GB2168977A - 4-aminoquinoline derivatives and intermediates for their preparation - Google Patents

Description

1 GB 2 168 977 A 1

SPECIFICATION

4-aminoquinoline derivatives and intermediates for their preparation The present invention concerns new 4-aminoquinoline derivatives, a process for their preparation and 5 pharmaceutical compositions containing them. The invention also relates to new benzenesulphonamide derivatives useful as intermediates for the preparation of the 4-amino- quinoline derivatives and proc esses for the preparation of the benzenesulphonamide derivatives.

British Patent 1,445,595 discloses a class of 4-aminoquinoline derivatives having anti-hypertensive ac- 1() tivity. The compounds specifically disclosed include 4-(7-chloro-4- quinolinylamino)-N-(2-diethylaminoethyl) benzenesulphonamide and 4-(7-chloro-4-quinolinylamino)-N-(1-ethyl3-piperidyi)benzene- sulphonamide. For short we shall refer to these compounds as compound A and compound B respec tively.

In accordance with the present invention another class of 4aminoquinoline derivatives have been found to be useful as anti-hypertensive agents. The 4-aminoquinoline derivative of the invention closest 15 in structure to compounds A and B is compared with compounds A and B in the pharmacological results herein.

The invention provides novel 4-aminoquinoline derivatives having the formula 1 N 20 1 11 ' 20 X (1) NH - so - x 25 2 2 25 and their pharmaceutically acceptable salts, wherein X, is halogen or trifluoromethyl and X, represents a group having the formula 11 30 -NR, -Q-CN-R, (11) 30 wherein Q is lower alkylene attached to a ring carbon atom of the ring illustrated in formula 11, R, is hydrogen or lower alkyl; R, is lower alkyl and the ring illustrated in formula 11 is a piperidine or pyrroli dine ring that may be substituted on one or more carbon ring members by lower alkyl. These corn 35 pounds are indicated for pharmaceutical use, particularly as anti- hypertensive agents. 35 It will be apparent to those skilled in the art that the above definition of X, includes moieties possess ing an asymmetric carbon atom, especially, for instance, where the group having the formula Ill -CN-R, 40 40 is 1-(lower alkyl)-2 or 3- pyrrolidinyl or 1-0ower alkyl)- 2 or 3- piperidyl. It is to be understood that for mula 1 is intended to encompass each enantiomer where the compound contains an asymmetric carbon atom and mixtures of enantiomers, for instance, a racemic mixture of enantiomers. Separation of enan tiomers can be carried out using general methods known in the literature.

X, in formula 1 may substitute any of the 5, 6, 7 and 8- positions of the quinoline ring system, but is 45 preferably at the 7- or 8- position, advantageously the 7- position. Where X, is at the 7- position, formula 1 may be represented as la X N, "Z 50 1 ' 1 50 1 - 0a) NH--- S02-X2 55 55 X, represents halogen, for instance, chlorine or bromine, or trifluoromethyl. X, is preferably chlorine.

In formula 11 R, represents hydrogen or lower alkyl (for instance methyl, ethyl, propyl, butyl). R, is pref- erably halogen. In formula 11, Q is lower alkylene which may be a straight chain, i.e. a chain of 1 to 6, preferably 1 to 4, methylene groups. Alternatively G may be a branched lower al ' kylene group, for in- stance, a chain of 1 to 4 methylene groups, the chain being mono- or di- substituted by methyl or monosubstituted by ethyl. Q is preferably methylene or unsubstituted methylene. Q is attached to the ring shown in formula 11 via a ring carbon atom not the ring nitrogen atom. G is preferably attached to carbon ring member that is itself attached to the ring nitrogen atom. IR,, in formula 11 is lower alkyl (for instance methyl, ethyl, propyl, or butyl). The ring attached to Q in formula 11 is a piperidine or pyrrolidine ring whose nitrogen atom is shown in the formula. The ring may be substituted on one or more ring carbon 65 2 GB 2 168 977 A 2 atoms by lower alkyl (for instance methyl, ethyl, propyl, butyl). The ring carbon atoms are preferably unsubstituted except, of course, by the lower alkylene group Q. Advantageously X, is a group having the formula IV R OV) -NR,-CR2R3 (C1,12)m 1 R 10. R 4 6 10 wherein R, and R, are as defined above; R, IR, R, and R, are independently selected from hydrogen and lower alky]; R, and R. are each attached to a ring member other than nitrogen and m is 0 or 1.

The term 1ower- as used herein to refer to such groups as alky], alkoxy and alkylene, indicates that 15 the group contains up to 6, preferably up to 4, carbon atoms. In the case of "lower alkanoyl" the group 15 contains 1 to 6, preferably 1 to 4 carbon atoms. The group may be in the form of a straight chain or may be branched.

The compounds having formula 1 form acid addition salts with acids. Examples of acid addition salts are those formed from inorganic and organic acids and in particular include the sulphate, hydrochloride, 20 hydrobromide, hydroiodide, nitrate, phosphate, sulphonates (for instance the methanesu 1 phonate or p- 20 toluenesulphonate), acetate, maleate, fumarate, tartrate, malonate, citrate and formate.

As illustrative compounds of the invention there may be mentioned, in the case of formula 1, 4-(7 chloro--quinolinylamino)-N-[(1-ethyi-2-pyrrolidinyl) methyl]benzenesulphonamide; 4-(7-chloro-4-quinoli nylamino) -N-[(1 -ethyl-2-piperidinyi) methyl] benzenesu 1 phonamide; 4(7-chloro-4-quinolinylamino)-N-[(1- 25 propyl-2-pyrrolidinyl) methyi]benzenesulphonamide; 4-(7-chloro-4- quinolinylamino) -N-[(1-butyi-2-pyrroli- 25 dinyi)methyi]benzenesulphonamide; 4-(7-chloro-4-quinolinylamino)-N-[(1- methyi-2-pyrrolindinyi) methyi]benzenesulphonamide and N-:(1-ethyi-2-pyrrolidinyl) methyl 1-4-(7trifl uoro m ethyl-4-q u ino 1 inyla m ino)benzene-sulphonamide and their pharmaceutical ly acceptable acid addition salts.

The invention also provides novel compounds having the formula V 30 -< N ",, 30- X 1 (V) f' 35 11 -NR 1 35 N R S02-Q-C- 7 and their acid addition salts (wherein X, is as defined under formula I; R, Q and the ring attached to a are as defined under formula 11 and R, is selected from latent lower alkyl, a protecting group and hydro- 40 gen. R, is preferably lower alkanoyl or hydrogen. The compounds having formula V and their salts - are indicated for use as chemical intermediates for the preparation of the compounds having formula 1 and their pharmaceutical ly acceptable acid addition salts.

Examples of compounds of the invention include, in the case of formula V, N-[(1-acetyi-2-pyrrolidi nyi)methyll -4-(7-chloro-4-quinolinylamino)benzenesulphonamide and W[(1 benzyi-2-pyrrol idi nyi) methyl4-(7-chloro-4-quinolinyi)benzenesulphonamide and their acid addition salts.

The compounds having formula 1 may be made by (a) sulphonylation of a compound having the formula X,H (where X is as defined above) or a salt thereof to introduce a sulphonyl group having the formula W 50., N 50 -c T X, 1. (VII) - N ?11 % - so 2_ 55 (where X, is as defined above); (b) reaction of a compound having the formula V[]] (VIII) X 1 -C 1 :-1 z 3 GB 2 168 977 A 3 (where X, is as defined above and Z is a leaving group or atom, preferably halogen such as chlorine) with a compound having the formula IX 5. NH, --, _Y S02-X2 OX) 5 (whereX2 is as defined above) or a salt thereof; or (c) alkylation of a sulphonamide having the formula 10 10 N X 15 1 -a? (X) 15 -S02-X2 (where X, and R, are as defined above) under alkaline conditions to introduce the substituted alkyl group 20 having the formula 20 - Q-CN - R, (xl) (where Q, the ring to which Q is attached and JR,, are as defined under formula 11) at the sulphonamide 25 nitrogen atom; or 25 (d) alkylating compound having the formula V as defined and illustrated above in which R, is hydrogen to introduce a lower alkyl group.as R,; or (e) converting latent lower alkyl in a compound of formula V in which R, is-latent lower alkyl into lower alkyl.

30 If desired the process of preparation of the compound having formula 1 or salt thereof may include 30 conversion of a salt of a compound having formula 1 into a compound having formula 1 or conversion of a compound having formula 1 into a salt thereof.

The compounds having formula V where R, is latent lower alkyl or a protecting group may be prepared in a similar manner to those of formula 1 (except that step (d) is not used) by replacing R, by latent lower 35 alkyl or a protecting group. Compounds having formula V in which R, is hydrogen may be prepared by 35 removing the protecting group in known manner from a compound having formula V in which R, is a protecting group.

The intermediate compounds useful for preparation of the compounds having formulae 1 and V are generally known or may be prepared in known manner. Compounds having formula IX are described in British Patent Application 8514648. 40 As sulphonylating agent in step (a) there is preferably used the sulphonyl chloride having the formula W-C] where W, is the sulphonyl group having the formula VII. The sulphonylation may be carried out in manner known for the sulphonylation of ammonia and amines. The sulphonylation may be performed in a solvent, for instance, chloroform or methylene chloride, in the presence of a base to neutralise the 45 hydrogen chloride formed. The base may be inorganic, for instance, an alkali metal carbonate or bicar- 45 bonate or may be an organic base, particularly one that is inert towards sulphonylating agent, for in stance, a tertiary amine such as triethylamine, or an excess of the amine to be sulphonylated.

The intermediate sulphonamides having formula V and their salts in which R. is latent lower alkyl m.ay be converted into the sulphonamides having formula 1 and their salts via step (e) in which the latent lower alkyl group is converted to lower alkyl. The latent lower alkyl group is preferably lower alkanoyl. 50 The conversion of the lower alkanoyl group % into the lower alkyl group R4, for instance, acetyl into ethyl, may be carried out in known manner for the reduction of amides to form amines. Where X, is halogen such as chlorine in formula V, the reduction conditions should be chosen so as to avoid replace ment of X, by hydrogen. As reducing agents alane and borane may be used. Lithium aluminium hydride may be used as reducing agent where X, is trifluoromethyl. 55 Alkylation according to step (d) may be carried out in manner known for the alkylation of amines. As alkylating agent there may be used a compound having the formula R,-Z where Z is a leaving group or atom, preferably halogen, for instance chlorine or bromine or organosulphonyloxy, for instance, lower alkanesulphonyloxy or tosyloxy.

60 Step (b) is a reaction that is preferably carried out in aqueous alcohol. The reaction may be carried out 60 with, or without acid catalysis.

In step (c) the sulphonamide X is alkylated under alkaline conditions to introduce the substituted alkyl group having the formula Xl. As substituted alkylating agent there may be used a compound having the formula W-Z where Z is as defined above and W represents the substituted alkyl group Xi. The reaction may be carried out in known manner for the alkylation of sulphonamide nitrogen atoms. The compounds 65 4 GB 2 168 977 A 4 having the formula W-Z are generally known, for instance 2-chloromethyl-l- ethyl-piperidine, or may be prepared by known methods. The alkaline conditions used for the reaction may be provided by converting the sulphonamide into an alkali metal salt thereof prior to adding the substituted alkylating agent.

The novel compounds having formula I and their pharmaceutically accpetable salts are indicated for use as anti-hypertensive agents. The compounds may be tested for their response on the blood pressure 5- of spontaneously hypertensive rats in the following procedure:

The blood pressure of male or female conscious rats that are spontaneously hypertensive are measured in a 390C constant temperature housing by means of a tail cuff. Rats with systolic pressures below 155mm Hg are not used. Groups of rats (4 per group) are dosed orally with the test substance in a suita- ble vehicle or with vehicle alone. Systolic pressures are recorded before dosing and at selected time 10 points afterwards (2 hours, 6 hours and 24 hours).

The compound of the invention according to Example 1 and the known 4aminoquinoline derivatives referred to above as compound A and compound B have been tested in the above procedure with the results given below in Table 1 at a dose of 0.03 millimoles/kg p.o. and the results given below in Table 2 at a dose of 0.003 millimoles/kg p.o. 15 TABLE 1

Blood pressure as % Heart rate as % of 20 of initial value after initial value after 20 Compound 2 hours 6 hours 24 hours 2 hours 6 hours 24 hours 25 Example 1 55 55 79 91 79 81 25 herein Compound 79 73 67 72 70 66 A Compound 64 66 60 81 66 70 30 B 30 TABLE 2

35 Blood pressure as % Heart rate as % of 35 of initial value after initial value after Compound 2 hours 6 hours 24 hours 2 hours 6 hours 24 hours 40 40 Example 1 74 51 69 104 102 87 herein Compound 89 73 83 93 86 81 A 45 Compound 97 91 97 95 85 95 45 B At the higher dose tested (0.03 millimoles/kg) all three compounds were active in reducing blood pres sure. The compound of the invention achieved the greatest reduction in blood pressure (a reduction of 50 55% of initial value). The compound of the invention also exhibited the advantage that it caused a smaller reduction in the- heart rate than compound A and compound B at each of the three times of measurement.

At the lower dose tested (0.003 millimoles/kg) compound B showed little effect in reducing blood pres sure. The compound of the invention and compound A were both active in reducing blood pressure. 55 Howe er, the compound of the invention caused a greater reduction in blood pressure than compound A at each of the three times of measurement. The compound of the invention also exhibited an advantage over compound A in that it caused a smaller reduction in heart rate at each of the three times tested.

Thus the compound of the invention is more active than compound A and compound B and also-has the advantage of a lower reduction (or no reduction) in the heart rate. 60 The end compounds of the invention prepared in Examples 1 to 6 herein have been tested in the pro cedure given above at 0.03 millimoles/kg p.o. The results obtained are given in Table 3.

5 GB 2 168 977 A 5 TABLE 3

Blood pressure as % Heart rate as % of Compound of initial value after initial value after 5 (Example 5

No) 2 hours 6 hours 24 hours 2 hours 6 hours 24 hours 1 55 55 79 91 79 81 2 58 52 73 92 90 87 10 3 53 57 65 80 78 73 10 4 63 56 92 93 95 93 5 50 54 68 79 84 83 6 56 58 76 88 81 76 15 When a compound having formula 1 or V or a salt thereof contains an asymmetric carbon atom, the 15 compound may exist in the form of an individual enantiomer or a mixture of enantiomers, for instance, a racemic mixture. Individual enantiomers may be prepared by using an optically active starting material, for instance, as in Example 5 or 6, or by separating a mixture of enantiomers, for instance, a racemic 20 mixture using known methods of separation. 20 The invention also provides a pharmaceutical composition comprising a compound having formula 1 or a pharmaceutically acceptable acid addition salt thereof in association or combination with a pharma ceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharma ceutical composition. In such a composition, the carrier is generally a solid or liquid or a mixture of a 25 solid and a liquid. - 25 Solid form compositions include powders, granules, tablets, capsules (e.g. hard and soft gelatin cap sules), suppositories and pessaries. A solid carrier can be for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compres sion aides, binders or tablet-disinteg rating agents; it can also be an encapsulating material. In powders 30 the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tab- 30 lets the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% e.g. from 0.03 to 99%, preferably 1 to 80% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellu 35 lose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion 35 exchange resins.

The term "composition" is intended to include the formulation of an active ingredient with encapsulat ing 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. Similarly cachets are included.

40 Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and 40 pressurised compositions. The active ingredient, for example, can be dissolved or suspended in a phar maceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharma ceutically acceptable oils and fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending 45 agents, thickening agents, colours, viscosity regulators, stabilisers or osmo-regulators. Suitable examples 45 of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycerol and glycols) and their derivatives and oils (e.g.

fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily es ter such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be adminis tered intravenously. When the compound is orally active it can be administered orally either in liquid or 55 solid composition form. 55 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 dose containing appropriate quantities of the active ingredi ent; the unit dosage forms can be packaged compositions, for example packeted powders, vials, am poules, prefilied syringes or sachets containing liquids. The unit dosage form can be, for example, a 60 capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. 60 The quantity of the active ingredient in unit dose of composition may be varied or adjusted from 0.5 mg or less to 750 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 invention is illustrated by the following examples:- 65 6. GB 2 168 977 A 6 Example 1

4-(7-Chloro-4-quinolinylamino)-N-f(l-ethyl-2-pyrrolidinyl)methyllbenzenesul phonamide 4-(7-Chloro-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (23. 49, 0.06 mol) was added portionwise to a well stirred mixture of aqueous sodium carbonate (60g in 600mi wate ' r) and 2-aminome thyl-l-ethyl pyrrolidine (7.8g, 0.06 mol) in chloroform (600m1) at about 1WC. The ice bath used for cooling 5 was removed and, after 1 112 hours, the mixture was filtered. The chloroform layer was separated and dried (M9S04). Concentration under reduced pressure caused precipitation of a solid, which was col lected by filtration and dried. Recrystallisation from ethanol gave the title compound (10.59), melting point 200-201.5'C.

10 10 Analysis Found: C, 59.3%; H, 5.85%; N, 12.3%.

C2,1-121CIN402S requires C, 59.40/6; H, 5.66%, N, 12.6%.

The title compound was dissolved in hot isopropanol and an ethereal solution of hydrogen chloride was added to give a precipitate of the title compound dihydrochloride hemihydrate 3/4 isopropanolate, 15 melting point 233-237'C.

Analysis Found: C, 51.1%; H, 6.02%; N, 9.68%.

20 C,,H,,CIN401S.2HCI.1/2H,0.3/4C,H,,0 requires C, 50.9%; H, 5.99%; N, 9. 80%. 20 Example 2

4-(7-Chloro4-quinolinylamino)-N-[(1-ethyl-2-piperindinyl)methyllbenzenesul phonamide 4-(7-Chloro-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (16. 6g, 0.017 mol) was added portionwise to a well stirred mixture of aqueous sodium carbonate (17g in 200m] water) and 2-aminome- 25 thyi-l-ethyi-piperidine hydrobromide (3.8g, 0.017 mol) in chloroform (180mi) at about WC. The ice bath used for cooling was removed. After 1 112 hours, the mixture was filtered. The chloroform layer was separated, dried (MgSOJ and evaporated under reduced pressure to give a gum. Crystallisation from ethanol gave the title compound (0.47g), melting point 203-2050C.

30 30 Analysis Found: C, 60.1%; H, 5.87%; N, 12.1%.

C2,1-1,,CiN,Ci,S requires C, 60.2%; H, 5.49%; N, 12.2%.

Example 3 35

4-(7-Trifluoromethyl-4-quinolinylamino)-N-[(1ethyf-2pyrrolidinyl)methyllbe nzenesulphonamide 4-(7-Trifiuoromethyi-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (4.3g, 0.01 mol) was added portionwise to a wel 1 stirred mixture of aqueous sodium carbonate (12.3g in 70 mi of water) and 2-aminomethyl-l -ethyl pyrrolidine (1.3g, 0.01 mol) in chloroform (70mJ) at about 100C. The ice bath used for cooling was removed and, after 1 112 hours, the mixture was filtered. The solid was washed with 40 water and then air-dried. Recrystallisation from ethanol-water, followed by drying, gave the title corn pound (1.35g), melting point 194-5'C.

Analysis.r Found: C, 57.9%; H, 5.30%; N, 11.5%. 45 C,,1-1j,N,0,S requires C, 57.7%, H, 5.27%; N, 11.7%.

Example 4

4-(8Chloro-4-quinolinylamino)-N-[(1-ethyl-2-pyrrolidinyl methyllbenzenesulphonamide 50 4-(8-Ch loro-4-quinol inylamino)benzenesui phony] chloride hydrochloride (7.9g, 0.02 mol) was added 50 portionwise to a well-stirred two-phase mixture of chloroform/water- (200mi/200ml) containing sodium carbonate (21.0g) and 2-aminomethy]-1 -ethyl pyrrolidine (2.6g, 0.02 mol) at about WC. The ice bath used for cooling was removed and after 1 112 hours the mixture was separated. The chloroform layer was dried (MgSO,) and evaporated under reduced pressure to give a dark brown solid. Purification was car ried out by column chromatography (basic A120.: 1% ROH/CHCl.) followed by trituration from ethyl ace- 55 tate giving the title compound (2.2g), melting point 171-172.5' (dec).

Analysis Found: C, 59.7%; H, 6.06%; N, 12.3%.

C,,%CIN402S requires: C, 59.4%; H, 5.66%; N, 12.6%. 60 Example 5

R-(+)-4-(7-Chloro-4-quinolinylamino)-N-f(l-ethyl-2pyrrolidinyl)methyllbenze nesulphonamide 4-(7-Chloro-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (4. 3g, 0.012 mol) was added portionwise to a well-stirred two phase mixture of water/chloroform (125m11125mi) containing sodium 65 7 GB 2 168 977 A 7 carbonate (12.7g) and R-(+)-2-a m i nomethylA -ethyl pyrrol idine ditartrate (5.2g, 0.012 mol), at about 100C.

The ice bath used for cooling was removed and after 1 1/2 hours, the mixture was separated. The chloro form layer was dried (MgSOJ and evaporated under reduced pressure to give a solid. Purification of the solid (8g) was carried out by column chromatography (basic A120.: CHCL/1% ROH) followed by recrys tallisation from ethanol, to give the title compound (0.9g), melting point 197-199'C, [a-I,D6 = + 330 (c 5 0.90% in 95% ethanol).

Analysis Found: C, 59.1%; H, 5.99%; N, 12.3%.

C,21-121CIN,0,S requires: C, 59.4%; H, 5.66%; N, 12.6%. 10 Example 6 1

S-(-)-4-(7-Chloro-4-quinolinylamino)-N-[(1-ethyl-2pyrrolidinyl)methyllbenze nesulphonamide 4-(7-Chloro-4-quinolinylamino)benzenesulphonyI chloride hydrochloride (14. 2g, 0.037 mol) was added portionwise to a well-stirred two phase mixture of water/choroform (400mi/400mi) containing sodium 15 carbonate (41.5g) and S-(-)-2-a minomethyl-l -ethyl pyrrolidi ne ditartrate (17.19, 0.04 mol), at about WC.

The ice bath used for cooling was removed and after 1 1/2 hours, the mixture was separated. The chloro form layer was dried (M9SOJ and evaporated under reduced pressure to give a solid. Purification was carried out by column chromatography (basic NJ,: CHC13) followed by recrystallisation from ethanol/ water, giving the title compound (0.69), melting point 194-197'C, [a121 = -33' (c = 1.21% in 95% ethanol). 20 D Analysis Found: C, 59.2%; H, 5.82%; N, 12.4%.

C221-12.CIN,,0,S requires: C, 59.4%; H, 5.66%; N, 12.6%.

25 25 Example 7

4-(7-Chloro-4-quinolinylamino)-N-[(1-propyl-2-pyrrolidinyl) methyllbenzenesulphonamide 4-(7-Chloro-4-quinolinylamino)benzenesulphonyI chloride hydrochloride (5. 4g, 0.014 mol) was added portionwise to a well-stirred two phase mixture of chloroform/water (140mi/140mi) containing sodium carbonate (14.8g) and 2-aminomethyi-l-propylpyrrolidine (2.09, 0.014 mol) at about WC. The mixture 30 was allowed to warm to room temperature, then stirred for 1 1/2 hours. The chloroform layer was sepa rated, dried (M9S04) and evaporated under reduced pressure to give a gum. The gum was crystallised from ethanollwater to give a pale yellow solid (1.8g). A further recrystallisation from ethanol gave the title compound (0.59), melting point 192.5-194'C.

35 35 Analysis:

Found: C, 60.0%; H, 5.66%; N, 12.0%.

C2,1-12.CIN401S requires: C, 60.2%; H, 5.93%; N, 12.2%.

Example 8 40

4-(7-Chloro-4-quinolylamino)-N[1-acetyl-2pyrrolidinyl) methyllbenzenesulphonamide The title compound is prepared in a similar manner to Example 1 by replacing 2-aminomethyl-l -ethyl pyrrolidine by an equimolar amount of 1-acetyi-2-aminomethylpyrrolidine.

Claims (14)

CLAIMS 45

1. A compound having the formula N 50 X 50 55 NH - CL - S02X2 55 or a pharmaceutically acceptable salt thereof, wherein X, is halogen or trifluoromethyl and X, represents a group having the formula -NR,-Q-CN-R4 60 where Q is lower alkylene attached to a ring carbon atom of the ring illustrated in formula 11; R, is hydrogen or lower alkyl; R, is lower alkyi and the ring illustrated in formula 11 is a piperidine or pyrrolidine ring or a piperidine or pyrrolidine ring substituted on one or more carbon ring members by lower alky].

2. A compound as claimed in Claim 1, wherein X, in formula 1 substitutes the 7- position of the quin- 65 8 GB 2 168 977 A 8 oline ring system.

3. 4-(7-Ch loro-4-quinolylamino)-N-[(l-ethyl-2-piperldinyl) methyllbenzenesulphonamide or a pharma ceutically acceptable salt thereof.

4. 4-(7-Trifluoromethyl-4-quinolylamino)-N-[(l-ethyl-2pyrrolidinyl)methyllbenz enesulphonamide ora pharmaceutically acceptable salt thereof.

5 5. 4-(7-Chloro-4-quinolylamino)-N-[(l-ethyl-2pyrrolidinyl)methyllbenzenesulpho namide or a pharma ceutically acceptable salt thereof.

6. 4-(8-Chloro-4-quinolylamino)-N-[(l-ethyl-2-pyrrolidinyl) methyllbenzenesulphonamide or a pharnia ceutically acceptable salt thereof.

7. R-(+)-4-(7-Ch I o ro-4-q u in o lyl am i no)-N-[(l -ethyl-2-pyrro I idi nyl) m ethyl I benzenesu I phona m i de or a 10 pharmaceutically acceptable salt thereof.

8. S-H-4-(7-Ch I oro-4-qu in o lyl am i no)-N -[(l -ethyl -2-pyrro I i nd i nyl) m ethyl] benzenesu I ph ona mide or _q pharmaceutically acceptable salt thereof.

9. 4-(7-Ch I o ro-4-q ui n olyla m ino)-N-[(l -pro pyl-2-pyr rolidinyl) methyl)benzenesulphonamide or a phar- maceutically acceptable salt thereof. 15

10. A compound having the formula V N - 20 4 20 (V) I t NH// SO _NR -R _x 1).1 _Q -CN7 or an acid addition salt thereof, wherein X, is halogen or trifl uo rom ethyl; R, is hydrogen or [owe r alkyl; Q 25 is lower alkylene attached to a ring carbon atom of the ring illustrated; R, is selected from latent lower alkyl, a protecting group and hydrogen and the ring illustrated is selected from pipeddine and pyrrolidine rings and piperidine and pyrrolidine rings substituted by lower _alkyl on one or more carbon ring mem bers. - 30

11. A compound as claimed in Claim 10, wherein X1 is at the 7- position of the quinoline ring. 30

12. A compound as claimed in Claim 10 or 11, wherein R, is hydrogen or lower alkanoyl.

13. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1 to 9 in association or combination with a pharmaceutically suitable carrier.

14. A compound as claimed in any one of Claims 1 to 9 for use as a pharmaceutical.

Printed in the UK for HMSO, D881 8935, 5/86, 7102.

Published by The Patent Office, 25 Southampton Buildings, London, WC2A 1AY, from which copies may be obtained.