Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-07
2004-03-02
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S242000, C544S335000
Reexamination Certificate
active
06699873
ABSTRACT:
BACKGROUND
Melanocortins are known to have a broad array of physiological actions (Nakanishi, et al.
Nature
(1979) 278:423-427). Aside from their well known effects on adrenal cortical functions and on melanocytes, melanocortins have been shown to affect behavior, learning, memory, control of the cardiovascular system, analgesia, thermoregulation, and the release of other neurohumoral agents including prolactin, luetinizing hormone, and biogenic amines (De Weid et al.
Methods Achiev. Exp. Pathol
. (1991) 15:167-199; De Weid et al.
Physiol Rev
. (1982) 62:977-1059; Gruber, K. A. et al.
Am. J Physiol
. (1989) 257:R681-R694; Murphy et al.
Science
(1980) 210:1247-1249; Murphy et al.
Science
(1983) 221:192-193; Ellerkmann, E. et al.
Endocrinol
. (1992) 130:133-138; Versteeg, D. H. G. et al.
Life Sci
. (1986) 835-840). Peripherally, melanocortins have been identified to have immunomodulatory and neurotrophic properties, and to be involved in events surrounding partition (Cannon, J. G. et al.
J. Immunol
. (1986) 137:2232-2236; Gispen, W. H.
Trends Pharm. Sci
. (1992) 11:221-222; Wilson, J. F.
Clin. Endocrinol
. (1982) 17:233-242; Clark, D. et al.
Nature
(1978) 273:163-164; Silman, R. E. et al.
Nature
(1976) 260:716-718). Furthermore, melanocortins are present in a myriad of normal human tissues including the brain, ovary, lung, thyroid, liver, colon, small intestine and pancreas (Tatro, J. B. et al.
Endocrinol
. (1987) 121:1900-1907; Mountjoy, K. G. et al.
Science (
1992) 257:1248-1251; Chhajlani, V. et al.,
FEBS Lett
. (1992) 309:417-420; Gantz, L. et al.,
J. Biol. Chem
. (1993)268:8246-8250; Gantz, L. et al,
J. Biol. Chem
. (1993)268:15174-15179).
Recent studies have described an unexpected diversity of subtypes of receptors for the melanocortin peptides and determined that they belong to the superfamily of seven transmembrane G-protein linked cell surface receptors (Mountjoy, K. G. et al.
Science
(1992), supra; Chhajlani, V. et al.,
FEBS Lett
. (1992), supra). Five melanocortin receptor subtypes have been cloned. The melanocortin-1 (MC1) receptor is found in melanoma cells, where it has a role in mediating pigmentation. The melanocortin-2 receptor (MC2-R or ACTH receptor) is found in the adrenal glands where it mediates the effects of ACTH (adrenocorticotrophic hormone). The melanocortin-3 receptor (MC3-R) is primarily found in the central nervous system (CNS) (Gantz, L. et al.,
J. Biol. Chem
. (1993) 268:8246-8250), but its physiological function is still unknown. The melanocortin-4 receptor (MC4-R) has been found in the brain, where it is widely distributed in several areas, including the cortex, thalamus, hypothalamus, brain stem, and spinal cord (Gantz, L. et al.
J. Biol. Chem
. (1993) 268:15174-15179; Mountjoy, K. G. et al.
Mol. Endocrinol
. (1994) 8:1298-1308). MC4-R has recently been related to weight homeostasis. MC4-R “knock out” mice have been shown to develop obesity (Huszar et al.
Cell
(1997) 88:131-141). The feeding behavior leading to the obesity can be inhibited by injection of MSH peptides (Vergoni et al.
Neuropeptides
(1986) 7:153-158; Vergoni et al.
Eur. J. Pharmacol
(1990) 179:347-355; Fan et al.
Nature
(1997) 385:165-168). The melanocortin-5 receptor (MC5-R) has a wide peripheral distribution and is believed to participate in the regulation of the exocrine gland function (Chen et al.
Cell
(1997) 91:789-798).
SUMMARY
In one aspect, the invention pertains to a method for treating a melanocortin-4 receptor (MC4-R) associated state in a mammal. The method involves administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated. The MC4-R binding compound is of the formula (I):
B—Z—E (I)
wherein B is an anchor moiety, Z is a central moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts, thereof.
In a further embodiment, the MC4-R binding compound is of the formula (II):
B—A—E (II)
wherein B is an anchor moiety, A is cyclic moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts, thereof.
In another embodiment, the invention pertains to another method for treating an MC4-R associated state in a mammal, by administering to a mammal an effective amount of a MC4-R binding compound of formula (III):
B—L
1
—A—L
2
—E (III)
wherein B is an anchor moiety, L
1
and L
2
are linking moieties, A is a cyclic moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts thereof.
The invention also pertains to treating MC4-R associated states with an MC4-R binding compound of formula III, wherein B is substituted or unsubstituted biaryl, unsubstituted or substituted heterocyclic, or unsubstituted or substituted phenyl, wherein one or more of said substituents are halogens, hydroxy, alkyl, alkynyl, alkoxy, aryl, amino, cyano, or nitro; L
1
is a covalent bond, C
1
-C
10
branched or unbranched alkyl, wherein one or two of the carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; L
2
is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; E is substituted or unsubstituted alkyl, amino, amidino, guanidino, heterocyclic, or aryl, wherein said substituents are amino, arylalkyl, aminoalkyl, alkyl, aryl, alkenyl, or alkynyl; and A is a substituted or unsubstituted phenyl, heteroaryl, cycloalkyl, or biaryl, and pharmaceutically acceptable salts thereof.
In another embodiment, the invention pertains to a method for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated. In this embodiment, the compound is of the formula (IV):
wherein B is substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or heteroaryl; A is aryl, heteroaryl, biaryl, cycloalkyl, heterocyclic, or cycloalkenyl; L
1
and L
2
are selected from the group consisting of a covalent bond, C
1
-C
6
branched or unbranched alkyl, wherein one or two of the carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; r is a covalent bond, CH, CH
2
, CHR
1
, CR
1
R
2
, or H; t is CH, CH
2
, CHR
3
, CR
3
R
4
, or H; s is CHR
5
, CR
5
, CR
5
R
6
or absent (e.g., leaving a non cyclic diamine); R is H, substituted or unsubstituted alkyl, arylalkyl, or heteroalkyl, and may optionally be linked to A, B, L
1
, or L
2
; R
1
, R
2
, R
3
, R
4
, R
5
, and R
6
are each substituted or unsubstituted alkyl alkenyl, halogen, thiol, thioether, thioalkyl, or alkoxy, and may optionally be linked to form a carbocyclic or heterocyclic ring. Pharmaceutically acceptable salts of the MC4-R binding compound are also included.
The invention also pertains to methods for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound of the formula (V):
wherein B is substituted or unsubstituted biaryl, unsubstituted or substituted heterocyclic, or unsubstituted or substituted phenyl, wherein one or more of said substituents are halogens, alkyl, alkynyl, alkoxy, aryl, amino, cyano, or nitro; L
1
is a covalent bond, C
1
-C
10
branched or unbranched alkyl, wherein one or two of the carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; L
2
is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; E is substituted or unsubstituted alkyl, amino, amidino, guanidino, heterocyclic, or aryl, wherein said substituents are amino, arylalkyl, aminoalkyl, alkyl, aryl, alkenyl, or alkynyl; Π is a covalent bond, a carbon atom, a nitrogen atom, heterocyclic, alkyl, cycloalkyl, or aryl; L
3
is a covalent bond, C
1
-C
6
branched, unbranched or cyclic alkyl, wherein one, two or three of the carbons are optionally replaced with oxygen, sulfur or nitrogen atoms, carbonyl, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, or aminothiocarbonyl; and &Lgr; is heterocyclic, aryl, alkoxy, amino, alkyl, alkenyl, alkynyl, or hydrogen; and &lgr; is 0, 1 or 2, and pharmaceutically acceptable salts th
Dai Mingshi
Maguire Martin P.
Vos Tricia J.
Fish & Richardson P.C.
Millennium Pharmaceuticals Inc.
Rao Deepak
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