Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-12-23
2001-09-11
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S885000
Reexamination Certificate
active
06288098
ABSTRACT:
European Patent 13,376 discloses N-(4-trifluoromethyl)-5-methylisoxazole-4-carboxanilide (compound 1) as being anti-inflammatory. Processes for the preparation of this compound are also described therein.
It is additionally known that the compound 1 and its metabolite N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide (compound 2) have immunomodulating properties, so that they are suitable as pharmaceuticals against chronic graft versus host diseases and against autoimmune disorders, in particular systemic Lupus erythematosus (EP-A-217,206).
U.S. Pat. No. 4,061,767 describes the use of 2-hydroxyethyl-idenecyanoacetanilide derivatives for the preparation of pharmaceuticals having anti-inflammatory and analgesic action.
In the USA, 15,000 organ transplantations were performed in 1990. The majority of the transplantations relate to the kidney, but hearts, skin, lungs, liver and pancreas are also being increasingly transplanted. In a large number of the patients, which have been transplanted with an organ of another individual a reaction can occure which lead to the rejection of the grafted organ. A differentiation can be made between three forms of graft rejection:
hyperacute, acute and chronic rejection.
Hyperacute rejection is essentially caused by circulating antibodies in the blood, which are directed against the tissue of the transplanted organ (transplant), and in a very short time—often in minutes—lead to necroses of the transplant.
In acute graft rejection reaction is somewhat delayed. Further, the chronic form of graft rejection can lead to a diseasestate. In this case the transplants survive the first year after transplantation, but can be rejected in the course of the next few years. It is additional known that transplant-host relationship is not restricted to rejection by the host organism alone; in certain cases an immune reaction originating from the transplant and directed against the host tissue can occur (EP-A-217,206). A differentiation is therefore made between a rejection between transplant and host and between host and transplant.
It is additionally known that transplanted organs from different animal species for example from the mouse to the rat are also rejected (Roitt et al., Immunology, Gower Medical Publishing Ltd., 1985).
To date, no pharmaceuticals are known which offer effective protection against hyperacute rejection reaction. In the clinic, until now donors and recipients of organs have been tested for incompatibility. In 20 to 40% of all patients waiting for a transplant, do not quality for a donor organ. The acute rejection reaction can be treated, but the meditation show side effects such as nephrotoxicity during treatment. To date, there are also no medicaments known which can treat the cause of the chronic graft rejection.
The essential pathogenic factor for tissue death in the transplant is regarded to be allophilic and xenophilic antibodies (Auchincloss B., Transplantation 46, 1, 1988).
These antibodies are essentially responsible for rejection in organ transplants within an animal species (allo) or between two different species (xeno).
Surprisingly, compound 1 and its metabolite, the abovementioned compound 2, show a potent inhibition of the formation of allophilic or xenophilic antibodies. There is thus possibility effectively treating the hyperacute, acute and chronic rejection reaction of the recipient to the transplanted organ.
The invention therefore relates to the use of N-(4-trifluoromethylphenyl)-5-methylisoxazole-4-carboxanilide and N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide and/or their physiologically tolerable salts for the preparation of pharmaceuticals for the treatment of graft rejection reactions of the organ recipient to the transplanted organ.
Suitable physiologically tolerable salts of compound 2 are, for example, alkali metal, alkaline earth metal or ammonium salts, including those of physiologically tolerable organic ammonium bases. The term organ is understood as meaning all organs in mammals, in particular the human, for example kidney, heart, skin, liver, pancreas, muscle, bone, intestine or stomach, but also blood or hair.
Rejection reaction means all defence mechanisms of the recipient organism which, in the end, lead to cell or tissue death of the transplanted organ or affect the viability of the transplanted organ.
The compounds 1 and 2 can be prepared by the following process:
A compound of the formula I
in which X represents a halogen atom, preferably chlorine or bromine, is reacted with the amine of the formula II
to give the compound 1, and this can then be reacted in the presence of a basic agent to give the compound 2.
The abovementioned reactions are carried out under standard conditions in a known manner (EP-B-13,376, U.S. Pat. No. 4,061,767).
The starting substances for the reactions are known or can be easily prepared by methods known from the literature.
The invention also relates to pharmaceuticals which contain an effective amount of compound 1 or compound 2 and/or physiologically tolerable salts of compound 2, in addition to pharmaceutically suitable and physiologically tolerable excipients, diluents and/or other active substances and auxiliaries.
The invention also relates to a process for the preparation of a pharmaceutical for the treatment of rejection reactions of the organ recipient against the transplanted organ, which comprises bringing compound 1 or 2 and/or a physiologically tolerable salt of compound 2 into a suitable administration form using a pharmaceutically suitable and physiologically acceptable excipient and, if appropriate, other suitable active substances, additives or auxiliaries.
The pharmaceutical according to the invention can be administered orally, topically, rectally, intravenously or alternatively parenterally. Administration is carried out before, during and after organ transplantation in the recipient and/or donor.
Suitable solid or liquid pharmaceutical administration forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and preparations having a protracted release of active substance, in whose preparation customary auxiliaries such as excipients, disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are used. Commonly used auxiliaries which may be mentioned are, for example, magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as, for example, sterile water and mono-or polyhydric alcohols, for example glycerol.
Preferably, the pharmaceutical preparations are prepared and administered in dosage units, each unit containing as the active constituent a certain dose of compound 1 or 2 and/or physiologically tolerable salts of compound 2. In the case of solid dosage units, such as tablets, capsules or suppositories, this dose can be up to about 300 mg, but preferably 10 to 200 mg.
For the treatment of a patient (70 kg) to whom an organ has been transplanted, in the early phases after transplantation an intravenous infusion treatment of at most 1200 mg per day and in the later rehabilitation phases an oral administration of 3 times 300 mg per day of compound 1 or 2 and/or of the corresponding salts of compound 2 are indicated.
Under certain circumstances, however, higher or lower doses may also be appropriate. The administration of the dose can be carried out both by single administration in the form of an individual dosage unit or else several smaller dosage units and by multiple administration of subdivided doses at specific intervals.
Finally, compound 1 or 2 and/or its corresponding salts can also be combined during the preparation of the abovementioned pharmaceutical administration forms together with other suitable active substances, for example antiuricopathics, thrombocyte aggregation inhibitors, analgesics and steroidal or
Aventis Pharma Deutschland GmbH
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Webman Edward J.
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