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US4616088A Expired / Lapsed US ⏱️ 0.0 years remaining

Amino acid ester and amide renin inhibitor

Assignee: ER Squibb and Sons LLC
•
Filing: 1984-12-14
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Granted: 1986-10-07
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Expires: 2004-12-14
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Abstract

Abstract Compounds of the formula <IMAGE> wherein A is <IMAGE> intervene in the conversion of angiotensinogen to angiotensin II by inhibiting renin and thus are useful as anti-hypertensive agents.

Inventors

  • 👤 Denis E. Ryono
  • 👤 Edward W. Petrillo, Jr.

Bibliographic Details

Application Number —
Jurisdiction US
Data Source google_patents
Last Synchronized 2026-11-08 15:01
CPC Classifications
C; C07; C07D; C07D233/00; C07D233/54; C07D233/64; C07K; C07K5/00; C07K5/02; C07K5/0227; Y; Y10; Y10S; Y10S530/00; Y10S530/86

Claims Analysis

Total Claims: 15
Claim 1
Independent Claim 307 words
A compound of the formula ##STR88## including a pharmaceutically acceptable salt thereof wherein: A is ##STR89## R 4 is --NR-R 5 ; R 5 is hydrogen, lower alkyl, --(CH 2 ) m -aryl or --(CH 2 ) m -heterocyclo; m is zero, one, two, three or four; R 8 is hydrogen, ##STR90## R 10 is hydrogen, ##STR91## R 2 , R 3 , R 7 and R 9 are independently selected from the group consisting of hydrogen, lower alkyl, halo substituted lower alkyl, --(CH 2 ) n --aryl, --(CH 2 ) n --heterocyclo, --(CH 2 ) n --OH, --(CH 2 ) n --NH 2 , --(CH 2 ) n --SH, --(CH 2 ) n --S-lower alkyl, ##STR92## n is an integer from 1 to 4; R 11 is ##STR93## R 1 hydrogen, lower alkyl, --(CH 2 ) n --aryl, --(CH 2 ) n --cycloalkyl, ##STR94## the term lower alkyl refers to straight or branched chain radicals having up to seven carbon atoms; the term cycloalkyl refers to saturated rings of 4 to 7 carbon atoms; the term halogen refers to Cl, Br, and F; the term halo substituted lower alkyl refers to such lower alkyl groups in which one or more hydrogens have been replaced by Cl, Br, or F groups; the term aryl refers to phenyl, 1-naphthyl, 2-naphthyl, mono substituted phenyl, 1-naphthyl, or 2-naphthyl wherein said substituent is lower alkyl of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, halogen, hydroxy, amino, --NH-alkyl wherein alkyl is of 1 to 4 carbons, or --N(alkyl) 2 wherein alkyl is of 1 to 4 carbons, di or tri substituted phenyl, 1-naphthyl or 2-naphthyl wherein said substituents are methyl, methoxy, methylthio, halogen, or hydroxy; and the term heterocyclo refers to 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, and indolyl.
Claim 2
Dependent Claim 307 words
A compound of the formula ##STR88## including a pharmaceutically acceptable salt thereof wherein: A is ##STR89## R 4 is --NR-R 5 ; R 5 is hydrogen, lower alkyl, --(CH 2 ) m -aryl or --(CH 2 ) m -heterocyclo; m is zero, one, two, three or four; R 8 is hydrogen, ##STR90## R 10 is hydrogen, ##STR91## R 2 , R 3 , R 7 and R 9 are independently selected from the group consisting of hydrogen, lower alkyl, halo substituted lower alkyl, --(CH 2 ) n --aryl, --(CH 2 ) n --heterocyclo, --(CH 2 ) n --OH, --(CH 2 ) n --NH 2 , --(CH 2 ) n --SH, --(CH 2 ) n --S-lower alkyl, ##STR92## n is an integer from 1 to 4; R 11 is ##STR93## R 1 hydrogen, lower alkyl, --(CH 2 ) n --aryl, --(CH 2 ) n --cycloalkyl, ##STR94## the term lower alkyl refers to straight or branched chain radicals having up to seven carbon atoms; the term cycloalkyl refers to saturated rings of 4 to 7 carbon atoms; the term halogen refers to Cl, Br, and F; the term halo substituted lower alkyl refers to such lower alkyl groups in which one or more hydrogens have been replaced by Cl, Br, or F groups; the term aryl refers to phenyl, 1-naphthyl, 2-naphthyl, mono substituted phenyl, 1-naphthyl, or 2-naphthyl wherein said substituent is lower alkyl of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, halogen, hydroxy, amino, --NH-alkyl wherein alkyl is of 1 to 4 carbons, or --N(alkyl) 2 wherein alkyl is of 1 to 4 carbons, di or tri substituted phenyl, 1-naphthyl or 2-naphthyl wherein said substituents are methyl, methoxy, methylthio, halogen, or hydroxy; and the term heterocyclo refers to 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, and indolyl.
Claim 3
Dependent Claim 9 words
A compound of claim 1 wherein: A is ##STR95##
Claim 4
Dependent Claim 9 words
A compound of claim 1 wherein: A is ##STR96##
Claim 5
Dependent Claim 114 words
A compound of claim 3 wherein: R 1 is hydrogen, ##STR97## R 2 is straight or branched chain lower alkyl of 1 to 4 carbons, benzyl, phenethyl or ##STR98## R 3 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, benzyl or phenethyl; R 4 is --NH 2 , --NH--(CH 2 ) n --aryl or --NH--(CH 2 ) n -heterocyclo wherein n is one, two or three, aryl is phenyl, and heterocyclo is 2-, 3- or 4-pyridyl; R 7 is ##STR99## R 8 is ##STR100## R 9 is --(CH 2 ) n -aryl wherein aryl is phenyl or 1-naphthyl and n is one or two; and R 10 is ##STR101##
Claim 6
Dependent Claim 51 words
A compound of claim 4 wherein R 1 is hydrogen; R 2 is --CH 2 --CH(CH 3 ) 2 ; R 3 is --CH 2 --CH(CH 3 ) 2 or --CH(CH 3 ) 2 ; R 4 is --NH 2 or ##STR102## R 9 is ##STR103## and R 10 is ##STR104##
Claim 7
Dependent Claim 29 words
A compound of claim 5 wherein: R 3 is --CH 2 CH(CH 3 ) 2 ; R 4 is ##STR105## R 7 is ##STR106## and R 8 is ##STR107##
Claim 8
Dependent Claim 12 words
The compound of claim 6, N 2 -[3-[[N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]-N-[2-(2-pyridinyl)ethyl]-L-leucinamide, acetic acid salt (1:2).
Claim 9
Dependent Claim 31 words
A compound of claim 5 wherein: R 3 is --CH 2 CH(CH 3 ) 2 ; R 4 is --NH 2 ; R 7 is ##STR108## and R 8 is ##STR109##
Claim 10
Dependent Claim 8 words
The compound of claim 8, (2R,3S)-[3-[[N-[(1,1,-dimethylethoxy)carbonyl]-L-phenylalanyl-L-histidyl]amino]-2-hydroxy-5-methylhexyl]-L-leucinamide, diacetate salt.
Claim 11
Dependent Claim 8 words
The compound of claim 8, (2S,3S)-[3-[[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-L-histidyl]amino]-2-hydroxy-5-methylhexyl]-L-leucinamide, diacetate salt.
Claim 12
Dependent Claim 31 words
A compound of claim 5 wherein: R 3 is --CH 2 CH(CH 3 ) 2 ; R 4 is --NH 2 ; R 7 is ##STR110## and R 8 is ##STR111##
Claim 13
Dependent Claim 8 words
The compound of claim 11, N-[(3S)-3-[[N-[(1,1-dimethylethoxy)carbonyl]-3-[(phenylmethoxy)methyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]-L-leucinamide, diacetate salt.
Claim 14
Dependent Claim 31 words
A compound of claim 5 wherein: R 3 is --CH 2 CH(CH 3 ) 2 ; R 4 is --NH 2 ; R 8 is ##STR112## and R 7 is ##STR113##
Claim 15
Dependent Claim 9 words
The compound of claim 13, N-[(3S)-3-[[N-[(1,1-dimethylethoxy)carbonyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]-L-leucinamide, acetate salt (1:1:6).

References Cited (Backward Citations)

US4470973A Cited
EP0104041A1 Cited
US4514391A Cited

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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