CA2303777A1 - Substituted isoquinolines as anticonvulsivants - Google Patents

Substituted isoquinolines as anticonvulsivants Download PDF

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CA2303777A1
CA2303777A1 CA002303777A CA2303777A CA2303777A1 CA 2303777 A1 CA2303777 A1 CA 2303777A1 CA 002303777 A CA002303777 A CA 002303777A CA 2303777 A CA2303777 A CA 2303777A CA 2303777 A1 CA2303777 A1 CA 2303777A1
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methyl
urea
tetrahydroisoquinolin
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Mervyn Thompson
Roderick Alan Porter
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SmithKline Beecham Ltd
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
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Abstract

N-(tetrahydroisoquinolinyl)-N'-phenyl-ureas/thioureas of general formula (I) are useful for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).

Description

WO 99/14197 PCTfGB98/02728 sussTrrtrrEn rsoQvaroLlrr~s as ~corrvut,smnrrrs This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
W09fi/39382 (Fujisawa) discloses the preparation of N-heterocycyl-ureas as 5-HT
antagonists, including the compound N-(1-methyl-IH-indol-5-yl)-N'-(1,2,3;4-tetrahydro-7-isoquinolinyl)-urea.
I o It has now been surprisingly found that urea compounds of formula (1) below possess anti-convulsant activity and are therefore believed to be useful in the treatment and/or prevention of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and t5 benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, 20 insomnia & narcolepsy), tics (e.g. Giles.de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
Accordingly, the present invention provides a compound of formula (I) or pharmaceutically acceptable salt thereof:
~ ~ ~ -N / H C H~Rx R~/ ~./
(n where X is O or S
R 1 is hydrogen, phenylC I-6 alkyl or C I _6 alkyl, SUSS11TUTE SHEET (PtUt.E 2~) R' is hydrogen or up to three substituents independently selected from halogen, NO~, CN, N3, C 1 _6 alkyl0-, C 1 _6 alkyls-, C 1 _6 alkyl, C 1 ~haloaikyl, C3_6cycloalkyi, C3_6cycloalkyl-C 1 _q.aikyl-, C 1 _halkenyl, C 1 _6alkynyl, C 1 _6haloalkylCO-, C 1 _galkylCO-, C3_6cycloalkylCO-, C3_6cycloalkyl-C 1 ~aikylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C 1 ,alkyl-, O-C I _6haloalkyl, CO~C 1 alkyl, S (O)2C 1 _dalkyl, C 1 ~alkylsulfamoyl or heterocyclyl, or -NR6R~ where R6 is hydrogen, C 1 ~ alkyl or S(O)2C 1..6a1ky1, and R~ is hydrogen, C 1 ,alkyl, -CHO, S (O)2C 1 _6alkyl -C02C 1 alkyl or -COC 1 alkyl, or an adjacent pair of R2 groups together with the carbon atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic ring.
The compounds of this invention are typically N-(tetrahydroisoquinolinyl)-N'-optionally substituted phenyl-ureas/thioureas. The compounds of the invention may be (tetrahydroisoquinolin-5-yl), (tetrahydroisoquinolin-6-yl), (tetrahydroisoquinolin-7-yl) or (tetrahydroisoquinolin-8-yl) ureas/thioureas, especially (tetrahydroisoquinolin-5-yl) and (tetrahydroisoquinolin-7-yl) ureas/thiourcas.
Zo The phenyl moiety may be substituted by up to three, preferably 2 or 1, groups.
In the formula (n, alkyl groups, including alkyl groups that are part of another moiety, may be straight chain or branched. Alkyl groups are typically C 1 _6 alkyl, especially C 1 ~ alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl.
Aromatic rings, such as the aromatic ring in the bicyclic heteracyclic moiety in formula (n and phenyl groups, including phenyl groups that are part of other moieties, in R2 may optionally be substituted with one or more independently selected substituents such as halogen or C1-6 alkyl, C1-6 alkoxy or Cl_6 alkylcarbonyl groups, or other optional 3o subdtuents indicated below.
Suitable C3_6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
Suitable halo substituents include fluoro, chloro, iodo and bromo, which may also appear in haloalkyl, haloalkyloxy and haloalkyl carbonyl groups mentioned above, examples of which are trifluoromethyl, trifluoromethoxy and trifluoroacetyl.
~UB$"MTtJTE SHE~E"T (R~11.E 26) 3 PGTIGB9$Ifl'Z728 When any Rx represents heterocyclyl, this group is preferably a 5- to 10-membered monocyclic or bicyclic ring, which may be saturated or unsaturated, for example containing 1, 2 or 3 hetematoms selected from oxygen, nitrogen or sulphur, for example oxazolyl, thienyl or piperidinyl. The hetcrocyclyl group may contain up to 5, more preferably 1, 2 or 3 optional substituents.
Preferably a substituent for a heterocyclyl group is selected from halogen, (C
1 _6)alkyl, aryl(C 1 _6)alkyl, (C 1 _6)alkoxy, (C 1 _~)alkoxy(C 1 _6)alkYl, halo(C 1 _6)alkyi, hydroxy, amino, to mono- and di-N-(C1_6)alkyl-amino, acylamino, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(C1_6)alkylcarbonyi, aryloxycarbonyl, (C1_ 6)alkoxycarbonyl(Cl_g)alkyl, aryl, oxy groups, ureido, guanidine, sulphonylamino, aminosulphonyl, (C 1 _~)alkylthio, (C 1 _6)alkylsulphinyl, (C 1 _,~)alkylsulphonyl, heterocyclyl and heterocyclyl(C 1 _6)alkyl.
When an adjacent pair of RZ together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring, it is preferably a 5- to 7-membered ring, which may be aromatic or non-aromatic. Heterocyclic rings preferably contain 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulphur; for example, pyrrole or pynrolidine. A
2o carbocyclic or heterocyclic ring formed by an adjacent pair of RZ together with the carbon atoms to which they are attached may be optionally substituted on carbon or nitrogen by one or more substituents, e.g. up to 3 substituents. Examples of suitable substituents for the carbocyclic or heterocyclic ring include; halogen, (C 1 _6)alkyl, aryl(C 1 _6)alkyl, (C 1 6)alkoxy, (C 1 _6)alkoxy(C 1 _6)alkyl, haio(C 1 _6)alkyl, hydroxy, amino, mono-and di-N-(C1_b)alkyl-amino, acylamino, carboxy, carboxy salts, carboxy esters, carbamoyl, mono-and di-N-(C 1 _6)alkylcarbonyl, aryloxycarbonyl, (C 1 _6)alkoxycarbonyl(C 1 _6)alkyl, aryl, oxy groups, ureido, guanidine, sulphonylamino, aminosulphonyl, (C1_b)alkylthio, (C 1 _6)alkylsulphinyl, (C 1 _b)alkylsulphonyl, heterocyclyl and heterocyclyl(C 1 _6)alkyl.
3o A suitable group of compounds of formula (n have R 1 as hydrogen, benzyl, methyl, ethyl, iso-propyi or t-butyl R2 as hydrogen, methyl, ethyl, n-butyl, iso-propyl, t-butyl, phenyl, benzyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, phenoxy, benzyloxy, bromo, chloro, lode, fluoro, vitro, cyano, acetyl, pivaloyl, iso-butyroyl, benzoyl, trifluoromethyl, trifluoromethoxy, trifluoroacetyl, carbomethoxy, carboethoxy, methylthio, n-propylsulfonyl, isopropylsulfonyl, dimethylsulfamoyl or oxazolyl, SUBSTI"fUTE ~aHEET (RULE 26) 4 PG"T/GB98/02728 R6 and R?are hydrogen, acetyl or methanesulfonyl, or two R2 groups linked to form naphthyl, indolyl or indolinyl, optionally substituted by acetyl or methyl.
In a particular group of compounds of formula (>j, R 1 is hydrogen or methyl, R2 is hydrogen, methyl, ethyl, t-butyl, methoxy, ethoxy, iso-propoxy, phenoxy, benzyloxy, methylthio, bromo, chloro, fluoro, vitro, cyano, acetyl, benzoyl, trifluoromethyl, trifluoromethoxy, carbomethoxy, carboethoxy, amino, 1o acetylamino, methanesulphonylamino or oxazolyl, or two R2 groups form methylindolyl or acetylindolinyl or naphthyl.
E~camples of compounds of formula (Tj are:
N-( 1,2,3,4-tetrahydroisoquinolin-?-yi)-N =(3-nitrophenyl) urea ~5 N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N=(3-nitmphenyl) urea N-(2-methyl-1,2,3,4-tetrahydioisoquinolin-?-yl)-N=(4-ethoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(4-ethoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N =(3-trifluoromethylphenyl)thiourea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N =(3-trifluoromethylphenyl)urea 20 N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N =(3-methoxyphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N =(3-bromophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N =(4-trifluoromethylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N =(5-chloro-2,4-dimethoxyphenyl) urea N-{2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N'-(4-tent-butyl, 2-methoxyphenyl)urea 25 N-{2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N=(phenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N =(3-acetylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N =(2-methylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N =(2-methoxyphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N =(3-chlorophenyl)urea 3o N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N=(3-chloro-6-methoxyphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N'-(3,S-di-trifluoromethylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N =(4-trifluoromethoxyphenyl)urea N-(2-methyl-1,2,3,4-tetrahdyroisoquinolin-?-yi)-N =(3-chloro-4-methylphenyl)urea N-{2-methyl-1,2,3,4; tetrahydroisoquinolin-5-yl)-N'-(3-trifluoromethylphenyl)urea 35 N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N -(5-chloro-2,4-dimethoxyphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N =(3-nitrophenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N =(3-bromophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N ={3-methoxyphenyi)urea SUBSTITUTE SHEET (RULE 213) WO 99/14197 '' PCTIGB98IOZ728 N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N =(4-trifluoromethyoxyphenyl )urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N =(4-trifluoromethylphenyl)urea N-{2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N =(phenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoqinolin-5-yl)-N =(3-acetylphenyl)urea 5 N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N=(3-chloro-4-methylphenyl)urea N-{2-methyl-1,2,3,4--tetrahydroisoquinolin-5-yl)-N =(3-chloro-6-methoxyphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3-chlorophenyl)urea N-{2-methyl-1,2,3,4,-tetrahydroisoquinolin-5-yl)-N =(2-methoxyphenyl)urea N-{2-methyl-1,2;3,4-tetrahydroisoquinolin-5-yl)-N =(2-methylphenyl)urea 1o N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3,5-di-trifluoromethylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl-N'-(3-trifluoromethylphenyl)thiourea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N =(2-carbomethoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N =(2, 3-dimethylphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-'7-yl)-N =(2-methoxy-3-chlorophenyl) urea 15 N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N =( 1-naphthyl) urea N-(2-methyl-i,2,3,4-tetrahydroisoquinolin-7-yl)-N =(2-methyl-3-nitrophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N=(2-cyanophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N=(2-cyano-3-methylphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N =( 1-acetylindolin-7-yl) urea 2o N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-cyanophenyl) urea N-{2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N=(3-ethylphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N =(3, 5-dinitrophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(2, 3-dichlorophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-chloro-4-fluorophenyl) urea 25 N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N=(2-chloro-5-trifluoromethylphenyl) urea N-{2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N =(3-isopropoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N =(3-ethoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N =(3-tertbutylphenyl) urea 3o N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yi)-N=[3-(1,3-oxazol-5-yl)phenyl] urea N-{2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N =(3-benzyloxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ={3-phenoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-ylrN =(3-fluorophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N=(2-fluorophenyl) urea 35 N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-methylthiophenyl) urea N-(2-methyl-1,2,3,4-tetrahydmisoquinolin-7-yl)-N =(3-carboethoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-'7-yl)-N'-(4-fluorophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N=(3, 4-difluorophenyl) urea SUB$'TITUTE SHEET (RUL.E 2B) N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N=(3-benzoylphenyl) urea N-(2-methyl-I,2,3,4-tetrahydroisoquinolin-?-yl)-N=(4-methoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)-N=(3-bromo-4-methoxyphenyl) urea N-(2-methyl-I,2,3,4-tetrahydroisoquinolin-5-yl)-N =(3-bromo-4-methoxyphenyi) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N =(2,3-dichlorophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N': (2-ehloro-5-trifluoromethylphenyt) urea N-{2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-{3-chloro-4-fluorophenyl) urea N-(2-methyl-I,2,3,4-tetrahydroisoquinolin-S-yl)-N=(4-methoxyphenyl) urea to N-(2-methyl-I,2,3,4-tetrahydroisoquinolin-5-yi)-N'-(3-ethylphenyl) urea N-(2-methyl-I,2,3,4-tetrahydroisoquinolin-5-yl)-N=(3, 5-dinitrophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yi)-N'-(3-cyanophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N=(3-bromo-4-methoxyphenyl) urea N-(2-methyl-I,2,3,4-tetrahydroisoquinolin-?-yl)-N=(3-aminophenyl) urea 15 N-{3-[3-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)ureido]phenyl}acetamide N-{ 3-[3-(2-methyl-1,2,3,4-tetrahydroisoquinolin-?-yl)ureido]phenyl ) bis methanesulphonimide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-S-yl)-N'-(1-m~ethylindol-5-yl) urea:
20 When synthesised, these compounds may be in salt form, such as the hydrochloride or trifluoroacetate; and such salts also form part of this invention. Such salts may be used in preparing pharmaceutically acceptable.salts. The compounds and their salts may be obtained as solvates, such as hydrates, and these also form part of this invention.
25 The above-listed compounds and pharmaceutically acceptable salts thereof, especially the hydrochloride, and pharmaceutically acceptable solvates, especially hydrates, form a preferred aspect of the present invention.
Where compounds of the present invention possess chiral centres and as such may exist in 3o different enantiomeric forms, the present invention extends to each enantiomeric form and mixtures thereof including diastereoisomers and racemates.
The compounds of this invention possess anti-conwlsant activity and are therefore believed to be useful for adminstration to mammals in the treatment and/or prevention of 35 the disorders mentioned above, especially for humans, but also as a veterinary treatment.
The administration of such compounds to a mammal may be by way of oral, parenteral, sub-lingual, nasal, rectal, topical or transdermal administration.
SUBTE SHEET ~R~ILE 2B}

w0 99/14197 ~ PCT/GB98/a2'138 An amount effective to treat the disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 rng, for example an amount in the range of from 2 to 400 mg such as 2, S, i0, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, for example 1 to 6 mg/kglday.
It is greatly preferred that the compound of formula {n is administered in the form of a unit-dose composition, such as a unit dose oral, including sub-lingual, nasal, rectal, topical or parenteral {especially intravenous composition.
Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusible solutions or suspensions or suppositories. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
Tablets and capsules for oral administration arc usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletdng agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.
Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium steatite.
Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
These solid oral compositions may be prepared by conventional methods of blending, filling, tabletdng or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for SUBSTITUTE SHEET (RULE 26~

WO 99114197 $ PCTIGB9$/02728 reconstitution with water or other suitable vehicle before use. Such liquid preparations ~-may contain conventional additives such as suspending agents, for example sorbitol, syrup.
methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan 5 monooleate, or acacia; nan-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oiI, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
to Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
For parenteral administration, fluid unit dose forms are prepared containing the compound and a sterile vehicle. The compound, depending on the vehicle and the concentration, can t 5 be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
3o Accordingly, in a further aspect, the present invention provides a pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with 35 anti-conwlsive agents, such a~ epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AmS, sleep disorders (including SUBSTITUTE SHEET (RULE 26) 7 9 PCTfGB98f02728 circadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer gain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone 5 disease; ataxias, muscular rigidity (spasticity); temporomandibular joint dysfunction, and arnyotrophic lateral sclerosis (ALS) which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carver.
io The present invention also provides a method of treatment andlor prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable andfor preventable with anti-convulsive agents, such as epilepsy including post-15 traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with. AIDS, sleep disorders (including circadian rhythm disorders, insomnia &
narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, 20 especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurndysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS) comprising administering to the sufferer in need thereof an eff~tive or prophylactic amount of a 25 compound of formula (n, or a pharmaceutically acceptable salt or solvate thereof.
In a further aspect the invention provides the use of a compound of formula (n, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or 3o aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-conwlsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as 35 Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with A117S, sleep disorders (including ciucadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer SUBSTITUTE SHEET (1'~IJLE 2B) WO 99114197 10 p~/GB98I02~28 pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
5 In a further aspect the invention provides the use of a compound of formula {I), or a pharmaceutically acceptable salt or solvate, thereof as a therapeutic agent, in particular for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AmS, sleep disorders (including circadian rhythm disorders, is insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in ncurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
Another aspect of the invention provides a process for the preparation of compounds of formula (17, which comprises reacting a compound of formula (I>]
2s (i~
where RlA is Rl as defined for formula (n or a group convertible to R1, and P is NH2 or NCX, X being as defined, for formula (1], 3o with a compound of formula ()~
3s (>IT) where Q is NCX or NH2 and different from P, X being as defined for formula (I), and R2A is R2 as defined for formula (17 or a group or groups convertible to R2, St~BST~UTE SHEET RULE 26) WO 99/14197 11 FCf/GB98102728 and where required converting a R 1 ~' or R2A group to a R 1 or R2 group, converting one R 1 or R2 group to another R 1 or R2 group, converting a salt product to the free base or another pharmaceutically acceptable salt, or converting a fret base product to a pharmaceutically acceptable salt.
Conventional conditions for condensation of isocyanates or isothiocyanates with amines may be used, for example treatment in an inert solvent such as toluene, DMF or dichloromethane at ambient or elevated temperature.
1 o Conversions of an R 1 A or RaA group to a R 1 or R2 group typically arise when a protecting group is needed during the above coupling reaction or during the preparation of the reactants by the procedures described below. lnterconversion of one R1 or R2 group to another typically arises when one compound of formula (n is used as the immediate precwsor of another compound of formula (n, or when it is easier to introduce a more 15 complex or reactive substituent at the end of a synthetic sequence.
Compounds of formula (II) in which P is NHS may be prepared from the corresponding unsaturated compound of formula (IV) 20 (IV) by reaction with a compound R1AZ where Z is a leaving group such as halogen, especially iodo, or tosylate to obtain an intermediate of formula (V) 2s (V) which can be reduced, for example using sodium borohydride, to the compound of formula (Ln. Alternatively the compound of formula (V) can be hydrogenated, for example using 30 hydrogen at SOpsi in a solution of acetic/sulphuric acid with a platinum oxide catalyst.
Another route is from a precursor of formula (Vn 3s suBSTmu~ s~ss'r (RUB a~) WO 99/1419'f 12 PGT/GB98l02928 which can be reacted with R 1 AZ, preferably as a tosylate, to obtain the intermediate of formula (VII) ) which can then be hydrogenated under the conditions previously described to prepare the compound of formula (II).
1o Compounds of formulae (N) and (VI) and the reagents used are commercially available, or can be prepared from commercially available materials using conventional procedures described in the literature.
Alternatively, a compound of formula (II) in which P is NHS may be prepared directly from ~5 the corresponding nitro compound.by catalytic hydrogenation. More specifically 7-amino-tetrahydroisoquinolines may be prepared by the procedure of G E Stokker, Tet.
Lett. 1996, 37, 5453.
When R 1 A is hydrogen, the compound of formula (1'n can be obtained by direct 2o hydrogenation of the compounds of formula (IV) or (VI), using the reagents already described. The NH may be protected conventionally, for example by making R 1 A
t-butoxycarbonyl, prior to formation of the urea, and then deprotected under standard conditions, for example using trifluoroacetic acid/methylene chloride.
25 Compounds of formula (III) in which Q is iso(thio)cyanate are commercially available or may be prepared by formation of iso(thio)cyanates from commercially available substituted phenyl compounds using conventional procedures such as described by I T Fortes et al , J.Med.Chem., 1993, 36, 1104, and in Fieser and Fieser, Reagents for Organic Synthesis Vol I. For example an isocyanate may be prepared by stirring a relevant amine with one 3o equivalent of carboxyl diimidazole in a suitable solvent such as dichloromethane at room temperature, and then evaporated to dryness in vacuo. Isothiocyanates may be prepared by reaction of the relevant amine with carbon disulphide in pyridine in the presence of dicyclohexylcarbodiimide.
35 Compounds of formula (II) in which P is iso(thiokyanate may be similarly prepared starting from the amines of formula (II) described above.
SUHST1TUTE SHEET (RULE ZB

WO 99/14197 13 PC"T/G898/02?28 Compounds of formula {IIT) in which Q is amino are commercially available or may be prepared by formation of amines on commercially available substituted phenyl compounds using conventional procedures.
Where intermediates disclosed for the above processes are novel compounds, they also form part of this invention.
The compounds of the present invention may contain a chiral centre, and therefore the above processes may produce a mixture of diastereoisomers. A single diastereoisomer may be prepared by separating such a mixture of diastereoisomers which has been synthesised using a racemic starting material, or by synthesis using an optically pure starting material.
The compounds of this invention rliay be in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated. When some of the compounds of this t5 invention are allowed to crystallise or are recrystallised from organic solvents, solvent of crystallisation may be present in the crystalline product. Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be present in the crystalline product.
Crystallisation procedures will usually produce stoichiometric hydrates. Compounds containing variable 2o amounts of water may be produced by processes such as lyophilisation.
The compounds according to the invention are suitably provided in substantially pure form, for example at least 5096 pure, suitable at least 609'o pure, advantageously at least 75%
pure, preferably at least 8596 pure, more preferably at least 959io pure, especially at least 25 989io pure, all percentages being calculated as weight/weight. An impure or less pure form of a compound according to the invention may, for example; be used in the preparation of a more pure form of the same compound or of a related compound {for example a corresponding derivative) suitable for pharmaceutical use.
30 The present invention also includes pharmaceutically acceptable salts and derivatives of the compounds of the invention. Salt formation may be possible when one of the substitueats carries an acidic or basic group. Salts may be prepared by salt exchange in conventional manner.
SUBSTITUTE SHEET (RtJl.E 2t3) WO 99/14197 pCT/GB18102~28 Acid-addition salts may be pharmaceutically acceptable or non-pharmaceutically acceptable. In the latter case, such salts may be useful for isolation and purification of the compound of the invention, or intermediates thereto, and will subsequently be converted into a pharmaceutically acceptable salt or the free base.
The preparation of compounds of formula (I>] is illustrated by the following Descriptions;
the preparation of compounds of this invention is illustrated by the following Examples.
The utility of compounds of this invention is shown by the Pharmacological Data that to follow the Examples.
Description 1 N-2-(4-Nitrophenyl)ethyl-tritluoroacetamide A solution of trifluoroacetic anhydride ( 10.6m1) in dichloromethane ( l0ornl) was added dropwise to a stirred solution of 2,6-lutidine ( 17.44m1) and 4-nitrophenethyiamine hydrochloride ( 15.2g; 75 mmol) at 0°C. The mixture was stirred at 25°C overnight under argon and then washed with dilute citric acid (x2), brine and dried over Na2S04. The material in the organic phase gave the title compound as a pale yellow solid ( 19.04g).
Description 2 7.Vitro-1,2,3,4-tetrahydTO-2-trifluoroacetyl-isaquinoline The vitro compound D1 (2.268; 9.15 mmoi) and paraformaidehyde (0.45g; 14.4 mmol) in acetic acid { l Oml) and conc. H2S04 ( 15m1) were stirred at 25°C for 20h according to the procedure of G.E: Stokker., Tet. Lett., 1996, 37, 5453. Work up afforded the title compound as a white solid (2.17g).
1 H NMR (CI3Cl3) b: 3.10 (2H, m), 3.92 (2H, m), 4.85 + 4.92 (2H, 2xs), 7.38 ( 1 H, t), 8.10 (2H, m); m~Z (En: 274 (M+) Description 3 7-Vitro-1,2,3,4-tetrahydroisoquinoline SUBSTITUTE SI~IEET (RULE 2~j The trifluoroacetamide D2 ( 17.22g; 63 mmol) was hydrolysed at room temperature using a solution of potassium carbonate (46:6g) in 10% aqueous methanol (660m1). Work-up with dichloromethane gave the title compound ( 11 g).
Description 4 2-Methyl-7-vitro-1,2,3,4-tetrahydroiso~quinoltne to The amine D3 (2.08g; 11.7 mmoi) was treated with 889'o formic acid (3:45m1) and 37~
aqueous formaldehyde (5.88m1) at 80°C for 2h according to the procedure of G.M. Camera and D.S. Garvey, J. Het. Chem., 1992, 29, 847. Basification with 109'o sodium hydroxide followed by work-up with ethyl acetate afforded an orange gum (2.3g).
Chromatography on Kiesegel 60 in 0-3°yo methanol - ethyl acetate gave the title compound as an orange solid i5 (1.7g).
m/Z {Cn; 193 (MH+).
DeBCriptlon 5 zo 7-Amfno-Z-methyl-1,2,3,4~tetrahydroiaoquinoline The 7-vitro compound D4 (0.25g; 1.3 mmol) in methanol (40m1) was hydrogenated over 109~o palladium on carbon ( l OOmg) at atmospheric pressure overnight. The catalyst was z5 removed by filtration through a pad of Kieselguhr and evaporation in vacuo gave the title compound as a white solid (213mg).
m/Z (Cl~: 163 (MH+) 3o Description 6 ~'-Amino-2-(t-butyloxyearbonyl)-1,2,3,4-tetrahydrois~aquinoline The title compound was prepared from the compound of Description D3 using di t-butyl 35 dicarbonate in 1090 aqueous hydroxide in dioxan at 25°C followed by catalytic hydrogenation according to the procedure described for D5.
Description 7 $UB1TE SHEET (PtUi.E 28) WO 99/14197 16 ~rics9s~oans 7-Amino-1,2,3,4-tetrahydro-2-trlfluoroacetyl-isoquinoline The 7-vitro compound D2 (0.99g; 3.6 mmol) in ethanol (50m1) was hydrogenated over 10% palladium on carbon (450mg) at atmospheric pressure for 4h. The catalyst was removed by filtration through a pad of Celite and evaporation in vacuo gave the title compound as a white solid (840mg).
iH NMR (250MHz, CDC13) F: 2.84 (2H, t), 3.23 (2H, b. s.), 3.82 (2H, m), 4.66 (2H,d, restricted rotation around C-1 ), 6.47 ( 1 H, m), b.57 ( 1 H,m ), 6.96 ( 1 H, m) Description 8 5-Amino-2-methylisoquinolinium iodide is To a solution of 5-aminoisoquinoline ( 14.4g, 104mrraol) in acetone (300m1) was add iodomethane ( 14.4m1). The solution was briefly stirred and then allowed to stand for 2h.
The yellow precipitate was then filtered, washed with acetone and dried to afford the title compound as a yellow solid ( 18.8g).
Description 9 5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline 25 Sodium borohydride ( 17.8g, 0.47mo1) was added portionwise over 2h to an ice cold solution of 5-amino-2-methylisoquinolinium iodide D8 ( 18.8g, 65mmo1) in methanol ( 1.5L) and water (60m1). The mixture was then stirred at 25°C for 18h.
and concentrated in vacuo. The residue was extracted into water and dichioromethane. The organic layer was dried (Na2S(34) and concentration in vacuo gave the title compound (8.87g).
Description 10 2-Methyl-1,2,3,4-tetrahydroisoquinoline-7-isocyanate 35 The amine D5 (0.25g) and carbonyl di-imidazole (0.24g) in dichloromethane were stirred at 25°C for lh. Solvent was removed at reduced pressure below 40°C.
~t~BSTITtJTE SHEET (MULE 26) WO 99/14197 ~ 7 PGT/GH98/027Z8 Example 1 , (a) N-(1,2,3,4~Tetrahydro-2-trifluoroacetyi-isoquinolin~7-yl)-N'-(3-nitrophenyi) urea s A solution of amine D7 (400mg; 1.64 mmol) in dichloromethane (5m1) was treated with a solution of 3-nitrophenylisocyanate (295mg; 1.80 mmol) in toluene ( lOml) and the mixture kept at room temperature under argon. After 20h., the resultant cream precipitate was removed by filtration and washed well with ether/hexane and dried in vacuo.
Cream solid (612mg; 91 R'o):
m/z (APi+): 408 (MH+; 10096) (b) N-(1,2,3,4~Tetrahydroisoquinolin-7-yl)-N'-(3-nitrophenyl) urea t5 The urea (a) (540mg; 1.32 mmol) in 10'~'o aqueous methanol(80m1) and potassium carbonate ( 1 g) was stirred at room temperature overnight. The mixture was partitioned between chloroform and water and the organic phase dried over magnesium sulfate.
Evaporation in vacuo gave a pale yellow solid which was recrystallised from chloroform:hcxane (300mg, 72%). m.p. 232-5 °C.
1H NMR (250MHz, d6-DMSO) 8: 2.48 {2H, t), 2.78 (2H, t), 3:67 {2H, s), 6.83 (1H, d), ?.O1 ( 1H, dd), 7.05 { 1H, s), 7.42 ( 1H, t), 7.53 ( 1H, d), 7.67 ( 1H, dd), 8.43 ( 1 H, t), 8.58 ( 1 H, s), 9.07 (1H, s) Exmnple 2 N-(2-Methyi~1,2,3,4-tetrahydrnisoquinolin~7-yl)-N'-(3~nitrophenyl) urea The title compound was prepared from amine DS and 3-nitrophenylisocyanate using a 3o method similar to that of Example 1(a).
1H NMR (250MHz, d6-DMSO) 8: 2.40 (3H, s), 2.58 (2H, t), 2.75 (2H, t), 3.44 (2H, s), 7.01 ( 1 H, dd), 7.02 ( 1 H, d), 7.20 ( 1 H, s), 7.53 ( 1 H, m), 7.68 ( 1 H, m), 7.80 (2H, m), 8.57 (1H, s), 9.19 (1H, s); "'/Z(API+): 327 (MH+; 10096) Example 3 N~(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7~yl)~N'-(4-ethoxyphenyl) urea SUBSTITUTE SHEET (RULE 2B) WO 99/14197 1 ~ PC"r/GB98/02728 The title compound (262mg) was prepared frorri amine DS and 4-ethoxyphenylisocyanate using a method simliar to that of Example 1 (a).
s m.p. 189-193 °C.
1H NMR (250MHz, d6-DMSO) $: 1.31 (3H, t), 2.33 (3H; s), 2.56 (2H, t), 2.73 (2H, t), 3.43 (2H, s), 3.97 (2H, q), 7.01 (1H, dd), 6.84 and 7:34 {4H, ABq), 6.98 (1H, d), 7.16 (2H, m), 8.40 ( 1 H, s), 8.44 { 1 H, S); "'/z (API+): 326 (MH+; 1009b) Example 4 N-(2-Methyl-1,2,3,4-tetrahydrofisoquinolin-5-yl)-N'-(4-ethoxyphenyi) urea 15 The title compound was prepared from amine I?9 (162mg; lmmol) in dichloromethane (8m1) and 4-ethoxyphenyl isoc~ranate (166mg; lmmol) in toluene (4m1) using a method simliar to that of Example 1{a). White powder (210mg).
1H NMR (250MHz, d6-DMSO) S:. 1.42 (3H, t), 2.45 (3H, s), 2.62 (2H, br), 2.76 (2H, br), 3.57 (2H, s), 4.08 (2H, q); 6.83 (1H, d, J=6.SHz), 5.96 and 7.45 (4H, Abq, J=7.SHz), 7.19 (1H, t, J=6.SHz), 7.82 (1H, d, J=6.SHz), 7.86 (1H, s), 8.95 (1H, s);
'"/z (API+): 326 (MH+; 5096) Example 5 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-tcifluoromethylphenyl)thiourea The title compound was prepared in 4796 yield from amine DS and 3-trifluommethylphenyl isothiocyanate using a method similar to that of Example 1 (a).

1H NMR (250MHz, d6-DMSO) 8: 2.28 (3H, s), 2.53 (2H, t, J = 6 Hz), 2.74 (2H, t, J = 6 Hz), 3.40 (2H, s), 7.04 (2H, m), 7.13 ( 1 H, dd, J = 2 and 8 Hz), 7.40 ( 1 H, d, J = 8 Hz), 7.50 ( 1 H, t, J = 8 Hz), 7.70 ( 1 H, d, J = 8 Hz), 7.90 ( 1 H, s), 9.87 (2H, b s);
n'/z (APn: 366 (MH'"; 9'0) Example b N-{2-Methyl-1,2,3,4-tetrahydroiaoquinolin-7-yl)-N'-(3-trlfluoromethylphenyl)urea SUBSTITUTE SHEI~1" (RUk.E 2B) The title compound was prepared in 21 ~v yield from amine D5 and 3-trifluoromethylphenyl isocyanate using a method similar to that of Example 1(a).
5 1H NMR (250MHz, CDCl3) b: 2.42 (3H, s), 2.64 (2H, t, J = 6 Hz), 2.84 (2H, t, J = 6 Hz), 3.45 (2H, s), 6.90 - ?.06 (3H, b. m.), 7.09 (1H, s), 7.22 - 7.44 {3H, b.
m.), 7.51 (1H, d, J = 8 Hz), 7.58 (1H, s); m/Z (APT''): 350 (MH+; 10096).
Example 7 N-(2-Methyl-1,2,3,4-tetrahydrolsoquinolin-7-yl)-N'-(3-rnethoxyphenyljurea The title compound was prepared in 7486 yield from amine D5 and 3-methoxyphenyl isocyanate using a method similar to that of Example 1(a).
~5 ~H NMR (250MHz, CDC13) S: 2.35 (3H, s), 2.58 {2H, t, J = 6 Hz), 2.77 {2H, t, J
= 6 Hz), 3.32 (2H, s), 3.68 (3H, s), 6.53 (1H, d, J = 8 Hz), 6.76 - 6.96 (3H, b. m.), 7.00 - 7.13 (3H, b. m.), 7.82 (1H, s), 7.93 (1H, s); m/Z (~'~): 312 (MH+; 1009b).
2o Example 8 N-{2-Methyl-1,2,3,4-tetrahydrolsoqulnolin-7-yl)~N'-(3-bromophenyl) urea The title compound was prepared in 9096 yield from amine D5 and 3-bromophenyl 25 isocyanate using a method similar to that of Example 1(a).
~H NMR (250MHz, CDC13) b: 2.44 (3H, s), 2.67 (2H, t, J = 6 Hz), 2.87 (2H, t, J
= 6 Hz), 3.50 (2H, s), 6.74 ( 1 H, s), 6.97 (2H, m), 7.02 (2H, d, J = 5 Hz), 7.08 ( 1 H, d, J = 3 Hz), 7.76 (2H, m), 7.53 (1H, s);'~/Z (API'): 360, 362 (MH'; 100°Xo).
Example 9 N-(2-Methyl-1,2,3,4-tetrahydroisoquf noun-7-yl)-N'-{4-trlfluoromethylphenyl) urea 35 The title compound was prepared in 9096 yield from amine D5 and 4-trifluoromethylphtnyl isocyanate using a method similar to that of Example 1(a).
SUBSTITUTE SHEET (RULE 26) WO 99/14197 2~ PGT/GB98/02728 ~H NMR (250MHz, CDCl3) 8: 2.41 (3H, s), 2.63 (2H, t, J = 6 Hz), 2.84 (2H, t, J
= 6 Hzj, 3.44 (2H, s), 6.93 (2H, m), 7.01 (2H, m), 7.37 (2H, m), 7.45 (3H, m);
"'/Z (API+): 350 (MH+; 10096).
s Example 10 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(5-chloro-2,4-d~imethoxy-phenyl) urea to The title compound was prepared in 939'o yield from amine DS and 5-chloro-2,4 dimethoxyphenyl isocyanate using a method similar to that of Example 1(a).
~H NMR (2SOMHz, CDC13) b: 2.42 (3H, s), 2.66 (2H, t, J = 6 Hz), 2.85 (2H, t, J
= 6 Hz), 3.48 (2H, s), 3.80 (3H, s), 3.86 (3H, s), 6.45 (1H, s), 7.00 (iH, d, J = 8 Hz), 7.06 - 7.12 15 (2H, m), 7.32 (1H, s), 7.40 (1H, s), 8.08 (1H, s);'"/Z (API+): 376 (MH'";
1000.
Example 11 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(4-tart-butyl, 2-20 methoxyphenyl)urea The title compound was prepared in 5296 yield from amine DS and 4-tart-butyl-2-methoxyphenyl isocyanate using a method similar to that of Example 1 (a).
25 ~H NMR (250MHz, CDCl3) 8: 1.30 (9H, s), 2.44 (3H, s), 2.67 (2H, t, J = 6 Hz), 2.87 (2H, t, J = 6 Hz), 3.52 (2H, s), 3.81 (3H, s), 6.81 ( 1 H, s), 6.87 ( 1 H, d, J = 2 Hz), 6.96 (1 H, dd, J
= 2 and 8 Hz), 7.07 (3H, m), 7.16 ( 1 H, s), 7.94 ( 1 H, d, J = 8 Hz);
"'/Z (API"'): 368 (MH+; 10096) 3o Example 12 N-(2-Methyl-1,2,3,4-tetrahydroisaquinolin-7-yl)-N'-{phenyl) urea The title compound was prepared in 9496 yield from amine DS and phenyl isocyanate using 35 a method similar to that of Example 1 (a).
~H NMR {250MHz, CDC13) 8: 2.41 (3H, s), 2.63 (2H, t, J = 6 Hz), 2.64 (2H, t, J
= 6 Hz), 3.45 (2H, s), 6.90 - 7.13 (6H, b. m.), 7.22 - 7.34 (4H, b. m.); m/Z (APIi'):
282 (MH'"; i00~o).
SUB8TtTUTE SHEET (RUNE 2B) Example 13 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-'7-yl)-N'-(3-acetylphenyl)urea s The title compound was prepared in 599~o yield from amine DS and 3-acetylphenyi isocyanate using a method similar to that of Example 1(a).
~H NMR (250MHz, CDC13) b: 2.39 (3H, s), 2.55 (3H, s), 2:62 (2H, t, J = 6 Hz), 2.82 (2H, to t, J = 6 Hz), 3.42 (2H, s), 6.92 - 7.13 (3H, m), 7.31 (1H, t, J = 8 Hz), 7.44 (1H, d, J = 8 Hz), 7.79 (3H, m), 7.95 (1H, s); "'/Z (API+): 324 (MH+; 1009'0).
Example 14 is N-(2-Methyl-1,2,3,4-tetrahydroisoqulnolin-7-yl)-N'-(2-methyiphenyl)urea The title compound was prepared in 989b yield from amine D5 and 2-methylphenyl isocyanate using a method similar to that at Example 1 (a).
20 1H NMR (250MHz, CDC13) 8: 2.18 (3H, s), 2.39 (3H, s), 2.61 (2H, t, J = 6 Hz), 2.81 (2H, t, J = 6 Hz), 3.41 (2H, s), 6.88 (1H, s), 6.92 - 7.20 (6H, b. m.), 7.26 (1H, s), 7.54 {1H, d, J =
8 Hz);'"/Z (API: 296 (MH+; 100'96).
Example 15 N-{2-Methyl-1,2,3,4-tetrahydroisoquinolin.'7-yl)-N'-(2-methoxyphenyl)urea The title compound was prepared in 45°~ yield from amine DS and 2-methoxyphenyl isocyanate using a method similar to that of Example 1(a).
~H NMR {250MHz, CDC13) s: 2.42 (3H, s), 2.67 (2H, t, J = 6 Hz), 2.85 (2H, t, J
= 6 Hz), 3.48 (2H, s), 3.78 (3H, s), 6.68 - 7.03 (4H, b. m.), 7.09 - 7.22 (2H, b. m.), 7.46 - 7.68 (2H, b. m.), 8.10 (1H, d, J = 7 Hz); '"/Z (APf~: 312 (MH+; 100°0) Example 16 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolln-7-yl)-N'-(3-chlorophenyl)urea SUBSTITUTE SHEET (RIUt-E 2B) The title compound was prepared in 929'o yield from amine DS and 3-chlorophenyl isocyanate using a method similar to that of Exariiple 1 (a).
~H NMR (250MHz, CDC13) b: 2.47 (3H, s), 2.64 (2H, t, J = 6 Hz), 2.85 (2H; t, J
= 6 Hz), 3.46 (2H, s), 6.90 - 7.06 (4H, b. m.); 7.13 - 7.23 (4H, b. m.), 7.37 (1H, s);
'"~z (API+): 316 (MH+'100%) Example 17 io N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)~N'-(3-chloro-6-methoxyphenyl)urea The title compound was prepared in 98% yield from amine DS and 3-chlom-6-methoxyphenyl isocyanate using a method similar to that of Example 1 (a).
'H NMR (2SOMHz, CDC13) 8: 2.42 (3H, s), 2.56 (2H, t, J = 6 Hz), 2.85 (2H, t, J
= 6 Hz), 3.47 (2H, s), 3.77 (3H, s), 6.73 (1H, m), 6.90 (1H, dd, J = 2 and 9 Hz), 7.00 -7.17 (3H, b.
m.), 7.43 ( i H, s), 7.60 ( 1 H, s), 8.23 ( 1 H, d, J = 2 Hz); '~/Z (APIA: 346 ( 1009b) Example 18 N-(2-Methyl-1,2,3,4-tetrshydroiaoqufnotin-7-yl)-N =(3,5-df-trlfluoromethylphenyl)urea The title compound was prepared in 4190 yield form amine DS and 3,5-ditrifluoromethylphenyl isocyanatc using a method similar to that of Example 1 (a).
~H NMR (250MHz, CDCl3) 8: 242 (3H, s), 2.66 (2H, t, 3 = 6 Hz), 2.82 (2H, t, J
= 6 Hz), 3.43 (2H, s), 6.89 (1H, s), 6.95 (2H, s), 7.46 (2H, s), 7.81 (2H, s), 8.23 (1H, s);
"'~z (APT"): 418 ( 100°J'o) Example 19 N»(2-Methyl-1,2,3,4-tetrahydroisoquinolln-7-yl)-N'-(4~triftuoromethoxyphenyl)urea The title compound was prepared in 92~ yield from amine DS and 4-trifluoromethoxyphenyl isocyanate using a method similar to that at Example 1(a).
SUBBTlTtJTE IaHEET (RULE i16) WO 99!14197 23 PCT/GB98/02?28 'H NMR {250MHz, d6-DMSO) s: 2.49 (3H, s), 2.74 {2H, t, J = 6 Hz), 2.9? (2H, t, J = 6 Hz), 3.61 (2H, s), 7.18 (1H, d, J = 9 Hz), 7.33 (2H, m), 7.45 (2H, d, J = 9 Hz). 7.72 (2H, d, J = 9 Hz), 8.77 (1H, s), 9.03 {1H, s); m/Z (APT''): 366 (MH';
100°0.
SI~~TtTUTE SHEET (RULE ?d3j WO 99/14197 . 24 PCT/GB98I02728 Example 2fl N-(2-Methyl-1,2,3,4-tetrahdyroisoquinoiin-7-yl)-N'-(3-chloro-4-methylphenyl)urea 5 The title compound was prepared in 9896 yield from amine DS and 3-chloro-4-methylphenyl isocyanate using a method similar to that of Example 1(a).
'H NMR (2SOMHz; CDC13) s: 2.28 (3H, s), 2.41 (3H, s), 2.64 (2H, t, J = 6 Hz), 2.84 (2H, t, J = 6 Hz), 3.44 (2H, s), 6.97 ( 1H, s), 7.01 - 7.16 (4H, b. m.), 7.19 ( 1 H, s), 7.34 (2H, m);
to ~'/Z (APIA): 330 (MH+; 10096).
Example 21 N-(2-Methyl-1,2,3,4,-tetrahydroisoquinolin-5-yl)-N'-(3-triftuoromethylphenyl)urea is The title compound was prepared from the amine D9 and 3-trifluommethylphenyl isocyanate using a method similar to that of Example 1(a).
'H NMR (2SOMHz, d6-DMSO) 8: 2.41 (3H, s), 2.72 (4H, m), 3.54 (2H, s), 6.85 (1H, d, J
20 = 7 Hz), 7.16 ( 1 H, dd, J = 7 and 8 Hz), ?.37 ( 1H, d, J = 7 Hz), 7.61 (2H, m), 7.74 ( 1 H, d, J
= 8 liz), 8.02 (1H, s), 8.10 (1H, s), 9.44 (1H, s);'~/z (APT''): 3S0 (MH+;
10090).
Example 22 2s N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)~N'-(5-chtoro-2,4-dimethoxyphenyl)urea The title compound was prepared in 5496 yield from the amine D9 and S-chloro-2,4-dimethoxyphenyl isocyanate using a method similar to that of Example 1(a).
1H NMR (2SOMHz, d6-DMSO) 8: 2.32 (3H, s), 2.64 (4H, m), 3.46 (2H, s), 3.84 (3H, s), 3.94 (3H, s), 6.75 ( 1 H, d, J = 7 Hz), 6.85 ( 1 H, s), 7.06 ( 1H, dd, J = 7 and 8 Hz), 7.67 ( 1 H, d, J = 8 Hz), 8.16 ( 1 H, s), 8.36 ( 1 H, s), 8.62 ( 1 H, s); "'lZ (APT'');
376 (MH+; 100°0) Example 23 N-(Z-Methyl-1,2,3,4-tetrahydroisoquitzolin-5-yl)-N'-(3-nitrophenyl)urea StIBFl'ITUTE SHEET (RIJIE 2fl) WO 99/14197 25 PCT/GB98/o2728 The title compound was prepared in 739'o yield from amine D9 and 3-nitrophenyl isocyanate using a method similar to that of Example 1(a).
1H NMR (250MHz, d6-DMSO) 8: 2.24 (3H, s), 2.57 (4H, m), 3.37 (2H, s), 6.70 (1H, d, J
= 7 Hz), 7.02 ( 1 H, t, J = 8 Hz), 7.47 ( 1 H, t, J = 8 Hz), 7.58 (2H, m), 7.73 ( 1 H, m), 7.89 ( 1H, s), 8.46 { 1H, m), 9.43 ( 1 H, s); '"/z (API''); 327 {MH+; 10090).
Example 24 to N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3-bromophenyl) urea The title compound was prepared in 719'o yield from amine D9 and 3-bromophenyl isocyanate using a method similar to that of Example 1 (a).
15 ~H NMR (250MHz, d6-DMSO) b: 2.15 (3H, s), 2.48 (4H, m), 3.27 (2H, s), 6.57 {1H, d, J
= 7 Hz), 6.85 - 7.10 (4H, b. ~m. ), 7.46 ( 1 H, d, J = 8 Hz), 7.69 ( 1 H, s), 7.71 ( 1 H, s), 9.03 ( 1 H, s); "'/Z (APT"): 360, 362 (MH+; 100'x'0).
Example 25 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3-methoxyphenyl)urea The title compound was prepared in 479b yield from amine D9 and 3-methoxyphenyl isocyanate using a method similar to that of Example 1(a).
~H NMR (250MHz, d6-DMSO) b: 2.36 (3H, s), 2.69 (4H, m), 3.52 (2H, s), 3.73 (3H, s), 6.56(lH,d,J= IOHz),6.76(lH,d,J=8Hz),6.94(lH,d,J=IOHz),7.14(3H,m),7.72 ( 1H, d, J = 8 Hz), 7.86 ( 1 H, s), 9.08 { 1 H, s); ~'/t (API): 312 (MH+;
1009'0) 3o Eatample 26 N-(2-Methyl-1,2,3,4-tetrahydroisoqufnolin-5-yl)-N'-(4-trlfluoramethoxy-phenyl)urea The title compound was prepared in 7496 yield from amine D9 and 4-trifluoromethoxyphenyl isocyanate using a method similar to Example 1(a).
SUBSTITUTE SHEET (RULE 26j ~H NMR (250MHz, d6-DMSO) F: 2.59 (3H, s), 2.84 (2H, t, J = 5 Hz), 3.03 (2H, t, J = 5 Hz), 3.84 (2H, s), 6.82 ( 1 H, d, J = 7 Hz), 7.15 ( 1 H, s), 7.30 (2H, d, J =
8 Hz), 7.58 (2H, d, J
= 8 Hz), 7.74 (1H, d, J = 7 Hz), 8.24 (1H, s), 9.59 (1H, s); "'/z (APT"): 366 (MH+; 10096) Example 27 N-(2-Methyl-1,2,3,4-tetrahydroisoqufnolfn-5-yl)-N'-(4»trifluoromethyl-phenyl)urea The title compound was prepared in 6996 yield from amine D9 and 4-trifluoromethylphenyl 1o isocyanate using a method similar to that of Example 1(a).
'H NMR (250MHz, d6-DMSO) ~: 2.332 (3H, s), 2.58 (2H, t, J = 5 Hz); 2.74 (2H, t, J = S
Hz), 3.58 (2H, s), 6.60 (1H, d, J = 7 Hz), 6:93 (1H, dd, J = 7 and 8 Hz), 7.45 (SH, m), 8.03 (1H, s), 9.52 (1H, s); "'/z (APT: 350 (MH+; 10096) Example ZS
N-(2-Methyl-1,2,3,4-tetrahydcoisoquinolin-5-yl~N'-(phenyl)urea 20 The title compound was prepared in 7996 yield from amine D9 and phenyl isocyanate using a method similar to that of Example 1(a).
~H NMR (250MHz, d6-DMSO) S: 2.35 (3H, s), 2.66 (4H, iri), 3.48 (2H, s), 6.76 (1H, d, J =
8Hz),6.95(lH,t,J=8Hz),7.08(lH,t,J=8Hz),7.28(2H,t,J=8Hz),7.46(2H,d,J=
8 Hz), 7.71 (1H, d, J = 8 Hz), 7.83 (1H, s), 9:03 (1H; s);'"/z (API"''): 282 (MH''; 1009'0).
Example 29 N-(2-Methyl-1,2,3,4-tetrahydroisoqinoiin-5-yl)-N'-(3-acetylphenyi)urea The title compound was prepared in 7496 yield from amine D9 and 3-acxtylphenyl isocyanate using a method similar to that of Example 1(a).
~H NMR (250MHz, CDC13) 8: 2.43 (3H, S), 2.61 (SH, m), 2.78 (2H, b. m.), 3.56 (2H, s), 6.74 ( 1 H, s), 6.92 ( 1 H, d, J = 7 Hz), 7.16 ( 1 H, t, J = 8 Hz), 7.35 (3H, m), 7.59 ( 1 H, d, J = 8 Hz), 7.80 (2H, m);'"/z (APIA: 324 (MH'"; 10096) Example 30 SUBS"fITUTE SHEET (RUI:E Zb) WO 9911419') 27 PCT/G~98102728 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3-chloro-4-methytphenyl)urea The title compound was prepared in 9896 yield from amine D9 and 3-chloro-4-methylphenyl isocyanate using a method similar that of Example 1(a).
~H NMR (250MHz, CDC13) b: 2.29 (3H, s), 2.44 (3H, s), 2.65 (2H, t, J = 6 Hz), 2.76 (2H, t, J = 6 Hz), 3.57 (2H, s), 6.37 ( 1 H, s), 6.71 ( 1 H, s), 6.94 ( 1 H, d, J =
8 Hz), 7.04 - 7.22 (3H, b. m.), 7.33 (2H, m); "'/Z (APf*): 330 (MH+; 10096).
Example 31 N--{2~Methyl-1,2,3,4--tetrahydroisoquinottn-5-yl)-N'-(3-chloro-6~methoxyphenyl)urea The title compound was prepared in 61 ~v yield from amine D9 and 3-chloro-6 methoxyphenyl isocyanate using a method similar to that of Example 1(a).
'H NMR (250MHz, CDCI~) 8: 2.45 (3H, s), 2.69 (2H, t, J = 6 Hz), 2.82 (2H; t, J
= 6 Hz), 3.59 (2H, s), 3.73 (3H, s), 6.41 (1H, s), 6.70 (1H, d, J = 9 Hz), 6.93 (2H, t, J = 6 Hz), 7.18 (1H, t, J = 8 Hz), 7.35 (2H, m), 8.25 (1H, s); ~'/Z (APf~: 346 (MH+;10096) Example 32 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-S-yl)-N'-(3-chlorophenyl)urea The title compound was prepared in 8386 yield form amine D9 and 3-chlorophenyl isocyanate using a method similar to that of Example 1 (a).
~H NMR (250MHz, CDC13) $: 2.42 (3H, s), 2.150 (2H, t, J = 6 Hz), 2.73 (2H, t, J = 6 Hz), 3.53 (2H, s), 6.70 ( 1 H, s), 6.89{ 1 H, d, J = 8 Hz), 6.98 ( 1 H, m), 7.04 -7.20 (4H, m), 7.31 ( 1 H, d, J = 8 Hz), 7.37 ( 1 H, s); '"/Z (API's: 316 (MH'"; 10096).
Example 33 N-(2-Methyl-1,2,3,4; tetrahydroisoqulnolin-5-yl)-N'-(2-methoxyphenyl)urea The title compound was prepared in 58°~'n yield from amiae D9 and 2-methoxyphenyl isocyanate using a method similar to that of Example 1 (a).
SU~STtTI:ITE SME~eT E~tUI.E 2B) WO 99/14197 2g FCT/GH98/02728 ~H NMR (250MHz, CDCl~) ~: 2.45 (3H, s), 2.68 (2H, t, J = 6 Hz), 2.81 (2H, t, J
= 6 Hz), 3.59 (2H, s), 3.75 (3H, s), 6.38 (1H, s), 6.82 (1H, d, J = 7 Hz), 6.88 - 7.44 (3H, b. m.), 7.18 ( 1 H, t, J = 8 Hz), 7.27 ( 1 H, m), 7.40 ( 1 H, d, J = 8 Hz), 8.12 ( 1 H, d, J = 6 Hz); "'/Z (API+'):
312 (MH+; 100%) Example 34 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-ylj-N'-(2-methylphenyl)urea The title compound was prepared in 8896 yield from amine D9 and 2-rnethylphenyl isocyanate using a method similar to that of Example 1(a).
~NMR (250MHz, CDCl3) 8: 1.71 (3H, s), 2:43 (3H, s), 2.66 (4H, m), 3.55 (2H, s), 6.40 ~ 5 ( 1 H, s), 6.89 ( 1 H, d, J = 8 Hz), 7.05 - 7.28 (5H, m), 7.48 ( 1 H, d, J
= 8 Hz), 7.61 ( 1 H, d, J =
8 Hz);'"/Z (API+): 296 (MH+; 1000) Example 35 2o N-(2-lVlethyl-1,2,3,4-tetrahydroi~soquinolin-5-yl)-N'-(3,5-dl-trifluornmethylphenyl)urea The title compound was prepared in 5896 yield from amine D9 and 3,5-di-trifluoromethylphenyl isocyanate usng a method similar to that of Example 1(a).
~H NMR (250MHz, CDC13) b: 2.46 (3H, s), 2.67 (2H, t, J = 6 Hz), 2.81 (2H, t, J
= 6 Hz), 3.59 (2H, s), 6.49 (1H, s), 6.86 (2H, d, J = 8 Hz), 7.16 - 7.34 (2H, b. m.), 7.51(1H, s), 7.83 (2H, s); "'/z (API"): 41$ (MH+; 1000).
3o Example 36 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-ylrN'-(3-trifluoromethylphenyljthioure~a The title compound was prepared in 5796 yield froze amine D9 and 3-tzifluoromethylphenyl isothiocyanate using a method similar to that of Example 1(a).
'H NMR (250MHz, d6-DMSO) ~: 2.46 (3H, s), 2.63 (2H, t, J = 6 Hz), 2.79 (2H, t, J = 6 Hz), 3.54 (2H, s), 7.00 ( 1 H, dd, J = 3 and 6 Hz), 7.14 (2H, m), 7.45 ( 1 H, d, J = 8 Hz), 7.55 SUB&TITUTE FHEES (RULE 26) ( 1 H, t, J = 8 Hz), 7.79 ( 1 H, d, J = 8 Hz), 8.00 ( 1 H, s), 9.56 ( 1 H, bs), 9.94 ( i H. bs); "'/Z
(API"): 366 {MH+; 95%) Example 37 s N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-?-yl):N'-(2-carbomethoxyphenyl) urea The title compound was prepared in 69~'o yield from amine D5 and 2-carbomethoxyphenyl isocyanate using a method similar to that of Example 1{a).
to 'H NMR (250MHz, CDC13) S: 2.46 (3H, s), 2.68 (2H, t, J = 6 Hz), 2.89 (2H, t, J
= 6 Hz), 3.57 (2H, s), 6.53(1H, br. s.), 7.00 (1H, t), 7.09 (2H, m), 7.19 (1H, s), 7.52 (1H, t), 7.99 ( 1 H, d), 8.54 ( 1 H, d), 10.52 ( 1 H, bs);
n'/z (API''): 340 (MH+; 95R~) Example 38 N~(2-Methyl-1,2,3,4-tetrahydroisoquin~olin-7~yl)-N'-(2, 3-dfmethylphenyl) urea The title compound was prepared in 1696 yield from amine D5 and 2, 3-dimethylphenyl isocyanate using a method similar to that of Example 1 (a).
'H NMIt (250MHz, CDC13) 8: 2.19 (3H, s), 2.31 (3H, s), 2.43 (3H, s), 2.66 (2H, t, J = 6 Hz), 2.86 (2H, t, J = 6 Hz); 3.53 (2H, s), 6.22 (1H, br. s.), 6.38 (br. s.
1H), 7.02 - 7.27 (6H, m); "'/Z (API"'): 310 (MH+; 950) Example 39 N-(2~Methyl-1,2,3,4-tetrahydroi~~quinolin-7-yl)-N'-(2-methoxy-3-chlorophenyl) urea The title compound was prepared in 61 ~'v yield from amine D5 and 2-methoxy-3-chlorophenyl isocyanate using a method similar to that of Example 1 (a).
~H NMR (250MHz, CDCl3) S: 2.31 (3H, s), 2.56 (2H, t, J = 6 Hz), 2.70 {2H, t, J
= 6 Hz), 3.44 (2H, s), 3.77 (3H, s), 6.97 - 7.16 (5H, m), 8.14 (1H, dd), 8.43 (s, 1H) and 9.22 (s, 1H);
'"/z (API"'): 346 (MH'"; 9596) Example 40 SUBSTITUTE SHEET QRULE 26) wo ~n4m 30 ~ rcrics9aro2~as N-(2-Methyl-1,2;3,4-tetrahydmisoquinolin-7-yl)-N'-(1-napl~thyl) urea The title compound was prepared in 54~ yield fram amine D5 and 1-naphthyl isocyanate using a method similar to that of Example 1 (a).
~H NMR (250MHz, CDC13) 8: 2.42 (3H, s), 2.56 (2H, t, J = 6 Hz), 2.85 (2H, t, J
= 6 Hz), 3.51 (2H, s), 6.53 ( 1 H, s), 6.74 ( 1 H, s), 7.01 (2H, d), 7.08 ( 1 H, s), 7.47 - 7.56 (3H,. m), 7.67 ( 1 H, d), 7.79 ( 1 H, d), 7.90 ( 1 H, m) and 7.99 (m 1 H, m).;
to '"/z (API: 332 (MH+; 95~Xv) Example 41 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yi)-N'-(2-methyl-3-nltrophenyl) urn ~5 The title compound was prepared in 8790 yield from amine D5 and 2-methyl-3-nitrophenyl isocyanate using a method similar to that of Example 1 (a)..
1H NMR (250MHz, CDCl3) S: 2.27 (3H, s), 2.44 (3H, s), 2.69 (2H, t, J ~ 6 Hz), 2;89 (2H, 2o t, J = 6 Hz), 3.53 (2H, s), 6.80 (1H, br. s), b.86 (1H, br. s), 7.06 (3H, s), 7.30 (1H, t, J = 8 Hz), 7.57 ( 1 H, d, J = 7 Hz) and 7.95 ( 1 H, d, J = 8 Hz);
'"~z (AI'I~'): 339 (MHO; 9590) Example 42 N-(2-Methyl-1,2;3,4-tetrahydroiaoquinolun-7-yl)~N'-(2-cyanophenyl) urea The title compound was prepared in 13~n yield from amine D5 and 2-cyanophenyl isocyanate using a method similar to that of Example 1(a).

'H NMR (250MHz; CDC13) b: 2.47(3H, s) 2.70(2H, br. s.) 3.02(2H, br, s), 3.62(2H, br. s) other aliphatics poorly resolved 6.89(1H, d), 6.97(1H, s), 7.05(1H, d), 7.16(1H, t), 7.32(1H, d), 7.47(1H, s), 8.19(1H, d) and 9.14(1H~, br. s.);
'"~z (API"): 307 (MH''; 95~) Example 43 N-(2-Methyl-1,2,3,4-tetrahydroisoquinoiin-7-yl)-N'-(2-cyano-3-methylphenyl) urea SUBSTITUTE SHEET (RULE 26) The isocyanate D 10 ( 160mg) was dissolved in dimethylformamide ( lOml), 6-methyl-2-aminobenzonitrile (0.13g) added and.the mixture heated at 100°C for 3h.
Dimethylformamide was removed at reduced pressure and the residue partitioned between 5 dichloromethane and water. The organic phase was washed with water, dried MgS04) and solvent removed at reduced pressure. The residue was column chromatographed using a gradient of 0 -> 10 % [9:1 EtOH - ammonia] in MDC (silica gel ethanol/dichloromethane 1:9 ~ ammonia/ethanol/dichloromethane 1:9:90) to give the title compound (O.Olg 3010), 'H NMR (250MHz, d6-DMSO) 8: 2.27(3H, s), 2.40 (3H, s), 2.51 (2H, t, J = 6 Hz), 2.69 (2H, t, J = 6 Hz), 3.38 {2H, s), 6.96{ 1 H, d, J = 9 Hz), 7.02( 1 H, d, J =
8Hz), 7,11 ( 1 H, s), 7.14( 1 H, d), 7.45{ 1 H, t, J = 8 Hz), 7.84( 1 H, d, 8 Hz), 8.56( 1 H, s) and 9.25 ( 1 H, s);
'"/z (API'): 32b (MH''; 95q6) Example 44 is N-(2-Methyl-1;2,3,4-tetra6ydroisoquinolln-'7-yl)-N'-(1-acetylindolin-7-yl) urea The title compound was prepared in 14°~ yield from 7-amino-l-acetylindoline and the isocyanate D10 using the-method of Example 43 .
20 ~H NMR (250MHz, d6-DMSO) $: 2.41(3H, s), 2.46 (2H, t, J = 5.5 Hz), 2.63(2H, t, J = 5,4 Hz), 2.96(2H, t, J = 7.5 Hz), 3.31(2H, s), 4.03(2H, t, 7.6 Hz), 6.85(2H, m), 7.00(1H, t, J =
7.7 Hz), 7.1{2H, m), 7.45(1H, d; J = 8.0 Hz), 8.65(1H, br. s.) and 9.15{1H, br. s.);
'"/z {API''): 365 (MH+; 95~n) 25 Example 45 N-(2-Methyl-1,Z,3,4-tetrahydroisoqulnolin-7-yl)-N'-(3-cyanophenyl) urea The title compound was prepared in 120k~ yield from3-aminobenzonitrile and the isocyanate 3o D 10 using the method of Example 43 'H NMR {250MHz, CDCl3) 8: 2.44 (3H, s), 2.68 (2H, t, J = 5.8Hz), 2.89 (2H, t, J = 5.8Hz);
3.52 (2H, s), 6.88 {1H, br.s), 6.98 - 7.09 (3H, m), 7.19 - 7.39 (3H, m), 7.62 (2H, m).
"'/z (API''): 307 (MH+) 35 Example 4b N-(2-Methyl-1,2,3,4-tetrahydrofsoquinolln-7-yl)-N'-(3-ethylphenyl) urea SUQSTI1'tJTE SKEET (RULE 2E) WO 99/14197 32 PG"1'/GB98102728 The title compound was prepared in 12% yield from 3-ethylaniline and the isocyanate D 10 using the method of Example 43 ~H NMR (250MHz. CDCI3) b: 1.19 (3H, t, J = 7.SHz), 2.42 (3H, s), 2.54 - 2.66 (4H, m), 2:85 (2H, m), 3.48 (2H, s) and 6.90 - 7.26 (7H, m).
m/Z (API'): 310(MH+) Example 47 N-(2~Met~yt-1,2,3,4-tetrahydroiaoquinotin-7-yt)-N'-(3, S-dinitrophenyl) urea to The title compound was prepared in 129b yield from 3,5-dinitroaniline and the isocyanate D 10 using the method of Example 43.
'H NMR (250MHz, d6-DMSO) 8: 2.18 (3H, s), 2.42 (2H, t, J = 5.5Hz), 2.60 (2H, t, J =
5.5Hz), 3.29 (2H, s), 6.88 (1H, d; J = 8.8Hz), 7.06 (2H, br. s), 8.24 (1H, s), 8.59 (2H, d), 8.80 ( 1 H, s) and 9.52 ( 1 H, s).
"'/Z (API"): 372 (MH+) Example 48 2o N-(2-Methyl-1,2,3,4~tetrahydroisflquinotin~7~yl~.N'-(2,3-dichlorophenyt) urea The title compound was prepared in 669~b yield from amine D5 and 2, 3-dichlomphenyl isocyanate using a method similar to that of Example 1(a).
1H NMR (250MHz, CDCl3) b: 2.46 (3H, s), 2.70 (2H, t, J = 5.8Hz), 2.91 (2H, t, 3 = 5.8Hz), 3.55 (2H, s), 6.93 ( 1 H, br. s), 7.06 - 7.21 (5H, rn), 7.37 ( 1 H, s) and 8.18 ( 1 H, dd, J = 2.1, 7.8Hz).
"'/Z (API"): 350, 352 (MH'~
Example 49 N~(2-Methyl-1,2,3,4-tetrahyd~roisatuinotin~7-yt)-N'-(3-chioro-4-fluorophenyl) urea The title compound was pnypared in 95~'o yield from amine D5 and 3-chloro-4-fluorophenyl isocyanate using a method similar to that of Example 1(a).
~H NMR (250MHz, CDC13) 8: 2.40 (3H, s), 2.61 (2H, t, J = 5.2Hz), 2.82 {2H, t, J = 5:2Hz), 3.41 {2H, s), 6.76 - 7.07 (5H, m), 7.26 - 7.35 (2H, m) and 7.42 (1H, s).
'"/Z (APf~): 334, 336 (MH'~
I~UBSTITU'TE SHEET (R~U~E 2B) Example 50 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(2-chloro-5-tritluoromethylphenyl) urea The title compound was prepared in 249'o yield from amine D5 and 2-chioro-5-trifluoromethylphenyl isocyanate using a method sinvlar to that of Example 1 (a).
1H NMR (250MHz, CDC13) b: 2.44 (3H, s), 2.70 (2H, t, J = 5.2Hz), 2.88 (2H, t, J = 5.2Hz), 3.51 (2H, s), 7.02 - 7.20 {4H, m), 7.38 - ?.49 (2H, m), 8.50 (1H, s) and 8.61 (1H, s), "'/Z (API+): 384, 386 (MH+) Example 51 N-(Z~Methyl-1,2,3,4-tetrahydroisoquinolin-7~yl)-N'-(3-i8opropoxyphenyl) urea The title compound was prepared in 429'o yield from 3-isopropoxyaniline and the isocyanate D 10 using the method of Example 43.
~H NMR (250MHz, CDC13) b: 1.27 (6H, d, J = 6.0Hz), 2.40 (3H, s), 2.62 (2H, t, J =
20 5.7Hz), 2.83 (2H, t, J = 5.7Hz), 3.44 (2H, s), 4.48 ( 1 H, m), 6.58 ( 1 H, dd, J = 2.0, 8.2Hz), 6.76 ( 1 H, d, J = 8.OHz), 6.97 - 7,15 (6H, m) and 7.21 ( 1 H, s).
m/z (API"'): 340 {MH~
Example 52 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-ethoxyphenyl) urea The title compound was prepared in 4596 yield from 3-ethoxyaniline and the isocyanate D 10 using the method of Example 43.

~H NMR (250MHz, CDC13) 8: 1.34 {3H, t, J = 6.8Hz), 2.39 (3H, s), 2.62 (2H, t, J = 5.7Hz), 2.81 (2H, m), 3.41 (2H, s), 6.57 {lH, d, 7.7Hz), 6.?6 (1H, d, J = 8.OHz), 6.92 - 6.98 {3H, m) 7.11 (1H, t, J = 8Hz), 7.26 (1H, s) and 7.49 (1H, s).
"'/Z (APT~): 326 (MH''~
Example 53 N-(2-Methyl-1,2,3,4~tetrahydrofsoquinolin-7-yl)-N'-(3-t~rtbutylphenyl) urea SU98TITIJ'1"~ ShIEET (FlU1-E 2B) WO 99/141'97 34 PCT/G89810Z7Z$
The title compound was prepared in 39q6 yield from 3-tertbutylaniiine and the isocyanate D 10 using the method of Example 43.
5 'H NMR (250MHz, d6-DMSO) 8: 1.27 (9H, s), 2.32 (3H, s), 2.56 (2H, m), 2.72 (2H, m), 3.43 (2H, s), 7.00 {3H, m), 7.16 - 7.25 (4H, m), 7.45 ( 1 H, s), 8.45 ( 1 H, s) and 8.58 ( 1 H, s).
'"~z (APT: 338 {MH+) Example 54 N-(2-Methyl-1,2,3,4-tetrahydrolsoqulnolin-7-yl)-N'-j3-(1,3-ox$zol-5-yi)phenyl]
urea The title compound was prepared in 72% yield from 3-{1,3-oxazol-5-yl)aniline and the isocyanate D 10 using the method of Example 43.

1H NMR (250MHz, d6-DMSO) 8: 2.33 {3H, s), 2.57 (2H, t, J = 5.6Hz), 2.75 (2H, m), 3.45 (2H, s), 7.01 ( 1 H, d, 3 = 8.3Hz), 7.17 - 7.20, (2H, m), 7.35 (3H, m7.65 ( 1H, s), 7.94 ( 1H, s), 8.48 (1H, s), 8.63 (1H, s) and 8.83 (1H, s).
'n~z (APT''): 349 (MH~
Example 55 N-(2-Methyi-1,2,3,4-tetrshydroiso~quinolln-7-yl~N'-(3-benzyloxyphenyl) wrea 25 The title compound was prepared in 7896 yield from 3-benzyloxyaniiine and the isocyanate D 10 using the method of Example 43.
~H NMR (250MHz, d6-DMSO) s: 2.32 (3H, s), 2.55 (2H, t, J = 5.5Hz), 2.73 (2H, m), 3.43 {2H, s), 5.07 (2H, s), 6.62 (1H, d, J = 8.OHz), 6.92 (1H, d, J = 7.8Hz), 7.00 (1H, d, J =
3o 8.8Hz), 7.17 (3H, m), 7.33 {1H, s), 7.33 - 7.47 (5H, m), 8.58 (1H, s) and 8.68 (1H, s).
'"~z (APf~: 388 (MH''~
Example 56 35 N-(2-Methyt-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-phenoxyphenyl) urea The title compound was prepared in 7596 yield from 3-phenoxyaniline and the isocyanate D10 using the method of Example 43.
SUBSTITUTE SHEET (RULE 26) WO 99114197 35 PGT/G898J02'128 1H NMR (250MHz, d6-DMSO) b: 2.31 (3H, s), 2.55 (2H, t, J = 5.5Hz), 2.73 (2H, m), 3.42 (2H, s), 6.60 ( 1 H, d, J = 7.1 Hz), b.95 - 7.29 (9H, m), 7.40 (2H, m), 8.48 {
1 H, s) and 8.74 (1H, s).
"'/Z (APT'): 374 (MH'') Example S7 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolln-7-yl)-N'-(3-fluorophenyl) urea to The title compound was prepared in 37~ yield from amine D5 and 3-fluorophenyl isocyanate using a method similar to that of Example 1(a).
~H NMR (250MHz, d6-DMSO) 8: 2.33 (3H; s), 2.58 {2H, m), 2.72 (2H, m), 3.45 (2H, s), 6.76 (1H, t, J = 6.7Hz), 6.99 - 7.33 (5H, m), 7.48 (1H, d, J = l2Hz), 8.58 (1H, s) and 8.85 1s (1H, s).
"'/Z (APf''): 300 (MH+) Example 57 2o N-(2-Methyl~1,2,3,4-tetrahydroisoquinolin-7-yl)-1~T'-(2-tluorophenyl) urea The title compound was prepared in 45~ yield from amine D5 and 2-fluomphenyl isocyanate using a method similar to that of Example 1(a).
~H NMR (250MHz, d6-DMSO) S: 2.32 (3H, s), 2.5b (2H, t, J = 5.bHz), 2.74 (2H, m), 3.44 25 (2H, s), 6.95 - 7.31 (6H, m), 8.15 ( 1 H, t), 8.50 ( 1 H, s) and 8.96 ( 1 H, s).
"'/~-{APT): 300 (MH+) Example S8 3o N-(2-Methyl-1,2,3,4-tetrahydrois~oquinolin-7-yl)-N'-(3-~nethylthiophenyl) urea The title compound was prepared in 58"% yield from amine D5 and 3-methylthiophenyl isocyanate using a method similar to that of Example 1 (a).
1H NMR (250MHz, d6-DMSO) 8: 2.33 (3H, s), 2.45 (3H, s), 2.5b (2H, t, J =
5.6Hz), 2.74 35 (2I3, m), 3.44 (2H, s), 6.85 ( 1 H, d, J = 7.5Hz), 6.99 ( 1 H, d, J =
8.8Hz), 7.10 - 7.24 (4H, m), 7.47 (1H, s), 8.53 (1H, s) and 8.65 (1H, s).
"'/Z (APT+): 328 (MH'") SUBSTITUTE SHEET (RULE 26) w0 99n419"! 36 PCT/GB98/02728 Example 59 N-(2-Methyl-1,2,3,4-tetrahydrolsoquinolln-7-yl)-N'-(3-carboethoxyphenyl) urea 5 The title compound was prepared in 91'9 yield from amine D5 and 3-carboethoxyphenyl isocyanate using a method similar to that of Example 1 (a).
'H NMR (250MHz, CDCl3) 8: 1.33 (3H, t, J = 7.OHz), 2.37 (3H, s), 2.60 (2H, m), 2.78 (2H, m), 3.37 (2H, s), 4.30 (2H, q, J = 7.OHz), 6.91 - 7.05 (3H, m), 7.26 (1H, t, J = 7.8Hz), 7.66 (3H, m) and 7.82 - 7.90 (2H, m).
to "'/Z (API+): 354 (MH+) Example d0 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(4-ftuorophenyl) urea The title compound was prepared in 9896 yield from amine D5 and 4-fluorophenyl isocyanate using a method similar to that of Example 1 (a).
'H NMR {250MHz, d6-DMSO) 8: 2.32 (3H, s), 2.55 (2H, m), 2.74 (ZH, m), 3.43 (2H, s), 6.9? - 7.15 (5H, m), 7.45 (2H, m), 7.52 ( 1 H, s) and 7.67 ( 1 H, s).
~'/Z (APB): 300 (MHO
Example bl N-(2-Methyl-1,2,3,4-tetrahydrnisoqui~oliu-7-yl)-N'-(3, 4-diiluorophenyl) urea The title compound was prepared in 72gb yield from amine D5 and 3, 4-difluorophenyl isocyanate using a method similar to that of Example 1(a).
'H NMR (250MHz, d6-DMSO) 8: 2.32 {3H, s), 2.56 (2H, t, J = 5.5Hz), 2.74 (2H, m), 3.43 (2H, s), 7.0 { 1 H, d, J = 8.7Hz), 7.08 - 7.15 (2H, m), 7.27 - 7.37 {2H, m), 7.61 - 7.73 ( 1 H, m), 8.60 ( 1 H, s) and 8.84 ( 1 H, s).
"'~z (APT"): 318 (MH'") Example 62 N-(2-Methyl-1,2,3,4-tetrahydrofsoqulnolin-7-yi)-N'-(3-benzoylphenyl) urea The title compound was prepared in 67~v yield from 3-lxnzoylaniline and the isocyanat~
D10 using the method of Example 43.
SUB~STITU1'E SHEET (RUL"E ?~) 'H NMR (2S0MHz, d6-DMSO) 8: 2.32 (3H, s), 2.56 (2H, m), 2.73 (2H, m), 3.42 (2H, s).
6.99 ( 1H, d), 7.16 (2H, m), 7.32 ( 1 H, d), 7.39 - 7.80 (7H, m), 7.87 ( 1 H, s), 8.SS ( 1 H, s) and 8.92 ( 1 H, s).
"'/z (API''): 3$b (MH'") S
Example 63 N-(2-Methyl-1,2,3,4-tetrahydrolsoqulnolln-7-yt)-N'-(4-methoxyphenyl) urea 1o The title compound was prepared in 969~v yield from 4-methoxyaniline and the isocyanate D 10 using the method of Example 43.
'H NMR (2SOMHz, d6-DMSO) 8: 2.32 (3H, s), 2.Sb (2H, m), 2.73 (2H, m), 3.43 (2H, s), 3.71 (3H, s), 6.85 (2H, d, J = 8.7Hz), 6.98 (1H, d, J = 9.OHz), 7.14 (2H, m), 7.33 (2H, d, J
= 8.7Hz), 8:45 (1H, s) and 8.48 (1H, s).
1S 'n/z (API+): 312 (MH+) Example 64 N-(2-Methyl-1,2,3;4-tetrahydrolsoqulnolin-7-yl)-N'-(3-bromo-4-methoxyphenyl) urea A solution of 3-bromo-4-methoxybenzoic acid (0.924g) in dioxan ( lOml) was treated with 1,8-bis(dimethylamino)naphthalenc (0.8S7g). After stirring for 30min diphenylphosporyl azide was added and the mixture boiled for 6h. After cooling to room tem~rature the amine DS (0.24Sg) in dichloromethane ( lOml) was added and the mixture stirred for 16h.
Solvent was removed at reduced pressure, the residue column chromatographed (methanol/dichloromethane mixtures) to give the title compound (0.34g).
'H NMR (2SOMHz, d6-DMSO) 8: 2.82 (3H, s), 2.96 (2H, m); 3.38 (4H, m), 3.79 (3H, s), 4.20 (2H, s), b.9S - 7.35 (SH, m), 7.79 ( 1 H, m), 9.10 ( 1 H, s), 9. i 3 ( 1 H, s) and 10.30 ( 1 H, br. s).
n'/z (API: 390, 392 (MH+) Example 65 N-(2-Methyl-1,2,3,4-tetrahydroisogulnotln-5-yl):N'-(3-bromo-4-methoxyphenyl) urea The title compound was prepared in 249b yield from amine D9 and 3-bromo-4-methoxybenzoic acid using the method of Example 64.
SUBSTITUTE St~IEET (RULE 2B) WO 99/14197 3$ PGT/GB98/D2728 'H NMR (250MHz, CDCI~) 8: 2.38 (3H, s), 2.76 (2H, m), 2.83 (2H, m), 3.66 (2H, s), 3:81 (3H,s),6.60(lH,d,J=7.SHz),6.67(lH,d,J=8.9Hz),7.17(lH,m),7.60(lH,d,J=
2.4Hz), 7.69 ( 1 H, d), 8.02 ( 1 H, s), 8.70 ( 1 H, s).
'"/Z (APIA): 390, 392 (MH+) Example bb N-(2-Methyl-1,2,3,4-tetrahydrnisoquinolin-5-yl)-N'-(2,3-dichlorophenyi) urea io The title compound was prepared in 95~v yield from amine D9 and 2,3-dichloropphenyl isocyanate using a method similar to that.of Example 1(a).
1H NMR (250MHz, CDCl3) 8: 2.47 (3H, s), 2.71 (2H, m), 2.85 (2H, m), 3.62 (2H, s), 6.51 { 1 H, br. s), 7.00 ( 1H, d, J = 7.7Hz), 7.09 - 7.35 (SH, m) and 8.17 ( 1 H, d, J = 7.7Hz).
"'/Z (API"): 350, 352 (MH'') Example 67 N-(2-Methyl-1,2,3,4-tetrahydroisoquinoitn-S-yl)-N'-(2-chloro-5-trifluoromethylphenyl) urea The title compound was p~ in 3696 yield from amine D9 aad 2-chiom-5-trifluoromethylphenyl isocyanate using a method similar to that of Example 1(a).
iH NMR {250MHz, CDC13) s: 2.45 (3H, s), 2.67 (2H, m), 2.83 (2H, m), 3.58 (2H, s), 6.91 ( 1 H, br. s), 6.98 ( 1 H, d, J = 7.SHz), 7.17 - 7.46 (SH, m) and 8.60 ( 1 H, s).
"'/Z (APT''): 384, 386 (MH'") Example b8 N-(2-Methyl-1,2,3;4-tetrahydrolsoquinolin-5-yl)-N'-(3-chloro-4-tiuorophenyl) urea The title compound was prepared in 90°~ yield from amine D9 and 3-chloro-4-fluorophenyl isocyanate using a method similar to that of Example 1(a).
1H NMR (250MHz, CDCl3) s: 2.44 (3H, s), 2:b4 (2H, m), 2.75 {2H, m), 3.56 (2H, s), 6.44 ( 1H, br. s), 6.82 ( 1H, br. s), 6.94 - 7.29 (SH, m) and 7.44 ( 1H, m).
"'/Z (APT: 334, 336 (MH'") Example b9 SUBSTITUTE SHEET (RULE 26) wo ~/141m 39 pcr/cs9s/oz~zs N-(2-Methyl-~,2,3~4-tetrahydroisoquinolin-5-yl)-N'-(4-metttoxyphenyl) urea A mixture of the amine D9 (0.245g) and carbonyl diimidazole {0.245g) in dichloromethane ( l Oml) was stirred for 45 min at room temperature. Solvent was removed at reduced pressure and a solution of 4-methoxyaniline (0.185g) in dimethylformamide (10m1) added.
The mixture was heated at 100°C for 1 h. solvent removed at reduced pressure and the residue column chromatographed (silica gel, etherlmethanol and dichloromethane/methanol mixtures) to give the title compound (0.25g).
1H NMR (250MHz, d6-DMSO) 2.33 (3H, s), 2.65 (4H, m), 3.46 (2H, s), 3.71 (3H, s), 6.72 ( 1 H, d, J = 7.SHz), 6.8b (2H, d, 3 = 8.9Hz), 7.0b ( i H, t, J = 7.8Hz), 7.35 (2H, d, J = 8.9Hz), 7.70 ( 1 H, d, J = 8.OHz), 7.77 ( 1 H, s) and 8.88 ( 1 H, s).
'°/Z (API"): 311 (MH+) Example 70 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yI)-N'-(3-ethylphenyl) urea The title compound was prepared in 5590 yield from amine D9 and 3-ethylaniline using a method similar to that of Example b9.
1H NMR (250MHz, CDCl3) b: 1.19 (3H, t, J = 7.bHz), 2.43 {3H, s), 2.55 - 2.96 (bH, m), 3.5b (2H, s), 6.43 (1H, s), b.77 (1H, s), 6.91 (2H, d, J = 7.5Hz), 7.11= 7.23 (4H, m) and 7.40 (1H, d, J = 7.8Hz).
"'/Z (APT''): 310 (MH+) Example 71 N-(2-Methyl-1,2,3,4-tetrahydroisoquinulin-5-yl)-N'-(3, 5-dinitrrc~phenyl) urea The title compound was prepared in 24q6 yield from amine D9 and 3, 5-dinitroaniline using 3o a method similar to that of Example 69.
1H NMR (250MHz, d6-DMSO) $: 2.35 (3H, s), 2.b4-2.7b (4H, m), 3.63 (2H, s), 6.85 (1H, d, J = 7.5Hz), 7.13 ( 1 H, t, J = 7.7Hz), 7.56 ( 1 H, d, J = B.OHz), 8.21 ( 1 H, s), 8.39 ( 1 H, t), 8.73 (2H, d) and 10.04 ( 1 H, s).
n'/z (APT''): 372 {MH+) Example 72 N-(2-Methyl-1,2,3,4-tetrahydroisoquinalin-S-yl)-N'-(3-cyanophenyl) urea SU~~TITUTE SHEET (RILE 2B) The title compound was prepared in 56°70 yield from amine D9 and 3-aminobenzonitrile using a method similar to that of Example 69.
~H NMR (250MHz, CDC13) 8: 2.44 (3H, s), 2.64 (2H, m), 2.74 (2H, m), 3.57 (2H, s}, 6.23 (1H, s), 6.82 (1H, d, J = 7.3Hz), 7.14 - 7.36 (SH, m), 7.55 (1H, d, J =
8.OHz). 7.64 (1H, s).
ro/z (~'~: 307 (MH'') Example 73 io N-(2-Methyl-1,2,3,4-tetrahydroisoqufnotin-S-yi)-N'-(3-bromo-4-rnethoxyphenyl) urea The title compound was prepared in 209 yield from amine D9 and 3-bromo-4-methoxyarriline using a method similar to that of Example 69.
~H NMR (250MHz, CDC13) b: 2.46 (3H, s), 2.72 - 2.77 (4H, m), 3.57 (2H, s), 3.89 (3H, s), 6.61 ( 1 H, dd, J = 2.5, 8.5Hz}, 7.13 ( 1 H, t, J = 7.7Hz), 7.35 ( 1 H, d, J =
8.4Hz), 7.54 ( 1 H, s), 7.65 ( 1 H, d, J = 2.5Hz), 7.70 ( 1 H, d, J = 8.OHz} and 8.67 91 H, s).
"'/z (APT''): 3$9, 391 (MH+) 2o Example 74 N-(2-Methyl-1,2,3,4-tetrahydroisoqulnolin-7-yl)-N'-(3-aminophenyl) urea N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-nitrophenyi) urea E2 (1.2g) was dissolved in ethanol (SOmI), purged with argon and treated with 10%
palladiumlcharcoal (O.lg, paste) and ammonium formate (1.16g). The mixture was stirred at room temperature for 16h, filtered (celite pad) and the filtrate evaporated under reduced pressure. The obtained residue was dissolved in water, basified with sodium carbonate and the precipitated title compound (0.98g) collected by filtration.
'H NMR (250MHz, d6-DMSO) 8: 2.71 (3H, s}, 2.76 (2H, m), 2.93 (2H, m), 3.63 (2H, s), 5.22 (2H, br. s), 6.08 91 H, d, J = 7.8Hz), 6.45 ( 1 H, d, J = 7.9Hz), 6.67 ( 1 H, s), 6..78 ( 1 H, t, J = 8.0Hz), 6.88 (1H, m), 7.06(2H, m), 8.26 (1H, s) and 8.36 (1H, s).'"/z (APIA: 297 ( Example 75 N-{3-[3-(2-rl!iethyl-1,2,3,4-tetrahydroisoqulrtoiln-7-yl~~reido]phenyljacetam#de hydrochloride SUB~T~'fUTE SHEET (RULE 26) WO 99114197 41 PCT/GB98I02'fZ8 A solution of N-{2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N=(3-aminophenyl) urea E74 (0.296g) and triethylamine (0.151g) in dichloromethane was treated with acetyl chloride (0.078g) and stirred for 6h. Aqueous sodium hydrogen carbonate was added with 5 vigorous stirring and the precipitated solid collected by filtration. The material was dissolved in methanol and treated with an excess of ethereal HCI. The precipitated title compond (0.145g) was collected by filtration.and dried in vacuo.
~H NMR (400MHz, d6-DMSO) 8: 2.03 (3H, s), 2.86 (3H, s), 2.94 (1H, m), 3.17 (IH, m), 1 resonance under HOD, 3.58 ( 1 H, m), 4.21 ( 1 H, m), 4.40 ( 1 H, m), 7.12 -7.15 (3H, m), 7.26 - 7.32 (2H, m), 7.35 91 H, s), 7.68 91 H, s), 9.44 91 H, s), 9.62 ( 1 H, s) and 10.00 ( 1 H, s).
"'~z (APf~: 339 (MH+) Example 7b is N-{3-[3-(2-Methyl-1,2,3,Mtekrahydroiisoquinolin-7-yl)ureido}phenyl}bis methanesulphonimlde hydrochloride A solution of N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-y1)-N'-(3-aminophenyl) urea 2o E74 (0.150g) and triethylamine (0.21u1) in dichloroethane was treated with methanesulphonyl chloride (0.085u1) and stirred for 16h. The organic phase was washed with water, aqueous sodium hydrogcn carbonate and brine. Solvent was removed at reduced pressure and the residue converted to the HCl salt (see Example 75) of the title compound (0.082g).
25 ~H NMR (250MHz, CDC13) 8: 2.44 (3H, s), 2.690 (2H, m), 2.85 (2H, m), 3.40 (6H, s), 3,50 (2H, s), 6.97 - 7.02 (4H, m), 7.19 ( 1 H, s), 7.20 - 7.29 (2H, m), 7.49 { 1 H, s) and 7.68 ( 1 H, m).
"'~z (API+): 453 (MH+) 3o Example 77 N-(2-Methyl-1,2,3,4-tetrahydrolsoqulnolin-5-yl)-N'-(1-methyllndol-5~yl) urea The title compound was prepared in 689~c yield from amine D9 and 1-methyl-5-35 aminoindole using a method similar to that of Example 69.
~H NMR (250MHz, CDC13) 5: 2.33 (3H, s), 2.65 (4H, m), 3.45 (2H, s), 3.75 (3H, s), 6.34 ( 1 H, d, J = 2.8Hz), 6.72 ( 1H, d, J = 7.5Hz), 6.03 - 7.16 (2H, m), 7.26 ( I
H, d, J = 3.OHz), 7.33 (1H, d, J = 8.7Hz), 7.51 -7.58 (3H, m) and 8.63 (1H, s).
S1JBSTITUTf SHEET (RU4E 26) "'~Z (APi+): 335 (MH+) , 1. Binding Assay Method WO 92/22293 (SmithKline Beecham) discloses compounds having anti-convulsant activity, including inter alia the compound trans-(+)-6-acetyl-4S-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-of (hereinafter referred to as Compound to A). It has been found that the compounds of WO 92f22293 bind to a novel receptor obtainable from rat forebrain tissue, as described in WO 96118650 (SmithKline Beecham).
The affinity of test compounds to the novel receptor site is assessed as follows.
Method Whole forebrain tissue is obtained from rats. The tissue is first homogenised in buffer (usually 50mM Tris/HCl, pH 7.4). The homogenised tissue is washed by centrifugation and resuspension in the same buffer, then stored at -70°C until used.
2o To carry out the radioligand binding assay, aliquots of tissue prepared as above (usually at a concentration of 1-2mg protein/mi) are mixed with aliquots of [3H]-Compound A
dissolved in buffer. The final concentration of [3H]-Compound A in the mixture is usually 20nM. The mixture is incubated at room temperature for 1 hour. [3H]-Compound A
bound to the tissue is then separated from unbound [3H]-Compound A by filtration through Whatman GFB glass fibre filters. The filters are then washed rapidly with ice-cold buffer.
The amount of radioactivity bound to the tissue trapped on the filters is measured by addition of liquid scintillation cocktail to the filters followed by counting in a liquid scintillation counter.
3o In order to determine the amount of "specific" binding of [3H]-Compound A, parallel assays are carried out as above in which [3H]-Compound A and tissue are incubated together in the presence of unlabelled Compound A (usually 3 pM). The amount of binding of [3H]-Compound A remaining in the presence of this unlabelled compound is defined as "non-specific" binding. This amount is subtracted from the total amount of [3H]-Compound A binding (i.e. that present in the absence of unlabelled compound) to obtain the amount of "specific" binding of [3H]-Compound A to the novel site.
wesmur~ sHf~r cAU~ ~s) The affinity of the binding of test compounds to the novel site can be estimated by incubating together [3H]-Compound A and tissue in the presence of a range of concentrations of the compound to be tested. The decrease in the level of specific [3H]-Compound A binding as a result of competition by increasing concentrations of the 5 compound under test is plotted graphically, and non-linear regression analysis of the resultant curve is used to provide an estimate of compound affinity in terms of pKi value.
Results Compounds of this invention were active in this test with pKi values greater than 6. For to example, compounds of Examples 1, 2, 6, 7, 8, 16 and 23 gave pKi values greater than 8.
2. MEST Test The maximal electroshock seizure (MEST) threshold test in radcnts is particularly sensitive 15 for detecting potential anticonwlsant properties 1. In this model, anticonvulsant agents elevate the threshold to electrically-induced seizures whilst proconvulsants lower the seizure threshold.
Method Mice (naive m~aic, Charles River, U.I~. CD-1 strain, 25 - 30g) are randomly assigned to groups of 10 - 20 and dosed orally or intraperitoneally at a dose volume of 10 ml/kg with various doses of compound (0.3 - 304 mg/kg) or vehicle. Mice are then subjected at 30 or 60 min post dose to a single electroshock (0.1 sec, 50Hz, sine wave form) administered via 25 corneal electrodes. The mean current and standard error required to induce a tonic seizure in SO~o (CCgO) of the mice in a particular treatment group is determined by the 'up and down' method of Dixon and Mood ( 1948)2. Statistical comparisons between vehicle- and drug-treated groups are made using the method of Litchficld and Wilcoxon (1949)3.
3o In control animals the CCSp is usually 14 - 18 mA. Hence the first animal in the control group is subjected to a current of 16 mA. If a tonic seizure does not ensue, the current is increased for a subsequent mouse. If a tonic convulsion does occur, then the current is decreased, and so on until all the animals in the group have been tested.
35 The percentage increase or decrease in CC50 for each group compared to the control is calculated.
SUBSTITUTE 3HE~ET (RU!LE 26~

WO 99114197 ~ PC"T/GB98I02728 Studies are carried out using a Hugo Sachs Electronik Constant Current Shock Generator with totally variable control of shock level from 0 to 300 mA and steps of 2 mA are usually used.
Drugs are suspended in 1 ~'o methyl cellulose.
References 1. Loscher, W. and Schmidt, D. (1988). Epilepsy Res., 2, 145-181 2. Dixon, W.J. and Mood, A.M. ( 1948): J. Amer. Stat. Assn., 43, 109-126 3. Litchfield, J.T. and Wilcoxon, F.(1949). J. Pharmacol. exp. Ther., 96, 99-Results t5 Compounds of this invention dosed by the oral route as a suspension in methyl cellulose and tested one hour post dosing show an increase in seizure threshold. For example, the product of Example 1 showed a statistically significant increase (3S9'o) when examined at a dose of 10 mg/kg p.o.
3U8~'D'TUTE SHEET (RULE 26~

Claims (10)

1. A compound of formula (I) or pharmaceutically acceptable salt thereof:
where X is O or S
R1 is hydrogen, phenylC1-6 alkyl or C1-6 alkyl, R2 is hydrogen or up to three substituents independently selected from halogen, NO2, CN, N3, C1-6 alkylO-, C1-6 alkylS-, C1-6 alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl-, C1-6alkenyl, C1-6alkynyl, C1-6haloalkylCO-, C1-6alkylCO-, C3-6cycloalkylCO-, C3-6cycloalkyl-C1-4alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-, O-C1-6haloalkyl, CO2C1-4alkyl, S(O)2C1-6alkyl, C1-4alkylsulfamoyl or heterocyclyl, or -NR6R7 where R6 is hydrogen, C1-4, alkyl or S(O)2C1-6alkyl, and R7 is hydrogen, C1-4alkyl, -CHO, S(O)2C1-6alkyl -CO2C1-4alkyl or -COC1-4alkyl, or an adjacent pair of R2 groups together with the carbon atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic ring.
2. A compound of claim 1 which is a (tetrahydroisoquinolin-5-yl) or (tetrahydroisoquinolin-7-yl) urea or thiourea.
3. A compound of claim 1 in which R1 is hydrogen, benzyl, methyl, ethyl, iso-propyl or t-butyl R2 is hydrogen, methyl, ethyl, n-butyl, iso-propyl, t-butyl, phenyl, benzyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, phenoxy, benzyloxy, bromo, chloro, iodo, fluoro, nitro, cyano, acetyl, pivaloyl, iso-butyroyl, benzoyl, trifluoromethyl, trifluoromethoxy, trifluoroacetyl, carbomethoxy, carboethoxy, methylthio, n-propylsulfonyl, isopropylsulfonyl, dimethylsulfamoyl or oxazolyl, R6 and R7 are independently hydrogen, acetyl or methanesulfonyl, or two R2 groups linked to form naphthyl, indolyl or idolinyl, optionally substituted by acetyl or methyl.
4. A compound of claim 1 in which R1 is hydrogen or methyl, R2 is hydrogen, methyl, ethyl, t-butyl, methoxy, ethoxy, iso-propoxy, phenoxy, benzyloxy, methylthio, bromo, chloro, fluoro, nitro, cyano, acetyl, benzoyl, trifluoromethyl, trifluoromethoxy, carbomethoxy, carboethoxy, amino, acetylamino, methanesulphonylamino or oxazolyl, or two R2 groups form methylindolyl or acetylindolinyl or naphthyl.
5. A compound of claim 1 which is N-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-nitrophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-nitrophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(4-ethoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(4-ethoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-trifluoromethylphenyl)thiourea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-trifluoromethylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-methoxyphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-bromophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(4-trifluoromethylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(5-chloro-2,4-dimethoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(4-tert-butyl, 2-methoxyphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)N'-(phenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-acetylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(2-methylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(2-methoxyphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-chlorophenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-chloro-6-methoxyphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3,5-di-trifluoromethylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(4-trifluoromethoxyphenyl)urea N-(2-methyl-1,2,3,4-tetrahdyroisoquinolin-7-yl)-N'-(3-chloro-4-methylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3-trifluoromethylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(5-chloro-2,4-dimethoxyphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3-nitrophenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3-bromophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3-methoxyphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(4-trifluoromethyoxyphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(4-trifluoromethylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(phenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoqinolin-5-yl)-N'-(3-acetylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3-chloro-4-methylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3-chloro-6-methoxyphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3-chlorophenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(2-methoxyphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(2-methylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3,5-di-trifluoromethylphenyl)urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl-N'-(3-trifluoromethylphenyl)thiourea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(2-carbomethoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(2,3-dimethylphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(2-methoxy-3-chlorophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(1-naphthyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(2-methyl-3-nitrophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(2-cyanophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(2-cyano-3-methylphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(1-acetylindolin-7-yl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-cyanophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-ethylphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3,5-dinitrophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(2,3-dichlorophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-chloro-4-fluorophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(2-chloro-5-trifluoromethylphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-isopropoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-ethoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-tertbutylphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-[3-(1,3-oxazol-5-yl)phenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-benzyloxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-phenoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-fluorophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(2-fluorophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-methylthiophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-carboethoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(4-fluorophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3,4-difluorophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-benzoylphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(4-methoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-bromo-4-methoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3-bromo-4-methoxyphenyl) urea N-(2-methyl-1,2,3;4-tetrahydroisoquinolin-5-yl)-N'-(2,3-dichlorophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(2-chloro-5-trifluoromethylphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3-chloro-4-fluorophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(4-methoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3-ethylphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3,5-dinitrophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3-cyanophenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(3-bromo-4-methoxyphenyl) urea N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-aminophenyl) urea N-(3-[3-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)ureido]phenyl) acetamide N-(3-[3-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)ureido]phenyl) bis methanesulphonimide or N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-N'-(1-methylindol-5-yl) urea.
6. A process for the preparation of compounds of formula (I), which comprises reacting a compound of formula (II) (II) where R1 A is R1 as defined for formula (I) or a group convertible to R1, and P is NH2 or NCX, X being as defined for formula (I), with a compound of formula (III) (III) where Q is NCX or NH2 and different from P, X being as defined for formula (I), and R2A is R2 as defined for formula (I) or a group or groups convertible to R2, and where required converting a R1A or R2A group to a R1 or R2 group, converting one R1 or R2 group to another R1 or R2 group, converting a salt product to the free base or another pharmaceutically acceptable salt, or converting a free base product to a pharmaceutically acceptable salt.
7. A pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia &
narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and/or amyotrophic lateral sclerosis (ALS) which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
8. A method of treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and/or amyotrophic lateral sclerosis (ALS) comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
9. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia &
narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia; neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and/or amyotrophic lateral sclerosis (ALS).
10. A compound of formula (I) or pharmaceutically acceptable salt thereof:
where X is O or S, R1 is hydrogen or C1-6 alkyl, R2 is hydrogen or up to three substituents independently selected from halogen, CF3, NO2, CN, N3, C1-6 alkylO-, C1-6 alkylS-, C1-6 alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl-, C1-6alkenyl, C1-6alkynyl, CF3CO-, CF3O, C1-6alkylCO-, C3-6cycloalkylCO-, C3-6cycloalkyl-C1-4alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-, heterocyclyl, or -NR6R7 where R6 is hydrogen or C1-4 alkyl, and R7 is hydrogen, C1-4alkyl, -CHO, -CO2C1-4alkyl or -COC1-4alkyl.
CA002303777A 1997-09-12 1998-09-09 Substituted isoquinolines as anticonvulsivants Abandoned CA2303777A1 (en)

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GBGB9719530.9A GB9719530D0 (en) 1997-09-12 1997-09-12 Novel compounds
PCT/GB1998/002728 WO1999014197A1 (en) 1997-09-12 1998-09-09 Substituted isoquinolines as anticonvulsivants

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CN103003236A (en) * 2010-06-18 2013-03-27 爱维斯健有限公司 Novel thiourea or urea derivatives, preparation method thereof, and pharmaceutical composition containing it as an active ingredient for preventing or treating AIDS

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GB9816982D0 (en) * 1998-08-05 1998-09-30 Smithkline Beecham Plc Novel compounds
US6949574B2 (en) * 2002-02-08 2005-09-27 Bristol-Myers Squibb Company (Oxime)carbamoyl fatty acid amide hydrolase inhibitors
WO2004085433A2 (en) * 2003-03-28 2004-10-07 Pharmacia & Upjohn Company Llc Positive allosteric modulators of the nicotinic acetylcholine receptor

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US5508288A (en) * 1992-03-12 1996-04-16 Smithkline Beecham, P.L.C. Indole derivatives as 5HT1C antagonists
WO1994014801A1 (en) * 1992-12-29 1994-07-07 Smithkline Beecham Plc Heterocyclic urea derivatives as 5ht2c and 5ht2b antagonists
TW397812B (en) * 1995-02-11 2000-07-11 Astra Ab Bicyclic isothiourea derivatives useful in therapy
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CN103003236A (en) * 2010-06-18 2013-03-27 爱维斯健有限公司 Novel thiourea or urea derivatives, preparation method thereof, and pharmaceutical composition containing it as an active ingredient for preventing or treating AIDS

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