# US 8,785,494 B2 · Calcium sensing receptor modulating compounds and pharmaceutical use thereof

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- Number: US 8,785,494 B2
- Document ID: US8785494B2
- Status: Granted
- Kind: B2
- Application number: 13/322,522
- Filed: 2010-05-26
- Published: 2012-05-24
- Granted: 2014-07-22
- Earliest claimed: 2009-05-27
- Assignees: Leo Pharma A/S
- Applicants: Bjarne Nørremark
- Inventors: Bjarne Nørremark
- Web page: https://patentgrep.com/patent/US8785494B2

## CPC

- A61K 31/195: having an amino group
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/12: Antidiarrhoeals
- A61P 3/02: Nutrients, e.g. vitamins, minerals
- A61P 3/14: for calcium homeostasis (vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04)
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/20: for decreasing, blocking or antagonising the activity of PTH
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 13/12: of the kidneys
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 229/46: having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C 2601/08: the ring being saturated
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The invention relates to novel calcium-sensing receptor (CaSR) modulating trifluoromethylphenylene cyclopentylene compounds represented in formula (I) and derivatives thereof, to said compounds for use as a medicament, to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds, to methods of treating diseases with said compounds, and to the use of said compounds in the manufacture of medicaments.

## Claims

### Claim 1

A compound according to formula I
wherein
A represents C6-10aryl, C1-9heterocycloalkylphenyl, C1-9heteroaryl or C3-7cycloalkyl, wherein said C6-10aryl, C1-9heterocycloalkylphenyl, C1-9heteroaryl or C3-7cycloalkyl is optionally further substituted with one or more, same or different substituents represented by halogen, hydroxy, mercapto, trifluoromethyl, cyano, carboxy, —C(O)H, —NH2, —C(O)NH2, nitro, oxo, —S(O)2NH2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6alkoxy, C1-4alkoxycarbonyl, C1-4alkylcarbonyloxy, C1-4alkoxycarbonyloxy, C1-4alkoxysulfonyloxy, C1-4alkoxycarbamoyl, C1-4aminocarbonyl, C1-4alkylthio, C3-7cycloalkyl, C3-7cycloalkenyl, C1-6amino, iminomethyl, C1-4aminosulfonyl, C1-4aminocarbonyloxy, C1-4alkylsulfonylamino, hydroxyiminomethyl, C1-4alkylcarbonylamino, C1-4alkylsulfonyl, C1-6 heterocycloalkyl, C2-6heterocycloalkenyl, C1-5heteroaryl or phenyl;
R1 represents one or more, same or different substituents selected from halogen, cyano, —NH2, carboxy, C1-6-amino, hydroxy, mercapto, —C(O)H, —C(O)NH2, nitro, oxo, hydroxymethyl, C1-6alkoxy, carboxyC1-4alkoxy, C1-6alkoxycarbonyl, C1-6alkoxycarbonylC1-6 alkoxy, carboxyC1-4alkyl, C1-6alkoxycarbonylC1-4alkyl, C1-6alkylcarbonyl, C1-6aminocarbonyl, hydroxyaminocarbonyl, C3-6cycloalkylaminocarbonyl, C1-6heterocycloalkylaminocarbonyl, C3-6cycloalkylamino, C1-6 heterocycloalkylcarbonyl, C6-14aryl, C1-9heteroaryl, C1-6heteroarylaminocarbonyl, —S(O)2NH2, C1-6ureido, C1-6thioureido, C1-4alkylcarbonyloxy, C1-4alkoxycarbonyloxy, C1-4alkoxysulfonyloxy, C1-6heterocycloalkyloxy, C1-6alkylthio, C1-6aminosulfonyl, C1-6aminocarbonyloxy, C1-6alkylsulfonylamino, C1-6alkylsulfonylaminoC1-3 alkyl, C6-10 arylamino, C6-10arylaminocarbonyl, C6-10aryloxycarbonyl, C1-4alkoxycarbamoyl, C6-10arylcarbonylamino, C6-10arylsulfonylamino, C1-6alkylcarbonylamino, C1-3 alkylcarbonylaminoalkyl, C2-6alkenylcarbonylamino, C3-6cycloalkenylcarbonylamino, C3-6 cycloalkylcarbonylamino, C1-4alkoxycarbonylamino, C1-6heterocycloalkylcarbonylamino, C1-6alkylsulfonyl, C1-6hetero cycloalkylsulfonyl or C1-4 alkylsulfonylamino carbonyl, iminomethyl, hydroxyiminomethyl, amidino, trifluoromethyl, C1-6alkyl, C2-4alkenyl, C2-6alkynyl, C1-6hydroxyalkyl, aminoC1-6alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, C3-7cycloalkenyl, C1-6 heterocycloalkyl, C2-6heterocycloalkenyl, methoxycarbonylC1-3 alkyl or carboxyC6-10aryl, wherein said C1-6amino, C1-6alkoxy, carboxyC1-4alkoxy, C1-6alkoxycarbonyl, C1-6alkylcarbonyl, C1-6aminocarbonyl, C3-6cycloalkylaminocarbonyl, C1-6 heterocycloalkylaminocarbonyl, C3-6cycloalkylamino, C1-6 heterocycloalkylcarbonyl, C6-14aryl, C1-9heteroaryl, C1-6heteroarylaminocarbonyl, C1-6ureido, C1-6thioureido, C1-4alkylcarbonyloxy, C1-4alkoxycarbonyloxy, C1-4alkoxysulfonyloxy, C1-6heterocycloalkyloxy, C1-6 alkylthio, C1-6aminosulfonyl, C1-6aminocarbonyloxy, C1-6alkylsulfonylamino, C1-6 alkylsulfonylamino C1-3alkyl, C6-10arylamino, C6-10arylaminocarbonyl, C6-10aryloxycarbonyl, C1-4alkoxycarbamoyl, C6-10 arylcarbonylamino, C6-10arylsulfonylamino, C1-6alkylcarbonylamino, C2-6alkenylcarbonylamino, C3-6cycloalkenylcarbonylamino, C3-6cycloalkylcarbonylamino, C1-6alkoxycarbonylamino, C1-6heterocycloalkylcarbonylamino, C1-6alkylsulfonyl, C1-6heterocycloalkylsulfonyl or C1-4alkylsulfonylaminocarbonyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6hydroxyalkyl, aminoC1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, C3-7cycloalkenyl, C1-6heterocycloalkyl, C2-6heterocycloalkenyl, or carboxyC6-10aryl are optionally substituted with one or more, same or different substituents selected from the group consisting of halogen, trifluoromethyl, hydroxy, cyano or C1-4alkyl;
R2 represents one or more, same or different substituents selected from hydrogen, cyano, halogen, carboxy, —C(O)NH2, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-6hydroxyalkyl, C1-6haloalkyl, aminoC1-6alkyl, C3-6cycloalkyl, C1-6heterocycloalkyl, C1-6alkoxy, C1-6aminocarbonyl, C6-10aryloxycarbonyl, C1-6amino, C6-10 arylamino, C1-4 alkoxycarbonylamino, C1-4 alkylcarbonylamino, C2-4 alkenylcarbonylamino, C3-6 cycloalkylcarbonylamino or C1-6 heterocycloalkylcarbonylamino,
or pharmaceutically acceptable stereoisomers, salts or in vivo hydrolysable esters thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, of formula Ia

### Claim 3 (depends on 1)

A compound according to claim 1, of formula Ib,

### Claim 4 (depends on 1)

A compound according to claim 1, wherein R2 represents hydrogen.

### Claim 5 (depends on 1, 2, 3, 4)

A compound according to any one of claims 1-4, wherein R1 represents halogen, cyano, —NH2, carboxy, hydroxy, —C(O)H, oxo, hydroxymethyl, C1-4alkoxy, C1-4amino, mercapto, —C(O)NH2, nitro, carboxyC1-4alkoxy, C1-4alkoxycarbonyl, C1-4alkoxycarbonylC1-4alkoxy, carboxyC1-4alkyl, C1-4alkoxycarbonylC1-4alkyl, C1-4alkylcarbonyl, C1-4aminocarbonyl, hydroxyaminocarbonyl, C3-6 cycloalkylaminocarbonyl, C1-5heterocycloalkylaminocarbonyl, C3-6 cycloalkylamino, C1-5heterocycloalkylcarbonyl, C6-10 aryl, C3-9heteroaryl, C1-5heteroarylaminocarbonyl, —S(O)2NH2, C1-4ureido, C1-4thioureido, C1-4 alkylcarbonyloxy, C1-4alkoxycarbonyloxy, C1-4alkoxysulfonyloxy, C1-5heterocycloalkyloxy, C1-4alkylthio, C1-4aminosulfonyl, C1-4aminocarbonyloxy, C1-4 alkylsulfonylamino, C1-4alkylsulfonylaminoC1-3alkyl, C6-10arylamino, C6-10arylaminocarbonyl, C6-10aryloxycarbonyl, C1-3alkoxycarbamoyl, C6-10arylcarbonylamino, C6-10arylsulfonylamino, C1-4alkylcarbonylamino, C1-3alkylcarbonylaminomethyl, C2-4alkenylcarbonylamino, C3-6cycloalkenylcarbonylamino, C3-6 cycloalkylcarbonylamino, C1-4alkoxycarbonylamino, C1-5heterocycloalkylcarbonylamino, C1-4 alkylsulfonyl, C1-5heterocycloalkylsulfonyl or C1-4alkylsulfonylaminocarbonyl, iminomethyl, hydroxyiminomethyl, amidino, trifluoromethyl, C1-5alkyl, C2-4alkenyl, C2-4alkynyl, C1-4hydroxyalkyl, aminoC1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6cycloalkenyl, C1-5heterocycloalkyl or C2-5heterocycloalkenyl.

### Claim 6 (depends on 1)

A compound according to claim 1, wherein R1 represents hydroxy, C1-4alkyl or C1-4alkoxy, wherein said C1-4alkyl or C1-4alkoxy is optionally substituted with carboxy or C1-4alkoxycarbonyl.

### Claim 7 (depends on 6)

A compound according to claim 6, wherein R1 represents carboxyethyl, hydroxy, carboxymethoxy, carboxylsopropoxy, methoxycarbonylethyl, or ethoxycarbonylethyl.

### Claim 8 (depends on 1)

A compound according to claim 1, wherein A represents C6-10aryl optionally further substituted with one or more, same or different substituents represented by halogen, hydroxy, trifluoromethyl, cyano, carboxy, —C(O)H, —NH2, —C(O)NH2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6hydroxyalkyl, C1-6haloalkyl, C1-4alkoxy or phenyl.

### Claim 9 (depends on 8)

A compound according to claim 8, wherein A represents naphthyl or phenyl, wherein said naphthyl or phenyl is optionally substituted with one or more, same or different substituents represented by halogen, hydroxy, trifluoromethyl, cyano, carboxy, —NH2, C1-6alkyl, C1-6hydroxyalkyl, C1-6haloalkyl or C1-4alkoxy.

### Claim 10 (depends on 9)

A compound according to claim 9, wherein A represents naphthyl, 4-fluoro-3-methoxy-phenyl or 4-fluoro-2-methoxy-phenyl.

### Claim 11 (depends on 1)

A compound according to claim 1 selected from the group consisting of:
3-{4-[(1R, 3R)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-2-trifluoromethyl-phenyl}-propionic acid methyl ester,
3-{4-[(1R, 3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-2-trifluoromethyl-phenyl}-propionic acid methyl ester,
3-{4-[(1S, 3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-2-trifluoromethyl-phenyl}-propionic acid methyl ester,
3-{4-[(1S, 3R)-3 ((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-2-trifluoromethyl-phenyl}-propionic acid methyl ester,
3-{4-[(1R, 3R)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-2-trifluoromethyl-phenyl}-propionic acid,
3-{4-[(1R, 3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-2-trifluoromethyl-phenyl}-propionic acid,
3-{-4-[(1S, 3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-2-trifluoromethyl-phenyl}-propionic acid,
3-{4-[(1S, 3R)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-2-trifluoromethyl-phenyl}-propionic acid,
3-(4-{(1S, 3R)-3-[(R)-1-(4-fluoro-3-methoxy-phenyl)-ethylamino]-cyclopentyl}-2-trifluoromethyl-phenyl)-propionic acid methyl ester,
3-(4-{(1S, 3S)-3-[(R)-1-(4-fluoro-3-methoxy-phenyl)-ethylamino]-cyclopentyl}-2-trifluoromethyl-phenyl)-propionic acid methyl ester,
3-[4-[(1S, 3R)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]cyclopentyl]-2-(trifluoromethyl)phenyl]propionic acid,
3-[4-[(1S, 3S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]cyclopentyl]-2-(trifluoromethyl)phenyl]propanoic acid,
3-[4-[(1S, 3S)-3-[[(1R)-1-(4-fluoro-2-methoxy-phenyl)ethyl]amino]cyclopentyl]-2-(trifluoromethyl)phenyl]propanoic acid,
3-[4-[(1S, 3R)-3-[[(1R)-1-(4-fluoro-2-methoxy-phenyl)ethyl]amino]cyclopentyl]-2-(trifluoromethyl)phenyl]propanoic acid,
ethyl 3-[4-[(1R, 3R)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]cyclopentyl]-2-(trifluoromethyl)phenyl]propanoate,
ethyl 3-[4-[(1R, 3S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]cyclopentyl]-2-(trifluoromethyl)phenyl]propanoate,
3-[4-[(1R, 3S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]cyclopentyl]-2-(trifluoromethyl)phenyl]propanoic acid,
3-[4-[(1R, 3R)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]cyclopentyl]-2-(trifluoromethyl)phenyl]propanoic acid,
4-[(1S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]cyclopentyl]-2-(trifluoromethyl)phenol (mixture of two diastereomers),
2-[4-[(1S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]cyclopentyl]-2-(trifluoromethyl)phenoxy]-2-methyl-propanoic acid (mixture of two diastereomers), and
2-[4-[(1S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]cyclopentyl]-2-(trifluoromethyl)phenoxy]acetic acid (mixture of two diastereomers).

### Claim 12 (depends on 1)

A compound according to claim 1 selected from the group consisting of:
2-[3-[(1R)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]-cyclopentyl]-5-(trifluoromethyl)phenoxy]acetic acid,
{3-[(1R,3R/S)-3-((1R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-5-trifluoromethyl-phenoxy}-acetic acid, and
3-[5-[(1R)-3-[[(1R)-1-(1-naphthyl)ethyl]amino]cyclopentyl]-2-(trifluoromethyl)phenyl]propanoic acid.

### Claim 13 (depends on 1)

An intermediate for the preparation of compounds according to claim 1 selected from the group consisting of:
3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-phenyl]-acrylic acid methyl ester,
3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-phenyl]-propionic acid methyl ester,
rac-3-[4-(3-oxo-cyclopentyl)-2-trifluoromethyl-phenyl]-propionic acid methyl ester,
3-[4-((1S)-3-oxo-cyclopentyl)-2-trifluoromethyl-phenyl]-propionic acid methyl ester,
2-[4-bromo-3-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,
(R)-3-(4-bromo-3-trifluoromethyl-phenyl)-cyclopentanone,
(R)-3-[4-(3-oxo-cyclopentyl)-2-trifluoromethyl-phenyl]-acrylic acid ethyl ester,
ethyl 3-[4-[(1R)-3-oxocyclopentyl]-2-(trifluoromethyl)phenyl]propanoate,
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-phenol, or
(S)-3-(4-hydroxy-3-trifluoromethyl-phenyl)-cyclopentanone,
Ethyl 2-[3-[(1R)-3-oxocyclopentyl]-5-(trifluoromethyl)phenoxy]acetate,
4-Bromo-2-iodo-1-trifluoromethyl-benzene,
3-(5-Bromo-2-trifluoromethyl-phenyl)-acrylic acid methyl ester,
3-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-phenyl]-acrylic acid methyl ester,
Methyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl propanoate, and
3-[5-((1R)-3-Oxo-cyclopentyl)-2-trifluoromethyl-phenyl]-propionic acid methyl ester.

### Claim 14 (depends on 1)

A method of treating or ameliorating hyperparathyroidism the method comprising administering to a patient in need thereof an effective amount of a compound according to claim 1.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable stereoisomer, salt or in vivo hydrolysable ester thereof, together with a pharmaceutically acceptable vehicle or excipient.

### Claim 16 (depends on 1)

A method of treating or ameliorating parathyroid carcinoma, parathyroid adenoma, primary parathyroid hyperplasia, chronic renal failure, chronic kidney disease, polycystic kidney disorder, podocyte-related diseases, primary hyperparathyroidism, secondary hyperparathyroidism, tertiary hyperparathyroidism, anemia, cardiovascular diseases, osteitis fibrosa, adynamic bone disease, osteoporosis, steroid induced osteoporosis, senile osteoporosis, post menopausal osteoporosis, osteomalacia, bone loss post renal transplantation, gastrointestinal diseases, cancer, Alzheimer's disease, IBS, IBD, malassimilation, malnutrition, diarrhea, vascular calcification, abnormal calcium homeostasis, and hypercalcemia, the method comprising administering to a patient in need thereof an effective amount of a compound according to claim 1.