Tetrahydroisoquinoline compounds, process for preparing them and pharmaceutical compositions containing them

Claim 2

A tetrahydroisoquinoline compound of the formula: wherein R 1 is alkyl of one to six carbon atoms, cycloalkyl of three to six carbon atoms, allyl or propargyl, R 2 is hydrogen or alkyl of one to six carbon atoms, and R 3 is hydrogen, alkyl of one to six carbon atoms or benzyl, or a pharmaceutically acceptable salt thereof.

Claim 3

The compound of Claim 1, in which R3 is hydrogen.

Claim 4

The compound of Claim 2, in which R 2 is hydrogen.

Claim 5

The compound of Claim 2, in which R 2 is alkyl of one to six carbon atoms.

Claim 6

The compound of Claim 3, in which R 1 is alkyl of one to four carbon atoms, cyclopropyl, allyl or propargyl.

Claim 7

The compound of Claim 4, in which R 1 is alkyl of one to four carbon atoms, cyclopropyl, allyl or propargyl, and R 2 is alkyl of one to four carbon atoms.

Claim 8

The compound of Claim 5, in which R is alkyl of one to four carbon atoms.

Claim 9

The compound of Claim 5, in which R 1 is cyclopropyl, allyl or propargyl.

Claim 10

The compound of Claim 6, in which R 1 is alkyl of one to four carbon atoms.

Claim 11

The compound of Claim 7 which is 3(S)-2-[N-ethyl- N -(2-carboxyethyl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

Claim 12

The compound of Claim 7 which is 3(S)-2-(N-isopropyl-N-(2-carboxyethyl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

Claim 13

The compoud of Claim 8 which is 3(S)-2-( N -propargyl N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid or pharmaceutically acceptable salt thereof.

Claim 14

The compound of Claim 9 which is 3(S)-2-(N-ethyl- N -(2-ethoxycarbonylethyl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

Claim 15

The compound of Claim 9 which is 3(S)-2-(N-ethyl-N-(2-n-butoxycarbonylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

Claim 16

The compound of Claim 9 which is 3(S)-2-(N-isopropyl-N-(2-ethyoxycarbonylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

Claim 17

The compound of Claim 9 which.is 3(S)-2-(N-isopropyl-N-(2-n-butoxycarbonylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

Claim 18

17 . A process for preparing a tetrahydroisoquinoline compound of the formula: wherein R 1 is alkyl of one to six carbon atoms, cycloalkyl of three to six carbon atoms, allyl or propargyl, R 2 is hydrogen or alkyl of one to six carbon atoms, and R 3 is hydrogen, alkyl of one to six carbon atoms or benzyl, or a pharmaceutically acceptable salt thereof, which comprises the steps of: i) reacting a compound of the formula: wherein R 3' is alkyl of one to six carbon atoms or benzyl, with phosgene to give a compound of the formula: wherein R 31 is the same as defined above, ii) condensing the compound (III) with a compound of the formula: wherein R 1 is the same as defined above, and R 2' is alkyl of one to six carbon atoms, to give a compound of the formula: wherein R , R 2 and R are the same as defined above, and iii-a) when R 3' is alkyl of one to six carbon atoms, if required, further hydrolyzing the compound (I-a) to give a compound of the formula: wherein R 1 is the same as defined above, or iii-b) when R 31 is benzyl, if required, further subjecting the compound (I-a) to catalytic hydrogenation to give a compound of the formula: wherein R 1 and R 2' are the same as defined above, and iv) if required, further converting the product to a pharmaceutically acceptable salt thereof.

Claim 19

17 . A process for preparing a tetrahydroisoquinoline compound of the formula: wherein R 1 is alkyl of one to six carbon atoms, cycloalkyl of three to six carbon atoms, allyl or propargyl, R 2 is hydrogen or alkyl of one to six carbon atoms, and R 3 is hydrogen, alkyl of one to six carbon atoms or benzyl, or a pharmaceutically acceptable salt thereof, which comprises the steps of: i) reacting a compound of the formula: wherein R 3' is alkyl of one to six carbon atoms or benzyl, with phosgene to give a compound of the formula: wherein R 31 is the same as defined above, ii) condensing the compound (III) with a compound of the formula: wherein R 1 is the same as defined above, and R 2' is alkyl of one to six carbon atoms, to give a compound of the formula: wherein R , R 2 and R are the same as defined above, and iii-a) when R 3' is alkyl of one to six carbon atoms, if required, further hydrolyzing the compound (I-a) to give a compound of the formula: wherein R 1 is the same as defined above, or iii-b) when R 31 is benzyl, if required, further subjecting the compound (I-a) to catalytic hydrogenation to give a compound of the formula: wherein R 1 and R 2' are the same as defined above, and iv) if required, further converting the product to a pharmaceutically acceptable salt thereof.

Claim 20

The process according to Claim 17, wherein the compound (II) is reacted with phosgene at a temperature between -40° and 0°C in the presence or absence of an acid acceptor in a solvent, the resultant compound (III) is condensed with the compound (IV) at a temperature between 0° and 80°C in the presence of an acid acceptor in a solvent, and then the resultant compound (I-a) is hydrolyzed by treating said compound with an alkali or an acid at a temperature between o° and 100°C in a solvent.

Claim 21

The precess according to Claim 17, wherein the compound (II) is reacted with phosgene at a temperature between -40° and 0°C in the presence or absence of an acid acceptor in a solvent, the resultant compound (III) is condensed with the compound (IV) at a temperature between 0° and 80°C in the presence of an acid acceptor in a solvent, and then the resultant compound (I-a) is subjected to catalytic hydrogenation at a temperature between 20° and 60°C in the presence of a catalyst in a solvent.

Claim 22

A process for preparing a tetrahydroisoquinoline compound of the formula: wherein R 1 is alkyl of one to six carbon atoms, cycloalkyl of three to six carbon atoms, allyl or propargyl, R2 is hydrogen or alkyl of one to six carbon atoms, and R 3 is hydrogen, alkyl of one to six carbon atoms or benzyl, or a pharmaceutically acceptable salt thereof, which comprises the steps of: i) reacting a compound of the formula: wherein R 1 is the same as defined above, and R 2' is alkyl of one to six carbon atoms, with phosgene to give a compound of the formula: wherein R 1 and R 2' are the same as defined above, ii) condensing the compound of the formula: ; wherein R 3' is alkyl of one to six carbon atoms or benzyl, to give a compound of the formula: wherein R 1 , R 2' and R 3' are the same as defined above, and iii-a) when R 3' is alkyl of one to six carbon atoms, if required, further hydrolyzing the compound (I-a) to give a compound the formula: wherein R 1 is the same as defined above, or iii-b) whtn R 3' is benzyl, if required, further subjecting the compound (I-a) to catalytic hydrogenation to give a compound of the formula: wherein R 1 and R21 are the same as defined above, and iv) if required, further converting the product to a pharmaceutically acceptable salt thereof.

Claim 23

A process for preparing a tetrahydroisoquinoline compound of the formula: wherein R 1 is alkyl of one to six carbon atoms, cycloalkyl of three to six carbon atoms, allyl or propargyl, R2 is hydrogen or alkyl of one to six carbon atoms, and R 3 is hydrogen, alkyl of one to six carbon atoms or benzyl, or a pharmaceutically acceptable salt thereof, which comprises the steps of: i) reacting a compound of the formula: wherein R 1 is the same as defined above, and R 2' is alkyl of one to six carbon atoms, with phosgene to give a compound of the formula: wherein R 1 and R 2' are the same as defined above, ii) condensing the compound of the formula: ; wherein R 3' is alkyl of one to six carbon atoms or benzyl, to give a compound of the formula: wherein R 1 , R 2' and R 3' are the same as defined above, and iii-a) when R 3' is alkyl of one to six carbon atoms, if required, further hydrolyzing the compound (I-a) to give a compound the formula: wherein R 1 is the same as defined above, or iii-b) whtn R 3' is benzyl, if required, further subjecting the compound (I-a) to catalytic hydrogenation to give a compound of the formula: wherein R 1 and R21 are the same as defined above, and iv) if required, further converting the product to a pharmaceutically acceptable salt thereof.

Claim 24

The process according to Claim 20, wherein the compound (IV) is reacted with phosgene at a temperature between -40° and 0°C in the presence or absence of an acid acceptor in a solvent, the resultant compound (V) is condensed with the compound (II) at a temperature between 0° and 80°C in the presence of an acid acceptor in a solvent, and then the resultant compound (I-a) is hydrolyzed by treating said compound with an alkali or an acid at a temperature between 0° and 100°C in a solvent.

Claim 25

The process according to Claim 20, wherein the compound (IV) is reacted with phosgene at a temperature between -40° and 0°C in the presence or absence of an acid acceptor in a solvent, the resultant compound (V) is condensed with the compound (II) at a tempreature between 0° and 80°C in the presence of an acid acceptor in a solvent, and then the resultant compound (I-a) is subjected to catalytic hydrogenation at a temperature between 20° and 60°C in the presence of a catalyst in a solvent.

Claim 26

A pharmaceutical composition which comprises a tetrahydroisoquinoline compound of the formula: wherein R 1 is alkyl of one to six carbon atoms, cycloalkyl of three to six carbon atoms, allyl or propargyl, R 2 is hydrogen or alkyl of one to six carbon atoms, and R 3 is hydrogen, alkyl of one to six carbon atoms or benzyl, or a pharmaceutically acceptable salt thereof, and a phamaceutica acceptable carrier thereof.

Claim 27

A pharmaceutical composition which comprises a tetrahydroisoquinoline compound of the formula: wherein R 1 is alkyl of one to six carbon atoms, cycloalkyl of three to six carbon atoms, allyl or propargyl, R 2 is hydrogen or alkyl of one to six carbon atoms, and R 3 is hydrogen, alkyl of one to six carbon atoms or benzyl, or a pharmaceutically acceptable salt thereof, and a phamaceutica acceptable carrier thereof.