiltration of tissues lined with epithelium, pancreatitis, mastitis, hepatitis, cholecystitis, cholangitis or pericholangitis, bronchitis, sinusitis, inflammatory diseases of the lungs, collagenosis, osteoarthritis, osteoarthritis atherosclerosis, neoplastic diseases, wounds, eye diseases, Sjogren's syndrome, rejection after transplantation, diseases “host versus transplant” and “graft versus host”, hyper asia intimal arteriosclerosis, reinfarction or repeated after surgery sclerosis, nephritis, tumor angiogenesis, cancers, multiple myeloma and myeloma-induced bone resorption and lesions of the central nervous system. 12. The method according to claim 11, characterized in that the above condition is asthma, allergic conditions, inflammatory bowel disease, rheumatoid arthritis, atopic dermatitis, multiple sclerosis or rejection after transplantation. 13. A method of obtaining a compound representing a phenylalanine derivative with the formula [I]

where X ¹ is a halogen atom; X ² is a halogen atom; Q is a —CH ₂ group or - (CH ₂ ) ₂ group; Y is a C _1-6 alkyl group; CO ₂ R is a carboxyl group that can be esterified, or a pharmaceutically acceptable salt thereof, which comprises converting a compound of formula [II]

where CO ₂ R ¹ is an esterified carboxyl group, and other designations are the same as defined above, in the compound with the formula [Ia]

where the designations are the same as defined above, followed by conversion of the esterified carboxyl group of the formed compound [Ia] to a carboxyl group, if necessary, and subsequent conversion of the resulting compound to its pharmaceutically acceptable salt, if desired. 14. The method according to item 13, wherein the conversion of compound [II] to compound [Ia] includes the oxidation of compound [II] followed by reductive condensation of the obtained compound with a compound of formula [IV]

where Y is a C _1-6 alkyl group. 15. The method according to item 13, wherein the conversion of compound [II] to compound [Ia] includes the conversion of compound [II] to the compound of formula [V]

where X ¹ is a halogen atom; X ² is a halogen atom; Q is —CH ₂ - group or - (CH ₂ ) ₂ —group; Z is a leaving group; CO ₂ R ¹ is an esterified carboxyl group, followed by reaction of the resulting compound [V] with a compound of the formula [IV]

where Y is a C _1-6 alkyl group. 16. The method according to item 13, wherein the conversion of compound [II] to compound [Ia] includes the alkylation of compound [II] with a compound of formula [VI]

where Y is a C _1-6 alkyl group. 17. The method according to item 13, wherein the conversion of compound [II] to compound [Ia] involves condensing a compound [II] with a compound of formula [IV]

where Y is a C _1-6 alkyl group.