Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-08
2004-04-06
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S144000, C544S373000, C546S201000, C548S465000, C514S254010
Reexamination Certificate
active
06716840
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to melanocortin-4 receptor (MC4-R) agonists and methods of their preparation. The invention also relates to methods of treating melanocortin-4 receptor-mediated diseases, such as obesity or diabetes, by activating the melanocortin-4 receptor with compounds provided herein.
BACKGROUND OF THE INVENTION
Melanocortins are peptide products resulting from post-translational processing of pro-opiomelanocortin and are known to have a broad array of physiological activities. The natural melanocortins include the different types of melanocyte stimulating hormone (&agr;-MSH, &bgr;-MSH, &ggr;-MSH) and ACTH. Of these, &agr;-MSH and ACTH are considered to be the main endogenous melanocortins.
The melanocortins mediate their effects through melanocortin receptors (MC-R), a subfamily of G-protein coupled receptors. There are at least five different receptor subtypes (MC1-R to MC5-R). MC1-R mediates pigmentation of the hair and skin. MC2-R mediates the effects of ACTH on steroidogenisis in the adrenal gland. MC3-R and MC4-R are predominantly expressed in the brain. MC5-R is considered to have a role in the exocrine gland system.
The melanocortin-4 receptor (MC4-R) is a seven-transmembrane receptor. MC4-R may participate in modulating the flow of visual and sensory information, coordinate aspects of somatomotor control, and/or participate in the modulation of autonomic outflow to the heart.
Science
1992 257:1248-125. Significantly, inactivation of this receptor by gene targeting has resulted in mice that develop a maturity onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycemia.
Cell
Jan. 10, 1997; 88(1): 131-41. MC4-R has also been implicated in other disease states including erectile disorders, cardiovascular disorders, neuronal injuries or disorders, inflammation, fever, cognitive disorders, and sexual behavior disorders. Hadley M. E. and Haskell-Luevano C., The proopiomelanocortin system.
Ann N Y Acad Sci, Oct.
20, 1999; 885:1.
Furthermore, observations in connection with endogenous MCx-R antagonists indicate that MC4-R is implicated in endogenous energy regulation. For example, an agouti protein is normally expressed in the skin and is an antagonist of the cutaneous MC receptor involved in pigmentation, MC1-R. M. M. Ollmann et al.,
Science,
278:135-138 (1997). However, overexpression of agouti protein in mice leads to a yellow coat color due to antagonism of MC1-R and increased food intake and body weight due to antagonism of MC4-R. L. L. Kiefer et al.,
Biochemistry,
36: 2084-2090 (1997); D. S. Lu et al.,
Nature,
371:799-802 (1994). Agouti related protein (AGRP), an agouti protein homologue, antagonizes MC4-R but not MC1-R. T. M. Fong et al.,
Biochem. Biophys. Res. Commun.
237:629-631 (1997). Administration of AGRP in mice increases food intake and causes obesity but does not alter pigmentation. M. Rossi et al.,
Endocnnology,
139:4428-4431 (1998). Together, this research indicates that MC4-R participates in energy regulation, and therefore, identifies this receptor as a target for a rational drug design for the treatment of obesity.
In connection with MC4-R and its uncovered role in the etiology of obesity and food intake, the prior art has reported compounds or compositions that act as agonists or antagonists of MC4-R. As examples, U.S. Pat. No. 6,060,589 describes polypeptides that are capable of modulating signaling activity of melanocortin receptors. Also, U.S. Pat. Nos. 6,054,556 and 5,731,408 describe families of agonists and antagonists for MC4-R receptors that are lactam heptapeptides having a cyclic structure.
There is a need to for potent and specific agonists of MC4-R that are low molecular weight non-peptide small molecules. Methods of treating a melanocortin-4 receptor mediated disease, such as obesity, with such non-peptide drugs, are also particularly desirable.
SUMMARY OF THE INVENTION
The instant invention provides potent and specific agonists of MC4-R that are low molecular weight non-peptide small molecules. Thus, there has been provided, in accordance with one aspect of the invention, a compound of formula I:
wherein
X and Y are independently selected from the group consisting of CH
2
, N, NR
9
, C═O, C═S, S═O, SO
2
, S, O, (CR
6
R
7
)
n
, C(═O)—(CR
6
R
7
)
n
; and C(═S)—(CR
6
R
7
)
n
;
n is 1, 2, or 3;
W is selected from the group consisting of
L is selected from the group consisting of N, O, S, S═O, SO
2
, C(O), NC(O), NC(S), OC(O), OC(S), C(NR
10
), C(NOR
10
), and a covalent bond;
Z
1
, Z
2
, and Z
3
are independently selected from the group consisting of CR
8
and N;
R
1
is selected from the group consisting of H, and substituted and unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups;
R
2
is selected from the group consisting of H, and substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkylalkyl, aryl, and arylalkyl groups;
R
3
is selected from the group consisting of H, and substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, or R
2
and R
3
may join together to form a ring containing at least two N atoms;
R
4
is selected from the group consisting of H, and substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, or R
2
and R
4
may join together to form a ring containing at least two N atoms;
R
5
is selected from the group consisting of H, and substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups, or R
4
and R
5
, together with the nitrogen to which they are bound, form a substituted or unsubstituted heterocyclyl or heteroaryl group, or R
3
and R
5
may join together to form a ring containing at least two N atoms;
R
6
and R
7
may be the same or different, and are each independently selected from the group consisting of H, Cl, I, F, Br, OH, NH
2
, CN, NO
2
, and substituted and unsubstituted alkoxy, amino, alkyl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl, heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups;
R
8
is independently selected from the group consisting of H, Cl, I, F, Br, OH, NH
2
, CN, NO
2
, and substituted and unsubstituted alkoxy, amino, alkyl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl, heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups; and
R
9
and R
10
are independently selected from the group consisting of H, and substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, alkylcarbonyl, and arylcarbonyl groups.
Compounds provided by the invention further include prodrugs of the compound of formula I, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, hydrates thereof, hydrides thereof, or solvates thereof.
In one embodiment, X is CH
2
and Y is C═O.
In another embodiment, X is C═O and Y is CH
2
.
In another embodiment, X is C═O and Y is C═O.
In other embodiments, L is a covalent bond, and X and Y have the values according to any of the previous embodiments.
In another embodiment, Z
1
, Z
2
, and Z
3
are all CH, and X, Y, and L have the values according to any of the previous embodiments.
In another embodiment, at least one of Z
1
, Z
2
, or Z
3
is N, and X, Y, and L have the values according to any of the previous embodiments.
In another embodiment, X, Y, L, Z
1
, Z
2
, and Z
3
have any of the values of previous embodiments, and R
1
Boyce Rustum S.
Chang Bryan H.
Chu Daniel
Duhl David
Blackbur Robert P.
Chiron Corporation
Collier Steven W.
Friedrichsen Bernard P.
McKane Joseph K.
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