# US 5,708,135 A · Cyclic peptide analogs of somatostatin

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- Number: US 5,708,135 A
- Document ID: US5708135A
- Status: Granted
- Kind: A
- Application number: 08/578,037
- Filed: 1995-12-26
- Granted: 1998-01-13
- Earliest claimed: 1995-12-26
- Assignees: Biomeasure, Inc.; The Administrators of the Tulane Educational Fund
- Inventors: David H. Coy; John E. Taylor
- Web page: https://patentgrep.com/patent/US5708135A

## CPC

- C07K 14/6555: {at least 1 amino acid in D-form}
- 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

A cyclic peptide analog of somatostatin wherein a disulfide bond links the N-terminus residue and the C-terminus residue.

## Claims

### Claim 1

A peptide of the formula: ##STR2## in which A.sub.1 is the D- or L-isomer of Cys;
A.sub.2 is Asn, Gln, an aliphatic amino acid, an aromatic amino acid, or is deleted;
A.sub.3 is an aromatic amino acid;
A.sub.4 is His or an aromatic amino acid;
A.sub.7 is Thr, Ser, or an aliphatic amino acid;
A.sub.8 is an aromatic amino acid;
A.sub.9 is the D- or L-isomer or Cys;
each of R.sub.1 and R.sub.2 is, independently, H, C.sub.1-12 alkyl, C.sub.7-20 phenylalkyl, C.sub.11-20 naphthylalkyl, C.sub.1-12 hydroxyalkyl, C.sub.7-20 hydroxyphenylalkyl, C.sub.11-20 hydroxynaphthylalkyl, or COE.sub.1 where E.sub.1 is C.sub.1-12 alkyl, C.sub.7-20 phenylalkyl, C.sub.11-20 naphthylalkyl, C.sub.1-12 hydroxyalkyl, C.sub.7-20 hydroxyphenylalkyl, or C.sub.11-20 hydroxynaphthylalkyl; and
R.sub.3 is NH.sub.2 or NH--Y--CH.sub.2 --Z where Y is a C.sub.1-12 hydrocarbon moiety and Z is H, OH, CO.sub.2 H, or CONH.sub.2 ; and
a disulfide bond links the side chains of residues A.sub.1 and A.sub.9 ; or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A peptide of claim 1, wherein each of A.sub.3 and A.sub.8, independently, is Phe, p-X-Phe (where X is a halogen, OH, OCH.sub.3, CH.sub.3, NO.sub.2), o-X-Phe (where X is a halogen, OH, OCH.sub.3, CH.sub.3, or NO.sub.2), pyridyl-Ala, Trp, .beta.-Nal, 2,4-dichloro-Phe, Tyr(I), or F.sub.5 -Phe, and A.sub.4 is His, Phe, p-X-Phe (where X is a halogen, OH, OCH.sub.3, CH.sub.3, or NO.sub.2), o-X-Phe (where X is a halogen, OH, OCH.sub.3, CH.sub.3, or NO.sub.2), pyridyl-Ala, Trp, .beta.-Nal, 2,4-dichloro-Phe, Tyr(I), or F.sub.5 -Phe.

### Claim 3 (depends on 2)

A peptide of claim 2, wherein A.sub.2 is deleted, and A.sub.7 is Thr, Ser, Ala, Aib, Val, Leu, Ile, Nle, Nva, or Abu.

### Claim 4 (depends on 3)

A peptide of claim 3, wherein A.sub.9 is Cys.

### Claim 5 (depends on 4)

A peptide of claim 4, wherein each of A.sub.3 and A.sub.8, independently, is Phe, p-X-Phe (where X is a halogen, OH, OCH.sub.3, CH.sub.3, or NO.sub.2) Tyr(I), or Trp, and A.sub.4 is His, Phe, p-X-Phe (where X is a halogen, OH, OCH.sub.3, CH.sub.3, or NO.sub.2) Tyr(I), or Trp.

### Claim 6 (depends on 5)

A peptide of claim 5, wherein A.sub.7 is Thr or Ser.

### Claim 7 (depends on 6)

A peptide of claim 6, wherein A.sub.3 is Phe, A.sub.4 is Phe, His, p-X-Phe (where X is a halogen, OH, OCH.sub.3, CH.sub.3, or NO.sub.2), Tyr(I), or Trp, and A.sub.8 is Phe or p-X-Phe (where X is a halogen, OH, OCH.sub.3, CH.sub.3, or NO.sup.2).

### Claim 8 (depends on 7)

A peptide of claim 7 of the formula:
H.sub.2 -c›Cys-Phe-Trp-D-Trp-Lys-Thr-Phe-Cys!-NH.sub.2,
H.sub.2 -c›D-Cys-Phe-Trp-D-Trp-Lys-Thr-Phe-Cys!-NH.sub.2,
H.sub.2 -c›Cys-Phe-His-D-Trp-Lys-Thr-Phe-Cys!-NH.sub.2,
H.sub.2 -c›D-Cys-Phe-His-D-Trp-Lys-Thr-Phe-Cys!-NH.sub.2,
H.sub.2 -c›D-Cys-Phe-Phe-D-Trp-Lys-Ser-Phe-Cys!-NH.sub.2,
H.sub.2 -c›D-Cys-Phe-Trp-D-Trp-Lys-Ser-Phe-Cys!-NH.sub.2,
H.sub.2 -c›Cys-Phe-His-D-Trp-Lys-Ser-Phe-Cys!-NH.sub.2,
H.sub.2 -c›D-Cys-Phe-His-D-Trp-Lys-Ser-Phe-Cys!-NH.sub.2,
H.sub.2 -c›Cys-Phe-Tyr(I)-D-Trp-Lys-Thr-Phe-Cys!-NH.sub.2,
H.sub.2 -c›D-Cys-Phe-Tyr(I)-D-Trp-Lys-Thr-Phe-Cys!-NH.sub.2,
H.sub.2 -c›Cys-Phe-Tyr(I)-D-Trp-Lys-Ser-Phe-Cys!-NH.sub.2, or
H.sub.2 -c›D-Cys-Phe-Tyr(I)-D-Trp-Lys-Ser-Phe-Cys!-NH.sub.2.

### Claim 9 (depends on 6)

A peptide of claim 6, wherein A.sub.3 is Phe, A.sub.4 is Phe, Tyr(I) or Trp, and A.sub.8 is Phe.

### Claim 10 (depends on 9)

A peptide of claim 9, wherein each of R.sub.1 and R.sub.2, independently, is H, and R.sub.3 is NH.sub.2.

### Claim 11 (depends on 10)

A peptide of claim 10 of the formula:
______________________________________ H.sub.2 -c›Cys--Phe--Phe-D-Trp--Lys--Thr--Phe--Cys!--NH.sub.2, H.sub.2 -c›D-Cys--Phe--Phe-D-Trp--Lys--Thr--Phe--Cys!--NH.sub.2, H.sub.2 -c›Cys--Phe--Trp-D-Trp--Lys--Ser--Phe--Cys!--NH.sub.2, H.sub.2 -c›Cys--Phe--Phe-D-Trp--Lys--Ser--Phe--Cys!--NH.sub.2, or H.sub.2 -c›Cys--Phe--Tyr(I)-D-Trp--Lys--Thr--Phe--Cys!--NH.sub.2, ______________________________________

### Claim 12 (depends on 2)

A peptide of claim 2, wherein A.sub.2 is Asn, Gln, Ala, Aib, Val, Leu, Ile, Nle, Nva, Abu, Phe, p-X-Phe (where X is a halogen, OH, OCH.sub.3, CH.sub.3, or NO.sub.2), o-X-Phe (where X is a halogen, OH, OCH.sub.3, CH.sub.3, or NO.sub.2), pyridyl-Ala, Trp, .beta.-Nal, 2,4-dichloro-Phe, Tyr(I), or F.sub.5 -Phe, and A.sub.7 is Thr, Ser, Ala, Aib, Val, Leu, Ile, Nle, Nva, or Abu.

### Claim 13 (depends on 12)

A peptide of claim 12, wherein A.sub.9 is Cys.

### Claim 14 (depends on 13)

A peptide of claim 13, wherein each of A.sub.3, A.sub.4, and A.sub.8, independently, is Phe, p-X-Phe (where X is a halogen, OH, OCH.sub.3, CH.sub.3, or NO.sub.2), Tyr(I), or Trp, and A.sup.4 is His, Phe, or p-X-Phe (where X is a halogen, OH, OCH.sub.3, CH.sub.3, or NO.sub.2), Tyr(I), or Trp.

### Claim 15 (depends on 14)

A peptide of claim 14, wherein A.sub.2 is Asn or Gln, and A.sub.7 is Thr or Ser.

### Claim 16 (depends on 15)

A peptide of claim 15, wherein A.sub.3 is Phe, A.sub.4 is Phe, His, p-X-Phe (where X is a halogen, OH, OCH.sub.3, CH.sub.3, or NO.sub.2), Tyr(I), or Trp, and A.sub.8 is Phe or p-X-Phe (where X is a halogen, OH, OCH.sub.3, CH.sub.3, or NO.sub.2).

### Claim 17 (depends on 16)

A peptide of claim 16, wherein A.sub.3 is Phe, A.sub.4 is Phe, Tyr(I) or Trp, and A.sub.8 is Phe.

### Claim 18 (depends on 17)

A peptide of claim 17, wherein A.sub.2 is Asn, each of R.sub.1 and R.sub.2, independently, is H, and R.sub.3 is NH.sub.2.

### Claim 19 (depends on 18)

A peptide of claim 18 of the formula:
H.sub.2 -c›Cys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys!-NH.sub.2.

### Claim 20 (depends on 16)

A peptide of claim 16 of the formula:
H.sub.2 -c›D-Cys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys!-NH.sub.2,
H.sub.2 -c›Cys-Asn-Phe-Trp-D-Trp-Lys-Thr-Phe-Cys!-NH.sub.2,
H.sub.2 -c›D-Cys-Asn-Phe-Trp-D-Trp-Lys-Thr-Phe-Cys!-NH.sub.2,
H.sub.2 -c›Cys-Asn-Phe-His-D-Trp-Lys-Thr-Phe-Cys!-NH.sub.2,
H.sub.2 -c›D-Cys-Asn-Phe-His-D-Trp-Lys-Thr-Phe-Cys!-NH.sub.2,
H.sub.2 -c›Cys-Asn-Phe-Phe-D-Trp-Lys-Ser-Phe-Cys!-NH.sub.2,
H.sub.2 -c›D-Cys-Asn-Phe-Phe-D-Trp-Lys-Ser-Phe-Cys!-NH.sub.2,
H.sub.2 -c›Cys-Asn-Phe-Trp-D-Trp-Lys-Ser-Phe-Cys!-NH.sub.2,
H.sub.2 -c›D-Cys-Asn-Phe-Trp-D-Trp-Lys-Ser-Phe-Cys!-NH.sub.2,
H.sub.2 -c›Cys-Asn-Phe-His-D-Trp-Lys-Ser-Phe-Cys!-NH.sub.2,
H.sub.2 -c›D-Cys-Asn-Phe-His-D-Trp-Lys-Ser-Phe-Cys!-NH.sub.2,
H.sub.2 -c›Cys-Asn-Phe-Tyr(I)-D-Trp-Lys-Thr-Phe-Cys!-NH.sub.2,
H.sub.2 -c›D-Cys-Asn-Phe-Tyr(I)-D-Trp-Lys-Thr-Phe-Cys!-NH.sub.2,
H.sub.2 -c›Cys-Asn-Phe-Tyr(I)-D-Trp-Lys-Ser-Phe-Cys!-NH.sub.2, or
H.sub.2 -c›D-Cys-Asn-Phe-Tyr(I)-D-Trp-Lys-Ser-Phe-Cys!-NH.sub.2.

### Claim 21 (depends on 1)

A peptide of claim 1 of the formula:
H.sub.2 -c›Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys!-NH.sub.2.