Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-05-28
2004-11-30
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S295000
Reexamination Certificate
active
06825198
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pyrimidine compounds that act as 5-HT receptor ligands, in particular 5-HT
2c
receptor ligands, and their uses in the prevention or treatment of diseases linked to the activation of 5-HT
2c
receptors in animals.
BACKGROUND
Receptors for serotonin (5-hydroxytryptamine, 5-HT) are an important class of G protein-coupled receptors. Serotonin is thought to play a role in processes related to learning and memory, sleep, thermoregulation, mood, motor activity, pain, sexual and aggressive behaviors, appetite, neurodegenerative regulation, and biological rhythms. As expected, serotonin is linked to pathophysiological conditions such as anxiety, depression, obsessive-compulsive disorders, schizophrenia, suicide, autism, migraine, emesis, alcoholism and neurodegenerative disorders.
The serotonin receptors are currently classified into seven subfamilies (5-HT
1
through 5-HT
7
). See, Hoyer, D., et al., “VII International Union of Pharmacology classification of receptors for 5-hydroxytryptamine”,
Pharmacol. Rev.,
56, 157-203 (1994). The subfamilies have been further divided into subtypes. For example, the 5-HT
2
receptor is currently divided into three subtypes: 5-HT
2a
, 5-HT
2b
and 5-HT
2c
. The three subtypes of 5-HT
2
receptors are linked to phospholipase C with the generation of two second messengers, diacylglycerol (which activates protein kinase C) and inositol trisphosphate (which releases intracellular stores of Ca
2+
). The 5-HT
2c
receptors have a very high density in the choroid plexus, an epithelial tissue that is the primary site of cerebrospinal fluid production. See, Sanders-Bush, E. and S. E. Mayer, “5-Hydroxytryptamine (Serotonin) Receptor agonists and Antagonists”,
Goodman
&
Gilman's The Pharmacological Basis of Therapeutics
, Chapter 11, 9
th
Ed., McGraw-Hill, New York, N.Y. (1996).
Julius, et al., isolated and characterized the 5-HT
2c
receptor and later reported that transgenic mice lacking the 5-HT
2c
receptor exhibit seizures and an eating disorder resulting in increased consumption of food (see, U.S. Pat. Nos. 4,985,352 and 5,698,766, respectively). Consequently, compounds selective for the 5-HT
2c
receptor may provide useful therapies for the treatment of seizure and eating disorders without the side effects typically associated with nonselectivity of the ligand.
Several compounds have been proposed as 5-HT
2c
receptor agonists or antagonists for use in the treatment of obesity and other related diseases associated with decreased neurotransmission of serotonin in mammals. See, e.g., EP 863136 (azetidine and pyrrolidine derivatives); EP 657426 (tricyclic pyrrole derivatives); EP 655440 (substituted 1-aminoethyl indoles); EP 572863 (pyrazinoindole derivatives); WO98/030548 (aminoalkylindazole compounds); WO 98/56768 (tricyclic pyrrole and pyrazole derivatives); WO 99/43647 (azetidine and pyrrolidine derivatives); WO 99/58490 (aryl-hydronaphthalenalkanamine derivatives); WO 00/12475 (indoline derivatives); WO 00/12482 (indazole derivatives); WO 00/12502 (pyrroloquinoline derivatives); WO 00/12510 (pyrroloindole, pyridoindole and azepinoindole derivatives); WO 00/28993 (naphthylacetylpiperazine derivatives); WO 00/44737 (aminoalkylbenzofuran derivatives); and WO 00/76984 (2,3-disubstituted pyrazines).
The non-selectivity of ligands for the various 5-HT receptors remains a challenge. It is suspected that the non-selectivity of some ligands contributes to various adverse side effects such as hallucinations and cardiovascular complications. Therefore, there remains a need for 5-HT
2c
selective receptor ligands.
SUMMARY
The present invention provides compounds of Formula (IA) which are useful as 5-HT
2
receptor ligands (in particular, 5-HT
2a
and 5-HT
2c
receptor ligands).
wherein
X and Y are CR and Z is N, or X is N and Y and Z are CR, where R for each occurrence is hydrogen, halogen, (C
1
-C
4
)alkyl, amino, or (C
1
-C
4
)alkylamino;
W is oxy, thio, amino, (C
1
-C
4
)alkylamino, or acetylamino;
at least one of R
1a
, R
1b
, R
1d
, and R
1e
is independently selected from the group consisting of halogen, nitro, amino, cyano, —C(O)NH
2
, (C
1
-C
4
)alkyl, halo-substituted(C
1
-C
4
)alkyl, (C
1
-C
4
) alkoxy, and halo-substituted(C
1
-C
4
)alkoxy, or R
1a
and R
1b
taken together form a five- or six-membered, aromatic or partially or fully saturated fused ring, or R
1a
taken together with R
2a
or R
2b
forms a five- or six-membered, fully saturated fused ring;
R
1c
is hydrogen;
R
2a
and R
2b
are each independently hydrogen, (C
1
-C
4
)alkyl, partially or fully saturated (C
3
-C
6
)cycloalkyl, or one of which taken together with R
1a
forms a five- or six-membered, fully saturated fused ring;
n is 0, 1, or 2;
R
3a
and R
3b
are each independently hydrogen, (C
1
-C
4
)alkyl, or (C
1
-C
4
)alkyl substituted with hydroxy, fluoro, or (C
1
-C
4
)alkoxy;
R
4
is hydrogen, hydroxy, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkyl substituted with hydroxy or cyano, (C
1
-C
4
)alkylcarbonyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkoxy-carbonyl, (C
3
-C
4
)alkenyl, or an amino-protecting group;
a nitrogen oxide thereof, a prodrug of the compound or the nitrogen oxide; a pharmaceutically acceptable salt of the compound, the nitrogen oxide, or the prodrug, or a solvate or hydrate of the compound, the nitrogen oxide, the prodrug, or the salt.
Preferred compounds of Formula (IA) are those where X and Y are CR and Z is N, or X is N and Y and Z are CR, where R is hydrogen, chloro, fluoro, or methyl;
(i) R
1a
is halogen, (C
1
-C
4
)alkyl, trifluoromethyl, methoxy, or trifluoromethoxy, and R
1b
, R
1d
and R
1e
are each hydrogen,
(ii) R
1b
is halogen, methyl, or methoxy and R
1a
, R
1d
and R
1e
are each hydrogen,
(iii) R
1a
and R
1b
are each independently halogen or methyl and R
1d
and R
1e
are each hydrogen,
(iv) R
1b
and R
1d
are each independently halogen or methyl and R
1a
and R
1e
are each hydrogen,
(v) R
1a
and R
1d
are each independently halogen or methyl and R
1b
and R
1e
are each hydrogen,
(vi) R
1a
and R
1e
are each independently halogen or methyl and R
1b
and R
1d
are each hydrogen, or
(vii) R
1a
, R
1b
and R
1d
are each independently halogen or methyl and R
1e
is hydrogen;
W is oxy or amino; n is 1; R
2a
and R
2b
are each independently methyl or hydrogen; R
3a
and R
3b
are each independently hydrogen or (C
1
-C
2
)alkyl (preferably (2R)-methyl or (2R)-ethyl); and R
4
is hydrogen or (C
1
-C
4
)alkyl; a nitrogen oxide thereof, a prodrug of the compound or the nitrogen oxide; a pharmaceutically acceptable salt of the compound, the nitrogen oxide, or the prodrug, or a solvate or hydrate of the compound, the nitrogen oxide, the prodrug, or the salt.
When Z is N, then X is preferably CH; Y is CR, where R for each occurrence is hydrogen or methyl; (i) R
1a
is halogen, (C
1
-C
4
)alkyl, trifluoromethyl, methoxy, or trifluoromethoxy, and R
1b
, R
1d
and R
1e
are each hydrogen, (ii) R
1b
is halogen, methyl, or methoxy and R
1a
, R
1d
and R
1e
are each hydrogen, (iii) R
1a
and R
1b
are each independently halogen or methyl and R
1d
and R
1e
are each hydrogen, (iv) R
1b
and R
1d
are each independently halogen or methyl and R
1a
and R
1e
are each hydrogen, (v) R
1a
and R
1d
are each independently halogen or methyl and R
1b
and R
1e
are each hydrogen, (vi) R
1a
and R
1e
are each independently halogen or methyl and R
1b
and R
1d
are each hydrogen, or (vii) R
1a
, R
1b
and R
1d
are each independently halogen or methyl and R
1e
is hydrogen; W is oxy or amino; n is 1; R
2a
and R
2b
are each independently methyl or hydrogen; and R
3a
is hydrogen, (2R)-methyl, or (2R)-ethyl; and R
3b
is hydrogen; and R
4
is hydrogen or (C
1
-C
4
)alkyl; a nitrogen oxide thereof, a prodrug of the compound or the nitrogen oxide; a pharmaceutically acceptable salt of the compound, the nitrogen oxide, or the prodrug, or a solvate or hydrate of the compound, the nitrogen oxide, the prodrug, or the salt.
When X is N, then Y is preferably CR, where R is hydrogen or methyl; Z is CH; (i) R
1a
Chiang Phoebe
Novomisle William A.
Welch, Jr. Willard M.
Liu Hong
Musser Arlene K.
Pfizer Inc
Raymond Richard L.
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