Phosphonyl hydroxyacyl amino acid derivatives as antihypertensives

Claim 2

A compound of the formula ##STR431## and pharmaceutically acceptable salts thereof wherein: ##STR432## R 4 is hydrogen, lower alkyl, halogen, keto, hydroxy, ##STR433## azido, amino, ##STR434## a 1- or 2-naphthyl of the formula ##STR435## --(CH 2 ) m --cycloalkyl, ##STR436## --O--lower alkyl, ##STR437## a 1- or 2-naphthyloxy of the formula ##STR438## --S--lower alkyl, ##STR439## or a 1- or 2-naphthylthio of the formula ##STR440##

Claim 3

R 5 is keto, halogen, ##STR441## --O--lower alkyl, a 1- or 2-naphthyloxy of the formula ##STR442## --S--lower alkyl, ##STR443## or a 1- or 2-naphthylthio of the formula ##STR444## R 7 is keto or ##STR445## each R 8 is the same or different and is halogen or --Y--R 14 ; R 11 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl; R 12 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, or hydroxy; m is zero, one, two or three; p is one, two or three provided that p is more than one only if R 11 or R 12 is hydrogen, methyl, methoxy, chloro, or fluoro; R 13 is hydrogen or lower alkyl of 1 to 4 carbons; Y is oxygen or sulfur; R 14 is lower alkyl of 1 to 4 carbons, ##STR446## or the R 14 groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a lower alkyl of 1 to 4 carbons or a di(lower alkyl of 1 to 4 carbons) substituent; R 1 is alkyl of 1 to 10 carbons, aminoalkyl, haloalkyl, ##STR447## wherein q is zero or an integer from 1 to 7 and R 11 and p are as defined above; and R 19 and R 20 are independently selected from the group consisting of hydrogen, lower alkyl, halo substituted lower alkyl, ##STR448## wherein m, R 11 and p are as defined above; R 2 is hydrogen, lower alkyl, halo substituted lower alkyl, ##STR449## wherein r is as defined hereinbefore; R 3 and R 6 are independently selected from hydrogen, lower alkyl, benzyl, benzhydryl, alkali metal, or ##STR450## wherein R 15 is hydrogen, lower alkyl, cycloalkyl, or phenyl, and R 16 is hydrogen, lower alkyl, lower alkoxy, phenyl, or R 15 and R 16 taken together are --(CH 2 ) 2 --, --(CH 2 ) 3 , --CH═CH-- or ##STR451## R 17 is lower alkyl, benzyl, or phenethyl; and R 18 is hydrogen, lower alkyl, benzyl, or phenethyl.

Claim 4

R 5 is keto, halogen, ##STR441## --O--lower alkyl, a 1- or 2-naphthyloxy of the formula ##STR442## --S--lower alkyl, ##STR443## or a 1- or 2-naphthylthio of the formula ##STR444## R 7 is keto or ##STR445## each R 8 is the same or different and is halogen or --Y--R 14 ; R 11 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl; R 12 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, or hydroxy; m is zero, one, two or three; p is one, two or three provided that p is more than one only if R 11 or R 12 is hydrogen, methyl, methoxy, chloro, or fluoro; R 13 is hydrogen or lower alkyl of 1 to 4 carbons; Y is oxygen or sulfur; R 14 is lower alkyl of 1 to 4 carbons, ##STR446## or the R 14 groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a lower alkyl of 1 to 4 carbons or a di(lower alkyl of 1 to 4 carbons) substituent; R 1 is alkyl of 1 to 10 carbons, aminoalkyl, haloalkyl, ##STR447## wherein q is zero or an integer from 1 to 7 and R 11 and p are as defined above; and R 19 and R 20 are independently selected from the group consisting of hydrogen, lower alkyl, halo substituted lower alkyl, ##STR448## wherein m, R 11 and p are as defined above; R 2 is hydrogen, lower alkyl, halo substituted lower alkyl, ##STR449## wherein r is as defined hereinbefore; R 3 and R 6 are independently selected from hydrogen, lower alkyl, benzyl, benzhydryl, alkali metal, or ##STR450## wherein R 15 is hydrogen, lower alkyl, cycloalkyl, or phenyl, and R 16 is hydrogen, lower alkyl, lower alkoxy, phenyl, or R 15 and R 16 taken together are --(CH 2 ) 2 --, --(CH 2 ) 3 , --CH═CH-- or ##STR451## R 17 is lower alkyl, benzyl, or phenethyl; and R 18 is hydrogen, lower alkyl, benzyl, or phenethyl.

Claim 5

A compound of claim 1 wherein: R 4 is hydrogen, hydroxy, chloro, fluoro, lower alkyl of 1 to 4 carbons, cyclohexyl, amino, --O--lower alkyl wherein lower alkyl is of 1 to 4 carbons, ##STR452## 1- or 2-naphthyloxy, --S--lower alkyl wherein lower alkyl is of 1 to 4 carbons, ##STR453## or 1- or 2-naphthylthio; R 5 is --O--lower alkyl wherein lower alkyl is of 1 to 4 carbons, --S--lower alkyl wherein lower alkyl is of 1 to 4 carbons, ##STR454## R 7 is phenyl, 2-hydroxyphenyl, or 4-hydroxyphenyl; each R 8 is fluoro, chloro or --Y--R 14 ; Y is oxygen or sulfur; R 14 is lower alkyl of 1 to 4 carbons or the R 14 groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a methyl or dimethyl substituent; m is zero, one or two; R 11 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy; R 2 is hydrogen, lower alkyl of 1 to 4 carbons, CF 3 , or amino substituted lower alkyl of 1 to 4 carbons; R 1 is alkyl of 1 to 10 carbons, ##STR455## --(CH 2 ) q --cycloalkyl wherein cycloalkyl is of 5 or 6 carbons, ##STR456## wherein q is zero or an integer from 1 to 4 and R 11 is as defined above; R 19 and R 20 are independently selected from lower alkyl of 1 to 4 carbons or ##STR457## wherein q and R 11 are as defined above; R 3 and R 6 are independently selected from hydrogen, alkali metal salt, lower alkyl of 1 to 4 carbons, or ##STR458## R 15 is hydrogen, methyl or isopropyl; and R 16 is lower alkyl of 1 to 4 carbons or phenyl.

Claim 6

A compound of claim 2 wherein X is ##STR459## R 4 is hydrogen, cyclohexyl, lower alkoxy of 1 to 4 carbons, ##STR460## m is zero, one or two; R 11 is hydrogen, methyl, methoxy, methylthio, bromo, fluoro, or hydroxy; Y is oxygen or sulfur; t is two or three; and R 6 is hydrogen, ##STR461## or an alkali metal salt, R 1 is ##STR462## R 2 is hydrogen or lower alkyl; and R 3 is hydrogen, alkali metal or phenylalkyl.

Claim 7

A compound of claim 3 wherein R 1 is phenylalkyl or ##STR463## wherein R 19 is phenylalkyl and R 20 is phenyl; R 2 is hydrogen, methyl, or --(CH 2 ) 4 --NH 2 ; and R 3 is hydrogen, phenylmethyl, ##STR464## or an alkali metal salt.

Claim 8

A compound of claim 4 wherein R 1 is alkyl of 1 to 10 carbons.

Claim 9

A compound of claim 5 wherein X is ##STR465## and R 4 is hydrogen.

Claim 10

The compound of claim 3 wherein R 1 is phenylbutyl; R 2 is methyl; and R 3 and R 6 are an alkali metal salt.

Claim 11

The compound of claim 3 wherein R 1 is ##STR466## R 2 is methyl; and R 3 and R 6 are an alkali metal salt.

Claim 12

The compound of claim 6 wherein R 1 is ##STR467## R 2 is methyl; R 3 is ethyl; and R 6 is an alkali metal salt.

Claim 13

The compound of claim 6 wherein R 1 is ##STR468## R 2 is methyl; and R 3 and R 6 are an alkali metal salt.

Claim 14

The compound of claim 6 wherein R 1 is ##STR469## R 2 is methyl; R 3 is ##STR470## and R 6 is an alkali metal salt.

Claim 15

The compound of claim 6 wherein R 1 is ##STR471## R 2 is methyl; and R 3 and R 6 are an alkali metal salt.

Claim 16

The compound of claim 6 wherein R 1 is ##STR472## R 2 is methyl; and R 3 and R 6 are an alkali metal salt.

Claim 17

The compound of claim 6 wherein R 1 is ##STR473## R 2 is methyl; and R 3 and R 6 are an alkali metal salt.

Claim 18

The compound of claim 6 wherein R 1 is ##STR474## R 2 is hydrogen; and R 3 and R 6 are an alkali metal salt.

Claim 19

The compound of claim 6 wherein R 1 is ##STR475## R 2 is hydrogen; and R 3 and R 6 are an alkali metal salt.

Claim 20

The compound of claim 1 wherein X is ##STR476##

Claim 21

The compound of claim 1 wherein R 1 is ##STR477## and R 19 and R 20 are independently selected from lower alkyl of 1 to 4 carbons or ##STR478## wherein q is zero or an integer from 1 to 4 and R 11 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.

Claim 22

A compound of claim 18 wherein X is ##STR479## and R 4 is hydrogen.

Claim 23

A composition useful for treating hypertension comprising a pharmaceutically acceptable carrier and a hypotensive compound or pharmaceutically acceptable salt thereof defined in claim 1.

Claim 24

The method of alleviating hypertension in a mammalian specie which comprises administering an effective amount of the composition of claim 20.