Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-06
2003-05-27
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S392000, C544S393000, C544S394000, C544S391000, C546S192000, C546S226000, C546S236000, C514S317000, C435S007100, C435S007200, C206S568000, C206S570000
Reexamination Certificate
active
06569861
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to phenylcycloalkylmethylamino and phenylalkenylamino derivatives, including 1-phenyl-2-aminomethylcyclopropanes, that are modulators of melanin concentrating hormone type 1 (MCH 1) receptors. This invention also relates to pharmaceutical compositions comprising such compounds.
2. Description of the Related Art
Melanin concentrating hormone, or MCH, is a cyclic 19 amino acid neuropeptide that is produced within the hypothalamus of many vertebrate species including man. I.C.V. injection of MCH into the lateral ventricle of the hypothalamus has been shown to increase caloric consumption in rats over similarly treated control animals. Furthermore, rats having the ob/ob genotype exhibit a 50-80% increase in MCH mRNA expression as compared to leaner ob/+ genotype mice. MCH knockout mice are leaner than their MCH-producing siblings due to hypophagia and an increased metabolic rate. Thus, MCH is thought to be an important regulator of feeding behavior and body weight.
The MCH 1 receptor was originally obtained from human cDNA and genomic libraries and characterized as a 402 amino acid G-coupled protein receptor having substantial sequence identity to the somatostatin receptors. This receptor was named the SLC-1 receptor. A rat orthologue of the MCH 1 receptor was isolated from a rat brain cDNA library by Lakaye, et al. (BBA (1998) 1401: 216-220) and found to encode a 353 amino acid protein having seven transmembrane alpha helices and three consensus N-glycosylation sites. The rat MCH 1 receptor reported by Lakaye also disclosed was homologous to the human MCH 1 receptor disclosed earlier except for the removal of a 5′ intron. Accordingly, Lakaye, et al., deduced the “corrected” amino acid sequence of the N-terminus of MCH 1 receptor is found within a sequence deposited for a 128 kb fragment of human chromosome 22 encompassing the earlier disclosed MCH 1 receptor gene (Genbank accession number: Z86090).
The earlier reported 402 amino acid MCH 1 receptor protein does not interact with MCH. Thus, the 353 amino acid receptor first reported by Lakaye, is now considered to be the correct full-length sequence for the human MCH 1 receptor.
Immunohistochemistry studies of rat brain sections indicate that the MCH 1receptor is widely expressed in the brain. MCH 1 receptor expression was found in the olfactory tubercle, cerebral cortex, substantia nigra, basal forebrain CA1, CA2, and CA3 field of the hippocampus, amygdala, and in nuclei in the hypothalamus, thalamus, midbrain and hindbrain. Strong signals have been observed in the ventromedial and dorsomedial nuclei of the hypothalamus, two areas of the brain known to be involved in feeding behavior.
Upon binding MCH, MCH 1 receptors expressed in HEK 293 cell mediate a dose dependent release of intracellular calcium. Cells expressing MCH receptors have also been shown to exhibit a pertussis toxin sensitive dose-dependent inhibition of forskolin-elevated cyclic AMP, indicating that the receptor couples to a G
i/o
G-protein alpha subunit.
Because MCH has been shown to be an important regulator of food intake and energy balance, ligands capable of modulating the activity of the MCH 1 receptor are highly desirable for the treatment of eating disorders and metabolic disorders. Orally available, small molecule, non-peptide antagonists of the MCH 1 receptor are particularly sought for the treatment of obesity.
SUMMARY OF THE INVENTION
The invention provides novel compounds, particularly phenylcycloalkylmethylamino and phenylalkenylamino compounds, including 1-phenyl-2-aminomethylcyclopropanes, that are small molecule MCH receptor ligands, especially MCH 1 receptor ligands, that are non-peptide and amino acid free, which compounds exhibit a K
i
at the MCH receptor of less than 1 micromolar. Preferred MCH 1 receptors are mammalian receptors, including human and monkey MCH receptors and may either be cloned, recombinantly expressed receptors or naturally expressed receptors.
In certain embodiments these compounds also possess one or more, and preferably two or more, three or more, or all of the following properties in that they are: 1) multi-aryl in structure (having a plurality of un-fused or fused aryl groups), 2) orally available in vivo (such that a sub-lethal or pharmaceutically acceptable oral dose can provide a detectable in vivo effect such as a reduction of appetite), 3) capable of inhibiting the binding of MCH to the MCH receptor at nanonmolar concentrations or 4) capable of inhibiting the binding of MCH to the MCH receptor at sub-nanomolar concentrations.
The invention also provides novel compounds of Formula I, shown below, that bind specifically, and preferably with high affinity, to MCH receptors.
The invention also provides pharmaceutical compositions comprising compounds of Formula I together with at least one pharmaceutically acceptable carrier. The compounds are particularly useful in the treatment of metabolic, feeding, and sexual disorders. The invention further comprises a method of treating a patient in need of such treatment with a sufficient concentration of a compound of the invention. A preferred concentration is one sufficient to inhibit the binding of MCH to MCH 1 receptors in vitro. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering such conditions with an effective amount of a compound of the invention is contemplated by the invention.
Also included in the invention are methods of treating eating disorders, particularly obesity and bulimia nervosa, comprising administering to a patient in need of such treatment a MCH 1 receptor modulator together with leptin, a leptin receptor agonist, or a melanocortin receptor 4 (MC4) agonist.
In a separate aspect, the invention provides methods of using compounds of this invention as positive controls in assays for receptor activity and using appropriately labeled compounds of the invention as probes for the localization of receptors, particularly MCH receptors, in tissue sections.
The invention provides compounds and compositions that are useful as inhibitors of MCH binding to MCH 1 receptor, and as inhibitors of MCH mediated signal transduction (e.g., they may be used as standards in assays of MCH binding and MCH-mediated signal transduction). The invention additionally comprises methods of inhibiting MCH binding to MCH receptors in vivo, preferably MCH 1 receptors present in the hypothalamus.
Accordingly, a broad embodiment of the invention is directed to a compounds and pharmaceutically acceptable salts of Formula I:
wherein:
Q is a group of the Formula:
wherein
A is C
1
-C
5
alkylene optionally mono-, di, or trisubstituted with substitutuents independently chosen from C
1
-C
3
alkyl, C
1
-C
3
alkoxy, halogen, halo(C
1
-C
3
)alkyl, halo(C
1
-C
3
)alkoxy, hydroxy, amino, and mono- or di(C
1
-C
3
)alkylamino;
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, and R
8
are the same or different and represent hydrogen, halogen, cyano, nitro, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
1
-C
6
alkoxy, C
1
-C
6
alkylthio, hydroxy, amino, mono or di(C
1
-C
6
)alkyl amino, halo(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkoxy, C
1
-C
6
alkanoyl, C
1
-C
6
alkoxycarbonyl, —COOH, —SO
2
NH
2
, mono or dialkylsulfonamido, —C(O)NH
2
, or mono or di(C
1
-C
6
)alkylcarboxamido;
R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
17
, R
18
, and R
19
independently represent hydrogen or C
1
-C
6
alkyl;
W is nitrogen or C—R
a
where R
a
represents hydrogen, hydroxy, C
1
-C
6
alkoxy, C
1
-C
6
alkyl or cyano;
X represents halogen, cyano, nitro, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
1
-C
6
alkoxy, C
1
-C
6
alkylthio, hydroxy, amino, mono or di(C
1
-C
6
)alkylamino, halo(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkoxy, C
1
-C
6
alkanoyl, C
1
-C
6
alkoxycarbonyl, —COOH, —CONH
2
, mono- or di(C
1
-C
6
)alkylcarboxamido, —SO
2
NH
2
, mono or di(C
1
-C
6
)alkylsulfonamido; or
X represents phenyl which may be optionally substituted by up to five substit
Bakthavatchalam Rajagopal
Hutchison Alan
Thurkauf Andrew
Bernhardt Emily
Fidel Seth A.
Horvath Leslie-Anna
Kadlecek Ann T.
Neurogen Corporation
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