GB2184443A - Indole derivatives - Google Patents

Description

1 -1 1 GB2184443A 1

SPECIFICATION

Indole derivatives This invention relates to indole derivatives possessing pharmaceutical activity, more particularly 5 to indolylpiperidine derivatives, processes for their preparation and pharmaceutical compositions containing them.

In our UK Patent Specification No. 1,218,570 there are described and claimed a class of indole derivatives possessing (inter alia) antihypertensive activity and having the formula:

in which formula - N RI- NHCZR 5 3 R 7-1 Q [\I 4 N R2 R CA NHCM 5 represents a ring system of the general formula NHCOR NHCOR 5 WC7 5 35 G L-R N N:

Q 40 T4 4 R X (E) 11C) 110) 116) 45 R' represents hydrogen, lower alky], lower aralkyl or aroyl, R2 represents hydrogen, lower alkyl or ary], R3 represents hydrogen, halogen, lower alkoxy, hydroxy or lower alkyl R4 represents hydrogen, halogen or lower alkyl, R5 represents aryl (including heterocyclic aryl), lower alkoxy, 50 aryloxy, lower aralkyl, lower aralkyloxy or diaryHower alkyl, XO is an anion, A represents an alkylene or mono- or di-keto alkylene radical containing up to 4 carbon atoms, and Z is an oxo (i.e. =0) group with the proviso that Z in formula ll(c) may also represent two hydrogen atoms when A is alkylene and R5 is aryl.

Examples of heterocyclic aryl groups for R5 were given as 3-indoly], 2thienyl and 2-furyl. One 55 of the compounds falling within the scope of formula A is a valuable anti hypertensive agent having the generic name indoramin and the chemical name 3-[2-(4-benzamido- l-piperidyi)-ethyllindole.

Indoramin is used for the treatment of elevated blood pressure in patients and is extensively described in the literature, see-for example -Indoramin in the Treatment of hypertension- The 60 Practitioner, October 1983 Vol. 227 page 1677. As UK Patent Specification No. 1,218,570 acknowledges, the compounds of formula A also possess central nervous system activity and in the case of indoramin such activity is manifest as sedation in a proportion of patients. Latest available figures suggest sedation is not serious but is the main side effect occurring in about 18 per cent of patients. It appears to contribute to the withdrawal of only 3.8% of patients which 65 2 GB2184443A 2 is regarded as very acceptable in the context of antihypertensive treatment. Nevertheless sedation is the dose limiting side effect for indoramin.

We have surprisingly found a class of bicyclic nitrogen containing heteroaryl compounds, more specifically quinolyl and isoquinolyl derivatives, failing within the scope of formula A, which compounds possess antihypertensive activity of the same order as indoramin but do not have the same propensity as indoramin to cause depression of the central nervous system. In particular sedation is less likely to occur.

Accordingly this invention provides compounds of formula:

R3 P A-ND-NHCO N R2 H wherein R, is hydrogen, lower alkyl, halogen, lower alkoxy or hydroxy; R2 represents hydrogen 20 or lower alkyl; A represents an alkylene, oxoalkylene or hydroxyalkylene chain each having 2 to 6 carbon atoms, R3 and R, may be in the same or different rings and independently represent hydrogen, lower alkyl, lower alkoxy, amino or halogen and one of X and Y represents nitrogen the other represents CR, wherein R, is one of the values for R, or R, is the bond to the NI-IC0 group; and pharmaceutically acceptable salts thereof.

By the term lower as used herein is meant groups having 1 to 6 carbon atoms, preferably 1 to 4. Examples of lower alkyl groups for each of R, R2, R3, R, and R, are methyl, ethyl, n-propyl and isopropyl.

Examples of lower alkoxy groups for R, are methoxy, ethoxy, n-propoxy and n-butoxy.

Examples of alkylene chains for A are -(CH2)6-1 -CO(CH2)Fi, and CHOH(CH2)i7I., in which n is 30 an integer from 2 to 4. Branched chain groups are also included such as CH, 1 -CH2CH- at least 2 carbon atoms in the main chain linking indole to piperidine. Other examples include CH, 1 -COCH- and CH, 1 -CHOH-CH Preferred halogen groups for R, R3, R4 and R, include chlorine and bromine. When Y is nitrogen the compounds are isoquinolyl derivatives and when X is nitrogen they are quinoly] 50 derivatives.

The quinolyl and isoquinolyl group is bonded to the -NHCO- group via any of the ring carbon atoms and is preferably quinol-4-yI, or quinol-3-yl or quinol-6-yl. Other examples include isoqui nol-3-yl, isoquinol-4-yl and quinol-2-yl. Such groups may be substituted as above.

The compounds of formula 1 possess pharmaceutical activity, in particular antihypertensive and/or hypotensive activity when tested on warm blooded animals and hence are indicated for the treatment of high blood pressure.

The compounds of formula 1 were tested for antihypertensive activity by the following standard procedure.

The blood pressures of male or female spontaneously hypertensive rats are measured in a 37'C constant temperature housing by means of a tail cuff. Rats with systolic pressures below 155 mmHg are discarded. Groups of rats are dosed orally with the test substance in a suitable vehicle or with vehicle alone. Systolic pressures are recorded before dosing and at selected time points afterwards. Heart rates are derived from caudal artery pulses. Results are analysed statistically by means of 2 way analysis of variance (within group).

c 1 4 3 GB2184443A 3 In this procedure representative compounds of the invention gave the results shown in the following Table:- 1%.

TABLE 1

COMPOUND DOSE/LEVEL BLOOD PRESSURE (mmol/kg po) as % of pre-dose level (time t after dosing) t = 2 hrs.

6 hrs 0:p, 1 1 H 2 CH 2NC- NHCO-[quinol-4-yll 0.15 78% 73% ZLI, 7N H CH2 CH 2 GNHCO-[quinol-3-y1] 0.15 N H 55% 66% CH2 CH 2NC- NHCO-[quinol-6-yll 0.15 80% 57% N H CH 2 CH 2 NCNHCO-Ph 0.15 62% 66% 1 7NDA H (indoramin) c) W hi co 4h.

_Pb -bW -pb GB2184443A 5 The results in Table 1 show that the representative compounds of this invention possess the same order of antihypertensive activity as the commercially available antihypertensive agent indoramin.

The compounds of formula 1 were also tested for central nervous system activity in mice specifically to determine whether and at what dose levels symptoms associated with sedation 5 were present. The following test procedure was used:

Groups of three female mice (18-25g) are dosed with the test compound. The usual doses tested are 400, 127, 40 and 12.7 mg/kg and both the oral and intraperitoneal routes are used.

The drug is routinely suspended in 5% hydroxy-propyimethylcellulose (HPMC).

The animals are observed over a two hour period. The activities looked for during the observation period include:

i) signs of general stimulation (i.e. increased motor activity, tremor, stereotypy) ii) signs of general depression (i.e. decreased motor activity, sedation, hypothermia The following results were obtained for representative compounds of formula 1:

1 0 v 0) TABLE 2

COMPOUND Sedation CH 2 CH 2 D G NHCO-[quinol-4-yll > 400 NT H CH 2 CH 2 N N H NHCO-[quinol-3-yll > 400 HCH GNHCO-[qu 2 H H CH -NO-NHCOPh 2 2 CNj H (indoramin) -1 inol-6-yll Drug level at which following symptoms were first observed (mg/kg) Hypothermia Decreased Motor Activity > 400 400 400 400 127 4 0) 7 GB2184443A 7 A The results in Table 2 show the compounds of formula 1 are much weaker MS depressants than indoramin requiring much high dose levels to produce the symptoms of sedation, hypothermia and decreased motor activity. Accordingly, the compounds of formula 1 whilst being as potent as indoramin in lowering blood pressure are much more selective in that they do not 5 have the same propensity to cause depression in the MS.

This invention also provides processes for preparing the compounds of formula 1. In general these methods correspond to those for preparing the compounds of formula A described in UK Patent specification Nos. 1,218, 570, 1,375,836, 1,399,608, 1,543,619 and 1,542,137 and generally involve building up the molecule in known manner from appropriate starting materials 10 comprising reactive substituent groups.

A first process for preparing compounds of formula 1 which comprises acylating a compound of formula 11 A -N,NH R1 -C NC 2 1 R2 H with an acid of formula R4 25 HOO 30 or a reactive derivative thereof, wherein A, R,, R2, R3 and R, are as defined above and one of X, and Y1 is nitrogen the other is CR. where R6 is one of the values defined for R, or the bond to the COOH group.

As reactive derivatives of the acid of formula Ill mention is made of the acid halide, e.g. 35 chloride or the anhydride, e.g. mixed anhydride, which derivatives give corresponding compounds of formula 1 Acids of formula Ill may also be coupled to the amine of formula 11 by using a coupling reagent such as those well known in the art of peptide chemistry, in particular a carbodiimide e.g. dicyclohexylcarbodiimide. Other reactive derivatives of the acids of formula Ill include ester 40 derivatives, e.g. methyl, phenyl or substituted phenyl esters such as nitro- or halo-substituted phenyl esters.

In a second general process compounds of formula 1 may be prepared by reacting a com pound of formula 45 A N H R2 50 (V) with a compound of general formula:

3 R 14 H-N3-NHCO 1 X.

(V1) 8 GB2184443A 8 in which formulae X,YAR1,132,1R,R4 are as defined above and T is a halogen atom or an equivalent replaceable radical, e.g. an organic sulphonyl radical such as tosyl. Examples of T are chlorine, bromine. Alternatively T can represent OH in which case the reaction may be effected using a catalyst, e.g. Raney nickel, according to the procedure set forth in UK Pat.Spec.No. 5 1,375,836.

The starting materials of general formula V are known compounds or can be made following the methods known for preparing compounds of this type, e. g. by reducing the corresponding carboxyl compounds followed by halogenation. The starting material of general formula VI can be prepared by forming the oxime of a N-benzyi-4-piperidone, reducing to give the amine, 10 acylating with an acid of general formula 3 R4 15 HOO or a reactive derivative thereof, as described above in connection with the first process, and 20 then hydrogenolysing to replace the N-benzyl group by N-H.

In a third process compounds of formula 1 may be prepared by reducing compounds of formula R 4 A- NHCO R1 Z- 11 o.-. X"l_y <)EJ N Rn H IL-1 wherein -N is a ring system of formula )N'/-- (VIT.) ze or N/ - (VID (V116) X, Y, A and R,4 are as defined above and ZO is an anion. Methods for carrying out this 55 reduction are extensively described in our UK Patent Specifications Nos. 1218570 and 1542137.

For example reduction of either ring system VIIa or V11b may be carried out using an alkali metal borohydride in a secondary alkanol solvent having 3-5 carbon atoms, e.g. isopropanol. Alterna tively reduction may be effected by catalytic hydrogenation, e.g. using palladium on charcoal.

Starting materials of formula VII having a ring system VIIa may be prepared by acylating a 4- 60 amino-pyridine with an acid of formula Ill, or a reactive derivative thereof, and reacting the product with a compound of formula V in the manner described for the first process. Com pounds of formula VII having a ring system of formula Vilb can be prepared by reducing a corresponding compound of formula VII having a ring system Vila using an alkali metal borohy- dride in methanol solvent. In any of the aforementioned reductions, when A is oxoalkylene, such 65 1 9 GB2184443A 9 groups may also be reduced to alkylene or hydroxyalkylene or if desired may be protected by methods known in the art, e.g. by forming a ketal.

Accordingly this invention also provides a further process for preparing compounds of formula 1 wherein A is lower alkylene or hydroxyalkylene which comprises reducing a compound of formula 1 wherein A is oxoalkylene.

Yet a further process for preparing compounds of formula 1 comprises carrying out a Fischer indole synthesis on a compound of general formula R F-a N-N=C 1 H 1 R2 CH2 -A-NYNHCO P3 _ 1 wherein X, Y, R, IR,, R2, R3, R4 and A are as defined above.

The starting material can be prepared by condensing a phenyl hydrazine of formula RdD,' N-NH2 UX) H with an aldehyde or ketone of general formula 1 0 =C "2 Z, P3 P4 CH;-A-N3-NHCO y X" (X) in which formulae X, Y, R, R2, R31 R4 and A are as defined above.

The reactions outlined above usually are carried out in a solvent which is inert under the reaction conditions, for example an alcohol such as methanol, ethanol or propan-2-ol, ether, dioxane, dimethylformamide, pyridine, water, dimethoxy-ethane, methylene chloride, tetrahydrofuran and acetic acid or mixtures of such solvents. The most suitable solvent system is chosen and varies depending on the particular reactants being employed. If necessary heating the reactants in solution under reflux can be carried out, and if necessary heating under high pressures may also be used.

A still further process for preparing a compound of formula 1 comprises treating a compound 55 of formula XI GB2184443A 10 e 3 R4 A N NHCO J3- to R1 1 1)CY 17 eN R2 H 1 ZE) (Xl) P7 10 1 wherein R,-,, X and Y are as defined above, R, is an organic quaternizing group which can be removed under mild conditions, e.g. hydrogenolysis, and ZO is an anion, under mild conditions 15 effective to remove the group R, For a description of this process and methods for making compounds of formula XI see UK Patent Specification No. 1,399,608.

Compounds of formula 1 wherein A is an alkylene chain may be prepared from corresponding compounds of formula 1 wherein A is -CO(CHA,- by reduction according to the process de scribed in UK Patent Specification No. 1,543,619 using an alkali metal borohydride in a solvent 20 such as alkanols of 2 to 4 carbon atoms, glycol ethers or dioxane.

If necessary, in any of the reactions hereinbefore described, reactive substituent groups may be blocked during a reaction and released at a later stage. As already indicated the novel compounds provided by the invention contain a basic nitrogen atom and thus can form acid addition salts with acids (particularly pharmaceutical ly acceptable acids) or quaternary ammonium salts, for example with alkyl halides or aralkyl halides (particualrly methyl iodide or benzy] chloride or bromide). The acid addition salts may either be formed in situ during the hereinbefore described processes and isolated therefrom or a free base may be treated with the appropriate acid in the presence of a suitable solvent and then the salt isolated. The quaternary salts may be prepared by treating the free base with the appropriate halide in.the presence or absence of 30 a solvent.

Examples of acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic and p-toluenesulphonic acids.

The invention provides a pharmaceutical composition comprising a compound of formula 1 or a 35 pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier.

Any suitable carrier known in the art can be used to prepare the pharmaceutical compositions. In such a composition, the carrier may be a solid, liquid or mixture of a solid and a liquid. Solid form compositions include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, 40 binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99%, preferably 10-80% of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl-cellulose, sodium carboxymethyl cellulose, a low melting wax and cocoa butter. The term -composition- is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it. 50 Similarly cachets are included. Sterile liquid form compositions include sterile solutions, suspen sions, emulsions, syrups and elixirs. The active ingredients can be dissolved or suspended in a pharmaceutically acceptable sterile liquid carrier, such as sterile water, sterile organic solvent or a mixture of both. Preferably a liquid carrier is one suitable for parenteral injection. Where the active ingredient is sufficiently soluble it can be dissolved in normal saline as a carrier; if it is too 55 insoluble for this it can often be dissolved in suitable organic solvent, for instance aqueous propylene glycol or polyethylene glycol solutions. Aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable. In other instances other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxy methyl cellulose solution, or in a suitable oil, for instance arachis oil. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by intramuscular, intraper itoneal or subcutaneous injection. In many instances a compound is orally active and can be administered orally either in liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.

In such form, the composition is sub-divided in unit doses containing appropriate quantities of 65 11 GB2184443A 11 the active ingredients; the unit dosage forms can be packaged compositions, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of any of these in package form. The quantity of the active ingredient in a unit dose of composition may be varied or adjusted from 5 mg. or less to 500 mg. or more, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of the carrier where the compounds are in unit dosage form.

The following Examples illustrate the invention:

EXAMPLE 1 N-[ 1-(2-[indol-3-yllethyl)piperid-4-yllquinotine-6-carboxamide A solution of isobutylchloroformate (0.65g, 5.01 mmol) in dry THF (10 cm3) was added dropwise to a suspension of qwinoline-6-carboxylic acid (0. 87g, 5.03 mmol) and triethylamine (0.69, 5.94 mmol) in dry THF (10 cm3) with stirring and cooling at -20'C. Stirring was continued while the temperature rose to ambient over 2 hours, then the mixture was cooled to 15 -20'C again and a solution of 3-[2-(4-amino-l-piperidyi)ethyi]indole (1. 20 9, 4.94 mmol) in dry THF (20 CM3) was added dropwise. The mixture was stirred at room temperature overnight then evaporated to dryness and the residue triturated with water, aqueous potassium carbonate and water to give 1.4 9. of the title compound.

The sample was suspended in boiling ethanol and ethanolic HCI added to give an acidic 20 solution which rapidly crystallised. After cooling in ice for 1,5 hours the solid was collected and washed well with ethanol on the sinter. Drying at 80' in vacuo gave 1.42g of the dihydrochlo ride hernihydrate salt of the title compound, m.p. 273-5'C (dec).

Analysis:

Found: C, 62.72; H, 6.07; N, 11.42% C,,H,,N40.2HCI.IH,0 requires C, 62.50; H, 6.08; N, 11.66%.

2 EXAMPLE 2

N-[ 1-(2-[indole3-yllethyl)piperid-4-yllquinoline-3-carboxamide Quinoline-3-carboxylic acid (0.879, 5.03 mmol) was refluxed in thionyl chloride (8 CM3) for 1.3 30 hours. The solvent was evaporated, then toluene added to the residue and evaporated twice.

The resulting qtinoline-3-carbonyl chloride hydrochloride (0.80 g, 3.51 mmol) was added to a rapidly-stirred suspension of 3-[2-(4-amino-l-piperidyl)-ethyllindole (0. 85g, 3.50 mmol) in dichlo romethane (10 CM3). The mixture was stirred overnight then the solid collected and suspended in boiling ethanol. Water and ethanolic HCI were added to give an acidic solution which was cooled 35 in ice. A solid was deposited and collected. Recrystallisation of the solid twice from aqueous ethanol and drying gave the title compound as the dihydrochloride, one and a quarter hydrate salt (0.80 g,) mp=183-5'C. Analysis:

Found: C, 60.51; H, 6.52; N, 11.55% C,,H,^0.21-ICIA1H20 requires C, 60.79; H, 6.22; N, 11.34%.

4 f EXAMPLE 3

N-[ 1-(2-[indol-3-yllethyl)piperid-4-yll-quinoline-4-carboxamide A suspension of quinoline-4-carboxylic acid (0.87g, 5.03 mmol) and triethylamine (0.6g, 5.94 45 mmol) in dry THF (10 CM3) was stirred at -20'C while a solution of isobutylchloroformate (0.65g, 5.01 mmol) was added dropwise. The mixture was allowed to warm to room tempera ture over 31. hours then was cooled to -20'C again and a solution of 3-[2(4-amino-l-piperidy 2 1)ethyllindole (1.2g, 4.94 mmol) in dry THF (20 CM3) was added dropwise. The mixture was stirred at room temperature overnight then the solvent was evaporated and the residue triturated 50 with water and aqueous potassium carbonate to give 1.39g of crude title compound.

The sample was dissolved in hot ethanolic HCI, filtered, and evaporated to dryness. The residue was triturated with a small quantity of ethanol, and the solid collected and dried (1.109). This was dissolved in water and filtered, the filtrate was basified with concentrated ammonia to precipitate the title compound as the 1 hydrate (0.59g), mp 237-40'C. 4 Analysis: Found: C, 72.81; H, 6.70; N, 13.31% C25H26N40 -1 H20 requires: C, 72.88; H, 6.73; N, 13.60%. 4

Claims (16)

1. A compound of formula:

f 12 GB2184443A 12 R3 P A-N-NHCO,9 ey N R2 H (I) wherein R, is hydrogen, lower alkyl, halogen, lower alkoxy or hydroxy; R2 represents hydrogen or lower alkyl; A represents an. alkylene, oxoalkylene or hydroxyalkylene chain each having 2 to 6 carbon atoms, R3 and R4 may be in the same or different rings and independently represent hydrogen, lower alkyl, lower alkoxy, amino or halogen and one of X and Y represents nitrogen 15 the other represents CR, wherein R, is one of the values for R3 or R5 is the bond to the NHCO group; or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in Claim 1 wherein A is -CH2CH(CH3)-, -COCH(CH,)or -CHOH(CH3)- or a chain of formula -(CHA,-, -CO(CH2)F7=-1 or -CHOH(CH, )77I, wherein n is an integer from 2 to 4.

3. A compound as claimed in Claim 2 wherein A is ethylene.

4. A compound as claimed in any one of Claims 1 to 3 wherein the group bonded to the -NHCO- group is quinol-4-yl, quinol-3-yI, quinol-6-yL

5. N-[1-(2-[lndol-3-yilethyl)piperid-4-yllquinoline-6-carboxamide or a pharmaceutically accept- able salt thereof.

6. N-[1-(2-[indol-3-yilethyi)piperid-4-yilquinoline-3-carboxamide or a pharmaceutically acceptable salt thereof.

7. W[ 1 -(2-[1 ndol-3-y1) ethyl) piperid-4-y11-4-ca rboxamide or a pharmaceutically acceptable salt thereof.

8. A compound as claimed in any one of Claims 1 to 7 when in the form of a salt from a pharmaceutically acceptable acid selected from sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic and p-toluenesulphonic acid.

9. A process for preparing a compound of formula 1 as defined in Claim 1 which comprises acylating a compound of formula 11 R /\-NI-NH2 N R2 1 (IT) H with an acid of formula 33 R 4 50 HOOC 1 or a reactive derivative thereof, wherein A, R, R, R3 and R4 are as defined above and one of X, and Y, is nitrogen the other is CR, where R, is one of the values defined for R3 or the bond to 55 the COOH group, and if desired converting the product to an acid addition or quaternary ammonium salt thereof.

1-0. A process as claimed in Claim 9 in which the reactive derivative of the acid of formula Ill is an acid halide, anhydride or a methyl, phenyl, nitrophenyl or halophenyl ester.

11. A process as claimed in Claim 9 in which the acid of formula 111 is used in the presence 60 of a coupling reagent.

12. A process for preparing a compound of formula 1 as claimed in Claim 1 which comprises a) reacting a compound of formula:

A 13 GB2184443A 13 A - IHN R2 (V) with a compound of general formula:

3 4 15 H-N,NHCO-O Y (V1) Ri A- N R2 H wherein -N Y is a ring system of formula k in which formulae X, Y, A, R, R2, R3, R4 are as defined above and T is a halogen atom or an equivalent replaceable radical, or b) reducing a compound of formula z (D or P3 R4 NHCO:l-Y X (VID "N'/-- (VII.) - ND/ - (VI16) X, Y, A and R,-4 are as defined in Claim 1 and ZO is an anion. or c) reducing a compound of formula 1 wherein A is oxoalkylene to give a compound of formula 1 wherein A is alkylene or hydroxyalkylene, or d) carrying out a Fischer-Indole synthesis a compound of formula 14 GB2184443A 14 px Fa N-N=C 1 m 1 P2 3 P-At - CH -A-NENHCO,nT 1 2 wherein X, Y, R, IR, R2, IR, R4 and A are as defined in Claim 1, or e) acidifying or quaternizing a basic compound of formula 1 as defined in Claim 1 to form an 15 acid addition or quaternary ammonium salt, or f) treating a compound of formula Xl e 3 R4 A-N NHCO R 7C V, N R2 H R 7 e ZE) (Xl) wherein IR,-, X and Y are as defined above, R, is an organic quatemising group which can be removed under mild conditions and ZO is an anion, under mild conditions effective to remove the group R7.

13. A process for preparing a compound of formula 1 as defined in Claim 1 substantially as 35 hereinbefore described with reference to any one of Examples 1 to 3.

14. A compound of formula 1 whenever prepared by a process as claimed in any one of Claims 9 to 13.

15. A pharmaceutical composition comprising a compound of formula 1 as claimed in any one of Claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable 40 carrier.

16. A pharmaceutically composition as claimed in Claim 15 when in unit dosage form.

Printed for Her Majesty's Stationery Office by Burgess & Son (Abingdon) Ltd, Dd 8991685, 1987. Published at The Patent Office, 25 Southampton Buildings, London, WC2A 'I AY, from which copies may be obtained.

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