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US 5,296,499 AGranted
Indole derivatives, their production and use
AssigneeTakeda Chemical Industries, Ltd.
InventorsTakashi Sohda, Iwao Yamazaki, Noriaki Kawamura
Life of this patent
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Abstract
An agent for inhibiting bone resorption comprising an indole derivative of the formula (I): ##STR1## wherein each ring of A and B is optionally substituted, R is a hydrogen atom, a lower alkyl group or an acyl group, and A is a hydroxymethyl group or an esterified or amidated carboxyl group; or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, diluent or excipient.
Claims11
An agent for inhibiting bone resorption, which comprises a therapeutically effective amount of an indole compound of the formula (I):
- ##STR21## wherein each of the rings A and B may be optionally substituted with one to four substituents selected from the group consisting of:
- a. a halogen;
- b. C.sub.1-10 alkyl which is unsubstituted or substituted by a halogen, nitro, amino (which may be substituted by a carboxylic C.sub.1-6 acyl, C.sub.1-10 alkyl, iminomethyl, imino(aryl-substituted)methyl, amidino and/or amino), phosphoryl, C.sub.1-4 alkoxyphosphoryl, sulfo, cyano, hydroxy, carboxy, hydrazino, imino, amidino, carbamoyl, aryl (which may be substituted with a halogen, C.sub.1-10 alkyl, C.sub.1-4 alkoxy, C.sub.1-10 alkylamino, amino, carbamoyl, sulfo, C.sub.1-10 alkylsulfonyl, cyano, hydroxy, carboxy, nitro, C.sub.1-6 acyloxy, arylalkyloxy, phosphonyl, C.sub.1-4 alkoxyphosphoryl and/or sulfoxyl), pyridine, pyridazine, thiazole, oxazole or morpholine (which may be substituted by nitro, oxo, aryl, C.sub.2-10 alkenylene, halogeno C.sub.1-10 alkyl, C.sub.1-10 alkyl sulfonyl, C.sub.1-10 alkyl, C.sub.1-4 alkoxy, C.sub.1-10 alkylamino, amino, halogen, carbamoyl, C.sub.1-10 hydroxy, cyano, carboxy, phosphonyl, C.sub.1-4 alkoxyphosphoryl and/or sulfo), wherein the aryl in the above moiety or groups is phenyl or naphthyl;
- c. phenyl, naphthyl, biphenyl, anthryl or indenyl which is unsubstituted or substituted by a halogen, nitro, cyano, amino (which may be substituted by a C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.3-6 cycloalkyl, phenyl and/or naphthyl, phosphoryl, sulfo, hydroxy, sulfoxy, sulfamoyl, C.sub.1-10 alkyl (which may be substituted by an amino, halogen, hydroxy, cyano and/or C.sub.1-4 alkoxyphosphoryl), C.sub.1-4 alkoxy, benzyloxy, phenethyloxy, phenylpropyloxy, C.sub.1-10 alkylsulfonamido, methylenedioxy, C.sub.1-4 alkoxyphosphoryl, C.sub.1-10 alkylsulfonyl, C.sub.1-10 alkylsulfonylamino, or which may form a condensed ring together with a C.sub.3-6 cycloalkyl;
- d. C.sub.2-10 alkenyl, which is unsubstituted or substituted by a C.sub.1-6 alkyl (said C.sub.1-6 alkyl group optionally being substituted by the substituents for the C.sub.1-10 alkyl group), halogen, nitro, amino (which may be substituted by a carboxylic C.sub.1-6 acyl, iminomethyl, amidino, C.sub.1-10 alkyl and/or aryl), phosphoryl, sulfo, cyano, hydroxy, carboxy, C.sub.1-10 alkyloxycarbonyl, carbamoyl, C.sub.1-10 alkylthio, arylthio, C.sub.1-10 alkylsulfinyl, arylsulfinyl, C.sub.1-4 alkylphosphoryl, C.sub.1-10 alkylsulfonyl, arylsulfonyl, sulfamoyl, aryl or carboxylic C.sub.1-6 acyl, and which includes the E or Z form isomers with respect to the double bond of the C.sub.2-10 alkenyl group;
- wherein the aryl in the above moiety or groups is phenyl or naphthyl;
- and
- e. hydroxy which is unsubstituted or substituted by a C.sub.1-10 alkyl, C.sub.2-10 alkenyl, phenyl-C.sub.1-4 alkyl, carboxylic C.sub.2-4 acyl, carboxylic C.sub.2-4 phenoxy, or a 4-chlorophenoxy;
- R is hydrogen, C.sub.1-6 straight chain, branched-chain or cyclic alkyl or an acyl group formed by combining a C.sub.1-6 alkyl group with a carbonyl group;
- and
- A is a hydroxymethyl group, an esterified carboxyl group in which the ester residue is a straight-chain, branched-chain or cyclic alkyl having 1 to 6 carbon atoms or an aralkyl having 7 to 15 carbon atoms, or an amidated carboxyl group formed by combining a carboxyl group with an amino group which is unsubstituted or substituted by the alkyl, aryl or alkenyl substituents defined as substituents for rings A and B, or by a 5-7 membered heterocyclic group for rings A and B, or by a 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrido)2,3-d)pyrimidyl, benzopyranyl, 1,8-naphthyridyl, 1,5-naphthyridyl, 1,6-naphthyridyl, 1,7-naphthyridyl, quinolyl, thieno(2,3-b)pyridyl, tetrazolyl, thiadiazolyl, oxadiazolyl, triazinyl, triazolyl, thienyl, pyrrolyl, pyrrolinyl, furyl, pyrrolindinyl, benzothienyl, indolyl, imidazolidinyl, piperidyl, piperidino, piperazinyl, morpholinyl or morpholino group which may be substituted by a substituent selected from the group consisting of an amino (which may be substituted by a (1) C.sub.1-6 acyl, halogen, phenyl and/or C.sub.1-10 alkyl), (2) halogen, (3) nitro, (4) sulfo, (5) cyano, (6) hydroxy, (7) carboxy, (8) oxo, (9) thioxo, (10) C.sub.1-10 alkyl (which may be substituted by a phenyl, naphthyl, halogen, amino, hydroxy, carboxy, C.sub.1-4 alkoxy, C.sub.1-10 alkylsulfonyl and/or di-C.sub. 1-10 alkylamino), (11) C.sub.3-6 cycloalkyl, (12) C.sub.1-4 alkoxy (which may be substituted by a halogen and/or hydroxy), (13) C.sub.1-4 acyl and (14) phenyl or naphthyl (which may be substituted by a halogen, nitro, C.sub.1-10 alkyl, C.sub.1-4 alkoxy, amino, sulfo, hydroxy and/or cyano) group;
- or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent or excipient.
9 more elements
An indole compound of the formula (I'):
- ##STR22## wherein R.sup.1 and R.sup.2 can be the same or different and are selected from the group consisting of:
- a. hydroxy which is unsubstituted or substituted by C.sub.1-10 alkyl, C.sub.2-10 alkenyl, phenyl-C.sub.1-4 alkyl, carboxylic C.sub.2-4 acyl or aryl;
- and
- b. a halogen;
- or two of each of R.sup.1 and R.sup.2 may be a bivalent hydrocarbon residue or alkylenedioxy group which form a condensed ring system together with the ring to which they are attached;
- R is hydrogen, C.sub.1-6 straight chain, branched-chain or cyclic alkyl or an acyl group formed by combining a C.sub.1-6 alkyl group with a carbonyl group;
- and
- A is a hydroxymethyl group, an esterified carboxyl group in which the ester residue is a straight-chain, branched-chain or cyclic alkyl having 1 to 6 carbon atoms or an aralkyl having 7 to 15 carbon atoms, or an amidated carboxyl group formed by combining a carboxyl group with an amino group which is unsubstituted or substituted by the alkyl, aryl or alkenyl substituents defined as substituents for rings A and B, or by a 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrido(2,3-d)pyrimidyl, benzopyranyl, 1,8-naphthyridyl, 1,5-naphthyridyl, 1,6-naphthyridyl, 1,7-naphthyridyl, quinolyl, thieno(2,3-b)pyridyl, tetrazolyl, thiadiazolyl, oxadiazolyl, triazinyl, triazolyl, thienyl, pyrrolyl, pyrrolinyl, furyl, pyrrolindinyl, benzothienyl, indolyl, imidazolidinyl, piperidyl, piperidino, piperazinyl, morpholinyl or morpholino group which may be substituted by a substituent selected from the group consisting of an amino (which may be substituted by a (1) C.sub.1-6 acyl, halogen, phenyl and/or C.sub.1-10 alkyl), (2) halogen, (3) nitro, (4) sulfo, (5) cyano, (6) hydroxy, (7) carboxy, (8) oxo, (9) thioxo, (10) C.sub.1-10 alkyl (which may be substituted by a phenyl, naphthyl, halogen, amino, hydroxy, carboxy, C.sub.1-4 alkoxy, C.sub.1-10 alkylsulfonyl and/or di-C.sub.1-10 alkylamino), (11) C.sub.3-6 cycloalkyl, (12) C.sub.1-4 alkoxy (which may be substituted by a halogen and/or hydroxy), (13) C.sub.1-4 acyl and (14) phenyl or naphthyl (which may be substituted by a halogen, nitro, C.sub.1-10 alkyl, C.sub.1-4 alkoxy, amino, sulfo, hydroxy and/or cyano) group;
- and n and m each is an integer of 2 to 4;
- or its salt.
7 more elements
A process for preparing an indole compound of the formula (I'):
- ##STR23## wherein R.sup.1 and R.sup.2 can be the same or different and are selected from the group consisting of:
- a. hydroxy which is unsubstituted or substituted by C.sub.1-10 alkyl, C.sub.2-10 alkenyl, phenyl-C.sub.1-4 alkyl, carboxylic C.sub.2-4 acyl or aryl;
- and
- b. a halogen;
- or two of each of R.sup.1 and R.sup.2 may be a bivalent hydrocarbon residue or alkylenedioxy group which form a condensed ring system together with the ring to which they are attached;
- R is hydrogen, C.sub.1-6 straight chain, branched-chain or cyclic alkyl or an acyl group formed by combining a C.sub.1-6 alkyl group with a carbonyl group;
- and
- A is a hydroxymethyl group, an esterified carboxyl group in which the ester residue is a straight-chain, branched-chain or cyclic alkyl having 1 to 6 carbon atoms or an aralkyl having 7 to 15 carbon atoms, or an amidated carboxyl group formed by combining a carboxyl group with an amino group which is unsubstituted or substituted by the alkyl, aryl or alkenyl substituents defined as substituents for rings A and B, or by a 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrido(2,3-d)pyrimidyl, benzopyranyl, 1,8-naphthyridyl, 1,5-naphthyridinyl, 1,6-naphthyridyl, 1,7-naphthyridyl, quinolyl, thieno(2,3-b)pyridyl, tetrazolyl, thiadiazolyl, oxadiazolyl, triazinyl, triazolyl, thieyl, pyrrolyl, pyrrolinyl, furyl, pyrrolindinyl, benzothienyl, indolyl, imidazolidinyl, piperidyl, piperidino, piperazinyl, morpholinyl or morpholino group which may be substituted by a substituted selected from the group consisting of an amino (which may be substituted by a (1) C.sub.1-6 acyl, halogen, phenyl and/or C.sub.1-10 alkyl), (2) halogen, (3) nitro, (4) sulfo, (5) cyano, (6) hydroxy, (7) carboxy, (8) oxo, (9) thioxo, (10) C.sub.1-10 alkyl (which may be substituted by a phenyl, naphthyl, halogen, amino, hydroxy, carboxy, C.sub.1-4 alkoxy, C.sub.1-10 alkylsulfonyl and/or di-C.sub.1-10 alkylamino), (11) C.sub.3-6 cycloalkyl, (12) C.sub.1-4 alkoxy (which may be substituted by a halogen and/or hydroxy), (13) C.sub.1-4 acyl and (14) phenyl or naphthyl (which may be substituted by a halogen, nitro, C.sub.1-10 alkyl, C.sub.1-4 alkoxy, amino, sulfo, hydroxy and/or cyano) group;
- and n and m each is an integer of 2 to 4;
- or its salt, which comprises:
- A. heating, at a temperature of from approximately 10.degree. to approximately 200.degree. C., for a period of from 0.5 to 100 hours, a compound of the formula (II):
- ##STR24## to obtain a compound of the formula (I-1):
- ##STR25## wherein E is an ester residue for the esterified carboxyl, the ring A and ring B have the substituents (R.sup.1).sub.n and (R.sup.2).sub.m as in the formula (I'), respectively;
- B. reacting a compound of the formula (I-1), at a temperature of from approximately -20.degree. to approximately 100.degree. C., in a solvent, in the presence of a base, with a compound of the formula R-X wherein R has the same meaning as in the formula (I') and X is a leaving group selected from the group consisting of halogens and sulfonyloxys to obtain a compound of the formula (I-2):
- ##STR26## wherein the symbols are as defined above;
- C. reducing a compound of the formula (I-2) to obtain a compound of the formula (I-3):
- ##STR27## wherein the symbols are as defined above;
- D. hydrolyzing a compound of the formula (I-1) or (I-2), at a temperature of from approximately -20.degree. to approximately 150.degree. C., to obtain a compound of the formula (I-1) or (I-2) to obtain a compound of the formula (I-4):
- ##STR28## wherein the symbols are as defined above;
- E. esterifying a compound of the formula (I-4) to obtain a compound of the formula (I-5):
- ##STR29## wherein E' has the same meanings as defined for E and the other symbols are as defined above;
- F. amidating a compound of the formula (I-4) to obtain a compound of the formula (I-6):
- ##STR30## wherein C is an amidated carboxyl group and the other symbols are as defined above;
- G. eliminating a substituent in the substituted hydroxyl group of a compound of the formula (I') to obtain a compound of the formula (I') wherein R.sup.1 and/or R.sup.2 are hydroxyl group;
- or
- H. converting a compound of the formula (I') wherein R.sup.1 and/or R.sup.2 are hydroxyl group into the corresponding compound wherein R.sup.1 and/or R.sup.2 are a substituted hydroxyl group through alkylation, aralkylation or acylation;
- and if necessary
- I. converting a compound of the formula (I') into the corresponding salt.
25 more elements
Dependencies are inferred from the claim text.