WO1990001929A1 - New medical use - Google Patents

Abstract

The present invention is concerned with combinations comprising a compound of formula (I): Ar-(L-Ar')q-(X)k-(Y)p-Q, which is a hydroxamic acid aryl derivative and a non-steroidal anti-inflammatory drug.

Description

"NEW MEDICAL USE "

The present invention relates to a new use of certain compounds which are hydroxamic acid aryl derivatives, to methods of preparing such compounds, compositions containing them and to their use in medicine and in other applications.

A class of agents defined in European patent specification no. 0055 418 are described therein as dual inhibitors of the lipoxygenase and cyclo-oxygenase enzymes of the mammalian arachidonic acid metabolism and were found to exhibit anti-inflammatory and related activities. Other compounds which have been described as lipoxygenase and/or cyclo-oxygenase inhibitors include certain naphthyloxy derivatives (e.g. as described in US patent specification 3 740437 or in Proc. Ann. Symp. Inst. Basic Med. Sci., Royal College of Surgeons of

England, October 1982, pp 263-274) .

We have now unexpectedly found that, subject to the provisos set forth below, compounds of formula (I) as defined hereinbelow, have a cytoprotective action and thus have useful medical prophylatic and therapeutic properties, especially when used in conjunction with a non-steroidai anti-inflammatory drug (NSAID).

The definition of formula (I)

Ar-(L-Ar')_q-(X)_k-(Y)_p-Q (I) is thus: k, p and q are independently 0 or 1, provided that when k is 1, then p must also be 1; Ar represents either:

(i) furyl, thienyl, thienyl 1,1-dioxide, pyrryl, pyridyl,

benzofuryl, benzothienyl, benzothienyl 1,1-dioxide, indolyl, naphthyl, quinolyl, or tetrahydronaphthyl, any of which is optionally substituted by one or more substituents

independently selected from C_1-4 alkyl (which may itself optionally be substituted by one or more halogen atoms), C_1-4 alkoxy, halo, nitro, amino, carboxy, C_1-4 alkoxycarbonyl and hydroxy, or (ii) phenyl optionally substituted by one or more substituents independently selected from phenyl (optionally substituted by one or more substituents independently selected from those specified as optional substituents in (i) above) and said optional substituents specified in (i) above; L is selected from -(CH₂)_r- (where r is 1-4), -O-, -CH₂O-, -CH₂S-, -OCH₂-, - CONH-, -NHCO-, -CO- and -CH₂NH-, and,

Ar' represents phenylene, thienylene or pyridylene, any of which may be optionally substituted by one or more substituents independently selected from those specified as optional substituents in definition (i) o f Ar; X represents oxygen, sulphur or carbonyl, provided that at least one atom separates said carbonyl group from any carbonyl group in Q as defined below;

Y is C_1-10 alkylene or C_1-10 alkenylene;

Q represents a non-cyclic moiety selected from groups of formula

in which one of m and n is 0 and the other is 1, and when n is 1 and m is 0, R¹ and R² are independently selected from hydrogen and C_{1 -4} alkyl, with the possibility that R² can also be C_{1 -7} cycloalkyl, or when n is 0 and m is 1, R¹ is independently selected from hydrogen, C_1-4 alkyl, groups as defined for Ar above and groups of formula -COR³ in which R³ is selected from C_1-4 alkyl (optionally substituted by a carboxy or C_1-4 alkoxycarbonyl group) and groups of Ormula -N(R⁴)R⁵ in which R⁴ is hydrogen or C_1-4 alkyl and R⁵ represents hydrogen C_1-4 alkyl or phenyl optionally substituted by one or more substituents independently selected from those specified as optional substituents in the definition (i) of Ar, and R² is selected from hydrogen, C _{1 -4} alkyl, amino, C_1-4 alkylamino, di- C_1-4 alkylamino, C_5-7 cycloalkylamino, C_5-7 cycloalkyl (C_1-4 alkyl) amino, anilino, N-C_1-4 alkylanilino and groups as defined for Ar above; or Q represents a cyclic moiety selected from 1-hydroxy-1,3-dihydroimidazoi-2-one and groups of formula

in which Z represents a C_2-5 alkylene chain in which one of the carbon atoms may be replaced by a hetero atom; and physiologically acceptable salts thereof and salts thereof; with the proviso that:- when q is 0, k is 0 or 1 and p is 1, Ar is phenyl or naphthyl, either being optionally substituted by one or more substituents as specified in definition (i) of Ar, and X is oxygen or sulphur (in the case when k is 1) Y is C_1-10 alkylene and Q represents said non-cyclic moiety as hereinbefore defined in which one of

R¹ and R² is hydrogen or C_1-4 alkyl; then the other of R¹ and R² is neither hydrogen nor C_1-4 alkyl.

Accordingly the present invention provides the use of a compound of formula (I) as herein defined for the manufacture of a medicament for the treatment or prevention of inflammatory joint conditions such as rheumatoid arthritis, rheumatoid spondylitis, osteo-arthritis, gouty arthritis and other arthritic conditions.

Alternatively, the present invention provides a method for the treatment or prevention of such inflammatory joint conditions which comprises the administration of an effective cytoprotective amount of a compound of formula (I) as hereinbefore defined to a human or non-human mammal in need thereof.

Itshould be appreciated that we make no claim to those compounds of formula (I) and their salts, processes for their preparation, compositions containing them and their use, which are not novel having regard to the following references :

a) Patent Specifications:

FP 0161939 A

GB 1226344 GB 1427114

GB 1278739 GB 1437783

GB 1315830 GB 1444492

GB 1382996 GB 2047234 A

GB 1396726

US 3600437 US 3972934

US 3821289 US 3978116

US 3890377

JP 57035543 JP 57062239 b) Literature references:-

Tetrahedron 1970 26 (23) 5653-64

Fur. 3. Med. Chem. Chimica. Therapeutica 1975 10 (2) 125-128

Fur. J. Med. Chem. Chimica. Therapeutica 1970 13 (2) 211-13

3. Chem. Fng. Data 1985 30 237-9

Chem. Biol. Hydroxamic Acids [Proc. Int. Symp.] 1981, 51-62

Arzneim. Forsch. 1978 28 (11) 2087-92

Thus for example, Furopean patent specification 0 161 939 A discloses a genus of compounds which are alleged to be anti-allergic and anti-asthmatic inhibitors of delta-5 lipoxygenase. This genus embraces compounds of formula (I) as hereinbefore defined which inter alia, are excluded by the proviso that:- when Q represents said non-cyclic moiety as hereinbefore defined,

(1) then when n is 1 and m is 0, when q is 0 and Ar is as definition (ii) or q is 1, Ar is as definition (i) and L is -CH₂-, -O- or -CH₂O- and Ar' is phenylene optionally substituted as defined, then at least one of k and p must be 1; (2) and when n is 0 and m is 1, when R¹ is hydrogen or C_{1- 4} alkyl and R² is phenyl optionally substituted by a single substituent selected from C_{1- 4} alkyl, C_{1- 4} alkoxy and phenyl optionally substituted by one or more substituents independently selected from these specified as optional substituents in definition (i) of Ar, then at least one of k and p must be 1, and in the case when k is 0 and p is 1, Y must be C_{1- 10} alkenylene.

US patent specification 3,600,437 discloses a genus of compounds said to be anti-inflammatory, analgesic and anti-pyretic agents. This genus embraces compounds of formula (I) as hereinbefore defined which are excluded by the proviso that:- when q and p are 1, k is 0, Ar is unsubstituted phenyl, L is -O-, Q is said non-cyclic moiety as hereinbefore defined, m is 0 and n is 1, L and -(Y)_p- are meta-substituted relative to one another on the Ar', Ar' is phenylene and is unsubstituted or bears a substituent selected from hydroxy, amino, nitro, halo, methyl, ethyl, and C_{1- 3} alkoxy and/or a substituent selected from hydroxy, halo, methyl and ethyl, R² is hydrogen or C_{1- 4} alkyl and Y is a group of formula

-CHG-(CH₂)_s- in which G is hydrogen or C_{1- 5} alkyl and s is 0-3; then R¹ is C_{1- 4} alkyl. The aforementioned US patent specification 3,600,437 also discloses inter alia, the individual compound 2-(3-phenoxyphenyl)propionohydroxamic acid.

Throughout this specification, unless indicated to the contrary, alkyl and alkyl- containing moieties (such as alkylene and alkoxy) can be either straight or branched. Alkyl of 1-4 carbon atoms whether alone or part of another moiety comprises methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and t -butyl. For use in medicine, the salts of the compounds of formula (I) are those salts which are physiologically acceptable. However, non-physiologically acceptable salts are included within the ambit of the present invention, either for use in non-medical applications such as further described hereinbelow, or as may be used in the preparation of compounds of formula (I) and their physiologically acceptable salts. When Ar represents optionally-substituted naphthyl, this may represent naphth-1-yl or naphth-2-yl, although the latter is generally preferred.

When Ar represents optionally substituted tetrahydronaphthyl, 5, 6, 7, 8-tetrahydronaphth -1-and -2-yl are preferred, especially -2-yl. When Ar represents optionally substituted pyridyl, pyrid-2-yl and pyrid-4-yl are preferred.

When q is 1 and Ar' represents optionally substituted phenylene, -L- and -(X)_k- are preferably meta- or para-substituted relative to one another on the phenyl ring. When q is 1 and Ar' represents optionally substituted thienylene, -L- and -(X)_k - are preferably attached in the 1- and the 5- positions of the phenylene ring.

When q is 1 and Ar' represents optionally substituted pyridylene, -L- and -(X)_k- are preferably attached in the 1- and the 6- positions of the pyridyline ring.

When Q represents a group of formula

and Z contains a hetero-atom, this may be sulphur, oxygen or nitrogen (-NH-). However, preferably, Z contains 3 carbon atoms. This includes the case when Z does not contain a hetero atom. Of these compounds and salts, especially preferred are those wherein Q represents -5- pyrrolidin-2-one.

One preferred sub-class of the compounds of formula (I) comprises those compounds wherein q is 0 and p is 1;

Ar represents naphthyl optionally substituted by one or more substituents independently selected from those defined in definition (i) of Ar; X (in the case when k is 1) is oxygen; and

Q is said non-cyclic moiety as hereinbefore defined in which n is 0, m is 1 and R² is C_{1 -4} alkyl; and salts thereof.

An especially preferred group of compounds and salts within the latter defined sub-class comprises those wherein R¹ is hydrogen and R² is methyl. This group includes compounds and salts wherein Ar is unsubstituted. q and p are 1 and k is 0;

Another preferred sub-class of the compounds of formula (I) comprises those compounds wherein Ar represents phenyl optionally substituted by one or more substituents independently selected from those defined in definition (ii) of Ar;

L is -O- or -CH₂O-;

Ar' is phenylene optionally substituted by one or more substituents independently selected from those defined in definition (i) of Ar; and Q is said non-cyclic moiety as hereinbefore defined, provided that when L is -CH₂O- and y is C_{1 -6} alkenylene, then m is 1 and n is 0; and salts thereof.

An especially preferred group of compounds and salts within the latter defined sub-class comprises those wherein Ar and/or Ar' are substituted only by one or two fluorine atoms or both are unsubstituted, and R² is C_{1 -4} alkyl, particularly methyl. Of this group, meta- or para- relative substitution of L and -(X)_k- on Ar' is preferred.

Included within the general class of the compounds of formula (I) and their salts are the following which we may claim separately, namely those wherein:- (i) k is 1 and X represents oxygen;

(ii) k is 1 and X represents sulphur; (iii) Q represents said non-cyclic moiety and m is 0 and n is 1;

(iv) Q represents said non-cyclic moiety and m is 1 and n is 0;

(v) Q represents a cyclic moiety as hereinbefore defined;

(vi) q is 0; (vii) q is 1;

(viii) q is 1 and -L- is selected from -O-, -CH₂O-, -CH₂S-, -NHCO- and

-CO- ;

(ix) Ar' is optionally substituted phenylene;

(x) Ar' is optionally substituted thienylene; (xi) Ar' is optionally substituted pyridylene;

(xii) Ar is optionally substituted naphthyl;

(xiii) Ar is optionally substituted tetrahydronaphthyl;

(xiv) Ar is optionally substituted pyridyl;

(xv) k is 0; (xvi) p is 0;

(xvii) p is 1 and Y is C_1-10 alkylene;

(xviii) p is 1 and Y is C_1-10 alkenylene;

(xix) any two or more of (i)-(xviii) together in combination, provided the combination is compatible with the provisos contained within formula (I) as hereinbefore defined.

Preferred compounds of formula (I) include 3-phenoxy-N- methylcinnamohydroxamic acid, N-(3-phenoxycinnamyl)acetohydroxamic acid,

N-(4-benzyloxybenzyl)acetohydroxamic acid, N -[2-(5,6,7,8-tetrahydro-2-naphthyloxy) ethyllacetohydroxamic acid and N-(5,6,7,8-Tetrahydro-2-naphthylaliyl)acetohydroxamic acid. Salts of the latter compounds are also preferred. Examples of other compounds of formula (I) and their salts include the following and salts thereof:

1-Hydroxy-5-[2-(2-naphthyl)ethyl]pyrrolidin-2-one

5,6-Dihydro-N-hydroxy-5-phenyl-1,4-thiazin-3(2H,4H)-one

5,-[2-(4-Biphenyl)ethyl]-1-hydroxy-2-pyrrolidone

5,6-Dihydro-4-hydroxy-6-(1-naphthyl)-1,4-thiazin-3(2H,4H)-one

6-(4-Biphenylyl)-5,6-dihydro-4-hydroxy-1,4-thiazin-3(2H,4H)-one

5-(4-Biphenylyl)-1-hydroxy-2-pyrrolidone

1-Hydroxy-5-(4-isobutylphenethyl)-2-pyrrolldone

1-Hydroxy-5-phenethyl-2-pyrrolidone

1-Hydroxy-5-(3-phenylpropyl)-2-pyrrolidone

1-Hydroxy-5-[3-(6-methoxy-2-naphthyl)butyl]-2-pyrrolidone

5,6-Dihydro-4-hydroxy-6-[1-(6-methoxy-2-naphthyl)ethyl]-1,4-thiazin-3-(2H,4H)-one

5-[3-(2-Fluoro-4-biphenylyl)butyl]-1-hydroxy-2-pyrrolidone

6-[1-(2-Fluoro-4-biphenylyl)ethyl]-5,6-dihydro-4-hydroxy-1,4-thiazin-3(2H,4H)-one 1-Hydroxy-5-[3-(4-isobutylphenyl)butyl]-2-pyrrolidone

5,6-Dihydro-4-hydroxy-6-[1-(4-isobutylphenyl)butyl]-1,4-thiazin-3-(2H,4H)-one

N-[1-(4-biphenylyl)ethyl]acetohydroxamic acid

4-(4-biphenylyl)-N-methyl-4-oxobutanohydroxamic acid

2-(2-fluorαbIphenyl-4-yl)-N-methylpropanohydroxamic acid

N-[2-(2-Fluoro-4-biphenylyl)propyl]acetohydroxamic acid

4-(2-FIuoro-4-biphenylyl)-N-methylpentanohydroxam'c acid

5-(4-Biphenylyl)-N-methyl-5-oxopentanohydroxamic acid

N-[2-(4-Biphenylyloxy)ethyl]acetohydroxamic acid

N-[2-(4-Biphenylyloxy)ethyl]isobutyrohydroxamic acid

N[-[3-(4-Biphenylyloxy)propyl]acetohydroxamic acid

2-(4-Biphenylyloxy)-N-methylacetohydroxamic acid

3-(4-Biphenylyloxy)-N-methylpropionohydroxamic acid

7-(4-Biphenylyloxy)-N-methylheptanohydroxamic acid

3-(4-Biphenylyl)-N-methylpropionohydroxamic acid

5-(4-Biphenylyl)-N-methylpentanohydroxamic acid

N-Methyl-2-(5,6,7,8-tetrahydro-1-(or 2-)naphthoxy)acetohydroxamic acid

N-Methyl-3-(5,6,7,8-tetrahydro-1-(or 2-)naphthoxy)propionohydroxamic acid N-Methyl-7-(5,6,7,8-tetrahydro-1-(or 2-)naphthoxy)heptanohydroxamic acid

Methyl N-methyl-3-(5,6,7,8-tetrahydro-1-(or 2-)naphthoxy)propionohydroxamate N-[3-(5,6,7,8-tetrahydro-1-(or 2-)naphthoxy)propyl]acetohydroxamic acid

N-[6-(5,6,7,8-tetrahydro-1-(or 2-)naphthoxy)hexyl]acetohydroxamic acid

N-[2-(5,6,7,8-tetrahydro-1-(or 2-)naphthoxyl)ethyl]isobutyrohydroxamic acid

N-Methyl-3-(5,6,7,8-tetrahydro-1-(or 2)naphthyl)propionohydroxamic acid

N-Methyl-5-(5,6,7,8-tetrahydro-1-(or 2-)naphthyl)pentanohydroxamic acid

N-[3-(5,6,7,8-tetrahydro-1-(or 2-)naphthyl)propyl]acetohydrαxamic acid

N-[5-(5,6,7,8-tetrahydro-1-(or 2-)naphthyl)pentyl]acetohydroxamic acid

N-[3-(5,6,7,8-tetrahydro-1-(or 2-)naphthyl)propyl]isobutyrohydroxamic acid

N-[2-(2-naphthyloxy)ethyl]benzohydroxamic acid

2-Benzyloxy-N-methylbenzohydroxamic acid

N-methyl-3-benzyloxybenzohydroxmic acid

4-benzyloxy-N-methylbenzohydroxamic acid

N-methyl-3-(2-naphthyloxymethyl)benzohydroxamic acid

3-(2-biphenylyloxymethyl)-N-methylbenzohydroxamic acid

4-(4-biphenylyloxymethyl)-N-methylbenzohydroxamic acid

N-methyl-2-[5-methyl-2-(4-methylphenylcarbamoyl)phenoxy]acetohydroxamic acid,N-[1-(4-benzyloxy-2-hydroxyphenyl)ethyl]-acetohydroxamic acid

N-(2-benzyloxybenzyl)acetohydroxamic acid,

2-(3-benzoylphenyl)-N-methylpropionohydroxamic acid

N-methyl-4-(3-propoxybenzoyl)benzohydroxamic acid

N-[4-(1-naphthylmethoxy)benzyl] acetohydroxamic acid

N-(3-phenoxybenzyl)acetohydroxamic acid

N-(3-benzyloxybenzyl)acetohydroxamic acid

N-methyl-3-(1-naphthyloxymethyl)benzohydroxamic acid

3-benzylamino-N-methylbenzohydroxamic acid

4-benzylamino-N-methylbenzohydroxamic acid

5-benzyloxy-2-hydroxy-N-methylbenzohydroxamic acid

4-benzyloxy-2-hydroxy-N-methylbenzohydroxamic acid

4-benzamido-N-methylbenzohydroxamic acid

3-benzamido-N-methylbenzohydroxamic acid

3-benzoyl-N-methylbenzohydroxamic acid

5-benzoyloxy-N-methylthiophen-2-carbohydroxamic acid

4-benzoyloxy-N-methylthiophen-2-carbohydroxamic acid

3-(biphenyl-2-yloxymethyl)-N-methylbenzohydroxamic acid

N-methyl-3-(1-naphthyl)propenohydroxamic acid

N-methyl-4-methylcinnamohydroxamic acid

2-benzyloxy-N-methylcinnamohydroxamic acid N-Methyl-3-trifluoromethylcinnamohydroxamic acid

N-Methyl-3-phenoxybenzohydroxamic acid

N-Methyl-4-phenoxybenzohydroxamic acid

2-(4-Biphenylyl)-N-methylpropanohydroxamic acid

N-Methyl-3-(3-propoxybenzoyl)benzohydroxamic acid

N-(Cyclohexyl)-2-[4-(2-methylpropyl)phenyl]propanohydroxamic acid

N-Methyl-3-(2-naρhthyl)propenohydroxamic acid

2-(2-Fluorobiphenyl-4-yl)-N-cyclohexylpropanohydroxamic acid

2-(2-Fluorobiphenyl-4-yl)-N-t-butylpropanohydroxamic acid

N-(1,1-Dimethylethyl)-3-phenoxycinnamohydroxamic acid

2-(4-Biphenylyloxy)-N-methylpropanohydroxamic acid

N-[1-(4-Biphenylyl)ethyl]acetohydroxamic acid

N-(4-Biphenylylmethyl)acetohydroxamic acid

N-[4-(2-Naphthylmethoxy)benzyl]acetohydroxamic acid

N-(4-Phenoxybenzyl)acetohydroxamic acid

N-(4-Benzyloxybenzyl)pivalohydroxamic acid

2-(2-Fluoro-4-biphenylyl)-N-isopropylpropanohydroxamic acid

N-(4-Benzyloxybenzyl)-2-methylpropanohydroxamic acid

N-(4-Phenylcarbamoylbenzyl)acetohydroxamic acid

N-[(2',4'-Difluoro-4-biphenylyI)methyl]acetohydroxamic acid

N-[1-(2',4'-Difluoro-4-biphenylyl)ethyl]-2,2-dimethylpropanohydroxamic acid

N-[4-(4-Biphenylylmethoxy)benzyl]acetohydroxamic acid

N-[4-(2,4-Dlfluorobenzyloxy)benzyl]acetohydroxamic acid

N-[4-(2,4-Difiuorobenzyloxy)benzyl]pivalohydroxamic acid

N-[5,6,7,8-Tetrahydro-2-naphthyl)methyl]acetohydroxamic acid

N-[2-(5,6,7,8-Tetrahydro-2-naphthyloxy)ethyl]-pivalo hydroxamic acid N-(5,6,7,8-Tetrahydro-2-naphthylallyl)pivalohydroxamic acid

N-(5,6,7,8-Tetrahydro-2-naphthylmethyl)pivaIohydroxamic acid

N-[2-(2',4'-Difluoro-4-biphenyIyl) ethyl] acetohydroxamic acid

N-(4-Isobutylbenzyl)acetohydroxamic acid

N-[1-(4-Biphenyl)ethyI3pivalohydroxamic acid

N-[(4-Biphenylyl)methyl]pivalohydroxamic acid

5-[2-(4-Benxyloxyphenyl)ethyl]-1-hydroxy-2-pyrrolidone

5,6-Dihydro-4-hydroxy-6-(2-naρhthyl)-1,4-thiazin-3(2H,4H)-one

6-(4-Benzyloxyphenyl)-5,6-dihydro-4-hydroxy-1,4-thiazin-3(2H,4H)one

1-Hydroxy-1-[2-(2-naphthyloxy)ethyl]-3-phenylurea

N-(4-Benzyloxybenzyl)-N-hydroxy-N-methylurea

3-(4-Benzyloxybenzyl)-1,3-dihydro-1-hydroxylmidazol-2-one

1,3-Dihydro-1-hydroxy-3-(4-phenylbenzyl) imidazol-2-one N-(4-Benzyloxybenzyl)-0-methylcarbamoylacetohydroxamic acid

N-[2-(2-Naphthylthio)ethyl]-N-(phenylcarbamoyloxy)acetamide

N- [4-(Benzyloxybenzyl)-0-(methylcarbamoyl)pivalohydroxamic acid

N-(4-Benzyloxybenzyl)-2-(2,2-dimethylethyl)carbamoylacetohydroxamic acid N-(4-Benzyloxybenzyl)-N-(t-butylcarbonyloxy)acetamide

3-[N-(4-Benzyloxybenzyl)acetamidooxycarbonyl]proρanoic acid

N-[3-(4-Benzyloxyphenyl)prop-2-enyl]acetohydrαxamic acid

N- (3-Phenαxycinnamyl)acetohydroxamic acid

N-[2-(4-Biphenylyloxy)ethyl]acetohydroxamic acid

4-(Biphenyl-4-yloxy)-N-methylbut-2-enohydroxamic acid

3-(3-Fluoro-4-phenoxyphenyl)-N-methylprop-2-enohydroxamic acid

N-[3-(4-Benzyloxyphenyl)prop-2-enyl]acetohydroxamic acid

N-[4-(2-Pyridyl)benzyl]acetohydroxamic acid

N-[4-(2,4-Difluorophenoxymethyl)benzyl]acetohydroxamic acid

N-[4-(2-Pyridyloxy)benzyl]acetohydroxamic acid

N-(5-Phenoxymethyl-2-thienylmethyl)acetohydroxamic acid

3-(4-Fluoro-3-phenoxyphenyl)-N-methylprop-2-enohydroxamic acid

N-(6-Phenoxy-2-pyridylmethyl)acetohydroxamic acid

N-[3-(4-Fluoro-3-phenoxyphenyl)prop-2-enyl]acetohydroxamic acid

N-[4-(Benzylthio)benzyl]acetohydroxamic acid

N-[3-(2-Pyridyloxy)benzyl]acetohydroxamic acid

N-[3-(4-Fluoro-3-phenoxyphenyl)prop-2-enyl]-N-hydroxy-N'-methylurea

N-[3-(4-Fluoro-3-phenoxyphenyl)prop-2-enyl]-N-hydroxy-N'-t-butylurea

N-[3-(4-Fluoro-3-phenoxyρhenyl)prop-2-enyl]-N-hydroxy-N'-cyclohexy-lurea N-[3-(4-FIuoro-3-phenoxyphenyl)prop-2-enyl]-N-hydroxy-N'-phenylurea

N-(Biphenyl-4-ylmethyl)-N-hydroxy-N'-methylurea

N-(Biphenyl-4-ylmethyl)-N-hydroxy-N'-t-butylurea

N-(Biphenyl-4-ylmethyl)-N-hydroxy-N'-cyclohexylurea

N-(Biphenyl-4-ylmethyl)-N-hydroxy-N'-ρhenylurea

N-Hydroxy-N'-methyl-N-[3-(2-pyridyloxy)benzyl]urea

1-Hydroxy-3-(3-phenoxybenzyl)-1,3-dihydroimidazol-2-one

1-Hydroxy-3-(6-phenoxy-2-pyridylmethyl)-1,3-dihydroimidazol-2-one

3-(2-Pyridyloxy)prop-2-enohydroxamic acid

1-Hydroxy-5-(2-pyridyl)piperazin-2-one

N-(2-[4-(2-Pyridylmethoxy)phenoxy]ethyl)acetohydroxamic acid

N-(2-[3-(2-Pyridylmethoxy)phenoxy3ethyl)acetohydroxamic acid

N-(2-[4-(Benzyloxy)phenoxy}ethyl)acetohydrαxamic acid

N-[4-Fluoro-2-phenoxyphenyl)methyl]-N-hydroxy-N'-methylurea

N-[4-Fluoro-3-phenoxyphenyl)methyl]-N-hydroxy-N'-phenylurea N-[3-(Biphenyl-4-yl)prop-2-enyl]-N-hydrαxy-N'-methylurea

N-[3-(Biphenyl-4-yl)prop-2-enyl]-N-hydroxy-N'-phenylurea

N-[(4-Benzyloxyphenyl)methyl]-N-hydroxyurea

N-[(4-Benzyloxyphenyl)methyl]-N-hydroxy-N'-methylurea

N-[4-(4-hydroxybenzyloxy)benzyl]acetohydroxamic acid

N-[4-(4-pyridylmethoxy)methyl]acetohydroxamic acid

3-[(4-Fluoro-3-phenoxyphenyl)methyI3-1-hydroxy-1,3-dihydroimidazol-2-one 3-[(2-Fluorobiphenyl-4-yl)methyl]-1-hydroxy-1,3-dihydroimidazol-2-one

1-Hydroxy-3-[3-(4-phenoxyphenyl)prop-2-enyl]-1,3-dihydroimidazol-2-one

3-[4-(4-Fluoro-3-phenoxyphenyl)prop-2-enyl]-1-hydroxy-1,3-dihydroimidazol-2-one

Further examples of compounds of formula (I) include each and every specific compound listed below:- N-Methyl-3-(Ar)acrylohydroxamic acid,

N-Methyl-5-(Ar)-2,4-pentadienohydroxamic acid,

N-Methyl-4-(4-isobutylphenyl)-2-butenohydroxamic acid,

N-[3-(Ar)-2-propenyl]acetohydroxamic acid and

N-[3-(Ar)-2-propenyl]isobutyrohydrαxamic acid wherein Ar represents i) 1 (or 2)-naphthyl

ii) 4-isobutylphenyl

(iii) 4-biphenylyl

(iv) 2 (or 3 or 4)-benzyloxyphenyl

(v) phenyl or

(vi) 4-methylphenyl It should be appreciated that any compound in the 'foregoing list may be claimed alone or with one or more of the others as constituting a preferred aspect of the present invention. For general cytoprotective use, the amount required of a compound of formula (I) or physiologically acceptable salt thereof (hereinafter referred to as the active ingredient) to achieve a cytoprotective effect will, of course, vary both with the particular compound, the route of administration and the mammal under treatment and the particular disorder or disease concerned. A suitable dose of a compound of formula (I) or physiologically acceptable salt thereof for a mammal suffering from, or likely to suffer from any condition as described

hereinbefore is 0.1 ug to 500 mg of base per kilogram bodyweight. In the case of systemic administration, the dose may be in the range 0.5 to 500 mg of base per kilogram bodyweight, the most preferred dosage being 0.5 to 50 mg/kg of mammal bodyweight for example 5 to 25 mg/kg;

administered two or three times daily.

While it is possible for an active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation comprising a compound of formula (I) or a pharmacologically acceptable acid addition salt thereof and a physiologically acceptable carrier therefor. Such formulations constitute a further feature of the present invention. Conveniently, the active ingredient comprises from 0.1% to 99.9% by weight of the formulation. Conveniently, unit doses of a formulation contain between 0.1 mg and 1 g of the active ingredient. The formulations, both for veterinary and for human medical use of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefor and optionally other therapeutic ingredient(s). The carrier(s) must be 'acceptable' in the sense of being compatible with the other i edients of the formulations and not deieterious to the recipient thereof.

The formulations include those in a form suitable for oral, ophthalmic, rectal, patenteral (including subcutaneous, intramuscular and intravenous) administration.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration may be in the form of discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be in the form of a bolus, electuary or paste.

A tablet may be made by compressing or moulding the active ingredient optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the

powdered active ingredient and a suitable carrier moistened with an inert liquid diluent.

Formulations for rectal administration may be in the form of a

suppository incorporating the active ingredient and a carrier such .as cocoa butter, or in the form of an enema.

Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.

In addition to the aforementioned ingredients, the formulations of this invention may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives, e.g. methylhydroxybenzoate (including anti-oxidants), emulsifying agents and the like.

In a particular aspect of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in conjunction with a non-steroidal anti-inflammatory drug (NSAID) for the treatment or prevention of inflammatory joint conditions such as those referred to above or in the manufacture of a medicament therefor. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt

thereof is administered separately, by any suitable route, sequentially in either order or simultaneously with the oral administration of one or more NSAID's. in another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is formulated as a combined medicament also comprising one or mere NSAID' s. It has been found that the use of such combinations in the treatment of inflammatory joint conditions produces a therapeutic effect superior to that obtained using either drug alone. In particular, the reduction in joint swelling and the decrease in the thickness of the synovial lining of the joint are significantly improved when using the combination therapy. Furthermore, there is a reduction in the loss of proteoglycan from the articular cartilage of the joint and a reduced infiltration of leucocytes, notably polymorphs, into the synovial tissue which are not observed when using either drug alone.

Accordingly the present invention also provides a pharmaceutical composition comprising a compound of formula (I) as hereinbefore defined and at least one NSAID, for oral administration. Suitable NSAID's for use in

accordance with this aspect of the invention include acemetacin, alminoprofen, amfenac sodium, aminoprofen, antitrazafen, antrafenine, auranofin, bendazac lysinate, benzydamine, beprozin, broperamole, bufezolac, carprofen, cinmetacin, ciproquazone, clidanac, cloximate, dazidamine, deboxamet, delmetacin, detomidine, dexindoprofen,

diacerein, di-fisalamine, difenpyramide, emorfozone, enfenamic acid, enolicam, epirizole, etersalate, etodolac, etofenamate, fanetizole mesylate, fenclofenac, fenclorac, fendosal, feniflumizole, fentiazac, feprazone,

floctafenine, flunixin, flunoxaprofen, fluproquazone, fopirtoline, fosfosal, furcloprofen, furofenac,

glucametacin, guaimesal, ibuproxam, isofezolac, isonixim, isoprofen, isoxepac, isoxicam, lefetamine HCl, leflunomide, lofemizole, lonazolac calcium, lotifazole, loxoprofen, lysin clonixinate, meclofenamate sodium, meseclazone, miroprofen, nabumetone, nictindole, nimesulide, orpanoxin, oxametacin, oxapadol, oxaprozin, perisoxal citrate,

pimeprofen, pimetacin, piproxen, pirazolac, pirfenidone, pirprofen, pranoprofen, proglumetacin maleate, proquazone, pyridoxiprofen, sudoxicam, suprofen, talmetacin,

talniflumate, tenoxicam, thiazolinobutazone, thielavin B, tiaprofenic acid, tiaramide HCl, tiflamizole, timegadine, tioxaprofen, tolfenamic acid, tolpadol, tryptamid,

ufenamate, zidometacin, flurbiprofen, ibuprofen,

indomethacin, ketoprofen, naproxen, piroxicam, diclofenac and tiaprofenic acid.

Preferred such NSAID's are naproxen, flurbiprofen,

ketoprofen, aminoprofen, carprofen, clidanac, dexindoprofen, enfenamic acid, fenclofenac, flunoxaprofen, ibuprofen, isoprofen, loxoprofen, meclofenamate sodium, miroprofen, pirprofen, pranoprofen, suprofen, tioxaprofen, zidometacin, indomethacin, piroxicam, diclofenac and tiaprofenic acid.

Particularly preferred NSAID's for use according to the present invention are clidanac, ibuprofen, suprofen, naproxen, flurbiprofen, ketoprofen, indomethacin, piroxicam, diclofenac and tiaprofenic acid.

The following NSAID's, designated by company code number, may also be used:

480156S, AA861, AD1491, AD1590, AFP802, AFP860, AHR6293, A177B, AP504, AU8001, BAYo8276, BPPC, BW540C, BW755C,

CHIN0IN 127, CN100, C0893XX, CPP, D10242, DKA9, DV17, EB382, EGYT2829, EL508, F1044, FZ, GP53633, GP650, GV3658, HG/3, ITC1, ITF, ITF182, KB1043, KC8973, KCNTEI6090, KME4, LA2851, LT696, LU20884, M7074, MED15, MG18311, MR714,

MR897, MY309, N0164, 0N03144, PR823, PV102, PV108, QZ16, R830, RS2131, RU15029, RU25559, RUB265, SCR152, SH440, SIR133, SIR136, SIR92, SPAS510, SQ27239, ST281, SX1032, SY6001, SaH46798, TA60, TAI901, TEI615, TVX2705, TVX960, TZI615, U60257, UR2310, WY23205, WY41770, YM09561, YM131162, YS1033, and ZK31945.

Finally, NSAID's which may also be used inlcude the salicylates, specifically aspirin, and the

phenylbutazomes and pharmaceutically acceptable salts thereof.

Suitably the composition comprises a non-toxic cytoprotective amount of the compound of formula (I) and a non-toxic (but potentially ulcerogenic) effective amount of the NSAID. The composition may further comprise one or more carriers and other pharmaceutically acceptable

excipients as hereinbefore

described.

The quantity of NSAID in the formulation will depend on the intended effect thereof and will be selected, e.g. by the physician, as appropriate to the age, body weight, general health etc of the patient. The quantity of compound of formula (I) or pharmaceutically acceptable salt thereof to be included in the composition will be selected to be compatible with the amount of NSAID and to provide a sufficient cytoprotective effect as necessary to ameliorate or prevent the gastric ulcerogenic effect of the amount of NSAID.

Typical cytoprotective doses of compounds of formula (I) when used in conjunction with oral

administration of an ulcerogenic NSAID are as previously indicated above. The compounds of formula (I) and their salts may be prepared by the following process which (subject to any provisos expressed herein) constitutes a further aspect of the present invention:- a) for the preparation of compounds of formula (I) in which Q represents a non-cyclic moiety (as hereinbefore defined) in which R represents hydrogen, reacting a compound of formula (II)

R⁶ NHOH (II) with a compound of formula (III)

R⁷-R⁸ (III)

(in which one of R⁶ and R⁷ is a group R² as hereinbefore defined and the other is a group of formula Ar-(L-Ar')_q-(X)_k-(Y)_p- as hereinbefore defined, and R⁸ is a group capable of reacting with the NH group in the compound of formula (II) thereby to bring about formation of the corresponding hydroxamic acid or derivative thereof); b) for the preparation of compounds of formula (I) in which Q represents a non-cyclic moiety (as hereinbefore defined) in which R¹ represents hydrogen, n is 1 and m is 0. reacting a compound of formula (IV)

Ar-(L-Ar')_q-(X)_k-(Y)_p-CH=0 (IV)

(wherein q, k, p, Ar, Ar', L, X and Y are as hereinbefore defined) with Piloty's acid, i.e. the compound of formula PhSO₂NHOH, or an appropriate analogue or derivative thereof; c) for the preparation of compounds of formula (I) in which Q represents a non-cyclic moiety (as hereinbefore defined) in which R¹ represents hydrogen, reacting a compound of formula (V)

R⁹N (OZ¹)H (V)

(wherein R⁹ is a group R² as hereinbefore defined or a group of formula

Ar-(L-Ar')_q-(X)_k-(Y)_p- as hereinbefore defined, as appropriate, and

Z¹ is hydrogen or an appropriate protecting group) with an appropriate acylating agent, and where Z¹ is a protecting group, subjecting the reaction product to such conditions and/or reacting with one or more reagents as appropriate to effect removal of said protecting group;

or; d) for the preparation of compounds of formula (I) in which Q represents

a cyclic group as hereinbefore defined, treating a compounds of formula (VI)

(where Ar, Ar', L, X, Y,q, k and p are as hereinbefore defined and R¹⁰- R¹¹-R¹² are chosen to be capable of cyclisation) with an agent or agents and under such reaction conditions to bring about cyclisation of said R¹⁰- R¹¹-R¹²; and optionally if desired, effecting one or more of the following interconversions in any desired order:- (i) when in the compound of formula (I) so formed, any of R¹, R² and (in the definition of R¹) R⁴ and R⁵ are hydrogen atoms, converting said compound to a corresponding compound of formula (I) wherein any of said hydrogen atoms as desired, are converted to C _{1- 4} alkyl groups;

(ii) converting the compound of formula (I) to a corresponding salt thereof; (iii) when in the compound of formula (I) so formed, n is 0, m is 1 and R¹ is hydrogen, converting said compound to a corresponding compound of formula (I) wherein R¹ is a group of formula -COR³ as hereinbefore defined; (iv) when in a compound of formula (I), n is O, m is 1 and R¹ is a group of formula -COR³ in which R³ is a C _1-4 alkyl group substituted by carboxy, converting said compound to a corresponding compound in which R³ is C_{1- 4} alkyl substituted by C _1-4 alkoxycarbonyl. In process option (a) above, the compound of formula (II) may be used in the form of a salt thereof and the compound of formula (III) for example is an appropriate mixed anhydride or activated acid such as an acid halide (e.g. the chloride). Preferably, the reaction is effected in a suitable solvent and where the compound of formula (II) is in the form of a salt, in the presence of a base, such as an appropriate amine, to liberate the free hydroxylamine compound in situ.

Process option (b) may for example be effected in the presence of a base such as an alkali metal hydroxide or aikoxide, e.g. sodium hydroxide or sodium methoxlde. In process option (c), where the group Z in the compound of formula (V) is a protecting group, this may for example be selected from and acetyl, benzyl, O-benzyl, trityl, tetrahydropyranyl, O-tetrahydropyranyl, O-t-butyl and benzoyl. The protecting group may be removed by treatment with acid or base or by hydrogenation as will readily be apparent to those skilled in the art. In general, suitable protecting groups and methods for their removal will be found in T.W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1981. Particular examples of removal of such leaving groups include removal of an O- benzyl group by hydrogenolysis over 5% palladium on charcoal at room temperature, or removal of O-tetrahydropyranyl with pyridinium para-toluene sulphate in refluxing methanαl.

When process option (c) is a used to prepare a compound of formula (I) wherein

Q represents a non-cyclic moiety (as hereinbefore defined) in which n is 0 and m is 1, R² is an amino group or a mono-amine derivative and Z¹ is a protecting group the acylating agent may be an isocyanate of formula (VII).

Q¹NCO (VII) (wherein Q¹ is said R² group minus the -NH portion) and the reaction is effected in a suitable solvent such as toluene, optionally at a temperature above ambient. When process option (c) is used to prepare a compound of formula (I) in which Q represents a non-cyclic moiety (as hereinbefore defined) and R² is other than as specified in the preceding paragraph (whether Z is hydrogen or a protecting group), the acylating agent may for example be an appropriate mixed anhydride or activated acid, such as an acid haiide (for example chloride),

When process option (d) is used to prepare a compound of formula (I) in which Q is a group of formula

(wherein Z is as hereinbefore defined) one of the groups R ¹⁰ and R¹² may terminate with a group of formula -CO₂Q² (where Q² is hydrogen, amino, C _{1- 6} alkyl or aryl (e.g. phenyl)) and the other then terminates with an appropriate reactive group such as a group of formula -OQ³ (wherein Q³ is hydrogen or a protecting group such as benzyl or any of those defined above in respect of Z¹) or else the other terminates with a group of formula -NO ₂ or -NHOH. Generally, the reaction may be effected in a suitable solvent such as toluene, in the presence of an acid catalyst such as para-toluenesulphonic acid, if necessary at an elevated temperature. When one of R¹⁰ and R¹² terminates with -NHOH, the reaction may be effected under appropriate reducing conditions, such as in the presence of zinc powder and aqueous ammonium chloride, or with aluminium amalgam. When process option (d) is used to prepare a compound of formula (I) in which Q is 1-hydroxy-1,3-dihydro-imidazol-2-one, the compound of formula (VI) may be a compound of formula (VIII)

(wherein Ar, Ar', L, X, Y, q, k and p are as hereinbefore defined) and the cyclisation may be initiated by removal of the acetal group with an appropriate reagent such as trifluoroacetic acid.

Optional conversion (i) may for example be effected by reaction with an appropriate alkyl halide or sulphate in the presence of a mild base. Where one or more but not all of a number of hydrogen atoms are to be selectively alkylated, the conversation may require one or more steps of protection and subsequent deprotection.

Optional conversion (ii) conveniently may be effected by reaction with an appropriate organic or mineral acid, or with a base.

Optional conversion (iii) when used for the preparation of compounds wherein R³ is a group of formula -N(R⁴)R⁵, may comprise reacting the compound of formula (I) with an appropriate isocyanate, suitably in an appropriate solvent such as tetrahydrofuran or toluene, optionally in the presence of a catalyst such as 1,8-diazabicyclo [5.4.0]undec-7-ene.

Optional conversion (iii) when used for the preparation of compounds wherein R³ is an alkyl group optionally substituted by a carboxy group or a C_1-4 alkoxycarbonyl group, may comprise reacting the compound of formula (I) with an appropriate acylating agent such as a mixed anhydride or a suitable activated acid, for example an acid halide such as a chloride. Preferably, the reaction is effected in a solvent such as methylene dichloride or tetrahydrofuran, suitably at from around 0 º to ambient temperature.

Optional conversation (iv) may be effected by reaction with the appropriate alcohol in the presence of a suitable mineral acid such as sulphuric. Salts derived from acids include the acetate, adipate, alginate, aspartate, benzoate, benzenesuiphonate, bisulphate, butyrate, citrate, camphorate, camphorsulphonate, cyclopentanepropionate, digluconate, dodecylsulphate, ethanesulphonate, fumarate, glucoheptanoate, glycerophos-phate, hemisulphate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulphonate, lactate, maleate, methanesulphonate, 2- naphthalenesulphonate, nicotinate, oxalate, palmoate, pectinate, persulphate, 3-phenyl-proprionate, picrate, pivalate, proprionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts,

N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine.

Quaternary ammonium salts can be formed where a nitrogen-containing group is present, for example by reaction with lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulphates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides and benzyl and phenethyl bromides.

The following Examples are provided by way of an illustration of the production of compounds of formula (I) as hereinbefore defined and should in no way be construed as a limitation of the invention. All temperatures

indicated are in degrees Celsius.

Examples Example 1

Preparation of 3-Phenoxy-N-methylcinnamohydroxamic Acid

Methyl chloroformate (2.6ml) was added dropwise to a solution of m-phenoxycinnamic acid (Bg) and triethylamine (18.5g) in tetrahydrofuran (60ml) at 0 º. A solution of N-methylhydroxylamine hydrochloride (5.6g) in water (5ml) was added, and the mixture was stirred for 2 hours. Isolation with ethyl acetate afforded 3-phenoxy-N-methylcinnamohydroxamϊc acid (ca 4.3g), m.pt. 124-125 º [from ethyl acetate/light petroleum (b.pt. 60-80 º C)]. The m-Phenoxycinnamic acid used as starting material was prepared by condensation of m-phenoxybenzaldehyde with malonic acid in the presence of piperidine and pyridine.

Example 2

Preparation of 2-(2-Fluorobiphenyl-4-yl)-N-methylpropanohvdroxamic Acid

2-(2-Fluorobiphenyl-4-yl)propionic acid chloride (prepared in the normal manner from 1.75g of acid, ca 1ml of oxalyl chloride, toluene, and 3 drops of N,N- (dimethylformamide) was dissolved in tetrahydrofuran (30 ml) and added over 5- 10 minutes to a solution of N-Methylhydroxylamine hydrochloride (ca 2g) in water (5 ml) containing triethylamine (5 ml) at 0 º. Solvent was evaporated, and neutral material was isolated with ethyl acetate. Recrystallization from ether-light petroleum (b.pt. 40-60 º) afforded 2-(2-fluorobiphenyl-4-yl)-N- methylpropanohydroxamic acid (1.25g), m.pt. 125-126 ºC.

Examples 3-24

The following compounds were prepared in a manner generally analogous to the method of Examples 1/2:-

3) 4-(4-Biphenylyl)-N-methyl-4-oxobutanohydroxamic acid, m.pt. 159-162 ºC, decomp

4) N-Methyl-3-(1-naphthyl)prαpenohydroxamic acid, m.pt. 153-155 ºC

5) N-Methyl-4-methylcinnamohydroxamic acid, m.pt. 140-142 ºC

6) 2-Benzyloxy-N-methylcinnamohydroxamic acid, m.pt. 99-100 ºC

7) N-Methyl-3-trifluoromethylcinnamohydroxamic acid, m.pt. 122-125 ºC

8) N-Methyl-2-[5-methyl-2-(4-methylphenylcarbamoyl)phenoxy]acetohydroxamic acid, m.pt. 191-192 ºC

9) 2-(3-Benzoylphenyl)-N-methylpropionohydroxamic acid, m.pt. 121- 122 ºC

10) 4-(4-Biphenylyloxymethyl)-N-methylbenzohydroxamic acid, m.pt. 104- 105 ºC

11) N-Methyl-4-(3-propoxybenzoyl)benzohydroxamic acid, m.pt. 107- 108 ºC

12) 4-Benzyloxy-N-methylcinnamohydroxamic acid, m.pt. 181-182 ºC

13) N-Methyl-3-phenoxybenzohydroxamic acid, m.pt. 71-72 ºC

14) N-Methyl-4-phenoxybenzohydroxamic acid, m.pt. 92-93 ºC

15) 2-(4-Biphenylyl)-N-methylpropanohydroxamic acid, m.pt. 125-127 ºC

16) N-Methyl-3-(3-propoxybenzoyl)benzohydrDxamic acid, m.pt. 75-76 ºC

17) N-(Cyclohexyl)-2-[4-(2-methylpropyl)phenyl]propanohydroxamic acid,

m.pt. 133-135 ºC

18) 3-(4-Biphenylyl)-N-methylpropenohydroxamic acid, m.pt. 198-199 ºC (preheated)

19) N-Methyl-3-(2-naphthyl)propenohydroxamic acid, m.pt. 150-151 ºC

20) 2-(2-Fluorobiphenyl-4-yl)-N-cyclohexylpropanohydroxamic acid, m.pt.

195-196 ºC

21) 2-(2-Fluorobiphenyl-4-yl)-N-t-butylpropanohydroxamic acid, m.pt. 180- 181 ºC)

22) N-(1,1-Dimethylethyl)-3-phenoxycinnamohydroxamic acid, m.pt. 108- 109 ºC 23) 2-(4-Biphenylyloxy)-N-methylproρanohydroxamic acid, m.pt. 166- 167 ºC

24) N-[3-(4-benzyloxyphenyl)prop-2-enyl]acetohydroxamic acid, m.pt.

148-149 ºC

25) 4-(Biphenyl-4-yloxy)-N-methylbut-2-enohydroxamic acid

26) 3-(3-Fluoro-4-phenoxyphenyl)-N-methylprop-2-enohydroxamic acid,

m.pt. 150-152 ºC

Example 27

Preparation o f N-(4-Benzyloxybenzyl)acetohydroxamic Acid Sodium cyanoborohydride (21.3g) was added in portions to a solution of 4-benzyloxybenzaldehyde oxime (51g) in acetic acid (250ml) at ca 50 º (cooling). After the reduction was complete, acetic anhydride (22.5ml) was added in one portion, and the mixture was stirred for 1 hour. The mixture was then poured into water, and the neutral product was isolated with ethyl acetate. The residue was treated with potassium carbonate (2g) in methanol (400ml) to hydrolyse the O-acetyl material, then the solvent was evaporated. Addition of 20% citric acid solution (400ml) and isolation with ethyl acetate furnished N-(4-Benzyloxybenzyl) acetohydroxamic acid (32g), m.pt. 119-120 º [ from ethyl acetate-light petroleum (b.pt. 60-80º )].

Example 28

Preparation of N-[4-(2-Pyridyloxy)benzyl]acetohydroxamic Acid

2-Bromopyridine (4.74g) was added to the sodium salt of 4-methylphenol [from 50% sodium hydride (1.58g) and the phenol (3.56g)] in dimethyl sulphoxide, and the mixture was stirred for 20 hours at 150 ºC. Addition of water, and isolation of non-phenolic material with ether gave the pyridyloxy compound (4.81g). Without purification, this compound (4.74g) was refluxed in carbon tetracholoride (125ml) with N-bromosuccinimide (5.02g) and azo-bisisobutyronitrile initiator (50mg). After 1 hour (more initiator added after 15 and 30 minutes), the filtered solution was evaporated in vacuo. The crude product (6.76g) was immediately stirred with O-(tetrahydropyran-2-yl)hydroxylamine (8.99g) in N,N- dimethylformamide (65ml) for 65 hours at room temperature. Addition of water and isolation with ether provided the protected hydroxylamine as a viscous oil. Acetylation of the crude protected hydroxylamine (3.84g) in methylene dichloride (30ml) was effected with acetic anhydride (1.44g) for 2 hours at room temperature. Fvaporation of solvent, and isolation of non-acidic material with ether furnished the O-protected hydroxamic acid, which was purified by chromatography over silica gel [elution with 1:1 ethyl acetate/light petroleum (b.pt. 60-80 º)](2.61g). A mixture of the O-tetrahydroxpyranyl hydroxamic acid (2.6g) and pyridinium P-toluenesulphonate (191mg) in methanol (25ml) was refluxed for 9 hours, then evaporated in vacuo. Isolation with ethyl acetate afforded N-[4-(2-pyridyloxy)benzyl]acetohydroxamic acid (1.42g), m.pt. 97-99 ºC after recrystallization from ethyl acetate-light petroleum (b.pt. 60-80f ).

Examples 29-69

The following compounds were prepared in a manner generally analogous to the method of Examples 27 and 28:-

29) N-[2-(2-Naphthyloxy)ethyl]benzohydroxamic acid, m.pt. 163-165 ºC

30) N-[2-(5,6,7,8-Tetrahydro-2-naphthyloxy)ethyl]-acetohydroxamic acid,

m.pt. 73-74 ºC

31) N-[1-(4-Biphenylyl)ethyl]acetohydroxamic acid, m.pt. 143-153 ºC, vague m.pt.

32) N-[1-(4-Benzyloxy-2-hydroxyphenyl)ethyl]acetohydroxamic acid, m.pt.

149-150 ºC

33) N-(2-Benzyloxybenzyl)acetohydroxamic acid, oil

34) N-(3-Benzyloxybenzyl)acetohydroxamic acid, m.pt. 95-98 ºC

35) N-(3-Phenoxylbenzyl)acetohydroxamic acid, m.pt. 81-82 ºC

36) N-(4-Biphenylylmethyl)acetohydroxamic acid, m.pt. 152-155 ºC

37) N-[4-(1-Naphthylmethoxy)benzyl]acetohydroxamic acid, m.pt. 127- 130 ºC

38) N-[4-(2-Naphthylmethoxy)benzyl]acetohydroxamic acid, m.pt. 161- 14 ºC

39) N-(4-Phenoxybenzyl)acetohydroxamic acid, m.pt. 116-119 ºC

40) N-(4-Benzyloxybenzyl)pivalohydroxamic acid, m.pt. 143-144 ºC

41) 2-(2-Fluoro-4-biphenylyl)-N-isopropylpropanohydroxamic acid, m.pt.

151-152 ºC

42) N-(4-Benzyloxybenzyl)-2-methylρropanohydroxamic acid, m.pt. 113- 115 ºC

43) N-(4-Phenylcarbamoylbenzyl)acetohydroxamic acid, m.pt. 194-196 ºC 44) N-[(2',4'-Difluoro-4-biphenylyl)methyl]acetohydroxamic acid, m.pt.

134-135 ºC 45) N-[1-(2',4'-Difluoro-4-biphenylyl)ethyl]-2,2-dimethylpropanohydroxamic acid, m.pt. 152-153 ºC

46) N-[4-(4-Biphenylylmethoxy)benzyl]acetohydroxamic acid, m.pt. vague, softens 165 ºC melts 175 ºC

47) N-[4-(2,4-Difluorobenzyloxy)benzyl]acetohydroxamic acid, m.pt. 113- 115 ºC

48) N-[4-(2,4-Difiuorobenzyloxy)benzyl]pivaiohydroxamic acid, m.pt. 134- 136 ºC

49) N-[5,6,7,8-Tetrahydro-2-naphthyI)methyl]acetohydroxamic acid, m.pt.

79-81 ºC

50) N-[2-(5,6,7,8-Tetrohydro-2-naphthyloxy)ethyl]-pivalohydroxamic acid, m.pt. 85-87 ºC

51) N-(5,6,7,8-Tetrahydro-2-naphthylallyl)acetohydroxamic acid, softens, 95 ºC melts, 106-107 ºC

52) N-(5,6,7,8-Tetrahydro-2-naphthylallyl)pivalohydroxamic acid, m.pt.

144-145 ºC

53) N-(5,6,7,8-Tetrahydro-2-naphthylmethyl)pivalohydroxamic acid, m.pt.

103-105 ºC

54) N-[2-(2',4'-Difluoro-4-biphenylyl)ethylacetohydroxamic acid, m.pt.

122-123 ºC

55) N-(4-Isobutylbenzyl)acetohydroxamic acid, m.pt. 89-90 ºC

56) N-[1-(4-Biphenyl)ethyl]pivaiohydroxamic acid, m.pt. 170-171 ºC

57) N-[(4-Biphenylyl)methyl]pivalohydroxamic acid, m.pt. 164-165 ºC

58) N-(3-Phenoxycinnamyl)acetohydroxamic acid, light brown oil

59) N-[2-(4-Biphenylyloxy)ethyl]acetohydroxamic acid, m.pt. 125-127 ºC

60) N-[3-(4-Benzyloxyphenyl)prop-2-enyl]acetohydroxamic acid, m.pt.

148-149 ºC

61) N-[4-(2-Pyridyl)benzyl]acetohydroxamic acid, m.pt. 134-135 ºC (softens ca 125 ºC)

62) N-[4-(2,4-Difluorophenoxymethyl)benzyI]acetohydroxamic acid, m.pt.

112-113 ºC

63) N-[4-(2-PyridyIoxy)benzyl]acetohydroxamic acid, m.pt. 97-99 ºC

64) N-(5-PhenoxymethyI-2-thienylmethyl)acetohydroxamic acid, m.pt.

103-104 ºC

65) 3-(4-Fluoro-3-phenoxyphenyl)-N-methylprop-2-enohydroxamic acid, m.pt. 150-152 ºC

66) N-(6-Phenoxy-2-pyridylmethyl)acetohydroxamic acid

67) N-[3-(4-Fluoro-3-phenoxyphenyl)prop-2-enyl]acetohydroxamic acid

68) N-[4-(Benzylthio)benzyl]acetohydroxamιc acid 69) N-[3-(2-Pyridyloxy)benzyl]acetohydroxamic acid

Example 70

Preparation of 5-[2-(4-Biphenylyl)ethyl]-1-hydroxy-2-pyrrolidinone

Methyl-1-(4-biphenylyl)-2-oxobutanoate (1.48g) in ethanol (40ml) with hydroxylamine hydrochloride (0.348g) and sodium acetate (0.41g) was stirred for 16 hours at ambient temperature. Dilution with water precipitated the oxime (1.368g) which was dissolved (without purification) in acetic acid (15ml) and treated with sodium cyanoborohydride (0.41g) under nitrogen. The mixture was stirred for 3 hours at room temperature, then non-acidic material was isolated with ethyl acetate. The resulting crude hydroxylamine in toluene (25ml) containing p-toluenesulphonic acid catalyst (80mg) was heated for 1.25 hours at 100 º to precipitate 5-[2-(4-Biphenylyl)ethyl]-1-hydroxy-2-pyrrolidinone (0.875g), m.pt. 192-194º C after recrystailization from methanol.

Examples 71-75 The following compounds were prepared in a manner generally analogous to that described in Example 70:-

71) 1-Hydroxy-5-[2-(2-naphthyl)ethyl]pyrrolidin-2-one, m.pt. 163-164 ºC

72) 5-(4-Biphenylyl)-1-hydroxy-2-pyrrolidone, decomp. at 195 ºC in preheated apparatus

73) 1-Hydroxy-5-(2-phenylethyl)-2-pyrrolidinone m.pt. 120-122 ºC

74) 1-Hydroxy-5-(3-phenylpropyl)-2-pyrrolidinone m.pt. 63-65 ºC

75) 5-[2-(4-Benxyloxyphenyl)ethyl]-1-hydroxy-2-pyrrolidone, m.pt. 155- 157 ºC

Example 76

Preparation of 5,6-Dihydro-1-hvdroxy-5-(1-naphthyl)-1,4-thiazin-3(2H,4H)-one

A solution of methyl mercaptoacetate (2.3g) in tetrahydrofuran (15ml) was added dropwise to 1-(1-Naphthyl)-2-nitroethene (4.32g) and triethylamine (0.219ml) in tetrahydrofuran (100ml). The mixture was stirred for 30 minutes at room temperature, then evaporated in vacua. The residue (6.12g) was dissolved in saturated aqueous ammonium chloride solution (120ml) and 95% ethanol (to give homogeneous solution), then stirred while powdered zinc (2.62g) was added. The mixture was stirred for 30 minutes at room temperature, then concentrated. Isolation with ethyl acetate furnished 5,6-Dihydro-1-hydroxy-5-(1-naphthyl)-1,4-thiazine-3(2H,4H)-one (2.09g), m.pt. 155-157 ºC after recrystallization from ethyl acetate.

Examples 77-80 The following compounds were prepared in a manner generally analogous to that described in Example 76:-

77) 5,6-DIhydro-N-hydroxy-phenyl-1,4-thiazin-3(2H,4H)-one, m.pt. 159- 160 ºC

78) 6-(4-Biphenylyl)-5,6-dihydro-4-hydroxy-1,4-thiazin-3-(2H,4H)-one,

m.pt. 198-201 ºC

79) 5,6-Dihydro-4-hydroxy-6-(2-naphthyl)-1,4-thiazin-3(2H,4H)-one, m.pt.

184-86 ºC

80) 6-(4-BenzyloxyphenyI)-5,6-dihydro-4-hydroxy-1,4-thiazin-3(2H,4H)one,

m.pt. 179-181 ºC

Example 81

Preparation of 1-Hydroxy-1-[2-(2-nanhthyloxy)ethyl]-3-phenylurea

A mixture of 2-naphthyloxyacetaldehyde hydrate (9.85g), benzyloxyamine (5.94g) and ethanol (100ml) was stirred overnight under nitrogen to precipitate 11.21g of the protected oxime, m.pt. 68-69.5 ºC. The oxime (10.1g) in acetic acid (100ml) was reduced with sodium cyanoborohydride, then the isolated O-benzyl hydroxylamine, without purification, was treated with phenyl isocyanate (1 equivalent) in toluene for 4 hours at 110 ºC. The product had m.pt. 75-77 ºC after chromatography over silica gel (elution with methylene chloride) and recrystallization from SVM. Hydrogenation of the last-mentioned O- benzylhydroxyurea over 5% palladium on charcoal in ethanol containing a few drops of acetic acid provided 1-Hydroxy-1-[2-(2-naphthyloxy)ethyl]-3-phenylurea, m.pt. 165-167 ºC (from ethanol).

Example 82

Preparation of N-(4-Benzyloxybenzyl)-N-hydroxy-N-methylurea Sodium cyanoborohydride (1.94g) was added to 4-Benzylαxybenzaldoxime (3.5g) in acetic acid (30ml) under N₂, and the mixture was stirred overnight at room temperature. Solvent was evaporated, and the product (4g) was isolated with ether. Methyl isocyanate (0.88g) in ether (10ml) was added dropwise to a solution of the crude hydroxylamine in toluene (100ml) at 0 º, and the mixture was stirred for 3 hours at room temperature to precipitate N-(4-Benzyloxybenzyl)-N-hydroxy-N¹-methylurea (2.2g), m.pt. 152-154 º after recrystallization from ethyl acetate-light petroleum (b.pt. 60-80 º).

Examples 83-91

The following compounds were prepared in a manner generally analogous to that described in Examples 81 and 82:-

83) N-[3-(4-Fluoro-3-phenoxyphenyl)prop-2-enyl]-N-hydroxy-N'-methylurea

84) N-[3-(4-Fluoro-3-phenoxyphenyl)prop-2-enyl}-N-hydroxy-N'-t-butylurea

85) N-[3-(4-Fluoro-3-phenoxyphenyl)prop-2-enyl]-N-hydroxy-N'-cyclohexylurea

86) N-[3-(4-Fluoro-3-phenoxyphenyl)prop-2-enyl]-N-hydroxy-N'-phenylurea

87) N-(Biphenyl-4-ylmethyl)-N-hydroxy-N'-methylurea

88) N-(Biphenyl-4-ylmethyl)-N-hydroxy-N'-t-butylurea

89) N-(Biphenyl-4-ylmethyl)-N-hydroxy-N'-cyclohexylurea

90) N-(Biphenyl-4-ylmethyl)-N-hydroxy-N'-phenylurea

91) N-Hydroxy-N'-methyl-N-[3-(2-pyridyloxy)benzyl]urea

Example 92

Preparation of 3-(4-Benzyloxybenzyl)-1,3-dihvdro-1-hydroxyimidazol-2-one A mixture of 4-benzyloxybenzaldehyde (9.1g), aminoacetaldehyde diethyl acetal (6.9g) and p-toluenesulphonic acid (0.5g) in toluene (250ml) as refluxed through a Dean-Stark trap until ca 1ml of water had been collected. Solvent was evaporated in vacuo, and the crude imine was dissolved in acetic acid (100ml). Sodium cyanoborohydride (3.15g) was added in portions under nitrogen, and the mixture was stirred until the reaction was complete. Solvent was evaporated in vacuo, and the amine was isolated free of acidic material with ethyl acetate.

To the crude amine (14.15g) with triethylamine (14ml) in toluene (40ml) was added to 12% phosgene in toluene solution (250ml) to -40 º, and the mixture was warmed to room temperature over 1 hour. Solvent was evaporated, and material soluble in ether was dissolved in tetrahydrofuran (150ml) and treated with triethylamine (25ml), hydroxylamine hydrochloride (llg) and water (25ml). The mixture was stirred for 1 hour, and evaporated in vacuo. The crude hydroxyurea was isolated with ethyl acetate, then (18g) dissolved in chloroform (50ml) and treated with trifluoroacetic acid (25ml) and water (25ml). After 1 hour, the precipitated solid was collected and recrystallized from ethanol/N,N-dimethylformamide to give 3-(4-Benzyloxybenzyl)-1,3-dihydro-1-hydroxylmidazol-2-one (6g) which darkens without melting at greater than 175 º.

Examples 93-95

The following compounds were prepared in a manner generally analogous to that described in Fxample 92:-

93) 1,3-Dihydro-1-hydroxy-3-(4-phenylbenzyl) imidazol-2-one, softens

180º gradually decomposed to 220 ºC

94) 1-Hydroxy-3-(3-phenoxybenzyl)-1,3-dihydroimidazol-2-one

95) 1-Hydroxy-3-(6-phenoxy-2-pyridylmethyl)-1,3-dihydroimidazol-2-one

Example 96

Preparation of N-(4-Benzyloxybeπzyl)-O-methylcarbamoylacetohydroxamic Acid A mixture of N-(4-benzyloxybenzyl)acetohydroxamic acid (1.35g), methyl isocyanate (0.65g) and 1,8-diazablcyclo [5.4.0] undec-7-ene catalyst (1 drop) in tetrahydrofuran (10ml) was stirred for 3 hours then left overnight to provide N- (4-benzyloxybenzyl)-O-methylcarbamoylacetohydroxamic acid (1.35g) m.pt. 101- 102 º [from ethyl acetate-light petroleum (b.pt. 60-80 º)].

Example 97-99

The following compounds were prepared in a manner generally analogous to that described in Example 96:-

97) N-[2-(2-Naphthylthio)ethyl]-N-(phenylcarbamoyloxy)acetamide, m.pt.

96-98 ºC

98) N-[4-(Benzyloxybenzyl)-0-(methyIcarbamoyl)pivalohydroxamic acid,

rn.pt. 135-136 ºC

99) N-(4-Benzyloxybenzyl)-2-(2j2-dimethylethyl)carbamoylacetohydroxamic acid, m.pt. 82-83 ºC

Example 100 Preparation of N-(4-Benzyloxybenzyl)-N-(t-butylcarbonyloxy )aceta m ide

Pivaloylchloride (1.36ml) was added dropwise to a solution of N-(4-benzyloxybenzyl) acetohydroxamic acid (2.71g) and triethylamine (1.7ml) in methylene dichloride (15ml) and dimethylaminopyridine (100ml). The mixture was stirred for 2 hours at room temperature, then neutral material was isolated with ether. The product, N-(4-Benzyloxybenzyl)-N-(t-butylcarbonyloxy)acetamide, was a colourless oil.

Example 101

3-[N-(4-Benzyloxybenzyl)acetamidooxycarbonyl]propanoic acid, m.pt. 102-105 º was prepared in a manner generally analogous to that described in Example 100.

Pharmaceutical Formulations

In the following formulation Examples, the "Active Ingredient" may be any compound of formula (I) or a physiologically acceptabie salt thereof, for example the compound of Example 27.

Example A: Tablet:

In one tablet

Active Ingredient 5.0 mg

Lactose 82.0 mg

Starch 10.0 mg

Povidone 2.0 mg

Magnesium Stearate 1.0 mg

Mix together the active ingredient, lactose and starch. Granulate the powders using a solution of povidone in purified water. Dry the granules, add the magnesium stearate and compress to produce tablets, 100mg per tablet.

Example B: Injection Solution

Active Ingredient 10.0 mg

Water for Injections B.P. to 1.0 ml

The active ingredient was dissolved in half of the Water for Injections and then made up to volume and sterilised by filtration. The resulting solution was distributed into ampoules under asceptic conditions.

BIOLOGICAL EXAMPLE

Male New Zealand White rabbits (2.5-3kg) were immunised with intradermal injections of 4mg of ovalbumin in 1ml of Freund's complete adjuvant. Animals were reimmunised 14 days later in the same way. Five days after the second immunisation, arthritis was induced in the right knee joint by injecting 1ml of a sterile solution of ovalbumin (5mg/ml) into the joint cavity.

Joint diameters were measured (on a randomised blind basis) with calipers at frequent intervals after antigen challenge. Animals were killed after 16-17 days and the joint space was washed with 1ml of saline and the resultant fluid was taken for total and differential leukocyte counts.

Sensitised animals were randomly allocated to groups of 5-8. N-(3-phenoxycinnamyl)acetohydroxamic acid (compound A) was administered in suspension following 5h ball-milling in 0.25% Celacol as vehicle. The non-steroidal anti-inflammatory indomethacin was dissolved in a small volume of 1M Tris buffer pH8 and then made up to volume with 0.25% Celacol. Control animals received 0.25% Celacol. Each animal received an oral dose (approximately 5ml) of vehicle or drug 3 times every 24h. Doses were administered at 8.0am, 4.0pm and 12 midnight for 16-17 days commencing 1h before antigen challenge on day 0. All doses were given orally by stomach tube. The groups were as follows :

1-8 Controls (5ml 0.25% Celacol ×3/24h)

9-14 1mg/kg indomethacin dissolved in 0.25% Celacol ×3/24h.

15-19 50mg/kg compound A suspended in 0.25% Celacol ×3/24h

20-24 50mg/kg compound A suspended in 0.25% Celacol plus 1mg/kg indomethacin dissolved in 0.25% Celacol.

Joint swelling

In control animals, antigen challenge caused an increase in joint diameter of 6-7mm which peaked 2 days after challenge. Joint swelling was sustained in the control group for the period of the experiment (16-17 days) and by the time the animals were killed, the diameters of the arthritic joints were approximately 5mm greater than the contralateral joints. None of the drug treatments reduced joint swelling for the first 2 days after challenge, but from day 3 onwards, compound A reduced swelling by up to 18% and indomethacin by up to 38% compared to the vehicle-treated controls. The greatest and most consistent reductions in swelling (up to 51%) were seen in the group receiving a combination of compound A and indomethacin. Results are shown in Table 1.

TABLE 1

JOINT SWELLING (MM)

Duration of Compound A Indomethacin A + Indo. Control arthritis

1 5.7 5.3 4.3 4.9

2 6.9 6.6 5 .5 6.4

3 (4.9) 4.9 3.8 6.4

4 5.8 4.9 3 .5 6.0

8 4.8 3.4 2.9 5.5

11 4.2 3.4 2.7 5.1

16 3.8 2.8 2.1 4.3

Synovial tissue/fluid studies

Synovial lining tissue was removed from the joint, fixed, processed, cut and stained for microscopic examination. Histological scores were derived for the total mass of inflamed synovial lining, lymphocyte infiltration and polymorph content. The slides were read on a randomised blind basis.

Synovial fluids from the arthritic joints of control animal s contained approximately 20 × 10 leukocytes of which about 80% were polymorphs. Indomethacin had no effect on total leukocyte numbers in synovial fluids, compound A showed some reduction (50%) and compound A with indomethacin gave an 80% reduction. Tissues from control animals showed a marked synovitis and thickening of the synovial layer. The pattern of lymphoplasmacytic infiltration below the tissue surface was stereotyped and measurable. Small lymphocyte clusters and persistent polymorph infiltration were associated with high total lymphoid cell counts.

Compound A or indomethacin alone both increased the mean lymphocyte infiltrate in the synovial tissue, but the combination therapy resulted in a reduced number of lymphocytes. The most striking finding was the virtual absence of polymorphs in the tissues from animals treated with compound A and indomethacin. Results are shown in Tables 2 and 3.

TABLE 2

LYMPHOCYTES (CELL NUMBER PER 10μm TISSUE BAND)

Compound A Indomethacin A + Indo. Control

94 104 38 58

TABLE 3

POLYMORPHS (CELL NUMBER PER 10μm TISSUE BAND)

Compound A Indomethacin A + Indo. Control

40 82 94

The mean score for the synovial tissue mass was not significantly different in the compound A, indomethacin, or control groups. In tissues from animals treated with compound A and indomethacin, the synovial mass was 40% less than controls. Results are shown in Table 4. TABLE 4

SYNOVIAL WIDTH LINING (MEAN SCORES)

Compound A Indomethacin A + Indo. Control

4.3 4.0 2.8 4.5

Cartilage proteoglycan assay

Articular cartilage was dissected from the ends of the femurs and digested with papain prior to measurement of the concentration of sulphated glycosaminoglycans (GAGs). The proteoglycan content was expressed as μg GAG/mg wet weight of cartilage and compared with values obtained with cartilage from the contralateral control joint.

Articular cartilage dissected from the arthritic joints of vehicle-treated animals 16-17 days after antigen challenge contained 36% less proteoglycan than cartilage from the contralateral joints of the same animals. Treatment with compound A did not significantly alter proteoglycan loss from the cartilage, but indomethacin augmented it. In the group receiving both compound A and indomethacin, there was a significant reduction in the loss of proteoglycan compared with control animals. Results are shown in Table 5.

TABLE 5

PROTEOGLYCAN LOSS (%)

Compound A Indomethacin A + Indo. Control

32 52 27 36

The foregoing data clearly demonstrate the cytoprotective effect of compound A in arthritis, especially in the presence of the non-steroidal anti-inflammatory indomethacin.

Claims

1. A combination comprising a compound of formula (I)

Ar-(L-Ar')_q-(X)_k-(Y)_p-Q (I)

wherein k, p and q are independently 0 or 1, provided that when k is 1, then p must also be 1;

Ar represents either:

(i) furyl, thienyl, thienyl 1,1-dioxide, pyrryl, pyridyl, benzofuryl, benzothienyl, benzothienyl 1,1-dioxide, indolyl, naphthyl, quinolyl, or tetrahydronaphthyl, any of which is optionally substituted by one or more substituents independently selected from C_1-6 alkyl (which may itself optionally be substituted by one or more halogen atoms), aralkyl, C_1-4 alkoxy, halo, nitro, amino, carboxy, C_1-6 alkoxycarbonyl, aroyl, alkylsulphonyl and hydroxy, or

(ii) phenyl optionally substituted by one or more substituents independently selected from phenyl (optionally substituted by one or more substituents independently selected from those specified as optional substituents in (i) above) and said optional substituents specified in (i) above;

L is selected from -(CH₂)_r- (where r is 1-4), -O-, -CH₂O-, -CH₂S-, -OCH₂-, -CONH-, -NHCO-, -CO- and -CH₂NH-;

Ar' represents phenylene, thienylene, or pyridylene, any of which may be optionally substituted by one or more substituents independently selected from those specified as optional substituents in definition (i) of Ar;

X represents oxygen, sulphur, or carbonyl, provided that at least one atom separates said carbonyl group from any carbonyl group in Q as defined below;

Y is C_1-10 alkylene or C_1-10 alkenylene;

Q represents a non-cyclic moiety selected from groups of formula

in which one of m and n is O and the other is 1, and when n is 1 and m is O, R¹ and R² are independently selected from hydrogen and C_1-4 alkyl, with the possiblity that R² can also be C_5-7 cycloalkyl, or when n is O and m is 1, R¹ is independently selected from hydrogen, C_1-4 alkyl, groups as defined for Ar above and groups of formula -COR³ in which R³ Is selected from C_1-4 alkyl (optionally substituted by a carboxy or C_1-4 alkoxycarbonyl group) and groups of formula -N(R⁴)R⁵, in which R⁴ is hydrogen or C_1-4 alkyl and R⁵ represents hydrogen, C_1-4 alkyl, or phenyl optionally substituted by one or more substituents independently selected from those specified as optional substituents in definition (i) of Ar, and R² is selected from hydrogen, C_1-4 alkyl, amino, C_1-4 alkylamino, di-C_1-4 alkylamino, C_5-7 cycloalkylamino, C_5-7 cycloalkyl(C_1-4 alkyl)amino, anilino, N-C_1-4 alkylanilino and groups as defined for Ar above; or Q represents a cyclic moiety selected from 1-hydroxy-1,3-dihydroimidazol-2-one and groups of formula

in which Z represents a C_2-5 alkylene chain in which one of the carbon atoms may be replaced by a hetero atom; with the proviso that: when q is O, k is O or 1 and p is 1, Ar is phenyl or naphthyl, either being optionally substituted by one or more substituents as specified in definition (i) of Ar, and X is oxygen or sulphur (in the case when k is 1), Y is C_1-10 alkylene and Q represents said non-cyclic moiety as hereinbefore defined in which one of R¹ and R² is hydrogen or C_1-4 alkyl; then the other of R¹ and R² is neither hydrogen nor C_1-4 alkyl; or a pharmaceutically acceptable salt thereof, and a non-steroidal anti-inflammatory drug for use in therapy.

2. A combination according to claim 1 for use in the treatment or prevention of inflammatory j oint conditions .

3. A combination according to claim 2 for use in the treatment or prevention of arthritis.

4. A combination according to claim 2 for use in the treatment or prevention of rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, or reactive arthritis.

5. A combination according to any of claims 1 to 3, wherein in the compound of formula (I) or its pharmaceutically acceptable salt: q is 1 , k is O and p is 1;

Ar is phenyl optionally substituted by one or more substituents independently selected from C_1-4 alkyl (which may be substituted by one or more halogen atoms) and halogen;

L is -O-;

Ar' is 1,3- or 1,4-phenylene;

Y is (E)-CH=CH-CH(R)- where R is C_1-4 alkyl; and

Q is a moiety of formula

wherein R¹ is hydrogen and R² is C_1-4 alkyl.

6. A combination according to claim 5, wherein the compound of formula (I) Is selected from N-(3-phenoxycinnamyl)acetohydroxamic acid, (E)-N-{1-methyl-3-[3-(4-fluorophenoxy)phenyl]prop-2-en-1-yl}acetohydroxamic acid and (E)-N-[1-methyl-3-(3-phenoxyphenyl)prop-2-en-1- yl]acetohydroxamic acid.

7. A combination according to any of claims 1 to 6, wherein the non-steroidal anti-inflammatory drug is selected from clidanac, flurbiprofen, Ibuprofen, Indomethacin, ketoprofen, naproxen, suprofen, piroxicam, diclofenac and tiaprofenic acid.

8. Use of a combination according to any of claims 1 to 7 in the manufacture of a medicament for the treatment or prevention of inflammatory joint conditions.

9. Use according to claim 8, wherein the medicament is for the treatment or prevention of arthritis.

10. Use according to claim 9, wherein the medicament is for the treatment or prevention of rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, or gouty arthritis.

11. A medicament comprising a compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof, one or more acceptable carriers and/or excipients and, optionally, one or more other therapeutic ingredients.

12. A medicament according to claim 11, wherein the compound of formula (I) or its pharmaceutically acceptable salt is as described in claim 4.

13. A medicament according to claim 12, wherein the compound of formula (I) is selected from N- (3-phenoxycinnamyl)acetohydroxamic acid, (E)-N-{1-methyl-3-[3-(4-fluorophenoxy)phenyl]prop-2-en-1-yl)acetohydroxamic acid and (E)-N-[1-methyl-3-(3-phenoxyphenyl)prop-2-en-1- yl]acetohydroxamic acid.

14. A medicament according to any of claims 11 to 13, wherein the non-steroidal anti-inflammatory drug is selected from clidanac, flurbiprofen, ibuproxam, indomethacin, ketoprofen, naproxen and suprofen.

15. A medicament according to any of claims 11 to 14, which is adapted for oral administration or for administration by intra-articular injection.

16. A method for the treatment or prevention of inflammatory joint conditions which comprises the administration of a therapeutically effective amount of a combination comprising a compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof, and a non-steroidal anti-inflammatory drug.

17. A method according to claim 8, which is for the treatment or prevention of arthritis.

18. A method according to claim 9, which is for the treatment or prevention of rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, or gouty arthritis.