IP Library › Granted Patent US 7,419,990

Granted Patent B2

US 7,419,990 · App. 10/560,290 · Granted Sep 2, 2008

Piperidine derivatives as melanocortin-4 receptor agonists

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Quick Facts

Patent No.: US 7,419,990
App. No.: 10/560,290
Granted: Sep 2, 2008
Kind: B2

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Abstract

Certain novel piperidine derivatives are agonists of the human melanocortin receptor(s) and, in particular, are selective agonists of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the activation of MC-4R, such as obesity, diabetes, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.

Claims (293)

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein:

R 1 is selected from the group consisting of:

(1) hydrogen,

(2) amidino,

(3) C 1-4 alkyliminoyl,

(4) C 1-10 alkyl,

(5) —(CH 2 ) n —NR 7 R 8 ,

(6) —(CH 2 ) n —C 3-7 cycloalkyl,

(7) —(CH 2 ) n -phenyl,

(8) —(CH 2 ) n -naphthyl, and

(9) —(CH 2 ) n -heteroaryl,

wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo;

R 2 is selected from the group consisting of:

(1) phenyl,

(2) naphthyl, and

(3) heteroaryl,

wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 ;

each R 3 is independently selected from the group consisting of:

(1) hydrogen,

(2) C 1-6 alkyl,

(3) —(CH 2 ) n -phenyl,

(4) —(CH 2 ) n -naphthyl,

(5) —(CH 2 ) n -heteroaryl,

(6) —(CH 2 ) n -heterocycloalkyl,

(7) —(CH 2 ) n C 3-7 cycloalkyl,

(8) halogen,

(9) OR 6 ,

(10) —(CH 2 ) n N(R 6 ) 2 ,

(11) —(CH 2 ) n C≡N,

(12) —(CH 2 ) n CO 2 R 6 ,

(13) NO 2 ,

(14) —(CH 2 ) n NR 6 SO 2 R 6 ,

(15) —(CH 2 ) n SO 2 N(R 6 ) 2 ,

(16) —(CH 2 ) n S(O) p R 6 ,

(17) —(CH 2 ) n NR 6 C(O)N(R 6 ) 2 ,

(18) —(CH 2 ) n C(O)N(R 6 ) 2 ,

(19) —(CH 2 ) n NR 6 C(O)R 6 ,

(20) —(CH 2 ) n NR 6 CO 2 R 6 ,

(21) —(CH 2 ) n NR 6 C(O)-heteroaryl,

(22) —(CH 2 ) n C(O)NR 6 N(R 6 ) 2 ,

(23) —(CH 2 ) n C(O)NR 6 NR 6 C(O)R 6 ,

(24) O(CH 2 ) n C(O)N(R 6 ) 2 ,

(25) CF 3 ,

(26) CH 2 CF 3 ,

(27) OCF 3 , and

(28) OCH 2 CF 3 ,

wherein phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy, and wherein any methylene (CH 2 ) carbon atom in R 3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl, or wherein two substituents when on the same methylene (CH 2 ) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group;

R 4 is selected from the group consisting of:

(1) —(CH 2 ) n —N(R 5 )—NR 5 R 6 ,

(2) —(CH 2 ) n —N(R 5 )—(CH 2 ) q —NR 5 R 6 ,

(3) —(CH 2 ) n —N(R 5 )—C(═NR 5 )—NR 5 R 6 ,

(4) —(CH 2 ) n —N(R 5 )—(CH 2 ) q —N(R 5 )—(C═NR 5 )—NR 5 R 6 ,

(5) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —C(R 5 )(N(R 5 ) 2 )—(CH 2 ) q —OR 6 ,

(6) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —C(R 5 )(N(R 5 ) 2 )(CH 2 ) n —R 6 ,

(7) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —C(R 5 )(N(R 5 ) 2 )(CH 2 ) q —S(O)p—R 6 ,

(8) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —C(R 5 )(N(R 5 ) 2 )(CH 2 ) q —NR 5 R 6 ,

(9) —(CH 2 ) n —N(R 5 )—C(O)(CH 2 ) n —C(R 5 )(N(R 5 ) 2 )(CH 2 ) n —R 6 ,

(10) —(CH 2 ) n —N(R 5 )—C(O)(CH 2 ) n —C(R 5 )(N(R 5 ) 2 )(CH 2 ) q —S(O)p—R 6 ,

(11) —(CH 2 ) n —N(R 5 )—C(O)(CH 2 ) n —C(R 5 )(N(R 5 ) 2 )(CH 2 ) q —NR 5 R 6 ,

(12) —(CH 2 ) n —N(R 5 )—C(O)(CH 2 ) n —C(R 5 )(N(R 5 ) 2 )(CH 2 ) q —O—R 6 , and

wherein (CH 2 ) n is unsubstituted or substituted with one to three groups independently selected from halogen, C 1-4 alkyl, hydroxy, oxo, and C 1-4 alkoxy;

R 5 is selected from the group consisting of:

(1) hydrogen,

(2) C 1-6 alkyl, and

(3) C(O)C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, C 1-4 alkyl, hydroxy, oxo, and C 1-4 alkoxy;

R 6 is selected from the group consisting of:

(1) hydrogen,

(2) C 1-6 alkyl,

(3) C(O)C 1-6 alkyl,

(4) —(CH 2 ) n C 3-7 cycloalkyl,

(5) —(CH 2 ) n C 2-7 heterocycloalkyl,

(6) —(CH 2 ) n -phenyl,

(7) —(CH 2 ) n -naphthyl,

(8) —(CH 2 ) n -heteroaryl, and

(9) —(CH 2 ) n C 3-7 bicycloalkyl,

wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, naphthyl, cycloalkyl, bicycloalkyl and (CH 2 ) n are unsubstituted or substituted with one to three groups independently selected from halogen, C 1-4 alkyl, hydroxy, and C 1-4 alkoxy, or wherein two R 6 groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and —NC 1-4 alkyl;

each R 7 and R 8 is independently selected from the group consisting of:

(1) hydrogen,

(2) amidino,

(3) C 1-4 alkyliminoyl,

(4) C 1-10 alkyl,

(5) —(CH 2 ) n —C 3-7 cycloalkyl,

(6) —(CH 2 ) n -phenyl,

(7) —(CH 2 ) n -naphthyl, and

(8) —(CH 2 ) n -heteroaryl,

R 9 is selected from the group consisting of:

Z represents N;

r is 1 or 2;

s is 0, 1, or 2;

n is 0, 1, 2, or 3;

p is 0, 1, or 2; and

q is 1, 2, 3, or 4.

2. The compound of claim 1 wherein R 1 is selected from the group consisting of: hydrogen, C 1-6 alkyl, —(CH 2 ) 0-1 C 3-6 cycloalkyl, and —(CH 2 ) 0-1 -phenyl, wherein phenyl is unsubstituted or substituted with one to three groups independently selected from R 3 , and alkyl and cycloalkyl are optionally substituted with one to three groups independently selected from R 3 and oxo; and pharmaceutically acceptable salts thereof.

3. The compound of claim 2 wherein R 2 is phenyl or thienyl, optionally substituted with one to three groups independently selected from R 3 ; and pharmaceutically acceptable salts thereof.

4. The compound of claim 3 wherein R 2 is phenyl optionally substituted with one to three groups independently selected from R 3 ; and pharmaceutically acceptable salts thereof.

5. The compound of claim 1 wherein each R 3 is independently selected from the group consisting of: C 1-6 alkyl, —(CH 2 ) n -phenyl, -(CH 2 ) n -heteroaryl, —(CH 2 ) n C 2-7 heterocycloalkyl, —(CH 2 ) n C 3-7 cycloalkyl, halogen, OR 5 , —(CH 2 ) n N(R 5 ) 2 , —(CH 2 ) n CO 2 R 5 , NO 2 , and CF 3 , wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH 2 ) n are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy, or wherein two substituents when on the same methylene (CH 2 ) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; and pharmaceutically acceptable salts thereof.

6. The compound of claim 1 wherein R 4 is selected from the group consisting of:

(1) —(CH 2 ) n —N(R 5 )—NH 2 ,

(2) —(CH 2 ) n —N(R 5 )—(CH 2 ) q —NH 2 ,

(3) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —NR 5 R 6 ,

(4) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —NHC 1-6 alkyl,

(5) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —N(C 1-6 alkyl) 2 ,

(6) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —NHC(O)C 1-6 alkyl,

(7) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —N(R 5 )C(O)C 1-6 alkyl,

(8) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —N(C(O)C 1-6 alkyl) 2 ,

(9) —(CH 2 ) n —N(R 5 )—C(═NH)—NH 2 ,

(10) —(CH 2 ) n —N(R 5 )—(CH 2 ) q —NH(C═NH)—NH 2, 2n 5 2n2

(11) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —C(R 5 )(NH 2 )(CH 2 ) q —OH,

(12) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —C(R 5 )(NH 2 )(CH 2 ) q —OC 1-6 alkyl,

(13) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —C(R 5 )(NH 2 )(CH 2 ) q —OR 6 ,

(14) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —C(R 5 )(NH 2 )(CH 2 ) n -heteroaryl,

(15) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —C(R 5 )(NH 2 )(CH 2 ) n —R 6 ,

(16) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —C(R 5 )(NH 2 )(CH 2 ) q —SH,

(17) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —C(R 5 )(NH 2 )(CH 2 ) q —S—C 1-6 alkyl,

(18) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —C(R 5 )(NH 2 )(CH 2 ) q —S—R 6 ,

(19) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —C(R 5 )(NH 2 )(CH 2 ) q —NH 2 ,

(20) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —C(R 5 )(NH 2 )(CH 2 ) q —NHR 6 ,

(21) —(CH 2 ) n —N(R 5 )—(CH 2 ) n —C(R 5 )(NH 2 )(CH 2 ) q —NR 5 R 6 ,

(22) —(CH 2 ) n —N(R 5 )—C(O)(CH 2 ) n —C(R 5 )(NH 2 )(CH 2 ) n -heteroaryl,

(23) —(CH 2 ) n —N(R 5 )—C(O)(CH 2 ) n —C(R 5 )(NH 2 )(CH 2 ) q —SH,

(24) —(CH 2 ) n —N(R 5 )—C(O)(CH 2 ) n —C(R 5 )(NH 2 )(CH 2 ) q —S—C 1-6 alkyl,

(25) —(CH 2 ) n —N(R 5 )—C(O)(CH 2 ) n —C(R 5 )(NH 2 )(CH 2 ) q —NR 5 R 6 , and

wherein alkyl and (CH 2 ) n are unsubstituted or substituted with one to three groups independently selected from halogen, C 1-4 alkyl, hydroxy, oxo, and C 1-4 alkoxy, and heteroaryl is unsubstituted or substituted with one to three groups independently selected from halogen, C 1-4 alkyl, hydroxy, and C 1-4 alkoxy; and pharmaceutically acceptable salts thereof.

7. The compound of claim 1 wherein R 6 is selected from the group consisting of: hydrogen, C 1-6 alkyl, C(O)C 1-6 alkyl, and —(CH 2 ) n -heteroaryl; and pharmaceutically acceptable salts thereof.

8. The compound of claim 1 wherein r is 1 and s is 1; and pharmaceutically acceptable salts thereof.

9. The compound of claim 1 wherein r is 2 and s is 1; and pharmaceutically acceptable salts thereof.

10. The compound of claim 1 of structural formula IIa or IIb of the indicated trans relative stereochemical configuration:

or a pharmaceutically acceptable salt thereof; wherein:

R 1 is selected from the group consisting of: hydrogen, amidino, C 1-4 alkyliminoyl, C 1-6 alkyl, C 5-6 cycloalkyl, —(CH 2 ) 0-1 phenyl, and —(CH 2 ) 0-1 heteroaryl, wherein phenyl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo;

each R 3 is independently selected from the group consisting of:

(1) hydrogen,

(2) C 1-6 alkyl,

(3) —(CH 2 ) n -phenyl,

(4) —(CH 2 ) n -naphthyl,

(5) —(CH 2 ) n -heteroaryl,

(6) —(CH 2 ) n -heterocycloalkyl,

(7) —(CH 2 ) n C 3-7 cycloalkyl,

(8) halogen,

(9) OR 64 ,

(10) —(CH 2 ) n N(R 64 ) 2 ,

(11) —(CH 2 ) n C≡N,

(12) —(CH 2 ) n CO 2 R 64 ,

(13) NO 2 ,

(14) —(CH 2 ) n NR 4 SO 2 R 64 ,

(15) —(CH 2 ) n SO 2 N(R 64 ) 2 ,

(16) —(CH 2 ) n S(O) 0-1 R 64 ,

(17) —(CH 2 ) n NR 64 C(O)N(R 64 ) 2 ,

(18) —(CH 2 ) n C(O)N(R 64 ) 2 ,

(19) —(CH 2 ) n NR 64 C(O)R 64 ,

(20) —(CH 2 ) n NR 64 CO 2 R 64 ,

(21) —(CH 2 ) n NR 64 C(O)-heteroaryl,

(22) —(CH 2 ) n C(O)NR 64 N(R 64 ) 2 ,

(23) —(CH 2 ) n C(O)NR 64 NR 64 C(O)R 64 ,

(24) O(CH 2 ) n C(O)N(R 64 ) 2 ,

(25) CF 3 ,

(26) CH 2 CF 3 ,

(27) OCF 3 , and

(28) OCH 2 CF 3 ,

R 4 is selected from the group consisting of:

(1) —(CH 2 )—N(R 5 )—NR 5 R 6 ,

(2) —(CH 2 )—N(R 5 )—(CH 2 ) 1-3 —NR 5 R 6 ,

(3) —(CH 2 )—N(R 5 )—C(═NR 5 )—NR 5 R 6 ,

(4) —(CH 2 )—N(R 5 )—(CH 2 ) 1-3 —N(R 5 )—(C═NR 5 )—NR 5 R 6 ,

(5) —(CH 2 )—N(R 5 )—(CH 2 ) 0-2 —C(R 5 )(N(R 5 ) 2 )—(CH 2 ) 1-2 —OR 6 ,

(6) —(CH 2 )—N(R 5 )—(CH 2 ) 0-2 —C(R 5 )(N(R 5 ) 2 )(CH 2 ) 1-2 —R 6 ,

(7) —(CH 2 )—N(R 5 )—(CH 2 ) 0-2 —C(R 5 )(N(R 5 ) 2 )(CH 2 ) 1-2 —S—R 6 ,

(8) —(CH 2 )—N(R 5 )—(CH 2 ) 0-2 —C(R 5 )(N(R 5 ) 2 )(CH 2 ) 1-4 —NR 5 R 6 ,

(9) —(CH 2 )—N(R 5 )—C(O)(CH 2 ) 0-2 —C(R 5 )(N(R 5 ) 2 )(CH 2 ) 1-2 —R 6 ,

(10) —(CH 2 )—N(R 5 )—C(O)(CH 2 ) 0-2 —C(R 5 )(N(R 5 ) 2 )(CH 2 ) 1-2 —S—R 6 ,

(11) —(CH 2 )—N(R 5 )—C(O)(CH 2 ) 0-2 —C(R 5 )(N(R 5 ) 2 )(CH 2 ) 1-4 —NR 5 R 6 , and

wherein (CH 2 ) n is unsubstituted or substituted with one to three groups independently selected from halogen, C 1-4 alkyl, hydroxy, oxo, and C 1-4 alkoxy;

R 5 is selected from the group consisting of:

(1) hydrogen,

(2) C 1-6 alkyl, and

(3) C(O)C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, C 1-4 alkyl, hydroxy, oxo, and C 1-4 alkoxy;

R 6 is selected from the group consisting of:

(1) hydrogen,

(2) C 1-6 alkyl,

(3) C(O)C 1-6 alkyl,

(4) —(CH 2 ) n C 3-7 cycloalkyl,

(5) —(CH 2 ) n C 2-7 heterocycloalkyl,

(6) —(CH 2 ) n -phenyl,

(7) —(CH 2 ) n -naphthyl,

(8) —(CH 2 ) n -heteroaryl, and

(9) —(CH 2 ) n C 3-7 bicycloalkyl,

each R 7 and R 8 is independently selected from the group consisting of:

(1) hydrogen,

(2) amidino,

(3) C 1-4 alkyliminoyl,

(4) C 1-10 alkyl,

(5) —(CH 2 ) n —C 3-7 cycloalkyl,

(6) —(CH 2 ) n -phenyl,

(7) —(CH 2 ) n -naphthyl, and

(8) —(CH 2 ) n -heteroaryl,

R 9 is selected from the group consisting of:

Z represents N;

r is 1 or 2;

s is 0, 1, or 2; and

n is 0, 1, 2, 3 or 4.

11. The compound of claim 1 of structural formula IIIa or IIIb of the indicated trans relative stereochemical configuration:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from the group consisting of: hydrogen, C 1-4 alkyl, and —(CH 2 ) 0-1 phenyl;

each R 3 is independently selected from the group consisting of:

(1) hydrogen,

(2) C 1-6 alkyl,

(3) —(CH 2 ) n -phenyl,

(4) —(CH 2 ) n -naphthyl,

(5) —(CH 2 ) n -heteroaryl,

(6) —(CH 2 ) n -heterocycloalkyl,

(7) —(CH 2 ) n C 3-7 cycloalkyl,

(8) halogen,

(9) OR 64 ,

(10) —(CH 2 ) n N(R 64 ) 2 ,

(11) —(CH 2 ) n C≡N,

(12) —(CH 2 ) n CO 2 R 64 ,

(13) NO 2 ,

(14) —(CH 2 ) n NR 64 SO 2 R 64 ,