US4411890A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Synthetic peptides having pituitary growth hormone releasing activity
Assignee: SmithKline Beecham Corp
•
Filing: 1981-12-28
•
Granted: 1983-10-25
•
Expires: 2001-12-28
Abstract
Abstract Novel peptides having the following amino acid sequence ##STR1## wherein X 1 , X 2 , and X 3 are selected from a group consisting of N-terminal and desamino alpha-carbon substitutions and a and b are 0 or 1, provided that a and b are always 0 when A 1 is a desamino residue; A 1 and A 4 are selected from a group consisting of histidyl, arginyl, lysyl, α-naphthylalanyl, β-naphthylalanyl, isoquinolyl, tyrosyl, tryptophyl, phenylalanyl, homologues and analogues thereof, and, with respect to A 1 only the desamino forms thereof; A 2 and A 5 are selected from a group consisting of D-histidyl, D-arginyl, D-lysyl, D-α-naphthylalanyl, D-β-naphthylalanyl, D-isoquinolyl, D-tyrosyl, D-tryptophyl, D-phenylalanyl, homologues and analogues thereof; A 3 is selected from a group consisting of glycyl, alanyl, valyl, leucyl, isoleucyl, prolyl, seryl, threonyl, methionyl, aspartyl, glutamyl, asparginyl, glutaminyl, histidyl, D-alanyl, D-valyl, D-leucyl, D-isoleucyl, D-prolyl, D-seryl, D-threonyl, D-methionyl, D-aspartyl, D-glutamyl, D-asparaginyl, D-glutaminyl, D-histidyl, and homologues and analogues thereof; A 6 is selected from a group consisting of amino acids of the L- and D- configuration, homologues and analogues thereof, and the descarboxy forms thereof; and Y is selected from a group consisting of C-terminal and descarboxy alpha-carbon substitutions; and the pharmaceutically acceptable salts thereof.
Inventors
- 👤 Frank A. Momany
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-28 22:06
CPC Classifications
C; C07; C07K; C07K7/00; C07K7/04; C07K7/06; A; A61; A61K; A61K38/00; Y; Y10; Y10S; Y10S930/00; Y10S930/01; Y10S930/12
Claims Analysis
Total Claims: 50
Claim 1
Independent Claim
217 words
A peptide having a formula ##STR72## wherein X 1 , X 2 , and X 3 are selected from a group consisting of --R, --OR, RC(O)-- wherein R is selected from a group consisting of hydrogen and straight chain and branched chain alkyl groups containing 1-6 carbon atoms; a and b are 0 or 1, provided that a and b are 0 when A 1 is a desamino residue; A 1 and A 4 are selected from a group consisting of His, Arg, Lys, α-Naphth, β-Naphth, IQl, Tyr, Trp, Phe, homologues and analogues thereof, and, with respect to A 1 , the desamino forms thereof; A 2 and A 5 are selected from a group consisting of D-His, D-Arg, D-Lys, D-α-Naphth, D-β-Naphth, D-Iql, D-Tyr, D-Trp, D-Phe, and homologues and analogues thereof; A 3 is selected from a group consisting of Gly, Ala, Val, Leu, Ile, Pro, Ser, Thr, Met, Asp, Glu, Asn, Gln, His, D-Ala, D-Val, D-Leu, D-Ile, D-Pro, D-Ser, D-Thr, D-Met, D-Asp, D-Glu, D-Asn, D-Gln, D-His, and homologues and analogues thereof; A 6 is selected from a group consisting of amino acids of the L- and D-configuration, homologues and analogues thereof, and the descarboxy forms thereof; and Y is selected from a group consisting of C-terminal and descarboxy alpha-carbon substitutions; and the pharmaceutically acceptable salts thereof.
Claim 2
Dependent Claim
217 words
A peptide having a formula ##STR72## wherein X 1 , X 2 , and X 3 are selected from a group consisting of --R, --OR, RC(O)-- wherein R is selected from a group consisting of hydrogen and straight chain and branched chain alkyl groups containing 1-6 carbon atoms; a and b are 0 or 1, provided that a and b are 0 when A 1 is a desamino residue; A 1 and A 4 are selected from a group consisting of His, Arg, Lys, α-Naphth, β-Naphth, IQl, Tyr, Trp, Phe, homologues and analogues thereof, and, with respect to A 1 , the desamino forms thereof; A 2 and A 5 are selected from a group consisting of D-His, D-Arg, D-Lys, D-α-Naphth, D-β-Naphth, D-Iql, D-Tyr, D-Trp, D-Phe, and homologues and analogues thereof; A 3 is selected from a group consisting of Gly, Ala, Val, Leu, Ile, Pro, Ser, Thr, Met, Asp, Glu, Asn, Gln, His, D-Ala, D-Val, D-Leu, D-Ile, D-Pro, D-Ser, D-Thr, D-Met, D-Asp, D-Glu, D-Asn, D-Gln, D-His, and homologues and analogues thereof; A 6 is selected from a group consisting of amino acids of the L- and D-configuration, homologues and analogues thereof, and the descarboxy forms thereof; and Y is selected from a group consisting of C-terminal and descarboxy alpha-carbon substitutions; and the pharmaceutically acceptable salts thereof.
Claim 3
Dependent Claim
174 words
The peptide of claim 1 wherein: a is 0 or 1 and b is 0; A 1 and A 4 are selected from the group consisting of His, Tyr, Trp, Phe, homologues and analogues thereof, and with respect to A 1 , the desamino forms thereof; A 2 and A 5 are selected from the group consisting of D-His, D-Tyr, D-Trp, D-Phe, and homologues and analogues thereof; A 3 is selected from the group consisting of Gly, Ala, Ser, Asn, Pro, D-Ala, D-Ser, D-Asn, D-Pro, and homologues and analogues thereof; A 6 is selected from the group consisting of Arg, Lys, Orn, His, Asp, Glu, Asn, Gln, D-Arg, D-Lys, D-Orn, D-His, D-Asp, D-Glu, D-Asn, D-Gln, D-Arg, homologues and analogues thereof, and descarboxy forms thereof; Y is selected from the group consisting of --CH 2 OH, --OR, and --NR 1 R 2 , wherein R, R 1 and R 2 are selected from the group consisting of hydrogen and straight and branched chain alkyl groups containing 1-6 carbon atoms; and the pharmaceutically acceptable salts thereof.
Claim 4
Dependent Claim
155 words
The peptide of claim 1 having the formula ##STR73## wherein a is 0 or 1; X 2 is selected from the group consisting of RCO and R-- wherein R is selected from the group consisting of hydrogen and alkyl groups containing 1-2 carbon atoms; A 1 is selected from the group consisting of Tyr, O-Me-Tyr, His, 3-N-Me-His, p-Cl-Phe, and the desamino forms thereof; A 3 is selected from the group consisting of Ala, Ser, and D-Ala; A 4 is selected from the group consisting of Trp and Tyr; A 5 is selected from the group consisting of D-Phe, D-His, D-Tyr, and D-p-Cl-Phe; A 6 is selected from the group consisting of Arg, HomoArg, Lys, Orn, Asp, Glu, Asn, Gln, and D-Lys; Y is selected from the group consisting of --OR, and --NHR, wherein R is selected from the group consisting of hydrogen and alkyl groups containing 1-2 carbon atoms; and the pharmaceutically acceptable salts thereof.
Claim 5
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -Tyr-D-Trp-Ala-Trp-D-Phe-Met-NH 2 .
Claim 6
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -Tyr-D-Trp-Ala-Trp-D-Phe-Thr-NH 2 .
Claim 7
Dependent Claim
11 words
The peptide of claim 1 of the formula H 2 -Tyr-D-Trp-Ala-Trp-D-Phe-Gln-OH.
Claim 8
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -Tyr-D-Trp-ALa-Trp-D-Phe-Gln-NH 2 .
Claim 9
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -Tyr-D-Trp-Ala-Trp-D-Phe-Asn-NH 2 .
Claim 10
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -His-D-Trp-Ala-Trp-D-Phe-Lys-NH 2 .
Claim 11
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -Tyr-Phe-D-Trp-Ala-Trp-D-Phe-Lys-NH 2 .
Claim 12
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -Tyr-D-Trp-Ala-Trp-D-Phe-Glu-NH 2 .
Claim 13
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -Tyr-D-Trp-Ala-Trp-D-Phe-Phe-NH 2 .
Claim 14
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -Tyr-D-Trp-Ala-Trp-D-Phe-Gln-NH 2 .
Claim 15
Dependent Claim
11 words
The peptide of claim 1 of the formula H 2 -His-D-Trp-Ala-Trp-D-Phe-Lys-OH.
Claim 16
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -His-D-Trp-Ala-Trp-D-Phe-Arg-NH 2 .
Claim 17
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -His-D-Trp-Ala-Trp-D-Phe-Gln-NH 2 .
Claim 18
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -His-D-Trp-Ala-Trp-D-Phe-Glu-NH 2 .
Claim 19
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -His-D-Trp-Ala-Trp-D-Phe-HomoArg-NH 2 .
Claim 20
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -3-N-Me-His-D-Trp-Ala-Trp-D-Phe-Lys-NH 2 .
Claim 21
Dependent Claim
15 words
The peptide of claim 1 of the formula H 2 -His-D-Trp-ALa-Trp-D-Phe-Lys-NHCH 2 CH 3 .
Claim 22
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -His-D-Trp-Ala-Trp-D-Phe-Orn-NH 2 .
Claim 23
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -His-D-Trp-Val-Trp-D-Phe-Lys-NH 2 .
Claim 24
Dependent Claim
13 words
The peptide of claim 1 of the formula H 2 -His-D-Trp-Ser-Trp-D-Phe-Lys-NH 2 .
Claim 25
Independent Claim
42 words
A method of releasing growth hormone from a pituitary comprising contacting said pituitary with the peptide of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.
Claim 26
Dependent Claim
29 words
A method of releasing growth hormone in vivo from a pituitary comprising contacting said pituitary with the peptide of claim 9, 14, 15, 16, 17, 18, 19, or 20.
Claim 27
Dependent Claim
216 words
An intermediate composition having a formula selected from a group consisting of ##STR74## B.sub.1 -B.sub.2 -B.sub.3 -B.sub.4 -B.sub.5 -B'.sub.6 -Y (VI) wherein Pr 1 is an α-amino acid protecting group; a, b, m, q, r, and s are each 0 or 1; X' 1 , X' 2 , and X' 3 are selected from a group consisting of --R, --OR, RC(O)-- wherein R is selected from the group consisting of hydrogen and straight chain and branched chain alkyl groups containing 1-6 carbon atoms; B 1 and B 4 are selected from a group consisting of His, Arg, Lys, α-Naphth, β-Naphth, Igl, Tyr, Trp, Phe, homologues and analogues thereof, the side-chain protected forms thereof, and, with respect to B 1 , the desamino forms thereof; B 2 and B 5 are selected from a group consisting of D-His, D-Arg, D-Lys, D-α-Naphth, D-β-Naphth, D-Igl, D-Tyr, D-Trp, D-Phe, homologues and analogues thereof, and the side-chain protected forms thereof; B 3 is selected from a group consisting of amino acids of the L- and D-configurations, homologues and analogues thereof, the side-chain protected forms thereof, and, with respect to B' 6 , the descarboxy forms thereof; ® is a resin; Y is selected from a group consisting of C-terminal and descarboxy alpha-carbon substitutions; and Pr 2 is a carboxyl protecting group.
Claim 28
Dependent Claim
216 words
An intermediate composition having a formula selected from a group consisting of ##STR74## B.sub.1 -B.sub.2 -B.sub.3 -B.sub.4 -B.sub.5 -B'.sub.6 -Y (VI) wherein Pr 1 is an α-amino acid protecting group; a, b, m, q, r, and s are each 0 or 1; X' 1 , X' 2 , and X' 3 are selected from a group consisting of --R, --OR, RC(O)-- wherein R is selected from the group consisting of hydrogen and straight chain and branched chain alkyl groups containing 1-6 carbon atoms; B 1 and B 4 are selected from a group consisting of His, Arg, Lys, α-Naphth, β-Naphth, Igl, Tyr, Trp, Phe, homologues and analogues thereof, the side-chain protected forms thereof, and, with respect to B 1 , the desamino forms thereof; B 2 and B 5 are selected from a group consisting of D-His, D-Arg, D-Lys, D-α-Naphth, D-β-Naphth, D-Igl, D-Tyr, D-Trp, D-Phe, homologues and analogues thereof, and the side-chain protected forms thereof; B 3 is selected from a group consisting of amino acids of the L- and D-configurations, homologues and analogues thereof, the side-chain protected forms thereof, and, with respect to B' 6 , the descarboxy forms thereof; ® is a resin; Y is selected from a group consisting of C-terminal and descarboxy alpha-carbon substitutions; and Pr 2 is a carboxyl protecting group.
Claim 29
Dependent Claim
148 words
The intermediate composition of claim 26 wherein: B 1 and B 4 are selected from the group consisting of His, Tyr, Trp, Phe, homologues and analogues thereof, and, with respect to B 1 , the desamino forms thereof, and the side-chain protected forms thereof; B 2 and B 5 are selected from the group consisting of D-His, D-Tyr, D-Trp, D-Phe, homologues and analogues thereof, and the side-chain protected forms thereof; B 3 is selected from the group consisting of Gly, Ala, Ser, Asn, Pro, D-Ala, D-Ser, D-Asn, D-Pro, homologues and analogues thereof, and the side-chain protected forms thereof; and B 6 and B' 6 are selected from the group consisting of Arg, Lys, Orn, His, Asp, Glu, Asn, Gln, D-Arg, D-Lys, D-Orn, D-His, D-Asp, D-Glu, D-Asn, D-Gln, homologues and analogues thereof, and, with respect to B' 6 , the descarboxy forms thereof, and the side-chain protected forms thereof.
Claim 30
Dependent Claim
134 words
The intermediate composition of claim 26 having the formula selected from the group consisting of ##STR75## B.sub.1 -D-Trp-B.sub.3 -B.sub.4 -B.sub.5 -B'.sub.6 -Y (VI) wherein B 1 is selected from the group consisting of Tyr, O-Me-Tyr, His, 3-N-Me-His, p-Cl-Phe, the desamino forms thereof, and the side-chain protected forms thereof; B 3 is selected from the group consisting of Ala, Ser, D-Ala, and the side-chain protected forms thereof; B 4 is selected from the group consisting of Trp, Tyr, and the side-chain protected forms thereof; B 5 is selected from the group consisting of D-Phe, D-His, D-Tyr, D-p-Cl-Phe, and the side-chain protected forms thereof; and B 6 and B' 6 are selected from the group consisting of Arg, HomoArg, Lys, Orn, Asp, Glu, Asn, Gln, D-Lys, the descarboxy forms thereof, and the side-chain protected forms thereof.
Claim 31
Dependent Claim
22 words
The intermediate composition of claim 26 of the formula Boc-Tyr(Brz)-D-Trp-Ala-Trp-D-Phe-Met-® wherein Brz is o-bromobenzyloxycarbonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydrylamine resin.
Claim 32
Dependent Claim
25 words
The intermediate composition of claim 26 of the formula Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-Thr(Bzl)-® wherein Bzl is benzyl BrZ is p-bromobenzyloxycarbonyl; Boc is t-Butyloxycarbonyl; and ® is p-methylbenzhydrylamine resin.
Claim 33
Dependent Claim
23 words
The intermediate composition of claim 26 of the formula Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-Glu-α-benzyl ester-® wherein BrZ is p-bromobenzyloxycarbonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydrylamine resin.
Claim 34
Dependent Claim
22 words
The intermediate composition of claim 26 of the formula Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-Gln-® wherein BrZ is p-bromobenzyloxycarbonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydrylamine resin.
Claim 35
Dependent Claim
22 words
The intermediate composition of claim 26 of the formula Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-Asn-® wherein BrZ is p-bromobenzyloxycarbonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydrylamine resin.
Claim 36
Dependent Claim
25 words
The intermediate composition of claim 26 of the formula Boc-His(Tos)-D-Trp-Ala-Trp-D-Phe-Lys(ClZ)-® wherein ClZ is o-chloro-benzyloxycarbonyl; Tos is p-toluenesulfonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydrylamine resin.
Claim 37
Dependent Claim
28 words
The intermediate composition of claim 26 of the formula Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-His(Tos)-Lys(ClZ)-® wherein ClZ is o-chloro-benzyloxycarbonyl; Tos is p-toluenesulfonyl; BrZ is p-bromobenzyloxycarbonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydryalmine resin.
Claim 38
Dependent Claim
26 words
The intermediate composition of claim 26 of the formula Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-Glu-γ-Bzl-® wherein γ-Bzl denotes γ-benzyl ester; BrZ is p-bromobenzyloxycarbonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydrylamine resin.
Claim 39
Dependent Claim
22 words
The intermediate composition of claim 26 of the formula Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-Phe-® wherein BrZ is p-bromobenzyloxycarbonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydrylamine resin.
Claim 40
Dependent Claim
26 words
The intermediate composition of claim 26 of the formula Boc-Tyr(BrZ)-D-Trp-Gly-Trp-D-Phe-Gln-ONP-® wherein ONP is p-nitrophenyl ester; BrZ is p-bromobenzyloxycarbonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydryalmine resin.
Claim 41
Dependent Claim
25 words
The intermediate composition of claim 26 of the formula Boc-His(Tos)-D-Trp-Ala-Trp-D-Phe-Lys(ClZ)-® wherein ClZ is o-chloro-benzyloxycarbonyl Tos is p-toluenesulfonyl; Boc is t-butyloxycarbonyl; and ® is hydroxymethyl resin.
Claim 42
Dependent Claim
22 words
The intermediate composition of claim 26 of the formula Boc-His(Tos)-D-Trp-Ala-Trp-D-Phe-Arg(Tos)-® wherein Tos is p-toluenesulfonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydryalmine resin.
Claim 43
Dependent Claim
26 words
The intermediate composition of claim 26 of the formula Boc-His(Tos)-D-Trp-Ala-Trp-D-Phe-Gln-ONP-® wherein ONP is p-nitrophenyl ester; Tos is p-toluenesulfonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydryalmine resin.
Claim 44
Dependent Claim
26 words
The intermediate composition of claim 26 of the formula Boc-His(Tos)-D-Trp-Ala-Trp-D-Phe-Glu-γ-Bzl-® wherein γ-Bzl denotes γ-benzyl ester; Tos is p-toluenesulfonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydryalmine resin.
Claim 45
Dependent Claim
22 words
The intermediate composition of claim 26 of the formula Boc-His(Tos)-D-Trp-Ala-Trp-D-Phe-HomoArg(Tos)-® wherein Tos is p-toluenesulfonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydryalmine resin.
Claim 46
Dependent Claim
22 words
The intermediate composition of claim 26 of the formula Boc-3-N-Me-His-D-Trp-Ala-Trp-D-Phe-Lys(ClZ)-® wherein ClZ is o-chloro-benzyloxycarbonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydryalmine resin.
Claim 47
Dependent Claim
25 words
The intermediate composition of claim 26 of the formula Boc-His(Tos)-D-Trp-Ala-Trp-D-Phe-Lys(ClZ)-® wherein ClZ is o-chloro-benzyloxycarbonyl; Tos is p-toluenesulfonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydryalmine resin.
Claim 48
Dependent Claim
25 words
The intermediate composition of claim 26 of the formula Boc-His(Tos)-D-Trp-Ala-Trp-D-Phe-Orn(Z)-® wherein Z is benzyloxycarbonyl; Tos is p-toluenesulfonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydryalmine resin.
Claim 49
Dependent Claim
25 words
The intermediate composition of claim 26 of the formula Boc-His(Tos)-D-Trp-Val-Trp-D-Phe-Lys(ClZ)-® wherein ClZ is o-chlorobenzyloxycarbonyl; Tos is p-toluenesulfonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydryalmine resin.
Claim 50
Dependent Claim
28 words
The intermediate composition of claim 26 of the formula Boc-His(Tos)-D-Trp-Ser(Bzl)-Trp-D-Phe-Lys(ClZ)-® wherein ClZ is o-chloro-benzyloxycarbonyl; Bzl is benzyl; Tos is p-toluenesulfonyl; Boc is t-butyloxycarbonyl; and ® is p-methylbenzhydryalmine resin.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1986-10-24 | 1987-04-25 | 1987-10-25 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1990-10-24 | 1991-04-25 | 1991-10-25 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1994-10-24 | 1995-04-25 | 1995-10-25 | $7700.00 | Window Closed / Lapsed |