NZ247630A

NZ247630A - Preparation comprising 9-cis or 13-cis-retinoic acid or acitretin and a vitamin d derivative

Info

Publication number: NZ247630A
Application number: NZ247630A
Authority: NZ
Inventors: Werner Bollag; Manfred Brockhaus; Willi Hunziker
Original assignee: Hoffmann La Roche
Priority date: 1992-05-20
Filing date: 1993-05-14
Publication date: 1995-12-21
Also published as: CN1080525A; HU9301404D0; AU3716193A; JPH0632740A; HUT66864A; CA2096196A1; KR940005278A; TW272187B; CZ83293A3; NO931831L; IL105700A0; NO931831D0; EP0579915A1

Description

<div class="application article clearfix" id="description"> Priority Date(s):/ £.4.:.$...... Complete Specification Filed: Class: (S) Publication Date:. 2.1 ..DEC 1995 P.O. Journal No: ./M: No.: Date: NEW ZEALAND PATENTS ACT, 1953 N.Z. PATENT OFFICE H MAY 1993 .RECEIVED COMPLETE SPECIFICATION PHARMACEUTICAL COMPOSITIONS We, F. HOFFMANN-LA ROCHE AG 124 Grenzacherstrasse, CH-4002 Basle, Switzerland, a Swiss Company, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 -(followed by page la) 15 247630 - la - z,-- ? M e A *:. /7 s- - ~S // ^■s> J The present invention is concerned with synergistic -<4^ pharmaceutical preparations containing 9-cis- or 13-cis-retinoic acid or acitretin (all(E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl--2,4,6,8-nonatetraeonic acid), or a pharmaceutical^ usable salt or ester 5 thereof and a vitamin D derivative. It has been found that such preparations can be used for the treatment of psoriasis, of osteoporosis, of precanceroses and of tumours, as well as for the treatment of pathological or undesired immune reactions. The invention is also concerned with the use of 9-cis- or 13-cis-retinoic acid or acitretin, or io pharmaceutical^ usable salts or esters thereof and a vitamin D derivative in the manufacture of pharmaceutical preparations for the treatment of the aforementioned diseases and anomalies. Examples of pharmaceutical^ usable salts of 9-cis- or 13-cis-retinoic acid or acitretin are alkali salts such as the Na and K salt, alkaline earth metal salts such as the Ca and Mg salt; as well as the ammonium salt and alkylammonium salts. Examples of esters are lower-alkyl esters such as the methyl and ethyl ester such as etretinate, and aromatic esters such as the benzyl ester. 20 Examples of vitamin D derivatives which can be used in accordance with the invention are hydroxylated vitamin D3 derivatives such as 1 a-hydroxy-vitamin D3, la,25-dihydroxy-vitamin D3 (calcitriol), 1a,25,26-trihydroxy-vitamin D3, la,23,25-trihydroxy-vitamin D3, 24-fluoro-1 a,25-dihydroxy-vitamin D3, 25 24,24-difluoro-la,25-dihydroxy-vitamin D3, 26,26,26-trifluoro-1 a,25-dihydroxy-vitamin D3, 26,26,26,27,27,27-hexafluoro-la,25-dihydroxy-vitamin D3; 1 a,25-dihydroxy-22,23-dehydro-vitamin D3, 26,26,26-trisdeutero-22,23-dehydro-la,25-dihydroxy-vitamin D3, 26,26,26,27,27,27-hexakisdeutero-22,23-dehydro-la,25-dihydroxy- 30 'L k / • ■'& - 2 vitamin D3, 26,26,26-trifluoro-1 a,25-dihydroxy-22,23-dehydro-vitamin D3, 26,26,26,27,27,27-hexafluoro-1a,25-dihydroxy-22,23-dehydro-vitamin D3, 26,26,26,27,27,27-hexafluoro-1 a,25-dihydroxy-23,24-dehydro-vitamin D3, 1a,25-dihydroxy-vitamin D2, 5 26,26,26,27,27,27-hexakisdeutero-1 a,25-vitamin D2, la,25- dihydroxy-27-nor-vitamin D2, 1a,25,26-trihydroxy-22,23-dehydro-vitamin D3, 1a,25,26-trihydroxy-vitamin D2, 1a,25-dihydroxy-23,24-didehydro-vitamin D3, 1a,25-dihydroxy-16,17-dehydro-vitamin D3, 1 a,25-dihydroxy-16,1 7;23,24-bisdehydro-vitamin D3, 10 1 a,25-dihydroxy-1 6,1 7-dehydro-23,24-didehydro-vitamin D3, 26,26,26,27,27,27-hexafluoro-1 a,25-dihydroxy-16,17-dehydro-23,24-didehydro-vitamin D3, 1a,26,26,26,27,27,27-heptafluoro-25-hydroxy-23,24-didehydro-vitamin D3, 1a,25-dihydroxy-3-deoxy-23,24-didehydro-vitamin D3 and 25-hydroxy-23,24-didehydro-15 vitamin D2. The aforementioned vitamin D derivatives and their preparation are known, see, e.g., the US patent specifications 3 993 675, 4 022 768, 4 407 754, 4 421 690, 4 594 432, 20 4 594 346,4 612 308,4 613 594,4 652 405,4 749 710, 4 804 502,4 898 855,4 906 785,4 929 609,5 087 619 and 5 120 722. 26,26,26,27,27,27-Hexafluoro-l a,25-dihydroxy-16,17-25 dehydro-23,24-didehydro vitamin D3 has not yet been described and can be obtained as follows: A. To 522 mg of [3aS-[3(S*),3aa,7a,7ap]]-[[3a,4,5,6,7,7a-hexahydro-3a-methyl-3-(1 -methyl-3-butynyl)-1 H-inden-7-30 yl]oxy]trimethylsilane in 15 ml of anhydrous tetrahydrofuran, 1.85 ml of 1.6M solution of n-butyllithium in hexane was added dropwise after cooling at -75°C over 5 minutes and the mixture was stirred at -75°C for 30 min. Then a stream of hexafluoroacetone was bubbled into the mixture for 15 min with temperature maintained at 35 -75°C. The reaction mixture was stirred for one additional hour, and then quenched with 1:1 mixture of 2M KHCO3 and 1M Rochelle salt added dropwise. The mixture was stirred at room temperature for one hour and then diluted with 25 ml of the same salt solution. After n I - - 3 - extraction with CH2CI2, the organic phase was washed with 50 ml of the same salt solution, dried and evaporated. The residue was azeotroped with benzene to give 2.38 g of crude oily product. Purification was performed by flash chromatography (EtOAc-hexane 5 1:9) to give 817 mg of [3aS-[3(S*),3[3aa,7a,7ap]]-1,1,1-trifluoro-6[3a,4,5,6,7,7a-hexahydro-3a-methyl-7-[(trimethylsilyl)oxy]-l H-inden-3-yl]-2-(trifluoro-methyl)-3-heptyn-2-ol. B. To a solution of 812 mg of [3aS-[3(S*),3aa,7a,7ap]]-1,1,1-10 trifluoro-6[3a,4,5,6,7,7a-hexahydro-3a-methyl-7-[(trimethylsilyl)-oxy]-1 H-inden-3-yl]-2-(trifluoromethyl)-3-heptin-2-ol in 18 ml of anhydrous tetrahydrofuran there was added 5.34 ml of tetra-butyl-ammonium fluoride in tetrahydrofuran, and the mixture was stirred at room temperature under argon for 80 min. The reaction was then 15 quenched by addition of 9 ml of half-saturated NaHC03 and stirred at room temperature for an additional 20 min. Excess of tetrahydrofuran was removed by evaporation and additional 9 ml of bicarbonate was added. The mixture was extracted with ethyl acetate, the extract was washed with brine, dried and evaporated. After 20 purification by flash chromatography (EtOAc-hexane 1:2), it gave 690 mg of [3aR-[l (R*),3aa,4p,7ap]]-3,3a,5,6,7,7a-hexahydro-7a-methyl-1 -[6,6,6-trifluoro-5-hydroxy-l -methyl-5-(trifluoro-methyl)-3-hexynyl]-4H-inden-4-ol. 25 C. To a solution of 100 mg of [3aR,-[l (R*),3aa,4p,7ap]]- 3,3a,5,6,7,7a-hexahydro-7a-methyl-1 -[6,6,6-trifluoro-5-hydroxy-1-methyl-5-(trifluoromethyl)-3-hexynyl]-4H-inden-4-ol in 6 ml of anhydrous CH2CI2 there was added at room temperature, 176 mg of pyridinium chlorochromate, and the mixture was stirred at room 30 temperature for 50 min under argon. To this mixture there was added 9 ml of ether under stirring, then it was filtered and the filtrate evaporated to dryness. The crude product thus obtained was purified by chromatography on silicagel column with ethyl acetate-hexane 1:3 to give [3aR-[1 (R*),3acc,7ap]]-3,3a,5,6,7,7a-hexahydro-7a-35 methyl-1 -[6,6,6-trifluoro-5-hydroxy-1 -methyl-5-(trifluoro-methyl)-3-hexinyl]-4H-inden-4-one. D. To a solution of 333 mg of [3S-(3a,5p,Z)]-2-[2-[2-methylene-3,5-bis[[(1,1 -dimethylethyl)dimethylsilyl]oxy]cyclohexylidene]-ethyl]diphenyl phosphine oxide in 7 ml anhydrous tetrahydrofuran there was added at -75°C, 0.325 ml of 1.6M n-butyllithium in hexane 5 under argon. After stirring for 6 min, a solution of 73 mg of [3aR-[1(R*),3aa,7a(S]]-3,3a,5,6,7,7a-hexahydro-7a-methyl-1-[6,6,6-trifluoro-5-hydroxy-l -methyl-5-(trifluoromethyl)-3-hexiny]-4H-inden-4-one in 5 ml anhydrous tetrahydrofuran was added dropwise. The reaction mixture was stirred for 1 hour at -75°C, and then 10 quenched with 2.6 ml of 1:1 mixture of 2N Rochelle salt and 2N KHCO3 solutions and was allowed to warm to room temperature. It was then diluted with 10 ml of the same salt solution and extracted with ethyl acetate. The extract was washed with brine, dried and evaporated. The crude intermediate was purified by flash chromato-15 graphy on silica gel column with ethyl acetate-hexane 1:5 to give disilyl-protected 1,25-dihydroxy-16-ene-23-yne-26,27-hexafluoro-cholecalciferol. E. To 92 mg of the disilyl protected 1,25-dihydroxy-l 6-ene-23-20 yne-26,27-hexafluoro-cholecalciferol in 5 ml anhydrous tetrahydrofuran in a dark wall flask there was added 0.89 ml of 1M tetrabutyl-ammonium fluoride in tetrahydrofuran, and the mixture was stirred for 16 hrs under argon. The reaction was then quenched with 3 ml of half-saturated NaHC03 and stirred at room temperature. It was then 25 extracted with ethyl acetate. The extract was washed with half-saturated NaHC03 and brine, then dried and evaporated. The crude product was purified by flash chromatography with ethyl-acetate 4:1, to give 1,25-dihydroxy-l 6-ene-23-yne-26,27-hexafluoro-cholecalciferol as a foamy glass; [a]zD5 = +59.1° (c 0.11, CH3OH). 30 In accordance with the invention the 9-cis- or 13-cis-retinoic acid or acitretin or a salt or ester thereof can be used in the form of pharmaceutical preparations which also contain a vitamin D derivative or as preparations which contain an ad hoc combination 35 with vitamin D derivatives. The use of 9-cis-retinoic acid, pharmaceutical^ usable salts or esters thereof and vitamin D derivatives, especially 9-cis-retinoic acid and calciferol is preferred. 5 The active substances can be administered topically or orally for the treatment of psoriasis. Topical preparations can be present as creams, ointments, lotions, tinctures or gels which contain the active substances together with carriers which are usual in such preparations. The content of 9-cis- or 13-cis-retinoic acid or 10 acitretin, salts or esters thereof in these preparations can be about 0.001-0.1 wt.%, preferably 0.003-0.03 wt.%. The content of vitamin D derivative in such preparations can be about 1 \ig/g to about 100 n.g/g. These preparations are applied to the diseased site on the skin according to the requirements of the patient, e.g. once or is twice per day. Preparations for oral administration can be present in the form of tablets, capsules, solutions or emulsions. For the treatment of psoriasis, such preparations can be administered in dosages of 20 about 0.01 mg to about 3 mg of 9-cis-or 13-cis-retinoic acid or acitretin or salt or ester thereof per kg body weight per day, preferably about 0.025 mg/kg to about 1.5 mg/kg per day; and about 0.001 tig/kg to about 0.1 ng/kg of vitamin D derivative, preferably about 0.005 ng/kg to about 0.05 ng/kg, per day. Solid dosage forms 25 such as tablets and capsules conveniently contain per dosage unit about 1 mg to about 50 mg of 9-cis- or 13-cis-retinoic acid or acitretin and, respectively, about 0.1 ng to about 1 jj.g of vitamin D derivative. 30 For the treatment and prevention of tumours, the active substances or the preparations in accordance with the invention can be administered enterally, parenterally or topically. Examples of tumours which can be treated with the preparations in accordance with the invention or the active substance combination in 35 accordance with the invention are haematological tumours such as leukaemia, especially acute promyelocytaric leukaemia and lymphomas. Furthermore precancerous lesions of the epithelial tissue such as actinic keratoses of the skin, oral leukoplakias, - 6 - dysplasias of the larynx, bronchi and cervix; as well as carcinomas of the skin, buccal cavity, the bronchi, the larynx, pharynx, stomach, colon, uterus, pancreas, the bladder, breast and prostate can be treated by the administration of an effective amount of the 5 preparations or active substance combination in accordance with the invention. Examples of pathological or undesired immune reactions are autoimmune diseases such as rheumatoid arthritis, multiple 10 sclerosis, insulin-dependent diabetes, lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, myasthenia gravis, ankylosing spondylitis, autoimmune diseases of the thyroid gland such as Hashimoto's disease and primary thyroid gland failure; scleroderma, uveitis, Behcet's disease, Crohn's disease, auto-15 immune-conditioned myocarditis and autoimmune-conditioned polyglandular syndrome; as well as allergies such as allergic rhinitis, atopic dermatitis, asthma and celiaca. Other indications are undesired immune reactions in organ or cell transplants such as kidney, heart, pancreas beta-islet cell, bone marrow and liver 20 transplants. A further aspect of the invention is concerned with the use of the preparations and, respectively, active substance combination in accordance with the invention for the preferably enteral or 25 parenteral treatment and prevention of osteoporosis. In all of these indications the active substances can be used in the dosage ranges given above, whereby the individual dosage will depend on the nature of the disease to be treated and on the age and condition of the patient and can be determined within the framework of medical 30 expertise. The invention is illustrated in more detail by the following Examples. Example 1 Capsules containing 9-cis-retinoic acid 9-cis-Retinoic acid 20.0 mg Gelatine (Bloom number 30) 70.0 mg Maltodextrin 108.0mg dl-a-Tocopherol 2.0 mg Na ascorbate 10.0 mg Microcrystalline cellulose 48.0 mg Mg stearate 2.0 mg Total 260 mg The active substance is wet-ground in a solution of gelatine, maltodextrin, tocopherol and Na ascorbate and the suspension obtained is spray-dried. Thereafter, the cellulose and the Mg stearate are admixed and 260 mg aliquots of the mixture are filled into hard gelatine capsules. Example 2 Capsules containing calcitriol Calcitriol Butylated hydroxytoluene Buylated hydroxyanisole Fractionated coconut oil 0.25 ^ig 0.016 mg 0.016 mg ad 160.0 mg The ingredients are mixed and the oily solution is filled under an inert gas into soft gelatine capsules each containing 160 mg. Example 3 Capsules containing 9-cis-retinoic acid and calcitriol Calcitriol 0.25 \ig 9-cis-Retinoic acid 20 mg Polyethylene glycol 400 200 mg Butylated hydroxyanisole 0.1 mg The ingredients are mixed and filled under an inert gas into soft gelatine capsules having a fill weight of 220 mg. Example 4 Cream containing 9-cis-retinoic acid and calcitriol Calcitriol 2 mg 9-cis-Retinoic acid 30 mg Cetyl alcohol 1.5 mg Stearyl alcohol 2.5 mg Sorbitan monostearate 2.0 mg Glyceryl monostearate and polyoxyethylene glycolstearate 4.0 mg Polysorbate 60 1.0 mg Mineral oil 4.0 mg Propylene glycol 5.0 mg Propylparaben 0.05 mg Butylated hydroxyanisole 0.05 mg Sorbitol solution 2.0 mg Na EDTA 0.01 mg Methylparaben 0.18 mg Dist. water q.s. ad 100 g Example 5 The activity of the combination in accordance with the invention of 9-cis-retinoic acid and calcitriol on the differentiation of human promyelocytic leukaemia cells (HL-60) can be 10 15 30 247630 {) ^ A.' y x - li" tf \(* "9" » ^ ... " ' / X~"' - C". ,r-T> /' demonstrated in vitro in the test procedure describ^d-ih 'Cancer Research 45, 4244 (1985). The effects obtained with various concentrations of the active substances on cell differentiation (measured by detecting the reduction effect on nitroblue-tetra-zolium, NBT) can be concluded from Figure 1. The measurement of the NBT reduction was effected according to a modified method of Pick et al. in J. Reticul. Soc. 30, 581 (1981). In each case, 3*104 cells in 200 \i\ were incubated for 48 hours with the active substances. The cells were centrifuged off and treated with in each case 100 ^il of pre-warmed NBT solution (1 mg/ml, diluted with Dulbeccos PBS) and PMA (123 mg/ml in DMSO) and incubated at 37°C for 1 hour. After centrifugation, 100 nl of 90% DMF, diluted with 10% SDS, were added, the mixture was incubated at 37°C and the extinction (OD) was measured at 550 mm. The curves in Fig. 1 show the effect of calcitriol alone and of combinations of varying amounts of calcitriol with (from above downwards) 80 nM, 16 nM and 3.2 nM 9-cis-retinoic acid. With concentrations of from 10"11 to 10'9 the activity of calcitriol 20 alone (bottom curve) is almost unchanged while the activity of combinations with 9-cis retinoic acid increases markedly. If the effects of calcitriol and 9-cis retinoic acid were merely additive the 9-cis retinoic acid curves would parallel the calcitriol curve. Hence the curves in Fig. 1 provide evidence of synergism in the combinations in 25 accordance with the present invention. Example 6 Patients with multiple actinic keratoses were treated topically with 9-cis-retinoic acid and calcitriol. 9-cis-retinoic acid was applied as a 0.01% (v/v) solution in ethanol/propylene glycol (50:50). Calcitriol was applied as a 0.0025% (w/w) cream. Treatment was carried out for 4-16 weeks with administration of the preparations to the skin once daily. 9-cis-retinoic acid was applied first, followed, after drying (3 minutes), by calcitriol cream. Occlusive dressing was not used. The following results were obtained with various patient groups: - 10 - A. Patient group: 16 patients Duration of treatment: 4 weeks Result of treatment: 6 patients: slight improvement 5 5 patients: moderate improvement 5 patients: marked improvement B. Patient group: 16 patients Duration of treatment: 8 weeks 10 Result of treatment: 3 patients: slight improvement 4 patients: moderate improvement 9 patients: marked improvement 15 C. Patient group: 7 patients Duration of treatment: 12 weeks Result of treatment: in all 7 patients: marked improvement 20 D. Patient group: 3 patients Duration of treatment: 16 weeks Result of treatment: in all 3 patients: marked improvement 25 In all cases, slight erythema but no disturbing symptoms (burning, itching) developed. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 247630 - 11 - WHAT WE CLAIM IS:

1. A synergistic pharmaceutical preparation containing 9-cis- or 13-cis retinoic acid, or acitretin, or a pharmaceutically usable salt or ester thereof, and a vitamin D derivative as active ingredients, and one or more usual pharmaceutical carriers.

2. A preparation according to claim 1, wherein the active ingredients are 9-cis retinoic acid or a pharmaceutically usable salt or ester thereof and a vitamin D derivative.

3. A preparation according to claim 2, wherein the active ingredients are 9-cis retinoic acid and calcitriol.

4. A preparation according to claim 1, wherein the active ingredients are 13-cis retinoic acid or a pharmaceutically usable salt or ester thereof and a vitamin D derivative.

5. A preparation according to claim 4, wherein the active ingredients are 13-cis retinoic acid and calcitriol.

6. A preparation according to any one of claims 1 to 5 for use in the treatment of psoriasis, osteoporosis or tumours.

7. A preparation according to any one of claims 1 to 5 for use in the treatment of pathological or undesired immune reactions.

8. A preparation according to claim 1, substantially as hereinbefore described with particular reference to either of the foregoing Examples 3 and 4. DATED THIS ^ DAY OF A. J. PARK & SON AGENTS FOR THF APPl ?OANTS </div>