Patent EA-000699-B1 (EA)
Title: Indazolecarboxamides methods preparing thereof, pharmaceutical composition and method of affecting the 5-ht4 receptor
Inventor: CATLOW JOHN T
IPC: A61K31/535
Filed: 1996-03-14
Abstract: 1. A compound of the formula   wherein R is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; R<1> is hydrogen, halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy or alkylthio, cyano, trifluoromethyl, carboxamido, mono- or di(C1-C4 alkyl) carboxamido; m, n and o are independently 0-5, provided that the sum of m, n and o is 2-5; R<2> is hydrogen or C1-C4 alkyl; R<3> and R<4> combine with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-piperazinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 2,3-dihydro-1-indolinyl, 4-morpholinyl, 1-piperidinyl or 1-hexamethyleneiminyl, substituted with phenyl, naphthyl, (phenyl or naphthyl) (C1-C3 alkyl), (phenyl or naphthyl) (C1-C3 alkanoyl), amino, mono- or di(C1-C4 alkyl)amino, or a group of the formula -NH-Y-R<5>; provided that a piperazinyl or morpholinyl group may not be substituted with amino, mono- or di(C1-C4 alkyl)amino, or -NH-Y-R<5>; wherein a phenyl or naphthyl group is unsubstituted or substituted with 1-3 halo, C1-C3 alkyl or C1-C3 alkoxy groups; Y is carbonyl, sulfonyl, aminocarbonyl or oxycarbonyl; R<5> is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C11 bicyclo- or tricycloalkyl, (phenyl or naphthyl)( C1-C3 alkyl), phenyl or naphthyl; wherein a cycloalkyl, bicyclo- or tricycloalkyl, phenyl or naphthyl group is unsubstituted or substituted with 1-3 hydroxy, halo, C1-C3 alkyl or C1-C3 alkoxy groups; or a pharmaceutically acceptable salt thereof. 2. A compound of claim 1 wherein m + n + o is 2-4. 3. A compound of claim 2 wherein R is hydrogen or alkyl. 4. A compound of claim 3 wherein R<1> is hydrogen, halo, alkyl or alkoxy. 5. A compound of claim 4 wherein the group formed by the combination of R<3> and R<4> with the nitrogen atom to which they are attached is substituted with phenyl, naphtyl (phenyl or naphthyl)( C1-C3 alkyl) (phenyl or naphthyl)(C1-C3 alkanoyl). 6. A compound of claim 4 wherein the group formed by the combination of R<3> and R<4> with the nitrogen atom to which they are attached is substituted with a group of the formula -NH-Y-R<5>. 7. A compound of claim 1 which is N-[2-(4-(3-hydroxy-1-adamantylcarbonylamino)-1-piperidinyl)ethyl]-1(2-propyl)-1H-indazole-3-carboxamide or N-[2-(4-hydroxy-1-adamantylcarbonylamino)-1-piperidinyl)ethyl]-1-(2-propyl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 8. A compound of claim 1 which is N-[2-(4-benzyloxycarbonylamino-1-piperidinyl)ethyl]-1-(2-propyl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 9. A compound of claim 1 which is N-[2-((4-acetylamino-1-piperidinyl)ethyl]-1-(2-propyl)-1H-indazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 10. A compound of claim 1 which is N-[2-(4-(1-adamantylcarbonylamino)-1-piperidinyl)ethyl]-1-(2-propyl)-1H-indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and an effective amount of a compound of claim 1. 12. A pharmaceutical formulation of claim 11 wherein a compound is a compound of claim 3. 13. A pharmaceutical formulation of claim 11 wherein a compound is a compound of claim 4. 14. A pharmaceutical formulation of claim 11 wherein a compound is a compound of claim 10. 15. A method of providing treatment or prophylaxis for anxiety, pain, depression, schizophrenia, memory disorders, dementia, irritable bowel syndrome, nausea, gastroesophageal reflux disease, dyspepsia, atrial fibrillation, arrythmias, tachycardia, urinary retention, urinary incontinence, or pain on urination caused by or affected by dysfunction of the 5-HT4 receptor, comprising administering to a subject in need of such treatment or prophylaxis an effective amount of a compound of the formula   wherein R is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; R<1> is hydrogen, halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy or alkylthio, cyano, trifluoromethyl, carboxamido, mono- or di(C1-C4 alkyl) carboxamido; m, n and o are independently 0-5, provided that the sum of m, n and o is 2-5; R<2> is hydrogen or C1-C4 alkyl; R<3> and R<4> combine with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-piperazinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 2,3-dihydro-1-indolinyl, 4-morpholinyl, 1-piperidinyl or 1-hexamethyleneiminyl, substituted or unsubstituted with phenyl, naphthyl, (phenyl or naphthyl) (C1-C3 alkyl), (phenyl or naphthyl) (C1-C3 alkanoyl), amino, mono- or di(C1-C4 alkyl)amino, or a group of the formula -NH-Y-R<5>; provided that a piperazinyl or morpholinyl group may not be substituted with amino, mono- or di(C1-C4 alkyl)amino, or -NH-Y-R<5>; wherein a phenyl or naphthyl group is unsubstituted or substituted with 1-3 halo, C1-C3 alkyl or C1-C3 alkoxy groups; Y is carbonyl, sulfonyl, aminocarbonyl or oxycarbonyl; R<5> is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C11 bicyclo- or tricycloalkyl, (phenyl or naphthyl)( C1-C3 alkyl), phenyl or naphthyl; wherein a cycloalkyl, bicyclo- or tricycloalkyl, phenyl or naphthyl group is unsubstituted or substituted with 1-3 hydroxy, halo, C1-C3 alkyl or C1-C3 alkoxy groups; or a pharmaceutically acceptable salt thereof. 16. A method of claim 15 wherein said compound is a compound wherein m + n + o is 2-4 and R is hydrogen or alkyl. 17. A method of claim 15 wherein said compound is N-[2-(4-(1-adamantylcarbonylamino)-1-piperidinyl)ethyl]-1-(2-propyl)-1H-indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof. 18. A method for obtaining a compound of the formula   wherein R is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; R<1> is hydrogen, halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy or alkylthio, cyano, trifluoromethyl, carboxamido, mono- or di(C1-C4 alkyl) carboxamido; m, n and o are independently 0-5, provided that the sum of m, n and o is 2-5; R<2> is hydrogen or C1-C4 alkyl; R<3> and R<4> combine with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-piperazinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 2,3-dihydro-1-indolinyl, 1-piperidinyl or 1- hexamethyleneiminyl, unsubstituted with a group of the formula -NH-Y-R<5;>; Y is carbonyl; R<5> is C3-C8 cycloalkyl, C6-C11 bicyclo- or tricycloalkyl, (phenyl or naphthyl)( C1-C3 alkyl), phenyl or naphthyl; wherein a cycloalkyl, bicyclo- or tricycloalkyl, phenyl or naphthyl group is substituted with 1-3 hydroxy groups; or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula I wherein R<3> and R<4> combine with the nitrogen atom to which they are attached to form amino-substituted 1-pyrrolidinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 2,3-dihydro-1-indolinyl, 1-piperidinyl or 1-hexamethyleneiminyl, with a compound of the formula HO2C-R<5> in the presence of a coupling agent for amide-forming reactions.  19. A method of claim 18 wherein said compound of formula I is a compound wherein R<5> is hydroxy-substituted cycloalkyl, bicyclo- or tricycloalkyl. 20. A method of claim 18 wherein said compound of formula I is a compound wherein R<5> is hydroxy-substituted adamantyl.