Substituted morpholines as modulators for the calcium sensing receptor

Patent metadata

Field	Value
Publication number	US-9382216-B2
Application number	US-201214003853-A
Country	US
Kind code	B2
Filing date	Mar 9, 2012
Priority date	Mar 10, 2011
Publication date	Jul 5, 2016
Grant date	Jul 5, 2016

Abstract

Compounds of Formula (I) along with processes for their preparation that are useful for treating, managing and/or lessening the diseases, disorders, syndromes or conditions associated with the modulation of calcium sensing (CaSR) receptors. Methods of treating, managing and/or lessening the diseases, disorders, syndromes or conditions associated with the modulation of calcium sensing (CaSR) receptors of Formula (I).

First claim

The invention claimed is:

1. A compound of Formula (I):

wherein,
Q is

R a is hydrogen;
R b is hydrogen;

L is a bond or —(CR c R d ) m ;
R c and R d are independently selected from hydrogen or substituted or unsubstituted alkyl;
R 1 is

ring Ar is phenyl or naphthyl;
R, 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, substituted or unsubstituted haloalkyl, —OR 6 , —C(O)R 6 , —(CR e R f ) 0-3 —C(O)OR 6 , —(CR e R f ) 1-2 cycloalkylene-C(O)OR 6 , -cycloalkylene (CR e R f ) 0-2 —C(O)OR 6 , —O(CR e R f ) 0-3 —C(O)OR 6 , —O-cycloalkylene-C(O)OR 6 , —C(O)NR 7 —(CR e R f ) 1-2 —C(O)OR 6 , —C(O)NR 7 R 8 , —S(O) 0-2 R 6 , and —S(O) 2 NR 7 R 8 ;
R e and R f are independently hydrogen or substituted or unsubstituted alkyl;
R 2 is substituted or unsubstituted aryl;
R 3 and R 4 are independently selected from hydrogen, halogen, and substituted or unsubstituted alkyl;
R 5 is substituted or unsubstituted alkyl or haloalkyl;
R 6 , which may be same or different at each occurrence, is independently selected from hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted haloalkyl;
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 cycloalkyl, and substituted or unsubstituted aryl;
Z is —CR g R h —;
R g and R h are hydrogen;
‘m’ is an integer ranging from 1 to 3, both inclusive;
‘n’ is an integer ranging from 1 to 3, both inclusive; and
‘q’ is an integer ranging from 0 to 4, both inclusive;

or its pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , having the Formula (II):

wherein,
L is a bond or —(CR c R d ) m ;
R 2 is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;
R c , R d , R, ‘m’, ‘n’ and ‘q’ are as defined in claim 1 ;
or pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein L is a bond or —(CR c R d ) m ; wherein R c , R d are hydrogen or substituted or unsubstituted alkyl; and ‘m’ is 1 or 2.

4. The compound of claim 1 , wherein R 1 is

wherein ring Ar is phenyl or naphthyl;
R, 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, substituted or unsubstituted haloalkyl, —OR 6 , —C(O)R 6 , —(CR e R f ) 0-3 —C(O)OR 6 , —(CR e R f ) 1-2 cycloalkylene-C(O)OR 6 , -cycloalkylene (CR e R f ) 0-2 —C(O)OR 6 , —O(CR e R f ) 0-3 —C(O)OR 6 , —O-cycloalkylene-C(O)OR 6 , —C(O)NR 7 —(CR e R f ) 1-2 —C(O)OR 6 , —C(O)NR 7 R 8 , —S(O) 0-2 R 6 , and —S(O) 2 NR 7 R 8 ;
wherein R 6 is hydrogen or alkyl; R 7 and R 8 are hydrogen or substituted or unsubstituted alkyl; R e and R f are independently hydrogen or substituted or unsubstituted alkyl; and ‘q’ is 0 to 3;

or its pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein Q is

where R 3 and R 4 are hydrogen; ‘n’ is 1 or 2; R 2 is substituted or unsubstituted aryl; R 5 is alkyl; R a is hydrogen; and R b is hydrogen.

6. The compound of claim 5 , wherein the aryl is substituted or unsubstituted wherein the substituents may be one or more, same or different and are independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy or substituted or unsubstituted haloalkoxy.

7. The compound of claim 1 , wherein L is a bond, —(CR c R d ) m , wherein R c and R d are hydrogen or substituted or unsubstituted alkyl, ‘m’ is 1 or 2;
and R 1 is

wherein ring Ar is phenyl or naphthyl;
R, 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, substituted or unsubstituted haloalkyl, —OR 6 , —C(O)R 6 , —(CR e R f ) 0-3 —C(O)OR 6 , —(CR e R f ) 1-2 cycloalkylene-C(O)OR 6 , -cycloalkylene (CR e R f ) 1-2 —C(O)OR 6 , —O(CR e R f ) 0-3 —C(O)OR 6 , —O-cycloalkylene-C(O)OR 6 , —C(O)NR 7 —(CR e R f ) 1-2 —C(O)OR 6 , —C(O)NR 7 R 8 , —S(O) 0-2 R 6 , and —S(O) 2 NR 7 R 8 ; wherein R 6 is hydrogen or alkyl; R 7 and R 8 are hydrogen or substituted or unsubstituted alkyl; R e and R f may be same or different and are independently hydrogen or substituted or unsubstituted alkyl; and ‘q’ is 0 to 3; or its pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein Q is

R a is hydrogen; R b is hydrogen; Z is —CH 2 —;
L is a bond or —(CR c R d ) m ;
R 1 is

ring Ar is phenyl or naphthyl;
R, 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, substituted or unsubstituted haloalkyl, —OR 6 , —CR e R f ) 0-3 —C(O)OR 6 , —(CR e R f ) 1-2 cycloalkylene-C(O)OR 6 , -cycloalkylene(CR e R f ) 1-2 —C(O)OR 6 , —O(CR e R f ) 0-3 —C(O)OR 6 , —O-cycloalkylene-C(O)OR 6 , —C(O)NR 7 —(CR e R f ) 1-2 —C(O)OR 6 , —C(O)NR 7 R 8 , —S(O) 0-2 R 6 , and —S(O) 2 NR 7 R 8 ; wherein R 6 is hydrogen or alkyl;
R 7 and R 8 are hydrogen or substituted or unsubstituted alkyl;
R e and R f may be same or different and are independently hydrogen or substituted or unsubstituted alkyl; ‘q’ is 0 to 3;
R 2 is substituted or unsubstituted aryl, wherein the substituent(s) may be one or more same or different and independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy and substituted or unsubstituted haloalkoxy;
R 3 and R 4 are hydrogen; and R 5 is substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl; or
a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein the pharmaceutically acceptable salt is hydrochloride salt.

10. A compound which is selected from:
(1R)-N-((4-(3-Fluorophenyl)morpholin-2-yl)methyl)-1-(naphthalen-1-yl)ethanamine hydrochloride;
(1R)-1-(Naphthalen-1-yl)-N-((4-(3-(trifluoromethyl)phenyl)morpholin-2-yl)methyl)ethanamine;
(1R)-1-(3-Methoxyphenyl)-N-((4-(3-methoxyphenyl)morpholin-2-yl)methyl)ethana

Assignees

• Shukla Manojkumar Ramprasad
• Chaudhari Vinod Dinkar
• Sayyed Majid Bashir
• Phadtare Ramesh Dattatraya
• Walke Navnath Bajirao
• Kulkarni Sanjeev Anant
• Palle Venkata P
• Kamboj Rajender Kumar
• Lupin Ltd

Inventors

• Shukla Manojkumar Ramprasad
• Chaudhari Vinod Dinkar
• Sayyed Majid Bashir
• Phadtare Ramesh Dattatraya
• Walke Navnath Bajirao
• Kulkarni Sanjeev Anant
• Palle Venkata P
• Kamboj Rajender Kumar

Classifications

• C07D265/30 Primary

  not condensed with other rings · CPC title

• A61P3/14

  for calcium homeostasis (vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04) · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/5375 Primary

  1,4-Oxazines, e.g. morpholine · CPC title

• A61P5/20

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