WO1999052857A1 - Novel compounds - Google Patents

Abstract

Compounds of formula (I) or pharmaceutically acceptable salt thereof where the broken circle is a monocyclic or bicyclic aryl or heteroaryl ring; n and p are independently integers from 1 to 4 and (n+p) is from 2 to 5; R is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3O-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6perfluoroalkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl-, C1-6alkylO-, C1-6alkylCO-, C3-6cycloalkylO-, C3-6cycloalkylCO-, C3-6cycloalkyl-C1-4alkylO-, C3-6cycloalkyl-C1-4alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-, C1-6alkylS-, C1-6alkylSO2-, (C1-4alkyl)2NSO2-,(C1-4alkyl) and HSO2-, (C1-4alkyl)2, and CO-, (C1-4alkyl)NHCO, CONH2, CF3SO2, C1-6alkenyl, C1-6alkynyl or C1-6hydroxyalkyl; or -NRaRb where Ra is hydrogen or C¿1-4?alkyl, and R?b¿ is hydrogen, C¿1-4?alkyl, formyl, -CO2C1-4alkyl or -COC1-4alkyl; or two R groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by -OH or =O; and R?4¿ is hydrogen or C¿1-6?alkyl, R?5¿ is hydrogen or C¿1-6?alkyl, are useful in the treatment and prophylaxis of certains CNS disorders.

Description

NOVEL COMPOUNDS

This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.

5

US-A-4022900 (Marion), FR-A-2004748 (Marion) and DE-A-2101691 (Marion) disclose benzamido-tetrahydroisoquinolines having anti-hypertensive and vasodilator properties.

It has now been surprisingly found that benzamide compounds of formula (I) and (la) 10 below possess anti-convulsant activity and are therefore believed to be useful in the treatment and or prevention of anxiety, mania, depression, panic disorders and or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive 15 agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, 20 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) (hereinafter "the Disorders").

J.5

Accordingly, a first aspect of the present invention provides a compound of formula (I) or pharmaceutically acceptable salt thereof:

NHCO— — — H-R

30 (I)

where the broken circle is a monocyclic or bicyclic aryl or heteroaryl ring; n and p are independently integers from 1 to 4 and (n+p) is from 2 to 5; R is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3O-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, C₁.₆alkyl, C^galkenyl, Ci .galkynyl, Ci.gperfluoroalkyl, C3_6cycloalkyl, C₃.₆cycloalkyl-C 1 _₄alkyl-, C 1 _₆alkylO-, C _j .₆alkylCO-,

C3-6^cy^cloalkylO-, C3_6cycloalkylCO-, C3_6cycloalkyl-C _ alkylO-, C3_ cycloalkyl-Cι_4alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C^alkyl-, C galkylS-, C j .₆alkylSO₂-, (C₁.₄alkyl)₂NSO₂-, (C₁.₄alkyl)NHSO₂-, (C j _₄alkyl)₂NCO- , (Cι _₄alkyl)NHCO, CONH₂, CF3SO , C galkenyl, C galkynyl or Ci.^hydroxyalkyl; or -NR^aR^b where R^a is hydrogen or C_T _₄ alkyl, and R^b is hydrogen, Cι .₄alkyl, formyl, -CO^^alkyl or -COC₁. alkyl; or two R groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by -OH or =O; and

R⁴ is hydrogen or C μg alkyl, R is hydrogen or Cμ₆ alkyl.

The ring system represented by a broken circle is typically optionally substituted phenyl or optionally substituted thiophenyl. When two R groups form a carbocyclic ring, this is typically a 5-7 membered ring, so that the broken circle may be a naphthalene or an indane or indanone ring system.

A second aspect of the present invention provides a compound of formula (la) or pharmaceutically acceptable salt thereof:

(la)

where n and p are independently integers from 1 to 4 and (n+p) is from 2 to 5; R¹ is C^alkylO-;

R² is hydrogen, halogen, CN, N₃, CF₃, CF₃O-, CF3S-, CF₃CO-, Cι _₆alkyl, C3.6^cy ^loa^ylC3._t5cycloalkyl-C 1 _₄alkyl-, CμgalkylO-, C galkylCO-, C₃.₆cycloalkylCO-, C .₆cycloalkyl-C₁.₄alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C₁.₄alkyl-, C₁.₆alkylS-, C₁.₆alkylSO₂-, (C!.₄alkyl)₂NSO₂- or (C!.₄alkyl)NHSO₂-; R³ is hydrogen, halogen, NO₂, CN, N₃,

Cμ₆ alkylO-, C, _₆ alkylS-, C^ alkyl, C₃.₆cycloalkyl, C₃.₆cycloalkyl-C₁.₄alkyl-, C galkenyl, C galkynyl, CF₃CO-, Cι .₆alkylCO-, C₃.₆cycloalkylCO-, C₃.₆cycloalkyl-Cι .₄alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C^alkyl-, or -NR⁶R⁷ where R⁶ is hydrogen or C 1 _₄ alkyl, and

R⁷ is hydrogen, Cι _ alkyl, -CHO,

-CO₂Cι _₄alkyl or -COCι .₄alkyl;

R⁴ is hydrogen or C \ _g alkyl

R⁵ is hydrogen or C,.₆ alkyl.

The compounds of this invention are typically amino-indanyl-benzamides, such as amino- (indan-4-yl)-benzamides, amino-(indan-5-yl)-benzamides or amino-(indan-ό-yl)- benzamides, or amino-tetralinyl-benzamides, such as amino-(tetralin-5-yl)-benzamides or amino-(tetralin-7-yl)-benzamides.

In the formula (la), R¹ alkoxy groups are typically based on straight chain alkyl groups, but in general alkyl groups, including alkyl groups that are part of another moiety, may be straight chain or branched. Aromatic rings, including rings that are part of another moiety, may optionally be substituted with one or more independently selected halogen or Cμg alkyl, C j _g alkoxy or C j _g alkylcarbonyl.

Suitable C^ cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Suitable halo substituents include fluoro, chloro, iodo and bromo.

A suitable group of compounds of formula (la) have R' as methoxy, ethoxy or n-propoxy

R² as hydrogen, methoxy, bromo, chloro, iodo, acetyl, pivaloyl, wo-butyroyl, benzoyl, trifluoromethyl, trifluoroacetyl, n-propylsulfonyl, wo-propylsulfonyl or dimethylsulfamoyl R³ as hydrogen, methyl, ethyl, w-butyl, t-butyl, methoxy, ethoxy, wø-propoxy, «-butoxy, benzyloxy, amino, acetylamino, nitro, benzoyl, iodobenzoyl, chloro or azido

R⁴ as hydrogen, methyl, ethyl or propyl R-> as hydrogen, methyl, ethyl or propyl.

Examples of compounds of formula (la) are:

N-(2-aminoindan-5-yl)-5-bromo-2,4-dimethoxybenzamide

N-(2-dimethylaminoindan-5-yl)-5-bromo-2,4-dimethoxybenzamide N-( 1 -amino- 1 ,2,3 ,4-tetrahydronaphthalen-7-yl)-5-bromo-2,4-dimethoxybenzamide

N-( 1 -dimethylamino- 1 ,2,3 ,4-tetrahydronaphthalen-7-yl)-4-t-butyl-2-methoxybenzamide

N-(l-amino-l,2,3,4-tetrahydronaphthalen-5-yl)-4-t-butyl-2-methoxybenzamide

N-( 1 -aminoindan-4-yl)-4-t-butyl-2-methoxybenzamide

N-( 1 -aminoindan-6-yl)-5-bromo-2,4-dimethoxybenzamide N-( 1 -methylaminoindan-6-yl)-4-t-butyl-2-methoxybenzamide

When synthesised, these compounds are often in salt form, typically the hydrochloride or trifiuoroacetate, 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-listed 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 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, 50, 100, 200, 300 and 400 mg of the active compound. Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, for example 1 to 6 mg/kg/day.

It is greatly preferred that the compound of formula (I) or (la) 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.

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, iηjectable 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, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.

Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.

Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium 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 />-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 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, in a further aspect, the present invention provides a pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and/or amyotrophic lateral sclerosis (ALS), which comprises a compound of formula (I) or (la), 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 cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post- traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and/or amyotrophic lateral sclerosis (ALS) comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof.

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

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

Another aspect of the invention provides a process for the preparation of compounds of formula (la), which comprises reacting a compound of formula (II)

(CH₂)n

4A

R N

>5A

(ID

where n and p are as defined for formula (la) and R ^ and R^ are R⁴ and R⁵as defined for formula (la) or a group convertible to R⁴ and R-¹

with a compound of formula (III)

(III)

where Y is Cl or OH, and Rl^A, R^2A' and R^3A are respectively R , R²' and R³ as defined for formula (la) or groups convertible to R , R > and R³, and where required converting a R ^A, R^2A' R^3A , R^4A or R^^A group to a R¹, R²' R³ , R⁴ or R⁵ group, converting one R , R²' R³ , R⁴ or R⁵ group to another R¹, R²' R³, R⁴ or R⁵ 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 a benzoyl chloride derivative (Y=C1) will lead directly to the hydrochloride salt. Suitable solvents include ethyl acetate. When the compound of formula (III) is a benzoic acid derivative (Y=OH), conventional conditions for condensation of aromatic acids with amines may be used, for example reacting the components in a mixture of (dimethylaminopropyl)-ethyl- carbodiimide/hydroxybenzotriazole in a suitable solvent, such as dimethyl formamide.

Conversions of an R^{1 A}, R^2A , R^3A , R^4A or R^5A group to a R¹, R²' R³ , R⁴ or R⁵ 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 R , R ' R-* , R⁴ or R-> group to another typically arises when one compound of formula (la) is used as the immediate precursor of another compound of formula (la), or when it is easier to introduce a more complex or reactive substituent at the end of a synthetic sequence.

Compounds of formula (II) may be prepared starting from a compound of formula (IV)

NH,

(IV). As a first step the NH₂ group is converted to NR^4AR ^Λ, where R^4A and R ^Λ are preferably protecting groups convertible to the intended R and R , especially when R and R are intended to be hydrogen. This may be carried out using conventional conditions for substituting amines or forming protecting groups. A suitable procedure is to convert the amine to a carbamic acid ester, for example by reaction with di-t-butyl carbonate to form the t-butyl carbamate, typically in a suitable solvent such as tetrahydrofuran or dioxan in the presence of a suitable base such as triethylamine and dimethylaminopyridine.

As a second step, the nitro group is hydrogenated to obtain the compound of formula (II). Suitably this is carried out in an ethanolic solution using a palladium/carbon catalyst, typically at ambient pressure and temperature.

After the coupling step with the compound of formula (II) to form the benzamide of formula (la), any protecting group can be removed under conventional conditions. For example, the t-butyl carbamic acid ester can be returned to the amine group by treatment

4 with trifluoroacetic acid in dichloromethane. Compounds of formula (la) in which R and R are hydrogen can be converted to other compounds of formula (la) by interconversion, for example, reductive alkylations with aldehydes and ketones under standard conditions with sodium cyanoborohydride. Also methyl groups can be introduced by treatment with aqueous formaldehyde and formic acid at elevated temperature. In general it may be more convenient to introduce R and R groups which are other than hydrogen at this stage, after removal of a protecting group, rather than carry the R and R groups through the synthetic steps leading up to the coupling of the compounds of formulae (II) and (III).

Compounds of formula (IV) can be prepared by introducing the nitro group into the corresponding amine, for example reacting the amine hydrochloride with potassium nitrate in sulphuric acid. Alternatively a nitro compound, such as indanone or tetralone, can be reacted with methoxylamine hydrochloride to introduce a methoximino group, which can be converted into amino by treatment with a borane-tetrahydrofuran complex. These procedures are illustrated in the Descriptions below.

Compounds of formula (III) can be prepared by further substitution of commercially available benzoic acid derivatives using conventional procedures, [by analogy with the procedures set out in the Descriptions below]. Suitable starting materials are 2,4-dimethoxy benzoic acid, 2-methoxy 4-amino benzoic acid and 2-methoxy 4-chloro benzoic acid.

Compounds of formula (I) can be prepared analagously.

10 The preparation of compounds of this invention is further illustrated by the following Descriptions (to obtain compunds of formula II), Preparations (to obtain compounds of formula III) and Examples (to obtain compounds of formula la). The utility of compounds of this invention is shown by the Pharmacological Data that follow the Examples. Description 1 2-Amino-5-nitroindane, monohydrochloride

2-Aminoindane hydrochloride (0.88g; 5.2 mmol) in sulfuric acid (SG 1.84; 3ml) was stirred at 0°C and treated with solid potassium nitrate (0.56g, 5.5 mmol) using a method similar to that described in PCT GB95/01041 p. 24. Work-up with ether gave an oil which on treatment with ethereal HC1 gave the title compound Dl as a beige powder (0.4g; 31%).

Description 2 N-(5-Nitroindan-2-yl)carbamic acid, f-butyl ester

The compound Dl (0.35g; 1.62 mmol) in 2:1 dichloromethane: tetrahydrofuran (40ml) containing triethylamine (164mg; 1.62 mmol) and dimethylaminopyridine (36mg; 0.3 mmol) was treated with di-t-butylcarbonate (0.43g; 2 mmol)). The mixture was kept at room temperature for 18h and then diluted with chloroform (30ml), washed with water (4x25ml) and dried (MgSO₄). Evaporation in vacuo gave the title compound D2 as a beige solid (0.47g; 100%).

Η NMR (CDCl₃)δ: 1.45 (9H, s), 2.89 (2H, dd), 3.37 (2H, dd), 4.54 (1H, br), 7.35 (1H. d), 8.08 (2H, m).

Description 3

N-(5-Aminoindan-2-yI)carbamic acid, f-butyl ester

The nitro compound D2 (0.47g, 1.62 mmol) in ethanol (40ml) was hydrogenated over 10% palladium on carbon (60mg) at atmospheric pressure and room temperature. After 3h. the

1 1 catalyst was removed by filtration through Kieselguhr and evaporation in vacuo gave the title compound as a pale yellow oil (0.37g, 91%).

Η NMR (CDCl₃)δ: 1.44 (9H, s), 2.66 (2H, m), 3.18 (2H, m), 3.57 (2H, br), 4.42 (1H, br), 6.52 (1H, dd), 6.58 (1H, br s), 6.98 (1H, d).

Description 4 l-(N-methoxylimino)-7-nitro-tetraIin

7-Nitro-l-tetralone (2.0g, 10.5 mmol) in methanol (160ml) was treated with a solution of methoxylamine hydrochloride (9.0g; 0.11 mol) and sodium acetate (8.84g; 0.11 mol) in water (40ml). The mixture was heated under reflux for 17h and evaporated in vacuo. The residue was partitioned between water and ethyl acetate and the material in the organic layer gave the title compound D4 as lemon crystals (2.27g; 99%).

Description 5

(±) l-Amino-7-nitrotetralin

The methoximine D4 (4.93g; 22.4 mmol) and borane-THF complex (IM solution, 60ml) in dry THF (45ml) were heated under reflux using a method similar to that of H. Feuer and D.M. Braunstein, J. Org. Chem., 1969, 34, 1817. The mixture was quenched with water followed by an excess of 5N HC1 (10ml) in methanol (50ml) and stirred at 25°C overnight. Concentration in vacuo followed by neutralisation with NaHCO₃ and extraction with dichloromethane afforded the title compound D5 as a yellow solid (2.74g).

Η NMR (CDCl₃)δ: 1.55 - 2.18 (6H, m), 2.86 (2H, m), 4.05 (1H, t), 7.21 (1H, d), 7.98 (1H, dd), 8.35 (lH, d).

Description 6

(±) N-(7-Aminotetralin-l-yl)carbamic acid, /-butyl ester

12 The title compound was prepared from tetralin D5 using a procedure similar to that employed in Descriptions 2 and 3.

Η NMR (CDCl₃)δ: 1.50 (9H, s), 1.60 - 2.15 (4H, m), 2.65 (2H, m, 2H), 3.55 (2H, br), 4.75 (2H, br), 6.55 (1H, dd), 6.67 (1H, d), 6.88 (1H, d).

Description 7

(±) N-(5-Nitrotetralin-l-yI)carbamic acid, /-butyl ester

5-Nitrotetralone (prepared according to T.R. Nieduzak and F.E. Boyer, Syn. Commun., 1996, 26, 3443) was converted into the corresponding t-butylcarbamate D7 using methods similar to those described in Description 2.

Η NMR (CDCl₃)δ: 1.50 (9H, s), 1.70 - 2.18 (4H, m), 2.83 - 3.05 (2H, m), 4.75 - 5.00 (2H, m), 7.30 (1H, t), 7.65 (1H, dd), 7.75 (1H, dd).

Description 8

(±) N-(5-Aminotetralin-l-yl)carbamic acid, /-butyl ester

Nitro compound D7 (0.3 lg; 1.06 mmol) and 10% Pd/C (50mg) in ethanol (30ml) was hydrogenated under atmospheric pressure at room temperature for 4h. Work-up gave the title compound D8 as an off white foam (0.30g).

'H NMR (CDCl₃)δ: 1.49 (9H, s), 1.70 - 2.05 (4H, m), 2.45 (2H, m), 4.78 (2H, br), 6.60 (1H, d), 6.82 (1H, d), 7.03 (1H, t).

Description 9

(±) l-Amino-4-nitroindane

13 The title compound D9 was prepared from 4-nitro-l-indanone and methoxylamine hydrochloride followed by treatment with borane-THF complex in a manner similar to that employed in Descriptions 4 and 5.

'H NMR (CDCl₃)δ: 1.56 - 1.83 (3H, m), 2.45 - 2.65 (IH, m), 3.06 - 3.26 (IH, m), 3.45 (IH, ddd), 4.39 (IH, t), 7.35 (IH, t), 7.60 (IH, d), 8.00 (IH, d).

Description 10

(±) N-(4-Nitroindan-l-yl)carbamic acid, /-butyl ester

The title compound D10 was prepared from l-amino-5-nitroindane and di-t- butyldicarbonate similar to that method used in Description 2.

Description 11 (±) N-(4-Amino-indan-l-yl)carbamic acid, /-butyl ester

The title compound Dl 1 was prepared from the nitro compound D10 using a method similar to that of Description 3.

^m/_z (CI): 249 (MH⁺; 18%), 149 (MH⁺-CO₂Bu'; 100%).

Preparation 1

4-Azido-5-iodo-2-methoxybenzoic acid

To a solution of 4-amino-5-iodo-2-methoxybenzoic acid (300 mg, 1.02 mmol) in trifluoroacetic acid (4 ml) at 5°C, was added sodium nitrite (283 mg, 4.1 mmol) portionwise, and the mixture allowed to stir for 30 min. Sodium azide (200 mg, 3.07 mmol) was then added portionwise and the mixture stirred for a further 30 min at 0°C.

14 The mixture was diluted with water, and a yellow solid precipitated. The solid was filtered, washed with cold water and dried, to afford the title compound (274 mg, 84%).

Preparation 2 4,5-Dichloro-2-methoxybenzoic acid

To an ice cold solution of 4-chloro-2-methoxybenzoic acid (l.Og, 5.36mmol) in trifluoroacetic acid (7ml) was added N-chloromorpholine (0.67g, 5.5mmol) dropwise, maintaining the internal temperature below 10°C. After stirring overnight at room temperature the trifluoroacetic acid was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, concentrated in vacuo and the residue recrystallised from methanol to afford the title compound as a white solid (200mg).

Preparation 3

5-Chloro-2,4-dimethoxybenzoic acid

The title compound was prepared in an analogous fashion to Preparation 2 from 2,4- dimethoxybenzoic acid (1.3g). Recrystallisation of the crude product from methanol afforded the title compound as a white solid (1.3g).

Preparation 4 5-Brorao-2,4-dimethoxybenzoic acid

To a solution of 2,4-dimethoxybenzoic acid (4.0g, 0.022mol) in chloroform (60ml) was added bromine (1.13ml, 0.022mol) in chloroform (20ml) dropwise. After stirring overnight at room temperature the precipitate was filtered off and dried to afford the title compound as a white solid (2.87g).

Preparation 5

15 (5-Bromo-2-methoxybenzyloxy)-/£?/-/-butyIdimethylsilane

To a solution of 5-bromo-2-methoxybenzyl alcohol (1.0 g, 4.6 mmol) and imidazole (470 mg, 7.01 mmol) in DMF (15 ml) was added tert-butyldimethylsilyl chloride (1.04 g, 6.91 mmol). The mixture was allowed to stir for 4 h, poured onto water (100 ml) and extracted with ether (3 x 30 ml). The combined organic phases were washed with water (50 ml), brine (50 ml), dried over sodium sulfate and evaporated under reduced pressure to leave a pale yellow oil. This was purified by chromatography (SiO₂, 5% ether/petrol), to give the title compound (1.46g, 96%) as a colourless oil.

Preparation 6 (5-Trifluoroacetyl-2-methoxybenzyloxy)-/e/-/-butyldimethylsilane

To a solution of 5-bromo-2-methoxybenzyloxy)-tert-butyldimethylsilane (1.0 g, 3.02 mmol) in THF (5 ml) at -78°C, was added «-BuLi (2.26 ml of a 1.6 M solution in pentane, 3.62 mmol) dropwise over 10 min. The solution was allowed to stir for a further 1 h at - 78°C, to give a bright yellow solution. N,N-diethyltrifluoroacetamide (561 mg, 3.32 mmol) in THF (2 ml) was added dropwise over 30 min, and the solution was stirred for a further 1 h at -78°C. Saturated aqueous ammonium chloride (5 ml) was added and the mixture allowed to warm to room temperature, and extracted with ether (3 x 10 ml). The combined organic phases were washed with water (10 ml), brine (10 ml), dried over sodium sulfate and evaporated in vacuo. Chromatography (SiO₂, 5% ether/petrol) of the residue gave the title compound (0.99g, 94%) as a white solid.

Preparation 7

5-Chloro-2,4-dimethoxybenzoyl chloride

A solution of 5-chloro-2,4-dimethoxybenzoic acid (6.4g) in dichloromethane (250ml) was treated with thionyl chloride (30ml) and the mixture heated at reflux for 18h. Removal of volatile material in vacuo afforded the title compound as a white solid (6.6g).

16 Preparation 8 5-Chloro-2-methoxy-4-methylbenzoic acid

The title compound was prepared in an analogous manner to Preparation 2 from 2- methoxy-4-methylbenzoic acid (3.0g, 0.018mol). Purification of the crude product using a Chromatotron (SiO2, 10% ethyl acetate in hexane) gave the title P8 as a white solid (0.40g)

Preparation 9 4-Benzyloxy-5-chloro-2-methoxybenzoic acid

A solution of chlorine (5.1g) in acetic acid (100ml) was added dropwise to a solution of methyl 4-benzyloxy-2-methoxybenzoate (lOg) in acetic acid (40ml) whilst maintaining the temperature at 20-25°C. The mixture was poured into ice-water and extracted with dichloromethane. The organic extract was dried over sodium sulfate and concentrated in vacuo. The resulting crude material was suspended in ethanol (500ml) and treated with 10%) aqueous sodium hydroxide (16ml). The mixture was heated at reflux overnight and then concentrated in vacuo. The residue was treated with excess 5M HC1 and extracted into dichloromethane. The extract was dried over sodium sulfate and concentrated in vacuo to afford a white solid which was crystallised from ethanol to give the title compound (6.3g).

Preparation 10

4-Hydroxy-2-methoxybenzoic acid methyl ester.

4-Amino-2-methoxy benzoic acid methyl ester (15g, 82.7mmol) was dissolved in sulfuric acid ( 80ml of a 25% solution). The solution was cooled in an ice bath and diazotized with saturated sodium nitrite solution (8.57g, 124mmol) maintaining the temperature below 5°C. The diazonium solution was poured slowly into boiling sulphuric acid (1L of a 3% solution) and the mixture was heated for an additional 5 mins. The mixture was then allowed to cool before being extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate and concentration in vacuo gave a brown solid (9.7g).

17 Preparation 11

4-Ethoxy-2-methoxy-benzoic acid methyl ester

To a solution of 4-hydroxy-2-methoxybenzoic acid methyl ester (4!7g, 22.mmol) in DMF (50ml) under argon was added potassium carbonate (6.33g, 4.6mmol) followed by iodoethane (7.15g, 4.6mmol). The mixture was then heated to 50°C under argon for 12h. On cooling the mixture was poured into a large excess of water and extracted with ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a brown oil (4.8g).

Preparation 12 5-Chloro-4-ethoxy-2-methoxybenzoic acid

Trifluoroacetic acid (35ml) was cooled in an ice bath. 4-Ethoxy-2-methoxy- benzoic acid methyl ester (4.85g, 23mmol) was then added slowly. N-chloromorpholine (3.64g, 29.9mmol) was then added dropwise maintaining the reaction mixture temperature below 10°C. The ice bath was removed and the mixture stirred under argon for 12h at room temperature. The solvent was then removed in vacuo and the residue taken up in ethyl acetate and washed wth water. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford a brown oil which was triturated with ether and 60/80 petrol. The resulting brown solid was then recrystallised from 60/80 petrol, taken up into ether and washed with sodium hydroxide solution (2M). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the methyl ester as a pale yellow solid (0.9g). A mixture of this ester (0.9g, 3.6mmol), methanol (22ml) and sodium hydroxide solution (20ml, 2M) was heated to 70°C overnight. On cooling the mixture was acidified to pH 6-7 and the solvent was removed in vacuo. The residue was taken up in ethanol and the inorganic solid filtered off. The filtrate was concentrated in vacuo to afford the title compound as a pale brown solid (0.44g)._

Preparation 13 5-Bromo-2-methoxy-4-methylbenzoic acid

The title compound was prepared in an analogous manner to Preparation 4 from 2- methoxy-4-nιethylbenzoic acid (3.0g, O.Olδmol). Recrystallisation of the crude product from dichloromethane afforded the title compound as a white solid (0.99g).

Preparation 14 [4-(/er/-Butyldimethylsilanyloxymethyl)-3-methoxyphenyl]-phenylmethanol

To 2-(tert-Butyldimethylsilanyloxymethyl)-5-bromoanisole (500 mg, 1.51 mmol) in THF (10 ml) at -78°C was added n-BuLi (1.13 ml of a 1.6M solution in pentane, 1.81 mmol) and the mixture allowed to stir for 1 h at -78°C. Benzaldehyde (176 mg, 1.66 mmol) was added and the mixture allowed to warm to room temperature and stirred for 1 h. Water (20 ml) was added and the mixture extracted with ether (3 x 10 ml). The combined extracts were washed with water (10 ml), brine (10 ml), dried (Na₂SO₄) and evaporated under reduced pressure. The resulting residue was purified by chromatography (SiO₂, 50% ether/petrol) to give the title compound as a colourless oil (303 mg, 56%).

Preparation 15 [5-(/er/-ButyldimethylsilanyloxymethyI)-4-methoxypheny!]-phenylmethanol

The title compound was prepared in an analogous manner to Preparation 19 from 2-{tert- butyldimethylsilanyloxymethyl)-4-bromoanisole (500 mg, 1.51 mmol). The crude product was purified by chromatography (SiO₂, 50% ether/petrol) to give the title compound as a colourless oil (63%).

Preparation 16 4-Benzoyl-2-methoxybenzoic acid

A solution of 4-(tert-butyldimethylsilanyloxymethyl)-3-methoxyphenyl]-phenylmethanol (200 mg, 0.56 mmol) in THF (5 ml) was stirred with 5N HC1 (5 ml) for 1 h. The mixture

19 was poured onto saturated aqueous sodium bicarbonate (10 ml) and extracted with ether (3 x 10 ml). The combined organic extracts were dried (Na SO ), and evaporated under reduced pressure. The residue was taken up in dioxane (4 ml) and aqueous KOH (5.6 ml of a 0.2M solution), potassium permanganate (266 mg, 1.68 mmol) was added and the mixture stirred for 4 h. The mixture was filtered through a pad of Celite and washed with water. The filtrate was extracted with ether (2 x 10 ml) and the aqueous phase was brought to pH 1 and extracted with ether (2 10 ml). These extracts were dried over sodium sulfate and evaporation in vacuo gave the title compound as a white foam (102 mg, 71%).

Preparation 17

5-Benzoyl-2-methoxybenzoic acid

The title compound was prepared in an analogous manner to Preparation 21 from [5-{tert- butyldimethylsilanyloxymethyl)-4-methoxyphenyl]-phenylmethanol (200mg, 0.56mmol). The title compound was obtained as a white foam (74%)

Preparation 18 4-/er/-Butyl-2-methoxybenzoic acid

A mixture of 3-tert-butylphenol (25.25g, 0.1680 mole), acetic anhydride (34.3 lg, 0.336 mole) and sodium acetate (13.78g, 0.1680 mole) was heated at 100°C for 2h. On cooling the mixture was poured into water (200ml) and extracted with ethyl acetate (200ml). The combined organic extracts were dried over sodium sulphate and concentrated in vacuo to afford the acetate compound as an oil (33.33g).

Preparation 19 4-/er/-Butyl-2-hydroxy acetophenone

20 A mixture of the acetate of Preparation 23 (33.23g, 0.173 mole) and AICI3 (25.61g, 0.192 mole) was placed in an oil bath preheated to 120°C and stirred mechanically. Then the oil bath temperature was raised to 165°C and maintained for 45 min before being allowed to cool to 120°C. Then water was added dropwise into the reaction mixture (4x250ml) to steam distil the product (bath temp 190-200°C). The distillate was extracted with ether and the combined organic extracts were dried over sodium sulphate and concentrated in vacuo to afford 4-tert-butyl-2-hydroxy acetophenone as an oil (18.05g).

Preparation 20 4-/er/-Butyl-2-methoxy acetophenone

A suspension of 4-tert-butyl-2-hydroxy acetophenone (12.65g), potassium carbonate (13.14g) and dimethyl sulphate (8.99ml) in acetone (200ml) was refluxed for 48h. After cooling, the mixture was filtered. The solvent was then removed in vacuo and the residue taken up in dichloromethane and washed with brine. The organic layer was dried over sodium sulphate and concentrated in vacuo to afford a yellow oil (12.05g).

Preparation 21 4-/£r/-ButyI-2-methoxybenzoic acid

The acetophenone of Preparation 25 (1 l.Og, 53 mmol) was added to a solution of sodium hydroxide (28.68g), sodium hypochlorite (182ml, 12% w/w) and water (70ml) at 80°C with stirring. After heating for 1.25h, the mixture was cooled to 0°C and a solution of sodium metabisulphite (41.1 g) in water (170ml) was added. The mixture was stirred for 15 min and then acidified (pHl) with cone. HCl (45ml). Extraction with ethyl acetate gave the title compound as a white solid (8.9g).

Η NMR (DMSO-d^ή) δ: 1.30 (9H, s), 3.85 (3H, s), 6.96 - 7.12 (2H, m), 7.60 (IH, d), 12.30 - 12.60 (lH, br).

Preparation 22 4-«-ButyI-2-methoxybenzoic acid

A mixture of 4-bromo-2-methoxybenzoic acid methyl ester (3.0g, 0.0122 mole), lithium chloride (1.56g), tetra butyl tin (4.5 lg) and bis (triphenyl phosphine palladium (II) chloride (214mg, 0.3 mmol) were heated at 100°C for 24h. The solvent was then removed under vacuo and the residue taken up in dichloromethane. The black solid was removed by filtration and the filtrate concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography (Biotage) on silica gel using 10% ether in hexane to afford a colourless oil (1.63g). A portion of the foregoing 4-n-butyl-2-methoxybenzoic acid methyl ester (1.50g) was dissolved in methanol (35 ml) with sodium hydroxide solution (2N, 30ml). The mixture was allowed to stir at room temperature overnight. Then added dil. HCl until pH-5. The solvent was then removed in vacuo and the residue taken up in ethyl acetate and washed with brine. The organic layer was dried over sodium sulphate and concentrated in vacuo to afford an oil (1.02g).

Preparation 23

4-/ι-ButyI-2-methoxy-5 chlorobenzoic acid

4-tt-Butyl-2-methoxybenzoic acid (0.5g; 2.9 mmol) and N-chloromorpholine (356mg; 2.9 mmol) were treated in a similar manner to that described in Preparation 24 to give the title compound as a white soid (0.4g).

Preparation 24 5-Bromo-4-isø-propyl-2-methoxybenzoic acid

To a solution of 2-methoxy-4-wo-propyl benzoic acid (prepared in an analogous manner to Preparation 26, 4-tert-butyl-2-methoxy 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).

^ml_z (CI): 275, 273 (MH⁺; 70%).

22 Preparation 25 Methyl-5-bromo-4-isø-propyI-2-methoxy benzoate

5-Bromo-4-wo-propyl-2-methoxybenzoic acid (9.268g 34.0 mmol) was dissolved in ethanol (250 ml) and cone. H SO₄ (2 ml) added. The mixture was refluxed for 5h and concentrated in vacuo. The residue was taken up into ethyl acetate and water, and the organic layer, dried (MgSO₄). Concentration in vacuo gave an oil, which was purified by Biotage Chromatography on silica gel with 10% etheπhexane. An oil (5.5g) was obtained.

Preparation 26 MethyI-4-ιsσ-propyl-2-methoxy-5-trifluoromethyl benzoate

A mixture of methyl-5-bromo-4-wo-propyl-2-methoxy benzoate (5.43g, 0.0189 mole), potassium trifluoroacetate (5.75g, 0.0378 mole) and copper (I) iodide (7.92g, 0.042 mole) in DMF (100ml) and toluene (30ml) were heated at 170°C under argon to remove water (Dean-Stark Trap) and then heated to 155°C overnight. On cooling, after concentration in vacuo, the mixture was poured into ether (300ml) and water (300ml). After filtration through Kieselguhr, the organic layer was separated, washed with brine and dried (Na₂SO ). Concentration in vacuo afforded a brown yellow solid (4.85g).

Preparation 27 4-iso-Propyl-2-methoxy-5-trifluoromethyl benzoic acid

Methyl-4-wø-propyl-2-methoxy-5-trifluoromethyl benzoate was dissolved in methanol (100ml), containing sodium hydroxide solution (2N, 100ml). The mixture was allowed to stir at R.T. overnight and then dil. HCl added until pH~5 . The solvent was then removed in vacuo and the residue taken up in ethyl acetate and washed with brine. The organic layer was dried over sodium sulphate and concentrated in vacuo to afford a crude solid which was recrystallised with dichloromethane and hexane to give a solid (2.59g). Preparation 28

5-PivaloyI-2-methoxy benzyl TBDMS Ether

n-Butyllithium (11.43ml, 0.0183 mole, 1.6M in hexane) was slowly added to a solution of 5-bromo-2-methoxy benzyl TBDMS ether in tetrahydrofuran (30ml) over 45 mins at - 78°C. The reaction mixture was maintained under argon at -78°C for lh. Then N,O- dimethylhydroxy pivaloyl amide (2.43g, 0.0167 mole) was added dropwise with stirring at -78°C. The resulting mixture was allowed to stir at -78°C for 2.5h, quenched with NH₄C1 solution and allowed to warm to room temperature. The mixture was extracted with ether (2x50ml), the combined organics were dried (Na SO₄) and concentrated in vacuo to give an oil. The oil was purified by Biotage column chromatography on silica gel using 5% ether in hexane to afford the title compound as a colourless oil (2.95g).

Preparation 29

5-PivaloyI-2-methoxy benzyl alcohol

5-Pivaloyl-2-methoxy benzyl TBDMS ether (1.8g, 5.35 mmol) was dissolved in methanol (30ml); cone. HCl (20 drops) was added and the whole allowed to stir at room temperature for 4h. Saturated NaHCO3 solution was added and the mixture extracted with ether

(2x100ml). The organic layer was dried over sodium sulphate and concentrated in vacuo to afford the title compound as a colourless oil (1.19g).

Preparation 30 5-Pivaloyl-2-methoxy benzoic acid

5-Pivaloyl-2-methoxy benzyl alcohol (1.19g, 5.35 mmol) was dissolved in dioxane (20ml). A solution of KOH (0.449g, 8.025 mmol in water (5ml)) was added followed by KMnO (1.69g, 10.7 mmol). The mixture was allowed to stir at room temperature over the weekend. The solution was filtered through Celite and extracted with ether. The aqueous phase was acidified with dil. HCl and extracted with ether (3x50ml). The organic layer

24 was dried over magnesium sulphate and concentrated in vacuo to afford the title compound as a white solid (1.06g).

Preparation 31 2,4-Dimethoxy-5-trifluoromethylbenzoic acid

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 (I) iodide (2!g, 10.9 mmol). The mixture was heated to 170°C with removal of water (Dean/Stark), and then at 155°C overnight. The mixture was allowed to cool, poured into ether and water and filtered through Kieselguhr. The organic layer was dried (Na₂SO₄) and concentrated in vacuo to give a brown solid. Chromatography on Kieselgel 60 with 1 :1 ether/petrol gave a white 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).

Example 1

(a) N-(2-/-Butoxycarbonylaminoindan-5-yI)-5-bromo-2,4-di-methoxybenzamide

The amine D3 (0.37g, 1.48 mmol), 5-bromo-2,4-dimethoxybenzoic acid (0.39g, 1.48 mmol), 1-hydroxybenzotriazole (0.20g, 1.48 mmol) and ethyl dimethylaminopropylcarbodiimide (EDC, 0.28g; 1.48 mmol) in dry DMF (15ml) were kept at 25°C for 18h. Work-up with ethyl acetate followed by chromatography on Kieselgel 60 in 25-50%) ethyl acetate-hexane gave the title compound as an off white solid (0.5 lg; 70%).

Η NMR (CDCl₃)δ: 1.45 (9H, s), 2.78 (2H, m), 3.27 (2H, m), 3.98 (3H, s), 4.09 (3H, s), 4.48 (IH, br), 4.76 (IH, br), 6.53 (IH, s), 7.19 (IH, d). 7.33 (IH, dd), 7.63 (IH, d), 8.46 (IH, s), 9.55 (IH, s).

(b) N-(2-Aminoindan-5-yl)-5-bromo-2,4-dimethoxybenzamide, trifluoroacetate

25 The N-boc amine (a) (0.44g; 0.90 mmol) in dichloromethane (40ml) containing trifluoroacetic acid (4ml) was kept at 25°C for 18h and then evaporated in vacuo. Trituration of the resultant pale gum followed by recrystallisation from ethanol-ether gave the title compound as off-white crystals (0.22g; 47%), m.p. 220-3°C.

Η NMR (DMSO-d⁶)δ: 2.92 (2H, m), 3.28 (2H, m), 3.99 (3H, s), 4.04 (3H, s), 6.88 (IH, s), 7.24 and 7.50 (2H, ABq), 7.73 (IH, s), 7.89 (IH, s), 8.03 (3H, br), 9.95 (IH, s); ^*7_Z Found; M⁺ 390.0577 Calc. for C₁₈H₁₉BrN₂O₃ 3990.0575.

Example 2

N-(2-Dimethylaminoindan-5-yl)-5-bromo-2,4-dimethoxybenzamide

The compound of Example 1(b) (150mg; 0.30 mmol) and 40% aqueous formaldehyde (0.12ml; 1.5 mmol) in acetonitrile (3ml) was stirred at 0°C and sodium cyanoborohydride (38mg; 1 mmol) added. Treatment according to the procedure of R.F. Borch, J. Org. Chem., 1972, 37, 1673 followed by work-up with ethyl acetate gave a residue. Chromatography on Kieselgel 60 in 10% methanol-ethyl acetate gave the title compound as an off white solid (44mg; 35%).

'H NMR (CDCl₃)δ: 2.60 (3H, s), 2.62 (3H, s), 3.25 (4H, m), 3.96 (3H, s), 4.05 - 4.20 (IH, m), 4.10 (3H, s), 6.50 (IH, s), 7.18 (IH, d), 7.26 (IH, dd), 7.70 (IH, narrow, d), 8.42 (IH, s), 9.56 (IH, br); "V_z (EIMS): 418 (MH⁺; 32%), 373 (5), 243 (100), 175 (30).

Example 3

(a) (±) N-(l-/-Butyloxycarbonylaminotetralin-7-yl)-5-bromo-2,4-dimethoxy benzamide

26 The amine D6 (0.43g; 1.64 mmol), EDC (0.32g; 1.65 mmol), 1-HOBT (223mg;'1.65 mmol) and triethylamine (0.23ml; 1.65 mmol) in dry dimethylformamide (20ml) were treated in a similar manner to that of Example 1(a). Work-up gave the title compound as a white solid (0.82g; 99%).

'H NMR (CDCl₃)δ: 1.51 (9H, s), 1.64 - 2.12 (4H, m), 2.75 (2H, m), 3.96 (3H, s), 4.08 (3H, s), 4.83 (2H, br), 6.52 (IH, s), 7.08 (IH, d), 7.35 (IH, d), 7.70 (IH, dd), 8.45 (IH, s), 9.50 (IH, br s).

(b) (±) N-(l-Amino-l,2,3,4-tetrahydronaphthalen-7-yl)-5-bromo-2,4- dimethoxybenzamide, trifluoroacetate

The title compound was prepared from (a) using a method similar to that of Example 1(b).

Η NMR (DMSO-d⁶)δ: 1.70 - 2.15 (4H, m), 2.72 (2H, m), 3.98 (3H, s), 4.04 (3H, s), 4.45 (IH, br), 6.90 (IH, s), 7.18 (IH, d), 7.55 (IH, dd), 7.90 (IH, d), 7.92 (IH, s), 8.30 (3H, br), 9.98 (IH, s); % (CI): 407, 405 (MH⁺; 5%), 390, 388 (MH⁺-NH₃; 100%).

The following Examples were prepared using methods similar to those described described above.

Example 4:

(±) N-(l-Dimethylamino-l,2,3,4-tetrahydronaphthalen-7-yl)-4-/-butyl-2- methoxybenzamide

Prepared from the compound of Example 3 by a method similar to Example 2.

'H NMR (CDCl₃)δ: 1.36 (9H, s), 1.60 - 1.75 (2H, m), 1.86 - 2.05 (2H, m), 2.30 (6H, s), 2.72 (2H, m), 3.80 (IH, m), 4.07 (3H, s), 7.01 (IH, d), 7.07 (IH, d), 7.15 (IH, dd), 7.64 (IH, d), 7.70 (IH, dd), 8.21 (IH, d), 9.70 (IH, br s); ' _Z (CI): 381 (MH⁺; 100%).

27 Example 5

(a) (±) N-(l-/-Butyloxycarbonylamino-l,2,3,4-tetrahydronaphthalen-5-yl)-4-/- butyl-2-methoxybenzamide

The title compound was prepared in 85% yield from D8 and 4-t-butyl-2-methoxybenzoic acid using a method similar to that of Example 1(a).

(b) (+) N-(l-Amino-l,2,3,4-tetrahydronaphthalen-5-yl)-4-/-butyl-2- methoxybenzamide, trifluoroacetate

The N-boc amine (a) (0.38g; 0.84 mmol) in dichloromethane (30ml) containing trifluoroacetic acid (2ml) was kept at room temperature overnight. Work-up similar to that for Example 1(b) followed by crystallisation from ethyl acetate:ether gave the title compound as beige crystals (0.27g; 69%).

Η NMR (DMSO-d⁶)δ: 1.34 (9H, s), 1.80 - 2.15 (4H, m), 2.72 (2H, br), 4.05 (3H, s), 4.50 (IH, br m), 7.10 - 7.22 (2H, m), 7.26 - 7.35 (2H, m), 7.86 (IH, d), 8.00 (IH, dd), 8.30 (3H, br s), 9.83 (IH, s); "7_Z (CI): 336 (MH-NH₃ ⁺, 100%).

Example 6

(a) (±) N-(l-/-Butyloxcarbonylaminoindan-4-yl)-4-/-butyI-2-methoxybenzamide

The title compound was prepared from compound D 1 1 using a method similar to that of Examples 1(a) and 5(a).

28 'H NMR (CDCl₃)δ: 1.36 (9H, s), 1.50 (9H, s), 1.90 (IH, m), 2.48 - 3.03 (3H, br m), 4.10 (3H, s), 4.83 (IH, m), 5.24 (IH, m), 7.04 (IH, d), 7.10 (IH, d), 7.18 (IH, dd), 7.27 (IH, t), 8.25 (2H, t), 9.85 (lH, br s).

(b) (+) N-(l-Aminoindan-4-yl)-4-/-butyI-2-methoxybenzamide, trifluoroacetate

The title compound was prepared from the N-boc amine (a) using a method similar to that of Examples 1(b) and 5(b).

Η NMR (DMSO-d⁶)δ: 1.34 (9H, s), 2.06 (IH, m), 2.45 - 2.65 (IH, m), 2.83 - 3.19 (2H, m), 4.07 (3H, s), 4.80 (IH, br m), 7.16 (2H, m), 7.33 (2H, m), 7.86 (IH, d), 8.14 (IH, dd), 8.35 (3H, br s), 9.95 (IH, s); ^m/_z (CI): 339 (MH⁺; 2%), 322 (MH⁺-NH₃; 100%).

Example 7

(±) N-(l-Aminoindan-6-yl)-5-bromo-2,4-dimethoxybenzamide, trifluoroacetate

Prepared from l-amino-6-nitroindane using methods similar to Descriptions 1 to 3 and Example 1.

^m/_z (API+): 391, 393 (MH⁺; 70%),

Example 8

(±) N-(l-Methylaminoindan-6-yl)-4-/-butyl-2-methoxybenzamide, hydrochloride Prepared from 1 -amino-6-nitroindane using methods similar to Descriptions 1 to 3 and Examples 1 and 2.

' ₂ (API+): 353 (MH⁺; 80%),

29 PHARMACOGICAL DATA

1. Binding Assay Method

WO 92/22293 (SmithKline Beecham) discloses compounds having anti-convulsant activity, including inter alia the compound trα/w-(+)-6-acetyl-4S-(4-fluorobenzoylamino)- 3,4-dihydro-2,2-dimethyl-2H-l-benzopyran-3R-ol (hereinafter referred to as Compound A). 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 7.4). The homogenised tissue is washed by centrifugation and resuspension in the same buffer, then stored at -70°C until used.

To carry out the radioligand binding assay, aliquots of tissue prepared as above (usually at a concentration of l-2mg protein/ml) are mixed with aliquots of [3 H] -Compound A dissolved in buffer. The final concentration of [3H]-Compound A in the mixture is usually 20nM. The mixture is incubated at room temperature for 1 hour. [3H]-Compound A bound to the tissue is then separated from unbound [3H]-Compound A by filtration through Whatman 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 μM). The amount of binding of [3H]-Compound A remaining in the presence of this unlabelled compound is defined as "non-specific" binding. This amount is subtracted from the total amount of [3H]- Compound A binding (i.e. that present in the absence of unlabelled compound) to obtain the amount of "specific" binding of [3H]-Compound A to the novel site.

30 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 5, 6, 7 and 8 gave pKi values greater than 6.5.

2. MEST Test

The maximal electroshock seizure (MEST) threshold test in rodents is particularly sensitive for detecting potential anticonvulsant properties! . In this model, anticonvulsant agents elevate the threshold to electrically-induced seizures whilst proconvulsants lower the seizure threshold.

Method

Mice (naive male, Charles River, U.K. CD-I 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 60 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%) (CC50) of the mice in a particular treatment group is determined by the 'up and down' method of Dixon and Mood (1948)2. Statistical comparisons between vehicle- and drug-treated groups are made using the method of Litchfield and Wilcoxon (1949)3.

In control animals the CC50 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.

The percentage increase or decrease in CC50 for each group compared to the control is calculated.

31 Studies are carried out using a Hugo Sachs Electronik Constant Current Shock Generator with totally variable control of shock level from 0 to 300 mA and steps of 2 mA are usually used.

Drugs are suspended in 1% methyl cellulose.

References

1. Loscher, W. and Schmidt, D. (1988). Epilepsy Res., 2, 145-181

2. Dixon, W.J. and Mood, A.M. (1948). J. Amer. Stat. Assn., 43, 109-126

3. Litchfield, J.T. and Wilcoxon, F.(1949). J. Pharmacol, exp. Ther., 96, 99-113

Results

Compounds of this invention dosed 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 compound of Example 5 showed a 43% increase at lOmg/kg p.o.

32

Claims

Claims

1. A compound of formula (I) or pharmaceutically acceptable salt thereof:

(CH₂)n .

^ _NHCO-

. (CH₂)p

R I.⁵

(I)

where the broken circle is a monocyclic or bicyclic aryl or heteroaryl ring; n and p are independently integers from 1 to 4 and (n+p) is from 2 to 5;

R is hydrogen or up to three substituents selected from halogen, NO , CN, N3, CF3O-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, C^galkyl, C╬╣ _₆alkenyl, Ci.galkynyl, C╬╣_6perfIuoroalkyl, C3_6cycloalkyl, C₃.₆cycloalkyl-C╬╣ _₄alkyl-, C╬╣ _₆alkylO-, C galkylCO-, C3_6cycloalkylO-, C₃_6cycloalkylCO-, C3_6cycloalkyl-C╬╣_₄alkylO-,

C3_ cycloalkyl-C╬╣ _₄alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C^alkyl-, C^galkylS-, C₁.₆alkylSO₂-, (C!_₄alkyl)₂NSO₂-, (C₁.₄alkyl)NHSO₂-, (C╬╣ _₄alkyl)₂NCO- , (C╬╣_₄alkyl)NHCO, CONH₂, CF3SO , C^.galkenyl, C_j._╬▓alkynyl or Ci.ghydroxyalkyl; or -NR^aR^b where R^a is hydrogen or C 1.4 alkyl, and

R^b is hydrogen, C1 _₄alkyl, formyl, -CO^i^alkyl or -COC^alkyl; or two R groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by -OH or =O; and

R⁴ is hydrogen or C_j.g alkyl,

R is hydrogen or C^g alkyl.

2. A compound of formula (la) or pharmaceutically acceptable salt thereof:

33 (CH,)n

R^' N

R*

(la)

where n and p are independently integers from 1 to 4 and (n+p) is from 2 to 5; R¹ is C galkylO-;

R² is hydrogen, halogen, CN, N₃, CF₃, CF₃O-, CF₃S-, CF₃CO-, C╬╣ .₆alkyl, C3_gcycloalkyl,C3_5cycloalkyl-C ₄alkyl-, C galkylO-, C galkylCO-, C₃.₆cycloalkylCO-, C3_5cycloalkyl-C|. alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C╬╣.₄alkyl-, C╬╣ _₆alkylS-, C╬╣ .₆alkylSO₂-, (C!_ alkyl)₂NSO₂- or (C₁.₄alkyl)NHSO₂-; R^J is hydrogen, halogen, NO₂, CN, N3,

C╬╣ .₆ alkylO-, C_╧ç_₆ alkylS-, C╬╣ _₆ alkyl, C₃.₆cycloalkyl, C₃_₆cycloalkyl-C╬╣ _ alkyl-, C galkenyl, C₁.₆alkynyl, CF3CO-, C╬╣ .₆alkylCO-, C₃.₆cycloalkylCO-, C₃.₆cycloalkyl-C₁.₄alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C╬╣_ alkyl-, or -NR⁶R⁷ where R is hydrogen or C ₄ alkyl, and

R⁷ is hydrogen, C^alkyl, -CHO,

-CO₂C!_₄alkyl or -COC _x .₄alkyl;

R⁴ is hydrogen or C \ _g alkyl, R is hydrogen or C╬╣_₆ alkyl.

A compound according to claim 2 having:

RI as methoxy, ethoxy or «-propoxy

R² as hydrogen, methoxy, bromo, chloro, iodo, acetyl, pivaloyl, wo-butyroyl, benzoyl, trifluoromethyl, trifluoroacetyl, n-propylsulfonyl, /.yo-propylsulfonyl or dimethylsulfamoyl

R as hydrogen, methyl, ethyl, «-butyl, t-butyl, methoxy, ethoxy, wo-propoxy, n-butoxy, benzyloxy, amino, acetylamino, nitro, benzoyl, iodobenzoyl, chloro or azido

R⁴ as hydrogen, methyl, ethyl or propyl

R5 as hydrogen, methyl, ethyl or propyl.

34

4. A compound selected from the group consisting of: N-(2-aminoindan-5-yl)-5-bromo-2,4-dimethoxybenzamide N-(2-dimethylaminoindan-5-yl)-5-bromo-2,4-dimethoxybenzamide

N-( 1 -amino- 1 ,2,3 ,4-tetrahydronaphthalen-7-yl)-5-bromo-2,4-dimethoxybenzamide

N-( 1 -dimethylamino- 1 ,2,3 ,4-tetrahydronaphthalen-7-yl)-4-t-butyl-2-methoxybenzamide

N-(l-amino-l,2,3,4-tetrahydronaphthalen-5-yl)-4-t-butyl-2-methoxybenzamide

N-( 1 -aminoindan-4-yl)-4-t-butyl-2-methoxybenzamide

N-( 1 -aminoindan-6-yl)-5-bromo-2,4-dimethoxybenzamide

N-( 1 -methylaminoindan-6-yl)-4-t-butyl-2-methoxybenzamide

5. A process for the preparation of a compound of formula (la), which comprises reacting a compound of formula (II)

,4A

R

(ID

where n and p are as defined for formula (la) and R^4A and R^^A are R⁴ and R⁵as defined for formula (la) or a group convertible to R⁴ and R^

with a compound of formula (III)

(III)

where Y is CI or OH, and Rl^A, R^2A' and R ^A are respectively R , R²' and R³ as defined for formula (la) or groups convertible to Rl , R²' and R³, and where required converting a Rl^A, R^2A' R^^A , R^4A or R^^A group to a R , R²' R^J , R⁴ or R^ group, converting one R¹, R²' R³ , R⁴ or R⁵ group to another R , R²> R³, R⁴ or R⁵

35 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.

6. A compound of formula (I) or (la), for use in therapy.

7. A compound of formula (I) or (la), for use in treatment or prophylaxis of the Disorders.

8. Use of a compound of formula (I) or (la) in the manufacture of a medicament for use in the treatment or prophylaxis of the Disorders.

9. A method of treatment or prophylaxis of the Disorders which comprises administering to a patient in need thereof an effective amount of a compound of formula (I) or (la).

10. A pharmaceutical composition comprising a compound of formula (I) or (la), together with a pharmaceutically acceptable carrier.

36