# US 9,040,482 B2 · Octapeptide compounds and therapeutic use thereof

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- Number: US 9,040,482 B2
- Document ID: US9040482B2
- Status: Granted
- Kind: B2
- Application number: 13/806,510
- Filed: 2011-06-21
- Published: 2013-09-26
- Granted: 2015-05-26
- Earliest claimed: 2010-06-22
- Assignees: Ipsen Pharma S.A.S.; Commissariat à l'Energie Atomique (CEA); Centre National de la Recherche Scientifique (CNRS)
- Applicants: Jean-Christophe Cintrat; Melinda Ligeti; Bernard Rousseau; Franck Artzner; Christophe Tarabout; Marie-Thérèse Paternostre; Nicolas Fay; Roland Cherif-Cheikh; Céline Valery
- Inventors: Jean-Christophe Cintrat; Melinda Ligeti; Bernard Rousseau; Franck Artzner; Christophe Tarabout; Marie-Thérèse Paternostre; Nicolas Fay; Roland Cherif-Cheikh; Céline Valery
- Web page: https://patentgrep.com/patent/US9040482B2

## CPC

- C07K 7/54: with at least one abnormal peptide link in the ring
- A61P 5/02: of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
- A61P 5/10: of the posterior pituitary hormones, e.g. oxytocin, ADH
- C07K 14/655: Somatostatins
- C07K 14/6555: {at least 1 amino acid in D-form}
- 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)
- 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)

## Abstract

The present invention relates to novel octapeptide compounds of general formula (I), R-AA1-cyclo(AA2-Tyr3-D-Trp4-AA5-Val6-Cys7)-Thr8-NH2 (I) As these products have a good affinity for certain sub-types of somatostatin receptors, they are particularly useful for treating the pathological states or diseases in which one (or more) of the somatostatin receptors is (are) involved. The invention also relates to pharmaceutical compositions containing said products and their use for the preparation of a medicament.

## Claims

### Claim 1

An octapeptide compound of general formula (I)
R-AA1-cyclo(AA2-Tyr3-D-Trp4-AA5-Val6-Cys7)-Thr8-NH2 (I)
wherein
(i) AA1 represents an amino acid radical linked to the radical R and to the amino acid AA2 according to the formula
wherein
R1 represents a naphthyl radical optionally substituted by one or more alkyl radicals; and
R represents a hydrogen atom, an alkyl or an acetyl radical;
(ii) AA2 represents an amino acid radical linked to the amino acids AA1 and Tyr3 according to the formula
wherein n2 represents an integer ranging from 1 to 2; and
(iii) AA5 represents an amino acid radical linked to the amino acids Trp4 and Val6 according to the formula
wherein R5 and R′5 represent independently a hydrogen atom, an alkyl or an acetyl radical, and n5 represents an integer ranging from 1 to 6;
and
if AA2 represents a cysteine amino acid radical, then either:
AA1 does not represent a naphthylalanine amino acid radical and AA5 represents a lysine amino acid radical;
AA1 represents a naphthylalanine amino acid radical and AA5 does not represent a lysine amino acid radical; or
AA1 does not represent a radical of naphthylalanine and AA5 does not represent a lysine radical;
or if AA2 does not represent a cysteine radical, then AA1 represents a naphthylalanine amino acid radical and AA5 represents a lysine amino acid radical,
and wherein all the amino acids are in D or L configuration; or
a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The octapeptide according to claim 1, wherein n5 represents an integer ranging from 1 to 4.

### Claim 3 (depends on 1)

The octapeptide according to claim 1, wherein AA2 represents a cysteine amino acid radical.

### Claim 4 (depends on 1)

The octapeptide according to claim 1, wherein AA2 does not represent a cysteine amino acid radical.

### Claim 5 (depends on 1)

The octapeptide according to claim 1, wherein AA1 does not represent a naphthylalanine amino acid radical and AA5 represents a lysine amino acid radical.

### Claim 6 (depends on 1)

The octapeptide according to claim 1, wherein AA1 represents a naphthylalanine amino acid radical and AA5 does not represent a lysine amino acid radical.

### Claim 7 (depends on 1)

The octapeptide according to claim 1, wherein AA1 does not represent a naphthylalanine amino acid radical and AA5 does not represent a lysine amino acid radical.

### Claim 8 (depends on 1)

The octapeptide according to claim 1, wherein AA1 represents the amino acid radical of 2-Nal, Ac-2-Nal or CH3-2-Nal.

### Claim 9 (depends on 1)

The octapeptide according to claim 1, wherein AA2 represents the amino acid radical of Cys or Hcy.

### Claim 10 (depends on 1)

The octapeptide according to claim 1, wherein AA5 represents the amino acid radical of Lys, Lys(Ac), Orn, (CH3)2Lys, Dab or Dap.

### Claim 11 (depends on 1)

The octapeptide according to claim 1, comprising:
H-D-2-Nal1-cyclo(Cys2-Tyr3-D-Trp4-Lys(Ac)5-Val6-Cys7)-Thr8-NH2;
Ac-D-2-Nal1-cyclo(Cys2-Tyr3-D-Trp4-Lys(Ac)5-Val6-Cys7)-Thr8-NH2;
H-D-2-Nal1-cyclo(Cys2-Tyr3-D-Trp4-Orn5-Val6-Cys7)-Thr8-NH2;
H-D-2-Nal1-cyclo(Cys2-Tyr3-D-Trp4-(Me)2Lys5-Val6-Cys7)-Thr8-NH2;
H-D-2-Nal1-cyclo(Hcy2-Tyr3-D-Trp4-Lys5-Val6-Cys7)-Thr8-NH2;
Ac-D-2-Nal1-cyclo(Cys2-Tyr3-D-Trp4-Lys5-Val6-Cys7)-Thr8-NH2;
CH3-D-2-Nal1-cyclo(Cys2-Tyr3-D-Trp4-Lys5-Val6-Cys7)-Thr8-NH2;
H-D-2-Nal1-cyclo(Cys2-Tyr3-D-Trp4-Dab5-Val6-Cys7)-Thr8-NH2; or
H-D-2-Nal1-cyclo(Cys2-Tyr3-D-Trp4-Dap5-Val6-Cys7)-Thr8-NH2;
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 11)

The octapeptide according to claim 11, comprising:
H-D-2-Nal1-cyclo(Cys2-Tyr3-D-Trp4-Orn5-Val6-Cys7)-Thr8-NH2;
H-D-2-Nal1-cyclo(Cys2-Tyr3-D-Trp4-(Me)2Lys5-Val6-Cys7)-Thr8-NH2;
H-D-2-Nal1-cyclo(Hcy2-Tyr3-D-Trp4-Lys5-Val6-Cys7)-Thr8-NH2; or
Ac-D-2-Nal1-cyclo(Cys2-Tyr3-D-Trp4-Lys5-Val6-Cys7)-Thr8-NH2;
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 12)

The octapeptide according to claim 12, comprising:
H-D-2-Nal1-cyclo(Hcy2-Tyr3-D-Trp4-Lys5-Val6-Cys7)-Thr8-NH2 or
a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

A medicament comprising a compound according to claim 1 and at least one pharmaceutically acceptable carrier.

### Claim 15 (depends on 1)

A composition comprising a compound according to claim 1, as active ingredient in combination with at least one pharmaceutically acceptable excipient.

### Claim 16 (depends on 1)

A method of treating a pathological state or disease related to a growth hormone, comprising administering an effective amount of the octapeptide of claim 1 in a subject in need thereof.

### Claim 17 (depends on 16)

The method according to claim 16, wherein the octapeptide binds to a somatostatin receptor.

### Claim 18 (depends on 15)

A method of treating a pathological state or disease related to a growth hormone, comprising administering the composition of claim 15.