IL43948A - Adamantane carboxylates of 21-hydroxy pregnanes and compositions containing them - Google Patents

Description

.43948/3 9a-FLU0R0~16-METHYLENE PREDNISOLONES!-ADAMANTANE T¾ CARBOXYLATE AND PHARMACEUTICAL COMPOSITION CONTAINING ADAMANTANE CARBOXYLATES OF 21-HYDROXY PREGNANES '·- "■ j"» « J - t-21 ') .TOR- iύρΐΝ τ The present invention is concerned with improvements in or relating to the medicinal use of certain steroid 21-adamantane- 1 ' -carboxylates of the pregnane series as more particularly described hereinafter.

Israeli Patent No. 3 821 describes and claims betamethasone 21-adamantane- 1 ' -carboxylate and its corresponding 9cc-chloro analogue, these compounds being as described in our said Specificatiofl having prolonged anti¬ inflammatory activity upon internal administration. ■ As our said indicated in / pecifi cation , the above-mentioned compounds may advantageously be administered at intervals of several days in view of their prolonged duration of activity, an interval of 14 days being mentioned for intramuscular and intraarticular administration of the compounds to humans and an interval of 7-21 days for administration to animals. Our said Specification further . describes dosages at which the compounds may be administered over such intervals to achieve a satisfactory anti¬ inflammatory effect. Thus, for intramuscular administration to adult humans a dosage rate of 5-40 mg , preferably 10-20 mg of steroid is recommended, while for intra-articular administration the recommended dosage is 1-20 mg, preferably 3-6 mg of steroid. . For animals, a recommended dose rate is 0.1 to 0.5 mg steroid per kg animal weight. Dosage British Patent specification No. 1,056,198 describes the 21-adamantane-l'-cart)0)vlates of fluorstfndrenolone, paramethasone, hydrocortisone and prednisolone but no suggestion is made 1n this specification that the dosage levels for these compounds are other than those conventionally employed for systemic antiinflammatory steroids, nor Is any reference made in the specification to prolonged anti -Inflammator or immunosuppressive activity for these compounds.

We have now discovered that in treating . inflammatory diseases associated with a significant immunological component, very valuable long- lasting therapeutic effects can be achieved by the administration of certain 21-adamantane- l'-carboxylate esters of 17a, 21-dihydroxy-20-keto-pregnanes in larger initial doses than those hitherto proposed in our said Specification.

These 21-adamantane- 1-carboxylates comprise the steroids of formula [wherein R represents a methyl group in the a- or β-configuration , a methylene group or (when X and Y both represents chlorine atoms) an a-chlorine atom; X represents a chlorine or fluorine atom; and Y represents' a hydroxy group in the β-configuration, a keto group or (when X represents a chlorine atom) a chlorine atom, providing that when X represents a fluorine atom R is methylene ] and the 21-adamantane- paramethasone and fluorandrenolone.

Prednisolone and beclomethasone 21-adamantane-l '-carboxylates are preferred. Other steroids which may be used include the 21-adamantane-l ' -carboxyl ates of 9 a, -f 1 uoro-16-methyl ene-predni sol one , 9a > Πβ »°16a -trichloro-pregna-l ,4- diene-17at , 21-diol-3,20-dione, 9« -chloro-ΐββ -methyl -prednisolone and 9a -chloro-16ja -methyl -prednisolone.

According to one feature of the present invention we provide a method of systemically treating immunological disorders or inflammatory disorders having a significant immunological component which comprises administering within a period of up to 7 days to a non-human animal suffering from such a disorder an initial dosage of 50 to 500mg of a steroid 21-adamantane-l '-carboxyl ate of formula I (as hereinbefore defined), or the 21-adamantane-l -carboxyl ate of prednisolone, hydrocortisone, paramethasone or fluorandrenolone.

In order to take advantage of the present finding that high initial doses of the adamantoates are exceptionally beneficial, it is more convenient to formulate them in dosage units containing more than 50mg active steroid and it will be appreciated that dosage units containing such large quantities of corticoids represent a radical departure from previous practice. Thus, betamethasone and dexamethasone are usually administered systemically for treating inflammatory conditions in man in rather low doses, for example about 2 mg. Our above-mentioned Specification describes dosage units containing up to 50 mg of betamethasone 21-adamantane-l '-carboxyl ate. 4 - According to a further feature of the invention, therefore, we provide pharmaceutical and veterinary compositions in dosage unit form, each dosage unit containing more than 50 mg but not more than 500 mg, preferably more than 50 mg but not more than 200 mg of steroid 21-adamantane-l '-carboxylate of formula I (as defined above) or the 21-adamantane-l -carboxylate of prednisolone, hydrocortisone, paramethaS;one or fluorandrenolone, together with at least one pharmaceutical or veterinary carrier or excipient.

By the use of such initial large doses of the active steroid in treating the above-mentioned disorders a systemic effect may be obtained having a far longer duration of action than would have been expected solely from the increase in the amount of the compound employed. Indeed, the duration of the effect may be significantly greater than that of any comparable steroid. For example, the active steroids according to the present invention can, in certain cases, provide relief from inflammatory disorders having a high immunological component, for periods of up to 4-8 weeks or even longer using a suitable initial dose of the steroid, as more particularly described hereinafter, whereas steroids such as belamethasone are not observed to give relief for prolonged periods after administration and in some cases symptoms recur rapidly and may be at an increased level.

We have further discovered that the use of large doses of the active steroids provides an unusually valuable immunosupressi e effect. Experiments have shown that there appears to be arrest of the pathological immune response whilst normal immunological competence recovers. Thus, the steroids can generally be employed for the treatment of disorders having an immunological basis, e.g. for the suppression of harmful immunological reactions.' It is further observed from experimen s on rats that blood 1] -hydroxy corticosteroid levels are lowered for only a relatively short period of time whereas the anti- inflammato and/or immunosuppressive effects appear to persist for longer periods of time.

In the above-described method, an initial dose is preferably .200-500 mg.

The initial dosage of steroid given both to human desired adults and children and to animals can f / be expressed on a mg/kg basis." Thus, the dosage range 50 to 500 mg given above is " equivale t to 0.7 to 7.1 g / kg for a 70 kg human adult. . Although those dosages will also be affected by 'the surface area when considering children and animals, the dosages will still fall within the above range. A preferred dosage range is 3 to 7 mg/kg in animals.

In order to achieve the desired therapeutic effect, the above-defined initial dosage may be given on a single day or may be divided into separate doses given over a period.. up to . 7 days, for example at 1-3 day intervals. The dosage regime may thus, for example, comprise three administrations of the steroid over three days or two administrations over two or three days, the total dosage over this initial period being within the limits set out above.

It will be appreciated that the precise initial dosage and the number and frequency of separate divided dosages will generally depend inter alia upon the nature of the disorder being treated, its severity, the precise route of liquid. Such orally administrable compositions may be or/ formulated for example as tablets, capsules granules , For oral administration, the dosages of the steroid may be greater (for example up to 4 times greater) than those indicated above for administration of the compound by injectipn. large doses of . ' The use of^ the steroid compounds . as described above enables one to treat a wide variety of disorders which in general may be roughly classified as disorders associated with in lammatory conditions having a significaitimmunological component and disorders arising from harmful immunolo ical reactions.

The administration of the compounds in the above described manner will be particula ly valuable for the treatment of rheumatoid arthritis since the large dosagewill rapidly i?ring the disorder under control, as indicated by a reduction in fever (if the disorder is severe' relief of pain and reduction in the swelling at the joints. Medical opinion considers that rheumatoid arthritis is a disease in which both immunological and inflammatory reactions play a part.

The immuno- suppressive component of the activity of the corticosteroids discussed herein can be demonstrated by their effects in treating experimental allergic encephalomyelitis in rats . This experimental condition which is known to have a considerable immunological component can be regarded as a model for multiple sclerosis in the hurrian. Results have shown that the disorders can be treated successfully using large doses of■ steroid as des¬ cribed above.

The large doses of steroid may be sed to treat disorders where there is an inflammatory and/or. immunological process causing damage to the tissues. Disorders where such a mechanism is' believed to play a part in the pathogenesis are listed below.

In the literature some of these disorders have been referred to as "autoimmune" which in the strict senee of the word means an immune response by the patient to his own tissues. The initiating aetiological event may not itself have been autoimmune but may have been brought about by infectious or toxic agents. However, these agents directly or indirectly set up immunological processes which damage the tissues. For the present purposes such disorders are included. in humans /The disorders /which may be treated wit ^he compositions of the present invention include exfoliative dermatitis and severe pemphigus, severe systemic lupus erythematosus, status asthmaticus and severe as hma, complications arising from acute lymphatic leukaemia and other leukaemias, (such as haemolytic anaemia and thrombocytopenic purpura), acquired haemolytic anaemia, severe hypersensitivity reactions (e.g. serum sickness, angioneurotic oedema and trichiniasis) , collagen diseases, rheumatic fever especially if there is cardiac involvement , chronic discoid lupus erythematosus, polyarteritis nodosa, scleroderma',' polymyositis, dermstomyositis , giant-cell arteritis (especially if vision is affected), ankylosing spondylitis, ulcerative colitis, regional ileitis, sarcoidosis (especiall) if there is hyperc lcaerni , pulmonary fibrosis or CNS involvement) , blood diseases due to circulating antibodies , (e.g. haemolytic anaemias, thrombocy openic purpura, agranulocytosis), eye diseases (such as Sjogrens syndrome), nephrotic syndromes, post-hepatic cirrhosis with fever and other autoimmune disorders such as Hashimoto's disease. The steroid compound's can also be employed in accordance with the invention to control or prevent transplant rejection.

The method of the present invention can, as indicated above, be used to treat veterinary disorders associated with inflammatory conditions having a significant immunological component and/or disorders caused by harmful immunological reactions . Such disorders include, for example :- 1. Chronic eczema in cats and dogs . 2. Inflammatory conditions of the lung (pneumonia) (especially in the bovine). 3. Inflammatory conditions of the bovine udder (mastitis). 4. Inflammatory conditions of the gastrointestinal tract (e.g. calf or piglet scours). 5. Muscle and joint conditions (rheumatic and arthritic).

The adamantoate steroids here concerned may be prepared, for example, as described in the following Preparations .

The following compounds are new and constitute further, features of the present invention, namely compounds of the general formula (wherein R represents r\ methyl group- in the a- or β-configuration, X represents a chlorine atom and Y represents a ho to group or (when R represents a methyl group in the o con figura ion) Y may also represent a β-hyd oxy group, K further representing a methylene group when X represents Pyridine (0.4 ml) was added and the mixture heated on the steam-bath for 14 hours. A further portion of acid chloride (from 260 mg adamantane carboxylic acid) was added and the mixture refluxed for a further 2.5 hours. The cooled solution was poured into dilute sodium bicarbonate and the precipitated solid removed by filtration, and purified by preparative thin layer chromatography and crystallization from acetone-petroleum ether to give 9oc-chloro-16p-methylprednisolone 21- adamantane-1 ' -carboxylate m. p. 240°, + 144.9° (c 1.0, dioxan), λ 238-239 nm (ε 16,440). — max 9a-Fluoro-16-methyleneprednisolone-21-adamantane-l ' - carboxylate To 9a-fluoro-16-methyleneprednisolone (600 mg) in tetrahydrofuran (20 ml) was added adamantane carbonyl chloride (.152 g) in tetrahydrofuran (6 ml) and pyridine 14 (1.3 ml). The mixture was refluxed for 5 hours and then evaporated to small bulk in vacuo. Dilution with sodium bicarbonate solution afforded an oil which was extracted with ethyl acetate. The off-white solid obtained by evaporation of the extract was reheated on the steambath with pyridine (10 ml) and water (1.5 ml) for 4 hours. Dilution with water gave the crude ester which was extracted with ethyl acetate. The washed and dried extract was evaporated and the residue purified by preparative thin layer chromatography over silica and crystallization from methanol to yield 9a-fluoro-16-methyleneprednisolone 21-adamantane-l' -carboxylate m.p. 292-296° decomp. , [ccL. + 43° (c 1.0, dioxan) λ 237.5 nm (e 16,100. 15 The active steroids employed in accordance with the present invention may be administered in the form of the following injectable preparation Example 1 Composition Active steroid (particle size; 2.00% w/v < 100 μ; 10-75% > 5μ) Benzalkonium chloride (anhydrous equivalent) 0.015 " Tween 80 (polyoxyethylene-(20) sorbitan mono-oleate) . 0.010 Tween 81 0.005 Hydroxyethylcellulose 0.100 Sodium dihydrogen phosphate (dihydrate) 0.017 Disodium hydrogen phosphate (anhydrous) 0.043 Sodium chloride 0.710 Benzyl alcohol 1.00% v/v Water for injection to 100.00 pH 6,0 - 7.0 Preparation of Injectable Suspension The sodium chloride and phosphates are mixed with the hydroxyethyl cellulose, dissolved in water, benzyl alcohol added and the solution then sieved or filtered 16 and then sterilized by autoclaving to provide the vehicle for the suspension. The Tweens and ben-zalkonium chloride are together dissolved or dispersed in a small portion of the available water, mixed with the active steroid and the suspension is sterilized by autoclaving at 10 psi for 1 hour.

The sterile vehicle and the steroid suspension are then mixed aseptically and subjected to high shear stirring. The suspension is made up to volume with water, sieved, and filled into 3, 4, or 5 ml ampoules each containing 20 mg/ml of active steroid .

Similar preparations may be made in 1, 2, 3, 4 or 5 ml ampoules each containing 50 mg/ml of active steroid or 2, 3, 4 or 5 ml ampoules each containing 30 mg/ml active steroid.

Claims (1)

1. What we claim A method of systemically or in lammatory disorders having a significant component which comprises administering within a period of up to 7 days to a animal suffering from such a disorder an initial dosage of 50 to 500mg of steroid of formula herein represents methyl group in the or methylene group or X Y both represent chlorine an X represents a chlorine or fluorine and Y represents a group the a group or X represents a chlorine a chlorine providing that when X represents a atom R is methylene J or the of or 18 A method as claimed in claim 1 wherein the initial dosage is 200 to 500 of the said A as defined in claim 1 wherein the initial dosage is to of the said carboxylate of body weight of the A method defined in claim 3 wherein the initial dosage is 3 to 7 mg of the said carboxylate of body weight of the 5 A method as defined in claim 1 wherein the said initial is divided and is to the two or more days over a period of up to 7 days 6 A method defined in claim 5 wherein said initial dosage is divided and is administered to animal on two or more period of up to 7 days at 2 or 3 day interv A as defined in m wherein said initial dosage is divid d is administered to the animal three method a defined in wherein said initial dosage is divided and is administered to the animal two days over a period of 2 or 3 days 8 Λ method in claim 1 wherein of to the effected by A method de in claim 9 wherein is effected by intramuscular A as defined in claim 1 wherein said e is or Pharmaceutical veterinary compositions in dosage unit each dosage unit containing than but not more than of a as claim together w at least one ph c carrier as defined in claim 12 wherein each dosage unit co more 50mg but not more 200mg of the said Compositions as defined in claim 12 adapted for Compos as defined in claim 14 adapted for intramuscular as defined in claim containing a sterile as in claim in the form of ampoules or as cl aim 12 wherein each dosage unit contains more than 50mg but not more than 500mg of prednisol one 21 Composi tions as claimed 1n claim 12 wherein each dosage unit contains more than 50mg but not more than 500mg of beciomethasone prednisolone 21 A process for preparing a compound as cl aimed 1n claim 20 as herein insufficientOCRQuality