Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-24
2001-06-26
Raymond, Richard L. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S307000, C514S311000, C544S135000, C544S137000, C544S283000, C544S286000, C546S134000, C546S139000, C546S201000, C548S495000, C560S312000, C562S623000
Reexamination Certificate
active
06251913
ABSTRACT:
This application is the national phase of international application PCT /GB98/00910 filed Mar. 25, 1998.
This invention relates to hydroxamic acid compounds and in particular to such compounds with a heterocyclicalkoxy substituent. This invention further relates to processes for preparing such compounds, to pharmaceutical compositions containing them and to their use in methods of therapeutic treatment.
The compounds of this invention are inhibitors of the production of TNF (Tumour Necrosis Factor) which is believed to be formed by the cleavage of a pro-form, or larger precursor, by the enzyme pro-TNF Convertase. Applicants believe that the compounds of the present invention inhibit TNF production by mechanisms which include inhibition of pro-TNF Convertase. The term ‘TNF’ is used herein to refer to Tumour Necrosis Factor in general but, in particular to TNF&agr;.
The compounds of this invention will be useful in the treatment of disease or medical conditions in which excessive TNF production is known to give rise via a cascade of processes to a variety of physiological sequelae including the production of physiologically-active eicosanoids such as the prostaglandins and leukotrienes, the stimulation of the release of proteolytic enzymes such as collagenase, the activation of osteoclast activity leading to the resorption of calcium, the stimulation of the release of proteoglycans from, for example, cartilage, the stimulation of cell proliferations and to angiogenesis. It is also known that, in certain cellular systems, TNF production precedes and mediates the production of other cytokines such as interleukin-1 (IL-1) and interleukin-2 (IL-2) which are also believed to contribute to the pathology of disease states such as inflammatory and allergic diseases and cytokine-induced toxicity. Excessive TNF production has also been implicated in mediating or exacerbating the development of various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract inflammatory bowel disease, ulcerative colitis and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), and in the production and development of various cardiovascular disorders such as myocardial infarction, angina and peripheral vascular disease. Excessive TNF production has also been implicated in mediating complications of bacterial, fungal and/or viral infections such as endotoxic shock, septic shock and toxic shock syndrome. Excessive TNF production has also been implicated in mediating or exacerbating the development of adult respiratory distress syndrome, diseases involving cartilage or muscle resorption, Paget's disease and osteoporosis, pulmonary fibrosis, cirrhosis, renal fibrosis, the cachexia found in certain chronic diseases such as malignant disease and acquired immune deficiency syndrome (AIDS), tumour invasiveness and tumour metastasis and multiple sclerosis.
The compounds of the invention may also be inhibitors of one or more matrix metalloproteinases such as collagenases, stromelysins and gelatinases. Thus they may also be of use in the therapeutic treatment of disease conditions mediated by such enzymes for example arthritis (rheumatoid and osteoarthritis), osteoporosis and tumour metastasis.
The present invention provides novel compounds which have activity as inhibitors of TNF and/or are inhibitors of one or more matrix metalloproteinase enzymes.
Accordingly the present invention provides a compound of the formula (I):
wherein:
n is 1 to 6;
Het is a nitrogen containing ring fused to the benzene ring on two adjacent carbon atoms to form a bicyclic ring system which ring system may be optionally substituted;
R
1
is is hydrogen, C
1-8
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-8
cycloalkyl, aryl, heteroaryl, heterocyclyl, arylC
1-6
alkyl, heteroarylC
1-6
alkyl, heterocyclylC
1-6
alkyl or C
3-8
cycloalkylC
1-6
alkyl;
R
2
is C
1-6
alkyl, C
2-6
alkenyl, arylC
1-6
alkyl, heteroarylC
1-6
alkyl or the side-chain of a naturally occurring amino acid;
R
3
is hydrogen, C
1-6
alkyl, C
3-8
cycloalkyl, C
4-8
cycloalkenyl, arylC
1-6
alkyl, heteroarylC
1-6
alkyl or heterocyclylC
1-6
alkyl;
R
4
is hydrogen or C
1-6
alkyl; or R
3
or R
4
together with the nitrogen atom to which they are joined form a heterocyclic ring;
wherein any group or ring, in R
1
-R
4
, is optionally substituted;
or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
“Aryl in the terms “aryl ” and “aryl C
1-6
alkyl” typically means phenyl or naphthyl, preferably phenyl, “Heteroaryl” in the terms “heteroaryl” and “heteroarylC
1-6
alkyl” means an aromatic mono- or bicyclic 5-10 membered ring with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur. Examples of ‘heteroaryl ’ include thienyl, pyrrolyl, furanyl, imidazolyl, thiazolyl, pyrimidinyl, pyridinyl, indolyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl. “Heterocyclyl” in the terms “heterocyclyl” and heterocyclyl-C
1-6
alkyl” means a non-aromatic mono- or bicyclic 5-10 membered ring with up to five ring hetero atoms selected from nitrogen, oxygen and sulphur. Examples of ‘heterocyclyl’ include pyrrolidinyl, morpholinyl, piperidinyl, dihydropyridinyl and dihydropyrimidinyl.
Any group or ring in R
1
-R
4
may be optionally substituted, for example by up to three substituents which may be the same or different. Typical substituents include: hydroxy, C
1-6
alkoxy for example methoxy, mercapto, C
1-6
alkylthio for example methylthio, amino, C
1-6
alkylamino for example methylamino, di-(C
1-6
alkyl)amino for example dimethylamino, carboxy, carbamoyl, C
1-6
alkylcarbamoyl for example methylcarbamoyl, di-C
1-6
alkylcarbamoyl for example dimethylcarbamoyl, C
1-6
alkylsulphonyl for example methylsulphonyl, arylsulphonyl for example phenylsulphonyl, C
1-6
alkylaminosulphonyl for example methylaminosulphonyl, di-(C
1-6
alkyl)aminosulphonyl for example dimethylamino-sulphonyl, nitro, cyano, cyanoC
1-6
alkyl for example cyanomethyl, hydroxyC
1-6
alkyl for example hydroxymethyl, amino C
1-6
alkyl for example aminoethyl, C
1-6
alkanoylamino for example acetamido, C
1-6
alkoxycarbonylamino for example methoxycarbonylamino, C
1-6
Alkanoyl for example acetyl, C
1-6
alkanoyloxy for example acetoxy, C
1-6
alkyl for example methyl, ethyl, isopropyl or tert-butyl, halo for example fluoro, chloro or bromo, trifluoromethyl, aryl for example phenyl, arylC
1-6
alkyl for example benzyl, aryloxy for example phenoxy, arylC
1-6
alkoxy for example benzyloxy, heteroaryl, heteroarylC
1-6
alkyl, heterocyclyl and heterocyclylC
1-6
alkyl, The term “side chain of a naturally occurring amino acid” means the side chain X of an amino acid NH
2
—CHX—COOH. Suitable amino acids include alanine, arginine, aspartic acid, cysteine, asparagine, glutamine, histidine, homoserine, isoleucine, leucine, lysine, methionine, norleucine, norvaline, ornithine, serine, theonine, tryptophan, tyrosine and valine.
The compounds of the present invention possess a number of chiral centres, at the carbon atom adjacent to the HONHOC— group, at —CHR
2
—, at —CHR
1
—(when R
1
is not hydrogen) and possibly in the variables R
1
-R
4
. The present invention covers all diastereoisomers and mixtures thereof that inhibit TNF Convertase and/or inhibit matrix metalloproteinase enzymes.
n is 1 to 6, preferably n is 1 or 2 forming a methylene or ethylene moiety. Most preferably n is 1 forming a methylene moiety.
Suitably Het is a ring containing one or two ring nitrogen atoms. Suitably Het, together with the two fused carbon atoms, is a 5- or 6-membered ring. Therefore in a particular aspect Het is a 5- or 6-membered ring containing one or two ring nitrogen atoms.
In one aspect Het and the benzene ring to which it is fused form a bicyclic heteroaryl ring system for example quinoline, quinazoline, phthalazine, cinnoline, isoquinoline, indole, isoindole or indazole. In a further aspect Het and the benzene ring t
Balasubramanian Venkataraman
Pillsbury & Winthrop LLP
Raymond Richard L.
Zeneca Limited
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