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Phosphonyl hydroxyacyl amino acid derivatives as antihypertensives

Assignee: ER Squibb and Sons LLC
•
Filing: 1985-12-16
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Granted: 1986-10-07
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Expires: 2005-12-16
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Abstract

Abstract Phosphonyl hydroxyacyl amino acids of the formula ##STR1## wherein X is a substituted or unsubstituted imino or amino acid or ester. These compounds possess angiotensin converting enzyme activity and are thus useful as hypotensive agents.

Inventors

  • 👤 Donald S. Karanewsky
  • 👤 Edward W. Petrillo, Jr.

Bibliographic Details

Application Number —
Jurisdiction US
Data Source google_patents
Last Synchronized 2026-11-07 02:09
CPC Classifications
C; C07; C07F; C07F9/00; C07F9/02; C07F9/547; C07F9/6561; C07F9/65615; C07F9/28; C07F9/38; C07F9/3804; C07F9/3882; C07F9/40; C07F9/4003; C07F9/4056; C07F9/4071; C07F9/4075; C07F9/553; C07F9/572; C07F9/5728; C07F9/576; C07F9/59; C07F9/62; C07F9/645; C07F9/6503; C07F9/6506

Claims Analysis

Total Claims: 22
Claim 1
Independent Claim 316 words
A compound of the formula ##STR428## and pharmaceutically acceptable salts thereof wherein: X is ##STR429## R 9 , R' 9 , R 10 and R' 10 are independently selected from hydrogen and lower alkyl or R' 9 , R 10 , R' 10 are hydrogen and R 9 is ##STR430## 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 21 is hydrogen, lower alkyl, cycloalkyl, phenyl or ##STR431## R 22 is hydrogen, lower alkyl, ##STR432## r is an integer from 1 to 4; R 1 is alkyl of 1 to 10 carbons, aminoalkyl, haloalkyl, ##STR433## 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, ##STR434## wherein m, R 11 and p are as defined above; R 2 is hydrogen, lower alkyl, halo substituted lower alkyl, ##STR435## wherein r is as defined hereinbefore; R 3 and R 6 are independently selected from hydrogen, lower alkyl, benzyl, benzhydryl, alkali metal or ##STR436## 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 ##STR437##
Claim 2
Dependent Claim 316 words
A compound of the formula ##STR428## and pharmaceutically acceptable salts thereof wherein: X is ##STR429## R 9 , R' 9 , R 10 and R' 10 are independently selected from hydrogen and lower alkyl or R' 9 , R 10 , R' 10 are hydrogen and R 9 is ##STR430## 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 21 is hydrogen, lower alkyl, cycloalkyl, phenyl or ##STR431## R 22 is hydrogen, lower alkyl, ##STR432## r is an integer from 1 to 4; R 1 is alkyl of 1 to 10 carbons, aminoalkyl, haloalkyl, ##STR433## 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, ##STR434## wherein m, R 11 and p are as defined above; R 2 is hydrogen, lower alkyl, halo substituted lower alkyl, ##STR435## wherein r is as defined hereinbefore; R 3 and R 6 are independently selected from hydrogen, lower alkyl, benzyl, benzhydryl, alkali metal or ##STR436## 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 ##STR437##
Claim 3
Dependent Claim 192 words
A compound of claim 1 wherein: R 9 , R' 9 , R 10 and R' 10 are all hydrogen, or R 9 is phenyl, 2-hydroxyphenyl or 4-hydroxyphenyl and R' 9 , R 10 and R' 10 are hydrogen; m is zero, one or two; R 11 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy; R 2 is hydrogen, lower alkyl or 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, ##STR438## --(CH 2 ) q -cycloalkyl wherein cycloalkyl is of 5 or 6 carbons, ##STR439## 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 ##STR440## 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 ##STR441## R 15 is hydrogen, methyl or isopropyl; and R 16 is lower alkyl of 1 to 4 carbons or phenyl.
Claim 4
Dependent Claim 69 words
A compound of claim 2 wherein X is ##STR442## m is zero, one or two; R 11 is hydrogen, methyl, methoxy, methylthio, bromo, fluoro, or hydroxy; and R 6 is hydrogen, ##STR443## or an alkali metal salt; R 1 is ##STR444## R 21 is cycloalkyl or H, R 22 is H or benzyl; R 2 is hydrogen or lower alkyl; and R 3 is hydrogen, alkali metal or benzyl.
Claim 5
Dependent Claim 51 words
A compound of claim 1 wherein R 1 is phenylalkyl or ##STR445## 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, ##STR446## or an alkali metal CH(CH 3 ) 2 salt.
Claim 6
Dependent Claim 15 words
A compound of claim 2 wherein R 1 is alkyl of 1 to 10 carbons.
Claim 7
Dependent Claim 9 words
A compound of claim 5 wherein X is ##STR447##
Claim 8
Dependent Claim 25 words
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 9
Dependent Claim 26 words
The compound of claim 2 wherein R 1 is ##STR448## R 2 is methyl; R 3 is ethyl; and R 6 is an alkali metal salt.
Claim 10
Dependent Claim 26 words
The compound of claim 2 wherein R 1 is ##STR449## R 2 is methyl; R 3 is ##STR450## and R 6 is an alkali metal salt.
Claim 11
Dependent Claim 25 words
The compound of claim 6 wherein R 1 is ##STR451## R 2 is methyl; and R 3 and R 6 are an alkali metal salt.
Claim 12
Dependent Claim 25 words
The compound of claim 6 wherein R 1 is ##STR452## R 2 is hydrogen; and R 3 and R 6 are an alkali metal salt.
Claim 13
Dependent Claim 25 words
The compound of claim 7 wherein R 1 is ##STR453## R 2 is methyl; and R 3 and R 6 are an alkali metal salt.
Claim 14
Dependent Claim 53 words
The compound of claim 1 wherein R 1 is ##STR454## and R 19 and R 20 are independently selected from lower alkyl of 1 to 4 carbons or ##STR455## 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 15
Dependent Claim 45 words
The compound of claim 2 wherein R 21 is hydrogen, methyl, phenyl, cyclopentyl or cyclohexyl; R 22 is hydrogen, lower alkyl of 1 to 4 carbons, ##STR456## --(CH 2 ) 4 --NH 2 , --CH 2 SH, --(CH 2 ) 2 --S--CH 3 , ##STR457##
Claim 16
Dependent Claim 20 words
A compound of claim 14 wherein X is ##STR458## and R 6 is hydrogen, ##STR459## or an alkali metal salt.
Claim 17
Dependent Claim 13 words
The compound of claim 1 having the name (S)-N-[6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-N-cyclohexylglycine, or its dilithium salt.
Claim 18
Dependent Claim 13 words
The compound of claim 1 having the name N-[(S)-6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-phenylalanine or its dilithium salt.
Claim 19
Dependent Claim 15 words
The compound of claim 1 having the name 3-[(S)-6-amino-2-[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-4-thiazolidine carboxylic acid, or its dilithium salt.
Claim 20
Dependent Claim 44 words
A composition useful for treating hypertension comprising a pharmaceutically acceptable carrier and an effective amount of a hypotensive agent or pharmaceutically acceptable salt thereof of the formula ##STR460## wherein X, R 1 , R 2 and R 3 are as defined in claim 1.
Claim 21
Dependent Claim 9 words
The composition of claim 20 also including a diuretic.
Claim 22
Dependent Claim 21 words
The method of alleviating hypertension in a mammalian specie which comprises administering an effective amount of the composition of claim 20.

USPTO Annuity & Maintenance Windows

Annuity Stage Window Opens Payment Deadline Surcharge Period Until Estimated Fee Status
3.5 Years (Year 4) 1989-10-06 1990-04-07 1990-10-07 $2000.00 Window Closed / Lapsed
7.5 Years (Year 8) 1993-10-06 1994-04-07 1994-10-07 $3760.00 Window Closed / Lapsed
11.5 Years (Year 12) 1997-10-06 1998-04-07 1998-10-07 $7700.00 Window Closed / Lapsed

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