PL174902B1 - Novel compounds of witting-horner reagent type - Google Patents

Abstract

The new compounds of the Wittig-Horner reaction substance with the general formula 1, where R1 and R2 substituents refer to an atom of hydrogen or a methyl group, Z refers to an atom of hydrogen or a hydroxyl group, possibly protected, R9 refers to an atom of hydrogen or a protecting hydroxyl group.

Description

The subject of the invention are new compounds of the Wittig-Horner reagent type, used as intermediates in the synthesis of new pharmacologically active compounds from the group of vitamins D.

It is generally known that vitamin D compounds and vitamin D analogues have a strong biological activity and can be used in therapy in all cases where problems with calcium metabolism may play a role. Several years ago, it was found that various compounds with vitamin D activity also have other pharmacological activities and can be successfully used, for example, in the treatment of certain skin and bone diseases, in cosmetic preparations and in the treatment of diseases related to cell differentiation, cell proliferation or disorders Immune system balance, including the treatment of diabetes, high blood pressure and inflammatory diseases such as rheumatoid arthritis! asthma. In addition, these compounds may find various veterinary applications.

It is important to have a number of different compounds available with vitamin D activity for different uses, so that the best choice of drug in a given case can be made. For this purpose, recently research has been carried out on a number of compounds with vitamin D activity. However, in general, the results of these works are not entirely satisfactory with regard to the selectivity of these compounds, i.e. showing the intended pharmacological activity without deleterious side effects.

The aim of the invention is to obtain new compounds which are intermediates in the synthesis of vitamin D derivatives.

From the letter (J. Org. Chem. 51, 3090 (1986)) there are known compounds which are a reagent of the Wittig-Horner type and can be used in the enolization of the carbonyl group of ketones. The preparation of this type of reagents is based on the transformation cycle of the starting monocyclic or aliphatic natural compounds.

The subject of the invention are new compounds of the Wittig-Horner reagent type of the general formula I, in which the substituent Ri represents a hydrogen atom or a methyl group, R2 represents a methyl group, R9 represents a hydrogen atom or a protecting group, and Z represents a hydrogen atom or a hydroxyl group, optionally safe. The new compounds are obtained by dialkylating the corresponding carbonyl compounds or fragmenting the corresponding natural compounds.

Reagents Wittig-Horner type of this invention are useful in the synthesis of pharmacologically active compounds of the general formula 2, wherein the symbol == is a single or double carbon-carbon bond wherein R3-C ™, C ⁵ -C ⁶ and C ⁷ -C8 or C ¹⁰ -C ⁵ , C ⁶ -C 'and C-C9 bonds form a conjugated system of double bonds to which other double bonds optionally present in the molecule are coupled, the substituents Ri, R2, R4, R5 and R6 are independently each other a hydrogen atom or a methyl group, R3 represents a hydrogen atom or a methyl group if the R3-C1 bond is a single bond or a methylene group if the R3-C10 bond is a bond

174 902 double, R7 and Rs represent, independently of each other, a straight or branched alkyl group having from 1 to 4 carbon atoms or R7 and Rs taken together form a cycloaliphatic group having 3 to 5 carbon atoms, Z is a hydrogen atom or a group hydroxy, and n is an integer from 0 to 3.

The numbering of the carbon atoms in the molecule used above is as shown in general formula 2. Compounds of general formula 2 can exist as two isomers. First isomer are compounds of the general formula 2, wherein the symbol represents a single or double carbon-carbon bond having a conjugated double bond system ^{R3-C10, C5-C6} and C7-CS, which are coupled to the other double bonds optionally present in the molecule, and Ri, R2, R4, R5 and R6 are independently of each other a hydrogen atom or a methyl group, R3 is a methylene group, R7 and Rs are, independently of each other, a straight or branched alkyl group having from 1 to 4 carbon atoms or R7 and Rs taken together form a cycloaliphatic group having 3 to 5 carbon atoms, Z is hydrogen or hydroxy and n is an integer from 0 to 3 corresponding to the general formula 3.

The second isomer are compounds of the general formula 2, wherein the symbol == is a single or double carbon-carbon bond having a conjugated bond system C C5, ^C6 and C7 C8 ^C-9, which are different from conjugated double bonds, optionally present in the molecule, and the substituents Ri, R2, R4, R5 and R6 are independently of each other a hydrogen atom or a methyl group, the substituent R3 is a hydrogen atom or a methyl group, the substituents R7 and Rs are, independently of each other, a straight or branched alkyl group, having from 1 to 4 carbon atoms or R7 and Rs taken together form a cycloaliphatic group having 3 to 5 carbon atoms, Z is hydrogen or hydroxy and n is an integer from 0 to 3.

The compounds of formula II have chiral centers at positions 1 and 3 of formula 2, as well as at other positions of the aliphatic chain, and therefore may exist in the form of diastereoisomers differing in the configuration of these carbon atoms. All diastereoisomeric forms can be produced using the compounds of the present invention.

In terms of biological activity, the compounds according to the present invention are preferably used for the preparation of compounds of general formula II in which R1 and R2 are hydrogen, Z, R4, R5, R6, R7, Rs and n are as defined above, the configuration as shown in general formula 3.

The novel compounds of the invention represented by the general formula 1 are valuable intermediates and can be used for the preparation of promising biologically active compounds used in those cases where problems with calcium metabolism may play a role, in particular in the treatment of certain bone diseases such as osteoporosis, osteodystrophy. renal, osteomalacia, in the treatment of skin diseases such as psoriasis and other hyperproliferative skin diseases, eczema and dermatitis, and in the treatment of diseases related to cell differentiation, cell proliferation or imbalance of the immune system, such as myopathy, leukemia, breast and colon cancer. osteosarcomas, squamous cell carcinomas, melanoma, certain diseases of the immune system and in the prevention of transplant rejection, and in addition to wound healing, and as ingredients in cosmetic preparations such as creams, lotions, ointments and the like, with protective, conditioning and / or protects the skin and improves skin conditions such as wrinkles, dry skin, sagging skin and insufficient secretory activity of the sebaceous glands.

The invention is described in more detail below with examples which are illustrative and explanatory only and should not be construed as limiting the invention in any way.

Example 1 shows the preparation of a compound of formula 22 corresponding to the general formula 1 when R1, R2 and Z are hydrogen and R9 is

174,902 trimethylsilyl also illustrated in Scheme B. The compound of formula 22 is then used to prepare a compound of formula 24, corresponding to the general formula 2 when R1, R2, R4, R5 and Z are hydrogen, R3 is a methylene group, R6, R7 and Rs are methyl groups, n is equal to 1, bonds R3-C ^Yo , CC ⁶ and C7-C ⁸ form a conjugated double bond system, and the remaining symbols represent single bonds, also illustrated in scheme C.

Example II illustrates the preparation of a compound of formula 31, corresponding to general formula 1 when Ri and R2 are hydrogen, R9 is trimethylsilyl and Z is a trimethylsilyl protected hydroxy group also illustrated in Scheme D. The compound of formula 31 is then used for for the preparation of a compound of formula 33 corresponding to the general formula 2 when Ri, R2, Rt and R5 are hydrogen, R3 is a methylene group, R6, R7 and Rs are methyl groups, Z is a hydroxyl group, and n is equal to 1, the R3-Cl bond ^0, C5-C6 and ^C7 -Ć® form a system of conjugated double bonds, and the other symbols are single bonds, also illustrated in scheme E.

Scheme A illustrates the preparation of ketone derivatives as another intermediate in the synthesis of compounds of general formula 2 with the compounds of the invention.

The following abbreviations are used in the examples and figures:

THF - tetrahydrofuran

DMF - dimethylphannamide

DMAP - dimethylpyridma

TMS for trimethylsilyl

TBDMS - tributyl d ^^^ t ^^^ ylo ^ ilil

B114NF - tetrabutyioammonium fluoride ^/

Ph - phenyl

Example 1: {[(1Z), (5S)] - 2- [5- (t-butyldimethylsilyl) -rxy-2-methylenecyclohexylldene] ethyl} diphenylphosphine oxide (Formula 22)

I.1. (5Z, 7E) - (3R) -3,7,8-Trihydrrxy-9,10-sec-5,7,10 (19) -ergostatriene (Formula 18)

To a solution of 2 g of vitamin D2 (formula 17) in 200 ml of ethanol was added dropwise at -20 ° C a solution of 0.9 g of KMnO4 in 30 ml of water. The solution was stirred for 45 min. at -30 - -20 ° C, then -15- -17 ° for another 45 min and warmed to room temperature. The mixture was heated at 45 ° C for 10 min and filtered. After crystallization from a water-methanol mixture, 1.9 g of the title compound were obtained in a crystalline form, m.p. 178-180 ° C.

I.2 [(1Z), ^ S ^ -h, - ^ - hydroxy ^ -methylene cyclohexyndene butanol (formula 19)

Lead tetraacetate (6.3 g) was added in portions to a solution of the triol of formula 18 (5.7 g) in 50 ml of anhydrous benzene at 20 ° C. The solution was stirred under nitrogen at 20 ° C for 1.5 h. The mixture was filtered and concentrated. 40 ml of benzene was added and placed in an ice bath. 8.2 ml of a 65% Red-Al solution was added dropwise and stirred at room temperature for 1 h. Water was added, the mixture was filtered and evaporated to dryness. 300 ml of diethyl ether and 300 ml of hexane were added to the residue and extracted with water (7 x 5 ml). The aqueous layer was evaporated under reduced pressure and the product was crystallized from a methanol-ether mixture. 1.12 g of a crystalline product with mp. 96-99 ° C. Rf = 0.42 (ethyl acetate-hexane-methanol 2: 3: 1);

Ή-NMR (ppm) 5.50 (t, 1H), 4.99 (s, 1H), 4.63 (s, 1H), 4.23 (t, 2H), 3.95 (m, 1H) , 2.57-1.60 (m, 6H); ⁿ C-NMR (ppm) 147.8, 143.4, 127.1, 11, R, 72.0, 61.5, 47.2, 37.1, 34.5.

I.3. [(IZ), (5S)] 52- [5- (t-butylaminylsilyloyloxy-2-metalaocyclo-kexylidene-ethanol (formula 20)

To a solution of the diol of formula 19 (0.97 g) in 20 ml of pyridine was added, under nitrogen, 0.15 g of DMAP and 0.7 g of trimethylacetyl chloride. The solution was stirred at 0 ° C for an hour. After extraction with ether and filtration through silica gel, 1.26 g of product were obtained in the form of a colorless oil; Rf = 0.52, ethyl acetate, hexane 1: 1. The oil was dissolved in 30 ml of DMF, 1.43 g of imidazole and 3.2 g of t-butylrdimethylsilylvegr chloride were added. The solution was stirred under nitrogen at 60 ° C for 1 h. After extraction with diethyl ether and

174,902 chromatography gave 1.78 g of product as an oil; Rf = 0.45, hexane-ethyl acetate 20: 1. The oil was dissolved under nitrogen in 20 mL of anhydrous THF. The solution was cooled in an ice bath and 5 ml of a 1M solution of LiAlH4 in THF was added. The solution was stirred at 0 ° C for 2 h. The mixture was quenched with aq. NH 4 Cl and filtered. The solution was evaporated and filtered through silica gel to give 1.28 g of the compound of formula 20 as a colorless oil; Rf = 0.38, ethyl acetate-hexane 1: 3.

1.4. ((1Z), (5S)] - 2- [5- (t-Butyl dimethylsilyl) oxy-2-methylencyclohexylidene] -1chloroethane (formula 21)

To a solution of N-chloro succinimide (85 mg) in 2 ml of CH 2 Cl 2 was added 47 mg of methyl sulfide under nitrogen. The solution was cooled to -20 ° C and 34 mg of alcohol of formula 20 was added. The solution was stirred at 0 ° C for 0.5 h and poured onto ice brine. After extraction with ether and chromatography, 29.7 mg of product were obtained in the form of a colorless oil; Rf = 0.67, ethyl acetate-hexane 1:10.

1.5. {[(1Z), (5S)] - 2- [5- (t-butyldimethylsilyl) oxy-2-methylenecyclohexylldene] ethyl} diphenylphosphine oxide (formula 22)

To a solution of chloride of formula 21 (81 mg) in 3 ml of THF cooled in an ice bath, 1.2 ml of a 0.28 M solution of LiP (Ph) 2 in THF was added dropwise under nitrogen until a persistent red color appeared. Water was added and the solution was evaporated. The residue was dissolved in chloroform and shaken with 5% H 2 O 2 solution. After removal of the solvents and chromatography, 86.5 mg of product was obtained; Rf = 0.46, hexane: ethyl acetate 1: 1.

Example II. {[(1Z), (3S, 5S)] - 2- [3,5-Bis (t-butyldimethylsilyl) oxy-2-methylenecyclohexylidene] ethyl} diphenylphosphine oxide (formula 31)

IL1 (5Z, 7E) - (1S, 3R) -1,3,7,8-Tetrahydroxy-9,1C0seko-5,7, 'l () (19) -cholestatriene (formula 26)

To a solution of 500 mg of 1a-hydroxyvitamin D 3 (formula 25) in 10 ml of ethanol, cooled to -15 ° C, a solution of 600 mg of KMnO4 in 3.5 ml of water was added under argon so that the temperature of the reaction solution did not exceed -10 ° C . The solution was stirred for 2 h, the precipitate was centrifuged and the solvents were removed under reduced pressure. Chromatography on silica gel afforded 300 mg of the product (64%) as a solid white foam.

II. 2 (5Z, 7E) - (1S, 3R) -1,3-Bis [(tsbutyldimethylsilyl) oxy-7,8-dihydroxy-9.10ssek Os 5.7s10 (19) scholestatriene (Formula 27)

To a solution of 300 mg of tetrol of formula 26 in 2 ml of DMF was added, under argon, 306 mg of imidazole and a solution of 318 mg of ts-butyldimethylsilyl chloride. The solution was stirred under argon at room temperature for 1.5 h. Extraction with ethyl acetate and chromatography gave 340 mg of the product (74%) as solid white foam.

II. 3. [(1Z) - (3S, 5R)] - 2- [3,5-B [s (t-butyldimethylsilyl) oxyl-2-nytylene (7 -klohexylidene] ethanol (formula 28)

Lead tetraacetate (74 mg) was added to a solution of the diol of formula 27 (100 mg) in 4 ml of anhydrous benzene at 20 ° C. The solution was stirred under nitrogen at 20 ° C for 1.5 h. The mixture was filtered and placed in an ice bath. 154 mg of Li (t-BuO) 3AlH was added and stirred for 1h. After destroying the reaction mixture, extraction and chromatography gave the alcohol of Formula 28 as a colorless oil. The product was reacted without further purification.

II. 4. [(1Z.) - (3S, SR) -2- [3,5-Bίs (tsbut3ls) dime-yiosilyl-oxy-2-meSySenocycloheclic sylidene] -1-chloroethane (formula 30)

To a solution of N-chloro succinimide (74 mg) in CH2Cl2 was added 41 mg of methyl sulfide under nitrogen. The solution was cooled to -20 ° C and the alcohol of formula 28 prepared as described above was added. The solution was stirred at 0 ° C for 0.5 h and poured onto ice brine. Extraction with ether and chromatography gave 22 mg of product (35% based on diol of formula 29) as a colorless oil.

II. 5. {[(1Zj ^ S, 5S) -2-) 5,5 -bis (t-butyl-bmelylsilyl) oxy-2-methylenecyclohexylidene] ethyl} diphenylphosphine oxide (formula 31)

To a solution of the chloride of formula 30 (22 mg) in 0.5 ml of THF, cooled in an ice bath, 0.2 ml of a 0.28 M solution of LiP (Ph) 2 in THF was added dropwise under nitrogen until

174 902 of permanent red color. Water was added and the solution was evaporated. The residue was dissolved in chloroform and shaken with 5% H 2 O 2 solution. After evaporation and chromatography 19 mg of the product of formula 31 (70%) was obtained, which was then used for the synthesis of [(1Z), (3S, 5R)] - 12- [3,5-dihydroxy-2-methylenecyclohexylidene] -2.6- dimethyiododeca-10-en-2-ol of the formula 33, whose Rf = 0.66 (acetone-hexane 11: 9); HPLC Rv = 19 ml (12% propanol-2 in hexane); Amx = 250.2nm (CH3CN); EIMS m / z (relative intensity) 318 [M + -H2O, 12], 300 (13), 282 (14.4), 215 (8), 145 (67), 129 (100), 59 (32); LSIMS m / z 359 [M + Na] +; cal. for C21H34O2 (M-H2O) 318.2559 exper. 318.2558;

¹ H-NMR (ppm) 6.40 (q, 1H), 6.02 (d, J = 11 Hz, 1H), 5.73 (m, 1H), 5.31 (s, 1H), δ, 00 (s, 1H), 4.44 (t, 1H), 4.23 (m, 1H), 2.74-0.59 (env, 17H), 1.22 (s, 6H), 0.88 (d, J = 6 Hz, 3H).

174 902

pattern 1

HO 3 ₂ ¹

pattern 2 pattern 3

174 902

SCHEME A

Formula 13

Formula 14

Formula 15

Formula 1 6

Formula 18

Pattern 19

174 902

SCHEME C

Formula 16

Pattern 22

Pattern 23

Pattern 24

174 902

SCHEME D

Pattern 25 Pattern 26

Pattern 30

Pattern 31

174 902

SCHEME E

Pattern 32 Pattern 33

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Claims (1)

Patent claim New compounds of the Wittig-Horner reagent type of the general formula I, in which R1 and R2 represent a hydrogen atom or a methyl group, Z is a hydrogen atom or an optionally protected hydroxyl group, and R9 is a hydrogen atom or a hydroxyl protecting group.