AU737955B2 - Substituted isoquinoline derivatives and their use as anticonvulsants - Google Patents

Substituted isoquinoline derivatives and their use as anticonvulsants Download PDF

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AU737955B2
AU737955B2 AU64128/98A AU6412898A AU737955B2 AU 737955 B2 AU737955 B2 AU 737955B2 AU 64128/98 A AU64128/98 A AU 64128/98A AU 6412898 A AU6412898 A AU 6412898A AU 737955 B2 AU737955 B2 AU 737955B2
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tetrahydroisoquinolin
methyl
bromo
iso
hydrochloride
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AU6412898A (en
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Peter David Edwards
Mervyn Thompson
Robert William Ward
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Priority claimed from GBGB9726695.1A external-priority patent/GB9726695D0/en
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    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • A61P25/20—Hypnotics; Sedatives
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Description

WO 98/41508 PCT/GB98/00782 SUBSTITUTED ISOQUINOLINE DERIVATIVES AND THEIR USE AS ANTICONVULSANTS This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
W097/48683 (SmithKline Beecham), unpublished at the filing date of this application, discloses tetrahydroisoquinolinyl benzamides in which the benzamide moiety has a 2alkoxy substituent, including the compounds: N-(7-iodo-2-methyl-1,2,3,4tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide, N-(7-iodo-1,23,4tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide, N-(5-iodo-1,2,3,4tetrahydroisoquinolin-7-yl)-5-benzoyl-2-methoxybenzamide, N-(5-iodo-1,2,3,4tetrahydroisoquinolin-7-yl)-2-methoxy-4-trifluoromethyldiazirinylbenzamide, N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-5-trifluoromethyldiazirinylbenzamide, N-(7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5trifluoromethyldiazirinyl-benzamide and N-(8-fluoro-2-methyl-1,2,3,4tetrahydroisoquinolin-5-yl)-4-t-butyl-2-methoxybenzamide.
It has now been surprisingly found that carboxamide compounds of formula 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 ***e, 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 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 or pharmaceutically acceptable salt thereof: P:'OPER\M.KR'SPECI,64I 28-9 197.do.-1&07101 -2- N NHO Q R R where Q is a monocyclic or bicyclic aryl or heteroaryl ring, R is hydrogen, CI-6allcyl (optionally substituted by hydroxy or C 1 4 alkoxy) or C I-C 6 alkylSO 2 R2 is hydrogen, hydroxy or up to three substituents selected from halogen, NO 2 CN, N 3
CF
3
CF
3
CF
3 CO-, trifluoromethyldiazirinyl, C 1 6alkyl, C 1 6 allcenyl, C I-6alkynyl, C 1 6perfluoroalkyl, C 3 6 CYCloalkyl,
C
3 6 cycloallcyl-C l~alkyl-, CI 6 alkylO-, C 1 6 alkylCO-,
C
3 6 cycloalkylO-, C 3 6 cycloalkylCO-, C 36 Cycloalkyl-C 1 ~alkylO-, C3-6cycloallcyl-Cl4allcylCO-, acetoxy, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C 1 Aalkyl-, CI-6allcylS-, C 1 6alkylSO 2 (Cl-4alkyl) 2 NS0 2
(C
1 Aalkyl)NHS 02-, (C 1 Aallcyl)2NCO-, (CI~alkyl)NHCO- or CONH 2 or -NR 3
R
4 where R 3 is hydrogen or C14 alkyl, and
R
4 is hydrogen, C14alkyl, formnyl, -CO2CI-4alkyI or -COC14alkyl; or two R 2 groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by -OH or and X is hydrogen, halogen, CI-6 aikoxy, C 1 6 alkyl, amino or trifluoroacetylamino; but excluding the compound 7-(3,4,5-trimethoxybenzamido)-2-methyl-1 ,2,3,4tetrahydroisoquinoline and compounds in which Q is phenyl and R 2 is 2-ailkoxy.
The compounds of this invention are typically, (tetrahydroisoquinolin-7-yl) carboxamides, especially (tetrahydroisoquinolin-7-yl)benzamides. When the substituent X is not hydrogen it may be at the 5, 6 or 8 position of the tetrahydroisoquinolmne moiety, especially position The ring system Q is typically optionally substituted phenyl or optionally substituted P:'OPER\MKR'SPECP64128-98 197 do.-I160701 -3heteroaryl, typically thiophenyl or 3-isoxazolyl. When two R 2 groups form a carbocyclic ring, this is typically a 5-7 membered ring, and Q may be a naphthalene or an indane or indanone ring system or a bicyclic heteroaryl such as In the formula alkyl groups, including alkyl groups that are part of other moieties, such as alkoxy or acyl, may be straight chain or branched. Phenyl groups, including phenyl groups that are part of other moieties, in R 2 may optionally be substituted with one or more independently selected from halogen or CI- 6 alkyl, C1- 6 alkoxy or CI- 6 alkylcarbonyl.
10 Suitable C36 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Suitable halo substituents include fluoro, chloro, iodo and bromo.
One suitable group of compounds of this invention are of formula (IA) a 15 I I I
NHCO
a t i 4c (IA) and another suitable group of formula (IB) 0N R X (IB) A suitable group of compounds of formula have R' as hydrogen, methyl, ethyl, propyl, hydroxyethyl, methoxyethyl, formyl, acetyl, trifluoroacetyl or methanesulfonyl, WO 98/41508 WO 9841508PCT/GB98/00782
R
2 as hydrogen or one or more of methyl, ethyl, n-butyl, iso-propyl, iso-butyl, tbutyl, phenyl, methoxy, ethoxy, iso-propoxy, n-butoxy, cyclopropylmethoxy, phenoxy, benzyloxy, amino, acetylamino, nitro, azido, cyano, bromno, chioro, fluoro, iodo, acetyl, pivaloyl, iso-butyroyl, benzoyl, iodobenzoyl, trifluoromethyl, perfluoroethyl, trifluoromethoxy, trifluoroacetyl, trifluoromethyldiazirinyl, methanesulonyl, n-propylsulfonyl, isopropylsulfonyl, dimethylsulfamnoyl; or two groups R 2form a benzene, cyclopentane or cyclopentanone ring; X as hydrogen, chloro, bromo, iodo, fluoro, amino, trifluoroacetylamino.
A preferred group of compounds of formula have RIas hydrogen, methyl, methoxyethyl, R2as hydrogen or one or more of methyl, n-butyl, t-butyl, iso-propyl, phenyl, methoxy, ethoxy, iso-propoxy, phenoxy, acetyl, itro, cyano, bromo, chloro, fluoro, iodo, pivaloyl, trifluoromethyl, azido, trifluoromethoxy.
X as hydrogen, iodo, chloro, bromo or trifluoroacetylamino.
Examples of compounds of formula are: N-(1 ,2,3,4-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-carboxamide N-(2-methyl- 1, 2, 3, 4-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-carboxamide N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chlorobenzamide N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-t-butylbenzamide N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propoxybenzamide N- (2-methyl-i ,2,3,4-tetrahydroisoquinolin-7-yl)-4-phenoxybenzamide N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-nitrobenzamide N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-phenylbenzamide N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylbenzamide N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluorobenzamide N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyanobenzamide N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dichlorobenzamide N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iodobenzamide N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-bromobenzamide N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methylbenzamide N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-nitrobenzamide N-(2-methyl-l1 2,3,4-tetrahydroisoquinolin-7-yl)-4-ethoxybenzamide N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-n-butylbenzamide -4- N-(2-medzyl-1,2,4ctrah in 7-yl)-2-aceoybenmide N-(2-meshyl-1,23,4-wuuhydroioquinoin-7-yl)-3-trfhwowneylbeamide N-(2-metbyl-123,-m driounl-7I) N-(2-metbyl-1,2,3,4-teuhydsoquinoli-7-yl)-3,4-dhnctoxybemnide N-(2-mechy-123-tetihyrosoqinoin-7-yI)-2fluaro4-rfurmzy benzamide N-(2-methy1-1,3,-eayriounin7y)cir--uobzzid N-(2-medyl-,3hdo~qioi--1-,-itf N-(2-methyl-1,23,4-cahy ~~ln7-yl)-3-flixro-5-iarmsslbeamide N-C2-medbyl-,2,3A-ta -~--ntayem N-(2-metby1-1,23,4-ezrbydoquinoln-7-yi)4-Iucomtbhyem de N-(2-nethyl-1,7j,44erhydroiaoquinolin-7-yl)-3-pivaloylbenzamide N-(2-MethyI- 1,2,3,-trabydoisoquino7- y)-3-bromomoxbnaide~ N-(2-Metbyl-1,23.4-tetrahydroisoquinoli-7-y)4actoxybennmide N-(2-Methy-124-rhydwiqu mn oin-7-y)-4-cycopntyoxybenzamide N-(2-Medhyl-1,2,3,4-teuhydroisoqinolin-7-yl)-4-cycimmid N-(2-Mehyl-1,2,34-ehydrosoquinolin-7-yl)-3-cyn cazbm idee N-(2-Methyl-1234-erahyloisoquinolin-7-y)-2-naphtbamidd 7~d N-(2-Mehyl-U,4ihydroisoquinolin-7-yl)-3-bromo-4-ezyeamd 20N-(2-Metbyl-1,2,3,4-tetrhydnisoquinolin-7-yl)-naphhaew.-1-carboaumie .*N-(2-Meday1-1,23,4-tcuhydroisoquino~in-7-yl)-3-cb~o4-eobm id N-(2-Methyl-1,23,4-terahydrosoquinolin-7-yl)-4-tart-b rtoxybenm N-2-Mehyl-,23,4etrhydroiKoqInon-7-y)---pooxbezmnd N-(2-Methyl-1,2,3,4-tuaydroisoquinoli-7-yl) N-(2-Mehyl-1,2.3,4-terahydosoquinoi-7-yl)bcazotiazoe--croamd N-(2-Methyl-1,34-ahyrosquinolin-7-yl)-2,3-iydbzzzfura-5carboxmid N-(2-Mcdhyl-1,2,3,hyniquinori-7-yl)-2-methylbmrimidmis-5-crboxamide N-(2-Mthyl-lZ34-ahyoisoquini-7-yl)-3-ckioro4- wobeamd N-(2-Metayl-1,3,4-tcrhydoisoquinofn-7-yW)3-bwioI th, bwaa N-C2-Mehyl-1,23,4-tcuhydroiaoqinolin-7-yl)-3-cblm-4-tbozybazamdf N-(2-Metyl-U23,4hy oioquinolin-7-y)4-medhoxy-3-UiflormetbyI benmide N-(2-Medhyl-1,23Auhydisoquinolin-7-yl)-35-diclo-4- vd N-(2-Medy)-1,2,34-thydroisoquinolin-7-yi)-3,5-dichkmi I dojrkemmid& N-(2-McthyD)-1,234-tetahydroisoquinolin-7-yI)-3,S-dicho4-iio-prooxbczai N-(2-Medhyl,2,3,4-terah doqiol7-yi)-3- j *su ji ni N-(2-metbyl-1,3,4mayriqion7y)3bm-- 'i t.
WO 98/41508 PCT/GB98/00782 N- (2-Methyl-i ,2,3,4-tetrahydroisoquinolin-7-yl)-2-bromo-5-methoxybenzamide N-(2-Methyl- 1 2,3,4-tetrahydroisoquinolin-7-yl)-4-fluoro-3-methoxybenzamide, hydrochloride N- (2-Methyl-i ,2,3,4-tetrahydroisoquinolin-7-yl)-l1-methylpyrazole-4-carboxamide N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-trifluoromethylpyrazole-3carboxamide N- (2-Methyl-i ,2,3,4-tetrahydroisoquinolin-7-yl)-2-methyithiazole-4-carboxamide N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yi)-5-methylisoxazole-3-carboxamide N-(2-Methyl- 1,2,3,4-tetrahydroLsoquinolin-7-yl)-5-tert-butylisoxazole-3-carboxamide N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methoxyisoxazole-5-carboxamide hydrochloride N-(2-methyl- 1,2,3,4-teirahydroisoquinolin-7-yl)indole-2-carboxamide.
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-iso-propylbenzamide, hydrochloride N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propylbenzamide, hydrochloride N-(2-Methyl- 1,2,3,A-tetrahydroisoquinolin-7-yI)-3-fluoro-4-methoxybenzaniide N- (2-Methyl-i ,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-n-propoxybenzamide N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethoxybenzamide N- (2-Methyl-i ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-n-propoxybenzamide N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yi)-3-bromo-4-ethylbenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-iodo-4-methoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propoxy-3-trifluoromethyl benzamide N-(2-Methyl- 1 2,3,4-tetrahydroisoquinolin-7-yl)-4-chloro-3-methoxybenzamide N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-y)-4-n-propoxy-3-trifluoromethy benzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-tert-butylbenzamide, hydrochloride N- (2-Methyl-i ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxybenzamide hydrochloride.
N-(2-Methyl- 1,2,34-tetahydroisoquinolin-7-yl)4-fluoro-3-methylbenzamide, hydrochloride N-(2-Methyl- i,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-iso-propylbenzamide N-(2-Methyl- i,2,3,4-tetrahydroisoquinolin-7-yi)-3-cyano-4-ethylbenzaniide hydrochloride N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propyl-3-trifluoromethylbenzamide hydrochloride -6i 1, WO 98/41508 PCT/GB98/00782 N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethy-3-trifluoromethylbelzafide hydrochloride N-(2-Methyl- 12,3,4-tetrahydroisoquinolin-7-yl)-3-cyalo-4iso-propoxybenzamfide hydrochloride N-(1 ,2,3,4-Teturhydroisoquinolin-7-yl)-4-methoxy-3-trifluoromfethylbelzamide N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methyl-3-methylsulfonyl-benzanide N-(2-Methyl- 1,2,3,4-tetahydroisoquinolin-7-y)-4-ethy-3-methysufoflbenzamide N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylsulfonyl-4-isopropylbenzamide, N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylsulfonyl-4-mfethoxybeflzamide N-(2-Methyl- 1 ,2,3,4-.tetrahydroisoquinolin-7-yl)-3-trifluoroacetylbelzamfide, hydrochloride N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-pefltafluoroethylbenzamnide hydrochloride N-(2-n-Propyl- 12,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide N-(2-n-Propyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3trifluoromethylbenzamide N-(2-n-Propyl- 1,2,3,4-tetrahydroisquinolin-7-yl)-3-chloro-4-iso-propoxybenzamide N-(2-Methyl- 12,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-butylbelzamide hydrochloride N-(2-Methyl- 1,2,3,4-tetrahydroisoquinoin-7y)-4-iso-buty-3-tfluoromfethylbenzamide hydrochloride N-(2-E~thyl- 1,2,3,4-tetrahydroisoquinoin-7-y)-3-bromo-4-ethoxybenzaTnide N-(2-Ethyl- 1,2,3,4-tetrahydro-isoquinolin-7.yl)-4-methoxy.3-trifluoromethyI benzamnide N-(2-iso-Propyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide N-(2-iso-Propyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromlethyl benzamide N-(2-Methyl-1,,,-erhdosqinln7y 4ehx--mtysloy-ezmd N-(2-Methyl- 1,2,3,4-teurahydroisoquinolin-7-yl)-4-oxochroman-6-carboxamfide hydrochloride N-(2-Formyl-- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3trifuoromethylbenzamide N-(2-Hydroxyethyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybeflzamide N-(2-Hydroxyethyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamfide N-(2-Methyl- 1,2,3,Atrahydroisoquinolin7-y)4-phenymethoxy-3-uifluoromethy benzamide N-(2-Methyl- 1 ,2,3,4-tetahydroisoquinolin-7-yl)-4-hydroxy-3-trifluoronlethyI benzamide 1 1, WO 98/41508 PCT/GB98/00782 N-(2-Methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-isopropoxybenzamide N-(2-Methoxyethyl-1 ,A4-tetrahydroisoquinolin-7-yl)-3-chloro-4-isopropoxybenzamide N-(2-Methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3trifluoromethylbenzamide 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-azidobenzamide, trifluoroacetate N-(2-Methyl-5-trifluoroacetylamino-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4methoxybenzamide N-(2-Methyl-5-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide N-(2-Methyl-5-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide When synthesised, these compounds are often 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.
The above compounds and pharmaceutically acceptable salts thereof, especially the hydrochloride, and pharmaceutically acceptable solvates, especially hydrates, form a preferred aspect of the present invention.
The administration of such compounds to a mammal may be by way of oral, parenteral, sub-lingual, nasal, rectal, topical or transdermal administration.
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 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 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/kg/day.
It is greatly preferred that the compound of formula is administered in the form of a unit-dose composition, such as a unit dose oral, including sub-lingual, rectal, topical or parenteral (especially intravenous) composition.
-8- WO 98/41508 PCT/GB98/00782 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 infusable 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 are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, 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 stearate.
Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
These solid oral compositions may be prepared by conventional methods of blending, filling, tabletting 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 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 monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, 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. 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 be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving -9l WO 98/41508 PCT/GB98/00782 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.
Accordingly, the present invention further 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 ***e, 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 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) which comprises a compound of formula or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
The present invention also provides 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 ***e, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including posttraumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, WO 98/41508 PCT/GB98/00782 schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia narcolepsy), tics 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) comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula or a pharmaceutically acceptable salt or solvate thereof.
In a further aspect the invention provides the use of a compound of formula 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 ***e, 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 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).
In a further aspect the invention provides the use of a compound of formula 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 ***e, 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 Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer -11- P'OPER\MKR\SPEC\64128-98 197.dmc.I&7/01 -12pain, 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).
Another aspect of the invention is a process for the preparation of compounds of formula which comprises reacting a compound of formula (II) A INH
(II)
*I .i 1 E i 2 1
X
10 where RI A is R' as defined for formula or a group convertible to R 1 and X is as defined for formula (I) with a compound of formula (III) where Q is as defined in formula Y is Cl or OH, and R2A groups are independently R2 as defined for formula or groups convertible to R2 and where required converting an RIA or R2A group to a R' or R2 grOup, converting one R' or R2 group to another R' 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.
Reaction of a compound of formula (III) which is an acid chloride (Y=Cl) will lead directly to the hydrochloride salt. Suitable solvents include ethyl acetate or dichloromethane, optionally in the presence of a base such as triethylamine. When the I *i) where Q is as defined in formula Y is Cl or OH, and R 2 A groups are independently R 2 compouas defined for formula (III) is an aroups convertic acid conventional conditions forto
R
and where required convertingds with amines may be used, for example reacting theroup, converting one R 1 or R 2 group to another R' or R 2 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.
Reaction of a compound of formula (III) which is an acid chloride (Y=C1) will lead directly to the hydrochloride salt. Suitable solvents include ethyl acetate or dichloromethane, optionally in the presence of a base such as triethylamine. When the compound of formula (III) is an aromatic acid conventional conditions for =condensation of such acids with amines may be used, for example reacting the WO 98/41508 PCT/GB98/00782 components in a mixture of (dimethylaminopropyl)-ethylcarbodiimide/hydroxybenzotriazole in a suitable solvent such as dimethyl formamide.
Conversions of an R 1 A or R 2A group to a R 1 or R 2 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. Interconversion of one R1 or R2 group to another typically arises when one compound of formula is used as the immediate precursor of another compound of formula or when it is easier to introduce a more complex or reactive substituent at the end of a synthetic sequence.
Compounds of formula (lI) in which X is hydrogen may be prepared from a nitrotetrahydroisoquinoline of formula (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) which can be reduced, for example using either tin (II) chloride and HCL or hydrogen and a palladium/activated carbon catalyst, to obtain an amino-tetrahydroisoquinoline of formula When the intended group is methyl, the compound of formula (IV) may also be reacted with formic acid and formaldehyde to introduce the N-methyl group.
The nitro-tetrahydroisoquinoline of formula (IV) may be prepared by hydrolysis of 2trifluoroacetyl-nitro-tetrahydroisoquinoline obtained by reaction of an N- (nitrophenyl)ethyl-trifluoroacetamide and parafonnaldehyde in acidic conditions using the procedure of Stokker, TetLett.,1996, 37, 5453. N-(nitrophenyl)ethyl-trifluoroacetamides -13- WO 98/41508 PCT/GB98/00782 can be prepared from readily available materials by reaction of trifluoracetic anhydride with lutidine and nitrophenethylamine hydrochloride, as illustrated in the Descriptions below.
Compounds of formula (II) may also be prepared from the corresponding aminoisoquinoline (or its nitro-analogue)of formula (VI)
RN
N R (v)
X
where RN is NH 2 or NO 2 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 (VII) R (VII) which can be reduced, for example using sodium borohydride, or hydrogenated, for example using hydrogen and a palladium/activated carbon catalyst, to obtain a tetrahydroisoquinoline of formula When the compound of formula (VII) is replaced by a nitro-isoquinoline, the nitro group is converted to an amino group in the hydrogenation step.
When the intended R 1 is hydrogen, the N of the tetrahydroisoquinoline or isoquinoline is preferably protected conventionally, prior to the coupling step that forms the carboxamide of formula for example by tert.-butoxycarbonyl or trifluoroacetyl. The compound can be deprotected under standard conditions, for example using trifluoroacetic acid/methylene chloride.
Amino/nitro-isoquinolines of formulae (VI) and the reagents used are commercially available, or can be prepared from commercially available materials using conventional procedures described in the literature.
-14- WO 98/41508 PCT/GB98/00782 When the substituent X is other than hydrogen it may be introduced during any of the procedures above, for example by conventional substitution of the aromatic ring of compounds of formula or (VII) or may be present on commercially available starting materials usable in the above described procedures. Most suitably the substituent X is introduced to a compound of formula (II) in which X is hydrogen. For example X as halogen may be incorporated via an amino group using Sandmeyer chemistry as illustrated in the descriptions below.
Compounds of formula may be prepared by further substitution of commercially available benzoic acid or thiophene carboxylic acid derivatives using conventional procedures, or by oxidation of corresponding substituted benzyl alcohols. Alternatively benzoic acids can be prepared from correpondingly substituted phenols, for example by formation of the acetate, conversion to an acetophenone and then to the desired acid.
Where the above described intermediates are novel compounds, they also form part of this invention.
The preparation of compounds of this invention is further illustrated by the following Descriptions and Examples. The utility of compounds of this invention is shown by the Pharmacological Data that follow the Examples.
Description 1 N-2-(4-Nitrophenyl)ethyl-trifluoroacetamide A solution of trifluoroacetic anhydride (10.6ml) in dichloromethane (100ml) was added dropwise to a stirred solution of 2,6- lutidine (17.44ml) and 4-nitrophenethylamine hydrochloride (15.2g; 75 mmol) at 0°C. The mixture was stirred at 25 0 C overnight under argon and then washed with dilute citric acid brine and dried over Na 2
SO
4 The material in the organic phase gave the title compound as a pale yellow solid (19.04g).
Description 2 7-Nitro-1,2,3,4-tetrahydro-2-trifluoroacetylisoquinolne The nitro compound D1 (2.26g; 9.15 mmol) and paraformaldehyde (0.45g; 14.4 mmol) in acetic acid (10ml) and conc. H 2 S0 4 (15ml) were stirred at 25 0 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 (CDC1 3 8: 3.10 (2H, 3.92 (2H, 4.85 4.92 (2H, 2xs), 7.38 (1H, t), 8.10 (2H, m/z 274 WO 98/41508 PCT/GB98/00782 Description 3 7-Nltro-1,2,3,4-tetrahydrolsoquinoline 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 dichioromethane gave the title compound (1 ig).
Description 4 2.Methyl-7-nltro-1,2,3,4-tetrahydroisoquinollne The amine D3 (2.08g; 11.7 mmol) was treated with 88% formic acid (3.45m1) and 37% aqueous formaldehyde (5.88m1) at 80 0 C for 2h according to the procedure of G.M.
Carrera and D.S. Garvey, J. Het. Chem., 1992, 29,847. Basification with 10% sodium hydroxide followed by work-up with ethyl acetate afforded an orange gum(2.3g).
Chromatography on Kiesegel 60 in 0-3% methanol ethyl acetate gave the title compound as an orange solid (1.7g).
m/tz 193 Description 7-Amlno-2-methyl-1,2,3,4-tetrahydroisoquf noline The 7-nitro compound D4 (0.25g; 1.3 mmol) in methanol (40m1) was hydrogenated over palladium on carbon (100mg) at atmospheric pressure overnight. The catalyst was removed by filtration through a pad of Kieselguhr and evaporation in vacuo gave the title compound as a white solid (213mg).
m/z 163 (MH+) Description 6 7-Amlino-2-Q$-butyloxycarbonyl)-1,2,3,4-teftrahydrolsoqulnollne The title compound was prepared from the compound of Description D3 using di t-butyl dicarbonate in 10% aqueous hydroxide in dioxan at 25*C followed by catalytic hydrogenation according to the procedure described for -16- WO 98/41508 PCT/GB98/00782 Description 7 N-(2-4-Butyloxycarbonyl-1,,3,4-terhydroisoqunoine7-yI)-5-chlorohlophene-2carboxamide 5-Chlorothiophene-2-carboxylic acid (2 14mg; 1 .3mmol), ethyldimethylaxninopropyl carbodiimide, (250mg; 1.3mmol) and 1-hydroxybenzotriazole (176mg; 1.3 mmol) in dry DMF (25m1) was stirred at room temperature for 30 min. A solution of the N-boc amine D6 (300mg; 1.21mmol) in dichioromethane (5mil) was added and the mixture kept at room temperature overnight. Work-up gave a pink gum which was chromnatographed on Kieselgel, 60 in 30% ethyl acetate-hexane. Combination of appropriate fractions gave the title compound as an off white solid 1 H NMR (400MHz, CDCI 3 8:1.51 (9H, 2.82 (2H, 3.65 (2H, 4.56 (2H, 6.95 and 7.37 (2H, ABq), 7.12 (1H, 7.28 (1H, 7.46 O1H, br).
Description 8 7-Nitro-2-n-propyl-1,2,3,4-tetrahydrolsoquinoine Nitro compound D3 (1.55g, 8.7mmol) and propionaldehyde (2.52g, 43.5mmol) in 1,2dichioroethane (50mi) were treated with sodium triacetoxyborohydride, (0.28g, 13.1 mmol) and glacial acetic acid (0.6m1, 9.Ommol). The mixture was stirred at 25 0 C over the weekend and then diluted with dichloromethane, (50mI). The mixture was washed with saturated NaHCO 3 dried (Na 2
SO
4 and evaporated in vacuo. Chromatography on Kieselgel 60 in ethyl acetate gave the title compound.
Description 9 7-Amlno-2-n-propyl-1,2,3,4-tetrahydroisoquinoline The nitro compound D8 (0.73g, 3.32mmol) in ethanol (lO0mI) was heated to 50 0 C and treated with a solution of tin (HI) chloride (2.52g, 13.27mmol) in conc. HC1 (l0ml) and stirring continued for 3h. The mixture was basified with 40% NaOH and the product extracted into dichloromethane. Work-up and chromatography on Kieselgel 60 in methanol~ichloromethane gave the title compound as a viscous yellow oil (0.26g; 41%).
mz 191 Description 7-An ino-2-iso-propyl-1,2,3,4-tetrahydrolsoqunoine The title compound was prepared from D3 and acetone in 10% overall yield using a method similar to that described in Descriptions 8 and 9.
17 t WO 98/41508 PCT/GB98/00782 Description 11 7-Amlno-2-ethyl-1,2,3,4-tetraliydroisoquinoline The title compound was prepared in 14% overall yield from D3 and acetaldehyde using a method similar to that described in Descriptions 5 and 8.
Description 12 2-Formyl-7-nltro-1,2,3,4-tetrahydroisoquinoline A mixture of acetic anhydride (l.4ml) and formic acid (0.7m1) was stirred at 50'C for min. After cooling to 0 0 C, a solution of D3 (1.78g) and 4-dimethylaminopyridine Ig) in dickloromethane (30m1) was added and stirring continued at.25 0 C for 2h. The reaction mixture was washed with aq. potassium carbonate, water, brine and dried (MgSO 4 Evaporation in vacuo gave the title compound (2.4g).
1H NMR (250 MHz, CDC1 3 6: 3.0 (2H, mn), 3.72(t) and 3.88 (together 21H), 4.68 (t) and 4.80 (together 2H), 7.28-7.40 (1H, mn), 8.04 (2H, in), 8.22 and 8.30 (s) (together LH), mz 207 Description 13 7-Amlino-2-formyl-1,2,3,4-tetrahydroisoquinoline The compound D12 (2.3g) was dissolved in ethanol (50ml) and shaken at room temperature and 50psi with hydrogen in the presence of 5% Pd/C catalyst (0.8g).
Filtration and evaporation then provided the title compound as a white solid (1.6g).
111 NMR (250 MHz, d 6 -DMSO) 8: 2.55(t) and 2.59(t) (together 2H1), 3.56 (2H, 3.39 and 3.41(s) (together 211), 6.35-6.45 (2H1, in), 6.79 (1H, 8.15 and 8.18 (s) (together 1H), mlz(API+): 177 Description 14 2-(2-terl-Butyldlmethylsilyloxyethyl)-7-ntro-.1,2,3,4-tetrahydrodisoquinoline 7-Nitro-tetrahydroisoquinoline (5.0g; 28.Ommol) was dissolved in DMF (iS5ini). This solution was treated with (2-bromoethoxy)-tert-butyl-dimethylsilane (12.Oml; 56.Ommol), and stirred at 80 0 C overnight. The mixture was cooled to room temperature and the solvent removed in vacuo. Purification by column chromatography through Sic) 2 eluting with 50% diethyl ether/petroleum ether gave the title compound (4.2g, 44%).
18 WO 98/41508 PCT/GR98/00782 1 H NMR (250 MHz; CDCl 3 8: 0.00 (6H, 0.83 (9H, 2.66 (2H, t, J 6 Hz), 2.79 (2H, t, J 6 Hz), 2.90 (2H, t, J 6 Hz), 3.71 (2H, 3.77 (2H, t, J 6 Hz), 7.16 (1H, d, J 9 Hz), 7.82 (lH, d, J 2 Hz), 7.89 (1H, dd, J 9, 2 Hz).
Description 7 -Andno-2-( 2 -tert-butyldimethylsiyloxyethyI)4,,3,4-tetrahydrosoquinoijne 2-(2-tert-Butyldimethylsilyloxyethyl) compound D14 (2.88g; 8..S7mmol) and 10% Pd/C 60% paste in water) in methanol (lO0mi) was hydrogenated in a manner similar to that of Description 5 to give the title compound (2.62g).
IH NMvR (250 MHz, CDCl 3 8: 0.00 (6H, 0.83 (9H, 2.61 (2H, t, J 6 Hz), 2.71 (4H, s, overlapping signals), 3.55 (2H, 3.77 (2H, t, J 6 Hz), 6.27 (1H, d, J 2 Hz), 6.43 (1H, d, I=8 Hz), 6.80 (1H, d, J 8 Hz).
Description 16 2 2 -4ertButyldimethysiyoxyethy).13,tahydroisoquinoun7y1)3bromo- 4-ethoxybenzamlde Trietbylamine 112m1; 0.8l1mmol) and 3-bromo-4-ethoxybenzoyl chloride (1 93mg; 0.73mmol) were dissolved in dichloromethane (lO0mi) with stirring. To this mixture was added the compound of D15 (204mg; 0.67mmol). The mixture was stirred overnight, and then evaporated in vacuo. The resultant residue was purified by chromatography on silica with 10% methanol:dichloromethae to give the title compound (123mg; 1 H NMR (250 MHz; CDCl 3 8: 0.0 (6H, 0.82 (9H, 1.42 (3H, t, J 7 Hz), 2.80 (2H, t, J 5 Hz), 2.91 (2H, t, J1=5 Hz), 2.95 (2H, L, J 4 Hz), 3.81 (2H, 3.87 (2H, t, J 6 Hz), 4.08 (2H, q, J 7 Hz), 6.84 (lH, d, J 9 Hz), 7.00 (11, d, J =8 Hz), 7.29 (2H, d, J 8 Hz), 7.33 (11, 7.77 (11, dd, J 9, 2 Hz), 8.00 (111, d, J 2 Hz).
Description 17 7-Amino-2-(2methoxyethy)-1,2,34-tetrahydroisoquinoline IH NMR (250 MHz; CDC1 3 8: 2.74 (6H, in), 3.38 (311, 3.60 (4H, in), 3.20 3.70 (2H, br), 6.37 (111, 6.50 (1H1, dd, J3= 82 Hz), 6.88 (111, d, J =8 Hz).
19 WO 98/41508 WO 9841508PCT/GB98/00782 Description 18 5-Iodo-7-nitro-1,2,3,4-tetrahydrolsoqulnoilne The nitro compound of Description 3 (750mng; 3.9mmol) and N-iodosuccinimide 13g) in trific acid (5mi) was stirred at 25*C overnight. The mixture was poured cautiously into saturated NaHCO 3 and then extracted into ether The combined organic extracts were washed with aqueous sodium thiosulfate, dried (MgSO 4 and evaporation in vacuo gave a residue. Chromatography on Kieselgel 60 in 2% methanol dichloromethane gave the title compound (650mg).
Description 19 7-Amiino-5-iodo-1,2,3,4-tetraliydroisoquinoline A solution of the nitro compound D18 (650mg, 2. l4mmol) in ethanol (20ml) at 50 0 C was treated with a solution of tin (HI) chloride (1 .42g) in c. HCI (3 ml). The resultant yellow solution was basified with 10% aqueous sodium hydroxide and the product extracted into dichloromethane. Flash chromatography on Kieselgel 60 methanol dichloromethane) gave the title compound (428mg; 73%).
Description 7-Amlino-5-iodo-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline The iodoamine D19 (580mng, 2.l2mmol) in DMF (30m1) was treated with DMAP and di-tent-butyl-dicarbonate (466mg, 2.13mmol.) and the solution was stirred at room temperature overnight. The reaction mixture was evaporated to dryness in vacuc.
Chromatography on Kieselgel 60 methanol dichloromethane) gave the title compound (745mg; 94%).
Description 21 5,7-Dlnltro-1,2,3,4-tetrahydroisoquinoline 5-Nitro-1,2,3,4-tetrahydroisoquinoline (1.0g, 5.6mmol) in conc. sulfuric acid (3m1) was treated with conc. nitric acid (lml) and the mixture stirred at room temperature for lb.
The mixture was cooled, basified with 40% aqueous NaGH and work-up with dichloromethane gave the title compound (1.14g).
Description 22 5,7-Dlnltro-2-methyl-1,2,3,4-tetrahydroisoquinoline The amnine D21 (1.8g) in formic acid (5m1) and paraformaldehyde (7m1) were reacted in a similar manner to that of Description 2 to give the title compound (1.74g, 9 1 WO 98/41508 PCT/GB98/00782 IH NMR (CDC1 3 2.51 O3H, 2.75 (2H, 3.27 (2H, 3.75(2H, 8.16 (1H, di, J =2Hz), 8.66 (1H, d, J 2Hz); m/z 238.1(MH+; 100%).
Description 23 5-Amlno-7-nltro-2-metliyl-1,2,3,4-tetrahydroisoquinoline The dinitro, compound D22 (1.7g) was reduced with tin(ll)chloride (5.42g) in a manner similar to that of Description 19 to give the title compound (0.6g).
Description 24 5-Trifiuoroacetylamldno-7-nitro-2-methyl-1,2,3,4-tetrahydroisoqunollne The amine D23 (0.5g) in dichioromethane (l0mi) and triethylamine (1.5eq) was treated with trifluoroacetic anhydride leq) and the mixture stirred at 250C for 3h. Work-up with dichioromethane followed by chromatography on Kieselgel 60 in 3%methanol:dichloromethane gave the title compound (0.7g, 96%).
In/z 304 Description 7-Amino-5-trifluoroacetylaxnino-2-metliyl-1,2,3,4-tetrahydroisoquinoline The nitro compound D24 (0.7g, 2.28mmoI) in ethanol (20m1) was hydrogenated over Pd/C (70mg). The catalyst was removed by filtration through Celite, and evaporation in vacuo gave the title compound as a pale solid (0.6g, 93%).
Description 26 5-Chloro-7-nltro-2-methyl-1,2,3,4-tetrahydroisoquinoine The 5-amino compound D23 (1.6g, 7.7mmol) in 5MHCl (25m1) at 0 0 C was treated with a solution of sodium nitrite (0.55g, 8.Ommol) in water (3m1) over 5min. The cold solution was then added gradually to a solution of copper(l)chloride (1.0g, 10mmol) in (25m1). The mixture was stirred at 25 0 C for 3Omin and then basified with NaQH. Work-up with dichioromethane (300m1) followed by flash chromatography on Kieselgel 60 methanol:dichloromethae) gave the title compound 1g, 62%) as a yellow solid.
IH NMR (CDC1 3 2.32 (3H, 2.61 (2H, 2.79 (2H, 3.57(2H, 7.96 (1H, di, J 2H~z), 8.08 O1H, di, J 2H~z).
-21- WO 98/41508 WO 9841508PCT/GB98/00782 Description 27 7-Amino-5-chloro-2-methyl-1,2,3,4-tetrahydrolsoquinoline The nitro D26 (0.80g, 3.5mmol) in ethanol (70m1) and conc. HCl (7m1) was heated to 0 C and tin(ll)chloride (2.66g. l4mmol) was added. The mixture was heated for and allowed to cool; work-up similar to that described in Description 19 gave the title compound as a yellow oil (0.48g).
1 H NMR (CDCl 3 2.42 (3H, 2.64 (2H, in), 2.77 (2H, in), 3.45(2H, 6.27 (1H, d, J 2Hz), 6.59 (1H, d, J 2Hz).
Preparation 1 3-Bromobenzyl TBMS ether To a solution of 3-bromobenzyl alcohol (5.00g, O.O27rnole) in dichloromethane (30m1) and Et 3 N (4.2m1, 0.03 mole) was added a 1M solution tert-butyldimethylsilyl chloride in dichloromethane (28.Oml) dropwise. The mixture was allowed to stir at room temperature overnight, then water (30m1) was added. The organic layer was washed with brine, dried (Na 2
SO
4 and evaporated to give a red oil which was purified by flash chromatography on silica gel using 20% ether in hexane to give a colourless oil Preparation 2 3-Pivaloylbenzylalcohol TBDMS Ether n-Butyllithiumn (2.80m1, 7.O(kmmol, 2.5M in hexane) was slowly added to a solution of Preparation 1 TBDMS ether (1.80g, 6.Ommol) in dry THE (l0ml) over 5 min at -78*C.
The reaction mixture was maintained under argon at -78*C for lh. and N,O-dimethylhydroxy pivaloyl amide (0.86g, 6.6Omnmol) in THF (2m1) was added dropwise with stirring at -78*C. The resulting mixture was allowed to stir at -78 0 C for 2.5h, quenched with
NH
4 Cl solution and allowed to warm to room temperature. The mixture was extracted with ether (2x50m1), the combined organics were dried (Na 2
SO
4 and concentrated in vacuo to give the title compound as a colourless oil (1.75g mf/z 307 Preparaton 3 3-Pivaloylbenzylalcohol The ether of Preparation 2 (1.47g, 4.8Ommol) was dissolved in methanol (25mm); conc.
HCl (20 drops) was added and the whole allowed to stir at room temperature for Ah.
Saturated NaHCO 3 solution was added and the mixture extracted with ether (2x50m1).
-22- WO 98/41508 PCT/GB98/00782 The organic layer was dried over sodium sulfate and evaporation in vacuo gave title compound as a colourless oil (0.80g).
mz 193 17%).
Preparation 4 3-Pivaloylbenzoic acd 3-Pivaloylbenzyl alcohol (0.80g, 4.l6mmol) was dissolved in dioxane (20m1). A solution of KOH (0.35g, 6.3Ommol) in water (5mi) was added followed by KMnO 4 (1.45g, 9.17 mmol). The mixture was stirred at room temperature over the weekend. The solution was filtered through Celite and extracted with ether. The aqueous phase was acidified with dii. HCl and extracted with ether (3x50m1).. The organic layer was dried over magnesium sulphate and concentrated in vacuo to afford the title compound as a white solid (0.80g).
1 H NMR (250MHz, CDC1 3 1.38 (9H, 7.55 (1H, 7.92 (lH, d, J 6.5Hz), 8.20 O1H, d, J 6.5Hz), 8.44 (1H, s).
Preparation 3-Trlfluoroacetylbenzoic acid The title compound was prepared from diethyl trifluoroacetaniide and 3-bromobenzyl TBDMS ether using a method similar to that described in Preparations 1, 2, 3 and 4.
M/z 217 Preparation 6 Methyl 3-Chloro-4-iso-propoxybenzoate Methyl 3-chloro-4-hydroxybenzoate (5g, 26.8mmol) in DMF (45m1) was treated with potassium carbonate (7.4 1g, 53.6mmol), 2-iodopropane (3.85m1, 40.2mmol) and then stiffed at 250C for 18h. Work-up with ethyl acetate gave the title compound (6.1g).
Preparation 7 3-Chloro-4-iso-propoxybenzolc acd Methyl 3-chloro-4-iso-propoxybenzoate (5.5g, 24.lmmol) was hydrolysed using IM NaQH (36m1) in methanol (80m1). Extraction and work-up with ethyl acetate gave the title compound (4.3g).
'H NMR (DMSO-D 6 8:1.33 (6H, 4.79 (1H, in), 7.24 (1H, 7.87 (2H, in).
-23 WO 98/41508 PCT/GB98/00782 Preparation 8 3-Bromo-4-ethoxybenzoic add The title compound was prepared from 4-ethoxybenzoic acid in a manner similar to that of Procedure 1.
'H NMR (DMSO-D 6 8:1.45 (3H, t, J1=7 Hz), 4.26 (2H, q, J1=7 Hz), 7.26 (1H, d, J= 9 Hz), 7.98 (1H, dd, J 2, 9 Hz), 8.12 GLH, d, J 2 Hz) Preparation 9 3-Bromo-4-ethylbenzoic acd The title compound was prepared from 4-ethylbenzoic acid.
'H NMR (DMSO-D 6 8: 1.20 (3H, t, J 7 Hz), 2.78 (2H, q, J 7Hz), 7.50 (1H, d, J =8 Hz), 7.90 (1H, dd, J 2, 8 Hz), 8.07 (1H, d, J 8 Hz Preparation 3-Cyano-4-aso-propylbenzoic acd The title compound was prepared from 4-iso-propylbenzoic acid similar to that described in Procedure 'H NMR (DMSO-D 6 8:1.07 (6H, d, J1=7 Hz), 3.13 (1H,m, overlapped), 7.48 (1H, d, J =7 Hz), 7.96 (1H, dd, J1=2, 8 8.00 (1H, d, J1=2 Hz).
Preparation 11 4-Methoxy-3-trlfluoromethylbenzoic add The title compound was prepared from 3-bromo-4-methoxybenzoic acid and potassium trifluoroacetate in a manner similat to that of Procedures 3 and 4.
'H NMR (DMSO-D 6 8: 3.78 (3H, 7.18 (1H. d, J1=9 Hz), 7.90 (1H, d, J 2 Hz), 8.00 (1H, dd, J1=2, 9 Hz), 12.70 13.10 (1H, brexchangeable) Preparation 12 4-Methoxy-3-trifluoromethylbenzoyl chloride Te title compound was prepared from 4-methoxy-3-trifluoromethylbenzoic acid with oxalyl chloride and DMF in chloroform at room temperature Levin, Chem. Br., 1977, followed by evaporation in vacuo.
_24- WO 98/41508 PCT/GB98/00782 Preparation 13 Methyl 3-Bromo-4-iso-propoxybenzoate Methyl 3-bromo-4hydroxybenzoate (2.5g, l.8nmol) in DMF (35m1) was treated with potassium carbonate (3.0g, 21.6mmol), 2-iodopropane (2.76, 21.6mmol) and then stirred at 25 0 C for 48h. Work-up with ethyl acetate gave the title compound 1H NMR (250MHz, CDCl 3 8:1.41 (611, d. J=7 Hz), 3-89 (3H, 4.66 (1H, in), 6-90 (1H, d, J 8 Hz), 7.93 (1H, dd, J 8, 2 Hz), 8-22 (lH, d, J 2 Hz) Preparation 14 Methyl 3-Cyano-4-iso-propoxybenzoate Methyl 3-bromo-4iso-propoxybenzoate (2.0g, 7.3mmol) and copper(Icyanide in Nmethyl pyrrolidone (50m1) were heated under vigorous reflux for 4h. Work-up with ethyl acetate gave the title compound 'H NMR (250MHz, CDC1 3 8: 156 (6H, d, J=7 Hz), 4.05 (3H, 4.88 (lH, in), 7.13 (1H, d, J 8 Hz), 8.31 (1H, dd, J 8, 2 Hz), 8-38 (lH, d, J 2 Hz) Preparation Methyl 3,5 Dichloro-4-ethoxybenzoate The title compound was prepared in 69% yield from methyl 3,5-dichloro-4hydroxybenzoic acid and iodoethane in a manner similar to that of Preparation 6.
'H NMR (250MHz, CDC1 3 8:1.*47 (3H, t, J=7 Hz), 3.91 (3H, 4.16 (2H, q, J =7 Hz), 7.96 (2H, s).
Preparation 16 3-Methanesulfonyl-4-iso-propylbenzoic acdd 3-Chlorosulfonyl-4-iso-propylbenzoic acid (2.62g, 10mmol) [made from 4-iso-propyl benzoic acid in a manner similar to that described in Procedures 7 and 8] was added slowly to a slurry of NaHCO 3 (2.52g, 3Ommol) and Na 2
SO
3 (1.26g l0mmol) in water (9m1) at 75 0 C. The mixture was stirred for lh and then treated with bromoacetic acid (2.08g, l5mmol) and NaOH (0.60g, l~mmol). The temperature was raised to 105 0 C and the mixture heated at reflux for 24h. The mixture was cooled, acidified to pH 1 and the resultant precipitate collected, washed and dried to give the title compound (1.43g, 59%).
WO 98/41508 WO 9841508PCT/GB98/00782 'H NMR (250MHz, acetone-D 6 8: 1-24 (6H, d, J=7 Hz), 3.13 (3H, 3.88 (1H, in), 7.72 (1H, d, J 7 Hz), 8.15 (1H, dd, J 7 Hz), 8.52 (lIl, d, J 2 Hz).
Preparation 17 4-Methyl-3-methanesulfonylbenzolc add Prepared in 30% overall yield in a manner similar to that of Preparation 16.
'H NMR (250MHz, acetone-D 6 8: 2.57 (3H, 2.99 (3H, 7.39 (1H, d, J 7 Hz), 7.97 (1H, dd, J 7, 2 Hz), 8.39 (1H, d, J 2 Hz).
Preparation 18 4-Ethyl-3-methanesulfonylbenzolc add Prepared in 44% overall yield in a manner similar to that of Preparation 16.
'H NMvR (250NMz, acetone-D 6 8: 1.22 (3H, t, J 7 Hz), (3H, 3.05 (2H, q, J1=7 Hz), 3.12 O3H, 7.57 (1H, d, J 7 Hz), 8.13 O1H, dd, J 7, 2 Hz), 8.51 (1H, d, J 2 Hz).
Preparation 19 3-Methanesulfonyl-4-inethoxybenzoic acdd Prepared in 20% overall yield in a manner similar to that of Preparation 16.
'H NMvR (2501Mz, acetone-D 6 8: 3.00 (3H, 3.89 (3H, 7.17 (1 H, d, J 7 Hz), 8.06 (1H, dd, J 7, 2 Hz), 8.31 (1H, d, J 2 Hz).
Preparation 4-Ethoxy-3-methanesulfonylbenzoic acd Prepared in 20% overall yield in a manner similar to that of Preparation 16.
1 H NMR (250MHz, acetone-D 6 8:1.44 (3H, L, J 7 Hz), (3H, 3.30 (3H, 4.35 (2H, q, J 7 Hz), 7.40 (1H, d, J 7 Hz), 8.20 (lH, dd, J1=7, 2Hz), 8.37 (1H, d, J 2 Hz).
Preparation 21 3-Chloro-4-ethoxybenzoic acd 'H NMR (DMSO-D 6 8:1.39 (3H, tJ 1=7 Hz), 4.20 (2H, q, J 7 Hz), 7.22 (1H, d, J=7 Hz), 7.87 (2H, mn).
-26 WO 98/41508 PCT/GB98/00782 Preparation 22 4-wso-Propyloxy-3-trifluoromethylbenzolc add Methyl 3-bromo-4-iso-propyloxybenzoate (828mg; 3.03 mmol) in DMF (25m1) was treated with potassium trifluoroacetate (922mg; 6.06 mmol), copper iodide 6.06 mmol) and toluene (50mi). Thbe resulting mixture was heated at reflux for (Dean and Stark with removal of ca 50mI of distillate) followed by reflux for 18h then cooled. The mixture was poured into Et 2 O (lO0mi) and H 2 0 (IlO0mI). The two-phase mixture was stirred at room temperature for 0.5h then filtered through Celite. The two phases were separated, the aq. phase further extracted with Et 2 O (50m1) and the organic extracts combined, washed with saturated, aq. Na2S 2 0 3 H120, saturated brine, dried (MgSO 4 and evaporated in vacuo to give a brown oil. This was dissolved in MeGH (ca 20m1) and treated with 2M NaOH (2m1; 4 mmol) and the resulting solution heated at reflux for 3h. The volatiles were removed in vacuo and the residue partitioned between EtOAc and H20. The phases were separated, the aq. phase acidified to pH I with 2M HCl in the presence of EtOAc and the phases separated. The aq. phase was further extracted with EtOAc, the extracts combined, washed with H 2 0, saturated brine, dried (MgSO 4 and evaporated to dryness in vacuo to give the title compound as a white solid (67 1mg; 89%).
'H NMR (250MHz; 8: 1.02 (6H, d, J 6 Hz), 4.53 4.63 (1H1, in), 7.01 (1H, d, J 9 Hz), 7.85 7.88 (2H, in); (API): 205.0 Preparation 23 4-Ethyl-3-trifluoromethylbenzoic add Prepared as described in Preparation 22 from methyl 4-ethyl-3-broinobenzoate (1.l10g; 4.52 iniol) and isolated as a white solid (923mg; 'H NMR (250MHz; (CD,) 2 C0) 8: 0.98 (3H, t, J 7 Hz), 2.60 (2H, q, J 7 Hz), 7.36 (1H, d, J 8 Hz), 7.89 and 7.93 (1H, in), 7.96 (1H1, br (API): 217.1 Preparation 24 4-n-Propyloxy-3-trifluoromethylbenzoic add Prepared as described in Preparation 22 from methyl 3-bromo-4-n-propyloxybenzoate (1.43g; 5.23 iniol) and isolated as a white solid 18g; 9 1 'H NMR (250MHz; (CD 3 2 S0) 8: 1.09 (3H1, t, J =7 Hz), 1.79 1.93 (2H, in), 4.26 (2H. t, j 6 Hz), 7.45 (1H, d, J 9 Hz), 8.19(1OH, d, J =2 Hz), 8.25 and 8.28 (11, dd, J 9, 2 Hz); (API): 203.1 [M-CO 2
H].
-27 WO 98/41508 WO 9841508PCT/GB98/00782 Preparation 4-1-Butyl-3-trlfluoromethylbenzoic acid Prepared as described in Preparation 22 from methyl 3-bromo-4-t-butylbenzoate (2.46g; 9.1 mmol) and isolated as a white solid (1.55g; 69%).
'H NMR (250MHz; (CD,) 2 S0) 8: 1.42 (9H, 7.86 7.90 (1H. in), 8.09 8.13 (1H, in), 8.23 (1H, d, J 2 Hz); (API): 245.1 [M-11].
Preparation 26 4-Oxochroman-6-carboxylic acdd 3-(4-Carboxyphenoxy)propionic acid (2.5g) [prepared according to the procedure of J.
Lichtenberger and R. Geyer. Bull. Soc. Chim. Fr., 1963 275] in conc. sulfuric acid (20m1) was heated to 100 0 OC for 4h and then poured onto crushed ice. The resultant precipitate was filtered and dried in vacuo to give the tide compound (1.6g).
'H NMR (DMSO-D 6 8: 2.99 (2H, t, J 7 Hz), 4.77 (2H, t, J 7 Hz), 7.28 (1H, d, J 8 Hz), 8.21 (1H,dd, J 8, 2 Hz), 8.46 (1H, d, J 2 Hz).
Preparation 27 3-Bromo-4-iso-propoxybenzoic acid The title compound was prepared using a method similar to that of Preparation 7.
'H NMR (DMSO-D 6 8:1.29 (6H, d, J 7 Hz), 4.77 (1H, sep, J 7 Hz), 7.20 (1H, d, J 8 Hz), 7.87 (1 H, dd, J 8, 2 Hz), 8.02 (11H, d, J 2 Hz), 12.92 (1 H, brs).
Preparation 28 4-Azidobenzoic acd To a solution of 4-axninobenzoic: acid (2.00g, 14.O0mmol) in trifluoroacetic acid (l0mi) at 0 C, was added sodium nitrite (3.50g) portionwise, and the mixture allowed to stir for min. Sodium azide (3.79g,) was then added portionwise and the mixture stirred for a further 30 min at 0 0 C. The* mixture was diluted with water, and a white solid precipitated.
The solid was filtered, washed with cold water and dried, to afford the title compound (1.66g, 73%).
Procedure 1 5-Bromo-2,4-dlmethoxybenzolc acdd To a solution of 2,4-dimethoxybenzoic acid (4.0g, O.022mol) in chloroform (60m1) was added bromine 13m1, 0.022mol) in chloroform (20m1) dropwise. After stirring overnight -28- WO 98/41508 PCT/GB98/00782 at room temperature the precipitate was filtered off and dried to afford the title compound as a white solid (2.87g).
Procedure 2 5-Bromo-4-iso-propyl-2-methoxybenzoic add To a solution of 2-methoxy-4-iso-propyl benzoic acid (7.0g, 36.0 mmol) in chloroform (100 ml) was added bromine (1.86 ml) in chloroform (20 ml) dropwise. The reaction was stirred at room temperature overnight. Evaporation in vacuo afforded an oil (9.27g).
275, 273 Procedure 3 Methyl 5-bromo-4-iso-propyl-2-methoxy benzoate 5-Bromo-4-iso-propyl-2-methoxybenzoic acid (9.268g 34.0 mmol) was dissolved in methanol (250 ml) and conc. H 2
SO
4 (2 ml) added. The mixture was refluxed for 5h and concentrated in vacuo. Residual material was taken up into ethyl acetate and water, and the organic layer, dried (MgSO 4 Concentration in vacuo afforded an oil, which was purified by Biotage Column Chromatography on silica gel using 10% ether in hexane to give an oil Procedure 4 2,4-Dimethoxy-5-trifluoromethylbenzoic add 2,4-Dimethoxy-5-bromobenzoic acid methyl ester (1.5g; 5.4 mmol) in DMF (25ml) and toluene (8ml) under argon was treated with potassium trifluoroacetate (1.53g; 10.1 mmol) and copper iodide (2.1g, 10.9 mmol). The mixture was heated to 170 0 C with removal of water (Dean/Stark), and then at 155C overnight. The mixture was allowed to cool, poured into ether and water and filtered through Kieselguhr. The organic layer was dried (Na 2
SO
4 and concentrated in vacuo to give a brown solid. Chromatography on Kieselgel with 1:1 ether/petrol gave a solid (1.03g) which was hydrolysed in 1:1 methanolic: aqueous NaOH (50ml) at 50*C. Work-up gave the title compound as a white solid (lg).
Procedure Methyl 2-methoxy-5-cyano-4-iso-propylbenzoate Copper cyanide (550mg, 6mmol) was added to a solution of methyl bromo-4-iso-propylbenzoate (861mg) in N-methyl-2-pyrrolidinone (30ml). The mixture was stirred under argon and boiled under reflux for 4h. The mixture was cooled, poured into excess ice/water and ethyl acetate and filtered. The organic phase was separated, washed with water, brine and dried(MgSO 4 Evaporation gave a crude brown solid -29- WO 98/41508 PCT/GB98/00782 which was purified by chromatography on silica gel eluting with ethyl acetateln-hexane The product was obtained as a white solid (523 mg).
'H NMR (250MHz, CDCl 3 8: 133 (6H, d, J=7Hz), 3-38 (LH, sep, 1=7Hz), 3.89 (3H, s), 3-98 (3H, 6-91 (lH, 8-08 (1H, mltz 234 Procedure Sb 2-Methoxy.5-cyano-4-Lwo-propylbenzoic add 2N NaGH (l*25m1) was added to a solution of the methyl ester P~a (490mg) in methanol (l0mi). The solution was stirred overnight at room temperature. The solution was then diluted with water, concentrated in .vacuo and washed with ethyl acetate. The aqueous phase was then acidified with 2N HCl and extracted with ethyl -acetate. The extract was washed with brine, dried (MgSO4) and evaporated to dryness giving the product as a white solid (418mg).
'H NMR (250MHz, CDCl 3 8:1l*35 (6H, d, J=7Hz), 3-43 (lH, sep, 1=7Hz), 4-14 (3H,s), 7-00 (1H, 8-41 (lH, miz 220 100%).
Procedure 6a Ethyl 2-ethoxy-4-iso-propyl-5-cyanobenzoate Ethyl 2-ethoxy-4-iso-propyl-5-bromobenzoate (1-2g, 3*8mmol) was treated with copper cyanide (682mg, 7.6 m.mol) in N-methyl-2-pyrrolidinone (40m1) as described in Procedure 5 to give the title compound as an oil (400mg).
'H NMR (250MHz, CDCl 3 8: 1.12 (6H, d, 1=7Hz), 1.30 (3H, t, 1=7Hz), 1.84 (OH, tL 1=7Hz), 3.17 (1H, sep, J=7Hz), 3.99 (2H, q, 1=9Hz), 4.16 (2H, q, J=7Hz), 6.69 (lH, s), 7.86 (IH, m/z 262 100%).
Procedure 6b 2-Ethoxy-4-iso-propyl-5-cyanobenzoic add The ester P6a (370mg, l.4lmmol) was dissolved in methanol (5mi) and over a 24 h period 1N NaOH (2.lml, 2.lmmol) was added. The solution was concentrated under vacuum, diluted with water and washed with ethyl acetate. The aqueous phase was acidified with 2N HCl and extracted with ethyl acetate. The extract was washed with brine, dried (Mg
SO
4 and evaporated to give the title acid (306 mg).
'H NMR (250MHz CDC1 3 8:1.39 (3H, d, J=7Hz), 1.66 (3H, t, 1=7Hz), 3.47 (1H, sep.
1=7Hz), 4.46 (2H, q, 1=7Hz), 7.03 (1H, 8.47 (111, m/z 234 100%).
WO 98/41508 PCT/GB98/00782 Procedure 7 add 4-Ethoxy-2-metoxy5chorosulonyI benzoic acid was prepared in 49% yield using the procedure of M.W. Harrold et al., J. Med. Chem., 1989, 32 874. This was used according to the method of R.W. Brown, J. Org. Chem., 1991, 56, 4974, to the title compound in 19% yield.
'H NMR (DMSO-D 6 8: 1.30 (31H, 3.10 (3H, 3.83 (3H, 4.24 (2H, 6.73 (1 H, 8.07 (1 H, s).
Procedure 8 4 -iso-Propyl-2-methoxcy.5methylsufonylbenzojc add This was prepared in a similar manner to the procedure of C. Hansch, B. Schmidhalter, F. Reiter, W. Saltonstall J. Org. Chem., 1956, 21, 265 to afford the intermediate chlorosufonyl4isopropy12methoxyenzoic acid which was converted into the title compound using the method of Procedure 7.
'H NMR (DMSO-D 6 5:1.30 (611, 3.21 (3H, 3.80 (111, in), 3.94 (3H1, 7.26 (111, 8.19 (1 H, s).
Example 1 N-1234Tf-hdosqioi--y)Sclrtdpee2croade monotrifluoroacetate The N-boc amine D7 (0.48g; 1.22 inmol) in dichioromethane (25m1) containing trifluoroacetic: acid (2m1) was kept at 25*C for 18h. Evaporation in vacuo followed by crystallisation of the residue from ethyl acetate ether gave the title compound as offwhite crystals 0.46g; m.p. 153-5*C.
111 NMvR (400MHz, DMSO-d 6 2.96 (2H1, 3.38 (211, 4.29 (2H1, 7.23 (111, d), 7.28 (1H1, d, ABq), 7.51 (111, dd), 7.63 (1H, 7.90 (1H, d, ABq), 9.01 (211, br, s), 10.33 (1H, m/ 293 100%).
Example 2 N-2Mty-erhdosqioi--i--hoohohn- abxnd The compound of Example 1 (200mg; 0.5 mmol), 98% formic acid (0.4m1) and aqueous formaldehyde (0.6ml) were treated according to the procedure of Description 4.
-31- WO 98/41508 PCT/GB98/00782 Chromatography on Kieselgel 60 in methanol ethyl acetate followed by crystallisation from ethyl acetate ether gave the tidle compound as an off-white powder, m.p. 138- 0
C.
1 H NMR (250MHz, CDC1 3 2.46 (3H, 2.69 (2H, 2.89 (2H, 3.54 (2H, 6.93 and 7.37 (211, AIBq), 7.07 (lH, 7.25 (1H, dd), 7.34 (lH, 7.63 (1H, br, s); M/z 307 100%).
Example 3 N-(2-Methyl.1,23,4.tetrahydroisoquinolin-7-y)benzamlde The N-methyl amine D5 in dichloromethane (25m1)-containing triethylaxnine (0.5m1) was treated with benzoyl chloride and the mixture kept at 25 0 C for 18h. Normal work-up gave the product which was chromatographed on Kieselgel 60 by gradient elution in ethyl acetate:hexane. Combination of appropriate fractions gave the tidle compound.
1H NMR (250MHz, CDCl 3 2.46 (3H, 2.69 (2H, 2.91 (2H, 3.58 (2H, 7. (1H, 7.30 (1H, dd), 7.40 7.60 (4H, overlapping in), 7.75 (1H, br 7.87 (2H, in).
Thsefollowing Eramples were made using procedures similar to the methods described earlier.
Example 4 N-(2-Methyl-1,2,3,4-tetrahydrolsoquinolin-7-yI)-3-chlorobenzamlde IH NMR (250MHz, CDCl 3 2.46.(3H, 2.68 (2H, 2.90 (2H, 3.57 (2H, 7.10 (1H, 7.29 (1H, dd, overlapping with CH0l 3 (1H, 7.42 (1H, 7.52 (iH, mn), 7.73 (1H, in), 7.83 (2H, in).
Example N-(2-Metliyl-1,2,3,4-tetrahydroisoquinolin-7-yI)-4-t-butylbenzanlde 1 H NMR (250MHz, CDCl 3 1.34 (9H, 2.44 (3H, 2.68 (2H, 2.89 (2H, 3.55 (2H, 7.07 (1H, 7.29 OlH, dd overlapping with CHC1 3 signal), 7.38 7.53 (3H, in, overlapping signals), 7.75 7.90 (3H, in, overlapping signals).
-32- WO 98/41508 PCT/GB98/00782 Example 6 N-(2-Methyl-1,2,3,4-terahydroLsoquinol7-y)4-Wo-propoxybelzahde 1 H NMR (250MHz, CDCl 3 1.38 (6H, di), 2.46 (3H, 2.69 (2H, 2.90 (2H, 3.58 (2H, 4.64 (1H, septet), 6.94 (2H, in), 7.09 (1H, 7.23 7.34 (1H, mn, overlapping CHC1 3 .42 (11H, 7.70 (1H, br 7.81 (2H, mn); In/ 325 100%).
Example 7 N.(2-MethyI.1,3,4tetrahydroisoquinoln-7-yl)-4-pheoxybenzanflde IH NMR (250MHz, CDCl 3 )8:2.46 (3H, 2.69 (2H, 2.91 (2H1, 3.59 7.00 7.50 (10H, overlapping in), 7.72 (1H, br 7.83 (2H, in).
Example 8 N-(2-Methyl.1,2,3,4-tetrahydroisoquinolin7-yl)-4-lltrobnzanlhde 1 H NMR (CDCl 3 2.45 (3H, 2.70 (2H, in), 2.90 (2H, in), 3.60 (2H, 7.10 (2H, dd), 7.25 (1H, dd), 7.40 (11H, 8.00 (2H, dd), 8.35 (2H1, dd), 7.80 (1H, s).
In/z 312 Example 9 N-(2-Methyl-1,2,3,4-tetrahydroisoqunolil-7-y)-4-phelylbenzanlhde III NMR (CDCl 3 2.45 (3H, 2.70 (2H, in), 2.90 (2H, in), 3.60 (2H, 6.30 (11H, 6.50 (1H, dd), 6.90 (1H, dd), 7.10 (1H, 7.40 (2H, in), 7.60 (1H, dd), 7.70 (1H, cid), 7.80 O1H, 7.90 (1H, 8.05 (1H, m/ 343 Example N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin7-yl)-3-ethylbelzanfldd 1 H NMR (CDCl 3 2.43 (3H, 2.47 (3H, 2.70 (2H, 2.90 (2H, 3.60 (2H, s), 7.05 (1H, dd), 7.30 (1H, in), 7.35 (2H, in), 7.45 (1H, 7.65 (314, in).
I/ 281 -33- WO 98/41508 WO 9841508PCT/GB98/00782 Example 11 N-(2-Methyl-1,2,3,4tetrahydrolsoqulnolin-7-yl)-.3-fluorobenzamide IH NMR (CDC1 3 2.50 (3H, 2.75 (2H, 2.90 (2H, 3.65 (2H, 7.10 (1H, dd), 7.28 (211, in), 7.40 (2H1, mn), 7.60 (2H, in), 7.75 (111, inIz 285 100%).
Example 12 N-(2-Methyl-1,2,3,4-tetraliydroisoquinolin-7-yl).3-cyanobenzamide 1 11 NMR (CDCl 3 2.47 2.70 (2H, 2.90 (2H, 3.60 (2H, 7.12 (1H, cid), 7.30 (1H, in), 7.40 O1H, 7.65 (1H,4dt, 7.80 (2H, in), 8.10 (1H, 8.15 (1H, s).
in/z 292 Example 13 N-(2-Methyl-1,23,4-tetrahydroisoquinolin-7-yl)-3,4-dichlorobenzamide 1 H NMR (CDC1 3 2.50 (3H, 2.80 (2H,t4, 2.90 (2H, 3.70 (2H, 7.10 (1H, d), 7.30 (1H, dd), 7.40 (11H, 7.55 (1H, 7.70 (1H, dcl), 8.00 (2H, in).
Example 14 N-(2-Metliyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iodobenzamide 1 H NMR (CDC1 3 2.47 (3H, 2.71 2.89 (2H, 3.58 (2H, 7.10 (1H, d), 7.30 (1H, in), 7.43 (111, 7.60 and 7.85 (411, ABq), 7.82 (1H, s).
mIz 393 100%).
Example N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-bromobenzamide 1 H NMR (CDC1 3 2.47 (3H, 2.71 (2H, 2.89 (2H, 3.60 (2H, 7.10 (1H, d), 7.30 (1H, in), 7.43 (1H, 7.64 and 7.74 (4H, ABq), 7.70 (1H, s).
MZ 347, 345 100%).
-34- WO 98/41508 PCT/GB98/00782 Example 16 N-(2-Methyl-1,2,3,4-tetrahydrosoquinolin-7-yl).4-methylbenzamlde 1 H NMR (CDC1 3 2.44 (3H, 2.48 (3H, 2.75 (2H, 2.90 (2H, 3.63 (2H, s), 7.10 (1H, 7.28 and 7.78 (4H, ABq), 7.30 (1H, 11), 7.44 (1H, 7.74 (1H, i).
m/z 281.2 100%).
Example 17 N-(2-Methyl-1,2,3,4tetrahydrolsoquinolin-7-yl)-3-nltrobenzanide 1 H NMR (CDC1 3 2.48 (3H, 2.71 (2H, 2.92 (211, 3.61 (2H, 7.13 (1H, d), 7.34 (1H, dd), 7.42 (1H, 7.71 (1H, 8.00 (1H, 8.26 (1H, 8.40 (1H, 8.70 (1H, m/Z 312.1 100%).
Example 18 N-(2-Methyl-123,4tetrahydroisoquinolin-7-y)-4-ethoxybenzamdde IH NMR (CDC1 3 1.46 (3H, 2.47 (3H, 2.71 (2H, 2.90 (2H, 3.61 (211, s), 4.11 (211, 7.14 (1H, 7.30 (1H, 7.49 (1H, 7.68 (1H, 7.82 (2H, 8.10 (311, mIz 311.2 100%).
Example 19 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-n-butylbenzamide 111 NMR (CDC1 3 0.93 (311, 1.25 1.48 (2H, 1.52 1.70 (2H, 2.51 (311, s), 2.66 (211, 2.80 (2H, 2.95 (2H, 3.69 (2H, 7.12 (1H, 7.20 (1H, 7.29 (211, 7.32 (1H, 7.47 (1H, 7.78 (211, 7.93 M/i 323.2 (MH+; 100%).
Example N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-acetoxybenazmide 1H NMR (CDC1 3 2.33 (311, 2.48 (3H, 2.71 (211 2.91 (211, 3.61 (2H, s), 7.10 (1H, 7.16 (1H, 7.23 (1H, 7.32 7.45 (211, 7.52 (1H, 7.83 (11, d), 7.94 (1H, mIz 325.2 100%).
WO 98/41508 WO 9841508PCT/GB98/00782 Example 21 N-(2..Methyl-1,2,3,4-tetrahydroLsoqulnolln.7-yl)-3-trlfluoromethylbenzamide 1 H NMR (CDCl 3 2.48 (3H, 2.73 (2H, 2.92 (2H, 3.62 (2H, 7.11(1H, d), 7.32 (1H, 7.42 (1H, 7.63 (111, 7.75 7.91 (2H, in), 8.07 (11H, 8.12 (1H, s).
m/ 335.1 100%) Example 22 N-(2-Methyl-1,,3,4-tetrahydrolsoquinolln-7-yl)-2,4-dfluorobenzamide 1 H NMR (CDC1 3 2.47 (3H, 2.71 (2H, 2.92 (2H, 3.61 (2H, 6.95 (1H, in), 7.00 7.18 (2H, in), 7.32 (1H, dd), 7.44 (1H, 8.14 8.36 (2H, in).
mIz 303.1 100%).
Example 23 N-(2-Methyl-1,2,3,4-tetrahydroisoquinoin-7-yl)-3,4-dimethoxybenzamide mz (CID: 327.2 100%).
Example 24 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-fluoro-4-trifluoromethyI benzamide 1 H NMR (CDC1 3 2.47 (3H, 2.70 (2H, 2.92 (2H, 3.61 (2H, 7.11 (11H, d), 7.35 (1H, dd), 7.45 (2H, 7.50 (1H, 7.59 (1H, 8.20 8.40 (2H, br mn).
mIz (CID: 353.1 100%).
Example N-(2-Methyl-1,2,3,4-tetrahydrolsoquinolin-7-yl)-4-chloro-3-nitrobenzanlde 1 H NMR (CDC1 3 2.48 (3H, 2.72 (2H, 2.94 (2H, 3.60 (2H, 7.10 (1H, d), 7.32 (1H, 7.38 (1H, 7.67 (1H, 7.95 8.13 (2H, br in), 8.38 (1H, d).
m/z 348 33%),346.1 100%).
-36- WO 98/41508 PCTGB98/00782 Example 26 N-(2-Metthyl-1,23,4-tetahydroisoqulnolin-7-yl)-3,5-d.trifluoromethyibenzanide 1 H NMR (CDC1 3 2.52 (3H, 2.78 (2H, 2.94 (2H, 3.66 (2H, 7.14 (1H, d), 7.36 (1H, 7.42 (1H, 7.94 (1H, 8.04 (1H, 8.32 (2H, s).
m/ 403.1 100%).
Example 27 N-(2-Methyl-123,4-tetrahydroisoquinoln-7-yl)-2,dchloro-5-fluorobenzamide 1H NMR (CDC1 3 2.47 (3H, 2.70 (2H, 2.91 (2H, 3.60 (2H, 7.11 (1H, d), 7.25 (1H, 7.38 (1H, 7.52 (1H, dd), 7.62 (1H, dd), 7.90 (1H, brs).
m/z 353.0 100%).
Example 28 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin.7-yl).3-fluoro-5-trfluoromethyI benzamide 1 H NMR (CDC1 3 2.49 (3H, 2.73 (2H, 2.91 (2H, 3.62 (2H, 7.13 (1H, d), 7.32 (1H, dd), 7.40 (1H, 7.50 (1H, 7.80 (1H, 7.90 (1H, 8.02 (1H, s).
mz 353.1 100%).
Example 29 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methoxybenzanide 1 H NMR (CDC1 3 2.47 (311, 2.71 (2H, 2.91 (2H, 3.60 (211, 3.97 (3H, s), 6.96 (1H, 7.10 (1H, 7.29 (LH, 7.40 (1H, 7.67 (1H, 7.84 (1H, dd), 8.02 (1H, 8.05 (1H, m/z 377, 375 Example N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4,5-trimethoxybenzamide IH NMR (CDC1 3 2.42 (311, 2.66 (2H, 2.88 (2H, 3.55 (2H, 3.83 (3H, s), 3.86 (6H, 7.00 (1H, 7.05 (1H, 7.19 (1H, 7.26 (1H, 7.34 (1H, 7.68 (1H, 7.94 (1H, m/z 357.2 100%).
-37- WO 98/41508 PTG9/08 PCT/GB98/00782 Example 31 N-2Mty-,,,-e~hdosqio~--l--rfurmtoyeznd IH NMR (CDC1 3 2.47 (3H, 2.70 (2H, 2.91 (2H, 3.60 7.10 (1H, d), 7.25 (1H, in), 7.32 (2H, 7.40 (1H, 7.74 (1H, 7.90 (2H, d); m/ 35 1.1 100%).
Example 32 N-(2-Methyl-1,2,3,4-tetrahydrolsoquinolin7y).3-pivaoylbenzandde, hydrochloride The acid of Preparation 5 (200mg, 1.Ommol) and oxalyl chloride (I140mg, 1.lImmol) in dichioromethane (l0mi) containing DMF (5 drops) was stirred at 25 0 C for lh and then evaporated to dryness in vacuo. The residue in dichioromethane was treated with the amine D5 (162mg, 1.Ommol) and kept at 25 0 C overnight. Work-up similar to that of Example 2 gave the title compound (1 10mg), m.p. 197 20 1 C (from methaol:ether).
1 H NMR (free base; 250 M]Hz; CDC1 3 1.38 (9H, 2.45 (3H, 2.68 (2H, 2.89 (2H, 3.55 P2H, 7.08 (1H, 7.30 (1H, 7.40 (1H, 7.49 (1H, 7.83 (1H, d), 7.95 (1H, 8.08 (1H, 8.14 (1H, mIz 351.2 100%).
Example 33 N-2Mty-,,,-erhdosqioin7y)3boo4iopooyeznd IH NMR (CDC1 3 8: 1.42 (6H, d, J 6 Hz), 2.47 (3H, 2.71 (2H, t, J 6 Hz), 2.91 (2H, t, J 6 Hz), 3.60 (2H, 4.67 (1 H, dt, J 6 Hz), 6.96 (1H, d, J 9 Hz), 7. 10 (1H, d, J 8 Hz), 7.30 (OH, mn), 7.40 (1H, d, J 2 Hz), 7.71 (1H, 7.80 (1H, dd, J 2 and 9 Hz), 8.05 (1H, d, J 2 Hz).
Example 34 N-(2-Methyl12,3,4taydroisoquinon7yi)4-eeobenzanjde IH NMR (CDC1 3 6: 2.34 (3H, 2.48 (3H, 2.73 (2H, t, J 6 Hz), 2.92 (2H, t, J =6 HZ), 3.62 (2H, 7.11 (1H, d, J 8 Hz), 7.21 (2H, in), 7.31 (1H, in), 7.43 (1H, 7.75 O1H, 7.88 (2H, in); in/z (CI: 325 100%) 38 WO 98/41508 PCTIGB98/00782 Example N-(2-MethyI-1,2,3,4-terahydroisoquinolin7-yl)-4-Cycopefloxybenzandde 1 H NMR (CDC1 3 8: 1.56 1.68 (2H, bi), 1.74 1.97 (6H, bi), 2.61 (3H, 2.95 (4H, 3.79 (2H, 4.81 (1H, 6.38 (1H, 6.54 (1H, dd, J 2 and 8 Hz), 6.85 (2H, i), 6.93 (2H, d, J 8 Hz), 7.95 (2H, d, J 8 Hz); mIz 349 Example 36 N-(2-Methyl1,2,3,4traiuydrosoquinolin-7-yl)-4-cylopropyIIethoxybenzandde 1 H NMR (CDC1 3 6: 0.36 (2H, 0.66 (2H, 1.28 (1H, 2.44 (311, 2.81 (211, tJ 6 Hz), 2.89 (211, t, J =6 Hz), 3.51 (2H, 3.86 (2H, 6.34 (1H, d, J 2 Hz), 6.50 (1H, dd, J 2 and 8 Hz), 6.92 (211, 7.06 (1H, d, J 8 Hz), 7.31 (1H, dd, J 2 and 8 Hz), 7.82 (1H, 8.00 (1H, m/z 337 100%).
Example 37 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano4-methoxybenzamide 1 H NMR (CDC1 3 5: 2.47 (3H, 2.70 (2H, t, J 6 Hz), 2.91 (2H, t, J 6 Hz), 3.59 (2H, 4.02 (311, 7.09 (2H, t, J 8 Hz), 7.29 (1H, dd, J 2 and 8 Hz), 7.39 (1H, d, J =2 Hz), 7.80 (1H, 8.10 (2H, i/z 322 100%) Example 38 N-(2Metyl1,2,3,4tetrahyroisoquinolin-7-yl)-2-naphthainide 1 H NMR (CDC1 3 6: 2.50 (3H, 2.75 (2H, tJ 6 Hz), 2.94 (2H, t,J 6 Hz), 3.65 (211, 7.13 (1H, d, J 8 Hz), 7.38 (1H, dd, J 2 and 8 Hz), 7.50 (1H, d, J 2 Hz), 7.56 7.22 (311, bi), 7.88 8.07 (4H, bi), 8.38 (1H, m/z 317 100%) Example 39 N-(2Metyl-123,4-terahydroisoquinon-7-yl)-3bromo-4-ethybenzahde 1 H NMR (CDC1 3 6: 2.47 (6H, bs), 2.71 (2H, tJ 6 Hz), 2.91 (2H, t,J 6 Hz), 3.60 (2H, 7.10 (1H, d, J 8 Hz), 7.23 7.39 (2H, bi), 7.42 (1H, 7.70 (2H, dd, J 2 and 8 Hz), 8.02 (1H, d, J 2 Hz); m/z 359, 361 100%) -39b WO 98/41508 PCT/GB98/00782 Example N-(2-Methyl-1,2,3,4-tetrahydroisoqulnolin-7-yl)-naphthalene-1-carboxamde 1 H NMR (CDC1 3 8: 2.50 (3H, 2.75 (211, t, J 6 Hz), 2.92 (2H, t, J 6 Hz), 3.66 (2H, 7.12 (1H, d, J 8 Hz), 7.35 (1H, d, J 8 Hz), 7.45 7.70 (5H, 7.75 (1H, d, J 8 Hz), 7.90 (1H, 7.96 (1H, d, J 7 Hz), 8.36 (1H, d, J 8 Hz).
M/z 317.2 100%).
Example 41 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin4-yl)-3.dioro4-metloxybenzamide 1 H NMR (CDC1 3 8: 2.47 (3H, 2.70 (2H, t, J Hz), 2.91 (2H, t, J 6 Hz), 3.59 (2H, 3.97 (3H, 6.99 (1H, d, J 9 Hz), 7.09 (1H, d, J 8 Hz), 7.32 (1H, dd, J 2 and 8 Hz), 7.40 (1H, 7.79 (2H, 7.90 (1H, d, J 2 Hz).
Example 42 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)4-tert-butoxybenzamide 1 H NMR (CDC1 3 8: 1.41 (911, 2.47 (311, 2.71 (2H, t,J 6 Hz), 2.91 (2H, t, J 6 Hz), 3.61 (2H, 7.03 7.12 (311, b 7.30 (1H, dd, J 2 and 8 Hz), 7.43 (1H, d, J 2 Hz), 7.68 (1H, 7.79 (2H, d, J 9 Hz); Iz 339 100%).
Example 43 N-(2-Metlyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-n-propoxybenzamide 1 H NMR (CDCl 3 8:1.01 (3H, t, J 7 Hz), 1.83 (2H, 2.87 (3H, 3.19 (2H, i), 3.44 (211, t,J =7 Hz), 3.61 (2H, 3.87 (2H, 4.40 (2H, 6.93 (2H, 7.09 (1H, 7.51 (1H, dc, J 8, 2 Hz), 7.61 (1H, 7.92 (2H, 8.39 (1H, s).
Example 44 N-(2-Metlyl-1,2,3,4-tetrahydroisoqulnolln-7-yl) mlz 308 WO 98/41508 PCT/GB98/00782 Example N-(2-Methyl-1,2,3,4-tetrahydroLsoquinolin-7-yl)benzotldazole-6-carboxanide IH NMR (CDC1 3 8: 2.48 (3H, 2.72 (2H, t, I 6 Hz), 2.93 (2H, t, J 6 Hz), 3.62 (2H, 7.13 (11H, d, J 8 Hz), 7.34 (111, dcl, J 2 and 8 Hz), 7.45 (1H, d, J 2 Hz), 7.88 (1H, 7.97 (1H, dcl, J 2 and 8 Hz), 8.22 (11H, d, J 8 Hz), 8.56 (1H, d, J 2 Hz), 9.15 (11H, m,/z 322 100%) Example 46 N-(2-Methyl-1,2,3,4-tetraliydroisoquinolin-7-yl)-2,3-diydrobenzofuran-5carboxamide 1 H NMr (CDC1 3 8: 2.48 (3H, 2.73 (2H, t, J 6 Hz), 2.91 (2H, t, J 6 Hz), 3.27 (211, J, 9 Hz), 3.62 (2H, 4.66 (2H, t, J 9 Hz), 6.83 (1H, d, J 8 Hz), 7.08 (1H, d, J 8 Hz), 7.28 (1H, dcl, J1=2 and 8 Hz), 7.42 (111, 7.64 (1H, d, J=8 Hz), 7.76 (2H, in).
Mlz 309 100%).
Example 47 N-(2-Methyl-1,2,3,4-tetrahydrolsoquinolin-7-yl)-2-methylbenzimlddazole-5carboxamlde IH NMR (d4MeOH) 8: 2.51 (3H, 2.61 (3H, 2.92 (2H, t, J 6 Hz), 2.96 (2H, t, J 6 Hz), 3.69 (2H, 7.14 (1H, d, J 9 Hz), 7.47 (311, in), 7.56 (1H, d, J 8 Hz), 7.80 (LH, dd, J 2 and 8 Hz), 8. 10 (111, MIz 321 100%).
Example 48 N-(2-Methyl-1,2,3,4-tetrahydroisoqulnolln-7-yl)-3-chloro-4-iso-propoxybenzamlde III NMR (CDCl 3 8:1.42 (6H. d, J1=6 Hz), 2.49 (3H, 2.74 (2H, J 6 Hz), 2.92 (2H, t, 1=6 Hz), 3.63 (2H, 4.67 (11H, quintet, J1=6 Hz), 6.98 (1H, d, J1=9 Hz), 7.09 (1H, d, J =8 Hz), 7.28 (1H, dd, J 2 and 8 Hz), 7.40 (1H, d, J1=2 Hz), 7.67 7.81 (2H1, bin), 7.88 (111, d, J1=2 Hz); in/z 359 100%).
Example 49 N-(2-Methyl-1,2,3,4-tetrahydrolsoquinolin-7-yl)-3-bromo..4.ethoxybenzamlde 1 H NMR (CDC1 3 8:1.51 (311, t, J1=7 Hz), 2.49 (3H, 2.74 (2H, t, J1=6 Hz), 2.92 (2H1, t. J1= 6Hz), 3.62 (211, 4.17 (2H, q, J 7 Hz), 6.93 (111, d, J1=9 Hz), 7.09 (1H, d, -41 WO 98/41508 PCT/GB98/00782 J 8 Hz), 7.28 (1H, dd, J 2 and 8 Hz), 7.39 (1H, d, J 2 Hz), 7.71 (1H, 7.80 (1H, dcl, J 2 and 9 Hz), 8.05 d, J 2 Hz); mIz 389,391 100%) Example N-(2-Methyl-1,2,3,4-tetrahydrolsoquinoln-7-yl)-3-chloro-4-ethoxybenzamlde 1 H NMR (CDCI 3 8: 1.51 (3H, t, J 7 Hz), 2.49 (3H1, 2.74 (2H1, t, J 6 Hz), 2.92 (2H4, t J 6 Hz), 3.62 (2H1, 4.18 (2H, q, J 7 Hz), 6.96 (111, d, J 9 Hz), 7.09 (1H, d, J 8 Hz), 7.31 (1H, dd, I 2 and 8 Hz), 7.39 (111, d, J 2 Hz), 7.76 (2H, in), 7.89 (1H, d, J1 2 Hiz); mIz 345 100%).
Example 51 N-(2-Metliyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethyI benzamile 1 H NMR (CDC1 3 8: 2.48 (3H, 2.72 (2H, t, J 6 Hz), 2.92 (2H, t, J 6 Hz), 3.60 (2H, 3.98 (311, 7.09 (2H1, mn), 7.32 (1H, dd, J 2 and 8 Hz), 7.41 (1H, d, J 2 Hz), 7.83 (LH, 8.07 in); inIz 365 100%) Example 52 N-(2-Methyl-1,2,3,4-tetrahydroisoquinoin-7-yl)-3,5-dichloro-4-methoxybenzamide
I
1 H NMR (CDCl 3 8: 2.46 (3H4, 2.69 (2H, t, J 6 Hz), 2.90 (2H, t, J 6 Hz), 3.57 (2H, 3.96 O3H, 7.09 (1H, d, J 8 Hz), 7.30 (1H, dd, J 2 and 8 Hz), 7.34 (1H, d, J 2 Hz), 7.81 (2H, 7.89 (111, inlz 365 100%) Example 53 N-(2-Methyl).123,4-tetrahydroisoquinoln-7-y)-3,5.dchloro-4-ethoxybenzamlde 1 H NMR (CDCl 3 6:1.49 (3H, t, J 7 Hz), 2.46 (3H, 2.69 (2H1, t, J 7 Hz), 2.90 (2H, t, J 6 Hz), 3.56 (2H, 4.17 (2H, q, J 7 Hz), 7.09 (1H, d, J 8 Hz), 7.29 (1H, dd, J 2 and 8 Hz), 7.32 (111, 7.80 (211, 7.86 (1H, in/z 379 100%) Example 54 N-(2-Methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5doro-4-wopropoxybenzamide -42- WO 98/41508 PCT/GB98/00782 1 H NMR (CDCl 3 8:1.39 (6H1, d, 1= 6 Hz), 2.47 (311, 2.70 (2H, t, J1=6 Hz), 2.91 (2H, t, J1=6 Hz), 3.59 (2H, 4.72 (1H, quintet, J1=6 Hz), 7. 10 (1H, d, 8 Hz), 7.30 O1H, dd, J 2 and 8 Hz), 7.36 (1H, 7.76 J 2 Hz), 7.80 (2H, s).
m/z 393 100%) Example N-(2-Methyl-1,2,3,4tetrahydrolsoquinolln-7-yl)-3-methylsulfonylbenzamide IH NMR (CDC1 3 8: 2.48 (3H, 2.71 (2H, t, J1=6 Hz), 2.92 (2H, t, J1=6 Hz), 3.12 (3H1, 3.60 (2H, 7.12 (11H, d, J 8 Hz), 7.35 (1H, dd, J 2 and 8 Hz), 7.42 (1H, s), 7.73 011, t, J 8 Hz), 8.05 (1H, 8.11 (1H, d, J 8 Hz), 8.22 (111, d, J 8 Hz), 8.40 (1H, m/z 345 100%) Example 56 N-(2-methyl-1,2,3,4-tetraliydroisoquinolin-7-yl)-3-bromo-4-tert-butylbenzamlde A solution of the amine D5 (162mg; 1.0 mmol) and 3-bromo-4-tert-butylbenzoic acid (257mg; 1.0 mmol) in anhydrous N,N-dimethylformamide (7m1), was treated with 1hydroxybenzotriazole (135mg; 1.0 mmol) and 1-(3-Dimethylaminopropyl)-3ethylcarbodiiniide (192mg; 1.0 mmol) at 25*C. The mixture was shaken for 48h before extracting the product into dichloromethane and washing with 10% aqueous NaHCO3, water and finally brine. The organic layer was dried over MgSO 4 and evaporated in vacuo to afford 373mg of the title compound in 93% yield.
1 H NMR (CDC1 3 8: 1.54 (9H, 2.47 (3H, 2.71 (2H, t, J 6 Hz), 2.91 (2H, t, 1 =6 Hz), 3.60 (2H, 7.10 (111, d, J 8 Hz), 7.31 (11H, dd, J 2 and 8 Hz), 7.41 (111, d, J 2 Hz), 7.54 (111, d, 1 =8 Hz), 7.72 (2H, mn), 8.06 (111, d, 1 =2 Hz).
Example 57 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl).2-bromo-S-methoxybenzamlde 1 H NMR (CDCl 3 8: 2.47 (3H, 2.70 (2H, t, J1=6 Hz), 2.91 (2H1, t, 1 =6 Hz), 3.61 (2H, 3.83 (3H, 6.88 (111, dd), 7.11 (1H, d, J 8 Hz), 7.21 (111, 7.31 (1H, dd, I 2 Hz), 7.44 (1H, 7.50 (1H, 7.71 (1H, m/z 375.0 100%) -43- WO 98/41508 PCT/GR98/00782 Example 58 N-(2-Methyl-1,2,3,4-tetrahydrolsoquinolln-7-yl)-4-fluoro-3-methoxybenzamlde, hydrochloride 1H NMR (free base CDC1 3 8: 2.53 (3H, 2.76 (2H. t, J 6 Hz), 2.97 (2H. t, J 6 Hz), 3.63 (2H, 4.01 (3H, 7.16 (1H, dd, J 6,2Hz), 7.21 (LH, d) 7.32 7.50 O3H, in), 7.64 (1H, dci, J 6, 2Hz), 8.00 (1H, brs); rn/z (APIi): 315.1 100%) Example 59 N.(2-Methyl.1,2,3,4ttrahydroisoqunolin-7-y)--methylpyrazole-4-carboxamlde 1 H NMR (250 MHz, CDCl 3 8: 2.30 (3H, 2.53 (2H, in), 3.40 (2H, 3.78 (3H, s), 6.91 (1H, di, J 8 Hz), 7.11 (1H, in), 7.21 (1H, 7.20 (1H, brs), -7.46 (1H, br), 7.68 (1H, 7.76 (1H, mlz (APIi): 271 100%) Example N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-trifluoromethylpyrazole-3carboxamide.
1H NMR (250 MHz, D 6 DMSO) 8: 2.41 (3H, 2.81 2.85 (4H, mn), 7.13 (1H, d, J 8 Hz), 7.46 (2H, in), 8.64 (1H, in/z 325 100%) Example 61 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin7-yl)-2-methylthiazole-4-carboxaxnide IH NMvR (250 MHz, CDCl 3 8: 2.47 (3H, 2.67 2.76 (5H, mn), 2.89 (2H, mn), 3.60 (2H, 7. 10 (1H, J 8 Hz), 7.40 (1H, cid, J 8, 2 Hz), 7.49 (1H, brs), 8.02 (1H, br), 9.12 (1H, br); in/z (APIi): 288 100%) Example 62 N-(2-Methyl-1,24-tetrahydrosoqunon-7yl)--ethylisoxazole-3-carboxamlde IH NMR (250 MHz, CDCl 3 8: 2.46 (3H, 2.51 (3H, 2.68 (2H, mn), 2.90 (2H, mn), 3.58 (2H, 6.51 (1H, 7. 10 (1H, d, J 8 Hz), 7.33 (Ili. dcl, J 8, 2 Hz), 7.41 (1H, brs), 8.47 (1H, brs); inIz (APIi): 272 100%) -44- WO 98/41508 WO 9841508PCT/GB98/00782 Example 63 N-(2-Methyl-1,3,4.tahydrosoqunon7-yl--te-butylsoxazole-3.
carboxamide 1 H NUR (250 MHz, CDC1 3 8:1.38 (9H, 2.46 (314, 2.66 2.71 (2H, in), 2.89 (2H, in), 3.59 (2H, 6.48 (1H, 7.10 (111, d, J =8 Hz), 7.30 (2H, brd, J 8 Hz), 7.41 (1H, brs), 8.43 (1H, brs); mIz 314 100%) Example 64 N-(2-Methyl-1,2,3,4-tetrahydrolsoqulnolin-7-yl)-.3-methoxylsoxazole-5-carboxamlde hydrochloride 1 H NMR (250 MHz, DMSO-d 6 8: inter alia 2.81 (3H, brs), 3.88 (3H, 7.00 (1H, s), 7.16 (2H, d, J1=8 Hz), 7.52 (2H, mn); mIz 288 100%) Example N-(2-methyl-1,2,3,4-tetrahydroisoquinolin.7-yl)indole-2-carboxaniide.
was converted into the title compound by reaction with indole-2-carboxylic acid, in a similar manner to the procedure of Description 7.
1 H NMR (D 6 DMSO) 5: 2.84 (3H, 3.07 (2H, t, J =6 Hz), 3.29 (2H,t, J 6 Hz), 3.97 (2H, 5.01 (111, in), 7.53 (2H1, mn), 7.70 (211, in), 8.08 (4H, in), 9.90 1H, brs).
m/z 306 100%) Example 66 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-uso-propylbenzamlde, hydrochloride 1 H NMR (free base, CDC1 3 8: 1.26 (6H, d, J 7 Hz), 2.48 (3H1, 2.75 (2H1, mn), 2.90 (2H, mn), 3.41 (1H, sep. J 7 Hz), 3.62 (2H, 7.09 (111, d, J 8 Hz), 7.31 (2H, dd, J 8, 2 Hz), 7.37 (2H, mn), 7.76 (1H, dd, J 8, 2 Hz), 7.90 (1H1, brs), 8.02 (1H, d, J 2 Hz); 1 mIz 387, 389 100%) WO 98/41508 PCT/GB98/00782 Example 67 N-(2-Methyl-1,2,,4-tetrahydrolsoqnon.7-yl)3-cyan-4-iso-propylbenzamde, hydrochloride 1 H NMR (free base, CDC1 3 8:1.25 (6H, d, J 7 Hz), 2.37 (3H, 2.60 (2H, 2.80 (211, 3.45 (1H, Sep, J =7 Hz), 3.62 (2H, 7.00 (1H, d, J 8 Hz), 7.25 (2H, m), 7.41 (1H, 7.97 (1H, dd, J 8, 2 Hz), 8.03 (1H, d, J 2 Hz), 8.10 (1H, brs); m/Z 334 100%) Example 68 N-(2-Methyl-lA,3,4-tetrahydrolsoquinolln-7-yl)-3-fluoro-4-methoxybenzamlde 1 H NMR (250 MHz CDC1 3 8: 2.48 (3H, 2.73 (2H, t, J 6 Hz), 2.92 (2H, t, J 6 Hz), 3.61 (2H, 3.96 (3H, 7.05 (2H, 7.30 (1H, dd, J 6, 2Hz), 7.40 (1H, s), 7.63 (2H, 7.80 (1H, m/z 315.2 100%) Example 69 N-(2-Methyl-1,2,3,4-tetrahydrosoqnolin-7-yl)-3-cyano-4-n-propoxybenzamlde IH NMR (250 MHz CDC1 3 8:1.10 (3H, t, J 8 Hz), 1.92 (2H, 2.47 (3H, 2.70 (2H, t,J 6 Hz), 2.90 (2H, t,J 6 Hz), 3.58 (2H, 4.10 (2H,,J 8 Hz), 7.02 (1H, 7.09 (1H, 7.33 (1H, dd, J 6, 2Hz), 7.38 (1H, 8.02 (1H, 8.08 (2H, i); m/z 350.2 100%) Example N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethoxybenzamlde IH NMR (250 MHz CDCI 3 8: 1.53 (3H, t, J 8 Hz), 2.49 (311, 2.74 (2H, tJ 6 Hz), 2.92 (2H, t, J 6 Hz), 3.62 (2H, 4.23 (2H, q, J 8 Hz), 7.04 (1H, 7.10 (1H, 7.32 (11, dd, J 6, 2Hz), 7.40 (1H, 7.92 (1H, 8.09 (2H, i); m/z 336.2 100%) Example 71 N-(2-Methyl-1,2,3,4-tetrahydrosoquinolin-7-yl)-3-bromo-4-n-propoxybenzainde 1 H NMR (250 MHz CDC1 3 8: 1.10 (311, t, J 8 Hz), 1.90 (2H, 2.46 (311, 2.69 (2H, t, J 6 Hz), 2.90 (211, t, J 6 Hz), 3.58 (2H, 4.05 (2H, t, J 8 Hz), 6.93 (111, d), -46- WO 98/41508 PCT/GB98/00782 7.09 (1H, 7.30 (1H, dd, J 6, 2Hz), 7.39 (1H, 7.72 (1H, 7.80 (1H, dc, J 6, 2Hz), 8.05 (1H, mz 403.1 Example 72 N-(2Methy21,,4 tetrahydrosoquinolin 1 H NMR (250 MHz CDCI 3 8: 1.26 (3H, t, J 8 Hz), 2.46 (3H, 2.69 (2H, t, J=6 Hz), 2.82 (2H, q, J 8 Hz), 2.90 (2H, t, J 6.Hz), 3.59 (2H, 7.10 (1H, 7.28 (1H, dd, J 6, 2 Hz), 7.34 (1H, 7.41 (1H, 7.74 (2H, dd), 8.03 (1Hs); mlz 373.1 100%) Example 73 N-(-Mehyl1,23,4tehahydoisquioli-7dl)--iod-4-ethxybnzaiid IH NMR (250 MHz CDCI 3 8: 2.50 (3H, 2.79 (2H, t J 6 Hz), 2.93 (2H, t, J=6 Hz), 3.64 (2H, 3.94 (3H, 6.85 (1H, 7.21 (1H, 7.08 (1H, 7.34 (1H, dd, J= 6, 2Hz), 7.38 (1H, 7.89 (1H, dd), 8.12 (1H, 8.29 (1H, d); m/ 423.0 100%) Example 74
N-(
2 Metyl13,4teydroisouinoin7-yl)prpoxy 3 -jfl 0 0 e 1 benzamlde 1 H NMR (250 MHz CDC1 3 8:1.39 (6H, d, J 8 Hz), 2.48 (3H, 2.70 (2H, t, J=6 Hz), 2.87 (2H, t, J 6 Hz), 3.54 (2H, 4.72 (1H, 7.06 (2H, 7.30 (1H, dd, J 6, 2Hz), 7.37 (1H, 8.03 (3H, mi/ 393.2 100%) Example N-(-Methyl-1,2,34-tetrahydroisoqoi n-7-yl)c hlo 1 H NMR (250 MHz CDC1 3 8: 2.47 (311, 2.70 (2H, tJ =6 Hz), 2.88 (2H, t,J =6 Hz), 3.59 (2H, 3.98 (311, 7.11 (1H, 7.21 (1H, 7.30 (2H, 7.40 (1H, 7.45 (1H, 7.75 (1H, m/z 331.1 100%) -47- WO 98/41508 WO 9841508PCT/GB98/00782 Example 76 N-(2-Methyl-1,2,3,4-tetrahydrolsoqulnolin.7-yI)-4-ia-propoxy-3-trlfluoromethyI benzamide IH NMR (250 MHz CDC1 3 8:1.08 (3H, t, J 8 Hz), 1.86 (2H, in), 2.46 (3H, 2.70 (2H, t, J 6 Hz), 2.90 (2H, t, J 6 Hz), 3.58 (2H, 4.08 (2H, t, J =8 Hz), 7.07 (2H, in), 7.29 (1H, dd, J 6, 2Hz), 7.41 (1H, 7.97 (1H, 8.03 (1H, d) 8.07 (1H, s); mz 393.2 100%) Example 77 N-(2-Methyl-1,2,3,4-tetrahydrolsoqulnolln-7-yl)-3-chloro-4-tern-butylbenzanlde, hydrochloride IH NMvR (250 MHz, DMSO-d 6 8: inter alia 1.68 (9H, 7.36 (1H, d, J 8 Hz), 7.77 (3H, in), 8.00 (1H, dd, J 8, 2 Hz), 8.11 (1H, d, J 2 Hz); mz 357 100%) Example 78 N-(2-Methyl-1,2,3,4-teftrhydroisoquinolin-7-y)-4-methoxybenzamide hydrochloride.
was converted into the title compound in 95% yield by reaction with 4methoxybenzoyl chloride in a manner similar to that described in Example 3.
1 H NMR (1)20) 8: 3.13 (3H, 3.25 (2H, brs), 3.68 (2H, brs), 3.96 (3H, 4.48 (2H, brs), 7.15 (2H, d, J =9 Hz), 7.35-7.50 (3H, in), 7.90 (2H, d, J1=9 Hz).
Example 79 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-fluoro-3-methylbenzanlde, hydrochloride IH NMR (free base CDC1 3 8: 2.34 (3H, 2.46 (3H, s) 2.69 (2H, t, J 6 Hz), 2.90 (2H, t, 1=6 Hz), 3.58 (2H, 7.08 (2H,mi), 7.30 (1H, dd), 7.40 (1H,d, ),7.60 -7.80 (2H, in), 7.74 (1H, in/z 299.2 100%) -48 WO 98/41508 PCT/GB98/00782 Example -(2Methyl 1;2 ,tetrahydrooquinolin-7y3 lo 4sppinn 1 H NMR (free base 250 MHz CDC1 3 8: 1.40 (6H, d, J 7 Hz), 2.59 (3H, 2.82 (2H, 3.03 (2H, 3.58 (LH, sep, J 7 Hz), 3.71 (2H, 7.23 (1H, d, J 8 Hz), 7.42 (1H, dd, J 8, 2 Hz), 7.53 (2H, 7.82 (2H, 7.96 (1H, d, J 2 Hz); m/ (API): 343, 345 100, Example 81 N-(2-Methyl-1,2,3,4-tetrahydrolsoquinolln.7.yl).3-cyano4-etlyenzamlde hydrochloride 1H NMR (free base 250 MHz, CDC1 3 8: 1.31 (3H, t, J 8 Hz), 2.43 (3H, 2.66 (2H, 2.90 (4H, 3.55 (2H, 7.09 (1H, d, J 8 Hz), 7.28 (2H, dd, J 8, 2 Hz), 7.36 (1H, brs), 7.44 (1H, d, J 8 Hz), 7.86 (1H, brs), 8.00 (1H, dl, J 8, 2 Hz), 8.09 (1H, d, J 2 Hz); T/z 320 100%) Example 82 N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin.7.yl).4..wo-propyl.3..triruorometyl.
benzamlde hydrochloride 1 H NMR (free base 250 MHz, CDC1 3 8: inter alia 1.38 (6H, d, J 6 Hz), 2.32 (311, s), 2.57 (2H, 2.76 (2H, 3.25 (lH, 3.45 (2H, 6.95 (1H, d, J 8 Hz), 7.16 (1H, brd, J 8 Hz), 7.26 (1H, brs), 7.43 (1H, d, J 8 Hz), 7.72 (LH, brs), 7.84 (1H, d, J 8 Hz), 7.93 (1H, brs); mlz 377 100%) Example 83 N-(2-Methyl.1,2,3,4-tetrahydroisoquinoln-7-yl).4-ethyl.3trlfluoromethylbenzamlde hydrochloride 1 H NvR (free base 250 MHz, CDC1 3 8: inter alia 1.25 (311, t, 1 8 Hz), 2.46 (3H. s), 2.68 (2H, 2.90 (2H, 3.58 (2H, brs), 7.10 (LH, d, J 8 Hz), 7.30 (1H, dd, J 8, 2 Hz), 7.47 (1H, d, J 8 Hz), 7.40 (1H, brs), 7.78 (1H, brs), 7.97 (1H, dd), 8.08 (1H, brs); m/z 361 100%) -49- WO 98/41508 PCT/GB98/00782 Example 84 N.(2-Methyl-1,2,3,4-tetrahydrosoquinoin-y1).3-cyano-4-aso-propoxybenzandde hydrochloride 1 H NMR (250 MHz CDC1 3 5:1.45 (6H, d, J 8 Hz), 2.47 (3H, 2.70 (2H, t, J 6 Hz), 2.91 (2H, t, J 6 Hz), 3.59 (2H, 4.75 (1H, 7.04 (1H, 7.10 (1H, 7.29 (1H, dd, J 6, 2Hz), 7.37 (1H, 7.71 (1H, 8.05 (2H, m); m/Z 350.2 100%) Example N-(1,2,3,4-Tetrahydroisoquinolin-7-yl)-4-methoxy-3-trlfluoromethylbenzanlde 1 H NMR (250 MHz CDCl 3 8: 2.65 (2H, t,J 6 Hz), 3.00 (2H, L J 6 Hz), 3.85 (3H, 3.89 (2H, 6.95 (2H, 7.17 (1H, cd, J 6, 2Hz), 7.25 (1H, 7.57 (1H, 7.93 (2H, m/z 351.1 100%) Example 86 N-(2-Methyl-1,2,3,4-tetrahydroisoqunolin-7yl)4-mehyl.3-methylsulfonylbenzamide 1 H NMR (CDCI 3 8: 2.48 (3H, 2.71 (2H, t J 7 Hz), 2.80 (3H, 2.92 (2H, t, J 7 Hz), 3.15 (3H, 3.61 (2H, 7.13 (2H, 7.35 (LH, dd), 7.43 (1H, 7.52 (1H, d), 7.93 (1H, 8.14 (1H, dc), 8.45 (LH, m/z 359.2 100%) Example 87
N-(
2 -Methyl-1,2,3,4tetrahydroisoquinolin-7-yl)-4-ethyI.3-methylsulfonylbeinzJde 1 H NMR (CDC1 3 8:1.49 (3H, t,J 8 Hz), 2.59 (3H, 2.81 (2H, t, J 7 Hz), 3.03 (2H, t, J =7 Hz), 3.27 (5H, 3.71 (2H, 7.23 (2H, 7.46 (1H, dc), 7.54 (1H, d), 7.69 (1H, 8.04 (1H, 8.29 (1H, dc), 8.55 (1H, mIz 373.2 100%) Example 88 N-(2Methyl2,,4tetrahydrosoquinolin-7 propylbeuzamide IH NMR (CDCl 3 5: 1.27 (6H, d, J 8 Hz), 2.37 (3H, 2.60 (2H, t,J =7 Hz), 2.81 (2H, t, 3 =7 Hz), 3.06 (3H, 3.46 (2H, 3.85 (LH, 7.00 (2H, 7.26 (1H, dc), 7.31 (1H, 7.57 (1H, 8.10 (1H, dc), 8.21 (1H, 8.37 (1H, d); WO 98/41508 PCTIGB98/00782 387.2 100%) Example 89 N-(2-Metlyl-1,2,3,4-tetrahydrolsoquinoln-7-yl)-3-methylsulfonyl-4methoxybenzamide 1 H NMR (CDCl 3 8: 2.31 (3H, 2.54 (2H, t, J 7 Hz), 2.75 (2H, t, J 7 Hz), 3.09 (3H, 3.42 (2H, 3.87 (3H, 6.95 (2H, 7.12 (11, 7.21 (1 H, 8.08 (211, i), 8.23 (11, mIz 375.2 Example N.(2-Methyl-1,2,3,4-terahydroisoquinolin-7-yl)-3-trifluoroacetylbenzamide, hydrochloride 1H NMR (free base CDC1 3 8: 2.47 (3H, 2.46 (3H, s) 2.77 (2H, t, J 6 Hz), 2.94 (2H, t, J 6 Hz), 3.63 (2H, 7.13 (11, d, J 6 Hz), 7.45 (1H, d, J 6 Hz), 7.54 (11, t, J 6 Hz), 7.81 (11, d, J 6 Hz), 7.97 (11, d, J 6 Hz); 8.20 (11, s); m/z 363.2 Example 91 N-(2-Methyl-1,2,3,4-tetrahydrosoquinolin-7-yl)-4-methoxy-3-pentafluoroetbylbenzamlde hydrochloride 1H NMR (free base 250 MHz, CDC1 3 8: 2.46 (3H, 2.70 (2H, 2.90 (2H, 3.59 (211, 3.94 (311, 7.10 (211, 7.30 dd, J 8, 2Hz), 7.39 (11, brs), 7.73 (1H, brs), 8.01 (11, d, J 2 Hz), 8.06 (1H, dl, J 9, 2 Hz); m/z 415 100%) Example 92 N-(Zn-nPropyl-1,2,3,,4tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamlde 1 H NMR (CDC1 3 8: 0.95 (3H, t, J 7 Hz), 1.51 (3H, t,J 7 Hz), 1.62 (2H, 2.47 (2H, t, J 8 Hz), 2.72 (211, t, J 6 Hz), 2.88 (211, t, J 6 Hz), 3.61 (2H, 4.17 (211, q, J 7 Hz), 6.92 (111, d, J 9 Hz), 7.07 (111, d, J 8 Hz), 7.26 (1H, dd, J 8, 2 Hz), 7.39 (11, d, J 2 Hz), 7.72(111, brs), 7.79 (1H, dd, J 9, 2 Hz), 8.04 (11, d, J 2 Hz).
m/z 417,419 -51- WO 98/41508 WO 9841508PCT/GB98/00782 Example 93 N-(2-n-ropyl-1,3,4tetrahydrolsoqunoln-7-y)-4-methoxy-3trifluoromethylbenzamide 1 H NMR (CDC1 3 8: 0.96 (3H, t, J 7 Hz), 1.61 (2H, in), 2.47 (2H, t, J 8 Hz), 2.73 (2H, t, J 6 Hz), 2.88 (2H, t, J 6 Hz), 3.62 (2H, 3.98 (3H, 7.08 (2H, in), 7.30 (1H, in), 7.41 O1H, d, J 2 Hz), 7.76 (11H, brs), 8.05 (2H, in); inIz 393 (MH+; 100%) Example 94 N-(2-n..Propyl-1,2,3,4-tetrahydroisquinolin-7-yl)-3-chloro-4-iso-propoxybenzamlde 1 H NMR (CDC1 3 5: 0.95 (3H, t, J 7 Hz), 1.42 (6H, d, J 6 Hz), 1.62 (2H, mn), 2.48 (2H, t, J 8 Hz), 2.73 (2H, t, J 6 Hz), 2.88 (2H, t, J 6 Hz), 3.63 (2H, 4.66 (1H, sept, J 6 Hz), 6.98 (1H, d, J=9 Hz), 7.08 (1H, d, J1=8 Hz), 7.26 (1H, in), 7.41 (1H, d, J 2 Hz), 7.65 (1H, brs), 7.73 (1H, dcl, J 9, 2 Hz), 7.87 (1H, d, J 2 Hz).
inlz 387 Example N-(2-Metliyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-butylbenzamlide hydrochloride 1 H NMR (250 MHz, DMSO-d 6 8: inter alia 0.95 (6H, d, J1=7 Hz), 1.99 (1H, sep, J =7 Hz), 2.77 (2H, brs), 7.26 (1H, d, J 8 Hz), 7.65 (3H, in), 8.21 (1H, dcl, J 8, 2 Hz), 8.41 (111, d, J =8 Hz); in/z 348 100%) Example 96 N-(2-Methyl-1,2,3,4-tetrahydroisoquinoln-7yl)-4-iso-butyl-3-trifluoromethylbenzamlde hydrochloride IH NMR (250 MHz, DMSO-d 6 8: inter alla 1.0 1 (6H, d, J 6.5 Hz), 2.09 O1H, sep. J Hz), 7.35 (1H, d, J 8 Hz), 7.75 (3H, in), 8.32 (1H, d, J 8 Hz); m/z 391 100%) -52 WO 98/41508 PCT/GB98/00782 Example 97 N-(2-Ethyl-1,2,3,4-tetrahydrolsoquinolln.7.yl)-3.bromo-4-ethoxybemamlde 1 I NMR (CDC1 3 5:1.20 (3H, t, J 7 Hz), 1.51 (3H, t, J 7 Hz), 2.61 (2H, q, J 7 Hz), 2.76 (2H, 2.90 (2H, 3.64 (2H, 4.16 (2H, q, J 7 Hz), 6.91 (1H, d, J 9 Hz), 7.07 (1H, d, J 8 Hz), 7.26 (1H, 7.40 (1H, d, J 2 Hz), 7.79 (2H, 8.05 (1H, d, J 2 Hz); mz 403,405 Example 98 N-(2-Ethyl-1,23,4tetrahydro-isoqunolin-7yl)-4methoxy-3-trifluoromethyI benzamide 1 H NMR (CDC1 3 8:1.21 (311, t, J 7 Hz), 2.65 (2H, q, J 7 Hz), 2.80 (2H, d, J 6 Hz), 2.92 (2H, t, J 6 Hz), 3.67 (2H, 3.97 (3H, 7.07 (2H, 7.30 (1H, 7.41 (LH, d, J 2 Hz), 7.89 (1H, brs), 8.06 (2H, inI 379 100%) Example 99 N-(2-iso-Propyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide 1 H NMR (CDCl 3 5:1.13 (6H, d, i 7 Hz), 1.51 (3H, tJ 7 Hz), 2.84 (5H, 3.71 (2H, 4.16 (2H, q, J 7 Hz), 6.91 (1H, d, J 9 Hz), 7.06 (1H, d, J 8 Hz), 7.25 (1H, 7.42 (1H, d, J 2 Hz), 7.78 (2H, 8.04 (1H, d, J 2 Hz).
m/z 419 Example 100 N-(24w-Propyl-1,2,3,4-tetrahydroisoquinolin-7-y)-4-methoxy-3-trrnuoromethyI benzamide 1 H NMR (CDC1 3 5:1.13 (6H, d, J 7 Hz), 2.84 (5H, 3.72 (2H, 3.97 (311, s), 7.07 (2H, 7.26 (1H, 7.43 (1H, d, J= 2 Hz), 7.83 (1H, brs), 8.04 (2H, m) m/z 393 100%) -53- WO 98/41508 PCT/GB98/00782 Example 101 N-(2-Methyl-1,2,3,4-tetrahydrolsoquinoin-7-yl)-4-ethoxy-3-methylsulfonyl.
benzamlde 1H NMR (CDCl 3 8:1.52 (3H, t, J 8 Hz), 2.46 (3H, 2.69 (2H, t, J 7 Hz), 2.90 (2H, t, J 7 Hz), 3.26 (3H, 3.57 (2H, 4.27 (2H, q, J 7 Hz), 7.09 (2H, dd), 7.36 (1H, dd), 7.42 (1H1, 7.83 (1H, brs), 8.12 (1H, 8.20 (1H, dcl), 8.37 (1H, d); Mz 389.2 100%) Example 102 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-oxochroman-6-carboxamide hydrochloride 1 H NMR (D 6 DMSO) 8: 2.63 (3H, narrow 3.02 (2H, t, J 7Hz), 3.14 (2H, brm), 3.60 (2H, brm), 4.54 (2h, brs), 4.77 (2H, d, J 7 Hz), 7.25 (1H, in), 7.31 (1H, d, J 8 Hz), 7.44 (2H, d, J 6 Hz), 8.20 (1H, dcl, J 8, 2 Hz), 8.59 (1H, d, J 2 Hz), 10.31 (1H, 10.95 (1H, brs); ni/z 337.4 100%) Example 103 N-(2-Formyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3trifluoromethylbenzamlde 7-Amino-2-formyl- 1,2,3,4-tetrahydroisoquinoline 176g) was converted into the title compound by reaction with 4-methoxy-3-trifluoromethylbenzoyl chloride, following the procedure of Example 3. The product was isolated as a white solid (0.035g).
IH NMR (d 6 -DMSO) 8: 2.80 (2H, in), 3.65 (2H, broad 4.00 (3H1, 4.59 (211, d), 7.17 (11, d, J 8 Hz), 7.45 (11, d, J 8 Hz), 7.60 (2H1, in), 8.26 (311, in), 10.30 (111, s).
in/z 379 Example 104 N-(2-Hydroxyethyl-1,2,3,4tetraliydroisoquinolin-7-yi)-3-bromo-4-etioxybenzanlde The compound D16 (115mg; 0.22 inmol) was dissolved in THF with stirring and tetrabutylainmonium fluoride (1 M in THF; 0.216 minol) added. Thbe reaction was stirred overnight and the mixture purified by column chromatography through SiC), eluting with methanol~ichloromethane. Trituration with petroleum ether, gave the title compound (48mg; 49%).
-54- WO 98/41508 PCT/GB98/00782 1H NMR (250 MHz, CDCI 3 8:1.51 (3H, t, J 7 Hz), 2.77 (2H, t, J 5 Hz), 2.90 (4H, m, overlapping signal), 3.74 (4H, m, overlapping signal), 4.17 (2H, q, J 7 Hz), 6.93 (1H, d, J 10 Hz), 7.10 (1H, d, J 8 Hz), 7.36 (1H, dd, J 8, 2 Hz), 7.48 (1H, d, J 2 Hz), 7.87 (1H, dd, J 9, 2 Hz), 7.97 (1H, 8.08 (1H, d, J= 2 Hz) Example 105 N-(2-Hydroxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide The title compound was prepared in 40% overall yield from D15 in.a manner similar to that of Descriptions 16 and Example 106.
1 H NMR (250 MHz, CDCl 3 8: 2.77 (10H, m, overlapping signals), 3.68 (5H, m, overlapping signals), 7.08 (1H, d, J 8 Hz), 7.30 (2H, m, overlapping signals), 7.48 (1H, d, J 2 Hz), 7.75 dd, J 8, 2 Hz), 8.02 (1H, d, J 2 Hz), 8.17 (1H, s).
Example 106 N-(2-Methyl-1,2,3,4-tetrahydrolsoquinolin-7-yl)-4-phenylmethoxy-3-trifluoromethy benzamide 1 H NMR (CDCI 3 8: 2.50 (3H, 2.75 (2H, t, J 6 Hz), 2.94 (2H, t, J 6 Hz), 3.64 (2H, 7.10 (2H, d, J 8 Hz), 7.30 7.60 (7H, m, overlapping), 7.70 (1H, brs), 8.04 (1H, dd, J 8, 2 Hz), 8.10 (1H, d, J 2 Hz); m/z 441.2 100%) Example 107 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-hydroxy-3-trifluoromethy benzamide m/z 351.1 100%) Example 108 N-(2-Methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-Isopropoxybenzamide 1 H NMR (250 MHz, CDC13) 8: 1.41 (6H, d, J= 6 Hz), 2.75 (4H, t, overlapping, J 6 Hz), 2.83 (2H, d, J 5 Hz), 3.39 (3H, 3.61 (4H, t, overlapping, J 6 Hz), 4.64 WO 98/41508 WO 9841508PCT/GB98/00782 6.91 OlH, d, J 9 Hz), 7.01 (1H, d, J 8 Hz), 7.20 (1H, dd, J 8, 2 Hz), 7.29 (OH, d, J 2 Hz), 7.80 O1H, dd, J 9, 2 Hz), 8.07 (1H, d, J 2 Hz), 8.10 (1H, s); m/z 447,449 Example 109 N-(2-Methoxyethyl-1,2,3,4-tetrahydrosoqunon-7-y).3-hldoro-4-Wopropoxybenzamide 1 H NMR (250 MHz, CDCl 3 8:1.41 (6H, d, J 6 Hz), 2.75 (4H, t, overlapping, J 6 Hz), 2.83 (2H, d, J 5 Hz), 3.39 (3H, 3.61 (4H, t, overlapping, J 5 Hz), 4.64 (1H, in), 6.94 (1H, d, J 9 Hz), 7.01 (1H, d, J =8 Hz), 7.20 (1H, d, J 8 Hz), 7.30 (1H, s), 7.75 (1H, dd, J =9,2 Hz), 7.90 (1H, d, J =2 Hz); m/z 403,405 (MH+) Example 110 N-(2-Methoxyethyl123,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3trifluoromethylbenzamide 1 H NMR (250 MHz, CDCI 3 8: 2.75 (4H, in), 2.85 (2H, d, J 5 Hz), 3.39 (3H, 3.61 (4H, t, overlapping), 3.96 (3H, 7.04 (2H, mn), 7.25 (1H, d, J 10Hz), 7.35 (1H, s), 8.07 O3H, in); m/z (APIi): 409 (MH-i, 100%) Example 111 N-(2-t-Butyloxycarbonyl-54odo1,2,3,4-tetrahydroisoquinoif-7-yl)- 4 azidobenzamide The title compound was prepared in 8 1% yield from the acid Preparation 28 and amine D6.
N.(5-Iodo-123,4-tetrahydroisoquinolin-7-y)-4azidobeflzamide, trilluoroacetate.
The title compound was prepared in 9 1% yield from using a method similar to that of Example 1.
Intz 420 (MH 4 100%).
-56- WO 98/41508 WO 9841508PCTIGB98/00782 Example 112 N-42-Methyl-5-trifluoroacetylamidno-1,2,3,4-tetrahydroisoqunoin-7-y)-3-bromo-4methoxybenzamlde The title compound (0.66g) was prepared f romn D25 (0.50g) and 3-bromo-4methoxybenzoic acid (0.63g) using a procedure similar to that of Description 7.
4, rfl/z (CIU: 486,488 Example 113 N-(2-Methyl-5-chloro-1,2,3,4-tetrahydroisoquinoln-7-y)-3-bromo-4ethoxybenzamide mIz 425 (MH 4 expected isotope pattern).
Example 114 N-42-Methyl-S-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide 1 H NMR (CDCl 3 1.25 (3H, t, J =7Hz), 2.48 (3H, 2.70-3.00 (6H, m, overlapping signals), 3.59 (2H, 7.29 (LH, d, J =2Hz), 7.33 (1H, d, J 7Hz), 7.51 (1H, d, J 2Hz), 7.71 (1H, dd, J 7,2Hz), 7.83 (1Hbrs), 8.01 (1H,dJ 2H1z); m/z 409 (MH+; expected isotope pattern).
PHARMACOLOGICAL DATA 1. Binding Assay Method WO 92/22293 (Smidtdine Beecham) discloses compounds having anti-convulsant activity, including inter alia the compound trans-(+)-6-acetyl-4S-(4-fluorobenzoylainino)- 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-oI (hereinafter referred to as Compound It has been found that the compounds of WO 92/22293 bind to a novel receptor obtainable from rat forebrain tissue, as described in WO 96/18650 (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 The homogenised tissue is washed by centrifugation and resuspension in the same buffer, then stored at -70 0 C until used.
-57 WO 98/41508 PCT/GB98/00782 To carry out the radioligand binding assay, aliquots of tissue prepared as above (usually at a concentration of 1-2mg-protein/ml) are mixed with aliquots of [3H]-Compound A dissolved in buffer. The final concentration of [3H]-Compound A in the mixture is usually 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 GF/B 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.
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 that present in the absence of unlabelled compound) to obtain the amount of "specific" binding of [3H]-Compound A to the novel site.
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 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. For example, compounds of Examples 1, 4, 5, 6, 7, 10 and 13 gave pKi values greater than 7.
2. MEST Test The maximal electroshock seizure (MEST) threshold test in rodents is particularly sensitive for detecting potential anticonvulsant propertiesl. In this model, anticonvulsant agents elevate the threshold to electrically-induced seizures whilst proconvulsants lower the seizure threshold.
-58- 1. WO 98/41508 PCT/GB98/00782 Method for mouse model Mice (naive male, Charles River, U.K. 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 (0.3 300 mg/kg) or vehicle. Mice are then subjected at 30 or min post dose to a single electroshock (0.1 sec, 50Hz, sine wave form) administered via corneal electrodes. The mean current and standard error required to induce a tonic seizure in 50% (CC 5 0 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 vehicleand drug-treated groups are made using the method of Litchfield and Wilcoxon (1949)3.
In control animals the CC 5 0 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.
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.
Results Compounds of this invention dosed at 10 mg/kg by the oral route as a suspension in methyl cellulose and tested one hour post dosing showed an increase in seizure threshold.
For example, the compounds of Examples 4, 5, 6 and 7 show increases of 24%, 36%, and 23% respectively.
Method for rat model The threshold for maximal (tonic hindlimb extension) electroshock seizures in male rats (Sprague Dawley, 80 150g, 6 weeks old) was determined by a Hugo Sachs Electronik stimulator which delivered a constant current (0.3 sec duration; from 1-300mA in steps of 5-20mA). The procedure is similar to that outlined above for mouse and full details are as published by Upton et al,.
4 The percentage increase or decrease in CC 5 0 for each group compared to the control is calculated.
-59- P:OPER\MKR\SPEC64128-98 197.doc-I/07/01 Drugs are suspended in 1% methyl cellulose.
Results At a dosage of 2 mg/kg p.o. at 2h, the compounds of Examples 48, 49, 51 and 67 show increases of 389%, 325%, 545% and 303% increases respectively.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will 10 be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
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, 99-113 4. N. Upton, T.P. Blackburn, C.A. Campbell, D. Cooper, M.L. Evans, H.J. Herdon, P.D. King, A.M. Ray, T. O. Stean, W. N. Chan, J.M. Evans and M. Thompson.
(1997). B. J. Pharmacol., 121, 1679-1686

Claims (6)

1. A compound of formula or a pharmaceutically acceptable salt thereof: where Q is a monocyclic or bicyclic aryl or heteroaryl ring, R' is hydrogen, C 1 -6allcyl (optionally substituted by hydroxy or C 1 4 alkoxy) or C 1 -C 6 alkylSO 2 R 2is hydrogen, hydroxy or up to three substituents selected from halogen, NO 2 CN, N 3 CF 3 CF 3 CF 3 CO-, trifluoromethyldiazirinyl, C 1 6 alkyl, C 1 6 alkenyl, C 1 6 alkynyl, C 1 6 perfluoroalkyl, C 3 6 cycloalkyl, C 3 6 cycloalkyl-C I 4alkyl-, C 1 6 alkylO-, C I 6 alkylCO-, C 3 6 cycloalkylO-, C 3 6 cycloalkylCO-, C 3 6 cycloalkyl-C 1 I 4 alkylO-, C 3 6 cycloalkyl-CI 1 4 alkylCO-, acetoxy, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C I 4 alkyl-, C 1 6 alkylS-, C I 6 alkylSO 2 (C 1 4 alkyl) 2 NS0 2 (C I 4 alkyl)NHSO 2 (C 1 4 alkyl) 2 NCO- (C 1 4 alkyl)NHCO- or CONH 2 or -NR 3 R 4 where R3is hydrogen or C 1 4 alkyl, and R4is hydrogen, C 1 4 alkyl, formyl, -CO 2 C I 4 alkyl or -COC 1 .I 4 alkyl; or two R 2groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by -OH or =0; and X is hydrogen, halogen, C 1 6 alkoxy, C 1 alkyl, amino or trifluOrOacetylaniino; 62 but excluding the compound 7-(3,4,5-trimethoxybenzamido)-2-methyl- 1,2,3,4- tetrahydroisoquinoline and compounds in which Q is phenyl and R 2 is 2-alkoxy.
2. A compound according to claim 1 of formula (LA) or (IB): N NHCO (IA) R X S N NHC 1/ 00 2
4. 4 X (IB) wherein R 1 R 2 and X are as defined in claim 1. 3. A compound selected from the group consisting of: N41 2 3 4 t t r h d o s q i ol n74 45 c h o o h o h n -2 c r o a i d N-(2-ehl 1, 3, 4-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-xnd carboxamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)benzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-chlorobenzarnide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-t-butylbenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propoxybenzamide N-(2-methyl- I ,2,3,4-tetrahydroisoquinolin-7-yI)-4-phenoxybenzaniide N-(2-methyl- I ,2,3,4-tetrahydroisoquinolin-7-yl)-4-nitrobenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-phenylbenzamide N-(2-methyl- I ,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylbenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluorobenzanide N-(2-methyl- I ,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyanobenzaniide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dichlorobenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-iodobenzaxnide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-bromobenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methylbenzamide N-(2-methyl- 1 ,2,3,4-tetrabydroisoquinolin-7-yl)-3-nitrobenzamide 63 N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)-4-ethoxybenzanide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-n-butylbenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-2-acetoxybenzanide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-trifluoromethylbenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)-2,4-difluorobenzainide N-(2-methyl- I ,2,3,4-tetrahydroisoquinolin-7-yI)-3,4-dimethoxybenzamnde N-(2-methyl- I ,2,3,4-tetrahydroisoquinolin-7-yl)-2-fluoro-4-trifluoromethy benzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-chloro-3-nitrobenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-di-trifluoromethylbenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)-2,4-dichloro-5-fluorobenzamide :0@.:N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)-3-fluoro-5-trifluoromethy benzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)-3-bromo-4-methoxybenzanide N-2mty-,,34ttayrisqioi-0 0-rfurmthxbnand ~N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-trifloolemethxyenz N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-y)-3-bromo-4-iso- propoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)-4-acetoxybenzamide N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yI)-4-cyclopentyloxybenzamiide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)-4- cyclopropylmethoxybenzamide N-(2-Methyl- 1,2,3 ,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-methoxybenzamide N-(2-Methyl- 1,2,3 ,4-tetrahydroisoquinolin-7-yl)-2-naphthaniide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methybenzarmide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-naphthalene- 1 -carboxanude N-(2-Methyl-1I,2,3,4-tetrahydroisoquinolin-7-yI)-3-chloro-4-methoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-tert-butoxybenzamide N-(2-Metbyl-1I,2,3,4-tetrahydroisoquinolin-7-yI)-4-n-propoxybenzamide N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl) N-(2-Methyl-1I,2,3,4-tetrahydroisoquinolin-7-yl)benzothiazole-6-carboxamide N-(2-Methyl- 1,2,3 ,4-tetrahydroisoquinolin-7-yl)-2,3-dihydrobenzofuran-5- carboxamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylbenzimidazole-5- carboxamide -64- N-(2-Methyl- 1 ,2,3,4-tetrabydroisoquinolin-7-yl)-3-chloro-4-iso- propoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide N-(2-Methyl- I ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)-3,5-dichloro-4- methoxybenzamide N-(2-Methyl)- 1 ,2,3,4-tetrabydroisoquinolin-7-yl)-3,5-dichloro-4- ethoxybenzamide N-(2-Methyl)- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)-3 ,5-dichloro-4-iso- propoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylsulfonylbenzainide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-tert-butylbenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)-2-bromo-5-methoxybenzaxnide N-(2-Methyl- I ,2,3,4-tetrahydroisoquinolin-7-yl)-4-fluoro-3-methoxybenzamide, hydrochloride N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)- I -methylpyrazole-4- N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-trifluoromethylpyrazole-3- carboxamide N-2MtyC.....erhyriounli--l--etytizl---abxmd ~~N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)-2-methyltioazole--abxmd carboxamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-5-tert-butylisoxazole-3- carboxamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-methoxyisoxazole-5- carboxamide hydrochloride N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)indole-2-carboxamide. N-(2-Methyl- I ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-iso- propylbenzamide, hydrochloride N-(2-Methyl- I ,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propylbenzamide, hydrochloride 65 N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)-3-fluoro-4-methoxybenzanide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-n-propoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethoxybenzamide N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-n-propoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-iodo-4-methoxybenzanmide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propoxy-3-trifluoromethyl benzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)-4-chloro-3-methoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-n-propoxy-3-trifluoromethyl benzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-tert-butylbenzamide, hydrochloride N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxybenzamide hydrochloride. N-(2-Methyl- 1,2,3 ,4-tetrahydroisoquinolin-7-yl)-4-fluoro-3-methylbenzamide, hydrochloride N-(2-Methyl- I ,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-iso-propylbenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)-3-cyano-4-ethylbenzamide hydrochloride N-(2-Methyl- I ,2,3,4-tetrahydroisoquinolin-7-yI)-4-iso-propyl-3-trifluoromethyl- benzamide hydrochloride N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethyl-3- trifluoromethylbenzamide, hydrochloride N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso- propoxybenzamnide hydrochloride 1,2,3,4-Tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methyl-3-methylsulfonyl- benzaxnide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethyl-3- methylsulfonylbenzamide N-(2-Methyl- I ,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylsulfonyl-4-iso- propylbenzamnide 66 N-(2-Methyl- I ,2,3,4-tetrahydroisoquinolin-7-yI)-3-methylsulfonyl-4- methoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-trifluoroacetylbenzamide, hydrochloride N-(2-Methyl- I ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-pentafluoroethyl- benzamide hydrochloride N-(2-n-Propyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)-3-bromo-4-ethoxybcnzamide N-(2-n-Propyl- I ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3- trifluoromethylbenzamnide N-(2-n-Propyl-l1,2,3,4-tetrahydroisquinolin-7-yI)-3-chloro-4-iso- N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-butylbenzamide see: hydrochloride N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-butyl-3-trifluoromethyl- benzamide hydrochloride N-(2-Ethyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide N-(2-Ethyl- 1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-4-methoxy-3-trifluoromethy benzamide N-(2-iso-Propyl- 1,2,3 ,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzanide N-(2-iso-Propyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethy benzamide N-(2-Methyl- 1,2,3 ,4-tetrahydroisoquinolin-7-yl)-4-ethoxy-3-methylsulfonyl- benzamide N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4-oxochroman-6-carboxamide hydrochloride N-(2-Formnyl-- I ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3- trifluoromethylbenzarnide N-(2-Hydroxyethyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4- ethoxybenzamide N-(2-Hydroxyethyl- I ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4- ethylbenzarnide N-(2-Methyl- I ,2,3,4-tetrahydroisoquinolin-7-yl)-4-phenylmethoxy-3- trifluoromethyl benzamide -67- N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-hydroxy-3-trifluoromethy benzamide N-(2-Methoxyethyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-iso- propoxybenzamide N-(2-Methoxyethyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yI)-3-chloro-4-iso- propoxybenzamide N-(2-Methoxyethyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3- trifluoromethylbenzamide N-(5-Iodo-1I,2,3,4-tetrahydroisoquinolin-7-yl)-4-azidobenzamide, trifluoroacetate N-(2-Methyl-5-trifluoroacetylamino- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo- 4-methoxybenzamide 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4- ethoxybenzaniide 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4- ethylbenzamnide 4. 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 ***e, 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 ischaemnia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AID)S, sleep disorders (including circadian rhythm disorders, insomnia narcolepsy), tics 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 aniyotrophic lateral sclerosis (ALS) which comprises a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically R A acceptable carrier. -68- 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 ***e, 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 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) comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof.
6. Use of a compound according to any one of claims 1 to 3, 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 ***e, 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 Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate -69- 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)
7. A process for the preparation of a compound according to any one of claims 1 to 3, which comprises reacting a compound of formula (II) p 0Spp S p S PUS 4 p p 0 *S 4 S -NH 2 where RIA is R 1 as defined for formula or a group convertible to R1 and X is as defined in claim 1 with a compound of formula (III) OY Q 2A where Q is as defined in formula Y is Cl or OH, and R2A groups are independently R 2 as defined for formula or groups convertible to R 2 and where required converting an R1A or R 2 A group to a R 1 or R 2 group, converting one R 1 or R 2 group to another R 1 or R 2 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. P:\OPERWNKRSPECI\6428.98 197.doc.I6107/01 70
8. A compound according to claim 1, substantially as hereinbefore described with reference to the examples. DATED this 16th day of July, 2001 SmithKline Beecham plc By DAVIES COLLISON CAVE Patent Attorneys for the Applicant
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