Phenylurea and phenylthio urea derivatives

Details Phenylurea and phenylthio urea derivatives Phenylurea and phenylthio urea derivatives

2000-11-08

2002-04-16

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S230500, C544S105000, C546S122000

Reexamination Certificate

active

06372757

ABSTRACT:

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 polynucletides encoding the human 7-transmembrance 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 such as pathologies including, but not limited to, depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis/disorder; depressive neurosis/disorder; anxiety neurosis; dysthymic disorder; behavior 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; feeding disorders such as anorexia, bulimia, cachexia and obesity; diabetes; appetite/taste disorders; vomiting
ausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor/adeoma; hypothalamic diseases; Froehlich's syndrome; adrenohypopohysis disease; hypophysis disease; hypophysis tumor/adenoma; pituitary growth hormone; adrenohypophysis hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposima); 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; distributed biological and circadian rhythms; and sleep disturbances associated with diseases such 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 haemmorhage; 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 such as irritable bowel syndrome, migraine and angina; urinary bladder incontinence e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolespy; insomnia; parasomnia; jet-lag syndrome; and neurodegenerative disorders including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration, epilepsy and seizure disorders.
Experiments have shown that central administration of orexin-A stimulates food intake in freely-feeding rats during a 4 hour time period. This increase is approximately four-fold over control rats receiving vehicle. These data suggest that orexin-A may be an endogenous regulator of appetite. Therefore, antagonists of orexin receptors may be useful in the treatment of obesity and diabetes, see
Cell
, 1998, 92, 573-585.
Rat sleep/EEG studies have also shown that central administration of orexin-A causes a does-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 orexin receptors 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 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.
International Patent Application PCT/GB98/02437 (published after the priority date of the present application) discloses various phenyl urea derivatives as orexin receptor antagonists.
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 sulphur;
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
7
CO— or NR
8
R
9
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
)alkythio, any of which may be optionally substituted; hydrogen, halogen, nitro, cyano, aryloxy, aryl(C
1-6
)alkyloxy, aryl(C
1-6
)alkyl, R
7
CO—, R
7
SO
2
NH—, R
7
CON(R
10
)—, NR
8
R
9
—, NR
8
R
9
CO—, —COOR
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 or aryl;
R
8
and R
9
independently represent hydrogen, (C
1-6
)alkyl, aryl or aryl(C
1-6
)alkyl;
R
10
is hydrogen or (C
1-6
)alkyl; and
n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
When a halogen atom is present in the compound of formula (I) it may be fluorine, chlorine, bromine or iodine.
Z preferably represents oxygen.
n is preferably 0 or 1.
X is preferably N and Y is CH.
When n is 1, the group R
1
is preferably in the 6- or 8-position, particularly the 8-position.
R
1
is preferably halogen e.g. fluoro, or (C
1-6
)alkoxy e.g. methoxy. R
1
is most preferably fluoro.
When any of R
1
to R
6
comprise a (C
1-6
)alkyl group, whether alone or forming part of a larger group, e.g. alkoxy or alkylthio, the alkyl group may be straight chain, branched or cyclic, it preferably contains 1 to 4 carbon atoms and is most preferably methyl or ethyl.
When any of R
1
to R
6
comprise a (C
2-6
)alkenyl group, whether alone or forming part of a larger group, the alkenyl group may be straight chain, branched or cyclic, it preferably contains 2 to 4 carbon atoms and is most preferably allyl.
Suitable optional substituents for (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
1-6
)alkoxy and (C
1-6
)alkylthio groups include one or more substituents selected from halogen e.g. fluoro, (C
1-6
)alkoxy e.g. methoxy, hydroxy, carboxy and (C
1-6
)alkyl esters thereof, amino, mono- or di-(C
1-6
)alkylamino and cyano.
When used herein the term “aryl”, whether alone or forming part of a larger group, includes optionally substituted aryl groups such as phenyl and naphthyl, preferably phenyl. The aryl group may have up to 5, preferably 1, 2 or 3 optional substituents. Examples of suitable substituents include halogen, (C
1-4
)alkyl e.g. methyl, (C
1-4
)haloalakyl e.g. trifluoromethyl, (C
1-4
)alkoxy e.g. methoxy, (C
1-4
)alkoxy(C
1-4
)alkyl e.g. methoxymethyl, hydroxy, carboxy and (C
1-6
)alkyl esters thereof, amino, nitro, arylsulphonyl e.g. p-toluenesulphonyl, and (C
1-4
)alkylsulphonyl e.g. methanesulphonyl.
When any of R
2
to R
6
represent heterocyclyl or heterocyclyl(C
1-6
)alkyl the heterocyclyl group is preferably a 5- to 10-membered monocyclic or bicyclic ring, which may be saturated or unsaturated,

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