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Synthesis of Potential Biodynamic Drugs

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Synthesis of Potential Biodynamic Drugs SYNTHESIS OF POTENTIAL BIODYNAMIC DRUGS (SUMMARY) A THESIS SUBMITTED FOR THE DEGREE OF Doctor of PhjIosophM IN Chenalstrq TO THE ALIGARH MUSLIM UNIVERSITY, ALIGARH BY AKHIL Q. JHINQRAN DIVISION OF MEDICINAL CHEMISTRY CENTRAL DRUG RESEARCH INSTITUTE LUCKNOW - 226001 JUNE, 1983 SUMMARY The work embodied in the thesLs is concerned with the synthesis of some potential post-ooital antifertiliiy agents, spermicides and antidepressants. This work is described in four chapters. In the first chapter the present status of seco-steroids is re-viewed as this topic has not so far been properly reviewed. The second chapter describes the synthesis of some 5»6-seco-estradiols and their antiimplantation activities. In the third chapter the synthesis and bio- evaluation of N-substituted a-(2-aminoeth5'-l)acrylophenones and 3-amino-2-substituted met]iyleneindan-l-ones as possible spermicides has been described. The fourth chapter consists of the synthesis and pharmacological evaluation of some iminothiazolidine derivatives as potential antidepressants. CMj£tGr__I The sex steroid hormones, estrogens, progestogens and androgens play an important role in the regulation of mammalian reproductive system. Compounds which could interfere with the action of ihese hormones could in principal block conception. One approach to 1iie design of such agents is to build analogues of these hormones, yjtilch. lack one of the bonds in different rings of the tetracyclic stiucture of the steroid (seco-steroid); puch compounds having greater flexibility would thus be able to assume a larger number of discreet conformations, only one of which, would mimic the prototype and would Uius have altered affinity for "the receptors involved and hopefully a changed biological activity profile. In this approach a number of 5»6-seco-steroids have been synthesized and "their contracoptLve activity studies are described in Chapter II. _Gha£;fcer_n Syniai_esis of 5,,6-sec(>-estradiols 1~"^ In earlier work -^ carried out in tliis laboi'atory 2a, 63~diethyl"3g"(P"hydrcxyphenyl)"trans<"bi<yclo[ 4« 3» 0] nonan- 7p-ol (1) was found to inhibit implantation in rats at 2 mg/ kg when administered orally. The RBA for iiiis molecjile (l) was 23.85^ as compared to estradiol* In this chapter wts have described the ^nthesis of other tvro isomers of 1 vi z. 2a, 6p~diethyl-3a-(_p-hydro3:yphenyl)-trans-bicyclo[ 4» 3* 0] nonaii-7p-ol (_11 .cig-a^^ti-jteiaSlS) ^^'^ 2p» 6p~diethyl-3p(p- hydroxypheny 1 )-tran3-biqyclo[ 4« 3• 0]nonan-713-ol (I2, cis­ sy n>-trans) (Scheme 1). With ihe hope of increasing the oral absorption and consequently the activity 'uhe synthesis of Ta-ethynyl derivatives of IJL, and 1 lias also been carried out« Synthesis of the corresponding p-methoxyphenyl derivatives of 11 and _12 (i.e. 16 and 18, respeotively) has also been carried out. Synthesis of 17a-ethynyl-13p~ethyl-5, 6-seco-estradiols Hie ketoenol 6 was prepared "by the condensation of 2-ethylcyclopentane~l,3-cLione(.2) with propyl vinyl ketone (2), As a refinement over the method of Grupta et al. this condensation was carr5-ed out by simply stirring the two reactants in demineralized water f otr 5 days under nitrogen atmosphere, unlike the earlier method where the tt-ro were re fluxed in methanol in the presence of an alkali. Cyclization of the triketonc (4) thus obtained with _£-toluene sulfonic acid gave 2,6p-diethylbicyGlo[ 4» ^•OJi'ion-l- en-^, 7-dione (^). Reduction of 7-keto group of _5 with sodium borohydride in a mixture of isopropanol and ethanol afforded _6. Treatment of _6 with j>-methoxyphenyllithium in ether-THF at -40° furnished 2, 6p-.dLethyl-3-hydroxy-3-{^ me thcKy phenyl )bi cyclo[ 4» 3« 0] non-l-en-7p-ol (J), which without isolation was converted to the dienol 8 by the addition of one drop of HCl. Catalytic hydrogenation of 8 in ethanol over lOfo pd-C at R05?, till 2 mol of hydrogen was absorbed furnished a mixture of two isomers (_9 and 10). These two isomers were obtained in pure form in a ratio of r^ 0 0 a ^ O^Gf^ ^ 0 d^^ -> 7 8 Gontd... OH C)J~ H H 4 \ \\^ H. H H 5 CH„0 5 10 g V N^ H0-^"^^ ^ 11 12 h \K ,o CsOH 14 Contd.. • 6 vvC=CH 9 > r<^^ 15 vvCsCH 10 - 17 13 a, De mine rail zed water/Ngf b, PTSAi c, NaBH.} d, p-BrCgH^OGH /n-BuLi| e, HClj f, IC^ Pd-C/H2» 2 molj g, KOH, diethylene gLyoolj li, Jones reagentj i, LiG=OH/ethylene diamine Scheme 1 40:60 by fractional crystallization from a mixture of ether and hexane. In the nmr spectrum the major isomer showed a highly shielded OH^ resonance (0.I5 6)» This isomer 10 was assigned cis-syn-trans stereochemistry on the basis of earlier vjork . The reason for this was -tiiat due to sterio interaction between S-CHpCH, and 2-CH2CH„ group the latter would be held in a plane away from the former. As a result of this steric compression the ring may undergo some c on for ma Honal chaiage which would bring 2-.ethyl chain T-dthin the shielding cone of the phenyl group. Formation of 1£| in major amount could be due to less steric hindrance for the a-face attach of hydrogen during reduction. Demethylation of 3 and 10 separately with potassium hydroxide in dieth^ylene glycol/hydrazine hydrate under nitrogen aljnosphere gave the corresponding phenols viz- 2a, 6p- and 2p, Sp-diethyl-3a/|3- (_2-Jwdroxyphenyl}-^trans-•bicyclo[ 4» 3* 0]nonan--7p-ol (12 and 12)- To synthesize the correBpondj.ng 7a-ethynyl derivative (C-I7 of estradiol molecule), 3 \TQ,B oxidised to the 7-keto analogue (ij) by Jones reagent and subsequently ethynylated with lithium ace tylidej ethylene diamine under an atmosphere of acetylene by the method of Hlraga . Similar oxidation and ethyr^lation reaction of 3 and 1_0 afforded the corresponding 7a:-ethynyl-3p-(jg-.methoxyphenyl) derivatives 16 and 18. 8 ¥ith a view to increase liie oral absorptivity of 1, the synthesis of ihe corresponding 7a-ethynyl compound ^ was carried out according to Scheme 2. Controlled catalytLo hydrogenation of 8 in ethanol over lOfo pd-0 at B.TP till 1 mol of hydrogen was absorbed gave 1^, which on Birch reduction gave 2a, 6p-diethyl-3j3-(p-methoxyphenyl)-ti3ns--bicyclo[4»3»0] nonan-7p-ol (20), Jones oxidation of 2j) and subsequent ethynylation furnished the corresponding 7a-ethynyl compound 22 (Scheme 2)» Demethylation of 2jD, Jones oxidation and subsequent ethynylation of the product thus obtained (2j) produced the desired compound _2J.. Synthesis of 2a,6p-dietliyl-7a-ethynyl-3p-(cyclohex-2-.en-4- one )-toaiis-.bicyclo[ 4« 3» 0] nonan-7p'-ol Reduction of the aromatic ring in _2^ was carried out with lithium in liquid ammonia in the presence of a protic solvent such as ethanol to give ^ (Scheme 5). Oxidation of 2 3 could not be carried out with Jones reagent as this 5 results in the rearomatization of ring A • Opponauer oxidation of 23 gave the 7-keto analogue 2_6. Ethyaylation of _26 and treatment of the product 27 thus obtained gave 28, the desired 5>6-seco analogue of norgestrol. 9 OH a, l.(3fo Pd-G/Hg, 1 moll b, K-NH„j o, Jones reagentj d, Li^C=CH/ethylene diaminei e, KOH, d3.ethy3.ene gl^odl. Scheme 2 10 OH N a 20 > H H H GH„0' 5 25 26 .svCaOH (5^^^"^^ 28 27 a, Li-NH /G2H^0H| b, Al [t-BuO]^ /benzenoj c, LiCsOH/ethyIcnediaminei d, HGl/methanol Scheme 5 11 Synthesis of 2, 6p-diethyl-5-(2-«ie-thyl-4-.hydrc)ix:yphQnyl) bicyclo[ 4r 3» 0] non-l-en-7p-ol Condensation of ^ with 2-methyl-4—methoxyphenyllithii^m gave 2, 6p-diethyl-3-hydroxy-3-.(2-.methyl-4-meihoxj'-phenyl) lDicyclo[4-i-5«0]non-.l-en~.7p-ol (29). Unlike 7 this hydroxy intermediate (_29) was quite stable and ihe dehydrati-:jn could he carried out only after refLuxing 2J in benzene with _£--toluenesulfonic acid. Catalytic reduction ^ in ethanol over lOfo Pd-C at R!CP till 1 mol of Hp was absorbed resulted in the formation of _31» I*urther reduction of 2, 5-double bond was tried with 10^ Pd-C, a mixture of dfo wet and lofs pd-C, Raney-nickel and PtOp at pressures ranging from RIP to 1500 p.s.i., but without success. Steric hindrance could be a reason for the inertness of the double bond towards reduction. The migration of this double bond to 5,4-positLon was then attempted but this also could not be carried out successfully. iEriethylsilane in GP„GOOH, a hydiride donor could also not reduce ttiis productj the reaction with this reagent went only to the intermediate stage J4» Forcing conditions for the forward reaction gave back Jl, the starting material. 12 29 12 ^ ii y Reduction M/ a, 2-Methyl-4-tromoanisolG/n-BuIij b, pTSAj c, 1C^» Pd-G/H2» 1 inol» d, Jones reagenti e, KOH, diethylene glycol. Schemo_ 4 13 OH P„COOO H H aH,o 0 14 Jones oxidation of yL gave the 7-keto analogue J^ whereas demethylation of ^1 led to the oori<5sponding hydroxyphenyl compound y^ (Scheme 4). £ha£ter_III One of the oldest and simplest method for fertility regulation is the use of spermicides for vagina. Though the failure rates encountered with these agents are as high as five percent, they find their use mainly out of the disadvantages which users find or fear with other methods.
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