WO1986006068A1

WO1986006068A1 - Novel compounds

Info

Publication number: WO1986006068A1
Application number: PCT/GB1986/000205
Authority: WO
Inventors: Roger Edward Markwell; Stephen Allan Smith
Original assignee: Beecham Group PLC
Current assignee: Beecham Group PLC
Priority date: 1985-04-17
Filing date: 1986-04-11
Publication date: 1986-10-23
Anticipated expiration: 1987-10-17
Also published as: EP0220226A1; PT82410B; ZA862791B; PT82410A; AU5663786A; GB8509834D0

Abstract

Compounds of general formula (I) wherein: R1 and R2 are independently hydrogen, C1-6 alkyl or together are a group X which is C3-6 polymethylene optionally interrupted by O, S or NR6 wherein R6 is hydrogen or C1-6 alkyl; R3 is phenyl, optionally substituted by one or more substituents selected from halogen, CF3, nitro, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C2-7 alkanoyl, carboxyl, C1-6 alkoxycarbonyl, cyano, CONR7R8 wherein R7 and R8 are selected from hydrogen or C1-6 alkyl or together are a group X; NR9 R10 wherein R9 and R10 are selected from hydrogen, C1-6 alkyl, C2-7 alkanoyl or C1-6 alkylsulphonyl or together are a group X; SO2NR11R12 wherein R11 and R12 are selected from hydrogen or C1-6 alkyl or together are a group X; or S(O)mR13 wherein m is 1 or 2 and R13 is C1-6 alkyl; R4 and R5 are independently selected from hydrogen, C1-6 alkyl, cyano, amino, aminocarbonyl, or aminocarbamoyl optionally substituted by one or two C1-6 alkyl groups or together are a group X, halogen, CF3, nitro, C1-6 alkoxy, C1-6 alkylthio, C2-7 alkanoyloxy or hydroxy, or together are methylenedioxy or C3-5 polymethylene; are of value in the prophylaxis and treatment of allergic and inflammatory disorders.

Description

NOVEL COMPOUNDS

This invention relates to novel compounds having pharmacological activity, to a process for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of mammals.

Khim-Farm Zh. 15(5) 44 (1981) discloses dihydroisoquinoline derivatives of formula (A):

wherein n is 1 or 2. No pharmacological activity has been disclosed for these compounds.

A novel class of compounds which are dihydroisoquinoline derivatives has now been discovered, these compounds having anti-inflammatory and/or anti-rheumatic activity and/or anti-allergy activity.

Accordingly, the present invention provides a compound of formula (I) or a salt or solvate thereof:

wherein: R₁ and R₂ are independently hydrogen, C_1-6 alkyl or together are a group X which is C_{3 -6} polymethylene optionally interrupted by O, S or NR₆ wherein R₆ is hydrogen or C_1-6 alkyl;

R₃ is phenyl, optionally substituted by one or more substituents selected from halogen, CF₃, nitro, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylthio, C_2-7 alkanoyl, carboxyl, C_1-6 alkoxycarbonyl, cyano, CONR₇R₈ wherein R₇ and R₈ are selected from hydrogen or C_1-6 alkyl or together are a group X;NR₉ R₁₀ wherein R₉ and R₁₀ are selected from hydrogen, C_1-6 alkyl, C_2-7 alkanoyl or C_1-6 alkylsulphonyl or together are a group X; SO₂NR₁₁R₁₂ wherein R₁₁ and R₁₂ are selected from hydrogen or C_1-6 alkyl or together are a group X; or S(O)_mR₁₃ wherein m is 1 or 2 and R₁₃ is C_1-6 alkyl;

R₄ and R₅ are independently selected from hydrogen, C_1-6 alkyl, cyano, amino, aminocarbonyl, or aminocarbamoyl optionally substituted by one or two C_1-6 alkyl groups or together are a group X, halogen, CF₃, nitro, C_1-6 alkoxy, C_1-6 alkylthio, C_2-7 alkanoyloxy or hydroxy, or together are methylenedioxy or C_3-5 polymethylene.

Suitable values for R₁ and R₂ include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec and tert-butyl, or R₁ and R₂ together are χ¹ which is C₄ or C₅ polymethylene or -(CH₂)₂-O-(CH₂)₂-. Preferably R₁ is hydrogen or methyl and R₂ is methyl.

Suitable values for R₃ include phenyl and phenyl substituted by one or more of fluoro, chloro, bromo, CF₃, nitro, methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl, methoxy, ethoxy, n- and iso-propoxy, methylthio, ethylthio, n- and iso-propylthio, acetyl, propionyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, CONH₂,NR₉ ¹R₁₀ ¹ wherein R₉ ¹ and R₁₀ ¹ are selected from hydrogen, methyl, methylsulphonyl or together are a group χ¹ as defined; SO₂ NR₁₁ ¹ R₁₂ ¹ wherein R₁₁ ¹ and R₁₂ ¹ are selected from hydrogen or methyl, methylsulphonyl, ethylsulphonyl, methylsulphinyl or ethylsulphinyl. Favourably R₃ is phenyl optionally substituted by one or two of fluoro, chloro, bromo, CF₃, nitro, methyl, cyano, methoxy, or methylthio, for example 2-chlorophenyl, 2-bromophenyl, 2-fluorophenyl, 2-chloro-6-fluorophenyl, or 4-chlorophenyl.

Suitable values for R₄ and R₅ include hydrogen, methyl, ethyl, n- and iso-propyl, cyano, amino, aminocarbonyl or aminocarbamoyl optionally substituted by one or two methyl groups, fluoro, chloro, bromo, nitro, methoxy, hydroxy, acetoxy, n-butyryloxy or 2,2-dimethylpropionyloxy, or together are methylenedioxy. Favourably R₄ and R₅ are selected from hydrogen, methoxy or hydroxy.

There is a group of compounds within formula (I) of formula (II) :

wherein R₃ ¹ is phenyl optionally substituted by one or two of halo, nitro, cyano or methyl; and the remaining variables are as defined for formula (I). Suitable and preferred values for R₁, R₂ and R₃ ¹ are as described for the corresponding variables in formula (I).

There is a further group of compounds within formula (I) of formula (III):

wherein R₄ ¹ is hydrogen, halogen, C_1-6 alkoxy, C_2-7 alkanoyloxy or hydroxy and R₅ ¹ is C_1-6 alkoxy, C_2-7 alkanoyloxy or hydroxy; or R₄ ¹ and R₅ ¹ together are methylenedioxy; and R₃ ¹ is as defined for formula (II)

Suitable and preferred values for the variable groups are as described for the corresponding variables under formula (I) .

There is a favoured sub-group of compounds within formula (III) of formula (IV):

wherein R₃ ² is phenyl substituted by one or two of fluoro, chloro or bromo or cyano and the remaining variables are as defined for formula (I).

The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable form and/or substantially pure form.

By pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. In the case of salts and solvates the additional ionic and solvent moieties must also be non-toxic.

A substantially pure form will generally be at least 50% pure, excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and still more preferably 95% pure.

One preferred pharmaceutically acceptable form is the crystalline form.

Examples of a pharmaceutically acceptable salt of a compound of formula (I) include the acid addition salts for example the hydrochloride and hydrobromide salts.

Examples of a pharmaceutically acceptable solvate of a compound of formula (I) include the hydrate.

The compounds of the formula (I) can form acid addition salts with acids, such as the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic. Such salts, preferably the pharmaceutically acceptable salts, form an aspect of this invention.

Where compounds of formula (I) form solvates such as hydrates, these also form an aspect of the invention.

The compounds of formula (I) have at least one asymmetric centre and therefore exist in more than one stereoisomeric form. The invention extends to all such forms and to mixtures thereof, including racemates.

The present invention also provides a process for the preparation of a compound of formula (I), which process comprises the reaction of a compound of formula (V):

wherein R₃', R₄' and R₅'are R₃, R₄ and R₅ or groups or atoms convertible thereto; with either

i) R₁'R₂'NCOQ

or

ii) (a) an alkylating agent or (b) a halogenating agent followed by treatment with R₁'R₂'NH where R₁'and R₂'are R₁ and R₂ or groups or atoms convertible thereto and Q is a leaving group; to form a compound of formula (la)

and thereafter where necessary converting R₁' R₂', R₃', R₄'and/or R₅' to R₁, R₂, R₃, R₄ and/or R₅ respectively; and/or forming a salt or solvate thereof.

It will be appreciated that a compound of formula (la) may be converted to a compound of formula (I), or one compound of formula (I) may be converted to another compound of formula (I), by interconversion of suitable substituents. Thus certain compounds of formula (I) are useful intermediates in forming other compounds of the present invention.

Also salts or solvates of the compounds of formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. Accordingly such salts or solvates also form part of this invention.

Suitable values for Q include halogen, such as chloro or bromo, preferably chloro. The reaction i) of a compound of formula (V) with R₁'R₂'NCOQ₁ may either take place in an inert solvent, such as xylene or higher boiling solvent or, more preferably in neat R₁ 'R₂ 'NCOQ₁ at high temperature, for example 150-180ºC, preferably 170-175°C.

Suitable values for the alkyl group in ii) (a) include methyl, ethyl, n- and iso-propyl. Preferably the alkyl group is methyl or ethyl. Suitable alkylating agents include dialkylsulphate, alkyl iodide or trialkyloxonium tetrafluoroborate. The reaction is preferably carried out in an inert solvent such as dichloromethane and the alkylating agent is preferably triethyloxonium tetrafluoroborate. The reaction proceeds through an intermediate of formula (VI) or a salt thereof:

wherein Alk is an alkyl group and the remaining variables are as defined in formula (VI). The intermediate of formula (VIla) is the tetrafluoroborate salt when the alkylating agent is a trialkyloxonium tetrafluoroborate.

HNR₁'R₂'may then be added to the compound of formula (VI), without isolation, and the compound of formula (I) extracted by conventional methods. Alternatively, the compound of formula (VI) may be isolated, and, for example, converted to a salt, such as its hydrochloride salt, before reaction with HNR₁'R₂'. Suitable halogenating agents in ii) b) include phosgene or phosphorous oxychloride. The reaction proceeds through an intermediate of formula (VII):

wherein Hal is a halogen atom, in particular chlorine, and the remaining variables are as defined for formula (VI).

The intermediate of formula (VII) may then be reacted with HNR₁'R₂', with or without prior isolation of the intermediate. If isolated, the intermediate may be converted to a salt, for example its hydrochloride, before reaction.

R₁' and R₂' may be alkyl or acyl groups and converted to R₁/R₂ hydrogen atoms by conventional amine dealkylation or deacylation. When R₁' or R₂' is benzyl or substituted benzyl it may be converted to an R ₁ or R₂ hydrogen atom by catalytic hydrogenation or other method of reduction. Ri'and R₂ as hydrogen atoms may be converted to R₁ and R₂ alkyl groups by conventional amine alkylation, or by acylation followed by reduction. R₁' and R₂' are preferably R₁ and R₂ respectively.

Conversions of substituents on an aromatic group R₃' to obtain R₃ are generally known in the art of aromatic chemistry. For example, a nitro substituent may be converted to an amino group by conventional catalytic hydrogenation. R₃' is preferably R₃.

Compounds of formula (V) may be prepared as follows:

iii) by reaction of a compound of formula (VIII):

wherein L is a leaving group, for example a hydroxyl group, with an acid catalyst, especially polyphosphoric acid, or

iv) by reaction of a compound of formula (IX):

wherein A is CN or CONH₂, with formaldehyde or paraformaldehyde and an acid or with a dihalomethane and a Lewis acid.

In iii) and iv), the groups R₃', R₄' and R₅' are as defined for the compound of formula (V). The compound of formula (VIII) may be prepared by reaction of a compound of formula (X):

with a compound of formula (XI)

When L is OH, then suitable reaction conditions are to reflux the compounds (X) and (XI) in xylene with azeotropic removal of water, following the procedure described by J. Gardent and M. Hamon [Bull. Soc. Chim. France 1966, 556].

As mentioned previously, the compounds of formula ( I ) exist in more than one stereoisomeric form and the processes of the invention produces mixtures thereof. The individual isomers may be separated one from another by resolution using an optically active acid such as tartaric acid. Alternatively, an asymmetric synthesis would offer a route to the individual form. Novel intermediates in the above synthetic routes, particularly compounds of formula (V) and formula (VIII), each form an aspect of the invention, together with the above described processes for their preparation.

The compounds of this invention are indicated as of ulitity in the treatment of rheumatism and arthritis and in the treatment of pain and other inflammatory conditions and also in the treatment of and prophylaxis of bronchial asthma, rhinitis, hay fever and allergic eczema, by their activity in relevant animal disease models.

Accordingly, the present invention further provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaeutically acceptable carrier.

A composition of the invention, which may be prepared by admixture, may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant, preservative in conventional manner. These conventional excipients may be employed in conventional manner, for example as in the preparation of compositions of ketoprofen, indomethacin, naproxeh, acetylsalicyclic acid and other analgesic or anti-inflammatory agents.

A composition of the invention may be adapted for oral, topical, rectal or parenteral - intravenous or intramuscular - administration but oral administration is preferred. A composition of the invention will preferably be in the form of a unit dose, such as a tablet or capsule or a sachet containing reconstitutable powder. A unit dose for inflammatory diseases will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg. The composition may be administered once or more times a day, for example 2, 3 or 4 times daily, so that the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg. Alternatively the unit dose will contain from 2 to 20 mg of a compound of the invention and be administered in multiples, if desired, to give the preceding daily dose.

For use in the treatment or prophylaxis of allergic disorders, in any of the preceding formulations, a suitable dosage unit may contain 0.01 to 500 mg of active ingredient, more suitably 1 to 500 mg for use via the oral route, 0.01 to 10 mg via inhalation, which is preferred. The effective dose of compound depends on the particular compound employed, the condition of the patient and the frequency and route of administration, but in general is in the range of from 0.001 mg/day to 100 mg/day per kilogram of the patient's body weight.

Where appropriate, small amounts of other anti-asthmatics and bronchodilators, for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included. A particular composition of the invention for inflammatory diseases is a hard gelatin capsule containing the required amount of a compound of the invention in the form of a powder or granulate in intimate mixture with a lubricant, such as magnesium stearate, a filler, such as microcrystalline cellulose, and a disintegrant, such as sodium starch glycollate.

Preparations especially suitable for administration to the respiratory tract include, for example, a snuff, an aerosol, a solution for a nebulizer, or a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case the particles of active compound suitably have diameters of less than 50 microns, preferably less than 10 microns.

For topical administration, the preparations may also be presented as an ointment, cream, lotion, gel, gelstick, spray, aerosol, mouth wash or skin paint or in any other vehicle suitable for topical application.

The present invention additionally provides a method of treating an inflammatory and/or a painful condition such as rheumatism and/or allergic conditions in mammals, such as humans, which comprises administering an effective amount of a compound, pharmaceutically acceptable salt or solvate, or composition of the invention to the mammal.

The present invention also provides a compound, pharmaceutically acceptable salt or solvate, or composition of the invention for use as an active therapeutic substance, particularly in the treatment of inflammatory and/or painful conditions, such as rheumatism, and/or allergic conditions in mammals. The present invention further provides the use of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of inflammatory and/or painful conditions, and/or allergic conditions.

The following Descriptions and Examples illustrate the preparation of compounds of the invention and the following biological data illustrates their pharmacological activity. All temperatures are expressed in °C.

DESCRIPTION 1

N-benzyl-2-chloromandelamide (D1)

The procedure of J. Gardent and M. Hamon [Bull. Soc. Cnim. France 1966, 556] was followed. Thus a mixture of 2-chloromandelic acid (20 g, 108 mmol) and benzylamine (11.5 g, 107 mmol) were heated to reflux temperature in xylene (230 ml) and the water so formed was removed azeotropically. After 27 h, the solution was cooled to 95°, filtered and allowed to cool to 20°. After 16 h, the solid so formed was filtered off, washed with n-pentane (2x50 ml), water (2x80 ml) and dried in the vacuum oven (60°/3mm). This gave the desired product (26.9 g, 91%) m.p. 77-77.5°. Analysis: C₁₅H₁₄NO₂CI requires: C, 65.34; H,5.12; N,5.08; Cl,12.86%. Found: C,65.34; H,5.08; N,5.02; Cl,12.96%. Similarly prepared were the compounds of Description 2 and Description 3:-

DESCRIPTION 2

N-benzyl-4-chloromandelamide (D2)

from 4-chloromandelic acid and benzylamine m.p. 105-7° (Toluene)

Analysis: C₁₅H₁₄NO₂CI requires: C, 65.34; H,5.12;

N,5.08; Cl,12.86%. Found: C,65.35; H,5.05; N,5.02;

Cl,12.57%.

DESCRIPTION 3

N-( 3-methoxybenzyl)-2-chloromandelamide (D3)

from 2-chloromandelic acid and 3-methoxybenzylamine

(oil)

Analysis: C₁₆H₁₆NO₃Cl requires: C, 62.85; H,5.27;

N,4.58; Cl,11.59%. Found: C,62.94; H,5.40; N,4.64;

Cl,11.61%. DESCRIPTION 4

4-(2-Chlorophenyl)-1,4-dihydroisoquinol-3-one (D4 )

A variation of the procedure of J. Gardent and M. Hamon [Bull. Soc. Chim. France 1966, 556] was used. Thus N-benzyl-2-chloromandelamide (25.8 g, 94 mmol) was added to stirred polyphosphoric acid (180 ml) and the mixture was warmed at 75° for 2 h, cooled to room temperature for 16 h, warmed at 75° for a further 2 h and was poured into ice/water (1.6 litres). The mixture was stirred for 3 h, filtered and air dried. The residue was triturated with ethanol (600 ml), cooled and filtered and the solid washed with ethanol. The combined ethanol layers were evaporated and the residue was treated with hot ethanol (60 ml) as above. The solid was filtered off and was washed with ethanol (2x20 ml) and dried under reduced pressure. This gave 4-(2-chlorophenyl)-1,2-dihydroisoquinol-3-one (14.4 g, 60%), m.p. 207-9° (Ethanol). Analysis: C₁₅H₁₂NOCI requires: C,69.91; H,4.69; N,5.43; Cl,13.76%. Found: C,69.81; H,4.64; N,5.36; Cl, 13.83%.

Similarly prepared was:- DESCRIPTION 5

4-(4-Chlorophenyl)-1,4-dihydroisoquinol-3-one (D5 )

from N-benzyl-4-chloromandelamide m.p. 182-4° (Ethanol)

Analysis: C₁₅H₁₂NOCI requires: C69.91; H,4.69;

N,5.43; Cl,13.76%. Found: C,69.54; H,4.62; N,5.35;

Cl,14.09%.

DESCRIPTION 6 and 7

4-(2-Chloroρhenyl)-5-methoxy-1,4-dihydroisoquinol-3-one (D 6) and 4-(2-chlorophenyl)-7-methoxy-1,4-dihydroisoquinol-3-one (D7)

DESCRIPTION 6 DESCRIPTION 7

To well stirred polyphosphoric acid (200 g) held at 65°, was added N-(3-methoxybenzyl)-2-chloromandelic amide over twenty min. The mixture was stirred for 2½h and poured into ice/water (1 litre). The solid so formed was filtered and air dried to give a pale yellow solid (8 g) . This material was chromatographed on silica gel (200 g) using chloroform as eluent. 4- (2-chlorophenyl ) -5-methoxy-1 , 4-dihydroisoquinol-3-one (D6) was eluted first:- m.p. 281-3° (Ethanol) Analysis: C₁₆N₁₄NO₂CI requires: C,66.79; H,4.90; N.4.87; Cl,12.32%. Found: C,66.54; H,4.70; N,4.82; Cl, 12.42%.

Further elution gave 4-(2-chlorophenyl)-7-methoxy-1,4-dihydroisoquinol-3-one (D7):- m.p. 177-9° (Ethanol) Analysis: C₁₆H₁₄NO₂CI requires: C,66.79; H,4.90; N,4.87; Cl,12.32%. Found: C, 66.78; H,4.93; N,4.82.

Prepared in a similar manner to the compound of Description 1 was:-

DESCRIPTION 8

N-Benzyl-2-fluoromandelamide (D8)

From 2-fluoromandelic acid and benzylamine. m.p. 90-2° (toluene). Analysis: C₁₅H₁₄NO₂F requires: C, 69.49; H,5.44; N,5.40%. Found: C,69.43; H,5.41; N,5.28%.

Prepared in a similar manner to the compound of Description 4 was:- DESCRIPTION 9

4- (2-Fluorophenyl)-1,4-dihydroisoquinol-3-one (D9 )

From N-Benzyl-2-fluoromandelamide. m.p. 203-5° (ethanol)

Analysis: C₁₅H₁₂NOF requires: C, 74.68; H,5.01;

N,5.81%. Found: C, 74.77; H,5.11; N,5.99%.

EXAMPLE 1

4-(2-Chlorophenyl)-3-dimethylamino-1,4-dihydroisoquinoline hydrochloride (El)

4-(2-chlorophenyl)-1,4-dihydroisoquinol-3-one (D4) (13.2 g, 51 mmol) was heated and stirred in dimethylcarbamyl chloride (oil bath temperature 168°) for 2 h. The solution was cooled, evaporated under reduced pressure and was partitioned between water (180 ml), 5M hydrochloric acid (10 ml), ethyl acetate (120 ml) and chloroform (80 ml). The organic layer was separated and extracted with water (50 ml). The combined aqueous layers were washed with ethyl acetate (3x30 ml), cooled in ice and basified (10% sodium hydroxide) to pH 14. The oil so formed was extracted with ethyl acetate (2x150 ml) and the combined ethyl acetate layers were washed with brine (50 ml) and dried over sodium sulphate. The solution was filtered and reduced to 100 ml under reduced pressure. Ethereal hydrogen chloride was added to precipitate the salt. The solvent was removed under reduced pressure to give 4-(2-chloro-phenyl)-3-dimethylamino-1, 4-dihydroisoquinoline hydrochloride (3.2 g, 19%). m.p. 262-5° (Chloroform/Dichloroethane/Ethyl acetate). I.R. v_max (Nujol) 1660 cm^-1. N.M.R. (CDCI₃) δ 3.2 and 3.6 (2x3H, s), 5.1 (2H, b) , 5.8 (1H, bs) , 7.0-7.8 (8H, m) , 12.1 (1H, b exchanges on D₂O shake). H.R.M.S. (m/z) C₁₇H₁₇N₂CI requires 284.1081; found, 284.1065. Similarly prepared were:-

EXAMPLE 2

4-(4-Chlorophenyl)-3-dimethylamino-1,4-dihydroisoquinoline hydrochloride (E2 )

From 4-(4-Chlorophenyl)-1,4- dihydroisoquinol-3-one (D5) and dimethylcarbamyl chloride. m.p. 305-7° (Ethanol/Ethyl Acetate) Analysis: C₁₇H₁₈N₂Cl requires C,63.56; H,5.65; N,8.72; Cl,22.07%. Found: C,63,42; H,5.75; N,8.56; Cl, 22.38%. EXAMPLE 3

4- (2-Chlorophenyl ) -3-dimethylamino-7-methoxy-1 , 4-dihydroisoquinoline hydrochloride hydrate ( E3 )

From 4-(2-chlorophenyl)-7-methoxy-1,4- dihydroisoquinol-3-one (D7) and dimethylcarbamyl chloride. m.p. 242-4° ( chloroform/dichloroethane/ ethanol/ethyl acetate).

Analysis: C₁₈H₂₀N2OCl₂.H₂o requires C, 58.54: H,6.01; N,7.58%. Found C,58.54; H,5.76; N,7.58%.

EXAMPLE 4

4- (2-Chlorophenyl)-3-dimethylamino-5-methoxy-1,4-dihydroisoquinoline hydrochloride (E4)

From 4-(2-chloroρhenyl)-5-methoxy-1,4-dihydroisoquinol -3-one (D6) and dimethylcarbamyl chloride m.p. 258-61° (chloroform/dichloroethane/ethanol/ethyl acetate) . Analysis: C₁₈H₂₀N₂OCl₂ requires C,61.55; H,5.74; N,7.97%. Found C, 61.15; H,5.69; N,7.94%.

EXAMPLE 5

4- ( 2-fluorophenyl)-3-dimethylamino-1,4-dihydroisoquinoline hydrochloride (E5)

From 4-(2-fluorophenyl)-1,4-dihydroisoquinol-3-one

(D9). m.p. 218-21° ( toluene/dichloroethane) n.m.r. (CDCl₃/d⁶DMSO) δ 3.3 (2x3H, 2xs)

4.8 (2H, bs)

5.9 (1H, bs)

HRMS C₁₇H₁₇N₂F requires m/z 268.1376, found m/z 268.1370.

EXAMPLE 6

4-( 2-Chlorophenyl)-3-dimethylamino-7-hydroxy-1,4-dihydroisoquinoline hydrobromide (E6)

4- (2-Chlorophenyl)-3-dimethylamino-7-methoxy-1,4- dihydroisoquinoline hydrochloride (E3) (1.3g) was heated, and stirred, at 110° in 46% HBr (aq.) for three and a half hours. The dark solution was cooled and evaporated under reduced pressure to give 4-(2-chloro phenyl)-3-dimethylamino-7-hydroxy-1,4-dihydroisoquinoline hydrobromide 0.5g, m.p. 269-74° (ethanol/ethyl acetate).

Analysis: C₁₇H₁₃N₂OClBr requires: C, 53.49; H,4.75; N,7.34%. Found: C,53.58; H,4.96; N,7.23%.

Similarly prepared as Example 6 was

EXAMPLE 7

4-(2-Chlorophenyl)-3-dimethylamino-5-hydroxy-1,4-dihydroisoquinoline hydrobromide (E7)

From 4-(2-Chlorophenyl)-3-dimethylamino-5-methoxy-1,4-dihydroisoquinoline hydrochloride (E4). m.p. 288-92° (methanol/ethanol/ethyl acetate). n.m.r. (CDCl₃/d⁶DMSO) δ 3.4 (2x3H, 2xs)

5.0 (2H, br)

5.8 (1H, br) H.R.M.S. C₁₇H₁₇N₂OCI requires m/z 300.1029, found m/z 300.1003. ADJUVANT ARTHRITIS TEST IN THE RAT The test is as described by Newbould, Brit. J. Pharmacol., 1963, 21, 127-136.

In this test, the compounds of Examples 1 and 2 were active at 25mg/kg (p.o.) and 12.5 mg/kg (p.o.) respectively.

CARRAGEENIN-INDUCED PLEURISY IN THE RAT This model of monocyte accumulation is based on the method of R. Vinegar, J.F. Truax, J.L. Selph and F.A. Voelker [Federation Proceedings 41, 2588-2595, 1982].

0.2 ml of a 2.0% solution of λ-carrageenin (Viscarin 402) in saline was injected intrapleurally in anaesthetised rats (wt. approx. 175-200g). Compounds were administered 1 hour before carrageenin and at 24 and 48 hours after carrageenin. 72 hours after carrageenin injection, 4.0 ml of EDTA solution (5g EDTA in 100 ml of 0.9% saline and 325 mg phenol red added together with saline to 1 litre) was injected intrapleurally after killing the animals, and the exudate removed with a syringe through the diaphragm. Exudate volume was measured spectrophotometrically (560 nm) and cellular content estimated with a DNA assay [Karsten U. and Wollenberger A. Anal. Biochem. 77, 464-470, 1977].

Compounds were active in this test at the following doses.

Example 2 9 mg/kg (p.o.) Example 4 12 mg/kg (p.o.) Example 7 15 mg/kg (p.o.)

No toxic effects were observed in the above tests using the cited compounds at the indicated doses.

Claims

1. A compound of formula (I) or a salt or solvate thereof:

wherein:

R₁ and R₂ are independently hydrogen, C_1-6 alkyl or together are a group X which is C_3-6 polymethylene optionally interrupted by O, S or NR₆ wherein R₆ is hydrogen or C_1-6 alkyl;

R₃ is phenyl, optionally substituted by one or more substituents selected from halogen, CF₃, nitro, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylthio, C_2-7 alkanoyl, carboxyl, C_1-6 alkoxycarbonyl, cyano, CONR₇R₈ wherein R₇ and R₈ are selected from hydrogen or C_1-6 alkyl or together are a group X;NR₉ R₁₀ wherein R₉ and R₁₀ are selected from hydrogen, C_1-6 alkyl, C_2-7 alkanoyl or C_1-6 alkylsulphonyl or together are a group X; SO₂NR₁₁R₁₂ wherein R₁₁ and R₁₂ are selected from hydrogen or C_1-6 alkyl or together are a group X; or S(O)_mR₁₃ wherein m is 1 or 2 and R₁₃ is C_1-6 alkyl; R₄ and R₅ are independently selected from hydrogen, C_1-6 alkyl, cyano, amino, aminocarbonyl, or aminocarbamoyl optionally substituted by one or two C_1-6 alkyl groups or together are a group X, halogen, CF₃, nitro, C_1-6 alkoxy, C_1-6 alkylthio, C_2-7 alkanoyloxy or hydroxy, or together are methylenedioxy or C_3-5 polymethylene.

2. A compound according to claim 1 in which R₁ and R₂ are selected from hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec and tert-butyl, or R₁ and R₂ together are χ¹ which is C₄ or C₅ polymethylene or -(CH₂)2-O-(CH₂)₂-.

3. A compound according to claim 1 or 2 in which R₃ is selected from phenyl and phenyl substituted by one or more of fluoro, chloro, bromo, CF₃, nitro, methyl, ethyl, n- and iso-propyl, n-, sec-and tert-butyl, methoxy, ethoxy, n- and iso-propoxy, methylthio, ethylthio, n- and iso-propylthio, acetyl, propionyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, CONH₂, NR₉ ¹R₁₀ ¹ wherein R₉ ¹ and R₁₀ ¹ are selected from hydrogen, methyl, methylsulphonyl or together are a group χ¹ as defined; SO₂ NR₁₁ ¹ R₁₂ ¹ wherein R _{1 1} ¹ and R₁₂ ¹ are selected from hydrogen or methyl, methylsulphonyl, ethylsulphonyl, methylsulphinyl or ethylsulphinyl.

4. A compound according to any one of claims 1 to 3 in which R₄ and R₅ are selected from hydrogen, methyl, ethyl, n- and iso-propyl, cyano; amino, aminocarbonyl or aminocarbamoyl optionally substituted by one or two methyl groups; fluoro, chloro, bromo, nitro, methoxy, hydroxy, acetoxy, n-butyryloxy or 2,2-dimethylpropionyloxy; or together are methylenedioxy.

5. A compound according to claim 1 which is selected from:

4-(2-chlorophenyl-3-dimethylamino-1,4- dihydroisoquinoline;

4-(4-chlorophenyl)-3-dimethylamino-1,4-dihydroisoquinoline;

4-(2-chlorophenyl)-3-dimethylamino-7-methoxy-1,4-dihydroisoquinoline;

4-(2-chlorophenyl)-3-dimethylamino-5-methoxy-1,4-dihydroisoquinoline;

4-(2-fluorophenyl)-3-dimethylamino-1,4-dihydroisoquinoline;

4-(2-chlorophenyl)-3-dimethylamino-7-hydroxy-1,4-dihydroisoquinoline;

4- (2-chlorophenyl)-3-dimethylamino-5-hydroxy-1,4-dihydroisoquinoline;

and salts and/or solvates thereof.

6. A compound, salt or solvate according to any one of claims 1 to 10 which is in pharmaceutically acceptable form and/or substantially pure form.

7. A compound of formula (V):

in which R₁ , R₂ , R₃, R₄ and R₅ are as defined in claim 1.

8. A compound according to claim 7 which is selected from:

4-(2-chlorophenyl)-1,4-dihydroisoquinol-3-one;

4-(4-chlorophenyl)-1,4-dihydroisoquinol-3-one;

4-(2-chlorophenyl)-5-methoxy-1,4-dihydroisoquinol-3-one

4-(2-chlorophenyl)-7-methoxy-1,4-dihydroisoquino1-3-one and

4-(2-fluorophenyl)-1,4-dihydroisoquinol-3-one;

9. A process for the preparation of a compound of formula (I), as claimed in claim 1, which process comprises the reaction of a compound of formula (V):

i) R₁'R₂'NCOQ

or

ii) (a) an alkylating agent or (b) a halogenating agent followed by treatment with R₁ 'R₂ 'NH

where R₁'and R₂'are R₁ and R₂ or groups or atoms convertible thereto and Q is a leaving group;

to form a compound of formula (la)

and thereafter where necessary converting R₁', R₂', R₃', R₄' and/or R5' to R₁, R₂, R₃, R₄ and/or R₅ respectively; and/or forming a salt or solvate thereof.

10. A pharmaceutical composition, which comprises a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

11. A compound as claimed in claim 1 or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance, particularly in the treatment of inflammatory and/or painful conditions, such as rheumatism, and/or allergic conditions in mammals.

12. The use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of inflammatory and/or painful conditions, and/or allergic conditions.