GB2114569A - Cholestenes for use in preparing cholecalciferol derivatives - Google Patents

Cholestenes for use in preparing cholecalciferol derivatives Download PDF

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GB2114569A
GB2114569A GB08304071A GB8304071A GB2114569A GB 2114569 A GB2114569 A GB 2114569A GB 08304071 A GB08304071 A GB 08304071A GB 8304071 A GB8304071 A GB 8304071A GB 2114569 A GB2114569 A GB 2114569A
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formula
compound
hydroxy
represent
alkyl
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GB8304071D0 (en
GB2114569B (en
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Richard Barner
Josef Hubscher
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Priority claimed from CH834679A external-priority patent/CH644100A5/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/24—Radicals substituted by singly bound oxygen or sulfur atoms esterified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/16—Radicals substituted by halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Steroid Compounds (AREA)

Abstract

The invention relates to cholestenes of formula VIII <IMAGE> and of formula IX <IMAGE> wherein R<1> and R<2> represent lower-alkyl or R<1> and R<2> together represent lower-alkylene or R and R' represent etherfied or esterfied hydroxy readily cleavable to hydroxy. The cholestene of formula IX is made by reacting a compound of formula X <IMAGE> in a Wittig reaction with a compound of the formula XI <IMAGE> wherein Ar represents an aryl group and R<1> and R<2> have the significance given above. The cholestenes are useful in preparing cholecalciferol derivatives.

Description

SPECIFICATION Cholestenesfor use in preparing cholecalciferol derivatives The present application is a divisional application derived from our copending application No.
8029544.
The invention which is the subject of our copending application is concerned with a novel vitamin D3 derivative, namely 1 a, 25,26- trihydroxycholecalciferol of the formula
That invention is also concerned with pharmaceutical preparations on the basis of the compound of formula I, a process for the manufacture of the compound of formula I, and intermediates occurring in said process.
The compound of formula I is manufactured by thermally isomerising the compound of the formula
This isomerisation can be carried out according to the method described in Steroids 24(1974) 463 for the isomerisation of 25,26 - dihydroxyprecholecalciferol to 25,26 - dihydroxycholecalciferol (e.g. in ethanol at reflux temperature).
The compound of formula II can be manufactured by irradiating the compound of the formula
according to the method described in Steroids 24 (1974) 463 for the irradiation of 3P, 25, 26 - trihydroxycholesta -5,7- diene to 25, 26 - dihydroxy precholecalciferol.
The compound of formula Ill can be manufactured by deketalising a compound of the formula
wherein R1 and R2 represent lower - alkyl or R1 and R2 together represent lower - alkylene, according to the method described in German Offenlegungsschrift 27 10 062 for the deketalisation of 24,25 ketals.
As used herein, the term "lower" refers to groups containing 1 to 6 carbon atoms. Examples of lower alkyl groups are methyl, ethyl, propyl and isopropyl.
Examples of lower - alkylene groups are ethylene and propylene.
The compounds of formula IV can be manufactured by reacting a compound of the formula
wherein R1 and R2 have the significance given earlier, R and R' represent etherified or esterified hydroxy readily cleavable to hydroxy and X represents phenyl optionally substituted by lower - alkyl or nitro, with an alkali metal hydride such as lithium hydride in a solvent, preferably a hydrocarbon such as toluene, at a temperature up to reflux temperature.
Ether groups which can be cleaved readily, i.e.
without affecting other positions of the molecule, are, for example, groups of the formula RXO C(RY,RZ)-O- in which Rv represents hydrogen or lower - alkyl, Rx and RZ represent lower - alkyl or RX and RZ together represent C6 - alkylene. Examples of such groups are tetrahydropyran - 2 - yloxy and methoxymethoxy. Examples of esterified hydroxy groups denoted by R and Rare formyloxy and C2 < alkanoyloxy groups such as acetoxy. Examples of groups denoted by X are phenyl, p - nitrophenyl and p - tolyl, preferably the latter.
The compounds of formula V can be manufactured by reacting a compound of the formula
with a compound of the formula H2N-NH-X VII wherein X, R, R', R1 and R2 have the significance given earlier, in a solvent such as methanol at a temperature up to reflux temperature.
The compound of formula VI can be manufactured by oxidising a compound of the formula
wherein R, R', R1 and R2 have the significance given earlier, for example, using chromium trioxide in the presence of 3,5 - dimethylpyrazole or pyridine in a solvent such as methylene chloride.
The compounds of formula VIII can be manufactured by hydrogenating a compound of the formula
wherein R, R', R1 and R2 have the significance given earlier, for example, using Raney - nickel under a hydrogen atmosphere in a solvent such as ethanol.
The compounds of formulae VIII and IX are novel and form part of the present invention.
The present invention is also concerned with a process for the manufacture of the compounds of formula IX.
This process of the present invention comprises reacting a compound of the formula
wherein R and R' have the significance given earlier, in a Wittig reaction with a compound of the formula
wherein Ar represents an aryl group and R' and R2 have the significance given earlier.
The reaction can be carried out under conditions which are known for Wittig reactions. Examples of solvents which can be used are ethers such as tetrahydrofuran, dioxan or diethyl ether or hydrocarbons such as toluene, and examples of bases which can be used are butyl lithium, sodium hydride, sodium amide or potassium tert. butylate.
Preferably, the ylid is manufactured at a low temperature (e.g. at -300C to -800C, especially -600C) in order to exclude the possibility of cleaving the i-steroid grouping.
The reaction of the ylid with a compound of formula Xis preferably also carried out at a low temperature (e.g. at-200Cto 0 C) in order to guarantee the preservation of the stereochemistry at C-20.
Examples of aryl groups denoted by Ar are phenyl optionally substituted by lower-alkyl or lower-alkoxy, preferably phenyl.
The compounds of formula Xl can be manufactured by reacting a compound of the formula
wherein R1 and R2 have the significance given earlier, with a triarylphosphine in an inert organic solvent while warming.
Since the compounds of formula Xl begin to be unstable at temperatures above 1 00 C, the reaction is conveniently carried out at a temperature up to 100"C in a solvent in which a sufficient reaction velocity is achieved at such a temperature. The preferred solvent is acetonitrile.
The compounds of formula XII can be manufactured by reacting a compound of the formula
wherein R3 represents lower-alkyl or phenyl optionally substituted by lower-alkyl or nitro and R and R2 have the significance given earlier, with an alkali metal iodide.
The reaction is conveniently carried out in a solvent such as acetone at a temperature of from room temperature up to reflux temperature, preferably at the latter.
The compounds of formula XIII can be manufactured by reacting a compound of the formula
wherein R1 and R2 have the significance given earlier, with a compound of the formula R3(S02)Z XV wherein R3 has the significance given earlier and Z represents chlorine, bromine or iodine.
The reaction is conveniently carried out in a solvent such as methylene chloride in the presence of a weak base such as pyridine at a temperature of O"C.
The C-atom in position 25 in the compounds of formulae I to Vl, Vlil and IX and the C-atom in position 4 in the compounds of formulae XI to XIV have the R- orthe S- configuration. In addition, the 22,23-double bond in a compound of formula IX can have the E- or the Z- configuration. The aforementioned compounds can, however, also exist in the form of mixtures of the Rand S-forms or of mixtures of the E- and Z- forms. R1 and R2 preferably represent methyl in the compounds of formulae IV to VI, VIII, IX and Xl to XIV, and Rand R' preferably represent acetoxy in the compounds of formulae V, VI, VIII and IX.
The compound of formula I has similar properties to other biologically active metabolites of vitamin D3 (e.g. 25,26 - dihydroxycholecalciferol) and can therefore, in principle, be adminstered in the same manner and dosage as the said metabolites; for example for regulating the calcium metabolism or calcium transport in the body. The compound of formula I should find use especially for the treatment of patients with kidney failure or kidney insufficiency.
The compound of formula I can be used as a medicament; for example, in the form of phrmaceutical preparations which contain it in association with a pharmaceutical, organic or inorganic inert carrier material which is suitable for enteral or parenteral administration such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols and petroleum jelly. The pharmaceutical preparations can be made up in solid form (e.g. as tablets, dragées, suppositories or capsules) or in a liquid form (e.g. as solutions, suspensions or emulsions). The pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preserving, stabilising, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They can also contain still other therapeutically valuable substances.
The following Examples illustrate the process of the present invention and the use of the compounds ofthe present invention in preparing a compound of the formula Example I 2.303 g of (R,S) - [2 - (2,2,4 - trimethyl - 1,3 dioxolan - 4 - yl) - ethyl] - triphenylphosphonium iodide were mixed with 10 ml of tetrahydrofuran under argon. 2.5 ml of butyl lithium as a 2 molar solution in hexane were added dropwise at-78 C and the mixture was stirred for 1.5 hours. To the resulting solution there were added dropwise at -60 C 1.10 g of a solution of (20S) - 1 a,3ss - diacetoxy - 20 - formyl - pregn - 5 - ene in tetrahydrofuran. After 30 minutes, the mixture was left to stand at room temperature and stirred overnight.Then, water was added and the mixture was extracted with ether.
After drying, concentration and chromatography on 100 g of silica gel with hexane / ether ethyl acetate (4:4:1), there were obtained 0.69 g (47%) of 1 a,25(R,S),26 - trihydroxy -22 - dehydrocholesterol 25,26 - acetonide - 1,3 - diacetate.
The aforementioned phosphonium iodide can be manufactured as follows: 4.38 g of 2 - methyibutane - 1,2,4 - triol - 1,2 acetonide and 5.50 g of tosyl chloride were dissolved in 10 ml of methylene chloride. 4 ml of pyridine were added dropwise at 0 C and the mixture was then left to stand at 0'for 1 hour and at room temperature for 1 hour. After the addition of 100 g of ice and then of 100 ml of 1 N sulphuric acid, the mixture was extracted with methylene chloride. After drying and concentration, there were obtained 6.5 g (97%) of 4 (2 -tosyloxyethyl - 2,2,4 - trimethyl - 1,3 - dioxolane.
6.5 g of 4 - (2 - tosyloxyethyl) - 2,2,4 - trimethyl - 1,3 - dioxolane were heated at reflux temperature for 1 hour with 50 g of sodium iodide and 500 ml of acetone, then concentrated, suspended in 100 ml of toluene and filtered. The toluene solution was washed with sodium thiosulphate solution, dried and concentrated. There were obtained 6.0 g (97%) of 4 - (2 - iodoethyl) - 2,2,4 - trimethyl - 1,3 dioxolane.
6.0 g of 4 - (2 - iodoethyl) - 2,2,4 - trimethyl - 1,3 dioxolane and 10 g oftriphenylphosphinewere dissolved in 200 ml of acetonitrile and heated at reflux temperature for 70 hours. The yellow solution was concentrated, mixed with ether, left to stand, then washed with ether and dried in a high vacuum.
There were obtained 10.6 g (91%) of (R,S) - [2 - (2,2,4 - trimethyl - 1,3 - dioxolan - 4 - yl) - ethyl] triphenylphosphonium iodide in the form of hygroscopic crystals of melting point 49"-50"C.
Example 2 0.94 g of (R,S) - 12,2,4 - trimethyl - 1,3 - dioxolan - 4 - yl) - ethyl] - triphenylphosphonium iodide were dissolved in 10 ml of tetrahydrofuran under argon.
2.5 ml of butyl lithium (2 molar in hexane) were added dropwise at-30 C. The mixture was stirred for 2 hours. A solution of 0.40 g of (20S) - 1 a, 3ss diacetoxy - 20 -formyl - pregn - 5 - ene in 1 ml of tetrahydrofuran at the same temperature as before.
The mixture was stirred at room temperature overnight. After working-up in a manner analogous to that described in Example 1, there were obtained 321 mg (78%) of 1 a, 25(R,S), 26 - trihydroxy 22- dehydrocholesterol - 25, 26 - acetonide - 1,3 - diacetate.
Example 3 61 mg of la, 25 (R,S), 26 -trihydroxy - 22 dehydrocholesterol - 25,26 - acetonide - 1,3 - diacetate were dissolved in 10 ml of ethanol and shaken for 8 hours with Raney - nickel under a hydrogen atmosphere. After filtration and concentration, there were obtained 64 mg (100%) of 1 a, 25(R,S), 26 trihydroxycholesterol - 25,26 - acetonide - 1,3 - diacetate; [aJ20 = -13.6" (c = 0.55% in chloroform).
Example 4 1.4 g of chromium trioxide were suspended in 10 ml of methylene chloride. 1.4 g of 3,5 - dimethylpyrazole were added thereto at-20 C. The mixture was then stirred for 15 minutes. Then, a solution of 0.55 g of 1 a, 25(R,S), 26- trihydroxycholesterol -25,26acetonide - 1,3 - diacetate in 1 ml of methylene chloride was added dropwise. The mixture was stirred at-20 C for 1 hour and at room temperature for 3 hours, then the solution was treated with 20 ml of ether, filtered, washed with ether, concentrated and purified on silica gel with toluene/ethyl acetate (2:1). There were obtained 0.35 g (62%) of 7 - keto la, 25 (R,S), 26 -trihydroxycholesterol - 25,26 acetonide- 1,3- diacetate.
Example 5 0.35 g of 7 - keto - 1 a, 25 (R,S), 26 - trihydroxycholesterol - 25,26 - acetonide - 1,3 - diacetate and 0.32 g of tosyl hydrazine were dissolved in 10 ml of methanol. The mixture was heated at reflux tem per- ature for 5 hours, then concentrated and chromatographed on silica gel with toluene/ethyl acetate (2:1).
There were obtained 0.45 g (100%) of 1 a, 25 (R,S), 26 -trihydroxycholesterol - 25,26 - acetonide - 1,3 - diacetate - 7 - tosylhydrazone.
Example 6 0.45 g of 1 a, 25(R,S), 26 - trihydroxycholesterol 25,26 - acetonide - 1,3 - diacetate - 7 - tosylhydrazone were dissolved in 20 ml of toluene and heated at reflux temperature for 2 hours with 0.50 g of lithium hydride 10 ml of methanol and 10 g of ice were added at 0 C. The mixture was extracted with ethyl acetate, the organic phase was dried with magnesium sulphate and, after concentration, chromatographed on silica gel with toluenelethyl acetate 2:1.
There were obtained 0.20 g (70%) of 1 a, Ia, 25 (R,S), 26 - trihydroxy - 7- dehydrocholesterol -25,26 - acetonide.
Example 7 0.20 g of ,25 (R,S), 26,trihydroxy - 7 dehydrocholesterol - 25,26 - acetonide were dissolved in 30 ml of methanol and stirred at room temperature for 3 hours with 2 g of acid ion-exchanger. Then, the mixture was filtered and concentrated to give 0.15 g (82%) of crude product. Crystallisation from methylene chloride gave 80 mg (44%) of 1a, 25 (R,S), 26 -trihydroxy - 7 - dehydrocholesterol of melting point 1249-126"C.
The provitamin obtained was converted according to the method described in Steroids 24(1974)463 via 1 a, 25 (R,S), 26 - trihydroxyprecholecalciferol into ice, 25 (R,S), 26 - trihydroxycholecalciferol; UV in 95% ethanol, Ajax. 266 nm, Arn1n. 228 nm; TLC [ethyl acetate/methanol (9:1)], Rf = 0.32.

Claims (6)

1. A cholestene of the formula
wherein R1 and R2 represent lower-alkyl or R1 and R2 together represent lower-alkylene and R and R' represent etherified or esterified hydroxy readily cleavable to hydroxy.
2. 1 ,25(R,S),26-Trihydroxycholesterol-25,26- acetonide - 1,3- diacetate.
3. Acholestene oftheformula
wherein R1 and R2 represent lower-alkyl or R1 and R2 together represent lower-alkylene and R and R' represent etherified or esterified hydroxy readily cleavableto hydroxy.
4. 1 a,25(R,S),26 - Trihydroxy - 22 - dehydrocholesterol - 25,26 - acetonide - 1,3- diacetate.
5. A process for the manufactureofthecholesta- dienes of the formula
wherein R1 and R2 represent lower-alkyl or R1 and R2 together represent lower-alkylene and R and R' represent etherified or esterified hydroxy readily cleavable to hydroxy, which process comprises reacting a compound of the formula
wherein R and R' have the significance given earlier in this claim, in a Wittig reaction with a compound of the formula
wherein Ar represents an aryl group and R1 and R2 have the significance given earlier in this claim.
6. A process according to claim 25, wherein (R,S) - [(2,2,4 - trimethyl - 1,3 - dioxolan - 4 - yl) - ethyl] triphenylphosphonium iodide is converted at a temperature between -30 C and -80 C with butyl lithium into the ylid and this is reacted with (20S) 1 a,3ss - diacetoxy - 20 - formyl - pregn - 5 - ene.
GB08304071A 1979-09-14 1983-02-14 Cholestenes for use in preparing cholecalciferol derivatives Expired GB2114569B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH834679A CH644100A5 (en) 1979-09-14 1979-09-14 CHOLECALCIFEROL DERIVATIVES.
GB8029544A GB2060642B (en) 1979-09-14 1980-09-12 Vitamin d3 derivative

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GB8304071D0 GB8304071D0 (en) 1983-03-16
GB2114569A true GB2114569A (en) 1983-08-24
GB2114569B GB2114569B (en) 1984-05-23

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100756823B1 (en) * 2001-10-23 2007-09-07 주식회사 엘지생활건강 Polyethoxylated cholecalciferol derivatives and its preparation
CN101381389B (en) * 2008-09-29 2011-05-25 浙江工业大学 Chemical synthesis method of 5,7-diene steroids compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100756823B1 (en) * 2001-10-23 2007-09-07 주식회사 엘지생활건강 Polyethoxylated cholecalciferol derivatives and its preparation
CN101381389B (en) * 2008-09-29 2011-05-25 浙江工业大学 Chemical synthesis method of 5,7-diene steroids compounds

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GB2114569B (en) 1984-05-23

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PCNP Patent ceased through non-payment of renewal fee

Effective date: 19920912