US4256736A
Expired / Lapsed
US
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Psychopharmacological peptides
Assignee: Akzona Inc
•
Filing: 1979-02-22
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Granted: 1981-03-17
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Expires: 1999-02-22
Abstract
Abstract Novel and biologically useful peptides of the formula: A1-A2-L-Phe-X-L-Thr-L-Ser-R1-Y-L-Ser-R2-L-Thr-L-Pro-L-Leu-L-Val-L-Thr-B are disclosed (together with pharmaceutical compositions comprising a pharmaceutically effective amount of same) wherein: (a) A1 and A2 each represent an aminoacid residue of the formula H2N-ALK-CO-, where ALK is an alkylidene group with 1 to 6 carbon atoms inclusively; (b) X is an amino-acid residue selected from the group consisting of L-Met, L-Met(O), L-Met(O2) and L-Leu; (c) R1 and R2 each represent one of the amino-acid residues selected from the group consisting of L-Glu and L-Gln; (d) Y represents an amino acid residue selected from the group consisting of L-Lys and D-Lys; and (e) B represents one of the amino-acid or peptide moieties selected from L-Leu-OH, D-Leu-OH, L-Leu-L-Phe-OH, L-Leu-L-Phe-L-Lys-OH, L-Leu-L-Phe-D-Lys-OH, L-leucinol and L-MeLeu-OH or a functional derivative thereof; these peptides have psychopharmacological properties capable of accelerating the inhibition of the conditioned flight response, so that they are eminently suitable for the treatment of certain mental disorders in which reduction of the brain function is desired; more particularly the peptides have neuroleptic activity. Peptides of formula (I) wherein one of R1 and R2 is L-Glu and the other L-Gln are preferred, and compositions containing compositions of formula (I) wherein R1 is L-Glu and R2 is L-Gln are especially suitable.
Inventors
- 👤 David DE Wied
- 👤 Hendrik M. Greven
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-01 19:13
CPC Classifications
C; C07; C07K; C07K14/00; C07K14/435; C07K14/665; C07K14/67; C07K14/672; A; A61; A61P; A61P25/00; A61P25/20; C07K14/675; C07K14/6755; A61K; A61K38/00
Claims Analysis
Total Claims: 38
Claim 1
Independent Claim
183 words
A compound of the formula: A.sub.1 -A.sub.2 -L-Phe-X-L-Thr-L-Ser-R.sub.1 -Y-L-Ser-R.sub.2 -L-Thr-L-Pro-L-Leu-L-Val-L-Thr-B (I) wherein: (a) A 1 and A 2 each represent an L-amino-acid residue of the formula H 2 N-ALK-CO-, wherein ALK is an alkylidene group with 1 to 6 carbon atoms; (b) X is an amino-acid residue selected from the group consisting of L-Met, L-Met(O), L-Met(O 2 ) and L-Leu; (c) R 1 and R 2 each represent one of the amino-acid residues selected from the group consisting of L-Glu and L-Gln; (d) Y represents an amino-acid residue selected from the group consisting of L-Lys and D-Lys; and (e) B represents one of the amino-acid- or peptide-moieties selected from L-Leu-OH, D-Leu-OH, L-Leu-L-Phe-OH, L-Leu-L-Phe-L-Lys-OH, L-Leu-L-Phe-D-Lys-OH, L-leucinol and L-MeLeu and functional derivatives of said compound selected from the group consisting of pharmaceutically acceptable salts addition salts, pharmaceutically acceptable metal salts, aliphatic esters containing up to about eighteen carbon atoms, unsubstituted amides, amides substituted with alkyl group (s) containing up to about six carbon atoms, N-acyl derivatives wherein the aliphatic carboxylic acid group has from one to about six carbon atoms, and pharmaceutically acceptable metal complexes.
Claim 2
Dependent Claim
183 words
A compound of the formula: A.sub.1 -A.sub.2 -L-Phe-X-L-Thr-L-Ser-R.sub.1 -Y-L-Ser-R.sub.2 -L-Thr-L-Pro-L-Leu-L-Val-L-Thr-B (I) wherein: (a) A 1 and A 2 each represent an L-amino-acid residue of the formula H 2 N-ALK-CO-, wherein ALK is an alkylidene group with 1 to 6 carbon atoms; (b) X is an amino-acid residue selected from the group consisting of L-Met, L-Met(O), L-Met(O 2 ) and L-Leu; (c) R 1 and R 2 each represent one of the amino-acid residues selected from the group consisting of L-Glu and L-Gln; (d) Y represents an amino-acid residue selected from the group consisting of L-Lys and D-Lys; and (e) B represents one of the amino-acid- or peptide-moieties selected from L-Leu-OH, D-Leu-OH, L-Leu-L-Phe-OH, L-Leu-L-Phe-L-Lys-OH, L-Leu-L-Phe-D-Lys-OH, L-leucinol and L-MeLeu and functional derivatives of said compound selected from the group consisting of pharmaceutically acceptable salts addition salts, pharmaceutically acceptable metal salts, aliphatic esters containing up to about eighteen carbon atoms, unsubstituted amides, amides substituted with alkyl group (s) containing up to about six carbon atoms, N-acyl derivatives wherein the aliphatic carboxylic acid group has from one to about six carbon atoms, and pharmaceutically acceptable metal complexes.
Claim 3
Dependent Claim
18 words
The compound of claim 1 wherein A 1 is selected from the group consisting of H-Gly and H-L-Ala.
Claim 4
Dependent Claim
18 words
The compound of claim 1 wherein A 2 is selected from the group consisting of H-Gly and H-L-Ala.
Claim 5
Dependent Claim
18 words
The compound of claim 1 wherein B is selected from the group consisting of L-Leu-OH, D-Leu-OH and L-Leu-L-Phe-D-Lys-OH.
Claim 6
Dependent Claim
20 words
The compound of claim 1 wherein X is selected from the group consisting of L-Met, L-Met(O), and L-Met(O 2 ).
Claim 7
Dependent Claim
15 words
The compound of claim 1 wherein R 1 is L-Glu and R 2 is L-Gln.
Claim 8
Dependent Claim
9 words
The compound of claim 1 wherein Y is L-Lys.
Claim 9
Dependent Claim
31 words
The compound of claim 1 wherein A 1 and A 2 are H-Gly, X is L-Met, R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is L-Leu-OH.
Claim 10
Dependent Claim
31 words
The compound of claim 1 wherein A 1 and A 2 are H-Gly, X is L-Met(0), R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is L-Leu-OH.
Claim 11
Dependent Claim
33 words
The compound of claim 1 wherein A 1 and A 2 are H-Gly, X is L-Met(O 2 ), R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is L-Leu-OH.
Claim 12
Dependent Claim
31 words
The compound of claim 1 wherein A 1 and A 2 are H-Gly, X is L-Met, R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys, and B is D-Leu-OH.
Claim 13
Dependent Claim
33 words
The compound of claim 1 wherein A 1 and A 2 are H-Gly, X is L-Met, R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is L-Leu-NHCH 3 .
Claim 14
Dependent Claim
33 words
The compound of claim 1 wherein A 1 and A 2 are H-Gly, X is L-Met, R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is L-Leu-OCH 3 .
Claim 15
Dependent Claim
31 words
The compound of claim 1 wherein A 1 and A 2 are H-Gly, X is L-Met, R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is L-Leu-L-Phe-L-Lys-OH.
Claim 16
Dependent Claim
31 words
The compound of claim 1 wherein A 1 and A 2 are H-Gly, X is L-Met, R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is L-Leu-L-Phe-OH.
Claim 17
Dependent Claim
31 words
The compound of claim 1 wherein A 1 and A 2 are H-Gly, X is L-Met, R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is L-Leu-L-Phe-D-Lys-OH.
Claim 18
Dependent Claim
203 words
A pharmaceutical composition effective for treating schizophrenia, comprising: (A) a pharmaceutically effective amount of a compound of the formula: A.sub.1 -A.sub.2 -L-Phe-X-L-Thr-L-Ser-R.sub.1 -Y-L-Ser-R.sub.2 -L-Thr-L-Pro-L-Leu-Val-L-Thr-B wherein: (1) A 1 and A 2 each represent an L-amino-acid residue of the formula H 2 N-ALK-CO-, wherein ALK is an alkylidene group with 1 to 6 carbon atoms; (2) X is an amino-acid residue selected from the group consisting of L-Met, L-Met(O), L-Met(O 2 ), and L-Leu; (3) R 1 and R 2 each represent one of the amino-acid residues selected from the group consisting of L-Glu and L-Gln; (4) Y represents an amino-acid residue selected from the group consisting of L-Lys and D-Lys; and (5) B represents one of the amino-acid- or peptide-moieties selected from L-Leu-OH, D-Leu-OH, L-Leu-L-Phe-OH, L-Leu-L-Phe-L-Lys-OH, L-Leu-L-Phe-D-Lys-OH, L-leucinol and L-MeLeu-OH; and functional derivatives of said compound selected from the group consisting of pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, aliphatic esters containing up to about eighteen carbon atoms unsubstituted amides, amides substituted with alkyl group (s) having up to about six carbon atoms, N-acyl derivatives wherein the aliphatic carboxylic acid group has from up to about six carbon atoms, and pharmaceutically acceptable metal complexes, and (B) a pharmaceutically effective carrier therefor.
Claim 19
Dependent Claim
203 words
A pharmaceutical composition effective for treating schizophrenia, comprising: (A) a pharmaceutically effective amount of a compound of the formula: A.sub.1 -A.sub.2 -L-Phe-X-L-Thr-L-Ser-R.sub.1 -Y-L-Ser-R.sub.2 -L-Thr-L-Pro-L-Leu-Val-L-Thr-B wherein: (1) A 1 and A 2 each represent an L-amino-acid residue of the formula H 2 N-ALK-CO-, wherein ALK is an alkylidene group with 1 to 6 carbon atoms; (2) X is an amino-acid residue selected from the group consisting of L-Met, L-Met(O), L-Met(O 2 ), and L-Leu; (3) R 1 and R 2 each represent one of the amino-acid residues selected from the group consisting of L-Glu and L-Gln; (4) Y represents an amino-acid residue selected from the group consisting of L-Lys and D-Lys; and (5) B represents one of the amino-acid- or peptide-moieties selected from L-Leu-OH, D-Leu-OH, L-Leu-L-Phe-OH, L-Leu-L-Phe-L-Lys-OH, L-Leu-L-Phe-D-Lys-OH, L-leucinol and L-MeLeu-OH; and functional derivatives of said compound selected from the group consisting of pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, aliphatic esters containing up to about eighteen carbon atoms unsubstituted amides, amides substituted with alkyl group (s) having up to about six carbon atoms, N-acyl derivatives wherein the aliphatic carboxylic acid group has from up to about six carbon atoms, and pharmaceutically acceptable metal complexes, and (B) a pharmaceutically effective carrier therefor.
Claim 20
Dependent Claim
18 words
The composition of claim 17 wherein A 1 is selected from the group consisting of H-Gly and H-L-Ala.
Claim 21
Dependent Claim
18 words
The composition of claim 17 wherein A 2 is selected from the group consisting of H-Gly and H-L-Ala.
Claim 22
Dependent Claim
18 words
The composition of claim 17 wherein B is selected from the group consisting of L-Leu-OH, D-Leu-OH and L-Leu-L-Phe-D-Lys-OH.
Claim 23
Dependent Claim
20 words
The composition of claim 17 wherein X is selected from the group consisting of L-Met, L-Met(O), and L-Met(O 2 ).
Claim 24
Dependent Claim
15 words
The composition of claim 17 wherein R 1 is L-Glu and R 2 is L-Gln.
Claim 25
Dependent Claim
9 words
The composition of claim 17 wherein Y is L-Lys.
Claim 26
Dependent Claim
31 words
The composition of claim 17 wherein A 1 and A 2 are H-Gly, X is L-Met, R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is L-Leu-OH.
Claim 27
Dependent Claim
31 words
The composition of claim 17 wherein A 1 and A 2 are H-Gly, X is L-Met(O), R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is L-Leu-OH.
Claim 28
Dependent Claim
33 words
The composition of claim 17 wherein A 1 and A 2 are H-Gly, X is L-Met(O 2 ), R 2 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is L-Leu-OH.
Claim 29
Dependent Claim
31 words
The composition of claim 17 wherein A 1 and A 2 are H-Gly, X is L-Met, R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is D-Leu-OH.
Claim 30
Dependent Claim
33 words
The composition of claim 17 wherein A 1 and A 2 are H-Gly, X is L-Met, R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is L-Leu-NHCH 3 .
Claim 31
Dependent Claim
33 words
The composition of claim 17 wherein A 1 and A 2 are H-Gly, X is L-Met, R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is L-Leu-OCH 3 .
Claim 32
Dependent Claim
31 words
The composition of claim 17 wherein A 1 and A 2 are H-Gly, X is L-Met, R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is L-Leu-L-Phe-L-Lys-OH.
Claim 33
Dependent Claim
31 words
The composition of claim 17 wherein A 1 and A 2 are H-Gly, X is L-Met, R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is L-Leu-L-Phe-OH.
Claim 34
Dependent Claim
31 words
The composition of claim 17 wherein A 1 and A 2 are H-Gly, X is L-Met, R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys and B is L-Leu-L-Phe-D-Lys-OH.
Claim 35
Dependent Claim
133 words
Method for the treatment of schizofrenia in humans, comprising: administering a pharmaceutically effective amount of a compound of the formula: A.sub.1 -A.sub.2 -L-Phe-X-L-Thr-L-Ser-R.sub.1 -Y-L-Ser-R.sub.2 -L-Thr-L-Pro-L-Leu-L-Val-L-Thr-B wherein: (a) A 1 and A 2 each represent an L-amino-acid residue of the formula H 2 N-ALK-CO-, wherein ALK is an alkylidene group with 1 to 6 carbon atoms; (b) X is an amino-acid residue selected from the group consisting of L-Met, L-Met(0), L-Met(0 2 ) and L-Leu; (c) R 1 and R 2 each represent one of the amino-acid residues selected from the group consisting of L-Glu and L-Gln; (d) Y represents an amino-acid residue selected from the group consisting of L-Lys and D-Lys; and (e) B represents one of the peptides selected from the group consisting of L-Leu-OH, D-Leu-OH, 1-MeLeu-OH, L-Leu-L-Phe-OH, L-Leu-L-Phe-L-Lys-OH, L-Leu-L-Phe-D-Lys-OH and L-Leucinol.
Claim 36
Dependent Claim
133 words
Method for the treatment of schizofrenia in humans, comprising: administering a pharmaceutically effective amount of a compound of the formula: A.sub.1 -A.sub.2 -L-Phe-X-L-Thr-L-Ser-R.sub.1 -Y-L-Ser-R.sub.2 -L-Thr-L-Pro-L-Leu-L-Val-L-Thr-B wherein: (a) A 1 and A 2 each represent an L-amino-acid residue of the formula H 2 N-ALK-CO-, wherein ALK is an alkylidene group with 1 to 6 carbon atoms; (b) X is an amino-acid residue selected from the group consisting of L-Met, L-Met(0), L-Met(0 2 ) and L-Leu; (c) R 1 and R 2 each represent one of the amino-acid residues selected from the group consisting of L-Glu and L-Gln; (d) Y represents an amino-acid residue selected from the group consisting of L-Lys and D-Lys; and (e) B represents one of the peptides selected from the group consisting of L-Leu-OH, D-Leu-OH, 1-MeLeu-OH, L-Leu-L-Phe-OH, L-Leu-L-Phe-L-Lys-OH, L-Leu-L-Phe-D-Lys-OH and L-Leucinol.
Claim 37
Dependent Claim
90 words
The method of claim 33 wherein the compound is administered in a dosage of 1 μg to 1 mg per kg body weight per day functional derivatives of said compound selected from the group consisting of pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, aliphatic esters containing up to about eighteen carbon atoms, unsubstituted amides, amides substituted with alkyl group (s) having up to about six carbon atoms, N-acyl derivatives wherein the aliphatic carboxylic acid group has from up to about six carbon atoms, and pharmaceutically acceptable metal complexes.
Claim 38
Dependent Claim
31 words
The method of claim 33 wherein A 1 and A 2 are H-Gly, X is L-Met, R 1 is L-Glu, R 2 is L-Gln, Y is L-Lys, and B is L-Leu-OH.
References Cited (Backward Citations)
US4098778A
Cited
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| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 1984-03-16 | 1984-09-15 | 1985-03-17 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1988-03-16 | 1988-09-15 | 1989-03-17 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1992-03-16 | 1992-09-15 | 1993-03-17 | $7700.00 | Window Closed / Lapsed |