WO1995019963A1

WO1995019963A1 - New pharmacotherapeutically active compounds

Info

Publication number: WO1995019963A1
Application number: PCT/NL1995/000031
Authority: WO
Inventors: Andrzej Kutner; Hong Zhao; Hanna Fitak; Michael CHODYN^´SKI; Sebastianus J. Halkes; Stephen R. Wilson; Jan-Paul Van Del Velde
Original assignee: Duphar International Research BV
Current assignee: Duphar International Research BV
Priority date: 1994-01-24
Filing date: 1995-01-23
Publication date: 1995-07-27
Anticipated expiration: 1996-07-24
Also published as: PL174912B1; PL302010A1

Abstract

The invention relates to a compound of general formula (I), wherein R1, R2, R4, R5 and R6 are each individually hydrogen atoms or methyl groups; R3 represents a methyl group or a methylene group; R7 and R8 are each individually straight or branched alkyl groups having 1 to 4 carbon atoms or cycloalkyl groups having 3 to 6 carbon atoms; Z is a hydrogen atom or a hydroxy group; n is an integer from 0 to 3; and the (a) bonds represent single or double carbon - carbon bonds; with the provisos: (1) that no cumulated double bonds are present in the molecule; (2) that either R3-C10, C5-C6 and C7-C8 or C10-C5, C6-C7 and C8-C9 form double bonds, with which optionally present additional double bonds are conjugated; and (3) that R3 represents a methyl group if R3-C10 is a single bond, and a methylene group if R3-C10 is a double bond. The invention also relates to a method of preparing this compound and to its use for the treament and/or prevention of certain disorders and diseases.

Description

New pharmacotherapeuticallv active compounds

The invention relates to new pharmacotherapeutically active compounds, to a method of preparing these compounds and to their use in pharmacology.

It is generally known, that vitamin D compounds or vitamin D related compounds have a strong biological activity and may be used in all those cases in which problems with the calcium metabolism play a part. A few years ago it was found that various active vitamin D compounds also have other pharmacotherapeutic activities and may be used successfully, for example, for the treatment of certain skin and bone diseases, for cosmetic applications and for treating diseases which are related to cell differentiation, cell proliferation or .imbalance in the immune system, including diabetes mellitus, hypertension and inflammatory diseases such as rheumatoid arthritis and asthma. In addition, these compounds may be used in various veterinary applications.

It is of importance to have the disposal of a variety of compounds having vitamin D - like activity for the above various application fields, so as to be able to make the best possible choice for the application in view. Rather recently a number of vitamin D compounds have been taken into development for this purpose. Generally, however, such modified vitamin D compounds are still not completely satisfactory as regards their selective activity, i.e. the intended activity without detrimental side-effects.

It is therefore the objective of the present invention to provide new pharmacotherapeutically active compounds, in particular compounds having a vitamin D - like activity.

According to the present invention this objective can be achieved with new compounds which are characterized by the general formula

wherein:

R_1# R₂, R₄, R₅ and R₆ are each individually hydrogen atoms or methyl groups;

R₃ represents a methyl group or a methylene group;

R₇ and R_β are each individually straight or branched alkyl groups having 1 to 4 carbon atoms or cycloalkyl groups having 3 to 6 carbon atoms;

Z is a hydrogen atom or a hydroxy group;

II is an integer from 0 to 3; and the C C bonds represent single or double carbon - carbon bonds; with the provisos:

(1) that no cumulated double bonds are present in the molecule;

(2) that either R₃-C₁₀, C₅-C₆ and C₇-C₈ or C₁₀-C₅, C₆-C₇ and C₈-C₉ form double bonds, with which optionally present additional double bonds are conjugated; and

(3) that R₃ represents a methyl group if R₃-C₁₀ is a single bond, and a methylene group if R₃-C₁₀ is a double bond.

The above new compounds of the invention, presented by the general formula I, are valuable substances. The compounds are promising biologically active substances and may be used in all above-mentioned pharmacotherapeutic indications, more in particular for the treatment of osteoporosis, renal osteodystrophy, osteomalacia, skin disorders such as psoriasis (and other hyperproliterative skin diseases) , eczema and dermatitis, myopathy, leukemia, breast and colon cancer, osteosarco as, squamous cell carcinomas, melanoma, certain immunological disorders, and transplant rejections.

Furthermore, the new compounds of the invention may be used for wound healing and may be incorporated in cosmetic compositions, such as creams, lotions, ointments and the like, in order to preserve, condition and/or protect the skin and to improve various skin conditions, such as wrinkles, dry skin, skin slackness and insufficient sebum secretion.

The above new compounds of formula I can occur in two isomers, which can be represented by the general formulas IA and IB below.

In view of their biological properties those compounds are preferred, which, according to the present invention, are characterized by the general formula

wherein the symbols have the meanings given above. Suitable examples of groups R₇ and R₈ are methyl, ethyl, n-propyl, isopropyl and cyclopropyl.

The invention also relates to a method of preparing a compound of the above formula I as defined above, in that a ketone of the general formula

wherein

R₄, R₅, R₆, R₇, R₈ and β have the meanings given above, and

R₉ is a hydroxy-protecting group; is converted, in a manner known per se for related compounds, either (a) with a ittig reagent of the general formula

or (b) , after enolization, with an enyne compound of the general formula

wherein R-, R₂ and Z have the meanings given above, followed by hydrogenation; after which the hydroxy groups are deprotected.

The above reaction (a) produces compounds of the above general formula reaction. In order to protect hydroxy groups in the form of an ether, in principle any etherification agent known for this purpose is suitable: for example, a trialkylsilylimidazole, a trialkylsilylhalide, a tri- alkylsilyltriflate (-trifluoromethanesulfonate) , a diphenylalkylsilyl- halide, methoxymethylchloride or a diphenylalkylsilyltriflate, or a derivative thereof, the alkyl groups of which have 1 to 6 carbon atoms.

Particularly suitable for this purpose are trimethylsilylchloride, tert.-butyldimethylsilylchloride, dimethyl-(1,1,2-trimethylpropyl)- silylchloride, tert.-butyldimethylsilyl triflate, or trimethylsilyl- imidazole, because these etherification agents readily react with the hydroxy group to be protected to form an ether function, which on the one hand is sufficiently stable under the conditions of the reaction or reactions in view, but on the other hand can easily be removed [deprotection] to recover the original hydroxy group; tert.-butyldime- thylsilylchloride or triflate is to be preferred, because these groups have been found to be excellently suitable as a protective group.

The enolic hydroxy group of enolized compound III is preferably derivatized by a reaction with N-phenyltriflimide to produce a triflate.

The starting ketones of formula III can conveniently be prepared from readily available substances. For example, a ketone of formula III, wherein R₄ and R_j are hydrogen atoms, R₆, R₇ and Rg are methyl groups, n is 1, and the C : C bonds are single bonds, can be prepared as indicated in appended Reaction Scheme A. The reaction conditions will be clear from the Examples.

A Wittig reagent of the general formula IV, wherein R₁ and R₂ are hydrogen atoms, can be prepared in a manner known per se, e.g. as indicated in appended Reaction Scheme B. The coupling of the ketone obtained with this Wittig reagent is indicated in appended Reaction Scheme C; the reaction conditions are also illustrated in the Examples. Alternatively, after conversion of ketone III with N-phenyltriflimide to a triflate, this triflate can be reacted with an enyne compound of the general formula V, well-known in the art, as indicated under (b) above. This reaction can be performed in a corresponding manner as known for related compounds and produces, after hydrogenation, a compound of the structure presented by the above formula IB.

To improve the applicability of the new compounds of the invention for the above-described pharmacotherapeutic indications, the compounds are usually processed to pharmaceutical compositions, comprising an effective amount of said compound as the active ingredient in addition to a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance. Such a composition may be delivered in a dosage unit form for oral, topical (dermal) or parenteral administration.

A cosmetical composition may comprise, in addition to an effective amount of the new compound of the present invention, a cosmetically acceptable, non-toxic carrier and/or at least one auxiliary substance.

Finally the invention relates to a method for the treatment and prophylaxis of a number of disease states including autoiummune diseases (including diabetes mellitus), acne, alopecia, skin aging (including photo-aging), imbalance in the immune system, inflammatory diseases such as rheumatoid arthritis and asthma, as well as diseases related to abnormal cell differentiation and/or proliferation, in a warm-blooded living being, comprising administering to said being or treating said being with a pharmaceutical composition as defined above in a quantity effective for the intended purpose. Examples of such diseases are psoriasis and other hyperproliferative skin diseases. The present invention also relates to the use of the above pharmaceutical compositions for the treatment of solid, skin and blood cancers, in particular of blood cancers such as leukemia, of breast cancer, and of skin cancers such as melanoma and squamous cell carcinoma. The above-defined cosmetical compositions, in particular selected from the group consisting of creams, lotions, ointments, liposomes and gels, can be used for the treatment and prevention of a number of skin disorders, such as inadequate skin firmness or texture, insufficient skin hydration, wrinkles and insufficient sebum secretion.

The invention will now be described in greater detail with reference to the following specific Examples. Examples

Example I Preparation of (5RΪ-5.9-dimethyl-9-f (trimethylsilyl)oxyl-decanal 11. The reaction equations are presented in the Reaction Scheme A appended.

(a). Preparation of compound 5.

Imidazole (326 mg) and t-butyldimethylsilyl chloride (725 mg) are added to a solution of 0.5 g of (S)-(-)-β-citronellol (1) in 15 ml of CH₂C1₂ and 15 ml of DMF. The mixture is stirred overnight at 60°C. Extraction and chromatography gives 834 mg of silyl ether (2) as a colorless oil. This oil (3.5 g) is dissolved in 60 ml of CH_jCl-, and 1.5 g 3- chloroperbenzoic acid is added. The mixture is stirred at 0°C for 1.5 hours. Extraction gives 3.6 g of epoxide (3) as a colorless oil. This oil (0.6 g) is dissolved in 25 ml of THF and 25 ml of a IM solution of lithium triethylborohydride is added. The mixture is stirred at ambient temperature for 30 minutes. Extraction gives 3.2 g of alcohol (4) as a colorless oil. To the solution of this oil (0.2 g) in 2 ml of THF, 1.3 ml of a IM solution of tetrabutylammonium fluoride is added. The mixture is stirred at room temperature for 40 minutes. Extraction yields 119 mg of diol (5) as a colorless oil. The product (5) (R_f=0.38 (EtOAc) ) is identified by ¹H-NMR and ¹³C-NMR.

¹H-NMR (δ): 3.66 (2H, t). 1.59-1.31 (9H, m) , 1.21 (6H, s), 0.91 (3H, d, J=6 Hz) . ¹³C-NMR (δ): 71.1, 61.1, 44.1, 39.9, 37.6, 29.5, 29.3, 29.2, 21.6, 19.7.

(b) . Preparation of compound 9.

Pyridinium chlorochromate (1.2 g) is added to a solution of 0.5 g of diol (5) in 50 ml of CH_jCl_j. The mixture is stirred at room temperature for 1 hour. Extraction gives 0.37 g of aldehyde (6) as a colorless oil. Ethoxycarbonylmethyltriphenylphosphine (1.3 g) is added to a solution of 374 mg of aldehyde (6) in 10 ml of THF. The mixture is stirred at 60°C for 1 hour. Extraction gives 487 mg of α,β-unsaturated ester (7) as a colorless oil. To the solution of 100 mg of (7) in 20 ml of methanol, 10% Pd/C is added and the mixture is treated with hydrogen at ambient temperature overnight. Isolation gives 81 mg of saturated ester (8). To a solution of 81 mg of (8) in 0.5 ml THF, 0.4 ml of a IM solution of LiAlH^ in THF is added. The mixture is stirred for 20 minutes at 0°C. Isolation gives 67 mg of diol (9) as a colorless oil. The product (9) (R_f=0.29 (EtOAc/hexane=2/l) ) is identified by ¹H-NMR and ¹³C-NMR. ¹H-NMR (δ): 3.59 (2H, t), 1.51-1.47 (13H, m) , 1.18 (6H, s), 0.85 (3H, d, J=6 Hz).

¹³C-NMR (δ): 70.9, 62.7, 44.1, 37.4, 36.7, 33.0, 32.6, 29.2, 29.1, 23.1, 21.6, 19.5.

(c) . Preparation of compound 11. To a solution of 67 mg of (9) in 6 ml CH₂C1₂, 55 mg of sodium acetate and

143 mg of pyridinium chlorochromate are added. The mixture is stirred at room temperature for 1 hour. Isolation gives 44 mg of aldehyde (10) as a colorless oil. This oil is dissolved in 4 ml of CH₂C1₂ and 0.8 mg of dimethylaminopyridine, 217 mg of triethylamine and 117 mg of trimethylsilyl chloride are added. The mixture is stirred at 0°C for 30 minutes. Isolation gives 44 mg of (11) as a colorless oil. The product (11) (R_f=0.44 (EtOAc/hexane=l/10) is identified by ¹H-NMR and ¹³C-NMR. ¹H-NMR (δ): 9.76 (1H, s), 2.41 (2H, t), 1.70-1.10 (?H, m) , ? , 0.89 (3H, d, J=6 Hz) . ¹³C-NMR (δ): 202.7, 73.9, 45.0, 44.1, 37.3, 36.6, 32.5, 29.8, 21.6, 19.6,

19.4, 2.6.

Example II Preparation of r f1Z .. f5S> 1-2-r i5-(t-butyldimethylsilyl>oxy-2- methylcvclohexylideneVethylldiphenylphosphine oxide 16 from compound 12. The reaction equations are presented in the Reaction Scheme B appended.

(a). Preparation of compound 13. A solution of 0.9 g of KMn0₄ in 30 ml of water is added dropwise to a solution of 2 g of Vitamin D₂ (12) in 200 ml of ethanol at -20°C. The mixture is stirred for 45 minutes at -30 to -20°C, and then for 45 minutes at -15 to -17°C, and warmed up to room temperature. Stirring is continued at 45°C for 10 minutes and the precipitate is filtered off. Crystallization from water-methanol gives 1.9 g of crystalline triol (13); m.p. 178-180°C. (b) . Preparation of compound 14.

Lead tetraacetate (6.3 g) is added in portions to a solution of triol (13) (5.7 g) in 50 ml of benzene at 20°C. The mixture is stirred under nitrogen at 20°C for 1.5 hours, filtered off and concentrated. Benzene (40 ml) is added and the reaction mixture is placed in an ice bath. A solution of Red-Al (65%, 8.2 ml) is added dropwise and the mixture is stirred at room temperture for 1 hour. Water is added, the mixture is filtered off and dried. Diethylether (300 ml) and 300 ml of hexane are added to the residue and the mixture is extracted with water (7 x 5 ml). The water phase is evaporated and the residue is crystallized from methanol-diethylether to give 1.12 g of crystalline diol (14). M.p. 96- 99°C; R_f=0.42 (EtOAC/hexane/methanol=2/3/l) . Identification by NMR. ¹H-NMR (δ): 5.50 (1H, t), 4.99 (1H, s), 4.63 (1H, s), 4.23 (2H, t), 3.95 (1H, m), 2.57 - 1.60 (6H, m) ; ¹³C-NMR (δ): 147.8, 143.4, 127.1, 114.8, 72.0, 61.5, 47.2, 37.1, 34.5.

(c) Preparation of compound 15.

Dimethylaminopyridine (0.15 g) and 0.7 g of trimethylacetyl chloride are added, under nitrogen, to a solution of diol (14) (0.97 g) in 20 ml of pyridine. The mixture is stirred at 0°C for 1 hour. Extraction with diethyl ether and filtration over silica gel give 1.26 g of a colourless oil. This oil is dissolved in 30 ml of DMF and 1.43 g of imidazole and 3.2 g of t-butyldimethyl-silyl chloride are added. The mixture is stirred under nitrogen at 60°C for 1 hour. Extraction and chromatography over silica gel give 1.78 g of an oil. This oil is dissolved, under nitrogen, in 20 ml of THF. The mixture is placed in an ice bath and 5 ml of an 1 M solution of LiAlH₄ in THF is added. The mixture is stirred at 0°C for 2 hours. Isolation and filtration over silica gel give 1.28 g of a colourless oil. Methyl sulfide (47 mg) is added, under nitrogen, to a solution of 85 mg of N-chlorosuccinimide in 2 ml of CH₂C1₂. The mixture is cooled down to 20°C and 34 mg of the above-prepared oil is added. The mixture is stirred at 0°C for 0.5 hour and diluted with ice brine. Extraction and chromatography over silica gel give 29.7 mg of the chloride (15) as a colourless oil. R^=0.67 (EtOAc/hexane=l/10) .

(d) . Preparation of compound 16.

A solution of LiPPh₂ in THF (0.28 M, 1.2 ml) is added dropwise, under nitrogen, to a solution of chloride (15) (81 mg) in 3 ml THF, cooled down in an ice bath, until a red colouration persists. The mixture is quenched with water and evaporated. The residue is dissolved in chloroform and shaken with 5% H₂0-,. Extraction and chromatography over silica gel give 86.5 mg of phosphine oxide (16). R_f=0.46 (EtOAc/hexane=l/l) .

In a corresponding manner as described above, compound (19) is prepared from lα-hydroxyvitamin D_j instead of vitamin D₂ (12).

Example III

Preparation of compounds 18 and 21.

The reaction equations are presented in Reaction Scheme C appended.

Preparation of [(1Z), (5R)]-12-[5-hydroxy-2-methylcyclohexylidβne]-2,6- diaethyl-10-dodenane-2-ol (18) .

A solution of n-BuLi (61 μl, 2.5 M??) is added to a solution of phosphine oxide (16) (75 mg) in 1 ml of THF, cooled down, under nitrogen, to -78°C. The mixture is stirred for 30 minutes. A solution of 8.2 mg of the aldehyde (11) in 0.5 ml THF is then added and the mixture is stirred at -78°C for 1 hour. Isolation and chromatography give 41 mg of the disilylated diol (17) as an oil. This oil is dissolved in 2 ml of THF, and 2 ml of an 1 M solution of n-Bu^NF is added. The mixture is stirred at 65°C for 1 hour. Isolation and chromatography give 27 mg of diol (18). HPLC: R_v=28 ml (2.9% 2-propanol in hexane); λ^ = 252.0 nm

(2.8% propanol-2 in hexane); EIMS m/z (relative intensity) 320 (M⁺, 0.24), 302 (7.3), 284 (10.9), 199 (5.9), 145 (22), 131 (100), 59 (32); calc. for C₂₁H₃₄0 (M-H₂0) 302.2609, obtd. 302.2608.

In a corresponding manner [(1Z), (3S,5R)]-12-[3,5-dihydroxy-2- methylcyclohexylidene]-2,6-dimethyl-10-dodenane-2-ol (21) is prepared, using aldehyde (11) and phosphine oxide (19) as starting materials. The intermediate protected triol (20) is obtained as a colourless oil and deprotected as described above. The title compound is identified as follows: R_f=0.66 (acetone/hexane=ll/9) ; HPLC R_y=19 ml (12% 2-propanol in hexane) ; k _mx ='253.2 nm (CH_jCN); EIMS m/z (relative intensity) 318 [M⁺-H₂0, 12], 300 (13), 282 (14.4), 215 (8), 145 (67), 129 (100), 59 (32); LSIMS m/z 359 [M+Na]⁺; calc. for C^H^O-, (M-H-,0) 318.2559, obtd.

318.2558;

¹H-NMR (δ): 6.40 (IH, q) , 6.02 (IH, d, J=llHz), 5.73 (IH, m) , 5.31 (IH, s), 5.00 (IH, s), 4.44 (IH, t), 4.23 (IH, m) , 2.74-0.59 (17H, env.),

1.22 (6H, s), 0.88 (3H, d, J=6Hz) .

Claims

1. A compound of the general formula

wherein :

Ri, R₂, R„, R₅ and R₆ are each individually hydrogen atoms or methyl groups;

R₃ represents a methyl group or a methylene group;

R₇ and R₈ are each individually straight or branched alkyl groups having 1 to 4 carbon atoms or cycloalkyl groups having 3 to 6 carbon atoms;

Z is a hydrogen atom or a hydroxy group;

(1) that no cumulated double bonds are present in the molecule;

(2) that either R₃-C₁₀, C₅-C₆ and C₇-C₈ or C₁₀-C₅, C₃-C₇ and C_e-C₉ form double bonds, with which optionally present additional double bonds are conjugated; and

2. A compound as claimed in claim 1, having the general formula

wherein the symbols have the meanings given in claim 1.

3. A method of preparing a compound of the general formula I as claimed in claim 1, characterized in that a ketone of the general formula

wherein

R₄, R₅, R₆, R₇, R_s and n have the meanings given in claim 1, and

R₉ is a hydroxy-protecting group; is converted, in a manner known per se for related compounds, either (a) with a Wittig reagent of the general formula

or (b) , after enolization, with an enyne compound of the general formula

wherein R., R₂ and Z have the meanings given in claim 1, followed by hydrogenatio ; after which the hydroxy groups are deprotected.

4. A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance, as the active ingredient at least one compound as defined in claim 1 or 2 in an effective amount.

5. A method for the treatment and/or prevention of a number of skin disorders or of a number of diseases, including autoimmune diseases, acne, alopecia, skin aging, imbalance in the immune system, inflammatory diseases such as rheumatoid arthritis and asthma, as well as diseases related to abnormal cell differentiation and/or proliferation, as well as solid, skin or blood cancers, in a warm-blooded living being, comprising administering to said being or treating said being with a composition as claimed in Claim 4 in a quantity effective for the intended purpose.