Substituted chroman compounds as calcium sensing receptor modulators

Patent metadata

Field	Value
Publication number	US-9987249-B2
Application number	US-201715416684-A
Country	US
Kind code	B2
Filing date	Jan 26, 2017
Priority date	Feb 24, 2012
Publication date	Jun 5, 2018
Grant date	Jun 5, 2018

Abstract

The present invention provides calcium sensing receptor modulators (CaSR). In particular, the compounds described herein are useful for treating, managing, and/or lessening the severity of diseases, disorders, syndromes and/or conditions associated with the modulation of calcium sensing receptors (CaSR). The invention also provides herein the pharmaceutical compositions thereof, and methods for treating, managing, and/or lessening the severity of diseases, disorders, syndromes and/or conditions associated with the modulation of CaSR. The invention also relates to process for the preparation of the compounds of the invention.

First claim

The invention claimed is:

1. A compound of Formula (V):

wherein,
X is selected from a bond, —(CR c R d ) r —, —O—, —NR 7 —, —NR 7 (CR c R d ) r —, —O(CR c R d ) r —, —C(O)NR 7 —, —C(O)NR 7 (CR c R d ) r —, —(CR c R d ) r NR 7 (CR c R d ) r —, —(CR c R d ) r cycloalkylene-, cycloalkylene, -cycloalkylene(CR c R d ) r — and —O-cycloalkylene where cycloalkylene may be substituted or unsubstituted;
R c and R d , which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, haloalkyl and substituted or unsubstituted cycloalkyl; or R c and R d , together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 7 membered saturated carbocyclic ring;
Z is —OR 6 or —NR 10 R 11 ;
R 1 , which may be same or different at each occurrence, is independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, haloalkyl, substituted or unsubstituted cycloalkyl, —OR 6 , —C(O)R 9 , —NR 7 R 8 , —(CH 2 ) r NR 7 R 8 —, —(CH 2 ) r —C(O)OR 6 , —O—C(O)OR 6 , —O(CH 2 ) r —C(O)OR 6 , —C(O)NR 7 R 8 , —(CH 2 ) r —C(O)NR 7 R 8 , —NR 7 C(O)R 9 , —S(O) 0-2 R 7 , —S(O) 2 NR 7 R 8 and —NR 7 S(O) 2 R 9 ;
R 2 is substituted or unsubstituted aryl;
R 6 , which may be same or different at each occurrence, is independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl;
R 7 and R 8 , which may be same or different at each occurrence, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl; or R 7 and R 8 , together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted, saturated or unsaturated 3 to 12 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds;
at each occurrence, R 9 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
R 10 and R 11 may be same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —(CR c R d ) r —C(O)OR 6 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl; or R 10 and R 11 together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted, saturated or unsaturated 3 to 12 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds;
‘n’ is an integer ranging from 1 to 3, both inclusive;
‘q’ is an integer ranging from 0 to 3, both inclusive; and
‘r’ is an integer ranging from 1 to 3, both inclusive;
or its pharmaceutically acceptable salt thereof.

2. A compound of claim 1 having the Formula (VI):

or its pharmaceutically acceptable salt thereof,
wherein X, Z, R 1 , R 2 , ‘q’ and ‘n’ are as defined in claim 1 .

3. The compound of claim 1 , wherein ‘q’ is 0, 1 or 2.

4. The compound of claim 1 , wherein ‘n’ is 1, 2 or 3.

5. The compound of claim 1 , wherein R 1 is selected from halogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, cyano, —OR 6 , —C(O)alkyl, wherein R 6 is hydrogen, substituted or unsubstituted alkyl or haloalkyl; and ‘q’ is 0, 1, or 2.

6. The compound of claim 1 , wherein R 2 is substituted or unsubstituted aryl wherein the aryl is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.

7. The compound of claim 6 , wherein the substituent(s) on phenyl or naphthyl may be one or more and are independently selected from halogen, hydroxyl, substituted or unsubstituted alkyl, haloalkyl, and substituted or unsubstituted alkoxy.

8. The compound of claim 1 , wherein X is selected from a bond, —(CR c R d ) r —, —O—, —NR 7 —, —NR 7 (CR c R d ) r —, —O(CR c R d ) r —, —C(O)NR 7 —, —C(O)NR 7 (CR c R d ) r , —(CR c R d ) r NR 7 (CR c R d ) r , —(CR c R d ) r cycloalkylene-, cycloalkylene, -cycloalkylene(CR c R d ) r — and —O— cycloalkylene where cycloalkylene may be substituted or unsubstituted; R 7 is hydrogen or substituted or unsubstituted alkyl; R c and R d are hydrogen or alkyl and ‘r’ is 1, 2 or 3.

9. The compound of claim 1 , wherein Z is —OR 6 wherein R 6 is selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl and substituted or unsubstituted aryl.

10. The compound of claim 1 , wherein Z is NR 10 R 11 wherein R 10 and R 11 may be same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl, —(CR c R d ) r —C(O)OH, —(CR c R d ) r —C(O)O-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylalkyl; or R 10 and R 11 together with the nitrogen atom to which they are attached, may form a saturated or unsaturated 3 to 12 membered cyclic ring, where the unsaturated cyclic ring may have one or two double bonds; wherein R c and R d are hydrogen or substituted or unsubstituted alkyl and ‘r’ is 1, 2 or 3.

11. The compound of claim 1 , wherein R 1 is selected from halogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, cyano, —OR 6 , —C(O)alkyl wherein R 6 is hydrogen, substituted or unsubstituted alkyl, and haloalkyl; ‘q’ is 0, 1, or 2; R 2 is substituted or unsubstituted aryl; X is selected from a bond, —(CR c R d ) r , —O—, —NR 7 —, —NR 7 (CR c R d ) r , —O(CR c R d ) r , —C(O)NR 7 —, —C(O)NR 7 (CR c R d ) r — wherein R 7 is hydrogen or substituted or unsubstituted alkyl, R c and R d are hydrogen or substituted or unsubstituted alkyl, ‘r’ is 1, 2, or 3; Z is —OR 6 or NR 10 R 11 wherein R 6 is selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, and substituted or unsubstituted aryl; R 10 and R 11 may be same or different and are independently selected from hydrogen, substituted or unsubstituted alkyl, —(CR c R d ) r —C(O)OH, —(CR c R d ) r —C(O)O-alkyl, substituted or unsubstituted cycloalkyl or R 10 and R 11 together may form a substituted or unsubstituted, saturated or unsaturated 3 to 12 membered cyclic ring, where the unsaturated cyclic ring may have one or two double bonds; and ‘n’ is 1, 2 or 3.

12. The compound which is selected from:
2, 6-Dimethyl-3-((2R, 4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino) methyl) chroman-4-yl)benzoic acid hydrochloride;
2-Methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino) methyl)chroman-4-yl)benzoic acid hydrochloride;
3-((2R,4S)-2-((((R)-1-(4-Fluoro-3-methoxyphenyl) ethyl) amino)methyl)chroman-4-yl)-5-methylbenzoic acid hydrochloride;
5-((2R,4 S)-2-((((R)-1-(4-Fluoronaphthalen-1

Assignees

• Lupin Atlantis Holdings Sa
• Lupin Ltd

Inventors

• Shukla Manojkumar Ramprasad
• Sarde Ankush Gangaram
• Loriya Rajeshkumar Maganlal
• Pachpute Vipul Dilip
• Walke Navnath Bajirao
• Khan Talha Hussain
• Kulkarni Sanjeev Anant
• Palle Venkata P
• Kamboj Rajender Kumar

Classifications

• A61P5/18

  of the parathyroid hormones · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P5/20

  for decreasing, blocking or antagonising the activity of PTH · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title