Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/30—Oestrogens
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
  • C07J1/0051—Estrane derivatives
  • C07J1/0081—Substituted in position 17 alfa and 17 beta
  • C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
  • C07J1/0096—Alkynyl derivatives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J11/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
  • C07J21/005—Ketals
  • C07J21/008—Ketals at position 17
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
  • C07J33/005—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton spiro-condensed
  • C07J33/007—Cyclic thioketals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
  • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
  • C07J41/0044—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an estrane or gonane skeleton, including 18-substituted derivatives and derivatives where position 17-beta is substituted by a carbon atom not directly bonded to another carbon atom and not being part of an amide group
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
  • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
  • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00

Definitions

• the invention relates to the use of steroids for the manufacture of a medicament for treating or preventing menopausal complaints, especially for treating or preventing osteoporosis.
• ll ⁇ -alkyl steroid are known from USP 3,983,144. These steroids are described to have
• R-L represents 0, (H,OH), or two hydrogens atoms;
• R 2 is hydroxy, optionally etherified or esterified;
• R 3 is (2-6 C) alkynyl, optionally substituted with hydroxy;
• R is CN or one of the hydrocarbon groups selected from (1-6 C) alkyl, (1-6 C) alkoxy, (2-6 C) alkenyl, (2-6 C) alkynyl, and (2-6 C) alkylidene, each of said hydro ⁇ carbon groups may optionally be substituted with halogen, hydroxy or (1-6 C) alkoxy; and
• R 5 is hydrogen or (1-6 C) alkyl, can be used for treating or preventing postmenopausal complaints, and especially osteoporosis.
• the aim of this invention is to provide a medicament which is able to prevent bone loss, and possibly to increase bone mass, and further to treat climacteric complaints.
• the active ingre ⁇ pros of these medicaments have strong estrogen and weak or non-existing androgenic activity.
• Preferred medicaments further have favourable bleeding properties , do not induce endometrium proliferation, and have a favourable HDL/LDL (high/low density lipid) ratio.
• the compounds have the general formula I wherein R-L represents 0 or two hydrogens atoms; R is hydroxy; R 3 is ethynyl; R 4 is selected from the group consisting of methyl, (2-6 C) alkynyl, (2-6 C) alkylidene, and one of (2-6 C) alkyl, (2-7 C) alkoxy- alkyl, (1-6 C) alkoxy, or (2-6 C) alkenyl, which may optionally be substituted with halogen; and R 5 is hydro- gen or (1-6 C) alkyl.
• R ⁇ is 0; R 2 is hydroxy; R 3 is ethyn- yl; R 4 is ethyl, 2-fluoroethyl, ethynyl, (2-6 C) alkenyl optionally substituted with fluorine, or (2-6 C) alkyli ⁇ dene optionally substituted with fluorine; and R 5 is hydrogen or methyl. In the preferred embodiment R 5 is hydrogen.
• steroids having the general formula I wherein: R- ⁇ is O; R 2 is hydroxy; R 3 is ethynyl; R 4 is ethyl or ethynyl; and R 5 is hydrogen.
• the invention further relates to new steroids having the general formula I wherein:
• R ⁇ represents 0
• R 2 is hydroxy, optionally etherified or esterified;
• R 3 is (2-6 C) alkynyl, optionally substituted with hydroxy;
• R 4 is CN, (2-6 C) alkyl optionally substituted with halogen, or (2-6 C) alkenyl substituted with halogen; and R 5 is hydrogen or (1-6 C) alkyl; or wherein
• R- L represents two hydrogens atoms
• R 2 is hydroxy, optionally etherified or esterified;
• R 3 is (2-6 C) alkynyl, optionally substituted with hydroxy;
• R 4 is CN or one of the hydrocarbon groups selected from (2-6 C) alkyl, (1-6 C) alkoxy, (2-6 C) alkenyl, (2-6 C) alkynyl, and (2-6 C) alkylidene, each of said hydro ⁇ carbon groups may optionally be substituted with halogen, hydroxy or (1-6 C) alkoxy; and R 5 is (1-6 C) alkyl.
• steroids of general formula I wherein R ⁇ is O; R 2 is hydroxy; R 3 is ethynyl; R 4 is 2-fluoroethyl or 2-fluoro- ethenyl; and R 5 is hydrogen are preferred steroids.
• Other preferred steroids are steroids of general formula I wherein R j represents two hydrogens atoms; R 2 is hydroxy; R 3 is ethynyl; R 4 is (2-6 C) alkyl, (2-6 C) alkylidene or (2-6 C) alkenyl, each of which groups may be substituted with fluorine; and R 5 is methyl.
• the OH group may be etherified or esterified.
• etherified means that the hydroxy group is etherified with a lower alkyl group, preferably having 1-6 carbon atoms, such as methyl, ethyl, propyl, sec-butyl and the like.
• esterified means that the hydroxy group is esterified with a lower alkanoyl group, preferably having 2-6 carbon atoms, like acetyl, propionyl, and the like. In principle any ester suffices as long as the ester group cleaves when the compound is administered in vivo .
• the (1-6 C) alkyl group in the definition of formula I is a branched or unbranched alkyl group having 1-6 carbon atoms, such as methyl, ethyl, propyl, butyl, tert-butyl, pentyl and hexyl.
• the alkyl group is methyl (especially for R 5 ) and ethyl (especially for R 4 ).
• the term (2-6 C) alkyl has the same meaning with the exception of methyl.
• the (2-6 C) alkenyl group is a branched or unbranched alkenyl group having 2-6 carbon atoms, like vinyl, 2- propenyl, and 1,3-butadienyl.
• the (2-6 C) alkynyl group is a branched or unbranched alkynyl group having 2-6 carbon atoms, like ethynyl, propynyl, butynyl, and the like.
• the (2-6 C) alkylidene group is a branched or unbranched alkylidene group having 2-6 ' carbon atoms, like ethylidene, propylidene, 2-methylpropylidene, and the like.
• halogen used in the definition of formula I means fluorine, chlorine, bromine or iodine. Fluorine is the preferred halogen.
• (1-6 C) alkoxy means an alkoxy group, the alkyl moiety of which is a (1-6 C) alkyl group as previously defined.
• (2-7 C) alkoxyalkyl means a (1-6 C) alkyl group as previously defined substituted by a (1-6 C) alkoxy group as previously defined, the total number of carbon atoms being between 2 and 7.
• the new compounds of this invention can be prepared by condensation of 11-keto steroids of the general formula:
• R- L represents 0
• R 2 is hydroxy, optionally etherified or esterified
• R 3 is (2-6 C) alkynyl, optionally substituted with hydroxy
• R 5 is hydrogen or (1-6 C) alkyl; or wherein
• R- L represents two hydrogens atoms
• R 2 is hydroxy, optionally etherified or esterified
• R 3 is (2-6 C) alkynyl, optionally substituted with hydroxy
• R 5 is (1-6 C) alkyl; the active groups of which are optionally protected, is condensed with a Wittig(-like) compound of the formula
• R 'R 4 "CH-W wherein R 4 R 4 // C forms the group R 4 which is the optionally halogen, hydroxy, or (1-6 C) alkoxy substituted (2-6 C) alkylidene group as previously defined, or R 4 "'Li, wherein R 4 '" is (2-6 C) alkyl or (2-6 C) alkenyl optionally substituted with halogen, hydroxy, or (1-6 C) alkoxy, in which reactive groups can be protected by protective groups which are known in the art (see for example T.W.
• W is a Wittig, Wittig-Horner or Peterson-like moiety, optionally followed by halogenation and dehydration or by hydration, after which the compound obtained is converted into a nitrile or condensed with a Wittig(*- like) compound of the formula R g W, wherein W has the previously given meaning and R 6 is independently hydrogen, halogen or (1-6 C) alkyl, followed by hydroboration, optionally followed by alkylation, halogenation, or halogenation and dehydrohalogenation, or (partial) hydrogenation, after which optionally present protective groups are removed.
• Suitable reagents are triphenylphosphoranes such as R 4 R 4 / CH-P(Hal)Ph 3 and the like, and suitable Peterson reagents are, for example, trimethylsilane reagents like R 4 'R ' , C(MgHal)Si(CH 3 ) 3 , wherein Hal denotes a halogen like chlorine or bromine.
• the steroids of the invention can be used to prevent and treat estrogen deficiency induced disorders such as menopausal complaints, as is demonstrated in the estrogen-induced bone loss assay.
• young mature female Wistar rats are ovariectomized and treated with the test compound for 1 month.
• blood is collected and in the lithium-heparin plasma the bone turnover parameter (osteocalcin) is determined according to the method of Verhaeghe et al., J. Endrocrinol. , 120 , 143-151.
• the right femur is dissected and the bone density of the distal part of the metaphyse is measured using an X-ray densitometric method.
• the bone density, in mm aluminum equivalent is expressed in a percentage relative to the intact control group which is 100 % by definition, and to the ovariectomized control group which is 0 % by definition.
• osteocalcin is defined as 100 % for the ovariectomized group and 0 % for the intact group. Active compounds inhibit the bone turnover, and thus have an osteocalcin value lower than 100 %. Table I gives the results of this assay.
• the compounds of the invention may be administered enterally or parenterally, and for humans preferably in a daily dosage of 0,001-10 mg per kg body weight.
• pharmaceutically suitable auxiliaries e.g. as described in the standard reference, Gennaro et al.. Remington's Pharmaceutical Sciences, (18th ed. , Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture
• the compounds may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories.
• the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.
• a spray e.g. a nasal spray.
• dosage units e.g. tablets
• conventional additives such as fillers, colorants, poly ⁇ meric binders and the like is contemplated.
• any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used.
• Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
• Rf 0.77 (toluene-ethyl acetate 9/1) .
• a mixture of 6.1 g of (7 ⁇ )-3,3-ethanedithio-17,17- ethylenedioxy-7-methyl-ll-methylene-estr-4-en, 90 ml of acetone, 50 ml of tetrahydrofuran and 3 ml of 6 N hydrochloric acid was stirred at ambient temperature. After 1 h the mixture was diluted by addition of 700 ml of 5% sodium carbonate and stirred for h. The precipitate was filtered and dried to provide 5.4 g of (7 ⁇ )-3,3-ethanedithio-7-methyl-ll-methylene-estr-4-en- 17-one.
• R f 0.74 (toluene-ethyl acetate 9/1).
• Acetylene gas was passed through a solution of 50 g of potassium tert-butoxide in 500 ml of dry tetrahydro ⁇ furan. After 2 h a solution of 30 g of (7 ⁇ )-3,3- ethanedithio-7-methyl-ll-methylene-estr-4-en-17-one in 400 ml of tetrahydrofuran was introduced dropwise at 0 °C. After stirring for an additional 1 h the mixture was poured into 7 1 of water and stirred for an additional h.
• Dehydration of the oxime was effected by reacting 0.8 g of (7 ⁇ ,ll ⁇ ,17 ⁇ )-3,3-ethanedithio-17-tetrahydropyranyl- oxy-7-methylestr-4-en-ll-carboxaldehyde oxime in 8 ml of acetic anhydride during 45 min. Concomitant replacement of the 17-tetrahydropyran ether by an acetate group was observed. The reaction mixture was poured into 50 ml of ice water and stirred for 30 min.
• Acetylene gas was passed through a solution of 10.5 g of potassium tert-butoxide in 60 ml of dry tetrahydrofuran for 1 h at 0 °C. Then a solution of 9.3 g of (7 ⁇ ,ll ⁇ )- 3,3-ethanedithio-17-oxo-7-methylestr-4-en-ll-carbo- nitrile in 100 ml of tetrahydrofuran were added drop- wise. After stirring for 1 h at 0-5 °C the mixture was poured into 500 ml of saturated ammonium chloride solution and the product was extracted with ethyl acetate.
• lithium diisopropylamide prepared from 250 mg of dii ⁇ opropylamine and 1.6 ml of a 1.6M butyl lithium-hexane ⁇ olution
• 3 ml of tetrahydrofuran wa ⁇ added a solution of 600 mg of difluoromethyldiphenyl- pho ⁇ phinoxide in 2 ml of tetrahydrofuran at -50 °C.
• Acetylene gas was bubbled into a solution of 0.48 g of potassium tert-butoxide in a mixture of 5 ml of tetrahydrofuran and 0.5 ml of t-butanol. After 15 min a solution of 250 mg of ll ⁇ -(2,2-difluoroethylene)-estr-4- en-3,17-dione in 3 ml of tetrahydrofuran was added and 15 min later the mixture was quenched with water and the product extracted with ethyl acetate.
• the organic material wa ⁇ purified by chromatography to provide 1.9 g of (ll ⁇ ,E,17 ⁇ )-ll-(2-chloroethenyl-17-hydroxy-19-norpregn- 4-en-20-yn-3-one; M.p. 180 °C.
• Ba ⁇ e granule ⁇ were prepared by mixing the lactose with a portion of starch. The remainder of the starch wa ⁇ mixed to a slurry with water and added to the mixture. The whole was granulated and dried. The ⁇ e ba ⁇ e granule ⁇ were mixed with ascorbyl palmitate and the active ingredient, sieved, finely mixed with magnesium ⁇ tearate and then tabletted.
• Example 9 The components were mixed with one another in the manner described in Example 9, granulated and filled into gelatin cap ⁇ ule ⁇ .

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