# US 4,395,403 A · Polypeptides, processes for their production, pharmaceutical compositions comprising said polypeptides and their use

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 4,395,403 A
- Document ID: US4395403A
- Status: Granted
- Kind: A
- Application number: 06/321,663
- Filed: 1981-11-16
- Granted: 1983-07-26
- Earliest claimed: 1979-11-27
- Assignees: Sandoz Ltd.
- Inventors: Wilfried Bauer; Janos Pless
- Web page: https://patentgrep.com/patent/US4395403A

## CPC

- C07K 14/6555: {at least 1 amino acid in D-form}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 5/00: Drugs for disorders of the endocrine system
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- Y10S 930/26: Containing cys-cys disulfide bridge between nonadjacent cysteine residues
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS

## Abstract

Straight-chain and mono-cyclic polypeptides containing the basic sequence ##STR1## wherein X is an amino acid residue, the residues in the 1- and 6-positions being linked by an --S--S-- bridge when the polypeptide is monocyclic, have pharmacological, in particular GH--, gastric- and pancreatic-secretion inhibiting activity.

## Claims

### Claim 1

A polypeptide of formula (I) ##STR39## wherein A is C.sub.1-12 alkyl, C.sub.7-10 phenylalkyl or a group of formula RCO--, whereby
(i) R is hydrogen, C.sub.1-11 alkyl, phenyl or
C.sub.7-10 phenylalkyl, or
(ii) RCO-- is
(a) an L- or D-phenylalanine residue optionally ring-substituted by halogen, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl and/or C.sub.1-3 alkoxy
(b) --Asn-- or the residue of a natural .alpha.-amino acid having a hydrocarbyl side chain other than defined under (a) above or of a corresponding D-amino acid, or
(c) a dipeptide residue in which the individual amino acid residues are the same or different and are selected from those defined under (a) and/or (b) above, the .alpha.-amino group of amino acid residues (a) and (b) and the N-terminal amino group of dipeptide residues (c) being optionally mono- or di-C.sub.1-12 alkylated,
A' is hydrogen or, when A is C.sub.1-12 alkyl or C.sub.7-10 phenylalkyl, also C.sub.1-12 alkyl or C.sub.7-10 phenylalkyl,
B is --Phe-- optionally ring-substituted by halogen, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl and/or C.sub.1-3 alkoxy,
C is --(L)-- or --(D)--Trp-- optionally .alpha.-N-methylated and optionally benzene-ring-substituted by halogen, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl and/or C.sub.1-3 alkoxy,
D is --Lys-- optionally .alpha.-N-methylated and optionally .epsilon.-N-C.sub.1-3 alkylated,
E is --Thr-- or --Ala-- each in (D)- or (L)- form and each being optionally .alpha.-N-methylated,
F is a group of formula ##STR40## wherein R.sub.1 is hydrogen or C.sub.1-3 alkyl,
R.sub.2 is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester,
R.sub.3 is hydrogen, C.sub.1-3 alkyl, phenyl, benzyl or C.sub.9-10 phenylalkyl,
R.sub.4 is hydrogen, C.sub.1-3 alkyl or, when R.sub.3 is hydrogen or methyl, also a group of formula --CH(R.sub.5)--X wherein
R.sub.5 is hydrogen, --(CH.sub.2).sub.2 --OH, --(CH.sub.2).sub.3 --OH, --CH.sub.2 --OH, --CH(CH.sub.3)--OH, isobutyl or benzyl and
X is a group of formula ##STR41## wherein R.sub.1 and R.sub.2 have the meanings given above,
R.sub.6 is hydrogen or C.sub.1-3 alkyl and
R.sub.7 is hydrogen, C.sub.1-3 alkyl, phenyl or C.sub.7-10 phenylalkyl, the group --CH(R.sub.5)--X having the D- or L-configuration, and
Y.sub.1 and Y.sub.2 are each hydrogen or together represent a direct bond,
whereby the residues in the 1- and 6-position each independently have the L- or D-configuration,
with the proviso (i) that D- and/or L-cysteine residues are present at the 1- and 6-positions only, and (ii) that when R.sub.5 is benzyl, X is a group of formula ##STR42## or a group of formula --COOR.sub.1, wherein R.sub.1 is C.sub.1-3 alkyl, or a pharmaceutically acceptable acid addition salt or complex thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein R.sub.3 is hydrogen, C.sub.1-3 alkyl or phenyl.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein, when R.sub.5 is benzyl, X is a group of formula ##STR43##

### Claim 4 (depends on 1)

A compound according to claim 1, wherein
R.sub.3 is hydrogen or methyl and
R.sub.4 is a group of formula --CH(R.sub.5)--X.

### Claim 5 (depends on 3)

A compound according to claim 3, wherein
R.sub.3 is hydrogen or methyl and
R.sub.4 is a group of formula --CH(R.sub.5)--X.

### Claim 6 (depends on 1)

A compound according to claim 1, wherein
A is a group of formula RCO--, whereby
(i) R is C.sub.1-11 alkyl or C.sub.7-10 phenylalkyl, or
(ii) RCO-- is
(a) an L- or D-N-(C.sub.1-8 alkyl)-phenylalanine residue, or
(b) a leucine or nor-leucine residue, said residues having the L- or D-configuration,
A' is hydrogen, and
F is a group of formula ##STR44##

### Claim 7 (depends on 6)

A compound according to claim 6, wherein
F is a group of formula ##STR45## wherein R.sub.3 is hydrogen or methyl,
R.sub.5 is --CH.sub.2 OH, --CH(CH.sub.3)--OH, isobutyl, benzyl --(CH.sub.2).sub.2 --OH or --(CH.sub.2).sub.3 --OH, and
X is a group of formula ##STR46## or a group of formula --CH.sub.2 --OR.sub.2, wherein R.sub.2 is hydrogen, HCO, C.sub.2-12 alkylcarbonyl, C.sub.8-12 phenylalkylcarbonyl or benzoyl.

### Claim 8 (depends on 1)

A compound according to claim 1, wherein
B is --Phe--,
C is --(D)Trp--,
D is --Lys--, --MeLys-- or --Lys(.epsilon.--Me)--, and
E is --Thr--.

### Claim 9 (depends on 6)

A compound according to claim 6, wherein
B is --Phe--,
C is --(D)Trp--,
D is --Lys--, --MeLys-- or --Lys(.epsilon.--Me)--, and
E is --Thr--.

### Claim 10 (depends on 1)

A compound according to claim 1, wherein X is a group of formula --CH.sub.2 OR.sub.2.

### Claim 11 (depends on 7)

A compound according to claim 7, wherein X is a group of formula --CH.sub.2 OR.sub.2.

### Claim 12 (depends on 1)

A polypeptide according to claim 1, wherein
A is C.sub.1-3 alkyl, C.sub.7-10 phenylalkyl or a group of formula RCO--,
A' is hydrogen,
R is hydrogen, C.sub.1-3 alkyl, phenyl or C.sub.7-10 phenylalkyl or
RCO is
(a) an L- or D-phenylalanine residue optionally mono-ring-substituted by halogen, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl or C.sub.1-3 alkoxy, or
(b) the residue of a natural .alpha.-amino acid having a hydrocarbyl side chain other than defined under (a) above or of a corresponding D-amino acid, the amino group of amino acid residues (a) and (b) being optionally mono-C.sub.1-3 alkylated,
F is a group of formula ##STR47## R.sub.2 is hydrogen, R.sub.3 is hydrogen or C.sub.1-3 alkyl,
R.sub.7 is hydrogen or C.sub.1-3 alkyl and
Y.sub.1 and Y.sub.2 together represent a direct bond,
and B, C, D, E, R.sub.1, R.sub.4, R.sub.5, R.sub.6 and X have the meanings given above in claim 1, as well as the acid addition salts and complexes thereof.

### Claim 13 (depends on 1)

A polypeptide according to claim 1 of formula ##STR48## or a salt form or a complex thereof.

### Claim 14 (depends on 1)

A polypeptide according to claim 1 of formula ##STR49## or a salt form or a complex thereof.

### Claim 15 (depends on 1)

A compound according to claim 1 selected from the group consisting of ##STR50## (u) H--(D)Phe--Cys--Phe--(D)Trp--Lys--Thr--Cys--Thr--ol or a pharmaceutically acceptable acid addition salt or complex thereof.

### Claim 16 (depends on 1)

A compound according to claim 1 of the formula ##STR51## wherein A is RCO-- and
R is C.sub.7-10 phenalkyl or
RCO is H--(D)Phe-- or H--(D)MePhe--, optionally ring substituted by halo; H--Nle--, H--Asn-- or H--Nle--Asn--;
B is Phe, optionally ring substituted by halo;
E is --Thr--, --(D)Thr-- or --(D)Ala--; and
F is ##STR52## where R.sub.3 is hydrogen;
R.sub.5 is --(CH.sub.2).sub.2 --OH, --CH.sub.2 --OH, --CH(CH.sub.3)--OH, isobutyl or benzyl; and
X is --CONH.sub.2 or --CH.sub.2 OR.sub.2
where
R.sub.2 is hydrogen or a physiologically acceptable, physiologically hydrolysable ester thereof and
Y.sub.1 and Y.sub.2 are each hydrogen or together are a direct bond,
wherein the amino acid residues represented by F and in the 1- and 6-position each independently have the L- or D-configuration or
a pharmaceutically acceptable acid addition salt or complex thereof.

### Claim 17 (depends on 1)

A compound according to claim 1 having the structure ##STR53## selected from the group in which A, E and F are respectively (a) H--(D)Phe--, --Thr--, and --(D)Ser--NH.sub.2 ;
(b) H--(D)Phe--, --Thr--, and --NH.sub.2 ;
(c) H--(D)Phe--, --Thr--, and --Phe--ol;
(d) H--(D)Phe--, --Thr--, and --Asp--diol;
(e) H--Nle--, --Thr--, and --(D)Ser--NH.sub.2 ;
(f) H--(D)Phe--, --(D)Ala--, and --(D)Ser--NH.sub.2 ;
(g) H--Asn--, --Thr--, and --(D)Ser--NH.sub.2 ;
(h) H--(D)MePhe--, --Thr--, and --Thr--ol;
(i) H--Nle--Asn--, --Thr--, and --Thr--ol;
(j) H--(D)Phe--, --(D)Ala--, and --Thr--ol;
(k) H--(D)Phe--, --Thr--, and --Ser--ol;
(l) H--(D)Phe--, --(D)Thr--, and --Thr--ol; ##STR54## (n) H--(D)Phe(pF)--, --Thr--, and --Thr--ol; or a pharmaceutically acceptable acid addition salt or complex thereof.

### Claim 18 (depends on 1)

A compound according to claim 1 in which E is --(L) or --(D)Thr-- or --(D)Ala--.

### Claim 19 (depends on 1)

A method of treating disorders with an aetiology comprising or associated with excess GH-secretion in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a polypeptide as claimed in claim 1 or of a pharmaceutically acceptable salt form or complex thereof.

### Claim 20 (depends on 1)

A method of treating gastro-intestinal disorders in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a polypeptide as claimed in claim 1 or of a pharmaceutically acceptable salt form or complex thereof.

### Claim 21 (depends on 1)

A pharmaceutical composition useful in the treatment of excess GH-secretion or gastro-intestinal disorders comprising a polypeptide as claimed in claim 1 or a pharmaceutically acceptable salt form or complex thereof together with a pharmaceutically acceptable diluent or carrier therefor.