US 4,880,781 AGranted

Renin inhibitory peptides containing an N-alkyl-histidine moiety

AssigneeThe Upjohn Company

InventorsJackson B. Hester, Jr., Suvit Thaisrivongs, Tomi K. Sawyer, Ruth E. TenBrink, Hossain H. Saneii, Heinrich J. Schostarez, Donald T. Pals

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Abstract

The present invention provides novel renin-inhibiting peptides and novel processes and intermediates for the preparation of both novel and known renin-inhibiting peptide analogs. Such inhibitors are useful for the diagnosis and control of renin-dependent hypertension.

Claims29

Dependent claims

A renin inhibitory peptide of the formula X-A.sub.6 -B.sub.7 -C.sub.8 -D.sub.9 -E.sub.10 -F.sub.11 -G.sub.12 -H.sub.13 -I.sub.14 -Z, wherein X is

(a) hydrogen,
(b) C.sub.1 -C.sub.5 alkyl
(c) R.sub.5 --O--CH.sub.2 --C(O)--,
(d) R.sub.5 --CH.sub.2 --O--C(O)--,
(e) R.sub.5 --O--C(O)--,
(f) R.sub.5 --(CH.sub.2).sub.n --C(O)--,
(g) R.sub.4 N(R.sub.4)--(CH.sub.2).sub.n --C(O),
(h) R.sub.5 --SO.sub.2 --(CH.sub.2).sub.q --C(O)--, or
(i) R.sub.5 --SO.sub.2 --(CH.sub.2).sub.q --O--C(O)--;
wherein A.sub.6 is absent or a divalent moiety of the formula XL.sub.1, XL.sub.2, or XL.sub.2a ##STR5## wherein B.sub.7 is absent or a divalent moiety of the formula XL.sub.b ##STR6## wherein C.sub.8 is absent or a divalent moiety of the formula XL.sub.1, XL.sub.2 or XL.sub.2a, ##STR7## wherein D.sub.9 is a divalent moiety of the formula XL.sub.3, ##STR8## wherein E.sub.10 -F.sub.11 is a divalent moiety of the formula XL.sub.6, XL.sub.6a, XL.sub.6b, XL.sub.6c, XL.sub.6d, or XL.sub.6e, ##STR9## wherein * indicates an asymmetric center which is either in the R or S configuration;
wherein G.sub.12 is absent or a divalent moiety of the formula XL.sub.4 or XL.sub.4a ##STR10## wherein H.sub.13 is absent or a divalent moiety of the formula XL.sub.4 ##STR11## wherein I.sub.14 is absent or a divalent moiety of the formula XL.sub.5 ##STR12## wherein Z is (a) --O--R.sub.10,
(b) --N(R.sub.4)R.sub.14, or
(c) C.sub.4 -C.sub.8 cyclic amino;
wherein R is
(a) isopropyl,
(b) isobutyl,
(c) phenylmethyl, or
(d) C.sub.3 -C.sub.7 cycloalkyl;
wherein R.sub.1 is
(a) hydrogen,
(b) C.sub.1 -C.sub.5 alkyl,
(c) aryl,
(d) C.sub.3 -C.sub.7 cycloalkyl,
(e) --Het,
(f) C.sub.1 -C.sub.3 alkoxy, or
(g) C.sub.1 -C.sub.3 alkylthio;
wherein R.sub.2 is
(a) hydrogen, or
(b) --CH(R.sub.3)R.sub.4 ;
wherein R.sub.3 is
(a) hydrogen,
(b) hydroxy,
(c) C.sub.1 -C.sub.5 alkyl,
(d) C.sub.3 -C.sub.7 cycloalkyl,
(e) aryl,
(f) --Het,
(g) C.sub.1 -C.sub.3 alkoxy, or
(h) C.sub.1 -C.sub.3 alkylthio;
wherein R.sub.4 at each occurrence is the same or different and is
(a) hydrogen, or
(b) C.sub.1 -C.sub.5 alkyl;
wherein R.sub.4 in D.sub.9 is C.sub.1 -C.sub.5 alkyl;
wherein R.sub.5 is
(a) C.sub.1 -C.sub.6 alkyl,
(b) C.sub.3 -C.sub.7 cycloalkyl,
(c) aryl,
(d) --Het, or
(e) 5-oxo-2-pyrrolidinyl;
wherein R.sub.6 is
(a) hydrogen,
(b) C.sub.1 -C.sub.5 alkyl,
(c) --(CH.sub.2).sub.p --aryl,
(d) --(CH.sub.2).sub.p --Het,
(e) C.sub.3 -C.sub.7 cycloalkyl, or
(f) 1- or 2-adamantyl;
wherein R.sub.7 is
(a) hydrogen,
(b) C.sub.1 -C.sub.5 alkyl,
(c) hydroxy,
(d) amino C.sub.1 -C.sub.4 alkyl--,
(e) guanidinyl C.sub.1 -C.sub.3 alkyl-,
(f) aryl,
(g) --Het,
(h) methylthio,
(i) C.sub.3 -C.sub.7 cycloalkyl, or
(j) amino;
wherein R.sub.7 in D.sub.9 is 1H-imidazol-4-yl;
wherein R.sub.8 is
(a) hydrogen,
(b) C.sub.1 -C.sub.5 alkyl,
(c) hydroxy,
(d) aryl,
(e) --Het,
(f) guanidinyl C.sub.1 -C.sub.3 alkyl-, or
(g) C.sub.3 -C.sub.7 cycloalkyl;
wherein R.sub.9 is
(a) hydrogen,
(b) hydroxy,
(c) amino C.sub.1 -C.sub.4 alkyl-, or
(d) guanidinyl C.sub.1 -C.sub.3 alkyl-;
wherein R.sub.10 is
(a) hydrogen,
(b) C.sub.1 -C.sub.5 alkyl,
(c) --(CH.sub.2).sub.n R.sub.16,
(d) --(CH.sub.2).sub.n R.sub.17,
(e) C.sub.3 -C.sub.7 cycloalkyl,
(f) a pharmaceutically acceptable cation,
(g) --(CHR.sub.25)--CH.sub.2 --R.sub.15, or
(h) --CH.sub.2 --(CHR.sub.12)--R.sub.15 ;
wherein R.sub.11 is --R or --R.sub.2 ;
wherein R.sub.12 is --(CH.sub.2).sub.n --R.sub.13 ;
wherein R.sub.13 is
(a) aryl,
(b) amino,
(c) mono-, di or tri-C.sub.1 -C.sub.3 alkylamino,
(d) --Het,
(e) C.sub.1 -C.sub.5 alkyl
(f) C.sub.3 -C.sub.7 cycloalkyl,
(g) C.sub.1 -C.sub.5 alkenyl,
(h) C.sub.3 -C.sub.7 cycloalkenyl,
(i) hydroxy,
(j) C.sub.1 -C.sub.3 alkoxy,
(k) C.sub.1 -C.sub.3 alkanoyloxy,
(l) mercapto,
(m) C.sub.1 -C.sub.3 alkylthio,
(n) --COOH,
(o) --CO--O--C.sub.1 -C.sub.6 alkyl,
(p) --CO--O--CH.sub.2 --(C.sub.1 -C.sub.3 alkyl)---N(C.sub.1 -C.sub.3 alkyl).sub.2,
(q) --CO--NR.sub.22 R.sub.26 ;
(r) C.sub.4 -C.sub.7 cyclic amino,
(s) C.sub.4 -C.sub.7 cycloalkylamino,
(t) guanidyl,
(u) cyano,
(v) N-cyanoguanidyl,
(w) cyanoamino,
(x) (hydroxy C.sub.2 -C.sub.4 alkyl)amino, or
(y) di-(hydroxyC.sub.2 -C.sub.4 alkyl)amino;
wherein R.sub.14 is
(a) hydrogen,
(b) C.sub.1 -C.sub.10 alkyl,
(c) --(CH.sub.2).sub.n --R.sub.18,
(d) --(CH.sub.2).sub.n --R.sub.19,
(e) --(CHR.sub.25)--CH.sub.2 --R.sub.15,
(f) --CH.sub.2 --(CHR.sub.12)--R.sub.15,
(g) (hydroxy C.sub.1 -C.sub.8 alkyl), or
(h) (C.sub.1 -C.sub.3 alkoxy)C.sub.1 -C.sub.8 alkyl;
wherein R.sub.15 is
(a) hydroxy,
(b) C.sub.3 -C.sub.7 cycloalkyl,
(c) aryl,
(d) amino,
(e) mono-, di-, or tri- C.sub.1 -C.sub.3 alkylamino,
(f) mono- or di-[hydroxy C.sub.2 -C.sub.4 alkyl]amino,
(g) --Het,
(h) C.sub.1 -C.sub.3 alkoxy-,
(i) C.sub.1 -C.sub.3 alkanoyloxy-,
(j) mercapto,
(k) C.sub.1 -C.sub.3 alkylthio-,
(l) C.sub.1 -C.sub.5 alkyl,
(m) C.sub.4 -C.sub.7 cyclic amino,
(n) C.sub.4 -C.sub.7 cycloalkylamino,
(o) C.sub.1 -C.sub.5 alkenyloxy,
(p) C.sub.3 -C.sub.7 cycloalkenyl;
wherein R.sub.16 is
(a) aryl,
(b) amino,
(c) mono- or di- C.sub.1 -C.sub.3 alkylamino,
(d) hydroxy,
(e) C.sub.3 -C.sub.7 cycloalkyl,
(f) C.sub.4 -C.sub.7 cyclic amino, or
(g) C.sub.1 -C.sub.3 alkanoyloxy;
wherein R.sub.17 is
(a) --Het,
(b) C.sub.1 -C.sub.5 alkenyl,
(c) C.sub.3 -C.sub.7 cycloalkenyl,
(d) C.sub.1 -C.sub.3 alkoxy,
(e) mercapto,
(f) C.sub.1 -C.sub.3 alkylthio,
(g) --COOH,
(h) --CO--O--C.sub.1 -C.sub.6 alkyl,
(i) --CO--O--CH.sub.2 --(C.sub.1 -C.sub.3 alkyl)--N(C.sub.1 -C.sub.3 alkyl).sub.2,
(j) --CO--NR.sub.22 R.sub.26,
(k) tri-C.sub.1 -C.sub.3 alkylamino,
(l) guanidyl,
(m) cyano,
(n) N-cyanoguanidyl,
(o) (hydroxy C.sub.2 -C.sub.4 alkyl)amino,
(p) di-(hydroxy C.sub.2 -C.sub.4 alkyl)amino, or
(q) cyanoamino;
wherein R.sub.18 is
(a) amino,
(b) mono-, or di- C.sub.1 -C.sub.3 alkylamino,
(c) C.sub.4 -C.sub.7 cyclic amino, or
(d) C.sub.4 -C.sub.7 cycloalkylamino;
wherein R.sub.19 is
(a) aryl,
(b) --Het,
(c) tri-C.sub.1 -C.sub.3 alkylamino,
(d) C.sub.3 -C.sub.7 cycloalkyl,
(e) C.sub.1 -C.sub.5 alkenyl,
(f) C.sub.3 -C.sub.7 cycloalkenyl,
(g) hydroxy,
(h) C.sub.1 -C.sub.3 alkoxy,
(i) C.sub.1 -C.sub.3 alkanoyloxy,
(j) mercapto,
(k) C.sub.1 -C.sub.3 alkylthio,
(l) --COOH,
(m) --CO--O--C.sub.1 -C.sub.6 alkyl,
(n) --CO--O--CH.sub.2 --(C.sub.1 -C.sub.3 alkyl)--N(C.sub.1 -C.sub.3 alkyl).sub.2,
(o) --CO--NR.sub.22 R.sub.26,
(p) guanidyl,
(q) cyano,
(r) N-cyanoguanidyl,
(s) cyanoamino,
(t) (hydroxy C.sub.2 -C.sub.4 alkyl)amino, (u) di-(hydroxy C.sub.2 -C.sub.4 alkyl)amino;
or
(v) --SO.sub.3 H;
wherein R.sub.20 is
(a) hydrogen,
(b) C.sub.1 -C.sub.5 alkyl, or
(c) aryl-C.sub.1 -C.sub.5 alkyl;
wherein R.sub.21 is
(a) --NH.sub.2, or
(b) --OH;
wherein R.sub.22 is
(a) hydrogen, or
(b) C.sub.1 -C.sub.3 alkyl;
wherein R.sub.23 is
(a) --(CH.sub.2).sub.n --OH,
(b) --(CH.sub.2).sub.n --NH.sub.2,
(c) aryl, or
(d) C.sub.1 -C.sub.3 alkyl;
wherein R.sub.24 is
(a) --R.sub.1,
(b) --(CH.sub.2).sub.n --OH, or
(c) --(CH.sub.2).sub.n --NH.sub.2 ;
wherein R.sub.25 is --(CH.sub.2).sub.n --R.sub.13 ;
wherein R.sub.26 is
(a) hydrogen,
(b) C.sub.1 -C.sub.3 alkyl, or
(c) phenyl-C.sub.1 -C.sub.3 alkyl;
wherein m is one or two;
wherein for each occurrence n is independently an integer of zero to five, inclusive;
wherein p is zero to 2 inclusive;
wherein q is 1 to 5, inclusive;
wherein Q is
(a) --CH.sub.2 --,
(b) --CH(OH)--,
(c) --O--, or
(d) --S--;
and
wherein M is
(a) --CO--, or
(b) --CH.sub.2 --;
wherein aryl is phenyl or naphthyl substituted by zero to 3 of the following:
(a) C.sub.1 -C.sub.3 alkyl,
(b) hydroxy,
(c) C.sub.1 -C.sub.3 alkoxy,
(d) halo,
(e) amino,
(f) mono- or di-C.sub.1 -C.sub.3 alkylamino,
(g) --CHO,
(h) --COOH,
(i) COOR.sub.26,
(j) COHR.sub.26,
(k) nitro,
(l) mercapto,
(m) C.sub.1 -C.sub.3 alkylthio,
(n) C.sub.1 -C.sub.3 alkylsulfinyl,
(o) C.sub.1 -C.sub.3 alkylsulfonyl,
(p) C.sub.1 -C.sub.3 alkylsulfonyl--N(R.sub.4)--
(q) SO.sub.3 H,
(r) SO.sub.2 NH.sub.2,
(s) --CN, or
(t) --CN.sub.2 NH.sub.2 ;
wherein --Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;
and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring, which heterocyclic moiety is substituted with zero to 3 of the following:
(i) C.sub.1 -C.sub.6 alkyl,
(ii) hydroxy,
(iii) trifluoromethyl,
(iv) C.sub.1 -C.sub.4 alkoxy,
(v) halo,
(vi) aryl,
(vii) aryl C.sub.1 -C.sub.4 alkyl-,
(viii) amino, and
(ix) mono- or di-C.sub.1 -C.sub.4 alkylamino;
with the overall provisos that
(1) E.sub.10 -F.sub.11 is XL.sub.6a, XL.sub.6b, XL.sub.6c, XL.sub.6d, or XL.sub.6e only when at least one of the following occurs:
(i) A.sub.6 is present and
(A) A.sub.6 is XL.sub.1 or
(B) A.sub.6 is XL.sub.2 wherein R.sub.6 is Het which is N.sup.in -formyl-Trp,
(ii) B.sub.7 is present and R.sub.4 of B.sub.7 is other than hydrogen,
(iii) C.sub.8 is present and is XL.sub.1,
(iv) D.sub.9 is N.sub..alpha. -methyl-histidine,
(v) B.sub.7 and C.sub.8 both are present and B.sub.7 is XL.sub.b wherein M is --CH.sub.2 -- and C.sub.8 is XL.sub.1 ;
or
(vi) X is R.sub.5 --SO.sub.2 --(CH.sub.2).sub.q --C(O)-- or R.sub.5 --SO.sub.2 --C(CH.sub.2).sub.q --OC(O)--;
(2) E.sub.10 F.sub.11 is XL.sub.6e only when G.sub.12, H.sub.13 and I.sub.14 are absent;
(3) B.sub.7 C.sub.8 D.sub.9 is Pro-Phe-His, E.sub.10 F.sub.11 is XL.sub.6, R.sub.1 is isopropyl, or isobutyl;
and R.sub.11 is isopropyl, isobutyl, or benzyl, only when one of the following occurs:
(a) only 1 of G.sub.12,H.sub.13, and I.sub.14 is present;
(b) G.sub.12 is other than D or L val or D or L Ile;
(c) H.sub.13 is other than D or L Tyr, D or L Phe, or D or L His;
or
(d) A.sub.6 is FTrp or XL.sub.1 ;
(4) R.sub.16 or R.sub.17 is an amino-containing substituent, hydroxy, mercapto, or --Het bonded through the hetero atom only when n for that substituent is an integer from two to five, inclusive;
(5) R.sub.18 or R.sub.19 is hydroxy, mercapto, or amino, or a monosubstituted nitrogen containing group bonded through the nitrogen only when n is not one;
(6) A.sub.6, B.sub.7, C.sub.8, H.sub.13 and I.sub.14 are all absent, D.sub.9 and G.sub.12 are both present, and --NR.sub.4 --of D.sub.9 is --NH-- and Z is --OR.sub.10 and R.sub.10 is hydrogen, C.sub.1 -C.sub.5 alkyl, or --(CH.sub.2).sub.m --R.sub.16 or Z is --N(R.sub.4)R.sub.14 and R.sub.14 is hydrogen, C.sub.1 -C.sub.10 alkyl or --(CH.sub.2).sub.n --R.sub.18, or Z is C.sub.4 -C.sub.8 cyclic amino, only when R.sub.5 --(CH.sub.2).sub.n -- is other than C.sub.1 -C.sub.8 alkyl, C.sub.5 -C.sub.7 cycloalkyl or aryl;
(7) A.sub.6, B.sub.7, C.sub.8, D.sub.9, H.sub.13, I.sub.14 are all absent and G.sub.12 is present only when Z is --OR.sub.10 and R.sub.10 is --(CH.sub.2).sub.n --R.sub.17, --(CHR.sub.25)--CH.sub.2 R.sub.15 or --CH.sub.2 -- (CHR.sub.12)--R.sub.15 or when Z is --N(R.sub.4)R.sub.14 and R.sub.14 is --(CH.sub.2).sub.n --R.sub.19, --(CHR.sub.25)-- CH.sub.2 R.sub.15, or --CH.sub.2 --(CHR.sub.12)--R.sub.15 ;
(8) R.sub.12 is --(CH.sub.2).sub.n --R.sub.13 and n is zero and both R.sub.13 and R.sub.15 are oxygen-, nitrogen-, or sulfur-containing substituents bonded through the hetero atom, only when the hetero atom is not also bonded to hydrogen;
(9) when R.sub.12 is --(CH.sub.2).sub.n --R.sub.13 and n is zero, then R.sub.13 and R.sub.15 cannot both be --COOH;
(10) R.sub.25 is --(CH.sub.2).sub.n --R.sub.13 and n is zero only when R.sub.13 is other than a primary or secondary nitrogen-containing group hydroxy or mercapto group or when R.sub.4 of --N(R.sub.4)R.sub.14 is other than hydrogen;
(11) Z is C.sub.4 -C.sub.8 cyclic amino, only when at least one of G.sub.12, H.sub.13, and I.sub.14 is present;
(12) R.sub.17 or R.sub.19 is --Het, only when --Het is other than cyclic amino;
(13) R.sub.17 or R.sub.19 is --COOH only when n for that moiety is other than zero;
and
(14) at least one of A.sub.6, B.sub.7, C.sub.8, D.sub.9, G.sub.12, H.sub.13 or I.sub.14 must be present;
or a carboxy-, amino-, or other reactive group-protected form
or a pharmaceutically acceptable acid addition salt thereof.

296 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/147,073Filed 20 Jan 1988 · continuation in part
Priority: 6 Aug 1984
Granted: 14 Nov 1989
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07K 5/0227
Containing at least one abnormal peptide link: containing the peptide sequence -Phe-His-NH-2-C-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6…
C12Q 1/37
Involving hydrolase: involving peptidase or proteinase
G01N 33/573
Immunoassay; Biospecific binding assay; Materials therefor: for enzymes or isoenzymes
G01N 33/6893
Involving proteins, peptides or amino acids: related to diseases not provided for elsewhere

Family

Serial638,027Parent of this continuation-in-part · filed 6 Aug 1984
Serial638,041Parent of this continuation-in-part · filed 6 Aug 1984
Serial638,025Parent of this continuation-in-part · filed 6 Aug 1984
Serial38,023Parent of this continuation-in-part · filed 6 Aug 1984
Serial638,024Parent of this continuation-in-part · filed 6 Aug 1984
Serial638,026Parent of this continuation-in-part · filed 6 Aug 1984
Serial663,028Parent of this continuation-in-part · filed 19 Oct 1984
Serial663,024Parent of this continuation-in-part · filed 19 Oct 1984
Serial663,027Parent of this continuation-in-part · filed 19 Oct 1984
Serial663,023Parent of this continuation-in-part · filed 19 Oct 1984
Serial663,026Parent of this continuation-in-part · filed 19 Oct 1984
Serial663,093Parent of this continuation-in-part · filed 19 Oct 1984
Serial693,320Parent of this continuation-in-part · filed 22 Jan 1985
Serial753,198Parent of this continuation-in-part · filed 9 Jul 1985
US 4,880,781 AThis patent

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Abstract

A renin inhibitory peptide of the formula X-A.sub.6 -B.sub.7 -C.sub.8 -D.sub.9 -E.sub.10 -F.sub.11 -G.sub.12 -H.sub.13 -I.sub.14 -Z, wherein X is

(a) hydrogen,
(b) C.sub.1 -C.sub.5 alkyl
(c) R.sub.5 --O--CH.sub.2 --C(O)--,
(d) R.sub.5 --CH.sub.2 --O--C(O)--,
(e) R.sub.5 --O--C(O)--,
(f) R.sub.5 --(CH.sub.2).sub.n --C(O)--,
(g) R.sub.4 N(R.sub.4)--(CH.sub.2).sub.n --C(O),
(h) R.sub.5 --SO.sub.2 --(CH.sub.2).sub.q --C(O)--, or
(i) R.sub.5 --SO.sub.2 --(CH.sub.2).sub.q --O--C(O)--;
wherein A.sub.6 is absent or a divalent moiety of the formula XL.sub.1, XL.sub.2, or XL.sub.2a ##STR5## wherein B.sub.7 is absent or a divalent moiety of the formula XL.sub.b ##STR6## wherein C.sub.8 is absent or a divalent moiety of the formula XL.sub.1, XL.sub.2 or XL.sub.2a, ##STR7## wherein D.sub.9 is a divalent moiety of the formula XL.sub.3, ##STR8## wherein E.sub.10 -F.sub.11 is a divalent moiety of the formula XL.sub.6, XL.sub.6a, XL.sub.6b, XL.sub.6c, XL.sub.6d, or XL.sub.6e, ##STR9## wherein * indicates an asymmetric center which is either in the R or S configuration;
wherein G.sub.12 is absent or a divalent moiety of the formula XL.sub.4 or XL.sub.4a ##STR10## wherein H.sub.13 is absent or a divalent moiety of the formula XL.sub.4 ##STR11## wherein I.sub.14 is absent or a divalent moiety of the formula XL.sub.5 ##STR12## wherein Z is (a) --O--R.sub.10,
(b) --N(R.sub.4)R.sub.14, or
(c) C.sub.4 -C.sub.8 cyclic amino;
wherein R is
(a) isopropyl,
(b) isobutyl,
(c) phenylmethyl, or
(d) C.sub.3 -C.sub.7 cycloalkyl;
wherein R.sub.1 is
(a) hydrogen,
(b) C.sub.1 -C.sub.5 alkyl,
(c) aryl,
(d) C.sub.3 -C.sub.7 cycloalkyl,
(e) --Het,
(f) C.sub.1 -C.sub.3 alkoxy, or
(g) C.sub.1 -C.sub.3 alkylthio;
wherein R.sub.2 is
(a) hydrogen, or
(b) --CH(R.sub.3)R.sub.4 ;
wherein R.sub.3 is
(a) hydrogen,
(b) hydroxy,
(c) C.sub.1 -C.sub.5 alkyl,
(d) C.sub.3 -C.sub.7 cycloalkyl,
(e) aryl,
(f) --Het,
(g) C.sub.1 -C.sub.3 alkoxy, or
(h) C.sub.1 -C.sub.3 alkylthio;
wherein R.sub.4 at each occurrence is the same or different and is
(a) hydrogen, or
(b) C.sub.1 -C.sub.5 alkyl;
wherein R.sub.4 in D.sub.9 is C.sub.1 -C.sub.5 alkyl;
wherein R.sub.5 is
(a) C.sub.1 -C.sub.6 alkyl,
(b) C.sub.3 -C.sub.7 cycloalkyl,
(c) aryl,
(d) --Het, or
(e) 5-oxo-2-pyrrolidinyl;
wherein R.sub.6 is
(a) hydrogen,
(b) C.sub.1 -C.sub.5 alkyl,
(c) --(CH.sub.2).sub.p --aryl,
(d) --(CH.sub.2).sub.p --Het,
(e) C.sub.3 -C.sub.7 cycloalkyl, or
(f) 1- or 2-adamantyl;
wherein R.sub.7 is
(a) hydrogen,
(b) C.sub.1 -C.sub.5 alkyl,
(c) hydroxy,
(d) amino C.sub.1 -C.sub.4 alkyl--,
(e) guanidinyl C.sub.1 -C.sub.3 alkyl-,
(f) aryl,
(g) --Het,
(h) methylthio,
(i) C.sub.3 -C.sub.7 cycloalkyl, or
(j) amino;
wherein R.sub.7 in D.sub.9 is 1H-imidazol-4-yl;
wherein R.sub.8 is
(a) hydrogen,
(b) C.sub.1 -C.sub.5 alkyl,
(c) hydroxy,
(d) aryl,
(e) --Het,
(f) guanidinyl C.sub.1 -C.sub.3 alkyl-, or
(g) C.sub.3 -C.sub.7 cycloalkyl;
wherein R.sub.9 is
(a) hydrogen,
(b) hydroxy,
(c) amino C.sub.1 -C.sub.4 alkyl-, or
(d) guanidinyl C.sub.1 -C.sub.3 alkyl-;
wherein R.sub.10 is
(a) hydrogen,
(b) C.sub.1 -C.sub.5 alkyl,
(c) --(CH.sub.2).sub.n R.sub.16,
(d) --(CH.sub.2).sub.n R.sub.17,
(e) C.sub.3 -C.sub.7 cycloalkyl,
(f) a pharmaceutically acceptable cation,
(g) --(CHR.sub.25)--CH.sub.2 --R.sub.15, or
(h) --CH.sub.2 --(CHR.sub.12)--R.sub.15 ;
wherein R.sub.11 is --R or --R.sub.2 ;
wherein R.sub.12 is --(CH.sub.2).sub.n --R.sub.13 ;
wherein R.sub.13 is
(a) aryl,
(b) amino,
(c) mono-, di or tri-C.sub.1 -C.sub.3 alkylamino,
(d) --Het,
(e) C.sub.1 -C.sub.5 alkyl
(f) C.sub.3 -C.sub.7 cycloalkyl,
(g) C.sub.1 -C.sub.5 alkenyl,
(h) C.sub.3 -C.sub.7 cycloalkenyl,
(i) hydroxy,
(j) C.sub.1 -C.sub.3 alkoxy,
(k) C.sub.1 -C.sub.3 alkanoyloxy,
(l) mercapto,
(m) C.sub.1 -C.sub.3 alkylthio,
(n) --COOH,
(o) --CO--O--C.sub.1 -C.sub.6 alkyl,
(p) --CO--O--CH.sub.2 --(C.sub.1 -C.sub.3 alkyl)---N(C.sub.1 -C.sub.3 alkyl).sub.2,
(q) --CO--NR.sub.22 R.sub.26 ;
(r) C.sub.4 -C.sub.7 cyclic amino,
(s) C.sub.4 -C.sub.7 cycloalkylamino,
(t) guanidyl,
(u) cyano,
(v) N-cyanoguanidyl,
(w) cyanoamino,
(x) (hydroxy C.sub.2 -C.sub.4 alkyl)amino, or
(y) di-(hydroxyC.sub.2 -C.sub.4 alkyl)amino;
wherein R.sub.14 is
(a) hydrogen,
(b) C.sub.1 -C.sub.10 alkyl,
(c) --(CH.sub.2).sub.n --R.sub.18,
(d) --(CH.sub.2).sub.n --R.sub.19,
(e) --(CHR.sub.25)--CH.sub.2 --R.sub.15,
(f) --CH.sub.2 --(CHR.sub.12)--R.sub.15,
(g) (hydroxy C.sub.1 -C.sub.8 alkyl), or
(h) (C.sub.1 -C.sub.3 alkoxy)C.sub.1 -C.sub.8 alkyl;
wherein R.sub.15 is
(a) hydroxy,
(b) C.sub.3 -C.sub.7 cycloalkyl,
(c) aryl,
(d) amino,
(e) mono-, di-, or tri- C.sub.1 -C.sub.3 alkylamino,
(f) mono- or di-[hydroxy C.sub.2 -C.sub.4 alkyl]amino,
(g) --Het,
(h) C.sub.1 -C.sub.3 alkoxy-,
(i) C.sub.1 -C.sub.3 alkanoyloxy-,
(j) mercapto,
(k) C.sub.1 -C.sub.3 alkylthio-,
(l) C.sub.1 -C.sub.5 alkyl,
(m) C.sub.4 -C.sub.7 cyclic amino,
(n) C.sub.4 -C.sub.7 cycloalkylamino,
(o) C.sub.1 -C.sub.5 alkenyloxy,
(p) C.sub.3 -C.sub.7 cycloalkenyl;
wherein R.sub.16 is
(a) aryl,
(b) amino,
(c) mono- or di- C.sub.1 -C.sub.3 alkylamino,
(d) hydroxy,
(e) C.sub.3 -C.sub.7 cycloalkyl,
(f) C.sub.4 -C.sub.7 cyclic amino, or
(g) C.sub.1 -C.sub.3 alkanoyloxy;
wherein R.sub.17 is
(a) --Het,
(b) C.sub.1 -C.sub.5 alkenyl,
(c) C.sub.3 -C.sub.7 cycloalkenyl,
(d) C.sub.1 -C.sub.3 alkoxy,
(e) mercapto,
(f) C.sub.1 -C.sub.3 alkylthio,
(g) --COOH,
(h) --CO--O--C.sub.1 -C.sub.6 alkyl,
(i) --CO--O--CH.sub.2 --(C.sub.1 -C.sub.3 alkyl)--N(C.sub.1 -C.sub.3 alkyl).sub.2,
(j) --CO--NR.sub.22 R.sub.26,
(k) tri-C.sub.1 -C.sub.3 alkylamino,
(l) guanidyl,
(m) cyano,
(n) N-cyanoguanidyl,
(o) (hydroxy C.sub.2 -C.sub.4 alkyl)amino,
(p) di-(hydroxy C.sub.2 -C.sub.4 alkyl)amino, or
(q) cyanoamino;
wherein R.sub.18 is
(a) amino,
(b) mono-, or di- C.sub.1 -C.sub.3 alkylamino,
(c) C.sub.4 -C.sub.7 cyclic amino, or
(d) C.sub.4 -C.sub.7 cycloalkylamino;
wherein R.sub.19 is
(a) aryl,
(b) --Het,
(c) tri-C.sub.1 -C.sub.3 alkylamino,
(d) C.sub.3 -C.sub.7 cycloalkyl,
(e) C.sub.1 -C.sub.5 alkenyl,
(f) C.sub.3 -C.sub.7 cycloalkenyl,
(g) hydroxy,
(h) C.sub.1 -C.sub.3 alkoxy,
(i) C.sub.1 -C.sub.3 alkanoyloxy,
(j) mercapto,
(k) C.sub.1 -C.sub.3 alkylthio,
(l) --COOH,
(m) --CO--O--C.sub.1 -C.sub.6 alkyl,
(n) --CO--O--CH.sub.2 --(C.sub.1 -C.sub.3 alkyl)--N(C.sub.1 -C.sub.3 alkyl).sub.2,
(o) --CO--NR.sub.22 R.sub.26,
(p) guanidyl,
(q) cyano,
(r) N-cyanoguanidyl,
(s) cyanoamino,
(t) (hydroxy C.sub.2 -C.sub.4 alkyl)amino, (u) di-(hydroxy C.sub.2 -C.sub.4 alkyl)amino;
or
(v) --SO.sub.3 H;
wherein R.sub.20 is
(a) hydrogen,
(b) C.sub.1 -C.sub.5 alkyl, or
(c) aryl-C.sub.1 -C.sub.5 alkyl;
wherein R.sub.21 is
(a) --NH.sub.2, or
(b) --OH;
wherein R.sub.22 is
(a) hydrogen, or
(b) C.sub.1 -C.sub.3 alkyl;
wherein R.sub.23 is
(a) --(CH.sub.2).sub.n --OH,
(b) --(CH.sub.2).sub.n --NH.sub.2,
(c) aryl, or
(d) C.sub.1 -C.sub.3 alkyl;
wherein R.sub.24 is
(a) --R.sub.1,
(b) --(CH.sub.2).sub.n --OH, or
(c) --(CH.sub.2).sub.n --NH.sub.2 ;
wherein R.sub.25 is --(CH.sub.2).sub.n --R.sub.13 ;
wherein R.sub.26 is
(a) hydrogen,
(b) C.sub.1 -C.sub.3 alkyl, or
(c) phenyl-C.sub.1 -C.sub.3 alkyl;
wherein m is one or two;
wherein for each occurrence n is independently an integer of zero to five, inclusive;
wherein p is zero to 2 inclusive;
wherein q is 1 to 5, inclusive;
wherein Q is
(a) --CH.sub.2 --,
(b) --CH(OH)--,
(c) --O--, or
(d) --S--;
and
wherein M is
(a) --CO--, or
(b) --CH.sub.2 --;
wherein aryl is phenyl or naphthyl substituted by zero to 3 of the following:
(a) C.sub.1 -C.sub.3 alkyl,
(b) hydroxy,
(c) C.sub.1 -C.sub.3 alkoxy,
(d) halo,
(e) amino,
(f) mono- or di-C.sub.1 -C.sub.3 alkylamino,
(g) --CHO,
(h) --COOH,
(i) COOR.sub.26,
(j) COHR.sub.26,
(k) nitro,
(l) mercapto,
(m) C.sub.1 -C.sub.3 alkylthio,
(n) C.sub.1 -C.sub.3 alkylsulfinyl,
(o) C.sub.1 -C.sub.3 alkylsulfonyl,
(p) C.sub.1 -C.sub.3 alkylsulfonyl--N(R.sub.4)--
(q) SO.sub.3 H,
(r) SO.sub.2 NH.sub.2,
(s) --CN, or
(t) --CN.sub.2 NH.sub.2 ;
wherein --Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;
and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring, which heterocyclic moiety is substituted with zero to 3 of the following:
(i) C.sub.1 -C.sub.6 alkyl,
(ii) hydroxy,
(iii) trifluoromethyl,
(iv) C.sub.1 -C.sub.4 alkoxy,
(v) halo,
(vi) aryl,
(vii) aryl C.sub.1 -C.sub.4 alkyl-,
(viii) amino, and
(ix) mono- or di-C.sub.1 -C.sub.4 alkylamino;
with the overall provisos that
(1) E.sub.10 -F.sub.11 is XL.sub.6a, XL.sub.6b, XL.sub.6c, XL.sub.6d, or XL.sub.6e only when at least one of the following occurs:
(i) A.sub.6 is present and
(A) A.sub.6 is XL.sub.1 or
(B) A.sub.6 is XL.sub.2 wherein R.sub.6 is Het which is N.sup.in -formyl-Trp,
(ii) B.sub.7 is present and R.sub.4 of B.sub.7 is other than hydrogen,
(iii) C.sub.8 is present and is XL.sub.1,
(iv) D.sub.9 is N.sub..alpha. -methyl-histidine,
(v) B.sub.7 and C.sub.8 both are present and B.sub.7 is XL.sub.b wherein M is --CH.sub.2 -- and C.sub.8 is XL.sub.1 ;
or
(vi) X is R.sub.5 --SO.sub.2 --(CH.sub.2).sub.q --C(O)-- or R.sub.5 --SO.sub.2 --C(CH.sub.2).sub.q --OC(O)--;
(2) E.sub.10 F.sub.11 is XL.sub.6e only when G.sub.12, H.sub.13 and I.sub.14 are absent;
(3) B.sub.7 C.sub.8 D.sub.9 is Pro-Phe-His, E.sub.10 F.sub.11 is XL.sub.6, R.sub.1 is isopropyl, or isobutyl;
and R.sub.11 is isopropyl, isobutyl, or benzyl, only when one of the following occurs:
(a) only 1 of G.sub.12,H.sub.13, and I.sub.14 is present;
(b) G.sub.12 is other than D or L val or D or L Ile;
(c) H.sub.13 is other than D or L Tyr, D or L Phe, or D or L His;
or
(d) A.sub.6 is FTrp or XL.sub.1 ;
(4) R.sub.16 or R.sub.17 is an amino-containing substituent, hydroxy, mercapto, or --Het bonded through the hetero atom only when n for that substituent is an integer from two to five, inclusive;
(5) R.sub.18 or R.sub.19 is hydroxy, mercapto, or amino, or a monosubstituted nitrogen containing group bonded through the nitrogen only when n is not one;
(6) A.sub.6, B.sub.7, C.sub.8, H.sub.13 and I.sub.14 are all absent, D.sub.9 and G.sub.12 are both present, and --NR.sub.4 --of D.sub.9 is --NH-- and Z is --OR.sub.10 and R.sub.10 is hydrogen, C.sub.1 -C.sub.5 alkyl, or --(CH.sub.2).sub.m --R.sub.16 or Z is --N(R.sub.4)R.sub.14 and R.sub.14 is hydrogen, C.sub.1 -C.sub.10 alkyl or --(CH.sub.2).sub.n --R.sub.18, or Z is C.sub.4 -C.sub.8 cyclic amino, only when R.sub.5 --(CH.sub.2).sub.n -- is other than C.sub.1 -C.sub.8 alkyl, C.sub.5 -C.sub.7 cycloalkyl or aryl;
(7) A.sub.6, B.sub.7, C.sub.8, D.sub.9, H.sub.13, I.sub.14 are all absent and G.sub.12 is present only when Z is --OR.sub.10 and R.sub.10 is --(CH.sub.2).sub.n --R.sub.17, --(CHR.sub.25)--CH.sub.2 R.sub.15 or --CH.sub.2 -- (CHR.sub.12)--R.sub.15 or when Z is --N(R.sub.4)R.sub.14 and R.sub.14 is --(CH.sub.2).sub.n --R.sub.19, --(CHR.sub.25)-- CH.sub.2 R.sub.15, or --CH.sub.2 --(CHR.sub.12)--R.sub.15 ;
(8) R.sub.12 is --(CH.sub.2).sub.n --R.sub.13 and n is zero and both R.sub.13 and R.sub.15 are oxygen-, nitrogen-, or sulfur-containing substituents bonded through the hetero atom, only when the hetero atom is not also bonded to hydrogen;
(9) when R.sub.12 is --(CH.sub.2).sub.n --R.sub.13 and n is zero, then R.sub.13 and R.sub.15 cannot both be --COOH;
(10) R.sub.25 is --(CH.sub.2).sub.n --R.sub.13 and n is zero only when R.sub.13 is other than a primary or secondary nitrogen-containing group hydroxy or mercapto group or when R.sub.4 of --N(R.sub.4)R.sub.14 is other than hydrogen;
(11) Z is C.sub.4 -C.sub.8 cyclic amino, only when at least one of G.sub.12, H.sub.13, and I.sub.14 is present;
(12) R.sub.17 or R.sub.19 is --Het, only when --Het is other than cyclic amino;
(13) R.sub.17 or R.sub.19 is --COOH only when n for that moiety is other than zero;
and
(14) at least one of A.sub.6, B.sub.7, C.sub.8, D.sub.9, G.sub.12, H.sub.13 or I.sub.14 must be present;
or a carboxy-, amino-, or other reactive group-protected form
or a pharmaceutically acceptable acid addition salt thereof.

296 more elements

Facts

Application

07/147,073Filed 20 Jan 1988 · continuation in part

Priority

6 Aug 1984

Granted

14 Nov 1989

Term ends

Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07K 5/0227
Containing at least one abnormal peptide link: containing the peptide sequence -Phe-His-NH-2-C-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6…
C12Q 1/37
Involving hydrolase: involving peptidase or proteinase
G01N 33/573
Immunoassay; Biospecific binding assay; Materials therefor: for enzymes or isoenzymes
G01N 33/6893
Involving proteins, peptides or amino acids: related to diseases not provided for elsewhere

Family

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Serial638,024Parent of this continuation-in-part · filed 6 Aug 1984

Serial638,026Parent of this continuation-in-part · filed 6 Aug 1984

Serial663,028Parent of this continuation-in-part · filed 19 Oct 1984

Serial663,024Parent of this continuation-in-part · filed 19 Oct 1984

Serial663,027Parent of this continuation-in-part · filed 19 Oct 1984

Serial663,023Parent of this continuation-in-part · filed 19 Oct 1984

Serial663,026Parent of this continuation-in-part · filed 19 Oct 1984

Serial663,093Parent of this continuation-in-part · filed 19 Oct 1984

Serial693,320Parent of this continuation-in-part · filed 22 Jan 1985

Serial753,198Parent of this continuation-in-part · filed 9 Jul 1985

US 4,880,781 AThis patent

From the US filing history. Foreign family members aren’t listed.