New amino acid derivatives, processes for the preparation thereof and pharmaceutical composition comprising the same

Claim 2

A compound of the formula : wherein R 1 is lower alkyl optionally substituted with a substituent selected from the group consisting of acyl,hydroxy, lower alkoxy, aryl, lower alkylthio and a group of the formula : in which R 5 is hydrogen or acyl and R 6 is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and R 2 is hydrogen or lower alkyl; or R 1 and R 2 are taken together with the attached nitrogen atom to form a heterocyclic group optionally substituted with substituent(s) selected from the group consisting of lower alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, acyl(lower)alkyl, oxo and acyl; R 3 is hydrogen or lower alkyl; and R 4 is lower alkyl; and its pharmaceutically acceptable salt.

Claim 3

A compound of claim 1, wherein R 1 is lower alkyl optionally substituted with a substituent selected from the group consisting of hydroxy, lower alkoxy, aryl, lower alkylthio, a group of the formula : [in which R 9 and R 10 are each hydrogen, aryl, cyclo(lower)alkyl, a heterocyclic group or lower alkyl optionally substituted with a substituent selected from the group consisting of lower alkoxycarbonyl, lower alkoxy, aryl and a heterocyclic group, or R 9 and R 10 are taken together with the attached nitrogen atom to form a heterocyclic group optionally substituted with lower alkyl, and R 11 is aryl, cyclo(lower)alkyl, lower alkyl optionally substituted with a substituent selected from the group consisting of lower alkoxy and mono- or di(lower)alkylamino, or lower alkoxy optionally substituted with a substituent selected from the group consisting of lower alkanoyl and aryl] and a group of the formula [in which R 5 is hydrogen or a group of the formula : (in which R 9 , R 10 and R 11 are each as defined above), and R 6 is hydrogen or lower alkyl]; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and a group of the formula : [in which R 9 , R 10 and R" are each as defined above]; and R 2 is hydrogen or lower alkyl; or R 1 and R 2 are taken together with the attached nitrogen atom to form a heterocyclic group optionally substituted with substituent(s) selected from the group consisting of lower alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, heterocycliccarbonyl(lower)alkyl, oxo, amino-protected or unprotected amino acid residue and a group of the formula : [in which R 9 , R 10 and R 11 are each as defined above].

Claim 4

A compound of claim 2, wherein R 1 is lower alkyl optionally substituted with a substituent selected from the group consisting of hydroxy, lower alkoxy, aryl, lower alkylthio, a group of the formula : and a group of the formula :

Claim 5

A compound of claim 3, wherein R 1 is lower alkyl substituted with a group of the formula : in which R 9 and R 10 are each hydrogen or lower alkyl, or R 9 and R 10 are taken together with the attached nitrogen atom to form morpholino.

Claim 6

A compound of claim 4, which is 2(S)-[N α -[2(S)-(N-(2-morpholinocarbonylethyl)-N-methylaminocarbonyloxy}-3-phenylpropionyl]-N α -methyl-L-histidyl]amino-1-cydohexyl-3(S)-hydroxy-6-methylheptane or its hydrochloride.

Claim 7

A compound of claim 3, wherein R 1 is lower alkyl substituted with a group of the formula : in which R 5 is hydrogen or a group of the formula : [in which R 9 and R 10 are taken together with the attached nitrogen atom to form morpholino, and R 11 is lower alkyl], and R 6 is hydrogen or lower alkyl.

Claim 8

A compound of claim 6, which is 2(S)-[N α [2(S)-[N-methyl-N-[2-{N-(morpholinocarbonyl)-N-methylamino}ethyl]aminocarbonyloxy]-3-pheny(propionyl]-N α -methyl-L-histidyl]amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane or its hydrochloride.

Claim 9

A compound of claim 6, which is 2(S)-[N α -[2(S)-[N-methy(-N-{2-(N-isobutyryl-N-methylamino)ethyl}aminocarbonyloxy]-3-phenylpropionyl]-Na-methyl-L-histidyl]amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane or its hydrochloride.

Claim 10

A compound of claim 2, wherein R 1 is amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and a group of the formula :

Claim 13

A compound of claim 2, wherein R 1 and R 2 are taken together with the attached nitrogen atom to form a heterocyclic group optionally substituted with substituent(s) selected from the group consisting of lower alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, heterocycliccarbonyl(lower)alkyl, oxo, amino-protected or unprotected amino acid residue and a group of the formula :

Claim 16

A process for preparing a compound of the formula : wherein R 1 is lower alkyl optionally substituted with a substituent selected from the group consisting of acyl,hydroxy, lower alkoxy, aryl, lower alkylthio and a group of the formula : in which R 5 is hydrogen or acyl and R 6 is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and R 2 is hydrogen or lower alkyl; or R 1 and R 2 are taken together with the attached nitrogen atom to form a heterocyclic group optionally substituted with substituent(s) selected from the group consisting of lower alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, acyl(lower)alkyl, oxo and acyl; R 3 is hydrogen or lower alkyl; and R 4 is lower alkyl; or its salt which comprises a) reacting a compound of the formula : wherein R 8 is hydrogen or an N-protective group, and R 3 and R 4 are each as defined above, or its reactive derivative at the amino group or a salt thereof with a compound of the formula : wherein R 1 and R 2 are each as defined above, or its reactive derivative at the carboxy group or a salt thereof, and, if necessary, eliminating the N-protective group to give a compound of the formula : wherein R 1 , R 2 , R 3 and R 4 are each as defined above, or its salt, or b) subjecting a compound of the formula wherein R 7 is an N-protective group, A is lower alkylene, and R 2, R3, R 4 and R 6 are each as defined above, or its salt to elimination reaction of the N-protective group to give a compound of the formula : wherein R 2 , R 3 , R 4 , R 6 and A are each as defined above, or its salt.

Claim 17

A process for preparing a compound of the formula : wherein R 1 is lower alkyl optionally substituted with a substituent selected from the group consisting of acyl,hydroxy, lower alkoxy, aryl, lower alkylthio and a group of the formula : in which R 5 is hydrogen or acyl and R 6 is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and R 2 is hydrogen or lower alkyl; or R 1 and R 2 are taken together with the attached nitrogen atom to form a heterocyclic group optionally substituted with substituent(s) selected from the group consisting of lower alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, acyl(lower)alkyl, oxo and acyl; R 3 is hydrogen or lower alkyl; and R 4 is lower alkyl; or its salt which comprises a) reacting a compound of the formula : wherein R 8 is hydrogen or an N-protective group, and R 3 and R 4 are each as defined above, or its reactive derivative at the amino group or a salt thereof with a compound of the formula : wherein R 1 and R 2 are each as defined above, or its reactive derivative at the carboxy group or a salt thereof, and, if necessary, eliminating the N-protective group to give a compound of the formula : wherein R 1 , R 2 , R 3 and R 4 are each as defined above, or its salt, or b) subjecting a compound of the formula wherein R 7 is an N-protective group, A is lower alkylene, and R 2, R3, R 4 and R 6 are each as defined above, or its salt to elimination reaction of the N-protective group to give a compound of the formula : wherein R 2 , R 3 , R 4 , R 6 and A are each as defined above, or its salt.

Claim 18

A compound of the formula : wherein R 1 is lower alkyl substituted with a substituent selected from the group consisting of acyl,lower alkoxy, aryl, lower alkylthio and a group of the formula : in which R 5 is hydrogen or acyl and R 6 is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and R 2 is hydrogen or lower alkyl; and its salt.

Claim 19

A compound of the formula : wherein R 1 is lower alkyl substituted with a substituent selected from the group consisting of acyl,lower alkoxy, aryl, lower alkylthio and a group of the formula : in which R 5 is hydrogen or acyl and R 6 is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and R 2 is hydrogen or lower alkyl; and its salt.

Claim 20

A pharmaceutical composition comprising a compound of claim 1, as an active ingredient, in association with a pharmaceutically acceptable, substantially nontoxic carrier or excipient.

Claim 21

A compound of claim 1 for use as a medicament.

Claim 22

A method for the therapeutic treatment of hypertension and heart failure which comprises administering a compound of claim 1 in human being or animals.