DE1810477A1 - A-furan steroids - Google Patents

Description

P 1353

Shionogi & Co ₀₉ Ltd, Osaka, Japan

A-furan steroids

The invention relates to new hot erosionoids and, more particularly, relates to oxasteroid compounds with; a furan ring as ring A ₅ . a process for their preparation and the use of these compounds as pharmaceutical agents *

There are a number of publications on heterosteroids and steroids with an aromatic ring as Ring A A-furan steroids.! ie 3-0xa "A.19 ^s " d.inc £ rK, 5 (i0) -diene steroids were hitherto unknown. Such A- * furan steroids have now been produced; and they have been found ₉ to have remarkable pharmacological activity ^

The A-purane steroids of the present invention are as follows Partly marked trulctural formula

\ -Π

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which showed the ring A or the positions 1, 2, 3, 5 and 10 of the steroid molecule. The new compounds can belong to the estran »j Pregnan, Cholan = and Cholestan series! * ^ - Subs tuents exist, e.g. hydroxyl groups., Acyloxy groups, alky lend ioxy groups., Ether groups, ester groups? Oxo groups, laetongruppen, lower Alkylresteg alkenyl., Alkynyl, amino. Substituted amino groups _B double bonds · formyl groups and carboxyl groups on the ₅ ¥ erfindiingsgemäßen compounds are those of formula

CiD

where X is a carbonyl group, a ketal group _? a Hydroxymethylengruppeg a Kohlenv / asserstoffhydroxymethylengruppej in the Kohlenv / asserst off rest up to 5 carbon atoms "a Acyloxymethylengruppe _s in the Aeylgruppe a Kohlenwassers'coffGarbonsäu ^ eacylrest with up to 11 carbon atoms _f or pages" chain of pregnane = _s Cholan- oCar Cholestanreihen means _p tone of particular importance ο to the preferred hydrocarbon radicals with up to 5 carbon atoms

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Methyl, ethyl, propyl »isopropyl, butyl, isobutyl, Pentyl, xsopentyl, vinyl, propenyl, butenyl, pentenyl, Isopentenyl, pentadienyl, ethynyl, propynyl, butynyl and pentynyl «. Preferred hydrocarbon acyl radicals with up to 11 carbon atoms are, for example, pormyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, Isovaleryl, trimethylacetyl, caproyl, tert-butylacetyl, oenanthyl, octanoyl, decanoyl, undeoanoyl, acrylic, Vinylaoetyl, Crotonyl, Allylaoetyl, Undocenoyl, Benzoyl, Nitrobenssoyl, Phenylpropionyl, Phenoasyacetyl, Cyclopentylpropionyl, Adamantanoyl, Oinnamoyl and Cathylo Some island compounds according to the invention that are derived from the ™ Formula II are included, for example

17 j 17 ~ ethylenedioxy-3-oxa-A-noröstra-1,5 (10) -diene 3 «Oxa ~ A-novöstra ~ 1,5 (10) -dien-17-one 3-0xa ~ A-noröstra- 1,5 (1Q) -dien-17β-ol 17α 'methyl-3-oxa-A-norÖstra-i, 5 (10) -dien-17β-ol 17a ethyl = 3-oxa-A-noröetra-1,5 (10) -dien-17ß-ol i 7a propyl-3-oxa-A-noröstra-1,5 (10) »dien-» 17ß-ol 17 a butyl-3-oxa ~ A »noröstra-1,5 ( t0) = dien-17ß-ol 17a-isobutyl-3-oxa-A _T n:> röstra-1,5 (10) -dien-17ß ° ol 17a-.pentyl-3-oxa-A-noröstra-1, 5 (10) -dien ~ 17β-ol

17tt ~ Viny1-3-oxa ~ A-noröetra-1,5 (10) -dien-17β-ol μ

Ua-AlIy l ™ 3-oxa-A "noröstra-1,5 (10) ~ diene-17β-» ol 17a-butenyl-3-oxa-A-noröstra-1,5 (10) -diene-17β "ol 17a ~ pentenyl-3-oxa-A-norÖ8tra «1,5 (10) -diene-17ß- = ol 17tt" ethynyl "3 ~oxa-A-noröstra-1,5 (10) -diene« 17ß-ol 17a "Propynyl-3-oxa-A-noröstra ~ 1,5 (10)» diene »17β-ol ¹ 7a-butynyl« 3-oxa-A-noröstra-1,5 (10) -dien-17β ~ ol i / α-Pentynyl ^ -oxa-A-norÖstra-i, 5 (10) -dien-17ß-ol 17 20:20 _t 21-bismethylenedioxy-3- = oxa = A ₉ 19-dinorpregna-105 (10) »diene

3 Oxa A, 19-dinorchalestC! - 1,5 (10) -dien 3 Qxa ~ A j. 19-dinorchola «1 ₁ 5 (10th) - dienoic acid

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-as well as their Eeteräerivatfig ss »3. Formi®te ₉ Acetate, Propio nate, Butyrate, Isobutyratej, Feieret® _s Ieovalerate,

Dteanoat®, Aerjlate, Allylaoetatf »Undeotnoate _f aylpropionat®, Pheno3Eytcet / damantoate _t .Oinnamate and

Vinyl acetate "". örotoBate, ^ Hitrotoneoat® «

e.rf indigenous - method only production of A = FmianeteroidTerbinduEgsa of the above mentioned partial formula I includes a reduction üiwaadlimg eia®ea ^ i-unsaturatedea Laoton ring in the ÄEtepreohenden. Ptaranritig® piping generally Arb © © © itsw®is is described in part in the britiechen Patent 1081647 ... 'ErfindungsgemäO a Auegangsetoff 2-0xo-3-oxa-T (10) -e_n-A-noreteroid mi $ an active reducing agent in the compound according to the invention. Di @ ®e_ Auegange @ toffe can also d «n eniqjreoliendea 19-Ior-5 ~ oaEo-4-en ~ eteroidesi 'duroh oxidation and Beearboxylation au" 5-0xo-A-dinor- "2,5-eeQo-tS -norsteroid-g-earbofösäwre iteirgeetellt. ₉ the - successively through, drlgnard reaction _for hydration and oxidation ma 5-Pxo-A ~ dino-2 _f 5-eeoo-i 9 ~ norsteroid- 2 «acids without water and then dureii Ül »ergofführung is» The details of the invention® process are fer-Vorntl

(HD

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wherein X is as defined above. Starting materials of the general are my formula IXX for the purposes of the invention for example:

17 »17-ethylenedioxy ~ 3-oxa ~ A ° noröstr -1 {10) ~ en ~ 2-one 2,17-Dioxo-3-oxa-A-noröstrn1 (10) ~ en 2 - = - 0xo-3 ~ oxa-A ~ norößtr-1 (10) -en ~ i7ß-ol 17a ~ methyl ~ 2-oxa ~ 3 ~ c> xa ~ A-norös tr-1 (10) -en »17β-ol 17a-ethyl-2-oxo-3-oxa <= A "norb" str-1 (10) -en-17β-ol

? a-Butyl ~ 2-oxo = 3-oxa-A-noröstr-1 (10) = en-17ß ~ ol 7a-isobutyl »2-oxo-3-oxa-A ~ noröstr ~ 1 (10) -en- 17β- 7a-pentyl-2-oxo-3 = oxa-A-norö s tr ~ 1 (10) -en ™ 17β = ol

7a ~ AllyX ~ 2-oxo-3-oxa ~ A "noröstr ~ 1

ι roestr-1 (10)

17a-Propynyl-2-oxo-3Qxa ~ A-norostr ~ 1 {10) «- en ~ 17ß ~ ol 1TK'Butynyl-2-οχα« 3 ~ oxa-A-norostr-1 (10) -en ~ 17ß- ol 17a-pentynyl-2 = oxo-3 "= oxa- = A-noröstr-1 (10) ™ en-17β-ol 17" 20:20 _f 21 ^ bismethylenedioxy - 2 "OXo-3-oxa» A _ß 19-dinor-

pregn "1 (10) s
2-0XO-3-oxa-A, 19-dinorsholest "! (10)" en

1 (i0) = enoic acid _s

and their ester derivatives _s z _a Bo acetates, yalerates or benzoates ₉ and ither derivatives ZoB ₀ tetrahydropyranyl ether and tetrahydrofuranyl ether

The active reducing agent for the invention Process is an active aluminum compound, the general

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mean I ¹ or me 1:

^M n ^A1R m ^H (n + 3) -m

where M is an alkali metal, R is a lower alkyl radical or a lower alkoxy radicalj η 0 or 1 and m is an integer from 0 to 3 s when η is 0, and an integer from 0 to 4 when η is 1 »The reaction can take place within a wide temperature range even at -80 ⁰ G; can be carried out depending on the reagent which is used for the preparation of the A-furaneteroid fertilizers according to the invention of the sub-formula I given above.

Examples denoted by R lower alkyl groups of active aluminum compounds IV are methyl ₉ ethyl _P propyl, isopropyl, butyl and isobutyl "Some examples of the active aluminum compounds of the general formula IY are lithium aluminum ,, thy Lithiurame! Aluminum hydride _p Li thiumä thy aluminum hydride!, Li = thiumpropy aluminum hydride _p Lithiumisopropylaliminiumhy · = -! di ^ö _s Lithiumbuty aluminum hydride ₇ Lithiumisobuty aluminum hydride = ₈ Lithiumdiathylaluminiuiflliydrid _s, Lithiumdiisopropyl = aluminum hydride, lithium Lithiumtripropylaluminiumhydrid ₃ "triisobutylaluminum ₈ Lithiumtetraäthylaluminium, Lithiummethr.xyaluminiumhydrid ₃ Lithiumäthoxyaljminium» hydride s, Lithiuiapropyloxyaluminiumiiydrid, , Lithiumisopropyloxyaluminiumnydrid ₈ Lithiumljutoxyaluminiumhydrid "Lithiumisobutyloxyaluminiumhydrid, LithiumdimethozyaluminiuDhydrid" LithiuHidipropyloxyaluminiumhydrid ₉ Lithtiara = ■ ^ feriätho yaluminiuKihydrid, Lithiiurtriisopropyloxyaluminiumhy drid "lithium aluminum tetrabutoxide" aluminum hydride _g methylaluminium hydride, ethylaluminium hydride _y Prx> pylalumi- "niurahyörid, isopropy! aluminum hydride, Bu"5; y! aluminum · "-

909833 / U74 BA _D ORI _QIN AL

ft * *

hydride, Isobuty aluminum hydride, Diäthy aluminum hydride _v -!> dipropylene aluminum hydride, tripropyl, triisobutylaluminum, Tripenty aluminum hydride, Methoxyaluminiumhydrid, Äthoxyaluminiumhydrid, Propyloxyaluminiumhydrid, Isopropyloxyaluminiumhydrid, Butyloxyaluminiumhydrid, Isobutyloxyaluminiumhydrid, Dimethoxyaluminiumhydrid, Dlpropyloxyaluminiumhydrid, Alumlniumtriäthoxi ^d and however Aluminiumtriiaopropyloxid "The foregoing list iet not exhaustive. Been of these aluminum compounds for their beneficial ability to react Di-niederalkylaluminiumhydriie (eg Diäthy! Aluminum hydride, Diisopropy! Aluminum hydride ₉ Biieobutylaluminiumhydrid) and Aluminiuotriniederalkyle (eg Triisopropy! Aluminum, Triisobuty! Aluminum) most preferred. Other reducing agents, e.g. sodium aluminum hydride, potassium aluminum hydride, sodium alkyl aluminum hydrides, potassium alkyl aluminum hydride and pyridine-borane can also be used for this reaction,

The reaction of the starting materials with the active reducing agents can be carried out in an inert solvent. Such inert solvents include, for example, liquid hydrocarbons such as petroleum ether, bensine fraction, ligroln, benzene and toluene, and ethers such as diethyl ether, dipropyl ether, dibutyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, tetrahydropyran and dioxane. The Verfahrenn can be carried out within a wide temperature range, preferably the reaction is carried out, however - made 3 through 0 ⁰ C, Weden when a Dialkylaluminiuehydrid or Lithiuaaluminiumhydrld as the reagent used. The reaction is preferably stirred and air is replaced by an inert gas,

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ζ. B. nitrogen or argon, replaces «, in many cases the desired furan compounds can be produced in almost quantitative yields with the aid of these reducing agents. After the reaction has ended, the reaction mixture is mixed with water or an organic or inorganic acid such as hydrochloric acid, hydrobromic acid, Sulfuric acid, benzenesulfonic acid, or acetic acid mixed together to decompose the adduct and excess reagent, then with a suitable solvent extracted to isolate the desired A-furan steroid compounds. In some cases, intermediate 2-hydroxy-1 (10) -ene-eteroid compounds can be isolated which can be converted into the desired A-furan steroids by treatment with acid. By diluting the Reaction mixture is sometimes the crystalline product in high yield. The crude product can be further purified in the usual way, e.g. by crystallization or chromatography. If the starting material contains an ester group or an oxo group, this will be BODhBaI is hydrolyzed or reduced by the reagent to form a hydroxyl group. Such and others • Obligatory substituents can be formed through ether formation, ketal formation, the introduction of more stable acyl groups and in countries known to be protected or they can can be restored by oxidation or esterification of the product using conventional methods <> The A-furaneteroid compounds according to the invention are characterized by pharaakological activities, and can be used as Means for controlling physiological functions are used. In particular, A-furanoöstran-17ß ^ olderivate of the formula II show antideoiduomatogenic activity, antiuterotropic activity, antianabolic activity, anti • androgenic activity, uterotropic activity, antiestrogens Activity, contragestive activity and lipidotropic activity. It is noteworthy that it is, almost all

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these effects. are anti-hormonal activities. When these new compounds, for example 3-Oxa-A-norestra-1t5 (10) -dien-17B-ol, are administered subcutaneously, they cause a complete blockage of the progesterone-induced decidual weight gymnastics. Subcutaneous administration of the compound inhibits the growth of the eeminails and levator ani muscles caused by testosterone propionate by 10 to 30 degrees.

The compounds according to the invention can be used in various oral or parenteral dosage forms, alone or in admixture with other substances which interact therewith. They can be administered in conjunction with a pharmaceutical carrier which consists of a solid or a liquid in which the compound is dissolved, dispersed or suspended. The solid preparations may dft form of tablets, powders, granules, capsules or pills have ₀ The liquid preparations may be Injekfcionslösungen, ointments, dispersions, suspensions, solutions, emulsions, syrups or elixirs. They can contain flavoring and coloring substances. Tablets and granules can have coatings. In connection with the compounds according to the invention, diluents such as starch, smecharose, lactose, carbonate and kaolin, coloring agents, flavorings, wholesalers, fillers, for example lactose, salt, glycine, starch, calcium carbonate, kaolin, bentonite can be used and calcium phosphate, binders, e.g. Starch, acacia, gelatine, glucose, sodium alginate, tragacanth and carboxymethyl cellulose, disintegrants and swelling agents, ISoBo starch, agar and carbonates, lubricants, e.g. 3tearic acid, talc, paraffin, boric acid, sodium benzoate, Carbowax and cocoa oil, ointment bases, e.g. fats , oils.

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• · 9 «··« ■

- ίο -

Lard, wool fat, vaseline, glycerine, harse, Glycol®, and emulsifying agents, solvents, eg water, polyethylene glycol, olirenol, sesame oil, cocoa oil, methyl or ethyl oleate, liquid detergents, buffers and stabilizing agents, if these agents do not cause any disadvantageous effects Have an effect on the connections

Duron dl the following examples, the preferred execution forums represent, the invention is explained in more detail. The abbreviations have the usual meanings.

" " Example 1

. Bim® solution clay. 517 mg. 17ß ~ Aeetyloxy-3-oxa-'A-noröstr-1 (ίθ) -βη-2-οη Im '' 14 al Setrahydrofuran ₉ which is cooled to -? 0 f-25 ° C iet _{9 is'} droplet with one of 0.8 g of BiisobutylaluBiiniuiiäjdrid in 4®7 al tetrahydrofuran rereet & t. The Mie.Ohung obtained is stirred for 20 ΗΙεϊιΊοώ at the glitzton temperature ", then aaa excess Diieobutylalumiaittnhyiflcl the addition of a few drops of 10 j (-lgtx Celiwtfeleaure" espaetstc "The Biectang is extracted with Waeser re ^ eetst ait The extract is washed with old water, dried and ®ingeia «p £ t® laeli telrlatalläiies'ea de® crude products tue a Mieetais won acetone« mi lesao receives naa 294 Hg 9 * 0m-A-morteteA-1, § (10) -dion-17S-o3. _v F.t37 _f 5-, 5 ⁰ C. IHslf ^CC1 4

chromatogramitx Kf 0 ^ 52- (11 © @ © ΐ3ΐιΐϊ? ββ © 1 | ej © lol © xaB-ethyl acetate (1: 1)). ■ "

In the same white · © become 17®
1 _t 5 (10) - ^ ien-17e-ol, na-ÄÄyl-J-oxa ^ Ä-aorSetea ^ i, 5 (TQ) dien-170-ol, 17a-Propyl-3-oza ~ A- »norSatra -1 ₉ 5 (10) -dien-17§ ~ ol, 17-a «XthJLnyl-3 ~ ozB-A-no? S8'tra-r1, 5 ( 10) -di © n-17i-ol

• 9 Θ 9 8 3 3/1

_ 11 -

and 3 0xa-A-noröstra-1,5 (10) -dien-17-one from 17a ~ methyl-2 ~ oxo-3 ~ oxa <-A-noro * str-1 (1O) -en-17ß-ol, 17a-ethyl ~ 2-oxo-3-oxa-A-norBatr-1 (1 Ö) -en-17ß- ol, 17ct-Propyl-2-oxo-3-oxa-A-norb "str-1 (10) -en-17fl-ol, 17a-Xthynyl-2-oxo-3-oxa-A-noröstr-1 (10 ) -en-17ß-oi. b «w.17,17-ethylenedioxy-2-oxo-3-oxa-A-noröstr-1 (10) -en produced *

Example 2

Sin Mieohunf from 10 ag 3-0xa-A-nor5stra-1 _t 5 (1O) -dlen-. 170-olf 1 al pyridine and 1 ml Äacetanhydrld is left to stand for 15 hours at room temperature. The Heaktioneaieohuiie is poured in Eiewaeeer and extracted old methy-, lenohlorid. The extract is washed with water, aqueous latrlusoarb inate solution and rerdUnntsr nalic acid, dried over sodium sulfate and evaporated, whereby mb 3-0xa-A-norÖetra-1,5 (10) -dien-17fl-ol 17-aoetst is obtained. IR: W ^CC1 4 1740, 15Ö2, 1243 o «" ¹ .

rünneöhiohtohroaatograant Rf 0.80 (KieselsKuregel; CyolohexanrXth / laoetat (11 f))

3-0xa-A-nortSetra-1,5 (10) -dlen-17B-ol is converted into its propionate, biityrate, talrat, benzoate and citrate in the same way. ·

ti.

Example 5

A solution of 251 ag 17.20: 20,21-bis «thylenedioxy-2-oxo-3-oxa-A, 19 ~ dinorpregn 1 (10) -en in 10 al tetrahydrofuran, adjusted to -20 to -25 ° C is cooled, is added dropwise with a solution τοη 0.5 g of Biieobutylaluainiuahydrld and 4.5 ml of tetrahydrofuran are added. The obtained mixture is stirred for 20 minutes at the same temperature. Then we ^ the excess dileobutylaluainium-

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hydride decomposed by adding 1 drop of 10% sulfuric acid. The reaction mixture is diluted with water and extracted with methylene chloride. The organic layer is made with Vaster, aqueous sodium hydroxide solution and. Water washed, dried and oingedmepft. After chromatographic purification of the residue on aluminum oxide is obtained 17,20: 20,21-Bisaethylendioxy-5 ~ oxa-A _r 19 "4inorprefna-1,5 (10; -diene IR ** ¹ Ξ5Ϊ4 1504 oa ~ ^1..

In the same way, 3 ~ Oxa ~ A _t 19- ~ dinorcholesta ~ 1,5 (10) -diene and ethyl-J-oxa-A, 19-dinorchola "1,5 (10) -serves on · 2-Ojco -5-o ² * -A _l 19-dinooÄoleet-1 (10) · en bsw »Ethyl-2-OJtO-J-OJCa-A, 19-dinorchol- ΐ (10) -enat produced *

90983 37 U7A

Claims (1)

- 13 - Claims 1. Steroid blinding, characterized by the part forael for ring A. 2. Compounds according to claim 1, characterized by the formula in which 1 is a carbonyl group, a ketal group, hydroxymethylene group, a lohltnwaeeeretoffhydroiy -bethylene group in which the hydrocarbon radical Ms su contains 5 carbon a ^ ones, an aoyloxymethylene group in which the aoyl group is an iiohXenwaeacarbonoarbonsäureaoylrest or a side chain of the Pregnanatonen up to 11 , Means cholan or choleetan series., 909833 / U74 • Λ · · · ■ «■« 1810 * 77 - 14 - 4. 3-0xs / -A-norö8tra-1,5 (10) -diene-17B-olaeylate. 5 · 3-0xa ~ A ~ norö8tra-1,5 (10) -di * a-1Tfi-ol-aoetat. 6. 17a-Iitderalkyl-3-oxa-A-noröetra-1 _t 5 (10) -dien-17fi-ol. 7 ο 17o-Xthynyl-3-oxa-A-noröetra-1,5 (10) -dien-17β-ol. Θ. 3 ~ 0ia-A, 19-dinorcholeβta-1 »5 (1O) ^ aItHa 9 π 3-Oxm-K , 19-dlnorohola-1,5 (1 (»-dltmeäureäthyleeter. 10. 17.20: 20,21-Bieiaethylendioxy-3-o la-Α, 19-dinorpregna-1,5 (10) -di «n. 11. y '^ rfalirtti only Keretellsn the Verbladuiigen according Aaepruoh 1 _f ^ characterized in that, "at" la " Aer! « -for 11% A with etM »aktivea ReiultionsBittia see below implement the connection according to claim 1 » The method according to claim 11, thereby resulting in that wm «in connection according to claim 2 !! 90S833 / 1474 Process according to Claim 11 or 12, characterized in that the active reducing agent used is a active aluminum compound of the formula used * where M is an alkali metal, H a lower one Alkylreet, or lower alkyloxyreat, η 0 or 1 and m a whole number bon O to 3 c when η is O, and one means an integer from 0 to 4 if η 1 let. 14α method according to any one of claims 11 to 13, characterized recognized that the reducing agent used is a di-lower alkyl aluminum hydride or aluminum tri-lower alkyl " 15 »The method according to any one of claims 11 to 14, characterized It is noted that the reducing agent used was dilaeiratylaluminum hydride 16o PharmaKeutleohee means for human and vtterlnärmedl-Klniaokt Sweoke, linked by «la · or mekwre of the compounds according to claim 1 · _Λ 909833/1474