Phenyl urea and phenyl thiourea derivatives as HFGAN72...

Details Phenyl urea and phenyl thiourea derivatives as HFGAN72... Phenyl urea and phenyl thiourea derivatives as HFGAN72...

2000-05-10

2002-06-25

Davis, Zinna Northington (Department: 1627)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252010, C514S307000, C514S311000, C546S146000, C546S167000, C544S128000, C544S235000

Reexamination Certificate

active

06410529

ABSTRACT:

This invention relates to phenyl urea and phenyl thiourea derivatives and their use as pharmaceuticals
It is well established that many medically significant biological processes are mediated by proteins participating in signal transduction pathways that involve G-proteins and/or second messengers, e.g. cAMP (Letkowitz,
Nature,
1991, 351:353-354). Examples of these proteins include the GPC receptors, such as those for adrenergic agents and dopamine (Kobilka B. K. et al,
Proc. Natl Acad Sci.,
USA, 1987, 84:46-50; Kobila B. K. et at,
Science,
1987, 238:650-656; Bunzow, J. R. et al,
Nature,
1988, 336:783-787), G-proteins themselves, effector proteins, e.g. phospholipase C, adenyl cyclase, and phosphodiesterase, and actator proteins, e.g. protein kinase A and protein kinase C (Simon, M. I. et al,
Science,
1991, 252:802-8).
The membrane protein gene superfamily of G-protein coupled receptors has been characterised as having seven putative transmembrane domains. The domains are believed to represent transmembrane &agr;-helices connected by extracellular or cytoplasmic loops. G-protein coupled receptors include a wide range of biologically active receptors, such as hormone, viral, growth factor and neuro-receptors.
G-protein coupled receptors have been characterised as including these seven conserved hydrophobic stretches of about 20 to 30 amino acids, connecting six divergent hydrophilic loops. The G-protein family of coupled receptors includes dopamine receptors which bind to neuroleptic drugs used for treating psychotic and neurological disorders. Other examples of members of this family include, but are not limited to, calcitonin, adrenergic, endothelin, cAMP, adenosine, muscarinic, acetylcholine, serotonin, histamine, thrombin, kinin, follicle stimulating hormone, opsins, endothelial differentiation gene-1, rhodopsins, odorant, and cytomegalovirus receptors.
Polypeptides and polynucleotides encoding the human 7-transmembrane G-protein coupled neuropeptide receptor, HFGAN72, have been identified and are disclosed in U.S. Ser. Nos. 08/846,704 and 08/846,705, both of which were filed on Apr. 30, 1997, as well as in WO 96/34877.
Polypeptides and polynucleotides encoding polypeptides which are ligands for the HFGAN72 receptor are disclosed in U.S. Ser. No. 08/939,093 filed Jul. 2, 1997, U.S. Ser. No. 08/820,519 filed Mar. 19, 1997 and U.S. Ser. No. 08/033,604 filed Dec. 17, 1996.
HFGAN72 receptors are found in the mammalian host and, thus, may be responsible for many biological functions, including many pathologies including, but not limited to, depression; anxiety; obsessive compulsive disorder, affective neurosis/disorder; depressive neurosis/disorder, anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; sexual disorder; schizophrenia; manic depression; delerium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Gilles de la Tourett's syndrome; disturbed biological and circadian rhythms; feeding disorders, such as anorexia, bulimia, cachexia, and obesity; diabetes; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma; hypothalamic diseases; Froehlich's syndrome; adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma; pituitary growth hormone; adrenohypophysis hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth hormone deficiency; dwarfism; gigantism; acromegaly; disturbed biological and circadian rhythms; and sleep disturbances associated with such diseases as neurological disorders, neuropathic pain and restless leg syndrome, heart and lung diseases, mental illness such as depression or schizophrenia, and addictions; acute and congestive heart failue; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain, such as hyperalgesia, causalgia and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; arthritic pain; sports injury pain; pain related to infection, e.g. HIV, post-polio syndrome, and post-herpetic neuralgia; phantom limb pain; labour pain; cancer pain; post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; and tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lag syndrome; and other neurodegenerative disorders, which includes nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration, epilepsy, and seizure disorders.
Experiments have shown that central administration of Lig 72A for the HFGAN72 receptor (Lig 72A is described in more detail below) stimulated food intake in freely-feeding rats during a 4 hour time period. This increase was approximately four-fold over control rats receiving vehicle. These data suggest that Lig 72A may be an endogenous regulator of appetite. Therefore, antagonists of its receptor may be useful in the treatment of obesity and diabetes, see
Cell,
1998, 92, 573-585.
There is a significant incidence of obesity in westernised societies. According to WHO definitions a mean of 35% of subjects in 39 studies were overweight and a furter 22% clinically obese. It has been estimated that 5.7% of all healthcare costs in the USA are a consequence of obesity. About 85% of Type 2 diabetics are obese, and diet and exercise are of value in all diabetics. The incidence of diagnosed diabetes in westernised countries is typically 5% and there are estimated to be an equal number undiagnosed. The incidence of both diseases is rising, demonstrating the inadequacy of current treatments which may be either ineffective or have toxicity risks including cardiovascular effects. Treatment of diabetes with sulfonylureas or insulin can cause hypoglycaemia, whilst metformin causes GI side-effects. No drug treatment for Type 2 diabetes has been shown to reduce the long-term complications of the disease. Insulin sensitisers will be useful for many diabetics, however they do not have an anti-obesity effect.
Rat sleep/EEG studies have also shown that central administration of LIG72A, an agonist of HFGAN72 receptors, causes a dose-related increase in arousal, largely at the expense of a reduction in paradoxical sleep and slow wave sleep 2, when administered at the onset of the normal sleep period. Therefore antagonists of its receptor may be useful in the treatment of sleep disorders including insomnia
The present invention provides phenyl urea and phenyl thiourea derivatives which are non-peptide antagonists of the human HFGAN72 receptor. In particular, these compounds are of potential use in the treatment of obesity including obesity observed in Type 2 (non-insulin-dependent) diabetes patients and/or sleep disorders.
Several phenyl urea derivatives are known in the literature, viz:
WO 93/18028 discloses the compound N-1-isoquinolinyl-N′-(1-methyl-1H-indol-5-yl)urea;
DE 2928485 discloses the compounds N-(3-chloro-4-trifluoromethylphenyl)-N′-4-quinolinylurea, and N-(3-chloro-4-trifluoromethylphenyl)-N′-(5-nitro-4-quinolinyl)urea;
DE 2801187 discloses the compound N-(3,4,5-trimethoxyphenyl)-N′-(7-chloro-4-quinolinyl)urea; and
U.S. Pat. No. 3,406,176 discloses the compounds N-(4-methoxyphenyl)-N′-(7-chloro-4-quinolinyl)urea, and N-(4-chlorophenyl)-N′-(7-chloro-4-quinolinyl)urea;
none of these documents suggest the use of phenyl urea derivatives as HFG

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