# US 4,393,050 A · Analogs of extended N-terminal somatostatin

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- Number: US 4,393,050 A
- Document ID: US4393050A
- Status: Granted
- Kind: A
- Application number: 06/258,878
- Filed: 1981-04-29
- Granted: 1983-07-12
- Earliest claimed: 1981-04-29
- Assignees: The Salk Institute for Biological Studies
- Inventors: Wylie W. Vale, Jr.; Jean E. F. Rivier; Marvin R. Brown
- Web page: https://patentgrep.com/patent/US4393050A

## CPC

- C07K 14/6555: {at least 1 amino acid in D-form}
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/02: of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
- 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 930/16: Somatostatin; related peptides
- 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

Somatostatin-28 has the formula: ##STR1## Analogs have been synthesized that are more potent than somatostatin-28, and these analogs or pharmaceutically acceptable salts thereof, dispersed in a pharmaceutically acceptable liquid or solid carrier, can be administered to mammals in the same manner as somatostatin. In the analogs, Leu may be substituted in the 8-position in combination with D-Trp in the 22-position and/or Tyr in the 25-position. D-Cys may also be substituted in the 28-position, and D-Ser may be substituted in the 27-position. Certain residues may also be deleted. D-Trp.sup.22 somatostation-28 has surprisingly been found to be insulin-selective when administered in vivo and is useful for the treatment of insulinoma.

## Claims

### Claim 1

A pharmaceutical composition for decreasing gastric acid secretion comprising an effective amount of an analog of SS-28 having the formula: ##STR6## wherein R.sub.18 is Lys or des R.sub.18, R.sub.19 is Asn or des R.sub.19, R.sub.25 is Phe or Tyr, R.sub.26 is Thr or des R.sub.26, R.sub.27 is Ser or D--Ser and R.sub.28 is D--Cys or Cys, or a nontoxic addition salt thereof, and a pharmaceutically acceptable liquid or solid carrier therefor.

### Claim 2 (depends on 1)

The composition of claim 1 wherein R.sub.18 is Lys, R.sub.19 is Asn, R.sub.26 is Thr, R.sub.27 is Ser and R.sub.28 is Cys.

### Claim 3 (depends on 2)

The composition of claim 2 wherein R.sub.25 is Phe.

### Claim 4 (depends on 2)

The composition of claim 2 wherein R.sub.25 is Tyr.

### Claim 5

A method of inhibiting the release of growth hormone, insulin, adrenal epenephrine and or glucagon in a mammal or modifying the temperature regulation or the gastrointestinal function of a mammal, which method comprises administering to said mammal an effective amount of a material selected from the class consisting of analogs of SS-28 having the formula: ##STR7## wherein R.sub.18 is Lys or des R.sub.18, R.sub.19 is Asn or des R.sub.19, R.sub.25 is Phe or Tyr, R.sub.26 is Thr or des R.sub.26, R.sub.27 is Ser or D-Ser and R.sub.28 is D-Cys or Cys and the nontoxic acid addition salts thereof.

### Claim 6 (depends on 5)

A method in accordance with claim 5 wherein said administering is carried out either orally, intravenously, subcutaneously, intranasally or intramuscularly.

### Claim 7 (depends on 5)

The method of claim 5 wherein R.sub.18 is Lys, R.sub.19 is Asn, R.sub.26 is Thr, R.sub.27 is Ser and R.sub.28 is Cys.

### Claim 8 (depends on 5)

The method of claim 5 wherein R.sub.25 is Phe.

### Claim 9 (depends on 5)

The method of claim 5 wherein R.sub.25 is Tyr.

### Claim 10

##STR8## wherein R.sub.18 is Lys or des R.sub.18, R.sub.19 is Asn or des R.sub.19, R.sub.25 is Phe or Tyr, R.sub.26 is Thr or des R.sub.26, R.sub.27 is Ser or D-Ser and R.sub.28 is D--Cys or Cys, or the linear version thereof where the disulfide bridge is replaced by hydrogen.

### Claim 11 (depends on 10)

The compound of claim 10 wherein R.sub.18 is Lys, R.sub.19 is Asn, R.sub.26 is Thr, R.sub.27 is Ser and R.sub.28 is Cys.

### Claim 12 (depends on 11)

The compound of claim 11 wherein R.sub.25 is Phe.

### Claim 13 (depends on 11)

The compound of claim 11 wherein R.sub.25 is Tyr.

### Claim 14

##STR9## wherein R.sub.8 is Met or Leu, R.sub.18 is Lys or des R.sub.18, R.sub.19 is Asn or des R.sub.19, R.sub.25 is Phe or Tyr, R.sub.26 is Thr or des R.sub.26, R.sub.27 is Ser or D-Ser and R.sub.28 is D-Cys or Cys, provided however that when R.sub.27 is Ser, R.sub.28 is D-Cys, or the linear version thereof where the disulfide bridge is replaced by hydrogen.

### Claim 15 (depends on 14)

The compound of claim 14 wherein R.sub.8 is Met, R.sub.18 is Lys, R.sub.25 is Phe, R.sub.27 is D-Ser and R.sub.28 is Cys.

### Claim 16 (depends on 14)

The compound of claim 14 wherein R.sub.8 is Met, R.sub.18 is des R.sub.18, R.sub.26 is des R.sub.26, R.sub.25 is Phe, R.sub.27 is Ser and R.sub.28 is D-Cys.