Bicyclic compounds, their production and use

Claim 2

A compound of the formula: wherein R 1 and R 2 independently represent hydrogen, hydroxyl or C 1-4 alkoxy, or R 1 and R 2 jointly form C 1-4 alkylenedioxy, R 3 is hydrogen or C 1-4 alkyl R 4 is hydrogen, C 1-4 alkyl or amino-C 1-4 alkyl which is unsubstituted or substituted by acyl of the class consisting of C 2-4 alkanoyl, benzoyl, C 2-4 alkoxycarbonyl or benzyloxycarbonyl, R 5 is hydrogen, C 1-4 alkyl or phenyl-C 1-4 alkyl which is unsubstituted or substituted by 1 to 3 members of halogen, C l-4 alkyl, C 1-4 alkoxy, amino, nitro and hydroxyl, R 6 is hydroxyl, C 1-4 alkoxy, amino or mono- or d i-C l-4 alkylamino, and m and n each means 1 or 2, or a pharmaceutically acceptable salt thereof.

Claim 3

A compound according to Claim 1, wherein R l , R 2 and R 3 are hydrogen.

Claim 4

A compound according to Claim 1, wherein R 4 is C 1-4 alkyl or amino-C 1-4 alkyl.

Claim 5

A compound according to Claim 1, wherein R 5 is phenethyl.

Claim 6

A compound according to Claim 1, wherein R 6 is hydroxyl or C l-4 alkoxy.

Claim 7

A compound according to Claim 1, wherein m and n are 1.

Claim 8

A compound of the formula: wherein R 41 is hydrogen or C l-4 alkyl, R 5 , is hydrogen, C l-4 alkyl or phenyl-C 1-4 alkyl, and R is hydroxyl or C 1-4 alkoxy, or a pharmaceutically acceptable salt thereof.

Claim 9

A compound of the formula: wherein R 41 is hydrogen or C l-4 alkyl, R 5 , is hydrogen, C l-4 alkyl or phenyl-C 1-4 alkyl, and R is hydroxyl or C 1-4 alkoxy, or a pharmaceutically acceptable salt thereof.

Claim 10

A compound according to Claim 7, wherein R 4' is C 1-4 alkyl, R 5' is phenyl-C 1-4 alkyl, and R 6' is C l-4 alkoxy.

Claim 11

A compound according to Claim 8, which is an isomer having S configuration at each of the asymmetric carbon atoms to which the substituents R 4' and R 5' respectively are connected.

Claim 12

A compound according to any one of Claims 1 to 9, wherein the pharmaceutically acceptable salt is hydrochloride.

Claim 13

The compound according to Claim 1, which is N-(l-ethoxycarbonyl-3-p-tolylpropyl)-L-alanyl-N-(indan-2-yl)-glycine.

Claim 14

The compound according to Claim 1, which is N-[1-ethoxycarbonyl-3-(4-hydroxyphenyl),propyl]-L-alanyl-N-(indan-2-yl)glycine.

Claim 15

The compound according to Claim 7, which is N-(1-carboxy-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)glycine.

Claim 16

The compound according to Claim 7, which is N-(3-phenyl-l-propoxycarbonylpropyl)-L-alanyl-N-(indan-2-yl)-glycine.

Claim 17

The compound according to Claim 7, which is N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)-glycine.

Claim 18

The compound according to Claim 7, which is N-[l-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine.

Claim 19

The.compound according to Claim 7, which is N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine hydrochloride.

Claim 20

A pharmaceutical composition which comprises, as an active ingredient, an effective amount of a compound as claimed in any one of Claims 1 to 17 in association with a pharmaceutically acceptable carrier, excipient or diluent therefor.

Claim 21

A compound as claimed in any one of Claims 1 to 17 or a pharmaceutical composition as claimed in Claim 18 for use in therapeutical treatment of a warm-blooded animal.

Claim 22

A process for producing a bicyclic compound of the formula (I): wherein R 1 and R 2 independently represent hydrogen, hydroxyl or C 1-4 alkoxy, or R 1 and R 2 jointly form C1-4 alkylenedioxy, R 3 is hydrogen or C 1-4 alkyl, R 4 is hydrogen, C 1-4 alkyl or amino-C 1-4 alkyl which is unsubstituted or substituted by acyl of the class consisting of C 2-4 alkanoyl, benzoyl, C 2-4 alkoxycarbonyl or benzyloxycarbonyl, R is hydrogen, C 1-4 alkyl or phenyl-C l-4 alkyl which is unsubstituted or substituted by 1 to 3 members of halogen, C l-4 alkyl, C 1-4 alkoxy, amino, nitro and hydroxyl, R 6 is hydroxyl, C 1-4 alkoxy, amino or mono- or di-C 1-4 alkylamino, and m and n each means 1 or 2, or a pharmaceutically acceptable salt thereof, which comprises a) subjecting a compound of the formula (II): wherein all the symbols are as defined above, and a compound of the formula (III): wherein R and R 6 are as defined above, to condensation under reductive conditions, or b) hydrolyzing an ester compound of the formula (I) wherein R 3 is C 1-4 alkyl and/or R 6 is C 1-4 alkoxy and all other symbols are as defined above, to provide a compound of the formula (I) wherein R 3 is hydrogen and/or R 6 is hydroxyl and all other symbols are as defined above, or c) subjecting a benzyl ester of a compound of the formula (I) wherein R 3 is benzyl and/or R 6 is benzyloxy and all other symbols are as defined above, to catalytic reduction to provide a compound of the formula (I) whereir R 3 is hydrogen and/or R 6 is hydroxyl and all other symbols are as defined above, or d) subjecting a compound of the formula (IV): wherein Z is a protective group removable by hydrolysis or catalytic reduction and the other symbols are as defined above, to hydrolysis or catalytic reduction, or e) reacting a compound of the formula (II) with a compound of the formula (V): wherein R 5 and R 6 are as defined above, and X is halogen or a group of the formula R 7 SO 2 -O- in which R 7 is C l-4 alkyl, phenyl or p-tolyl, and f) if desired, converting the thus obtained compound of the formula (I) into a pharmaceutically acceptable salt thereof.

Claim 23

A process for producing a bicyclic compound of the formula (I): wherein R 1 and R 2 independently represent hydrogen, hydroxyl or C 1-4 alkoxy, or R 1 and R 2 jointly form C1-4 alkylenedioxy, R 3 is hydrogen or C 1-4 alkyl, R 4 is hydrogen, C 1-4 alkyl or amino-C 1-4 alkyl which is unsubstituted or substituted by acyl of the class consisting of C 2-4 alkanoyl, benzoyl, C 2-4 alkoxycarbonyl or benzyloxycarbonyl, R is hydrogen, C 1-4 alkyl or phenyl-C l-4 alkyl which is unsubstituted or substituted by 1 to 3 members of halogen, C l-4 alkyl, C 1-4 alkoxy, amino, nitro and hydroxyl, R 6 is hydroxyl, C 1-4 alkoxy, amino or mono- or di-C 1-4 alkylamino, and m and n each means 1 or 2, or a pharmaceutically acceptable salt thereof, which comprises a) subjecting a compound of the formula (II): wherein all the symbols are as defined above, and a compound of the formula (III): wherein R and R 6 are as defined above, to condensation under reductive conditions, or b) hydrolyzing an ester compound of the formula (I) wherein R 3 is C 1-4 alkyl and/or R 6 is C 1-4 alkoxy and all other symbols are as defined above, to provide a compound of the formula (I) wherein R 3 is hydrogen and/or R 6 is hydroxyl and all other symbols are as defined above, or c) subjecting a benzyl ester of a compound of the formula (I) wherein R 3 is benzyl and/or R 6 is benzyloxy and all other symbols are as defined above, to catalytic reduction to provide a compound of the formula (I) whereir R 3 is hydrogen and/or R 6 is hydroxyl and all other symbols are as defined above, or d) subjecting a compound of the formula (IV): wherein Z is a protective group removable by hydrolysis or catalytic reduction and the other symbols are as defined above, to hydrolysis or catalytic reduction, or e) reacting a compound of the formula (II) with a compound of the formula (V): wherein R 5 and R 6 are as defined above, and X is halogen or a group of the formula R 7 SO 2 -O- in which R 7 is C l-4 alkyl, phenyl or p-tolyl, and f) if desired, converting the thus obtained compound of the formula (I) into a pharmaceutically acceptable salt thereof.

Claim 24

CLAIMS (AUSTRIA):

Claim 25

A process for producing a bicyclic compound of the formula (I): wherein R 1 and R 2 independently represent hydrogen, hydroxyl or C l-4 alkoxy, or R 1 and R 2 jointly form C l-4 alkylenedioxy, R 3 is hydrogen or C l-4 alkyl, R 4 is hydrogen, C 1-4 alkyl or amino-C 1-4 alkyl which is unsubstituted or substituted by acyl of the class consisting of C 2-4 alkanoyl, benzoyl, C 2-4 alkoxycarbonyl or benzyloxycarbonyl, R 5 is hydrogen, C 1-4 alkyl or phenyl-C 1-4 alkyl which is unsubstituted or substituted by 1 to 3 members of halogen, C 1-4 alkyl, C l-4 alkox y , amino, nitro and hydroxyl, R 6 is hydroxyl, C 1-4 alkoxy, amino or mono-or di- C 1-4 alkylamino, and m and n each means 1 or 2, or a pharmaceutically acceptable salt thereof, which comprises a) subjecting a compound of the formula (II): wherein all the symbols are as defined above, and a compound of the formula (III): wherein R 5 and R 6 are as defined above, to condensation under reductive conditions, or b) hydrolyzing an ester compound of the formula (I) wherein R 3 is C 1-4 alkyl and/or R 6 is C 1-4 alkoxy and all other symbols are as defined above, to provide a compound of the formula (I) wherein R 3 is hydrogen and/or R 6 is hydroxyl and all other symbols are as defined above, or c) subjecting a benzyl ester of a compound of the formula (I) wherein R 3 is benzyl and/or R 6 is benzyloxy and all other symbols are as defined above, to catalytic reduction to provide a compound of the formula (I) wherein R3 is hydrogen and/or R 6 is hydroxyl and all other symbols are as defined above, or d) subjecting a compound of the formula (IV): wherein Z is a protective group removable by hydrolysis or catalytic reduction and the other symbols are as defined above, to hydrolysis or catalytic reduction, or e) reacting a compound of the formula (II) with a compound of the formula (V): wherein R 5 and R 6 are as defined above, and X is halogen or a group of the formula R 7 SO 2 -O- in which R 7 is C 1-4 alkyl, phenyl or p-tolyl, and f) if desired, converting the thus obtained compound of the formula (I) into a pharmaceutically acceptable salt thereof.

Claim 26

A process for producing a bicyclic compound of the formula (I): wherein R 1 and R 2 independently represent hydrogen, hydroxyl or C l-4 alkoxy, or R 1 and R 2 jointly form C l-4 alkylenedioxy, R 3 is hydrogen or C l-4 alkyl, R 4 is hydrogen, C 1-4 alkyl or amino-C 1-4 alkyl which is unsubstituted or substituted by acyl of the class consisting of C 2-4 alkanoyl, benzoyl, C 2-4 alkoxycarbonyl or benzyloxycarbonyl, R 5 is hydrogen, C 1-4 alkyl or phenyl-C 1-4 alkyl which is unsubstituted or substituted by 1 to 3 members of halogen, C 1-4 alkyl, C l-4 alkox y , amino, nitro and hydroxyl, R 6 is hydroxyl, C 1-4 alkoxy, amino or mono-or di- C 1-4 alkylamino, and m and n each means 1 or 2, or a pharmaceutically acceptable salt thereof, which comprises a) subjecting a compound of the formula (II): wherein all the symbols are as defined above, and a compound of the formula (III): wherein R 5 and R 6 are as defined above, to condensation under reductive conditions, or b) hydrolyzing an ester compound of the formula (I) wherein R 3 is C 1-4 alkyl and/or R 6 is C 1-4 alkoxy and all other symbols are as defined above, to provide a compound of the formula (I) wherein R 3 is hydrogen and/or R 6 is hydroxyl and all other symbols are as defined above, or c) subjecting a benzyl ester of a compound of the formula (I) wherein R 3 is benzyl and/or R 6 is benzyloxy and all other symbols are as defined above, to catalytic reduction to provide a compound of the formula (I) wherein R3 is hydrogen and/or R 6 is hydroxyl and all other symbols are as defined above, or d) subjecting a compound of the formula (IV): wherein Z is a protective group removable by hydrolysis or catalytic reduction and the other symbols are as defined above, to hydrolysis or catalytic reduction, or e) reacting a compound of the formula (II) with a compound of the formula (V): wherein R 5 and R 6 are as defined above, and X is halogen or a group of the formula R 7 SO 2 -O- in which R 7 is C 1-4 alkyl, phenyl or p-tolyl, and f) if desired, converting the thus obtained compound of the formula (I) into a pharmaceutically acceptable salt thereof.

Claim 27

A process according to Claim 1, wherein R l , R 2 and R 3 are hydrogen.

Claim 28

A process according to Claim 1, wherein R 4 is C 1-4 alkyl or amino-C 1-4 alkyl.

Claim 29

A process according to Claim 1, wherein R 5 is phenethyl.

Claim 30

A process according to Claim 1, wherein R 6 is hydroxyl or C 1-4 alkox y.

Claim 31

A process according to Claim 1, wherein m and n are 1.

Claim 32

A process according to Claim 1, wherein the product is a compound of the formula: wherein R 4' is hydrogen or C 1-4 alkyl, R 5' is hydrogen, C 1-4 alkyl or phenyl-C 1-4 alkyl, and R 6' is hydroxyl or C l-4 alkox y , or a pharmaceutically acceptable salt thereof.

Claim 33

A process according to Claim 7, wherein R 4' is C 1-4 alkyl, R 5' is phenyl-C 1-4 alkyl, and R 6' is C l-4 alkoxy.

Claim 34

A process according to Claim 8, wherein the product is an isomer having S configuration at each of the asymmetric carbon atoms to which the substituents R 4' and R 5' respectively are connected.

Claim 35

A process according to any one of Claims 1 to 9, wherein the pharmaceutically acceptable salt is hydrochloride. 11. A process according to Claim 1, wherein the product is N-(1-ethoxycarbonyl-3-p-tolylpropyl)-L-alanyl-N-(indan-2-yl)-glycine; N-[l-ethoxycarbonyl-3-(4-hydroxyphenyl)propyl]- L -alanyl-N-(indan-2-yl)glycine; N-(l-carboxy-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)glycine; N-(3-phenyl-l-propoxy- carbonylpropyl)-L-alanyl-N-(indan-2-yl)-glycine; N-(1- ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)-glycine; N-[ 1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine; or N-[ l-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine hydrochloride.

Claim 36

A process according to any of Claims 1 to 11, wherein the product is associated with a pharmaceutically acceptable carrier, excipient or diluent therefor to form a pharmaceutical composition.

Claim 37

A compound produced by the process as claimed in any one of Claims 1 to 11 or a pharmaceutical composition produced by the process as claimed in Claim 12 for use in therapeutical treatment of a warm-blooded animal.