# US 8,772,498 B2 · Alkylamine-substituted dicyanopyridine and amino acid ester prodrugs thereof

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- Number: US 8,772,498 B2
- Document ID: US8772498B2
- Status: Granted
- Kind: B2
- Application number: 13/801,484
- Filed: 2013-03-13
- Published: 2013-10-10
- Granted: 2014-07-08
- Earliest claimed: 2009-01-29
- Assignees: Bayer Intellectual Property GmbH
- Applicants: Bayer Intellectual Property GmbH
- Inventors: Alexandros Vakalopoulos; Daniel Meibom; Barbara Albrecht-Küpper; Katja Zimmermann; Jörg Keldenich; Hans-Georg Lerchen; Peter Nell; Frank Süβmeier; Ursula Krenz
- Web page: https://patentgrep.com/patent/US8772498B2

## CPC

- C07D 417/14: containing three or more hetero rings
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- 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 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/08: Vasodilators for multiple indications
- 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
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07K 5/0202: {containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids}
- C07K 5/06026: {the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala}
- C07K 5/06034: {the side chain containing 2 to 4 carbon atoms}
- C07K 5/06086: {with the first amino acid being basic}
- C07K 5/06147: {and His-amino acid; Derivatives thereof}
- C07K 5/06165: {and Pro-amino acid; Derivatives thereof}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)
- 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)

## Abstract

The present application relates to novel 6-alkylamino-substituted dicyanopyridines, to their amino acid ester prodrugs, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, preferably for the treatment and/or prevention of cardiovascular disorders.

## Claims

### Claim 1

A compound of formula (VII)
wherein,
R1 represents hydrogen or (C1-C4)-alkyl,
R2 represents (C1-C6)-alkyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl or (C3-C7)-cycloalkyl,
where (C1-C6)-alkyl may be substituted by 1 to 3 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, trifluoromethoxy, (C1-C4)-alkoxy, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkoxy, (C1-C4)-alkylsulfanyl and (C1-C4)-alkylsulfonyl,
and
where (C2-C4)-alkenyl and (C2-C4)-alkynyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, (C1-C4)-alkyl, trifluoromethoxy and (C1-C4)-alkoxy,
and
where (C3-C7)-cycloalkyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, (C1-C4)-alkyl, trifluoromethoxy and (C1-C4)-alkoxy,
or
R1 and R2 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S,
where the 4- to 7-membered heterocycle may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, oxo, trifluoromethyl, (C1-C4)-alkyl, trifluoromethoxy and (C1-C4)-alkoxy,
R4 represents hydrogen or the side group of a natural α-amino acid or its homologs or isomers,
R5 represents hydrogen or methyl,
R6A represents hydrogen, (C1-C4)-alkyl, or an amino protective group,
R7A represents hydrogen, (C1-C4)-alkyl, or an amino protective group,
or
R6A and R7A together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle,
where the 5- or 6-membered heterocycle may be substituted by 1 or 2 substituents independently selected from the group consisting of (C1-C4)-alkyl, amino, hydroxyl and (C1-C4)-alkoxy,
or
R7A together with R4 and the atoms, to which they are attached, forms a pyrrolidine or piperidine ring,
or a salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein
R1 represents hydrogen, methyl, or ethyl;
R2 represents (C1-C3)-alkyl, cyclopropyl, or cyclobutyl,
where (C1-C3)-alkyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl;
or
R1 and R2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom from the group consisting of N, O, and S,
where the 4- to 6-membered heterocycle may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, methoxy, and ethoxy;
R4 represents methyl or 3-aminopropan-1-yl;
R5 represents hydrogen;
R6A represents hydrogen, methyl, or an amino protecting group; and
R7A represents hydrogen, or an amino protecting group; or
R7A together with R4 and the atoms, to which they are attached, forms a pyrrolidine ring.

### Claim 3 (depends on 1)

The compound of claim 1, wherein
R1 represents hydrogen, methyl, or ethyl;
R2 represents methyl, ethyl, or n-propyl, where methyl, ethyl, and n-propyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, and methoxy;
or
R1 and R2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, or piperidinyl ring, where the azetidinyl, and piperidinyl ring may be substituted by a methoxy substituent.

### Claim 4 (depends on 1)

The compound of claim 1, wherein
R1 represents hydrogen, methyl or ethyl,
R2 represents (C1-C3)-alkyl, cyclopropyl or cyclobutyl,
where (C1-C3)-alkyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl.

### Claim 5

A compound of formula (VIII)
wherein
R1 represents hydrogen or (C1-C4)-alkyl,
R2 represents (C1-C6)-alkyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl or (C3-C7)-cycloalkyl,
where (C1-C6)-alkyl may be substituted by 1 to 3 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, trifluoromethoxy, (C1-C4)-alkoxy, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkoxy, (C1-C4)-alkylsulfanyl and (C1-C4)-alkylsulfonyl,
where (C2-C4)-alkenyl and (C2-C4)-alkynyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, (C1-C4)-alkyl, trifluoromethoxy and (C1-C4)-alkoxy,
and
where (C3-C7)-cycloalkyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, (C1-C4)-alkyl, trifluoromethoxy and (C1-C4)-alkoxy,
or
R1 and R2 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S,
where the 4- to 7-membered heterocycle may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, oxo, trifluoromethyl, (C1-C4)-alkyl, trifluoromethoxy and (C1-C4)-alkoxy;
L2 represents (C2-C6)-alkanediyl;
R17A represents hydrogen, (C1-C4)-alkyl, or an amino protective group, and
R18A represents hydrogen, (C1-C4)-alkyl, or an amino protective group; or
R17 and R18 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle, where the 5- or 6-membered heterocycle may be substituted by 1 or 2 substituents independently selected from the group consisting of (C1-C4)-alkyl, amino, hydroxyl, and (C1-C4)-alkoxy.

### Claim 6 (depends on 5)

The compound of claim 5, wherein
R1 represents hydrogen, methyl, or ethyl;
R2 represents (C1-C3)-alkyl, cyclopropyl, or cyclobutyl, where (C1-C3)-alkyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, chlorine, trifluoromethyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl;
or
R1 and R2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom from the group consisting of N, O, and S,
where the 4- to 6-membered heterocycle may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, methoxy, and ethoxy;
L2 represents ethane-1,2-diyl or propane-1,3-diyl,
R17 represents hydrogen, methyl, or an amino protecting group; and
R18 represents hydrogen, methyl, or an amino protecting group.

### Claim 7 (depends on 5)

The compound of claim 5, wherein
R1 represents hydrogen, methyl, or ethyl;
R2 represents methyl, ethyl, or n-propyl, where methyl, ethyl, and n-propyl may be substituted by 1 or 2 substituents selected independently of one another from the group consisting of fluorine, trifluoromethyl, and methoxy;
or
R1 and R2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, or piperidinyl ring, where the azetidinyl, and piperidinyl ring may be substituted by a methoxy substituent.