TH97792A - Indazole benzamides, pharmaceutical constituents Containing that compound, the process for preparing that compound, the chemical agent used for the preparation That compound And the use of that compound for drug production, especially for the treatment of inflammatory and / or allergic conditions. - Google Patents

Abstract

DC60 (28/01/52) This invention proposes a compound with the formula (I): (chemical formula) *= chiral center (I), a pharmaceutical composition in which the compound is incorporated, and the use of the compound in the manufacture of medicines, particularly for the treatment of inflammation and/or allergies. This invention proposes a compound with the formula (I): (chemical formula) *= chiral center (I), a pharmaceutical composition in which the compound is incorporated, and the use of the compound in the manufacture of medicines, particularly for the treatment of inflammation and/or allergies.

Claims (33)

1. Compounds according to formula (I): (Chemical formula) *= Chiral center (I), where A' represents 5-fluoro-2-methoxy-phenyl or 5-fluoro-2-hydroxy-phenyl (chemical formula), R1 represents -N(R2)C (R3)(R4)CONHR5 or R2 represents hydrogen or methyl, R3 represents hydrogen, and R4 represents hydrogen, methyl, or hydroxymethyl, or R3 and R4 both represent methyl, and R5 represents hydrogen or methyl, or derivatives that perform the physiological function of such compounds. 2. The compound according to claim 1, where A1 represents 5-fluoro-2-methoxyphenyl (formula). 3. Compounds according to claim 1 or claim 2, where R1 represents... 4. Compounds including: N-(2-amino-2-oxoethyl)-3-(4-{[4-[5-fluoro-2-(methiloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)benzamide (Enansiomer A) N-(2-amino-2-oxoethyl)-3-(4-{[4-[5-fluoro-2-(methiloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)benzamide (Enansiomer B) N-(2-amino-2-oxoethyl)-3-(4-{[4-[5-fluoro-2-(methiloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)-N-methylbenzamide N-(2-amino-2-oxoethyl)-3-(4-{[4-[5-fluoro-2-(methiloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)-N-methylbenzamide (enanchiomer A) N-(2-amino-2-oxoethyl)-3-(4-{[4-[5-fluoro-2-(methiloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)-N-methylbenzamide (Enanchiomer B) N-[(1R)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[4-[5-fluoro-2-(methyloxyphenyl)]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)benzamide N-[(1R)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[4-[5-fluoro-2-(methyloxyphenyl)]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)benzamide (Diasteremer A) N-[(1R)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[4-[5-fluoro-2-(methyloxyphenyl)]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-yl)benzamide (Diasteremer B) N-[(1S)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-yl)benzamide N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(4-{[4-[5-fluoro-2-(methyloxyphenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)benzamide (Enanchiomer A) N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(4-{[4-[5-fluoro-2-(methiloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)benzamide (Enanchiomer B) 1-{[3-(4-{[4-[5-fluoro-2-(methiloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)phenyl]carbonyl}-L-prolinamide 1-{[3-(4-{[4-[5-fluoro-2-(methiloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)phenyl]carbonyl}-D-prolinamide 1-{[3-(4-{[4-[5-fluoro-2-(methiloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)phenyl]carbonyl}-D-prolinamide (Diasteremer A) 1-{[3-(4-{[4-[5-fluoro-2-(methyloxyphenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-yl)phenyl]carbonyl}-D-prolinamide (Diasteremer B) N-[(1S)-2-amino-1-(hydroxymethyl)-2-oxoethyl]-3-(4-{[4-[5-fluoro-2-(methyloxyphenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-yl)benzamide N-(2-amino-2-oxoethyl)-3-(4-{[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)-N-methylbenzamide N-[(1R)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)benzamide 1-{[3-(4-{[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)phenyl]carbonyl}-D-prolinamide 3-(4-{[4-[5-fluoro-2-(methyloxyphenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)-N-[2-(methylamino)-2-oxoethyl]benzamide N-[(1S)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[4-[5-fluoro-2-(methyloxyphenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)-N-methylbenzamide N-[(1R)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[4-[5-fluoro-2-(methyloxyphenyl)]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-il)-N-methylbenzamide 1-{[3-(4-{[(2R)-4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-yl)phenyl]carbonyl}-D-prolinamide or its derivatives that perform the physiological functions of the substance. 5. Compounds including: 1-{[3-(4-{[(2R)-4-[5-fluoro-2-(methyloxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-yl)phenyl]carbonyl}-D-prolinamide or its derivatives that perform the physiological functions of such compounds. 6. The compound is: 1-{[3-(4-{[(2R)-4-[5-fluoro-2-(methyloxyphenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-yl)phenyl]carbonyl}-D-prolinamide 7. Compounds including: 1-{[3-(4-{[(2R)-4-[5-fluoro-2-(methyloxyphenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazole-1-yl)phenyl]carbonyl]-D-prolinamide or its derivatives that perform the physiological functions of such compounds in crystalline form. 8. The compound holds any one of the claims under claims 1 through 7, or any derivative that performs the physiological function of the compound, for medical or veterinary use. 9. The compound holds any one of the claims under claims 1 through 7, or its physiological derivatives, for use in the treatment of inflammation and/or allergies. 10. The compound holds any one of the claims under claims 1 through 7, or its physiological derivatives, for use in the treatment of rheumatoid arthritis, asthma, COPD, allergies, and/or rhinitis. 11. The compound holds any one of the claims 1 through 7, or its derivatives perform the physiological functions for use in the treatment of rhinitis. 12. The compound holds any one of the claims under claims 1 through 7, or its derivatives perform the physiological functions for use in the treatment of patients with skin diseases. 13. The compound shall hold any one of the claims under claims 1 through 7, or its physiological derivatives, for use in the treatment of patients with eczema, psoriasis, atopic dermatitis, neuropathy and dermatitis, pruritus and/or hypersensitivity reactions. 14. The use of any of the compounds entitled under Rights 1 through 7, or their physiologically active derivatives, in the manufacture of drugs for the treatment of patients with inflammatory and/or allergic conditions. 15. The use of any of the compounds entitled under claims 1 through 7, or their physiologically active derivatives, in the manufacture of drugs for the treatment of patients with rheumatoid arthritis, asthma, allergies, and/or rhinitis. 16. The use of any of the compounds entitled under Rights 1 through 7, or their physiologically active derivatives, in the manufacture of drugs for the treatment of patients with rhinitis. 17. The use of any of the compounds entitled under claims 1 through 7, or their physiologically active derivatives, in the manufacture of drugs for the treatment of patients with skin diseases. 18. The use of any of the compounds entitled under claims 1 through 7, or their physiological derivatives, in the manufacture of drugs for the treatment of patients with eczema, psoriasis, atopic dermatitis, neurodermatitis, pruritus, and/or hypersensitivity reactions. 19. Pharmaceutical formulations containing any one of the compounds claimed under claims 1 through 7, or their physiologically active derivatives, mixed with one or more physiologically acceptable diluents and/or carriers, if desired. 20. Pharmaceutical components as per claim 19, whereby such components are modified for nasal drug delivery. 21. Pharmaceutical aerosol formulations incorporating any one of the compounds claimed under claims 1 through 7, or their physiologically active derivatives, and hydrogenated fluorocarbons or chlorofluorocarbons, or mixtures thereof, as propellants, which may be combined with surfactants and/or co-solvents. 22. The pharmaceutical aerosol composition is protected under claim 21, whereby the propellant is selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof. 23. A pharmaceutical component as per claim 19, which includes an additional therapeutic active substance. 24. Pharmaceutical components as per claim 23, whereby the other therapeutic active ingredient is B2-adrenoreceptoragonist. 25. Pharmaceutical formulations containing a combination of any one of the compounds claimed under claims 1 through 7, or a physiologically active derivative of such compounds, in combination with a PDE4 inhibitor. 26. Pharmaceutical compositions containing a mixture of any one of the compounds claimed under claims 1 through 7, or a physiologically active derivative of such compounds, together with the histamine precursor. 27. A compound consisting of any one of the compounds claimed under claims 1 through 7, or a derivative performing the physiological function of such compound, together with one or more therapeutic active substances. 28. The compound pursuant to claim 27, whereby the therapeutic active ingredient is B2-adreno receptor agonist. 29. The compound pursuant to claim 27, whereby the therapeutic active ingredient is a PDE4 inhibitor. 30. The compound as per claim 27, whereby the therapeutic active ingredient is an antihistamine. 31. The process for preparing a compound of formula (I) as provided in any one of the claims 1 through 7 or its physiologically functional derivatives, which includes: a) coupling of a carboxylic acid of formula (II): (chemical formula) (II) where A1 is as provided in claim 1 with the amine HN(R2)C(R3)(R4)CONHR5 or (chemical formula) where R2, R3, R4 and R5 are as provided in claim 1 or b) coupling of a carboxylic acid of formula (II): (chemical formula) (II) where A1 is as provided in claim 1 with the amine HN(R2)C(R3)(R4)CO2H or D- or L-proline followed by a second coupling with R5-NH2 where R2, R3, R4 and R5 are as provided in claim 1. 32. Compound with the formula (V): (chemical formula) (V), where P1 is an ester protection group. 33. Compound with formula (X): (Chemical formula) (X), where P1 is an ester protection group.