# US 2014/0155444 A1 · Tetrahydronaphthalene derivatives

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- Number: US 2014/0155444 A1
- Document ID: US20140155444A1
- Status: Published application
- Kind: A1
- Application number: 14/059,068
- Filed: 2013-10-21
- Published: 2014-06-05
- Earliest claimed: 2010-03-02
- Assignees: Concert Pharmaceuticals, Inc.
- Applicants: Concert Pharmaceuticals Inc.
- Inventors: Roger Tung; Craig E. Masse; Bhaumik A. Pandya
- Web page: https://patentgrep.com/patent/US20140155444A1

## CPC

- C07D 235/16: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- 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 9/06: Antiarrhythmics
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 235/14: Radicals substituted by nitrogen atoms (by nitro radicals C07D235/10)
- 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

## Abstract

This invention relates to novel tetrahydronaphthalene derivatives, and pharmaceutically acceptable salts thereof according to the following formulae, in one embodiment: as described herein. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a selective T-type calcium channel blocker.

## Claims

### Claim 1

A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Ra, Rb and Rc are each independently selected from —CH3 and —CD3;
Y1a and Y1b are each deuterium;
Y2a and Y2b are the same and are selected from hydrogen and deuterium;
Y3a and Y3b are each deuterium;
Y4a and Y4b are each deuterium;
and
R1 is selected from —CH3 and —CD3;
wherein any atom not designated as deuterium is present at its natural isotopic abundance.

### Claim 2 (depends on 1)

The compound of claim 1, wherein:
Ra, Rb and Rc are each —CH3.

### Claim 3

(canceled)

### Claim 4

(canceled)

### Claim 5

(canceled)

### Claim 6

(canceled)

### Claim 7 (depends on 1)

The compound of claim 1, wherein R1 is —CD3.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R1 is —CH3.

### Claim 9 (depends on 1)

The compound of claim 1, wherein each Y2 is hydrogen.

### Claim 10 (depends on 1)

The compound of claim 1, wherein each Y2 is deuterium.

### Claim 11

(canceled)

### Claim 12

(canceled)

### Claim 13 (depends on 2)

The compound of claim 2, wherein R1 is —CD3; and each Y2 is hydrogen.

### Claim 14 (depends on 2)

The compound of claim 2, wherein R1 is —CD3; and each Y2 is deuterium.

### Claim 15

(canceled)

### Claim 16

(canceled)

### Claim 17

(canceled)

### Claim 18 (depends on 2)

The compound of claim 2, wherein the compound is selected from any one of the compounds in the table below, or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance:
Cmpd #
Each Y1
R1
Each Y2
Each Y3
511
D
CH3
H
D
512
D
CD3
H
D
513
D
CH3
D
D
514
D
CD3
D
D

### Claim 19 (depends on 1)

A pyrogen free pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 20 (depends on 19)

The composition of claim 19, additionally comprising a second therapeutic agent selected from a beta blocker, an aldose reductase inhibitor, a NSAIDs, a 5HT1D agonist, a dopamine D2 receptor antagonist, a secale alkaloid, a second calcium channel blocker and a neurokinin antagonist.

### Claim 21 (depends on 19)

A method of treating a disease or condition selected from angina pectoris, ischemia, arrhythmias, congestive heart failure, high blood pressure, cardiac insufficiency, pain, visceral pain and diabetic complications in a subject comprising the step of administering to the subject in need thereof a composition of claim 19.

### Claim 22 (depends on 21)

The method of claim 21, wherein the disease or condition is selected from hypertension and angina pectoris.

### Claim 23 (depends on 21)

The method of claim 21, wherein the disease or condition is congestive heart failure.

### Claim 24 (depends on 21)

The method of claim 21, wherein the disease or condition is selected from arrhythmias, hypertension and angina pectoris, the method comprising the additional step of co-administering to the subject in need thereof a beta blocker.

### Claim 25

A compound of Formula A:
or a pharmaceutically acceptable salt thereof, wherein:
Ra, Rb and Rc are each independently selected from —CH3 and —CD3;
Y1a and Y1b are each deuterium;
Y2a and Y2b are each independently selected from hydrogen and deuterium;
Y3a and Y3b are each deuterium;
Y4a and Y4b are each deuterium;
Y5a and Y5b are each independently selected from hydrogen and deuterium;
Y6a and Y6b are each independently selected from hydrogen and deuterium;
Y7a and Y7b are each independently selected from hydrogen and deuterium;
Y8 is hydrogen;
Y9 is hydrogen;
and
R1 is selected from —CH3 and —CD3;
and wherein any atom not designated as deuterium is present at its natural isotopic abundance.

### Claim 26 (depends on 25)

A compound of claim 25 wherein Ra, Rb and Rc are each —CH3; each Y4 is deuterium; each Y1 is the same; each Y2 is the same; each Y3 is the same; each Y5 is hydrogen; each Y6 is deuterium; each Y7 is deuterium; each Y8 is hydrogen; each Y9 is hydrogen, and the compound is selected from any one of the compounds in the table below, or a pharmaceutically acceptable salt thereof:
Cmpd #
Each Y1
R1
Each Y2
Each Y3
611
D
CH3
H
D
612
D
CD3
H
D
613
D
CH3
D
D
614
D
CD3
D
D

### Claim 27 (depends on 25)

A pyrogen free pharmaceutical composition comprising a compound of claim 25 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 28 (depends on 27)

A method of treating a disease or condition selected from angina pectoris, ischemia, arrhythmias, congestive heart failure, high blood pressure, cardiac insufficiency, pain, visceral pain and diabetic complications in a subject comprising the step of administering to the subject in need thereof a composition of claim 27.

### Claim 29

A compound of Formula C:
or a pharmaceutically acceptable salt thereof, wherein
Rd and Re are each hydrogen;
Rf is ORc wherein Rc is —CH3;
Y3a and Y3b are each deuterium;
Y5a and Y5b are each independently selected from hydrogen and deuterium;
Y8 is hydrogen;
Y9 is hydrogen;
R1 is selected from —CH3 and —CD3; and
each of Y2a, Y2b, Y6a, Y6b, Y7a and Y7b is the same and is either hydrogen or deuterium, and wherein any atom not designated as deuterium is present at its natural isotopic abundance.

### Claim 30

(canceled)

### Claim 31 (depends on 29)

The compound of claim 29, wherein the compound is selected from any one of the compounds set forth in the table below, or a pharmaceutically acceptable salt thereof, wherein each of Y3a, Y3b, Y5a, and Y5b is deuterium:
Cmpd #
R1
Each of Y2a, Y2b, Y6a, Y6b, Y7a and Y7b
700b
CH3
H
CH2OCH3
701b
CH3
D
CH2OCH3
702b
CD3
H
CH2OCH3
703b
CD3
D
CH2OCH3

### Claim 32 (depends on 29)

A pyrogen free pharmaceutical composition comprising a compound of claim 29 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 33 (depends on 32)

A method of treating a disease or condition selected from angina pectoris, ischemia, arrhythmias, congestive heart failure, high blood pressure, cardiac insufficiency, pain, visceral pain and diabetic complications in a subject comprising the step of administering to the subject in need thereof a composition of claim 32.

### Claim 34

(canceled)

### Claim 35

(canceled)

### Claim 36

(canceled)

### Claim 37

(canceled)

### Claim 38

(canceled)