Carboxyalkyl amino acid derivatives of various substituted prolines

Claim 2

A compound of the formula and pharmaceutically acceptable salts thereof wherein R 6 is halogen, keto, azido, lower alkyl, , a 1- or 2-naphthyl of the formula -(CH 2 ) m -cycloalkyl, a 1- or 2-naphthyloxy of the formula -S-lower alkyl, ,or a 1- or 2-naphthylthio of the formula R 7 is halogen, keto, , a 1- or 2-naphthyloxy of the formula -S-lower alkyl, or a 1- or 2-naphthylthio of the formula R 8 is keto or R 9 is halogen or -Y-R 13 ; m is zero, one, two or three; R 10 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 11 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, or hydroxy; n is one, two, or three provided that n is more than one only if R 10 or R 11 is hydrogen, methyl, methoxy, chloro, or fluoro; R 12 is hydrogen or lower alkyl of 1 to 4 carbons; Y is oxygen or sulfur; R 13 is lower alkyl of 1 to 4 carbons, , or the R 13 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 and R 5 are independently selected from the group consisting of hydroxy, lower alkoxy, di(lower alkyl)-amino-lower alkoxy, lower alkyl-carbonyl-amino-lower alkoxy, lower alkyl- carbonyloxy-lower alkoxy, amino, lower alkyl-amino, di(lower alkyl)amino, hydroxyamino, benzylamino, or phenethylamino; R 1 is hydrogen, lower alkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, -(CH 2 )q-cycloalkyl, -(CH 2 ) q -carboxy, -(CH 2 ) q -S-lower alkyl, -(CH 2 ) q -guanidinyl, -(CH 2 ) q -NH 2 , -(CH 2 ) q -N (lower alkyl) 2 , -(CH 2 ) q lower alkyl, -(CH 2 ) q -SH, -(CH 2 )q-lower alkoxy, Lower alkoxy, or R 2 is hydrogen or lower alkyl; R 3 is hydrogen, lower alkyl,ha l o substituted lower alkyl, hydroxy substituted lower alkyl, -(CH 2 ) q -NH 2 , -(CH 2 ) q -N(lower alkyl) 2 , -(CH 2 ) q -guanidinyl, -(CH 2 ) q -SH, -(CH 2 ) q -S-lower alkyl, R 14 is lower alkyl, cycloalkyl or and q is an integer from 1 to 4.

Claim 3

A compound of Claim 1 wherein R is hydroxy, lower alkoxy of 1 to 4 carbons, or benzyloxy; R 1 is lower alkyl of 1 to 4 carbons, m is one, two, or three; R is hydrogen; and R 3 is methyl, -(CH 2 ) 4 -NH 2 , hydroxymethyl, benzyl, -CH 2 -SH, -CH 2 F, -(CH 2 ) 2 -S-CH 3 ,

Claim 4

A compound of Claim 2 wherein R 4 is R 6 is chloro, fluoro, cyclohexyl, -S-lower alkyl wherein lower alkyl is straight or branched chain of 1 to 4 carbons, or , -S-lower alkyl wherein lower alkyl is straight or branched chain of 1 to 4 carbons, or R 8 is phenyl, 2-hydroxyphenyl,or 4-hydroxyphenyl; R 9 is chloro, fluoro, or Y-R 13 ; Y is oxygen or sulfur; R 13 is straight or branched chain alkyl of 1 to 4 carbons or the R 13 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; R 10 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy; and m is zero, one or two.

Claim 5

A compound of Claim 3 wherein R 1 is ; R 2 is hydrogen and R is methyl.

Claim 6

A compound of Claim 3 wherein R is ethoxy; R 1 is R 2 is hydrogen; and R 3 is methyl.

Claim 7

A compound of the formula and pharmaceutically acceptable salts thereof wherein: R is hvdroxv or ethoxy; R 6 is chloro, fluoro, cyclohexyl, , a 1- or 2-naphthyloxy of the formula -S-lower alkyl wherein lower alkyl is straight or branched chain of 1 to 4 carbons, formula , a 1- or 2-naphthylthio of the Y is oxygen or sulfur; R13 is straight or branched chain alkyl of 1 to 4 carbons or the R 13 groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the ring carbons has a methyl or dimethyl substituent; R 10 and R 11 are independently selected from the group consisting of hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, and hydroxy; and m is zero, one or two.

Claim 8

A compound of the formula and pharmaceutically acceptable salts thereof wherein: R is hvdroxv or ethoxy; R 6 is chloro, fluoro, cyclohexyl, , a 1- or 2-naphthyloxy of the formula -S-lower alkyl wherein lower alkyl is straight or branched chain of 1 to 4 carbons, formula , a 1- or 2-naphthylthio of the Y is oxygen or sulfur; R13 is straight or branched chain alkyl of 1 to 4 carbons or the R 13 groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the ring carbons has a methyl or dimethyl substituent; R 10 and R 11 are independently selected from the group consisting of hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, and hydroxy; and m is zero, one or two.

Claim 9

A compound of Claim 6 wherein R 4 is

Claim 10

A compound of Claim 7 wherein R 6 is chloro or fluoro.

Claim 11

A compound of Claim 7 wherein R 6 is cyclohexyl.

Claim 12

The compound of Claim 9, (cis)-1-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyll-4-cyclohexyl-L-proline.

Claim 13

A compound of Claim 7 wherein R 6 is ; m is zero, one or two; and R 10 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.

Claim 14

A compound of Claim 11 wherein R6 is

Claim 15

The compound of Claim 12, (cis)-i-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-4-phenyl-L-proline.

Claim 16

The compound of Claim 7 wherein R 6 is ; m is zero, one, or two; and R 10 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.

Claim 17

A compound of Claim 14 wherein R 6 is

Claim 18

The compound of Claim 15, (S,S)-1-[N-(1-carboxy-3-phenylpropyl)-L-alanyl]-4-(4-fluorophenoxy)-L-proline.

Claim 19

A compound of Claim 7 wherein R 6 is 1- or 2-naphthyloxy of the formula wherein m is zero, one, or two and R 11 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.

Claim 20

A compound of Claim 17 wherein R 6 is

Claim 21

The compound of Claim 18,(cis)-l-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-4-(2-naphthalenyloxy)-L-proline.

Claim 22

A compound of Claim 7 wherein R 6 is -S- CH 3 .

Claim 23

The compound of Claim 20, (trans)-l-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-4-(methylthio)-L-proline.

Claim 24

22 . A compound of Claim 7 wherein R 6 is ; m is zero, one, or two; and R 10 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.

Claim 25

A compound of Claim 22 wherein R 6 is

Claim 26

The compound of Claim 23, [1(S),4S]-1-[N-(1-carboxy-3-phenylpropyl)-L-alanyl)-4-(phenylthio)-L-proline.

Claim 27

The compound of Claim 24, [1(S),4R]-1-[N-(1-carboxy-3-phenylpropyl)-L-alanyl)-4-(phenylthio)-L-proline.

Claim 28

A compound of Claim 22 wherein R 6 is

Claim 29

The compound of Claim 26, [1(S),4S]-1-[N-(l-carboxy-3-phenylpropyl)-L-alanyl]-4-[(phenylmethyl)thio]-L-proline.

Claim 30

28 . A compound fo Claim 7 wherein R 6 is

Claim 31

The compound of Claim 28, (cis)-l-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-4-[(phenylmethyl)amino]-L-proline.

Claim 32

30 . A compound of Claim 6 wherein R 4 is

Claim 33

A compound of Claim 30 wherein R 4 is

Claim 34

The compound of Claim 31, (S,S,S)-7-[2-[(1-carboxy-3-phenylpropyl)amino]-1-oxopropyl]-1, 4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid.

Claim 35

The compound of Claim 31, (S,S,S)-7-[2-[(1-ethoxycarbonyl-3-phenylpropyl)amino]-1- oxopropyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid.

Claim 36

A composition useful for treating hypertension comprising a pharmaceutically acceptable carrier and one or more hypotensive agents of the formula and pharmaceutically acceptable salts thereof wherein R 4 is R 6 is halogen, keto, azido, naphthyl of the formula lower alkyl, -(CH 2 ) m -cycloalkyl, , or a 1- or 2-naphthyloxy of the formula -S-lower alkyl, or a 1- or 2-naphthylthio of the formula R 7 is halogen, keto, a 1- or 2-naphthyloxy of the formula -S-lower alkyl, or a 1- or 2-naphthylthio of the formula R 8 is keto or R 9 is halogen or -Y-R 13 ; m is zero, one, two, or three; R 10 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 11 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, or hydroxy; n is one, two , or three provided that n is more than one only if R 10 or R 11 is hydrogen, methyl, methoxy, chloro, or fluoro; R 12 is hydrogen or lower alkyl of 1 to 4 carbons; Y is oxygen or sulfur; R 13 is lower alkyl of 1 to 4 carbons, or the R 13 groups join to complete an unsubstituted b- or b-memDerea 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 and R 5 are independently selected from the group consisting of hydroxy, lower alkoxy, di(lower alkyl)-amino-lower alkoxy, lower alkyl-carbonyl-amino-lower alkoxy, lower alkyl-carbonyloxy- lower alkoxy, amino, lower alkyl-amino, di(lower alkyl)-amino, hydroxyamino, benzylamino, or phenethylamino; R 1 is hydrogen, lower alkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, -(CH 2 ) q -cycloalkyl, -(CH 2 )q-carboxy, -(CH 2 ) q -S-lower alkyl, -(CH 2 ) q -guanidinyl, -(CH 2 ) q -NH 2 -(CH 2 ) q -N(lower alkyl) 2 , -(CH 2 ) q alkyl, -(CH 2 ) q -SH, -(CH 2 ) q -lower alkoxy, alkoxy, or R 2 is hydrogen or lower alkyl; R 3 is hydrogen, lower alkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, -(CH 2 ) q -NH 2 , -(CH 2 ) q -N(lower alkyl) 2 , -(CH 2 ) q -guanidinyl, -(CH 2 ) q -SH, -(CH 2 ) q -S-lower alkyl, lower alkyl, or R 14 is lower alkyl, cycloalkyl, ; and q is an integer from 1 to 4.

Claim 37

A composition useful for treating hypertension comprising a pharmaceutically acceptable carrier and one or more hypotensive agents of the formula and pharmaceutically acceptable salts thereof wherein R 4 is R 6 is halogen, keto, azido, naphthyl of the formula lower alkyl, -(CH 2 ) m -cycloalkyl, , or a 1- or 2-naphthyloxy of the formula -S-lower alkyl, or a 1- or 2-naphthylthio of the formula R 7 is halogen, keto, a 1- or 2-naphthyloxy of the formula -S-lower alkyl, or a 1- or 2-naphthylthio of the formula R 8 is keto or R 9 is halogen or -Y-R 13 ; m is zero, one, two, or three; R 10 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 11 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, or hydroxy; n is one, two , or three provided that n is more than one only if R 10 or R 11 is hydrogen, methyl, methoxy, chloro, or fluoro; R 12 is hydrogen or lower alkyl of 1 to 4 carbons; Y is oxygen or sulfur; R 13 is lower alkyl of 1 to 4 carbons, or the R 13 groups join to complete an unsubstituted b- or b-memDerea 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 and R 5 are independently selected from the group consisting of hydroxy, lower alkoxy, di(lower alkyl)-amino-lower alkoxy, lower alkyl-carbonyl-amino-lower alkoxy, lower alkyl-carbonyloxy- lower alkoxy, amino, lower alkyl-amino, di(lower alkyl)-amino, hydroxyamino, benzylamino, or phenethylamino; R 1 is hydrogen, lower alkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, -(CH 2 ) q -cycloalkyl, -(CH 2 )q-carboxy, -(CH 2 ) q -S-lower alkyl, -(CH 2 ) q -guanidinyl, -(CH 2 ) q -NH 2 -(CH 2 ) q -N(lower alkyl) 2 , -(CH 2 ) q alkyl, -(CH 2 ) q -SH, -(CH 2 ) q -lower alkoxy, alkoxy, or R 2 is hydrogen or lower alkyl; R 3 is hydrogen, lower alkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, -(CH 2 ) q -NH 2 , -(CH 2 ) q -N(lower alkyl) 2 , -(CH 2 ) q -guanidinyl, -(CH 2 ) q -SH, -(CH 2 ) q -S-lower alkyl, lower alkyl, or R 14 is lower alkyl, cycloalkyl, ; and q is an integer from 1 to 4.

Claim 38

The composition of Claim 34 also including a diuretic.