LT3533B

O-heyteroaryl, o-alkylheteroaryl, o-alkenylheteroaryl and o-alkynylheteroaryl macrolides

Abstract

This record has no abstract on file.

LT3533B, drawing sheet 1 — Sheet 1 of 61

Term

Term ended

Expired 27 April 2013, 13.4 years ago.

12 claims: 11 independent, 1 dependent

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IŠRADIMO APIBRĖŽTIS 1. Junginys, turintis formulę I:arba jo farmaciniu požiūriu priimtina druska, kurioje R 1 yra: (1) heteroarilas;
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(2) pakeistas heteroarilas, kuriame yra pakaitai X, Y ir Z;
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(3) heteroaril-C 1 _ 10 -alkilas;
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(4) pakeistas heteroaril-C 1 _ 10 -alkiias, kuriame heteroarilo grupėje yra pakaitai X, Y ir Z ir alkilo fragmentas gali būti pakeistas vienu arba daugiau pakaitų, kurie parinkti iš:(a) hidroksilo, (b) oksoc/rupės, (c) C^g-alkoksigrupės, UI! IBIU: I! .1 II 11:11 1.1Λ .I. 225 (d) aril-C 1 _ 3 -alkoksigrupės, (e) pakeistos arilC 1 _ 3 -alkoksigrupės, kurioje arilo grupėje yra pakaitai X, Y ir Z, (f) nepakeista arba pakeista ariloksigrupė, kurioje arilo grupėje yra pakaitai X, Y ir Z, (g) -OCO-C^g-aikilas, (h) -NR R , kai R ir R' nepriklausomai vienas nuo kito yra pasirinktinai (i) vandenilis, (ii) pakeistas arba nepakeistas C 1 . 10 -alkilas, turintis vieną ar daugiau pakaitų, tarp kurių pasirinktinai : (a 1 ) arilas, nepakeistas arba pakeistas X, Y, Z, (b 1 ) heteroarilas, nepakeistas arba pakeistas X, Y, Z, (C) -OH, (d') C^g-aikoksigrupė, (e') -CO 2 H, (f') -CO 2 -C 1 _ 6 -alkilas, (g') -C 3 .. 7 -cikloalkilas ir (h') -OR 11 , (iii) C 3 _ 10 -alkenilas, nepakeistas arba pakeistas vienu ar keliais pakaitais, tarp kurių pasirinktinai: (a') arilas, nepakeistas arba pakeistas X, Y, Z, (b') heteroarilas, nepakeistas arba pakeistas X, Y, Z, (c') -OH, (d' ) Cg.g-alkoksigrupė, UBUI. J. I 226 (e') -CO 2 H, (f) -CO 2 -C 1 _ 6 -alkilas, (g') -C 3 _ 7 -cikloalkilas ir (h') -OR 11 , 6 7 (iv) arba kai R , R ir N atomas, prie kurio jie prijungti, sudaro nepakeistą arba pakeistą 3-7 narių heterocikliną žiedą, kurio sudėtyje gali būti vienas arba du papildomi heteroatomai nepriklausomai vienas nuo kito parinkti iš grupės, sudarytos iš O, S(O) p , NR 14 , kai R 14 yra vandenilis arba C 1 _ 6 -alkilas, nepakeistas arba pakeistas fenilu, p lygus 0, 1 arba 2, (i) -NR 6 CO-C 1 _ 6 -alkil-R 7 , kuriame R 6 ir R 7 reikšmės apibrėžtos aukščiau, (j) -NR 6 CO 2 -C 1 _ 6 -alkil-R 7 , (k) -NR 6 CO-NR 6 R 7 , (l) -oconr 6 r 7 , (m) -COOR 6 , (n) -CHO, (o) arilas, (p) pakeistas arilas, kuriame yra pakaitai X, Y ir Z, (q) -OR 11 , ir (r) -S (O) p -C 1 _ 6 -alkilas;
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(5) heteroaril-C 1 _ 10 -alkilas, kuriame vienas arba keli anglies atomai pakeisti grupe pasirinktina iš:-NR 6 -, -0-, -S(O) p -, -CO 2 , -O 2 C-, -CONR 6 -, -NR 6 CO-, -NR 6 CONR 7 -;
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(6) pakeistas heteroaril-C 1 _ 10 -alkilas, kuriame vienas arba keli alkiliniai anglies atomai pakeisti grupe pasirinktinai iš:-NR 6 -, -0-, -S(O) p -, -CO 2 , -0 2 C-, -CONR 6 -, -NR b CO, -NR 6 CONR 7 -, heteroarilo grupė ι ικιι ιιι.ιι ι ι ι χι ω n ι 227 pakeista X, Y ir Z, o alkilo pakeista vienu arba keliais rinktinai, tarp jų: grupė gali būti pakaitais pasi(a) (b) (c) (d) (e) (f) (g) (h) (i) (j) (k) (D (m) (n) (o) (P) (g) (r)
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(7)
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(8) hidroksilas, oksogrupė, C 1 _ 6 -alkoksigrupė, aril-C 1 _ 3 -alkoksigrupė, pakeista arilC 1 _ 3 -alkoksigrupė, kurioje arilo grupėje yra pakaitai X, Y ir Z, nepakeista arba pakeista ariloksigrupė, kurioje arilo grupėje yra pakaitai X, Y ir Z, -OCO-C^g-alkilas, -NR 6 R 7 , kai R 6 ir R 7 turi aukščiau apibrėžtas reikšmes, -NR 6 CO-C 1 _ 6 -alkil-R 7 , -NR 6 CO 2 -C 1 _ 6 -alkil-R 7 , -nr 6 co-nr s r 7 , -oconr 6 r 7 , -COOR 6 , -CHO, arilas, pakeistas arilas, kuriame yra pakaitai X, Y ir Z, -OR 11 , ir -S (O) p-Cį-g-alkilas; heteroaril-C 3 . 10 -alkenilas, kuriame alkenilas turi nuo vienos iki keturių dvigubų jungčių; heteroaril-C 3 _ 10 -alkenilas, kuriame alkenilas turi nuo vienos iki keturių dvigubų jungčių ir kai vienas arba keli alkiliniai anglies atomai pakeisti I U:! I 228 grupe pasirinktinai iš: -NR 0 -, -0-, -S(O) p -, -CO 2 , -O 2 C-, -CONR 6 -, -NR S CO-, -NR 6 CONR 7 -;
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(9) pakeistas heteroaril-C 3 _ 10 -alkenilas, kuriame alkenilas turi nuo vienos iki keturių dvigubų jungčių ir kai vienas arba keli alkiliniai anglies atomai gali būti pakeisti grupe pasirinktinai iš:-NR 6 -, -0-, -S (O) p -, -CO 2 , -O 2 C-, -CONR 6 -, -NR 6 CO-, -NR°CONR 7 -, heteroarilinė grupė pakeista X, Y ir Z, o alkilo grupė gali būti pakeista vienu arba keliais pakaitais pasirinktinai, tarp jų: (a) hidroksidas, (b) oksogrupė, (c) Cj.g-alkoksigrupė, (d) aril-C 1 _ 3 -alkoksigrupė, (e) pakeista arilC 1 _ 3 -alkoksigrupė, kurioje arilo gruėje yra pakaitai X, Y ir Z, (f) nepakeista arba pakeista ariloksigrupė, kurioje arilo grupėje yra pakaitai X, Y ir Z, (g) -OCO-Ci-g-alkilas, (h) -NR S R 7 , kuriame R 6 ir R 7 reikšmės apibrėžtos aukščiau, (i) -NR°CO-C 1 _g-alkilas, kuriame R 6 reikšmės apibrėžtos aukščiau, (j) -NR 6 CO 2 -C 1 _ 6 -alkilas, (k) -nr 6 co-nr 6 r 7 , (l) -OCONR 6 R 7 , (m) -COOR 6 , (n) -CHO, (o) arilas, (p) pakeistas arilas, kuriame yra pakaitai X, Y ir Z, (q) -OR 11 , ir I III II I uiu .i! ι .ι ..ι;· υι.ι 229 (r) -S (O) p-C^g-alkilas;R 2 gali būti pasirinktinai: iui.ii iiuui ii ι i jnui 230 (k) -CHO, (i) fenilas, (m) pakeistas fenilas, turintis pakaitus X, Y ir Z, (n) 1- arba 2-naftilas, (c) pakeistas 1- arba 2-naftilas, turintis pakaitus X, Y, Z, (p) bifenilas, (q) pakeistas bifenilas, turintis pakaitus X, Y, Z, (r) -OR 11 , ir (s) S (O) p-Ci.g-alkilas;
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(11) C 3 _ 10 -alkenilas;
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(12) pakeistas C 3 _ 10 -alkenilas, turintis pasirinktinai vieną ar daugiau pakaitų, tarp jų:(a) hidroksilas, (b) oksogrupė, (c) C^g-alkoksigrupe, (d) fenil-C 1 _ 3 -alkoksigrupė, (e) pakeista fenil-C : . 3 -alkoksigrupė, kurioje fenilo grupėje yra pakaitai X, Y ir Z, (f) -OCO-C^g-alkiias, (g) -NR 6 R', kuriame R 6 ir R 7 turi aukščiau apibrėžtas reikšmes, (h) -NR 6 CO-C 1 _ 6 -alkilas, kuriame R 6 reikšmės apibrėžtos aukščiau, (i) -COOR 6 , kuriame R 6 reikšmės apibrėžtos aukščiau, (j) -CHO, (k) fenilas, (l) pakeistas fenilas, turintis pakaitus X, Y ir Z, (m) 1- arba 2-naftilas, I III t ! LKBIIK Ii I II ūmini 231 I.«11 m .ii .i i .imu !. 232 (q) -OR 11 , ir (r) -S (0) p-C^g-alkilas;
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(15) -R 11 ; R 3 yra vandenilis, hidroksilas, OR 11 arba C^g-alkoksigrupė; R 4 yra vandenilis arba R 3 ir R 4 kartu sudaro dvigubą jungtį; R 5 yra metilas, etilas, ptopilas arba alilas; R 10 yra vandenilis, hidroksigrupė, OR 11 arba fluoras; R 1 pasirinktinai gali būti :(a) -PO(OH)O M + , kai M + yra teigiamo krūvio neorganinis arba organinis jonas, (b) -SO 3 'M + , (c) -CO(CH 2 )qCO 2 M + , kai q lygus 1-3, ir (d) -CO-C 1 _ 6 -alkil-NR 6 R 7 , kuriame R 6 ir R 7 turi aukščiau apibrėžtas reikšmes ir alkilinę grupė nepakeista arba pakeista vienu arba keliais pakaitais pasirinktinai, tarp jų: (i) hidroksilas, (ii) C 1 . e -alkoksigrupė, (iii) -NR 16 R 17 , kuriame R 16 ir R 17 nepriklausomai vienas nuo kito gali būti pasirinktinai: (a') vandenilis, ir (b ' ) C 3 _ 6 -alkiias, (iv) -COOR 6 , kuriame R 6 reikšmės apibrėžtos aukščiau, (v) fenilas, (vi) pakeistas fenilas, turintis pakaitus X, Y ir Z, ιιιιικ Ji i i .iLig ui 233 (vii) heteroarilas, (viii) -SH, ir (ix) -S-Cį-g-alkilas ;W yra O arba (H, OH) ;X, Y ir Z nepriklausomai vienas nuo kito yra pasirinktinai : (a) vandenilis, (b) C^jo-alkilas, nepakeistas arba pakeistas vienu ar keliais pakaitais, tarp kurių pasirinktinai: (i) arilas, (ii) pakeistas arilas, turintis pakaitus X', Y' ir Z', (iii) heteroarilas, (iv) pakeistas heteroarilas, turintis pakaitus X', Y' ir Z ' , (v) nepakeistas arba pakeistas ariloksiradikalas, turintis arilo grupėje pakaitus X', Y' ir Z', (vi) -OR 6 , (vii) -OR 11 , (viii) -OCOR S , (ix) -OCO 2 R 6 , (x) -NR S R 7 , (xi) -CHO, (xii) -NR 6 CO-C : _ 6 -alkil-R 7 , (xiii) -NR 6 CO 2 -C ,_ 6 -alkil-R 7 , (xiv) -NR 6 CONR 6 R ? , (XV) -oconr 5 r\ (xvi) -CONR 6 R 7 , ιιιυι 234 (c) y.^-alkilas, kai vienas arba keli alkiliniai anglies atomai pakeisti grupe pasirinktinai iš: -NR 6 -, -0-, -S (O) p -, -CO 2 , -O 2 C-, -CONR 6 -, -NR 6 CO-, -NR 6 CONR 7 -, -CO-, -CH(OH)-, alkenilas arba alkinilas ir alkilas gali būti nepakeistas arba pakeistas vienu ar keliais pakaitais pasirinktinai, tarp jų: I.UIIK !;.1 II Jhll UI· 235 (i) -SR 8 , kai R 8 vandenilis, C^g-alkilas, trifluormetilas arba fenilas, (j) -SOR 8 , (k) -SO 2 R 8 , (l) -conr 6 r 7 , (m) R 9 O(CH 2 ) m -, kai R 9 yra vandenilis, C^g-alkilas, hidroksi-C 2 _ 3 -alkilas, -CF 3 , fenilas, R 11 arba naftilas ir m lygu 0, 1, 2 arba 3, (n) -CH (OR 12 ) (OR 13 ) , kai R 12 ir R 13 yra C 1 _ 3 -alkilas arba kartu sudaro etilinį ar propilinį tiltelį, (o) R 9 COO (CH 2 ) m ~, kuriame R 9 ir m reikšmės apibrėžtos aukščiau, (p) R 9 OCO (CH 2 ) n,-, kuriame R 9 ir m reikšmės apibrėžtos aukščiau, ir (q) -R 11 ;arba bet kurie du iš X, Y, Z gali būti sujungti norint sudaryti sotų žiedą, turintį 5, 6 arba 7 atomus, tarp šio žiedo atomų yra 1 arba 2 deguonies atomai, likusieji atomai yra anglies, X', Y' ir Z' nepriklausomai vienas nuo kito yra pasirinktinai : (a) vandenilis, (b) C^-alkilas, (c) C 2 _ 6 -alkenilas, (d) halogenas, 6 7 6 7 (e) (CH 2 ) m -NRR , kuriame R , R ir m reikšmės apibrėžtos aukščiau, (f) -CN, (g) -cho, imu . i i i.mi.ui 236 brėžtos aukščiau, J 1 (o) R CO(CH 2 ) m -, kuriame R ir m reikšmės apibrėžtos aukščiau, II 9 9 (p) R CO(CH 2 ) m -, kuriame R ir m reikšmės apibrėžtos aukščiau, ir (g) -R 11 ;n yra 1 arba 2. 2. Junginys pagal 1 punktą, besiskiriantis tuo, kad jame absoliuti konfigūracija Formulėje I yra apibrėžta Formule III: III ιι·!ΐ,ιι, .. I 1 ΙίΙΙΙΙ.';,;! LT 3533 Β 237 3. Junginys pagal 1 punktą, besiskiriantis tuo, kad jame heteroarilas yra pasirenkamas iš grupės, i, kurios sudėti, įeina: (Pirimidinas) (Pirazinas) lllll 238 X (Izochinolinas) X (Chinoksalinas) kai Q yra -N(X)-, -O arba -S-. 4. Junginys pagal 3 punktą, besiskiriantis tuo, kad jame heteroarilas yra parenkamas iš grupės, į kurios sudėtį įeina: I «1,1 U-l ιιι» m ·;Ί 1 .11 EB [,! . 239 MISI lllllllli I! .III lt I litui, :i 1.1 i 240 kuriame X reikšmės apibrėžtos 1 punkte i ui ai 241 5. Junginys pagal 1 punktą, besiskiriantis tuo, kad heteroarilas yra: R 2 yra pasirinktinai: (1) vandenilis, (2) metilas, (3) etilas, (4) propilas, (5) alilas, (6) R 11 , (7) -C 2 - 3 alkil-OH;ir (8) C 2 _ 3 alkil--OR 11 ;R 3 yra pasirinktinai: (1) vandenilis, (2) hidroksigrupė, (3) OR 11 , arba R 3 ir R 4 kartu sudaro dvigubą jungtį;R 10 yra vandenilis, hidroksigrupė, fluoras arba OR 11 ;W yra 0;ir n lygu 2. llll 11111«! JI Iii II IJIIUII .1 11,1 242 6. Junginys, kuris parinktas iš grupės, kurioje yra: 17-Eti1-1,14-dihidroksi-12-[ 2'-(4''-(2-furanil)metoksi3' '-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'-(4''-(2-furanil)metoksi3' '-hidroksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'- (4' '-hidroksi-3' '-(2furanil)-metoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas ;17-Etil-l,14-dihidroksi-12-[ 2' -(4' '-(2-tiofen)-metoksi3' '-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2' -(4' '-(2-tiofen)-metoksi3' '-hidroksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'-(4' '-(3-tiofen)-metoksi3' '-hidroksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'-(4''-hidroksi-3''-(2tiofen)-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa~4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16-tetraonas;1 111 ιΝ Ιλ·Ι· '1 Ί II. .11111.111 243 17-Etil-l,14-dihidroksi~12-[ 2'-(4''-hidroksi-3'’ — (3 — tiofen)-metoksicikloheksil)-1'-metilvinil] -23,25-dime toksi-13,19,21,27-tetrametii-ll,28-dioksa~4-azatricikio-[ 22.3.1. O 4,9 ] oktakoz-lS-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2’-(4’(2-tiofen)oksi-3’’metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi13.19.21.27- tetrametil-i1,28-dioksa-4-azatriciklo [ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2’—(4''-(2-benzotienil)oksi-3 ' '-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12—[ 2'-(4''-(5-indolil)oksi3' '-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi13.19.21.27- tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2’—(4''-(5-indolil)oksi3' '-hidroksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2 , 3,10,16-tetraonas;17-Eti1-1,14,20-trihidroksi-12-[ 2'-(4''-(5-indolil)oksi-3''-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4 ' 9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,20-dihidroksi-12-[ 2' — (4’'-(5-indolil)oksi3''-metoksicikloheksil)-1'-metilvinil]-23,25-dimetoksi13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16-tetraonas;17-Etil-l-hidroksi-12-[ 2'-(4''-(5-indolil)oksi-3''metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksiI III I Ullllllll .11 III II Lllll!. I 1..I.I 244 13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4 ' 9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l,14-dihidroksi-12-[ 2' — (4’ '-(5-indolil)oksi3' '-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16-tetraonas;17-Alil-l,14-dihidroksi-12-[ 2 ' - (4 ''-(5-indolil)oksi3''-hidroksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l,14,20-trihidroksi-12-[ 2'- (4' '-(5-indolil)oksi-3' '-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-l 3, 19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l,20-dihidroksi-12-[ 2'-(4''-(5-indolil)oksi3''-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3, 10, 16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'- (4' '-(5-indolil)oksi3' '-etoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2, 3,10, 16-tetraonas;17-Alil-l,14-dihidroksi-12-[ 2'-(4''-(5-indolil)oksi3' '-etoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi13.19.21.27- tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16-tetraonas;17-Alil-l-hidroksi-12-[ 2'- (4 ' '-(5-indolil)oksi-3''metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi13.19.21.27- tetrametil-ll,2S-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16-tetraonas;1 Illi »J 245 17-Eti1-1,14-dihidroksi-12-[ 2 ' - (4 ' '-(l-N-metil-5indolil)-oksi-3' '-metoksicikloheksil)-1’-metilvinil] 23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2, 3,10, 16-tetraonas;17-Etii-l,14-dihidroksi-12-[ 2'-(4''-(l-N-metil-5-indolil)-oksi-3’ '-hidroksicikloheksil)-1'-metilvinil] 23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas ;17-Etil-l,14,20-trihidroksi-12-[ 2'-(4' l-N-metil-5indoIii)-oksi-3' '-metoksicikloheksil)-!'-metilvinil] 23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas ;17-Eti1-1,14,20-trihidroksi-12-[ 2'-(4''-(l-N-metil-5indolil)-oksi-3''-hidroksicikloheksil)-1'-metilvinil] 23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa~4azatrici klo-[ 22.3.1.O 4 ' 9 ] oktakoz-18-en-2,3,10,16-tetraonas ;17-Etil-l,20-dihidroksi-12-[ 2'- (4' '-(l-N-metil-5-indolil)-oksi-3 ' '-metoksicikloheksil·)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,2 8-dioksa-4-azatriciklo-[ 22'. 3.1. O 4,9 ] oktakoz-18-en-2,3,10, 16-tetraonas;17-Etil-l,20-dihidroksi-12-[ 2'-(4' '-(l-N-metil-5-indolil)-oksi-3' '-hidroksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l,14-dihidroksi-12-[ 2'- (4' '-(l-N-metil-5-indo1i1)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] -23,25ιιιι ΙΙΙΙΙΜΙΙ! I! ,ΙΙί ,11 I„H I IJ J 246 dimetoksi-13,19,21,27-tetrametil-ll,2 8-dioksa-4-azatriciklo-[ 22.3.1.O 4 ' 9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l,14,2 0-trihidroksi-12-[ 2’- (4 ' '-(l-N-metil-5indolil)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] 23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1.O 4 ' 9 ] oktakoz-18-en-2,3, 10, 16-tetraonas;17-Ali1-1,20-dihidroksi-12-[ 2’-(4''-(l-N-metil-5-indolil)-oksi-3''-metoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10, 16-tetraonas;17-Etil-l-hidroksi-12-[ 2’—(4''-(l-N-metil-5-indolil)oksi-3' '-metoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.0 4 ' 9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Eti1-1,14-dihidroksi-12-[ 2'-(4''-(l-N-metil-5-indolil)-oksi-3' '-etoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21 ,.27-tetrametil-l 1,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Ali1-1,14-dihidroksi-12-[ 2'- (4' '-(l-N-metil-5-indolil)-oksi-3''-etoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2' -(4' '-(l-N-etil-5-indo1i1)-oksi-3' '-etoksicikloheksil)-1'-metilvinil] -23,2 5dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l-hidroksi-12-[ 2'-(4''-(l-N-etil-5-indolil)oksi-3' '-metoksicikloheksil)-1'-metilvinil] -2 3,2 5-dime1 Ml JI J UHIKI JI .1 1 I III Ll·· J! 247 toksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4 ' 9 ] oktakoz-18-en-2, 3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2’-(4’'-(l-N-metil-5-indolil)-oksi-3''-aliloksicikloheksil)-1'-metilvinil]-23, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3, 10, 16-tetraonas;17-Etil-l-hidroksi-12-[ 2'-(4''-(l-N-metil-5-indolil)oksi-3''-aliloksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2, 3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'-(4''-(1-N-metii-5-indolil) -oksi-3''-n-propiloksicikloheksil)-1'-metilvinil] 23.25- dimetoksi-13,19,21,27-tetrametil-ll, 28-dioksa-4azatriciklo-[ 22.3.1.O 4 ' 9 ] oktakoz-18-en-2,3,10,16-tetraonas ;17-Etil-l-hidroksi-12-[ 2’-(4''-(l-N-metil-5-indolil)oksi-3' '-n-propiloksicikloheksil)-1'-metilvinil]-23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'-(4''-(1-N-metil-5-indolil)-oksi-3''-i-propiloksicikloheksil)-1'-metilvinil] 23.25- dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1.0 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'-(4'’-(l-N-etil-5-indo111)-oksi-3''-metoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14,20-trihidroksi-12-[ 2'- (4''-(l-N-etil-5indoIii)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] ιιιι IUIUK L! ,11 11 J JIUIj , I 248 23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1.O 4 ' 9 ] oktakoz-18-en-2,3,10, 16-tetraonas ;17-Etil-l,2 0-dihidroksi-12-[ 2 ’ — (4 ’'-(l-N-etil-5-indolil)-oksi-3 ' '-metoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'-(4''-(l-N-etil-5-indolil)-oksi-3' '-hidroksicikloheksil)-1'-metilvinil] -2 3, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2, 3,10, 16-tetraonas;17-Alil-l,14-dihidroksi-12-[ 2'-(4''-(l-N-etil-5-indolil)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l,14,20-trihidroksi-12-[ 2'-(4''-(l-N-etil-5-indolil)-oksi-3''-metoksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.0 4 ' 9 ] oktakoz-18-en-2,3,10, 16-tetraonas;17-Alil-l,20-dihidroksi-12-[ 2’—(4’'-(l-N-etil-5-indolil) -oksi-3 ' '-metoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4 ' 9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Ali1-1,14-dihidroksi-12-[ 2'- (4''-(l-N-etil-5-indolil)-oksi-3''-hidroksicikloheksil)-1'-metilvinil]-23, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l-hidroksi-12-[ 2'- (4''- (l-N-etil-5-indolil)-oksi-3 ' '-metoksicikloheksil)-1'-metilvinil] -23,25-dime1 IIU 3) ŪMUI ·!;Ί 1 DU D'I. 249 toksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3, 10, 16-tetraonas;17-Alil-l-hidroksi-12-[ 2’-(4'(1-N-etil-5-indolii)oksi-3' '-metoksicikloheksil)-1'-metilvinil] -2 3,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l,14-dihidroksi-12-[ 2’ — (4' '-(1-N-etil-5-indolil)-oksi-3' '-etoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-l 3, 19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10, 16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'-(4''-(l-N-propil-5-indolil)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16-tetraonas;17-Etil-l,14,20-trihidroksi-12-[ 2'-(4''-(l-N-propil-5indolii)-oksi-3' '-metoksicikloheksil)-1’-metilvinil] 23,25-dimetoksi-l3,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,20-dihidroksi-12-[ 2'-(4' '-(l-N-propil-5-indolil)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-l 3, 19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2, 3, 10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'-(4''-(l-N-propil-5-indolil)-oksi-3' '-hidroksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi-l3,19,21,27-tetrametil-ll, 28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16-tetraonas;17-Etil-l, 14,20-trihidroksi--12-[ 2 ' - (4 ' ' - (1 -N-propil-5indolil)-oksi-3' '-hidroksicikloheksil)-1'-metilvinil] 23,25-dimetoksi-l3,19,21,27-tetrametil-ll,28-dioksa-4I 1)11 IUIMI IS iii J UB.IIIJ 250 azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas ;17-Etil-1,20-dihidroksi-12-[ 2’-(4'’-(l-N-propil-5-indolil)-oksi-3' '-hidroksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi-l3,19,21,27-tetrametil-ll,18-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l,14-dihidroksi-12-[ 2'-(4''-(l-N-propil-5-indolil)-oksi-3''-metoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.0 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l,14,20-trihidroksi-12-[ 2'-(4''-(l-N-propil-5indolil)-oksi-3''-metoksicikloheksil)-1'-metilvinil] 2 3,25-dimetoksi-l3,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas ;17-Alil-l,20-dihidroksi-12-[ 2'-(4'’-(l-N-propil-5-indolil) -oksi-3’'-metoksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi-l3,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16-tetraonas;17-Alil-l,14-dihidroksi-12-[ 2'-(4''-(l-N-propil-5-indolil)-oksi-3' '-hidroksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3, 10, 16-tetraonas;17-Etil-l-hidroksi-12-[ 2'-(4''-(l-N-propil-5-indolil) oksi-3' '-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Ali1-1-hidroksi-12-[ 2’-(4''-(l-N-propil-5-indolil) oksi-3' '-metoksicikloheksil)-1'-metilvinil] -23,25-dii iu i UUD i;ii 1 .1 .IMI. U* 251 metoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4 ' 9 ] oktakoz-18-en-2,3, 10, 16-tetraonas;17-Eti 1-1,14-dihidroksi-12-[ 2’-(4''-(l-N-propil-5-indolil)-oksi-3''-etoksicikloheksil)-1'-metilvinil] -2 3,2 5dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2, 3,10,16-tetraonas;17-Alil-l,14-dihidroksi-12-[ 2' — (4''-(l-N-propil-5-indolil)-oksi-3''-etoksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Eti1-1,14-dihidroksi-12-[ 2'- (4' '- (l-N-alil-5-indolil)-oksi-3''-metoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4 ' 9 ] oktakoz-18-en-2, 3,10, 16-tetraonas;17-Etil-l,14,20-trihidroksi-12-[ 2'-(4''-(l-N-alil-5indolil)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] 23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas ;17-Etil-l,20-dihidroksi-12-[ 2'-(4’'-(l-N-alil-5-indolil)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] -23, 25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'-(4''-(l-N-alil-5-indolil)-oksi-3' '-hidroksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14,20-trihidroksi-12-[ 2’—(4''-(l-N-alil-5-indolil)-oksi-3''-hidroksicikloheksil)-1'-metilvinil] -23, I III I imiaiš n iii. i UBU . 1 l ll 252 25-dimetoksi-l3,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4 ' 9 ] oktakoz-18-en-2,3,10, 16-tetraonas ;17-Etil-l,20-dihidroksi-12-[ 2’-(4' '-(l-N-alil-5-indolil)-oksi-3' '-hidroksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi-l3,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l,14-dihidroksi-12-[ 2'-(4''-(L-N-alil-5-indolil)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l,14,20-trihidroksi-12-[ 2'-(4’'-(l-N-alil-5-indolil)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi-l3,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l,20-dihidroksi-12-[ 2'-(4''-(l-N-alil-5-indolil)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] -2 3,2 5dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l,14-dihidroksi-12-[ 2'- (4' '- (l-N-alil-5-indolil)-oksi-3' '-hidroksicikloheksil)-i'-metilvinil] -23, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4 ' 9 ] oktakoz-18-en-2, 3,10,16-tetraonas;17-Etil-l-hidroksi-12-[ 2'-(4''-(l-N-alil-5-indolil)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4 ' 9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-1-hidroksi-12-[ 2 ' - (4 ' '-(l-N-alil-5-indolil)-oksi-3 ' '-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2, 3,10,16-tetraonas;1 »1 44 UBO I r I1U, IIIU 253 17-Etil-l,14-dihidroksi-12-[ 2'-(4''-(l-N-alil-5-indolil)-oksi-3''-etoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16-tetraonas;17-Alil-l,14-dihidroksi-12-[ 2'-(4''- (l-N-alil-5-indolil)-oksi-3''-etoksicikloheksil)-1'-metilvinil] -2 3,2 5dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'—(4''-(l-N-2-hidroksietil-5-indolil)-oksi-3''-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16- tetraonas;17- Etil-l,14,20-trihidroksi-12-[ 2' — (4''-(l-N-2-hidroksietii-5-indolil)-oksi-3''-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-l3,19,21,27-tetrametil-ll, 28dioksa-4-azatriciklo-[ 22.3.1.0 4,9 ] oktakoz-18-en-2,3,10, 16- tetraonas;17- Etil-l,20-dihidroksi-12-[ 2'—(4'’-(l-N-2-hidroksietil-5-indolil)-oksi-3''-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-l3,19,21,27-tetrametil-ll, 28dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16- tetraonas;17- Etil-l,14-dihidroksi-12-[ 2'-(4''-(l-N-2-hidroksietil-5-indolil)-oksi-3''-hidroksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-l3,19,21,27-tetrametil-ll, 2 8dioksa-4-azatriciklo-[ 22.3.1.0 4 ' 9 ] oktakoz-18-en-2,3,10, 16- tetraonas;17- Eti1-1,14,20-trihidroksi-12-[ 2' -(4' '-(l-N-2-hidroksietil-5-indolil) -oksi-3''-hidroksicikloheksil)-1'-metilvinil] -23,2 5-dimetoksi-13,19,21,27-tetrametil-ll,28IIIIL , 11111«! Ji ;IL I J.JIBJ;254 dioksa-4-azatriciklo-[ 22.3.1. O 4 ' 9 ] oktakoz-18-en-2,3,10, 16- tetraonas;17- Etil-l,2 0-dihidroksi-12-[ 2 ’ - (4 ’’ - (1-N-2-hidroksietil-5-indolil)-oksi-3’’-hidroksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-l3,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4 ' 9 ] oktakoz-18-en-2,3, 10,16tetraonas ;17-Alil-l,14-dihidroksi-12-[ 2’-(4’’-(1-N-2-hidroksietil-5-indolil)-oksi-3’’-metoksicikloheksil)-1’-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4 ' 9 ] oktakoz-18-en-2,3,10,16tetraonas ;17-Alil-l,14-dihidroksi-12-[ 2’—(4’'-(1-N-hidroksietil5-indolil)-oksi-3''-hidroksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-l3,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4 ' 9 ] oktakoz-18-en-2,3,10,16tetraonas ;17-Eti1-1,14-dihidroksi-12-[ 2'-(4''-(l-N-benzil-5-indoiii)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] -2 3, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Eti1-1,14,20-trihidroksi-12-[ 2'- (4' '-(l-N-benzil-5indolil)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] 23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas ;17-Etil-l,20-dihidroksi-12-[ 2 ' - (4' '-(l-N-benzil-5-indolil)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] -2 3, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] ok.takoz-18-en-2,3, 10, 16-tetraonas;I 1IU ELI IUHD Ϊ: !l 1 .1!« 1,113 255 17-Etil-l,14-dihidroksi-12-[ 2'- (4 ' '-(l-N-benzil-5-indolil)-oksi-3''-hidroksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14,20-trihidroksi-12-[ 2’-(4''-(l-N-benzil-5indolil)-oksi-3''-hidroksicikloheksil)-1'-metilvinil] 23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1. O 4 ' 9 ] oktakoz-18-en-2,3,10,16-tetraonas ;17-Etil-l,20-dihidroksi-12-[ 2'-(4' '-(l-N-benzil-5-indolil)-oksi-3''-hidroksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.0 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l,14-dihidroksi-12-[ 2'-(4' '-(l-N-benzil-5-indolil)-oksi-3''-metoksicikloheksil)-1'-metilvinil] -23, 25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l,14,20-trihidroksi-12-[ 2’—(4’'-(l-N-benzil-5indolil)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] 23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l,20-dihidroksi-12-[ 2'- (4' '- (1-N-benzi1-5-indo iii)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] -2 3, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3, 10, 16-tetraonas;17-Alil-l,14-dihidroksi-12-[ 2'- (4 ' '-(l-N-benzil-5-indolil)-oksi-3''-hidroksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2, 3,10,16-tetraonas;1111 256 17-Etil-l-hidroksi-12-[ 2' — (4’'-{l-N-benzil-5-indolil)oksi-3’’-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4 ' 9 ] oktakoz-18-en-2,3, 10,16-tetraonas;17-Alil-l-hidroksi-12-[ 2 1 -(4’’-(l-N-benzil-5-indolil)oksi-3' '-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'-(4''-(l-N-benzil-5-indolil)-oksi-3' '-etoksicikloheksil)-1'-metilvinil] -23,25dime toks i-13, 19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.0 4,9 ] oktakoz-18-en-2,3, 10,16-tetraonas;17-Alil-l,14-dihidroksi-12-[ 2'-(4''-(l-N-benzil-5-indolil)-oksi-3''-etoksicikloheksil)-1'-metilvinil] -23,25dime toks i-13, 19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, Ιβ-t-etraonas;17-Etil-l,14-dihidroksi-12-[ 2'—(4’'-(l-N-ciklopropil-5indolil)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] 23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2, 3,10,16-tetraonas ;17-Etil-l,14-dihidroksi-12-[ 2' — (4’ ' - (l-N-ciklopropil-5indolil)-oksi-3' '-hidroksicikloheksil)-1'-metilvinil] 23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2, 3,10,16-tetraonas ;17-Ali1-1,14-dihidroksi-12-[ 2’ — (4’'-(l-N-ciklopropil-5indolil)-oksi-3' '-metoksicikloheksil)-1'-metilvinil] 23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2, 3,10,16-tetraonas ;257 17-Alil-l,14-dihidroksi-12-[ 2'- (4' '-(l-N-ciklopropil-5indolil)-oksi-3' '-hidroksicikloheksil)-1'-metilvinil] 23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas ;17-Etil-l,14-dihidroksi-12-[ 2'- (4' '-(l-N-ciklopropil-5indolil)-oksi-3' '-etoksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4 ' 9 ] oktakoz-18-en-2,3,10, 16-tetraonas;17-Alil-l,14-dihidroksi-12-[ 2'-(4''-(l-N-ciklopropil-5indolil)-oksi-3' '-etoksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l-hidroksi-12-[ 2'- (4''-(l-N-ciklopropil-5-indolil)-oksi-3''-metoksicikloheksil)-1'-metilvinil] -23,25dime to ksi-13, 19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Alil-l-hidroksi-12-[ 2'-(4''-(l-N-ciklopropil-5-indolil)-oksi-3''-metoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l-hidroksi-12-[ 2'-(4' '-metoksi-N-triptofanilkarbonil-metoksi-3''-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3, 10, 16tetraonas ;17-Etil-l-hidroksi-12-[ 2'-(4''-(3-indolil)etilaminokarbonil-metoksi-3''-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.0 4,9 ] oktakoz-18-en-2,3, 10,16tetraonas ;lllil . IIHIIII! JI Jll III ILIIIIIJ. IU I 258 17-Etil-l,14-dihidroksi-12-[ 2'- (4' '-1-(3-hidroksipropil)-indolil-5-il)-oksi-3''-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-l3,19,21,27-tetrametil-ll,28dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16- tetraonas;17- Etil-l,14-dihidroksi-12-[ 2'-(3''-hidroksi-4''-(1hidroksietilindol-5-il)-oksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-l3,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2, 3,10,16tetraonas ;17-Etil-l,14-dihidroksi-12-[ 2'-(4''-(1-hidroksietilindol-6-il)oksi-3''-metoksicikloheksil)-1'-metilvinil] 23,25-dimetoksi-l3,19,21,27-tetrametil-ll,28-dioksa-4azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3, 10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'- (4' '-(l-metilindol-6il)oksi-3''-metoksicikloheksil)-1'-metilvinil]-23,25dimetoksi-l 3 , 19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2’—(4’'-(1-dibenzilfosfonoksi-etilindol-5-il)oksi-3''-metoksicikloheksil)-1'metilvinil] -2 3,25-dimetoksi-l3,19,21,27-tetrametil-ll, 28-dioksa-4-azatricik.lo-[ 22.3.1.0 4,9 ] oktakoz-18-en-2,3, 10,16-tetraonas;17-Eti1-1,14-dihidroksi-12-[ 2'-(4''-(1-fosfonoksi-etilindol-5-il)oksi-3''-metoksicikloheksil)-1'-metilvinil] -2 3,25-dimetoksi-l3,19,21,27-tetrametil-ll,28-dioksa-4-azatricii lo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2, 3,10,16tetraono mcnokalio druska;17-Etil-l,14-dihidroksi-12-[ 2 1 —(4’'-(1-(N,N-dimetilgliciloksi)etilindol-5-il)oksi-3''-metoksicikloheksil)-1'I Ui ELI 259 metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametilll, 28-dioksa-4-azatriciklo-[ 22.3.1.O 4 ' 9 ] oktakoz-18-en2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'-(4' '-(1-sukciniloksietilindol-5-il)oksi-3''-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16- tetraonas;17- Etil-l,14-dihidroksi-12-[ 2'-(4''-(l-metil-3-fenilindolil-5-il)oksi-3''-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16tetraonas ;17-Etil-l,14-dihidroksi-12-[ 2'-(4' '-(l-metil-3-(2-hidroksietil)-indol-5-il)oksi-3''-metoksicikloheksil)-1' metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll, 28-dioksa-4-azatriciklo-[ 22.3.1.0 4 ' 9 ] oktakoz-18-en-2,3, 10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'- (4' '-(1,3-dimetilindol5-il)oksi-3' ’-metoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4 ' 9 ] oktakoz-18-en-2, 3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'- (4' '-(9'-metilkarbazol3'-ii)oksi-3''-metoksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2' - (4' '- ( (2' '' '- (3'''''dietilaminopropioniloksi)etil)indol-5'''-ii)oksi-3''metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;ιιιι ΙΙΙίΙΙΙΙί Ii .III III I llllll, ,1,1,1 J 260 17-Etil-l,14-dihidroksi-12-[ 2 '- (4' '-( (2'’''- (3’''''dimetilaminopropioniloksi)etil)indol-5''’-il)oksi-3'' metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi13.19.21.27- tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2’-(4’ '-( (2' ’ ' '-(3' ' ' ' 'aminopropioniloksi)etil)indol-5'''-ii)oksi-3''-metoksicikloheksil) -1'-metilvinil] -23,25-dimetoksi-l3,19,21, 27-tetrametil-ll, 28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2’-(4 ,, -((2’'’'-(3' ,,, 'benziloksikarbonil-2'''''-benziloksikarbonilaminopropioniloksi)etil)indol-5'’'-il)oksi-3''-metoksicikloheksil) -1'-metilvinil] -2 3,25-dimetoksi-13,19,21,27tetrametil-ll, 28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-1,14-dihidroksi-12-[ 2'-(4''-((2''''-(aspartiloksi)etil)indol-5'''-il)oksi-3''-metoksicikloheksil)1'-metilvinil] -23,25-dimetoksi-l3,19,21,27-tetrametilll, 28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'-(4’ '-((2’'''-(1' ' ' ' 'imidazolilkarboniloksi)etil)indol-5'''-ii)oksi-3''metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi13.19.21.27- tetrametil-ll, 28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'-(4''-((2''''-(l'''''piperazinkarboniloksi)etil)indol-5'''-ii)oksi-3''metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi13.19.21.27- tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4 ' 9 ] oktakoz-18-en-2,3,10,16-tetraonas;261 17-Etil-l,14-dihidroksi-12-[ 2’-(4 IT -(l’''-(2’’’’(2 ' ' ' ' '-hidroksi)etilaminokarboniloksi)etil)indol-5'''ii)oksi-3''-metoksicikloheksil)-1'-metilvinil] -23,25dimetoksi-13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2'-(4’'- (1’'’- (2 '''’-(izopropi1aminokarboniloksi)etil)indol-5''’-il)oksi-3''-metoksicikloheksil ) -1'-metilvinil] -23,25-dimetoksi13.19.21.27- tetrametil-ll,28-dioksa-4-azhtriciklo[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l, 14-dihidroksi-12-[ 2^(4^-(1^-(2-^(1'''''-piperidinkarboniloksi)etil)indol-5'''-ii)oksi3''-metoksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi13.19.21.27- tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.0 4 ' 9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l, 14-dihidroksi-12-[ 2^(4^-(1^^(2^^(11 i * ι i-morfolinkarboniloksi)etil)indol-5'''-ii)oksi3''-metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l, 14-dihidroksi-12-[ 2'-(4''-(l’'’-(2'’'’(difenilaminokarboniloksi)etil)indol-5'''-ii)oksi-3''metoksicikloheksil)-1'-metilvinil] -23,25-dimetoksi13,19,21, 27-tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10, 16-tetraonas;17-Etil-l, 14-dihidroksi-12-[ 2--(4^-(1^^(2^^(dietilaminokarboniloksi)etil)indol-5'''-ii)oksi-3''metoksicikloheksil)-1'-metilvinil] -23, 25-dimetoksi13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3, 10,16-tetraonas;lllll· llhlllll .11 .III II J.II1BI, I 11 262 17-Etil-l,14-dihidroksi-12-[ 2’-(4 TT -(l’’’-(2’’ ,T (metansulfoniloksietil)indol-5'''-ii)oksi-3''-metoksicikloheksil) -1'-metilvinil] -23,25-dimetoksi13,19,21,27-tetrametil-ll,28-dioksa-4-azatriciklo[ 22.3.1.O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2 '- (4' '- (1' ''- (2 ' ' ' ' azidoetil)indol-5'''-ii)oksi-3''-metoksicikloheksil)1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametilll, 28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en2,3,10,16-tetraonas;17-Etil-l,14-dihidroksi-12-[ 2 '-(4'’-(1'''-(2 ''''-aminoetil)indol-5'''-ii)oksi-3''-metoksicikloheksil)-1'metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametilll, 28-dioksa-4-azatriciklo-[ 22.3.1.O 4 ' 9 ] oktakoz-18-en2,3,10,16-tetraonas;17-Etil-l, 14-dihidroksi-12-[ 2’-(4-(l ’-t-butildimetilsililoksietoksietilindol-5'''-ii)oksi-3’'-metoksicikloheksil) -1'-metilvinil]-23,25-dimetoksi-l3,19,21, 27-tetrametil-ll, 28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz-18-en-2,3,10,16-tetraonas;17-Etil-l, 14-dihidroksi-12-[ 2^(4^-(1^ '-hidroksietoksietilindol-5''’-il)oksi-3''-metoksicikloheksil)1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametilll, 28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz-18-en2,3,10,16-tetraonas;17- Etil-l,14-dihidroksi-12-[ 2'-(3''-metoksi-4' '- (1'’'(1''''-oksoprop-3'''’-il)indol-5''’-il)oksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-11,28-dioksa-4-azatriciklo-[ 22.3.1.O 4,9 ] oktakoz18- en-2,3,10,16-tetraonas;ir i nu ii.i 1UIUI1 Ji ii lt Lili L! .11,1 263 17-Etil-l,14-dihidroksi-12-[ 2'-(3''-metoksi-4''-(1''' (1'''’-karboksiet-2''''-ii)indol-5'’'-ii)oksicikloheksil)-1'-metilvinil] -23,25-dimetoksi-13,19,21,27-tetrametil-ll, 28-dioksa-4-azatriciklo-[ 22.3.1. O 4,9 ] oktakoz5 18-en-2,3,10,16-tetraonas;arba jų farmaciniu požiūriu priimtina druska. 7. Farmacinė kompozicija, besiskirianti 10 tuo, kad ą jos sudėtą ąeina farmacinis nešiklis ir terapiškai efektyvus kiekis junginio pagal 1 punktą. 8. Junginio pagal 1 punktą panaudojimas gaminti vaistus, kurie skirti imunoreguliacinių sutrikimų gydymui. 9. Junginio pagal 1 punktą panaudojimas gaminti vaistus, kurie skirti atsparumo transplantacijai gydymui. 10. Junginio pagal 1 punktą panaudojimas gaminti vais20 tus, kurie skirti uždegiminių ir hiperproliferatyvinių odos susirgimų gydymui arba ant odos pasireiškiančių su imunine sistema susijusių susirgimų gydymui.

Independent claims12

2,098 paragraphs in 182 sections, as filed

The present invention describes Ο-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylacrolides useful in the treatment of mammals for autoimmune diseases (such as juvenile diabetes mellitus, multiple sclerosis and rheumatoid arthritis), immunodepression, to prevent rejection of transplanted foreign organs (for example, bone marrow transplantation, heart and xenograft transplantation), also useful in the treatment of locally inflammatory and hyperproliferative skin conditions and skin-related immune-related disorders (such as psoriasis, atopic dermatitis, contact dermatitis, and other eczema dermatitis, seborrheic dermatitis, lichen erythema, vesicular, bullous, , urticaria, angioedema, angina, erythema, cutaneous euzinophilia, blistering alopecia, male alopecia, senile alopecia, reversible obstructive airway disease, particularly asthma, alopecia, lymph and blood vessel inflammation, cytomegalovirus infection, multiple drug resistance, idiopathic thrombocytopenic pink rash, Behcet syndrome, conjunctivitis, Crohn's disease, Mooren's ulcer, uveitis lesion associated with ischemic disease. In addition, some of the compounds of the present invention may have antagonistic properties and may therefore be adapted to eliminate the activity of other immunosuppressive agents and / or to reduce their toxicity.

More particularly, the present invention describes compounds of the general formula I:

I II I I I I I

in which R1F R2, R3, R4, R5, R10, W and n are defined below.

The present invention also describes a pharmaceutical composition containing the compounds and a method of using these compounds and other agents for the treatment and prophylaxis of certain disorders, disorders, diseases and conditions.

Fijisawa United States, European and Japanese Patents and Applications (U.S. Pat. Nos. 4, 894, 366, 1990, EPO 0, 184, 162, and PBJ Nos. 63-17884) and publications (J. Am.

Chem. Soc., 1987, 109, 5031 ir J Antibiotics 1987, £0

1249) 17-allyl-1, 14-dihydroxy-12- [2 '- (4' 'hydroxy-3' '- methoxy-cyclohexyl) -1'-methylvinyl] -23,

25-dimethoxy-13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4azatricyclo- [22. 3. 1. O4,9] Oktakoz 18 en 2, 3, 10, 16tetraoną (FR-900 506), (CF-506), (The 679, 934) with 17 ethyl,

14-dihydroxy-12- [2 '- (4' '- hydroxy-3' '- methoxycyclohexyl) -1' -methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27tetramethyl-1,11, 28-dioxa- 4-azatricyclo- [22. 3. 1.-04,9] octacos-18-en-2, 3, 10, 16-tetraone (FR-900520) 'and related compounds which are the starting materials for the synthesis of the described compounds. Synthesis of said starting material (FR-900506) has been recently described (J. Am. Chem. Soc., 1989, iii, 1157). Sandoz's European Patent Application (EPO No. 0 356 399) describes stereoisomers FR-900506 and their derivatives in position 17. Fison

I

<td>firms</td><td>in applications</td><td>3 European</td><td>and</td><td>WIPG patents</td><td>(EPO</td>

<td>No. 0</td><td>323,042) and</td><td colspan="2">WO 89/05304)</td><td>various are described</td><td>FR-</td>

<td> 900506</td><td>FR-900520 ir</td><td>similar</td><td colspan="3">compounds. Sandoz pads-</td>

This European Patent (EPO 0 437 680) describes chlorine, bromine, iodine and azide derivatives of FR900506, FR-900520 and the like. Merck's European Patent Application (EPO No. 0 428 365) describes various amino acids of FR-900506, FR900520 and similar compounds. Fujisawa's patent application (GB 2 245 891-A) describes various derivatives of FR-900506 having a heterocyclic group.

U.S. Pat. No. 4,929,611, 1990, U.S. Pat. No. 4,956,352, 1990, and U.S. Pat. No. 45, 110, 811, 1992, describe the use of FK-506-type compounds in overcoming the body's resistance to organ transplantation. Sandoz's European Patent Application (EPO No. 0 315 978) describes the use of FR-900506 and related compounds for the topical treatment of inflammatory and hyperproliferative skin disorders and of the skin immune system. Fisons patent application WIPO patent (WO 91/04025) describes the use of various derivatives of FR-900506 for the treatment of immunodepression. Fison's patent application WIPO patent (WO 90/14826) describes the use of FR-900506 and related compounds for the treatment of immunodepression and the treatment of reversible obstructive airways diseases, particularly asthma. Fujisawa's European Patent Application (EPO 0 423 714) describes the use of FK-506 and related compounds for the treatment of baldness. various studies have demonstrated the efficacy of FK-506 in the treatment of a variety of diseases such as rheumatoid arthritis (C. Arita et al., Clinical Exp. Immunol. 82: 456-461, 1990; N. Inamura et al., Clin. Immunol. Immunopathol, 1988, 46, 82-90), initial diabetes (N. Murase, et al., Diabetes, 1990, 39, 1584-86; N. Murase, et al., Lancet, 1990, 336, 373-74), posterior uveitis, (H. Kawashima, Invest. Ophtalmoi. Vis. Sci., 29, 1265-71, 1988), liver lesions associated with ischemic disease (M. Sakr, et ai., Life Sci., 1990, 47, 687-91), alern

Gentle encephalomyelitis (K. Deguchi, et al., Brain Nerve, 1990, 42, 391-97), glomerulonephritis (J. McCauley, et al., Lancet, 1990, 335,674), systemic lupus erythematosus (K. Takabayashi, et al. al., Clin. Immunol. Immunopathol. 1989, 51, 110-117), 110-117), multiple drug resistance (M. Naito, et al., Cancer Chemother. Pharmacol. blood vessel inflammation (WO 91/17754), cytomegalovirus infection (GB no. 2 247 620A) and idiopathic thrombocytopenic rash and Basedov's disease (WO 91/19495).

Immune regulatory disorders have been shown to occur in a variety of autoimmune diseases and chronic inflammations, including systemic lupus, chronic rheumatoid arthritis, type I and type II diabetes, intestinal inflammation, biliary cirrhosis, uveitis, multiple sclerosis, and other conditions such as C; disease, ulcerative colitis, bullous bullous, sarcoidosis, psoriasis, ichthyosis, and Graves ophthalmopathy. Although the pathogenesis of each of these conditions may be different, they have in common the development of multiple autoantibodies and self-reactive lymphocytes. Such auto-reactivity may, in part, lead to the loss of homeostatic control, which allows the immune system to function normally.

Similarly, after bone marrow or organ transplantation, host lymphocytes recognize foreign tissue antigens and start producing antibodies, which triggers a rejection reaction.

One end result of the autoimmune or rejection process is tissue destruction caused by inflammatory cells and substances released by the cells. The principle of the action of anti-inflammatory agents, such as NSAIDs (non-steroidal anti-inflammatory drugs) and corticosteroids, is based on these substances.

II, or their secretion, but has no effect on the immune nature of the disease. On the other hand, cytotoxic agents, such as cyclophosphamide, act so nonspecifically that they block both the normal and autoimmune responses. In fact, patients treated with such non-specific immunosuppressants are likely to die from both the infection and the autoimmune disease they are suffering from.

Ciclosporin A, approved in 1983 by the US FDA (Food and Drug Administration), is currently a major drug used to prevent organ transplant rejection. It works by suppressing the body's immune system, which prevents it from mobilizing a huge arsenal of natural protective agents that reject the foreign protein of the transplanted organ. Although cyclosporin A is effective in combating transplant rejection, it is toxic to the kidneys and causes some undesirable side effects such as kidney problems, abnormal liver function and gastrointestinal discomfort.

Newer, safer drugs with fewer side effects are constantly being sought in this area.

Tricyclic, 23-membered macrolide immunosuppressant - tacrolimus, FR-90D506, FK-506,

Ii ii I ii ll 1.1. I

(17-allyl-1,4-dihydroxy-12- [2 '- (4' '- hydroxy-3''methoxy-cyclohexyl) -1'-methylvinyl] -23,25-dimethoxy-13, 19, 21, 27-tetramethyl-1,11-28-dioxa-4-azatricyclo [22.3.1.4,9] octacozo-18-en-2, 3, 10, 16-tetraone) and similar compounds isolated and described by Tanaka, Kuroda and collaborators from Fujisawa Pharmaceutical Co. (Japan); J, Am. Chem. Soc., 1987, 109, 5031 and

U.S. Pat. No. 4,894,366, 1990), have been shown to exhibit particularly high immunosuppressive activity. U.S. Pat. No. 4,929,611 to Fujisawa, 1990, U.S. Pat.

No. 4,956,352, 1990 and U.S. Pat. No. 45 110 811, 1992) describes the use of FK-506-type compounds in overcoming organ transplant resistance. In particular, FR-900506 is reported to be 100-fold more potent than cephalosporin in suppressing the immune system in vitro (J. Antibiotics 1987, '40, '1256). In addition, these compounds are known to have local activity in the treatment of inflammatory and hyperproliferative skin disorders and skin immune responses (EPO No. 0 315 978).

Compound FK-506 and related compounds may be useful in the treatment of obstructive airways diseases, particularly asthma (WO 90/14826), male-type or senile-type alopecia (EPO No. 0 423 714), rheumatoid arthritis (C. Arita, et al. al., Clinical Exp. Immunol., 82, 1990,

II II II kk

456-461; Inamura N., et al., Clin. Immunol. Immunopathol. 1988, 46, 82-90) for initial diabetes (N. Murase, et al., Diabetes, 1990, 39, 1584-86; N. Murase, et al., Lancet, posterior uveitis, H. Kawashima, Vis. Sci. 1988,

1990, 336 373-74),

Invest. Ophtalmol

29, Liver lesions associated with ischemic disease et al., Life Sci., 47, 687-91 (1990),

1265-71), (M. Sakr, alerginio encefalomielito (K. Deguchi, et ai., Brain Nerve, 1990, 42, 391-97), glomerulonefrito (J. McCauley, et ai.,

Lancet, 1990, 335,674), systemic lupus erythematosus (K. Tabaa 1. Clin. Immunol. Immunopathol. 198 9, 51

110-117), multiple drug resistance kayashi, et 110-117), (M. Naito, et al., Cancer Chemother. Pharmacol., 1992, Inflammatory cytomegalovirus infections of the lymph and blood vessels (GB No. 2 (WO

195-200), 91/17754) ,

247 620A) and idiopathic thrombocytopenic rash and Basedov's disease (WO 91/19495).

A. Purpose of the Invention

The novel compound of this invention (or a pharmaceutically acceptable salt thereof) has the structural formula I:

-i 2

ch3o and3 in which

R1 is:

(1) heteroaryl;

(2) substituted heteroaryl substituted with X, Y and Z;

(3) heteroaril-C1_10-alkyl;

(4) substituted heteroaryl-C 1-4 alkyl wherein the heteroaryl group is substituted with X, Y, and Z and the alkyl moiety may be substituted with one or more substituents selected from:

(a) hydroxyl, (b) oxo, (c) yg-alkoxy, (d) arylC1_3-alkoxy groups (e) substituted with arylC1_3-alkoxy group in which the aryl group is substituted with X, Y and Z, (f) unsubstituted or substituted aryloxy group in which the aryl group is substituted by X, Y and Z, (g) -OCO-C 1-6 alkyl, (h) -NR R wherein R and R independently of one another are optionally (i) hydrogen, (ii) substituted or unsubstituted C 1-610, having one or more substituents, optionally including:

(a ') aryl, unsubstituted or substituted with X, Y, Z, (b') heteroaryl, unsubstituted or substituted with X,

Y, Z, (C) -OH,

II I,, ι j (d ') Vg-alkoxyigroup, (e') -CO2H, (f ') -CO2-C1_6-alkyl, (g ') -C3_7-cycloalkyl and (h ') -OR11(Iii) 1003_10-alkenyl, unsubstituted or substituted by one or more substituents, optionally:

(a ') aryl, unsubstituted or substituted with X, Y, Z, (b') heteroaryl, unsubstituted or substituted with X,

Y, Z, (C) -OH, (d ') Ci.g-alkoxide, (e') -CO2H, (f ') -CO2-C1_6-alkyl, (g ') -C3_7-cycloalkyl and (h ') -OR11,

7 (iv) or when the R, R and N atom to which they are attached form an unsubstituted or substituted 3- to 7-membered heterocyclic ring which may contain one or two additional heteroatoms independently selected from the group consisting of O, S (O)p, NO14, kai R.14 is hydrogen or C -._6-alkyl, unsubstituted or substituted with phenyl, p = 0, 1 or 2, for example morpholine, thiomorpholine, piperidine or piperazine, (i) -NR6-CO1_6-alkyl-R7, kai R.6 and R7 the meanings are defined above, (j) -NR6CO2-C1_6-alkyl-R7, (k) -NR6-CO-NR6R7, (l) -OCONRYR7, (m) -COOR6,

I u (n) (o) (p) (q) (r) (5)

-CHO, aryl, substituted heteroaryl substituted with X, Y and Z,

-OR11, and

-S (O) p-C1.6-alkyl;

heteroaril-C1_10-alkyl, where one or more carbon atoms are replaced by a group optionally selected from: NR6-, -o-, -S (O) p-, -CO2, -O2C-, -CONR6-, -NR6CO ~, no6conr7-, · (6) substituted heteroaryl-C1_10-alkyl, where one or more alkyl carbon atoms are optionally substituted with: -NR -, - Ο -, -S (O)p-, -CO2, heteroarylinė

-CONR6-, -NR6CO-,

-No6conr7groups

-O2C- is substituted with X, Y and Z, and the alkyl group may be substituted with one or more substituents optionally including:

(a) (b) (c) (d) (e) (f) (g) (h) (i) hidroksilas, oksogrupė,

C1_6-alkoxy, Ari lC1_3-al any group substituted with arylC1.3-the alkoxy group in which the aryl group is substituted with X, Y and Z, the unsubstituted or substituted aryloxy group in which the aryl group is substituted by X, Y and Z,

-OCO-C !_6-alkyl,

-NR6R7, kai R.6 and R7 have the meanings defined above,

-NR6CO -C1_6-alkyl-R7, kai R.6 and R7 meanings are defined above, t I. I ii 1.1, ι J u

<td>(j)</td><td>-NR6CO2-C1_6-alkyl-R7,</td><td></td><td></td>

<td>(D</td><td>-oconr6r7,</td><td></td><td></td>

<td>(O)</td><td>arilas,</td><td></td><td></td>

<td>(P)</td><td>substituted aryl in which</td><td>is a substituent X,</td><td>And go Z,</td>

<td>(r)</td><td>-S (O) p C 1-6 alkyl;</td><td></td><td></td>

<td> (7)</td><td>heteroaril-C3_10-alkenilas, one to four doubles</td><td>kai alkenilas connections;</td><td>has since</td>

<td> (8)</td><td>heteroaril-C3_10-alkenilas,</td><td>kai alkenilas</td><td>has since</td>

one to four double bonds and when one or more alkyl carbon atoms are replaced by a group optionally selected from: -NR6-, -0-, -S(O)p~, -CO2, -O2C-,

-CONR6-, -NR6CO-, -NR6CONR7-;

(9) substituted heteroaryl-C3_10-alkenics where alkenyl has one to four double bonds and when one or more alkyl carbon atoms are replaced by a group optionally selected from: -NR6-, -0-, -S(O)p-, -CO2,

-O2C—, -CONR6-, -NR6CO-, -NR6CONR7-, the heteroaryl group is substituted with X, Y and Z, and the alkyl group may be substituted with one or more substituents optionally including:

(a) hydroxyl, (b) oxogroup, (c) Vg-alkoxygroup, (d) aryl-C1_3-alkoxy, (e) substituted with arylC1_3-Alkoxy group in which the aryl group is substituted with X, Y and Z,

I.Uil 1 m III

I I illll'll·!

(f) an unsubstituted or substituted aryloxy group in which the aryl group is substituted with X, Y and Z, (g) -OCO-C 1-4 alkyl, (h) -NR R where R and R are as defined above for (i) -NR6CO -C1_6-alkyl wherein R6 the meanings are defined above, (j) -NR6CO2-C1_6-alkyl, (k) -NR6CO-NR6R7, (l) -OCONR6R7, (m) -COOR6, (n) -CHO, (o) aryl, (p) substituted aryl substituted with X, Y and Z, (q) -ORU, and (r) -S (O) p-C 1-8 alkyl;

R may be optionally:

(1) R1 meanings;

(2) hydrogen;

(3) phenyl;

(4) substituted phenyl substituted with X, Y, Z;

(5) 1- or 2-naphthyl;

(6) substituted 1- or 2-naphthyl substituted with X, Y, Z;

(7) bifenilas;

(8) substituted biphenyl substituted with X, Y, Z;

(9) C1_ic-alkyl;

(10) replaced by C1_10-alkyl optionally substituted with one or more substituents, including:

I

<td></td><td>(a)</td><td>hydroxilas,</td>

<td></td><td>(b)</td><td>oxo group,</td>

<td></td><td>(c)</td><td>C x_6what a group,</td>

<td></td><td>(d)</td><td>ar i l-C1_3-al ko ksigrupė,</td>

<td> 5</td><td>(e)</td><td>substituted arylC1_3-Alkoxy group in which the aryl group is substituted with X, Y and Z,</td>

<td></td><td>(f)</td><td>an unsubstituted or substituted aryloxy group in which the aryl group contains X, Y and Z,</td>

<td></td><td>(g)</td><td>-OCO-CYg-al kilas,</td>

<td> 10</td><td>(h)</td><td>6 7 6 7 -NR R where R and R are as defined above meanings,</td>

<td></td><td>(i)</td><td>-NR6CO -C1_6-alkyl-R 'wherein R6 and R7 meanings are defined above,</td>

<td></td><td>(j)</td><td>-COOR, where R values are as defined above,</td>

<td></td><td>(D</td><td>phenyl,</td>

<td></td><td>(m)</td><td>substituted phenyl substituted with X, Y and Z,</td>

<td></td><td>(n)</td><td>1- or 2-naphthyl,</td>

<td></td><td>(O)</td><td>substituted 1- or 2-naphthyl substituted with X,</td>

<td></td><td>(P)</td><td>bifenilas,</td>

<td></td><td>(q)</td><td>substituted biphenyl substituted with X, Y, Z,</td>

<td></td><td>(s)</td><td>-S (O) p C 1-4 alkyl;</td>

<td></td><td> (11)</td><td>C3.10-alkenilas;</td>

<td></td><td> (12)</td><td>replaced by C3_10-alkenyl optionally containing one or more substituents, including:</td>

<td></td><td>(a)</td><td>hydroxilas,</td>

<td> 30</td><td>(b)</td><td>oxo group,</td>

<td></td><td>(c)</td><td>. C ,_6-ai ko ksigrupė,</td>

(d) phenyl-C 1-4 -alkoxy, (e) substituted-phenyl-C1_3-alkoxy, wherein the phenyl group is substituted with X, Y and Z, (f) -OCO-C 1-6 -alkyl,

7 6 7 (g) -NR R where R and R are as defined above, (h) -NR6CO -C1_6-alkyl wherein R6 values as defined above, (i) -COOR where R values are as defined above, (j) -CHO, (k) phenyl, (l) substituted phenyl substituted with X, Y and Z, (m) 1- or 2-naphthyl , (n) substituted 1- or 2-naphthyl substituted with X, Y and Z, (o) biphenyl, (p) substituted biphenyl substituted with X, Y and Z, (q) -OR11, and (r) -S (O) p-C 1-8 alkyl;

(13) C3_10-alkinilas;

(14) replaced by C3_10-alkynyl optionally substituted with one or more substituents including:

(a) hydroxylase, (b) oxogroup, (c) C 1-6 alkoxygroup, (d) phenyl-C1_3-alkoxy, (e) substituted with phenyl-C1_3- an alkoxy group in which the phenyl group is substituted with X, Y and Z, (f) -OCO-C 1-8 -alkyl,

R7 has the meaning given above when the values of R are defined by (g) -NR6R7, kai R.6 and values, (h) -NR6CO -C1_6-alkyl, above, (i) -COOR6, kai R.6 the values are defined above, (j) -CHO, (k) phenyl, (l) substituted phenyl substituted with X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl, X, Y and Z, (o) biphenyl, (p) substituted biphenyl, substituted with X, Y and Z, (q) -OR11, ir (r) -S (O) p-C1_6-alkyl;

(15) -R11;

R is hydrogen, hydroxy, OR or C / g-alkoxy;

R4 is hydrogen or R3 and R4 together form a double bond;

R5 is methyl, ethyl, propyl or allyl;

R10 is hydrogen, hydroxy, OR11 or fluorine;

R11 optional:

(a) -PO(OH)O M+, kai M.+ is a positively charged inorganic or organic ion,

-so3, ”M+, (b) (C) (d) (i) (ii) (iii) (iv) (v) (vi) (vii) (viii) (ix)

-CO (CH2) qCO2_M+, when q equals 1-3, and

-CO-C1_6alkyl-NR6R7, in which R6 and R7 has the meanings defined above and the alkyl group may be substituted with one or more substituents optionally including:

hydroxilas,

CX6-alkoksigrupė,

-NRluR17, kai R.16 and R17 independently of each other may be optional:

(a ') hydrogen, and (b') C 1-8 alkyl,

-COOR5, kai R.6 the values defined above, phenyl, substituted phenyl substituted with X, Y and Z, heteroaryl,

-SH, go

-S-C1_6-alkyl;

W is O or (H, OH);

X, Y and Z are independently selected from:

(a) hydrogen, (b) C1_10-alkyl, unsubstituted or substituted by one or more substituents, optionally:

(i) aryl, (ii) substituted aryl substituted with X ', Y' and

Z ', (iii) heteroaryl, (iv) substituted heteroaryl substituted with X', Y 'and Z', (v) unsubstituted or substituted aryloxy radical substituted with X ', Y' and Z ', (vi) - OR6, (vii) -OR11, (viii) -OCOR6, (ix) -OCO2R6, (x) -NR6R7, (xi) -CHO, (xii) -NR6CO -C1.6-alkyl-R7, (xiii) -NR6CO2-C1_6-alkyl-R7, (xiv) -NR6CONR6R7, (xv) -OCONReR7, (xvi) -CONR6R7, (c) C,_10-alkyl, where one or more alkyl carbon atoms are replaced by a group optionally selected from: -NR6-, -0-, -S (O) p-, -CO2, -O2C-, -CONR6-, -NR6CO-,

-NR6CONR7-, -CO-, -CH (OH) -, alkenyl or alkynyl and alkyl may be unsubstituted or substituted with one or more substituents optionally including:

(i) aryl, (ii) substituted aryl substituted with X ', Y' and Z ', (iii) heteroaryl,

I III I 31 III ll I i ui «ι mum t

<td>(iv)</td><td>substituted heteroaryl substituted with X ', Y' and Z ',</td>

<td>(v)</td><td>unsubstituted or substituted aryloxy radical, substituted with X ', Y' and Z 'in the aryl group,</td>

<td>(ix)</td><td>-hollow2r6,</td>

<td>(xii)</td><td>-AcO-C/g-alkil-R7,</td>

<td>(xiii)</td><td>-NR6CO2-C1_6-alkyl-R7,</td>

<td>(xv)</td><td>-oconr6r7,</td>

<td>(d)</td><td>halogen,</td>

<td>(i)</td><td>8 8 -SR when R is hydrogen, C1-4 alkyl, trifluoromethyl- thyl or phenyl,</td>

<td>(m)</td><td>R9O(CH2)m-, kur R9 is hydrogen, C / g-alkyl, hydroxy-C2-3-alkyl, -CF3, phenyl, R11 or petroleum br and m is equal to 0, 1, 2 or 3,</td>

<td>(n)</td><td>-CH (OR12) (OR13), kai R.12 and R13 is C1.3-alkyl or together form an ethylene or propylene bridge,</td>

II 11

O

<td>(O)</td><td>R9CO (CH2)m-, when</td><td>R9</td><td>and M</td><td>meanings</td><td>defined</td>

<td>(P)</td><td>above, 0 9 f ROC(CH2)m-, when</td><td>R9</td><td>and M</td><td>meanings</td><td>defined</td>

<td>(q) or</td><td>above, and -R11; any two of X,</td><td>Y,</td><td>From the gala</td><td colspan="2">to be connected in order to</td>

to form a saturated ring containing 5, 6 or 7 atoms, there being 1 or 2 oxygen atoms between the atoms of the ring, the remaining atoms being carbon, for example dioxolanyl or dioxanyl;

X ', Y' and Z 'independently of one another are optionally:

(a) hydrogen, (b) C1_7-alkiias, (c) C2_6-alkenyl, (d) halogen, (e) {CH2)m-NR R where R, R and m are as defined above, (f) -CN, (g) -cho, (h) -CF3, (i) -SR8, kai R.3 hydrogen, C1_6-alkyl, trifluoromethyl or phenyl, (j) -SOR wherein R is as defined above, (k) -SO2R, wherein the values of R are as defined above, (l) -CONR6R7, where R6 and R7 the values are defined above, (m) R9O (CH2)m- where R9 and the values of m are defined above, m ui; mum (n) -CH (OR12) (OR13) where R12 and R13 meanings are defined above,

O

II (o) R9CO (CH2) m- where R9 and the values of m are defined above,

O

II (p) R9OC (CH2) m- where R9 and the values of m are defined above, and (q) -R11;

n is 1 or 2.

The compounds of the present invention have asymmetric centers and the present invention includes all optical isomers and mixtures thereof.

In addition, carbon-carbon double bonded compounds can exist in Z and E forms, so that all isomeric forms of these compounds are included in the present invention.

In the case where any variable (eg alkyl, aryl, R6, R7, R8, R9, R10, Rin, X, Y, Z, and 1.1.) Occurs more than once in any of the variables or in Formula 1, its value in each case is independent of its value in any other case.

The term alkyl, as used herein, includes alkylating groups having a defined number of carbon atoms which in configuration are straight, branched, or cyclic. Examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, secondary and tertiary butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. AlL1 coke is an alkyl group of a specified number of carbon atoms attached through an oxygen bridge such as methoxy, ethoxy, propoxy, butoxy and pentoxy. The term alkenyl includes a hydrocarbon chain of the indicated number of carbon atoms, linear or branched and containing at least one unsaturated bond which may be anywhere on the chain, such as ethenyl, propenyl, butenyl, pentenyl, dimethylpentyl, and the like, and includes E and Z forms, when present; the term heteroarylalkyl includes heteroaryl groups as defined herein and attached through a straight or branched alkyl chain of 1 to 10 carbon atoms. The term halogen as used in the present invention means fluorine, chlorine, bromine or iodine.

It will be understood by those skilled in the art that pharmaceutically acceptable salts include, but are not limited to, salts of inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate, or salts of organic acid such as malate, maleate, fumarate, tartrate, succinate, acetate, lactate, methanesulfonate, p-toluenesulfonate or palmoate, salicylate or stearate. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium (especially ammonium salts with amines of formula HNR).SR7) .

The heteroaryl group includes, as used in the present invention, acridine, carbazole, cinnoline, dibenzofuran, dibenzothiophene, quinoxaline, pyrazole, indole, benzotriazole, furan, benzofuran, quinoline, isoquinoline, pyrazine, pyridine, pyridine, to change or not to change.

I III I II II I I I I I IUU1

In the compounds of Formula 1, any heteroaryl or carbon atom (if any) in the heteroaryl group may be replaced by X, Y and Z, but the compounds in which the nitrogen atom has been replaced by some X, Y and Z may be relatively unstable and absent. more appropriate than others.

The term heteroaryl, as used in the present invention, includes the following heteroaromatic groups which may be substituted at X, Y and Z at the indicated positions when Q is -N (X) -, -O-, -S-, -SO- or -SO2-:

Y v

X (Piridazinas) (Piridinas)

Y z \ nJ (Pyrimidines) (Pyrazines)

X (Cinolines)

1, there is ί .11 3; T 1 3 3 Ιϊ'Iii f t

The aryl or aromatic groups may be phenyl or naphthyl, unsubstituted or substituted with 1-3 radicals independently selected from the group consisting of alkyl, alkenyl, halogen, carboxyl, CHO, amino, monoalkylamino, dialkylaminoalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, trifluoromethyl, amide, monoalkylamide, dialkylamide, hydroxy, hydroxyalkyl, R11 O-alkilas, alkoksi-, alkoksialkilas, formamidas, formami10 doalkilas, alkil-CO2-, alkyl-CO2-alkyl, carboxyl, acyl-CO2H, alkyl-O2C, alkyl-O2C-alkyl and ORU.

Compounds of formula I are more preferably heteroaryls selected from the group consisting of:

X

and

L il JI miimn: ii m where X values are defined above.

In the compound of formula 1, the following values are more suitable:

R2 is:

<td> (1)</td><td>hydrogen,</td>

<td> (2)</td><td>methyl,</td>

<td> (3)</td><td>etilas</td>

<td> (4)</td><td>propilas,</td>

<td> (7)</td><td>C2_3-alkil-OH,</td>

<td> (8)</td><td>C2.3-alkyl-R11;</td>

<td>(D</td><td>hydrogen,</td>

<td> (2)</td><td>hydroxy,</td>

R3 and R4 together form a double bond;

R10 is hydrogen, hydroxy, fluorine or -ORU;

W is O; and n equals 2.

In one example of the present invention, heteroaryl is an indole, which is represented by the following formulas:

I ίΙ

defined above when X, Y and Z have values.

More preferred examples of the present invention include:

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (2-furanyl) methoxy-3' '- methoxy-cyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13 , 19, 21, 27-Tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1. ON4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (2-furanyl) methoxy-3' '- hydroxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13,19 , 21, 27-Tetramethyl-1,11, 28-dioxa-4-azatricyclo [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- hydroxy-3' '- (2-furanyl) -methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo [22.3.1];

O4'9] octacos-18-en-2, 3, 10, 16-tet17-Ethyl-1, 14-dihydroxy-12- [2 '- (4' '- (2-thiophene) -methoxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4-aza-tricyclo- [22.3.1.0 raonas;

4,9.

octacos-18-en-2, 3, 10, 16-tet17-Ethyl-1, 14-dihydroxy-12- [2 '- (4' '- (2-thiophene) -methoxy-3' '-hydroxycyclohexyl) - 1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

I ui ί ji ιι jif ui .ki »i«.

17-Ethyl-1, 14-dihydroxy-12- [2 '(4' '- (3-thiophene) -methoxy3' '-hydroxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21 , 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo-L 22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- hydroxy-3' '- (2thiophene) -methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxsa-4-azatriciclo- [22.3.1. SHE IS4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- hydroxy-3' '- (3-thiophene) -methoxycyclohexyl) -1'-methylvinyl] -23,25-dimethoxy-13, 19,21,27-Tetramethyl-11,18-dioxa-4-azatricyclo [22.3.1.04'9] octacose-18-en-2,3,10, 16-tetraonas

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (2-thiophene) oxy3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21 , 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (2-benzothienyl) oxy -3' '-methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13,19 , 21, 27-Tetramethyl-1,11, 28-dioxa-4-azatricyclo [22.3.1. Oh4,9] oktakoz-18-en2, 3, 10, 16-tetraonas;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (5-indolyl) oxy3' '- methoxycyclohexyl) 1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27- tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1. SHE4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (5-indolyl) oxy3' '- hydroxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21 , 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1, 14, 20-trihydroxy-12- [2 '- (4' '- (5-indolyl) oxy-3' '-methoxycyclohexyl) -1'-methylvinyl] -23, 25I Ll Ll Ii I ! L II III .. Lili dimethoxy-13, 19, 21, 27-tetramethyl-11,18-dioxa-4azatricyclo- [22.3.1. Oh4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,2-dihydroxy-12- [2 '- (4' '- (5-indolyl) oxy3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21 , 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1-hydroxy-12- [2 '- (4' '- (5-indolyl) oxy-3' '- methoxycyclohexyl) -1' -methylvinyl) -23, 25-dimethoxy-13, 19, 21 , 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1,4-dihydroxy-12- [2 '- (4' '- (5-indolyl) oxy3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21 , 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1,4-dihydroxy-12- [2 '(4' '- (5-indolyl) oxy3' '- hydroxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-1,11-28-dioxa-4-azatricyclo [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1, 14, 20-trihydroxy-12- [2 '- (4 (5-indolyl) oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13,19. 21, 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-l, 20-dihydroxy-12- [2'- (4 '' (5-indolyl) oxy3 '' -methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-1,11-28-dioxa-4-azatricyclo [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

standing ί um

17-Ethyl-1,14-dihydroxy-12- [2'- (4 '' - (5-indolyl) oxy3 '' - ethoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27 -tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1. SHE4’9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1,4-dihydroxy-12- [2 '- (4' '- (5-indolyl) oxy3' '- ethoxycyclohexyl) -1'-methylvinyl] -23 ,. 25-dimethoxy13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1-hydroxy-12- [2 '- (4' '- (5-indolyl) oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21 , 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '(4' '- (1N-methyl-5-indolyl) -oxy-3' '-methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy -13, 19, 21, 27-Tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1N-methyl-5-indolyl) -oxy-3' '- hydroxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4, 20-trihydroxy-12- [2 '- (4' '- (1N-methyl-5-indolyl) oxy-3' '-methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy -13, 19, 21, 27-Tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1, 14, 20-trihydroxy-12- [2 '- (4' '- (1N-methyl-5-indolyl) oxy-3' '- hydroxycyclohexyl) -1'-methylvinyl] 23, 25-dimethoxy- 13, 19, 21, 27-tetramethyl-1,11-28-diLT 3533 B oxa-4-azatricyclo- [22.3.1. Oh4'9] octave-18-in-2, 3, 10,

16- tetraonas;

17-Ethyl-1,2-dihydroxy-12- [2 '- (4' '- (1N-methyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25 -Dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,2,2-dihydroxy-12- [2 '- (4' '- (1N-methyl-5-indolyl) -oxy-3' '-hydroxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1,4-dihydroxy-12- [2 '- (4' '- (1N-methyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1, 14, 20-trihydroxy-12- [2 '- (4' '- (1N-methyl-5-indolyl) oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy -13, 19, 21, 27-tetramethyl-11,18-dioxa-4azatricyclo- [22.3.1.04,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1,2-dihydroxy-12- [2 '- (4' '- (1N-methyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1-hydroxy-2- [2'- (4 '' - (1N-methyl-5-indolyl) oxy-3 '' - methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13 , 19, 21, 27-Tetramethyl-1,11, 28-dioxa-4-azaLT 3533 B tricyclo- [22.3.1. Oh4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1N-methyl-5-indolyl) -oxy-3' '- ethoxycyclohexyl) -1'-methylvinyl] -23, 25 dimethoxy- 13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1,4-dihydroxy-12- [2 '- (4' '- (1N-methyl-5-indolyl) -oxy-3' '- ethoxycyclohexyl) -1'-methylvinyl] -23, 25 dimethoxy- 13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '(1N-ethyl-5-indolyl) -oxy-3' '- ethoxycyclohexyl) -1'-methylvinyl] -23, 25dimethoxy-13 , 19, 21, 27-tetramethyl-11, 28-dioxa-4azatriciclo- [22. 3.1. SHE IS4,9] octacose-18-en-2, 3, 10, 16tetraonas;

17-Allyl-1-hydroxy-12- [2 '- (4' '- (1 N-ethyl-5-indolyl) -oxy-3' '-methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy- 13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1N-methyl-5-indolyl) -oxy-3' '- allyloxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Etil-l-hidroksi-12- [2 '- (4' '- (lN-metil-5-indolil) oksi-3' '- aliloksicikloheksil) -1'-metilvinil] -23, 25-dimetoksi-13 , 19, 21, 27-tetrametil-ll, 28-dioksa-4ι II II i II 2 1 1 Μ Ι.Ι1Η I.

LT 3533 Β azatricyclo- [22.3.1. ON4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1, 14-dihydroxy-12- [2 '- (4' '- (1N-methyl-5-indolyl) -oxy-3' '- propyloxycyclohexyl) -1'-methylvinyl] -23.

25-dimethoxy-1,3, 19, 21, 27-tetramethyl-1,1, 28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1-hydroxy-12- [21 -(41'- (1N-methyl-5-indolyl) oxy-3' '- propyloxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1N-methyl-5-indolyl) -oxy-3' '- 1-propyloxycyclohexyl) -1'-methylvinyl] 23, 25 -Dimethoxy-13, 19, 21, 27-tetramethyl-11,18-dioxa-4-azatricyclo- [22.3.1.04,9] octave-18-in-2, 3, 10,

16- tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '(4' '- (1N-ethyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy -13, 19, 21, 27-Tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-14,20-trihydroxy-12- [2 '- (4' '- (1N-ethyl-5indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] 23, 25-dimethoxy -13, 19, 21, 27-tetramethyl-ll, 28dioxsa-4-azatriciclo- [22.3.1.04,9] octave-18-in-2, 3, 10,

16- tetraonas;

17-Ethyl-1,2-dihydroxy-12- [2 '- (4' '- (1N-ethyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4ΙΙΙ, Ι II UI .1 I II III K mini azatricyclo- [22.3.1. Oh4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1N-ethyl-5-indolyl) -oxy-3' '- hydroxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1,4-dihydroxy-12- [2 '(4' '- (1N-ethyl-5-indolyl) -oxy-3' '-methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy -13, 19, 21, 27-Tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-28-en-2, 3, 10, 16-tetraonas;

17-Allyl-1, 14, 20-trihydroxy-12- [2 '- (4' '- (1 N-ethyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] 23, 25- dimethoxy-1,3, 19, 21, 27-tetramethyl-11,28 dioxa-4-azatricyclo- [22.3. 1. O4,9] octave-18-in-2, 3,

10, 16-tetraonas;

17-Allyl-1,2-dihydroxy-12- [2 '- (4' '- (1N-ethyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1,4-dihydroxy-12- [2 '(4' '- (1N-ethyl-5-indolyl) -oxy-3' '- hydroxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy -13, 19, 21, 27-Tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1-hydroxy-12- [2 '- (4' '- (1N-ethyl-5-indolyl) oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13 , 19, 21, 27-tetramethyl-11, 28-dioxa-4I Π ii Iii ii: i ii. utn and azatricyclo- [22.3.1. Oh4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1-hydroxy-12- [2 '- (4' '- (1N-ethyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy- 13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo-t 22.3.1.O4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1,4-dihydroxy-12- [2 '- (4' '- (1N-ethyl-5-indolyl) -oxy-3' '- ethoxycyclohexyl) -1'-methyvinyl] -23, 25 dimethoxy- 13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '(1N-propyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy -13, 19, 21, 27-Tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1, 14, 20-trihydroxy-12- [2 '- (4' '- (1-N-propyl5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] 23, 25 -Dimethoxy-13, 19, 21, 27-tetramethyl-11,28 dioxa-4-azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,2-dihydroxy-12- [2'- (4 '' - (1N-propyl-5-indolyl) -oxy-3 '' - methoxycyclohexyl) -1'-methylvinyl] -23,25 dimethoxy- 13,19,21,27-tetramethyl-1,11-28-dioxa-4-azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2,3,10,16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '(4' '- (1N-propyl-5-indolyl) -oxy-3' '- hydroxycyclohexyl) -1'-methylvinyl [-23,25-dimethoxy -13,19,21,27-tetramethyl-1,11-28-dioxa-4-azatricyclo- [22.3.1.O4,9] octacose-18-en-2,3,10,16-tetraonas;

m ι i m

17-Ethyl-1, 14,20-trihydroxy-12- [2 '- (4' '- (1N-propyl-5-indolyl) -oxy-3' '- hydroxycyclohexyl (-1'-methylvinyl] 23,25-dimethoxy -13,19,21,27-tetramethyl-11,18-dioxa-4azatricyclo- [22.3.1.O4,9] octacose-18-en-2,3,10,16-tetraonas;

17-Ethyl-1,2-dihydroxy-12- [2 '- (4' '- (1N-propyl-5-indolyl) -oxy-3' '- hydroxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16tetraonas;

17-Allyl-1,4-dihydroxy-12- [2 '- (4' '- (1N-propyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1, 14, 20-trihydroxy-12- [2 '- (4' '- (1-N-propyl5-indolyl-oxy-3' '- methoxycyclohexyl) -1'methylvinyl] 23, 25-dimethoxy -13, 19, 21, 27-Tetramethyl-1,11 dioxa-4-azatricyclo-f 22.3.1.4,9] octave-18-in-2, 3, 10,

16-tetraonas;

17-Allyl-1,2-dihydroxy-12- [2 '- (4' '(1N-propyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy -13, 19, 21, 27-Tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1. Oh4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Alil-l, 14-dihidroksi-12- [2 '- (4' '- (lN-propil-5-indolil) -oksi-3' '-hidroksicikloheksil) -1'-metilvinil] -23,

25-dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, tetraonas;

10, 16LT 3533 B

17-Ethyl-1-hydroxy-12- [2'- (4 '' - (1N-propyl-5-indolyl) oxy-3 '' - methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13 , 19, 21, 27-Tetramethyl-1,1, 28-dioxa-4-azatricyclo © 22.3.1.O4,9] oktkoz-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1-hydroxy-12- [2 '- (4' '- (1N-propyl-5-indolyl) oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13 , 19, 21, 27-Tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1, 14-dihydroxy-12- [2 '- (4' '- (1 N-propyl-5-indolyl) -oxy-3' '- texicyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas,

17-Alil-l, 14-dihidroksi-12- [2 '- (4' '- (lN-propil-5-indolil) -oksi-3' '- etoksicikloheksil) -1'-metilvinil] -23,

25-dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo-f 22.3.1. Oh4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1N-allyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1, 14, 20-trihydroxy-12- [2 '(4' '- (1N-allyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] 23, 25-dimethoxy- 13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1. Oh4'9] octave-18-in-2, 3, 10,

16-tetraonas;

17-Ethyl-l, 20-dihydroxy-12- [2 '- (4' '- (1 N-allyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tet5 raonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1N-allyl-5-indolyl) -oxy-3' '-hydroxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-410 azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1, 14, 20-trihydroxy-12- [2 '- (4- (1 N-allyl-5-indolyl) -oxy-3' '- hydroxycyclohexyl) -1'-methylvinyl] 15 23, 25-dimethoxy- 13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1. Oh4,9] octave-18-in-2, 3, 10,

16- tetraonas;

17- Ethyl-1,2-dihydroxy-12- [2 '- (4' '- (1N-allyl-5-indo20 III) -oxy-3' '-hydroxycyclohexyl) -1'-methylvinyl] -23,

25-dimethoxy-13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1_. Oh4,9] o«ktakoz-18-en-2, 3, 10, 16-tetraonas ;

17-Allyl-1,4-dihydroxy-12- [2- '(4' '- (1N-allyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,18-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Alil-l, 14, 20-trihidroksi-12- [2 '- (4' '- (lN-alil-5indolil) -oksi-3' '- metoksicikloheksil) -11-methylvinyl] 23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4-azatricyclo- [22.3.1. Oh4'9] octave-18-in-2, 3, 10,

16-tetraonas;

I NO

17-Allyl-1,2-dihydroxy-12- [2'- (4 '' - (1N-allyl-5-indolyl) -oxy-3 '' - methoxycyclohexyl) -1'-methylvinyl] -23, 25 -dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Alil-l, 14-dihidroksi-12- [2 '- (4' '- (lN-alil-5-indolil) -oksi-3' '- hidroksicikloheksil) -1'-metilvinil] -23, 25- dimetoksi-13, 19, 21, 27-tetrametil-ll, 28-dioksa-4azatriciklo- [22.3.1. O4,9] cktakoz-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1-hydroxy-12- [2'- (4 '' - (1N-allyl-5-indolyl) -oxy-3 '' - methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy- 13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1-hydroxy-12- [2 '- (4' '- (1N-allyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy- 13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1.04'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1 N-allyl-5-indolyl) -oxy-3' '-ethoxycyclohexyl) -1'-methylvinyl] -23, 25 dimethoxy- 13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-14-dihydroxy-12- [2 '(4'1 - (1N-Allyl-5-indolyl) -oxyl-3 '' -ethoxycyclohexyl) -1'-methylvinyl] -23, 25 dimethoxy-13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3 .1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,14-dihydroxy-12- [2'- (4 '' - (1N-2-hydroxyethyl-5-indolyl) -oxy-3 '' - methoxyciclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,

28-dioxa-4-azatricyclo- [22.3.1.O4'9] octave-18-in-2, 3,

10, 16-tetraonas;

17-Ethyl-1,14,20-trihydroxy-12- [2 '- (4' 1 - (1N-2-hydroxyethyl-5-indolyl) -oxy-3 '' - methoxycyclohexyl) -1'methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl11,28-dioxa-4-azatricyclo - [22.3.1. Oh4,9] oktakoz-18-en2, 3, 10, 16-tetraonas;

17-Ethyl-1,2-dihydroxy-12- [2 '- (4' '- (1-N-2-hydroxyethyl-5-indolyl) -oxy-3' '- methoxyciclohexyl) -1'-methylvinyl] - 23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,

28-dioxa-4-azatricyclo- [22.3.1. ABOUT4,9] octave-18-in-2, 3,

10, 16-tetraonas;

17-Ethyl-l ,. 14-dihydroxy-12- [2 '- (4' '- (1N-2-hydroxyethyl-5-indolyl) -oxy-3' '- hydroxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,

28-dioxa-4-azatricyclo- [22.3.1.O4,9] octave-18-in-2, 3,

10, 16-tetraonas;

17-Ethyl-1, 14, 20-trihydroxy-12- [2 '- (4' '- (1N-2-hydroxyethyl-5-indolyl) -oxy-3' '- hydroxycyclohexyl) -1'methylvinyl] -23 , 25-dimethoxy-13, 19, 21, 27-tetramethyl11,28-dioxa-4-azatricyclo- [22.3.1.O4'9] oktakoz-18-en2, 3, 10, 16-tetraonas;

17-Ethyl-1,2-dihydroxy-12- [2'- (4 '' - (1N-2-hydroxyethyl-5-indolyl) -oxy-3 '' - hydroxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,

28-dioxa-4-azatricyclo- [22.3.1. ABOUT4,9] octave-18-in-2, 3,

10, 16-tetraonas;

17-Allyl-1,4-dihydroxy-12- [2 '- (4' '- (1N-2-hydroxyethyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23. 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,

28-dioxa-4-azatricyclo- [22.3.1.O4'9] octave-18-in-2, 3,

10, 16-tetraonas;

17-Allyl-1,4-dihydroxy-12- [2 '- (4' '- (1-N-hydroxyethyl 5-indolyl) -oxy-3' '- hydroxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28 dioxa-4-azatricyclo- [22.3.1. Oh4,9] octave-18-in-2, 3, 10,

26-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1N-benzyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,12-dioxa-4azatricyclo- [22.3.1.04'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4, 20-trihydroxy-12- [2 '- (4' '- (1-N-benzyl5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] 23, 25 -Dimethoxy-13, 19, 21, 27-tetramethyl-11,18-dioxa-4-azatricyclo- [22.3.1.04,9] octave-18-in-2, 3, 10,

16- tetraonas;

17- Ethyl-1,2-dihydroxy-12- [2 '- (4' '- (1N-benzyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23,

25-dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '(4' '- (1N-benzyl-5-indolyl) -oxy-3' '- hydroxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy -13, 19, 21, 27-Tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1, 14, 20-trihydroxy-12- [2 '- (4' '- (1-N-benzyl 5-indolyl) -oxy-3' '- hydroxycyclohexyl) -1'-methylvinyl] -23. 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,12LT 3533 B dioxa-4-azatricyclo- [22.3.1. Oh4'9] octave-18-in-2, 3, 10,

16- tetraonas;

17-Ethyl-1,2-dihydroxy-12- [2 '- (4' '- (1N-benzyl-5-indolyl) -oxy-3' '- hydroxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1,4-dihydroxy-12- [2 '- (4' '- (1N-benzyl-5-indolyl) -oxy-3' '-methoxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,12-dioxa-4azatricyclo- [22.3.1.04'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1, 14, 20-trihydroxy-12- [2 '- (4' '- (1-N-benzyl 5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] 23, 25 -Dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4-azatricyclo- [22.3.1. Oh4,9] octave-18-in-2, 3, 10,

16- tetraonas;

17- Allyl-l, 20-dihydroxy-12- [2 '- (4' '- (1N-benzyl-5-ynyl) -oxy-3' '- methoxycyclohexyl) -1'methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-14-dihydroxy-12- [2 '- (4' '- (1N-benzyl-5-indolyl) -oxy-3' '-hydroxycyclohexyl) -11-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1-hydroxy-12- [2 '- (4' '- (1N-benzyl-5-indolyl) oxy-3' '-methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13 , 19, 21, 27-Tetramethyl-1,11, 28-dioxa-4-azaLT 3533 B tricyclo- [22.3.1. θ '*'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1-hydroxy-12- [2 '(4' '- (1N-benzyl-5-indolyl) oxy-3' '-methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-Tetramethyl-1,11, 28-dioxa-4azatricylchlo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2'- (4 '' - (1N-benzyl-5-indolyl) -oxy-3 '' - ethoxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4azatricyclo- [22.3.1. Oh4,9] -octakozo-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1,4-dihydroxy-12- [2 '- (4' '- (1N-benzyl-5-indolyl) -oxy-3' '-ethoxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,18-dioxa-4azatricyclo- [22.3.1, O4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1-N-cyclopropyl5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] 23, 25-dimethoxy -13,19,21,27-Tetramethyl-1,11-28-dioxa-4-azatricyclo- [22.3.1. Oh4,9] Oct-18-in-2, 3, 10,

16- tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1-N-cyclopropyl5-indolyl) -oxy-3' '- hydroxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28 dioxa-4-azatricyclo- [22.3.1. Oh4,9] octave-18-in-2, 3, 10,

16- tetraonas;

17-Allyl-1,4-dihydroxy-12- [2 '- (4' '- (1-N-cyclopropyl5-indolyl) -oxy-3' '-methoxycyclohexyl) -1'-methylvinyl] 23, 25-dimethoxy -13, 19, 21, 27-tetramethyl-11, 28-diΙ.ΚΙ I. J. UI .1 II III .Hl «..

oxa-4-aza-tricyclo [22.3.1. O4'9] octave-18-in-2, 3, 10,

16-tetraonas;

17-Allyl-1,4-dihydroxy-12- [2 '- (4' '- (1-N-cyclopropyl5-indolyl) -oxy-3' '- hydroxycyclohexyl) -1'-methylvinyl] -23, 25- dimethoxy-13, 19, 21, 27-tetramethyl-11,28 dioxa-4-azatricyclo- [22.3.1. Oh4'9] octave-18-in-2, 3, 10,

16- tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2'- (4 '' - (1N-cyclopropylS-indolyl) -oxy-3 '' - ethoxycyclohexyl) -1'-methylvinyl] 23, 25-dimethoxy-13 , 19, 21, 27-Tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1. Oh4,9] octave-18-in-2, 3, 10,

16- tetraonas;

17-Allyl-1,4-dihydroxy-12- [2 '- (4' '- (1N-cyclopropylS-indolyl) -oxy-3' '- ethoxycyclohexyl) -1'-methylvinyl] 23, 25-dimethoxy-13 , 19, 21, 27-Tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1. Oh4,9] Oct-18-in-2, 3, 10,

16- tetraonas;

17-Ethyl-1-hydroxy-12- [2 '- (4' '- (1N-cyclopropyl-5-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy- 13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1. ON4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Allyl-1-hydroxy-12- [2 '- (4' '- (1N-cyclopropyl-S-indolyl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy- 13, 19, 21, 27-tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1. ON4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1-hydroxy-12- [2 '- (4' '- (1-N-tryptophanyl-carbonyl-methoxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23,

25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxy-4I Ii ll iii ,; ι ii u azatriciklo interview- [22.3.1. O4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1-hydroxy-12- [2 '- 4' '- (3-indolyl) ethylamino-carbonyl-methoxy-3' '-methoxycyclohexyl) -1'-methylvinyl] 23, 25-dimethoxy-13,19 , 21, 27-Tetramethyl-11,12-dioxa-4-azatricyclo- [22.3.1. Oh4,9] octave-18-in-2, 3, 10,

16-tetraonas;

17-Ethyl-1,14-dihydroxy-12- [2 '- (41 '- (3-hydroxypropyl) -indol-5-yl) -oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,

28-dioxa-4-azatricyclo- [22.3.1.O4,9] octave-18-in-2, 3,

10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2'- (3 '' - hydroxy-4 '' - (1-hydroxyethylindol-5-yl) -oxycyclohexyl) -1'-methylvinyl] 23, 25-dimethoxy -13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatriciclo- [22.3.1. SHE IS4,9] octave-18-in-2, 3, 10,

16- tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1-hydroxyethylindol-6-yl) oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] 23, 25-dimethoxy- 13, 1,9, 21, 27-tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1. ON4,9] octave-18-in-2, 3, 10,

16- tetraonas;

17- Ethyl-1, '14-dihydroxy-12- [2' - (4 '' - (1-methylindole-6yl) oxy-3 '' - methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy- 13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatriciklo © 22.3.1. SHE IS4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

The 17 Ethyl, 14 dihidroksi-12 [2 - (4 '- (the dibenzilfosfonoksi-etilindol-5-) OKSI 3' - metoksicikloheksil) -1-metilvinil] -23, 25- dimetoksi 13, 19, 21, 27 tetrametilLT 3533 B

11, 28-dioxa-4-azatricyclo- [22.3.1.O4'9] oktakoz-18-en2, 3, 10, 16-tetraonas;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1-phosphonoxy-ethylindol-5-yl) oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25 -dimethoxy-13, 19, 21, 27-tetramethyl-11, 28dioxsa-4-azatriciclo- [22.3.1. SHE IS4,9] octave-18-in-2, 3, 10,

16- tetraon monocal salt;

The Ethyl 17-, 14 dihidroksi-12 [2 - (4 '- (1- (N, N-OKSI dimetilglicil) etilindol-5-) OKSI 3' - metoksicikloheksil) -1 ' -metilvinil] -23> 25 dimetoksi 13, 19, 21, 27tetrametil ll, 28 dioksa 4-azatriciklo- [22.3.1. O4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '(4' '- (1-succinyloxyethylindol-5-yl) oxy-3' '-methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy- 13, 19, 21, 27-tetramethyl-11,

28-dioxa-4-azatricyclo- [22.3.1.O4,9] octave-18-in-2, 3,

10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '(4' '- (1-methyl-3-phenylindol-5-yl) oxy-3' '- methoxycyclohexyl) -1' -methylvinyl] 23, 25-dimethoxy-l37 19, 21, 27-tetramethyl-l l, 28-dioxa-4-azatricyclo- [22.3.1. Oh4,9] octave-18-in-2, 3, 10,

16- tetraonas;

17- Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1-methyl-3- (2-hydroxyethyl) -indol-5-yl) oxy-3' '- methoxycyclohexyl) -1 'methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl11, 28-dioxsa-4-azatriciclo- [22.3.1.O4,9] oktakoz-18-en2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '(4' '- (1, 3-dimethylindol5-yl) oxy-3' '-methoxycyclohexyl) -1'-methylvinyl] -23,

25-dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4I II azatricyclo- [22.3.1. Oh4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (9'-methylcarbazol3'-ii) oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy -13, 19, 21, 27-Tetramethyl-1,11, 28-dioxa-4azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4 ”- ((2 - (3' -diethylaminopropionyloxy) ethyl) indole-5 '' '- ii) oxy-3' '- methoxyciclohexyl) - 1 '-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxsa-4-azatriciclo [22.3.1. SHE IS4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,14-dihydroxy-12- [2'- (4 '' - ((2 '' '' - (3 '' '' '- dimethylaminopropionyloxy) ethyl) indol-5' '' - yl) oxy-3 '' - methoxycyclohexyl) -1'-methylvinyl] -23,25-dimethoxy-13,19,21,17-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1. SHE4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- ((2' '' - (3 '' '' 'aminopropionyloxy) ethyl) indole-5' '' - ii) - oxy-3 '' - methoxycyclohexyl) -1 '-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxsa-4-azatriciclo [22.3.1.04,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- ((2' '' '- (3' '' 'benzyloxycarbonyl-2' '' '- benzyloxycarbonylamino-propionyloxy) ethyl ) indole-5 '' - ii) oxy-3 '' - methoxycyclohexyl) -1 '-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27 tetramethyl-1,1, 28-dioxa-4-azatricyclo- [ 22.3.1.O4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- ((2' '' - (aspartyloxy) ethyl) indol-5 '' -yl) oxy-3 '' - methoxycyclohexyl 1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetraIII I II III

II methyl-11,28-dioxa-4-azatricyclo- [22.3.1.O4'9] octakoz18-en-2, 3, 10, 16-tetraonas:

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- ((2' '' '- (11 '' '' -imidazolylcarbonyloxy) ethyl) indol-5 '' - yl) oxy-3 '' - methoxycyclohexyl) -1 '-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11 , 28-dioxa-4-azatricyclo- [22.3.1. Oh4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - ((2- (1 '' 'piperazinecarbonyloxy) ethyl) indole-5' '' - ii) oxy-3 '' - methoxycyclohexyl ) -1'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1. SHE4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,. 14-dihydroxy-12- [2'- (4 '' - (1 '' '- (2' '' '(2' '' '- hydroxy) ethylaminocarbonyloxy) ethyl) indole-5' '' yl) oxy -3 '' - methoxycyclohexyl) -1'-methylvinyl] -23, 25dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatriciclo- [22.3.1. SHE IS4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1' '' - (2 '' '- (isopropylaminocarbonyloxy) ethyl) indol-5' '-yl) oxy- 3 '' - methoxycyclohexyl) -1 '-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1. Oh4’9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (1' - (2 (1 '' '' '- piperidinecarbonyloxy) ethyl) indole-5' '' - ii) oxy 3 '' - methoxycyclohexyl) -1'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1. SHE4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1' - (2 (1 '' '' -morpholincarbonyloxy) ethyl) indole-5 '' '- ii) oxy

3 '' -methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4-azatricyclo- [22.3.1. Oh4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (1' '' - (2 '' '' - (diphenylaminocarbonyloxy) ethyl) indole-5 '' '- ii) oxy- 3''-methoxycyclohexyl) -1'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1. SHE4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Etil-l, 14-dihidroksi-l2- (2 '- (4' '- (l','- (2' '' '- (diethylaminocarbonyloxy) ethyl) indole-5' '' - ii) oxy-3 '' - methoxycyclohexyl) -1 '-methyl vinyl] -23,25-dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1. SHE4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1' - (2 '' '- (methanesulfonyloxyethyl) indole-5' '- ii) oxy-3' '- methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21,

27-Tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0.4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1, 14-dihydroxy-12- [2 '- (4' '- (1' '' - (2 '' '' - (azidoethyl) indole-5 '' '- ii) oxy-3' '-methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl, 28-dioxa-4-azatricyclo- [22.3.1.O4,9] oktakoz-18-en2, 3, 10, 16-tetraonas;

17-Ethyl-1, 14-dihydroxy-12- [2 '- (4' '- (1' '' - (2 '' '' - (aminoethyl) indole-5 '' '- ii) oxy-3' 'methoxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl, 28-dioxa-4-azatricyclo- [22.3.1.04,9] oktakoz-18-en2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1' '- t-butyldimethyl-silyloxyethoxyethyl) indol-5' '-yl) oxy-3' '- methoxycyclohexyl) -1 '-methylvinyl] -23, 25-dimethoxy-13, 19,

IIII E .1 III - I II IIIIIILIUl

21, 27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1. SHE4'9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (4' '- (1' '-hydroxyethoxy-ethyl) indol-5' '-yl) oxy-3' '- methoxycyclohexyl) 1' -methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4-azatricyclo- [22.3.1.O4,9] octacose-18-en-2, 3, 10, 16-tetraonas;

17-Ethyl-1,4-dihydroxy-12- [2 '- (3' '-methoxy-4' '- (1' '' (1 '' '- oxoprop-3' '' - ii) indole -5 '' '- ii) oxycyclohexyl) -1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27 tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1.O4,9] octacos-18-en-2, 3, 10, 16-tetraone; and

17-Ethyl-1,. 14-dihydroxy-12- [2 '- (3' '- methoxy-4' (1 '' '' - carboxyethyl-2 '' '' - ii) indole-5 '' '- ii) oxycyclohexyl) -1' -methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27 tetramethyl-1,11, 28-dioxa-4-azatricyclo- [22.3.1.O4,9] octacose-18-en-2, 3, 10, 16-tetraonas.

Compounds of the present invention include compounds of formula X, XI, XII and XIII:

II,

innm i t

XII

AND3 ch3O

. Ii

II III imm,

XIII kai R.ba the values of H and R 'are selected from the following substituent groups:

<td>phenyl</td><td>phenyl</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>phenyl</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>benzil</td><td>H .</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>4-HO2C-benzil</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>4-H; NCO-benzil</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>4-CH3O-benzyl</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>4-HO-benzil</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>4-Cl-benzil</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>4- (CH3) 2N-benzil</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>3-HO?C-benzil</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>3-H, NCO-benzil</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>3-CH3O-benzyl</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>3-l!O-benzil</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

I UI

UI

<td>3-Cl-benzil</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>3- (CH3) 2N-benzil</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>4-pyridyl</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>3-pyridyl</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>2-pyridyl</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>4-piridilmetil</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>3-piridilmetil</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>2-piridilmetil</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>phenyl</td><td>phenyl</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>phenyl</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>benzil</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>4-HO2C-benzil</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>4-H2NCO-benzil</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>4-CH3O-benzyl</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>4-HO-benzil</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>4-Cl-benzil</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>4- (CH3) 2N-benzil</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>3-HO2C-benzil</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>3-H2NCO-benz ii</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>3-CH3O-benzyl</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>3-HO-benzil</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>3-Cl-benzil</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>3- (CH3) 2N-benzil</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>4-pyridyl</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>3-pyridyl</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>2-pyridyl</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>4-piridilmetil</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>3-piridilmetil</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

i — pt

- TT — Tx

<td>2-piridilmetil</td><td>H</td><td>ch3</td><td>H</td>

<td>phenyl</td><td>phenyl</td><td>ch3</td><td>OH</td>

<td>phenyl</td><td>H</td><td>ch3</td><td>OH</td>

<td>benzil</td><td>H</td><td>ch3</td><td>OH</td>

<td>4-HO2C-benzil</td><td>H</td><td>ch3</td><td>OH</td>

<td>4-H2NCO-benzil</td><td>H</td><td>ch3</td><td>OH</td>

<td>4-CH3O-benzyl</td><td>H</td><td>ch3</td><td>OH</td>

<td>4-HO-benzil</td><td>H</td><td>ch3</td><td>OH</td>

<td>4-Cl-benzil</td><td>H</td><td>ch3</td><td>OH</td>

<td>4- (CH3) 2N-benzil</td><td>H</td><td>ch3</td><td>OH</td>

<td>3-HO2C-benzil</td><td>H</td><td>ch3</td><td>OH</td>

<td>3-H2NCO-benzil</td><td>H</td><td>ch3</td><td>OH</td>

<td>3-CH3O-benzyl</td><td>H</td><td>ch3</td><td>OH</td>

<td>3-HO-benzil</td><td>H</td><td>ch3</td><td>OH</td>

<td>3-Cl-benzil</td><td>H</td><td>ch3</td><td>OH</td>

<td>3- (CH3) 2N-benzil</td><td>H</td><td>ch3</td><td>OH</td>

<td>4-pyridyl</td><td>H</td><td>ch3</td><td>OH</td>

<td>3-pyridyl</td><td>H'</td><td>ch3</td><td>OH</td>

<td>2-pyridyl</td><td>H</td><td>ch3</td><td>OH</td>

<td>4-piridilmetil</td><td>H</td><td>ch3</td><td>OH</td>

<td>3-piridilmetil</td><td>H</td><td>ch3</td><td>OH</td>

<td>2-piridilmetil</td><td>H</td><td>ch3</td><td>OH</td>

<td>h2ncoch2ch2</td><td>H</td><td>ch3</td><td>OH</td>

etil alil alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil Alil

<td>HIGH2CH2</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>high2ch2ch2</td><td>H</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>ch3</td><td>ch3</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>ch3ch2</td><td>ch3ch2</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>ch3ch2ch2</td><td>ch3ch2ch2</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>high2ch2</td><td>high2ch2</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>high2ch2ch2</td><td>high2ch2ch2</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>ch3</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>ch3ch2</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>ch3ch2ch2</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>(CH3) 2ch</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>ho2ch2ch2</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>h2ncoch2ch2</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>high2ch2</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>high2ch2ch2</td><td>H</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>ch3</td><td>ch3</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>ch3ch2</td><td>ch3ch2</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>high2ch2</td><td>high2ch2</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>high2ch2ch2</td><td>high2ch2ch2</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>ch3</td><td>H</td><td>H</td><td>OH</td><td>ethyl</td>

<td>ch3ch2</td><td>H</td><td>H</td><td>OH</td><td>ethyl</td>

<td>ch3ch2ch2</td><td>H</td><td>H</td><td>OH</td><td>ethyl</td>

<td>(CH3) 2ch</td><td>H</td><td>H</td><td>OH</td><td>ethyl</td>

<td>ho2cch2ch2</td><td>H</td><td>H</td><td>OH</td><td>ethyl</td>

<td>h2ncoch2ch2</td><td>H</td><td>H</td><td>OH</td><td>ethyl</td>

<td>high2ch2</td><td>H</td><td>H</td><td>OH</td><td>ethyl</td>

<td>high2ch2ch2</td><td>H</td><td>H</td><td>OH</td><td>ethyl</td>

m: ii you! I. I 11. ί t

<td>ch3</td><td>ch3</td><td>H</td><td>OH</td><td>ethyl</td>

<td>ch3ch2</td><td>ch3ch2</td><td>H</td><td>OH</td><td>ethyl</td>

<td>ch3ch2ch2</td><td>ch3ch2ch2</td><td>H</td><td>OH</td><td>ethyl</td>

<td>high2ch2</td><td>high2ch2</td><td>H</td><td>OH</td><td>ethyl</td>

<td>high2ch2ch</td><td>2 HIGH2CH2CH2</td><td>H</td><td>OH</td><td>ethyl</td>

<td></td><td>-ch2ch2and2ch2-</td><td>ch3</td><td>H</td><td>ethyl</td>

<td></td><td>-ch2ch2ch2ch2ch2-</td><td>ch3</td><td>H</td><td>ethyl</td>

<td></td><td>-ch2ch2and2ch2-</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td></td><td>-ch2ch2ch2ch2ch2-</td><td>H</td><td>OH</td><td>ethyl</td>

<td></td><td>-ch2ch2and2ch2-</td><td>H</td><td>OH</td><td>ethyl</td>

<td></td><td>-ch2ch2ch2ch2ch2-</td><td>H</td><td> OH</td><td>ethyl</td>

The compounds of formula XIV, XV, XVI and XVII include, but are not limited to, compounds of the invention:

I illll III III i ui. , J.;

XIV 11111 1 iu 1 1 '[, K! I.

T Tm- t t | illll III 11 (j I j 1 ·· J ··1

ch3O

I IIINIHE

ch3o and3

I 1131 III II ,1 I I I1L L· L

<td>kai R.6a are H or selected from such</td><td>CH3, O alternate</td><td>R2, R3, groups:</td><td>R5 and R6</td><td>meanings</td>

<td>H</td><td></td><td>CH3</td><td>OH</td><td>ethyl</td>

<td>ch3</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>ch3ch2</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>ch2= chch2</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>ch3ch2ch2</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>(CH3)2CH</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>ho2cch2ch2</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>h2ncoch2ch2</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>high2ch2</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>high2ch2ch2</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>(CH3)2CH2</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>phenyl</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>4-pyridyl</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>3-pyridyl</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>2-pyridyl</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>4-piridilmetil</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>3-piridilmetil</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>2-piridilmetil</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>benzil</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>4-HO2C-benzil</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>4-H2NCO-benzil</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>4-CH3O-benzyl</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>4-HO-benzil</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>4-Cl-benzil</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>4- (CH3) 2N-benzil</td><td></td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>3-HO2C-benzil</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>3-H2NCO-benzil</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>3-CH3O-benzyl</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>3-HO-benzil</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>3-Cl-benzil</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>3- (CH3) 2N-benzil</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>2-HO-benzil</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>2-Cl-benzil</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>2- (CH3) 2N-benzil</td><td>ch3</td><td>OH</td><td>ethyl</td>

<td>CH3</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>pub3ch2</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>ch2= chch2</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>ch3ch2ch2</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>(CH3) 2ch</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>ho2cch2ch2</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>h2ncoch2ch2</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>high2ch2</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>high2ch2ch2</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>(CH3)2CH2</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>phenyl</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>4-pyridyl</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>3-pyridyl</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>2-pyridyl</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>4-piridilmetil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>3-piridilmetil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>2-piridilmetil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>4-HO2C-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

I III! III III ! I I I 1. K·I

<td>4-H2NCO-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>4-CH3O-benzyl</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>4-HO-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>4-Cl-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>4- (CH3) 2N-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>3-HO2C-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>3-H2NCO-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>3-CH3O-benzyl</td><td>' ch3</td><td>H</td><td>ethyl</td>

<td>3-HO-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>3-Cl-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>3- (CH3) 2N-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>2-HO2C-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>2-H2NCO-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>2-CH3O-benzyl</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>2-HO-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>2-Cl-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>2- (CH3) 2N-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>2-HO2C-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>2-H2NCO-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>2-CH3O-benzyl</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>2-HO-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>2-Cl-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

<td>2- (CH3) 2N-benzil</td><td>ch3</td><td>H</td><td>ethyl</td>

i, h. i. iii iii

I 1 HUDD

<td>h2ncoch2ch2</td><td>ch3</td><td>OH</td><td>alil</td>

<td>phenyl</td><td>ch3</td><td>OH</td><td>alil</td>

<td>4-pyridyl</td><td>ch3</td><td>OH</td><td>alil</td>

<td>3-pyridyl</td><td>ch3</td><td>OH</td><td>alil</td>

<td>2-pyridyl</td><td>ch3</td><td>OH</td><td>alil</td>

<td>4-piridilmetil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>3-piridilmetil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>2-piridilmetil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>benzil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>4-HO2C-benzil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>4-H2NCO-benzil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>4-CH3O-benzyl</td><td>ch3</td><td>OH</td><td>alil</td>

<td>4-HO-benzil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>4-Cl-benzil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>4- (CH3) 2N-benzil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>3-HO2C-benzil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>3-H2NCO-benzil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>3-CH3O-benzyl</td><td>ch3</td><td>OH</td><td>alil</td>

<td>3-HO-benzil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>3-Cl-benzil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>3- (CH3) 2N-benzil</td><td>ch3</td><td>OH</td><td>alil '</td>

<td>2-HO2C-benzil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>2-H2NCO-benzil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>2-CH3O-benzyl</td><td>ch3</td><td>OH</td><td>alil</td>

In enemy III .11; lf I i ajBii

<td>2-HO-benzil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>2-Cl-benzil</td><td>ch3</td><td>OH</td><td>alil</td>

<td>2- (CH3) 2N-benzil</td><td>ch3</td><td>OH</td><td>alil</td>

Compounds of the present invention include compounds of formula XVIII, XIX, XX and XXI:

1 III11' 1 “ll 11 I I, III: Hll;

Ra

XVIII ch3O

III III III

I I ,111,1,11

OH

AND,

CH3O

JOHN I 1111 YES

YOU'LL LIFE

no m ui: ι ii

ch3o and3

I .01 I 1111 III

<td rowspan="2">kai R.or are H or selected from such</td><td rowspan="2">CH3, O alternate</td><td colspan="3"> 71</td>

<td>R, R2, R3 groups:</td><td>and R5</td><td>meanings</td>

<td>ch3</td><td></td><td>CH3</td><td>OH</td><td>ethyl</td>