 Method of producing (4,2,0)-bicycloctane derivatives of their pharmaceutically acceptable non-toxic
专利摘要:
Compounds useful in treating cardiovascular disorders such as thrombosis, hypertension, and atherosclerosis are compounds depicted in formulas (1), (2), and (3): <IMAGE> (1) <IMAGE> (2) <IMAGE> (3) wherein: n is 2 or 3; R1 is CH2OH, CHO, CO2R or CO2H; R2 is hydrogen or methyl; and R3 is linear or branched alkyl having 5-10 carbon atoms, <IMAGE> +TR or (CH2)mphenyl optionally substituted with lower alkyl, lower alkoxy, trifluoromethyl, or halogen, in which a is 0, 1 or 2; b is 3-7; m is 1 or 2; and R is <IMAGE> +TR <IMAGE> in which each R4 is independently hydrogen or lower alkyl having 1-6 carbon atoms, and the pharmaceutically acceptable, non-toxic salts and esters thereof. 公开号:SU1588275A3 申请号:SU874202298 申请日:1987-04-08 公开日:1990-08-23 发明作者:Ф. Клюге Артур；Л. Виллис Энтони；Оъянг Каунд 申请人:Синтекс /Ю.С.А./ Инк. (Фирма)； IPC主号:
专利说明:
The invention relates to biologically active compounds, in particular to a method for producing (4,2,0) -b. cyclo-octane derivatives of general formulas RLiCliib H ( (V) - / OH Y OH R-; Pi lCHiln H 4 OH which are useful for treating cardiovascular diseases, in particular, have the inhibitory activity of T1 aggregation of bocytes and antihypertensive activity. The aim of the invention is to develop a process for the preparation of most compounds with a higher biological activity as compared with lime analogues. Example 1 Preparation of (ZJ-, (3S, 1S, 2S, 3R, 6S) -A- 2- (3-hydroxy-3-cyclohexylpropyl-1-vinyl) -3-oxybn-cyclo (4.2.2) -oct -7-lilenJ-butanoic acid and (E) - (W S, 1S, 2S, 3R, 6S) -4- 2- (3 -oxy-3 -cyclohexylpropan-1-ynyl) -3-oxybidiclo (4.2 , 0) -OCT-7-IL-ideas} -butanoic acid and related compounds of the formulas (T), (I) and (III), where R -. A. Prepare a solution of sodium dimsyl for storage by dissolving 1, 56 g of sodium hydride in 65 ml of dimethyl sulfoxide at 65 ° C under a nitrogen atmosphere. To a stirring paste, 2.06 g of 3-carboxypropyltriphenylphosphonium bromide and 10 ml of dimethyl sulphoxide, under nitrogen atmosphere, were added 9.4 ml of the stored dimsil sodium solution. After 20 mi 0 20 25 . 35 40 5 50 at 23 (llI lI lHyuT OjMiy Pp, CI iiriC thief 260mg SG S, 1R, 2S, 3R, 6S) 2- (3 - hydroxy-3 -pickle m-eksilpr: (, 2, 0) -11Ktan-7- (Ch {a n 1 M: I dimethyl: 1y |) (1x il. Li (-ic: i.e 4 hours n;) ii 23 C mixture Bf.ijniFjawTn 15 ml 5 -ni4 o pacTFJOpa carbonate; sodium Jry the mixture is washed with jiFrvMH g in 30 ml each of these. Exhaust gas: Elder extract extracts up to 20 ml and is stored cool;) T;) K at. -20 ° C for 2 hours. Filtering the precipitate formed and screening 1 st. Filtration gives 430 mg of oil. This material is somnated by flush chromatography on a split gel using a mixture of acetic acid, acid and hexane (0.25: 75: 25). Receive 337 mg of oil. Further purification of organic gel on silica gel using a mixture of acetic acid, methanol and dichloromethane (0.2: 5: 3: 94.5), once a mixture of products of indium; 1, The compounds of formulas (II) and (1) are respectively. The first is .. yuirovana (F.) - (3 S, 1 S, 2S, 3R, 6S) (3 -oxy-3 -dysk-eksyl-prop-1 -gill) -3-oxybicyclo (4,2,0 ) - oct-7-ylide1: J-butanoic acid, 138 mg. “U + MZ 1C 0.5, CHC1 h). Calculated,%: C 72.80, II 8.73. Found,%: C 72.58, H 8.44. The second is eluted by (Z) - (3S, 1S, 2S, 3R, 6S) -4- 2- (3 -oxy-3-cyclohexen: -prop-1-inside) -3-oxybidicdo (4.2.2) - oct-7-ilidea} -butano1: -; and acid 138 mg. , o / v + SW C (C 0 ,, SPSTZ). Calculated,%: C, 72.80, and 8.75. Found,%: C 73.00, H 8.51. B. Similarly, replacing (3 S, 1R, S, 3R, 6s) -2- (3-hydroxy-3 -cyclohexylprop-1-vinyl) -3-oxybihydro (4,2,0) -oct - 7- ( 1H friend1-: m | - approach of 1meth compounds obtained as oinicano P with: -outining A, the compounds of formulas (1) -and (1.1) are guluid and separated. (Z) - (3 S, 1S, 2S, 3R, 6S) (3 -Ox-oct-l-icid) -3-oxybidico (4.2, () - T-7-Hj + 114 (+ NHp. oct-7-ylide1} butaic acid. oQ +114 С (CHCli); MS m / 7, 352 (M + Calculated,%: C 71, 82-, H 9.04. Found,%: C 71, 94, H 8.97. (E) - (3 s, IS, 2S, 3R, 6S) (sooct-1 -nnyl) -3-oxybidaclo (4,2,0) - oct-7-ylidene J-butanoic acid g / 7, 2 ( CHCl); MS m / z 352 (M + 158 + NH four Calculated,%: from 71.80, - H 9.04. Found,%: with 71, 81, {8.83. C .. Similarly, typical compounds of the formulas (I) and (I) are obtained. (Z) - (3 s, 1S, 2S, 3R, 6S) -4-C2 - (3 -OK-seden-1-vinyl) -3-hydroxybicyclo (4.2.2) - oct-7-ylidene butane acid. (Z) - (3 s, lS, 2s, 3R, 6S) (3 -OK-Citride-1-vinyl) -3-hydroxycyclo (4,2,0) -Oct-7-ylidene-pentanoic acid. (Z) - (3 s, 5R, 1S, 2S, 3R, 6s) -4-r2- (3-Oxinon-1-vinyl) -3-hydroxybicyclo (4, 2, 0) oct-7-ylidene J -butanoic acid (Z) - (3 S, 1S, 2S, ЗR, 6S) (3-Oak-sioct-1 -inyl) -3-hydroxybitslo (4,2,0) - oct-7-ylidene pentanoic acid (Z) -a S, 1S, 2s, 3R, 6s) -4-C2- (3 -OK-sooct -G-orl) -3-hydroxybicyclo (4.2.2) - oct-7-ylideneJ-butane acid (Z) - (,) U -Oxyde-i -inyl) -3-hydroxybicyclo (, 2.0) -Oct-7-ylidene-butanoic acid. , (z) - () - 5-c2- (3 -Oxitride-1-vinyl) -3-hydroxybicylo (4, 2, 0) -oct-7-ylidene J-pentanoic acid. Z) - (, 2S, 3R, 6S) (3 -Oxy-5-methylnon-1-ynyl) -3-hydroxybic (A, 2.0) -oct-7-ylidene butanoic acid. - ± J: r ,, 6s) -4-C2 (o-41 i -, JL, -Oxinon-1 -inyl-3-hydroxybicyclo (4,2,0) -Oct-7-ylidene-J-butane acid. , (Z) - (3 S,) 3 -Oxyhexylprop-1-vinyl) -3-hydroxy-cyclo (4,2,0) -oct-7-ylidene-J-butane acid. MS m / z 364 (M + NH. Calculated,%: C 72.80 - H 8.73. Found,%: C 72, 52; K 8, 72. (Z) - (3, 2S,) 3 -Oxyoct-1 -inyl) -3-oxibicyclo 4,2,0) -oct-7-ylidene pentane acid. (Z) - (3 S, 15.2S, 3R, 65) (3 -OK-and-4-phenyl-but-1-vinyl) -3-hydroxybic-o (4 S2.0) -oct-7-ylidene-J- Butane Islota. (Z) - (3 S, 1S, 25.3R, 65) (3 -OK- and-5 -fe nilpent-1-vinyl) -3-oxybitslk40 45 50 55 1588275 - to 15 20 Lo (4,2, 0) -Oct-7-ylidene-7-butane acid. (Z) - (3 s, 1S, 2S, 3R, 6s) -5-r2- (3 -OK-si-3-methyl-4-phenylbut-1-vinyl) -3-oxybicyclo (4.2.2 ) octt-7-yl1-pentanoic acid. (Z) - (3 s, 1S, 2S, 3R, 6S) -5-C2- (3 -OK-si-4-m-trifluoromethylphenyl-but-1-vinyl) -3-oxybicyclo (4,2,0) - oct-7-ylidene-7-pentanoic acid. (Z) -. (3 SMS 2S, 3R, 6S -4-r2- (3-Oxyphenyl-1-vinyl) -3-hydroxybicylo (4,2,0) -oct-7-ylidene-J-butanoic acid. (Z) - (3 S, 1S, 2s,) - 4-C2- (3-Oxy-5-phenylpent-1-vinyl) -3-ok sibigslo (, 2.0) -oct-7-ylidene} - butanoic acid. (Z) - (3 SMs 2S,) - 5-r2- (3 -Oxy-3 methyl-4-phenyl-1-vinyl) 25 -I. . . .. l J J1P IltlJ i 3-oxbicyclo (4,2,0) -oct-7-ylidene-psntanoic acid. (z) - (z s ls 2s rR 6sm-5-2 (3-Oxy-4-m-trfluoromethylphenylbut-1 -inyl) -3-oxybicyclo (4,2,0) -oct. 7-ylidy-pentanoR kispot CZ) - (3 s, 1S, 2S, 3R, 6S) -4-r2-r3-Oxy-4 -znlobitsiklo (3,1,0) -hex-6-sh1-30 but-innl-3 -oxibicyclo (4,2,0) - oct-7-ylidene -butane cyst (Z) - (3-5,15,25, 3R, 6S) -5-f2- 3 -Okyl-4-endobic (3,1,0) -hex-6-yl-but-1-inn -3-hydroxybicyclo (4,2,0) - 35 oct-7-ylidene-j-pentanoic acid. (Z) - (35,15,25,3R, 65) -4- 2-p -OK-- - ci-4-exobicyclo (3,1,0) -hex-6-yl-but-1-vinyl -3-oxobicyclo (4,2,0) - oct-7-ylidene-butanoic acid. - (3 S. 1 I s; 1T, 40 45 50 five (Z) - (35,15,25,3R, 6S) -4-C2- (3-Oxy-3-methyl-3-cyclobutyl-prop-1 -. Ynyl) -3-oxybicyclo (4, 2, 0 oct-7-ylidene} -butanoic acid. (Z) - (35.1S, 25.3R, 65) -4-C2- (3 -OK-si-3-methyl-3-cyclopentyl-prop-l-ynyl) -3-oxybicyclo (D, 2, 0) oct-7-ylidene-butane acid. . (Z) - (35, l5,25,3R, 65) -5-C2- (3 -OK-si-3-cyclopentyl-prop-1-vinyl) -3-oxy-bicyclo (4,2,0) -oct -7-ylidene-j-pentanoic acid. (Z) - (35.1 S, 25.3R, 65) -4-C2- (3 -OK-si-3 -cyclopentyl-prop-1-vinyl) -3-oxybicyclo (4,2,0) -oct -7-ylidene-butanoic acid. (Z) - (35,15,25,3R, 65) (3 -OK-si-4-cyclopentylbut-1-in1m) -3-oxy-bicyclo (4,2,0) -oct-7-ylidene butano - wa acid. (Z) - (3S, 1S, 2S, 3R, 6S) --5-2- (3 -OK- and-3 -cyclohexylrop-y-nyl) -3-oxycyclics (4.2.0) -Oct-7-ilnden -foam - aic acid. (o () G 1 C (CHCl) S-m / z 378 (M + N11 +). Calculated,%: from 73.30, II 8.86. Found%: C 72.43, H 8 86 (Z) - (3 S, 13,25,3R, 6S) (3 -OKi-4 -cyclohexyl-but-1-aiyl) -3-oxy, Q cycle and (4 , 2,0) -ooct-7-ylidene-j-butane-a acid .g - (r (Z) - (3S, 1S, 2S, 3R, 6S) -4-2-Cj -OKsi-4 -cyclohexylbut- 1 -iyl) -3-hydroxy bicyclo (4,2,0) -oct-7-ylidene butio-, 5 your acid. (Z) - (3 S, 1S, 2S, 3R, 6S) (3 -Pxy-4-cyclohexyl-but-1 -iyl) - hydroxy-bicyclo (4.2.2) -oct-7-ylidene: gpenta nova acid . (Z) - (3 S ,, 2S,) -iV-GZ-Oxy-4-endobicyclo (3.1, 0) -hex 6-ylbut - 1 -iyl-3 oxybicy-o (4.2, 0 a) oct-7-ylidene 1-butanopic acid. (Z) - (3 s, (2- 25 3 -Oxy-4-endobicyclo (3.1,1) hex 6-ylbut-1 -iyl-3-hydroxycyclo (4.2, 0) -oct-7- ylidenj-ntntagovy acid. (Z) - (3 s 1SS2S, 3RS6S) -4-i2-3 -Oxy-t-exobye upsl (3.1 (0) 30 -c, .6 „„ lbut-1 -inylC-3-hydroxybisce qlc (4,2,0) -oct-7-ylidene -butanoic acid .J-, (Z) - (3 s, 1S, 2S, 6S ) (3 Pxy-3-methyl-3-cyclobugid-prop-1 - 35 ynyl) -3-hydroxybitslo (4, 2, Q) -oct-7-ylidene 7-butaic acid, (Z) - (3 PL, 1S, 2S, 3R, -6SA) -4- 2- (3 -Oxy-3 -methyl-3 -suploopente. -Iyl) 3-oxibi1 1clo (4.2.2) - (mt 40 7-org1, e} 13-butanoic acid. (Z) - (3S, 1S, 2S, 3R, 6S) (3-Oxy-3 -cyclopene-ylprop-1 -i-O-3-hydroxycyclo (4,2,0) -oct-7-yl, en I - pentaic acid, 15 (Z) - (3 s-1S -,) - A-L2- (3-Oxy-3-cyclopentyl-I-iiyl) -3-hydroxybitslo (4,2,0) -oct-7-yle-m. butane acid (Z) - (3 S) -4-L2-50 (3-Oxy-4-cyclopentylbut-G-vinyl) 3-hydroxybicyclo (4,2,0) -oct-7-ylidene butane acid (Z) - (, 2S,) - 5-C2 (3 -Oxy-3-cyclohexyl-pro-1-vinyl) 3-scSibicyclo (4,2,0) -oct-7-ylidsn - pentanoic acid. MS m / z 378 (AND | Calculated,%: C 73.30. Found,%: C 73.37; And 9.00. five 0 (Z) - (3 S tS ,, 3R, 6S) -4-G2- (3 -Oxy-4 -cyclohexyl but-1 -and -l-l) - 3-oxybicyclo (4.2, 0) -oct -7-i.ly,; en T-butane acid. (Z) - (3 S, 2S,) - 5-G2- (3 -Oxy-4 -C11-clohexyl-but-1-isyl) -3-ox and bicyclo (4.2, 0) -oct-7-iJIldeiJ - Pentane acid. (E) - (3S, 1S, 2S, 3R, 6S) -4-C2- (3 -Oxide of U-1-vinyl) -3-hydroxybicylo (4,2,0) - o to k-7-yl and de and Jbhtala (E) - (3 S, 1S, 2S, 3R, 6S) - (3 -Oxytride-1 -i; chyl) -3-hydroxybiclo v, 2, oct-7-ylidene 1-11 eiteic acids: .- . (E) - (3 S, 5 S, 1S, 2S, 3R, 6S) (3-Oxy-5-methyl} - 1-inide) -3-hydroxybicyclo (4,2,0) -oct-7-ylidene J-Sutanova acid. (E) - (3S, 1S, 2S, 3R, 6S) -4-p- (3 -Oxinos-1) -3-hydroxycyclic 4 ,, 2.0) - oct-7-ylide 1-butane kiglot ,, (E) - (3 s, fs, 2S, 3R, 6S) (3 -OK-sioct-1-ii.yl) -3-hydroxybitslo (4,2,0) -o kt-7 -i and d e -. - le nt a and o 3 a cis l o t ;;, (E) - (3 s, 1S, 2S, 3R, 6S) -4-r2 - (3 -OK-sioct-G-inid) -3-hydroxybicyclo (4,2,0) - ciKT-7-idid - Utanovy acid. (E) - (S S, 1S ,, 6S) (W-Oxydec-1 -inide) -3-oxibicyclo (4, 2, 0) -oct-7-ididene-butane kis / utah, (E) - (3S JS, 2S, ЗR, 6S) -5- (3 -Ok citratece-1-vinyl) -3-hydroxybicylo (4,2, 0) -oct-7-idideic-pectacic acid. (E) - (,) - 4- f2- (3-Oxy-5-methyl-non-vinyl) -3-hydroxybicyclo (4,2,0) -oct-7-ylden-by Tsuiva acid. (E) - (3 S; 1S, 2S,) (3 -Oxine-1-vinyl) -3-oxybyl; 1 (4,. 0) -oct-7-ylidene-1-butanoic acid, (E) - (3 s, 1S, 2S, 3R, 6S) -5 - &; (3 Oxynen-1-inide) -3-hydroxybicylo (4, 2, 0) -oct-7-hygen - Ientanoic acid (j7) (3S, IS, 2S, 3R, 6S) -4- 2- 3-Oxy-4-f.mshlbut-V-vinyl) -3-oxyb1 cyclo (4.2.2) -oct -7-ididen -butanova acid (1ta. (E) - (3 s, 1S ,, 2S, 3R, 6S) -4-L2-l3 - K, -phenylene-1-vinyl) -3-hydroxybike to (4,2,0) oct-7-ylidene -butanova acid., (E) - (S, 1S, 2S, 3R, 6s) (3 -P (and-3-methyl-4-phenide-but-1-vinyl) -. 3-oxybicyclo (4,2,0) -oct- 7-ylidene ientanova acid. (E) - (3 S; iS / 2S, 3f, GS) -5-t2- (3 -nK j, 4 -m-trifluoromethylphenyl - but-1 inil) -3-oxibicyclo (4,2,0) -oct-7-nlidene -pentanova to: slots (E) - (3 S,) (-Oxy-4-phenylbut-1 -inyl-3-sci-Oicyclo (4, 2, 0) -oct-7-or-butanoic acid. (E), 1S ,, 6S) U Oxy-5-phenylpent-1 ynyl) -3-hydroxy-bicyclo (4,2, 0) -oct-7-ylidene butaig, - your acid. .U ;-( 3 s,) - 5-C2- (3-Oxy-3-methyl-4-phenyl-1-nyl) -3-hydroxybitslo (4,2,0) -oct-7-ylidene: - pentanoic acid. / E) - (3s ,, 3r 6S) -5-C2- (3 Oxy-4-m-trifluoroM, gilphenylbut-1-ynyl) -3-oxybicyclo (4,2,0) -oct-7-ylidene pentanoic acid (E) - (3 s, 1S, 2s, 3R, 6s,) -Ok-20 si-4 -endobicyclo (3,1,0) -hex-6-ylbut-1-vinyl-3-oxybicyclo ( 4 2 0) - oct-7-ylidene -butanoic acid (E) - (S S, 1S, 2S, 3R, 6S) -5-2-i -OK-si-4-endobicyclo (3, 1, 0) -hex-6-ag, - 25 but-T - inil.-3-hydroxy bicyclo (4 2 0) oct-7-ylidec; -pentanoic acid CE) - (3S, 1S, 2S, 3R, 6S) - 4-f2-t3 - OK-si-4-endobicyclo (3,1,0) -gsc-6-yl-but-1 (-inil -3-oxibicyclo (4 2 0) - ZO oct-7-ylidene -pentakova acid (E) - (3S, 1S, 2S, 3R, 6S) -Oxy-4-exobicyclo (3.1,1) -hex-b-yl-but-1-vinyl-3-oxybicyclo (4.2 , 0) - oct-7-ylidene b-butanoic acid (E) - (3 S, 1S, 2s, 3R, 6s) (3 -OK-si-3-methy-1-3 -cyclobutyl-prop-1-ynyl) 3-oxybicyclo (A, 2.0) -oct-7- iliden} - butanoza acid. (E) - (3 s, 1S, 2S, 3R, 6S) -4-C2- (3 -OK-, 0 si-J-methyl-3 -cyclopentyl-prop-1-ynyl) -3-oxybicyclo (4.2 , 0) -oct-7-ylidene -butanoic acid (E) - (3 s, 1S, 2S, 3R, 6S) (3 -OK- - si-3 -cyclopentyl-prop-1-vinyl) -3-c-,. sibicyclo (4,2,0) -oct-7-ylidene-1-pentoic acid. (E) - (3 s, 1S, 2S, 3R, 6S) (3 -OK- and 3-Cyclooctane-1 -inyl) -3-hydroxycyclo (4,2,0) -oct-7-ylidene - butano-a acid. 5882 15 . 50 (E) - (3 s, 1S, 2s, 3R, 6s) -4-C2- (3 -OK- and-3 cyclopentyl-prop-1-vinyl) -3-oxycyclo (4,2,0) -oct-7 -ylidene -butanoic acid (E) - (3 s, lS, 2s, 3R, 6S) -4- 2- (3-Oki-4-cyclopentylbut-G-vinyl) -3-hydroxy-cyclo (4,2,0) -oct- 7-ylidene-butano-a acid. 55 P 3b and - - -, - ) - - 20 25 - AOR , 0 -, 588275-10 (E) - (3 s, 1S, 2s, 3R, 6S) -5-r2- (3 -OK- si J-1HClClohexylprop-1) -3-oxybicyclo (2.0) -oct-7-yn -3-hydroxy-5 bicyclo (4,2,0) -oct-7-ylidene-pentamic acid. 4-97.4 ° (CHC1) MS m / z 378 (M + NH). (E) - (35,15,25,) (h - Oxy-4-Cyclohexyl-but-1-in. P) -3-hydroxy-0 shiklo (4,2,0) -oct-7-nlidene butanoic acid. (E) - (3 s, 1S, 2S, 3R, 6s) -5-C2- (j-QK-si 4-Cyclohexyl-but-G-ish p) -3-oxy-6-CIC-PO (2.0) - oct-7-ylidene penta15 nova acid, (E) - (3 S ,) - 4-i: 2р, J - J j-IX) L-Oxy-4-endobicyclo (3,1,0) -hex-b-ylbut-G-ynil.-3-hydroxycyclo (4 2 0; oct-7-iliene -butanoic acid / (E) - (3 s ,, si, 2S, 3R, 6S) -5-r2-L3 -Ox 1-4 -e, 1, chobicyclo (3, 1, 0) -hex-6-ylbut-1 / -inyl-3-hydroxybic. on (4 2 0) -oct - /. - or - ilen - pentanoic acid. ,, L 63) -4-G2- - ° -f-exobicyclo (3,1,0) -hex-yl 3-hydroxybicyclo (4 2 and) oct-7-ylidene-butane kiapota. ,, (, 6s) -4-c2 ,, -methyl-3-cyclobutylprop-1-vinyl) -3-hydroxibic acid.: Clo (4,2,0) -oct-7-1: h1; den7-butane kis Tota (E) - (3 SMs 2S, 3R, 6P) -4-r2-, - ° - -3 - etsh: -3 -cyclopentylprots- -t-3-oxmicyclico (4,2,0) -oct-. / nlidene -but; and ogzl acid . ,, (E) - (s s-1s 2s s R 6sL-5-c2- U Scy 3-Cyclopenti. ; prop-1-vinyl) -3-hydroxybicyclo (4,2,0) -oct-7-ylidene pentanoic acid. .., Eb (3 sMs-, 2S, 3R, 6s) -4-C2- .3 Oxy-3 -Cyclopentyl-prop-1 - „Nile) - 3-hydroxycyclo (4, 2, 0) -oct-7-11lidene 7- butanoic acid. (E) - (, 2S, 3R, 6S) -4-C2- (3-Oxy-4-cyclohentylbut-1-vinyl) -3-hydroxybicylo (4,2,0) -oct-7-ylidene 7-butane acid (E) - (3 sMs 2S ЗR 6S -5-C2 П, Of. five - - ,one. , 0, 1h, o ((- - U -Oxy-3 -cyclohexyl-prop-1 -) - 3-hydroxybitslo (., 2, 0) -oct-7-ylideneJ-pentanoic acid. HS m / z 378 (M + Calculated,%: from 73.30, - H 8.95 Found,%: from 73.32, H 8 98 (E) - (3 S,) - 4-C2-U Oxy-3-Cycloxylprop-1-vinyl ) - 3oxybicyclo (4,2,0) -oct-7-ylidene butanoic acid, Calculated,%: C, 72.80; H 8.73. 20 25 111-88275 Found,%: C 73.05; And 8.65. (E) - (, 3R, 6S) -A-C23 -Oxy-4-cycloxy-but-1-H-O-3-xybicyclo (4,2,0) -oct-7-ylide 7 Utanova sour-ota. (E) - {3 s lS 2S ЗR 6S) -5-L2- 3-Oxy-4-cyclohexyl-but-1-and; shl) -oxy-bicyclo (4, 2, 0) -oct-7-ylide (; n acid, 10 D; It is illogical, using the corresponding compounds obtained as written in preparation C, to obtain compounds of formula (III). (Z) - (3 r ,, 1S, 2S, 3R, 6S) (3 -OK-, 5 i-3 -CYCLOhexyl-prop-1-vinyl) -3-ox-bipiplo (4, 2, 0) -oct-7-ylidene butapov acid. W) i -107 (СНС1з) - Calculated,%: С, 72.80, Н 8,; 3. Found%: C, 72.96,: H, 8.82 (Z) - (3S, 1R, 2R, 3S, 6RV-5-C2- .3 -OKsi-3 -cyclohexyl-prop-1 -inyl) - 3 - SI6ICIC.LO C4,2,0) -oct-7-ipiden-pentaic acid. (CHCU), KS m / z, 378 (M + NNL. (.5- (3 S, 1R, 2R, 3S, 6R) -4-C2- (3 -OK-oct-1-vinyl) -3-oxybicyclo (4,2,01-oct-7-ylidene-butane acid. E. Similarly, the compounds of 30 are obtained. Formula (III) .J.I (Z) - (3 S, 1S, 2S, 3R, 6S) (3-oxide-1-vinyl) -3-hydroxybicyclo (4.2.0; oct-7-ylidene-butyo Yuva sour. (Z) - (, 1S, 2S, 3R, 6S) -5-L2 - (-Ok- sitride-1-vinyl) -3-hydroxybicyclo (h, /., 0) -oct-7-Sh1idenZ-pentanone th acid. (Z) - (3 S, 1S, 2S, 3R, 6S) (3-Oak-synon-1 -inyl) -3-hydroxybicyclo (4,2,0) oct-7-ylidene butanoic acid. before (Z) - (3 S, 1R, 2R, 3S, 6R) -Oxy-5 1-methylnon-G-vinyl) -3-oxybipiclo (4,2,0) -oct-7-ylidene butane acid. (Z) - (3 S, 1S, 2S, 3R, 6S) -5-L2- (5 Cioct-1-vinyl) -3-hydroxybicyclo (4,2, v) Or t-7-ylidene-1-petanova acid, (Z) - (3S, lS, 2S, 3R, 6S) -4-t2 -. (3 Yuxioct-1-vinyl) -3-oxybiium (4.2 °; oct-7-ylidene-butanose acid. c / Jp 50. „, 0 /„, “S /, 1 (M-t-N1;). OCT - / - ILID (- iu 1 i.i 104 ° (CHCIJ. MS m / z 352 (M NH)) Calculated,%: C 71.82, H 9.04. Found, I: C 71.85 H 9 S4 (Z) - (3 S, 1 R, 2R 3S) -4- 2- (3 -Oxyoct-1 -inyl) -3-hydroxybicyclo (4,2,0) -oct-7-ylidene J-butane acid LOTZ .. "L i / 4 / n (Z) - (3 sN1R 2R 3S% 6S) (g-Oxidin-1-ynil) 3-hydroxybicyclo (four l about lo ki ok bu l l 35 0 five 75 five thirty before five 50 (4,2,0) -Oct-7-or; 1ene -butanov to the main. (Z) - (, 2R, 3S, 6R) -5-C2 (3-Oxitride-1 -inyl) -3-oxibicyclo (4, 2.0) -oct-7-ylidene pentanovl acid. (Z) - (,) - 4С2- (3-Oxy-5-methyl-1-1-1-1) -3-hydroxybicyclo (4,2,0) -oct-7-ylide - butanoic acid. (Z) - (, 2R 3S, 6R) (3 -Oxinon-1-vinyl) -3-oxibicyclg. (4,2,0) -Oct-7-ylidene -butanoic acid. (Z) - (3 S 1R, 2R, 3S, 6R) (3-Oxioct-1 -inyl) -3-hydroxybischlc (4,2,0) -oct-7-ylidene-pentanoic acid. P (Z) - (, 2R, 3S, 6R (3 -Oxy-4-phenylbut-1 -inyl) -3-hydroxybicyclo (4,2,0) -oct-7-ylidene-butanoic acid. (Z) - (3 S, 1R, 2R, 3S, 6R) -4-C2- (3-Oxy-5-phenylpent-G-vinyl) -3-oxybicyclo (4.2, 0) oct- 7-oridei-butanova acid. (Z) - (3 S, 1R, 2R, 3S, 6R) -5-L2- (j -Okl 3-methyl-V-phenylbut-1 -inyl) -3-hydroxybitslo (4, 2.0) oct-7-ylidene pentanoic acid. (Z) - (3 S, R, 2R, 3S, 6R) -5-2-C3 -OK (, -m-trifluoromethylphenylbut-G-ii.:;) - 3-hydroxycyclo (4,2,0) - Oct-7-ylg: 1 pentanoic acid. , (Z) - (, 2R, 3S, 6R) -4-L2 (3-Oxy-4 / -phenyl-1-vinyl) -3-oxy-bidiclo (4,2,0) -oct-7-ylidene-J- butane acid (Z) - (31 S 1R 2R 35.6R) -4-u2- (3-Oxy-5-Fenshent-1-vinyl) -3-oxybicyclo (4,2,0) -oct-7-ylidene 1-butanoic acid. (Z) - (,) - 5-i2 (3 -Oxy-4-m-trifluoromethylphenylbut-l-vinyl) -3-scsibicyclo (4,2,0) -oct-7-ylidene-pentanoic acid. (Z) - (3 S, 1R, 2R, 3S, 6R) -4-r2-p -Ok-, 4-endobicyclo (3,1, 0) -hex-6-ylbut-.1 ynyl - 3-hydroxybiclo (4,2,0) - oct-7-ylidene} -butanoic acid. (Z) - (3 SJR, 2R, 3S, 6R) - 5-V2- 3-Oxy-4 -endobicyclo (3,1,0) -hex-6-and p-bu .. -inyl - 3-hydroxybicyclo (4,2,0) - oct-7-ylidene 1, -pentanoic acid. (Z) - (3 S, 1R, 2R, 3S, 6R) -4- (2-r3-Oxy-4-exobicyclo (3,1,0) -hex-6-yl-ylZ-3- hydroxybicyclo (4,2,0) - oct-7-ylidene-Sutanoic acid 35 131 (Z) - (3 S, 1R, 2R, 3S, 6R) -4 - (; 2- (3 -OK si-3-methyl-3-cyclobutylprop-1-ynyl) -3-oxybicyclo (4.2, 0) oct-7-ylidene-butanoic acid. (Z) - (3 S, 1R, 2R, 3S, 6R) (3 -OK si-3-methyl-3-cyclopentyl-propyl-1-ynyl) -3-oxybicyclo (4,2,0) -oct-7- ilidene-butanoic acid. (Z) - (3 S, 1R, 2R, 3S, 6R) -4-2-r3 -OK si-3 -cyclopentyl-prop-1 -cyl) -3-oxybicyclo (4,2,0) -oct- 7-ylidene-buta nova acid. (Z) - (3 S, 1R, 2R, 3S, 6R) (3 -OK si-3 -cyclopentyl-prop-1-vinyl) -3-oxybicyclo (4,2,0) -oct-7-ylidene - Suta nova acid. (Z) - (3 S, 1R, 2R, 3S, 6R) (3-Oak si-4 -cyclopentyl-prop-1-vinyl) -3-oxybicyclo (4,2,0) -oct-7-ylidene - butanoic acid. (Z) - (3 S, 1R, 2R, 3S, 6R) (3 -OK-si-4-cyclopentylbut-1 -inyl) -3 oxy-bicyclo (4,2,0) -oct-7-ylidene J-butanoic acid. (Z) - (3 s, 1R, 2R, 3S, 6R) (-OK-si-4 -cyclohexyl-but-1-vinyl) -3-oxy-bicyclo (4,2,0) -oct-7-ylidene 7- butanoic acid. (Z) - (3 s, 1R, 2R, 3S, 6R) (3 -OK-si-4 -cyclohexylbut-G-vinyl) -3-oxy-bicyclo (4,2,0) -oct-7-ylidene J-pentavane acid. (Z) - (3 S, 1R 2R) 3 -Oxy-4-endobicyclo (3.1, 0) -hex-6-ylbut-1-vinyl-3-hydroxy-1 (4,2, 0) -Oct-7-ylidene butanoic acid. / Z) - (,, 6R) -542- 3 -Oxy-4-endobicyclo (1,1,0) -hex-6-ylbut-1 -inyl-3-oxybicyclo (4,2,0) -oct- 7-ylidene-pentanoic acid. (Z) - (3S, 1R, 2R, 3S 6R) -4-r2-3-Oxy-4-exobicyclo (3,1,0) -hex-6-ylbut-1-vinyl 3-hydroxybicyclo (4.2 , 0) -oct-7-ylidene} -butanoic acid. (Z) - (3 s ,,) (3 -Oxy-3 / -methy. butane acid (Z) - (3 S,) (3-Oxy-3-methyl-3-cyclopentyl-1-vinyl) -3-oxybate 1 (4,2,0) -oct-7-ylidene} -butanoic acid. (Z) - (3 S, 1R, 2R, 3S, 6R) (31 -Oxy-3-cyclopentylpro-1) 3 five 514 3-hydroxybicyclo (4,2,0) -oct-7-ylidene pentanoic acid, (Z) - (3 S «,) (3 -Oxy-3-cyclopentyl-prop-t-vinyl 3-hydroxyocyclo (4,2,0) -oct-7-ylidene-butanoic acid. (Z) - (3s, ,, 6R) -4-G2- (3-Oxy-4-picloplopylbut-1-vinyl) -3-hydroxybitslo (4,2,0) -oct-7-ylidene - butanoic acid . (Z) - (3 S, 1R, 2R) -4-C2- (3 -Oxy-3-cyclohexyl-prop-1-vinyl) 3-0Xybicyclo (4,2,0) -oct-7-ylidene-butanoic acid. , (Z) - (2R, ЗS, 6R) (3 -Oxy-3 -Diclopentograph-yl-yl-3-oxybicyclo (i, 2.0) -oct-7-ylidrk-butane in F l acido t; , (Z) - (3 SR 2R, 3S, 6S) -4-C2- (3-Oxy - i -cyclopentyl-1-vinyl) - 3-hydroxybipiclo (4,2,0) -oct-7-ylideneJ-byte .chip acid, (Z) - (3 S, i R 2R, 3S, 6R) -4-f 2- (3-Oxy-3-cyclolexyl-prop-1-vinyl) -3-hydroxybicyclo (4,2,0) -oct- 7-ylidene J-butanoic acid. fiS -fz 364 (M 4+ Mi +). four Calculated%: from 72.80; And 8.73, Found; ;;: C 7. 76; 18 . , (Z) - (, 3,6R -) (-3-Oxy-3-Cyclo-3-prop-1-vinyl) 3-hydroxy-5-cyclo (4,2,0) -oct-7-ylidene-pentanonel acid. MS m / z 378 (M V + NH,). Calculated:,: C / 3.30; And 8.95. NaHieno,%: C 73.38; H 9.01. (Z) - (3 S, 1R, 2R-, 3S (3 -Oxy-4-cyclohexyl but-1 -inyl) -3-hydroxybitslo (, L, 0) -oct-7-ylidene 1 - butane hydrochloride (Z) - (3 S,) (3 -Oxy-4-piclohexyl-but-1-vinyl) - 3-oxybicyclo (4,2,0) -oct-7-ylidene-pentanoic acid. Example 2. A. Preparation of (3 S, lS52S, 3R, 6S) -2- (3-tert-butyodimethylsilyl-OXY-3 -cyclohexylprop-1-vinyl) -3-tert-butythydimetyl yl oxy oxibicyclo ( 4,2,0) octane-7-one. The solution of 285 mg of (3S, 1S, 2s, 3R, 6S) -2- (3-Oxy-3-cyclohexyl-prop-1-vinyl) -3-oxybicyclo (4.2, 0 ) - Octan-7-one, 469 mg of tert-butyldimethylsilyl chloride and 423 g of imidazole in 8 ml of N, N-dimethylformamide. The reaction mixture is dissolved in water and extracted several times with ethyl acetate. The volume is 15138827. Indian extracts are washed with p; -. :: s, olome dried over sodium sulfate. The solvent and eyes are taken out: the residue is chromatographed on silica gel using a mixture of ethyl acetate and hexane (5:95). Obtain 385 mg of the target product. B. Preparation of (S S, 1S, 2S, 3R, 6S) -2- (3-tert-butyldimethylsilyloxy-3 - | Q iclohexyl-1-vinyl) -3-tert-butyldiethylsilyloxy-7-vinyl-endobiniclo (4 2.0) octane-7-ol. To a solution of 0.6 g (3 S, 1S, 2S, 3R, 6S) -2 (3-tert-butyldimethylsilyloxy-5, 5 niklo (4,2,0) -octan-7-one in No. 5 of tetrahydrofuran 1.8 ml of a 1 M solution of Green's vinyl reagent are slowly added to the tetrahydrofuranium solution, after 1 h the reaction mixture poured into saturated ammonium chloride solution and extracted with ethyl acetate. The combined extracts are washed with water and brine. After drying over sodium sulfate and evaporation of the 25 solvent, the residue is chromatographed on silica gel using a mixture of ethyladetate and hexane (7:93), two components are obtained: 190 ml of n-product (eluted first) and 60 mg of 30 (3S, LS) 2S, ЗR, 6S) -3- (3-tert-butyl-dimethyl-silyloxy-3-diclodioxy-r-1 ynyl) -3-tert-butyldimethylene: n1g: oxy 7-vinyl-exo-bidiclo (4, 2, 0) octane-7-ol (eluted second). j C. Preparation of ethyl- (3 S, 1 S, 2S, 3R, 55) (3-tert-butyldimethylsilyl-oxy-3 -diclohexyl-prop-1 -nHi-Ln) -3-tert-butyldimethylsilyloxybidiclo (4,2,0) -Oct-7-SH1Iden j-butyrate. d A mixture of 0.15 g of (3 s, lS, 2S, 3R, f) S) -2- (3-tert-butyldimethylsilyloxy-3 dicloxy-1-vinyl) -3-tert-butyldimethylsilyloxy-7-zinyl -Endo-bidiklo (4.2., 0) OKtan-7-ol, 1 ml of ethyl addetate and 10 μl of acetic acid N. heat at 1–20 ° C for 16 h Excess ethyl acetate and acetic acid are distilled off under reduced pressure. The residue is then chromatographed on silica gel using a mixture of ethyl acetate and hexane (7:93). 80 mg of the desired product are obtained in the form of a mixture of the E and Z isomers.55 D. Preparation of (Z) - (S S, 1S, 2S, 3R, 6S) - (3 -Oxy-3-Diclohexyl-prop-1-ynyl) -3-oxybihydro (4,2,0) -oct-7-ylidene butanoic acid. 4Z bu ok to 0, on Rera e n c in with o d O 55 Ifj A mixture of 35 mg of tgil- (3 S, 1 S, 2S, 3R,) (3-tert-butylphenylmethylsilylox-3-niclohexyl-prop-1 -nnyl) - -tre: - butyldimethylsilyloxybidic (4,2,0) - oct-7- ylidene-butyrate, 0.4 ml 0.5 n. an aqueous solution of lithium hydroxyl and 0.5 ml of methanol is stirred at room temperature for 2 hours. The reaction mixture is acidified with 0.5. bisulfate solution and then extracted with β-hydridedehyde. The combined extracts are rummed with brine and with cyniaT over sodium sulfate. After evaporation of the solvent, the residue is taken up in 0.3 ml of tet1) aha ;; rofuran and treated with 0.15 ml of a 1 M solution of tetrabutylammo; 1 fluoride in those of I according to the method of example 3. The crude product is the mixtures of E- and g-isomeoids are then separated by chromatography on silica gel using a mixture of acetic acid, methanol and dpllorstan (0.2: 5.3: 94.5). 7 mg of the p.e-Evs-G6 compound are obtained. Example 3. Preparation of methyl- (Z) - (3S, lS, 2S, 3R, 6S) (3 -oxy-β -diclohexylprop-vinyl) -3-ox1 bi-piyu (4.2, P) -7- ylidene-butyrate and other pharmacologically pleated esters. I A. To grow 0.5 g (Z) - (3 S, 1S, 2S, 3R, 6s) -4-1.2- (3-oxy-3 -riv; clo-silprop-1-vinyl) -3 -oxy-5-cyclo (4, 2,0) -oct-7-ylidene-butanoic acid: in 10 ml of diethyl ether, an excess of ether diazomethane is added until the yellow color disappears and Solvent yield 0, e2 g the product, (d) - - + 13-4 (MeOH). Calculated. %: C 73.30; H 8 / J5. Found,%: C 73.03; H 9.15. B, Analogously, proceeding from other compounds of the formulas (l), (I) and (, M I J and nscx esters). Methyl- (Z) - (3S, 1S, 2S, 3R, 6S) --- 2 (3 -oxy-3 - 11: and 1spohexylprop-1 - ng: l 3-oxybidiculo (4.2.0) - oKT-7-Hjn - ;: eH; butyrate ... Methyl- (Z) - (35.1 S, 2S, 3R, 6S) -4-L2 (3-oxy-3 -diklohexshtpr-iynyl 3-hydroxybicyclo (4,2,0) -oct-7-ylidene butyrate .MZ ra / z 378 (M + NH, MN 36 Calculated,%: C 73.30; H 8.95. Found,%: C 73.54; H 8.82. Methyl- (E) - (3S, 1S, 2S, 3R, 6S) (3-oxy-3 -diclohexylprop-1 -inyl171 3-hydroxybiclo (4,2, 0) oct-7-ylidene butyrate. Methyl- (E) - (35,13,25, WE, 63) -4-C2- (3 -oxy-3 -cyclopentyl-1-ynyl) -3-hydroxybicylo (4,2,0) -oct-7 -iliden - butyrate. Methyl- (Z) - (3S, 1S, 2S, 3R, 6S) (3-hydroxy-3-cyclopentyl-prop-1-vinyl) 3-hydroxybicyclo (4,2,0) -oct-7-ylidene - butyrate. Methyl- (g) - (35,15,23, 3K, b3) (3-oxy-3-cyclohexyl-prop-1-vinyl) 3-hydroxybitslo (4 5 2,0) -oct-7-ylidene butyrate. MS m / z 378 (M-t-NH MH + 361). Calculated,%: C 73.50; H 8.95, Found,%: C 73.47; H 8.81. Example 4. Compounds in which R - . A. Preparation of methyl- (Z) - (3S, 1S, 2S 3R, 6S) (3-tert-butylchimethyl-hydroxy-3-cyclohexyl-prop-1-ynyl) -3-tert-butyldimethylsilyloxy-bicyclo (4, 2, 0) -Oct-7-ylidene} -p; wipe. A mixture of 0.52 g of methyl- (Z) - (W S, 1S, 2S 3R, 6S) (3-oxy-3-cyclohexylprop-vinyl) -3-oxybicyclo (4.2.2) oct-7- ylidene-J-butyrate, 0.55 g of tert-butyldimethylsilyl chloride, 0.18 g of 4-dimethylamino-Vidine, 2 ml of triethyl amine, 10 ml of dichloromethane are stirred for 24 hours at. After diluting with 20 ml of dichloromethane, the mixture is washed with 10 ml of water, in three portions of 20 ml each of 1N HCl and 10 ml of saturated sodium bicarbonate solution. After drying over sodium sulfate, the solvent was distilled off to obtain 0.78 g of the desired compound. Similarly, but starting from the corresponding esters, other compounds are prepared. Methyl- (g) - (33,15,28, WN, 63) (3-tert-butyldimethylsilyloxy-3 - cyclohexylprop-1 -inyl) -3-tert-butyldimethylsilyloxybicyclo (4,2,0) - oct- 7-ylidene J-pentanoate, Methyl- (g) - (33, 13,23,3R, 63) -4- 2- (3-tert-butyldimethylsipyloxy-3 - cycloprop-1 -inyl) -3-tert-butyldimethylsilyloXibicyclo (4.2, 0) oct-7-or-denZ-butyrate. Methyl- (E) - (3 h, 13,23, ЗR, 63) (3-tert-butyldimethylsilyloxy-3-cyclohexyl-prop-1 -inyl) -3-tert-butyl-dimethylsilyloxybicyclo (4,2,0) -oct - 7-yliden1-butyrate. | 0 8 Methyl- (E) I 3 S 15 2S, 3R, 6S T20 five 0 five 0 five 0 five 4-P- (3-tert-butyldimethylsilyloxy-3-cyclohex; {lprop-1 -inyl) -3-tert-butyldimethylsilyloxy-bicyclo (4,2,0) - oct-7-ylidene-3-butyrate. , Methyl- (g) - (33,13,23, ЗК, ОЗ) (3-tert-butyldimethylsilyloxy-3 - cyclopentyl-prop-1 -inyl) -3-tert-butyldimersylsyloxy-bicyclo (4; 2,0) oct-7-nlidene 3-butyrate. Methyl- (Z) - (313% 13-, 23, 3R, 6S) - 4-C2- (3-tert-butyldimethylsilyloxy-3-cyclopentyl-prop-1 -inyl) -3-tert-, -butypdimethylsi-yloxybicyclo (4,2,0) - oct-7-ylanene-butyrate, B. Preparation of (Z) - (C 3,13,25,3R, 63) - (3-tert-butylmethylsilyloxy) -3-cyclohex 1lprop-1-vinyl) -3-tert-butyldimethylsilyloxybicyclo (4.2.2) - Oct-7-ylide} 3-1-Gl of tanol and similar compounds, To a stirred mixture of O, 1 g of lithium alumium: - Iygi; 1ridl in 15 ml of diethyl ether was added a dropwise solution of 0.78 g of methyl (35, 13,23,3R, 63) (3-tert-butyldimethylsilyloxy) - 3 - cyclohexylphen-1-iH1 and) -3-tert-butyl dimethyl; 1-siloxyb 1; cyclo (4,2, 0) -oct-7-ylidene} butyrpta s 5 diethyl ether. This mixture was refluxed for 2 hours. After cooling, the reaction mixture was treated, successively added dropwise 0.1 ml of water, 0.1 ml of 15% sodium hydroxide and 0.3 ml of water. Filter the precipitate formed. After evaporation of the filtrate, 0.7 g of the title compound is obtained. Similarly, but starting from the compounds prepared according to the method described, 1; ohm A, other compounds are obtained. (Z) - (33,13,2s, 3R, 63) -5-C2- (3-tert-BytI-Ldimethyl-Ioxy-3-cyclohexyl-prop-1-vinyl) -Z-tert-butyl-dickylsilyloxybicyclo (4.2, 0) oct-7-ylidene-1-pentanol. (Z) - (3.3,1 3,23, ЗК, 63) -4-Г2- (3-tert-Butyldimethylsilyloxy-3-cycloprop-1 -inyl) -3-tert-butyldimethylsilyloxy benzo (4.25 0) oct-7-yliden 1-butanol. (Е) - (З З, iЗ, 23, ЗR, 63) (3-ter-Butyldimethylyl-3-cnclohexyl-prop-1 -inyl) -3-tert-butyl-dimethylsilool-xibicyclo (4, 2, 0) -oct- 7 ilidene-butanol. (E) - (3 S, 1S, 2S, 3R, 6S) (3 - tert-Butyldimethylsilylox-3 -cyclo-1 exyl-prop-1 -inyl) -3-tert-butyldimethylsilyloxy bicyclo (4,2,0) - oct - ylidene -1-buta NOL. (z) - (3 S, 1 S, 2S, 3R 6S) -4-C2- (3-tert-Butyldimethyl-1-shsilyloxy-3 - cyclopentylprop-1 -inyl) -3-tert-G yrfiJi-D111 ethylsilyloxy bicyclic 1,4,2,0) -skt-7-ylidene-1 -butanol. (Z) - (3 S; 1S, 2S, ЗR, 6RA) (3-tert-Butyldimethylsilyloxy-3 - cyclopentyl-prop-1 -inyl) -3-tert-; utilized dimethylsilyloxybicyclo (4, 2, 0) -hcct-7-ylidene J- -butNOL. C. Preparation of (Z) - (3S, 1S, 2S, 3R, bS 4-C2- (3-hydroxy-3-cyclohexylprop-1-nyl) -3-oxybicyclo, (4,2,0) -oct -7-Jl-butanol and compounds of the formula (1), (II) and (GI), where R, - To a solution of 0.15 g of (Z) - (3S, 1S, 2S, 3R, 6S) -4-C2- (3-tert-butyldimethylsilyloxy-3 -cyclohexylprop-1 -inyl) -3-tert-butyldimethylsilyloxy beats1 - Clo (4, 2, 0) oct-7-ylidene} -1-butanol in 3 ml of tetrahydrofuran was added 5 ml of a 1 M solution of tetrabuty. ammonium naphthide in tetrahydrofuran. After 12 hours at 230 ° C, the solution is diluted with 20 ml of water. and extract the product with diethyl ether. By mixing the solvent and purifying the product using lash-chromatography on silica gel. with elution with ethyl acetate and hexane (1: 1), 0.8 g of the desired preparation was obtained. MS m / z 350 (M + KN). Yf 123.3 (in chloroform), A11, alogically, proceeding from other products, the preparation of which is oinca- num in B, gives the compounds of formulas (I), (II) and (III), where R, -. (Z) - (3 S, 1 S, 2S, 3R, 6S) -5- 2- C 3 -Oc si-3 -cyclohexyl-prop-and -E1hl) -3-oxybicyclo (4,2,0) -oct -7-ylidene J-1 - pentanol. (Z) - (3S ,, 3Rf 6R) -4. (3 -Oxy-3-cycloprop-1-vinyl) -3-oxibicyclo (4, 2, 0) -oct-7-ylidene, | - - butanol. (Z) - (3S, 1S, 2S, 3R, fSS) -4-C2- (3-Oxy-hlccloxolprosh L -inyl) -3-oxy-bicyclo (4, 2., O) -oct- 7-ylidene - 1 -butanol. (E) - () (3 -oxy-3 -cyclohexylprop-1-vinyl) - 3-hydroxybitslo (4,2, 0) -oct-7-ylidenJ-1-butanol ,. G20 (Z) - (3 S, 1 S :, 2S, 3R, 6S) -4- 2- (3 -oxy-3-cyclopentylgrop-1-inite:) -3- -v; - sibicyclo (4. 2 ,, 0) -Oct-7: iden 7-1-bu tanol. (Z) - (3 S, 1S, 2S,) (3-hydroxy-3-cy llopentilprop-1 -P; kil) 3-oxobicycles 5 (4, 2, 0) -of: T-7-vi4tb ioiij - 1 - butaiol. Example 5. Obtaining (Z) - (3 S JS, 2S, 3R, 5S) (3-Oxy-3 - C and a lggeck il p p about 1 - 2 - and and l) - 3 - ci to c and bi 11 and to to (4,2, 0) -oct-7-ylidene J-1 -6yi .n and compounds f ;; rmul (T), (II) and (GP where R is IT . L, K changeable mixture of 0.25 g of gsrolinikhl Orchromat in ml dih.-s; methane gribribav solution-0.2 i (Z) - (3 S, 1 S, 2S, 3R, 6S) (3-tert-butyldimethylsilylox-3 / -cyclohexane ripor; -1-vinyl) -3 -tert-bugildime gilg ililocobycyclo (4, 2,0) -oct-7-ylid1e 11 J 1-butanol, i-ray Foot O agree 3) measure FOR, in 3 ml of dichloromethane, Pos1: p 4 h at 23 C decantur about g solution from the precipitate and filtered through 10 g of syl with dichlorometage m. Filtrate is co-centrated to the residue,; : which is dissolved in 3 ml of tetrahydr;) furan, To this solution was added LT of 2 ml of 1 M 5 ;; st thief of the tetabuty: 1 ammopiifluoro: 1; , and in - (.1 O agidrofuran. After 16 hours at 23 ° C, the solvent was diluted with 20 ml and extracted with ethyl acetate. After evaporation of the solvent and subsequent (} 1. ash-chromate (; g-raf1: -1: on silica gel using is ethyl acetate and hexa (30:70), 0.1 g of the expected product is obtained. B Similarly, starting from the other compounds, the preparation of which is described in Example 3, one obtains coy ::, and -; formulas (I), (I) and (ljj, g; e R is CHO. (Z) - (3 R, lS, 2S, 3R, 6S) (3 -nK si-3 -d1-1clohexylprop-1 -ini. O-3-g; i-sibicyclo (4, 2.0) - oct-7-yliden 1- - pentanal, (Z) - (3, ЗR, 6S) -4-., (3 Oxy-3-dicloprol-1-vinyl) -3-oxibncyclo (4,2,0) -oct-7-yliden-1-butanal. (E) - (S S, 1S, 2S, 3R, 6S) (3 / -Oxy-3 -cyclohexyl-prop-1-vinyl) -3-oxy-ocyclo (4, 2, 0) -o1st-7-1-lidene J- - nu (E) - (W, 2S, 3R,) 3-hydroxybiclo (4,2,0) -oct-7-ylidene J-1-butanal. (Z) - (3 S, 1S, 2S, 3R, 6S) (3 -OK-si-3 -cyclopentyl-prop-1-vinyl) -3-oxybicyclo (4,2,0) -cot-7-ylideneJ -1- butanal. (2) - (3 S,) -4-C2- (3-Oxy-3 -cyclopentyl-propyl) -3-hydroxybicyclo (4,2,0) -oct-7-ylnden-1-butanal. Example 6 Preparation of p-benz-amidophenyl-g- (38,15,28, 3K, b5) -4-C2- (3-hydroxy-3-cyclohexyl-prop-l-vinyl) 1588275 22 ten prop-1 -nnyl) -3-oxybncyclo (4.2 oct-7 ylideneJ-buter. Calculated,%: C, 72.62; H 7.78: N 2.92. Found,%: C 72.25; H 7.86; N 2.56. p-Benzoylphenyl- (7) - (3B, 1S 2S) (3-oxy-3-cyclo 1 -inyl) -3-hydroxybicyclo (4,2,0) -ok 7-ylidene-butyrate. nN, N-Dimethidureidophenyl- (E) (3 s, 1S, 2S, 3R, 6S) -4-C2- (3-hydroxy-3 cyclohexylprop-1-vinyl) -3-oxybi - - - - .- .. 4-; i.ij. | - -ti ppl t / I 3-oxibicyclo (4,2,0) -oct-7-ylidene} - on (4,2,0) -oct-7-ylidene-butyrate. П 7 РЫ ПЫТ О TJT / f f r-гт ч ft Дч. l n ...,. butyrate and compounds of formulas (l), (II) and (III), where R CO ,. A. Solution ((3fS, 1S, 2S, 3R, 6S) - (3-hydroxy-3 -cyclohexyl-prop-1-ynyl) -3-hydroxybicyclo (4.2.2) -oct-7-ylidene-butanoic acid ( 35 mg, 0.101 mmol) in 2.7 ml of acetone are treated with 28.1 μl (0.202 mmol) of triethylamine. After 5 minutes, a solution of 109.2 mg (0.51 mmol) of p-benzamidophenol in 1.1 ml of dry pyridine is added at -5 ° C. After 3 hours at room temperature, the solvent is distilled off in vacuo. The residue is extracted with dichloromethane and filtered solid excess of n-benzamidophenol. After about The solvent solvent residue is purified by chromatography on a column using 30% acetone in hexane to give 12 mg of the title compound. m / z 541 (M-f). 20 25 thirty 35 C, 75.39; H 7.26; C, 75.28; H 7.23; 40 Mass spectrum: Calculated% N 2.59. Sz4N ssOjN-. Found,% N, 2.48. M.p. 154 - 155 ° C. 86.9 "(SNSC). B. Similarly, starting from the corresponding compounds of formulas (I), (c) and (III), where R is, and replacing the p-benzamidophenol by another approach with scimi-substituted phenols, typical compounds are obtained, where R, -. p-Acetylphenyl- (Z) - (3S, 1S, 2S, 3R, 6S) (3-hydroxy-3 -cyclohexylprop-1 -inyl) -3-oxybicyclo (4,2,0) -oct-7-ylideneJ Pentanoate p-Acetylaminophenyl- (g) - (3 S, 1S, 2S, 3R, 6S) (3-oxy-3, -cyclohexyl4S 50 p-Benzamidophenyl- (E) - (38 15 25, 3R 6S) -4 - /: 2- (3-hydroxy-3 -cyc hexylprop-1-vinyl) -3-hydroxybicyclo (4.2.2) oct -7-ylidene-butyrate. p-Benzoylphenyl- (Z) - (3S, 1S, 2S, 6s) -4-f2- (3-hydroxy-3-cyclopentyl 1-ynyl) -3-hydroxybicyclo (4,2,0) -octylideneJ-butyrate , p-Methylureidophenyl- (g) - (18 2S, 3R, 6S) -4-C2- (3-hydroxy-3-c cl heptyl-1-vinyl) -3-oxybicyclo (4,2,0) -oct- 7-ylidene-Sutirate. Example 7. Preparation of (Z) - (3S, 1S, 2S, 3R, 6S) -4-C2- (3 -oKCH-3 cyclohexylprop-1 -inyl) -3-oxybits (4.2.2) - Oct-7-ylidene sodium j-butyrate. 58.3 mg of 2-ethylhexane sodium acetate are dissolved in 0.2 ml of a mixture of diethyl ether and tetrahydrofuran (9: 1). Add an additional amount of tetrahydrofuran dropwise until a clear solution is obtained. Dissolve 70 mg of (Z) - (3 S, 1S, 2S, 3R 6S) (3 -ok |: and-3-cyclohexylpro inyl) -3-oxybi cyclo (4,2,0) -oxy 7-ylidene-butanoic acid in 5 ml of acetone and mixed with sodium 2-ethylhexanoate solution. The mixture is stirred for 30 minutes and then evaporated to dryness. 6 ml of a mixture of diethyl ether and tetrahydrofuran C9: i are added; to the dry mass and k p t t mixture with reverse refrigeration forOO min. The solid is filtered off with suction, washed with 2 ml of 9: 1 mixture of diethyl ether and tetrahydrof wound and dried in vacuo to give 56.0 mg of the desired product. Example 8. Obtaining (Z) - (3 1S, 2S, 3R, 6S) -4-t2- (3-hydroxy-3 -cyclohexylprop-1-ynyl) -3-oxybicyclo (4,2,0) -oct -7-ylidene-butyrate sodium. - 1588275 22 prop-1 -nnyl) -3-oxybncyclo (4,2,0) - oct-7 ylidenej-butirate. Calculated,%: C, 72.62; H 7.78: N 2.92. Found,%: C 72.25; H 7.86; N 2.56. p-Benzoylphenyl- (7) - (3B, 1S 2S) (3-oxy-3-cyclo-prop-1 -inyl) -3-hydroxybicyclo (4,2,0) -oct-7-ylidene-butyrate. nN, N-Dimetidureidophenyl- (E) - (3 s, 1S, 2S, 3R, 6S) -4-C2- (3-hydroxy-3 - cyclohexylprop-1-vinyl) -3-oxybic - - - .- ..4-; i.ij. | - -ti ppl t / I at (4,2,0) -Oct-7-ylidene-butyrate. at (4,2,0) -Oct-7-ylidene-butyrate. .,. 20 25 thirty 35 0 S 0 p-Benzamidophenyl- (E) - (38 15 25, 3R 6S) -4 - /: 2- (3-hydroxy-3-cyclo o-hexylprop-1-vinyl) -3-hydroxybicyclo (4.2.2) oct-7-ylidene-butyrate. p-Benzoylphenyl- (Z) - (3S, 1S, 2S, 3R, 6s) -4-f2- (3 -oxy-3 -cyclopentyl 1-ynyl) -3-oxybicyclo (4,2,0) -oct7 - ildenJ-butyrate, p-Methylureidophenyl- (g) - (18 2S, 3R, 6S) -4-C2- (3-hydroxy-3-c cloheptylprop-1-vinyl) -3-oxybicyclo (4,2,0) -oct -7-ylidene-Sutirate. Example 7. Preparation of (Z) - (3S, 1S, 2S, 3R, 6S) -4-C2- (3 -oKCH-3 t-cyclohexyl-prop-1-vinyl) -3-oxybicyclo (4.2.2) oct-7-ylidene sodium j-butyrate. 58.3 mg of sodium 2-ethylhexanoate are dissolved in 0.2 ml of a mixture of diethyl ether and tetrahydrofuran (9: 1). Additional tetrahydrofuran is added dropwise until a clear solution is obtained. Dissolve 70 mg of (Z) - (3S, 1S, 2S, 3R, 6S) (3 -ok |: and-3-cyclohexylprop-G-vinyl) -3-oxybi cyclo (4,2,0) -oxy - 7-ylidene-butanoic acid in 5 ml of acetone and mixed with a solution of 2-ethylhexanoate-sodium. The mixture is stirred for 30 minutes and then evaporated to dryness. 6 ml of a mixture of diethyl ether and tetrahydrofuran C9: i are added; dry and boil the mixture under reflux for 0 minutes. The solid product is filtered off, washed with 2 ml of a mixture of 9: 1 diethyl ether and tetrahydrofuran and dried in vacuo, to give 56.0 mg of the desired product. Example 8. Preparation of (Z) - (3S, 1S, 2S, 3R, 6S) -4-t2- (3-hydroxy-3-cyclohexyl-prop-1-ynyl) -3-hydroxybicyclo (4.2.2 oct-7-ylidene-butyrate sodium. 23 1588275 8.0 mg of (Z) - (3S, 1S, 2S, 31.63) g + -12- (3 -oxy-3 -cyclohexyl-niion-l-vinyl) -3-oxybicyclo (4.2 , 0); o1 |: t-7-ylidene butanoic acid E 1: ml of methanol and a solution of 18.5 mg of sodium bicarbonate dissolved in 1 ml of water is added to this solution. The mixture is stirred at room temperature for 1 hour, dried} with two-fold drying, with a mixture of benzene and dried in a high 1kume for 3 hours. The solid material is recrystallized from the mixture ten Oct-7-ylidene-3-butanoic acid in 5 ml of ether and 7.5 mg of ethylenediamine dissolved in 4 ml of ether are added to this solution. A precipitate immediately formed. The precipitate is filtered off, rinsed with ether, dried under high vacuum at room temperature overnight. 60 mg of the expected product are obtained. By the same procedure, the (Z) - (3S, 1S, 2S, 3R, 6S) -4-C2- {3 -oxy-3-diclohexylprop-1-vinyl) -3-hydroxybicyclo ( 4.2, J OOU dlVJ i I J i- JjUil: I lt-t -, - b-ethanol and diethyl ether and supe, 5 0) oct-7-ylidene butanoic acid. vacuum at room temperature. 75 mg of the expected product is obtained. J 112.4 °. M.p. 73 -. I In a similar way, (Z) - (3 S, .1S, 3R, 6S) -4-C2- (3 -oxy-3 -cyclohex-11prop-1-vinyl) -3-oxybicyclo (4.2, with | ) oct-7-ylidene-3 potassium butyrate. 1 110.3 (MeOH). M.p. 73. PRI me R. The preparation of (Z) - (| C S, 1 S, 2S, 3R, 6S) -4- 2- (3 -Oxy 3 - 1 |; iclohexyl-prop-1-vinyl) -3-hydroxy5 and 11-tb (4.2, 0) oct-7-ylidene-j-butyrate 1: alci. 96 mg of (Z) - (3S, 1S, 2S, 6s) -4-C2- (3 -oxy-3 -cyclohexyl-i | ipon-1-vinyl) -3-oxybicyclo (4,2,0 ) - (|) ct-7-ylidene-butanoic acid and t, 01 mg of calcium oxide in 1.5 ml of water | i 1.2 ml of tetrahydrofuran. The mixture is heated for 30 minutes at 50 ° C and filtered. The residue is dissolved in 1.2 ml of tetrahydrofuran and then 15 ml of ether is added. The precipitate is stirred at room temperature and then the filter is ioT. The solid is washed with anhydrous ether and dried under high vacuum at room temperature overnight. 66 mg of the title compound are obtained. c / JD lUjO C. m. 138-1.43 ° C. Similarly, (Z) - (3S, 1S, 2S, 3R, 6S) -4-2- (3 -oxy-3-cyclohexylprop-1-vinyl) -3-oxybicyclo- (4,2,0) is obtained oct-7-ylidene-butyrate magnesium. tft / jif 122.2. (Meon). M.p. 131 -, Example 10. Preparation of ethylene-diamine salt of (Z) - (3 S, 1S, 2S, 3R, 6S) -4-C2- (3 -oxy-3 -cyclohexylprop20 25 thirty 35 50 Example 11 - Preparation of the (Z) - (3 s, 1S, 2S, ZR, 6S) thimetaman salt 4-C2- (3 -oxy-3 -cyclohexylprop-1-ynyl) -3-hydroxybicyclo (4.2 , 0) oct-7-ylidene-butane acid. 75 mg of (Z) - (3S, 1S, 2S, 3R, 6S) (3 -oxy-3-cyclohexyl-pro-p-1-vinyl) -3-oxybicyclo (4.2.0) - oct- 7-ylidene-butanoic acid in 1 ml of methano.aa and 26.7 ml of tromethamine were added. The reaction mixture is heated at 50 ° C for 10 minutes, cooled to room temperature, and ethyl acetate is added dropwise until the clear solution becomes cloudy. The mixture is stirred at room temperature for 4 hours and filtered, washed with ethyl acetate and dried under high vacuum at room temperature overnight. 90 mg of the expected product is obtained, m.p. 48-51 C. UJo -83.8 ° (MeOH). MS m / z 364 (M + NHp, Calculated,%: C, 61.83; H 8.93; N 2.88, Found,%: C 62,12; H 8.90; N 2.93. Similarly, the diethyl salt of (Z) - (3S, 1S, 2S, 3R, 6S) -4-C2- (3-hydroxy-3-cyclohexyl-prop-1-vinyl) -3-oxybicyclo (4,2,0) -oct -7-yldenylbutanoic acid. EXAMPLE 12: Preparation of N-methyl-1-glucamine salt of (Z) - (3S, 1S, 2S, ZR, 6S) (3-cyclohexycipprep-1 ynyl) -3-hydroxybicyclo (4 , 2.0) oct-7-ylidene-butanoic acid. Dissolve 70 mg (Z) - (3 S, 1S, 2S, 1 -inyl) -3-hydroxybicyclo (4,2,0) -oct-7-55 3R, 6S) -: 4-C2- (3 -hydroxy-3-cyclohexylylideneJ-butanoic acid, 95.3 mg of (Z) - (3. S, 1S, 2S, 3R, 6S) -4-C2- (3-hydroxy-3 -cyclohexyl-prop-1-vinyl) -3-oxybicyclo (4, 2,0) prop-1-vinyl) -3-hydroxybicyclo (4,2,0) - oct-7-ylidene.} - butanoic acid in 2 ml of methanol and 38.7 mg of N-methyl- is added to this solution B-glucamine 24 Oct-7-ylidene-3-butanoic acid in 5 ml of ether and 7.5 mg of ethylenediamine dissolved in 4 ml of ether are added to this solution. A precipitate immediately formed. The precipitate is filtered off, rinsed with ether, dried under high vacuum at room temperature overnight. 60 mg of the expected product are obtained. By the same procedure, the (Z) - (3S, 1S, 2S, 3R, 6S) -4-C2- {3 -oxy-3-diclohexylprop-1-vinyl) -3-hydroxybicyclo ( 4.2, 0) oct-7-ylidene butanoic acid. 0 25 thirty 35 50 Example 11 - Preparation of the (Z) - (3 s, 1S, 2S, ZR, 6S) thimetaman salt 4-C2- (3 -oxy-3 -cyclohexylprop-1-ynyl) -3-hydroxybicyclo (4.2 , 0) oct-7-ylidene-butane acid. 75 mg of (Z) - (3S, 1S, 2S, 3R, 6S) (3 -oxy-3-cyclohexyl-pro-p-1-vinyl) -3-oxybicyclo (4.2.0) - oct- 7-ylidene-butanoic acid in 1 ml of methano.aa and 26.7 ml of tromethamine were added. The reaction mixture is heated at 50 ° C for 10 minutes, cooled to room temperature, and ethyl acetate is added dropwise until the clear solution becomes cloudy. The mixture is stirred at room temperature for 4 hours and filtered, washed with ethyl acetate and dried under high vacuum at room temperature overnight. 90 mg of the expected product is obtained, m.p. 48-51 C. UJo -83.8 ° (MeOH). MS m / z 364 (M + NHp, Calculated,%: C, 61.83; H 8.93; N 2.88, Found,%: C 62,12; H 8.90; N 2.93. Similarly, the diethyl salt of (Z) - (3S, 1S, 2S, 3R, 6S) -4-C2- (3-hydroxy-3-cyclohexyl-prop-1-vinyl) -3-oxybicyclo (4,2,0) -oct -7-yldenylbutanoic acid. EXAMPLE 12: Preparation of N-methyl-1-glucamine salt of (Z) - (3 S, 1S, 2S, ZR, 6S) (3-cyclohexyclipprop-1-ynyl) -3-hydroxybicyclo ( 4,2,0) oct-7-ylidene-butanoic acid. Dissolve 70 mg (Z) - (3 S, 1S, 2S, 3R, 6S) -: 4-C2- (3-hydroxy-3-cyclohexyl-prop-1-vinyl) -3-hydroxybicyclo (4,2,0) - oct-7-ylidene.} - butanoic acid in 2 ml of methanol and 38.7 mg of N-methyl-B-glucamine was added to this solution. The reaction mixture is stirred at room temperature for 30 minutes. To this homogeneous solution was added 10 m of ethyl acetate. The mixture is stirred at room temperature for 2 hours. The formed crystals are filtered, washed with ether and dried under high vacuum at room temperature overnight. 90 mg of the title compound are obtained, mp. 52 - 55 C. S. 12) 62.8 ° MS m / z 364 (M + NH). Calculated,%: C 62.09; H 8.75; N 2.59. Found,%: C 60.34; H 9.15; N 2.47; Example 13. A mixture of 448 mg of (Z) (3S, 1S, 2S, 3R, 6S) -4-C2- (3-hydroxy-3-cyclohexyl 1 Prop-1-vinyl) -3-oxybicylo (4.2, 0) -oct-7-ylidene-J-butanoic acid of the triethylamine salt in 7 ml of water and 6 ml of tetrahydrofuran are treated with 28 mg of calcium oxide and the mixture is heated for 1 hour at 50 ° C. The tetrahydrofuran is then evaporated under reduced pressure and the water is removed in vacuo. Receive (g) - (S S, 1S, 2S, RR, 6S) (3-hydroxy-3-cyclohexyl-prop-1-vinyl) -3-hydroxybicylo (4,2,0) -oct-7-ylidene J-butyrate calcium, which is then purified as described in example 8. Example 14. A solution of methyl- (g) - (35,15,25, LC, b5) -4-C2- (3 -oxy-3-cyclohexylprop-1-vinyl) -3-oxybicyclo (4.2, 0) -oct-7-P1Iden J-butyrate (200 mg) in 5 ml of isopropanol, containing a catalytic amount of sodium isopropoxide (10 mg), is refluxed for 3 hours, after which it is distilled from the flask approximately 2 ml of solvent. The resulting solution is evaporated to dryness, treated with 5 ml of phosphate buffer with pH 7, the isopropyl ester formed is extracted with ethyl acetate. After purification using silica gel chromatography, up to 40% ethyl acetate and hexane, pure ester is obtained. Example 15. A mixture of 448 mg of (Z) - (S, 1S, 2S, 3R, 6S) -4-C2- (3-hydroxy-3-cyclohexyl 1 Proc-1-vinyl) -3-oxybicylo (4.2, 0) -oct-7-ylidene-j-butanoic acid, 152 mg of diazabicycloundecane and 156 mg of iodoethane in 5 ml of dry benzene are refluxed for 6 hours. The solvent is then distilled off under reduced pressure and the residue is treated with an aqueous solution 0 sodium bicarbonate, extracted with ethyl acetate. The combined extracts are washed well with water, dried over magnesium sulfate and evaporated. Get ethyl- (g) - (38, 1S, 2S, 3R, 6S) -4 - (; 2- (3-oxy-3 -i-cyclohexyl-prop-1-vinyl) - 3-hydroxycyclo (4,2,0) - Oct-7-ylidene-butyrate. Example 16. To a mixture of 0.2 ml of 0.5N aqueous lithium hydroxide in 0.5 ml of methanol was added 35 mg of ethyl (Z) - (3 S, 1S, 2S, 3R, 6S) (3 -OKCH-3 -cyclohexylprop-1 -inyl) -3-oxy5 bicyclo- (4,2,0) -oct-7-ylidene J-butyrate and the mixture is stirred under nitrogen for 24 hours. The solvent is then distilled off in vacuo, and the residue is treated with ether. Get 0 (Z) - (3S, 1S, 2S, ЗR, 6S) -4-C2- (3 / -oxo-3-cyclohexyl-prop-1 -inyl) -3-oxybicyclo (4.2, 0) - Oct-7-ylidene | lithium butyrate. Example 17. The distribution between 5 ml of 100 ml of dichloromethane and 100 ml of 5% aqueous acetic acid, 1.52 g (g) - (S, 1S, 2S, 3R, 6S) -4- (3-oxy-3 - cyclohexylprop-1-vinyl) -3-hydroxybicyclo- (4,2,0) -oct-7-ylidene calcium calcium butyrate and shake well. The aqueous layer was separated and extracted with additional 100 ml of dichloromethane. The combined extracts are dried over anhydrous sodium sulphate and evaporated to dryness. 1.38 g of (Z) - (3S, 1S, 2S, 3R, 6S) are obtained (3-hydroxy-3 -cyclohexyl. Prop-1-vinyl) -3-oxybicyclo (4.2.2) - oct- 7-ylidene J-butanoic acid. Example 18. Inhibition of agQ platelet regimens. Collect human venous blood from non-administered medication of healthy volunteers in a 15 ml container (vacutainess) and anticoagulate 0.5 ml of 11.4% sodium citrate. The blood is centrifuged at room temperature for 15 minutes at 150 g in a Sorvoll GLC-28 centrifuge and the supernatant platelet-rich plasma (PRP) is sucked off. Platelet-poor plasma (PRP) is obtained by centrifuging blood from which PHP is removed, at 12,800g for 3 minutes in an Eppendorf centrifuge at room temperature. Platelet aggregation was carried out according to the Bourne method into Payton's aggregometr. Platelet aggregation is caused by the addition of 2-5 nmol ADP in 1 ml of PRP containing 0 five 0 five 1 µl of different concentrations of the tested compounds or carriers, injected into the cuvette of the njpH 37 ° C aggregator for 5 min at a stirring speed of 500 rpm. Then, for each test compound, the percent inhibition is plotted — the concentration on the semi logarithmic meters, and the concentration corresponding to 50% inhibition is expressed as the ICC for this compound. All test compounds (1-2 mg) were prepared as 0.01 M solutions in 10% ethanol and 59 mM sodium bicarbonate. Subsequent dilutions make water. I In tab. 1 systematized the test results. I Example. 19. Antihypertensives. activity. 1 Antihypertensive effects of prostag Aandin-like compounds are assessed for the spontaneously hypertensive Rats (SHR / NCIBR). Femoral arteries are implanted under ether anesthesia and venous cannulas and rats are left in a supine position. After exiting from anesthesia, lidocaine is administered. Blood pressure is determined with the help of a femoral arterial cannula k recorded on a Beksan 611 polygraph. Each compound is studied on a root of Fets rats. At the beginning of the study, the vehicle was injected and, with an interval of 30 minutes after that, compounds were injected intravenously with increasing doses of 1, 3, 10, 30 and 100 µg / kg, the background mean arterial blood pressure is the blood pressure directly. before the first zo of the compound. The ED is calculated by linear regression of the percent reduction in mean blood pressure after each dose of compound. The duration of activity is determined on the basis of a recovery to 90% of the control blood pressure after a dose of 100 µg / kg intravenously. The data are given in table. 2 Example 20. A solution of 80 mg of (Z) - (3S, 1S, 2S, 3R, 6S) (3-tert-butyldimethylsiloxy-3 -cyclohexyl-; PROP-1 -inyl) -3-tert-butyldimethylsilyloxybicyclo ( 4,2, 0) -oct-7-ylidene butyric acid in 3 ml of solvent consisting of a mixture of tetrahydrates 0 of rofuran, acetic acid and water (3: 1: 1), stirred at 55 ° C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extracts are washed with brine and dried over sodium sulfate. After evaporation of the solvent, the residue is purified by chromatography on silica gel. Elute with a mixture of dichloromethane, methanol and acetic acid (94.5: 5.3: 0.2). 29 mg of (Z) - (3S, 1S, 2S, 3R, 6s) -4-2- (3-hydroxy-3 -cyclohexylprop-g-ynyl) -3-oxybicycloprop-1 -inyl) -3- is obtained hydroxybicyclo (4,2,0) oct-7-ylideneJ-butyric acid Example 21 Antihypertensive activity of prostaglandin-like compounds is assessed in males g. and female cats of domestic cats, to whom arterial and venous cannulas are inserted under pentaborbital anesthesia and undergo thoractomy to place the Walton-Brodie device on the right ventricle of the myocardium. After surgery, animals are examined in a cardiovascular and autonomous test, which involves administering various autocoids before and after intravenous administration of each of several dose levels of the test compound. The regimen is co-inconsistent with mean blood pressure, immune cardiac strength and heart rate resulting from blood pressure. The test compound is administered intravenously in the amount of 1.3, 10 and 30 µg / kg, autocoids calls are not administered after a dose of 30 µg / kg. The background mean blood pressure is the blood pressure immediately before each administration of the test compound. From a linear regression, the percent decrease in mean blood pressure in several cats after each dose of compound was determined. The results are shown in Table. 3 five 0 five 0 Example 22. Toxicity. Four baboons, weighing about 9–14 kg, gave 1 mg / kg of the test compound (Z) - (3S, 1S, 2S, 3R, 6S) -4-2- (3-oxy-3 -cyclohexylprop-1-ynyl ) -3-hydroxybicyclo (4, 2,0) -oct-7-ylidene-butanoic acid in solution at the same time orally. No toxic effects are observed. Other compounds of formula (I) also have no toxic effect. The compositions are given in table. four. Cooking The ingredients listed above are homogenized and thoroughly mixed, then the powder mixture is pressed into tablets of 256 mg each, each of which contains 52.6 mg of the active ingredient. Thus, the proposed method allows to obtain compounds with a higher inhibitory activity of platelet aggregation compared with the known analogues and also showing antihypertensive activity.
权利要求:
Claims (1) [1] Invention Formula The method of obtaining (4,2,0) -bicyclo-2C octane derivatives of the general formulas I, II, HI Ri (CHi) n H SP OH f he g (W Rl (CHi) n H N. ai) 2-3; COOR or COOH group; hydrogen, methyl; radical SC (CH), where lower alkyl or group where X is a group -NHCCH or -NHC-C H and about I ABOUT or their pharmaceutically acceptable non-toxic salts, characterized in that the protecting group is removed — a trialkylsilyl group in compounds of the formulas IV, V, VI: Rl (CH) n H (Iv) Ri Opt g opt Ri H. ( (V) five R. 3 Opt y opt R2 Ri (CH) n. .H (Vi) fH ./ OH T Opi RI five; 40 50 where pt is a trialkylsilyl group, R j has the indicated meanings by treating with tetrabutylammonium fluoride in an organic solvent at 0- to obtain compounds of formulas (I) - (III) and, if necessary, compounds of formulas (I) - (III), where R is a COOH group, is converted into a corresponding derivative, where R is the COOR group, where R has the indicated values, or transform the acid of formulas (I) - (III) into pharmaceutically acceptable fat, or. transform a pharmaceutically acceptable non-toxic salt of the compounds of formulas (I) - (III) into its corresponding acid; or transform a pharmaceutically acceptable non-toxic salt of compounds of formulas (I) - (III) into another pharmaceutically acceptable non-toxic salt. 31 158827532 Table 1 PGE is an well-known compound, (Z) - (3 S, 1R, 2R, 3S, 6R) -4-C2-Ci-Oxy-3-cyclohexyl-prop-1-vinyl) -3-oxybicyclo (4, 2 , 0) -oct-7-ylidene) -butanova acid, - ... (Z) - (3S, 1S, 2S, 3R 1e5) -4-С2- (3-Oxy-3 - cyclohexylprop-1-vinyl) -3-oxybicylo (4.2 , 0) -oct-7-yliden} -butanoic acid 4-Acetylaminophenyl- (g) - (3S, 1S, 2S, 3Ri6S) -4-f2- (3 -oxy-3 -cyclohexylprop-1-vinyl) -3-xxybicyclo (4.2.0) - QKT- 7-ylidene-butyrate Tromethamine salt of (Z) - (3, S, 1.S, 2S, 3R, 6S) -4-t2- (3-oxy-3 -cyclohexyl-prop-1-vinyl) -3-oxybicyclo (4.2, 0) - Oct-7-ylidene} -butanoic acid M-Methyl-B-glucamine salt of (Z) - (3 S, 1S, 2S, 3R, 6S) (3-hydroxy-3-cyclohex-c-yl-prop-1-vinyl) -3-oxybicyclo. (4,2,0) - Oct-7-ylidene-6-uanoic acid Dicyclohexylamine salt of (Z) - (3 S, 1S ,, 2S, 3R, 6S) -4-C2- (3 -oxy-3 -cyclohexyl-prop-1-vinyl) -3-oxybicyclo (4, 2.0) - oct -7-ylidene-butanoic acid Diethanolamine salt of (Z) - (, 1S, 2S, 3R, 6S) (3 -oxy-3-cyclohexyl-prop-1 -inyl) -3-oxybium, iklo (4, 2, 0) -oct-7-ylidene-butane acids Ethylene Amine Salt of (Z) - (3 S, 1S, 2S, 3R, B8) (3-hydroxy-3 -cyclohexyl-prop-1-vinyl) 3-hydroxybicyclo (4, 2.0) -oct-7-ylidene-butanoic acid (Z) - (, 2S,) (3-Oxy-3-cyclohexyl-prop-vinyl) -3-oxybicyclo (4, 2,0) -oct-7-ylidene j-butanoic acid (Z) - (3S, lS, 2S, 3R, 6S) -5-E2- (3-Oxy-3 -cyclohexyl-prop-1-vinyl) -3-oxybicyclo (4.2.2) -oct- 7-ylidene-pentanoic acid XZ) - (3S, 1S, 2S, ЗR, 6S) -4-C2- (3-Oxy-3-cyclohexyl-prop-1-vinyl) -3-oxy-bicyclo- (4,2,0) -oct- 7-ylidene calcium j-butyrate (Z) - (3 S, 1R, 2R - ,, 6R) 0,0034 0,004 0,0042 0.011 0.012 0.014 0.011 0,0084 0.012. 0.01 0.015 - 1588275 About I ::; IIIL :::; I :::::::;: sibicyclo (4,2,0) -oct-7-ylidene 7c: Utanovy acid (Z) - (3 S, 1R, 2R, 3S, 6R) -5-t2- (3 -OKCH3 -cyclohexyl-prop-1-ynyl) -3-oxybitconne (4.2.2) -oct-7-ordec pentane acid (Z) - (3 sMS, 2S, 3R, 6S) -5-r2- (3 -OK si-3 -cyclohexyl-prop-1-vinyl) -3-oxy-bicyclo (4.2, 0) oct-7 -ylidene D-pentanoic acid (Z) - (3 S 1R, 2R,) (3 -Ok Ci-3-cyclohexyl-prop-1-ynyl) -3-oxy-cyclo (4,2,0) -oct-7-ylidene pentanoic acid () - (S S, 1S, 2S.ZR, 6S) -4-C2- (3 -Oxy-3-Cyclohexyl-prop-1 -inyl) -3-oxybicyclo (4,2,0) -oct-7-ylidene 1-butane acid Methyl- (g) -3 g, 6R) .- 4-C2- (3-oxy-3-cycloge -hyppro-1 -INIl) -3-oxybicyclo (4,2,0) -.oct-7-or butyrate (E) - (., 2S,) - 4-C2- (3-Oxy-3-cyclohexyl-prop-1 -nyl) -3-oxybicyclo (4,2,0) -oct-7-or-11-buta new acid (E) - (35,15,23, LC, B5) -5-C2- (3-hydroxy-3 -cyclohexyl-prop-1-vinyl) -3-oxy-cyclo (4,2,0) -oct-7 -ylidene-pentanoic acid Methyl- (g) - (3, 1S, 2S,) - 4-G2- (3-Cyclohexyl-prop-1 -inyl) -3-oxy-cyclo (4,2,0) -oct-7-ylidene butyrate (Z) - (3 S, 1S, 2S, 3R, 6S) (3-Oxy-oct-4-ynyl) -3-hydroxybicyclo (4,2,0) - ict-7-nlidene-3-butacic acid (E) .- (3 S, 1S, 2S, ЗR, 6S) (3 -Oxy 3-cyclohexyl-prop-1-vinyl) -3-hydroxy-cyclo (4,2,0) -oct-7-ylmdenZ-pentanoic acid. Methyl- (Z) - (3S, 1S, 2S, 3R, 6s) (3 Oxy-3-cyclohexyl-prop-1-vinyl) -3oxy-bicyclo (4,2,0) -oct-7-ylidene butyrate. (Z) - (3 s, 1R, 2R, 3S, 6R) -4-t2- (3 -OK-sioct-1 -inyl) -3-hydroxybicyclo (4.2.2) - oct-7-ylyden Sutanova acid 351588275 Continued :::::; i; i: i ::::::::::::: . (Z) - (3 S 1FL,) (3-Oxy-3-cyclohexyl-but-1-inip) -3-hydroxycyclo (4, 2, 0) -oct-7-ylidene J-butanoic acid .. (E) - (3 s, ls, 2S, 3R, 6S) -4-C2- (3 -OKCH-oct-1-vinyl) -3-oxy-6-cyclo (4,2,0) - oct-7-ylidene J -butanoic acid 4-Benzamidophenyl- {E) - (3 S, IS, 28, 3R, 6S) (3-oxy-3-cyclohexyl-prop-1-vinyl) -3-oxybicyclo (4.2, OX-oct-7- ilden j-butyrate (Z) - C3 S, 1S, 2S, 3R, 6S) -4-t2- (3 -OKM-3-cyclohexyl-prop-1-vinyl) -3-oxybicyclo (4,2,0) -oct-7 -lidene-sodium butyrate, (Z) - (3.S, 1S, 2S, 3R, 6S) -4- | L2- (3 -oKCH3 -cyclohexyl-prop-1 -inyl) -3-oxybicyclo (4, 2, 0) -oct-7- ylidene butyrate. Kali (Z) - (3S, 1S, 2S, 3R, 6S) -4-f2- (3 -oKCH3-cyclohexn1-prop-1 -inyl) -3-oxybicyclo (4,2,0) -oct-7-ylideneJ- butyrate magni (Z) - (3 S, 1S, 2S, 3R, 6S) (3-Oxy-3-endobicyclo (3,1,0) -hex-6-ylbyt-1-vinyl j-3-oxybicyclo (4.2 , 0) -oct-7-ylidene-butane acid (Z) -OS, 1S, 2S,) -4-C2- (3- -Oxy-3 -cyclopentyl-1-vinyl) -3-oxybicyclo (4,2,0) -oct-7-ylidene-J- butane acid (E) - (3 S IS, 2s,) (3 -Oxy-3-cyclpentyl-prop-1-vinyl) -3-hydroxy-bicyclo (4,2,0) -oct-7-ylidene-D-butanoic acid (Z) - (3 s, 1S, 2S, ЗR, 6S) (3-Oxy-3-cyclohexyl-prop-1 -yl) -3-oxy-cyclo (4,2,0) -oct-7-ylidene-J- butane acid (Z) - (3, 1S, 2S, 3R 6S) (: -Ok-si-3 -cyclohexyl-prop-1-vinyl) -3-hydroxybicyclo (4,2,0) -oct-7-ylidenJ-futanoic acid (Z) - (3 s, 1S, 2S, 3R, 6s) -5-C2- (3 -OKCH3 -cyclohexnylprop-1 -inyl) -3-oxbicyclo (4.2.2) oct-7-ylidene - pentanov acid (Z) - (,) - 4-C2- (3-Oxy-3-Cyclohexyl-prop-1-vinyl) -3-hydroxy-bicyclo (4.2.2) -oct-7-ylidene 7-butanoic acid (Z) - () - 5-C2- (3-Oxy-3-cyclohexyl-prop-1 -inyl) -3-oxybp cyclo (4,2,0) -oct-7-ylidene j-pentane acid Methyl- (g) - (35 J1S,) - 4-C2- (3-Oxy-3-cyclohexyl-prop-1-yn 11l) -3-hydroxybicyclo (4,2,0) -oct-7-yllen-butane-acid (Z) - (3 S, lS, 2S, ЗR, 6s) -4-C2- (3-Oxyoct-1-vinyl) -3-hydroxybicyclo (4,2,0) -oct-7-ylidene-butanoic acid (Z) - (3 S, 1R, 2R, 3S-, 6R) -4-C2- (3 oKCHOKT1 -ini O-3-hydroxybitslo (4,2,0) -oct-7idene} -butanoic acid (Z) - (3 S, lR, 2R, 3S, 6R) -u-L2- (3-OKCH- 3 -cyclohexyl-1-vinyl) -3-hydroxybicylo (4.2.2) -oct- 7-ylidene-Gutanoic acid (Z) - (3 s, lS, 2S, 3R, 6S) -4-C2- (3 -OKCH-3 -cyclohexyl-prop-1 -inyl) -3-oxy-bicyclo-1-vinyl) -3-oxybicyclo ( 4,2,0) - oct-7-ylidenJ-eutanoic acid (Z) - (3 s, 1S, 2S, 3R, 6S) -3-r2- (3 -OKCH-3-cyclohexyl-prop-1 -iyl) -5-oxybicyclo (4,2,0) -oct- 7-ylidene-pentanoic acid Table 3 Memory 1588275 (Z) - (3 S, 1S, 2S, 3R, 6S) -4-C2- (3 - Oxy-3-cyclohexylprop-4-vinyl) - 3-oxybicyclo (4.2.0) -oct-7 - or - AeHj-6yTHpaT calcium Spray-dried lactose Magnesium Stearate . 40 Table 4 52.6 200 3
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同族专利:
公开号 | 公开日 US4608388A|1986-08-26| PL148462B1|1989-10-31| ES8800146A1|1987-11-01| ES553437A0|1987-11-01| HU195634B|1988-06-28| ES8802482A1|1988-07-16| PL263592A1|1987-08-24| FI861324A0|1986-03-26| PL263591A1|1987-08-24| CS213586A2|1987-09-17| NO861244L|1986-09-29| NZ215610A|1989-04-26| CA1284654C|1991-06-04| PT82286B|1988-05-27| IL78273D0|1986-07-31| DK145286D0|1986-03-26| NO164017B|1990-05-14| AT43575T|1989-06-15| KR860007212A|1986-10-08| EP0196617B1|1989-05-31| DD244132A5|1987-03-25| DE3663660D1|1989-07-06| JPS61227544A|1986-10-09| PL148469B1|1989-10-31| SU1500153A3|1989-08-07| EP0196617A1|1986-10-08| AU5528986A|1986-10-02| CS257285B2|1988-04-15| PL263590A1|1987-08-24| HUT42426A|1987-07-28| GR860778B|1986-06-19| PL148468B1|1989-10-31| NO164017C|1990-08-22| ES557637A0|1988-07-16| KR910000254B1|1991-01-23| DK145286A|1986-09-28| PT82286A|1986-04-01| AU599018B2|1990-07-12| FI861324A|1986-09-28| PH23489A|1989-08-16| ZA862278B|1987-11-25| PL263593A1|1987-08-24|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题 US4705806A|1978-02-13|1987-11-10|Morton Jr Douglas R|Prostacyclin analogs| US4288606A|1979-06-14|1981-09-08|The Upjohn Company|Esters of prostacyclin-type compounds| US4267395A|1979-07-05|1981-05-12|The Upjohn Company|2-Decarboxy-2-hydroxymethyl-19-hydroxy-19-methyl-6A-carba-PGI2 compounds| US4420632A|1980-04-15|1983-12-13|The Upjohn Company|Composition and process| US4306076A|1980-04-23|1981-12-15|The Upjohn Company|Inter-phenylene CBA compounds|US4678805A|1985-03-27|1987-07-07|SyntexInc.|Novel 8-bicyclo[4.2.0]octane derivatives with valuable therapeutic properties| US4792561A|1986-05-29|1988-12-20|SyntexInc.|Carbostyril derivatives as combined thromboxane synthetase and cyclic-AMP phosphodiesterase inhibitors| US5049497A|1986-08-25|1991-09-17|SyntexInc.|Novel process for the synthesis of the enantiomers of bicyclooct-2-en-7-one and derivatives| US4735966A|1986-08-25|1988-04-05|SyntexInc.|Novel substituted bicyclooctane derivatives with valuable therapeutic properties| US4730078A|1987-05-13|1988-03-08|G. D. Searle & Co.|Allenic prostacyclins| US4983627A|1988-11-10|1991-01-08|SyntexInc.|Novel 6-alkyl and 6.8-dialkylbicyclooctane derivatives|
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申请号 | 申请日 | 专利标题 US06/716,872|US4608388A|1985-03-27|1985-03-27|Novel [4,2,0]bicyclooctane derivatives with valuable therapeutic properties| 相关专利
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