Spiropiperidine derivatives as melanocortin receptor agonists

Details Spiropiperidine derivatives as melanocortin receptor agonists Spiropiperidine derivatives as melanocortin receptor agonists

1999-06-10

2001-09-25

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252180, C514S253010, C514S278000, C544S124000, C544S128000, C544S362000, C544S363000, C544S242000, C546S017000, C546S018000

Reexamination Certificate

active

06294534

ABSTRACT:

SUMMARY OF THE INVENTION
Spiropiperidine derivatives are melanocortin receptor agonists, and as such are useful in the treatment of disorders responsive to the activation of melanocortin receptors, such as obesity, diabetes as well as male and/or female sexual dysfunction.
BACKGROUND OF THE INVENTION
Pro-opiomelanocortin (POMC) derived peptides are known to affect food intake. Several lines of evidence support the notion that the G-protein coupled receptors (GPCRs) of the melanocortin receptor (MC-R) family, several of which are expressed in the brain, are the targets of POMC derived peptides involved in the control of food intake and metabolism. A specific single MC-R that may be targeted for the control of obesity has not yet been identified.
Evidence for the involvement of MC-Rs in obesity includes: i) the agouti (A
vy
) mouse which ectopically expresses an antagonist of the MC-1R, MC-3R and -4R is obese, indicating that blocking the action of these three MC-Rs can lead to hyperphagia and metabolic disorders; ii) MC-4R knockout mice (Huszar et al., Cell, 88, 131-141, 1997) recapitulate the phenotype of the agouti mouse and these mice are obese; iii) the cyclic heptapeptide MT-II (MC-1R, -3R, -4R, -5R, agonist) injected intracerebroventricularly (ICV) in rodents, reduces food intake in several animal feeding models (NPY, ob/ob, agouti, fasted) while ICV injected SHU-9119 (MC-3R, -4R antagonist; MC-1R and -5R agonist) reverses this effect and can induce hyperphagia; iv) chronic intraperitoneal treatment of Zucker fatty rats with an &agr;-NDP-MSH derivative (HP228) has been reported to activate MC-1R, -3R, -4R and -5R and to attenuate food intake and body weight gain over a 12 week period.
Five MC-Rs have thus far been identified, and these are expressed in different tissues. MC-1R was initially characterized by dominant gain of function mutations at the Extension locus, affecting coat color by controlling phaeomelanin to eumelanin conversion through control of tyrosinase. MC-1R is mainly expressed in melanocytes. MC-2R is expressed in the adrenal gland and represents the ACTH receptor. MC-3R is expressed in the brain, gut and placenta and may be involved in the control of food intake and thermogenesis. MC-4R is uniquely expressed in the brain and its inactivation was shown to cause obesity. MC-5R is expressed in many tissues including white fat, placenta and exocrine glands. A low level of expression is also observed in the brain. MC-5R knock out mice reveal reduced sebaceous gland lipid production (Chen et al., Cell, 1997, 91, 789-798).
Intramuscular administration of the MC-1R, -3R, -4R, -5R agonist, melanotan-II (MT-II; 0.005-0.03 mg/kg; Dorr et al., Life Sciences, vol. 58, #20, 1777-1784, 1996) caused intermittent non-painful penile erections in three normal male volunteers for a period of 1-5 hours after dosing. Intramuscular administration of MT-II (0.025 mg/kg and 0.1 mg/kg) to 10 non-organic impotent patients caused transient erections (8 responders) with onset from 50-180 minutes; penile erections subsided after ejaculation (15th American Peptide Symposium Jun. 14-19, 1997, Nashville, Tenn., study now published in J. Urology, 160, 389-393, 1998).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds having the formula I:
wherein
Cy
2
is a six-membered aromatic ring containing 0 or 1N atom or cyclohexane;
Q is
X is O, CH
2
, SO
2
, CHCO
2
R
b
, CHSO
2
R
a
, CHC(O)N(R
b
)
2
, NR
b
, NSO
2
R
a
, NSO
2
N(R
b
)
2
, NCOR
a
, NCON(R
b
)
2
, CHN(R
b
)COR
a
, CHN(R
b
)SO
2
R
a
, CHCH
2
OR
b
, or CH(CH
2
)-heteroaryl;
Y is (CH
2
)
r
, CH—C
1-8
alkyl, O, C═O or SO
2
, with the proviso that when Y is O, the ring atom of X is carbon;
R
1
is H, C
1-8
alkyl, CH(R
b
)-aryl, CH(R
b
)-heteroaryl, (CH
2
)
n
—C
5-6
cycloalkyl in which aryl and heteroaryl are optionally substituted by one or two R
c
groups;
R
2
is H or halo;
R
a
is R
b
, (CH
2
)
n
N(R
b
)
2
, (CH
2
)
n
N(R
b
)C(═NR
d
)NR
b
, (CH
2
)
n
NH-2-pyridyl, (CH
2
)
n
NH-2-imidazolyl, (CH
2
)
n
NH-2-thiazolyl, (CH
2
)
n
NH-2-pyrimidinyl,
R
b
is H, C
1-8
alkyl, (CH
2
)
n
aryl, (CH
2
)
n
heteroaryl, C
3-6
cycloalkyl; or 2 R
b
together with the nitrogen atom to which they are attached form a 5- or 6-membered ring optionally containing an additional heteroatom selected from O, S, and NR
1
;
R
c
is R
b
, halo, OR
b
, NHSO
2
R
b
, N(R
b
)
2
, CN, NO
2
, SO
2
N(R
b
)
2
, SO
2
R
b
, CF
3
, OCF
3
; or two R
c
groups attached to adjacent carbon atoms together form methylenedioxy;
R
d
is H, NO
2
, or CN;
Cy is aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl, or 5-or 6-membered carbocyclyl;
n is 0 to 3;
m, p and q are independently 0, 1 or 2;
r is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
In one subset of compounds of formula I are compounds wherein Cy
2
is benzene or cyclohexane.
In another subset of compounds of formula I are compounds wherein X is CHCO
2
R
b
, CHC(O)N(R
b
)
2
, NSO
2
R
a
, CHN(R
b
)COR
a
, CHN(R
b
)SO
2
R
a
, CHCH
2
OR
b
or CHCH
2
-heteroaryl.
In another subset of compounds of formula I are compounds wherein Q is
R
b
and R
c
are as defined under formula I, and Cy is aryl, 5- or 6-membered heteroaryl, or 5- or 6-membered carbocyclyl. Preferably Cy is benzene or cyclohexane.
In another subset of compounds of formula I are compounds wherein R
1
is CH
2
-aryl in which aryl is optionally substituted by R
c
.
In a preferred embodiment there are provided compounds of formula Ia:
wherein
X is CHCO
2
R
b
, CHC(O)N(R
b
)
2
, NSO
2
R
a
, CHN(R
b
)COR
a
, or CHN(R
b
)SO
2
R
a
;
R
2
is H or halo;
R
a
is R
b
, (CH
2
)
n
N(R
b
)
2
, (CH
2
)
n
NH-2-pyridyl, (CH
2
)
n
NH-2-imidazolyl, (CH
2
)
n
NH-2-thiazolyl, (CH
2
)
n
NH-2-pyrimidinyl,
R
b
is H, C
1-8
alkyl, (CH
2
)
n
aryl, (CH
2
)
n
heteroaryl, or C
3-6
cycloalkyl;
R
c
is H, halo, R
b
, OR
b
, CF
3
, OCF
3
;
Cy is benzene, pyridine, imidazole or cyclohexane;
n is 0 to 3;
or a pharmaceutically acceptable salt thereof.
In another preferred embodiment are compounds of the formula Ib:
wherein
X is CHCO
2
R
b
, CHC(O)N(R
b
)
2
, CHCH
2
OR
b
or CHCH
2
-heteroaryl;
R
b
is H, C
1-8
alkyl, (CH
2
)
n
aryl, (CH
2
)
n
heteroaryl, or C
3-6
cycloalkyl;
R
c
is H, halo, R
b
, OR
b
, CF
3
, OCF
3
;
Cy is benzene, pyridine, imidazole or cyclohexane;
n is 0 to 3;
or a pharmaceutically acceptable salt thereof.
In a more preferred embodiment of compounds of formulas Ia and Ib, the carbon atom marked with * has the R configuration. In another more preferred embodiment of formulas Ia and Ib Cy is benzene or cyclohexane.
Representative compounds of formula I are as follows:
Another aspect of the present invention provides a method for the treatment or prevention of obesity or diabetes in a mammal which comprises administering to said mammal an effective amount of a compound of formula I.
Another aspect of the present invention provides a method for the treatment or prevention of male or female sexual dysfunction including erectile dysfunction which comprises administering to a patient in need of such treatment or prevention an effective amount of a compound of formula I.
Another aspect of the present invention provides a method for the treatment or prevention of male or female sexual dysfunction including erectile dysfunction which comprises administering to a patient in need of such treatment or prevention an effective amount of an agonist of melanocortin-4 receptor.
Yet another aspect of the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.
Throughout the instant application, the following terms have the indicated meanings:
The alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
The term “halogen” is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
The te

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