Inhibition of TNF production with matrix metaloproteinase inhibitors

The present invention is directed to the method of inhibiting the release of tumor necrosis factor (TNF) in a condition mediated by TNF by administration of certain hydroxamic add derivatives, also known as matrix metalloproteinase inhibitors, and thus the method of this invention is useful in the management of diseases or conditions mediated by TNF.

This application claims priority to PCT/GB93/02331 filed Nov. 12, 1993, 
published as WO94/10990 May 26, 1994, published as WO94/10990 May 26, 
1994. 
This invention relates to a new pharmaceutical and veterinary use of 
certain hydroxamic acid derivatives, previously known in the art as 
inhibitors of matrix metalloproteinases such as collagenase. In accordance 
with the invention the known compounds have been found to be capable of 
inhibiting the production of tumour necrosis factor (TNF) by cells, and 
thus to be useful in the management of diseases or conditions mediated by 
overproduction of, or over-responsiveness to, TNF. 
BACKGROUND OF THE INVENTION 
TNF 
TNF is a cytokine which is produced initially as a cell-associated 28 kD 
precursor. It is released as an active, 17 kD form (Jue, D-M et al., 
(1990) Biochemistry 29:8371-8377), which can mediate a large number of 
deleterious effects in vivo. When administered to animals or humans it 
causes inflammation, fever, cardiovascular effects, haemorrhage, 
coagulation and acute phase responses, similar to those seen during acute 
infections and shock states. Chronic administration can also cause 
cachexia and anorexia. Accumulation of excessive TNF can be lethal. 
There is considerable evidence from animal model studies that blocking the 
effects of TNF with specific antibodies can be beneficial in acute 
infections, shock states, graft versus host reactions and autoimmune 
disease. TNF is also an autocrine growth factor for some myelomas and 
lymphomas and can act to inhibit normal haematopoiesis in patients with 
these tumours. 
Preventing the production or action of TNF is, therefore, predicted to be a 
potent therapeutic strategy for many inflammatory, infectious, 
immunological or malignant diseases. 
It has been shown that the effects of TNF are mediated by two peptides, TNF 
.alpha. and TNF .beta.. Although these peptides have only 30% homology 
with each other, they activate the same receptors and are encoded by 
immediately adjacent genes. As used herein, the term tumour necrosis 
factor or TNF therefore means tumour necrosis factor .alpha. and peptides 
having a high degree of sequence homology with, and substantially similar 
physiological effects to, TNF .alpha., for example TNF .beta.. 
MMP Inhibitors 
It is known that metalloproteinases such as collagenase, stromelysin and 
gelatinase (known as "matrix metalloproteinases", and herein referred to 
as MMPs) are involved in connective tissue breakdown. The known hydroxamic 
acid-based MMP inhibitors with which this invention is concerned are those 
forming part of the state of the art by virtue of any of the following 
patent publications: 
______________________________________ 
US 4599361 ("Searle") 
EP-A-0236872 
("Roche 1") 
EP-A-0274453 
("Bellon") 
WO 90/05716 (British Biotechnology) ("BBL1") 
WO 90/05719 (British Biotechnology) ("BBL2") 
WO 91/02716 (British Biotechnology) ("BBL3") 
EP-A-0489577 
("Celltech 1") 
EP-A-0489579 
("Celltech 2") 
EP-A-0497192 
("Roche 2") 
WO 92/13831 (British Biotechnology) ("BBL4") 
WO 92/22523 (Research Corporation Technologies) ("RCT") 
WO 93/09090 ("Yamanouchi") 
WO 93/09097 ("Sankyo") 
______________________________________ 
The disclosure of each of those publications is hereby incorporated by 
reference, and the reader is referred thereto for details of the 
structures of the compounds disclosed and methods for their preparation. 
The MMP inhibiting hydroxamic acid derivatives disclosed therein can be 
regarded as having the following basic structure (I): 
##STR1## 
wherein the five substituents R.sub.1 -R.sub.5 may vary according to the 
detailed disclosure of each publication. However, neither the compounds 
per se nor the method of their preparation form part of this invention. 
Rather, the invention arises from the finding by the present inventors 
that representative members of the compound classes disclosed in each of 
those publications have the property of inhibiting release of TNF from 
cells, and the realisation that such activity is widespread amongst the 
disclosed compounds. 
General Composite Structural Definition of Known MMP Inhibitors 
Without prejudice to the true disclosures of the patent publications listed 
above, the following general composite structural definition of the 
disclosed compounds is offered as a guide. It has been compiled from the 
structural disclosures of the publications, but where further information 
is required concerning the identity of the compounds with which the 
present invention is concerned, the reader must consult the publication in 
question. Furthermore, where conflict arises between the disclosure of any 
of the patent publications listed above and the general composite 
structural definition set out below, the former prevails: 
The aforesaid composite structural definition is of compounds of formula 
(I) or (Ib) 
##STR2## 
wherein the five substituents R.sub.1 -R.sub.5 may vary as follows: 
R.sub.1 (Searle) hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl, phenyl(C.sub.1 
-C.sub.6 alkyl); (Roche 1) hydrogen, NH.sub.2, OH, SH, C.sub.1 -C.sub.6 
alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylamino, C.sub.1 
-C.sub.6 alkylthio or aryl(C.sub.1 -C.sub.6 alkyl) group or amino-C.sub.1 
-C.sub.6 alkyl, hydroxy-C.sub.1 -C.sub.6 alkyl, mercapto-C.sub.1 -C.sub.6 
alkyl or carboxy-C.sub.1 -C.sub.6 alkyl where the amino-, hydroxy-, 
mercapto or carboxyl group can be protected, the amino group acylated or 
the carboxyl group amidated; 
(Bellon) hydrogen; 
(BBL1) hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, phenyl, 
phenyl(C.sub.1 -C.sub.6 alkyl), or a group BSO.sub.n CH.sub.2 -- wherein n 
is 0, 1 or 2 and B is hydrogen or a (C.sub.1 -C.sub.6) alkyl, phenyl, 
substituted phenyl, phenyl(C.sub.1 -C.sub.6)alkyl, or heterocyclyl group; 
(BBL2) a group BSO.sub.n A-- wherein n is 0, 1 or 2 and B is hydrogen or an 
alkyl, phenyl, substituted phenyl, phenylalkyl, heterocyclyl, 
alkylcarbonyl, phenacyl or substituted phenacyl group, and A represents a 
hydrocarbon chain optionally substituted with one or more alkyl, phenyl, 
or substituted phenyl groups; 
(BBL3) hydrogen or a (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, 
phenyl, phenyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylthiomethyl, 
phenylthiomethyl, substituted phenylthiomethyl, phenyl(C.sub.1 
-C.sub.6)alkylthiomethyl or heterocyclylthiomethyl group; 
(Celltech 1) optionally substituted alkyl, alkenyl, aryl, aralkyl, 
heteroaralkyl, or heteroarylthioalkyl; 
(Celltech 2) optionally substituted alkyl, alkenyl, aryl, aralkyl, 
heteroaralkyl, or heteroarylthioalkyl; 
(Roche 2) hydrogen, amino, protected amino, acylamino, or lower alkyl 
optionally substituted by aryl, hydroxy, protected hydroxy, amino, 
protected amino, acylamino, maleimido, succinimido, naphthalimido, 
2,3-dihydro-1,3-dioxo-1H-benzd,e!isoquinol-2-yl, carboxy, protected 
carboxy, carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, 
di(lower alkyl)amino, carboxy-lower alkanoylamino, pyrrolidino or 
morpholino; 
(BBL4) hydrogen (C.sub.1 -C.sub.6)alkyl, phenyl, substituted phenyl, 
phenyl(C.sub.1 -C.sub.6)alkyl, or heterocyclyl; or R.sup.1 represents 
ASO.sub.n R.sup.7 wherein A represents a (C.sub.1 -C.sub.6) hydrocarbon 
chain, optionally substituted with one or more (C.sub.1 -C.sub.6)alkyl, 
phenyl or or substituted phenyl groups and n=0, 1 or 2; R.sup.7 is 
(C.sub.1 -C.sub.6)alkyl, phenyl, substituted phenyl, phenyl (C.sub.1 
-C.sub.6) alkyl, heterocyclyl, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 
-C.sub.6)acyl, thienyl or phenacyl; 
("RCT") hydrogen, lower alkyl, aryl, or aryl lower alkyl; 
(Yamanouchi) lower alkyl which may be substituted by a substituent selected 
from mercapto, loweralkylthio, arylthio and lower acylthio; 
(Sankyo) hydrogen; 
R.sub.2 (Searle) hydrogen, phenyl, phenyl(C.sub.1 -C.sub.6 alkyl), 
cycloalkyl, cycloalkyl(C.sub.1 -C.sub.6 alkyl); 
(Roche 1) C.sub.2 -C.sub.5 alkyl; 
(Bellon) isobutyl; 
(BBL 1) hydrogen atom or an (C.sub.1 -C.sub.6)alkyl, (C.sub.2 
-C.sub.6)alkenyl, phenyl(C.sub.1 -C.sub.6)alkyl, cycloalkyl (C.sub.1 
-C.sub.6)alkyl or cycloalkenyl (C.sub.1 -C.sub.6)alkyl group; 
(BBL2) a hydrogen atom or an alkyl, alkenyl, phenylalkyl, cycloalkylalkyl 
or cycloalkenylalkyl group; 
(BBL3) a hydrogen atom or an (C.sub.1 -C.sub.6)alkyl, (C.sub.2 
-C.sub.6)alkenyl, phenyl(C.sub.1 -C.sub.6)alkyl, cycloalkyl (C.sub.1 
-C.sub.6)alkyl or cycloalkenyl (C.sub.1 -C.sub.6)alkyl group; 
(Celltech 1) optionally substituted alkyl, alkenyl, cycloalkyl, aryl, 
aralkyl, aralkoxy, or aralkylthio group, or an amino, substituted amino, 
carboxyl, or esterified carboxyl group; 
(Celltech 2) optionally substituted phenylethyl, phenylpropyl or 
phenylbutyl group; 
(Roche 2) isobutyl; 
(BBL4) hydrogen or an (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, 
phenyl(C.sub.1 -C.sub.6)alkyl, or cycloalkyl (C.sub.1 -C.sub.6)alkyl 
group; 
("RCT") hydrogen, lower alkyl, aryl, or aryl lower alkyl; 
(Yamanouchi) a group --Y--X--Z wherein Y is a single bond or lower 
alkylene, X is O or S, and Z is lower alkyl; 
(Sankyo) hydrogen, alkyl or aralkyl; 
(Searle) C.sub.1 -C.sub.6 alkyl, benzyl, benzyloxybenzyl, (C.sub.1 -C.sub.6 
alkoxy)benzyl, benzyloxy(C.sub.1 -C.sub.6 alkyl); 
(Roche 1) the characterising group of a natural .alpha. amino acid, which 
may be protected if functional groups are present, eg acylation of amino 
groups and amidation of carboxylgroups, with the provision that R.sub.3 is 
not H or methyl; 
(Bellon) isopropyl, 4-aminobutyl, n-butyl, 2-methylmercaptoethyl; 
(BBL1) an amino acid residue with R or S stereochemistry or a (C.sub.1 
-C.sub.6)alkyl, benzyl, (C.sub.1 -C.sub.6)alkoxy benzyl or benzyloxy 
(C.sub.1 -C.sub.6)alkyl group; 
(BBL2) an amino acid residue with R or S stereochemistry or a (C.sub.1 
-C.sub.6)alkyl, benzyl, (C.sub.1 -C.sub.6 alkoxy) benzyl or benzyloxy 
(C.sub.1 -C.sub.6 alkyl) group; 
(BBL3) an amino acid residue with R or S stereochemistry or a (C.sub.1 
-C.sub.6)alkyl, benzyl, (C.sub.1 -C.sub.6)alkoxy benzyl, benzyloxy 
(C.sub.1 -C.sub.6)alkyl or benzyloxybenzyl group; 
(Celltech 1) a group -Alk!.sub.n R.sup.6 where Alk is an alkyl or alkenyl 
group optionally interrupted by one or more --O--, or --S-- atoms or 
--N(R.sup.7)-groups where R.sup.7 is a hydrogen atom or a C.sub.1 
-C.sub.6 alkyl group!, n is zero or an integer 1, and R.sup.6 is an 
optionally substituted cycloalkyl or cycloalkenyl group; 
(Celltech 2) optionally substituted alkyl or alkenyl group optionally 
interrupted by one or more --O--, or --S-- atoms or --N(R.sup.7)-groups 
where R.sup.7 is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group!; 
(Roche 2) tert-butyl; 
(BBL4) a benzyl group with one or two substituents in the phenyl ring 
selected from hydrogen, halogen, cyano amino, amino (C.sub.1 
-C.sub.6)alkyl, amino di (C.sub.1 -C.sub.6)alkyl, amino (C.sub.1 
-C.sub.6)alkylacyl, aminophenacyl, amino(substituted)phenacyl, amino acid 
or derivative thereof, hydroxy, oxy (C.sub.1 -C.sub.6)alkyl, oxyacyl, 
formyl, carboxylic acid, carboxamide, carboxy (C.sub.1 
-C.sub.6)alkylamide, carboxyphenylamide, carboxy (C.sub.1 -C.sub.6)alkyl, 
hydroxy (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyloxy (C.sub.1 
-C.sub.6)alkyl or acyloxy (C.sub.1 -C.sub.6)alkyl, (C.sub.1 
-C.sub.6)alkylcarboxylic acid, or (C.sub.1 -C.sub.6)alkylcarboxy (C.sub.1 
-C.sub.6)alkyl, amino(C.sub.1 -C.sub.6)alkylacyl carboxylic acid or 
amino(C.sub.1 -C.sub.6)alkylcarboxylate; or a benzyl group with one 
substituent in the phenyl ring selected from groups of formula --OCH.sub.2 
CN, --OCH.sub.2 COR.sup.8 and --OCH.sub.2 CH.sub.2 OR.sup.9, where R.sup.8 
is hydroxyl, (C.sub.1 -C.sub.6)oxyalkyl, (C.sub.1 -C.sub.6)oxyalkylphenyl, 
amino, (C.sub.1 -C.sub.6)aminoalkyl, (C.sub.1 -C.sub.6)aminodialkyl, 
(C.sub.1 -C.sub.6)aminoalkylphenyl, an amino acid or derivative thereof; 
and R.sup.9 is (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylphenyl, 
phenyl, substituted phenyl (C.sub.1 -C.sub.6)alkylacyl or phenacyl; 
("RCT") aryl lower alkyl, or heterocyclic lower alkyl, either being 
unsubstituted or mono- or di-substituted with fluoro, bromo, chloro, halo, 
nitro, carboxy, lower carbalkoxy, cyano, lower alkanoyl, trifluoromethyl 
lowere alkyl, hydroxy, lower alkoxy, formyl, amino, lower alkyl amino, 
di-lower alkyl amino, mercapto, lower alkylthio, or mercapto lower alkyl; 
(Yamanouchi) 4-(lower alkyl)phenylmethyl; 
(Sankyo) a group --CH.sub.2 --CH.sub.2 --CH.sub.2 --NH-- where the right 
hand bond is formed with the N atom adjacent the C atom carrying R.sub.3, 
thereby replacing the H atom shown on that C atom in formula (I); 
R.sub.4 (Searle) C.sub.1 -C.sub.6 alkyl; 
(Roche 1) a group --CHBD wherein B is H or methyl and D is H or C.sub.1 
-C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy-C.sub.1 -C.sub.6 alkyl, di(C.sub.1 
-C.sub.6 alkoxy)methyl, carboxy, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 
-C.sub.6 alkoxycarbonyl, arylmethoxycarbonyl, C.sub.1 -C.sub.6 
alkylaminocarbonyl or arylaminocarbonyl, or B and D together form a 
trimethylene group; or R.sub.3 and B together form a group (CH.sub.2)n 
where n is an integer from 4-11 ; 
(Bellon) hydrogen, phenyl(C.sub.1 -C.sub.2 alkyl), or 
trifluoromethylphenyl(C.sub.1 -C.sub.2 alkyl); 
(BBL1) a group --(CH.sub.2).sub.n A wherein n is an integer from 1 to 6 and 
A represents the group --NH.sub.2, a substituted acyclic amine or a 
heterocyclic base; 
(BBL2) a hydrogen atom or a (C.sub.1 -C.sub.6)alkyl group; 
(BBL3) a group (CH.sub.2).sub.n A wherein n is an integer from 1 to 6 and A 
represents a hydroxy, (C.sub.1 -C.sub.6)alkoxy, (C.sub.2 -C.sub.7)acyloxy, 
(C.sub.1 -C.sub.6)alkylthio, phenylthio, (C.sub.2 -C.sub.7)acylamino or 
N-pyrrolidone group; 
(Celltech 1) a hydrogen atom, an optionally substituted straight or 
branched alkyl group, optionally interrupted by one or more --O-- or --S-- 
atoms or --N(R.sup.7)-groups where R.sup.7 is a hydrogen atom or a 
C.sub.1 -C.sub.6 alkyl group!, or aminocarbonyloxy groups; or R.sup.4 and 
R.sup.5 together with the nitrogen atom to which they are attached may 
form an optionally substituted C.sub.3 -C.sub.6 cyclic amino group 
optionally possessing one or more other heteroatoms selected from --O-- or 
--S-- or --N(R.sup.7)-groups where R.sup.7 is a hydrogen atom or a 
C.sub.1 -C.sub.6 alkyl group!; 
(Celltech 2) a hydrogen atom, an optionally substituted straight or 
branched alkyl group, optionally interrupted by one or more --O-- or --S-- 
atoms or --N(R.sup.7)-groups where R.sup.7 is a hydrogen atom or a 
C.sub.1 -C.sub.6 alkyl group!, or aminocarbonyloxy groups; or R.sup.4 and 
R.sup.5 together with the nitrogen atom to which they are attached may 
form an optionally substituted C.sub.3 -C.sub.6 cyclic amino group 
optionally possessing one or more other heteroatoms selected from --O-- or 
--S-- or --N(R.sup.7)-groups where R.sup.7 is a hydrogen atom or a 
C.sub.1 -C.sub.6 alkyl group!; 
(Roche 2) hydrogen or lower alkyl optionally substituted by aryl, amino, 
protected amino, di(lower alkyl)amino, guanidino, carboxyl, protected 
carboxyl, carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, 
di(lower alkyl)phosphinyl, dihydroxyphosphinyl, pyrrolidino, piperidino or 
morpholino; 
(BBL4) hydrogen or a (C.sub.1 -C.sub.6)alkyl, or phenyl(C.sub.1 
-C.sub.6)alkyl group; 
("RCT") a group --XD wherein X is a bond, lower alkylene, or a group 
--(CAB).sub.m --C(O)--N(Z)--, or --(CAB).sub.m --CH.sub.2 O--, or 
--(CAB).sub.m --C(O)O-- wherein A is hydrogen, methyl or ethyl, and B and 
Z are independently hydrogen or lower alkyl, and m is 1,2 or 3 with the 
proviso that when X is a chemical bond then the group R.sub.3 (see above 
for RCT definition of R.sub.3) is not unsubstituted benzyl or benzyl 
monosubstituted with hydroxy or lower alkoxy, and the further proviso that 
when X is a group --(CAB).sub.m --C(O)--N(Z)-- wherein m is 1 and A, B and 
Z are as defined above, then the group R.sub.3 (see above for RCT 
definition of R.sub.3) is not indole or imidazole or unsubstituted benzyl 
or benzyl substituted with hydroxy or lower alkoxy; 
(Yamanouchi) lower alkyl; 
(Sankyo) hydrogen, alkyl, alkoxy, or (when R.sup.5 is hydrogen) 
--CH(R.sup.6)COR.sup.7 where R.sup.6 is hydrogen or alkyl and R.sup.7 is 
alkyl, or --CH(R.sup.6)COOR.sup.8 where R.sup.6 is hydrogen or alkyl and 
R.sup.8 is alkyl, or --CH(R.sup.6)CONR.sup.9 R.sup.10 where R.sup.9 and 
R.sup.10 are each alkyl, or R.sup.4 taken together with R.sup.5 and the 
nitrogen atom to which they are attached form a heterocyclic group; 
R.sub.5 (Searle) hydrogen; 
(Roche 1) H or methyl; 
(Bellon) hydrogen; 
(BBL1) a hydrogen atom or a methyl group; 
(BBL2) a hydrogen atom or a methyl group; 
(BBL3) a hydrogen atom or a methyl group; 
(Celltech 1 ) a hydrogen atom, an optionally substituted straight or 
branched alkyl group, optionally interrupted by one or more --O-- or --S-- 
atoms or --N(R.sup.7)-groups where R.sup.7 is a hydrogen atom or a 
C.sub.1 -C.sub.6 alkyl group!, or aminocarbonyloxy groups; 
(Celltech 2) a hydrogen atom, an optionally substituted straight or 
branched alkyl group, optionally interrupted by one or more --O-- or --S-- 
atoms or --N(R.sup.7)-groups where R.sup.7 is a hydrogen atom or a 
C.sub.1 -C.sub.6 alkyl group!, or aminocarbonyloxy groups; 
(Roche 2) hydrogen; 
(BBL4) hydrogen or methyl; 
("RCT") hydrogen or lower alkyl; 
(Yamanouch) hydrogen; 
(Sankyo) hydrogen or alkyl. 
In addition, the publication (Roche 1 ) discloses "reverse hydroxamic acid" 
MMP inhibitors of formula (Ib) 
##STR3## 
wherein the substituents R.sub.1 -R.sub.2 are the "Roche 2 substituents 
defined above in relation to formula (I). Salts of such known MMP 
inhibitors include physiologically acceptable acid addition salts for 
example hydrochlorides, hydrobromides, sulphates, methane sulphonates, 
p-toluenesulphonates, phosphates, acetates, citrates, succinates, 
lactates, tartrates, fumerates and maleates. Salts may also be formed with 
bases, for example sodium, potassium, magnesium, and calcium salts. 
There are several chiral centres in such known MMP inhibitors because of 
the presence of asymmetric carbon atoms. The presence of several 
asymmetric carbon atoms gives rise to a number of diastereomers with R or 
S Stereochemistry at each chiral centre. General formula (I), and (unless 
specified otherwise) all other formulae in this specification are to be 
understood to include all such stereoisomers and mixtures (for example 
racemic mixtures) thereof. 
The preferred stereochemistry is in general as follows: 
C atom adjacent the --CONHOH moiety --S, 
C atom adjacent the R.sub.2 group --R, 
C atom adjacent the R.sub.3 group --S, 
but mixtures in which the above configurations predominate are also 
contemplated. 
Reduced Composite Structural Definition of Known MMP Inhibitors 
Again without prejudice to the true disclosures of the patent publications 
listed above, the following reduced composite definition of the disclosed 
compounds is offered, it being understood that where further information 
is required concerning the identity of the disclosed compounds, the reader 
must consult the publication in question. The reduced composite definition 
is restricted to a core sub-set of the totality of structures encompassed 
by the patent publications listed above, namely compounds of formula (I) 
or (Ib): 
##STR4## 
wherein the five substituents R.sub.1 -R.sub.5 may vary as follows: 
R.sub.1 hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, 
phenyl, substituted phenyl, phenyl(C.sub.1 -C.sub.6 alkyl), heterocyclyl, 
or a group BSO.sub.n A-- wherein n is 0. 1 or 2 and B is hydrogen or a 
(C.sub.1 -C.sub.6)alkyl, phenyl, substituted phenyl, heterocyclyl, C.sub.1 
-C.sub.5 acyl, phenacyl or substituted phenacyl group, and A represents 
C.sub.1 -C.sub.6 alkyl, amino; protected amino; acylamino; OH; SH; C.sub.1 
-C.sub.6 alkoxy; C.sub.1 -C.sub.6 alkylamino; C.sub.1 -C.sub.6 alkylthio; 
aryl(C.sub.1 -C.sub.6 alkyl); amino(C.sub.1 -C.sub.6 alkyl); 
hydroxy(C.sub.1 -C.sub.6 alkyl), mercapto(C.sub.1 -C.sub.6 alkyl) or 
carboxy(C.sub.1 -C.sub.6 alkyl) wherein the amino-, hydroxy-, mercapto- or 
carboxyl-group are optionally protected or the carboxyl- group amidated; 
lower alkyl substituted by maleimido, succinimido, naphthalimido, 
2,3-dihydro-1,3-dioxo-1H-benzd,e!isoquinol-2-yl, carbamoyl, mono(lower 
alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, 
carboxy-lower alkanoylamino, pyrrolidino or morpholino; 
R.sub.2 (C.sub.1 -C.sub.)alkyl; (C.sub.2 -C.sub.6)alkenyl; phenyl(C.sub.1 
-C.sub.6)alkyl; cycloalkyl (C.sub.1 C.sub.6)alkyl; cycloalkenyl (C.sub.1 
-C.sub.6)alkyl; substituted amino; carboxyl; esterified carboxyl; or a 
group --Y--X--Z wherein Y is a single bond or (C.sub.1 -C.sub.6)alkylene. 
X is O or S, and Z is (C.sub.1 -C.sub.6)alkyl; 
R.sub.3 C.sub.1 -C.sub.6 alkyl; benzyl; benzyloxybenzyl; (C.sub.1 -C.sub.6 
alkoxy)benzyl; benzyloxy(C.sub.1 -C.sub.6 alkyl); the characterising group 
of a natural .alpha. amino acid, which may be protected if functional 
groups are present, eg by acylation of amino groups and amidation of 
carboxyl groups; a group --Alk!.sub.n R.sup.6 where Alk is an C.sub.1 
-C.sub.6 alkyl or C.sub.2 -C.sub.6 alkenyl group optionally interrupted by 
one or more --O--, or --S-- atoms or --N(R.sup.7)-groups where R.sup.7 is 
a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group!, n is 0 or 1, and 
R.sup.6 is an optionally substituted cycloalkyl or cycloalkenyl group; a 
benzyl group with one or two substituents in the phenyl ring selected from 
hydrogen, halogen, cyano amino, amino (C.sub.1 -C.sub.6)alkyl, amino di 
(C.sub.1 -C.sub.6)alkyl, amino (C.sub.1 -C.sub.6)alkylacyl, aminophenacyl, 
amino(substituted)phenacyl, amino acid or derivative thereof, hydroxy, oxy 
(C.sub.1 -C.sub.6)alkyl, oxyacyl, formyl, carboxylic acid, carboxamide, 
carboxy (C.sub.1 -C.sub.6)alkylamide, carboxyphenylamide, carboxy (C.sub.1 
-C.sub.6)alkyl, hydroxy (C.sub.1 -C.sub.6)alkyl, (C.sub.1 
-C.sub.6)alkyloxy (C.sub.1 -C.sub.6)alkyl or acyloxy (C.sub.1 
-C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylcarboxylic acid, or (C.sub.1 
-C.sub.6)alkylcarboxy (C.sub.1 -C.sub.6)alkyl, amino(C.sub.1 
-C.sub.6)alkylacyl carboxylic acid or amino(C.sub.1 
-C.sub.6)alkylcarboxylate; or a benzyl group with one substituent in the 
phenyl ring selected from groups of formula --OCH.sub.2 CN, --OCH.sub.2 
COR.sup.8 and --OCH.sub.2 CH.sub.2 OR.sup.9, where R.sup.8 is hydroxyl, 
(C.sub.1 -C.sub.6)oxyalkyl, (C.sub.1 -C.sub.6)oxyalkylphenyl, amino, 
(C.sub.1 -C.sub.6)aminoalkyl, (C.sub.1 -C.sub.6)aminodialkyl, (C.sub.1 
-C.sub.6)aminoalkylphenyl, an amino acid or derivative thereof; and 
R.sup.9 is (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylphenyl, phenyl, 
substituted phenyl (C.sub.1 -C.sub.6)alkylacyl or phenacyl; heterocyclic 
lower alkyl, either being unsubstituted or mono- or di-substituted with 
halo, nitro, carboxy, C.sub.1 -C.sub.6 alkoxy, cyano, C.sub.1 -C.sub.6 
alkanoyl, trifluoromethyl C.sub.1 -C.sub.6 alkyl, hydroxy, formyl, amino, 
C.sub.1 -C.sub.6 alkyl amino, di-C.sub.1 -C.sub.6 alkyl amino, mercapto, 
C.sub.1 -C.sub.6 alkylthio, or mercapto C.sub.1 -C.sub.6 alkyl; C.sub.1 
-C.sub.6 alkyl)phenylmethyl; 
R.sub.4 hydrogen, C.sub.1 -C.sub.6 alkyl; a group --CHBD wherein B is H and 
D is H or C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy-C.sub.1 -C.sub.6 
alkyl, di(C.sub.1 -C.sub.6 alkoxy)methyl, carboxy, C.sub.1 -C.sub.6 
alkylcarbonyl, C.sub.1 -C.sub.6 alkoxycarbonyl, arylmethoxycarbonyl, 
C.sub.1 -C.sub.6 alkylaminocarbonyl or arylaminocarbonyl; or R.sub.3 and B 
together form a group (CH.sub.2)n where n is an integer from 4-11; 
phenyl(C.sub.1 -C.sub.2 alkyl), or trifluoromethylphenyl(C.sub.1 -C.sub.2 
alkyl); a group --(CH.sub.2).sub.n A wherein n is an integer from 1 to 6 
and A represents the group --NH.sub.2, a substituted acyclic amine, a 
heterocyclic base, hydroxy, (C.sub.1 -C.sub.6)alkoxy, (C.sub.2 
-C.sub.7)acyloxy, (C.sub.1 -C.sub.6)alkylthio, phenylthio, (C.sub.2 
-C.sub.7)acylamino or an N-pyrrolidone group; an optionally substituted 
straight or branched alkyl group, optionally interrupted by one or more 
--O-- or --S-- atoms or --N(R.sup.7)-groups where R.sup.7 is a hydrogen 
atom or a C.sub.1 -C.sub.6 alkyl group!, or aminocarbonyloxy groups; 
C.sub.1 -C.sub.6 alkyl optionally substituted by aryl, amino, protected 
amino, di(lower alkyl)amino, guanidino, carboxyl, protected carboxyl, 
carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower 
alkyl)phosphinyl, dihydroxyphosphinyl, pyrrolidino, piperidino or 
morpholino; 
R.sub.5 hydrogen; 
Detailed Description of the Invention 
In a first aspect of the invention there is provided the use of a compound 
forming part of the state of the art by virtue of any of the patent 
publications listed above in the preparation of an agent for use in the 
treatment of diseases mediated by TNF. 
Without prejudice to the generality of the foregoing, the invention 
includes the use of a compound according to the general composite 
structural definition set out above in the preparation of an agent for use 
in the treatment of diseases mediated by TNF. 
More particularly the invention includes the use of a compound according to 
the general composite structural definition set out above in the 
preparation of an agent for use in the treatment of diseases mediated by 
TNF. 
In another aspect, this invention concerns a method of management (by which 
is meant treatment or prophylaxis) of diseases mediated by TNF in mammals, 
in particular in humans, which method comprises administering to the 
mammal an effective amount of a compound forming part of the state of the 
art by virtue of any of the patent publications listed above. 
Without prejudice to the generality of the foregoing, the invention 
includes a method of management (by which is meant treatment or 
prophylaxis) of diseases mediated by TNF in mammals, in particular in 
humans, which method comprises administering to the mammal an effective 
amount-of a compound according to the general composite structural 
definition set out above. 
More particularly, the invention includes a method of management (by which 
is meant treatment or prophylaxis) of diseases mediated by TNF in mammals, 
in particular in humans, which method comprises administering to the 
mammal an effective amount of a a compound according to the reduced 
composite structural definition set out above. 
Diseases mediated by TNF include, but are not limited to, inflammation, 
fever, cardiovascular effects, haemmorhage, coagulation and acute phase 
response, cachexia and anorexia, acute infections, shock states, graft 
versus host reactions and autoimmune disease. 
Specifically the target for the present invention is inhibition of the 
release of and the effects of TNF in septic shock, haemodynamic shock or 
sepsis syndrome, in post ischaemic reperfusion injury, in malaria, 
mycobacterial infection and meningitis, in psoriasis, in cancer, in 
cachexia, in fibrotic disease, in congestive heart failure, in graft 
rejection, in rheumatoid arthritis, in radiation damage and toxicity 
following administration of immunosuppressive monoclonal antibodies such 
as OKT3 or CAMPATH-1, in hyperoxic alveolar injury, in autoimmune disease 
for example AIDS and multiple sclerosis, and in any disease state where 
TNF is a mediator of host injury. 
Specific compounds having TNF inhibitory activity, for use in the present 
invention are those listed in the Examples below, particularly those 
listed in Example 2, Group A. 
The compounds with which the invention is concerned may be prepared for 
administration by any route consistent with their physicochemical and 
pharmacokinetic properties. The compositions thus may be in the form of 
tablets, capsules, powders, granules, lozenges, liquid or gel 
preparations, such as oral, topical, or sterile parenteral solutions or 
suspensions, as appropriate. Tablets and capsules for oral administration 
may be in unit dose presentation form, and may contain conventional 
excipients such as binding agents, for example syrup, acacia, gelatin, 
sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example 
lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; 
tabletting lubricant, for example magnesium stearate, talc, polyethylene 
glycol or silica; disintegrants for example potato starch, or acceptable 
wetting agents such as sodium lauryl sulphate. The tablets may be coated 
according to methods well known in normal pharmaceutical practice. Oral 
liquid preparations may be in the form of, for example, aqueous or oily 
suspensions, solutions, emulsions, syrups or elixirs, or may be presented 
as a dry product for reconstitution with water or other suitable vehicle 
before use. Such liquid preparations may contain conventional additives 
such as suspending agents, for example sorbitol, syrup, methyl cellulose, 
glucose syrup, gelatin hydrogenated edible fats; emulsifying agents for 
example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles 
(which may include edible oils), for example almond oil, fractionated 
coconut oily esters such as glycerine, propylene glycol, or ethyl alcohol; 
preservatives for example methyl or propyl p-hydroxybenzoate or sorbic 
acid, and if desired conventional flavouring or colouring agents. 
The dosage unit for oral administration may contain from about 1 to 250 mg 
for example from about 25 to 250 mg of a compound of general formula I. A 
suitable daily dose for a mammal may vary widely depending on the 
condition of the patient. However, a dose of a compound of general formula 
I of about, 0.1 to 300 mg/kg body weight, particularly from about 1 to 100 
mg/kg body weight may be appropriate. 
For topical application to the skin, the drug may be made up into a cream 
lotion or ointment. Cream or ointment formulations which may be used for 
the drug are conventional formulations well known in the art, for example 
as described standard textbooks of pharmaceutics such as the British 
Pharmacopoeia. 
For topical application to the eye, the drug may be made up into a solution 
or suspension in a suitable sterile aqueous or non aqueous vehicle. 
Additives, for instance buffers such as sodium metabisulphite or disodium 
edeate; preservatives including bactericidal and fungicidal agents such as 
phenyl mercuric acetates or nitrate, benzalkonium chloride or 
chlorhexidine, and thickening agents such as hypromellose may also be 
included. 
The dosage for topical administration will of course depend on the size of 
the area being treated. For the eyes, each dose may typically be in the 
range from 10 to 100 mg of the drug. 
The active ingredient may also be administered parenterally in a sterile 
medium. Depending on the vehicle and concentration used, the drug can 
either be suspended or dissolved in the vehicle. Advantageously, adjuvants 
such as a local anaesthetic, preservative and buffering agents can be 
dissolved in the vehicle. 
Although this invention is concerned with the use of certain matrix 
metalloproteinase inhibitors containing a hydroxamic acid group, known 
from specific patent publications as described above, it is thought highly 
probable that those other structural classes of compounds which are known 
in the art as matrix metalloproteinase inhibitors will, by analogous 
mechanisms, also have the property of inhibiting the production of TNF, 
and will therefore also be of use for the treatment of TNF-mediated 
diseases.