# US 9,040,663 B2 · Melanocortin receptor-specific peptides

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- Number: US 9,040,663 B2
- Document ID: US9040663B2
- Status: Granted
- Kind: B2
- Application number: 13/886,864
- Filed: 2013-05-03
- Published: 2013-09-12
- Granted: 2015-05-26
- Earliest claimed: 2009-06-08
- Assignees: AstraZeneca AB
- Applicants: AstraZeneca AB
- Inventors: John H. Dodd; Yi-Qun Shi; Wei Yang
- Web page: https://patentgrep.com/patent/US9040663B2

## CPC

- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- C07K 7/56: the cyclisation not occurring through 2,4-diamino-butanoic acid
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/50: for increasing or potentiating the activity of insulin
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/20: Hypnotics; Sedatives
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 7/06: having 5 to 11 amino acids
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)
- 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 invention relates to melanocortin receptor-specific cyclic peptides of Formula (I) or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4a, R4b, R4c, R5, x and y are as defined in the specification. These compounds are particularly useful in the treatments of energy homeostasis and metabolism related (e.g. diabetes), food intake related and/or energy balance and body weight related diseases, disorders and/or conditions, including obesity, overweight and diseases, disorders and/or conditions associated with obesity and/or overweight, such as type 2 diabetes and metabolic syndrome.

## Claims

### Claim 1

A cyclic peptide of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
R1 is —NH—C(═O)— or —C(═O)—NH—;
R2 is —H or —CH2—, wherein if R2 is —CH2—, then R2 forms with R3 a pyrrolidine ring, wherein the pyrrolidine ring is optionally substituted with —OH;
R3 is —(CH2)2— if R2 is —CH2—, and otherwise R3 is selected from the group consisting of: —(CH2)1-4NH2, CH3, —CH(CH3)2, —C(CH3)3, —CH2OH, —CH(OH)CH3, —(CH2)1-2CONH2, —CH2(imidazole), —(CH2)1-2CO2H, —CH2OBz, —CH(CH3)OBz, —CH2Ph(CONH2), —(CH2)2NHCOCH3, —(CH2)3NHC(═NH)NH2 and —(CH2)2SO2CH3;
R4a, R4b and R4c are each independently selected from the group consisting of: —H, —Cl, —F, —CN, —OH, —CF3, —CH3, —OCH3, —NO2, -Ph and —NH2, with the provisos that at least one of R4a, R4b and R4c is not hydrogen and that R4a, R4b and R4c cannot all be —Cl, —CH3 or —OCH3
R5 is —OH or —N(R6a)(R6b);
R6a and R6b are each H;
x is 1 to 4; and
y is 1 to 4.

### Claim 2 (depends on 1)

The cyclic peptide of claim 1 which is of Formula (II):
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The cyclic peptide of claim 1,
wherein:
R1 is —C(═O)—NH—;
x is 2; and
y is 3.

### Claim 4 (depends on 1)

The cyclic peptide of claim 1,
wherein:
R1 is —NH—C(═O)—;
x is 3; and
y is 2.

### Claim 5 (depends on 1)

The cyclic peptide of claim 1,
wherein:
R2 is H or —CH2—, wherein if R2 is —CH2—, then R2 forms with R3 a pyrrolidine ring, wherein the pyrrolidine ring is optionally substituted with —OH; and
R3 is —(CH2)2— if R2 is —CH2—, and otherwise R3 is selected from the group consisting of: —(CH2)1-4NH2, —CH3, —CH2OH, —CH(OH)CH3, —(CH2)1-2CONH2, —(CH2)2NHCOCH3, —(CH2)3NHC(═NH)NH2 and —(CH2)2SO2CH3.

### Claim 6 (depends on 1)

The cyclic peptide of claim 1,
wherein:
R2 is H; and
R3 is selected from the group consisting of:

### Claim 7 (depends on 1)

The cyclic peptide of claim 1, wherein R2 and R3 together form an unsubstituted pyrrolidine ring.

### Claim 8 (depends on 1)

The cyclic peptide of claim 1 wherein R4a is in the 4-position and is —C≡N and wherein R4b and R4c are each —H.

### Claim 9 (depends on 1)

The cyclic peptide of claim 1, wherein R4a is in the 4-position and is —F and wherein R4b and R4c are each —H.

### Claim 10

A cyclic peptide selected from the group consisting of:
Ac-Arg-cyclo(Glu-Asn-D-Phe(4-CN)-Arg-Trp-Orn)-NH2(SEQ ID NO:48);
Ac-Arg-cyclo(Glu-Gln-D-Phe(4-CN)-Arg-Trp-Orn)-NH2 (SEQ ID NO:51);
Ac-Arg-cyclo(Glu-Asn-D-Phe(4-F)-Arg-Trp-Orn)-NH2(SEQ ID NO:74);
Ac-Arg-cyclo(Glu-Asn-D-Phe(4-CN)-Arg-Trp-Orn)-OH (SEQ ID NO:90);
Ac-Arg-cyclo(Glu-Gln-D-Phe(4-CN)-Arg-Trp-Orn)-OH (SEQ ID NO:91);
Ac-Arg-cyclo(Glu-Gln-D-Phe(4-F)-Arg-Trp-Orn)-NH2 (SEQ ID NO:97);
Ac-Arg-cyclo(Glu-Pro-D-Phe(4-CN)-Arg-Trp-Orn)-NH2(SEQ ID NO:44);
Ac-Arg-cyclo(Glu-Pro-D-Phe(4-F)-Arg-Trp-Orn)-NH2(SEQ ID NO:72); and
Ac-Arg-cyclo(Glu-Pro-D-Phe(4-F)-Arg-Trp-Orn)-OH (SEQ ID NO:107);
or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a cyclic peptide or a pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically acceptable carrier.