TW201026718A - Use of 17β-cyano-19-androst-4-ene derivatives for preparing a medicament in depot form for parenteral administration and depot medicaments comprising 17β-cyano-19-androst-4-ene derivatives for parenteral administration - Google Patents
Use of 17β-cyano-19-androst-4-ene derivatives for preparing a medicament in depot form for parenteral administration and depot medicaments comprising 17β-cyano-19-androst-4-ene derivatives for parenteral administration Download PDFInfo
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201026718 六、發明說明: 【發明所屬之技術領域】 本發明係㈣某些導氰基_19_甲雄w稀衍生物 備非口服之供給型式藥物之用途,且亦關於包含此等_ 氰基-19-甲雄⑽·4_埽衍生物之非卩服供給藥物自身。 【先前技術】 導氰基]9-甲雄留_4_稀衍生物自身,其(例如)用於户 療停經前、近停經期及停經後症狀以及經前症狀之用途及 包含具有姓娠相關作用之該等衍生物的藥物已描述於至八 未公開之PCT/EP2008/057427 +,其揭示内容描述於下I 中。 由該文獻已知基於類固醇結構且具有姓娘相關、抗鹽皮 質激素、抗雄性激素或抗雌激素作用之化合物,其衍生自 例如19·甲雄留_4_烯_3,或其衍生物(類固醇結構之編號可 獲自例如 Fresenius/G5rlitzer 第 3 版 1991「 chemische Nomenklatur」[有機化學命名法]第6〇頁及其後 數頁)。 ' 因此WO 20_72467仰示具有姓娘相關作用之化合 物二亞曱基_3·側氧基_17利_4_稀21,導 羧内酯(曲螺酮(dr〇Spirenone)),其已用於例如口服避孕劑 及治療停經後症狀之製劑中。然而,由於曲螺酮對助孕素 受體之親和力相對較低,且其排卵抑制劑量相對較高,故 曲螺酮以3 mg之相對較高日劑量存在於避孕劑中。此外, 曲螺酮之不同之處亦在於除妊娠相關作用以外,其亦具有 144922.doc 201026718 拮抗醛固酮(抗鹽皮質激素)且具有抗雄性激素作用(s〇wie antiandrogene Wirkung verfttgt)。此兩種特性使得曲螺酮 之藥理學型態與天然助孕素孕酮極為類似,然而天然助孕 素孕酮與曲螺酮不同之處在於其不具有適當之口服生物利 用率。為了降低投與劑量,在WO 2006072467 A1中進一 步提出妊娠相關效能高於曲螺酮之18_甲基_19·去甲基_l7_ 孕甾-4-烯-21,1 7-羧内酯及包含其之醫藥製劑。201026718 VI. Description of the invention: [Technical field to which the invention pertains] The present invention is a use of a non-oral supply of a certain type of cyano- 19-methyl-andrazine derivative, and also relates to the inclusion of such a cyano group. -19-The non-anthraquinone of the Jiaxiong (10)·4_埽 derivative is supplied to the drug itself. [Prior Art] a cyano]9-methyl-andrazine _4_dilute derivative itself, which is used, for example, for the treatment of premenopausal, near menopause and postmenopausal symptoms, as well as the use of premenstrual symptoms and includes the presence of a surname Drugs of such derivatives of the relevant effects are described in PCT/EP2008/057427+, the disclosure of which is hereby incorporated by reference. Compounds based on steroid structures and having a genus-related, anti-mineral corticosteroid, anti-androgen or anti-estrogen action are known from this document, which are derived, for example, from 19·methylxanthene-4-ene-3 or a derivative thereof. (The steroid structure number is available, for example, from Fresenius/G5rlitzer, 3rd edition 1991, "Chemische Nomenklatur" [Organic Chemistry Nomenclature, page 6 and subsequent pages). ' Therefore WO 20_72467 indicates that the compound dimercapto group _3 · side oxy group _17 _ 4 _ thin 21, carboxy carbaryl lactone (dr 〇 Spirenone), which has been used For example, in oral contraceptives and in the treatment of post-menopausal symptoms. However, since trospireone has a relatively low affinity for the progesterone receptor and its ovulation inhibitor is relatively high, trospireone is present in the contraceptive at a relatively high daily dose of 3 mg. In addition, trospireone differs in that, in addition to pregnancy-related effects, it also has 144922.doc 201026718 antagonistic aldosterone (anti-mineral corticosteroid) and has anti-androgenic effects (s〇wie antiandrogene Wirkung verfttgt). These two properties make the pharmacological profile of trochodrone very similar to the natural progesterone progesterone, whereas the natural progesterone progesterone differs from trospireone in that it does not have an appropriate oral bioavailability. In order to reduce the dosage of administration, it is further proposed in WO 2006072467 A1 that the pregnancy-related efficacy is higher than that of the 18-methyl-19·demethyl-l7_pregnane-4-ene-21,1 7-carboxylactone of trochodrone and Contains pharmaceutical preparations thereof.
此外,例如US-A 3,705,179揭示具有抗雄性激素活性且 適於治療與雄激素相關疾病之類固醇。尤其揭示ΐ7β-氰 基-17α-甲基甲雄甾_4-婦_3_鲷衍生物。 在DE 22 26 552 Β2中,描述其他17•氰基_19_去甲雄 留-4令3,化合物,其顯示具有外源性特徵之擬孕綱、 抗雄性激素及抗雖激素作用。 【發明内容】 本文所述之發明目標為獲得與助孕素受體強力結合之化 合物。此外,該等化合物較佳應亦具有抗鹽皮質激素作 用。 49-甲雄 中說明於 此目標係由本文中所述之通式1之導氰基 留_4_婦衍生物達成。本發明之有利實施例在本文 附屬請求項甲。 通式1之17β-氰基-19_甲雄 本文所述之發明係關於化學 甾-4-稀衍生物 144922.doc 201026718Furthermore, for example, US-A 3,705,179 discloses steroids which have antiandrogenic activity and are suitable for the treatment of androgen related diseases. In particular, ΐ7β-cyano-17α-methylmethylanthryl _4-female _3_ 鲷 derivatives are disclosed. In DE 22 26 552 Β 2, other 17•cyano-19-nor-norsine-4-,3 compounds are shown which exhibit exogenous characteristics of the pseudo-mesh, antiandrogen and anti-hormonal effects. SUMMARY OF THE INVENTION The object of the invention described herein is to obtain a compound that binds strongly to a progestin receptor. In addition, these compounds preferably also have anti-mineralocorticoid action. 49-Hexagonal indicates that this target is achieved by the cyano-retaining _4_ feminine derivative of the formula 1 described herein. An advantageous embodiment of the invention is hereby attached to claim A. 17β-cyano-19_methylxine of the formula 1 The invention described herein relates to the chemical 甾-4-dilute derivative 144922.doc 201026718
NN
其中 Z 選自包含0、兩個氫原子、NOR及NNHS02R之 群’其中R為氫或Cl_C4烷基, R1,R2彼此獨立為氫或甲基或 R ’ R共同形成亞甲基或被省略而在c 1與c2之間 形成雙鍵, R4 為氫或_素, 此外: R R 共同形成亞甲基或1,2-乙二基或R6a為氫且R6b選 自包含氫、曱基及羥基亞曱基之群,且 R? 選自包含氫、烷基、C2-C3烯基及環丙基之 群, 或: R6a為氫且R6b與R7共同形成亞曱基或被省略而在 C6與C7之間形成雙鍵, 或: 144922.doc 201026718 R6a為甲基且1161)與R7被省略而在C6與C7之間形成 雙鍵, / R15 » P16 ^ ^ 為風或共同形成亞甲基, r17 .選自包含氫、CVCU烷基及烯丙基之群, ,其办劑0物、水合物、立體異構體、非對映異構體、 映異構體及鹽, 其限制條件為排除具有以下化學通式A之化合物:Wherein Z is selected from the group consisting of 0, two hydrogen atoms, NOR and NNHS02R wherein R is hydrogen or Cl_C4 alkyl, R1, R2 are independently hydrogen or methyl or R'R form a methylene group or are omitted A double bond is formed between c 1 and c 2 , R 4 is hydrogen or _, and further: RR forms a methylene group or a 1,2-ethanediyl group or R 6a is hydrogen and R 6b is selected from the group consisting of hydrogen, a thiol group and a hydroxyl group. a group of fluorenyl groups, and R? is selected from the group consisting of hydrogen, alkyl, C2-C3 alkenyl, and cyclopropyl, or: R6a is hydrogen and R6b and R7 together form a fluorenylene group or are omitted at C6 and C7 A double bond is formed between them, or: 144922.doc 201026718 R6a is methyl and 1161) is omitted from R7 and a double bond is formed between C6 and C7, /R15 » P16 ^ ^ is wind or co-formed methylene, r17 Selected from the group consisting of hydrogen, CVCU alkyl and allyl groups, which are agents, hydrates, stereoisomers, diastereomers, anomers and salts, the limitation of which is exclusion a compound having the following chemical formula A:
(A) 其中X為氫或甲基,且Θ與^之間以及卜與〜間之雙鍵 為視情況存在之雙鍵,且 ❿其限制條件進-步為亦排除,氰基甲雄@·4稀冬酮。 自本發明排除之化學通式Α之化合物為以下化合物: 排除之化合物 1 X c1=c2 c6=c7 17β-氰基-17α-甲基甲雄甾_4·烯-3-酮 ^' ./. 17β-氰基-6α,17α-二曱基曱雄留_4-浠-3-酮~~ + ./. 17|3-氰基-17α-曱基甲雄留-ΐ,4-二烯_3-銅 L./. + ./. ,-氰基如’^-一甲基曱雄^+二烯各^- + + ./. 17β-^基-17α-甲基曱雄留-4,6-二煤-3-酮 / / + 17β-氰基-6α,17α-二甲基曱雄甾-4,6-二嫌-3-lii^ ·/. + »/ · + 17β-氰基-17α-甲基曱雄留-1,4,6-三烯-3-酮 + + 17戸-氰基-6〇1,17〇1-一曱基-1,4,6-三稀-3-嗣 + + + 144922.doc -9- 201026718 「./.」.不存在;「+」:存在 本發明化學通式1之衍生物之c結構編號通常依據描述於 例如上述引文中Fresenius中的類固醇結構編號。申請專利(A) wherein X is hydrogen or methyl, and the double bond between Θ and ^ and between b and ~ is a double bond as the case may exist, and the restriction condition is also excluded, and cyanomethyl@@ · 4 leptone. The compound of the general formula 排除 excluded from the present invention is the following compound: Excluding compound 1 X c1=c2 c6=c7 17β-cyano-17α-methylmethylandrosin_4·en-3-one^'. 17β-Cyano-6α,17α-dimercaptopurine, _4-indol-3-one~~ + ./. 17|3-cyano-17α-indenyl-methyl---- 4-, 4- Alkene_3-copper L./. + ./., -Cyano group such as '^-monomethyl oxime ^+diene ^- + + ./. 17β-^-yl-α-methyl oxime -4,6-dico-3-one/ / + 17β-cyano-6α,17α-dimethylindole-4,6-di suspect-3-lii^ ·/. + »/ · + 17β -Cyano-17α-methyloxime male-1,4,6-trien-3-one+ 17戸-cyano-6〇1,17〇1-indolyl-1,4,6- Tris--3-嗣+ + + 144922.doc -9- 201026718 "./.". does not exist; "+": the structure number of the derivative of the chemical formula 1 of the present invention is generally described in, for example, the above citation The steroid structure number in Fresenius. apply for patent
範圍中所說明之基團編號類似地對應於其鍵結於衍生物C 結構之位置。舉例而言,基團R4鍵結至本發明衍生物之C4 位置。 關於針對Z定義之基團,基團]^0尺及>11^18〇211在各情況 中使用雙鍵經由N鍵結至衍生物之c結構,如以=N〇R及 =N-NH-S02R。NOR中之中之NHS〇2R可為 同位或反位。 C〗-C4烷基在各情況中應理解為意謂直鏈或分支鏈烷 基,諸如曱基、乙基、正丙基、異丙基、正丁基、異丁基 或第三丁基,特別是未分支基團。甲基、乙基及正丙基尤 佳。此外在位置17ct處鍵結之烷基可經全氟化,使得在 此情況下可另外為三氟曱基、五氟乙基、正七氟丙基、異 七氟丙基、正九氟丁基、異九氟丁基及第三九氟丁基。 C2-C3烯基較佳應理解為意謂乙烯基或烯丙基。 鹵素在各情況下應理解為意謂氟、氣、溴或碘。 異構體應理解為意謂經驗式相同,但化學結構不同之化 合物。明確地包括所有可能之異構體及異構體混合物(外 消旋體)’在本發明衍生物中指定〗7p_氰基位置。 一般而s ’應區分構造異構體與立體異構體。構造異構 體之經驗式相同’但其原子或原子團之鍵聯方式不同。此 等包括S能異構體、位置異構體、互變異構體或共價異構 144922.doc 201026718The group number stated in the range similarly corresponds to the position at which it is bonded to the structure of the derivative C. For example, the group R4 is bonded to the C4 position of the derivative of the invention. With respect to the group defined for Z, the group]^0 ft and >11^18〇211 are in each case a double bond via N bond to the c structure of the derivative, such as =N〇R and =N- NH-S02R. The NHS〇2R in the NOR can be in the same or inverted position. C-C4 alkyl is understood in each case to mean a straight or branched alkyl group, such as a decyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group. , especially unbranched groups. Methyl, ethyl and n-propyl are preferred. Further, the alkyl group bonded at the position 17ct may be perfluorinated, so that in this case, it may additionally be a trifluoromethyl group, a pentafluoroethyl group, a n-heptafluoropropyl group, an isoheptafluoropropyl group or a n-hexafluorobutyl group. , isohexafluorobutyl and third nonafluorobutyl. C2-C3 alkenyl is preferably understood to mean vinyl or allyl. Halogen is understood in each case to mean fluorine, gas, bromine or iodine. Isomers are understood to mean compounds which have the same empirical formula but differ in chemical structure. All possible isomers and isomer mixtures (racemates) are specifically included in the derivatives of the invention to specify the 7p-cyano position. In general, s ' should distinguish between structural isomers and stereoisomers. The structural formula of the isomer is the same 'but the bonding mode of its atom or atomic group is different. These include S energy isomers, positional isomers, tautomers or covalent isomers 144922.doc 201026718
體原則上,立體異構體之結構(構造)相同且因此經驗式 亦相同,但原子之空間排列不同。一般而言,應區分組態 異構體與構形異構體。組態異構體為僅可藉由鍵斷裂而彼 此轉化之立體異構體。此等包括對映異構體、非對映異構 體及E/Z(順/反)異構體。對映異構體為彼此表現為影像與 鏡像且不具有對稱面之立體異構體。所有不為對映異構體 之立體異構體稱為非對映異構體。雙鍵E/z(順/反)異構體 為特殊情況。構形異構體為可藉由旋轉單鍵而彼此轉化之 立體異構冑。關於異構性類型彼此間的區分之描^,亦參 見 UJPAC 規則,部分 E(Pure Αρρι % Η.% (1976)) 〇 ’ 化學通式1之衍生物亦包含可能之互變異構形式且包糾 或Ζ異構體’或若存在對掌中心、,則亦包括外消旋體及對 映異構體。應理解雙鍵異構體亦在其中。 衍生物亦可以溶劑合物形式,尤其水合物形式存在,本 發明化合物相應地含有極性溶劑,尤其是水,作為本發明 2合物晶格之結構元件β極性溶劑,尤其是水可以化學計 置比率或者非化學計量比率存在。在化學計量溶劑合物、 水合物之情況下,此等亦稱為半_、(半_)、單_、倍半_、 —-、二-、四-、五(等)溶劑合物或水合物。 通式1化 用。此外, 之括抗劑。 合物或衍生物具有優良的活體内姓娠相關作 -些相關的本發明化合物用作鹽皮質激素受體 較佳為上述化學通式!之衍生物,其中2選自包含〇 144922.doc 201026718 NOH及NNHS02H之群。Z尤佳為〇。 與ζ之選擇無關,具有上述化學通式w衍生物另外較 佳、,其中以下變異型替代地或至少在一些情況下共同出現 且被彼此獨立地選擇: R15與R“尤佳共同形成亞甲基,其中α亞甲基與卜亞甲 基兩者皆可在此等位置處鍵結。 R及R另外較佳各為氫或共同形成亞甲基 基。R1更佳為α_甲基。 亞曱 參 R4另外較佳為氫或氣。 /^R6b另外較佳共同形成H乙二基或在各情況下為 氫。 ”、' R7另外較佳選自包含氫與甲基之群,其"基可為α_及 β-兩者。 =及R7另外較佳共同形成亞甲基,其中亞甲基可為& 及β-兩者。 R另外較佳選自包含氫與甲基之群。 ❹ 基團 R6a、R6b、·ρ 7 〇 15 及R可另外為α-及β -兩者。 Ηβ-氰基_19_甲雄歸衍生物尤佳選自包含以下各物 之群:In principle, the structures (structures) of stereoisomers are the same and therefore the empirical formula is the same, but the spatial arrangement of atoms is different. In general, the configuration isomers and conformational isomers should be distinguished. The configuration isomers are stereoisomers which can only be converted by a bond cleavage. These include enantiomers, diastereomers and E/Z (cis/trans) isomers. Enantiomers are stereoisomers that appear as images and mirror images of each other and do not have a plane of symmetry. All stereoisomers that are not enantiomers are referred to as diastereomers. The double bond E/z (cis/trans) isomer is a special case. The conformation isomers are stereoisomers which can be converted into each other by rotating a single bond. For a description of the distinction between heterogeneous types, see also the UJPAC rules, Part E (Pure Αρρι % Η.% (1976)) 〇 'Chemical Formula 1 derivatives also contain possible tautomeric forms and The rectifying or purine isomer' or, if present, the racemate and enantiomer. It is understood that the double bond isomer is also in it. The derivative may also be present in the form of a solvate, especially a hydrate, and the compound of the invention accordingly contains a polar solvent, especially water, as a structural element of the crystal lattice of the present invention, a beta polar solvent, especially water. Ratio or non-stoichiometric ratio exists. In the case of stoichiometric solvates, hydrates, these are also referred to as semi-, (semi-), mono-, sesqui-, -, di-, tetra-, five (etc.) solvates or Hydrate. Formula 1 is used. In addition, it is an anti-agent. The compound or derivative has an excellent in vivo living name - some related compounds of the present invention are used as the mineralocorticoid receptor. Preferably, the above chemical formula! Derivatives of which 2 are selected from the group consisting of 144 144922.doc 201026718 NOH and NNHS02H. Z is especially good. Regardless of the choice of hydrazine, it is further preferred to have the above-described chemical formula w derivatives, wherein the following variants are alternatively or at least in some cases co-occurring and are selected independently of each other: R15 and R "are better together form a sub- a group wherein both the α-methylene group and the methylene group may be bonded at these positions. R and R are each preferably each hydrogen or a methylene group, and R1 is more preferably α-methyl. Further, R4 is preferably hydrogen or gas. /^R6b preferably further forms H ethylenediyl or in each case hydrogen. ", 'R7 is further preferably selected from the group consisting of hydrogen and methyl, " The base can be both α_ and β-. And R7 additionally preferably together form a methylene group, wherein the methylene group can be both & and β-. R is further preferably selected from the group consisting of hydrogen and methyl. The oxime groups R6a, R6b, · ρ 7 〇 15 and R may additionally be both α- and β-. The Ηβ-cyano_19_methanosine derivative is preferably selected from the group consisting of:
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佳0 144922.doc -18 - 201026718 新穎化學通式1之化合物由於其妊娠相關活性故可單獨 或與雌激素組合用於避孕藥物。 因此通式1化合物尤其適用於製造口服避孕及治療停經 - 刖、近停經期及停經後症狀之藥物,包括用於激素替代療 法(HRT)之製劑。 通式1化合物由於其適宜的作用型態,尤其適於治療經 削症狀,諸如頭痛、抑鬱心境、水滯留及乳腺痛。 通式1化合物特別適合用於製造具有㈣相關及抗鹽皮 質激素作用之藥物的用途。 使用通式1化合物治療較佳在人類中進行,但亦可對相 關哺乳動物物種(諸如犬及貓)進行。 對於通式1化合物用作藥物之用途而言,將其與至少一 種適合之醫藥學上無害的添加劑,例如媒劑組合。該添加 劑剌於(例如)非Π服投與,以口服投與較佳。此時其應 為醫藥學上適合之有機或無機惰性添加材料之物質,諸如 Φ 水、明膠、阿拉伯膠、乳糖、殿粉、硬脂酸鎂、滑石、植 物油、聚垸二醇等。藥物可1固體形式,例如鍵劑、包衣 錠劑、栓劑、膠囊;或呈液體形式,例如溶液、懸浮液或 %液存在。其視情況另外含有職形劑’諸如防腐劑、穩定 冑、濕_或乳化劑’改變滲透壓之鹽或緩衝液。對於非 口服投藥’油性溶液’諸如芝麻油溶液、萬麻油溶液及棉 軒油溶液特別適合。為了增加溶解度,可添加增溶劑諸 如苯甲酸节醋或节基醇。亦可能將通式“匕合物併入唾皮 系統中而以穿皮式投與。對於口服投藥,錠劑、包衣錠 144922.doc -19- 201026718 劑、膠囊、藥丸、懸浮液或溶液特別適合。 避孕製劑中通式1化合物之劑量應為每天〇 〇1至1〇 。 在治療經前症狀之情況下,曰劑量為大約〇丨至扣。本 發明之妊娠相關衍生物在避孕製劑及治療經前症狀之藥物 中較佳口服投與。曰劑量較佳以單一劑量投與。 妊娠相關及雌激素相關活性物質組份較佳共同在避孕製 劑中口服投與。日劑量較佳以單一劑量投與。 可能之雌激素為合成雌激素,較佳炔雌醇,但亦為雌醇 甲醚。 雌激素以對應於0_01至0.04 rng乙炔基雌二醇之曰劑量投佳 0 144922.doc -18 - 201026718 The novel chemical compound of formula 1 may be used alone or in combination with estrogen for contraceptives due to its pregnancy-related activity. The compounds of formula 1 are therefore particularly useful in the manufacture of oral contraceptives and in the treatment of menopause - sputum, near menopause and postmenopausal symptoms, including preparations for hormone replacement therapy (HRT). The compounds of formula 1 are particularly suitable for the treatment of symptoms of obstruction, such as headache, depression, water retention and breast pain, due to their suitable mode of action. The compounds of formula 1 are particularly suitable for use in the manufacture of medicaments having (iv) related and anti-salt corticosteroid effects. Treatment with a compound of formula 1 is preferably carried out in humans, but may also be carried out on related mammalian species such as dogs and cats. For the use of the compound of formula 1 as a medicament, it is combined with at least one suitable pharmaceutically injurious additive, such as a vehicle. The additive is administered, for example, in a non-dose administration, preferably by oral administration. In this case, it should be a pharmaceutically suitable organic or inorganic inert additive such as Φ water, gelatin, gum arabic, lactose, powder, magnesium stearate, talc, vegetable oil, polyglycol. The drug may be in a solid form, such as a key, a coated tablet, a suppository, a capsule, or in the form of a liquid, such as a solution, suspension or % solution. It may optionally contain a salt or buffer which changes the osmotic pressure, such as preservatives, stabilizing hydrazine, wet _ or emulsifier. For non-oral administration of 'oily solutions' such as sesame oil solution, sesame oil solution and cotton oil solution, it is particularly suitable. In order to increase the solubility, a solubilizing agent such as benzoic acid vinegar or stilbene alcohol may be added. It is also possible to incorporate the general formula "incorporation into the saliva system for transdermal administration. For oral administration, lozenges, coated tablets 144922.doc -19- 201026718 agents, capsules, pills, suspensions or solutions Particularly suitable. The dose of the compound of formula 1 in the contraceptive preparation should be 〇〇1 to 1 〇〇 per day. In the case of treating premenstrual symptoms, the sputum dose is about 〇丨 to buckle. The pregnancy-related derivative of the present invention is in the contraceptive preparation. And the oral administration of the drug for treating premenstrual symptoms is preferred. The sputum dose is preferably administered in a single dose. The pregnancy-related and estrogen-related active substance components are preferably co-administered in a contraceptive preparation. The daily dose is preferably A single dose is administered. Possible estrogen is synthetic estrogen, preferably ethinyl estradiol, but also estradiol methyl ether. Estrogen is dosed in a dose corresponding to 0_01 to 0.04 rng ethinyl estradiol.
與。 X 雌激素當然主要用作治療停經前、近停經期及停經後症 狀及激素替代療法之藥物中的雌激素,尤其為雌二醇戋其 酯,例如戊酸雌二醇或者經結合雌激素(CEE=^^妗人 、、、° 口兩 激素)。 若起始化合物之製備未在本文中描述,則其為熟習此項 技術者已知或可類似於已知化合物或本文中所述之製程製 備。異構體混合物可藉由習用方法,諸如結晶、層析或形 成鹽而分為對映異構體、E/Z異構體或差向異構體。 【實施方式】 如下文所述製備化學通式1之化合物。 描述於PCT/EP2008/057427中之17β-氰基甲雄甾·4_烯3 酮衍生物之適合起始物質為各種類固醇起始物質,諸如甲 雄甾-4·烯-3,17-二酮(參見例如丄s〇c 8'朽27 144922.doc -20- 201026718 (1965)),或者經部分還原之類似物,諸如睪固酮 (testosterone)或普拉雄酮(prasterone)。 由該文獻同樣已知具有15α,16α-或15β,16β-亞曱基之適 合起始材料(例如15α, 16α-亞曱基曱雄留-5-烯-17-酮基-3β-醇,參見CTzew· 106,888 (1973);相應^4-3,17-:8^^ 參見 DE-A 21 09 555 (1972))。15β,16β-亞曱基曱雄甾-4-稀-3,17-二_ 描述於/zv. iVawA: 及 Ser· 8,1893 (1985)及 C/iew. 107,128-134 (1974)中;相應 Δ5-3-醇 描述於』《gew. C/zew. 94 (9),718 (1982)中。 熟習此項技術者顯而易見,在合成轉化之描述中,總是 提供待以適合形式保護之視情況存在於類固醇結構上的其 他官能基。 在類固醇結構之位置17(C17)中引入腈可以各種方式進 行。在此處一步法及多步變異型皆可能。在此處最後引起 以氰化物置換氧官能基之方法較佳。許多可能之方法變異 型描述於*SWewce 〇/ Synthesis Houben-Weyl Methods of Molecular Transformations Category 3 第 19卷,第 197-213 頁(2004 Georg Thieme Verlag Stuttgart, New York)及 Houben-Weyl Methoden der organischen Chemie [Houben-Weyl Methods of organic chemistry]第 Έ5 卷,第 2部分,第 1318-1527 頁(1985 Georg Thieme Verlag Stuttgart, New York)中。 所想到的一步法為(例如)直接以氰基還原置換羰基氧原 子。為此,使17-酮類固醇與曱苯磺醯基甲基異氰化物在 144922.doc -21 - 201026718 適合溶劑中’諸如二甲氧基乙烷、二甲亞颯、醚、醇或者 其混合物中’使用適合鹼,諸如鹼金屬醇鹽、鹼金屬氫化 物、六甲基二矽烷胺化鉀或者鹼金屬醯胺(諸如二異丙基 醯胺鋰)在0°C至loot之間之溫度下反應。可藉由層析、 分步結晶或使用此等方法之組合來分離可能形成之17_差 向異構體混合物。 亦可能以氰化物SN2型置換位置17之適合脫離基,諸如 齒化物(較佳碘或溴)或者17_醇之磺酸酯。所用氛化物來源 較佳為無機氰化物’諸如氰化鋰、氰化鈉及氰化鉀。 馨 可提及以下作為引入腈之多步變異型的實例·· 1 7酮藉 助於雉蒂希烯化(Wittig 〇lefinati〇n)轉化為相應17_外亞甲 基化合物’蝴氫化且氧化為醛之後可反應得到相應17-甲 搭肪。接著肟脫水產生17_腈。 猜之引入可在合成序列開始時且亦可在稍後任何所需時 間點進行,只要可能存在之其他官能基以適合方式經保護 即可。 1 7-氣基化合物可視情況經烷基化產生立體化學均一 _ 之17β-氰基-17α經取代之衍生物。為此,17_氰基類固醇在 適合劑,諸如醚,例如四氫呋喃中去質子化。此處可使 用各種驗例如驗金屬酿胺,諸如二異丙基酿胺链。在添 加烧基化劑,諸如垸基齒化物或稀基齒化物且處理後,就 · 獲得17β-氰基-17α經取代之衍生物。 舉例而0 1藉助力以下合成流程說明進一步之合成程 序,提及已描述之化合物2(歸· k W外1835 144922.doc 、22· 201026718 (1976) ; US-A 3,705,179 (197 1))作為起始物質: 流程1versus. X Estrogen is of course mainly used as an estrogen in the treatment of premenopausal, near menopausal and postmenopausal symptoms and hormone replacement therapy, especially estradiol and its esters, such as estradiol valerate or bound estrogens ( CEE = ^ ^ 妗 people,,, ° mouth two hormones). If the preparation of the starting compound is not described herein, it is known to those skilled in the art or can be prepared analogously to known compounds or processes described herein. The mixture of isomers can be separated into enantiomers, E/Z isomers or epimers by conventional methods such as crystallization, chromatography or salt formation. [Examples] A compound of Chemical Formula 1 was prepared as described below. Suitable starting materials for the 17β-cyanoandrost-4-ene-3-one derivatives described in PCT/EP2008/057427 are various steroid starting materials, such as methylandrazine-4·ene-3,17-di Ketones (see, for example, 丄s〇c 8' 27 27 144922.doc -20- 201026718 (1965)), or partially reduced analogs, such as testosterone or prasterone. Suitable starting materials having 15α, 16α- or 15β, 16β-fluorenylene groups are also known from the literature (for example 15α, 16α-indenyl-indole-5-en-17-keto-3β-ol, See CTzew 106, 888 (1973); corresponding ^4-3, 17-:8^^ See DE-A 21 09 555 (1972)). 15β,16β-亚曱基曱雄甾-4-稀-3,17-二_ Described in /zv. iVawA: and Ser·8,1893 (1985) and C/iew. 107,128-134 (1974) The corresponding Δ5-3-ol is described in "gew. C/zew. 94 (9), 718 (1982). It will be apparent to those skilled in the art that in the description of synthetic transformations, other functional groups that are to be protected in a suitable form, as appropriate, are present on the steroid structure. The introduction of the nitrile in position 17 (C17) of the steroid structure can be carried out in various ways. Both one-step and multi-step variants are possible here. It is preferred here that the method of replacing the oxygen functional group with cyanide is preferred. Many possible method variants are described in *SWewce 〇/ Synthesis Houben-Weyl Methods of Molecular Transformations Category 3 Volume 19, pages 197-213 (2004 Georg Thieme Verlag Stuttgart, New York) and Houben-Weyl Methoden der organischen Chemie [ Houben-Weyl Methods of organic chemistry, Vol. 5, Part 2, pages 1318-1527 (1985 Georg Thieme Verlag Stuttgart, New York). One step envisaged is, for example, direct replacement of the carbonyl oxygen atom by cyano reduction. For this purpose, the 17-ketosteroid and the indenesulfonylmethyl isocyanide are suitable in a solvent such as dimethoxyethane, dimethylhydrazine, ether, alcohol or a mixture thereof in 144922.doc -21 - 201026718. Medium's use of a suitable base such as an alkali metal alkoxide, an alkali metal hydride, potassium hexamethyldioxanhydride or an alkali metal guanamine such as lithium diisopropylguanidinium at a temperature between 0 ° C and loot The next reaction. The 17-epimer mixture which may be formed may be separated by chromatography, fractional crystallization or a combination of such methods. It is also possible to replace the suitable cleavage group of position 17 with a cyanide SN2 type, such as a dentate (preferably iodine or bromine) or a 17-alcohol sulfonate. The source of the fragrance used is preferably inorganic cyanide such as lithium cyanide, sodium cyanide and potassium cyanide. The following may be mentioned as an example of a multi-step variant in which nitrile is introduced. The ketone is converted to the corresponding 17-exomethylene compound by means of hydrazinolation (Wittig 〇lefinati〇n) and is oxidized to The aldehyde can be reacted to give the corresponding 17-mole. Subsequent dehydration produces a 17-nitrile. The introduction of the guess can be made at the beginning of the synthesis sequence and also at any desired point in time later, as long as other functional groups that may be present are protected in a suitable manner. The 1 7-gas-based compound may optionally be subjected to alkylation to give a stereochemically uniform 171 17β-cyano-17α substituted derivative. To this end, the 17-cyanosteroid is deprotonated in a suitable agent such as an ether such as tetrahydrofuran. Here, various tests such as a metal-strength amine such as a diisopropyl-branched amine chain can be used. After the addition of an alkylating agent such as a decyl dentate or a dilute dentate and treatment, a 17β-cyano-17α substituted derivative is obtained. For example, 0 1 illustrates the further synthetic procedure by means of a synthetic scheme below the force, referring to the compound 2 already described (G.K W 1835 144922.doc, 22·201026718 (1976); US-A 3,705,179 (197 1)) as Starting material: Process 1
引入1,2-雙鍵至化合物2中就產生3。除其他脫水劑外, 適合者為二氧化鈿(J. Og. CTzem. 21,239 (1956))或 2,3-二 氯-5,6-二氰基苯醌心3 5 (5), 481 (1980))。可例如在 適合溶劑中使用三曱基鋁添加三甲基矽烷基氣化物及溴化 銅來進行1,4-加成得到1-甲基衍生物105 (9), 1429 (1993)) 〇 藉助於使3,5-二烯醇醚5溴化且隨後消除溴化氫來進行 6,7-雙鍵的引入(參見例如 J. Fried, J.A. Edwards, Reactions in Steroid Chemistry, von Nostrand Reinhold 144922.doc -23- 201026718The introduction of a 1,2-double bond to compound 2 produces 3. In addition to other dehydrating agents, it is suitable for cerium oxide (J. Og. CTzem. 21, 239 (1956)) or 2,3-dichloro-5,6-dicyanobenzoquinone 3 5 (5), 481 (1980)). The 1-methyl derivative can be obtained, for example, by adding trimethylsulfonium alkylate and copper bromide in a suitable solvent to a 1-methyl derivative 105 (9), 1429 (1993). The introduction of the 6,7-double bond is carried out by brominating the 3,5-dienol ether 5 and subsequently eliminating hydrogen bromide (see for example J. Fried, JA Edwards, Reactions in Steroid Chemistry, von Nostrand Reinhold 144922.doc) -23- 201026718
Company 1972, pp.)。 取代基R4之引入可例如以式2化合物為起始物,藉由在 鹼性條件下使用過氧化氫使4,5_雙鍵環氧化且使所得環氧 化物在適合溶劑中與化學通式H_R4之酸(其中R4可為鹵原 子或假iS素)反應,或藉由與催化量之無機酸反應且視情 況使所獲化學通式1之4_溴化合物(其中R4=溴)與2,2_二 氟-2-(氟磺醯基)乙酸曱酯在二曱基曱醯胺中在碘化銅〇)存 在下反應而達成。 化合物5之二烯醇醚溴化作用可(例如)類似於汾丄 233 (1963)之程序進行。溪化氫之消除可能藉由將&演化 合物與鹼性試劑(諸如LiBr或LiWO3)在非質子溶劑(諸如二 甲基甲醯胺)中在50。(:至12(^之溫度下加熱或藉由將6_漠 化合物在諸如三甲基吡啶或二甲基吡啶之溶劑中加熱來進 行而得到化合物6。 藉由根據已知製程,例如使用二甲基氧化疏亞甲基化物 (dimethylsulphoxonium methylide)使 67•雙鍵亞甲基化(參 見例如DE-A U 83 500、de_a 29 22 500、ep_a 〇 〇& 690 US-A 4,291,029 , J. Am. Chem. Soc. 84, 867 (1962)) 而將化合物7轉化為化合物8,獲得α•異構體與β•異構體之 此合物,其可例如藉由層析而分離為個別異構體。 類型7化合物可如實例中所述而獲得或類似於此等程序 使用類似於其中所述之彼等之試劑而獲得。 螺環化合物12之合成以2作為起始物,將其首先轉化為 3-胺基-3,5_二㈣生物9。#由與福馬林(f。腿Ηη)在醇溶 144922.doc -24· 201026718 液中反應,獲得6-經基亞甲基衍生物1〇。在將經基轉化為 脫離基,諸如甲磺酸酯基、曱苯磺酸酯基(化合物u)或者 苯曱酸酯基後,可藉由像用鹼(諸如鹼金屬氫氧化物或鹼 金屬醇鹽)在適合溶劑’諸如二曱亞;6風中與三甲基氧化鎳 埃反應而製備化合物13。 為引入6-亞曱基,可使用例如鹽酸於二噁烷/水中使化合 物10脫水。6-亞曱基亦可由η產生(參見DE-A 34 02 3291 ^ EP-A 0 150 157 ^ US-A 4,584,288 ; J. Med. Chem. 34, 2464 (1991)) 〇 製備6-亞甲基化合物之其他可能性在於使4(5)不飽和3_ 酮,諸如化合物2與甲醛之縮醛在乙酸鈉存在下,使用(例 士)氧氣化碟或五氣化填在適合溶劑,諸如氯仿中直接反 應(參見例如K. Annen,H. Hofmeister, H. Laurent and R. Wiechert,j孝(1982))。 6·亞曱基化合物可用於製備通Si化合物,其中R6a等於 甲基,且尺“及R7被省略而在c6與c7之間形成雙鍵。 為此,例如可使用描述於1619 (1965)中 之方法,其中藉由使在乙醇中的6_亞曱基化合物與經氫預 處理之5%飽/木炭催化劑一起升溫或藉由與少量環己烯一 起升溫而達成雙鍵之異構化。若添加少量環己烯至反應混 δ物中則異構化亦可使用未經預處理之催化劑進行。可 藉由添加過量乙酸鈉來防止出現少量氫化產物。 然而亦可直接製備6-曱基-4,6·二烯-3-酮衍生物(參見Κ. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Lieb. 144922.doc •25· 201026718Company 1972, pp.). The introduction of the substituent R4 can, for example, start with a compound of the formula 2, by epoxidizing the 4,5-double bond using hydrogen peroxide under basic conditions and bringing the resulting epoxide in a suitable solvent with a chemical formula An acid of H_R4 (wherein R4 may be a halogen atom or a pseudo iS), or by reacting with a catalytic amount of a mineral acid and optionally obtaining a 4-bromo compound of the formula 1 (wherein R4 = bromine) The 2, difluoro-2-(fluorosulfonyl)acetic acid oxime ester is reacted in the presence of ruthenium decylamine in the presence of copper ruthelium iodide. The bisenool ether bromination of compound 5 can be carried out, for example, analogously to the procedure of 汾丄 233 (1963). The elimination of hydrogen can be achieved by combining & evolution with an alkaline reagent such as LiBr or LiWO3 in an aprotic solvent such as dimethylformamide. (Compound to 12 or at a temperature of 2 or by heating a 6-g compound in a solvent such as trimethylpyridine or lutidine to obtain compound 6. By using a known process, for example, two Methyl oxidized dimethylsulphoxonium methylide methylates 67• double bonds (see for example DE-A U 83 500, de_a 29 22 500, ep_a 〇〇 & 690 US-A 4,291,029, J. Am Chem. Soc. 84, 867 (1962)) While converting compound 7 to compound 8, a compound of the ?-isomer and the ?-isomer is obtained, which can be separated into individual derivatives, for example, by chromatography. The type 7 compound can be obtained as described in the examples or similar to the procedures described above using reagents similar to those described therein. The synthesis of spiro compound 12 is carried out with 2 as the starting material, which is first Conversion to 3-amino-3,5-di(tetra)-organism 9. By reacting with formalin (f. leg Ηη) in alcohol solution 144922.doc -24· 201026718 to obtain 6-methylidene derivative 1). Conversion of a mesogenic group to a leaving group such as a mesylate group, an anthracenyl ester group (compound u) or a benzene After the acid ester group, compound 13 can be prepared by reacting with a solution of nickel methoxide such as a base such as an alkali metal hydroxide or an alkali metal alkoxide in a suitable solvent such as diterpene; The 6-fluorenylene group can be introduced, and the compound 10 can be dehydrated using, for example, hydrochloric acid in dioxane/water. The 6-fluorenylene group can also be produced by η (see DE-A 34 02 3291 ^ EP-A 0 150 157 ^ US-A 4,584,288 ; J. Med. Chem. 34, 2464 (1991)) Another possibility for the preparation of 6-methylene compounds by hydrazine is to make 4(5) unsaturated 3 ketones, such as the acetal of compound 2 with formaldehyde in the presence of sodium acetate. The direct reaction is carried out using a (s) oxygenated dish or a five gasification fill in a suitable solvent such as chloroform (see for example K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, j. (1982)). 6. The fluorenylene compound can be used to prepare a Si compound, wherein R6a is equal to a methyl group, and the ruler "and R7 are omitted to form a double bond between c6 and c7. For this, for example, it can be used as described in 1619 (1965). a method in which a 6-fluorenylene compound in ethanol and a 5% saturated/charcoal catalyst pretreated with hydrogen are used The temperature is raised or the isomerization of the double bond is achieved by heating with a small amount of cyclohexene. If a small amount of cyclohexene is added to the reaction mixture, the isomerization can also be carried out using a catalyst without pretreatment. A small amount of hydrogenated product is prevented from occurring by the addition of excess sodium acetate. However, it is also possible to directly prepare 6-mercapto-4,6-dien-3-one derivatives (see Κ. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Lieb. 144922.doc •25· 201026718
Ann. 712 (1983)) ° 化合物(其中R、a_甲基官能基)可由6亞甲基化合物藉 由在適合條件下氫化而製備。最佳結果(外亞f基官能基 之選擇性氫化)係藉由轉移氫化而達成(j cw ^」578 (1954))右將6-亞甲基衍生物在適合溶劑(諸如乙醇)中, 在氫化物供體(諸如己烯)存在下加熱,則獲得極佳產率 之6α甲基衍生物。少量邱_甲基化合物可經酸異構化 {Tetrahedron 1619 (1965)) 〇 亦可能選擇性製備6β-甲基化合物。為此,使4_烯_3_酮 (諸如化合物2)與例如乙二醇或原曱酸三甲酯在二氣甲烷 中,在催化量之酸(例如對曱苯磺酸)存在下反應,得到相 應3'缩酮。在此縮酮化期間,位置5(c5)處之雙鍵異構化。 可能例如藉由使用有機過酸’例如間氣過笨甲酸,在適合 溶劑,諸如二氯甲烷中,使此5_雙鍵選擇性環氧化。另一 種作法,亦可使用過氧化氫,在(例如)六氣丙酮或夂硝基 三氣苯乙畴在T進行環氧化。接著可錢適當院基鎮齒 化物或烷基鋰化合物,使所形成之5,6〇1_環氧化物軸向開 放。從而獲得5a-羥基_6β_烷基化合物。3_酮基保護基之裂 解可藉由在弱酸性條件下(乙酸或4 Ν鹽酸,〇它)處理,獲 得5α-羥基官能基而進行。使用例如稀氫氡化鈉水溶液鹼 性消除5α-羥基官能基提供具有β_6烷基之3_酮基_4·烯化合 物。另一種作法,在更劇烈條件下(鹽酸水溶液或另一種 強酸水溶液)進行縮酮裂解,提供相應6α_烷基化合物。 所獲化學通式1化合物(其中2為氧原子)可藉由與羥基胺 144922.doc -26- 201026718 鹽酸鹽,在三級胺存在下,在-20°C與+40°C之間之溫度下 反應’轉化為其相應肟(化學通式1,其中Z表示NOH,其 中輕·基可為同側-或反側-)。適合三級驗為例如三甲胺、三 乙胺、吡啶、N,N-二甲基胺基吡啶、1>5_二氮雜雙環 [4.3.0]壬 _5_ 烯(DBN)& 丨,5_ 二氮雜雙環[5 4 十一 _5烯 (DBU) ’以吡啶較佳。此反應類似WO-A 98/24801中針對 製備曲螺酮之相應3_氧基亞胺基衍生物所述之製法。Ann. 712 (1983)) ° Compounds (wherein R, a-methyl functional groups) can be prepared from 6 methylene compounds by hydrogenation under suitable conditions. The best result (selective hydrogenation of the exo-f-functional group) is achieved by transfer hydrogenation (j cw ^ 578 (1954)) to the right 6-methylene derivative in a suitable solvent such as ethanol. Heating in the presence of a hydride donor such as hexene gives an excellent yield of the 6α methyl derivative. A small amount of qi-methyl compound can be isomerized by acid {Tetrahedron 1619 (1965)) 6 It is also possible to selectively prepare 6β-methyl compound. To this end, a 4-olefin-3-one (such as compound 2) is reacted with, for example, ethylene glycol or trimethyl ortho-decanoate in dioxane in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid. , the corresponding 3' ketal is obtained. During this ketalization, the double bond at position 5 (c5) is isomerized. This 5-double bond may be selectively epoxidized, for example, by using an organic peracid 'e, such as meta-formic acid, in a suitable solvent such as dichloromethane. Alternatively, hydrogen peroxide can be used to epoxidize T at, for example, hexa-gas acetone or hydrazine nitrotris benzene. The formed 5,6〇1_epoxide can then be opened axially in the appropriate home base or alkyllithium compound. Thus, a 5a-hydroxy-6β-alkyl compound was obtained. The cleavage of the 3-keto protecting group can be carried out by treatment under weakly acidic conditions (acetic acid or 4 hydrazine hydrochloride, hydrazine) to obtain a 5?-hydroxyl functional group. The alkaline elimination of the 5?-hydroxyl group using, for example, an aqueous solution of dilute sodium hydrogensulfate provides a 3-keto-4-ene compound having a ?6 alkyl group. Alternatively, ketal cleavage can be carried out under more severe conditions (aqueous hydrochloric acid or another strong aqueous acid solution) to provide the corresponding 6a-alkyl compound. The obtained chemical formula 1 compound (wherein 2 is an oxygen atom) can be obtained by reacting with hydroxylamine 144922.doc -26- 201026718 hydrochloride in the presence of a tertiary amine at -20 ° C and +40 ° C The reaction at the temperature is converted to its corresponding oxime (Chemical Formula 1, wherein Z represents NOH, wherein the light base can be ipsilateral- or opposite--). Suitable for tertiary assays such as trimethylamine, triethylamine, pyridine, N,N-dimethylaminopyridine, 1>5-diazabicyclo[4.3.0]壬_5_ene (DBN) & 5_ Diazabicyclo[5 4 undecene (DBU)' is preferably pyridine. This reaction is similar to that described in WO-A 98/24801 for the preparation of the corresponding 3-methoxyimino derivative of trospireone.
移除3_側氧基以製備化學通式1之最終產物(其中Z表示 兩個氫原子)可例如藉由根據DE-A 28 05 490中所述之程 序’還原性裂解3-酮基化合物之硫縮酮而進行。 PCT/EP2008/057427中所述之化合物令人驚訝地因強妊 娠相關活性及在對大鼠皮下投與後在維持妊娠測試中之強 活性而出眾。 對大鼠進行維持妊娠測試: 在懷孕大鼠中,黃體移除或卵巢切除術誘發流產。藉助 於外源性投與助孕素(促孕素)以及適合劑量之雌激素可 能維持妊娠。對去卵巢大鼠進行之維持妞娠測試用於測定 化s物之外周杜娠相關(peripherai gestagenie)活性。 使大鼠在發情前期配對隔夜。次日早晨藉由評估陰道抹 片檢查配對。此處將精子之存在評估為開始妊娠的第i 天。在妊娠第8天,在醚麻醉下對動物施以去卵巢。在妊 娠第8天至第15天或第21天每天—次皮下進行以測試化合 物及外源性雌激素_,5响§/天)的治療。在第8天在 即巢切除術前兩小時進行首次投藥。完好之對照組動物僅 144922.doc -27· 201026718 接受媒劑。 評估: 在實驗結束時(第15天或第21天),在c〇2氛圍下處死動 物十數兩個子呂角中之存活胎兒(具有心跳之胎兒)及植 入位點(早期吸收及包括自溶及胎盤萎縮之死胎)。在第22 天’可能另外檢查胎兒畸形。在無胎兒或植人位點之子宮 中藉由以10%濃度之硫化銨溶液染色來測定子宮著床位 點數。維持姓娠率經計算為活胎兒數與子宮著床位點總數 (經吸收胎兒及死胎及子宮著床位點)之商。對於某些測試 物貝,測定表1中指示之妊娠維持劑量(ED5〇)。對於曲螺 酮而δ ’此值為3.5 mg/kg/天。 化學通式1之衍生物具有極強妊娠相關活性。另外發現 化學通式1之衍生物顯示活體外抗鹽皮質激素作用。因 此’其應具有活體内保鉀、促尿鈉排泄(抗鹽皮質激素)作 用。使用下述測試測定此等特性: 為培養用於檢定之細胞’所用之培養基為DMEM(杜貝 科氏改質伊格培養基(Dulbecco's Modified Eagle Medium): 4500 mg/ml葡萄糖;paA,第 E15-009 號)及 1〇〇/0 FCS(Biochrom,S0115 ’ 批號 615B)、4 mM L-麩胺醯胺、 1%青黴素/鏈黴素、1 mg/ml G418及0.5 pg/ml嘌呤黴素。 報導體細胞株以每孔4 X 1 〇4個細胞之密度生長於白色不 透明組織培養盤中’在各情況下具有96孔(PerkinElmer, 第P12-106-017號)且保持在6% DCC-FCS(經活性碳處理之 血清,以移除血清中所含干擾組份)中。八小時後添加待 144922.doc -28- 201026718 研究之化合物,且將細胞與化合物一起培育16小時。以一 式三份進行實驗。在培育結束時,移除含有效應物之培養 基且以溶解緩衝液置換。在添加螢光素酶檢定受質 (promega,第El5〇l號)後,接著將含有96孔之培養盤引入 微定量盤式光度計(Pherastar,BMG labtech)中,且量測發 光。使用計算劑量-活性關係之軟體來評估IC50值。將實 驗結果呈現於表1中: 表1 化合物 MR拮抗作用 IC50 [_ mr拮抗作用活性[最 大作用的百分比] PR活體内ED50 [mg/kg/d,皮下] 6β,7β; 15β,16β-雙亞曱基· 17β-氰基曱雄甾-4-烯-3-酮 4.7 98.06 7.3 Πβ-氰基-6,6-乙二基甲雄留-4-烯-3-酮 20.0 99.16 25.0 Πα-烯丙基-17β-氰基曱雄 留-4-稀-3-嗣 990.0 65.30 17β-氟基-17α-曱基-15β,16β-亞甲基甲雄甾冬烯-3-酮 42.0 98.30 10.0 以下合成較佳化合物之實例用於進一步說明 PCT/EP2008/057427中所述之發明。以下個別合成實例中 所揭示之新穎中間物,正如17β-氰基-19-去甲雄留-4-烯衍 生物,為PCT/EP2008/057427中所描述之發明之部分。 許多下述反應產生差向異構體混合物。通常,經由製備 型HPLC層析分離此等混合物在以下條件下進行:進行對 掌性正相之分離,常用固定相為Chiralpak AD-H 5μ。通 常,使用己烧與乙醇之混合物進行溶離。然而,在某些情 況下,使用其他溶離劑混合物,諸如甲醇與乙醇之混合 144922.doc -29- 201026718 物: 製備實例1 : 17P-氟基-15p,16p-亞甲基甲雄甾-4-烯-3-酮 la) 3-甲氧基_15β,16β-亞甲基甲雄甾_3(4),5(6)-二烯-17-酮 將5〇§150,160-亞甲基曱雄甾-4-烯-3,17-二酮溶解於11 曱醇及175 ml原甲酸三甲酯中。在25°C下,在攪拌下添加 25 0 mg對甲苯磺酸。短時間後,沈澱出產物。在25。〇下攪 拌混合物1小時且在-5°C下搜拌1小時。以η比咬中和混合物 且藉由抽吸過濾掉,得到3-甲氧基-ΐ5β,16β-亞曱基去甲雄 甾-3(4),5(6)-二烯-17-酮(48 g)。 (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=3·54 (s,0-CH3),5.12 (m,4-Η),5·25 (m,6-H)。 MS (CI+) m/z (相對密度)=312 (1〇〇);對應於C2iH28〇2。 lb) 17P-氰基-3-甲氧基_i5p,l6p-亞甲基甲雄甾烷-3(4),5(6)-二烯 在冰冷卻下,經1.5小時之時段將23 43 g TOSMIC®於 140 ml二甲氧基乙烷中之溶液緩慢添加至25 g 15β16卜亞 甲基-3-曱氧基曱雄甾院_3(4),5(6)_二烯_17_酮及458第三 丁醇鉀於1 1二曱氧基乙烷及300 ml第三丁醇中之溶液中, 且接著在室溫下再攪拌混合物3小時。將反應產物傾入冰 冷的半飽和氣化鈉溶液中,且藉由抽吸過濾掉經沈澱之產 物,以水洗滌且在真空乾燥箱(5(rc,2〇〇毫巴)中乾燥隔 144922.doc 201026718 夜。得到呈米色晶體之17β-|1基-3-甲氡基-ΐ5β,16β_亞甲基 曱雄留烷-3(4),5(6)-二烯(23.7 g)。 iH-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0.42 [m, 15·-Η(β)], 2.73 [d, /=4,5 Hz, 17-Η(α)], 5.14 (br. s,4-H), 5.27 (m,6-H) 〇 MS (CI+) m/z (相對密度)=324 (100),341 (85);對應於 C22H29NO。 lc)Removal of the 3_sideoxy group to prepare the final product of the chemical formula 1 (wherein Z represents two hydrogen atoms) can be 'reductively cleaved 3-keto compounds by, for example, the procedure described in DE-A 28 05 490 The thioketal is carried out. The compounds described in PCT/EP2008/057427 are surprisingly superior for their strong pregnancy-related activity and their potency in maintaining a pregnancy test after subcutaneous administration to rats. Maintenance of pregnancy test in rats: In pregnant rats, corpus luteum removal or oophorectomy induces miscarriage. Pregnancy can be maintained by exogenously administering progesterone (progestin) and a suitable dose of estrogen. The maintenance test for ovariectomized rats was used to determine the peripherai gestagenie activity of the s. Rats were paired overnight before estrus. The pairing was checked the next morning by evaluating the vaginal smear. The presence of sperm is assessed here as the first day of the start of pregnancy. On the 8th day of pregnancy, the animals were given an ovariectomized under ether anesthesia. Treatment with the test compound and exogenous estrogen _, 5 § § / day is performed subcutaneously on the 8th day to the 15th day or the 21st day of pregnancy. On the 8th day, the first administration was performed two hours before the nest resection. The intact control animals received only 144922.doc -27· 201026718 receiving vehicle. Assessment: At the end of the experiment (Day 15 or Day 21), the surviving fetus (fetal with heartbeat) and the implantation site (early absorption and Including autolysis and placental atrophy of the stillbirth). On day 22, fetal malformations may be additionally examined. The number of uterine implantation sites was determined by staining with a 10% ammonium sulfide solution in the uterus without fetus or implant site. Maintaining the surname rate is calculated as the number of live fetuses and the total number of uterine implantation sites (absorbed fetuses and stillbirths and uterine implantation sites). For certain test items, the pregnancy maintenance dose (ED5〇) indicated in Table 1 was determined. For tromethamine, the value of δ ' is 3.5 mg/kg/day. The derivative of the chemical formula 1 has extremely strong pregnancy-related activity. Further, it has been found that the derivative of the chemical formula 1 exhibits an action against mineralocorticoid in vitro. Therefore, it should have potassium in the body and urinary sodium excretion (anti-mineral corticosteroids). The following tests were used to determine these characteristics: The medium used to culture the cells used for assay was DMEM (Dulbecco's Modified Eagle Medium: 4500 mg/ml glucose; paA, E15- 009) and 1〇〇/0 FCS (Biochrom, S0115 'batch 615B), 4 mM L-glutamine, 1% penicillin/streptomycin, 1 mg/ml G418 and 0.5 pg/ml puromycin. The reporter cell line was grown in a white opaque tissue culture plate at a density of 4 X 1 〇 4 cells per well 'in each case 96 wells (PerkinElmer, No. P12-106-017) and kept at 6% DCC- FCS (activated carbon-treated serum to remove interfering components contained in serum). Compounds to be studied were added after 8.4922.doc -28-201026718, and the cells were incubated with the compounds for 16 hours. Experiments were performed in triplicate. At the end of the incubation, the medium containing the effector was removed and replaced with a lysis buffer. After the addition of the luciferase assay host (promega, No. El5〇1), a 96-well culture plate was introduced into a micro-quantitative disc luminometer (Pherastar, BMG labtech), and the luminescence was measured. The IC50 value was evaluated using a software that calculates the dose-activity relationship. The experimental results are presented in Table 1: Table 1 Compound MR antagonism IC50 [_ mr antagonism activity [% of maximum effect] PR in vivo ED50 [mg/kg/d, subcutaneous] 6β, 7β; 15β, 16β-double Ardenyl·17β-cyanoindole-4-4-en-3-one 4.7 98.06 7.3 Πβ-cyano-6,6-ethylenediyl-androst-4-en-3-one 20.0 99.16 25.0 Πα- Allyl-17β-cyanoguanidine male-4-pyrene-3-indole 990.0 65.30 17β-fluoroyl-17α-mercapto-15β,16β-methylene-androstene-3-one 42.0 98.30 10.0 The following examples of the synthesis of preferred compounds are used to further illustrate the invention described in PCT/EP2008/057427. The novel intermediates disclosed in the following individual synthesis examples, such as the 17β-cyano-19-nor-androst-4-ene derivative, are part of the invention described in PCT/EP2008/057427. Many of the reactions described below produce an epimer mixture. Typically, separation of these mixtures via preparative HPLC chromatography is carried out under the following conditions: separation of the positive palm phase, the usual stationary phase being Chiralpak AD-H 5μ. Usually, a mixture of hexane and ethanol is used for dissolution. However, in some cases, other dissolving agent mixtures are used, such as a mixture of methanol and ethanol 144922.doc -29- 201026718: Preparation Example 1: 17P-fluoro-15p, 16p-methylenemethylanthrene-4 -en-3-one la) 3-methoxy-15β,16β-methylenemethylanthrene_3(4),5(6)-dien-17-one will be 5〇§150,160-亚Methyl anthraquinone-4-ene-3,17-dione was dissolved in 11 sterol and 175 ml of trimethyl orthoformate. 25 mg of p-toluenesulfonic acid was added with stirring at 25 °C. After a short time, the product precipitated. At 25. The mixture was stirred under ankle for 1 hour and at -5 °C for 1 hour. Neutralize the mixture with η ratio and filter by suction to obtain 3-methoxy-ΐ5β, 16β-arylene-nor-androst-3(4),5(6)-dien-17-one (48 g). (300 MHz, CDC13 TMS as internal standard, selected signal): δ=3·54 (s,0-CH3), 5.12 (m,4-Η), 5·25 (m,6-H). MS (CI+) m/z (relative density) = 312 (1〇〇); corresponds to C2iH28〇2. Lb) 17P-cyano-3-methoxy_i5p, l6p-methylene methylandrostane-3(4),5(6)-diene, under ice cooling, will be 23 43 over a period of 1.5 hours g TOSMIC® in 140 ml of dimethoxyethane is slowly added to 25 g of 15β16, methylene-3-oxooxy oxime _3 (4), 5 (6) _ diene _17 ketone And 458 a solution of potassium t-butoxide in 1 1 dimethoxy ethane and 300 ml of tributanol, and then the mixture was further stirred at room temperature for 3 hours. The reaction product was poured into ice-cold semi-saturated sodium carbonate solution, and the precipitated product was filtered off by suction, washed with water and dried in a vacuum drying oven (5 (rc, 2 mbar). .doc 201026718 night. 17β-|1yl-3-carbamimido-indole 5β, 16β_methylene hydrazin-3(4),5(6)-diene (23.7 g) in beige crystals iH-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.42 [m, 15·-Η(β)], 2.73 [d, /=4,5 Hz, 17-Η(α )], 5.14 (br. s,4-H), 5.27 (m,6-H) 〇MS (CI+) m/z (relative density)=324 (100), 341 (85); corresponds to C22H29NO. lc )
B — 17P-氟基-15β,16ρ-亞甲基甲雄甾-4-烯-3-酮 在室溫下,將5 ml硫酸(8重量%)添加至700 mg 17β氰 基-3-曱氧基·ΐ5β,ι6β·亞甲基甲雄留烷_3(4) 5(6)·二烯於1〇 ml曱醇中之溶液中’且使混合物在此溫度下攪拌2小時。 以飽和碳酸氫鹽溶液中止反應,接著以二氣曱烷萃取混合 物且用Ηβ及飽和氣化鈉溶液洗滌萃取物,經硫酸鈉乾燥 且在旋轉蒸發器上濃縮。此導致17β-氰基-15β,16β-亞甲基 φ 甲雄甾_4·烯結晶(599 mg)。 hAMR (300 MHz,CDC13 TMS作為内標,經選擇信號): 6=0.44 [m, 15'-Η(β)]5 2.74 [d, J=4.5 Hz, 17-Η(α)], 5.44 (br. s, 4-H)。 MS (EI+) m/z (相對密度)=3〇9 (5〇);對應於c2iH27N〇。 製備實例2 : 17β-氟基-6p-羥基甲基_15p,16p亞甲基甲雄甾_4_烯_3綱 將9.5 g 17β-氰基-1Sp,16p_亞曱基曱雄甾烯_3_酮溶解 於〇 ml曱私中,添加4.8 mlD比嘻咬且使混合物在回流下升 144922.doc •31 - 201026718 溫歷時1小時。冷卻後,藉由抽吸過濾掉沈澱,用少許冷 曱醇洗務且吸乾。將晶體(11 g)溶解於j 3 5 mi甲苯及23 5 ml 乙醇中,且添加11·5 ml 30%濃度之甲醛溶液。在室溫下攪 拌2小時後,將混合物濃縮至乾燥且石夕膠層析。得到i7β_ 氰基-6β-羥基曱基- Ι5β,16β-亞甲基甲雄留_4_烯_3_酮(4·7 g)。 H_NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0.47 [m,15'-Η(β)], 2.76 [d,/=4.5 Ηζ,17-Η(α)],AB信號 (δΑ=3_68, δΒ=3·80, *7^10.5 Hz,另外以^=7.4 Hz, Aw,6-7/=10.5 Hz分裂),5.84 (s, 4-H)。 MS (EI+) m/z (相對密度)=339 (37);對應於 c22H29N〇2。 製備實例3 : 17卜氣基-6,6-伸乙基-15p,16卜亞甲基甲雄甾_4_烯_3__ 3a) 17β-氰基-15ρ,16β-亞甲基_6β·甲苯磧醢基氧基甲基甲雄 留·4-烤τ-3-明 將2.93 g甲苯磺醯基氯化物一次性添加至174 g ΐ7β_氰 基-6β-經基曱基-15β,16β-亞曱基曱雄甾-4-烯-3-酮於20 ml 。比咬中之溶液中且在室溫下攪拌6小時。其後,將反應混 合物傾入冰冷的1 N鹽酸中且以抽吸過濾掉經沈澱之粗產 物且再次溶解於乙酸乙酯中。在用水、飽和碳酸氫鹽溶液 及飽和氣化納溶液在各情況下洗滌兩次,且使用硫酸鈉乾 燥有機相後,在濃縮至乾燥後,獲得17β_氰基_15β,16β_# 甲基-6β-甲苯磺醯基氧基曱基甲雄留_4_烯_3•酮,將其立即 144922.doc •32- 201026718 用於下一步驟中。 iH-NMR (300 MHz’ CDC13 TMS作為内標,經選擇信號): δ = 0.46 [m,15’-Η(β)],AB信號(3a=3.95,5b=4.2〇,心忍=9 $ Hz ’ 額外由心⑷,<^=7.0 Hz,Hz分裂),5 72 (s 4-H)。 3b) 17P-氰基-6,6-伸乙基-15β,16β-亞甲基甲雄甾-4-烯-闲 在室溫下分批添加913 mg氫化鈉至6.02 g三曱基氧化斜 碘於50 ml無水DMSO中之溶液中且在添加完成後,在室溫 下攪拌混合物1小時。隨後’將3_13 g 17β-氰基_ΐ5ρ,16β_ 亞甲基-6β-曱苯磺醯基氧基甲基甲雄留_4_烯_3_酮之溶液添 加至所形成之内鏽鹽中且在室溫下攪拌混合物6小時。藉 由添加350 ml水終止反應後,以15〇⑹乙酸乙酯萃取兩 次,以水及飽和氣化鈉溶液洗滌有機相且經硫酸鈉乾燥, 在室溫下以活性碳處理有機相丨5分鐘。經Celite®層過濾 後,在濃縮有機相時17β-氰基-6,6-伸乙基-ΐ5β,16β·亞甲基 甲雄留-4-烯-3-酮結晶(Κ1 503 mg,Κ2 379 mg)。 ^-NMRQOO MHz’ CDCh TMS作為内標,經選擇信號): δ=〇·38-0·53 [m,(3H)螺伸乙基],〇 88 [m,(ih)螺^乙 基]’ 2_75 [d, J=4.5 Hz,17-H⑷],5.65 (s,4-H)。 MS (則m/z (相對密度)=335 (i 〇〇);對應於。 製備實例4 : 17P-氰基·6_外亞甲基_lsp,16p亞f基甲雄^4稀_3綱 在室溫下,添加1 ml 6 N鹽酸至1 g 17β-氰基-6β_經基甲 144922.doc ·33· 201026718 基_1邛斗亞甲基甲雄留_4-烯_3,於l〇 mi〉惡烷中之溶 液中,且使混合物保持在此溫度下2小時。接著添加反應 混合物至2S0 ml冰冷半飽和碳酸氫鹽溶液中且以15〇⑷乙 酸乙醋萃取兩次。在以硫酸納及活性碳處理經合併有機相 後,將混合物經由Celite®層過濾且濃縮至乾燥。矽膠急驟 層析[己烷/乙酸乙酯(0-25%)]得到l7p_氰基_6_外亞甲 基-15β,16β-亞曱基甲雄甾_4_烯_3_酮(399 mg)。 H-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): 5.12 (dd->t,在各情況下j=2.〇 Hz,=CH2),5.94 (d, J=0.6 Hz,4-H)。 MS (EI+) m/z (相對密度)=321 (96);對應於c22h27N〇。 製備實例5 : 17β-氰基_6α-甲基-Ι5β,16β-亞甲基甲雄甾-4-烯-3-酮 在氬氛圍下’將300 mg威爾金森催化劑(Wilkinson、 catalyst)添加至330 mg 17β-氰基-6-外亞曱基-15β,16β-亞曱 基曱雄甾-4-烯-3-鲷於40 ml甲苯及10 ml乙醇中之溶液中, 且使用震盪器設備在大氣壓下在氫下氫化混合物歷時3小 時。藉由矽膠急驟層析[己烷/乙酸乙酯(0-50%)]移除催化 劑得到17β-氰基·6β-甲基-15β,16β-亞曱基曱雄错-4-烯_3_ 酮:17β-氰基-6α-曱基-15β,16β-亞甲基甲雄甾-4-烯-3-輞的 比率=2.5 : 1之6-差向異構體混合物。使用催化量的對曱笨 磺酸在二氯曱烷中酸性差向異構及另一矽膠急驟層析[己 烷/乙酸乙酯(0-50%)]得到純17β-氰基_6α-曱基-15β,ΐ6β_亞 144922.doc -34- 201026718 甲基甲雄留-4-稀-3-酮(39 mg)。 ^•NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0·46 [m,15·-Η(β)],ι·ΐ2 (d,《7=6.3 Hz, 6-CH3),2.75 [d, J=4.6 Hz,17_H(cx)],5.82 (d,《7=1.3 Hz, 4-H)。 MS (EI+) m/z (相對密度)=324 (95),341 (55);對應於 C22H29NO 0 製備實例6 : 17P-氰基-15β,16ρ-亞甲基甲雄甾-4,6•二烯_3_阑 ® 將3.4 g 17卜氰基-3-曱氧基-15β,16β·亞曱基甲雄 甾-3(4),5(6)-二稀在1〇〇 mi 甲基_2_0比洛咬綱中之懸浮液 在〇°C下以4 ml 10%濃度之乙酸鈉溶液且在此溫度下以16 g —漠_5,5_ 一甲基乙内酿腺分批連續處理,在〇。匸(冰 浴)下攪拌0.5小時,以1.5 g溴化鋰及丨3 g碳酸鋰處理,且 在100°C之浴溫度下攪拌3.5小時。接著將混合物攪拌加入 冰-水/氣化鈉中且過濾掉沈澱。得到丨7β_氰基_丨5 p,丨6卜亞 ^ 甲基甲雄留-4,6-二烯-3-酮(2.42 g)。 W-NMR (300 MHz,CDCI3 TMS作為内標,經選擇信號): 6=0.53 [m, 15·-Η(β)], 2.78 [d, J=4.5 Hz, 17-Η(α)], 5.7〇 (s, 4-H), 6.18 (dd, 7=2.8 Hz, /=9.8 Hz, 5-H*), 6.33 (dd, J=2.1 Hz, *7=9.8 Hz,6-H*),* =分配可逆。 製備實例7 : 6ρ,7ρ-15ρ,16β·雙亞甲基-ΐ7ρ·氰基甲雄错-4_稀_3闲及 6α,7α-15ρ,16ρ-雙亞甲基-17Ρ-氱基甲雄甾-4_烯-3__ 在室溫下分批添加468 mg氫化鈉至3.09 g三甲義氧化餘 144922.doc •35- 201026718 碘於25 ml無水二甲亞颯中之溶液中且在添加完成後,在 室溫下授拌混合物1小時。隨後,將丨.〇 g 17β_氰 基-15β,16β-亞甲基甲雄留-4,6-二烯-3-酮溶液添加至所形 成之内錄鹽中且在至溫下授掉混合物6小時。藉由添加15〇 ml氯化敍溶液終止反應後’用75 ml乙酸乙酯萃取兩次, 用水及飽和氣化納溶液洗務有機相且經硫酸納乾燥,將有 機相濃縮至乾燥。兩次矽膠急驟層析[己烷/乙酸乙酯 (0-50%)]得到作為較低極性溶離份之6α,7α15β,16β雙亞甲 基-17β-氰基曱雄甾_4_烯-3-酮(59 mg)及作為較高極性溶離 參 份之6β,7β-15β,16β-雙亞曱基_17β·氰基曱雄崔_心烯_3酮 (67 mg)。 溶離份1 : 6(*,7<1-15杉,1叫-雙亞甲基_17衫_氰基甲雄甾_4-稀-3·明 H-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0.53, 0.63, 0.87及 0.98 [4xm,(在各情況下 1H)環丙基], 2·80 [d’《/=4·3 Ηζ, 17-Η(α)], 6.01 (s,4-H)。 MS (CI+) m/z (相對密度)=322 (1〇〇),339 (33);對應於 〇 C22H27NO。 溶離份2: 6p,7p-isp,l6p-雙亞甲基_17p_氟基甲雄甾·4_ 稀-3-9¾ : H-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號):. δ=0_57及0.92 [2xm,(在各情況下1H)環丙基],2 84 [d, •7=4.3 Ηζ,17-Η(α)],6 07 (s, 4_H)。 MS (EI+) m/z (相對密度)=322 〇〇〇),339 (33);對應於 144922.doc • 36 · 201026718 C22H27NO。 製備實例7-變異型2: 6卩,7於-15好,16杉-雙亞甲基_17释-氰基甲雄甾-4-烯-3-_ 7_變異型2_a) 6p,7p-15p,16p-雙亞甲基_3p_5p_雙羥基_17p_氰基甲雄甾烷 及6β,7β-15ρ,16β-雙亞甲基-3P-5P-雙羥基-17α-氰基甲雄留 烷 類似於實例lb中所給方法使6β,7β-15β,16β-雙亞曱 基_3β,5β-二經基甲雄甾烧-17-酮c/zewz'e 1982,Ρ4, 718-719)反應。使用己烷與乙酸乙酯之混合物矽膠層析得 到6β,7β-15β,16β-雙亞甲基_3β-5β-雙經基_ΐ7β_氰基甲雄甾 烷及6β,7β-15β,16β-雙亞甲基_3β-5β-雙羥基_17〇[_氰基甲雄 甾烷。 6於,73-15好,1邱-雙亞甲基-3释-5好-雙|^基_17杉-氟基甲雄留 烷: W-NMR (D6-DMSO): 0.41 (m,2Η),〇.61 (m,1H),〇 73 (s, 3H), 0.83 (s, 3H),2.97 (寬單蜂 ’ 1H), 3.79 (寬單峰,1H) 4.31 (寬單峰,1H), 4.79 (寬單峰,1H) 6衫,7於-15择,16?-雙亞甲基-;^-5衫-雙經基_17〇1_氰基甲雄错 烷: W-NMR (D6-DMSO): 0.41 (m,2H),0.61 (m,1H),0.73 (s, 3H),0.80 (s, 3H),3.05 (寬單峰,1H) 7-變異型2-b) 6p,7p-15p,16p-雙亞甲基-ΐ7ρ·氰基甲雄留_4_稀_3_酌 144922.doc 37· 201026718 類似於實例30e中所給之程序使6β,7β-ΐ5β,16β-雙亞曱 基-3β-5β-雙羥基-17β-氰基甲雄甾烷反應。此得到6β 7β_ 15β,16β-雙亞曱基-17β-氰基曱雄甾_4·烯_3_酮。 NMR資料與實例7中所給彼等者相同。 製備實例8 : 17β-氰基-7α-甲基-15β,16β-亞甲基甲雄甾_4稀_3_酮 在室溫下,將67 mg氣化鋼⑴添加至1〇 g 17卜氰 基-15β,16β-亞曱基曱雄甾烷-4,6-二烯-3-酮於50 ml四氫呋 喃中之溶液中且授拌混合物1〇分鐘且接著冷卻至_15。匚, 接著添加450 mg氯化鋁,在此溫度下攪拌混合物3〇分鐘, 逐滴添加4.5 ml溴化曱基鎂溶液(3 M於四氫呋喃中) 且在-15C下攪拌混合物一小時。為進行處理,在_15。〇 下添加30 ml 2 Μ鹽酸至反應混合物中,在室溫下攪拌混 合物0.5小時,添加至水中且用乙酸乙酯萃取三次且將 萃取物經硫酸鈉乾燥,在減壓下濃縮且使用己烧/乙酸乙 酯(〇-5〇%)矽膠層析。此得到丨7^氰基_7a f *_ΐ5β ΐ6ρ亞 甲基甲雄甾-4-烯-3-酮(149 mg)。 iNMR (3〇〇 MHz,CDCl3 TMS作為内標,經選擇信號): δ=〇·45 [m, 15·-Η(β)], 〇>88 (dj j=7.l Hz, 7-Me), 1.08^1.21 Μ,在各情況下(3H),2xMe],2 75 [山 j=4 6Hz i7_ H(a)],5.76 (s,4-H)。 MS (CI+) m/z (相對密度)=324 (1〇〇),% (55);對應於 C22H29NO。 製備實例9 : 144922.doc 201026718 17P-氰基_17α-甲基-15β,16β-亞甲基甲雄甾-4_烯-3-酮 9a) 17P-氰基-3-甲氧基-17α-甲基·ΐ5β,16β-亞甲基甲雄甾 烷-3(4),5(6)-二烯 在-78°C下,將二異丙基醯胺鋰(LDA)之新鮮冷溶液(事 先在0°C下在82 ml四氫呋喃中由12.1 ml二異丙基胺及54.1 ml n-BuLi( 1.6 Μ於己烷中)製備)添加至8 g 17-氰基-3-甲氧 基-15β,16β-亞甲基甲雄留烷-3(4),5(6)-二烯之溶液中,且 ¥ 使混合物保持在-78°C下1小時。在隨後添加6.9 ml甲基碘 化物之前,使混合物冷卻回-90°C。添加結束後,使反應 混合物緩慢升溫至室溫隔夜。藉由添加飽和氯化铵溶液終 止反應,以乙酸乙酯萃取混合物且以水及飽和氯化納溶液 洗滌萃取物。以硫酸鈉乾燥有機相’濃縮至乾燥且矽膠急 驟層析[己烷/乙酸乙酯(0-30%)]得到Ι7β-氰基-3-曱氧 基-17α-曱基·15β,16β-亞曱基曱雄甾烷-3(4),5(6)-二稀(6.5 ®g)。 iH-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): 6=0.40 [m, 15'-Η(β)], 1.01 (s, Me), l.l5 (s, Me), 1.38 (s,B-17P-fluoro-15β,16ρ-methylenemethylandrost-4-en-3-one 5 ml of sulfuric acid (8% by weight) was added to 700 mg of 17β cyano-3-anthracene at room temperature Oxyquinone 5β, ι6β·methylenemethylhectoride _3(4) 5(6)·diene was dissolved in 1 〇ml of sterol' and the mixture was stirred at this temperature for 2 hours. The reaction was quenched with saturated bicarbonate solution, then the mixture was extracted with dioxane and the extract was washed with EtOAc and sat. sodium sulphate, dried over sodium sulfate and concentrated on a rotary evaporator. This resulted in the crystallisation of 17β-cyano-15β,16β-methylene φ methylandroin-4·ene (599 mg). hAMR (300 MHz, CDC13 TMS as internal standard, selected signal): 6=0.44 [m, 15'-Η(β)]5 2.74 [d, J=4.5 Hz, 17-Η(α)], 5.44 ( Br. s, 4-H). MS (EI+) m/z (relative density) = 3〇9 (5〇); corresponds to c2iH27N〇. Preparation Example 2: 17β-fluoro-6p-hydroxymethyl-15p,16p methylenemethylandrosine_4_ene_3 9.5 g 17β-cyano-1Sp, 16p_arylene-androstene The _3_ ketone was dissolved in 〇ml曱, adding 4.8 mlD to the bite and the mixture was raised under reflux 144922.doc •31 - 201026718 The temperature was 1 hour. After cooling, the precipitate was filtered off by suction, washed with a little cold methanol and blotted dry. The crystals (11 g) were dissolved in j 3 5 mi of toluene and 23 5 ml of ethanol, and 11.5 ml of a 30% strength formaldehyde solution was added. After stirring at room temperature for 2 hours, the mixture was concentrated to dryness and chromatography. I7β_cyano-6β-hydroxyindenyl-purine 5β, 16β-methylenemethyl-androst-4-ene-3-one (4·7 g) was obtained. H_NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.47 [m, 15'-Η(β)], 2.76 [d, /=4.5 Ηζ, 17-Η(α)], AB signal (δΑ=3_68, δΒ=3·80, *7^10.5 Hz, additionally with ^=7.4 Hz, Aw, 6-7/=10.5 Hz split), 5.84 (s, 4-H). MS (EI+) m/z (relative density) = 339 (37); corresponds to c22H29N〇2. Preparation Example 3: 17Bu-based-6,6-Extended Ethyl-15p, 16-methylenemethyl-androstene_4_ene_3__ 3a) 17β-cyano-15ρ,16β-methylene-6β·toluene Mercaptooxymethylmethylxanthine·4-baked tau-3- Ming added 2.93 g of toluenesulfonyl chloride to 174 g ΐ7β_cyano-6β-pyridinyl-15β,16β-Asia曱基曱雄甾-4-en-3-one in 20 ml. Stir in the solution in the bite and at room temperature for 6 hours. Thereafter, the reaction mixture was poured into ice-cold 1 N hydrochloric acid and the precipitated crude product was filtered off with suction and dissolved again in ethyl acetate. After washing twice with water, a saturated bicarbonate solution and a saturated sodium hydride solution, and drying the organic phase with sodium sulfate, after concentration to dryness, 17β_cyano-15β, 16β_# methyl- 6β-Toluenesulfonyloxyindolyl-methyl- 4-ene ketone, which was immediately used in the next step, 144922.doc •32- 201026718. iH-NMR (300 MHz' CDC13 TMS as internal standard, selected signal): δ = 0.46 [m, 15'-Η(β)], AB signal (3a=3.95, 5b=4.2〇, heart tolerance = 9 $ Hz 'extra heart (4), <^=7.0 Hz, Hz split), 5 72 (s 4-H). 3b) 17P-cyano-6,6-extended ethyl-15β,16β-methylenemethylandrost-4-ene-freely added 913 mg of sodium hydride in batches to 6.02 g of trimethyl sulphate The solution of iodine in 50 ml of anhydrous DMSO and after the addition was completed, the mixture was stirred at room temperature for 1 hour. Subsequently, a solution of 3_13 g of 17β-cyano-ΐ5ρ,16β_methylene-6β-nonylsulfonyloxymethylmethyl-methyl- 4-ene--3-one is added to the formed internal rust salt. The mixture was stirred at room temperature for 6 hours. After the reaction was terminated by adding 350 ml of water, the mixture was extracted twice with 15 〇 (6) ethyl acetate. The organic phase was washed with water and a saturated sodium carbonate solution and dried over sodium sulfate, and the organic phase was treated with activated carbon at room temperature. minute. After filtration through the Celite® layer, 17β-cyano-6,6-extended ethyl-ΐ5β,16β·methylenemethyl-androst-4-en-3-one crystals (Κ1 503 mg, Κ2) when the organic phase is concentrated. 379 mg). ^-NMRQOO MHz' CDCh TMS as internal standard, selected signal): δ=〇·38-0·53 [m,(3H) spiroethyl),〇88 [m,(ih)spiro[ethyl] ' 2_75 [d, J=4.5 Hz, 17-H(4)], 5.65 (s, 4-H). MS (then m/z (relative density) = 335 (i 〇〇); corresponds to. Preparation Example 4: 17P-cyano·6_exomethylene _lsp, 16p subf group 甲雄^4 _3 At room temperature, add 1 ml of 6 N hydrochloric acid to 1 g of 17β-cyano-6β_ via ketone 144922.doc ·33· 201026718 base _1 邛 亚 甲基 甲基 _ _ _ _ _ _ 3, The solution was dissolved in methane, and the mixture was maintained at this temperature for 2 hours. The reaction mixture was then added to 2 s of ice-cold, half-saturated bicarbonate solution and extracted twice with 15 〇 (4) ethyl acetate. After the combined organic phases were treated with sodium sulphate and activated carbon, the mixture was filtered through Celite® layer and concentrated to dryness. EtOAc (hexane/ethyl acetate (0-25%)). 6_exomethylene-15β,16β-indolylmethylandrosine_4_ene_3_one (399 mg) H-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): 5.12 ( Dd->t, in each case j=2.〇Hz,=CH2), 5.94 (d, J=0.6 Hz, 4-H) MS (EI+) m/z (relative density)=321 (96 Corresponding to c22h27N〇. Preparation Example 5: 17β-cyano-6α-methyl-Ι5β, 16β-methylenemethylandrost-4-ene- 3-ketone in an argon atmosphere's addition of 300 mg Wilkinson catalyst (Wilkinson, catalyst) to 330 mg 17β-cyano-6-exo-indenyl-15β,16β-arylene-indenyl-indole-4-ene -3-In a solution of 40 ml of toluene and 10 ml of ethanol, and hydrogenating the mixture under hydrogen at atmospheric pressure for 3 hours using an oscillating device. Rapid chromatography by phthalocyanine [hexane/ethyl acetate (0- 50%)] remove the catalyst to obtain 17β-cyano·6β-methyl-15β,16β-arylene-indolyl-4-ene-3-enone: 17β-cyano-6α-mercapto-15β,16β- The ratio of methylene methyl androst-4-ene-3-indole = 2.5: 1 to 6-epimer mixture. The catalytic amount of p-sulfonic acid in dichlorosilane is used for acidic epimerization. And another gelatin flash chromatography [hexane / ethyl acetate (0-50%)] to obtain pure 17β-cyano_6α-mercapto-15β, ΐ6β_亚144922.doc -34- 201026718 methylmethyl male -4-thin-3-one (39 mg) ^•NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ=0·46 [m,15·-Η(β)], ι· Ϊ́2 (d, "7=6.3 Hz, 6-CH3), 2.75 [d, J=4.6 Hz, 17_H(cx)], 5.82 (d, "7=1.3 Hz, 4-H). MS (EI+) m/z (relative density) = 324 (95), 341 (55); corresponds to C22H29NO 0 Preparation Example 6 : 17P-cyano-15β,16ρ-methylenemethylanthrene-4,6• Diene _3_阑® will be 3.4 g 17 cyano-3-indolyl-15β,16β·arylene-methyl-androst-3(4),5(6)-diluted in 1〇〇mi A The suspension of the base 2_0 洛 洛 〇 以 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Processing, in the embarrassing. The mixture was stirred for 0.5 hour under hydrazine (ice bath), treated with 1.5 g of lithium bromide and 3 g of lithium carbonate, and stirred at a bath temperature of 100 ° C for 3.5 hours. The mixture was then stirred into ice-water/vaporized sodium and the precipitate was filtered off.丨7β_Cyano-丨5 p, 丨6buy^methylmethyl-androst-4,6-dien-3-one (2.42 g) was obtained. W-NMR (300 MHz, CDCI3 TMS as internal standard, selected signal): 6=0.53 [m, 15·-Η(β)], 2.78 [d, J=4.5 Hz, 17-Η(α)], 5.7〇(s, 4-H), 6.18 (dd, 7=2.8 Hz, /=9.8 Hz, 5-H*), 6.33 (dd, J=2.1 Hz, *7=9.8 Hz, 6-H*) , * = allocation is reversible. Preparation Example 7: 6ρ,7ρ-15ρ,16β·bismethylene-ΐ7ρ·cyanomethine-4_dilute_3 leisure and 6α,7α-15ρ,16ρ-bismethylene-17Ρ-氱基甲Male-4-ene-3__ Add 468 mg of sodium hydride in batches to 3.09 g of trimethoate 144922.doc •35- 201026718 Iodine in 25 ml of anhydrous dimethyl hydrazine in solution and added After that, the mixture was stirred at room temperature for 1 hour. Subsequently, a solution of 丨.〇g 17β_cyano-15β,16β-methylenemethylandrazine-4,6-dien-3-one is added to the formed internal salt and is given at temperature. The mixture was 6 hours. After the reaction was terminated by the addition of 15 〇 ml of the chlorinated solution, the organic phase was extracted twice with 75 ml of ethyl acetate, and the organic phase was washed with water and a saturated sodium chloride solution and dried over sodium sulfate, and the organic phase was concentrated to dryness. Two chromatographic flash chromatography [hexane/ethyl acetate (0-50%)] gave 6α,7α15β,16β bismethylene-17β-cyanoindole _4_ene as a lower polar dissolving fraction. 3-ketone (59 mg) and 6β,7β-15β,16β-bis-indenyl-17β·cyanoquinonexiong_xinene-3-one (67 mg) as a highly polar dissolving component. Dissolved fraction 1 : 6 (*, 7 < 1-15 cedar, 1 called - bismethylene _17 _ cyanomethyl guanidine _4-zinc-3 · Ming H-NMR (300 MHz, CDC13 TMS as Standard, selected signal): δ = 0.53, 0.63, 0.87 and 0.98 [4xm, (in each case 1H) cyclopropyl], 2·80 [d'"/=4·3 Ηζ, 17-Η(α )], 6.01 (s,4-H) MS (CI+) m/z (relative density) = 322 (1〇〇), 339 (33); corresponds to 〇C22H27NO. Dissolved fraction 2: 6p,7p-isp , l6p-bismethylene_17p_fluoromethyl-androsine·4_ dilute-3-93⁄4: H-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ=0_57 and 0.92 [2xm, (in each case 1H) cyclopropyl], 2 84 [d, •7=4.3 Ηζ, 17-Η(α)], 6 07 (s, 4_H) MS (EI+) m/z (relative density) =322 〇〇〇), 339 (33); corresponds to 144922.doc • 36 · 201026718 C22H27NO. Preparation Example 7 - Variant 2: 6卩, 7 at -15, 16 cedar-bismethylene_17-cyanomethylandrost-4-ene-3-_ 7_ variant 2_a) 6p, 7p -15p,16p-bismethylene_3p_5p_dihydroxy-17p_cyanomethyl androstane and 6β,7β-15ρ,16β-bismethylene-3P-5P-dihydroxy-17α-cyanomethyl The residual alkane is similar to the method given in Example lb. 6β,7β-15β,16β-bis-indenyl _3β,5β-diylmethyl oxazepine-17-one c/zewz'e 1982, Ρ4, 718- 719) Reaction. Using a mixture of hexane and ethyl acetate to obtain 6β,7β-15β,16β-bismethylene_3β-5β-bis-carbyl-ΐ7β-cyanomethyl-androstane and 6β,7β-15β,16β. - bismethylene_3β-5β-dihydroxy_17〇[_cyanomethylandrostane. 6, 73-15, 1 Qiu-bismethylene-3, -5, - bis, sylylene, succinyl, fluoro, sulphate, sulphate, sulphate, sulphate, sulphate, sulphate, sulphate, sulphate, sulphate 2Η), 〇.61 (m,1H), 〇73 (s, 3H), 0.83 (s, 3H), 2.97 (width single bee '1H), 3.79 (width single peak, 1H) 4.31 (wide single peak, 1H), 4.79 (wide single peak, 1H) 6 shirts, 7 to -15 choices, 16?-bismethylene-;^-5 shirts-double warp groups _17〇1_cyanomethyl-androsterane: W -NMR (D6-DMSO): 0.41 (m, 2H), 0.61 (m, 1H), 0.73 (s, 3H), 0.80 (s, 3H), 3.05 (single singular, 1H) 7-variant 2- b) 6p,7p-15p,16p-bismethylene-ΐ7ρ·cyanomethylxine retention_4_lean_3_discussion 144922.doc 37· 201026718 Similar to the procedure given in Example 30e, 6β, 7β- Ϊ́5β,16β-bis-indenyl-3β-5β-dihydroxy-17β-cyanomethyl-androstane. This gave 6β 7β _ 15β, 16β-bis-indenyl-17β-cyanoindole 甾4· ene-3-one. The NMR data were identical to those given in Example 7. Preparation Example 8: 17β-cyano-7α-methyl-15β, 16β-methylenemethylanthrene_4 dilute_3_one Add 67 mg of gasified steel (1) to 1〇g 17b at room temperature A solution of cyano-15β,16β-indenyl-androstane-4,6-dien-3-one in 50 ml of tetrahydrofuran was stirred and mixed for 1 min and then cooled to -15. Then, 450 mg of aluminum chloride was added, and the mixture was stirred at this temperature for 3 minutes, 4.5 ml of a solution of ruthenium bromide (3 M in tetrahydrofuran) was added dropwise, and the mixture was stirred at -15 C for one hour. For processing, at _15. 30 ml of 2 hydrazine hydrochloride was added to the reaction mixture, and the mixture was stirred at room temperature for 0.5 hr, added to water and extracted three times with ethyl acetate and dried over sodium sulfate. /ethyl acetate (〇-5〇%) gelatin chromatography. This gave 丨7^cyano_7af*_ΐ5β ΐ6ρ methylenemethylandrost-4-en-3-one (149 mg). iNMR (3〇〇MHz, CDCl3 TMS as internal standard, selected signal): δ=〇·45 [m, 15·-Η(β)], 〇>88 (dj j=7.l Hz, 7- Me), 1.08^1.21 Μ, in each case (3H), 2xMe], 2 75 [mountain j=4 6Hz i7_ H(a)], 5.76 (s, 4-H). MS (CI+) m/z (relative density) = 324 (1〇〇), % (55); corresponds to C22H29NO. Preparation Example 9: 144922.doc 201026718 17P-cyano_17α-methyl-15β,16β-methylenemethylandrosta-4-en-3-one 9a) 17P-cyano-3-methoxy-17α -methyl·ΐ5β,16β-methylenemethylandrostane-3(4),5(6)-diene, fresh cold solution of lithium diisopropylamide (LDA) at -78 °C (Prepared by preparing 12.1 ml of diisopropylamine and 54.1 ml of n-BuLi (1.6 Μ in hexane) in 82 ml of tetrahydrofuran at 0 ° C) to 8 g of 17-cyano-3-methoxy -15β, 16β-methylenemethylhistane-3(4), 5(6)-diene in solution, and ¥ kept the mixture at -78 ° C for 1 hour. The mixture was cooled back to -90 °C before the subsequent addition of 6.9 ml of methyl iodide. After the end of the addition, the reaction mixture was slowly warmed to room temperature overnight. The reaction was quenched by the addition of a saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate and washed with water and saturated sodium chloride. The organic phase was dried over sodium sulfate (concentrated to dryness and flash chromatography eluting hexane/ethyl acetate (0-30%) to afford Ι7β- cyano-3- methoxy s s s s s s s s s s Azinyl-androstane-3(4), 5(6)-diuret (6.5®g). iH-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): 6 = 0.40 [m, 15'-Η(β)], 1.01 (s, Me), l.l5 (s, Me), 1.38 (s,
Me),3.58 (s,0-CH3),5.15 (m,4-H),5.27 (m,6-H) » MS (CI+) m/z (相對密度)=355 (100),338 (53);對應於 C23H31NO。 9b) 17β-氰基-17α·甲基-15β,16β-亞甲基甲雄甾-4_稀_3_明 根據實例lc方法,385 mg 17β-氰基曱氧基-17α-甲 144922.doc -39- 201026718 基-15β,16β-亞曱基曱雄留烷_3(4),5(6)·二烯在自乙酸乙酯 結曰曰後得到17β-氮基_ΐ7α-曱基-15β,16β-亞曱基曱雄崔 烯-3-酮(285 mg)。 ^-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0.43 [m, 15’-Η(β)],1.16; 1.21 及 1.38 [3xs,在各情況下 (3H),3xMe],5.75 (d,《7=1.1 Hz,4-H)。 MS (CI+) m/z (相對密度)=324 (38),341 (100);對應於 C22H29NO。 製備實例10: 17α-烯丙基-17p-氰基-Ι5β,16ρ-亞曱基甲雄甾_4_烯_3-酮 10a) 17α-稀丙基-17β-氰基_3-甲氧基-15β,16β-亞甲基甲雄留 烷-3(4),5(6)-二烯 根據實例9a之方法,使用烯丙基溴化物作為烷基化劑, 1 g 17-氰基-3-曱氧基-15β,16β-亞甲基曱雄留烷_3(4) 5(6)_ 二烯在急驟層析後得到17α-稀丙基-17β-氛基-3-甲氧 基-15β,16β-亞曱基曱雄甾烷-3(4),5(6)-二烯(358 mg)。 ^-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0.41 [m, 15*-Η(β)], 3.58 (s, O-CH3), 5.15 (m, 4-H), 5.25 [m, (3H), 6-H及=CH2], 6.05 [m, (1H),-CH=]。 10b) 17a-烯丙基-17P-氰基-15p,16p-亞甲基甲雄甾_4_烯_3•酮 根據實例lc方法,300 mg 17α-稀丙基-Ι7β-氰基·3-甲氧 基-15β,16β-亞甲基f雄留烷-3(4),5(6)-二烯在急驟層析後 144922.doc -40· 201026718 得到17α_烯丙基_17β-氰基-15β,16β-亞甲基甲雄甾_4_烯_3_ 酮(210 mg)。 ^-NMR (300 MHz,CDCl3 為内標,經選擇信號): 6=0.45 [m, 15'-Η(β)]5 5.1 8-5.30 [m5 (2H), =CH2], 5.76 (d, J=1.7 Hz,4-H),6.03 [m,(ih),-CH=]。 MS (CI+) m/z (相對密度)=350 (1〇〇),367 (68);對應於 C24H31NO。 製備實例11: 17β-氰基-6ρ·羥基甲基·17α_甲基_15p,16p_亞甲基甲雄甾4-稀-3·明 根據實例2之方法,5·90 g 17β_氰基·17α_曱基_15β16ρ_ 亞甲基曱雄留-4-稀-3 -g同在自乙酸乙g旨結晶及母液石夕膠急 驟層析[己烷/乙酸乙酯(〇_5〇%)]後得到17β·氰基·6β_羥基曱 基-17α-曱基-15β,16β-亞曱基甲雄甾-4-烯-3-酮(2.22 g)。 WNMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0.50 [m,15’-Η(β)],1.21; 1_27及 1.43 [3xs,在各情況下 (3Η),3xMe],ΑΒ 信號(δΑ=3_73, δΒ=3.85,乃5 約 10_0 Hz 寬信 號,額外以人u=7.5 Hz,約 1〇.〇 Hz分裂),5.89 (s,4-H)。 MS (CI+) m/z (相對密度)=341 (100),354 (35),371 (22); 對應於c23h31no2。 製備實例12 : 17P-氰基-15α,16α-亞甲基甲雄甾-4-烯-3-酮 12a) 144922.doc •41 · 201026718 17P-氰基-3P-羥基-15α,16α-亞甲基曱雄甾_5(6)-烯 根據實例lb之方法,24.2 g 3β-乙醯氧基-15α,16α-亞曱 基甲雄崔-5(6)-烯在矽膠急驟層析[己烷/乙酸乙酯(0-50%)] 及自乙酸乙酯分步結晶後得到17β-氰基羥基-15α,16α-亞甲基甲雄错-5(6)-烯(3·2 g)以及i7<x-氰基_3β-羧 基-15α, 16α-亞甲基曱雄甾-5(6)-烯(3.6 g)。 17β-|1基-3β-經基-15α,16α-亞曱基甲雄堪_5(6)_稀: W-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0.54 [m,(2H),環丙基],〇·9〇 [m,(1H),環丙基],1.03 及 1.17 [2xs,在各情況下(3H),2xMe],3.52 Ο, 3-H),5.37 (m,6-H) » MS (EI+) m/z (相對密度)=311 (88);對應於C21H29NO。 17<*-氣基-3p-經基_ΐ5α,16α-亞甲基甲雄留_5(6)-稀: W-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號)·· δ=0.78 [m,(1H),環丙基],〇.89_0 99 [m,(2H),環丙 基]’ 1.02 及 1.08 [2xs,在各情況下(3h), 2><Me],2.79 [d, •7=7.7 Ηζ,17-Η(β)], 3.54 (m,3-H),5.38 (m, 6-H)。MS (EI+) m/z (相對密度)=3n (18);對應於C2ih29NO。 12b) 17P-氰基-15α,ΐ6α_亞甲基甲雄甾_4_烯_3贓 一次性添加2.10 g三異丙醇鋁至32 g Ι7β-氰基-3β-羥 基_15α,16α_亞甲基甲雄留-5(6)-烯於80 ml 2-丁酮之溶液 中’且在彿騰下加熱混合物15小時。接著藉由添加飽和氣 化銨溶液終止反應,以乙酸乙酯萃取混合物3次且以飽和 144922.doc •42- 201026718 氣化鈉溶液洗滌有機相且經硫酸鈉乾燥。濃縮後,碎膠魚 驟層析[己烧/乙酸乙酯(0-50%)]得到17β-氰基-ΐ5α,ΐ6α_亞 甲基甲雄留·4 -婦-3-嗣(3.0 g)。 ^-NMR (300 MHz, CDC13 TMS作為内標,經選擇信號): δ=0·55 [m,(2H),環丙基;|,〇·8ι_〇_97 [m,(3H)],i 21 ^ (6H),2xMe], 5.74 (br. s,4-H)。 MS (CI+) m/z (相對密度)=310 (100),327 (23);對應於 C21H27NO 0 製備實例13 : 17β-|1基-6β-幾基甲基-Ι5α,16α-亞甲基甲雄甾-4-稀-3-酮 根據實例2之方法,3·〇 g ι7β_氰基_15α,16α_亞甲基曱雄 甾-4-烯-3-酮在矽膠急驟層析[己烧/乙酸乙酯(〇_5〇〇/。)]後得 到17β-氰基-6β-羥基甲基-ΐ5α,16α-亞曱基曱雄甾-4-烯-3-酮 (850 mg)。 W-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0.56 [m,(2H) ’ 環丙基],0.91 [m,(1H),環丙基],1.22 [s,(6H),2xMe],AB 信號(δΑ=3.68,δΒ=3.77,極寬信號), 5.83 (s,4-Η)。 MS (CI+) m/z (相對密度)=340 (100),357 (51);對應於 C22H29NO2 0 製備實例14 : 17β-氟基-15α,16α-亞甲基-6β-甲苯磺醯基氧基甲基甲雄 错-4-稀-3-銅及 17β-氱基-6-外亞甲基-Ι5α,16α-亞甲基甲雄甾-4-稀-3-嗣 144922.doc -43- 201026718 根據實例3a之方法,700 mg 17β-氰基-6β-經基甲 基-15α,16α-亞曱基曱雄甾-4-烯-3-酮在矽膠急驟層析[己烧/ 乙酸乙酯(0-50%)]後得到17β-氰基-15α,16α·亞甲基·6β_甲 苯確醯基氧基甲基曱雄甾-4-稀-3-酮(880 mg)及在其預運行 過程(pre-run)中,得到呈次要組份之17β-氰基-6-外亞甲 基-15α,16α-亞曱基甲雄甾-4-浠-3-酮(22 mg)。 溶離份1 : 17p-氰基-6-外亞甲基-15α,16α-亞甲基甲雄留_4_ 稀-3-嗣: W-NMR (300 MHz, CDC13 TMS作為内標,經選擇信號): δ=0.64 [m,(2H),環丙基],1·〇9 [m,(1H),環丙基],116 及 1.25 [2xs,在各情況下(3H),2xMe],5.04 及 5.15 (dd-n, 在各情況下/=1.9«^,=(:1^2),5.97(8,4-11)。 MS (CI+) m/z (相對密度)=322 (1〇〇),339 (28);對應於 C22H27NO。 溶離份2 : 17P-氰基-15α,16α-亞甲基-6β-甲苯續醯基氧基 甲基甲雄留-4-烯-3-酮: W-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0.56 [m,(2H),環丙基],0.91 [m,(1H),環丙基],j 13 及 1.22 [2xs,在各情況下(3H),2xMe],2.50 [s, (3H),C6H4、 CH3],AB 信號(δΑ=3·95,δΒ=4·29,4=9.7 Hz,額外由 6-//=6.2 Hz, Hz 分裂),5.77 (s,4~jj) AA’BB’信號[δΑ=7·40, δΒ=7.82,在各情況下(2H),c6h4]。 MS (CI+) m/z (相對密度)=494 (5),511 (15);對應於 c29h35no4s。 144922.doc 44- 201026718 製備實例is : 17β-氰基-6,6-伸乙基-Ι5α,16α·亞甲基甲雄甾-4-烯-3-酮 根據實例3b之方法,860 mg 17β-氰基-15α,16α-亞甲 基-6β-曱苯磺醯基氧基甲基甲雄留-4-烯-3-酮在矽膠急驟層 析[己烷/乙酸乙酯(0-50%)]後得到17β-氰基-6,6-伸乙基 15α, 16α-亞甲基甲雄甾-4-烯-3-酮(265 mg)。Me), 3.58 (s, 0-CH3), 5.15 (m, 4-H), 5.27 (m, 6-H) » MS (CI+) m/z (relative density) = 355 (100), 338 (53 ); corresponds to C23H31NO. 9b) 17β-cyano-17α·methyl-15β,16β-methylenemethylandrosine-4_lean_3_ Ming according to the example lc method, 385 mg 17β-cyanodecyloxy-17α-methyl 144922. Doc -39- 201026718 -15β,16β-fluorenylene hydrazin-3-3(4),5(6)·diene obtained 17β-nitrogen-ΐ7α-fluorenyl group after scavenging from ethyl acetate -15β, 16β-indenyl 曱 xisculin-3-one (285 mg). ^-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.43 [m, 15'-Η(β)], 1.16; 1.21 and 1.38 [3xs, in each case (3H), 3xMe ], 5.75 (d, "7 = 1.1 Hz, 4-H). MS (CI+) m/z (relative density) = 324 (38), 341 (100); corresponds to C22H29NO. Preparation Example 10: 17α-allyl-17p-cyano-indenyl 5β,16ρ-indenyl-androstino- 4-ene-3-one 10a) 17α-dilyl-17β-cyano-3-methoxy Base-15β,16β-methylenemethylhistrol-3(4),5(6)-diene According to the method of Example 9a, allyl bromide was used as the alkylating agent, 1 g of 17-cyano group -3-decyloxy-15β,16β-methyleneindole-hydroxanthine_3(4) 5(6)_diene obtained by flash chromatography to obtain 17α-dilyl-17β-amino-3-methyl Oxy-15-β, 16β-arylene-androstane-3(4), 5(6)-diene (358 mg). ^-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.41 [m, 15*-Η(β)], 3.58 (s, O-CH3), 5.15 (m, 4-H) , 5.25 [m, (3H), 6-H and =CH2], 6.05 [m, (1H), -CH=]. 10b) 17a-allyl-17P-cyano-15p, 16p-methylenemethylandrosine_4_ene_3• ketone according to the example lc method, 300 mg 17α-l-propyl-Ι7β-cyano·3 -Methoxy-15β,16β-methylenefxixane-3(4),5(6)-diene after flash chromatography 144922.doc -40· 201026718 Obtain 17α_allyl_17β- Cyano-15β, 16β-methylenemethylanthrene-4-4-ene-3-one (210 mg). ^-NMR (300 MHz, CDCl3 is an internal standard, selected signal): 6=0.45 [m, 15'-Η(β)]5 5.1 8-5.30 [m5 (2H), =CH2], 5.76 (d, J = 1.7 Hz, 4-H), 6.03 [m, (ih), -CH=]. MS (CI+) m/z (relative density) = 350 (1〇〇), 367 (68); corresponds to C24H31NO. Preparation Example 11: 17β-cyano-6ρ·hydroxymethyl·17α_methyl_15p, 16p_methylenemethylanthrene 4-dil-3· Ming according to the method of Example 2, 5.90 g 17β-cyanide Base····················································· After the %)], 17β·cyano·6β-hydroxyindolyl-17α-mercapto-15β,16β-arylenemethylandrost-4-en-3-one (2.22 g) was obtained. WNMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.50 [m, 15'-Η(β)], 1.21; 1_27 and 1.43 [3xs, in each case (3Η), 3xMe], ΑΒ Signal (δΑ=3_73, δΒ=3.85, is a wide signal of about 10_0 Hz, extra is u=7.5 Hz, about 1〇.〇Hz split), 5.89 (s,4-H). MS (CI+) m/z (relative density) = 341 (100), 354 (35), 371 (22); corresponds to c23h31no2. Preparation Example 12: 17P-cyano-15α,16α-methylenemethylandrost-4-en-3-one 12a) 144922.doc •41 · 201026718 17P-cyano-3P-hydroxy-15α,16α-亚Methyl anthraquinone _5(6)-ene According to the method of Example lb, 24.2 g of 3β-acetoxy-15α,16α-arylene-methyl-Congxiu-5(6)-ene was rapidly chromatographed on silica gel [ Hexane/ethyl acetate (0-50%)] and crystallization from ethyl acetate to give 17β-cyanohydroxy-15α,16α-methylenemethylpyrazine-5(6)-ene (3·2) g) and i7<x-cyano_3β-carboxy-15α, 16α-methyleneindole-5(6)-ene (3.6 g). 17β-|1 yl-3β-radio-15α,16α-arylene-methyl-methyl ketone _5(6)_thin: W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ=0.54 [m, (2H), cyclopropyl], 〇·9〇[m,(1H), cyclopropyl], 1.03 and 1.17 [2xs, in each case (3H), 2xMe], 3.52 Ο, 3- H), 5.37 (m, 6-H) » MS (EI+) m/z (relative density) = 311 (88); corresponds to C21H29NO. 17<*-gas-based-3p-radio-ΐ5α,16α-methylenemethyl-xanthine_5(6)-diluted: W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal)·· δ =0.78 [m,(1H),cyclopropyl],〇.89_0 99 [m,(2H),cyclopropyl]' 1.02 and 1.08 [2xs, in each case (3h), 2><Me] , 2.79 [d, •7=7.7 Ηζ, 17-Η(β)], 3.54 (m,3-H), 5.38 (m, 6-H). MS (EI+) m/z (relative density) = 3n (18); corresponds to C2ih29NO. 12b) 17P-cyano-15α, ΐ6α_methylenemethylanthrene _4_ene_3赃 Add 2.10 g of aluminum triisopropoxide to 32 g Ι7β-cyano-3β-hydroxy _15α,16α_ The methylene methyl male-5-(6)-ene was dissolved in a solution of 80 ml of 2-butanone and the mixture was heated under a phort for 15 hours. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium sulphate, and the mixture was extracted three times with ethyl acetate and the organic phase was washed with saturated 144922.doc • 42- 201026718 sodium carbonate solution and dried over sodium sulfate. After concentration, the minced fish was subjected to flash chromatography [hexane/ethyl acetate (0-50%)] to give 17β-cyano-purine 5α, ΐ6α_methylenemethylxanthine-4-female-3-indole (3.0 g ). ^-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.55 [m, (2H), cyclopropyl; |, 〇·8ι_〇_97 [m, (3H)] , i 21 ^ (6H), 2xMe], 5.74 (br. s, 4-H). MS (CI+) m/z (relative density) = 310 (100), 327 (23); corresponds to C21H27NO 0 Preparation Example 13 : 17β-|1 -6-β-methyl- Ι5α, 16α-methylene Astragalo-4-pyrim-3-one according to the method of Example 2, 3·〇g ι7β_cyano _15α, 16α_methylene oxime oxime-4-en-3-one in gelatin flash chromatography [ After calcination/ethyl acetate (〇_5〇〇/.)], 17β-cyano-6β-hydroxymethyl-ΐ5α,16α-arylene-androst-4-en-3-one (850 mg) was obtained. ). W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.56 [m, (2H) 'cyclopropyl], 0.91 [m, (1H), cyclopropyl], 1.22 [s, (6H), 2xMe], AB signal (δΑ=3.68, δΒ=3.77, very wide signal), 5.83 (s,4-Η). MS (CI+) m/z (relative density) = 340 (100), 357 (51); corresponds to C22H29NO2 0 Preparation Example 14: 17β-fluoro-15α,16α-methylene-6β-toluenesulfonyloxy Methylmethylandrosine-4-diphenyl-3-copper and 17β-mercapto-6-exomethylene-Ι5α,16α-methylenemethylanthrene-4-diazon-3-嗣144922.doc -43 - 201026718 According to the method of Example 3a, 700 mg of 17β-cyano-6β-pyridylmethyl-15α,16α-arylene-androst-4-en-3-one was subjected to flash chromatography on silica gel [hexane/acetic acid] Ethyl ester (0-50%)] gave 17β-cyano-15α,16α·methylene·6β_toluene methoxymethylmethylindole-4-pyrim-3-one (880 mg) and In its pre-run, 17β-cyano-6-exomethylene-15α,16α-arylene-androst-4-indole-3-one (a minor component) was obtained. 22 mg). Dissolved fraction 1 : 17p-cyano-6-exomethylene-15α, 16α-methylenemethylxanthine_4_ dil-3-嗣: W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal ): δ = 0.64 [m, (2H), cyclopropyl], 1·〇9 [m, (1H), cyclopropyl], 116 and 1.25 [2xs, in each case (3H), 2xMe], 5.04 and 5.15 (dd-n, in each case /=1.9«^, =(:1^2), 5.97(8,4-11). MS (CI+) m/z (relative density)=322 (1 〇〇), 339 (28); corresponds to C22H27NO. Dissolved fraction 2: 17P-cyano-15α, 16α-methylene-6β-toluene decyloxymethylmethyl-androst-4-ene-3- Ketone: W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.56 [m, (2H), cyclopropyl], 0.91 [m, (1H), cyclopropyl], j 13 And 1.22 [2xs, in each case (3H), 2xMe], 2.50 [s, (3H), C6H4, CH3], AB signal (δΑ=3·95, δΒ=4·29, 4=9.7 Hz, extra From 6-//=6.2 Hz, Hz split), 5.77 (s, 4~jj) AA'BB' signal [δΑ=7·40, δΒ=7.82, in each case (2H), c6h4]. CI+) m/z (relative density) = 494 (5), 511 (15); corresponds to c29h35no4s. 144922.do c 44- 201026718 Preparation Example is : 17β-cyano-6,6-extended ethyl-hydrazine 5α,16α·methylenemethylandrost-4-en-3-one According to the method of Example 3b, 860 mg 17β-cyanide -15α,16α-methylene-6β-nonylbenzenesulfonyloxymethylmethyl-androst-4-en-3-one in gelatin chromatography [hexane/ethyl acetate (0-50%) After that, 17?-cyano-6,6-extended ethyl 15?,16?-methylenemethylandrost-4-en-3-one (265 mg) was obtained.
W-NMR (300 MHz, CDC13 TMS作為内標,經選擇信號): δ=0.45-0.63 [m,(4H)螺伸乙基及環丙基],0.88 [m,(1H)螺 伸乙基],1.02 [m,(1H),環丙基],1.28及 1.32 [2xs,在各 情況下(3H),2xMe],5.69 (s,4-H)。 MS (EI+) m/z (相對密度)=335 (88);對應於 C23H29NO。 製備實例16: 17β-氰基-17α-甲基-15α,16α-亞甲基甲雄甾-4-烯-3-酮 16a) 17α-氰基-15α,16α-亞甲基-3β-三異丙基矽烷基氧基甲雄 甾-5(6)-烯 在0C下,將5.44 ml三異丙基石夕燒基氣化物於2.5 ml四 氫呋喃中之溶液緩慢添加至3.6 g 17α-氰基-3β-羥 基-15α,16α-亞曱基曱雄甾-5(6)-烯,1.7 g咪唑及141 mg二 甲基胺基吡啶於20 ml二甲基曱醯胺(DMF)中之溶液中。接 著使混合物升溫至室溫隔夜,傾入飽和碳酸氫鹽溶液中且 以乙酸乙酯萃取。以水洗滌有機相5次且最後以飽和氣化 鈉溶液洗滌且濃縮至乾燥。粗產物1 7α-氰基-1 5α,1 6α-亞甲 基-3β-三異丙基矽烷基氧基甲雄崔-5(6)-烯(7.3 g)直接用於 I44922.doc •45- 201026718 下一步驟中。 ^-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號):W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.45-0.63 [m, (4H) spiroethyl and cyclopropyl], 0.88 [m, (1H) spiroethyl ], 1.02 [m, (1H), cyclopropyl], 1.28 and 1.32 [2xs, in each case (3H), 2xMe], 5.69 (s, 4-H). MS (EI+) m/z (relative density) = 335 (88); corresponds to C23H29NO. Preparation Example 16: 17β-cyano-17α-methyl-15α,16α-methylenemethylandrost-4-en-3-one 16a) 17α-cyano-15α,16α-methylene-3β-three Isopropyl nonyloxymethylandrost-5(6)-ene was slowly added to a solution of 5.44 ml of triisopropyl sulphate in 2.5 ml of tetrahydrofuran to 3.6 g of 17α-cyano at 0C. 3β-hydroxy-15α,16α-arylene-indole-5(6)-ene, 1.7 g imidazole and 141 mg dimethylaminopyridine in 20 ml of dimethyl decylamine (DMF) . The mixture was then warmed to room temperature overnight, poured into saturated bicarbonate solution and extracted with ethyl acetate. The organic phase was washed 5 times with water and finally washed with a saturated sodium carbonate solution and concentrated to dryness. The crude product 1 7α-cyano-1 5α,1 6α-methylene-3β-triisopropyldecyloxymethylxanthracene-5(6)-ene (7.3 g) was used directly in I44922.doc •45 - 201026718 In the next step. ^-NMR (300 MHz, CDC13 TMS as internal standard, selected signal):
δ=0·78 [m,(1H),環丙基],〇.88_〇.99 [m,(2H),環丙 基],1.02及1.08 [2xs,在各情況下(3H),2xMe,重疊 5=1.05, br. s, (18H), TiPS-Me], 2.79 [d, J=7.1 Hz, 17-H (β)],3.56 (m,3-H), 5.33 (d,*7=4.8 Hz,6-H)。 MS (EI+) m/z (相對密度)=468 (12);對應於 c30H49NOSi。 16b) 17β-氰基-17α-甲基_ΐ5α,ΐ6α-亞甲基_3p_三異丙基矽烷基氧 〇 基甲雄留-5(6)-烯與 17α-氰基-17β-甲基_ΐ5α,ΐ6α-亞甲基-3p-三異丙基梦炫基氧 基甲雄留-5(6)-烯之混合物 根據實例9a之方法,使用厘以作為烷基化劑,5·29 g 17α-氰基-15α,16α-亞曱基_3β_三異丙基矽烷基氧基甲雄甾-5(6)-烯在急驟層析後得到ι7_氰基_17_曱基-15(χ16α_亞曱 基-3β-三異丙基矽烷基氧基曱雄留_5(6)烯之17·差向異構 翁 體混合物(3.65 g)。 零 (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0·60-0·72 [m,(1H),環丙 *],i.05,[br.s,(i8H),TiPS-Me],3·54 (m,3-H),5.33 (m,6-H)。 MS (CI+) m/z (相對密度)=499 (55);對應於 c3iH51NOSi。 · 16c) 17P-氰基-3p-羥基-17a-甲基_15α16α亞甲基-甲雄甾_5(6)_ 烯與 144922.doc -46- 201026718 17α-氰基-3β-羥基·ΐ7β_甲基-15α,16α-亞甲基甲雄甾-5(6)- 烯之混合物 在室溫下’將9 ml氟化四丁基銨(TBAF)(1 Μ於四氫呋喃 中)添加至3.0 g 17-氰基-17-甲基-15α,16α-亞甲基-3β-三異 丙基石夕烧基氧基曱雄甾-5(6)-烯之17-差向異構體於5 ml四 氫吱喊中之溶液中,且攪拌混合物4小時。藉由添加飽和 碳酸氫鹽溶液終止反應後,以乙酸乙酯萃取,以水及飽和 氯化鈉溶液洗滌有機相,以硫酸鈉乾燥且濃縮至乾燥,隨 後急驟層析得到17-氰基-3β-羥基-17-曱基-ΐ5α,16α_亞曱基 甲雄留-5(6)-烯之17-差向異構體混合物(1.9 g)。 iH-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0.74 [m,(1H) ’ 環丙基],3.57 (m,3_H),5 42 (m, 6 H)。 16d) 17杉-氰基-17(*-甲基-15<*,16<*-亞甲基甲雄甾_4_烯_3_酮 根據實例12b之方法’ 1.9 g 17-氰基·3β_羥基-17_甲 基-15α,16α-亞曱基甲雄留_5(6)_烯之17_差向異構體在製備 型HPLC層析後得到17β_氰基-17α-甲基_15α16α亞甲基甲 雄留-4-稀-3-嗣(335 mg)。 W-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0·69 [m,(2H),環丙基]’ 〇.82 [m,(1H),環丙基],〇 % [m,(1H) ’環丙基],M4;丨上及丨七[3xs,在各情況下 (3H),3xMe],5.74 (s,4-H)。 MS (EI+) m/z (相對密度)=323 (100);對應於C22H29N〇。 製備實例17 : 144922.doc -47- 201026718 17P-氰基-15α,16α-亞甲基甲雄甾a-4,6-二稀-3-酮 17a) 17β-氟基-3-甲氧基_15α,16α-亞甲基甲雄甾_3(4),5(6>二 烯-17-輞與 17α-氟基-3-甲氧基-15α,16α-亞甲基甲雄留_3(4),5(6)二 烯-17_酮之混合物 根據實例la之方法,7 g 17-氰基-I5a,16cx-亞甲基甲雄 甾-4-烯-3-酮之17-差向異構體在處理後得到17_氰基曱 氧基-15α,16α-亞甲基曱雄甾-3(4),5(6)-二烯之17-差向異構 體(7.6g),其直接用於下一步驟。 17b) 17β-氰基-15α,16α-亞甲基甲雄甾-4,6-二稀-3-酮 根據實例6之方法’ 7.6 g 17-氰基甲氧基·15〇1,16〇1_亞 甲基曱雄崔-3(4),5(6)-二烯在製備型HPLC層析所獲之一些 粗產物後得到17β-氰基-15 α, 16α-亞甲基甲雄甾—4,6-二浠-3-_ (48 mg)。 W-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0·66 [m,(1H),環丙基]’ 0.78 [m,(1H),環丙基],i 19 及 1.32 [2xs,在各情況下(3H),2xMe],5 74 (s,4_H),621 (dd,/=2.8 Hz,J=9.8 Hz, 5-H*),6.34 (dd,*7=1.9 Ηζ,·7=10.0δ = 0.78 [m, (1H), cyclopropyl], 〇.88_〇.99 [m, (2H), cyclopropyl], 1.02 and 1.08 [2xs, in each case (3H), 2xMe, overlap 5=1.05, br. s, (18H), TiPS-Me], 2.79 [d, J=7.1 Hz, 17-H (β)], 3.56 (m,3-H), 5.33 (d, *7=4.8 Hz, 6-H). MS (EI+) m/z (relative density) = 468 (12); corresponds to c30H49NOSi. 16b) 17β-cyano-17α-methyl-ΐ5α,ΐ6α-methylene_3p_triisopropyldecyloxycarbonylmethyl-androst-5-(6)-ene and 17α-cyano-17β- Mixture of ΐ_α5α, ΐ6α-methylene-3p-triisopropylmethaneoxymethylxanthine-5(6)-ene According to the method of Example 9a, using PCT as an alkylating agent, 5· 29 g 17α-cyano-15α,16α-indenyl_3β_triisopropyldecyloxymethylandrosin-5(6)-ene obtained by flash chromatography to obtain ι7_cyano_17_fluorenyl -15 (χ16α_ fluorenyl-3β-triisopropyldecyloxy oxime male _5(6) olefin 17·episomeric complex (3.65 g). Zero (300 MHz, CDC13 TMS As an internal standard, the selected signal): δ = 0·60-0·72 [m, (1H), cyclopropyl*], i.05, [br.s, (i8H), TiPS-Me], 3· 54 (m,3-H), 5.33 (m,6-H) MS (CI+) m/z (relative density) = 499 (55); corresponds to c3iH51NOSi. · 16c) 17P-cyano-3p-hydroxyl -17a-methyl_15α16α methylene-methylandroxine_5(6)_ene and 144922.doc -46- 201026718 17α-cyano-3β-hydroxy·ΐ7β_methyl-15α,16α-methylene A mixture of methylaxoride-5(6)-ene at room temperature '9 ml of fluoride Base ammonium (TBAF) (1 Μ in tetrahydrofuran) was added to 3.0 g of 17-cyano-17-methyl-15α, 16α-methylene-3β-triisopropyl oxalate oxime oxime-5 (6)-Alkene 17-epimer in a solution of 5 ml of tetrahydropurine, and the mixture was stirred for 4 hours. After the reaction was quenched by the addition of a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness, followed by flash chromatography to give 17-cyano-3? -Hydroxy-17-mercapto-purine 5α, 16α-arylene-methyl-andrazine-5(6)-alkene 17-epimomer mixture (1.9 g). iH-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.74 [m, (1H) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 16d) 17 cedar-cyano-17(*-methyl-15<*,16<*-methylenemethylandrost-4_ene_3_one according to the method of Example 12b' 1.9 g 17-cyano group 3β_Hydroxy-17-methyl-15α,16α-indenylmethyl-andrazine _5(6)-ene 17_epimer, after preparative HPLC chromatography, 17β_cyano-17α-A _15α16α methylene methyl male-4-pyrim-3-ylide (335 mg) W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ=0·69 [m, (2H ), cyclopropyl]' 〇.82 [m,(1H), cyclopropyl], 〇% [m,(1H) 'cyclopropyl], M4; 丨上和丨七[3xs, in each case (3H), 3xMe], 5.74 (s, 4-H) MS (EI+) m/z (relative density) = 323 (100); corresponds to C22H29N〇. Preparation Example 17: 144922.doc -47- 201026718 17P -Cyano-15α,16α-methylenemethylanthridine a-4,6-disali-3-one 17a) 17β-fluoro-3-methoxy-15α,16α-methylenemethylanthrene_ 3(4),5(6>diene-17-anthracene and 17α-fluoro-3-methoxy-15α,16α-methylenemethylxanthine_3(4),5(6)diene- 17-ketone mixture according to the method of Example la, 17 g of 17-cyano-I5a, 16cx-methylenemethylandrost-4-en-3-one 17-difference The isomer is treated to give 17-cyanomethoxyl-15α,16α-methyleneindole male-3(4),5(6)-diene 17-epimer (7.6 g) , which was used directly in the next step. 17b) 17β-Cyano-15α,16α-methylenemethylandrost-4,6-dithia-3-one according to the method of Example 6 7.6 g 17-cyanomethyl Oxy·15〇1,16〇1_methylene oxime Cui-3(4), 5(6)-diene gives 17β-cyano-15 after some crude product obtained by preparative HPLC chromatography α, 16α-methylenemethylanthridine-4,6-diindole-3-_ (48 mg). W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.66 [m, (1H), cyclopropyl]' 0.78 [m, (1H), cyclopropyl], i 19 And 1.32 [2xs, in each case (3H), 2xMe], 5 74 (s, 4_H), 621 (dd, /=2.8 Hz, J=9.8 Hz, 5-H*), 6.34 (dd, *7 =1.9 Ηζ,·7=10.0
Hz,6-H*),* =分配可逆。 MS (EI+) m/z (相對密度)=307 (26);對應於 c21h25NO。 製備實例18 : 17β-氰基-7α·甲基_15α,16α_亞甲基甲雄甾_4烯_3_酮 144922.doc -48- 201026718 根據實例8之方法,2.2 g 17_氰基-15α,16〇ι-亞甲基曱雄 留-4,6-二烯_3_輞之ι7_差向異構體在製備型hplc層析後得 到17β-氰基-7α-甲基·15α,16α_亞曱基曱雄甾-4_烯_3_酮(257 mg)。 iHMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0·58 [m,(1H),環丙基]’ 〇 69 [m,(1H),環丙基],〇 % (d,/=7.2 Hz,6-Me),1.25 及 1.26 [2xS,在各情況下(3H), 2xMe],5.79 (s,4-H)。 MS (EI+) m/z (相對密度)=323 (1〇〇);對應於 c22H29N〇。 製備實例19 : 17β-氟基-甲雄甾-4,6·二稀-3-酮 19a) 17P-氰基-3-乙氧基甲雄甾_3,5_二烯 類似於實例1 a中所給之程序,改用原曱酸三乙酯替代原 甲酸三甲酯,與17β-氰基甲雄留-4-烯-3-酮反應。此得到 170-氰基-3-乙氧基曱雄甾_3,5-二稀 !H-NMR (D6-DMSO): 0.81 (s, 3H), 0.86 (s, 3H), 1.17 (t, 3H, J=7.1Hz, 3-0-CH2-CH3), 3.36 (m, 2H, 3-0-CH2-CH3), 5.09 (m,2H, H-4及 H-6)。 19b) 17β-氰基甲雄甾_4,6-二稀-3-嗣 類似於實例ό中所給之程序,與17β-氰基_3·乙氧基曱雄 甾-3,5-二烯反應。此得到Ι7β-氰基曱雄留-4,6-二烯-3-鲷。 W-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): 144922.doc •49- 201026718 δ=1.02 (s,3H),113 (S,3H),5.68 (s,1H,H-4), 6.06 6-H),6.13 (s, 1H,7-H)。 ,旧, 製備實例20 : 17P-氰基7α-甲基甲雄甾_4_烯_3•酮 類似於實例8中所給之程序,使17β-氰基甲雄甾_4 6 _ 烯-3·酮反應。此得到17|3_氰基-7{χ_曱基曱雄 ^ -3- 酮。 W-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號) 6=0.77 (d, 3H, 7-CH3, J=7.3 Hz)), 0.98 (s, 3H), 1>2l 3H), 5.74 (s, 1H, H-4) 〇 彎 製備實例21 : 17P-氰基-7α_乙基甲雄留_4_烯_3酮 類似於實例8中所給之方法’使用溴化乙基鎂替代溴化 曱基鎮使17β·氰基甲雄κ6•二烯_3_酮反應。得到、 基-7α-乙基曱雄留_4_烯_3酮。 iH-NMR (300 MHz,CDCl3 TMS作為内標經選擇信號) 5=0.88 (t? 3H, 7-CH2-CH3, J=7.3 Hz)), 〇.98 (s, 3H)5 1.22 ❹ (s,3H), 5.74 (s,iH, H_4)。 製備實例22 : 17P_氣基·6α,7α_亞甲基甲雄错I稀-3_ _及17p_ ι 基-6p,7p-亞甲基甲雄甾_4•烯_3酮 類似於實例7中所认之, 所、,口之程序,使P卜氰基甲雄留-4,6-二 稀-3-酮反應。此得到17β.氰基切α亞甲基甲雄留_4· 烯-3-酮及17β-氰基_6Μρ_亞曱基甲雄留m嗣。 144922.doc -50. 201026718 17β-氰基-6α,7α-亞甲基甲雄甾-4-稀-3-gg : H-NMR (3 00 MHz, CDCI3 TMS作為内標,經選擇作號): 5=0.46 (m, 1H), 0.77 (m, 1H), 0.85 (m, 1H), l.〇l (s, 3H), 1.15 (s, 3H), 5.95 (s, 1H,H-4)。 17P-氰基-6β,7β-亞甲基甲雄甾_4·烯_3_鲷·· H-NMR (300 MHz, CDC13 TMS作為内標,經選擇信號): δ-0.79 (m, 1H), 0.95 (s, 3H), 1.09 (s, 3H), 6.01 (s, 1H, H-4)。 製備實例23 : 17β-氰基-6β-經基甲基甲雄留_心稀 類似於實例2中所給之程序,使17p_氰基曱雄留_4_烯_3_ 酮反應。此得到17β-氰基-6β-羥基甲基甲雄留_4_烯_3_酮。 W-NMR (300 MHz’ CDC13 TMS作為内標,經選擇信號): δ-0.98 (s, 3H), 1.21 (s, 3H), 3.68 (m, 2H, 6-CH2-OH), 5.82 (s5 1H, H-4) 〇 製備實例24 : 17β-氰基亞乙基曱雄甾_4_烯_3_鲷 類似於實例3a與3b中所給之實例,使17卜氰基_6卜羥基 甲基甲雄甾-4-烯_3_酮反應’其中使粗曱笨磺酸鹽中間物 進一步反應。此得到17戸_氰基_6,6_亞乙基曱雄留_4_烯_3_ 酮。 W-NMR (300 MHz,CDCi3 TMS作為内標,經選擇信號): 6=0.42 (m, 2H), 0.77 (m} 1H), 0.99 (s, 3H), 1.26 (s, 3H), 5.62 (s, 1H, H-4)。 144922.doc -51 · 201026718 製備實例25 : 17P-氰基-17α-甲基甲雄甾-4-稀_3_網 25a) 17-氣基-3,3-乙二基雙氧基甲雄留_5_稀 在室溫下,將5 g氰基化合物在56 m]1二氣曱烷,14⑹乙 二醇,37 ml原甲酸三甲酯及丨·5 g對甲笨磺酸之混合物中 攪拌兩小時。在添加碳酸氫鈉溶液及乙酸乙酯後,分離各 相,且以水及飽和氯化鈉溶液洗滌有機相,經硫酸鈉乾 燥,過濾且濃縮。以此方式獲得之17β_氰基_3,3_乙二基雙 氧基甲雄留-5-烯無需任何進一步純化即可使用。 25b) 17β-氰基-3,3 -乙二基雙氧基_ΐ7α-甲基.甲雄甾_5•稀 類似於實例9a中所給之方法,使17ρ•氰基_33_乙二基雙 氧基甲雄留-5·烯反應。此得到17爲_氰基_3,3_乙二基雙氧 基-17α-曱基甲雄留-5-烯。 H-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=1.04 (寬單峰 ’ 6H),1.28 (s,3H),3.94 (m, 4H,縮酮), 5.34 (s,1H,H-6)。 25c) 17β-氰基-17α-甲基甲雄甾_4-烯-3-_ 類似於實例lc中所給之方法,使17卜氰基_3,3_乙二基雙 氧基-17α-甲基甲雄留_5_烯反應。此得到17卜氰基_17〇1_甲 基甲雄留-4-稀-3-嗣。 H-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號厂 144922.doc • 52· 201026718 δ=1.09 (s,3H),1.20 (s,3H),1.28 (s, 3H),5.73 (s,1H, H-4)。 製備實例26 : 17β-氟基·6ρ·幾基甲基-17α-甲基甲雄甾-4-稀-3-嗣 類似於實例2中所給之程序,使Ι7β-氰基-Ι7α·甲基甲雄 甾-4-烯-3-酮反應。此得到17β-氰基-6β-羥基甲基-ΐ7α-曱 基甲雄留-4-烯-3-酮。 丨H-NMR (D6-DMSO): 1.01 (s, 3Η),1.15 (s, 3Η), 1.25 (s, 3Η), 3.35 (m, 1H, 6-CH2-OH), 3.57 (m, 1H, 6-CH2-OH), 4.73 (t,1H, J=5.8 Hz, 6-CH2-OH), 5.65 (s, 1H, H-4)。 製備實例27: 17β-氛基-6,6-乙二基-17 α-甲基甲雄甾-4-稀_3__ 類似於實例3a及3b中所給之程序,使ΐ7β-氰基_6β_經基 曱基-17α-甲基曱雄留-4-烯-3-酮反應,其中使粗曱苯磺酸 鹽中間物進一步反應。此得到17β·氰基-6,6-乙二基_17〇1_曱 基曱雄锡-4-稀-3-酿1。 ^-NMR (300 MHz,CDCI3 TMS作為内標,經選擇信號): δ=0.42 (m, 2Η),0.78 (m, 1Η),1.10 〇, 3Η),1.27 (s,3Η) 1.29 (s,3H),5.63 (s,1H,H-4)。 製備實例28 : 17α-烯丙基_17p_氰基甲雄甾_4_烯_3_酮 28a) 17P-氰基-17α-甲基甲雄甾-4-烯-3-酮 類似於實例9a中所給之方法,使17-氰基·3,3_乙二基雙 氧基曱雄崔_5-烯反應,其中使用烯丙基溴化物替代甲基碘 144922.doc •53· 201026718 化物。此得到17α-烯丙基-ΐ7β-氰基-3,3-乙二基雙氧基曱雄 甾-5-烯。 W-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=1.10 (s, 3H),1.13 (s,3H),3.99 (m,4H,縮酮),5.26 (m, 2H,_CH=CH2),5.39 (s,1H,H-6),5.97 (m,1H,-CH=CH2)。 28b) 17a_烯丙基-17P-氰基甲雄甾-4-烯-3-酮 類似於實例lc中所給之方法,使17a_烯丙基_17β_氰 基-3,3-乙二基雙氧基曱雄甾-5-烯反應。此得到17〇1_烯丙 基_17β -氰基甲雄留-4 -烯-3- _。 ^-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): 5=0.97 (m5 1H), 1.17 (s, 3H), 1.25 (s, 3H), 5.25 (m, 2H,-CH=CH2),5.79 (s,1H,4-H), 5.96 (m,1H, -CH=CH2)。 製備實例29: 17β-氰基-la-甲基甲雄留-4-稀-3-嗣 29a) 17P-氟基甲雄甾-1,4-二烯-3-酮 使2.5 g 17β-氰基甲雄甾-4-烯-3-_及2.7 g二氣二氰基笨 酉昆在5 0 ml二e惡炫中彿騰3小時。冷卻後,以二氣甲烧稀释 混合物且過濾。以碳酸氫鈉溶液、水及飽和氣化鈉溶液洗 滌濾液。在經硫酸納乾燥,過濾且濃縮濾液後,使用己炫/ 乙酸乙酯混合物石夕膠層析殘餘物。此得到17β_氮基甲雄 甾-1,4-二烯-3-酮。 W-NMR (300 MHz, CDC13 TMS作為内標,經選擇信號): 144922.doc •54- 201026718 δ = 1_00 (s,3H),1.25 (s,3H),6·07 (s,1H, H-4), 6.25 (寬單 峰,1H,H-2), 7.06 (s, 1H,H-l)。 29b) 17β-氰基-la-甲基甲雄甾-4·締_3_酮 將6 mg》臭化銅(i),i.i ml三甲基鋁及〇 31 w三曱基矽烷 基氣化物連續添加至〇_6 g 17卜氰基甲雄甾·Μ_二烯_3_鲷 於6 ml四氫呋喃中之溶液中。在室溫下攪拌三小時後,使 混合物在水與乙酸乙酯之間分配。以水及飽和氣化鈉溶液 連續洗滌有機相,經硫酸鈉乾燥且過濾,且濃縮濾液。使 用己烷/乙酸乙酯之混合物矽膠層析得到17p_氰基_la-甲基 甲雄错-4-稀-3-嗣。 H-NMR (3 00 MHz,CDC13 TMS作為内標,經選擇信號): δ=0.94 (d, 3H, 1-CH3), 0.98 (s, 3H), 1.29 (s, 3H), 5.71 (s, 1H,H-4) 〇 製備實例30 : 0 6p,7p-15p,16P·雙亞甲基-17P-氟基-l7〇t-甲基甲雄甾_4_ 烯-3-酮 30a) 6p,7p-15p,16p-雙亞甲基·3ρ·第三丁基二甲基矽烷基氧 基-5β-經基甲雄留燒_17-朗 根據實例l6a之方法’ 6β,7β_15β,16β^亞曱基_3β 5β·二 經基曱雄留烧-17-酮c/2 謂 k 1982,Ρ4,718-719)及 作為石夕烧基化劑之第三丁基二甲基矽烷基氯化物在結晶後 得到60,70-150,160-雙亞甲基_3|3_第三丁基二甲基矽烷基氧 144922.doc •55- 201026718 基-5β-羥基曱雄错烷_17_酮。 ^-NMR (300 MHz, CDCh ^ ^ , i3 為内標,經選擇信號): δ=0·08 及 0.11 [2xs,在久/ 1 你合馆况下(3H), Si-Me],4·13 (s, 3-Η),4·40 (s,5-ΟΗ)。 MS (CI+) m/z (相對密度)=445 (5〇),462 (ΐ5) ·,對應於 C27H44N〇3Si 〇 30b) 6β,7β-15β,16β-雙亞甲基_3β_第三丁基二甲基梦炫基氧 基-17-氰基-5β-經基甲雄留烧_17_闺 類似於實例lb中所述之方法使6β,7β_15β16ρ雙亞甲 基-3 β-第二丁基二甲基矽烷基氧基_5β_羥基甲雄留烷4 7-酮 反應。此得到呈17-差向異構腈之混合物之6β,7β_15β,16β_ 雙亞曱基-3β-第三丁基二甲基矽烷基氧基_17_氰基_5β羥基 甲雄留烷-17-酮,進一步處理其而無需分離差向異構體。 'H-NMR (D6-DMSO): 〇.〇2 (s, 3H), 0.04 (s, 3H), 0.40 (m, 2H), 0.60 (m,1H),0.74 (s,3H),0.82 (寬單峰 ’ 12H), 2·36 (m,2H),2.97 (m,1H), 4.01 (m,1H)。 30c) 6p,7p-15p,16p-雙亞甲基_3p_5p_雙輕基_17p_氰基_17a_甲基 曱雄甾烷 類似於實例9a及16c之方法,使6β,7β-15β,16β-雙亞曱 基-3β-第三丁基二甲基矽烷基氧基_17_氰基_5卜羥基-曱雄 甾烷-17-酮反應。此得到6β,7β-15β,16β-雙亞甲基-3β-5β-雙 羥基-17 β-氰基-17α-甲基曱雄甾烧。 144922.doc •56- 201026718 丨H-NMR (D6-DMSO): 0.40 (m,2H),0.61 (m,1H),0.74 (s’ 3H),0.93 (s,3H),1.36 (s,3H),1.93 (m,1H),2.03 (m,1H), 3.79 (m, 1H)。 30e) 6β,7β-15β,16β-雙亞甲基-ΐ7β_氰基·ΐ7α•甲基甲雄留_4· 稀-3-闲 將 310 mg 6β,7β-15β,16β-雙亞曱基-3β-5β-雙羥基 _17β-氰 基-17α-甲基曱雄甾烷溶解於10 m丨丙酮中,且添加〇42 ml 瓊斯試劑(Jones reagent)。15分鐘後,向混合物中添加〇·4 ml異丙醇。接著使混合物在水與乙酸乙酯之間分配,以飽 和氣化鈉溶液洗滌有機相,經硫酸鈉乾燥且過遽,且濃縮 滤液。使用己烧與乙酸乙醋之混合物石夕膠層析得到6β,7β_ 15β,16β-雙亞甲基-17β-氰基-17 α-甲基曱雄甾_4_婦_3_酮。 'H-NMR (D6-DMSO): 0.41 (m, 1H), 0.85 (m, 1H), 0.99 (s, 3H),1.02 (s, 3H),1·31 (s,3H),5.86 (s,1H,4-H)。 製備實例31 : 17α-稀丙基-6释,73-15释,16释-雙亞甲基_173_氦基甲雄甾_4_ 稀-3-闲 31a) 17α-稀丙基-6p,7p-15p,16p-雙亞曱基_3β_5β-雙羥基-Ι7β-氰 基甲雄甾烷 類似於實例9a(使用烯丙基溴化物替代甲基蛾化物)及16c 中所給之方法使60,70-150,16择-雙亞曱基_3卜第三丁基二甲 基石夕烧基氧基-17-氰基-5β-羥基甲雄留院_ 17-酮反應。此得 144922.doc •57- 201026718 到17α-烯丙基_6β,7β_15β,16β_雙亞甲基_3β邛雙羥基“邛_ 氰基甲雄留烧。 !Η-ΝΜΚ (D6-DMSO): 0.40 (m, 2H), 〇.6i 1H), 〇.?4 (S} 3H), 0.96 (s, 3H), 2.02 (m, 2H), 3.79 (m, 1H), 4.78 (m, 1H)! 5.19 (s,1H),5.24 (m,1H),5.94 (m,1H)。 31b) 烯丙基-6υ,7Ρ-15Μ6Ρ-雙亞甲基_17p_氰基甲雄留_4_ 烯-3-¾ 類似於實例30e中所給之方法,使17α_烯丙基_6β,邛_ 15β,Ι6β_雙亞f基_3β_5β·雙經基氰基甲則炫反應。 此得到17α-烯丙基_6β,7β_15(3,16ρ_雙亞甲基丨邛-氰基甲雄 崔-4-稀-3 _嗣。 •H-NMR (D6-DMSO): 0.43 (m, 1H), 〇.86 (m, 1H), i.〇2 (s? 3H), 1.03 (s, 3H), 5.20 (m, 1H, -CH=CH2), 5.24 (m, 1H, -CH=CH2), 5.87 (s, 1H, 4-H), 5.94 (m, 1H, -CH=CH2) 〇 製備實例32: 17P-氰基-6-甲基-ΐ5ρ,16ρ·亞甲基甲雄甾-46二烯_3酮 將25 mg Pd-C(l〇%,以水濕潤)添加至1〇〇 mg 17β_氰 基-6-外亞甲基_ΐ5β,ι6β_亞曱基曱雄甾_4烯_3酮於1〇…乙 醇中之溶液中,且將混合物加熱至沸騰。接著在丨小時之 時段中’逐滴緩慢添加〇. 5 mi環己烯於2 mi乙醇中之溶 液’且在回流下再繼續加熱7小時。冷卻反應混合物,藉 由過濾移除催化劑且濃縮得到17卜氰基_6_甲基_150,160_亞 甲基曱雄锡-4,6-二烯_3_酮(25 mg)。 144922.doc 201026718 W-NMR (400 MHz,CDCl3 TMS作為内標,經選擇信號): δ=0·53 [m,(1H)環丙基],2.78 [d,片,5 沿,17 H⑷],5 的 及6.18 [2xs,(在各情況下 1H), 4_j^7_h]。 MS (CI+) m/Z (相對密度)=322 (1〇〇), 339 (5〇);對應於 C22H27NO。 製備實例33: 4-氣-17P-氰基-Ι5β,16β·亞甲基甲雄甾_4_烯_3鲖 將700 mg 17卜氰基·15Ρ,16卜亞甲基甲雄留-4-烯-3,溶 © 解於8 ml°比咬中且冷卻至〇°C。添加0.32⑹硫醯氯後,在 此溫度下㈣混合物丨.5小^在與飽和碳酸氫鈉水溶 液、水及乙酸乙醋混合後,分離各相,且用水及飽和氣化 鈉水溶液洗滌有機相。將有機相經硫酸鈉乾燥且過濾且接 著濃縮’且將產物自乙酸乙醋再結晶。此得到4-氯_17卜氛 基-15β,16β-亞曱基甲雄留_4_烯_3_酮(21l mg)。 H-NMR (300 MHz’ CDC13 TMS作為内標,經選擇信號): ❹ δ=〇_47 [m,(1H)環丙基],2.75 [d,J=4.5 Hz,17_H⑷],3 33 ((1(ΐ£ΐ,·//-15.3Ηζ,《/2=4·5Ηζ,«/3=2.6Ηζ)。 製備實例34 : 17Ρ-氰基-3-羥基亞胺基_15p,16pj甲基甲雄留领 將700 mg 17β-氰基_15p,16卜亞甲基甲雄崔_4稀·3-嗣溶 解於5 m卜比咬中且添加211 mg經基胺鹽酸鹽。在12代浴 溫度下授拌一小時後,使批次·在水與乙酸乙醋之間分配。 以水及飽和氯化納水溶液洗條有機相,經硫酸納乾燥且過 滤且滚縮滤液。管柱層析得到呈砖之E/z混合物之”卜氛 144922.doc -59· 201026718 基-3-羥基亞胺基- Ι5β,16β-亞曱基曱雄甾-4-烯-3-酮(157 mg)。 W-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0·43 [m,(1H)環丙基],2.73 [d,/=4.5 Ηζ,17-Η(α)], 3.05 (m, 5-Hj), 5.79 (m, 4-H) ° MS (CI+) m/z (相對密度)=325 (100), 342 (76);對應於 C21H28N2O。 製備實例35 : 17P-氟基-6-外亞甲基-17α-甲基-15β,16卜亞甲基甲雄错_4_ 稀·3·明 根據實例4之方法,130 mg 17β-氰基-6β-羥基曱基_ι7α_ 曱基-1 5β,16β-亞甲基曱雄甾-4-稀-3-酮在石夕膠層析後得到 17β-氰基-6-外亞甲基-17α-甲基-15β,16β-亞曱基甲雄留_4_ 稀-3-酮(86 mg)。 17β-氰基-6-外亞甲基_ΐ7α-曱基-15p,16p-亞甲基甲雄留 稀-3-明 ^-NMR (300 MHz, CDC13 TMS作為内標,經選擇信號): δ=0·47 [m,(1H) ’ 環丙基]’ 1.12,1.16及 1.39 [3xs,(在各 情況下 3H),3xMe],5.02及5.12 [2xt,/=2 Hz,(在各情況下 1H),=CH2],5.93 (br. s, 4-H)。 製備實例36 : 17β-氰基-17α-甲基-15p,16p-亞甲基甲雄甾a_4,6·二烯_3·_ 根據實例6之方法,17.7 g 17卜氰基·3-曱氧基_17〇1_甲 基-15β,16β-亞甲基甲雄留烷_3(4),5(6)_二烯在結晶後得到 144922.doc -60- 201026718 17β-氰基-17α-曱基_15β,16|3·亞甲基曱雄甾_4 6二烯 (5_84 g) 〇 ^-NMR (300 MHz,CDCl3 TMS作為内標,經選擇信號广 δ=0·52 [m,(1H) ’ 環丙基],114, 39 [3xs,(在各 情況下3H),3xMe],5·70 (s, 4·Η),6 18 ⑽,Λ = 9 8 办 •/2=2.8 Ηζ,6-Η),6.33 (dd,·7;=9·6 Hz,心=ι.8 Ηζ, 7_Η)。 ’ MS (CI+) m/z (相對密度)=322 (1〇〇),339 (32);許應於 C22H27N〇2 0 V 製備實例37: 6P,7p-lSp,16p-雙亞甲基·17p_氰基-17α甲基甲雄培4 烯-3-_及“,7«_15?,叫雙亞甲基_17ρ氰基-17〇[甲基甲雄 甾-4-稀-3-酮 根據實例7之方法,3.〇 g 17ρ·氰基_1?α甲基卜亞 甲基甲雄K6-二歸在石夕膠册^分離粗產物後得到 呈非極性溶離份之“^心丨邱’^卜雙亞曱基-丨邛氰基丨〜— 參 甲基甲雄甾_4_烯-3_酮(475 mg)及呈極性溶離份之6ρ,7β_ 150,160-雙亞曱基_170_氰基_17〇1_曱基曱雄甾_4_烯3_酮 (1.2 g)。 溶離份1 : 6a,7a-lSp,16p-雙亞曱基_17?_氰基-17〇[甲基甲 雄甾-4-稀-3-酮: H_:NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=〇·46’ 0,57, 0,80及 0·93 [4xm,(在各情況下⑴),4χ 環丙 基]’ 1.15,1.20 及 1.39 [3xs,(在各情況下 3H),3xMe],5·96 (s,4-H)。 144922.doc 61- 201026718 溶離份2 : 6p,7p-15p,16p-雙亞甲基_17?_氰基_17α_曱基甲 雄留-4·稀-3-網 H_MMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0.50及 0.87 [2xm ’(在各情況下 1H),2x環丙基],1 1〇, 1.14 及 1.41 [3xs,(在各情況下 3H),3xMe],6·〇2 (s,4_H)。 MS (CI+) m/z (相對密度)=336 (100),353 (28);對應於 C23H29NO 0 製備實例38 : 17β-氰基-17α-乙基-3-曱氧基·ΐ5β,ΐ6β-亞甲基甲雄甾 烷-3(4),5(6)-二烯及17β-氰基47α-乙基_ΐ5ρ,16β-亞甲基甲 雄留-4-稀-3-嗣 根據實例9a)之方法(使用乙基碘化物替代曱基碘化物), 18.0 g 17β-氰基-3-曱氧基_15β,16卜亞甲基甲雄甾 烷-3(4),5(6)-二烯在結晶後得到17β_氰基_17α_乙基_3_曱氧 基-15β,16β-亞曱基甲雄留烷_3(4),5(6)-二烯(6.85 g)以及在 母液急驟層析後得到17β-氰基·17α-乙基-15β,16β-亞甲基曱 雄留-4-稀-3·嗣(338 mg)。 17β_氰基-17α-乙基-3-甲氧基-15p,16p-亞甲基甲雄留 烷-3(4),5(6)-二烯: ^-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0·42 [m,(1H) ’ 環丙基],1.00及 1.17 [2xs,(在各情況下 3H),2xMe],1.21 (t,J=7.1 Hz,CH2-CH3),3.58 [s, (3H), OMe], 5·14 (m,4-H), 5.26 (m, 6-H)。 MS (CI+) m/z (相對密度)=352 (90),369 (100);對應於 144922.doc -62 - 201026718 C24H33NO 〇 17P-氰基-17α-乙基_iSp,16p-亞甲基甲雄甾_4_稀-3,: W-NMR (300 MHZ,CDC13 TMS作為内標,經選擇信號): δ=0.45 [m,(1H) ’ 環丙基],1>19 及 1.21 [2xs,(在各情況下 3H),2xMe ;重疊 i.23 (t, j 三 6·4 Hz,Ch2_CH3)], 5 75 幼 4-H)。 ’ MS (CI+) m/z (相對密度)=338 (1〇〇),355 (59);對應於 c23h31no。 ® 製備實例39 : 17β-氰基-17„_乙基-15p,16p_亞甲基甲雄甾_4 6二烯_3酮 根據實例6之方法,6〇 g 17卜氰基_ηα•乙基_3曱氧 基·15β,16β-亞甲基甲雄甾_3(4)5(6)_二烯在結晶及隨後急 驟層析母液後得到17β-氰基-17α-乙基-15β,16β-亞甲基甲雄 甾 _4,6-二稀-3-輞(4·87 g)。 (300 MHZ,CDC13 TMS作為内標,經選擇信號): φ 5一〇·59 [m,(1H)’ 環丙基],1.18 及 1.29 [2XS,(je 3H), 2xMe , ¢^1.27 (tj y=7.4 Hz, CH2-CH3)], 5.75 (s, 4-H), 6.22 (dd, J; = 9.8 Hz, J2=2.8 Hz, 6-H), 6.38 (dd, J}=9.6 Hz, </2=l·9 Hz, 7-H)。 MS (CI+) m/z (相對密度)=336 (100),353 (43);對應於 C23H29NO。 製備實例40 : όΡ,7ρ-15β,16ρ-雙亞甲基·17p氰基·i7〇[•乙基甲雄留_4_ 烯_3_酮及“’7α书Ρ,16Ρ-雙亞甲基-17Ρ-氰基-17α-乙基甲雄 144922.doc •63· 201026718 甾-4-烯-3-酮 根據實例7之方法,2_5 g 17β-氰基-17α-乙基-15β,16β-亞 曱基甲雄留-4,6-二烯-3-酮在矽膠HPLC分離粗產物後得到 呈非極性溶離份之6〇[,7〇1-150,160-雙亞甲基-170-氰基-17〇1-乙基甲雄甾-4-烯-3-酮(290 mg)及呈極性溶離份之6β,7β-15β,16β-雙亞甲基·17β-氰基-17α-乙基甲雄崔-4-烯-3-酮 (670 mg)。 溶離份1 : 6α,7α-15β,16ρ-雙亞甲基-17P-氰基-17α-乙基甲 雄甾-4-烯-3-酮: W-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0.48,0.53, 0.80 及 0.93 [4xm,(在各情況下 1H), 4x 環丙 基],1.16及1.23[2>^,(在各情況下311),2><?^;重疊1.22 (t,《7=6.3 Hz,CH2-CH3)],5.96 (s, 4-H)。 溶離份2 : 6p,7p-15p,16p-雙亞甲基-17p-氟基-17α-乙基甲 雄甾-4-稀-3-嗣 】H_NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0.50及0.86 [2xm,(在各情況下1H),2χ環丙基],1.09及 1.15 [2xS’(在各情況下 3Η),2xMe],1.22 (t,J=7.3 Ηζ, CH2-CH3),6.00 (s, 4-Η)。 製備實例41 : 17Ρ-氟基-17α-乙基_7ρ-甲基_15ρ,16ρ·亞甲基甲雄甾心 烯-3-酮及17ρ-氪基_17α_乙基-7α_甲基15ρ,16ρ亞甲基甲 雄留-4·稀-3-闲 根據實例8之方法,1 〇 g 17ρ_氰基_17α•乙基_15ρι6ρ亞 144922.doc • 64- 201026718 甲基甲雄留-4,6-二烯-3-酮在矽膠HPLC分離粗產物後得到 呈非極性溶離份之17β-氰基-17α-乙基-7α-曱基-Ι5β,ΐ6β-亞 甲基曱雄留-4-稀-3-_ (165 mg)及呈極性溶離份之ΐ7β_氛 基-17α-乙基-7β-甲基-15β,16β-亞曱基曱雄错-4_烯_3_酮 (292 mg)。 17P-氰基-17α-乙基_7α-甲基-15β,16β-亞甲基曱雄错-4_ 稀-3 -綱 W-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0.44 [m,(1H),環丙基],0.86 (d,/=7.2 Hz,7-Me),1.08 [m,(1H),環丙基],1.19及 1.21 [2xs,(在各情況下 3H), 2xMe ;重疊 1.22 (t,*7=7.4 Hz,CH2-CH3)],5.75 (s,4-H)。 17β-氰基-17α-乙基-7β-甲基-Ι5β,16ρ_亞甲基甲雄甾4 烯-3-酮 W-NMR (300 MHz,CDC13 TMS作為内標,經選擇信號): δ=0.53及1.04 [2xm,(在各情況下1H),2x環丙基],1 & 1.26 (m,7-Me,2xMe及 CH2-CH3)],5.73 (br· s,4-H)。 製備實例42 : 17P-氱基甲雄甾-4-烯 類似於實例ib中所給之方法,使甲雄留_4_烯_17•嗣(參 見例如 Helv. Chim_ Acta (45) 1962, 2575)反應。在使用乙 酸乙酯與正己烷之混合物矽膠層析所得粗產物後,濃縮含 產物之溶離份且藉由HPLC再層析。除17α氰基甲雄错 烯以外,亦獲得17β-氰基曱雄留_4_烯。 17p-氰基甲雄甾-4-烯 144922.doc •65- 201026718 W-NMR (CDC13 TMS作為内標,經選擇信號):δ=〇 94 [s, 3H, -CH3], 1.04 [s, 3H, -CH3], 1.13 [m, 1H], 1.21 [m, 1H], 2.11 [m,1H], 2.20 [m,1H],2.26 [m,1H], 5.31 [寬單峰, 1H, 4-H]。 製備實例43 : 4-氣-17β-氰基甲雄甾_4-烯 類似於實例33中所給之方法,使17β•氰基曱雄崔_4_稀_ 3-酮反應且經處理。此得到4-氣-Ι7β-氰基甲雄留_4_烯_3_ 酮。 W-NMR (CDC13 TMS作為内標,經選擇信號广δ=〇98 [s 3H, CH3], 1.24 [s, 3H, CH3], 2.58 [m, 1H, 17-H], 3.26 [ddd «/7 = 15.1 Hz, ·72=4.0 Hz,《/3=2.6 Hz]。 製備實例44 : 6β,7β·15ρ,16ρ-雙亞甲基-17p-|L基甲雄甾_i,4_二稀3明 使60,70-150,16戸-雙亞甲基-170-氰基甲雄甾_4_稀_3_ ^*4央貝 似於實例293反應,得到60,7择-1邱,16泛-雙亞甲基_170氛 基-曱雄留·1,4-二烯-3-酮。 ^-NMR (300 MHz, CDC13): δ=0.55 (m, 1ΗΊ 1 ιΛ , ^ (s, 3H), 1.14 (s, 3H), 2.81 (d, 1H, H-17) 6.18 (m, 1H, H-2^) ’ 1H,H-4), 6.85 (s,1H, H-l)。 製備實例45 : 1〇1,2〇1-外,7?-15?,16?-參亞甲基-17?-氰基甲雄铬 m 烯-3-亞曱 田締-3 使60,70-15戸,160-雙亞曱基-170-氰基甲雄留_14_ 酮類似於實例7反應,得到1α,2α-6β,7β-ΐ5βΐ6ρ灸 144922.doc * 66 - 201026718 基-17β-氰基甲雄留-4_烯_3_酮。 *H-NMR (300 MHz, CDC13): 6=0.52 (m, 1Η), 0.74 (m, 1H), 0.82 (m,1H),1.07 (s,3H),114 (s,3H),2 81 (d,m,H i7), 5.86 (m,1H,H-4)。 根據本發明,現已發現PCT/EP2008/057427中所述之化 學通式1之化合物亦適於陰道内或子宮内投與。此可使用 生理上可接受之溶液實現,諸如水溶液或油溶液,具有或 不具有適合增溶劑、分散劑或乳化劑。適合油為例如花生 油、棉籽油、蓖麻油或芝麻油。選擇不限於此等實例。 為進行陰道内或子宮内投藥,可能使用特定系統,諸如 陰道内系統(例如陰道環,VRS)或子宮内系統(IUS),其在 長時段(例如1、2、3、4或5年)内自貯器釋放本發明活性物 質。 可提及之子宮内系統之代表性實例為MIRENA®。此為 來自BAYER SCHERING PHARMA AG之釋放左炔諾孕酮之 T形子宮内系統。 投藥另外可能經由由惰性載體材料(諸如生物可降解聚 合物或合成聚矽氧聚合物)構成之經植入之供給系統。此 等供給系統以受控方式在長時段(例如3個月至3年)内釋放 活性物質且經皮下植入。 本發明調配物例如自IUS每天釋放與每天口服劑量相當 之量避孕製劑中口服使用之劑量應為每天0.01至10 mg。經W症狀治療中之每天劑量為約0· 1至20 mg。 本發明調配物例如自IUS每天釋放0.005至1〇 mg之量的 144922.doc -67- 201026718 通式1化合物。 可使用本發明系統來投與雌激素以及通式^化合物。 可能考慮合成雌激素(較佳乙炔基雌二酵,亦可為雌酵 曱醚)作為用於避孕製劑之雌激素。 雌激素以對應於0.01至〇.〇4 mg乙快基雌二醇之日劑量投 與。 又 雌激素當然主要用作治療停經前、近停經期及停經後症 狀及激素替代療法之藥物中的雌激素’尤其為雖二醇或其 酯,例如戊酸雌二醇或者經結合雌激素(CEE =經結合馬雌參 激素)。 相應地,本發明係關於化學通式氰基甲雄留_心 烯衍生物,Hz, 6-H*), * = allocation is reversible. MS (EI+) m/z (relative density) = 307 (26); corresponds to c21h25NO. Preparation Example 18: 17β-cyano-7α·methyl-15α,16α-methylenemethylandrosine-4-ene-3-butanone 144922.doc -48- 201026718 According to the method of Example 8, 2.2 g of 17-cyano -15α,16〇ι-methylene oxime, male-4,6-diene_3_辋, ι7_epimer, 17β-cyano-7α-methyl, after preparative hplc chromatography 15α, 16α_-indenyl-androst-4-ene-3-one (257 mg). iHMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ=0·58 [m,(1H),cyclopropyl]' 〇69 [m,(1H),cyclopropyl],〇% ( d, /= 7.2 Hz, 6-Me), 1.25 and 1.26 [2xS, in each case (3H), 2xMe], 5.79 (s, 4-H). MS (EI+) m/z (relative density) = 323 (1〇〇); corresponds to c22H29N〇. Preparation Example 19: 17β-fluoro-methyl-androstene-4,6·disali-3-one 19a) 17P-cyano-3-ethoxymethylanthrene_3,5-diene is similar to Example 1a In the procedure given, the original triethyl decanoate was used instead of trimethyl orthoformate to react with 17β-cyanomethyl-4-in-3-one. This gave 170-cyano-3-ethoxyindole _3,5-di-! H-NMR (D6-DMSO): 0.81 (s, 3H), 0.86 (s, 3H), 1.17 (t, 3H, J=7.1 Hz, 3-0-CH2-CH3), 3.36 (m, 2H, 3-0-CH2-CH3), 5.09 (m, 2H, H-4 and H-6). 19b) 17β-cyanomethylandrosine_4,6-dicarbea-3-oxime similar to the procedure given in the example, with 17β-cyano-3 ethoxy oxime-3,5-di Alkenes reaction. This gave Ι7β-cyanoindole male-4,6-dien-3-indole. W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): 144922.doc •49- 201026718 δ=1.02 (s,3H),113 (S,3H),5.68 (s,1H,H-4 ), 6.06 6-H), 6.13 (s, 1H, 7-H). , old, Preparation Example 20: 17P-cyano 7α-methylmethylandrosin-4-4-ene-3-enketone is similar to the procedure given in Example 8 to give 17β-cyanomethine _4 6 ene- 3. Ketone reaction. This gave 17|3-cyano-7{χ_mercapto-androst-3-ene. W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal) 6=0.77 (d, 3H, 7-CH3, J=7.3 Hz)), 0.98 (s, 3H), 1>2l 3H), 5.74 (s, 1H, H-4) 〇Bend Preparation Example 21: 17P-Cyano-7α-ethylmethanoyl _4-ene-3-one is similar to the method given in Example 8 'Using ethylmagnesium bromide Substituting the ruthenium bromide-based town to react 17β·cyanomethyl-oxo-6•diene_3_one. Obtained, -7-α-ethyl guanidine, _4_ ene ketone. iH-NMR (300 MHz, CDCl3 TMS as internal standard selection signal) 5=0.88 (t? 3H, 7-CH2-CH3, J=7.3 Hz)), 〇.98 (s, 3H)5 1.22 ❹ (s , 3H), 5.74 (s, iH, H_4). Preparation Example 22: 17P_gas-based·6α,7α-methylene-methyl-androsterin I-III_ _ and 17p_ ιyl-6p,7p-methylene-methyl-androstene-4-4-ene-3-one is similar to Example 7 Recognized by this, the procedure of the mouth, the reaction of P, cyanomethyl male-4,6-dithia-3-one. This gave 17β. cyano-cut α-methylenemethyl-andrazine-4·en-3-one and 17β-cyano-6Μρ_arylene-methyl-methyl group. 144922.doc -50. 201026718 17β-cyano-6α,7α-methylenemethylanthrene-4-zinc-3-gg: H-NMR (3 00 MHz, CDCI3 TMS as internal standard, selected for number) : 5 = 0.46 (m, 1H), 0.77 (m, 1H), 0.85 (m, 1H), l.〇l (s, 3H), 1.15 (s, 3H), 5.95 (s, 1H, H-4 ). 17P-Cyano-6β,7β-methylenemethylandrosine_4·ene_3_鲷·· H-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ-0.79 (m, 1H ), 0.95 (s, 3H), 1.09 (s, 3H), 6.01 (s, 1H, H-4). Preparation Example 23: 17β-Cyano-6β-radiomethylmethylxanthine_heart thinning Similar to the procedure given in Example 2, 17p-cyanoguanidine was left to react with _4-ene-3-one. This gave 17β-cyano-6β-hydroxymethylmethylxanthene-4_ene-3-one. W-NMR (300 MHz' CDC13 TMS as internal standard, selected signal): δ-0.98 (s, 3H), 1.21 (s, 3H), 3.68 (m, 2H, 6-CH2-OH), 5.82 (s5 1H, H-4) 〇Preparation Example 24: 17β-cyanoethylidene 曱4_ene_3_鲷 is similar to the examples given in Examples 3a and 3b, such that 17 cyano _6 hydroxy Methyl-androst-4-ene-3-enone reaction 'wherein the crude sulfonate intermediate is further reacted. This gave 17 戸 cyano-6,6-ethylidene oxime _4_ene_3 ketone. W-NMR (300 MHz, CDCi3 TMS as internal standard, selected signal): 6 = 0.42 (m, 2H), 0.77 (m} 1H), 0.99 (s, 3H), 1.26 (s, 3H), 5.62 ( s, 1H, H-4). 144922.doc -51 · 201026718 Preparation Example 25: 17P-cyano-17α-methylmethylandrosine-4-lean_3_net 25a) 17-carbyl-3,3-ethanediyldimethoxymethyl Leave _5_ dilute at room temperature, 5 g of cyano compound in 56 m]1 dioxane, 14 (6) ethylene glycol, 37 ml trimethyl orthoformate and 丨·5 g to methyl sulfonate mixture Stir for two hours. After the addition of sodium bicarbonate solution and ethyl acetate, the phases were separated and washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The 17?-cyano-3,3-ethanediyloxymethylstano-5-ene obtained in this manner can be used without any further purification. 25b) 17β-cyano-3,3-ethanediyldioxy_ΐ7α-methyl.methylanthogamine _5•rare similar to the method given in Example 9a, such that 17ρ•cyano_33_乙二The bis-dimethoxymethyl male-5-ene reaction. This gave 17 as _cyano-3,3-ethanediyl hydroxy-17α-indenyl-androst-5-ene. H-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 1.04 (wide single peak '6H), 1.28 (s, 3H), 3.94 (m, 4H, ketal), 5.34 (s, 1H, H-6). 25c) 17β-cyano-17α-methylmethylandrosine 4-4-ene-3-_ Similar to the method given in Example lc, 17 17-cyano-3,3-ethanediyldioxy-17α - methylmethyl male to _5_ene reaction. This gave 17 cyano _17 〇 1 _ methyl ketone -4- -3- -3-. H-NMR (300 MHz, CDC13 TMS as internal standard, selected signal factory 144922.doc • 52· 201026718 δ=1.09 (s, 3H), 1.20 (s, 3H), 1.28 (s, 3H), 5.73 (s , 1H, H-4). Preparation Example 26: 17β-fluoroyl·6ρ·ylmethyl-17α-methylmethylanthryl-4-pyrimidin-3-yl is similar to the procedure given in Example 2, Ι7β-cyano-Ι7α·methylmethylandrost-4-en-3-one is reacted. This gives 17β-cyano-6β-hydroxymethyl-ΐ7α-indenyl-androst-4-en-3-one丨H-NMR (D6-DMSO): 1.01 (s, 3Η), 1.15 (s, 3Η), 1.25 (s, 3Η), 3.35 (m, 1H, 6-CH2-OH), 3.57 (m, 1H) , 6-CH2-OH), 4.73 (t, 1H, J = 5.8 Hz, 6-CH2-OH), 5.65 (s, 1H, H-4). Preparation Example 27: 17β-Alkyl-6,6- Ethylenediyl-17 α-methylmethylandrosine-4-lean_3__ is similar to the procedure given in Examples 3a and 3b, allowing ΐ7β-cyano-6β_ via thiol-17α-methyl oxime 4- 4-en-3-one reaction in which the crude benzene sulfonate intermediate is further reacted. This gives 17β·cyano-6,6-ethanediyl_17〇1_fluorenylanthen-4- Dilute-3-branched 1. ^-NMR (300 MHz, CDCI3 TMS as internal standard, selected signal): δ = 0.42 (m, 2 Η), 0.78 (m, 1Η), 1.10 〇, 3Η), 1.27 (s, 3Η) 1.29 (s, 3H), 5.63 (s, 1H, H-4). Preparation Example 28: 17α-allyl-17p-cyanomethylanthryl-4-4-ene-3-one ketone 28a) 17P-cyano-17α-methylmethylandrost-4-en-3-one analogous to the example The method given in 9a, the reaction of 17-cyano·3,3_ethanediyldioxyanthracene 崔5-ene, in which allyl bromide is used instead of methyl iodide 144922.doc •53· 201026718 Compound. This gave 17?-allyl-ΐ7?-cyano-3,3-ethanediyldioxaindole-5-ene. W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 1.10 (s, 3H), 1.13 (s, 3H), 3.99 (m, 4H, ketal), 5.26 (m, 2H, _CH=CH2), 5.39 (s, 1H, H-6), 5.97 (m, 1H, -CH=CH2). 28b) 17a-allyl-17P-cyanoandrost-4-en-3-one is similar to the method given in Example lc, such that 17a-allyl-17β-cyano-3,3-ethyl Dikis bisoxyindole male-5-ene reaction. This gave 17〇1_allylyl-17β-cyanomethyl-androst-4-ene-3-. ^-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): 5 = 0.97 (m5 1H), 1.17 (s, 3H), 1.25 (s, 3H), 5.25 (m, 2H, -CH=CH2 ), 5.79 (s, 1H, 4-H), 5.96 (m, 1H, -CH=CH2). Preparation Example 29: 17β-cyano-la-methylmethyl-androst-4-iso-3-oxime 29a) 17P-fluoromethylandrostene-1,4-dien-3-one to give 2.5 g of 17β-cyanide The base of the male fluorene-4-ene-3-_ and 2.7 g of the di-dioxanyl cyanide in the 50 ml two e-dark in the Buddha for 3 hours. After cooling, the mixture was diluted with a second gas and filtered. The filtrate was washed with sodium hydrogen carbonate solution, water and a saturated sodium carbonate solution. After drying over sodium sulfate, filtration and concentration of the filtrate, the residue was chromatographed using hexane/ethyl acetate mixture. This gave 17?-aza-methyl-androst-1,4-dien-3-one. W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): 144922.doc •54- 201026718 δ = 1_00 (s,3H), 1.25 (s,3H),6·07 (s,1H, H -4), 6.25 (wide single peak, 1H, H-2), 7.06 (s, 1H, Hl). 29b) 17β-cyano-la-methyl-methyl-androst-4, -3- ketone 6 mg "smelting copper (i), ii ml of trimethylaluminum and cerium 31 w tridecyl decyl alkyl vapor It was continuously added to a solution of 〇_6 g 17 cyanomethyl male oxime Μ_diene _3_ oxime in 6 ml of tetrahydrofuran. After stirring at room temperature for three hours, the mixture was partitioned between water and ethyl acetate. The organic phase was washed successively with water and a saturated sodium carbonate solution, dried over sodium sulfate and filtered, and the filtrate was concentrated. Chromatography using a mixture of hexane/ethyl acetate afforded 17p-cyano-la-methylmethano-4-pyrimidine-3-indole. H-NMR (3 00 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.94 (d, 3H, 1-CH3), 0.98 (s, 3H), 1.29 (s, 3H), 5.71 (s, 1H, H-4) 〇Preparation Example 30: 0 6p, 7p-15p, 16P·bismethylene-17P-fluoro-l7〇t-methylmethylanthryl-4-4-en-3-one 30a) 6p, 7p-15p, 16p-bismethylene·3ρ·t-butyldimethylsilyloxy-5β- via keto-methyl _17-lang according to the method of Example l6a '6β,7β_15β,16β^ Mercapto- 3β 5β·di-based oxime-bearing -17-one c /2 k 1982, Ρ 4, 718-719) and as a butyl dimethyl hydrazide chloride After crystallization, 60,70-150,160-bismethylene_3|3_t-butyldimethylmethylalkyloxy 144922.doc •55- 201026718 keto-5β-hydroxyindole _17_ ketone. ^-NMR (300 MHz, CDCh ^ ^ , i3 is the internal standard, selected signal): δ=0·08 and 0.11 [2xs, in the long/1 (3H), Si-Me], 4 · 13 (s, 3-Η), 4·40 (s, 5-ΟΗ). MS (CI+) m/z (relative density) = 445 (5〇), 462 (ΐ5) ·, corresponding to C27H44N〇3Si 〇30b) 6β,7β-15β,16β-bismethylene_3β_third Methyl dimethyl seroyloxy-17-cyano-5β- via ketone male _17_ 闺 similar to the method described in Example lb to make 6β,7β_15β16ρ bis methylene-3 β-second Butyl dimethyl decyloxy _ 5 β hydroxymethyl male alkane 4 7-one reaction. This gave 6β,7β_15β,16β_bis-indenyl-3β-t-butyldimethylmethylalkyloxy_17-cyano-5β-hydroxymethylhectorol-17 as a mixture of 17-episo-nitrile nitriles. - Ketone, which is further processed without the need to separate the epimers. 'H-NMR (D6-DMSO): 〇.〇2 (s, 3H), 0.04 (s, 3H), 0.40 (m, 2H), 0.60 (m, 1H), 0.74 (s, 3H), 0.82 ( Wide single peak '12H), 2·36 (m, 2H), 2.97 (m, 1H), 4.01 (m, 1H). 30c) 6p, 7p-15p, 16p-bismethylene_3p_5p_bis-lightyl_17p_cyano_17a_methyl-androstane similar to the methods of Examples 9a and 16c, such that 6β, 7β-15β, 16β-bis-indenyl-3β-tert-butyldimethylsilyloxy_17-cyano-5 5-hydroxy-indole and oxane-17-one. This gave 6?,7?-15?,16?-bismethylene-3?-5?-bishydroxy-17?-cyano-17?-methyloxime. 144922.doc •56- 201026718 丨H-NMR (D6-DMSO): 0.40 (m, 2H), 0.61 (m, 1H), 0.74 (s' 3H), 0.93 (s, 3H), 1.36 (s, 3H) ), 1.93 (m, 1H), 2.03 (m, 1H), 3.79 (m, 1H). 30e) 6β,7β-15β,16β-bismethylene-ΐ7β_cyano·ΐ7α•methylmethine _4· 稀-3-闲将 310 mg 6β,7β-15β,16β-bis-indenylene -3β-5β-bishydroxy-17β-cyano-17α-methylindolerol was dissolved in 10 m guanidine acetone, and 〇42 ml Jones reagent was added. After 15 minutes, 4 ml of isopropanol was added to the mixture. The mixture was then partitioned between water and ethyl acetate. The organic phase was washed with saturated sodium sulfate, dried over sodium sulfate and filtered and concentrated. Using a mixture of hexane and ethyl acetate to obtain 6β,7β_15β,16β-bismethylene-17β-cyano-17 α-methyloxime 甾4_women-3- ketone. 'H-NMR (D6-DMSO): 0.41 (m, 1H), 0.85 (m, 1H), 0.99 (s, 3H), 1.02 (s, 3H),1·31 (s,3H), 5.86 (s) , 1H, 4-H). Preparation Example 31: 17α-dipropyl-6 release, 73-15 release, 16 release-bismethylene_173_氦基甲雄甾_4_ 稀-3-闲31a) 17α-propylpropyl-6p, 7p-15p, 16p-bis-indenyl_3β_5β-dihydroxy-Ι7β-cyanomethyl-androstane is similar to the method given in Example 9a (using allyl bromide instead of methyl moth) and 16c. , 70-150, 16-di-indenyl _3, butyl butyl dimethyl sulphate oxy-17-cyano-5β-hydroxymethylxiongrein _ 17-ketone reaction. This is 144922.doc •57- 201026718 to 17α-allyl_6β,7β_15β,16β_bismethylene_3β邛dihydroxy"邛_cyanomethyl male sulphonate. !Η-ΝΜΚ (D6-DMSO) : 0.40 (m, 2H), 〇.6i 1H), 〇.?4 (S} 3H), 0.96 (s, 3H), 2.02 (m, 2H), 3.79 (m, 1H), 4.78 (m, 1H) 5.19 (s,1H), 5.24 (m,1H), 5.94 (m,1H). 31b) Allyl-6υ,7Ρ-15Μ6Ρ-bismethylene_17p_cyanomethyl group _4_ene -3-3⁄4 Similar to the method given in Example 30e, the 17α-allyl_6β, 邛_ 15β, Ι6β_ bis-sub-fyl _3β_5β· bis-cyano cyanomethyl was decocted. This gave 17α- Allyl _6β,7β_15 (3,16ρ_bismethylene fluorenyl-cyanomethyl-andrazine-4-thin-3 _嗣. •H-NMR (D6-DMSO): 0.43 (m, 1H), 〇.86 (m, 1H), i.〇2 (s? 3H), 1.03 (s, 3H), 5.20 (m, 1H, -CH=CH2), 5.24 (m, 1H, -CH=CH2), 5.87 (s, 1H, 4-H), 5.94 (m, 1H, -CH=CH2) 〇Preparation Example 32: 17P-cyano-6-methyl-indole 5ρ,16ρ·methylenemethylanthrene-46 Alkenyl-3-ketone 25 mg Pd-C (10%, wetted with water) is added to 1 〇〇mg 17β_cyano-6-exomethylene_ΐ5β, ι6β_亚曱基曱雄甾_4ene _3 ketone in 1〇 In a solution in ethanol, and heating the mixture to boiling. Then, a solution of mi. 5 mi of cyclohexene in 2 mmol of ethanol was slowly added dropwise over a period of 丨 hours and heating was continued for another 7 hours under reflux. The reaction mixture was cooled, the catalyst was removed by filtration and concentrated to give <RTI ID=0.0>>&&&&&&&&&&&&&&& .doc 201026718 W-NMR (400 MHz, CDCl3 TMS as internal standard, selected signal): δ = 0·53 [m, (1H) cyclopropyl], 2.78 [d, plate, 5 edge, 17 H(4)], 5 and 6.18 [2xs, (1H in each case), 4_j^7_h]. MS (CI+) m/Z (relative density) = 322 (1〇〇), 339 (5〇); corresponds to C22H27NO. Example 33: 4-Gas-17P-cyano-indole 5β, 16β·methylenemethylanthrene_4_ene_3鲖 700 mg 17 cyano·15Ρ, 16 benzylidene-4-ene- 3, dissolve the solution in 8 ml ° than the bite and cool to 〇 ° C. After adding 0.32 (6) thioindole chloride, at this temperature, the mixture is mixed with a saturated aqueous solution of sodium hydrogencarbonate, water and ethyl acetate, and the phases are separated, and the organic phase is washed with water and a saturated aqueous solution of sodium sulphate. . The organic phase was dried over sodium sulfate and filtered and concentrated <RTI ID=0.0></RTI> and the product was recrystallised from ethyl acetate. This gave 4-chloro-17-mercapto- 15β,16β-indenyl-androst- 4-ene-3-one (21 l mg). H-NMR (300 MHz 'CDC13 TMS as internal standard, selected signal): ❹ δ=〇_47 [m,(1H)cyclopropyl], 2.75 [d, J=4.5 Hz, 17_H(4)], 3 33 ( (1 (ΐ£ΐ,·//-15.3Ηζ, "/2=4·5Ηζ, «/3=2.6Ηζ). Preparation Example 34: 17Ρ-cyano-3-hydroxyimino group _15p, 16pj A The base armored collar will dissolve 700 mg 17β-cyano _15p, 16 ymethylene methyl guano Cui _4 dilute 3- 嗣 in a 5 m buck bite and add 211 mg of the base amine hydrochloride. After one hour of mixing at the bath temperature, the batch was partitioned between water and ethyl acetate. The organic phase was washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate and filtered and the filtrate was rolled. Analysis of the brick E/z mixture "Bei 144922.doc -59· 201026718 base-3-hydroxyimino- Ι5β,16β-arylene-androst-4-en-3-one (157 mg W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.43 [m, (1H) cyclopropyl], 2.73 [d, /= 4.5 Ηζ, 17-Η (α )], 3.05 (m, 5-Hj), 5.79 (m, 4-H) ° MS (CI+) m/z (relative density) = 325 (100), 342 (76); corresponds to C21H28N2O. Preparation Example 35 : 17P-Fluoro-6-exomethylene-17α-methyl-15β, 16-methylenemethyl-androsteryl _4_ 稀·3·明 According to the method of Example 4, 130 mg 17β-cyano-6β-hydroxyindenyl _ι7α_ thiol-1 5β,16β-methylene oxime oxime-4-zol-3-one obtained 17β-cyano-6-exomethylene-17α-methyl-15β after chromatography , 16β-Amidinoyl malexyl _4_ dil-3-one (86 mg). 17β-cyano-6-exomethylene_ΐ7α-mercapto-15p, 16p-methylene methyl male-lean- 3- Ming ^-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.47 [m, (1H) 'cyclopropyl] ' 1.12, 1.16 and 1.39 [3xs, (in each case) 3H), 3xMe], 5.02 and 5.12 [2xt, /=2 Hz, (1H in each case), =CH2], 5.93 (br. s, 4-H). Preparation Example 36: 17β-cyano- 17α-methyl-15p,16p-methylenemethylanthridine a_4,6·diene_3·_ According to the method of Example 6, 17.7 g 17 cyano-3-indolyl _17〇1_methyl -15β,16β-methylenemethylhistrol _3(4),5(6)_diene obtained after crystallization 144922.doc -60- 201026718 17β-cyano-17α-mercapto _15β,16| 3·Methylene oxime 甾4 4 diene (5_84 g) 〇^-NMR (300 MHz CDCl3 TMS as an internal standard, the selected signal is wide δ = 0.52 [m, (1H) 'cyclopropyl], 114, 39 [3xs, (in each case 3H), 3xMe], 5.70 (s, 4·Η),6 18 (10),Λ=9 8 Do •/2=2.8 Ηζ,6-Η), 6.33 (dd,·7;=9·6 Hz, heart=ι.8 Ηζ, 7_Η). ' MS (CI+) m/z (relative density) = 322 (1〇〇), 339 (32); Xu should be C22H27N〇2 0 V Preparation Example 37: 6P, 7p-lSp, 16p-bismethylene· 17p_cyano-17αmethylmethyl male 4ene-3-_ and ",7«_15?, called bismethylene_17ρcyano-17〇[methylmethano-4-pyrene-3- The ketone according to the method of Example 7, 3. 〇g 17ρ·cyano_1?α-methyl-methylenemethyl-methyl-K6-di-return in the Shixi rubber book ^ separation of the crude product to obtain a non-polar solvate "^ heart 丨Qiu '^ Bu 曱 曱 丨邛 丨邛 丨邛 丨邛 — — — — — — — — — — 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 Base - 170 - cyano _17 〇 1 曱 曱 曱 曱 甾 _ 4 _ ene 3 ketone (1.2 g). Dissolved fraction 1 : 6a, 7a-lSp, 16p-bis-indenyl _17 _ cyano-17 〇 [methylmethylandrost-4-zol-3-one: H_: NMR (300 MHz, CDC13 TMS as Internal standard, selected signal): δ=〇·46' 0,57, 0,80 and 0·93 [4xm, (in each case (1)), 4χ cyclopropyl]' 1.15, 1.20 and 1.39 [3xs, (3H in each case), 3xMe], 5.96 (s, 4-H). 144922.doc 61- 201026718 Dissolved fraction 2 : 6p, 7p-15p, 16p-bismethylene_17?_cyano_17α_曱基甲雄留-4·稀-3-网H_MMR (300 MHz, CDC13 TMS as an internal standard, selected signal): δ = 0.50 and 0.87 [2xm '(1H in each case), 2x cyclopropyl], 1 1〇, 1.14 and 1.41 [3xs, (3H in each case), 3xMe], 6·〇2 (s, 4_H). MS (CI+) m/z (relative density) = 336 (100), 353 (28); corresponding to C23H29NO 0 Preparation Example 38: 17β-cyano-17α-ethyl-3-decyloxy·ΐ5β, ΐ6β- Methylene methylandrostane-3(4),5(6)-diene and 17β-cyano47α-ethyl_ΐ5ρ,16β-methylenemethyl-androst-4-pyrene-3-oxime according to an example Method 9a) (using ethyl iodide instead of mercapto iodide), 18.0 g 17β-cyano-3-indolyl _15β, 16 m-methylene methyl maleoxane-3(4), 5(6)- After the diene is crystallized, 17β_cyano_17α_ethyl_3_decyloxy-15β, 16β-arylene methyl malezane-3(4), 5(6)-diene (6.85 g) is obtained. And after the mother liquor flash chromatography, 17β-cyano·17α-ethyl-15β, 16β-methylene oxime male-4-pyre-3·嗣 (338 mg) was obtained. 17β_Cyano-17α-ethyl-3-methoxy-15p,16p-methylenemethylhistane-3(4),5(6)-diene: ^-NMR (300 MHz, CDC13 TMS As an internal standard, the selected signal): δ = 0.42 [m, (1H) 'cyclopropyl], 1.00 and 1.17 [2xs, (in each case 3H), 2xMe], 1.21 (t, J = 7.1 Hz, CH2-CH3), 3.58 [s, (3H), OMe], 5·14 (m, 4-H), 5.26 (m, 6-H). MS (CI+) m/z (relative density) = 352 (90), 369 (100); corresponds to 144922.doc -62 - 201026718 C24H33NO 〇17P-cyano-17α-ethyl_iSp, 16p-methylene甲雄甾_4_稀-3,: W-NMR (300 MHZ, CDC13 TMS as internal standard, selected signal): δ=0.45 [m,(1H) 'cyclopropyl],1>19 and 1.21 [ 2xs, (3H in each case), 2xMe; overlap i.23 (t, j three 6.4 Hz, Ch2_CH3)], 5 75 young 4-H). ' MS (CI+) m/z (relative density) = 338 (1〇〇), 355 (59); corresponds to c23h31no. ® Preparation Example 39: 17β-cyano-17 _ethyl-15p, 16p_methylenemethylanthrene _4 6 diene _3 ketone according to the method of Example 6, 6〇g 17 cyano _ηα• Ethyl-3 methoxyl·15β,16β-methylenemethylanthrene _3(4)5(6)-diene is obtained by crystallization and subsequent flash chromatography of the mother liquor to give 17β-cyano-17α-ethyl- 15β,16β-methylenemethylanthryl _4,6-dicarba-3-indole (4·87 g). (300 MHZ, CDC13 TMS as internal standard, selected signal): φ 5 〇·59 [ m,(1H)'cyclopropyl], 1.18 and 1.29 [2XS,(je 3H), 2xMe , ¢^1.27 (tj y=7.4 Hz, CH2-CH3)], 5.75 (s, 4-H), 6.22 (dd, J; = 9.8 Hz, J2 = 2.8 Hz, 6-H), 6.38 (dd, J}=9.6 Hz, </2=l·9 Hz, 7-H) MS (CI+) m/ z (relative density) = 336 (100), 353 (43); corresponds to C23H29NO. Preparation Example 40: όΡ, 7ρ-15β, 16ρ-bismethylene·17p cyano·i7〇[•ethylmethyl male _4_ ene_3_one and "'7α book Ρ, 16Ρ-bismethylene-17Ρ-cyano-17α-ethylmethyl 144922.doc •63· 201026718 甾-4-ene-3-one according to the example Method 7, 2_5 g 17β-cyano-17α-ethyl-15β, 16β-arylene-methyl- 4,6-di The 3-ketone was obtained by HPLC separation of the crude product to give a non-polar solvent of 6 〇 [,7〇1-150,160-bismethylene-170-cyano-17〇1-ethylmethylanthrene- 4-en-3-one (290 mg) and a polar dissolving 6β,7β-15β,16β-bismethylene·17β-cyano-17α-ethylmethylantre-4-en-3-one (670 mg). Dissolved fraction 1: 6α,7α-15β,16ρ-bismethylene-17P-cyano-17α-ethylmethylandrost-4-en-3-one: W-NMR (300 MHz, CDC13 TMS as internal standard , selected signal): δ = 0.48, 0.53, 0.80 and 0.93 [4xm, (in each case 1H), 4x cyclopropyl], 1.16 and 1.23 [2], (in each case 311), 2><?^; overlaps 1.22 (t, "7=6.3 Hz, CH2-CH3)], 5.96 (s, 4-H). Dissolved fraction 2 : 6p, 7p-15p, 16p-bismethylene-17p-fluoroyl-17α-ethylmethylandrosine-4-diphenyl-3-indole H_NMR (300 MHz, CDC13 TMS as internal standard, Selection signal): δ = 0.50 and 0.86 [2xm, (1H in each case), 2χcyclopropyl], 1.09 and 1.15 [2xS' (3Η in each case), 2xMe], 1.22 (t, J=7.3 Ηζ, CH2-CH3), 6.00 (s, 4-Η). Preparation Example 41: 17Ρ-Fluoro-17α-ethyl_7ρ-methyl_15ρ, 16ρ·methylenemethylandrosten-3-enone and 17ρ-indenyl_17α_ethyl-7α_methyl 15ρ, 16ρ methylene methyl male-4 - dilute-3-free according to the method of Example 8, 1 〇g 17ρ_cyano_17α•ethyl_15ρι6ρ亚144922.doc • 64- 201026718 methylmethyl male -4,6-dien-3-one is obtained by HPLC separation of the crude product to give a non-polar solvate of 17β-cyano-17α-ethyl-7α-mercapto-purine 5β, ΐ6β-methylene oxime male -4-thin-3-_ (165 mg) and a polar dissolving group of β7β_alkyl-17α-ethyl-7β-methyl-15β,16β-arylene-based oxime-4_ene_3_ Ketone (292 mg). 17P-Cyano-17α-ethyl_7α-methyl-15β,16β-methyleneindole-4-thin-3-class W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.44 [m, (1H), cyclopropyl], 0.86 (d, / = 7.2 Hz, 7-Me), 1.08 [m, (1H), cyclopropyl], 1.19 and 1.21 [2xs, 3H), 2xMe in each case; overlap 1.22 (t, *7 = 7.4 Hz, CH2-CH3)], 5.75 (s, 4-H). 17β-cyano-17α-ethyl-7β-methyl-Ι5β,16ρ-methylenemethylandrost-4-en-3-one W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ =0.53 and 1.04 [2xm, (1H in each case), 2x cyclopropyl], 1 & 1.26 (m,7-Me,2xMe and CH2-CH3)], 5.73 (br·s,4-H) . PREPARATION EXAMPLE 42: 17P-Indolyl-androst-4-ene is similar to the method given in Example ib, such that, for example, Helv. Chim_ Acta (45) 1962, 2575 )reaction. After the crude product was chromatographed using a mixture of ethyl acetate and n-hexane, the fractions containing the product were concentrated and re-chromatographed by HPLC. In addition to 17α-cyanomethine, 17β-cyanoindole is also obtained. 17p-cyanomethylandrosine-4-ene 144922.doc •65- 201026718 W-NMR (CDC13 TMS as internal standard, selected signal): δ=〇94 [s, 3H, -CH3], 1.04 [s, 3H, -CH3], 1.13 [m, 1H], 1.21 [m, 1H], 2.11 [m,1H], 2.20 [m,1H], 2.26 [m,1H], 5.31 [Wide single peak, 1H, 4 -H]. Preparation Example 43: 4-Gas-17β-cyanomethylandrosine-4-enene Similar to the method given in Example 33, 17β•cyanoquinonecium _4_lean-3-ketone was reacted and treated. This gave 4-gas-Ι7β-cyanomethyl-androst-4-ene-3-one. W-NMR (CDC13 TMS as internal standard, selected signal width δ=〇98 [s 3H, CH3], 1.24 [s, 3H, CH3], 2.58 [m, 1H, 17-H], 3.26 [ddd «/ 7 = 15.1 Hz, · 72 = 4.0 Hz, /3 = 2.6 Hz. Preparation Example 44: 6β,7β·15ρ,16ρ-bismethylene-17p-|L-methyl-methyl-methyl, ii_4_2 Dilute 3 Ming 60,70-150,16戸-bismethylene-170-cyanomethylanthryl _4_rare_3_ ^*4 yangbei is similar to the example 293 reaction, get 60,7 choose-1 Qiu , 16 pan-bismethylene_170-aryl-曱xiongliu·1,4-dien-3-one. ^-NMR (300 MHz, CDC13): δ=0.55 (m, 1ΗΊ 1 ιΛ , ^ ( s, 3H), 1.14 (s, 3H), 2.81 (d, 1H, H-17) 6.18 (m, 1H, H-2^) ' 1H, H-4), 6.85 (s, 1H, Hl). Preparation Example 45: 1〇1,2〇1-external, 7?-15?,16?-methyleneidene-17?-cyanomethyl-chromium m-ene-3-arsin-3 70-15戸,160-bis-indenyl-170-cyanomethyl-andrazine _14_ ketone is similar to the reaction of Example 7 to obtain 1α, 2α-6β, 7β-ΐ5βΐ6ρ moxibustion 144922.doc * 66 - 201026718 -17-17β- Cyanomethyl male-4-ene-3-one. *H-NMR (300 MHz, CDC13): 6 = 0.52 (m, 1 Η), 0.74 (m, 1H), 0.82 (m, 1H), 1.07 ( s, 3H), 114 (s, 3H), 2 81 (d, m, H i7), 5.86 (m, 1H, H-4). According to the present invention, it has now been found that the compound of the chemical formula 1 described in PCT/EP2008/057427 is also suitable for intravaginal or Intrauterine administration. This can be accomplished using a physiologically acceptable solution, such as an aqueous or oily solution, with or without suitable solubilizing, dispersing or emulsifying agents. Suitable oils are, for example, peanut oil, cottonseed oil, castor oil or sesame oil. The choice is not limited to such examples. For intravaginal or intrauterine administration, specific systems may be used, such as intravaginal systems (eg, vaginal ring, VRS) or intrauterine systems (IUS), which are for long periods of time (eg, 1, 2, 2). The active substance of the present invention is released from the reservoir within 3, 4 or 5 years. A representative example of an intrauterine system which may be mentioned is MIRENA®. This is a T-shaped uterus from the release of levonorgestrel from BAYER SCHERING PHARMA AG. system. It is additionally possible to administer via an implanted supply system consisting of an inert carrier material such as a biodegradable polymer or a synthetic polyoxyl polymer. These delivery systems release the active substance over a prolonged period of time (e.g., 3 months to 3 years) in a controlled manner and are implanted subcutaneously. The dosage of the present invention, for example, from the daily release of IUS to the oral dose equivalent to the daily oral dose, should be used orally in an amount of from 0.01 to 10 mg per day. The daily dose in the treatment of W symptoms is about 0.1 to 20 mg. The formulations of the present invention are, for example, 144922.doc-67-201026718 Formula 1 compound which is released from IUS per day in an amount of from 0.005 to 1 mg. The system of the invention can be used to administer estrogen as well as compounds of the formula. It is possible to consider the synthesis of estrogen (preferably ethynyl female disaccharide, or estramid ether) as estrogen for contraceptive preparations. Estrogen is administered at a daily dose corresponding to 0.01 to 0.4 mg of ethyl fast estrone. Estrogen is of course mainly used as an estrogen in the treatment of premenopausal, near menopausal and postmenopausal symptoms and hormone replacement therapy, especially for diols or their esters, such as estradiol valerate or conjugated estrogens ( CEE = combined with horse ginseng hormone). Accordingly, the present invention relates to a chemical formula of cyanomethyl-androstene derivatives,
NN
其中 2 選自包含〇、兩個氫原子、nor及nnhso2r之 群’其中R為氫或烷基,Wherein 2 is selected from the group consisting of ruthenium, two hydrogen atoms, nor and nhnso2r where R is hydrogen or an alkyl group,
Rl ’ R2彼此獨立為氫或曱基或 R與R 共同形成亞甲基或被省略而在C1與c2之間形成雙 144922.doc •68- 201026718 鍵, 為虱或南素, 此外: T?6a, p6b j, _ 共同形成亞甲基或U·乙二基或e為氫且R6b選 7 自包含氫、甲基及羥基亞甲基之群,且 選自包含氫、q-C4烷基、C2_C3烯基及環丙基之 群, 或:Rl ' R2 is independently hydrogen or sulfhydryl or R and R together form a methylene group or is omitted and forms a double 144922.doc •68- 201026718 bond between C1 and c2, which is 虱 or 素, in addition: T? 6a, p6b j, _ together form a methylene or U. ethanediyl group or e is hydrogen and R6b is selected from the group consisting of hydrogen, methyl and hydroxymethylene groups, and is selected from hydrogen, q-C4 alkyl groups. , a group of C2_C3 alkenyl groups and cyclopropyl groups, or:
R為氫且R6b與R7共同形成亞甲基或被省略而在 C6與C7之間形成雙鍵, 或·· R為甲基且尺“與尺7被省略而在c6與c7之間形成 雙鍵, R ,r16為氫或共同形成亞甲基, R17 « 選自包含氫、Ci-C:4烷基及烯丙基之群,R is hydrogen and R6b and R7 together form a methylene group or are omitted to form a double bond between C6 and C7, or R is a methyl group and the ruler "and ruler 7 is omitted and a double is formed between c6 and c7" The bond, R, r16 is hydrogen or together form a methylene group, and R17 « is selected from the group consisting of hydrogen, Ci-C: 4 alkyl and allyl groups.
及其溶劑合物、水合物、立體異構體、非對映異構體、對 144922.doc 映異構體及鹽之用於製備具有通式J化合物之非口服供給 型式之藥物的用途, 八限制條件為排除具有以下化學通式A之化合物:And the use of the solvates, hydrates, stereoisomers, diastereomers thereof, 144922.doc, and salts for the preparation of a medicament having a non-oral supply form of a compound of formula J, Eight limiting conditions are to exclude compounds having the following chemical formula A:
(A) -69- 201026718 其中X為氫或曱基且c1與c2之間以及C6與c7之間之雙鍵為 視情況存在之雙鍵,且 其限制條件進一步為亦排除17β-氰基甲雄甾-4-烯-3-酮。 根據本發明,通式1化合物較佳以子宮内系統或陰道環 投與。 根據本發明進一步之實施例,通式1化合物之投與亦可 藉由採用植入式供給系統。(A) -69- 201026718 wherein X is hydrogen or a fluorenyl group and the double bond between c1 and c2 and between C6 and c7 is a double bond which is optionally present, and the restriction further further excludes 17β-cyano Androst-4-en-3-one. According to the invention, the compound of formula 1 is preferably administered in the intrauterine system or the vaginal ring. According to a further embodiment of the invention, the administration of the compound of formula 1 can also be carried out by employing an implantable delivery system.
在進一步之實施例中,在待根據本發明使用之化學通式 1之17β-氰基甲雄甾-4-烯衍生物中:In a further embodiment, in the 17β-cyanoandrost-4-ene derivative of Chemical Formula 1 to be used in accordance with the present invention:
Rl5 ’ Rl6共同形成亞曱基, t-Ύ 選自包含Ο、NOH及NNHS02H之群, z 表示〇, R與R 各為氫或共同形成α_亞甲基,Rl5 ' Rl6 together form an anthracene group, t-Ύ is selected from the group consisting of ruthenium, NOH and NNHS02H, z is 〇, R and R are each hydrogen or form an α-methylene group,
Rl 為α-曱基, R4 為氫或氣, ϋ 6b 為甲基或經基曱基,Rl is α-fluorenyl, R4 is hydrogen or gas, and ϋ 6b is methyl or thiol,
ϋ 6a y p 6b ji , 八同形成亞甲基或乙二基或在各情況下為 氫, 選自包含氫、甲基及乙基之群, D 6b Yy 7 K R共同形成亞甲基, R 選自包含氫、甲基及烯丙基之群 R16及r17中至少 取代基 R1、R2、r4、R6a、R6b、r7、Ri5、 一者不為氫。 本發明另外關於非 口服之供給型式藥物,其包含至少— 144922.doc -70- 201026718 種通式1化合物作為活性物質。 非口服投藥為(例如)子宮内或陰道内投與至少一種通式 !化合物,且相應醫藥投與形式為例如子宮内系統(二 陰道環(IVR)。 作為醫藥投與形式之子宮内系統或陰道環為熟習此項技 術者熟知。可提及之子宮内系統為(例如)來自叫打ϋ 6a yp 6b ji , forming a methylene or ethylene group or, in each case, hydrogen, selected from the group consisting of hydrogen, methyl and ethyl, D 6b Yy 7 KR together forming a methylene group, R is selected At least the substituents R1, R2, r4, R6a, R6b, r7, Ri5, and one of the groups R16 and r17 containing hydrogen, a methyl group and an allyl group are not hydrogen. The present invention further relates to a non-oral supply type of a medicament comprising at least - 144922.doc -70 - 201026718 of the compound of the formula 1 as an active substance. Non-oral administration is, for example, intrauterine or intravaginal administration of at least one compound of the formula: and the corresponding pharmaceutical administration form is, for example, the intrauterine system (two vaginal rings (IVR). The intrauterine system or the vagina as a pharmaceutical administration form The ring is well known to those skilled in the art. The intrauterine system that can be mentioned is, for example, from a call
Schering Ph随a AG之產品Miren,,且可提及之陰道環為 產品 Nuvaring®。 根據本發明非口服投與通式丨化合物可類似於以上提及 之產品’且通式:!化合物之醫藥投與形式相應地可以類似 方式利用,諸如產品Mirena®及Nuvaring®。 以下實例用以更詳細說明本發明: 實例 ❿ 將易於子宮内*入且由生物可降解聚合物或合成聚石夕氧 聚合物(由按適當聚合物-活性物質混合比之含活性物質之 核心組成,周圍環繞聚合物膜以確保所要的每天釋放比 率)構成之惰性供給系統引入大鼠子宮内腔中。事先切除 雌性動物之印巢且以雌二醇預處理三天。使長度不同 mm)且直徑受限(1.i至2 mm)之植入物在大鼠子宮内保持* 至14天之間,以基於不同組織之各種參數研究所釋放活性 物質之局部及全身妊娠相關作用。量測以下參數:丨)基於 子宮重量、組織學上可偵測上皮高度及助孕素調控標記物 基因(例如KJFBP-D表現,對子宮之局部蛀娠相關作用;2) 基於助孕素調控標記物基因(例如RankL)表現,對乳腺之 144922.doc • 71· 201026718 全身妊娠相關作用;3)基於LH含量(雌激素誘導之LH含量 升高降低)對垂體之全身性妊娠相關作用。 通式1化合物在子宮中顯示顯著妊娠相關作用,其與使 用含左炔諾孕酮之供給系統(諸如MIRENA®)之相應治療相 當。 144922.doc -72-Schering Ph follows the product of a AG, Miren, and the vaginal ring that can be mentioned is the product Nuvaring®. The parenterally administered compound of the formula according to the present invention may be similar to the product mentioned above and the pharmaceutical dosage form of the compound:! compound may accordingly be utilized in a similar manner, such as the products Mirana® and Nuvaring®. The following examples are intended to illustrate the invention in more detail: Example ❿ Will be easy to enter the uterus and consist of a biodegradable polymer or a synthetic polyoxopolymer (from the core of the active substance in a mixture ratio of the appropriate polymer-active substance) An inert supply system consisting of a composition that surrounds the polymer membrane to ensure the desired daily release rate is introduced into the rat uterine cavity. The nests of female animals were removed beforehand and pretreated with estradiol for three days. Implants with different lengths of mm) and limited diameter (1.i to 2 mm) were maintained in the rat uterus for between 4 and 14 days to release the local and whole body of the active substance based on various parameters of different tissues. Pregnancy-related effects. The following parameters were measured: 丨 based on uterine weight, histologically detectable epithelial height and progesterone regulatory marker genes (eg KJFBP-D performance, local pregnancy related effects on the uterus; 2) based on progesterone regulation Marker genes (eg, RankL) show a systemic pregnancy-related effect on breast 144922.doc • 71· 201026718; 3) a systemic pregnancy-related effect on pituitary based on LH content (decreased estrogen-induced increase in LH content). The compound of formula 1 shows a significant pregnancy-related effect in the uterus which is comparable to the corresponding treatment using a levonorgestrel-containing supply system such as MIRENA®. 144922.doc -72-
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