# US 7,410,962 B2 · Amidomethyl-substituted 1-(carboxyalkyl) cyclopentyl-carbonylamino-benzazepine-N-acetic acid compounds, process and intermediate products for their preparation and pharmaceutical compositions containing them

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- Number: US 7,410,962 B2
- Document ID: US7410962B2
- Status: Granted
- Kind: B2
- Application number: 11/773,231
- Filed: 2007-07-03
- Published: 2007-11-15
- Granted: 2008-08-12
- Earliest claimed: 2003-09-26
- Assignees: Solvay Pharmaceuticals GmbH
- Inventors: Dagmar Hoeltje; Yvan Fischer; Dieter Ziegler; Michael Weske; Katrin Michaelis; Yasmin Karimi-Nejad; Josef Messinger; Axel Pahl; Constanze Hoefer; Hrissanthi Ikonomidou; Lechoslaw Turski
- Web page: https://patentgrep.com/patent/US7410962B2

## CPC

- C07K 5/06139: {with the first amino acid being heterocyclic}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/12: Antihypertensives
- C07K 5/0222: {with the first amino acid being heterocyclic, e.g. Pro, Trp}
- 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

## Abstract

Compounds having neutral endopeptidase (NEP) and/or human soluble endopeptidase (hSEP) inhibitory activity corresponding to the formula I, wherein the substituents R1, R2, R3 and R4 have the meanings given in the description and also pharmaceutical compositions containing these compounds, in particular pharmaceutical compositions suitable for treating or inhibiting cardiovascular diseases, sexual dysfunction and/or adverse conditions associated with apoptosis.

## Claims

### Claim 1

A compound corresponding to the formula I:
wherein
R1 is hydrogen or a group forming a biolabile ester,
R2 is methyl,
R3 is —(CH2)3—N(CH3)2, and
R4 is hydrogen or a group forming a biolabile ester,
or a physiologically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein R1 is hydrogen, ethyl, methoxyethoxymethyl, (RS)-1-[[(isopropyl)carbonyl]oxy]ethyl, (RS)-1-[[(ethyl)-carbonyl]oxy]-2-methylpropyl, (RS)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl, 5-methyl-2-oxo-1,3-dioxolen-4-yl-methyl, 2-oxo-1,3-dioxolan-4-yl-methyl or (RS)-1-[[(ethoxy)carbonyl]oxy]ethyl.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein R4 is hydrogen, C1-4-alkyl, p-methoxybenzyl, N,N-di-(C0-4-alkyl)amino-C1-6-alkyl, (RS)-1-[[(isopropyl)carbonyl]oxy]ethyl, (RS)-1-[[(ethyl)carbonyl]oxy]-2-methylpropyl, (RS)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl, 5-methyl-2-oxo-1,3-dioxolen-4-yl-methyl, 2-oxo-1,3-dioxolan-4-yl-methyl or (RS)-1-[[(ethoxy)carbonyl]oxy]ethyl.

### Claim 4 (depends on 1)

A compound according to claim 1, which is 2-[1-(1-carboxymethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamoyl)-cyclopentylmethyl]-N-(3-dimethylamino-propyl)-N-methyl-succinamic acid, or a biolabile ester or physiologically acceptable salt thereof.

### Claim 5 (depends on 1)

A compound according to claim 1, wherein the chiral carbon atom bearing the amide side chain in position 3 of the benzazepine skeleton is in the “S” configuration.

### Claim 6 (depends on 4)

A compound according to claim 4, wherein the chiral carbon atom bearing the amide side chain in position 3 of the benzazepine skeleton is in the “S” configuration.

### Claim 7 (depends on 1)

A compound according to claim 1, which is 2-(2“rel1”)-[1-((3S)-1-carboxymethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamoyl)-cyclopentylmethyl]-N-(3-dimethylamino-propyl)-N-methyl-succinamic acid, or a biolabile ester or physiologically acceptable salt thereof.

### Claim 8

A pharmaceutical composition comprising a compound corresponding to formula I:
wherein
R1 is hydrogen or a group forming a biolabile ester,
R2 is methyl,
R3 is —(CH2)3—N(CH3)2, and
R4 is hydrogen or a group forming a biolabile ester,
or a physiologically acceptable salt thereof and
at least one pharmaceutical carrier or excipient.

### Claim 9

A method of treating or inhibiting a cardiovascular disorder or disease in a patient, wherein said cardiovascular disorder or disease is selected from the group consisting of congestive heart failure, and primary and secondary hypertension, said method comprising administering to said patient a pharmaceutically effective amount of a compound corresponding to formula I:
wherein
R1 is hydrogen or a group forming a biolabile ester,
R2 is methyl,
R3 is —CH2)3—N(CH3)2, and
R4 is hydrogen or a group forming a biolabile ester,
or a physiologically acceptable salt thereof.

### Claim 10

A method of treating or inhibiting an adverse condition associated with apoptosis in a patient, wherein said adverse condition is a neurodegenerative disorder selected from the group consisting of ischemic stroke, cerebral ischemia and traumatic brain injury, said method comprising administering to said patient a pharmaceutically effective amount of a compound corresponding to formula I:
wherein
R1 is hydrogen or a group forming a biolabile ester,
R2 is methyl,
R3 is —(CH2)3—N(CH3)2, and
R4 is hydrogen or a group forming a biolabile ester,
or a physiologically acceptable salt thereof.

### Claim 11

A method of preparing a compound corresponding to formula I:
wherein
R1 is hydrogen or a group forming a biolabile ester,
R2 is methyl,
R3 is (—CH2)3—N(CH3)2, and
R4 is hydrogen or a group forming a biolabile ester,
or a physiologically acceptable salt thereof;
said method comprising:
reacting a compound corresponding to formula H:
wherein R101 and R401, independently of each other, are each an acid-protecting group,
with a compound corresponding to formula III,
wherein R2 and R3 have the above meanings, and
if at least one of R101 and R401 is not a desired biolabile ester forming group, cleaving off such groups to release an acid group, and thereafter converting the acid group to a biolabile ester, and optionally converting an acid or base of Formula I into a corresponding physiologically acceptable salt, or optionally converting a salt of formula I into a corresponding free acid or base.