[go: up one dir, main page]

WO1995019963A1 - Nouveaux composes a activite pharmacotherapeutique - Google Patents

Nouveaux composes a activite pharmacotherapeutique Download PDF

Info

Publication number
WO1995019963A1
WO1995019963A1 PCT/NL1995/000031 NL9500031W WO9519963A1 WO 1995019963 A1 WO1995019963 A1 WO 1995019963A1 NL 9500031 W NL9500031 W NL 9500031W WO 9519963 A1 WO9519963 A1 WO 9519963A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
general formula
bonds
group
diseases
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/NL1995/000031
Other languages
English (en)
Inventor
Andrzej Kutner
Hong Zhao
Hanna Fitak
Michael CHODYN^´SKI
Sebastianus J. Halkes
Stephen R. Wilson
Jan-Paul Van Del Velde
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Duphar International Research BV
Original Assignee
Duphar International Research BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Duphar International Research BV filed Critical Duphar International Research BV
Publication of WO1995019963A1 publication Critical patent/WO1995019963A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/08—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
    • 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
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/532—Cycloaliphatic phosphine oxides or thioxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the invention relates to new pharmacotherapeutically active compounds, to a method of preparing these compounds and to their use in pharmacology.
  • 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.
  • 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.
  • these compounds may be used in various veterinary applications.
  • R 1# R 2 , R 4 , R 5 and R 6 are each individually hydrogen atoms or methyl groups
  • R 3 represents a methyl group or a methylene group
  • R 7 and R ⁇ 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
  • R 3 represents a methyl group if R 3 -C 10 is a single bond, and a methylene group if R 3 -C 10 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.
  • 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.
  • 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.
  • Suitable examples of groups R 7 and R 8 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
  • R 4 , R 5 , R 6 , R 7 , R 8 and ⁇ have the meanings given above, and
  • R 9 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
  • R-, R 2 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.
  • 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.
  • trimethylsilylchloride tert.-butyldimethylsilylchloride, dimethyl-(1,1,2-trimethylpropyl)- silylchloride, tert.-butyldimethylsilyl triflate, or trimethylsilyl- imidazole
  • 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.
  • a ketone of formula III wherein R 4 and R j are hydrogen atoms, R 6 , R 7 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 R 1 and R 2 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • compound (19) is prepared from l ⁇ -hydroxyvitamin D j instead of vitamin D 2 (12).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé répondant à la formule générale (I), dans laquelle R1, R2, R4, R5 et R6, indépendamment les uns des autres, représentent des atomes d'hydrogène ou des groupes méthyle; R3 représente un groupe méthyle ou un groupe méthylène; R7 et R8, indépendamment l'un de l'autre, représentent des groupes alkyle linéaires ou ramifiés comportant de 1 à 4 atomes de carbone, ou des groupes cycloalkyle comportant de 3 à 6 atomes de carbone; Z représente un atome d'hydrogène ou un groupe hydroxy; n est un nombre entier compris entre 0 et 3; et les liaisons (a) représentent des liaisons carbone-carbone simples ou doubles, à condition que (1) aucune liaison double cumulée ne soit présente dans la molécule; (2) R3-C10, C5-C6 et C7-C8 ou C10-C5, C6-C7 et C8-C9 forment des liaisons doubles, auxquelles sont conjuguées des liaisons doubles supplémentaires éventuellement présentes; et (3) R3 représente un groupe méthyle si R3-C10 représente une liaison simple, et un groupe méthylène si R3-C10 représente une liaison double. On a également prévu un procédé de préparation de ce composé, ainsi que son utilisation dans le traitement et/ou la prophylaxie de certains troubles et de certaines maladies.
PCT/NL1995/000031 1994-01-24 1995-01-23 Nouveaux composes a activite pharmacotherapeutique Ceased WO1995019963A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PL94302010A PL174912B1 (pl) 1994-01-24 1994-01-24 Nowe związki farmakologicznie czynne z grupy witamin D i sposób ich otrzymywania
PLP.302010 1994-01-24

Publications (1)

Publication Number Publication Date
WO1995019963A1 true WO1995019963A1 (fr) 1995-07-27

Family

ID=20061687

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NL1995/000031 Ceased WO1995019963A1 (fr) 1994-01-24 1995-01-23 Nouveaux composes a activite pharmacotherapeutique

Country Status (2)

Country Link
PL (1) PL174912B1 (fr)
WO (1) WO1995019963A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999043646A1 (fr) * 1998-02-26 1999-09-02 F. Hoffmann-La Roche Ag Derives de cyclohexanediol
US5969190A (en) * 1997-05-23 1999-10-19 Hoffmann-La Roche Inc. Cyclohexanediol derivatives
KR20010051072A (ko) * 1999-10-18 2001-06-25 프리돌린 클라우스너, 롤란드 비. 보레르 레티페롤 유도체의 제조방법
WO2007105773A1 (fr) * 2006-03-15 2007-09-20 Mercian Corporation Procédé de synthèse d'un dérivé d'indène et intermédiaire de synthèse dudit dérivé
JP2009508813A (ja) * 2005-08-18 2009-03-05 ビオクセル エッセ ピ ア １α−フルオロー２５−ヒドロキシ−１６−２３Ｅ−ジエン−２６，２７−ビスホモ−２０−エピ−コレカルシフェロールの合成
US10315976B2 (en) 2013-01-10 2019-06-11 Givaudan S.A. Organic compounds
US10450532B2 (en) 2014-12-09 2019-10-22 Givaudan S.A. Organic compounds and their use as fragrance ingredients

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3311656A (en) * 1964-05-12 1967-03-28 Hoffmann La Roche Intermediates for the preparation of a carotenoid
WO1991005754A2 (fr) * 1989-10-13 1991-05-02 Medafor Derives des alcools gras a longue chaine, leurs applications, notamment en tant que molecules cytotrophiques et cytoprotectrices, et compositions pharmaceutiques les contenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3311656A (en) * 1964-05-12 1967-03-28 Hoffmann La Roche Intermediates for the preparation of a carotenoid
WO1991005754A2 (fr) * 1989-10-13 1991-05-02 Medafor Derives des alcools gras a longue chaine, leurs applications, notamment en tant que molecules cytotrophiques et cytoprotectrices, et compositions pharmaceutiques les contenant

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5969190A (en) * 1997-05-23 1999-10-19 Hoffmann-La Roche Inc. Cyclohexanediol derivatives
JP3276375B2 (ja) 1997-05-23 2002-04-22 バジリア ファルマスーチカ アーゲー シクロヘキサンジオール誘導体
WO1999043646A1 (fr) * 1998-02-26 1999-09-02 F. Hoffmann-La Roche Ag Derives de cyclohexanediol
US6184422B1 (en) 1998-02-26 2001-02-06 Hoffman-La Roche Inc. Cyclohexanediol derivatives
KR20010051072A (ko) * 1999-10-18 2001-06-25 프리돌린 클라우스너, 롤란드 비. 보레르 레티페롤 유도체의 제조방법
JP2009508813A (ja) * 2005-08-18 2009-03-05 ビオクセル エッセ ピ ア １α−フルオロー２５−ヒドロキシ−１６−２３Ｅ−ジエン−２６，２７−ビスホモ−２０−エピ−コレカルシフェロールの合成
WO2007105773A1 (fr) * 2006-03-15 2007-09-20 Mercian Corporation Procédé de synthèse d'un dérivé d'indène et intermédiaire de synthèse dudit dérivé
JP4882050B2 (ja) * 2006-03-15 2012-02-22 日本マイクロバイオファーマ株式会社 インデン誘導体の製造方法およびその製造中間体
US10315976B2 (en) 2013-01-10 2019-06-11 Givaudan S.A. Organic compounds
US10450532B2 (en) 2014-12-09 2019-10-22 Givaudan S.A. Organic compounds and their use as fragrance ingredients

Also Published As

Publication number Publication date
PL174912B1 (pl) 1998-10-30
PL302010A1 (en) 1995-08-07

Similar Documents

Publication Publication Date Title
EP0633245B1 (fr) Dérivés de vitamine D et procédé pour la préparation de ces composés
US5929056A (en) Vitamin D compounds and method of preparing these compounds
KR100195547B1 (ko) 비타민d 동족체, 이의 제조방법 및 이를 함유하는 약제학적조성물
KR100783856B1 (ko) 비타민d3동족체
EP0742203B1 (fr) Dérivés de vitamine D et un procédé de leur préparation
FR2634200A1 (fr) Nouveaux composes derives de la vitamine d, leur procede de preparation et compositions pharmaceutiques contenant ces composes
HU222775B1 (hu) D-vitamin analógok, eljárás előállításukra és ezeket tartalmazó gyógyszerkészítmények
RU2235721C2 (ru) Аналоги витамина d3
CA2140382C (fr) Composes de type vitamine d et methode pour leur preparation
RU2165923C2 (ru) Аналоги витамина d, способ их получения, фармацевтическая композиция
FR2573760A1 (fr) Composes derives du cholecalciferol, composition pharmaceutique antitumorale et utilisation desdits composes dans la preparation de cette composition pharmaceutique
WO1995019963A1 (fr) Nouveaux composes a activite pharmacotherapeutique
RU2126385C1 (ru) Аналоги витамина d3, способ их получения, фармацевтическая композиция
US6080878A (en) Method of preparing 16-dehydro vitamin D compounds
JP2801587B2 (ja) １，２５−ジヒドロキシ−１６，２２，２３−トリスデヒドロ−コレカルシフェロール誘導体
MXPA97002139A (en) Derivatives of 1,25-dihydroxy-16,22,23-trisdeshidro-colecalcife
CA2097997C (fr) Composes de vitamine d et methode de preparation de ces composes
JP2004277433A (ja) ビタミンｄ化合物およびそれらの製造方法
MXPA97003774A (en) Vitamin analogues

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA