AU627434B2 - W-arylsulphonamidoalkanoic acids for treatment of thromboxane mediated diseases - Google Patents

Description

I 7 4 4 ANNOUNCEMENTOF THE LATER PUBLICATION INTERNATIONAL APPL OF INTERNATIONAL SEARCH REPORTS INTERNATIONAL- APPL2....

a ERATION TREATY (PCT) 1 (51) International Patent Classification 4 A61K 31/19, 31/34, 31/38 A61K 31/63, C07C 143/78 C07D 307/64, 333/34 (11) International Publication Number: WO 89/ 01330 AS (43) International Publication Date: 23 February 1989 (23.02.89)

I

I

(21) International Application Number: PCT/GB88/00674 (22) International Filing Date: 16 August 1988 (16.08,88) (31) Priority Application Numbers: 8719717 8725540 (32) Priority Dates: (33) Priority Country: 20 August 1987 (20,08.87) October 1987 (30.10.87)

GB

65 Longmead, Letchworth, Hertfordshire SG6 4HR STEGMEJER, Karlheinz Kirchbergstrasse 17, D-6148 Heppenheim WITTE, Ernst-Christian Beethovenstrasse 2, D-6800 Mannheim I (DE).

(74) Agent: HUTCHINS, Corporate Patents, Smith Kline French Laboratories Limited, Mundells, Welwyn Garden City, Hertforshire AL7 IEY (GB).

(81) Designated States: AU, DK, FI, HU, JP, KR.

Published With international search reporL Before the expiration of the time limit for amending the claims and to be republished in the event of the receipt of amendments (88) Date of publication of the international search report: 5 May 1989 (05.05.89) (71) Applicants: SMITH KLINE FRENCH LABORAT- ORIES LIMITED [GB/GB]; Mundells, Welwyn Garden City, Hertfordshire AL7 IEY BOEHRING- ER MANNHEIM GMBH [DE/DE]; Sandhofer Strasse 116, Postfach 310120, D-6800 Mannheim 31

(DE).

(72) Inventors: IFE, Robert, John 9 Edmonds Drive, Aston Brook, Stevenage, Hertfordshire COOPER, David, Gwyn 59 Penn Way, Lordship Estate, Letchworth, Hertfordshire SG6 2SH SLAT1R, Robert, Antony i (54) Title: W-ARYLSULPHONAMIDOALKANOIC ACIDS FOR TREATMENT OF THROMBOXANE MEDIATED

DISEASES

(57) Abstract Th- present invention provides the use of a Compound of the formula RSO 2 NR'BCOZH or a salt or ester thereof, wherein R is a phenyl, furan or thiophene ring optionally substituted by one or more substituents which are the same or different and are chosen from halogen, nitro, cyano, trifluoromethyl, C.,4alkyl and C.4alkoxy; R' is hydrogen or C.4alkyl; and B is an acyclic hydrocarbon group having 4 to 11 linear carbon atoms, any one or more of the linear carbon at.

oms of which are optionally substituted by one or two C.

3 alkyl g'oups; in the preparation of a medicament for the treatment of thromboxane mediated diseases. Also provided are novel compounds of the formula compositions containing them and processes for their preparation, 4i hr ii WO 89/01330 PCT/GB88/00674 W-ARYLSULPHONAMIDOALKANOIC ACIDS FOR TRATEMENT OF THROMBOXANE MEDIATED DISEASES The present invention relates to the use of a class of A-arylsulphonamidoalkanoic acids in the preparation of medicaments for the treatment of thromboxane mediated diseases, and to novel W-arylsulphonamidoalkanoic acids.

Thromboxane A 2

(TXA

2 is a potent vasoconstricting and platelet aggregating agent which is formed in platelets and other tissues as a product of the "arachidonic acid cascade". TXA 2 is produced by the 2 thromboxane synthetase catalysed conversion of prostaglandin H 2

(PGH

2 which in turn is produced, via the intermediacy of prostaglandin G (PGG2), by the action of cyclooxygenase cn arachidonic acid. The potency of TXA 2 is such that very small amounts can I trigger serious biological consequences and it has been implicated in mediating pathophysiological actions in severe disorders such as circulatory shock and myocardial ischaemia.

One method of inhibiting the effects of thromboxane

A

2 is through the selective antagonism of TXA /PGH 2 at the receptor level and various compounds have been reported as TXA 2 receptor antagonists, see for example US 4,536,510 and EP 31954.

European Patent Application EP 68968A described a class of arylsulphonamidoalkanoic acids as hypolipidaemic agents. One particular class of compounds disclosed in EP 68968A it represented by formula Ar-SO2NR (CH2)nCHR6(CH2)mCOR 4

(A)

wherein Ar can be, inter alia, a phenyl ring having 1 2 3or attached thereto the groups R R and R or a -2- 2 1 1 2 thienyl ring bearing the group R wherein R R and R are the same or different and are hydrogen.

halogen, NO 2

NH

2

CF

3 C 6 alkyl, C 6 alkoxy, 2| 2* V 1 -6 1-6 CO H or a C ester thereof; the total n+m+l is in 2 2-7 4 the range from 3 to 11; and R is OH. C 4 alkoxy or a group NR R wherein R and R are the same or different and are C alkyl or together with the 1-6 nitrogen atom form a 5- or 6-membered heterocyclic ring; 5 6 R and R are the same or different and are hydrogen, C alkyl or C 7aralkyl.

1- 6 7 7 Preferred compounds are stated to be those wherein n+m+1 is 3, 5 or It has now been found that certain a-arylsulphonamidoalkanoic acids have thromboxane A 2 antagonist activity. Such activity has been found to be i particularly high in compounds with heptanoic, octanoic, nonanoic and decanoic acid side chains.

i In a first aspect, therefore, the present invention provides a method for treating thromboxane mediated diseases in a patient in need thereof comprising administering to said patient an effective amount of a compound of the formula 25 RSO 2

NR'BCO

2 H (I) or a salt or ester thereof, wherein R is a phenyl. furan or thiophene ring optionally substituted by one or more substituents which are the same or different and are chosen from halogen, nitro, cyano, trifluoromethyl, 30 cC alkyl and C 1 4 alkoxy: 1-4 1-4 R' is hydrogen or C alkyl; .and 1-4 B is an acyclic hydrocarbon group having 4 to l linear carbon atoms, preferably at least 5 linear carbon atoms and most preferably at least 6 linear carbon atoms, any one or more of the linear carbon atoms of which are optionally substituted by one or two CL 3 alkyl groups: er WO 89/01330 PCT/GB88/00674 -3in the preparation of a medicament for the treatment of thromboxane mediated diseases.

The present invention also provides an ad&antageous class of novel compounds of the formula wherein the group R is optionally substituted by one or two substituent groups which are the same or different and are chosen from halogen, nitro, cyano, trifluoromethyl, C alkyl and C alkoxy: and 1-4 1-4 B is an acyclic hydrocarbon group having 6 to 9 linear i carbon atoms, each linear carbon atom of B being optionally substituted by one or two C _3alkyl groups, Sbut provided that when B is an unbranched alkylene group and R is a phenyl ring, the phenyl ring is either S1" disubstituted or it has 'only one substituent which is chosen from halogen, nitro. cyano, trifluoromethyl, SC 4alkoxy, o- or m-C 4alkyl and p-C 2 4 alkyl.

SBy linear carbon atoms is meant those carbon atoms which form an unbranched chain between the sulphonamide I nitrogen atom and the carboxyl group.

i' Particular optional C alkyl substituents are 1-3 methyl and ethyl, preferably methyl.

The acyclic hydrocarbon group B can be an alkylene group or it can contain carbon-carbon multiple bonds such as double and triple bonds. The group can be a branched chain or straight chain group, for example a branched chain or straight chain alkylene group.

When the group B is a straight chain alkylene group, suitably it can be a group (CH 2 6

(CH

2 7

(CH

2 )9 or

(CH

2 9 but preferably it is (CH 2 7

(CH

2 8 or (CH 2 9 and when the group B is a branched chain alkylene group, preferably it is (CH 2 5

C(CH

3 2 (CH 2) 6 C(C 3) 2

(CH

2 7

C(CH

3 or (CH )C(CH 3 2 22 WO 89/01330 j -4- V! The group R is suitably pi Examples of subscituents on th bromine, fluorice, nitro, meth When R is phenyl, it is pi substituents are! located at the the phenyl ring.

Preferred compounds are ti U 10 of the phenyl ring is unsubsti PCT/G B88/00674 henyl or a thiophene ring.

e group R are chlorine, oxy and methyl.

referred that any e 3- and/or 4-positions of hose wherein the 3-position tuted or is substituted by fluorine, chlorine, or bromine; and the 4-position of the phenyl ring is substituted by fluorine, chlorine, bromine, nitro, methoxy or methyl.

Particularly preferred compounds are those wherein the 3-position of the phenyl ring is unsubstituted or substituted by chlorine, and the 4-position is substituted by chlorine, bromine or methyl.

A particular sub-group of compounds is the group wherein B is (CH 2 7

(CH

2 8 or (CH 2 9 R' is hydrogen and R is a phenyl ring wherein the 3-position of the phenyl ring is unsubstituted or substituted by chlorine, and the 4-position is substituted by chlorin bromine or methyl.

When R is a thiophene or furan group, suitably it is a 2-furyl, 2-thienyl or 3-thienyl group, and preferably it is a 2-thienyl group optionally substituted at the 4and/or 5-position of the thiophene ring, particularly the Preferably the thiophene ring is monosubstituted and particularly the substituent is a 5-bromo or 5-methyl 7roup.

R' is preferably hydrogen.

WO 89/01330 PCT/G B88/00674 Another class of novel compounds of the formula (1) according to the present invention is that class of compounds wherein B is a group (CH 2 yCRc Rd C2 wherain y is an integer f rom 2-9 and R aR are~ S the same or different and each i: a C alkyl group.

1-3 Such compounds will be referred to hereinafter for convenience as the 8-gem dialkyl compounds.

It is prefer. ld that, with regard to the B3-gem dialkyl compounds, *i is 4-7, particularly S. The groups Rc and R can be chosen from methyl, ethyl and propyl but preferably both are methyl.

Preferably the group R is a phenyl group.

conveniently, the phenyl group R -of the 8-gem dialkyl compounds has up to two Gubstituents defined hereinabove. Particular substituent groups are chlorine, bromine, fluorine, methyl, methoxy, nitro and trifluoromethyl.

Suitably the phortyl ring is monosubstituted and the substitUent -group is located at the Para-position of the phenyl ring. Thus, for exam~ple, a particularly preferred substituent group is p-chloro, Preferred novel compounds of the present invention include 8-.(4-chlorobenzem,7-sulphonamido)octanoic acid, 8- (4-chlorobenzenesulphonanhido)-2, 2-dimethyloctanoic acid, 9-(4-chlorobenzenesulphonamidlo)nonanolc acid, a8-(4-bromo benzene sul ph onamido) octano ic acid, 8-(3,4dichlorobenzenesu 1. poiamid o) oatanoic acid, 8-(4-tolylsuJlphonamido)octanoid acid, 9-(4-bromobenzenesulphonamido)nonanoic acid, 8-(S-chlorc-2-thlenylstulphonamido)octanoic acid,. 10-(4-chlorobenzenesulphonamido)decanoic -acid, 8-(4-chlorobenzenesulphonamido)- WO 89/01330 -6- 3,3-dimethyloctanoic acid and esters and ph, acceptable salts thereof.

Compounds of the formula can form bases and all such salts are within the sco invention. Preferred salts are carboxylat by interaction of the carboxylic acid group appropriate base.

Examples of carboxylate salts are alka ii alkaline earth metal and ammonium salts.

alkaline earth metal salts typically are foi interaction of a carboxylic acid with a met hydroxide whereas ammonium salts typically interaction of the carboxylic acid with the amine or the appropriate ammonium hydroxide

K

PCT/GB88/00674 armaceutically salts with pe of the e salts formed with an li metal, Alkali and rmed by al alkoxide or are formed by appropriate It is preferred :hat the salts are pharmaceutically acceptable, although i-n-pharmaceutical salts are also within the scope of the invention. Such salts can be converted into pharmaceutically acceptable salts or into the corresponding free acid.

Where compounds of formula exist as solvates, for example hydrates and alcoholates, all such forms are within the scope of the invention.

Examples of esters of the compounds of the formula include C1-6alkyl esters and C -aralkyl esters wherein the aryl ring is optionally substituted by one or more substituents, for example C- alkyl, halogen, nitro and C -4alkoxy, 1-4 Preferred esters are C _4alkyl esters.

1 L2 WO 89/01330 PCT/GB88/00674 -7- Compounds of the formula can be prepared by the reaction of a compound of the formula (II): E-B--Y (II) with a compound of the formula (III): RSO2G (III) wherein Y is CO2H or a group hydrolysable thereto; one of E and C is a group NHR' and the other is a leaving group displaceable by a group NHR' and R is as defined hereinbefore, and thereafter, where required, hydrolysing any hydrolysable group Y to give CO H.

Suitably the group hydrolysable to CO2H is a nitrile or an ester, for example a C alkyl or 1-6 -optionally substituted aralkyl ester such as benzyl.

Examples of leaving groups are halogens such as chlorine and bromine.

The reaction of a compound of the formula (II) with a compound of the formula (III) can be conducted in a polar solvent, usually aprotic and preferably dry, such as dry acetone, methylethylketone, dimethylformamida, pyridine or dichloromethane, with heating where required, for example at the reflux temperature of the solvent.

The reaction typically is conducted in the presence of another base such as pyridine, an alkali metal carbonate such as potassium carbonate, or a trialkylamine such as triethylamine.

Alternatively, when G is a leaving group such as a halogen e.g. chlorine, the reaction can be conducted under Schotten-BaUtann conditions, i.e. the reactants are 2-l WO 89/013 i

.I

i I 15 I 20 30 stirred alkali s Gen formula disclose PCT/GB88/00674 or shaken together in the presence of an aqueous uch as dilute sodium hydroxide.

eral methods for preparing compounds of the and chemical intermediates thereto are d in EP 68968A.

Many amino acids of the formula (II) wherein E is NHR' can be obtained commercially and those that are not can be prepared by well known and conventional synthetic methods, for example by reaction of the corresponding compound of the formula (II) wherein F 's a leaving group such as bromine, and Y is a group hydrolysable to CO 2 H. e.g. an ester or nitrile thereof; with an alkali metal salt of phthalimide, such as the potassium salt, to give the4)-phthalimido compound. The phthalimido compound can then be deprotected by standard methods, for example by treatment with HC1 to hydrolyse the group Y to give the carboxylic acid, and then by reaction with hydrazine, to remove the phthaloyl group to give the amine. This method of making amines is the well known Gabriel synthesis.

Compounds of the formula (II) wherein E is a leaving group can be prepared according to standard methods.

For example, when it is desired to prepare a compound wherein B is a group (CH 2 )nCRa RbCO 2 H n is 4 to and Ra and R are C -3alkyl groups such as methyl groups, such compounds can be prepared by reacting a compound Br(CH 2 )nBr with ethylisobutyrate in the presence of a strong base such as lithium diisopropylamide (LDA). under conditions described in US Patent No.

4,579,862, or similar thereto.

Compounds of the formula (II) which contain a double or triple bond can be prepared according to methods 1 i WO 89/01330 PCT/GB88/00674 -9described in Casey et al, Tetrahedron, 42, 5849 1 986) or methods closely analogous thereto.

Compounds of the formula (III) are commercially available or can 'e made according to standard methods, for example as described in EP 68968A.

The hydrolysis of a group Y to CO H can be carried out according to conventional methods or methods analagous thereto. Thus, for example, both nitrile and ester groups can be hydrolysed in aqueous alkali such as aqueous sodium hydroxide. Typically such reactions are carried out using an alkonol such as ethanol as a co-solvent and, when the group Y is a nitrile group, it is usual to heat the reaction mixture, e.g. to reflux temperature.

In addition to tha Method described above, the compounds of the present invention can also be prepared by the hydrolysis and decarboxylation of compounds of the formula (IV):

RSO

2 NR'-B'R R CH(Z) (IV) e wherein R and R' are as hereinbefore defined, R and R are the same or different and each is hydrogen or methyl, B' is an acyclic hydrocarbon group having 2 to 9 linear carbon atoms, and Z is a C alkoxycarbonyl 1-4 group or a nitrile group. This method is particularly

A

30 suitable for preparing compounds whei:ein B' is a straight R e an chain alkylene group and R e and R a'e both methyl.

Hydrolysis and decarboxylation suitably is achieved by heating the compound of the formula (IV) in an appropriately acidic or basic aqueous solvent. For example, when Z is C, alkoxycarbonyl such as ~-4 ~t WO 89/01330 PCT/G B88/00674 ethoxycarbonyl, the compound of the formula (IV) can be hydrolysed and decarboxylated by beating at reflux in the presence of aqueous alkali such as sodium hydroxide, Compounds of the formula (IV) can be prepared by the reaction of a metal salt, such as the sodium salt, of a compound of the formula (III) whiiein G is a group NHR with a compound of the formula to 10-BRef 2 wherein the carbon atom to which Br is attached is saturatied, in a polar aprotic solvent such as Sdimethylformatuide, suitably with heating.

CRmpounds of the formula can be prepared according to the methods llustrated in Reaction Scheme 1 or methods analogous thereto, Reaction Scheme 1 eoio hb Br-(CH 2 Br(CH 2 y 2-9 i) Mg. 12 (trace) (ii) CO Et v~

CO

2 Et i) MeSO 2 CI CO Et Br-(CH 2)v rCMe 2 HO-(CH,- 2)y-e2< 2 CO 2Et Ui) Lilt CO 2 E The reactions shown in Reaction Scheme 1. can be conducted 4 t WO 89/01330 PCT/GB88/00674 under conditions as described in the Examples or analogous thereto.

Compounds of the formula eo .seful in the treatment of diseases in which TXA 2 is a factor. Thus they would be useful in the treatment of disorders in which aggregation of blood platelets and vasoconstriction play a part.

Particular clinical indications in which the present compounds would be of interest include the treatment, or management of post myocardial infarction, coronary thromboses (eig. in combination with tissue plasminogen activator and other thrombolytics), unstable angina, transient ischaemia, coronary ortery bypass grafts, cardiac valve replacement and peripheral and vascular grafts including for example renal transplants.

The compounds of the formula can be administered as the pure compound but it is more usual to administer them as part of a pharmaceutical composition in association with a carrier and one or more exciients.

In a further aspect, therefore, the present invention provides a pharmaceutical composition comprising a compound of the formula and a pharmaceutically acceptable carrier.

The compositions can be administereo in standard manner, for example orally, parenterally, transdermally, rectally, via inhalation or via buccal administration.

Compounds of formula and their pharmaceutically acceptable salts which are active when given orally or vii buccal administration can be formulated as syrup6, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the 4, i wO 89/01330 PCT/GB88/00674 -12- 1compound or salt in a liquid carrier for example, ethanol, t glycerine t water with a flavouring or colouring agent.

SWhere the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, starch, lactose and sucrose.

Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the jaforementioned carriers in a hard gelatin capsule shell.

j 10 Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used i' for preparing dispersions or suspensions may be j considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin i 15 capsule shell.

Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, poly inylpyrrolidone, lecithin, arachis oil, or sesame oil. Such c'ompositions can be administered, for example, by bolus injection or by infusion.

A typical suppository formulation comprises a compound of formula (I1 or a pharmaceutically acceptable salt thereof which is active when administered in this way w'ith a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats.

Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster. patch or membrane.

4 t

I

WO 89/01330 PCT/GB88/00674 -13- Typical compositions for inhalation are in the form of a solution, suspension )r emulsion that may be administered in the form of an aerosol using a conventional propellant such as dichlorodifluorometha.e or trichlorofluoromethane.

Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to himself a single dose.

Each such dosage unit suitably contains from 0.1 mg to 1 g. preferably from 0.5 mg to 500 mg, e.g. 10 mg or mg, of a compound of the formula or a .pharmaceutically acceptable salt thereof calculated as the compound itself.

A typical daily dosage regimen is mg to 1 g for an average human weighing appzoAimately 70 kg, administered in 1 to 4 do:Age units, preferably 1 or 2.

The compositions Jf this invention, in addition to containing a compound of the formula can also contain other agents; for example one or more agents chosen from phosphodiesterase inhibitors, hypolipidaemic agents, platelet aggregation inhibitors, vasodilators, B-adrenergic receptor blockers, ACE inhibitors, tissue plasminogen activator and other thrombolytics, and antiarrhythmics.

Particular compositions of this invention are those containing a compound of the formula and a tissue plasminogen activator, and a particular method of .administering such compositions is by infusion or bolus injection.

4

I

WO 89/01330 I-The cs of 14 The compositions of the PCT/GB88/00674 )resent invention are prepared by bringing the active constituent into association with a pharmaceutically acceptable carrier and optionally other excipients and ingredients as defined above.

As indicated above, compounds of the formula (I) have biological activity that is indicative of an ability to antagonise TXA 2 receptors. The TXA 2 antagonist activity has been demonstrated in the human platelet binding assay.

The platelet binding assay used was essentially the method described by Mais et al, J. Pharm. Exp. Ther., 125 1985, 235(3), 729-734 where I]PTA-OH was used as the receptor ligand.

The IC50 values represent the concentration which 125 prodUces a 50% inhibition of specific 12 IjPTA-OH binding.

The activities of the compounds of the present invention in the assay are described in Example 33.

The following Examples are illustrative of the invention.

In the Examples, all temperatures are in °C.

Melting points are uncorrected and were obtained in an open capillary tube using a Bachi 510 Melting Point Apparatus.

WO 89/01330 PCT/G B88/00674 Exam le 1 7-(Benzenesulphonamido)heptanoic Acid Benzenesulphonzy1 chloride (7mmol) was added to a solution of 7-am-Inchieptanoic acid (7mmol) in 10% sodium hydroxide solution (l0mi). The mixture was stirred at h room temperature for 3 ho'irs. The pH was adjusted to I with 2NHCl and the solution was ,i tracted with chloroform (3xlO~ml). The chloroform extrav.ts were dried over magnesium sulphate, the solvent wao removed and the residue was recrystallioed from mechanol-water to give 7-(benzenesulpho.na.,,do)h, ptanoic acid (0.75g, 38%); m.p. 75-77 0

C.

r Example 2 8-(Benzenesulphonamido)octanoic Acid substituting 8-aminooctanoic acid for 7-akminoheptanoi-c acid in Example 1 and using corresponding molar proportions of other reagentc, gave 8-(benzenesulphonamido)octanoic acid (0.76g, 50%) from isopropanol/water: m.p. 82-84 0

C.

Example 3 8-(4-Chlorobenzenesulphonamido)octanoic Acid A solution of 4-chlorobenzenesulphonyl chloride (6mol) in chloroform (2.5m1) was added to a solution of 8-aminooctanoic acid-(6mmol) in 10% sodium hydroxide solution (L0ml). The mixture was stirred at room temperature for 24 hours and was then extracted with chloroform (4x40m.), the chloroform layers being discarded. The aqueous layer was acidified to pH. with WO 89/0 1330 PTGi8/07 -16- Iconc. HCl and was extracted with chloroform (4xl00ml).

The combined chloroform exctracts were then dried (Mg so 4 concentration and crystallisation from >1 isopropanol-water gave 8-(4-chlorobenzenesulphonamnido)octanoic acid (1.22g: m.p. 122 0 -124 0

C.

Example 4 V 10 (zj.enzenesul phonarnido)hexanoic Acid, Ii Benzenesulphonyl chloride (10inl) wras added to a V stirred solution of 6-aminocaproic acid (8.8g) in sodium hydroxide solution (50m1) over 30 minutes. The solui-ion was stirred for 1 hour, acidified with dilute hydrochloric acid and the precipitate was collected by filtration. Recrystallisation from chloroform yieldad 6-(benzenesulphonamido)hexanoic acid (10.5g) as white prisms. vip. 1.19-1.20 0

C.

Example 8-(4-Chlorobenenesulvhonamido)2,2-dimethyloctanoic Acid V 25 i)Ethvl 2.2-dimethyl-8-bromooctanoate A solution of lithium diisopropylamide in cyclohexane (0.15mol, loom].) and tetrahydrofuran (150mi) was cooled to -60 0 C and treated with ethyl isobi--yrate (18.59g, 0.16mole). The solution was stirred for 1 hour then treated with 1,6-dibromohexane (51,23g, 0.21mole), hexamethylphospttoramide (45g) and was stirred at -70 0

C

for 1 hour. The solution was then warmed to room temperature and the solvent was removed under reduced pressure. The remaining solution was treated with saturated ammonium chloride solution (400m1) and extracted with ethylacetate (2x200m1) The ethyl acetate WO 89/01330 WO 8901330PCT/G B88/00,674 -17extracts w-ore combined and was,hed with d .lute hydrochloric acid (lO0mi). sodium bicarbonate ClO0ml) 4nd then dried over magnesium sulphate. The solvent and unreacted starting material were removed by distillation to give the title compound as an cil.

ii) Ethyl 8-(4-chlorobenzenesulphonam>1 2 Io) 2. 2-dimethyloctanoate A mixture of 4-chlorobenzenesulphonamide ethyl 8-bromo-2,2-dimethyloctanoate (3.3g) and potassium carbonate (9.3g) in dry methylethylketone (l4Ornl) was refluxed for 9 hours. The inorganic residues were removed by filtration and the filtrate w..as evaporated to dryness to give an oil. chromatography on silica gel eluted with chlo ,roform-petroleum ether 15:1 gave the title compound (1.05g) as an oil.

iii) 8-(4-Chlorobenzenesulphonami.do)- 2,2-dimethyloctanoic Acid A solution of ethyl 8-(4-chlorobenzenesulphonamido)- 2.2-dimethyloqtanoate sodium hydroxide (1.5g) in ethanol (40m1) and water was stirred at room temperatute foic 90 hours then refluxed for 3 hours. The solvent was :amoved and the residue was dissolved in dilute hydrochloric acid, the resulting solution then being extracted with chloroform (3x50ml). The combined chloroform extracts were dried over magnesium sulphate, the solvent was removed and the residue was recrystallised from isopropanol-water to give t, e title compoun~d as a white solid (0.7g) m.p. 95-96 0

C.

C 16H 24NSO 4C1 Found: C 52.87, H 6.77. Cl 10.08, S 8.73 Required: C 53.10, H 6.68, CI 9,80, S 8.86 WO 89/01330 PCT/GB88/00674 -18- Infra-red (Nujol)' (cm 1 3590-2130 (broad, complex series of bands). 3254 (strong, v. sharp), 1702 strong, v. sharp), 1589 and 1575 (weak, sharp), 1330 strong, v. sharp), 1161 strong, v. sharp) N.M.R.U 250 MHz: 6(CDC1 3 (ppm): 1.2 68), 1.3 (m, 8H), 1.5 2H). 2.9 2H), 4.85 1H), 7.5 2H), 7.8 2H).

Example 6 9-(4-Chlorobenzenesulphonamido)nonanoic Acid i) 4-Chlorobenzenesulphonamido) nonanenitrile 15 A solution of 9-aminononanenitrile (2.0g) in pyridine (60m) was treated With 4-chlorobenzenesulphonyl chloride (2.74g) in portions. The solution was stirred for 18 hours then the solvent was removed in vacuo. The residue was dissolved in dilute hydrochloric acid and extracted with chloroform. The, chloroform extract was dried over magnesium sulphate, the solvent was removed and the residue was chromatographed on silica gel eluted with chloroform to give the title compound (0.7g1) as a low melting solid.

ii) 9-(4-Chlorobenzeneslphonamido)nornanoic Acid 9-(4-Chlorobenzenesulphonamido)nonanenittile (0.7g) was dissolved in ethanol (50ml) and water containing sodium hydroxide The mixture was refluxed for 20 hours then the solvent was removed. The residue was dissolved in water and treated with hydrochloric acid to give a white precipitate. This was collected by filtration and recrystallised from ethanol-water to give the title compound (0.56g) m.p. 121-123 0

C,

wo 89/01330 PCT/GB88/00674 j -32- WO 89/01330 PCT/GB88/00674 -19- C H 22ClNO S 15 22 4 Found: C 51.73, H 6.38, Cl 10.73, N 4.13, S 8.95 Required: C 51.79, i 6.37, Cl 10.19, N 4.03, S 9.22 Infra-red (Nujol) (cm 3580-2150 (broad, complex series of bands), 3287 strong, v. sharp), 1699 strong, v. sharp), 1588 (medium, sharp), 1574 (weak, sharp), 1331 strong, sharp), 1163 strong, sharp), 834 and 827 (medium, v. sharp).

250 MHz: S(CDC13) (ppm): 1,3 4H), 1.45 2H), 1.65 2H), 2.35 2H), 2.95 2H), 4.6 IH), 7.5 2H), 7.8 2H), Example 7 9-(Benzenesulphonamido)nonanoic Acid i) 9-(Benzenesulphonamido)nonanenitrile A solution of 9-aminononanenitrile (2.0g) in pyridine (60ml) was treated with benzenesulphonyl chloride (2.29g) in pyridine (10ml). The solution was stirred for 18 hours when the solvent was removed in vacuo, The residue was dissolved in dilute hydrochloric acid and extracted with chloroform. The chloroform extract was dried over magnesium sulphate, the solvent was removed and the residue was chromatographed on silica gel eluted with chloroform to give the title compound (0.74g) as a low melting solid.

ii) 9-(Benzenes.lphonamido)nonanoic Acid 9- (Benzenesulphonamido)nonanenitrile (0.72g) was dissolved in ethanol (50ml) and water (10ml) containing sodium hydroxide The mixture was refluxed tor 18 hours then the solvent was removed. The residue was WO89/01330PC dissolved in water and tteated with hydrochloric give a white precipitate. This was collected by filtration and recrystallised from methanol-wate the title compound (0.52g) m.p. 82-84 0

C.

*1 C H NO S Found: C 57.48, H 7.32. N 4.50, S 9.96 Requires: C 57.48, H 7.40, N 4.47, S 10.23 Example 8 7- (4-Chlorobenzenesul Phonamido~llet-5 -,ynoic Acid i) Methyl A mixture of potassium phthalimide (2.31g) methyl 7-bromohept-.5-ynoate (3.0g) in dimethylfo (35m1) was heated at 3.10 0 C for 4.5 hours. T.he c solution was poured into water (75rn1) and the pH solution was adjusted to 6. The resulting solut extracted with ether (4x200m1) and the combined extracts were dried over magnegium. sulphate, the was removed ,and the residue was chromatographed gel eluted with chloroform to give the title com (1..56g) m.p. 62-63 0 0.

ii) i-Phthalimidohept-5-ynoic Acid 'G8188/00674 acid to r to give and rmamide 001 ed of the ion was ether solvent on silica pound Methyl 7-phthalimidohept-5-ynoate (1.45g) was dis solved in a mixture of concentrated hydrochloric acid (7.3m1). acetone (30ml) and water (2.4.6m1) and the resulting solution was heated at reflux for 3.5 hours.

The solution was cooled and then poured into water (175m!). Ths, precipitate was collected by filtration and recrystallised from ethanol-water to give the title compound (1.12Zg) ua.p. 120-3.226Ci WO 8901330PCT/G B88/00674 -21iii) 7-Aminoh ept-5-vnoic Acid Hydrazine hydrate (0.Iml) was added to a solution of acid (0.55g) in ethanol (25ml). The mixture was refluxed for 3.5 hours and then the solvent was removed under reduced pressure. The residue suspended in water (20m1), the pH of the solution was adjusted to 5. and the solid was collected by filtration. The filtrate was evaporated to dryness and the residue was extracted with ethanol (3x~ml). The ethanol extracts were cooled (5 0 C) and the resulting precipitate was collected to give the title compound (0.19g) m.p. 180-183 0

C.

iv) 7-(4-Chlorobenzenesulphonamido)het-5--vnoic Acid 4 -Chlorobenzenesulphonyl chloride (0.31g) in chloroform (2ml) was added to a rapidly stirred sozution It of 7-aminohept-5-.ynoic acid (0.2g) and sodium hydro~xide (0421g) in water (3M1) and stirring was continued for 24 41ours, The solution was extracted with 'chloroform (4xloml). The remaining aqueous layer was cooled, treated with hydrochloric acid and the resulting precipitate was collected by filtration and recrystallised from isopropanol-water to give -he title c,)mpound (0.085g), m.p. 91-93 0

C.

C 1 3

H

14 C1W) 4

S

Found: C 49.46, H 4.42, N 4.31 Requires: C 49.45. H 4.47, N 4444 N.M.R; 250M.Uz; S(CDC 3 (ppm):6 1.7 (in. 2H), 2.1.(mn.

2H), 2.3 (in. 2H), 3.8 2H), 4.8 IH), 7.5 (mn, 2H), 7.8 (mn. 2H1).

PCT/GB88/00674 Example 9 (Z)-7-(4-Chlorobenzenesulphonamido~hept-5-enoic Acid i) Methyl (Z)-7-,phthalimidohe t---enoate V A mixture of methyl (1.9g) asd Lindlar catalyst (250mg) in methanol (130m1) was shaken under an atmosphere of hydrogen at 30psi for 2.5 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel eluted with chloroform to give the title compound (1..59g) as a low melting solid.

m.p. 47-49 0

C,

1 ii) (Z)-7-Phthalimidohept-5-enoic Acid A solution of methyl (1.56g) in acetone (30ml), concentrated hydrochloric acid (15m1) and water (15ml) was refluxed for 2.5 hours.

Water (180ml) was added and the solution was cooled, The precipitate was collected by filtration to givta the title compound m.p. 86-88 0

C.

C H NO Found: C 65,93, H 5,41.. N 5.12 Requires: C 65.92, H 5.53, N 5.13 iii) (Z)-7-Amli$ihept-5-enoic Acid Hydrazine hydrate (0.2.9m1) Was added to a Solution of (Z)-7-.phthalmidohept-5-enoic acid (1.05g) in ethanol (25m1) and water (Sml). The solution was refluxed for 3 hours and then the solvent was removed. The residue was suspended in water and the pH of tfle solution was adjusted to 5, The resu~lting precipitate was collected WO 89/01330 PCT/G B88/00674 -23by filtration. The filtrate was evaporated to dryness and extracted with ethanol. The ethanol extracts were evaporated to dryness to give the title compound as an oil (0.62g).

iv) (Z)-7-(4-Chlorobenzet, sulphorxamido) hept-5-enoic Acid A rapidly stirred solution of acid (0.61g), sodium hydroxide (0.51g) in water (5mi) was treated with 4-chlorobenzepesulphonyl chloride (0.9g) in chloroform (2.5ml). The solution was stirred for 24 hours then extracted with chloroform (4x15m1). The aqueous layer was treated with hydrochloric acid to pH=Il and extracted with chloroform (4x40m1). These chloroform extracts were combined, dried over magnesium sulphate and evaporated to dryness, The residue was recrystallised from isopropanol to give the title compound N.M.R: 250MHz: 6(CDC 3 (ppm): 1.7 (in, 2H) 2.05 (in, 2H). 2.35 2H), 3.6 2H), 4.9 1H) 5.3 1I), 5.45 (in. 18) 7.45 (mc 2H), 7.8 (mn, 2H), Example 2,2-Diinethvl-l-(4-chlorobenzonesulphonainido)decanoic Acid i) Ethyl 2,2-Ditinethvl-lo-brornodecanoate Using the method described in Example 1.8dibroinooctane (27.2g. 0.lmol) and ethylisobutyrate (10.44go 0.09mol) were reacted in the presence of lithium diisopropylainide (67m1. 0.linol) and hexainethylphOsphorainide (22g) to give the title compound (4.56g) as an oil.

W089/1330PCT/%G B88/00674 -24i)Ethyl-l0-(4-chlorobenzenesulphonamido)-2,2-dimethyldecanoate Ethyl 2.2-dimethyl-20-bromodecanoate (2.2g, 0.OO7mol) was treated with 4-chlorobenzenesulphonamide (2,6g, 0.02.4mol) and potassium carbonate by the method described in Example 5(ii) to give title compound (1.4g) as an oil.

iii) 2.2-Dinethvl-lo-(4-chilorobenzenesulphonamido)decanoic Acid Ethyl-l0-(4-qhlorobenzenesu~phonamndo)-.2,2-dimethyldecanoate (1,4g, 0,00~mol) was treated with sodium hydroxide by the method described, in Example 5(iii) to give the tO.tle compound which was recrystal].ised from etheripet. ether (0,59g, mo, 78-90C).

C

1 8 fl 2 8

GO

4

S

Found; C 55.32, 11 7,29, N 3,51, CI 9,52 Required: C 55.44, H 7.24, N 3#59, Cl 9,09 'Example 11 12 4Chlorbenzenesul hoiiamido)-dodecanoic Acid 12-Arninododecanoic acid (2,15Sg, 0,01 moles) was treated with 4-chlorobenzenesulphonyl chloride (2,11g, moles) as desoribed in Example 3 to give the title compoUnd (1*8g, mop, 144-60C), 4.30 WO 89/01330 PCT/G B88/00674 Example 12, 8-(4-Chlorobenzene'ulphonamidg~j-3 -dimethyloctanoic Acid i) Three drops of phosphoryl chloride were added to a stirred mixture of 5-bromopentanol (34.3 g. 205 mmol) and dihydropyran (1,9.0 g, 226 mmol). After standing for one hour. the mixture was fractionated. Yield 34.7 g, b-p, 102 0 C (0.2 bar). Chromatography on alumina eluted with petroleum ether gave the pure title compound (25.1 g, 52% of theory) as an oil.

ii) Diethyl (6-hydroxy-.l.1-dimethylhexyl)malonate At S0 0 C. a solution of pyranylether (13,8 g, 58.7 mmol) was dropped slowly into a mixture of magnesium (1,3 30 ml of dry tetrahydrofuran and one crystal of iodine. The zvesulting Grignard solution was then dropped at -10 0 C into a stirred solution of 11.9 g (58.7 mmol) of isoptopylidenemalonic acid diethylester in 100 ml of dry tetrahydrofuran. The resulting solution was stirred for one hour at room temperature., poured into a mixture of ice and hydrochloric acid and extracted with ether. After drying over sodium sulphate, the solvent was removed and the oily residue W.aAI taken up in ethanol. A small amount of Amberlyst was added and the mixture was heated for 15 minutes at 7SOC, After filtration, the solution was evaporated and the oil!( residue was chtomatogzraphed on silica gel with methylenie chloride, then eluted with ether.

Yield: 10.0 g. (34% of theory), colourless oil.

PCT/G

WO 89/01330 PCT/ -265iii) Diethyl e omo-1,1-dimethvlhexyl)malonate A solution of diethyl .5-,hydroxy-1,1-dimethy1 malonate (5.0 g, 17.3 mmol) in methylene chlorid, was treated with 2.2 g (19 mmol) of methansulphony chloride at -10 0 C. After one hour, the solution w extracted successively with diluted hydrochloric a sodium bicarbonhte Lolution and water, then dried sodium sulphate and evaporated. The oily residue taken up iii 200 ml of acetone, lithium bromide (5, was added and the mixture was heated for one hour 0 C. After removing the solvent. 100 ml water wa and the mixture was extracted with ether. The com ether extracts were dried over sodium sulphate and solvent was removed to give 5.3 g (87% of theory) title compound as an oil.

iv) Diethyl 6-k(4-chlorobenerstL onamido))-.1dimethvl)hexvllmalonate A solution of 6.45 g (30.2 mmol) of dry sodiu f 4hl obnzar nnspiol namide in 50 ml dimIthl f B88/00674 hexyl)- (50 ml) as C over was 0 g) at s added bined the of the m salt ormmieA r 11 was treated for 15 hrs at 70 0 C with 5.3 g (15.1 rnmol) of diethyl (6-bromo-,1L-dimeathylhexyl)malonate. The solution was then poured into water, the mixture was extracted with ether and the ether phase was dried over sodium sulphate., After evaporation of the ether, the oily residue va dissolved in toluene, cyclohexane was added and the precipitated 4-chlorobenzenesulphonamide was filtered off. The filtrate was stirred with silica, filtered and the solvent was evaporated off.

Yield: 5.2 g (75% of theory) as an oil.

cl iI WO 89/01330 PCT/GB88/00674 -27v) 8-(4-Chlorobenzenesulphonamido)-3,3-dimethyloctanoic Acid A mixture of diethyl [6-(4-chlorobenzenesulphonamido)-l,l-dimethyl)hexyl]malonate (5.0 g, 10.8 mmol), ml of 2 N NaOH, 20 ml of water and two drops of Adogen (Trade Mark) was kept for 12 hours at reflux temperature.

The mixture was cooled, extracted with ether and was then acidified. The acidic solution was extracted with ethyl acetate and the ethyl acetate solution was dried over sodium sulphate, then evaporated. The oily residue was kept for 20 minutes at 180 0 C, after which it was dissolved in sodium bicarbonate solution. The aqueous solution was extracted with ether, acidified by means of hydrochloric acid, and was then again extracted with ether. The ether extract was dried over Na2SO 4 the solvent was removed and the residue was purified by chromatography on silica gel with ether. Yield: 2.4 g (61% of theory), wax-like mass.

Example 13 7-(4-Chlorobenzenesulphonamido)heptanoic Acid A solution of 7-aminoheptanoic acid in 10% sodium hydroxide solution was treated with 4-chlorobenzenesulphonyl chloride in the manner of Example 1 to give the title compound which, after recrystallisation from aqueous ethanol, had a melting point of 128-1,29 0

C.

430 Calculated for CH13 Cl1NO S: C, 4.82, H, 5.67; N. 4.38; Cl. 11.09; S, 10.03.

Found: C, 48.96; H, 5.72: N, 4.29, Cl, 11.25; S, 9.98 NMR (DMSO-d6, 250MHz) 6 7.79, 7.68 (2m,'5H, aryl ring 6 H, NH). 2.72 2H, -NHCH 2.16 2H. -CHiC=O), 1.43, 1.34 (2m, 4H, -NHCH2H-, -CH 2

CH

2 C'O) 1.18 4H, -CH2(CH 2 2

CH

2 t 1 (If WO 89/01330 PCT/GB88/00674 -28- V Example 14 8-(3-Chlorobenzenesulphonamido)octanoic Acid A solution of 8-aminooctanoic acid in 10% sodium hydroxide solution was treated with 3-chlorobenzenesulphonylchloride in the manner of Example 2 to give the title compound which, aft:: recrystallisation from aqueous ethanol, had a melting point of 85-86 0

C.

Calculated ft, C 14 8 2 0 C1N0 S; C, SO.37; H, 6.04; N, 4.20; Cl,. 10.62; 9.61.

Found: C. 50.52; H, 6.07; N, 4.07; Cl, 10.69; S, 9.54.

NMR (DMSO-d6, 250MHz) 6 7.70, 5H, aryl ring H, NH), 60 2.77 28, -NHCH2-), 2.18 2H, -CH 1.47, 1.36 2 2 (2m, 4H, -NHCH 2 2 2 C2 C= 1.21 6H, -CH2 CE CH2 Example 8-(4-Nitrobenzenesulphonamidooctanoic Acid A solution of 8-aminooctanoic acid in 10% sodium hydroxide solution was treated with 4-nitrobenzenesulphanyl chloride in the manner of Example 2 to give the title compound which, on recryptallisation from aqueous ethanol, had a melting point of 126-7 0

C.

Calculated for C H N 0 S: C, 48.83; H, 5.86: N, 8.14; 14 20 2 6 9.31.

Found: C, 48.76; 8. 5.94; N, 8.09; 5, 9.15.

NMR (DMSO-d6, 250MHz) 6 8.42, 8.04 (2m, 48, aryl cr 4 .ng 6* 7.98 1H. NH), 2.80 (in, 2H. -NHCH 17 (t, 2H, -CH C0O), 1.43, 1.36 (2m. 4H, -NHCH 2 CH 2 2 2 2 -CH CHC=0) I.20 6H. -CH (C 2 3

-CH

2 -2 2 (9-"23 2) WO 89/01330 PCT/G B88/00674 -29- Example 16 8- (4-Bromobenzenesul phonamido) octanoic Acid A solution of 8-aminooctanoic acid in 10% sodium hydroxide solution was treated with 4-bromobenzene.

sulphonyl chloride in the manner of Example 2 to give the title compound which, on recrystallisation from aqueous ethanol, had a melting point of 115-.116 0

C.

Calculated for C 14H 20BrNSO 4C, 44.45; Hi, 5.33; N, 3.70.

Br 21.12: So 8.48.

Found: C. 44.49; H. 5.27; N, 3.69; Br, 21.14; S, 8.23 15 NMR (DVFO-d 250MHz), 6 7.81. 7.70 (2mn, 5H, aryl ring H, II6 K NH). 2.73 (in. 2H. -NHCH -,2.18 2HI, CH 1.44, -2 2 1.33 (2m, 4H, -NHCHCH O H CH 1.18 (in. 6H, 2 2 9H2 2 -CH" 2(CH2)3 CH 2) Example 17 8-(4-Methoxybenzenesulphonainido)octanoic Acid V A solution of 8-aininooctanoic acid in 10% sodium hydroxide solution was treated with 4-inethoxybenzenesulphonylchloride in the manner of Exainpla 2 to give the title compound which, on recrystallisation from aqueous 2-propanol, had a melting point of 102-103 0

C.

Calculat~ed for C 15

H

2 NS0 5 C, 54.69;1 H, 7.04; N. 4.25; 301 S. 9.73.

'Found; C 54.77. H 7.08, N 4.24, S 9.74.

NMR (DMSO-d .250MHz) 6 7.06 (2m, 4H. aryl ring 6 7.34 1H, NH), 3.78 3H, CH 3 O0), 2.62 (mn, 2H, -NHCH 2 2.11 (to 2H. CH 2 1.38, 1.27 (2m, 4H.

-NHCH

2

CH

2

-CH

2

CH

2 1.12 (min. 6H, -CH 2 (CH 2 3 CH 2 WO089/01330 PCT/G B88/00674 Example 18 8-(3,4-Dichlorobenzenesulphonamiido)octanoic Acid 8-Aminooctanoic acid (1.0g, 0.OO6mol) was treated with 3,4-dichlorobenzentesulphonylchloride (1-54g, 0.OO6mol). according to the method described in Example 4, K to give the title compound which was recrystallised from V 2-propanol/water (1.2g. m.p. 115-6 0

C)

C H Cl NO S 14 19 2 4 Found: C 45.65. H 5.23, N 3.81. Cl 19.29. S 8.75 Required: C 45.66. H 5.20. N 3.81, Cl 19.25. S 8.71 Eaml el 19 11-(4-C~ilorobenzenesulphonamjidoJundecanoic Acid V il-Aminoundecanoic acid (4.02g, 0.O2mol) was treated with 4-chlorobenzenesulphonyl chloride (4.22g. 0.02mol) as described in Example 4 to give the title compound which was recrystallised from 2-propanol/ether (1.8g, m.p. 128.-9 0

C).

C

17

H

2 ClNO S Found: C 54.50. H 7.03. N 3.72. Cl 9.54, S 8.46 Required: C.54.32. H 6.97. N 3.73. Cl 9.43. 8 8.53 xmle2 ll-(3-Chlorobenzenesulphoriamido)undecanoic Acid, Substituting 3-chlorobenzenesal.phonyl chloride for 4-chlorobenzenesulphonyl chloride in Example 19 gave the title compound, from 2-propanol/ether (1.9g. m.p. 116-7 0

C).

C 17H 26CNO 4S Found: C 54.40. H 7.03. N 3.78, Cl 9.65. S 8.46 .4 Required: C 54.32. H 6.97. N 3.73. Cl 9.43. S 8.53 WO 89/01330 PCT/G B88/00674 -31- Example 21 E j-(-TOlvlsulhoiam-ido)octanoic Acid 8-Aminooctanoic acid (1.0g. 0.OQ6inol) was treated with p-toluene suiphonyl chloride (1.2g. 0.OO6mol) according to the method described in Example 4 to give the titld compound which was recrystallised from 2-propanol/water (1.0g. m.p. 110-2 0

C).

C 1 5

H

2 3 NO 4S Found: C 57.45o H 7.45. N 4.43, S 10.36 Required: C 57.48. H 7.40, N 4.47, S 10.23 Example 22 6-(4-ChlorobenzeneE:ulphonamido)hbexanoic Acid 6-Aminohexanoic acid (2,62g. 0.O2mol) was treated with 4-chlorobenzenesulphonyl chloride (4.22g, 0.02mol) by the method described in Example 4 to give the title H compound which was recrystallised from ethylacetate-ether (1.92g, m.p. 126-7 0

C).

C H ClNO S 12 16 4 Found: C 47.04. H 5.18. N 4.60, S 10.77, Cl 11.60 Required: C 47.13. H 5.27, N 4.58, S 10.49, Cl 11.60 Example 23 9-(3-Chlorobenzenesulphonamido)nonanoic Acid i) 9-(3-Chl robenzenesulphonamido)nonanenitrile 9-Amiaonwov.'nenitrile (4.0g. 0.026mol) was treated with 3-chlorobenzene sulphonyl chloride (5.5g, 0.026mo1) by the method described in Example 6(i) to give the title compound (4.4g. m.p. 42-30C).

PCT/

WO89/01330 -32ii) 9-(3-Chlorobenzenesulphonamido)nonanoic Acid G B88/00674 11 9-(3-Chlorobenzenesulphonamido)nonaienitrile (4.4g, 5 0.013mo1) was treated with NaCH (5g, 0.1l5mol) in 30m1 water and 50ml ethanol by the method described in Example 6(ii). Chromatography in CHCl :MeOH 10:1 on silica and recrystallisation from 2-propanol/pet. ether 60-.800 gave the title compound (0.94g, m.p. 112-3 0

C).

C isH 22CiNO 4S Found: C 51.39, H 6.06. N 4.01, CI 10.31. S 9.23 Required: C 51.79. H 6.37, N 4.03, C1 10.19, S 9.22 Example 24 10-(4-Chlorobenzenesulphonamido)decanoic Acid i) Methyl-lo-bromodecanoate A mixture of 10-bromodecanoic acid (2.0g. 0.OQ8mol) methanol (50mi) and concentrated sulphuric acid (2m1) was refluxed for 3 hours. After evaporation to dryness the residue was basified with aqueous Na 2CO 3and extracted with dichloromethane. Evaporation of the solvent from the extracts yielded the title compound as an oil (1.64g).

ii) Methyl-lo-(4-chlorobenzenesulphonamido)decanoate A mixture of methyl 1O-bromodecanoate 0.OO6mol), 4-chlorobenzenesulphonamide (3.44g. 0.Ol8mol), potassium carbonate (6.2g. 0.O45mol) and dimethylformamide (50m1) was heated at 100-120 0 C for 3 hours. After cooling, the inorganic material Was removed by filtration.

The filtrate was evaporated to dryness and the residue was extracted with dichloromethane. The residual oil obtained by evaporation was chromatographed on silica gel WO 8901330PCT/G B88/00674 -33in petroleum ether (40-60 0 C) and the solid obtained on evaporation of the eluate was recrystallised (ether-pet.

ether 40-600) to give the title compound (0.9g, m.p.

68-700 C).

iii) 10-(4-Chlorobenzenesulphonamido)decpnoic Acid Methyl 10-(4-chlorobenzonesulphonamido)decaneite (0.85g. 0.0023mo1) was treated with 5N sodium hydroxide (15m1) in ethanol (25m1) at room temperature for 1 houz.

The pH was adjusted to 1 with dilute hydrochloric aqid and the precipitated solid was filtered off and recrystallised isopropanoI- ether) to give the ti,tle is compound (0.17g. m.p. 192-4 0

C).

C H- CiNO S 16 24 4 Found: C 53.36. H 6.62, N 3.75, Cl 10.01, S 8.77 Required: C 53.10, H 6.68. N 3.87, Cl 9.8*0, S 8.86 Example 8-(4-Fluorobenzenesu-lphonamido)octanoic. Acid 8-Aminoocta~aoic acid (1,Og, 0.OO6mol) was treated with 4-flluorobenzenesulphonyl chloride (1,22g, 0.OO6mol) in thie presence of sodium hydroxide 0.Olg9mol) in water. tetrabutylammonium hydroxide (4 drops. solution) and dichioromethane and the resulting mixture was subjected to vigorous stirring for 3 hours. The organic layer was then separated and evaporated to dryness and the residue was recrystallised from 2-propanol-water to give the title compound (0.88g, m.p. 97-.8 0

C).

C H FNO S 1.4 20 4 Found, C 53.25, H 6.46. N 4.53, S 9.84 'Requires: C 52.98. H- 6.35. N 4.41. S 10.10 PCT/G B88/00674 WO 89/01330 -34- NMR (DMSO-d60 250MHz). 6 7.86. 7.45 (2m. 4H, aryl ring H 7.63 LH. 2.74 2H. -NHCH2-). 2.18 2H;. CH 2 CO). 1.46, 1.35 (2m, 4H, -NHCH 2 2-# 2CH CH C=O. 1.20 6H, -CH H Example 26 9-(4-Bromobenzenesulphonam ido)ionanoic Acid i) 9-(4-Bromobenzenesul honamido)nonanenitrile 9-Aminononanenitrile (1.54g. 0.Omol) was treated with 4-broiobenzenesulphonylchloride (2.56g, 0.Olnol) by the method described in Example 6(i) to give the title compound (0.7g) as an oil^.

I ii) 9-(4-Brmobenzenesu__honmido)onnoic Acid 9-(4-Bromobenzcnesulphonamido)nonanenitrile (0.6g, 0.O0l6mol) was treated with sodium hydroxide (2g, 0.05ino1) in 10ml water plus 20m1 ethanol by the method described in Example 6(ii) to give the title compound (0.35g, m.p. 124-5 0 C) after recrystal2,isation from chloroformpetroleum ether 40-600.

C H BrNO S 2.5 22 4 Ftund: C 45.99. H 5.78. N 3.57, S 8.27 Required: C 45.92, H 5.65. N 3.57. S 8'.17 NMR (CDCl 3 250MHz). 6 7.80, 7.49 (2m. 4H. aryl ring 4.79 1H. 2.94 2H, -NHCH 1.49 (m, 4H, -NHC 2'2 -CH 2 1.24

-CH

2 (CH 2 5 CH 2 1.21 6H. 2.CH 3 WO 8901330PCT/G B88/00674 a~i Example 27 3.3-Dimethyl-5-(benzenesulphonamido)pentanoic Acid Ethyl 3,3-dimethvl- -(benzenesulphonamido)- Pentanoate Benzenesulphonamide (9.6 g, 61.1 mmol) was added to a stirred solution of sodium methoxide (1.6 g, 29.6 mmol) in methanol (100 ml). The clear solution was evaporated V. to dryness, then dimethyl 'Oprmamide (100 ml) and ethyl 5-bromo-3,3-dimethyl-pentanoate (7.0 g, 32.8 mmcl) were added and the mixture was heated for eight hours at 70 0

C.

The solution was then poured into water (600 ml), the mixture was extracted with ether and the ether phase, after being dried over sodium sulphate, was evaporated.

Treatment of the solid residue with a mixture of toluene and cyclohexane left most of the unreacted benzenesulphonamide undissolved. After filtration, the solution was evaporated and the residue was purified by chromatography on silica gel with a mixture of methylene chloride and ethanol Yield: 4.6 g(50% of substnce, theory), oily sbtne D 1,5083.

3,3-Dimethyl-5-(benzenesul-phonamido)pentanoic Acid A mixture of ethyl 3,3-dimethyl-5-(benzenesulphon-, amido)pentanoate (4.4 g, 1.4.1 tamol). methanol (30 ml) and 2 N NaOH (20 ml) was stirred for 5 hours at 60 0 C. The methanol was then evaporated, the aqueous phase was acidified (diluted HCl) and the oily acid was extracted with methylene chloride. After drying over sodium sulphate the solvent was removed. Yield: 4.0 g (100% of theory), oily product. n 1 1.5250.

WO 89/01330 PCT/G B88/00674 K -36ii Example 28 5-(4-Chlorobenzenesulphonamido)-3,.3-dimethyl-- S Pentanoic Acid Ethyl 5-(4--chlorobenzenesulphonamido)-3.,3-dimethyl Pentanoate i The title compound was prepared according to the i 20 method described in Example 27(i).

A 20 Yield: 47% of theory; colourless oil, n D =1.5162.

H(ii) 5-(4-Chlorobenzenesal~honam _do)-3,3-dinetyj- K Pentanoic Acid H The title compound was prepared according to the Ii method described in Example 27(ui).

Yield: 93% of theory; m.p. 107-08.

K 20 ExamTole 29 8-,(5-Chloro-2-thi,.4nvirulpohona ido)o2ctanoic Acid 8-Aminocaprylic acid (1.0g, 0.006 mole) was treated with S-chloro-2-thiophene sulphonyl chloride (1.37g, 0.0063 mole) according to the method described in Example 4 to give the title compound after recrystallisation from Isopropanol/water (1.39g, m.p. 1.08-9 0

C).

C 1H 1CINO S Found: C 42.46, H 5.39, N 4.112. Cl 10.49, S 19.02 Required: C 42.41, H 5.34, N 4.1.2. Cl 10.43, S 18.87 WO 89/01330 PCT/G B88/00674 -37- Example 9-(4-Chlorophenylsulphonamido)--2,2-dimethylnonanoic Acid i)Ethyl 2,2-dimethyl-9--bromononanoate Using the method described in Example 1~,7 dibromoheptane (25.8g, 0.1 mol) and ethylisobutyrate (10.4g. 0.09 moJ.) were reacted in the presence of lithium diisopropylamide mol) and hexamethylphosphoramide (22g) to give the title compound (24.7g) as an oil, ii) Ethyl-.9-(4-chlorobenzenesulphonamido)-2,2dimethylnonanoate Ethyl 2,2-dimethyl-9-bromononanoate (2.0g, 0.007 mol) was treated with 4-chlorobenzenesuJlphonamide (1.44g, 0.018 mol) and potassium carbonate (6,2g, 0,04,5 mol) by the method described in Example 5(ui) to give the title compound (1.5g) as an oil.

It iii) 9- (4-Chlorobenzenesulphonamido ,2-dimethylnonanoic Acid Ethyl-9-(4-chlorobenzenesulphonamido)-2,2-dimethy.

nonanoate (1.4g. 0.00.33 mol) was treated with sodium hydroxide by the method described in Example S(iij) to yield the title compound which was recrystallised from water (1,09g. m~p, 89-906C).

17

H

26 C1NO 4

S

Found: C 54.33, H 7.18. N 3,90, Cl 9.83., S 8.76 Reqluires-. C 54.32, H 6.97. N 3.73, Cl 9.43, S 8.53 wvo 89/013 -38- 7-(4-Chlorophenylsulphonamido)-.2-dimethv]heptanoic AciJ i) Ethyl,-2,2-dimethvl-7-bromohentanoate

I

Using the method described in Example 5(i (23g, 0.1 mol) and ethyliso (10,4g, 0.09 mol) were reacted in the presence diisopropylamide mol) and hexamethylphosp (22g) to give the title compound as an oil (7, ii) Ethy 7-(4 acahlorophenylsuphonamido' -2 .2 1 _imethvlhetanoat Ethyl-2.2-dimethyl-7-bromoheptanoate 0.026 mol) was treated witb, 4-chioroberizenesul (9,9g. 0,052 mol) and potatasium carbonate (21, 0.016 mol) by the method desicribed in Example give the title compound (1.3g) as an oil.

CT/GB88/00674

I

butyrate of lithium ho ramide 4g).

pha namio de 5(ii) to iii) 7-(4-ChldrO~ hen lsul'ona mldo"-I,.g.dimethvl l eanoic Acid Ethyl-7- (4-chlorophenylsulphonamido) 2-dimethylheptanoate (3.5g, 0.09 mol) was treated with sodium hydroxide by the method described in Example 5(iii) to give the title compound (1.9 g) m.p. 132-30C (dichloroethane/40-600 petroleum ether).

C

15 &i~CNO 4 S 2% CH 2 01 2 Found: C 50482 H 6.25, N 3.86, Cl 11,65 Requires'. C 51.20, H 6.29. N 3,95o C1 11486 WO 89/01330 PCT/G B88/00674 -39- Example 32 8- 5-Dichloro-3-thienylsulphoriamido)octanoic Acid 8-Aminocaprylic acid (1.0g, 0.0C06 mole) was treated with 2.5-dichloro-3-thiophene sultphory1 chloride (1.58g, 0,006 mole) according to the method described in Example 4 to give the title compound after reczystallisation from isopropariol/water (1.1g. m.p. 92-93 0

C).

C 12H 17Cl 2NO 4S2 Found: C 38.30, H 4,55o N 3,81, -01 18.77 Rlequired: C 38,50. H 4.58. N 3.74, C1. 18.94 WO089/01330 PCT/G B88/00674 Example 33 Platelet Binding Activity 125 InhiLbition of I PTA-OH Bindn to Washed Human Platelets Compound of I C 50

M)

Example No.

2.3 01,29 0.03 61 0. 0.018 0.28 5.4 1.6 0.47 7 0.16 0.11.

0.02 0.3 0.*07 0.6 1.9 0.075 0.25 0.06 0.22 0.04 0.04 0.36 0,33 0.65

Claims (13)

1. A method for treating thromboxane mediated diseases in a patient in need thereof comprising administering to said patient an effective amount of a compound of the formula RSO 2 NR'BCO 2 H or a salt or ester thereof, wherein R is a phenyl, furan or thiophene ring optionally substituted by one or more substituents which are the same or different and are chosen from halogen, nitro, cyano, trifluoromethyl, C 1 4 alkyl Si and C 1 .4 alkoxy; I R' is hydrogen or C1- 4 alkyl: and B is an acyclic hydrocarbon group naving 4 to 11 linear carbon atoms, any one or more of the linear carbon atoms of which are optionally substituted by one or two C 1 3 alkyl groups. *ss

2. The method according to claim 1 wherein B has at least 6 linear carbon atoms, "S i go S* 3. A compound of the formula as defined in claim 1 wherein the group R is optionally substituted by one or two substituent groups which are the same or different and are chosen from halogen, nitro, cyano, trifluoromethyl, C lalkyl acid C l alkoxy; and •t 'B is an acyclic hydrocarbon /qoup having 6 to 9 linear carbon atoms, each linear carbon atom of B being S. optionally substituted by one or two C1-3alkyl groups, but provided that when B is an unbranched alkylene group and R is a phenyl ring, the phenyl ring is either disubstituted or it has only one substituent which is chosen from halogen, nitro cyano, trifluoromethyl, C -4alkoxy, o- or m-C l alky l and P-C 4 alky l ,1326,eJhdat.081,22546.LET,41 it WO 89/01330 PCT/G B88/00674 -42-

4. A compound according to claim 3 wherein the group B is selected from (CH 2 6 (CH 2 7 v (CH 2 8 1 (CH1 2 9 0 (CH C(CH) 2 (CH )C(CH) 2 (CH CCIH) and (CH C(CH 2 8 3 2 A compound according to either of claims 3 or 4 wherein R is phenyl substituted at the 3- and/oz 4-positions by chlorine, bromine, fluorine. nitro, methoxy or methyl.

6. A compound according to either of claimsi 3 or 4 wherein R is 2-thienyl substituted at the S-position by 5-bromo or

7. A compound of the formula as defined in claim 1 where B is a group (CH )yCRc Rd C y c d wherein y is an integer from 2-9 and R and R~ are the same or different and each is a C 13alkyl. group.

8. A compound according to claim 7 wherein y is aRc andRdare both methyl.

9. A compound accordi,: to either of claims 7 or 8 wherein R is a 4-chioropheny. group. A compound selected from the group consisting of 8-(4-chlorobenzenesulphonamido)octanoic acid, 8-(4-chlorobenzenesulphonamidcj -2 .2-dimethyloctanoic acid, 9-(4-chlorobenzenasulphonamido)nonanoic acid, 8-(4-bromobenzenesulphonamido)octanoic qcid, 8-(3,4- dichlorobenze-tesulphonamido)octanoic acid, 8-(4-tolyl- sulphonamido)octanoic acid, 9-(4-bromobenzene- sulphonamido)nonanoic acid, 8-(5-chloro-2-thienyl- sulphonamido)octanoic acid, l0-(4-chlotobenzenesulphon- amido)decanoic Poid. 8-(4-chlorobenzenesulphonamido)- 3,3-dimethyloe.tanoic acid and eaters and pharmaceuatically I acceptable salts thereof. -43-

11. A pharmaceutical composition comprising a compound as hi defined in any one of claims 3 to 10 and a pharmaceutically acceptable carrier. j12. A compound of the formula RS0 2 N R'BCO 2 (I) when used in the treatment of thromboxane mediated diseases according to V claim 1 or 2.

13. The compound according to claim 12 wherein B has at least 6 linear carbon atoms.

14. A process for preparing a compound of the formula RSO 2 NRBCO 2 H (I) or a salt or ester thereof, wherein R is a phenyl, furan see: or thiophene ring optionally substituted by one or two .~.substituents which are the same or diffezent and are I *chosen from halt~qzn. nitro, cyano, trif luoroinethyl, *C 14alkyl and C 1 4 alkoxy; 1--4 B is an acyclic hydrocarbon group having 6 to 9 linear carbon atoms, each linear carbon atoui of B being *.:optionally substituted by one or two C 1 3 alkyl groups, but provided that when B is an unbranched alkylene group and R is a phenyl ring, the phenyl ring is either disiubstituted or it has only one substituent which is chosen from halogon. nitro, cyano. trifluoromethyl. C 14alkoxy. 2- or ly and p-C 2 4 alkyl; which process comprises: 0(i) the reaction of a compound of the formula (11): E-9-Y(II) W ~920326,ejhdat.081,225416.LET,43 -44- w ith a compound of the formula (III): RSO G(I) 2 wherein Y is CO2 or a gr'-p hydrolysable thereto; one of E and G is a group NHR' and the other is a leaving group displaceable by a :;'oup NHRI and R is as defined hereinbef ore. and thereafter, where required, hydrolysing any hydrolysable group Y to give CO H: or 2 A i41) the hydrcrlysis and decarboxylation of a compound of the formula (IV): RSO 2 NR'-B'CH-(Z) 2 (IV) wherein ReadRfare the same or different and *each is hydrogen or a methyl group, BI is an acyclic OV A hydrocarbon group having 4-9 linear carbon atoms and Z is a C alkoxycarbonyl group or a nitrile group. 1-4 A process according to claim 14 wherein *B is selected from (CH~6 (CH 2 7 (CH (CH 9 0 (CH 2 )C(CH 3 2 (CH 2 6 C (CH 3 2 (CH 2 7 C (CH 3 2 and (CH C(CH 2

16. A process according to either of claims 14 or SIP 15 wherein R is phenyl substituted at the 3- and/or 0> :it:on: by hlorine. bromine. fluorine. nitro, 17, A process according to either of claims 15 or 6 16 wherein R is 2-thienyl substituted at the by 5-chioro, 5-bromo or S-methyl.

18. A process according to claim 14 wherein the compound of the formula is selected f rom the group consisting of 8- (4-chlorobenzenesulphonamido) octanoic acid. 8-(4-chlorobenzenesulphonamido)-2.2-dimethyl- octanoic acid, 9- (4-chlorobenzenesulphonamido) nonanoic acid, 8-(4-bromobenzenesulphonamido)octanc-c acid, 8-(3,4- dichlorobenzenesulphonamido)octanoic acid,* 8- (4-tolyl- sulphonamido)octanoic 1cid, 9-(4-bromobenzene- sulphonamido)nonanoic acid, 8-(5-chloro-2-thienyl- sulphonamido)octanoic acid, 10- (4-chlorobenzenesulphon- amido)decanoic aqid. 8-(4-chlorobenzenesulphonamido) 3.3-dimethyloctanoic acid and esters and pharmaceutically acceptable salts thereof. fees19. A procr:;s as defined in claim 14 wherein R and RI are as def ined in claim 1 but B is a group (C R CH wh~erein y is an integer from 2y 2- 2-9 and Rc and R are the same or different and each is a C 1-3 alkyl group. A process according to claim 19 wherein y is c d and Rc and R are both methyl. :21. A process according to either of claims 19 or wherein R is a 4-chlorophenyl group. 2. A process for preparing a pharmaceutical composition comprising bringing a compound of the formula U as defined i any one of claims I. to 8 into V~ :.~.association with a pharmaceutically acceptable carrier. DATED this 30th day of March, 1992 BOEHRINGER MANNHEIM GmbH SMITHKLINE FRENCH LABORATORIES LIMITED By Their Patent Attorneys DAVIES COLLISON CAVE INTERNATIONAL SEARCH REPORT International Application No PCT/GB 88/00674 1. CLASSIFICATION OF SUGJECT MATTER (it several classification symools apply, indicate a0) According to International Patent Classification IIPC) or to bath National Classiication and IPC IC4:A 61 K 31/19; 31/34; 31/38; 31/63; C 07 C 143/78; C- 07 T) 107/64., 33.1/34 11, FIELDS SEARCHED Minimum Documentation qear,,hed Classification System Classification Symbols 4 IPC A 61 K 31'K; C 07 C 143/00; C 07 D 307/00; C 07 D 33371 Documentation Starched other than Minimum Documentation to the Extent that auch Documents are Included In ile Fields SearchedI jlII DOCUMENTS CONSIDERED TO 01 RKLEVANT9 Category *I Citation of Document, 11 with Indication, where ,tporoprlate, Pf the relevant Passages 12 Relevant to Claim No, i X,Y EP, A, 0068968 (CH0AY SA) 5 January 1983 1-21 see claims; pages 80-90 (cited in the application) Y Atherosclerosis, Vol. 5, 1980 1-23. R. Paoletti et al.; "Prostaglandins, thromnbin receptors and platelet aggregation in normal and hypercholesterolenic, subjects" 1 pages 772-775 see page 772 Y 'Basic. Res. Cardiol., vol. 81, 1986, 11-21 J. Ntmpf et al.: "Platelet activation in norino- and hyperlipoproteineniaslo, r pages 437-453 1see summixary; pages 440,441 A Chemical Abstracts, Vol. 88, 1978, 1l-21 (Columrbus, Ohio, us) T.A. Kutsenko et al.: "Effect of amino- caproic and p-aminornethylbenzoic aqid derivatives on the activity of the blood *Special categories of cited documenta,, to 'IT" later document Published alter the International tfln date 'A ocuentdefnin th geera stte f te at wichIs otor priority date and not in conilict with the application but ""dcun de t he ealsae of particularirelevance Cited to understand the principle or theory underlying the consdere tobe o paticuar elevnceinvention IE'O earlier document but published on or after the International xdomettpaiclreevnethcamdinntn filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or Involve an Inventive slap which Is Cited to establish the publication date ot another document of particular reloeance;' the Claimed Invention Citation or other special reason (as sPeclld) cannot be considered to involve an Inventive slap when trhe "0z" document referring to an oral disclosure. use, exhibition or document is Combined with one or more other such doCU. Whor risen* mantI, such combination being obvious to a person skilled IIP" docurvient published prior to the International filing date but I'fi the art, later than the priority date claimed "Ali document member 41 the same patent family lVo CERT!PICATION Date of the Attual Completion of the international Search Date of Maling of this International Search Report 16th March 1989 10-7 APR 1989 Internationat searching Authority 5 1*All T E EUROPEAN PATENT OFFICE DER PUTTEM' Form PCYIISA 1210 fsecond shest) (January 1913) internhtional Application No. P CT/GB 8 8 00 6 74 -2-

111. DOCUMENTS CONSIDERED TO BE RELEVANT (COF4TIP4UED FROM THE SECOND SHEET) Category Citation of Document, with indicsix..n. wtrwe appropriate, Of the rFtvant passages Relevant to Claim No coag~lating system" see page 20, abstract no. 44779g FIzilO. Akt. Veshchestva, 1977, 9, 72-5 A Chemical Abstracts, vol. 84, 1976, (Columbus, Ohio, US) see page 521, abstract no. 150347s JP, A, 75131942 (BANYU PHARMACEUTICAL CO., LTD) 18 Oct-,b)er 1975 A FR, A, 2321284 (BANI.,U PHARMACEUTICAL CO. LTD) 18 March 1977 see page 4 X GB, A, 1236638 (FARBWER E HOECHST) 23 June 1971 see claims X GB, A, 1222254 (FARBWERKE HOECHST) February 1971 1 see claims 11-21 1-21 3-10,13-20 3-10,13-20 Form PCT ISA 210 (smite sheet) (Januaryt 1$0$1 r >~y A Ti 1 International Anplication No, PCT/ GB 88 /00674 FURTHER INFORMATION CONTINUED FROM THE SECOND SHEET V.E OBSERVAT ON,- WHERE CERTAIN CLAIMS WEREK FOUND UNSIEARCHABLEI This International search report his not been established In respect of certain claims under Article 17(2) tar the, folowing reasons: I.E] claim numbers because they relate to subject metter not required to be searched by this Author"t, namet ZC] Claim numbers because they relate to parts of the International applIcatIon that. do not comply with the prescribed require. ments to such en extent that no meaninoful International sarcn can be carried out, specrtloailyt Cla0imn nurnar,...-. because tttely are dependeant claims and are not drafted In accordance with Ow~ second and tt'rd selenca of PCT Rule 5,4(a), VL.Z OBSERVATIONS WHERE UNITY OF INVENTION IS LACKINGI This International Searching Authority found multiple Inventions In this International application as follow, I Please refer to Form PCT/ISA 206 dated 26th October 1988 1.[g As all required additional search tooa were timely paid by the applicant, this International search report covers all searchable claims of the International application, 2.FE As only some of the required additional search feea wete timely paid by the applicant, Whs International search report covers only those claima of the International application for whi1ch fees were paid, epecfficaiy claimtdfi IrJ No required additional search fse were timely paid by the aprp"'Cint, Consequently, this International search report Is restricted to the Invention first mentioned in the claims: it is covered by claim riumberst 4,M As all searchable ctailnv could be sepsched without effort Justifying An additional fee, the InternatIonal Searchino Authority did not Invite payment of an11 additional Ie~d, Ramaerli on Protest The additional search fIs were accompanied by appuicantes proteet ENo Protest accompanied the payment of additional search less. Form PCT1I3AM2O (supplemental aheet (JawAwy 1Ie) I ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. GB 8800674 SA 23722 This annex lists the patent family members relating to the patent documents cited In the above-mentioned international search report. Te members are as contained in the European Patent Office EDP file on 05/04/89 The European Patent Office is in no way liable for ttiese liarticulars wihich are merely gi'.en for the purpose of information. Patent documentPulctoPaetfmyPbiain cited in search reportTdaembrs)at EP-A- 0068968 0-18 RAB 2058 1-28 CA-A- 1214170 A-11-86 UP-A- 63099048 30-04-88 US-A- 4761430 02-08-88 )FR-A 1 B 2507474 17-12-82 VFR-A- 2321284 18-03-77 BE-A- 834306 08-04-76 DE-A,C 2545496 03-03-77 US-A- 4069254 17-01-78 UP-A- 52025742 25-02-77 CA-A- 1075711 15-04-80 SE-A- 7511361 23-02-77 SE-B- 421309 14-12-81 GB-A- 1236638 23-06-71 3666779 30-05-72 GB-A- 1222254 10"02-71 NL-A- 6809823 17-01-69 FR-A- 1576681 01-08-69 US-A- 3556994 19-01-71 BE-A- 718091 15-01-69 0E-B- 1298672 OE-A,BC 1771548 23-12-71 r or more details about this iannex tsee Official Journal of the curopean Patent Oflict, No. I z/82