This invention relates to fibrotic diseases.
There are many fibrotic diseases in the human. These are sometimes referred to as chronic connective tissue diseases, and include degradative and proliferative conditions They include, for example, deterioration of the joints in arthritis, deformation of vessel walls in artherosclerosis, accelerated cardiovascular problems associated with diabetes, lung fibrosis and cirrhosis of the liver. These fibrotic diseases are generally considered and studied as separate and different problems. However, it is possible that common pathways exist in all these fibrotic diseases Indeed, corticosteriods are used in the treatment of many of these diseases to relieve symptoms and prevent associated tissue destruction and scarring; however, the use of corticosteroids is associated with dose and treatment duration side-effects which limit the usefulness of this type of compound.
Some fibrotic diseases are particularly distressing, such as, for example, those involving deterioration of cartilage and bone in the joint. Amelioration of such diseases is a particularly difficult target for the pharmaceutical industry. These conditions are often accompanied by distressing levels of pain and gradual impairment of structural body function and movement An added difficulty in attempting to find a satisfactory cure or improvement is that joint disease appears to be largely species specific. Therefore, research into joint disease in man is made more difficult in that animal models may not be appropriate.
In mankind, joint disease is generally progressive and affects all ages, but is particularly prevalent in middle and old age. Quality of life of the patient is severely reduced as the level of pain and reduction in mobility increase. Treatments hitherto have, therefore, been directed at manifestations of the disease or malfunction which are comparatively less difficult to treat. In rheumatoid arthritis, these include symptom-modifying anti-rheumatic drugs (so-called SMARD) for the relief of pain and decrease ill inflammation at the joint or in the synovial membrane, such as, for example non-sleroidal anti-inflammatory drugs (so-called NSAID) Some drugs are said to be disease modifying (so-called DMARD), such as, for example, non-cytotoxics such as anti-malarials, gold, sulphasalazine, D-penicillamine, and cytotoxics such as cyclophosphamide and chlorambucil However, such drug treatments are often associated with unpleasant or undesirable side effects, which limit their application and utility A new category of anti-rheumatic drugs, Disease Controlling Anti-Rheumatic Drugs, (so-called DCARD) has been proposed to describe drugs that effectively control the destructive processes but as yet no marketed anti-rheumatic drugs merit this classification although corticosteroids have some inhibitory effect on the articular damage at the low doses that can be tolerated for long term treatment.
However, consideration of the above fibrotic diseases as a class having a common pathway may prove valuable in attempting to invent new treatments.
It is known that corticosteriods can regulate gene transcription by binding to their specific receptor which is one member of the steroid receptor super-family (Physiology of the steroid-thyroid hormone nuclear receptor superfamily Williams G R, Franklyn J A Bailliere's Clinical Endocrinology and Metabolism Vol 8 No 2 pp241-266 1994) This super-family includes the glucocorticoid, oestrogen, progesterone, androgen, thyroid hormone, Vitamin D and retinoic acid receptors Such receptors are responsible for the regulation of many genes including those encoding tissue destructive proteolytic enzymes, for example, metalloproteinases (sometimes referred to as MMPs), One such MMP is collagenase 1. Corticosteroids interact specifically with the corticoid receptor which then binds to the promoters of the genes This liganded corticosteroid receptor represses activation of the collagenase gene by modulating the activity of transcription factor AP-1 (activating protein 1, heterodimer of c-fos and c-jun proteins; reviewed by Cato and Wade BioEssays Vol 18 No 5 pp371-378 1996). The liganded steroid receptor thus modulates production of protein destructive enzymes, thereby reducing degradation of joint tissues such as cartilage and bone.
Many of the members of the superfamily of steroid receptors can modulate tissue destructive proteolytic enzyme production when liganded with the natural hormone However, use of the natural hormone at pharmacological levels is associated with severe side effects due to their biological activity in many physiological systems. Corticosteroids effectively inhibit proteolytic enzyme production at the transcriptional level, through modulation of AP1, but the problem with corticosteroids is that they have additional transactivation effects on genes that lead to side effects, such as bone osteoporosis, diminishment of the immune response and water retention. Some of these side effects can be life threatening. Therefore, such inhibition or modulation in the substantial absence of the above hitherto undesirable associated side effects would represent a major therapeutic advance.
These undesirable additional transactivation effects are surprisingly substantially avoided in accordance with the present invention. It has been found that the use of the compounds described below have substantially no transactivation properties and do not transrepress body defence mechanisms signalled by immune hormones such as the cytokines, IL1 and TNF and the early response transcription factor NFκB (Mukaida N et al, J Biol Chem, 269, 13289-13295, 1994). The compounds below, and their associated pharmaceutical compositions, are not likely, therefore, to compromise the immune system, which is one of the one of the major problems associated with the use of corticosteroids. This is a surprising finding and clearly separates this class of molecule from the conventional steroid hormones.
It has been found that compounds (I) hereinafter described are able to regulate MMP gene activation, but surprisingly not through occupation of either the corticosteroid receptor or the androgen receptor. Therefore, surprisingly compounds (I) appear to regulate MMP gene activation through a different receptor and hence compounds (I) can thereby substantially prevent transcription of MMP), including collagenase 1. Indeed, it has been further found that compounds (I) acts through occupation of the thyroid hormone receptor. Herein lies the basis of the present invention.
Thus according to the present invention, a method is provided of alleviating fibrotic disease by regulating tissue destructive proteolytic enzyme production in the presence of thyroid receptor binding, but in the substantial absence of substantive corticosteroid and androgen receptor binding. This is effected by administration of an effective amount of at least one compound having the formula (I)
in which X stands for the oxygen or sulphur atom or for the imino (—NH—) or sulphonyl (—SO2—) radical, Y stands for a direct linkage, or for the oxygen or sulphur atom or for the sulphonyl (—SO2—) radical or for the radical of the formula —CR1R2—, wherein R1 and R2 which may be the same or different are hydrogen, alkyl or aryl radicals as hereinafter described, ring B may be optionally substituted by one or more substituents selected from halogen atoms and alkyl and aryl radicals, n is an integer having the value 0 or 1, and esters, amides and salts thereof.
In the compounds having the formula (I), R1 and R2 may be the same or different and preferably R1 is selected from hydrogen or 1-4C alkyl, and R2 from hydrogen, 1-4C alkyl or phenyl (which may be optionally substituted with at least one halogen atom, for example, chlorine, bromine), and R1 and R2 may be joined together to form a cycloalkyl ring (for example, cyclohexyl); the ring B may be optionally contain one or more substituents selected from halogen atoms and 1-4C alkyl. Most preferably, the 1-4C alkyl radicals are methyl or ethyl, and the halogen atom is chlorine.
Esters of compound (I) may be useful in the present invention. Such esters are preferably derived from alcohols having the formula R3—OH, where R3 is preferably I-4C alkyl, most preferably methyl or ethyl. Salts of compound (I) include alkali metal and alkaline earth salts, and include magnesium, aluminium, bismuth, ammonium, and preferably sodium, potassium and calcium. Where the compound (I) contains a strongly basic substituent, acid addition salts thereof, such as the hydrochloride, are comprehended.
Compounds having the formula (I), in which n is 1, and R1 and R2 which may be the same or different are hydrogen or alkyl radicals, are described in United Kingdom patent specification 1140748, the disclosure of which is incorporated herein. Such compounds are considered to be useful in the treatment or prophylaxis in humans and animals of such diseases as coronary artery disease and atherosclerosis. This is because they are said to reduce the concentration of cholesterol and/or triglycerides in the blood serum and the level of fibrinogen in blood plasma of rats. They are also said to possess anti-inflammatory activity in rats, and are, therefore, considered to be useful in the treatment of inflammatory signs and symptoms such as rheumatoid arthritis in man; further work has shown that such compounds have substantially no anti-inflammatory properties (Billingham M E J and Rushton A, Anti-inflammatory and Anti-arthritic Drugs, Vol III, Edited by. K D Rainsford, 31-63, 1985, CRC Press)).
A particularly preferred compound,
1-[4-(4-chlorophenyl)benzyloxy]-1-methylpropionic acid, has the formula (II)
European patent specification 0 037 698, the disclosure of which is incorporated herein, describes processes for the production of compounds having the formula (I) in which n takes the value 1, Y is a direct link and R1
which may be the same or different are hydrogen or (1-4C) alkyl. A preferred compound has the formula (III)
United Kingdom patent specification 860303, the disclosure of which is incorporated herein, describes compounds having the formula (I) in which n takes the value 0. A preferred compound has the formula (IV) and is known as clofibrate.
According to the present invention a method of modifying fibrotic disease in warm blooded animals is provided which comprises administering the animal an effective amount of at least one compound having the formula (I). In a further embodiment of the present invention a pharmaceutical composition is provided containing at least one compound having the formula (I) for the structural modification of fibrotic tissue in a warm blooded animal.
In accordance with the present invention, many fibrotic and proliferative conditions are considered to gain benefit from treatment with the pharmaceutical composition These include, for example, rheumatoid arthritis, psoriatic arthritis and psoriasis itself, the loosening of prosthetic joints, atherosclerosis of cardiac and coronary vessels and large arteries, the complications of diabetes, lung fibrosis, liver cirrhosis, systemic sclerosis, muscular dystrophy.
In order to be useful in the treatment of the above conditions in accordance with the present invention, the above compounds may be administered as a pharmaceutical composition by any suitable route, but preferably orally, as, for example, tablets, capsules, suspension, emulsions, powders, syrups, elixirs. They may be administered as suppositories. The pharmaceutical compositions may be formulated to include any pharmaceutically acceptable excipient and may be prepared by any suitable method known on the art, such as those described in any of the above patent specifications. The compositions should preferably be administered to ensure that the patient receives between 0.01 g and 0.5 g of active ingredient per day; the composition containing suitably between 0.01 g and 0.5 g of active ingredient.
The invention is illustrated with reference to the following experimental information.
Two plasmid constructs were introduced by standard calcium phosphate precipitation of DNA followed by glycerol shock (Ausubel F M, Brent R, Kingston D D, Moore J G et al Current protocols in molecular biology 1994 Greene Publishing Associates/Wiley-Interscience, New York, N.Y.) using a transformed African Green Monkey kidney cell line (CV1) (Schneikert J, Peterziel H, Defossez P- A, Klocker H, de Launoit Y and Cato A C B Androgen receptor-Ets protein interaction is a novel mechanism for steroid hormone-mediated down-modulation of matrix metalloproteinase expression. Journal of Biological Chemistry. Vol 271(39) (pp 23907-23913), 1996).