JP3972103B2

JP3972103B2 - Fusion compound containing pyridopyrimidine skeleton and steroid skeleton and method for producing the same

Info

Publication number: JP3972103B2
Application number: JP2003337640A
Authority: JP
Inventors: 朝文永松
Original assignee: 国立大学法人岡山大学
Priority date: 2003-09-29
Filing date: 2003-09-29
Publication date: 2007-09-05
Anticipated expiration: 2023-09-29
Also published as: JP2005104868A

Description

本発明は、創薬の分野におけるリード化合物として、ピリドピリミジン類とステロイド類のような現存する２つの異なる生理・薬理活性化合物を構造的に内蔵する新規な融合化合物及びその製造方法に関する。すなわち、ピリドピリミジン骨格とステロイド骨格を内蔵した融合化合物である、５’−デアザ−１７β−ヒドロキシ−２’−フェニル−５α−アンドロスト−２−エノ［２，３−ｇ］プテリジン−４’（８’Ｈ）−オン類、５’−デアザ−１７β−ヒドロキシ−５α−アンドロスト−２−エノ［２，３−ｇ］プテリジン−２’，４’（３’Ｈ，８’Ｈ）−ジオン類及び５’−デアザ−１７β−ヒドロキシアンドロスト−２，４−ジエノ［２，３−ｇ］プテリジン−２’，４’（３’Ｈ，８’Ｈ）−ジオン類並びにそれらの製造方法に関する。 The present invention relates to a novel fusion compound that structurally contains two existing physiological and pharmacologically active compounds such as pyridopyrimidines and steroids as lead compounds in the field of drug discovery, and a method for producing the same. That is, 5′-deaza-17β-hydroxy-2′-phenyl-5α-androst-2-eno [2,3- g ] pteridine-4 ′, which is a fusion compound containing a pyridopyrimidine skeleton and a steroid skeleton (8 ′ H ) -ones, 5′-deaza-17β-hydroxy-5α-androst-2-eno [2,3- g ] pteridine-2 ′, 4 ′ (3 ′ H , 8 ′ H ) — Diones and 5′-deaza-17β-hydroxyandrost-2,4-dieno [2,3- g ] pteridine-2 ′, 4 ′ (3 ′ H , 8 ′ H ) -diones and methods for producing them About.

新薬物活性分子設計として、ピリドピリミジン（デアザフラビン、デアザプテリジン又はデアザイソアロキサジン等）類とステロイド類のような現存する２つの異なる生理・薬理活性化合物を構造的に内蔵する融合化合物の合成はこれまで全く行われていないのが現状である。 As a new drug active molecule design, a fusion compound that structurally incorporates two different existing physiological and pharmacologically active compounds such as pyridopyrimidines (such as deazaflavin, deazapteridine or deazaisoalloxazine) and steroids The current situation is that no synthesis has been performed so far.

類似の骨格を有する化合物として、プテリジン骨格とステロイド骨格を内蔵する融合化合物が公知であるが、合成方法が煩雑で収率も低く（非特許文献１）、また、合成中間体として不安定なステロイドのモルフォリンやピペリジンのエナミン誘導体を用いるため（非特許文献２）、一般合成方法としては有用でない。 As a compound having a similar skeleton, a fusion compound containing a pteridine skeleton and a steroid skeleton is known, but the synthesis method is complicated, the yield is low (Non-patent Document 1), and an unstable steroid as a synthetic intermediate Morpholine and piperidine enamine derivatives (Non-patent Document 2) are not useful as general synthesis methods.

S. P. Raman, Z. F. Chmielewicz, T. J. Bardos, R. B. Gabbard, and A. Segaloff, J. Med. Chem., 7, 678 (1964)S. P. Raman, Z. F. Chmielewicz, T. J. Bardos, R. B. Gabbard, and A. Segaloff, J. Med. Chem., 7, 678 (1964) F. Yoneda, S. Fukazawa, and S. Nishigaki, Chem. Pharm. Bull., 20, 1428 (1972)F. Yoneda, S. Fukazawa, and S. Nishigaki, Chem. Pharm. Bull., 20, 1428 (1972)

本発明は、ピリドピリミジン骨格とステロイド骨格を内蔵する融合化合物の新規で簡便な合成方法を見いだすとともに、該方法によって得られる薬理的な混成増強作用や全く新しい生理活性もしくは薬理活性が期待できる有用な化合物を提供することを目的とするものである。 The present invention finds a novel and simple method for synthesizing a fusion compound containing a pyridopyrimidine skeleton and a steroid skeleton, and is useful for expecting a pharmacological hybrid enhancement effect or a completely new physiological activity or pharmacological activity obtained by the method. The object is to provide a simple compound.

本発明者は、上述の目的を達成するために鋭意研究を重ねた結果、ピリドピリミジン骨格とステロイド骨格を内蔵する融合化合物の簡便な新規合成方法を確立するとともに、該方法で得られた化合物に強い抗コクシジウム活性などの生物活性を見いだし、本発明を完成させた。 As a result of intensive studies to achieve the above-mentioned object, the present inventor established a simple novel synthesis method for a fusion compound containing a pyridopyrimidine skeleton and a steroid skeleton, and a compound obtained by the method. Biological activity such as anti-coccidial activity that is strong against water has been found and the present invention has been completed.

すなわち、本発明は、式

（式中、Ｒは炭素数１〜８の直鎖状、分岐鎖状もしくは環状である低級アルキル基または置換もしくは非置換のフェニル基を示す。）で表される５’−デアザ−１７β−ヒドロキシ−２’−フェニル−５α−アンドロスト−２−エノ［２，３−ｇ］プテリジン−４’（８’Ｈ）−オン類に関するものである。 That is, the present invention provides the formula

(Wherein, R represents a linear, branched or cyclic lower alkyl group having 1 to 8 carbon atoms or a substituted or unsubstituted phenyl group) 5′-deaza-17β-hydroxy 2'-phenyl -5α- androst-2-eno [2,3-g] pteridine -4 '(8' H) - relates-ones.

また、本発明は、式

（式中、Ｒ^１は水素または炭素数１〜８の直鎖状、分岐鎖状もしくは環状の低級アルキル基を示し、Ｒ^２は炭素数１〜８の直鎖状、分岐鎖状もしくは環状の低級アルキル基または置換もしくは非置換のフェニル基を示す。）で表される、５’−デアザ−１７β−ヒドロキシ−５α−アンドロスト−２−エノ［２，３−ｇ］プテリジン−２’，４’（３’Ｈ，８’Ｈ）−ジオン類に関するものである。 The present invention also provides a formula

(Wherein R ¹ represents hydrogen or a linear, branched or cyclic lower alkyl group having 1 to 8 carbon atoms, and R ² represents a linear, branched or cyclic group having 1 to 8 carbon atoms. 5′-deaza-17β-hydroxy-5α-androst-2-eno [2,3- g ] pteridine-2 ′, 4 represented by a lower alkyl group or a substituted or unsubstituted phenyl group. It relates to '(3 ′ H , 8 ′ H ) -diones.

さらに、本発明は、式

（式中、Ｒ^１は水素または炭素数１〜８の直鎖状、分岐鎖状もしくは環状の低級アルキル基を示し、Ｒ^２は炭素数１〜８の直鎖状、分岐鎖状もしくは環状の低級アルキル基または置換もしくは非置換のフェニル基を示す。）で表される、５’−デアザ−１７β−ヒドロキシアンドロスト−２，４−ジエノ［２，３−ｇ］プテリジン−２’，４’（３’Ｈ，８’Ｈ）−ジオン類に関するものである。 Furthermore, the present invention provides a formula

(Wherein R ¹ represents hydrogen or a linear, branched or cyclic lower alkyl group having 1 to 8 carbon atoms, and R ² represents a linear, branched or cyclic group having 1 to 8 carbon atoms. 5′-deaza-17β-hydroxyandrost-2,4-dieno [2,3- g ] pteridine-2 ′, 4 ′ represented by a lower alkyl group or a substituted or unsubstituted phenyl group. It relates to (3 ′ H , 8 ′ H ) -diones.

また、本発明は、式

（式中、Ｒは炭素数１〜８の直鎖状、分岐鎖状もしくは環状である低級アルキル基または置換もしくは非置換のフェニル基を示す。）で表される化合物と式

で表される2-ヒドロキシメチレンアンドロスタノロンを反応させた後、縮合閉環することにより式

（式中、Ｒは炭素数１〜８の直鎖状、分岐鎖状もしくは環状である低級アルキル基または置換もしくは非置換のフェニル基を示す。）で表される化合物を得ることを特徴とする、５’−デアザ−１７β−ヒドロキシ−２’−フェニル−５α−アンドロスト−２−エノ［２，３−ｇ］プテリジン−４’（８’Ｈ）−オン類の製造方法に関するものである。 The present invention also provides a formula

Wherein R represents a linear, branched or cyclic lower alkyl group having 1 to 8 carbon atoms or a substituted or unsubstituted phenyl group, and a formula

After reacting 2-hydroxymethyleneandrostanolone represented by

(Wherein R represents a linear, branched or cyclic lower alkyl group having 1 to 8 carbon atoms or a substituted or unsubstituted phenyl group). The present invention relates to a process for producing 5′-deaza-17β-hydroxy-2′-phenyl-5α-androst-2-eno [2,3- g ] pteridin-4 ′ (8 ′ H ) -ones.

また、本発明は、式

（式中、Ｒ^１は水素または炭素数１〜８の直鎖状、分岐鎖状もしくは環状の低級アルキル基を示し、Ｒ^２は炭素数１〜８の直鎖状、分岐鎖状もしくは環状の低級アルキル基または置換もしくは非置換のフェニル基を示す。）で表される化合物と式

で表される２-ヒドロキシメチレンアンドロスタノロンを反応させた後、縮合閉環することにより式

（式中、Ｒ^１は水素または炭素数１〜８の直鎖状、分岐鎖状もしくは環状の低級アルキル基を示し、Ｒ^２は炭素数１〜８の直鎖状、分岐鎖状もしくは環状の低級アルキル基または置換もしくは非置換のフェニル基を示す。）で表される化合物を得ることを特徴とする、５’−デアザ−１７β−ヒドロキシ−５α−アンドロスト−２−エノ［２，３−ｇ］プテリジン−２’，４’（３’Ｈ，８’Ｈ）−ジオン類の製造方法に関するものである。 The present invention also provides a formula

(Wherein R ¹ represents hydrogen or a linear, branched or cyclic lower alkyl group having 1 to 8 carbon atoms, and R ² represents a linear, branched or cyclic group having 1 to 8 carbon atoms. A lower alkyl group or a substituted or unsubstituted phenyl group.)

After reacting 2-hydroxymethyleneandrostanolone represented by the formula,

(Wherein R ¹ represents hydrogen or a linear, branched or cyclic lower alkyl group having 1 to 8 carbon atoms, and R ² represents a linear, branched or cyclic group having 1 to 8 carbon atoms. 5'-deaza-17β-hydroxy-5α-androst-2-eno [2,3-, which is obtained by obtaining a compound represented by: a lower alkyl group or a substituted or unsubstituted phenyl group. g ] relates to a method for producing pteridine-2 ′, 4 ′ (3 ′ H , 8 ′ H ) -diones.

さらにまた、本発明は、式

で表される２−ヒドロキシメチレンテストステロンを反応させた後、縮合閉環することにより式

（式中、Ｒ^１は水素または炭素数１〜８の直鎖状、分岐鎖状もしくは環状の低級アルキル基を示し、Ｒ^２は炭素数１〜８の直鎖状、分岐鎖状もしくは環状の低級アルキル基または置換もしくは非置換のフェニル基を示す。）で表される化合物を得ることを特徴とする、５’−デアザ−１７β−ヒドロキシアンドロスト−２，４−ジエノ［２，３−ｇ］プテリジン−２’，４’（３’Ｈ，８’Ｈ）−ジオン類の製造方法に関するものである。 Furthermore, the present invention provides a formula

After reacting 2-hydroxymethylene testosterone represented by

(Wherein R ¹ represents hydrogen or a linear, branched or cyclic lower alkyl group having 1 to 8 carbon atoms, and R ² represents a linear, branched or cyclic group having 1 to 8 carbon atoms. 5′-deaza-17β-hydroxyandrost-2,4-dieno [2,3- g] , characterized in that a compound represented by the following formula is obtained: a lower alkyl group or a substituted or unsubstituted phenyl group. ] It relates to a method for producing pteridine-2 ′, 4 ′ (3 ′ H , 8 ′ H ) -diones.

本発明の新規で簡便な合成方法により得られた融合化合物は、創薬の分野において有用で貴重なリード化合物となり、種々の薬理活性を持つ新薬として臨床薬開発に大きく期待できる。また、本発明の製造方法は、従来の多環性化合物のように段階的に全合成する製法とは異なり、２つの化合物を一挙に融合させる簡便な方法であり、目的化合物を収率よく合成でき、かつ広範囲な６−アミノウラシル類とα−ヒドロキシメチレンを有するアンドロスタノロンやテストステロンなどのステロイド誘導体との融合化合物の合成に応用できるため、多様な生物活性や生理活性に期待が持てるこのような融合化合物類のドラッグデザインに利用することができる有用な方法である。 The fusion compound obtained by the novel and simple synthesis method of the present invention is a valuable and valuable lead compound in the field of drug discovery, and it can be greatly expected in clinical drug development as a new drug having various pharmacological activities. In addition, the production method of the present invention is a simple method in which two compounds are fused at once, unlike the conventional method of total synthesis stepwise like conventional polycyclic compounds, and the target compound is synthesized in high yield. It can be applied to the synthesis of fusion compounds with a wide range of 6-aminouracils and steroid derivatives such as androstanolone and testosterone with α-hydroxymethylene, so it can be expected to have various biological and physiological activities. It is a useful method that can be used for drug design of various fusion compounds.

本発明の製造方法をフローチャートで示せば、図１、図２及び図３の通りである。以下、図中の化学式の番号を参照して説明する。 If the manufacturing method of this invention is shown with a flowchart, it is as FIG.1, FIG.2 and FIG.3. Hereinafter, description will be made with reference to the chemical formula numbers in the figure.

本発明の化合物は、図１〜３において式（３）、（５）および（７）で表されるものである。各図の式中、ＲおよびＲ^２は直鎖状、分岐鎖状もしくは環状である炭素数１〜８程度のアルキル基または置換もしくは非置換のフェニル基を示し、Ｒ^１は水素または直鎖状、分岐鎖状もしくは環状である炭素数１〜８程度のアルキル基を示す。ここで、直鎖状、分岐鎖状もしくは環状である炭素数１〜８程度のアルキル基としては、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、シクロペンチル基、シクロヘキシル基などを例示することができる。また、置換フェニル基としては、４−メチルフェニル（トリル）で代表されるアルキル置換フェニル基、４−メトキシフェニルで代表される炭素数１〜５程度のアルコキシを有するアルコキシ置換フェニル基、４−アミノフェニル基、２−クロロフェニル、４−ブロモフェニル、４−フルオロフェニルなどのハロゲン置換フェニル基、４−ヒドロキシフェニル基、４−ニトロフェニル基、３，４−メチレンジオキシフェニル基、４−カルボキシフェニル基などを例示することができる。また、前記式（３）、（５）および（７）で表される化合物は、発明者の知る限りにおいて従来全く報告されたことのない新規化合物である。このような本発明の化合物の具体例としては、例えば下記表１、表２および実施例に示すものなどが挙げられる。 The compounds of the present invention are represented by formulas (3), (5) and (7) in FIGS. In the formulas in each figure, R and R ² are linear, branched or cyclic alkyl groups having about 1 to 8 carbon atoms or substituted or unsubstituted phenyl groups, and R ¹ is hydrogen or linear Represents a branched or cyclic alkyl group having about 1 to 8 carbon atoms. Here, as the linear, branched or cyclic alkyl group having about 1 to 8 carbon atoms, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, cyclopentyl group, cyclohexyl group Etc. can be illustrated. The substituted phenyl group includes an alkyl-substituted phenyl group represented by 4-methylphenyl (tolyl), an alkoxy-substituted phenyl group having about 1 to 5 carbon atoms represented by 4-methoxyphenyl, 4-amino Halogen-substituted phenyl groups such as phenyl group, 2-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-hydroxyphenyl group, 4-nitrophenyl group, 3,4-methylenedioxyphenyl group, 4-carboxyphenyl group Etc. can be illustrated. Further, the compounds represented by the above formulas (3), (5) and (7) are novel compounds which have never been reported so far as far as the inventors know. Specific examples of the compound of the present invention include those shown in the following Tables 1 and 2 and Examples.

図１は、式（３）で表される本発明の化合物の製造方法を示す。式（１）で表される原料化合物、６−モノ置換アミノ−２−フェニルピリミジン−４（３Ｈ）−オン類は公知の方法（J. Chem. Soc., Perkin Trans. 1, 2101 (1992)）により調製することができる。このような化合物を具体的に例示すると、６−メチルアミノ−２−フェニルピリミジン−４（３Ｈ）−オン、６−イソプロピルアミノ−２−フェニルピリミジン−４（３Ｈ）−オン、６−シクロヘキシルアミノ−２−フェニルピリミジン−４（３Ｈ）−オン、６−アニリノ−２−フェニルピリミジン−４（３Ｈ）−オン、６−（４−クロロアニリノ）−２−フェニルピリミジン−４（３Ｈ）−オンなどが挙げられる。 FIG. 1 shows a method for producing the compound of the present invention represented by the formula (3). The starting compound represented by the formula (1), 6-monosubstituted amino-2-phenylpyrimidin-4 ( 3H ) -ones, can be obtained by a known method (J. Chem. Soc., Perkin Trans. 1, 2101 (1992). )). Specific examples of such compounds include 6-methylamino-2-phenylpyrimidin-4 ( 3H ) -one, 6-isopropylamino-2-phenylpyrimidin-4 ( 3H ) -one, and 6-cyclohexyl. Amino-2-phenylpyrimidin-4 ( 3H ) -one, 6-anilino-2-phenylpyrimidin-4 ( 3H ) -one, 6- (4-chloroanilino) -2-phenylpyrimidine-4 ( 3H ) -ON and the like.

図１及び図２において、式（２）で表される原料化合物、２−ヒドロキシメチレンアンドロスタノロンの合成は公知の方法（J. Am. Chem. Soc., 81, 1960 (1959)）により調製することができる。 1 and 2, the raw material compound represented by the formula (2), 2-hydroxymethyleneandrostanolone, was synthesized by a known method (J. Am. Chem. Soc., 81, 1960 (1959)). can do.

本発明の化合物（３）の製造方法は、上記の式（１）と（２）で表される原料化合物を同当量ずつ混合し、それにｐ−トルエンスルホン酸を０．１当量加え、ジフェニルエ−テル中で加熱後、縮合閉環して式（３）で表される化合物を得る反応である。この加熱反応は、アルゴン雰囲気下２００〜２２０℃で２０〜３０分間加熱撹拌させることにより行うことができる。本発明の化合物の単離精製は、通常の有機化合物の単離精製手段を採用すればよく、例えば、再結晶、各種クロマトグラフィーなどを用いて行うことができる。 In the production method of the compound (3) of the present invention, the raw material compounds represented by the above formulas (1) and (2) are mixed in the same equivalent amount, 0.1 equivalent of p-toluenesulfonic acid is added thereto, and diphenyl ether is added. -It is a reaction in which a compound represented by the formula (3) is obtained by heating in a tellurium followed by condensation and ring closure. This heating reaction can be performed by heating and stirring at 200 to 220 ° C. for 20 to 30 minutes in an argon atmosphere. Isolation and purification of the compound of the present invention may be carried out by employing a normal organic compound isolation and purification means, for example, using recrystallization, various chromatography and the like.

また、図２は、本発明の化合物（５）の製造方法を示す。式（４）で表される原料化合物、６−モノ置換アミノウラシル類は公知の方法（Justus Liebigs Ann. Chem., 691, 142 (1966)）により調製することができる。このような化合物を具体的に例示すると、６−メチルアミノウラシル、６−メチルアミノ−３−メチルウラシル、６−n−ブチルアミノウラシル、６−n−ブチルアミノ−３−メチルウラシル、６−ベンジルアミノウラシル、６−ベンジルアミノ−３−メチルウラシル、６−（４−フルオロアニリノ）ウラシル、６−（４−フルオロアニリノ）―３−メチルウラシル、６−（４−メトキシアニリノ）ウラシル、６−（４−メトキシアニリノ）―３−メチルウラシルなどが挙げられる。 Moreover, FIG. 2 shows the manufacturing method of the compound (5) of this invention. The starting compound represented by formula (4), 6-monosubstituted aminouracils, can be prepared by a known method (Justus Liebigs Ann. Chem., 691, 142 (1966)). Specific examples of such compounds include 6-methylaminouracil, 6-methylamino-3-methyluracil, 6-n-butylaminouracil, 6-n-butylamino-3-methyluracil, 6-benzyl. Aminouracil, 6-benzylamino-3-methyluracil, 6- (4-fluoroanilino) uracil, 6- (4-fluoroanilino) -3-methyluracil, 6- (4-methoxyanilino) uracil, Examples include 6- (4-methoxyanilino) -3-methyluracil.

本発明の化合物（５）の製造方法は、上記の式（４）と（２）で表される原料化合物を同当量ずつ混合し、それにｐ−トルエンスルホン酸を０．１当量加え、ジフェニルエ−テル中で加熱後、縮合閉環して式（５）で表される化合物を得る反応である。この加熱反応は、アルゴン雰囲気下２２０℃で１５分間加熱撹拌させることにより行うことができる。本発明の化合物の単離精製は、通常の有機化合物の単離精製手段を採用すればよく、例えば、再結晶、各種クロマトグラフィーなどを用いて行うことができる。 In the production method of the compound (5) of the present invention, the raw material compounds represented by the above formulas (4) and (2) are mixed in the same equivalent amount, 0.1 equivalent of p-toluenesulfonic acid is added thereto, and diphenyl ether is added. -It is a reaction for obtaining a compound represented by the formula (5) by heating in a tellurium followed by condensation and ring closure. This heating reaction can be performed by heating and stirring at 220 ° C. for 15 minutes in an argon atmosphere. Isolation and purification of the compound of the present invention may be carried out by employing a normal organic compound isolation and purification means, for example, using recrystallization, various chromatography and the like.

さらに、図３は、本発明の化合物（７）の製造方法を示す。式（６）で表される原料化合物、２−ヒドロキシメチレンテストステロンの合成は公知の方法（J. Am. Chem. Soc., 76, 552 (1954)）により調製することができる。 Further, FIG. 3 shows a method for producing the compound (7) of the present invention. The raw material compound represented by the formula (6), 2-hydroxymethylene testosterone, can be synthesized by a known method (J. Am. Chem. Soc., 76, 552 (1954)).

本発明の化合物（７）の製造方法は、上記の式（４）と（６）で表される原料化合物を同当量ずつ混合し、それにｐ−トルエンスルホン酸を０．１当量加え、ジフェニルエ−テル中で加熱後、縮合閉環して式（７）で表される化合物を得る反応である。この加熱反応は、アルゴン雰囲気下１８０〜２００℃で２０〜３０分間加熱撹拌させることにより行うことができる。本発明化合物の単離精製は、通常の有機化合物の単離精製手段を採用すればよく、例えば、再結晶、各種クロマトグラフィーなどを用いて行うことができる。 In the production method of the compound (7) of the present invention, the raw material compounds represented by the above formulas (4) and (6) are mixed in the same equivalent amount, 0.1 equivalent of p-toluenesulfonic acid is added thereto, and diphenyl ether is added. A reaction in which a compound represented by the formula (7) is obtained by heating and heating in tellurium followed by condensation and ring closure. This heating reaction can be performed by heating and stirring at 180 to 200 ° C. for 20 to 30 minutes in an argon atmosphere. Isolation and purification of the compound of the present invention may be carried out by employing usual organic compound isolation and purification means, for example, using recrystallization, various chromatography and the like.

以下、本発明について実施例をあげてさらに具体的に説明するが、本発明はこれらの実施例によって何ら限定されるものではない。なお、実施例における化合物の番号は、上記の表１、表２、下記の表３および表４に対応する。 EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated further more concretely, this invention is not limited at all by these Examples. In addition, the numbers of the compounds in the examples correspond to Tables 1 and 2 above, Tables 3 and 4 below.

（８−置換誘導体（３ａ―ｋ）の一般合成）
ジフェニルエ−テル（０．５ｍｌ）に、原料化合物（１ａ−ｋ）（３ｍｍｏｌ）と２−ヒドロキシメチレンアンドロスタノロン（２）（３ｍｍｏｌ）を加え、更に、この混合物へｐ−トルエンスルホン酸（０．３ｍｍｏｌ）加えた後、２００〜２２０℃でアルゴン雰囲気下２０〜３０分間加熱撹拌した。反応終了後、この反応物をカラムクロマトグラフィ−（Fuji Silysia 200〜400 mesh；溶出剤、酢酸エチル：エタノール＝９：１）に付し精製した。溶出液を減圧下濃縮し、その残渣を酢酸エチル又はアセトンで再結晶化して淡黄色の粉末結晶の目的物（３ａ−ｋ）を得た。得られた目的物のNMRデータを下記に示す。 (General synthesis of 8-substituted derivatives (3a-k))
The raw material compound (1a-k) (3 mmol) and 2-hydroxymethyleneandrostanolone (2) (3 mmol) were added to diphenyl ether (0.5 ml), and p-toluenesulfonic acid (0 After addition, the mixture was heated and stirred at 200 to 220 ° C. under an argon atmosphere for 20 to 30 minutes. After completion of the reaction, the reaction product was purified by column chromatography (Fuji Silysia 200-400 mesh; eluent, ethyl acetate: ethanol = 9: 1). The eluate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate or acetone to obtain the desired product (3a-k) as pale yellow powder crystals. The NMR data of the obtained target product are shown below.

化合物3a: ¹H-NMR (200 MHz, CDCl₃) δ: 0.78 (3H, s, 18-CH₃), 0.79 (3H, s, 19-CH₃), 2.52-2.70 (1H, br dd, 4β-H), 2.57 (1H, d, J=16.2 Hz, 1β-H), 2.91 (1H, d, J=16.2 Hz, 1α-H), 2.97 (1H, dd, J=19.3, 5.1 Hz, 4α-H), 3.69 (1H, dd, J_{16α, l7α}=8.4 Hz, J_{l6β, 17α}=7.8 Hz, 17α-H), 4.26 (3H, s, 8'-CH₃), 7.41-7.54 (3H, m, Ph-meta, para H), 8.56-8.65 (2H, m, Ph-ortho H), 8.69 (1H, s, 5'-H)。 Compound 3a: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.78 (3H, s, 18-CH ₃ ), 0.79 (3H, s, 19-CH ₃ ), 2.52-2.70 (1H, br dd, 4β -H), 2.57 (1H, d, J = 16.2 Hz, 1β-H), 2.91 (1H, d, J = 16.2 Hz, 1α-H), 2.97 (1H, dd, J = 19.3, 5.1 Hz, 4α -H), 3.69 (1H, dd, J _{16α, l7α} = 8.4 Hz, J _{l6β, 17α} = 7.8 Hz, 17α-H), 4.26 (3H, s, 8'-CH ₃ ), 7.41-7.54 (3H, m, Ph-meta, para H), 8.56-8.65 (2H, m, Ph-ortho H), 8.69 (1H, s, 5'-H).

化合物3b: ¹H-NMR (200 MHz, CDCl₃) δ: 0.79 (6H, s, 18 and 19-CH₃), 1.54 ( 3H, t, J=7.0 Hz, 8'-CH₂CH ₃), 2.57 (1H, d, J=16.7 Hz, 1β-H), 2.63 (1H, dd, J=19.6, 11.2 Hz, 4β-H), 2.89 (1H, d, J=16.7 Hz, 1α-H), 3.00 (1H, dd, J=19.6, 5.2Hz, 4α-H), 3.70 (1H, dd, J_{16α, 17α}=8.8 Hz, J_{16β, 17α}=8.0 Hz, 17α-H), 4.62-4.79 (1H, m, 8'-CH _aH_b), 4.90-5.07 (1H, m, 8'-CH_a H _b), 7.40-7.52 (3H, m, Ph-meta, para H), 8.53-8.65 (2H, m, Ph-ortho H), 8.62 (1H, s, 5'-H)。 Compound 3b: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.79 (6H, s, 18 and 19-CH ₃ ), 1.54 (3H, t, J = 7.0 Hz, 8'-CH ₂ C H ₃ ) , 2.57 (1H, d, J = 16.7 Hz, 1β-H), 2.63 (1H, dd, J = 19.6, 11.2 Hz, 4β-H), 2.89 (1H, d, J = 16.7 Hz, 1α-H) , 3.00 (1H, dd, J = 19.6, 5.2Hz, 4α-H), 3.70 (1H, dd, J _{16α, 17α} = 8.8 Hz, J _{16β, 17α} = 8.0 Hz, 17α-H), 4.62-4.79 ( 1H, m, 8'-C H _a H _b ), 4.90-5.07 (1H, m, 8'-CH _a H _b ), 7.40-7.52 (3H, m, Ph-meta, para H), 8.53-8.65 (2H, m, Ph-ortho H), 8.62 (1H, s, 5'-H).

化合物3c: ¹H-NMR (200 MHz, CDCl₃) δ: 0.79 (6H, s, 18 and 19-CH₃), 1.15 (3H, t, J=7.3 Hz, 8'-CH₂CH₂CH ₃), 2.57 (1H, d, J=16.2 Hz, 1β-H), 2.64 (1H, dd, J=18.8, 10.2 Hz, 4β-H), 2.91 (1H, d, J=16.2 Hz, lα-H), 2.98 (1H, dd, J=18.8, 5.2 Hz, 4α-H), 3.69 (1H, dd, J_{16α, 17α}=8.0 Hz, J_{16β, 17α}=7.8 Hz, 17α-H), 4.45-4.68(1H, m, 8'-CH _aH_b), 4.77-4.98 (1H, m, 8'-CH_a H _b), 7.40-7.53 (3H, m, Ph-meta, para H), 8.54-8.65 (2H, m, Ph-ortho H), 8.67 (1H, s, 5'-H)。 Compound 3c: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.79 (6H, s, 18 and 19-CH ₃ ), 1.15 (3H, t, J = 7.3 Hz, 8'-CH ₂ CH ₂ C H ₃ ), 2.57 (1H, d, J = 16.2 Hz, 1β-H), 2.64 (1H, dd, J = 18.8, 10.2 Hz, 4β-H), 2.91 (1H, d, J = 16.2 Hz, lα- H), 2.98 (1H, dd, J = 18.8, 5.2 Hz, 4α-H), 3.69 (1H, dd, J _{16α, 17α} = 8.0 Hz, J _{16β, 17α} = 7.8 Hz, 17α-H), 4.45- 4.68 (1H, m, 8'-C H _a H _b ), 4.77-4.98 (1H, m, 8'-CH _a H _b ), 7.40-7.53 (3H, m, Ph-meta, para H), 8.54 -8.65 (2H, m, Ph-ortho H), 8.67 (1H, s, 5'-H).

化合物3d: ¹H-NMR (200 MHz, CDCl₃) δ: 0.79 (3H, s, 18-CH₃), 0.81 (3H, s, 19-CH₃), 1.99 (3H, d, J_{Me, CH}=6.8 Hz, 8'-(CH₃)_a), 2.03 (3H, d, J_{Me, CH}=6.2 Hz, 8'-(CH₃)_b), 2.58 (1H, d, J=16.3 Hz, 1β-H), 2.66 (1H, dd, J=19.4, 10.8 Hz, 4β-H), 2.92 (1H, d, J=16.3 Hz, 1α-H), 2.99 (1H, dd, J=19.4, 5.2Hz, 4α-H), 3.70 (1H, dd, J_{16α, 17α}=8.8 Hz, J_{16β, 17α}= 7.8Hz, 17α-H), 5.16 (1H, sept, J=7.0 Hz, 8'-CH), 7.41-7.57 (3H, m, Ph-meta, para H), 8.55-8.66 (2H, m, Ph-ortho H), 8.72 (1H, s, 5'-H)。 Compound 3d: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.79 (3H, s, 18-CH ₃ ), 0.81 (3H, s, 19-CH ₃ ), 1.99 (3H, d, J _{Me, CH} = 6.8 Hz, 8 '-(CH ₃ ) _a ), 2.03 (3H, d, J _{Me, CH} = 6.2 Hz, 8'-(CH ₃ ) _b ), 2.58 (1H, d, J = 16.3 Hz, 1β -H), 2.66 (1H, dd, J = 19.4, 10.8 Hz, 4β-H), 2.92 (1H, d, J = 16.3 Hz, 1α-H), 2.99 (1H, dd, J = 19.4, 5.2Hz , 4α-H), 3.70 (1H, dd, J _{16α, 17α} = 8.8 Hz, J _{16β, 17α} = 7.8 Hz, 17α-H), 5.16 (1H, sept, J = 7.0 Hz, 8'-CH), 7.41-7.57 (3H, m, Ph-meta, para H), 8.55-8.66 (2H, m, Ph-ortho H), 8.72 (1H, s, 5'-H).

化合物3e: ¹H-NMR (200 MHz, CDCl₃) δ: 0.79 (6H, s, 18 and 19-CH₃), 1.06 (3H, t, J=7.2 Hz, 8'-CH₂CH₂CH₂CH ₃), 2.58 (1H, d, J=16.0 Hz, 1β-H), 2.63 (1H, dd, J=20.0, 11.3 Hz, 4β-H), 2.91 (1H, d, J=16.0 Hz, 1α-H), 3.00 (1H, dd, J=20.0, 5.0 Hz, 4α-H), 3.69 (1H, dd, J_{16α, l7α}=8.0 Hz, J_{16β, l7α}=7.2 Hz, 17α-H), 4.47-4.70 (1H, m, 8'-CH _aH_b), 4.80-5.03 (1H, m, 8'-CH_a H _b), 7.40-7.55 (3H, m, Ph-meta, para H), 8.53-8.63 (2H, m, Ph-ortho H), 8.65 (1H, s, 5'-H)。 Compound 3e: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.79 (6H, s, 18 and 19-CH ₃ ), 1.06 (3H, t, J = 7.2 Hz, 8'-CH ₂ CH ₂ CH ₂ C H ₃ ), 2.58 (1H, d, J = 16.0 Hz, 1β-H), 2.63 (1H, dd, J = 20.0, 11.3 Hz, 4β-H), 2.91 (1H, d, J = 16.0 Hz, 1α-H), 3.00 (1H, dd, J = 20.0, 5.0 Hz, 4α-H), 3.69 (1H, dd, J _{16α, l7α} = 8.0 Hz, J _{16β, l7α} = 7.2 Hz, 17α-H), 4.47-4.70 (1H, m, 8'-C H _a H _b ), 4.80-5.03 (1H, m, 8'-CH _a H _b ), 7.40-7.55 (3H, m, Ph-meta, para H) , 8.53-8.63 (2H, m, Ph-ortho H), 8.65 (1H, s, 5'-H).

化合物3f: ¹H-NMR (200 MHz, CDCl₃) δ: 0.67 (3H, s, 18-CH₃), 0.76 (3H, s, 19-CH₃), 2.46 (1H, dd, J=19.3, 11.0 Hz, 4β-H), 2.55 (1H, d, J=16.3Hz, 1β-H), 2.91 (1H, d, J=16.3 Hz, 1α-H), 3.02 (1H, dd, J=19.3, 4.8 Hz, 4α-H), 3.72 (1H, dd, J_{16α, 17α}=8.2 Hz, J_{l6β, 17α}=8.0 Hz, 17α-H), 5.98-6.25 (2H, br, 8'-CH₂), 7.00-7.15 (2H, m, Bn-meta H), 7.22-7.52 (6H, m, Bn-ortho, para H and Ph-meta, para H), 8.42-8.52 (2H, m, Ph-ortho H), 8.65 (1H, s, 5'-H)。 Compound 3f: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.67 (3H, s, 18-CH ₃ ), 0.76 (3H, s, 19-CH ₃ ), 2.46 (1H, dd, J = 19.3, 11.0 Hz, 4β-H), 2.55 (1H, d, J = 16.3Hz, 1β-H), 2.91 (1H, d, J = 16.3 Hz, 1α-H), 3.02 (1H, dd, J = 19.3, 4.8 Hz, 4α-H), 3.72 (1H, dd, J _{16α, 17α} = 8.2 Hz, J _{l6β, 17α} = 8.0 Hz, 17α-H), 5.98-6.25 (2H, br, 8'-CH ₂ ), 7.00-7.15 (2H, m, Bn-meta H), 7.22-7.52 (6H, m, Bn-ortho, para H and Ph-meta, para H), 8.42-8.52 (2H, m, Ph-ortho H) , 8.65 (1H, s, 5'-H).

化合物3g: ¹H-NMR (200 MHz, CDCl₃) δ: 0.79 (3H, s, 18-CH₃), 0.81 (3H, s, 19-CH₃), 1.30-2.15 (10H, m, Cyclohexyl-H), 2.58 (1H, d, J=16.8 Hz, 1β-H), 2.65 (1H, dd, J=18.3, 11.4 Hz, 4β-H), 2.92 (1H, d, J=16.8 Hz, 1α-H), 2.96 (1H, dd, J=18.3, 4.6 Hz, 4α-H), 3.69 (1H, dd, J_{l6α, 17α}=8.4 Hz, J_{16β, 17α}=8.0 Hz, 17α-H), 4.57-4.68 (1H, m, 1"-H), 7.44-7.56 (3H, m, Ph-meta, para H), 8.55-8.67 (2H, m, Ph-ortho H), 8.72 (1H, s, 5'-H)。 Compound 3g: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.79 (3H, s, 18-CH ₃ ), 0.81 (3H, s, 19-CH ₃ ), 1.30-2.15 (10H, m, Cyclohexyl- H), 2.58 (1H, d, J = 16.8 Hz, 1β-H), 2.65 (1H, dd, J = 18.3, 11.4 Hz, 4β-H), 2.92 (1H, d, J = 16.8 Hz, 1α- H), 2.96 (1H, dd, J = 18.3, 4.6 Hz, 4α-H), 3.69 (1H, dd, J _{l6α, 17α} = 8.4 Hz, J _{16β, 17α} = 8.0 Hz, 17α-H), 4.57- 4.68 (1H, m, 1 "-H), 7.44-7.56 (3H, m, Ph-meta, para H), 8.55-8.67 (2H, m, Ph-ortho H), 8.72 (1H, s, 5 ' -H).

化合物3h: ¹H-NMR (200 MHz, CDCl₃) δ: 0.77 (3H, s, 18-CH₃), 0.81 (3H, s, 19-CH₃), 2.45 (1H, dd, J=19.5, 5.3 Hz, 4α-H), 2.61 (1H, d, J=16.6 Hz, 1β-H), 2.98 (1H, d, J=16.6 Hz, 1α-H), 3.67 (1H, dd, J_{16α, 17α}=8.6 Hz, J_{l6β, l7α}=7.6 Hz, 17α-H), 7.18-7.45 (5H, m, 8'-Ph-H), 7.63-7.74 (3H, m, 2'-Ph-meta, para H), 8.08-8.20 (2H, m, 2'-Ph-ortho H), 8.84 (1H, s, 5'-H)。 Compound 3h: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.77 (3H, s, 18-CH ₃ ), 0.81 (3H, s, 19-CH ₃ ), 2.45 (1H, dd, J = 19.5, 5.3 Hz, 4α-H), 2.61 (1H, d, J = 16.6 Hz, 1β-H), 2.98 (1H, d, J = 16.6 Hz, 1α-H), 3.67 (1H, dd, J _{16α, 17α} = 8.6 Hz, J _{l6β, l7α} = 7.6 Hz, 17α-H), 7.18-7.45 (5H, m, 8'-Ph-H), 7.63-7.74 (3H, m, 2'-Ph-meta, para H ), 8.08-8.20 (2H, m, 2'-Ph-ortho H), 8.84 (1H, s, 5'-H).

化合物3i: ¹H-NMR (200 MHz, CDCl₃) δ: 0.78 (3H, s, 18-CH₃), 0.80 (3H, s, 19-CH₃), 1.85 (3H, s, 8'-Ar-CH₃), 1.93 (3H, s, 8'-Ar-CH₃), 2.28 (1H, dd, J=19.9, 5.9 Hz, 4α-H), 2.64 (1H, d, J=16.2 Hz, 1β-H), 3.00 (1H, d, J=16.2 Hz, 1α-H), 3.68 (1H, dd, J_{16α, l7α}=8.4 Hz, J_{16β, 17α}=8.2 Hz, 17α-H), 7.22-7.52 (6H, m, 2'-Ph-meta, para H & 8'-Ar-meta, para H), 8.16-8.28 (2H, m, 2'-Ph-ortho H), 8.88 (1H, s, 5'-H)。 Compound 3i: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.78 (3H, s, 18-CH ₃ ), 0.80 (3H, s, 19-CH ₃ ), 1.85 (3H, s, 8'-Ar -CH ₃ ), 1.93 (3H, s, 8'-Ar-CH ₃ ), 2.28 (1H, dd, J = 19.9, 5.9 Hz, 4α-H), 2.64 (1H, d, J = 16.2 Hz, 1β -H), 3.00 (1H, d, J = 16.2 Hz, 1α-H), 3.68 (1H, dd, J _{16α, l7α} = 8.4 Hz, J _{16β, 17α} = 8.2 Hz, 17α-H), 7.22-7.52 (6H, m, 2'-Ph-meta, para H &8'-Ar-meta, para H), 8.16-8.28 (2H, m, 2'-Ph-ortho H), 8.88 (1H, s, 5 '-H).

化合物3j: ¹H-NMR (200 MHz, CDCl₃) δ: 0.77 (3H, s, 18-CH₃), 0.81 (3H, s, 19-CH₃), 2.42 (1H, dd, J=19.6, 5.8 Hz, 4α-H), 2.60 (1H, d, J=16.2 Hz, 1β-H), 2.92 (1H, d, J=16.2 Hz, 1α-H), 3.68 (1H, dd, J_{16α, 17α}=8.0 Hz, J_{l6β, 17α}=7.8 Hz, 17α-H), 3.97 (3H, s, OCH₃), 7.09-7.48 (7H, m, 2'-Ph-meta, para H and 8'-Ar-ortho, meta H), 8.18-8.28 (2H, m, 2'-Ph-ortho H), 8.74 (1H, s, 5'-H)。 Compound 3j: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.77 (3H, s, 18-CH ₃ ), 0.81 (3H, s, 19-CH ₃ ), 2.42 (1H, dd, J = 19.6, 5.8 Hz, 4α-H), 2.60 (1H, d, J = 16.2 Hz, 1β-H), 2.92 (1H, d, J = 16.2 Hz, 1α-H), 3.68 (1H, dd, J _{16α, 17α} = 8.0 Hz, J _{l6β, 17α} = 7.8 Hz, 17α-H), 3.97 (3H, s, OCH ₃ ), 7.09-7.48 (7H, m, 2'-Ph-meta, para H and 8'-Ar- ortho, meta H), 8.18-8.28 (2H, m, 2'-Ph-ortho H), 8.74 (1H, s, 5'-H).

化合物3k: ¹H-NMR (200 MHz, CDCl₃) δ: 0.77 (3H, s, 18-CH₃), 0.82 (3H, s, 19-CH₃), 2.37 (1H, dd, J=19.4, 5.8 Hz, 4α-H), 2.55 (1H, d, J=17.3 Hz, 1β-H), 2.92 (1H, d, J=17.3 Hz, 1α-H), 3.68 (1H, dd, J_{16α, l7α}=8.8 Hz, J_{16β, 17α}=7.8 Hz, 17α-H), 7.21-7.69(7H, m, 2'-Ph-meta, para H and 8'-Ar-ortho, meta H), 8.10-8.20 (2H, m, 2'-Ph-ortho H), 8.62 (1H, s, 5'-H)。 Compound 3k: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.77 (3H, s, 18-CH ₃ ), 0.82 (3H, s, 19-CH ₃ ), 2.37 (1H, dd, J = 19.4, 5.8 Hz, 4α-H), 2.55 (1H, d, J = 17.3 Hz, 1β-H), 2.92 (1H, d, J = 17.3 Hz, 1α-H), 3.68 (1H, dd, J _{16α, l7α} = 8.8 Hz, J _{16β, 17α} = 7.8 Hz, 17α-H), 7.21-7.69 (7H, m, 2'-Ph-meta, para H and 8'-Ar-ortho, meta H), 8.10-8.20 ( 2H, m, 2'-Ph-ortho H), 8.62 (1H, s, 5'-H).

以下、上記の実施例で合成して得られた本発明化合物の収率及び理化学的性質を表５に示す。 The yields and physicochemical properties of the compounds of the present invention obtained by synthesis in the above examples are shown in Table 5 below.

（８−置換誘導体（５ａ―ｔ）の一般合成）
ジフェニルエ−テル（１ｍｌ）に、原料化合物（４ａ―ｔ）（４ｍｍｏｌ）と２−ヒドロキシメチレンアンドロスタノロン（２）（４ｍｍｏｌ）を加え、更に、この混合物へｐ−トルエンスルホン酸（０．４ｍｍｏｌ）加えた後、２２０℃でアルゴン雰囲気下１５分間加熱撹拌した。反応終了後、この反応物をカラムクロマトグラフィ−（Fuji Silysia 200〜400 mesh；溶出剤:酢酸エチル）に付し精製した。溶出液を減圧下濃縮し、その残渣を酢酸エチル、アセトニトリル又はアセトンで再結晶化して淡黄色の粉末結晶の目的物（５ａ―ｔ）を得た。得られた目的物のNMRデータを下記に示す。 (General synthesis of 8-substituted derivatives (5a-t))
To diphenyl ether (1 ml), raw material compound (4at) (4 mmol) and 2-hydroxymethyleneandrostanolone (2) (4 mmol) were added, and p-toluenesulfonic acid (0.4 mmol) was further added to this mixture. After the addition, the mixture was stirred with heating at 220 ° C. under an argon atmosphere for 15 minutes. After completion of the reaction, the reaction product was purified by column chromatography (Fuji Silysia 200-400 mesh; eluent: ethyl acetate). The eluate was concentrated under reduced pressure, and the residue was recrystallized with ethyl acetate, acetonitrile or acetone to obtain the desired product (5at) as light yellow powder crystals. The NMR data of the obtained target product are shown below.

化合物5a: ¹H-NMR (200 MHz, CDCl₃) δ: 0.78 (3H, s, 18-CH₃), 0.79 (3H, s, 19-CH₃), 2.44 (1H, d, J=16.1 Hz, 1β-H), 2.47 (1H, dd, J=17.7, 10.1 Hz, 4β-H), 2.77 (1H, d, J=16.1 Hz, 1α-H), 2.83 (1H, dd, J=17.7, 3.8 Hz, 4α-H), 3.67 (1H, dd, J_{l6α, 17α}=8.0 Hz, J_{16β, 17α}=8.0 Hz, 17α-H), 3.97 (3H, s, 8'-CH₃), 8.27 (1H, s, 5'-H), 8.29 (1H, s, exchangeable with D₂O, 3'-NH)。 Compound 5a: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.78 (3H, s, 18-CH ₃ ), 0.79 (3H, s, 19-CH ₃ ), 2.44 (1H, d, J = 16.1 Hz , 1β-H), 2.47 (1H, dd, J = 17.7, 10.1 Hz, 4β-H), 2.77 (1H, d, J = 16.1 Hz, 1α-H), 2.83 (1H, dd, J = 17.7, 3.8 Hz, 4α-H), 3.67 (1H, dd, J _{l6α, 17α} = 8.0 Hz, J _{16β, 17α} = 8.0 Hz, 17α-H), 3.97 (3H, s, 8'-CH ₃ ), 8.27 ( 1H, s, 5'-H) , 8.29 (1H, s, exchangeable with D 2 O, 3'-NH).

化合物5b: ¹H-NMR (200 MHz, CDCl₃) δ: 0.78 (6H, s, 18 and 19-CH₃), 1.44 (3H, t, J=6.9 Hz, 8'-CH₂CH ₃), 2.45 (1H, d, J=16.1 Hz, 1β-H), 2.57 (1H, dd, J=18.1, 10.2 Hz, 4β-H), 2.76 (1H, d, J=16.1 Hz, 1α-H), 2.88 (1H, dd, J=18.1, 4.4 Hz, 4α-H), 3.67 (1H, dd, J_{16α, 17α}=8.4 Hz, J_{16β, 17α}=8.2 Hz, 17α-H), 4.26-4.51 (1H, m, 8'-CH _aH_b), 4.67-4.92 (1H, m, 8'-CH_a H _b), 8.26 (1H, s, 5'-H), 8.37 (1H, s, exchangeable with D₂O, 3'-NH)。 Compound 5b: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.78 (6H, s, 18 and 19-CH ₃ ), 1.44 (3H, t, J = 6.9 Hz, 8'-CH ₂ C H ₃ ) , 2.45 (1H, d, J = 16.1 Hz, 1β-H), 2.57 (1H, dd, J = 18.1, 10.2 Hz, 4β-H), 2.76 (1H, d, J = 16.1 Hz, 1α-H) , 2.88 (1H, dd, J = 18.1, 4.4 Hz, 4α-H), 3.67 (1H, dd, J _{16α, 17α} = 8.4 Hz, J _{16β, 17α} = 8.2 Hz, 17α-H), 4.26-4.51 ( 1H, m, 8'-C H _a H _b ), 4.67-4.92 (1H, m, 8'-CH _a H _b ), 8.26 (1H, s, 5'-H), 8.37 (1H, s, exchangeable with D ₂ O, 3′-NH).

化合物5c: ¹H-NMR (200 MHz, CDCl₃) δ: 0.78 (6H, s, 18 and 19-CH₃), 1.06 (3H, t, J=7.4 Hz, 8'-CH₂CH₂CH ₃), 2.45 (1H, d, J=16.3 Hz, 1β-H), 2.54 (1H, dd, J=18.1, 11.0 Hz, 4β-H), 2.77 (1H, d, J=16.3 Hz, 1α-H), 2.85 (1H, dd, J=18.1, 4.6 Hz, 4α-H), 3.68 (1H, dd, J_{l6α, 17α}=8.4 Hz, J_{l6β, 17α}=8.2 Hz, 17α-H), 4.12-4.38 (1H, m, 8'-CH _aH_b), 4.54-4.76(1H, m, 8'-CH_a H _b), 8.26 (1H, s, 5'-H), 8.34 (1H, s, exchangeable with D₂O,3'-NH)。 Compound 5c: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.78 (6H, s, 18 and 19-CH ₃ ), 1.06 (3H, t, J = 7.4 Hz, 8'-CH ₂ CH ₂ C H ₃ ), 2.45 (1H, d, J = 16.3 Hz, 1β-H), 2.54 (1H, dd, J = 18.1, 11.0 Hz, 4β-H), 2.77 (1H, d, J = 16.3 Hz, 1α- H), 2.85 (1H, dd, J = 18.1, 4.6 Hz, 4α-H), 3.68 (1H, dd, J _{l6α, 17α} = 8.4 Hz, J _{l6β, 17α} = 8.2 Hz, 17α-H), 4.12- 4.38 (1H, m, 8'-C H _a H _b ), 4.54-4.76 (1H, m, 8'-CH _a H _b ), 8.26 (1H, s, 5'-H), 8.34 (1H, s , exchangeable with D ₂ O, 3'-NH).

化合物5d: ¹H-NMR (200 MHz, CDCl₃) δ: 0.71 (3H, s, 18-CH₃), 0.75 (3H, s, 19-CH₃), 2.32-2.52 (1H, m, 4β-H), 2.44 (1H, d, J=16.0 Hz, 1β-H), 2.68-2.88 (1H, m, 4α-H), 2.76 (1H, d, J=16.0 Hz, 1α-H), 3.65 (1H, dd, J_{l6α, 17α}=8.4 Hz, J_{l6β, 17α}=7.8 Hz, 17α-H), 5.67 (1H, br d, J=14.9 Hz, 8'-CH _aH_b), 6.13 (1H, br d, J=14.9 Hz, 8'-CH_a H _b), 6.96-7.13 (2H, m, Bn-meta H), 7.22-7.37 (3H, m, Bn-ortho, para H), 8.34 (1H, s, 5'-H), 8.44(1H, s, exchangeable with D₂O, 3'-NH)。 Compound 5d: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.71 (3H, s, 18-CH ₃ ), 0.75 (3H, s, 19-CH ₃ ), 2.32-2.52 (1H, m, 4β- H), 2.44 (1H, d, J = 16.0 Hz, 1β-H), 2.68-2.88 (1H, m, 4α-H), 2.76 (1H, d, J = 16.0 Hz, 1α-H), 3.65 ( 1H, dd, J _{l6α, 17α} = 8.4 Hz, J _{l6β, 17α} = 7.8 Hz, 17α-H), 5.67 (1H, br d, J = 14.9 Hz, 8'-C H _a H _b ), 6.13 (1H , br d, J = 14.9 Hz, 8'-CH _a H _b ), 6.96-7.13 (2H, m, Bn-meta H), 7.22-7.37 (3H, m, Bn-ortho, para H), 8.34 ( 1H, s, 5'-H) , 8.44 (1H, s, exchangeable with D 2 O, 3'-NH).

化合物5e: ¹H-NMR (200 MHz, CDCl₃) δ: 0.76 (3H, s, 18-CH₃), 0.78 (3H, s, 19-CH₃), 2.22 (1H, dd, J=19.8, 5.4 Hz, 4α-H), 2.47 (1H, d, J=16.5 Hz, 1β-H), 2.81 (1H, d, J=16.5 Hz, 1α-H), 3.65 (1H, dd, J_{l6α, 17α}=8.6 Hz, J_{l6β, 17α}=7.8 Hz, 17α-H), 7.03-7.24 (2H, m, Ph-meta H), 7.51-7.66 (3H, m, Ph-ortho, para H), 8.24 (1H, s, exchangeable with D₂O, 3'-NH), 8.38 (1H, s, 5'-H)。 Compound 5e: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.76 (3H, s, 18-CH ₃ ), 0.78 (3H, s, 19-CH ₃ ), 2.22 (1H, dd, J = 19.8, 5.4 Hz, 4α-H), 2.47 (1H, d, J = 16.5 Hz, 1β-H), 2.81 (1H, d, J = 16.5 Hz, 1α-H), 3.65 (1H, dd, J _{l6α, 17α} = 8.6 Hz, J _{l6β, 17α} = 7.8 Hz, 17α-H), 7.03-7.24 (2H, m, Ph-meta H), 7.51-7.66 (3H, m, Ph-ortho, para H), 8.24 (1H , s, exchangeable with D ₂ O, 3'-NH), 8.38 (1H, s, 5'-H).

化合物5f: ¹H-NMR (200 MHz, CDCl₃) δ: 0.76 (3H, s, 18-CH₃), 0.78 (3H, s, 19-CH₃), 2.27 (1H, dd, J=18.8, 5.4 Hz, 4α-H), 2.46 (1H, d, J=16.0 Hz, 1β-H), 2.80 (1H, d, J=16.0Hz, 1α-H), 3.66 (1H, dd, J_{l6α, 17α}=8.8 Hz, J_{l6β, 17α}=8.2 Hz, 17α-H), 3.88 (3H, s, OCH₃), 6.95-7.06 (2H, m, Ar-meta H), 7.06-7.15 (2H, m, Ar-ortho H), 8.25 (1H, s, exchangeable with D₂O, 3'-NH), 8.36 (1H, s, 5'-H)。 Compound 5f: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.76 (3H, s, 18-CH ₃ ), 0.78 (3H, s, 19-CH ₃ ), 2.27 (1H, dd, J = 18.8, 5.4 Hz, 4α-H), 2.46 (1H, d, J = 16.0 Hz, 1β-H), 2.80 (1H, d, J = 16.0Hz, 1α-H), 3.66 (1H, dd, J _{l6α, 17α} = 8.8 Hz, J _{l6β, 17α} = 8.2 Hz, 17α-H), 3.88 (3H, s, OCH ₃ ), 6.95-7.06 (2H, m, Ar-meta H), 7.06-7.15 (2H, m, Ar -ortho H), 8.25 (1H, s, exchangeable with D ₂ O, 3'-NH), 8.36 (1H, s, 5'-H).

化合物5g: ¹H-NMR (200 MHz, DMSO-d₆) δ: 0.64 (3H, s, 18-CH₃), 0.74 (3H, s, 19-CH₃), 2.13 (1H, dd, J=19.4, 5.8 Hz, 4α-H), 2.37 (1H, d, J=15.9 Hz, 1β-H), 2.86 (1H, d, J=15.9 Hz, 1α-H), 3.37-3.52 (1H, m, 17α-H), 4.45 (1H, d, J=4.6 Hz, exchangeable with D₂O, 17β-OH), 7.35-7.58 (4H, m, Ar-ortho, meta H), 8.30 (1H, s, 5'-H), 10.79 (1H, s, exchangeable with D₂O, 3'-NH)。 Compound 5g: ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.64 (3H, s, 18-CH ₃ ), 0.74 (3H, s, 19-CH ₃ ), 2.13 (1H, dd, J = 19.4, 5.8 Hz, 4α-H), 2.37 (1H, d, J = 15.9 Hz, 1β-H), 2.86 (1H, d, J = 15.9 Hz, 1α-H), 3.37-3.52 (1H, m, 17α-H), 4.45 (1H, d, J = 4.6 Hz, exchangeable with D ₂ O, 17β-OH), 7.35-7.58 (4H, m, Ar-ortho, meta H), 8.30 (1H, s, 5 '-H), 10.79 (1H, s, exchangeable with D ₂ O, 3'-NH).

化合物5h: ¹H-NMR (200 MHz, DMSO-d₆) δ: 0.64 (3H, s, 18-CH₃), 0.74 (3H, s, 19-CH₃), 2.14 (1H, dd, J=19.4, 5.4 Hz, 4α-H), 2.38 (1H, d, J=16.3 Hz, 1β-H), 2.87 (1H, d, J=16.3 Hz, 1α-H), 3.36-3.52 (1H, m, 17α-H), 4.45 (1H, d, J=4.6 Hz, exchangeable with D₂O, 17β-OH), 7.38-7.55 (2H, m, Ar-meta H), 7.68 (2H, d, J_AB=9.0 Hz, Ar-ortho H), 8.31 (1H, s, 5'-H), 10.79 (1H, s, exchangeable with D₂O, 3'-NH)。 Compound 5h: ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.64 (3H, s, 18-CH ₃ ), 0.74 (3H, s, 19-CH ₃ ), 2.14 (1H, dd, J = 19.4, 5.4 Hz, 4α-H), 2.38 (1H, d, J = 16.3 Hz, 1β-H), 2.87 (1H, d, J = 16.3 Hz, 1α-H), 3.36-3.52 (1H, m, 17α-H), 4.45 (1H, d, J = 4.6 Hz, exchangeable with D ₂ O, 17β-OH), 7.38-7.55 (2H, m, Ar-meta H), 7.68 (2H, d, J _AB = 9.0 Hz, Ar-ortho H) , 8.31 (1H, s, 5'-H), 10.79 (1H, s, exchangeable with D 2 O, 3'-NH).

化合物5i: ¹H-NMR (200 MHz, CDCl₃) δ: 0.78 (6H, s, 18 and 19-CH₃), 1.65 (1H, s, exchangeable with D₂O, 17β-OH), 2.45 (1H, d, J=15.7 Hz, 1β-H), 2.46 (1H, dd, J=18.5, 10.0 Hz, 4β-H), 2.78 (1H, d, J=15.7 Hz, 1α-H), 2.83 (1H, dd, J=18.5, 5.3 Hz, 4α-H), 3.45 (3H, s, 3'-CH₃), 3.67 (1H, dd, J_{16α, 17α}=8.4 Hz, J_{16β, 17α}=8.2 Hz, 17α-H), 3.96 (3H, s, 8'-CH₃), 8.28 (1H, s, 5'-H)。 Compound 5i: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.78 (6H, s, 18 and 19-CH ₃ ), 1.65 (1H, s, exchangeable with D ₂ O, 17β-OH), 2.45 (1H , d, J = 15.7 Hz, 1β-H), 2.46 (1H, dd, J = 18.5, 10.0 Hz, 4β-H), 2.78 (1H, d, J = 15.7 Hz, 1α-H), 2.83 (1H , dd, J = 18.5, 5.3 Hz, 4α-H), 3.45 (3H, s, 3'-CH ₃ ), 3.67 (1H, dd, J _{16α, 17α} = 8.4 Hz, J _{16β, 17α} = 8.2 Hz, 17α-H), 3.96 (3H, s, 8′-CH ₃ ), 8.28 (1H, s, 5′-H).

化合物5j: ¹H-NMR (200 MHz, CDCl₃) δ: 0.78 (6H, s, 18 and 19-CH₃), 1.43 (3H, t, J=7.0 Hz, 8'-CH₂CH ₃), 2.45 (1H, d, J=15.9 Hz, 1β-H), 2.54 (1H, dd, J=18.5, 10.6 Hz, 4β-H), 2.77 (1H, d, J=15.9 Hz, 1α-H), 2.87 (1H, dd, J=18.5, 4.9 Hz, 4α-H), 3.45 (3H, s, 3'-CH₃), 3.68 (1H, dd, J_{16α, 17α}=8.8 Hz, J_{16β, 17α}=8.2 Hz, 17α-H), 4.26-4.52 (1H, m, 8'-CH _aH_b), 4.68-4.93 (1H, m, 8'-CH_a H _b), 8.26 (1H, s, 5'-H)。 Compound 5j: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.78 (6H, s, 18 and 19-CH ₃ ), 1.43 (3H, t, J = 7.0 Hz, 8'-CH ₂ C H ₃ ) , 2.45 (1H, d, J = 15.9 Hz, 1β-H), 2.54 (1H, dd, J = 18.5, 10.6 Hz, 4β-H), 2.77 (1H, d, J = 15.9 Hz, 1α-H) , 2.87 (1H, dd, J = 18.5, 4.9 Hz, 4α-H), 3.45 (3H, s, 3'-CH ₃ ), 3.68 (1H, dd, J _{16α, 17α} = 8.8 Hz, J _{16β, 17α} = 8.2 Hz, 17α-H), 4.26-4.52 (1H, m, 8'-C H _a H _b ), 4.68-4.93 (1H, m, 8'-CH _a H _b ), 8.26 (1H, s, 5'-H).

化合物5k: ¹H-NMR (200 MHz, CDCl₃) δ: 0.78 (6H, s, 18 and 19-CH₃), 1.05 (3H, t, J=7.4 Hz, 8'-CH₂CH₂CH ₃), 2.45 (1H, d, J=16.6 Hz, 1β-H), 2.52 (1H, dd, J=18.1, 10.3 Hz, 4β-H), 2.77 (1H, d, J=16.6 Hz, 1α-H), 2.84 (1H, dd, J=18.1, 5.3 Hz, 4α-H), 3.44 (3H, s, 3'-CH₃), 3.67 (1H, dd, J_{16α, 17α}=8.4 Hz, J_{16β, 17α}=7.8 Hz, 17α-H), 4.15-4.40 (1H, m, 8'-CH _aH_b), 4.51-4.77 (1H, m, 8'-CH_a H _b), 8.25 (1H, s, 5'-H)。 Compound 5k: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.78 (6H, s, 18 and 19-CH ₃ ), 1.05 (3H, t, J = 7.4 Hz, 8'-CH ₂ CH ₂ C H ₃ ), 2.45 (1H, d, J = 16.6 Hz, 1β-H), 2.52 (1H, dd, J = 18.1, 10.3 Hz, 4β-H), 2.77 (1H, d, J = 16.6 Hz, 1α- H), 2.84 (1H, dd, J = 18.1, 5.3 Hz, 4α-H), 3.44 (3H, s, 3'-CH ₃ ), 3.67 (1H, dd, J _{16α, 17α} = 8.4 Hz, J _{16β , 17α} = 7.8 Hz, 17α-H), 4.15-4.40 (1H, m, 8'-C H _a H _b ), 4.51-4.77 (1H, m, 8'-CH _a H _b ), 8.25 (1H, s, 5'-H).

化合物5l: ¹H-NMR (200 MHz, CDCl₃) δ: 0.78 (6H, s, 18 and 19-CH₃), 1.85 (6H, d, J=4.4 Hz, 8'-CH(CH ₃)₂), 2.46 (1H, d, J=16.1 Hz, 1β-H), 2.52 (1H, dd, J=18.1, 10.9 Hz, 4β-H), 2.76 (1H, d, J=16.1 Hz, 1α-H), 2.83 (1H, dd, J=18.1, 5.7 Hz, 4α-H), 3.43 (3H, s, 3'-CH₃), 3.67 (1H, dd, J_{16α, 17α}=8.4 Hz, J_{16β, 17α}=8.2 Hz, 17α-H), 4.81-5.01 (1H, m, 8'-CH), 8.23 (1H, s, 5'-H)。 Compound 5l: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.78 (6H, s, 18 and 19-CH ₃ ), 1.85 (6H, d, J = 4.4 Hz, 8'-CH (C H ₃ ) ₂ ), 2.46 (1H, d, J = 16.1 Hz, 1β-H), 2.52 (1H, dd, J = 18.1, 10.9 Hz, 4β-H), 2.76 (1H, d, J = 16.1 Hz, 1α- H), 2.83 (1H, dd, J = 18.1, 5.7 Hz, 4α-H), 3.43 (3H, s, 3'-CH ₃ ), 3.67 (1H, dd, J _{16α, 17α} = 8.4 Hz, J _{16β , 17α} = 8.2 Hz, 17α-H), 4.81-5.01 (1H, m, 8'-CH), 8.23 (1H, s, 5'-H).

化合物5m: ¹H-NMR (200 MHz, CDCl₃) δ: 0.78 (6H, s, 18 and 19-CH₃), 0.98 (3H, t, J=7.2 Hz, 8'-CH₂CH₂CH₂CH ₃), 2.45 (1H, d, J=16.6 Hz, 1β-H), 2.52 (1H, dd, J=18.4, 10.9 Hz, 4β-H), 2.77 (1H, d, J=16.6 Hz, 1α-H), 2.85 (1H, dd, J=18.4, 4.8 Hz, 4α-H), 3.45 (3H, s, 3'-CH₃), 3.68 (1H, dd, J_{16α, 17α}=8.8 Hz, J_{16β, 17α}=7.6 Hz, 17α-H), 4.14-4.42 (1H, m, 8'-CH _aH_b), 4.56-4.82 (1H, m, 8'-CH_a H _b), 8.25 (1H, s, 5'-H)。 Compound 5m: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.78 (6H, s, 18 and 19-CH ₃ ), 0.98 (3H, t, J = 7.2 Hz, 8'-CH ₂ CH ₂ CH ₂ C H ₃ ), 2.45 (1H, d, J = 16.6 Hz, 1β-H), 2.52 (1H, dd, J = 18.4, 10.9 Hz, 4β-H), 2.77 (1H, d, J = 16.6 Hz, 1α-H), 2.85 (1H, dd, J = 18.4, 4.8 Hz, 4α-H), 3.45 (3H, s, 3'-CH ₃ ), 3.68 (1H, dd, J _{16α, 17α} = 8.8 Hz, J _{16β, 17α} = 7.6 Hz, 17α-H), 4.14-4.42 (1H, m, 8'-C H _a H _b ), 4.56-4.82 (1H, m, 8'-CH _a H _b ), 8.25 ( 1H, s, 5'-H).

化合物5n: ¹H-NMR (200 MHz, CDCl₃) δ: 0.70 (3H, s, 18-CH₃), 0.75 (3H, s, 19-CH₃), 2.35-2.52 (1H, m, 4β-H), 2.36 (1H, d, J=16.0 Hz, 1β-H), 2.68-2.86(1H, m, 4α-H), 2.77 (1H, d, J=16.0 Hz, 1α-H), 3.45 (3H, s, 3'-CH₃), 3.65 (1H, dd, J_{16α, 17α}=8.8 Hz, J_{16β, 17α}=7.8 Hz, 17α-H), 5.66 (1H, br d, J=15.7 Hz, 8'-CH _aH_b), 6.13 (1H, br d, J=15.7 Hz, 8'-CH_a H _b), 7.00-7.09 (2H, m, Bn-meta H), 7.25-7.36 (3H, m, Bn-ortho, para H),8.34 (1H, s, 5'-H)。 Compound 5n: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.70 (3H, s, 18-CH ₃ ), 0.75 (3H, s, 19-CH ₃ ), 2.35-2.52 (1H, m, 4β- H), 2.36 (1H, d, J = 16.0 Hz, 1β-H), 2.68-2.86 (1H, m, 4α-H), 2.77 (1H, d, J = 16.0 Hz, 1α-H), 3.45 ( 3H, s, 3'-CH ₃ ), 3.65 (1H, dd, J _{16α, 17α} = 8.8 Hz, J _{16β, 17α} = 7.8 Hz, 17α-H), 5.66 (1H, br d, J = 15.7 Hz, 8'-C H _a H _b ), 6.13 (1H, br d, J = 15.7 Hz, 8'-CH _a H _b ), 7.00-7.09 (2H, m, Bn-meta H), 7.25-7.36 (3H , m, Bn-ortho, para H), 8.34 (1H, s, 5'-H).

化合物5o: ¹H-NMR (200 MHz, CDCl₃) δ: 0.78 (3H, s, 18-CH₃), 0.80 (3H, s, 19-CH₃), 2.20-2.87 (9H, m, 4β-H and Cyclopentyl-H), 2.45 (1H, d, J=16.0 Hz, 1β-H), 2.76 (1H, d, J=16.0 Hz, 1α-H), 2.87 (1H, dd, J=19.0, 6.0 Hz,4α-H), 3.42 (3H, s, 3'-CH₃), 3.67 (1H, dd, J_{16α, 17α}=8.4 Hz, J_{16β, 17α}=7.2 Hz, 17α-H), 5.16-5.28 (1H, m, 1"-H), 8.22 (1H, s, 5'-H)。 Compound 5o: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.78 (3H, s, 18-CH ₃ ), 0.80 (3H, s, 19-CH ₃ ), 2.20-2.87 (9H, m, 4β- H and Cyclopentyl-H), 2.45 (1H, d, J = 16.0 Hz, 1β-H), 2.76 (1H, d, J = 16.0 Hz, 1α-H), 2.87 (1H, dd, J = 19.0, 6.0 Hz, 4α-H), 3.42 (3H, s, 3'-CH ₃ ), 3.67 (1H, dd, J _{16α, 17α} = 8.4 Hz, J _{16β, 17α} = 7.2 Hz, 17α-H), 5.16-5.28 (1H, m, 1 "-H), 8.22 (1H, s, 5'-H).

化合物5p: ¹H-NMR (200 MHz, CDCl₃) δ: 0.76 (3H, s, 18-CH₃), 0.78 (3H, s, 19-CH₃), 2.00 (1H, m, 4β-H), 2.19 (1H, dd, J=19.5, 5.7 Hz, 4α-H), 2.47 (1H, d, J=16.2 Hz, 1β-H), 2.81 (1H, d, J=16.2 Hz, 1α-H), 3.39 (3H, s, 3'-CH₃), 3.65 (1H, dd, J_{16α, 17α}=8.4 Hz, J_{16β, l7α}=7.8 Hz, 17α-H), 7.05-7.25 (2H, m, Ph-meta H), 7.50-7.66 (3H, m, Ph-ortho, para H), 8.38 (1H, s, 5'-H)。 Compound 5p: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.76 (3H, s, 18-CH ₃ ), 0.78 (3H, s, 19-CH ₃ ), 2.00 (1H, m, 4β-H) , 2.19 (1H, dd, J = 19.5, 5.7 Hz, 4α-H), 2.47 (1H, d, J = 16.2 Hz, 1β-H), 2.81 (1H, d, J = 16.2 Hz, 1α-H) , 3.39 (3H, s, 3'-CH ₃ ), 3.65 (1H, dd, J _{16α, 17α} = 8.4 Hz, J _{16β, l7α} = 7.8 Hz, 17α-H), 7.05-7.25 (2H, m, Ph -meta H), 7.50-7.66 (3H, m, Ph-ortho, para H), 8.38 (1H, s, 5'-H).

化合物5q: ¹H-NMR (200 MHz, CDCl₃) δ: 0.76 (3H, s, 18-CH₃), 0.78 (3H, s, 19-CH₃), 1.80 (1H, s, exchangeable with D₂O, 17β-OH), 2.24 (1H, dd, J=19.8, 5.6 Hz, 4α-H), 2.44 (3H, s, 8'CH₃), 2.47 (1H, d, J=16.1 Hz, 1β-H), 2.82 (1H, d, J=16.1 Hz, 1α-H), 3.39 (3H, s, 3'-CH₃), 3.65 (1H, dd, J_{l6α, 17α}=8.4 Hz, J_{16β, l7α}=7.8 Hz, 17α-H), 6.93-7.12 (2H, m, Ar-meta H), 7.35 (2H, d, J_AB=8.4 Hz, Ar-ortho H), 8.38 (1H, s, 5'-H)。 Compound 5q: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.76 (3H, s, 18-CH ₃ ), 0.78 (3H, s, 19-CH ₃ ), 1.80 (1H, s, exchangeable with D ₂ O, 17β-OH), 2.24 (1H, dd, J = 19.8, 5.6 Hz, 4α-H), 2.44 (3H, s, 8'CH ₃ ), 2.47 (1H, d, J = 16.1 Hz, 1β- H), 2.82 (1H, d, J = 16.1 Hz, 1α-H), 3.39 (3H, s, 3'-CH ₃ ), 3.65 (1H, dd, J _{l6α, 17α} = 8.4 Hz, J _{16β, l7α} = 7.8 Hz, 17α-H), 6.93-7.12 (2H, m, Ar-meta H), 7.35 (2H, d, J _AB = 8.4 Hz, Ar-ortho H), 8.38 (1H, s, 5'- H).

化合物5r: ¹H-NMR (200 MHz, CDCl₃) δ: 0.76 (3H, s, 18-CH₃), 0.78 (3H, s, 19-CH₃), 1.94 (1H, s, exchangeable with D₂O, 17β-OH), 2.26 (1H, dd, J=19.5, 5.3 Hz, 4α-H), 2.47 (1H, d, J=16.2 Hz, 1β-H), 2.81 (1H, d, J=16.2 Hz, 1α-H), 3.39 (3H, s, 3'-CH₃), 3.66 (1H, dd, J_{l6α, 17α}=8.6 Hz, J_{16β, 17α}=8.0 Hz, 17α-H), 3.88 (3H, s, OCH₃), 6.96-7.06 (2H, m, Ar-meta H), 7.06-7.16 (2H, m, Ar-ortho H), 8.37 (1H, s, 5'-H)。 Compound 5r: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.76 (3H, s, 18-CH ₃ ), 0.78 (3H, s, 19-CH ₃ ), 1.94 (1H, s, exchangeable with D ₂ O, 17β-OH), 2.26 (1H, dd, J = 19.5, 5.3 Hz, 4α-H), 2.47 (1H, d, J = 16.2 Hz, 1β-H), 2.81 (1H, d, J = 16.2 Hz, 1α-H), 3.39 (3H, s, 3'-CH ₃ ), 3.66 (1H, dd, J _{l6α, 17α} = 8.6 Hz, J _{16β, 17α} = 8.0 Hz, 17α-H), 3.88 (3H , s, OCH ₃ ), 6.96-7.06 (2H, m, Ar-meta H), 7.06-7.16 (2H, m, Ar-ortho H), 8.37 (1H, s, 5′-H).

化合物5s: ¹H-NMR (200 MHz, CDCl₃) δ: 0.76 (3H, s, 18-CH₃), 0.78 (3H, s, 19-CH₃), 1.65 (1H, s, exchangeable with D₂O, 17β-OH), 2.20 (1H, dd, J=19.6, 5.4Hz, 4α-H), 2.47 (1H, d, J=16.4 Hz, 1β-H), 2.82 (1H, d, J=16.4 Hz, 1α-H), 3.39 (3H, s, 3'-CH₃), 3.66 (1H, dd, J_{16α, 17α}=8.8 Hz, J_{16β, 17α}=8.4 Hz, 17α-H), 7.00-7.17 (2H, m, Ar-meta H), 7.18-7.34 (2H, m, Ar-ortho H), 8.38 (1H, s, 5'-H)。 Compound 5s: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.76 (3H, s, 18-CH ₃ ), 0.78 (3H, s, 19-CH ₃ ), 1.65 (1H, s, exchangeable with D ₂ O, 17β-OH), 2.20 (1H, dd, J = 19.6, 5.4Hz, 4α-H), 2.47 (1H, d, J = 16.4 Hz, 1β-H), 2.82 (1H, d, J = 16.4 Hz, 1α-H), 3.39 (3H, s, 3'-CH ₃ ), 3.66 (1H, dd, J _{16α, 17α} = 8.8 Hz, J _{16β, 17α} = 8.4 Hz, 17α-H), 7.00-7.17 (2H, m, Ar-meta H), 7.18-7.34 (2H, m, Ar-ortho H), 8.38 (1H, s, 5'-H).

化合物5t: ¹H-NMR (200 MHz, CDCl₃) δ: 0.76 (3H, s, 18-CH₃), 0.78 (3H, s, 19-CH₃), 1.71 (1H, s, exchangeable with D₂O, 17β-OH), 2.19 (1H, dd, J=19.5, 5.3 Hz, 4α-H), 2.47 (1H, d, J=16.4 Hz, 1β-H), 2.81 (1H, d, J=16.4 Hz, 1α-H), 3.38 (3H, s, 3'-CH₃), 3.65 (1H, dd, J_{16α, 17α}=8.6 Hz, J_{16β, 17α}=8.0 Hz, 17α-H), 7.00-7.21 (2H, m, Ar-meta H), 7.54 (2H, d, J_AB=8.8 Hz, Ar-ortho H), 8.37 (1H, s, 5'-H)。 Compound 5t: ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.76 (3H, s, 18-CH ₃ ), 0.78 (3H, s, 19-CH ₃ ), 1.71 (1H, s, exchangeable with D ₂ O, 17β-OH), 2.19 (1H, dd, J = 19.5, 5.3 Hz, 4α-H), 2.47 (1H, d, J = 16.4 Hz, 1β-H), 2.81 (1H, d, J = 16.4 Hz, 1α-H), 3.38 (3H, s, 3'-CH ₃ ), 3.65 (1H, dd, J _{16α, 17α} = 8.6 Hz, J _{16β, 17α} = 8.0 Hz, 17α-H), 7.00-7.21 (2H, m, Ar-meta H), 7.54 (2H, d, J _AB = 8.8 Hz, Ar-ortho H), 8.37 (1H, s, 5'-H).

以下、上記の実施例で合成して得られた本発明化合物の収率及び理化学的性質を表６に示す。 Table 6 shows the yield and physicochemical properties of the compounds of the present invention obtained by synthesis in the above examples.

（５’―デアザ−１７β−ヒドロキシ−８’−メチルアンドロスト−２，４−ジエノ[２，３−ｇ]プテリジン−２’，４’（３’Ｈ，８’Ｈ）−ジオン（７ａ、Ｒ^１＝Ｈ，Ｒ^２＝Ｍｅ）の合成）
ジフェニルエ−テル（０．３ｍｌ）に、６−メチルアミノウラシル（４ａ）（０．３ｇ、２．１３ｍｍｏｌ）と２−ヒドロキシメチレンテストステロン（６）（０．６７ｇ、２．１３ｍｍｏｌ）を加え、更に、この混合物へｐ−トルエンスルホン酸（４０．４ｍｇ、０．２１ｍｍｏｌ）加えた後、１８０℃でアルゴン雰囲気下３０分間加熱撹拌した。反応終了後、この反応物をカラムクロマトグラフィ−（Fuji Silysia 200〜400 mesh；溶出剤、酢酸エチル：エタノール＝１２：１）に付し精製した。溶出液を減圧下濃縮し、その残渣を酢酸エチルとエタノールの混合物で再結晶化して淡黄色の粉末結晶（７ａ）（０．３３ｇ、収率３７％），ｍｐ２５５℃（分解）を得た。得られた目的物のNMRデータを下記に示す。 (5′-deaza-17β-hydroxy-8′-methylandrost-2,4-dieno [2,3- g ] pteridine-2 ′, 4 ′ (3′H, 8′H) -dione (7a, Synthesis of R ¹ = H, R ² = Me)
To diphenyl ether (0.3 ml), 6-methylaminouracil (4a) (0.3 g, 2.13 mmol) and 2-hydroxymethylene testosterone (6) (0.67 g, 2.13 mmol) were added. P-Toluenesulfonic acid (40.4 mg, 0.21 mmol) was added to the mixture, and the mixture was heated and stirred at 180 ° C. for 30 minutes in an argon atmosphere. After completion of the reaction, the reaction product was purified by column chromatography (Fuji Silysia 200-400 mesh; eluent, ethyl acetate: ethanol = 12: 1). The eluate was concentrated under reduced pressure, and the residue was recrystallized with a mixture of ethyl acetate and ethanol to obtain pale yellow powder crystals (7a) (0.33 g, yield 37%), mp 255 ° C. (decomposition). . The NMR data of the obtained target product are shown below.

¹H-NMR (200 MHz, CDCl₃) δ: 0.81 (3H, s, 13-CH₃), 1.01 (3H, s, 10-CH₃), 2.49-2.61 (2H, br dd, 6-H), 2.66 (1H, d, J = 15.6 Hz, 1β-H), 2.91 (1H, d, J = 15.6 Hz, 1α-H), 3.70 (1H, dd, J_16α,17α= 8.4 Hz, J_16β,17α= 8.0 Hz, 17α-H), 4.06 (3H, s, 8'-CH₃), 6.43 (1H, s, 4-H), 8.20 (1H, s, exchangeable with D₂O, 3'-NH), 8.26 (1H, s, 5'-H)。 ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.81 (3H, s, 13-CH ₃ ), 1.01 (3H, s, 10-CH ₃ ), 2.49-2.61 (2H, br dd, 6-H) , 2.66 (1H, d, J = 15.6 Hz, 1β-H), 2.91 (1H, d, J = 15.6 Hz, 1α-H), 3.70 (1H, dd, J _{16α, 17α} = 8.4 Hz, J _{16β, 17α} = 8.0 Hz, 17α-H), 4.06 (3H, s, 8'-CH ₃ ), 6.43 (1H, s, 4-H), 8.20 (1H, s, exchangeable with D ₂ O, 3'-NH ), 8.26 (1H, s, 5'-H).

（５’―デアザ−１７β−ヒドロキシ−３’，８’−ジメチルアンドロスト−２，４−ジエノ[２，３−ｇ]プテリジン−２’，４’（３’Ｈ，８’Ｈ）−ジオン（７ｉ、Ｒ^１＝Ｒ^２＝Ｍｅ）の合成）
ジフェニルエ−テル（０．５ｍｌ）に、３−メチル−６−メチルアミノウラシル（４ｉ）（０．３ｇ、１．９３ｍｍｏｌ）と２−ヒドロキシメチレンテストステロン（６）（０．６１ｇ、１．９３ｍｍｏｌ）を加え、更に、この混合物へｐ−トルエンスルホン酸（３６．８ｍｇ、０．１９ｍｍｏｌ）加えた後、２００℃でアルゴン雰囲気下１５分間加熱撹拌した。反応終了後、この反応物をカラムクロマトグラフィ−（Fuji Silysia 200〜400 mesh；溶出剤、酢酸エチル：エタノール＝１２：１）に付し精製した。溶出液を減圧下濃縮し、その残渣を酢酸エチルとエタノールの混合物で再結晶化して淡黄色の粉末結晶（７ｉ）（０．３６ｇ、収率４３％），ｍｐ２３０℃（分解）を得た。 (5′-deaza-17β-hydroxy-3 ′, 8′-dimethylandrost-2,4-dieno [2,3- g ] pteridine-2 ′, 4 ′ (3′H, 8′H) -dione (Synthesis of 7i, R ¹ = R ² = Me)
To diphenyl ether (0.5 ml), 3-methyl-6-methylaminouracil (4i) (0.3 g, 1.93 mmol) and 2-hydroxymethylene testosterone (6) (0.61 g, 1.93 mmol) After adding p-toluenesulfonic acid (36.8 mg, 0.19 mmol) to this mixture, the mixture was stirred with heating at 200 ° C. under an argon atmosphere for 15 minutes. After completion of the reaction, the reaction product was purified by column chromatography (Fuji Silysia 200-400 mesh; eluent, ethyl acetate: ethanol = 12: 1). The eluate was concentrated under reduced pressure, and the residue was recrystallized with a mixture of ethyl acetate and ethanol to obtain pale yellow powder crystals (7i) (0.36 g, yield 43%), mp 230 ° C. (decomposition). It was.

¹H-NMR (200 MHz, CDCl₃) d: 0.81 (3H, s, 13-CH₃), 1.00 (3H, s, 10-CH₃), 2.49-2.60 (2H, br dd, 6-H), 2.66 (1H, d, J = 15.4 Hz, 1β-H), 2.92 (1H, d, J = 15.4 Hz, 1α-H), 3.45 (3H, s, 3'-CH₃), 3.69 (1H, dd, J_16α,17α= 8.4 Hz, J_16β,17α= 8.2 Hz, 17α-H), 4.04 (3H, s, 8'-CH₃), 6.42 (1H, s, 4-H), 8.26 (1H, s, 5'-H)。 ¹ H-NMR (200 MHz, CDCl ₃ ) d: 0.81 (3H, s, 13-CH ₃ ), 1.00 (3H, s, 10-CH ₃ ), 2.49-2.60 (2H, br dd, 6-H) , 2.66 (1H, d, J = 15.4 Hz, 1β-H), 2.92 (1H, d, J = 15.4 Hz, 1α-H), 3.45 (3H, s, 3'-CH ₃ ), 3.69 (1H, dd, J _{16α, 17α} = 8.4 Hz, J _{16β, 17α} = 8.2 Hz, 17α-H), 4.04 (3H, s, 8'-CH ₃ ), 6.42 (1H, s, 4-H), 8.26 (1H , s, 5'-H).

図１は、本発明の化合物（３）の製造方法を示す図である。FIG. 1 is a diagram showing a process for producing the compound (3) of the present invention. 図２は、本発明の化合物（５）の製造方法を示す図である。FIG. 2 is a diagram showing a process for producing the compound (5) of the present invention. 図３は、本発明の化合物（７）の製造方法を示す図である。FIG. 3 is a diagram showing a process for producing the compound (7) of the present invention.

Claims

formula

(Wherein, R represents a linear, branched or cyclic lower alkyl group having 1 to 8 carbon atoms or a substituted or unsubstituted phenyl group) 5′-deaza-17β-hydroxy 2'-phenyl -5α- androst-2-eno [2,3-g] pteridine -4 '(8' H) --ones.

The substituted phenyl group includes alkyl-substituted phenyl group, alkoxy-substituted phenyl group, halogen-substituted phenyl group, 4-aminophenyl group, 4-hydroxyphenyl group, 4-nitrophenyl group, 3,4-methylenedioxyphenyl group, and 4 5'-deaza-17β-hydroxy-2'-phenyl-5α-androst-2-eno [2,3- g according to claim 1, characterized in that it is selected from the group consisting of -carboxyphenyl groups. ] pteridine -4 '(8' H) --ones.

The alkyl-substituted phenyl group is an alkyl-substituted phenyl group typified by 4-methylphenyl (tolyl), and the alkoxy-substituted phenyl group is an alkoxy having 1 to 5 carbon alkoxy typified by 4-methoxyphenyl. The 5'-deaza-17β- of claim 2, wherein the halogen-substituted phenyl group is selected from the group consisting of 2-chlorophenyl, 4-bromophenyl and 4-fluorophenyl. Hydroxy-2′-phenyl-5α-androst-2-eno [2,3- g ] pteridin-4 ′ (8 ′ H ) -ones.

formula

(Wherein R ¹ represents hydrogen or a linear, branched or cyclic lower alkyl group having 1 to 8 carbon atoms, and R ² represents a linear, branched or cyclic group having 1 to 8 carbon atoms. 5′-deaza-17β-hydroxy-5α-androst-2-eno [2,3- g ] pteridine-2 ′, 4 represented by a lower alkyl group or a substituted or unsubstituted phenyl group. '(3' H , 8 ' H ) -diones.

The substituted phenyl group includes alkyl-substituted phenyl group, alkoxy-substituted phenyl group, halogen-substituted phenyl group, 4-aminophenyl group, 4-hydroxyphenyl group, 4-nitrophenyl group, 3,4-methylenedioxyphenyl group, and 4 5'-deaza-17β-hydroxy-5α-androst-2-eno [2,3- g ] pteridine-2 'according to claim 4, characterized in that it is selected from the group consisting of -carboxyphenyl groups , 4 ′ (3 ′ H , 8 ′ H ) -diones.

The alkyl-substituted phenyl group is an alkyl-substituted phenyl group typified by 4-methylphenyl (tolyl), and the alkoxy-substituted phenyl group is an alkoxy having 1 to 5 carbon alkoxy typified by 4-methoxyphenyl. The 5'-deaza-17β- of claim 5, wherein the 5'-deaza-17β- is a substituent, wherein the halogen-substituted phenyl group is selected from the group consisting of 2-chlorophenyl, 4-bromophenyl and 4-fluorophenyl. Hydroxy-5α-androst-2-eno [2,3- g ] pteridine-2 ′, 4 ′ (3 ′ H , 8 ′ H ) -diones.

formula

(Wherein R ¹ represents hydrogen or a linear, branched or cyclic lower alkyl group having 1 to 8 carbon atoms, and R ² represents a linear, branched or cyclic group having 1 to 8 carbon atoms. 5′-deaza-17β-hydroxyandrost-2,4-dieno [2,3- g ] pteridine-2 ′, 4 ′ represented by a lower alkyl group or a substituted or unsubstituted phenyl group. (3 ′ H , 8 ′ H ) -diones.

The substituted phenyl group includes alkyl-substituted phenyl group, alkoxy-substituted phenyl group, halogen-substituted phenyl group, 4-aminophenyl group, 4-hydroxyphenyl group, 4-nitrophenyl group, 3,4-methylenedioxyphenyl group, and 4 The 5'-deaza-17β-hydroxyandrost-2,4-dieno [2,3- g ] pteridine-2 ', according to claim 7, characterized in that it is selected from the group consisting of -carboxyphenyl groups. 4 '(3' H, 8 'H) - diones.

The alkyl-substituted phenyl group is an alkyl-substituted phenyl group typified by 4-methylphenyl (tolyl), and the alkoxy-substituted phenyl group is an alkoxy having 1 to 5 carbon alkoxy typified by 4-methoxyphenyl. The 5′-deaza-17β- of claim 8, wherein the halogen-substituted phenyl group is selected from the group consisting of 2-chlorophenyl, 4-bromophenyl and 4-fluorophenyl. Hydroxyandrost-2,4-dieno [2,3- g ] pteridine-2 ′, 4 ′ (3 ′ H , 8 ′ H ) -diones.

formula

(Wherein R represents a linear, branched or cyclic lower alkyl group having 1 to 8 carbon atoms or a substituted or unsubstituted phenyl group) and a formula

After reacting 2-hydroxymethyleneandrostanolone represented by

(Wherein R represents a linear, branched or cyclic lower alkyl group having 1 to 8 carbon atoms or a substituted or unsubstituted phenyl group). A method for producing 5′-deaza-17β-hydroxy-2′-phenyl-5α-androst-2-eno [2,3- g ] pteridin-4 ′ (8 ′ H ) -ones.

formula

After reacting 2-hydroxymethyleneandrostanolone represented by

(Wherein R ¹ represents hydrogen or a linear, branched or cyclic lower alkyl group having 1 to 8 carbon atoms, and R ² represents a linear, branched or cyclic group having 1 to 8 carbon atoms. 5'-deaza-17β-hydroxy-5α-androst-2-eno [2,3-, which is obtained by obtaining a compound represented by: a lower alkyl group or a substituted or unsubstituted phenyl group. g ] A method for producing pteridine-2 ′, 4 ′ (3 ′ H , 8 ′ H ) -diones.

formula

After reacting 2-hydroxymethylene testosterone represented by

(Wherein R ¹ represents hydrogen or a linear, branched or cyclic lower alkyl group having 1 to 8 carbon atoms, and R ² represents a linear, branched or cyclic group having 1 to 8 carbon atoms. 5′-deaza-17β-hydroxyandrost-2,4-dieno [2,3- g] , characterized in that a compound represented by the following formula is obtained: a lower alkyl group or a substituted or unsubstituted phenyl group. ] A method for producing pteridine-2 ′, 4 ′ (3 ′ H , 8 ′ H ) -diones.