Phenyl urea and phenyl thiourea derivatives

Details Phenyl urea and phenyl thiourea derivatives Phenyl urea and phenyl thiourea derivatives

2001-12-05

2003-07-22

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S122000

Reexamination Certificate

active

06596730

ABSTRACT:

This application is a 371 of PCT/EP00/01142, filed on Feb. 10, 2000.
This invention relates to phenyl urea and phenyl thiourea derivatives and their use as pharmaceuticals.
Many medically significant biological processes are mediated by proteins participating in signal transduction pathways that involve G-proteins and/or second messengers.
Polypeptides and polynucleotides encoding the human 7-transmembrane G-protein coupled neuropeptide receptor, orexin-1 (HFGAN72), have been identified and are disclosed in EP-A-875565, EP-A-875566 and WO 96/34877. Polypeptides and polynucleotides encoding a second human orexin receptor, orexin-2 (HFGANP), have been identified and are disclosed in EP-A-893498.
Polypeptides and polynucleotides encoding polypeptides which are ligands for the orexin-1 receptor, e.g. orexin-A (Lig72A) are disclosed in EP-A-849361.
Orexin receptors are found in the mammalian host and may be responsible for many biological functions, including pathologies including, but not limited to, depression; anxiety; addictions; 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; delirium; 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; appetite/taste disorders; vomiting
ausea; asthma; cancer; Parkinison'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; acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ischaemic or haemorrhagic stroke; subarachnoid haemorrhage; head injury such as subarachnoid haemorrhage associated with traumatic head injury; 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; conditions associated with visceral pain including irritable bowel syndrome, migraine and angina; urinary bladder incontinence e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lag syndrome; and 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 the ligand orexin-A (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 orexin-A 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 westemised societies. According to WHO definitions a mean of 35% of subjects in 39 studies were overweight and a further 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-tern 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 orexin-A, an agonist of the orexin 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.
International Patent Applications PCT/GB98/02437 and PCT/EP99/03100 (published after the priority date of the present application) disclose various phenyl urea derivatives as orexin receptor antagonists.
The present invention provides phenyl urea and phenyl thiourea derivatives which are non-peptide antagonists of human orexin receptors, in particular orexin-1 receptors. 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.
According to the invention there is provided a compound of formula (I):
in which:
one of X and Y is N and the other is CH;
Z represents oxygen or sulfur;
R
1
represents (C
1-6
)alkyl, (C
2-6
)alkenyl or (C
1-6
)alkoxy, any of which may be optionally substituted; halogen, R
8
CO— or NR
9
R
10
CO—;
R
2
, R
3
, R
4
, R
5
and R
6
independently represent (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
1-6
)alkoxy or (C
1-6
)alkylthio, any of which may be optionally substituted; hydrogen, halogen, nitro, cyano, aryloxy, aryl(C
1-6
)alkyloxy, aryl(C
1-6
)alkyl, R
8
CO—, R
8
SO
2
NH—, R
8
SO
2
O—, R
8
CON(R
11
)—, NR
9
R
10
—, NR
9
R
10
CO—, —COOR
9
, R
11
C(═NOR
8
), heterocyclyl or heterocyclyl(C
1-6
)alkyl;
or an adjacent pair of R
2
, R
3
, R
4
, R
5
and R
6
together with the carbon atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic ring;
R
7
is (C
1-6
)alkyl, (C
2 6
)alkenyl, (C
1-6
)alkoxy or (C
1-6
)alkylthio, any of which may be optionally substituted; halogen, hydroxy, nitro, cyano, NR
9
R
10
—, NR
9
R
10
CO—, N
3
, —OCOR
9
or R
8
CON(R
11
)—;
R
8
is (C
1-6
)alkyl, (C
2-6
)alkenyl, heterocyclyl, heterocyclyl(C
1-6
)alkyl, heterocyclyl(C
2-6
)alkenyl, aryl, aryl(C
1-6
)alkyl or aryl(C
1-6
)alkenyl any of which may be optionally substituted;
R
9
and R
10
independently represent hydrogen, (C
1-6
)alkyl, (C
2-6
)alkenyl, heterocyclyl, heterocyclyl(C
1-6
)alkyl, aryl or aryl(C
1-6
)alkyl, any of which may be optionally substituted;
R
11
is hydrogen or (C
1-6
)alkyl; and
n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
In formula (I) Z is preferably oxygen.
When a halogen atom is present in the compound of formula (I) this may be fluorine, chlorine, bromine or iodine.
n is preferably

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