Diazabicyclo[4.3.1]decane derivatives for treatment of psychiatric disorders
09914732 ยท 2018-03-13
Assignee
Inventors
- Yansong Wang (Sichaun, CN)
- Felix Hausch (Munich, DE)
- Matthias Bischoff (Munich, DE)
- Sebastian Pomplun (Munich, DE)
Cpc classification
A61K45/06
HUMAN NECESSITIES
C07D303/36
CHEMISTRY; METALLURGY
C07D211/60
CHEMISTRY; METALLURGY
Y02A50/30
GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
International classification
A61K45/06
HUMAN NECESSITIES
C07D211/60
CHEMISTRY; METALLURGY
C07D303/36
CHEMISTRY; METALLURGY
Abstract
The present invention relates to diazabicyclo[4.3.1]decane derivatives, pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said diazabicyclo[4.3.1]decane derivatives can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.
Claims
1. Compound of the general formula (I): ##STR00228## wherein R.sup.A represents CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, CH(CH.sub.3).sub.2, C.sub.4H.sub.9, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, C(CH.sub.3).sub.3, C.sub.5H.sub.11, CH(CH.sub.3)C.sub.3H.sub.7, CH.sub.2CH(CH.sub.3)C.sub.2H.sub.5, CH(CH.sub.3)CH(CH.sub.3).sub.2, C(CH.sub.3).sub.2C.sub.2H.sub.5, CH.sub.2C(CH.sub.3).sub.3, CH(C.sub.2H.sub.5).sub.2, C.sub.2H.sub.4CH(CH.sub.3).sub.2, C.sub.6H.sub.13, C.sub.7H.sub.15, C.sub.8H.sub.17, C.sub.3H.sub.6CH(CH.sub.3).sub.2, C.sub.2H.sub.4CH(CH.sub.3)C.sub.2H.sub.5, CH(CH.sub.3)C.sub.4H.sub.9, CH.sub.2CH(CH.sub.3)C.sub.3H.sub.7, CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH(CH.sub.3)CH(CH.sub.3).sub.2, CH.sub.2C(CH.sub.3).sub.2C.sub.2H.sub.5, C(CH.sub.3).sub.2C.sub.3H.sub.7, C(CH.sub.3).sub.2CH(CH.sub.3).sub.2, C.sub.2H.sub.4C(CH.sub.3).sub.3, CH(CH.sub.3)C(CH.sub.3).sub.3, CH.sub.2OH, C.sub.2H.sub.4OH, C.sub.3H.sub.6OH, C.sub.4H.sub.8OH, CH(CH.sub.3)C.sub.2H.sub.4OH, C.sub.5H.sub.10H, CH.sub.2OCH.sub.3, C.sub.2H.sub.4OCH.sub.3, C.sub.3H.sub.6OCH.sub.3, C.sub.4H.sub.8OCH.sub.3, CH(CH.sub.3)C.sub.2H.sub.4OCH.sub.3, C.sub.5H.sub.10CH.sub.3, CH.sub.2NH.sub.2, C.sub.2H.sub.4NH.sub.2, C.sub.3H.sub.6NH.sub.2, C.sub.4H.sub.8NH.sub.2, CH(CH.sub.3)C.sub.2H.sub.4NH.sub.2, C.sub.5H.sub.10NH.sub.2, C.sub.2H.sub.4NHCH.sub.3, C.sub.2H.sub.4N(CH.sub.3).sub.2, C.sub.2H.sub.4N(CH.sub.3).sub.2, C.sub.2H.sub.4NHCH(CH.sub.3).sub.2, C.sub.2H.sub.4NH(CH.sub.2CH.sub.3), C.sub.2H.sub.4N(CH.sub.2CH.sub.3).sub.2, CHCH.sub.2, CH.sub.2CHCH.sub.2, C(CH.sub.3)CH.sub.2, CHCHCH.sub.3, C.sub.2H.sub.4CHCH.sub.2, CH.sub.2CHCHCH.sub.3, CHCHC.sub.2H.sub.5, CH.sub.2C(CH.sub.3)CH.sub.2, CH(CH.sub.3)CHCH, CHC(CH.sub.3).sub.2, C(CH.sub.3)CHCH.sub.3, CHCHCHCH.sub.2, C.sub.3H.sub.6CHCH.sub.2, C.sub.2H.sub.4CHCHCH.sub.3, CH.sub.2CHCHC.sub.2H.sub.5, CHCHC.sub.3H.sub.7, CH.sub.2CHCHCHCH.sub.2, CHCHCHCHCH.sub.3, CHCHCH.sub.2CHCH.sub.2, C(CH.sub.3)CHCHCH.sub.2, CHC(CH.sub.3)CHCH.sub.2, CHCHC(CH.sub.3)CH.sub.2, C.sub.2H.sub.4C(CH.sub.3)CH.sub.2, CH.sub.2CH(CH.sub.3)CHCH.sub.2, CH(CH.sub.3)CH.sub.2CHCH.sub.2, CH.sub.2CHC(CH.sub.3).sub.2, CH.sub.2C(CH.sub.3)CHCH.sub.3, CH(CH.sub.3)CHCHCH.sub.3, CHCHCH(CH.sub.3).sub.2, CHC(CH.sub.3)C.sub.2H.sub.5, C(CH.sub.3)CHC.sub.2H.sub.5, C(CH.sub.3)C(CH.sub.3).sub.2, C(CH.sub.3).sub.2CHCH.sub.2, CH(CH.sub.3)C(CH.sub.3)CH.sub.2, C(CH.sub.3)CHCHCH.sub.2, CHC(CH.sub.3)CHCH.sub.2, CHCHC(CH.sub.3)CH.sub.2, C.sub.4H.sub.8CHCH.sub.2, C.sub.3H.sub.6CHCHCH.sub.3, C.sub.2H.sub.4CHCHC.sub.2H.sub.5, CH.sub.2CHCHC.sub.3H.sub.7, CHCHC.sub.4H.sub.9, C.sub.3H.sub.6C(CH.sub.3)CH.sub.2, C.sub.2H.sub.4CH(CH.sub.3)CHCH.sub.2, CH.sub.2CH(CH.sub.3)CH.sub.2CHCH.sub.2, C.sub.2H.sub.4CHC(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.4CHCH.sub.2, C.sub.2H.sub.4C(CH.sub.3)CHCH.sub.3, CH.sub.2CH(CH.sub.3)CHCHCH.sub.3, CH(CH.sub.3)CH.sub.2CHCHCH.sub.3, CH.sub.2CHCHCH(CH.sub.3).sub.2, CH.sub.2CHC(CH.sub.3)C.sub.2H.sub.5, CH.sub.2C(CH.sub.3)CHC.sub.2H.sub.5, CH(CH.sub.3)CHCHC.sub.2H.sub.5, CHCHCH.sub.2CH(CH.sub.3).sub.2, CHCHCH(CH.sub.3)C.sub.2H.sub.5, CHC(CH.sub.3)C.sub.3H.sub.7, C(CH.sub.3)CHC.sub.3H.sub.7, CH.sub.2CH(CH.sub.3)C(CH.sub.3)CH.sub.2, C[C(CH.sub.3).sub.3]CH.sub.2, CH(CH.sub.3)CH.sub.2C(CH.sub.3)CH.sub.2, CH(CH.sub.3)CH(CH.sub.3)CHCH.sub.2, CHCHC.sub.2H.sub.4CHCH.sub.2, CH.sub.2C(CH.sub.3).sub.2CHCH.sub.2, C(CH.sub.3).sub.2CH.sub.2CHCH.sub.2, CH.sub.2C(CH.sub.3)C(CH.sub.3).sub.2, CH(CH.sub.3)CHC(CH.sub.3).sub.2, C(CH.sub.3).sub.2CHCHCH.sub.3, CHCHCH.sub.2CHCHCH.sub.3, CH(CH.sub.3)C(CH.sub.3)CHCH.sub.3, CHC(CH.sub.3)CH(CH.sub.3).sub.2, C(CH.sub.3)CHCH(CH.sub.3).sub.2, C(CH.sub.3)C(CH.sub.3)C.sub.2H.sub.5, CHCHC(CH.sub.3).sub.3, C(CH.sub.3).sub.2C(CH.sub.3)CH.sub.2, CH(C.sub.2H.sub.5)C(CH.sub.3)CH.sub.2, C(CH.sub.3)(C.sub.2H.sub.5)CHCH.sub.2, CH(CH.sub.3)C(C.sub.2H.sub.5)CH.sub.2, CH.sub.2C(C.sub.3H.sub.7)CH.sub.2, CH.sub.2C(C.sub.2H.sub.5)CHCH.sub.3, CH(C.sub.2H.sub.5)CHCHCH.sub.3, C(C.sub.4H.sub.9)CH.sub.2, C(C.sub.3H.sub.7)CHCH.sub.3, C(C.sub.2H.sub.5)CHC.sub.2H.sub.5, C(C.sub.2H.sub.5)C(CH.sub.3).sub.2, C[CH(CH.sub.3)(C.sub.2H.sub.5)]CH.sub.2, C[CH.sub.2CH(CH.sub.3).sub.2]CH.sub.2, C.sub.2H.sub.4CHCHCHCH.sub.2, CH.sub.2CHCHCH.sub.2CHCH.sub.2, C.sub.3H.sub.6CCCH.sub.3, CH.sub.2CHCHCHCHCH.sub.3, CHCHCHCHC.sub.2H.sub.5, CH.sub.2CHCHC(CH.sub.3)CH.sub.2, CH.sub.2CHC(CH.sub.3)CHCH.sub.2, CH.sub.2C(CH.sub.3)CHCHCH.sub.2, CH(CH.sub.3)CH.sub.2CCH, CH(CH.sub.3)CHCHCHCH.sub.2, CHCHCH.sub.2C(CH.sub.3)CH.sub.2, CH(CH.sub.3)CCCH.sub.3, CHCHCH(CH.sub.3)CHCH.sub.2, CHC(CH.sub.3)CH.sub.2CHCH.sub.2, C.sub.2H.sub.4CH(CH.sub.3)CCH, C(CH.sub.3)CHCH.sub.2CHCH.sub.2, CHCHCHC(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3)CH.sub.2CCH, CHCHC(CH.sub.3)CHCH.sub.3, CHC(CH.sub.3)CHCHCH.sub.3, CH.sub.2CH(CH.sub.3)CCH, C(CH.sub.3)CHCHCHCH.sub.3, CHC(CH.sub.3)C(CH.sub.3)CH.sub.2, C(CH.sub.3)CHC(CH.sub.3)CH.sub.2, C(CH.sub.3)C(CH.sub.3)CHCH.sub.2, CHCHCHCHCHCH.sub.2, CCH, CCCH.sub.3, CH.sub.2CCH, C.sub.2H.sub.4CCH, CH.sub.2CCCH.sub.3, CCC.sub.2H.sub.5, C.sub.3H.sub.6CCH, C.sub.2H.sub.4CCCH.sub.3, CH.sub.2CCC.sub.2H.sub.5, CCC.sub.3H.sub.7, CH(CH.sub.3)CCH, C.sub.4H.sub.8CCH, C.sub.2H.sub.4CCC.sub.2H.sub.5, CH.sub.2CCC.sub.3H.sub.7, CCC.sub.4H.sub.9, CCC(CH.sub.3).sub.3, CH(CH.sub.3)C.sub.2H.sub.4CCH, CH.sub.2CH(CH.sub.3)CCCH.sub.3, CH(CH.sub.3)CH.sub.2CCCH.sub.3, CH(CH.sub.3)CCC.sub.2H.sub.5, CH.sub.2CCCH(CH.sub.3).sub.2, CCCH(CH.sub.3)C.sub.2H.sub.5, CCCH.sub.2CH(CH.sub.3).sub.2, CH(C.sub.2H.sub.5)CCCH.sub.3, C(CH.sub.3).sub.2CCCH.sub.3, CH(C.sub.2H.sub.5)CH.sub.2CCH, CH.sub.2CH(C.sub.2H.sub.5)CCH, C(CH.sub.3).sub.2CH.sub.2CCH, CH.sub.2C(CH.sub.3).sub.2CCH, CH(CH.sub.3)CH(CH.sub.3)CCH, CH(C.sub.3H.sub.7)CCH, C(CH.sub.3)(C.sub.2H.sub.5)CCH, CH.sub.2-Ph, CH.sub.2-L.sub.1-R.sup.D, ##STR00229## Y represents CH.sub.2, CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, CHCH, CHCHCH.sub.2, CH.sub.2CHCH, CH(CH.sub.3), CH(CH.sub.3)CH.sub.2, CH.sub.2CH(CH.sub.3), CH.sub.2CH(CH.sub.3)CH.sub.2, or CH.sub.2OCH.sub.2; R.sup.D represents: R.sup.22 or ##STR00230## ##STR00231## ##STR00232## R.sup.E represents: R.sup.23 or ##STR00233## ##STR00234## R.sup.F represents: R.sup.24 or ##STR00235## ##STR00236## L.sup.1, L.sup.2 and L.sup.3 represent independently of each other: a bond, CH.sub.2, C.sub.2H.sub.4, C.sub.3H.sub.6, C.sub.4H.sub.8, C.sub.6H.sub.10, C.sub.6H.sub.12, C.sub.7H.sub.14, C.sub.8H.sub.16, C.sub.9H.sub.18, C.sub.10H.sub.20, CH(CH.sub.3), C[(CH.sub.3).sub.2], CH.sub.2CH(CH.sub.3), CH(CH.sub.3)CH.sub.2, CH(CH.sub.3)C.sub.2H.sub.4, CH.sub.2CH(CH.sub.3)CH.sub.2, C.sub.2H.sub.4CH(CH.sub.3), CH.sub.2C[(CH.sub.3).sub.2], C[(CH.sub.3).sub.2]CH.sub.2, CH(CH.sub.3)CH(CH.sub.3), C[(C.sub.2H.sub.6)(CH.sub.3)], CH(C.sub.3H.sub.7), (CH.sub.2).sub.mO, (CH.sub.2).sub.pOCH.sub.2, (CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2, CHCH, C(CH.sub.3)CH, CHC(CH.sub.3), CH.sub.2CHCH, CH.sub.2C(CH.sub.3)CH, CH.sub.2CHC(CH.sub.3), CHCHCH.sub.2, C(CH.sub.3)CHCH.sub.2, CHC(CH.sub.3)CH.sub.2, C(CH.sub.3)CHC(CH.sub.3)CH, C.sub.2H.sub.4CHCHCHCH, CH.sub.2CHCHCH.sub.2CHCH, C.sub.3H.sub.6CCCH.sub.2, CH.sub.2CHCHCHCHCH.sub.2, CHCHCHCHC.sub.2H.sub.4, CH.sub.2CHCHC(CH.sub.3)CH, CH.sub.2CHC(CH.sub.3)CHCH, CH.sub.2C(CH.sub.3)CHCHCH, CH(CH.sub.3)CHCHCHCH, CHCHCH.sub.2C(CH.sub.3)CH, CH(CH.sub.3)CCCH.sub.2, CONH, NHCO, CH.sub.2CONH, CONHCH.sub.2, NHCOCH.sub.2, CH.sub.2NHCO; wherein n, m, p are independently an integer from 1 to 10; or L.sub.1-R.sup.D and L.sub.2-R.sup.E or L.sub.1-R.sup.D and L.sub.3-R.sup.F or L.sub.2-R.sup.E and L.sub.3-R.sup.F can form together a cyclic ring selected from the group consisting of: ##STR00237## R.sup.N represents H, CH.sub.2OCH.sub.3, C.sub.2H.sub.4OCH.sub.3, C.sub.3H.sub.6OCH.sub.3, CH.sub.2OC.sub.2H.sub.5, C.sub.2H.sub.4OC.sub.2H.sub.5, C.sub.3H.sub.6OC.sub.2H.sub.5, CH.sub.2OC.sub.3H.sub.7, C.sub.2H.sub.4OC.sub.3H.sub.7, C.sub.3H.sub.6OC.sub.3H.sub.7, CH.sub.2O-cyclo-C.sub.3H.sub.5, C.sub.2H.sub.4O-cyclo-C.sub.3H.sub.5, C.sub.3H.sub.6O-cyclo-C.sub.3H.sub.5, CH.sub.2OCH(CH.sub.3).sub.2, C.sub.2H.sub.4OCH(CH.sub.3).sub.2, C.sub.3H.sub.6OCH(CH.sub.3).sub.2, CH.sub.2OC(CH.sub.3).sub.3, C.sub.2H.sub.4OC(CH.sub.3).sub.3, C.sub.3H.sub.6OC(CH.sub.3).sub.3, CH.sub.2OC.sub.4H.sub.9, C.sub.2H.sub.4OC.sub.4H.sub.9, C.sub.3H.sub.6OC.sub.4H.sub.9, CH.sub.2OPh, C.sub.2H.sub.4OPh, C.sub.3H.sub.6OPh, CH.sub.2OCH.sub.2-Ph, C.sub.2H.sub.4OCH.sub.2-Ph, C.sub.3H.sub.6OCH.sub.2-Ph, CHO, COCH.sub.3, COC.sub.2H.sub.5, COC.sub.3H.sub.7, CO-cyclo-C.sub.3H.sub.5, COCH(CH.sub.3).sub.2, COC(CH.sub.3).sub.3, COPh, COCN, COOCH.sub.3, COOC.sub.2H.sub.5, COOC.sub.3H.sub.7, COO-cyclo-C.sub.3H.sub.5, COOCH(CH.sub.3).sub.2, COOC(CH.sub.3).sub.3, COCH.sub.2Ph, CONH.sub.2, CONHCH.sub.3, CONHC.sub.2H.sub.5, CONHC.sub.3H.sub.7, CONH-cyclo-C.sub.3H.sub.5, CONH[CH(CH.sub.3).sub.2], CONH[C(CH.sub.3).sub.3], CON(CH.sub.3).sub.2, CON(C.sub.2H.sub.5).sub.2, CON(C.sub.3H.sub.7).sub.2, CON(cyclo-C.sub.3H.sub.5).sub.2, CON[CH(CH.sub.3).sub.2].sub.2, CON[C(CH.sub.3).sub.3].sub.2, SO.sub.2CH.sub.3, SO.sub.2C.sub.2H.sub.5, SO.sub.2CH.sub.2Ph, SO.sub.2C.sub.3H.sub.7, SO.sub.2-cyclo-C.sub.3H.sub.5, SO.sub.2CH(CH.sub.3).sub.2, SO.sub.2C(CH.sub.3).sub.3, SO.sub.2Ph, CH.sub.2OCF.sub.3, C.sub.2H.sub.4OCF.sub.3, C.sub.3H.sub.6OCF.sub.3, OC.sub.2F.sub.5, CH.sub.2OC.sub.2F.sub.5, C.sub.2H.sub.4OC.sub.2F.sub.5, C.sub.3H.sub.6OC.sub.2F.sub.5, CH.sub.2F, CHF.sub.2, CF.sub.3, CH.sub.2Cl, CH.sub.2Br, CH.sub.2I, CH.sub.2CH.sub.2F, CH.sub.2CHF.sub.2, CH.sub.2CF.sub.3, CH.sub.2CH.sub.2Cl, CH.sub.2CH.sub.2Br, CH.sub.2CH.sub.2I, -cyclo-C.sub.8H.sub.15, -Ph, CH.sub.2-Ph, CH.sub.2CH.sub.2-Ph, CHCH-Ph, CPh.sub.3, CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, CH(CH.sub.3).sub.2, C.sub.4H.sub.9, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, C(CH.sub.3).sub.3, C.sub.5H.sub.11, CH(CH.sub.3)C.sub.3H.sub.7, CH.sub.2CH(CH.sub.3)C.sub.2H.sub.5, CH(CH.sub.3)CH(CH.sub.3).sub.2, C(CH.sub.3).sub.2C.sub.2H.sub.5, CH.sub.2C(CH.sub.3).sub.3, CH(C.sub.2H.sub.5).sub.2, C.sub.2H.sub.4CH(CH.sub.3).sub.2, C.sub.6H.sub.13, C.sub.7H.sub.15, C.sub.8H.sub.17, C.sub.3H.sub.6CH(CH.sub.3).sub.2, C.sub.2H.sub.4CH(CH.sub.3)C.sub.2H.sub.5, CH(CH.sub.3)C.sub.4H.sub.9, CH.sub.2CH(CH.sub.3)C.sub.3H.sub.7, CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH(CH.sub.3)CH(CH.sub.3).sub.2, CH.sub.2C(CH.sub.3).sub.2C.sub.2H.sub.5, C(CH.sub.3).sub.2C.sub.3H.sub.7, C(CH.sub.3).sub.2CH(CH.sub.3).sub.2, C.sub.2H.sub.4C(CH.sub.3).sub.3, CH(CH.sub.3)C(CH.sub.3).sub.3, CHCH.sub.2, CH.sub.2CHCH.sub.2, C(CH.sub.3)CH.sub.2, CHCHCH.sub.3, C.sub.2H.sub.4CHCH.sub.2, CH.sub.2CHCHCH.sub.3, CHCHC.sub.2H.sub.5, CH.sub.2C(CH.sub.3)CH.sub.2, CH(CH.sub.3)CHCH, CHC(CH.sub.3).sub.2, C(CH.sub.3)CHCH.sub.3, CHCHCHCH.sub.2, C.sub.3H.sub.6CHCH.sub.2, C.sub.2H.sub.4CHCHCH.sub.3, CH.sub.2CHCHC.sub.2H.sub.5, CHCHC.sub.3H.sub.7, CH.sub.2CHCHCHCH.sub.2, CHCHCHCHCH.sub.3, CHCHCH.sub.2CHCH.sub.2, C(CH.sub.3)CHCHCH.sub.2, CHC(CH.sub.3)CHCH.sub.2, CHCHC(CH.sub.3)CH.sub.2, C.sub.2H.sub.4C(CH.sub.3)CH.sub.2, CH.sub.2CH(CH.sub.3)CHCH.sub.2, CH(CH.sub.3)CH.sub.2CHCH.sub.2, CH.sub.2CHC(CH.sub.3).sub.2, CH.sub.2C(CH.sub.3)CHCH.sub.3, CH(CH.sub.3)CHCHCH.sub.3, CHCHCH(CH.sub.3).sub.2, CHC(CH.sub.3)C.sub.2H.sub.5, C(CH.sub.3)CHC.sub.2H.sub.5, C(CH.sub.3)C(CH.sub.3).sub.2, C(CH.sub.3).sub.2CHCH.sub.2, CH(CH.sub.3)C(CH.sub.3)CH.sub.2, C(CH.sub.3)CHCHCH.sub.2, CHC(CH.sub.3)CHCH.sub.2, CHCHC(CH.sub.3)CH.sub.2, C.sub.4H.sub.8CHCH.sub.2, C.sub.3H.sub.6CHCHCH.sub.3, C.sub.2H.sub.4CHCHC.sub.2H.sub.5, CH.sub.2CHCHC.sub.3H.sub.7, CHCHC.sub.4H.sub.9, C.sub.3H.sub.6C(CH.sub.3)CH.sub.2, C.sub.2H.sub.4CH(CH.sub.3)CHCH.sub.2, CH.sub.2CH(CH.sub.3)CH.sub.2CHCH.sub.2, C.sub.2H.sub.4CHC(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.4CHCH.sub.2, C.sub.2H.sub.4C(CH.sub.3)CHCH.sub.3, CH.sub.2CH(CH.sub.3)CHCHCH.sub.3, CH(CH.sub.3)CH.sub.2CHCHCH.sub.3, CH.sub.2CHCHCH(CH.sub.3).sub.2, CH.sub.2CHC(CH.sub.3)C.sub.2H.sub.5, CH.sub.2C(CH.sub.3)CHC.sub.2H.sub.5, CH(CH.sub.3)CHCHC.sub.2H.sub.5, CHCHCH.sub.2CH(CH.sub.3).sub.2, CHCHCH(CH.sub.3)C.sub.2H.sub.5, CHC(CH.sub.3)C.sub.3H.sub.7, C(CH.sub.3)CHC.sub.3H.sub.7, CH.sub.2CH(CH.sub.3)C(CH.sub.3)CH.sub.2, C[C(CH.sub.3).sub.3]CH.sub.2, CH(CH.sub.3)CH.sub.2C(CH.sub.3)CH.sub.2, CH(CH.sub.3)CH(CH.sub.3)CHCH.sub.2, CHCHC.sub.2H.sub.4CHCH.sub.2, CH.sub.2C(CH.sub.3).sub.2CHCH.sub.2, C(CH.sub.3).sub.2CH.sub.2CHCH.sub.2, CH.sub.2C(CH.sub.3)C(CH.sub.3).sub.2, CH(CH.sub.3)CHC(CH.sub.3).sub.2, C(CH.sub.3).sub.2CHCHCH.sub.3, CHCHCH.sub.2CHCHCH.sub.3, CH(CH.sub.3)C(CH.sub.3)CHCH.sub.3, CHC(CH.sub.3)CH(CH.sub.3).sub.2, C(CH.sub.3)CHCH(CH.sub.3).sub.2, C(CH.sub.3)C(CH.sub.3)C.sub.2H.sub.5, CHCHC(CH.sub.3).sub.3, C(CH.sub.3).sub.2C(CH.sub.3)CH.sub.2, CH(C.sub.2H.sub.5)C(CH.sub.3)CH.sub.2, C(CH.sub.3)(C.sub.2H.sub.5)CHCH.sub.2, CH(CH.sub.3)C(C.sub.2H.sub.5)CH.sub.2, CH.sub.2C(C.sub.3H.sub.7)CH.sub.2, CH.sub.2C(C.sub.2H.sub.5)CHCH.sub.3, CH(C.sub.2H.sub.5)CHCHCH.sub.3, C(C.sub.4H.sub.9)CH.sub.2, C(C.sub.3H.sub.7)CHCH.sub.3, C(C.sub.2H.sub.5)CHC.sub.2H.sub.5, C(C.sub.2H.sub.5)C(CH.sub.3).sub.2, C[CH(CH.sub.3)(C.sub.2H.sub.5)]CH.sub.2, C[CH.sub.2CH(CH.sub.3).sub.2]CH.sub.2, C.sub.2H.sub.4CHCHCHCH.sub.2, CH.sub.2CHCHCH.sub.2CHCH.sub.2, C.sub.3H.sub.6CCCH.sub.3, CH.sub.2CHCHCHCHCH.sub.3, CHCHCHCHC.sub.2H.sub.5, CH.sub.2CHCHC(CH.sub.3)CH.sub.2, CH.sub.2CHC(CH.sub.3)CHCH.sub.2, CH.sub.2C(CH.sub.3)CHCHCH.sub.2, CH(CH.sub.3)CH.sub.2CCH, CH(CH.sub.3)CHCHCHCH.sub.2, CHCHCH.sub.2C(CH.sub.3)CH.sub.2, CH(CH.sub.3)CCCH.sub.3, CHCHCH(CH.sub.3)CHCH.sub.2, CHC(CH.sub.3)CH.sub.2CHCH.sub.2, C.sub.2H.sub.4CH(CH.sub.3)CCH, C(CH.sub.3)CHCH.sub.2CHCH.sub.2, CH.sub.2CCC.sub.2H.sub.5, CHCHCHC(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3)CH.sub.2CCH, C.sub.2H.sub.4CCCH.sub.3, CHCHC(CH.sub.3)CHCH.sub.3, CHC(CH.sub.3)CHCHCH.sub.3, CH.sub.2CH(CH.sub.3)CCH, C(CH.sub.3)CHCHCHCH.sub.3, CHC(CH.sub.3)C(CH.sub.3)CH.sub.2, C(CH.sub.3)CHC(CH.sub.3)CH.sub.2, C(CH.sub.3)C(CH.sub.3)CHCH.sub.2, CHCHCHCHCHCH.sub.2, CCH, CCCH.sub.3, CH.sub.2CCH, C.sub.2H.sub.4CCH, CH.sub.2CCCH.sub.3, CCC.sub.2H.sub.5, C.sub.3H.sub.6CCH, CCC.sub.3H.sub.7, CH(CH.sub.3)CCH, C.sub.4H.sub.8CCH, C.sub.2H.sub.4CCC.sub.2H.sub.5, CH.sub.2CCC.sub.3H.sub.7, CCC.sub.4H.sub.9, CCC(CH.sub.3).sub.3, CH(CH.sub.3)C.sub.2H.sub.4CCH, CH.sub.2CH(CH.sub.3)CCCH.sub.3, CH(CH.sub.3)CH.sub.2CCCH.sub.3, CH(CH.sub.3)CCC.sub.2H.sub.5, CH.sub.2CCCH(CH.sub.3).sub.2, CCCH(CH.sub.3)C.sub.2H.sub.5, CCCH.sub.2CH(CH.sub.3).sub.2, CH(C.sub.2H.sub.5)CCCH.sub.3, C(CH.sub.3).sub.2CCCH.sub.3, CH(C.sub.2H.sub.5)CH.sub.2CCH, CH.sub.2CH(C.sub.2H.sub.5)CCH, C(CH.sub.3).sub.2CH.sub.2CCH, CH.sub.2C(CH.sub.3).sub.2CCH, CH(CH.sub.3)CH(CH.sub.3)CCH, CH(C.sub.3H.sub.7)CCH, C(CH.sub.3)(C.sub.2H.sub.5)CCH, CH.sub.2CH(CCH).sub.2, CCCCH, CH.sub.2CCCCH, CCCCCH.sub.3, CH(CCH).sub.2, C.sub.2H.sub.4CCCCH, CH.sub.2CCCH.sub.2CCH, CCC.sub.2H.sub.4CCH, CH.sub.2CCCCCH.sub.3, CCCH.sub.2CCCH.sub.3, CCCCC.sub.2H.sub.5, C(CCH).sub.2CH.sub.3, CCCH(CH.sub.3)CCH, CH(CH.sub.3)CCCCH, CH(CCH)CH.sub.2CCH, or CH(CCH)CCCH.sub.3; R.sup.B represents ##STR00238## ##STR00239## ##STR00240## ##STR00241## ##STR00242## ##STR00243## ##STR00244## Q represents O, S, or NR.sup.12; R.sup.C represents OH, CH.sub.2OH, CHO, CH.sub.2CHO, CH.sub.2CH.sub.2CHO, C.sub.2H.sub.4OH, C.sub.3H.sub.6OH, OCH.sub.3, OC.sub.2H.sub.5, OCH.sub.2OH, OCH(CH.sub.3).sub.2, OCH.sub.2OCH.sub.3, OC.sub.2H.sub.4OCH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2OH, CH.sub.2OC.sub.2H.sub.5, CH.sub.2OCH(CH.sub.3).sub.2, CH.sub.2OC.sub.3H.sub.7, COCH.sub.3, CH.sub.2COCH.sub.3, COCH.sub.2OH, CH(OH)CH.sub.3, C(OH)(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2OH, CH(OH)CH.sub.2OH, CH.sub.2CH(OH)CH.sub.3, CH.sub.2CH(OH)CH.sub.2OH, CH(OCH.sub.3)CH.sub.2OH, CH(OC.sub.2H.sub.5)CH.sub.2OH, CH(OCH.sub.3)CH.sub.2OCH.sub.3, CH(OC.sub.2H.sub.5)CH.sub.2OCH.sub.3, CH(OC.sub.2H.sub.5)CH.sub.2OC.sub.2H.sub.5, CH(OAc)CH.sub.2OH, CH(OAc)CH.sub.2OAc, CH(OH)CH.sub.2OAc, CH(OH)CH.sub.2NH.sub.2, CH.sub.2CH(OH)CH.sub.2NH.sub.2, CH(OCH.sub.3)CH.sub.2NH.sub.2, CH(OC.sub.2H.sub.5)CH.sub.2NH.sub.2, CH.sub.2CH(OCH.sub.3)CH.sub.2NH.sub.2, CH.sub.2CH(OC.sub.2H.sub.5)CH.sub.2NH.sub.2, CH(OH)CH.sub.2NHCH.sub.3, CH(OH)CH.sub.2NHC.sub.2H.sub.5, CH.sub.2CH(OH)CH.sub.2NHCH.sub.3, COC.sub.3H.sub.7, CH.sub.2CH(OH)CH.sub.2NHC.sub.2H.sub.5, CH(OCH.sub.3)CH.sub.2NHCH.sub.3, COC.sub.2H.sub.5, COCH(CH.sub.3).sub.2, CH(OC.sub.2H.sub.5)CH.sub.2NHCH.sub.3, CH.sub.2CH(OCH.sub.3)CH.sub.2NHCH.sub.3, OC.sub.3H.sub.7, CH.sub.2CH(OC.sub.2H.sub.5)CH.sub.2NHCH.sub.3, CH(OCH.sub.3)CH.sub.2NHC.sub.2H.sub.5, CH(OC.sub.2H.sub.5)CH.sub.2NHC.sub.2H.sub.5, CH(OCH.sub.3)CH.sub.2N(CH.sub.3).sub.2, CH(OC.sub.2H.sub.5)CH.sub.2N(CH.sub.3).sub.2, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3, CH.sub.2N(CH.sub.3).sub.2, C.sub.2H.sub.4NH.sub.2, C.sub.2H.sub.4NHCH.sub.3, C.sub.2H.sub.4N(CH.sub.3).sub.2, CH(NHCH.sub.3)CH.sub.3, CH(NHC.sub.2H.sub.5)CH.sub.3, CH(N(CH.sub.3).sub.2)CH.sub.3, CH(N(C.sub.2H.sub.5).sub.2)CH.sub.3, CH(NH.sub.2)CH.sub.2OH, CH(NHCH.sub.3)CH.sub.2OH, CH(NHC.sub.2H.sub.5)CH.sub.2OH, CH(N(CH.sub.3).sub.2)CH.sub.2OH, CH(N(C.sub.2H.sub.5).sub.2)CH.sub.2OH, CH(NH.sub.2)CH.sub.2OCH.sub.3, CH(NHCH.sub.3)CH.sub.2OCH.sub.3, CH(NHC.sub.2H.sub.5)CH.sub.2OCH.sub.3, CH(N(CH.sub.3).sub.2)CH.sub.2OCH.sub.3, CH(N(C.sub.2H.sub.5).sub.2)CH.sub.2OCH.sub.3, CH(NH.sub.2)CH.sub.2OC.sub.2H.sub.5, CH(NHCH.sub.3)CH.sub.2OC.sub.2H.sub.5, CH(NHC.sub.2H.sub.5)CH.sub.2OC.sub.2H.sub.5, CH(N(CH.sub.3).sub.2)CH.sub.2OC.sub.2H.sub.5, CH(N(C.sub.2H.sub.5).sub.2)CH.sub.2OC.sub.2H.sub.5, CH(NH.sub.2)CH.sub.2OAc, CH(NHCH.sub.3)CH.sub.2OAc, CH(NHC.sub.2H.sub.5)CH.sub.2OAc, CH(N(CH.sub.3).sub.2)CH.sub.2OAc, CH(N(C.sub.2H.sub.5).sub.2)CH.sub.2OAc, CH.sub.2CH(NHAc)CH.sub.2OH, CH.sub.2CH(NHAc)CH.sub.2OCH.sub.3, CH.sub.2CH(NHAc)CH.sub.2OC.sub.2H.sub.5, CH.sub.2CH(NHCH.sub.3)CH.sub.3, CH.sub.2CH(NHC.sub.2H.sub.5)CH.sub.3, CH.sub.2CH(N(CH.sub.3).sub.2)CH.sub.3, CH.sub.2CH(N(C.sub.2H.sub.5).sub.2)CH.sub.3, CH.sub.2CH(NH.sub.2)CH.sub.2OH, CH.sub.2CH(NHCH.sub.3)CH.sub.2OH, CH.sub.2CH(NHC.sub.2H.sub.5)CH.sub.2OH, CH.sub.2CH(N(CH.sub.3).sub.2)CH.sub.2OH, CH.sub.2CH(N(C.sub.2H.sub.5).sub.2)CH.sub.2OH, CH.sub.2CH(NH.sub.2)CH.sub.2OCH.sub.3, CH.sub.2CH(NHCH.sub.3)CH.sub.2OCH.sub.3, CH.sub.2CH(NHC.sub.2H.sub.5)CH.sub.2OCH.sub.3, CH.sub.2CH(N(CH.sub.3).sub.2)CH.sub.2OCH.sub.3, CH.sub.2CH(N(C.sub.2H.sub.5).sub.2)CH.sub.2OCH.sub.3, CH.sub.2CH(NH.sub.2)CH.sub.2OC.sub.2H.sub.5, CH.sub.2CH(NHCH.sub.3)CH.sub.2OC.sub.2H.sub.5, CH.sub.2CH(NHC.sub.2H.sub.5)CH.sub.2OC.sub.2H.sub.5, CH.sub.2CH(N(CH.sub.3).sub.2)CH.sub.2OC.sub.2H.sub.5, CH.sub.2CH(N(C.sub.2H.sub.5).sub.2)CH.sub.2OC.sub.2H.sub.5, CH.sub.2CH(NH.sub.2)CH.sub.2OAc, CH.sub.2CH(NHCH.sub.3)CH.sub.2OAc, CH.sub.2CH(NHC.sub.2H.sub.5)CH.sub.2OAc, CH.sub.2CH(N(CH.sub.3).sub.2)CH.sub.2OAc, CH.sub.2CH(N(C.sub.2H.sub.5).sub.2)CH.sub.2OAc, CH.sub.2CH(NHAc)CH.sub.2OH, CH.sub.2CH(NHAc)CH.sub.2OCH.sub.3, CH.sub.2CH(NHAc)CH.sub.2OC.sub.2H.sub.5, NHCOCH.sub.3, CH.sub.2NHCOCH.sub.3, C.sub.2H.sub.4NHCOCH.sub.3, NHCHO, CH.sub.2NHCHO, C.sub.2H.sub.4NHCHO, NHSO.sub.2CH.sub.3, NHSO.sub.2CF.sub.3, NHSO.sub.2CH.sub.2CF.sub.3, CH.sub.2NHSO.sub.2CH.sub.3, CH.sub.2NHSO.sub.2CF.sub.3, CH.sub.2NHSO.sub.2CH.sub.2CF.sub.3, C.sub.2H.sub.4NHSO.sub.2CH.sub.3, C.sub.2H.sub.4NHSO.sub.2CF.sub.3, C.sub.2H.sub.4NHSO.sub.2CH.sub.2CF.sub.3, CONH.sub.2, CONHCH.sub.3, CONHC.sub.2H.sub.5, CONHC.sub.3H.sub.7, NH(C.sub.2H.sub.5), N(C.sub.2H.sub.5).sub.2, CH.sub.2NH(C.sub.2H.sub.5), CH.sub.2N(C.sub.2H.sub.5).sub.2, C.sub.2H.sub.4NH(C.sub.2H.sub.5), C.sub.2H.sub.4N(C.sub.2H.sub.5).sub.2, NO.sub.2, CH.sub.2NO.sub.2, C.sub.2H.sub.4NO.sub.2, CH(OH)NO.sub.2, CH(NO.sub.2)OH, CO.sub.2H, CH.sub.2CO.sub.2H, C.sub.2H.sub.4CO.sub.2H, CHCHCO.sub.2H, CO.sub.2CH.sub.3, CO.sub.2C.sub.2H.sub.5, CO.sub.2CH(CH.sub.3).sub.2, CH.sub.2CO.sub.2CH.sub.3, CH.sub.2CO.sub.2C.sub.2H.sub.5, CH.sub.2CO.sub.2CH(CH.sub.3).sub.2, C.sub.2H.sub.4CO.sub.2CH.sub.3, C.sub.2H.sub.4CO.sub.2C.sub.2H.sub.5, C.sub.2H.sub.4CO.sub.2CH(CH.sub.3).sub.2, CO.sub.2NH.sub.2, CO.sub.2NHCH.sub.3, CO.sub.2N(CH.sub.3).sub.2, CH.sub.2CO.sub.2NH.sub.2, CH.sub.2CO.sub.2NHCH.sub.3, CH.sub.2CO.sub.2N(CH.sub.3).sub.2, C.sub.2H.sub.4CO.sub.2NH.sub.2, C.sub.2H.sub.4CO.sub.2NHCH.sub.3, C.sub.2H.sub.4CO.sub.2N(CH.sub.3).sub.2, OSi(CH.sub.3).sub.3, OSi(C.sub.2H.sub.5).sub.3, COCHO, COCOCH.sub.3, C(OH)COCH.sub.3, COC(OH)CH.sub.3, COCH.sub.2COCH.sub.3, C(OH)CH.sub.2COCH.sub.3, COCH.sub.2C(OH)CH.sub.3, C(OH)CH.sub.2C(OH)CH.sub.3, F, Cl, Br, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.2H.sub.4F, CH.sub.2CF.sub.3, CF.sub.2CF.sub.3, OCHF.sub.2, OCF.sub.3, OCH.sub.2CF.sub.3, OC.sub.2F.sub.5, CH.sub.3, CH.sub.2CH.sub.3, C.sub.3CH.sub.7, CH(CH.sub.3).sub.2; R.sup.1-R.sup.10 represent independently of each other H, OH, OCH.sub.3, OC.sub.2H.sub.5, OC.sub.3H.sub.7, O-cyclo-C.sub.3H.sub.5, OCH(CH.sub.3).sub.2, OC(CH.sub.3).sub.3, OC.sub.4H.sub.9, OCH.sub.2COOH, OPh, OCH.sub.2-Ph, OCPh.sub.3, CH.sub.2OCH.sub.3, CH.sub.2OH, C.sub.2H.sub.4OCH.sub.3, C.sub.3H.sub.6OCH.sub.3, CH.sub.2OC.sub.2H.sub.5, C.sub.2H.sub.4OC.sub.2H.sub.5, C.sub.3H.sub.6OC.sub.2H.sub.5, CH.sub.2OC.sub.3H.sub.7, C.sub.2H.sub.4OC.sub.3H.sub.7, C.sub.3H.sub.6OC.sub.3H.sub.7, CH.sub.2O-cyclo-C.sub.3H.sub.5, C.sub.2H.sub.4O-cyclo-C.sub.3H.sub.5, C.sub.3H.sub.6O-cyclo-C.sub.3H.sub.5, CH.sub.2OCH(CH.sub.3).sub.2, C.sub.2H.sub.4OCH(CH.sub.3).sub.2, C.sub.3H.sub.6OCH(CH.sub.3).sub.2, CH.sub.2OC(CH.sub.3).sub.3, C.sub.2H.sub.4OC(CH.sub.3).sub.3, C.sub.3H.sub.6OC(CH.sub.3).sub.3, CH.sub.2OC.sub.4H.sub.9, C.sub.2H.sub.4OC.sub.4H.sub.9, C.sub.3H.sub.6OC.sub.4H.sub.9, CH.sub.2OPh, C.sub.2H.sub.4OPh, C.sub.3H.sub.6OPh, CH.sub.2OCH.sub.2-Ph, C.sub.2H.sub.4OCH.sub.2-Ph, C.sub.3H.sub.6OCH.sub.2-Ph, SH, SCH.sub.3, SC.sub.2H.sub.5, SC.sub.3H.sub.7, S-cyclo-C.sub.3H.sub.6, SCH(CH.sub.3).sub.2, SC(CH.sub.3).sub.3, NO.sub.2, F, Cl, Br, I, P(O)(OH).sub.2, P(O)(OCH.sub.3).sub.2, P(O)(OC.sub.2H.sub.5).sub.2, P(O)(OCH(CH.sub.3).sub.2).sub.2, C(OH)[P(O)(OH).sub.2].sub.2, Si(CH.sub.3).sub.2(C(CH.sub.3).sub.3), Si(C.sub.2H.sub.5).sub.3, Si(CH.sub.3).sub.3, N.sub.3, CN, OCN, NCO, SCN, NCS, CHO, COCH.sub.3, COC.sub.2H.sub.5, COC.sub.3H.sub.7, CO-cyclo-C.sub.3H.sub.5, COCH(CH.sub.3).sub.2, COC(CH.sub.3).sub.3, COOH, COCN, COOCH.sub.3, COOC.sub.2H.sub.5, COOC.sub.3H.sub.7, COO-cyclo-C.sub.3H.sub.5, COOCH(CH.sub.3).sub.2, COOC(CH.sub.3).sub.3, OOCCH.sub.3, OOCC.sub.2H.sub.5, OOCC.sub.3H.sub.7, OOC-cyclo-C.sub.3H.sub.5, OOCCH(CH.sub.3).sub.2, OOCC(CH.sub.3).sub.3, CONH.sub.2, CONHCH.sub.3, CONHC.sub.2H.sub.5, CONHC.sub.3H.sub.7, CONH-cyclo-C.sub.3H.sub.5, CONH[CH(CH.sub.3).sub.2], CONH[C(CH.sub.3).sub.3], CON(CH.sub.3).sub.2, CON(C.sub.2H.sub.5).sub.2, CON(C.sub.3H.sub.7).sub.2, CON(cyclo-C.sub.3H.sub.5).sub.2, CON[CH(CH.sub.3).sub.2].sub.2, CON[C(CH.sub.3).sub.3].sub.2, NHCOCH.sub.3, NHCOC.sub.2H.sub.5, NHCOC.sub.3H.sub.7, NHCO-cyclo-C.sub.3H.sub.5, NHCOCH(CH.sub.3).sub.2, NHCOC(CH.sub.3).sub.3, NHCOOCH.sub.3, NHCOOC.sub.2H.sub.5, NHCOOC.sub.3H.sub.7, NHCOO-cyclo-C.sub.3H.sub.5, NHCOOCH(CH.sub.3).sub.2, NHCOOC(CH.sub.3).sub.3, NH.sub.2, NHCH.sub.3, NHC.sub.2H.sub.5, NHC.sub.3H.sub.7, NH-cyclo-C.sub.3H.sub.5, NHCH(CH.sub.3).sub.2, NHC(CH.sub.3).sub.3, N(CH.sub.3).sub.2, N(C.sub.2H.sub.5).sub.2, N(C.sub.3H.sub.7).sub.2, N(cyclo-C.sub.3H.sub.5).sub.2, N[CH(CH.sub.3).sub.2].sub.2, N[C(CH.sub.3).sub.3].sub.2, SOCH.sub.3, SOC.sub.2H.sub.5, SOC.sub.3H.sub.7, SO-cyclo-C.sub.3H.sub.5, SOCH(CH.sub.3).sub.2, SOC(CH.sub.3).sub.3, SO.sub.2CH.sub.3, SO.sub.2C.sub.2H.sub.5, SO.sub.2C.sub.3H.sub.7, SO.sub.2-cyclo-C.sub.3H.sub.6, SO.sub.2CH(CH.sub.3).sub.2, SO.sub.2C(CH.sub.3).sub.3, SO.sub.3H, SO.sub.3CH.sub.3, SO.sub.3C.sub.2H.sub.5, SO.sub.3C.sub.3H.sub.7, SO.sub.3-cyclo-C.sub.3H.sub.5, SO.sub.3CH(CH.sub.3).sub.2, SO.sub.3C(CH.sub.3).sub.3, SO.sub.2NH.sub.2, SO.sub.2NHCH.sub.3, SO.sub.2NHC.sub.2H.sub.5, SO.sub.2NHC.sub.3H.sub.7, SO.sub.2NH-cyclo-C.sub.3H.sub.5, SO.sub.2NHCH(CH.sub.3).sub.2, SO.sub.2NHC(CH.sub.3).sub.3, SO.sub.2N(CH.sub.3).sub.2, SO.sub.2N(C.sub.2H.sub.5).sub.2, SO.sub.2N(C.sub.3H.sub.7).sub.2, SO.sub.2N(cyclo-C.sub.3H.sub.5).sub.2, SO.sub.2N[CH(CH.sub.3).sub.2].sub.2, SO.sub.2N[C(CH.sub.3).sub.3].sub.2, OS(O)CH.sub.3, OS(O)C.sub.2H.sub.5, OS(O)C.sub.3H.sub.7, OS(O)-cyclo-C.sub.3H.sub.5, OS(O)CH(CH.sub.3).sub.2, OS(O)C(CH.sub.3).sub.3, S(O)(NH)CH.sub.3, S(O)(NH)C.sub.2H.sub.5, S(O)(NH)C.sub.3H.sub.7, S(O)(NH)-cyclo-C.sub.3H.sub.5, S(O)(NH)CH(CH.sub.3).sub.2, S(O)(NH)C(CH.sub.3).sub.3, NHSO.sub.2CH.sub.3, NHSO.sub.2C.sub.2H.sub.6, NHSO.sub.2C.sub.3H.sub.7, NHSO.sub.2-cyclo-C.sub.3H.sub.6, NHSO.sub.2CH(CH.sub.3).sub.2, NHSO.sub.2C(CH.sub.3).sub.3, OSO.sub.2CH.sub.3, OSO.sub.2C.sub.2H.sub.5, OSO.sub.2C.sub.3H.sub.7, OSO.sub.2-cyclo-C.sub.3H.sub.5, OSO.sub.2CH(CH.sub.3).sub.2, OSO.sub.2C(CH.sub.3).sub.3, OCF.sub.3, CH.sub.2OCF.sub.3, C.sub.2H.sub.4OCF.sub.3, C.sub.3H.sub.6OCF.sub.3, OC.sub.2F.sub.5, CH.sub.2OC.sub.2F.sub.5, C.sub.2H.sub.4OC.sub.2F.sub.5, C.sub.3H.sub.6OC.sub.2F.sub.5, OCOOCH.sub.3, OCOOC.sub.2H.sub.5, OCOOC.sub.3H.sub.7, OCOO-cyclo-C.sub.3H.sub.5, OCOOCH(CH.sub.3).sub.2, OCOOC(CH.sub.3).sub.3, NHCONH.sub.2, NHCONHCH.sub.3, NHCONHC.sub.2H.sub.5, NHCSN(C.sub.3H.sub.7).sub.2, NHCONHC.sub.3H.sub.7, NHCON(C.sub.3H.sub.7).sub.2, NHCONH[CH(CH.sub.3).sub.2], NHCONH[C(CH.sub.3).sub.3], NHCON(CH.sub.3).sub.2, NHCON(C.sub.2H.sub.5).sub.2, NHCONH-cyclo-C.sub.3H.sub.5, NHCON(cyclo-C.sub.3H.sub.5).sub.2, NHCON[CH(CH.sub.3).sub.2].sub.2, NHCSN(C.sub.2H.sub.5).sub.2, NHCON[C(CH.sub.3).sub.3].sub.2, NHCSNH.sub.2, NHCSNHCH.sub.3, NHCSN(CH.sub.3).sub.2, NHCSNHC.sub.2H.sub.5, NHCSNHC.sub.3H.sub.7, NHCSNH-cyclo-C.sub.3H.sub.5, NHCSNH[CH(CH.sub.3).sub.2], NHCSNH[C(CH.sub.3).sub.3], NHCSN(cyclo-C.sub.3H.sub.5).sub.2, NHCSN[CH(CH.sub.3).sub.2].sub.2, NHCSN[C(CH.sub.3).sub.3].sub.2, NHC(NH)NH.sub.2, NHC(NH)NHCH.sub.3, NHC(NH)NHC.sub.2H.sub.5, NHC(NH)NHC.sub.3H.sub.7, OCONH-cyclo-C.sub.3H.sub.5, NHC(NH)NH-cyclo-C.sub.3H.sub.5, NHC(NH)NH[CH(CH.sub.3).sub.2], OCONH[CH(CH.sub.3).sub.2], NHC(NH)NH[C(CH.sub.3).sub.3], NHC(NH)N(CH.sub.3).sub.2, NHC(NH)N(C.sub.2H.sub.5).sub.2, NHC(NH)N(C.sub.3H.sub.7).sub.2, NHC(NH)N(cyclo-C.sub.3H.sub.5).sub.2, OCONHC.sub.3H.sub.7, NHC(NH)N[CH(CH.sub.3).sub.2].sub.2, NHC(NH)N[C(CH.sub.3).sub.3].sub.2, OCONH.sub.2, OCONHCH.sub.3, OCONHC.sub.2H.sub.5, OCONH[C(CH.sub.3).sub.3], OCON(CH.sub.3).sub.2, OCON(C.sub.2H.sub.5).sub.2, OCON(C.sub.3H.sub.7).sub.2, OCON(cyclo-C.sub.3H.sub.5).sub.2, OCON [CH(CH.sub.3).sub.2].sub.2, OCON[C(CH.sub.3).sub.3].sub.2, OCOOCH.sub.3, OCOOC.sub.2H.sub.5, OCOOC.sub.3H.sub.7, OCOO-cyclo-C.sub.3H.sub.5, OCOOCH(CH.sub.3).sub.2, OCOOC(CH.sub.3).sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3, CH.sub.2Cl, CH.sub.2Br, CH.sub.2I, CH.sub.2CH.sub.2F, CH.sub.2CHF.sub.2, CH.sub.2CF.sub.3, CH.sub.2CH.sub.2Cl, CH.sub.2CH.sub.2Br, CH.sub.2CH.sub.2I, -cyclo-C.sub.3H.sub.5, -cyclo-C.sub.4H.sub.7, -cyclo-C.sub.5H.sub.9, -cyclo-C.sub.6H.sub.11, -cyclo-C.sub.7H.sub.13, -cyclo-C.sub.8H.sub.15, -Ph, CH.sub.2-Ph, CH.sub.2CH.sub.2-Ph, CHCH-Ph, CPh.sub.3, CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, CH(CH.sub.3).sub.2, C.sub.4H.sub.9, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, C(CH.sub.3).sub.3, C.sub.5H.sub.11, CH(CH.sub.3)C.sub.3H.sub.7, CH.sub.2CH(CH.sub.3)C.sub.2H.sub.5, CH(CH.sub.3)CH(CH.sub.3).sub.2, C(CH.sub.3).sub.2C.sub.2H.sub.5, CH.sub.2C(CH.sub.3).sub.3, CH(C.sub.2H.sub.5).sub.2, C.sub.2H.sub.4CH(CH.sub.3).sub.2, C.sub.6H.sub.13, C.sub.7H.sub.15, C.sub.8H.sub.17, C.sub.3H.sub.6CH(CH.sub.3).sub.2, C.sub.2H.sub.4CH(CH.sub.3)C.sub.2H.sub.5, CH(CH.sub.3)C.sub.4H.sub.9, CH.sub.2CH(CH.sub.3)C.sub.3H.sub.7, CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH(CH.sub.3)CH(CH.sub.3).sub.2, CH.sub.2C(CH.sub.3).sub.2C.sub.2H.sub.5, C(CH.sub.3).sub.2C.sub.3H.sub.7, C(CH.sub.3).sub.2CH(CH.sub.3).sub.2, C.sub.2H.sub.4C(CH.sub.3).sub.3, CH(CH.sub.3)C(CH.sub.3).sub.3, CHCH.sub.2, CH.sub.2CHCH.sub.2, C(CH.sub.3)CH.sub.2, CHCHCH.sub.3, C.sub.2H.sub.4CHCH.sub.2, CH.sub.2CHCHCH.sub.3, CHCHC.sub.2H.sub.5, CH.sub.2C(CH.sub.3)CH.sub.2, CH(CH.sub.3)CHCH, CHC(CH.sub.3).sub.2, C(CH.sub.3)CHCH.sub.3, CHCHCHCH.sub.2, C.sub.3H.sub.6CHCH.sub.2, C.sub.2H.sub.4CHCHCH.sub.3, CH.sub.2CHCHC.sub.2H.sub.5, CHCHC.sub.3H.sub.7, CH.sub.2CHCHCHCH.sub.2, CHCHCHCHCH.sub.3, CHCHCH.sub.2CHCH.sub.2, C(CH.sub.3)CHCHCH.sub.2, CHC(CH.sub.3)CHCH.sub.2, CHCHC(CH.sub.3)CH.sub.2, C.sub.2H.sub.4C(CH.sub.3)CH.sub.2, CH.sub.2CH(CH.sub.3)CHCH.sub.2, CH(CH.sub.3)CH.sub.2CHCH.sub.2, CH.sub.2CHC(CH.sub.3).sub.2, CH.sub.2C(CH.sub.3)CHCH.sub.3, CH(CH.sub.3)CHCHCH.sub.3, CHCHCH(CH.sub.3).sub.2, CHC(CH.sub.3)C.sub.2H.sub.5, C(CH.sub.3)CHC.sub.2H.sub.5, C(CH.sub.3)C(CH.sub.3).sub.2, C(CH.sub.3).sub.2CHCH.sub.2, CH(CH.sub.3)C(CH.sub.3)CH.sub.2, C(CH.sub.3)CHCHCH.sub.2, CHC(CH.sub.3)CHCH.sub.2, CHCHC(CH.sub.3)CH.sub.2, C.sub.4H.sub.8CHCH.sub.2, C.sub.3H.sub.6CHCHCH.sub.3, C.sub.2H.sub.4CHCHC.sub.2H.sub.5, CH.sub.2CHCHC.sub.3H.sub.7, CHCHC.sub.4H.sub.9, C.sub.3H.sub.6C(CH.sub.3)CH.sub.2, C.sub.2H.sub.4CH(CH.sub.3)CHCH.sub.2, CH.sub.2CH(CH.sub.3)CH.sub.2CHCH.sub.2, C.sub.2H.sub.4CHC(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.4CHCH.sub.2, C.sub.2H.sub.4C(CH.sub.3)CHCH.sub.3, CH.sub.2CH(CH.sub.3)CHCHCH.sub.3, CH(CH.sub.3)CH.sub.2CHCHCH.sub.3, CH.sub.2CHCHCH(CH.sub.3).sub.2, CH.sub.2CHC(CH.sub.3)C.sub.2H.sub.5, CH.sub.2C(CH.sub.3)CHC.sub.2H.sub.5, CH(CH.sub.3)CHCHC.sub.2H.sub.5, CHCHCH.sub.2CH(CH.sub.3).sub.2, CHCHCH(CH.sub.3)C.sub.2H.sub.5, CHC(CH.sub.3)C.sub.3H.sub.7, C(CH.sub.3)CHC.sub.3H.sub.7, CH.sub.2CH(CH.sub.3)C(CH.sub.3)CH.sub.2, C[C(CH.sub.3).sub.3]CH.sub.2, CH(CH.sub.3)CH.sub.2C(CH.sub.3)CH.sub.2, CH(CH.sub.3)CH(CH.sub.3)CHCH.sub.2, CH.sub.2C(CH.sub.3).sub.2CHCH.sub.2, C(CH.sub.3).sub.2CH.sub.2CHCH.sub.2, CH.sub.2C(CH.sub.3)C(CH.sub.3).sub.2, CH(CH.sub.3)CHC(CH.sub.3).sub.2, C(CH.sub.3).sub.2CHCHCH.sub.3, CH(CH.sub.3)C(CH.sub.3)CHCH.sub.3, CHC(CH.sub.3)CH(CH.sub.3).sub.2, C(CH.sub.3)CHCH(CH.sub.3).sub.2, C(CH.sub.3)C(CH.sub.3)C.sub.2H.sub.5, CHCHC(CH.sub.3).sub.3, C(CH.sub.3).sub.2C(CH.sub.3)CH.sub.2, CH(C.sub.2H.sub.5)C(CH.sub.3)CH.sub.2, C(CH.sub.3)(C.sub.2H.sub.5)CHCH.sub.2, CH(CH.sub.3)C(C.sub.2H.sub.5)CH.sub.2, CH.sub.2C(C.sub.3H.sub.7)CH.sub.2, CH.sub.2C(C.sub.2H.sub.5)CHCH.sub.3, CH(C.sub.2H.sub.5)CHCHCH.sub.3, C(C.sub.4H.sub.9)CH.sub.2, C(C.sub.3H.sub.7)CHCH.sub.3, C(C.sub.2H.sub.5)CHC.sub.2H.sub.5, C(C.sub.2H.sub.5)C(CH.sub.3).sub.2, C[CH(CH.sub.3)(C.sub.2H.sub.5)]CH.sub.2, C[CH.sub.2CH(CH.sub.3).sub.2]CH.sub.2, C.sub.3H.sub.6CCCH.sub.3, CH(CH.sub.3)CH.sub.2CCH, CH(CH.sub.3)CCCH.sub.3, C.sub.2H.sub.4CH(CH.sub.3)CCH, CH.sub.2CH(CH.sub.3)CH.sub.2CCH, CH.sub.2CH(CH.sub.3)CCH, CCH, CCCH.sub.3, CH.sub.2CCH, C.sub.2H.sub.4CCH, CH.sub.2CCCH.sub.3, CCC.sub.2H.sub.5, C.sub.3H.sub.6CCH, C.sub.2H.sub.4CCCH.sub.3, CH.sub.2CCC.sub.2H.sub.5, CCC.sub.3H.sub.7, CH(CH.sub.3)CCH, C.sub.4H.sub.8CCH, C.sub.2H.sub.4CCC.sub.2H.sub.5, CH.sub.2CCC.sub.3H.sub.7, CCC.sub.4H.sub.9, CCC(CH.sub.3).sub.3, CH(CH.sub.3)C.sub.2H.sub.4CCH, CH.sub.2CH(CH.sub.3)CCCH.sub.3, CH(CH.sub.3)CH.sub.2CCCH.sub.3, CH(CH.sub.3)CCC.sub.2H.sub.5, CH.sub.2CCCH(CH.sub.3).sub.2, CCCH(CH.sub.3)C.sub.2H.sub.5, CCCH.sub.2CH(CH.sub.3).sub.2, CH(C.sub.2H.sub.5)CCCH.sub.3, C(CH.sub.3).sub.2CCCH.sub.3, CH(C.sub.2H.sub.5)CH.sub.2CCH, CH.sub.2CH(C.sub.2H.sub.5)CCH, C(CH.sub.3).sub.2CH.sub.2CCH, CH.sub.2C(CH.sub.3).sub.2CCH, CH(CH.sub.3)CH(CH.sub.3)CCH, CH(C.sub.3H.sub.7)CCH, C(CH.sub.3)(C.sub.2H.sub.5)CCH, CH.sub.2CH(CCH).sub.2, ##STR00245## R.sup.15 represents R.sup.20, CN, CH.sub.2CN, CH.sub.2OR.sup.17, CH.sub.2CH.sub.2OR.sup.17, CH.sub.2NR.sup.17R.sup.18, CH.sub.2NR.sup.17COR.sup.19, CH.sub.2CH.sub.2NR.sup.17R.sup.18, CH.sub.2CH.sub.2NR.sup.17COR.sup.19, CO.sub.2R.sup.17, CONR.sup.17R.sup.18, CH.sub.2CO.sub.2R.sup.17, or CH.sub.2CONR.sup.17R.sup.18; R.sup.16 represents R.sup.21, H, CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, CH(CH.sub.3).sub.2, C.sub.4H.sub.9, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, C(CH.sub.3).sub.3, C.sub.5H.sub.11, CH(CH.sub.3)C.sub.3H.sub.7, CH.sub.2CH(CH.sub.3)C.sub.2H.sub.5, CH(CH.sub.3)CH(CH.sub.3).sub.2, C(CH.sub.3).sub.2C.sub.2H.sub.5, CH.sub.2C(CH.sub.3).sub.3, CH(C.sub.2H.sub.5).sub.2, C.sub.2H.sub.4CH(CH.sub.3).sub.2, C.sub.6H.sub.13, C.sub.7H.sub.15, C.sub.8H.sub.17, C.sub.3H.sub.6CH(CH.sub.3).sub.2, C.sub.2H.sub.4CH(CH.sub.3)C.sub.2H.sub.5, CH(CH.sub.3)C.sub.4H.sub.9, CH.sub.2CH(CH.sub.3)C.sub.3H.sub.7, CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH(CH.sub.3)CH(CH.sub.3).sub.2, CH.sub.2C(CH.sub.3).sub.2C.sub.2H.sub.5, C(CH.sub.3).sub.2C.sub.3H.sub.7, C(CH.sub.3).sub.2CH(CH.sub.3).sub.2, C.sub.2H.sub.4C(CH.sub.3).sub.3, CH(CH.sub.3)C(CH.sub.3).sub.3, CH.sub.2OH, CH.sub.2SH, CH(OH)CH.sub.3, C.sub.2H.sub.4OH, C.sub.3H.sub.6OH, C.sub.4H.sub.8OH, CH(CH.sub.3)C.sub.2H.sub.4OH, C.sub.5H.sub.10OH, CH.sub.2SCH.sub.3, CH.sub.2CH.sub.2SCH.sub.3, C.sub.3H.sub.6SCH.sub.3, CH.sub.2OCH.sub.3, C.sub.2H.sub.4OCH.sub.3, C.sub.3H.sub.6OCH.sub.3, C.sub.4H.sub.8OCH.sub.3, CH(CH.sub.3)C.sub.2H.sub.4OCH.sub.3, C.sub.5H.sub.10OCH.sub.3, CH.sub.2NH.sub.2, C.sub.2H.sub.4NH.sub.2, C.sub.3H.sub.6NH.sub.2, C.sub.4H.sub.8NH.sub.2, CH(CH.sub.3)C.sub.2H.sub.4NH.sub.2, C.sub.5H.sub.10NH.sub.2, CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2, CH.sub.2CO.sub.2H, CH.sub.2CONH.sub.2, CH.sub.2CH.sub.2CO.sub.2H, CH.sub.2CH.sub.2CONH.sub.2, CH.sub.2CO.sub.2CH.sub.3, CH.sub.2CONHCH.sub.3, CH.sub.2CON(CH.sub.3).sub.2, CH.sub.2CH.sub.2CO.sub.2CH.sub.3, CH.sub.2CH.sub.2CONHCH.sub.3, CH.sub.2CH.sub.2CONH(CH.sub.3).sub.2, CHCHCO.sub.2H, CHCHCO.sub.2CH.sub.3, CHCHCONHCH.sub.3, CHCHCONHC.sub.2H.sub.5, CHCHCON(CH.sub.3).sub.2, CHCHCON(C.sub.2H.sub.5).sub.2, CH.sub.2CHCHCO.sub.2H, CH.sub.2CHCHCO.sub.2CH.sub.3, CH.sub.2CHCHCONHCH.sub.3, CH.sub.2CHCHCON(CH.sub.3).sub.2, CH.sub.2CHCHCONHC.sub.2H.sub.5, CH.sub.2CHCHCON(C.sub.2H.sub.5).sub.2, CHCH.sub.2, CH.sub.2CHCH.sub.2, C(CH.sub.3)CH.sub.2, CHCHCH.sub.3, C.sub.2H.sub.4CHCH.sub.2, CH.sub.2CHCHCH.sub.3, CHCHC.sub.2H.sub.5, CH.sub.2C(CH.sub.3)CH.sub.2, CH(CH.sub.3)CHCH, CHC(CH.sub.3).sub.2, C(CH.sub.3)CHCH.sub.3, CHCHCHCH.sub.2, C.sub.3H.sub.6CHCH.sub.2, C.sub.2H.sub.4CHCHCH.sub.3, CH.sub.2CHCHC.sub.2H.sub.5, CHCHC.sub.3H.sub.7, CH.sub.2CHCHCHCH.sub.2, CHCHCHCHCH.sub.3, CHCHCH.sub.2CHCH.sub.2, C(CH.sub.3)CHCHCH.sub.2, CHC(CH.sub.3)CHCH.sub.2, CHCHC(CH.sub.3)CH.sub.2, C.sub.2H.sub.4C(CH.sub.3)CH.sub.2, CH.sub.2CH(CH.sub.3)CHCH.sub.2, CH(CH.sub.3)CH.sub.2CHCH.sub.2, CH.sub.2CHC(CH.sub.3).sub.2, CH.sub.2C(CH.sub.3)CHCH.sub.3, CH(CH.sub.3)CHCHCH.sub.3, CHCHCH(CH.sub.3).sub.2, CHC(CH.sub.3)C.sub.2H.sub.5, C(CH.sub.3)CHC.sub.2H.sub.5, C(CH.sub.3)C(CH.sub.3).sub.2, C(CH.sub.3).sub.2CHCH.sub.2, CH(CH.sub.3)C(CH.sub.3)CH.sub.2, C(CH.sub.3)CHCHCH.sub.2, CHC(CH.sub.3)CHCH.sub.2, CHCHC(CH.sub.3)CH.sub.2, C.sub.4H.sub.8CHCH.sub.2, C.sub.3H.sub.6CHCHCH.sub.3, C.sub.2H.sub.4CHCHC.sub.2H.sub.5, CH.sub.2CHCHC.sub.3H.sub.7, CHCHC.sub.4H.sub.9, C.sub.3H.sub.6C(CH.sub.3)CH.sub.2, C.sub.2H.sub.4CH(CH.sub.3)CHCH.sub.2, CH.sub.2CH(CH.sub.3)CH.sub.2CHCH.sub.2, C.sub.2H.sub.4CHC(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.4CHCH.sub.2, C.sub.2H.sub.4C(CH.sub.3)CHCH.sub.3, CH.sub.2CH(CH.sub.3)CHCHCH.sub.3, CH(CH.sub.3)CH.sub.2CHCHCH.sub.3, CH.sub.2CHCHCH(CH.sub.3).sub.2, CH.sub.2CHC(CH.sub.3)C.sub.2H.sub.5, CH.sub.2C(CH.sub.3)CHC.sub.2H.sub.5, CH(CH.sub.3)CHCHC.sub.2H.sub.5, CHCHCH.sub.2CH(CH.sub.3).sub.2, CHCHCH(CH.sub.3)C.sub.2H.sub.5, CHC(CH.sub.3)C.sub.3H.sub.7, C(CH.sub.3)CHC.sub.3H.sub.7, CH.sub.2CH(CH.sub.3)C(CH.sub.3)CH.sub.2, C[C(CH.sub.3).sub.3]CH.sub.2, CH(CH.sub.3)CH.sub.2C(CH.sub.3)CH.sub.2, CH(CH.sub.3)CH(CH.sub.3)CHCH.sub.2, CHCHC.sub.2H.sub.4CHCH.sub.2, CH.sub.2C(CH.sub.3).sub.2CHCH.sub.2, C(CH.sub.3).sub.2CH.sub.2CHCH.sub.2, CH.sub.2C(CH.sub.3)C(CH.sub.3).sub.2, CH(CH.sub.3)CHC(CH.sub.3).sub.2, C(CH.sub.3).sub.2CHCHCH.sub.3, CHCHCH.sub.2CHCHCH.sub.3, CH(CH.sub.3)C(CH.sub.3)CHCH.sub.3, CHC(CH.sub.3)CH(CH.sub.3).sub.2, C(CH.sub.3)CHCH(CH.sub.3).sub.2, C(CH.sub.3)C(CH.sub.3)C.sub.2H.sub.5, CHCHC(CH.sub.3).sub.3, C(CH.sub.3).sub.2C(CH.sub.3)CH.sub.2, CH(C.sub.2H.sub.5)C(CH.sub.3)CH.sub.2, C(CH.sub.3)(C.sub.2H.sub.5)CHCH.sub.2, CH(CH.sub.3)C(C.sub.2H.sub.5)CH.sub.2, CH.sub.2C(C.sub.3H.sub.7)CH.sub.2, CH.sub.2C(C.sub.2H.sub.5)CHCH.sub.3, CH(C.sub.2H.sub.5)CHCHCH.sub.3, C(C.sub.4H.sub.9)CH.sub.2, C(C.sub.3H.sub.7)CHCH.sub.3, C(C.sub.2H.sub.5)CHC.sub.2H.sub.5, C(C.sub.2H.sub.5)C(CH.sub.3).sub.2, C[CH(CH.sub.3)(C.sub.2H.sub.5)]CH.sub.2, C[CH.sub.2CH(CH.sub.3).sub.2]CH.sub.2, C.sub.2H.sub.4CHCHCHCH.sub.2, CH.sub.2CHCHCH.sub.2CHCH.sub.2, C.sub.3H.sub.6CCCH.sub.3, CH.sub.2CHCHCHCHCH.sub.3, CHCHCHCHC.sub.2H.sub.5, CH.sub.2CHCHC(CH.sub.3)CH.sub.2, CH.sub.2CHC(CH.sub.3)CHCH.sub.2, CH.sub.2C(CH.sub.3)CHCHCH.sub.2, CH(CH.sub.3)CH.sub.2CCH, CH(CH.sub.3)CHCHCHCH.sub.2, CHCHCH.sub.2C(CH.sub.3)CH.sub.2, CH(CH.sub.3)CCCH.sub.3, CHCHCH(CH.sub.3)CHCH.sub.2, CHC(CH.sub.3)CH.sub.2CHCH.sub.2, C.sub.2H.sub.4CH(CH.sub.3)CCH, C(CH.sub.3)CHCH.sub.2CHCH.sub.2, CHCHCHC(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3)CH.sub.2CCH, CHCHC(CH.sub.3)CHCH.sub.3, CHC(CH.sub.3)CHCHCH.sub.3, CH.sub.2CH(CH.sub.3)CCH, C(CH.sub.3)CHCHCHCH.sub.3, CHC(CH.sub.3)C(CH.sub.3)CH.sub.2, C(CH.sub.3)CHC(CH.sub.3)CH.sub.2, C(CH.sub.3)C(CH.sub.3)CHCH.sub.2, CHCHCHCHCHCH.sub.2, CCH, CCCH.sub.3, CH.sub.2CCH, C.sub.2H.sub.4CCH, CH.sub.2CCCH.sub.3, CCC.sub.2H.sub.5, C.sub.3H.sub.6CCH, C.sub.2H.sub.4CCCH.sub.3, CH.sub.2CCC.sub.2H.sub.5, CCC.sub.3H.sub.7, CH(CH.sub.3)CCH, C.sub.4H.sub.5CCH, C.sub.2H.sub.4CCC.sub.2H.sub.5, CH.sub.2CCC.sub.3H.sub.7, CCC.sub.4H.sub.9, CCC(CH.sub.3).sub.3, CH(CH.sub.3)C.sub.2H.sub.4CCH, CH.sub.2CH(CH.sub.3)CCCH.sub.3, CH(CH.sub.3)CH.sub.2CCCH.sub.3, CH(CH.sub.3)CCC.sub.2H.sub.5, CH.sub.2CCCH(CH.sub.3).sub.2, CCCH(CH.sub.3)C.sub.2H.sub.5, CCCH.sub.2CH(CH.sub.3).sub.2, CH(C.sub.2H.sub.5)CCCH.sub.3, C(CH.sub.3).sub.2CCCH.sub.3, CH(C.sub.2H.sub.5)CH.sub.2CCH, CH.sub.2CH(C.sub.2H.sub.5)CCH, C(CH.sub.3).sub.2CH.sub.2CCH, CH.sub.2C(CH.sub.3).sub.2CCH, CH(CH.sub.3)CH(CH.sub.3)CCH, CH(C.sub.3H.sub.7)CCH, C(CH.sub.3)(C.sub.2H.sub.5)CCH, CH.sub.2-Ph, ##STR00246## R.sup.11-R.sup.14 and R.sup.17-R.sup.21 represent independently of each other H, CH.sub.2F, CHF.sub.2, CH.sub.2OCH.sub.3, CH.sub.2OH, C.sub.2H.sub.4OCH.sub.3, C.sub.3H.sub.6OCH.sub.3, CH.sub.2OC.sub.2H.sub.5, C.sub.2H.sub.4OC.sub.2H.sub.5, C.sub.3H.sub.6OC.sub.2H.sub.5, CH.sub.2OC.sub.3H.sub.7, C.sub.2H.sub.4OC.sub.3H.sub.7, C.sub.3H.sub.6OC.sub.3H.sub.7, CH.sub.2O-cyclo-C.sub.3H.sub.5, C.sub.2H.sub.4O-cyclo-C.sub.3H.sub.5, C.sub.3H.sub.6O-cyclo-C.sub.3H.sub.5, CH.sub.2OCH(CH.sub.3).sub.2, C.sub.2H.sub.4OCH(CH.sub.3).sub.2, C.sub.3H.sub.6OCH(CH.sub.3).sub.2, CH.sub.2OC(CH.sub.3).sub.3, C.sub.2H.sub.4OC(CH.sub.3).sub.3, C.sub.3H.sub.6OC(CH.sub.3).sub.3, CH.sub.2OC.sub.4H.sub.9, C.sub.2H.sub.4OC.sub.4H.sub.9, C.sub.3H.sub.6OC.sub.4H.sub.9, CH.sub.2OPh, C.sub.2H.sub.4OPh, C.sub.3H.sub.6OPh, CH.sub.2OCH.sub.2-Ph, C.sub.2H.sub.4OCH.sub.2-Ph, C.sub.3H.sub.6OCH.sub.2-Ph, CF.sub.3, CH.sub.2Cl, CH.sub.2Br, CH.sub.2I, CH.sub.2CH.sub.2F, CH.sub.2CHF.sub.2, CH.sub.2CF.sub.3, CH.sub.2CH.sub.2Cl, CH.sub.2CH.sub.2Br, CH.sub.2CH.sub.2I, -cyclo-C.sub.3H.sub.5, -cyclo-C.sub.4H.sub.7, -cyclo-C.sub.5H.sub.9, -cyclo-C.sub.6H.sub.11, -cyclo-C.sub.7H.sub.13, -cyclo-C.sub.5H.sub.15, -Ph, CH.sub.2-Ph, CH.sub.2CH.sub.2-Ph, CHCH-Ph, CPh.sub.3, CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, CH(CH.sub.3).sub.2, C.sub.4H.sub.9, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, C(CH.sub.3).sub.3, C.sub.5H.sub.11, CH(CH.sub.3)C.sub.3H.sub.7, CH.sub.2CH(CH.sub.3)C.sub.2H.sub.5, CH(CH.sub.3)CH(CH.sub.3).sub.2, C(CH.sub.3).sub.2C.sub.2H.sub.5, CH.sub.2C(CH.sub.3).sub.3, CH(C.sub.2H.sub.5).sub.2, C.sub.2H.sub.4CH(CH.sub.3).sub.2, C.sub.6H.sub.13, C.sub.7H.sub.15, C.sub.8H.sub.17, C.sub.3H.sub.6CH(CH.sub.3).sub.2, C.sub.2H.sub.4CH(CH.sub.3)C.sub.2H.sub.5, CH(CH.sub.3)C.sub.4H.sub.9, CH.sub.2CH(CH.sub.3)C.sub.3H.sub.7, CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH(CH.sub.3)CH(CH.sub.3).sub.2, CH.sub.2C(CH.sub.3).sub.2C.sub.2H.sub.5, C(CH.sub.3).sub.2C.sub.3H.sub.7, C(CH.sub.3).sub.2CH(CH.sub.3).sub.2, C.sub.2H.sub.4C(CH.sub.3).sub.3, CH(CH.sub.3)C(CH.sub.3).sub.3, CHCH.sub.2, CH.sub.2CHCH.sub.2, C(CH.sub.3)CH.sub.2, CHCHCH.sub.3, C.sub.2H.sub.4CHCH.sub.2, CH.sub.2CHCHCH.sub.3, CHCHC.sub.2H.sub.5, CH.sub.2C(CH.sub.3)CH.sub.2, CH(CH.sub.3)CHCH, CHC(CH.sub.3).sub.2, C(CH.sub.3)CHCH.sub.3, CHCHCHCH.sub.2, C.sub.3H.sub.6CHCH.sub.2, C.sub.2H.sub.4CHCHCH.sub.3, CH.sub.2CHCHC.sub.2H.sub.5, CHCHC.sub.3H.sub.7, CH.sub.2CHCHCHCH.sub.2, CHCHCHCHCH.sub.3, CHCHCH.sub.2CHCH.sub.2, C(CH.sub.3)CHCHCH.sub.2, CHC(CH.sub.3)CHCH.sub.2, CHCHC(CH.sub.3)CH.sub.2, C.sub.2H.sub.4C(CH.sub.3)CH.sub.2, CH.sub.2CH(CH.sub.3)CHCH.sub.2, CH(CH.sub.3)CH.sub.2CHCH.sub.2, CH.sub.2CHC(CH.sub.3).sub.2, CH.sub.2C(CH.sub.3)CHCH.sub.3, CH(CH.sub.3)CHCHCH.sub.3, CHCHCH(CH.sub.3).sub.2, CHC(CH.sub.3)C.sub.2H.sub.5, C(CH.sub.3)CHC.sub.2H.sub.5, C(CH.sub.3)C(CH.sub.3).sub.2, C(CH.sub.3).sub.2CHCH.sub.2, CH(CH.sub.3)C(CH.sub.3)CH.sub.2, C(CH.sub.3)CHCHCH.sub.2, CHC(CH.sub.3)CHCH.sub.2, CHCHC(CH.sub.3)CH.sub.2, C.sub.4H.sub.8CHCH.sub.2, C.sub.3H.sub.6CHCHCH.sub.3, C.sub.2H.sub.4CHCHC.sub.2H.sub.5, CH.sub.2CHCHC.sub.3H.sub.7, CHCHC.sub.4H.sub.9, C.sub.3H.sub.6C(CH.sub.3)CH.sub.2, C.sub.2H.sub.4CH(CH.sub.3)CHCH.sub.2, CH.sub.2CH(CH.sub.3)CH.sub.2CHCH.sub.2, C.sub.2H.sub.4CHC(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.4CHCH.sub.2, C.sub.2H.sub.4C(CH.sub.3)CHCH.sub.3, CH.sub.2CH(CH.sub.3)CHCHCH.sub.3, CH(CH.sub.3)CH.sub.2CHCHCH.sub.3, CH.sub.2CHCHCH(CH.sub.3).sub.2, CH.sub.2CHC(CH.sub.3)C.sub.2H.sub.5, CH.sub.2C(CH.sub.3)CHC.sub.2H.sub.5, CH(CH.sub.3)CHCHC.sub.2H.sub.5, CHCHCH.sub.2CH(CH.sub.3).sub.2, CHCHCH(CH.sub.3)C.sub.2H.sub.5, CHC(CH.sub.3)C.sub.3H.sub.7, C(CH.sub.3)CHC.sub.3H.sub.7, CH.sub.2CH(CH.sub.3)C(CH.sub.3)CH.sub.2, C[C(CH.sub.3).sub.3]CH.sub.2, CH(CH.sub.3)CH.sub.2C(CH.sub.3)CH.sub.2, CH(CH.sub.3)CH(CH.sub.3)CHCH.sub.2, CH.sub.2C(CH.sub.3).sub.2CHCH.sub.2, C(CH.sub.3).sub.2CH.sub.2CHCH.sub.2, CH.sub.2C(CH.sub.3)C(CH.sub.3).sub.2, CH(CH.sub.3)CHC(CH.sub.3).sub.2, C(CH.sub.3).sub.2CHCHCH.sub.3, CH(CH.sub.3)C(CH.sub.3)CHCH.sub.3, CHC(CH.sub.3)CH(CH.sub.3).sub.2, C(CH.sub.3)CHCH(CH.sub.3).sub.2, C(CH.sub.3)C(CH.sub.3)C.sub.2H.sub.5, CHCHC(CH.sub.3).sub.3, C(CH.sub.3).sub.2C(CH.sub.3)CH.sub.2, CH(C.sub.2H.sub.5)C(CH.sub.3)CH.sub.2, C(CH.sub.3)(C.sub.2H.sub.5)CHCH.sub.2, CH(CH.sub.3)C(C.sub.2H.sub.5)CH.sub.2, CH.sub.2C(C.sub.3H.sub.7)CH.sub.2, CH.sub.2C(C.sub.2H.sub.5)CHCH.sub.3, CH(C.sub.2H.sub.5)CHCHCH.sub.3, C(C.sub.4H.sub.9)CH.sub.2, C(C.sub.3H.sub.7)CHCH.sub.3, C(C.sub.2H.sub.5)CHC.sub.2H.sub.5, C(C.sub.2H.sub.5)C(CH.sub.3).sub.2, C[CH(CH.sub.3)(C.sub.2H.sub.5)]CH.sub.2, C[CH.sub.2CH(CH.sub.3).sub.2]CH.sub.2, C.sub.3H.sub.6CCCH.sub.3, CH(CH.sub.3)CH.sub.2CCH, CH(CH.sub.3)CCCH.sub.3, C.sub.2H.sub.4CH(CH.sub.3)CCH, CH.sub.2CH(CH.sub.3)CH.sub.2CCH, CH.sub.2CH(CH.sub.3)CCH, CCH, CCCH.sub.3, CH.sub.2CCH, C.sub.2H.sub.4CCH, CH.sub.2CCCH.sub.3, CCC.sub.2H.sub.5, C.sub.3H.sub.6CCH, C.sub.2H.sub.4CCCH.sub.3, CH.sub.2CCC.sub.2H.sub.5, CCC.sub.3H.sub.7, CH(CH.sub.3)CCH, C.sub.4H.sub.8CCH, C.sub.2H.sub.4CCC.sub.2H.sub.5, CH.sub.2CCC.sub.3H.sub.7, CCC.sub.4H.sub.9, CCC(CH.sub.3).sub.3, CH(CH.sub.3)C.sub.2H.sub.4CCH, CH.sub.2CH(CH.sub.3)CCCH.sub.3, CH(CH.sub.3)CH.sub.2CCCH.sub.3, CH(CH.sub.3)CCC.sub.2H.sub.5, CH.sub.2CCCH(CH.sub.3).sub.2, CCCH(CH.sub.3)C.sub.2H.sub.5, CCCH.sub.2CH(CH.sub.3).sub.2, CH(C.sub.2H.sub.5)CCCH.sub.3, C(CH.sub.3).sub.2CCCH.sub.3, CH(C.sub.2H.sub.5)CH.sub.2CCH, CH.sub.2CH(C.sub.2H.sub.5)CCH, C(CH.sub.3).sub.2CH.sub.2CCH, CH.sub.2C(CH.sub.3).sub.2CCH, CH(CH.sub.3)CH(CH.sub.3)CCH, CH(C.sub.3H.sub.7)CCH, C(CH.sub.3)(C.sub.2H.sub.5)CCH, or CH.sub.2CH(CCH).sub.2; R.sup.22-R.sup.37 represent independently of each other H, OH, OCH.sub.3, OC.sub.2H.sub.5, OC.sub.3H.sub.7, O-cyclo-C.sub.3H.sub.5, OCH(CH.sub.3).sub.2, OC(CH.sub.3).sub.3, OC.sub.4H.sub.9, OCH.sub.2COOH, OPh, OCH.sub.2-Ph, OCPh.sub.3, CH.sub.2OH, C.sub.2H.sub.4OH, C.sub.3H.sub.6OH, CH(OH)CH.sub.2OH, CH.sub.2OCH.sub.3, C.sub.2H.sub.4OCH.sub.3, C.sub.3H.sub.6OCH.sub.3, CH.sub.2OC.sub.2H.sub.5, C.sub.2H.sub.4OC.sub.2H.sub.5, C.sub.3H.sub.6OC.sub.2H.sub.5, CH.sub.2OC.sub.3H.sub.7, C.sub.2H.sub.4OC.sub.3H.sub.7, C.sub.3H.sub.6OC.sub.3H.sub.7, CH.sub.2O-cyclo-C.sub.3H.sub.5, C.sub.2H.sub.4O-cyclo-C.sub.3H.sub.5, C.sub.3H.sub.6O-cyclo-C.sub.3H.sub.5, CH.sub.2OCH(CH.sub.3).sub.2, C.sub.2H.sub.4OCH(CH.sub.3).sub.2, C.sub.3H.sub.6OCH(CH.sub.3).sub.2, CH.sub.2OC(CH.sub.3).sub.3, C.sub.2H.sub.4OC(CH.sub.3).sub.3, C.sub.3H.sub.6OC(CH.sub.3).sub.3, CH.sub.2OC.sub.4H.sub.9, C.sub.2H.sub.4OC.sub.4H.sub.9, C.sub.3H.sub.6OC.sub.4H.sub.9, CH.sub.2OPh, C.sub.2H.sub.4OPh, C.sub.3H.sub.6OPh, CH.sub.2OCH.sub.2-Ph, C.sub.2H.sub.4OCH.sub.2-Ph, C.sub.3H.sub.6OCH.sub.2-Ph, SH, SCH.sub.3, SC.sub.2H.sub.5, SC.sub.3H.sub.7, S-cyclo-C.sub.3H.sub.5, SCH(CH.sub.3).sub.2, SC(CH.sub.3).sub.3, NO.sub.2, F, Cl, Br, I, P(O)(OH).sub.2, P(O)(OCH.sub.3).sub.2, P(O)(OC.sub.2H.sub.5).sub.2, P(O)(OCH(CH.sub.3).sub.2).sub.2, C(OH)[P(O)(OH).sub.2].sub.2, Si(CH.sub.3).sub.2(C(CH.sub.3).sub.3), Si(C.sub.2H.sub.5).sub.3, Si(CH.sub.3).sub.3, N.sub.3, CN, OCN, NCO, SCN, NCS, CHO, COCH.sub.3, COC.sub.2H.sub.5, COC.sub.3H.sub.7, CO-cyclo-C.sub.3H.sub.5, COCH(CH.sub.3).sub.2, COC(CH.sub.3).sub.3, COOH, COCN, COOCH.sub.3, COOC.sub.2H.sub.5, COOC.sub.3H.sub.7, COO-cyclo-C.sub.3H.sub.5, COOCH(CH.sub.3).sub.2, COOC(CH.sub.3).sub.3, OOCCH.sub.3, OOCC.sub.2H.sub.5, OOCC.sub.3H.sub.7, OOC-cyclo-C.sub.3H.sub.5, OOCCH(CH.sub.3).sub.2, OOCC(CH.sub.3).sub.3, CONH.sub.2, CH.sub.2CONH.sub.2, CONHCH.sub.3, CONHC.sub.2H.sub.5, CONHC.sub.3H.sub.7, CONH-cyclo-C.sub.3H.sub.5, CONH[CH(CH.sub.3).sub.2], CONH[C(CH.sub.3).sub.3], CON(CH.sub.3).sub.2, CON(C.sub.2H.sub.5).sub.2, CON(C.sub.3H.sub.7).sub.2, CON(cyclo-C.sub.3H.sub.5).sub.2, CON[CH(CH.sub.3).sub.2].sub.2, CON[C(CH.sub.3).sub.3].sub.2, NHCOCH.sub.3, NHCOC.sub.2H.sub.5, NHCOC.sub.3H.sub.7, NHCO-cyclo-C.sub.3H.sub.5, NHCOCH(CH.sub.3).sub.2, NHCOC(CH.sub.3).sub.3, NHCOOCH.sub.3, NHCOOC.sub.2H.sub.5, NHCOOC.sub.3H.sub.7, NHCOO-cyclo-C.sub.3H.sub.5, NHCOOCH(CH.sub.3).sub.2, NHCOOC(CH.sub.3).sub.3, NH.sub.2, NHCH.sub.3, NHC.sub.2H.sub.5, NHC.sub.3H.sub.7, NH-cyclo-C.sub.3H.sub.5, NHCH(CH.sub.3).sub.2, NHC(CH.sub.3).sub.3, N(CH.sub.3).sub.2, N(C.sub.2H.sub.5).sub.2, N(C.sub.3H.sub.7).sub.2, N(cyclo-C.sub.3H.sub.5).sub.2, N[CH(CH.sub.3).sub.2].sub.2, N[C(CH.sub.3).sub.3].sub.2, SOCH.sub.3, SOC.sub.2H.sub.5, SOC.sub.3H.sub.7, SO-cyclo-C.sub.3H.sub.5, SOCH(CH.sub.3).sub.2, SOC(CH.sub.3).sub.3, SO.sub.2CH.sub.3, SO.sub.2C.sub.2H.sub.5, SO.sub.2C.sub.3H.sub.7, SO.sub.2-cyclo-C.sub.3H.sub.5, SO.sub.2CH(CH.sub.3).sub.2, SO.sub.2C(CH.sub.3).sub.3, SO.sub.3H, SO.sub.3CH.sub.3, SO.sub.3C.sub.2H.sub.5, SO.sub.3C.sub.3H.sub.7, SO.sub.3-cyclo-C.sub.3H.sub.5, SO.sub.3CH(CH.sub.3).sub.2, SO.sub.3C(CH.sub.3).sub.3, SO.sub.2NH.sub.2, SO.sub.2NHCH.sub.3, SO.sub.2NHC.sub.2H.sub.5, SO.sub.2NHC.sub.3H.sub.7, SO.sub.2NH-cyclo-C.sub.3H.sub.5, SO.sub.2NHCH(CH.sub.3).sub.2, SO.sub.2NHC(CH.sub.3).sub.3, SO.sub.2N(CH.sub.3).sub.2, SO.sub.2N(C.sub.2H.sub.5).sub.2, SO.sub.2N(C.sub.3H.sub.7).sub.2, SO.sub.2N(cyclo-C.sub.3H.sub.5).sub.2, SO.sub.2N[CH(CH.sub.3).sub.2].sub.2, SO.sub.2N[C(CH.sub.3).sub.3].sub.2, OS(O)CH.sub.3, OS(O)C.sub.2H.sub.5, OS(O)C.sub.3H.sub.7, OS(O)-cyclo-C.sub.3H.sub.5, OS(O)CH(CH.sub.3).sub.2, OS(O)C(CH.sub.3).sub.3, S(O)(NH)CH.sub.3, S(O)(NH)C.sub.2H.sub.5, S(O)(NH)C.sub.3H.sub.7, S(O)(NH)-cyclo-C.sub.3H.sub.5, S(O)(NH)CH(CH.sub.3).sub.2, S(O)(NH)C(CH.sub.3).sub.3, NHSO.sub.2CH.sub.3, NHSO.sub.2C.sub.2H.sub.5, NHSO.sub.2C.sub.3H.sub.7, NHSO.sub.2-cyclo-C.sub.3H.sub.5, NHSO.sub.2CH(CH.sub.3).sub.2, NHSO.sub.2C(CH.sub.3).sub.3, OSO.sub.2CH.sub.3, OSO.sub.2C.sub.2H.sub.5, OSO.sub.2C.sub.3H.sub.7, OSO.sub.2-cyclo-C.sub.3H.sub.5, OSO.sub.2CH(CH.sub.3).sub.2, OSO.sub.2C(CH.sub.3).sub.3, OCF.sub.3, CH.sub.2OCF.sub.3, C.sub.2H.sub.4OCF.sub.3, C.sub.3H.sub.6OCF.sub.3, OC.sub.2F.sub.5, CH.sub.2OC.sub.2F.sub.5, C.sub.2H.sub.4OC.sub.2F.sub.5, C.sub.3H.sub.6OC.sub.2F.sub.5, OCOOCH.sub.3, OCOOC.sub.2H.sub.5, OCOOC.sub.3H.sub.7, OCOO-cyclo-C.sub.3H.sub.5, OCOOCH(CH.sub.3).sub.2, OCOOC(CH.sub.3).sub.3, NHCONH.sub.2, NHCONHCH.sub.3, NHCONHC.sub.2H.sub.5, NHCSN(C.sub.3H.sub.7).sub.2, NHCONHC.sub.3H.sub.7, NHCON(C.sub.3H.sub.7).sub.2, NHCONH[CH(CH.sub.3).sub.2], NHCONH[C(CH.sub.3).sub.3], NHCON(CH.sub.3).sub.2, NHCON(C.sub.2H.sub.5).sub.2, NHCONH-cyclo-C.sub.3H.sub.5, NHCON(cyclo-C.sub.3H.sub.5).sub.2, NHCON[CH(CH.sub.3).sub.2].sub.2, NHCSN(C.sub.2H.sub.5).sub.2, NHCON[C(CH.sub.3).sub.3].sub.2, NHCSNH.sub.2, NHCSNHCH.sub.3, NHCSN(CH.sub.3).sub.2, NHCSNHC.sub.2H.sub.5, NHCSNHC.sub.3H.sub.7, NHCSNH-cyclo-C.sub.3H.sub.5, NHCSNH[CH(CH.sub.3).sub.2], NHCSNH[C(CH.sub.3).sub.3], NHCSN(cyclo-C.sub.3H.sub.5).sub.2, NHCSN[CH(CH.sub.3).sub.2].sub.2, NHCSN[C(CH.sub.3).sub.3].sub.2, NHC(NH)NH.sub.2, NHC(NH)NHCH.sub.3, NHC(NH)NHC.sub.2H.sub.5, NHC(NH)NHC.sub.3H.sub.7, OCONH-cyclo-C.sub.3H.sub.5, NHC(NH)N H-cyclo-C.sub.3H.sub.5, NHC(NH)NH[CH(CH.sub.3).sub.2]OCONH[CH(CH.sub.3).sub.2], NHC(NH)NH[C(CH.sub.3).sub.3], NHC(NH)N(CH.sub.3).sub.2, NHC(NH)N(C.sub.2H.sub.5).sub.2, NHC(NH)N(C.sub.3H.sub.7).sub.2, NHC(NH)N(cyclo-C.sub.3H.sub.5).sub.2, OCONHC.sub.3H.sub.7, NHC(NH)N[CH(CH.sub.3).sub.2].sub.2, NHC(NH)N[C(CH.sub.3).sub.3].sub.2, OCONH.sub.2, OCONHCH.sub.3, OCONHC.sub.2H.sub.5, OCONH[C(CH.sub.3).sub.3], OCON(CH.sub.3).sub.2, OCON(C.sub.2H.sub.5).sub.2, OCON(C.sub.3H.sub.7).sub.2, OCON(cyclo-C.sub.3H.sub.5).sub.2, OCON [CH(CH.sub.3).sub.2].sub.2, OCON[C(CH.sub.3).sub.3].sub.2, OCOOCH.sub.3, OCOOC.sub.2H.sub.5, OCOOC.sub.3H.sub.7, OCOO-cyclo-C.sub.3H.sub.5, OCOOCH(CH.sub.3).sub.2, OCOOC(CH.sub.3).sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3, CH.sub.2Cl, CH.sub.2Br, CH.sub.2I, CH.sub.2CH.sub.2F, CH.sub.2CHF.sub.2, CH.sub.2CF.sub.3, CH.sub.2CH.sub.2Cl, CH.sub.2CH.sub.2Br, CH.sub.2CH.sub.2I, -cyclo-C.sub.5H.sub.9, -cyclo-C.sub.6H.sub.11, CH.sub.2-cyclo-C.sub.6H.sub.11, CH.sub.2CH.sub.2-cyclo-C.sub.6H.sub.11, -cyclo-C.sub.7H.sub.13, -cyclo-C.sub.8H.sub.15, -Ph, CH.sub.2-Ph, CH.sub.2CH.sub.2-Ph, CHCH-Ph, CPh.sub.3, CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, CH(CH.sub.3).sub.2, -C.sub.4H.sub.9, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.5, C(CH.sub.3).sub.3, C.sub.5H.sub.11, CH(CH.sub.3)C.sub.3H.sub.7, CH.sub.2CH(CH.sub.3)C.sub.2H.sub.5, CH(CH.sub.3)CH(CH.sub.3).sub.2, C(CH.sub.3).sub.2C.sub.2H.sub.5, CH.sub.2C(CH.sub.3).sub.3, CH(C.sub.2H.sub.5).sub.2, C.sub.2H.sub.4CH(CH.sub.3).sub.2, C.sub.6H.sub.13, C.sub.7H.sub.15, C.sub.8H.sub.17, C.sub.3H.sub.6CH(CH.sub.3).sub.2, C.sub.2H.sub.4CH(CH.sub.3)C.sub.2H.sub.5, CH(CH.sub.3)C.sub.4H.sub.9, CH.sub.2CH(CH.sub.3)C.sub.3H.sub.7, CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH(CH.sub.3)C.sub.2H.sub.5, CH.sub.2CH(CH.sub.3)CH(CH.sub.3).sub.2, CH.sub.2C(CH.sub.3).sub.2C.sub.2H.sub.5, C(CH.sub.3).sub.2C.sub.3H.sub.7, C(CH.sub.3).sub.2CH(CH.sub.3).sub.2, C.sub.2H.sub.4C(CH.sub.3).sub.3, CH(CH.sub.3)C(CH.sub.3).sub.3, CHCH.sub.2, CH.sub.2CHCH.sub.2, C(CH.sub.3)CH.sub.2, CHCHCH.sub.3, C.sub.2H.sub.4CHCH.sub.2, CH.sub.2CHCHCH.sub.3, CHCHC.sub.2H.sub.5, CH.sub.2C(CH.sub.3)CH.sub.2, CH(CH.sub.3)CHCH, CHC(CH.sub.3).sub.2, C(CH.sub.3)CHCH.sub.3, CHCHCHCH.sub.2, C.sub.3H.sub.6CHCH.sub.2, C.sub.2H.sub.4CHCHCH.sub.3, CH.sub.2CHCHC.sub.2H.sub.5, CHCHC.sub.3H.sub.7, CH.sub.2CHCHCHCH.sub.2, CHCHCHCHCH.sub.3, CHCHCH.sub.2CHCH.sub.2, C(CH.sub.3)CHCHCH.sub.2, CHC(CH.sub.3)CHCH.sub.2, CHCHC(CH.sub.3)CH.sub.2, C.sub.2H.sub.4C(CH.sub.3)CH.sub.2, CH.sub.2CH(CH.sub.3)CHCH.sub.2, CH(CH.sub.3)CH.sub.2CHCH.sub.2, CH.sub.2CHC(CH.sub.3).sub.2, CH.sub.2C(CH.sub.3)CHCH.sub.3, CH(CH.sub.3)CHCHCH.sub.3, CHCHCH(CH.sub.3).sub.2, CHC(CH.sub.3)C.sub.2H.sub.5, C(CH.sub.3)CHC.sub.2H.sub.5, C(CH.sub.3)C(CH.sub.3).sub.2, C(CH.sub.3).sub.2CHCH.sub.2, CH(CH.sub.3)C(CH.sub.3)CH.sub.2, C(CH.sub.3)CHCHCH.sub.2, CHC(CH.sub.3)CHCH.sub.2, CHCHC(CH.sub.3)CH.sub.2, C.sub.4H.sub.8CHCH.sub.2, C.sub.3H.sub.6CHCHCH.sub.3, C.sub.2H.sub.4CHCHC.sub.2H.sub.5, CH.sub.2CHCHC.sub.3H.sub.7, CHCHC.sub.4H.sub.9, C.sub.3H.sub.6C(CH.sub.3)CH.sub.2, C.sub.2H.sub.4CH(CH.sub.3)CHCH.sub.2, CH.sub.2CH(CH.sub.3)CH.sub.2CHCH.sub.2, C.sub.2H.sub.4CHC(CH.sub.3).sub.2, CH(CH.sub.3)C.sub.2H.sub.4CHCH.sub.2, C.sub.2H.sub.4C(CH.sub.3)CHCH.sub.3, CH.sub.2CH(CH.sub.3)CHCHCH.sub.3, CH(CH.sub.3)CH.sub.2CHCHCH.sub.3, CH.sub.2CHCHCH(CH.sub.3).sub.2, CH.sub.2CHC(CH.sub.3)C.sub.2H.sub.5, CH.sub.2C(CH.sub.3)CHC.sub.2H.sub.5, CH(CH.sub.3)CHCHC.sub.2H.sub.5, CHCHCH.sub.2CH(CH.sub.3).sub.2, CHCHCH(CH.sub.3)C.sub.2H.sub.5, CHC(CH.sub.3)C.sub.3H.sub.7, C(CH.sub.3)CHC.sub.3H.sub.7, CH.sub.2CH(CH.sub.3)C(CH.sub.3)CH.sub.2, C[C(CH.sub.3).sub.3]CH.sub.2, CH(CH.sub.3)CH.sub.2C(CH.sub.3)CH.sub.2, CH(CH.sub.3)CH(CH.sub.3)CHCH.sub.2, CHCHC.sub.2H.sub.4CHCH.sub.2, CH.sub.2C(CH.sub.3).sub.2CHCH.sub.2, C(CH.sub.3).sub.2CH.sub.2CHCH.sub.2, CH.sub.2C(CH.sub.3)C(CH.sub.3).sub.2, CH(CH.sub.3)CHC(CH.sub.3).sub.2, C(CH.sub.3).sub.2CHCHCH.sub.3, CHCHCH.sub.2CHCHCH.sub.3, CH(CH.sub.3)C(CH.sub.3)CHCH.sub.3, CHC(CH.sub.3)CH(CH.sub.3).sub.2, C(CH.sub.3)CHCH(CH.sub.3).sub.2, C(CH.sub.3)C(CH.sub.3)C.sub.2H.sub.5, CHCHC(CH.sub.3).sub.3, C(CH.sub.3).sub.2C(CH.sub.3)CH.sub.2, CH(C.sub.2H.sub.5)C(CH.sub.3)CH.sub.2, C(CH.sub.3)(C.sub.2H.sub.5)CHCH.sub.2, CH(CH.sub.3)C(C.sub.2H.sub.5)CH.sub.2, CH.sub.2C(C.sub.3H.sub.7)CH.sub.2, CH.sub.2C(C.sub.2H.sub.5)CHCH.sub.3, CH(C.sub.2H.sub.5)CHCHCH.sub.3, C(C.sub.4H.sub.9)CH.sub.2, C(C.sub.3H.sub.7)CHCH.sub.3, C(C.sub.2H.sub.5)CHC.sub.2H.sub.5, C(C.sub.2H.sub.5)C(CH.sub.3).sub.2, C[CH(CH.sub.3)(C.sub.2H.sub.5)]CH.sub.2, C[CH.sub.2CH(CH.sub.3).sub.2]CH.sub.2, C.sub.2H.sub.4CHCHCHCH.sub.2, CH.sub.2CHCHCH.sub.2CHCH.sub.2, C.sub.3H.sub.6CCCH.sub.3, CH.sub.2CHCHCHCHCH.sub.3, CHCHCHCHC.sub.2H.sub.5, CH.sub.2CHCHC(CH.sub.3)CH.sub.2, CH.sub.2CHC(CH.sub.3)CHCH.sub.2, CH.sub.2C(CH.sub.3)CHCHCH.sub.2, CH(CH.sub.3)CH.sub.2CCH, CH(CH.sub.3)CHCHCHCH.sub.2, CHCHCH.sub.2C(CH.sub.3)CH.sub.2, CH(CH.sub.3)CCCH.sub.3, CHCHCH(CH.sub.3)CHCH.sub.2, CHC(CH.sub.3)CH.sub.2CHCH.sub.2, C.sub.2H.sub.4CH(CH.sub.3)CCH, C(CH.sub.3)CHCH.sub.2CHCH.sub.2, CHCHCHC(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3)CH.sub.2CCH, CHCHC(CH.sub.3)CHCH.sub.3, CHC(CH.sub.3)CHCHCH.sub.3, CH.sub.2CH(CH.sub.3)CCH, C(CH.sub.3)CHCHCHCH.sub.3, CHC(CH.sub.3)C(CH.sub.3)CH.sub.2, C(CH.sub.3)CHC(CH.sub.3)CH.sub.2, C(CH.sub.3)C(CH.sub.3)CHCH.sub.2, CHCHCHCHCHCH.sub.2, CCH, CCCH.sub.3, CH.sub.2CCH, C.sub.2H.sub.4CCH, CH.sub.2CCCH.sub.3, CCC.sub.2H.sub.5, C.sub.3H.sub.6CCH, C.sub.2H.sub.4CCCH.sub.3, CH.sub.2CCC.sub.2H.sub.5, CCC.sub.3H.sub.7, CH(CH.sub.3)CCH, C.sub.4H.sub.8CCH, C.sub.2H.sub.4CCC.sub.2H.sub.5, CH.sub.2CCC.sub.3H.sub.7, CCC.sub.4H.sub.9, CCC(CH.sub.3).sub.3, CH(CH.sub.3)C.sub.2H.sub.4CCH, CH.sub.2CH(CH.sub.3)CCCH.sub.3, CH(CH.sub.3)CH.sub.2CCCH.sub.3, CH(CH.sub.3)CCC.sub.2H.sub.5, CH.sub.2CCCH(CH.sub.3).sub.2, CCCH(CH.sub.3)C.sub.2H.sub.5, CCCH.sub.2CH(CH.sub.3).sub.2, CH(C.sub.2H.sub.5)CCCH.sub.3, C(CH.sub.3).sub.2CCCH.sub.3, CH(C.sub.2H.sub.5)CH.sub.2CCH, CH.sub.2CH(C.sub.2H.sub.5)CCH, C(CH.sub.3).sub.2CH.sub.2CCH, CH.sub.2C(CH.sub.3).sub.2CCH, CH(CH.sub.3)CH(CH.sub.3)CCH, CH(C.sub.3H.sub.7)CCH, C(CH.sub.3)(C.sub.2H.sub.5)CCH, CH.sub.2CH(CCH).sub.2, CCCCH, CH.sub.2CCCCH, CCCCCH.sub.3, CH(CCH).sub.2, C.sub.2H.sub.4CCCCH, CH.sub.2CCCH.sub.2CCH, CCC.sub.2H.sub.4CCH, CH.sub.2CCCCCH.sub.3, CCCH.sub.2CCCH.sub.3, CCCCC.sub.2H.sub.5, C(CCH).sub.2CH.sub.3, CCCH(CH.sub.3)CCH, CH(CH.sub.3)CCCCH, CH(CCH)CH.sub.2CCH, CH(CCH)CCCH.sub.3, ##STR00247## and enantiomers, stereoisomeric forms, mixtures of enantiomers, anomers, deoxy-forms, diastereomers, mixtures of diastereomers, tautomers, or racemates of the above mentioned compounds or pharmaceutically acceptable salts.
2. Compound according to claim 1 of the general formula (II): ##STR00248## wherein Y, R.sup.B, R.sup.C and R.sup.1-R.sup.5 have the meanings as defined in claim 1.
3. Compound according to claim 1 of the general formula (VII): ##STR00249## wherein R.sup.B and R.sup.C have the meanings as defined in claim 1.
4. Compound selected from the group consisting of: (1S,5S,6R)-5-acetyl-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, 2-((1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-5-yl)acetaldehyde, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(2-hydroxypropan-2-yl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-((R)-1-hydroxyethyl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-((S)-1-hydroxyethyl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(2-hydroxyethyl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decane-5-carbaldehyde, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decane-5-carboxylic acid, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decane-5-carboxamide, (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-5-((methylamino)methyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(hydroxymethyl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-5-(methoxymethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-ethyl-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-hydroxyethyl)-5-(hydroxymethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(1,2-dihydroxyethyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(1,2-dihydroxyethyl)-3-(2-ethoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-5-acetyl-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, 2-((1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-5-yl)acetaldehyde, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy) ethyl)-5-(2-hydroxypropan-2-yl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy) ethyl)-5-(2-hydroxypropyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy) ethyl)-5-(2-hydroxypropyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy) ethyl)-5-((R)-1-hydroxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy) ethyl)-5-((R)-1-hydroxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy) ethyl)-5-(2-hydroxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-hydroxy-3,10-diazabicyclo-[4.3.1]decan-2-one, (1S,5R,6R)-5-amino-10-((3,5-dichlorophenyl)sulfonyl)-3,10-diazabicyclo-[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-methoxy-3-methyl-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-hydroxy-3,10-diazabicyclo-[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(2-methoxyethoxy)-3-(2-methoxy-ethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(methoxymethoxy)-3,10-diaza-bicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy) ethyl)-5-hydroxy-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(hydroxymethyl)-3-(3-hydroxypropyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(hydroxymethyl)-3-(3-methoxypropyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(hydroxymethyl)-3-(4-methoxybutyl)-3,10-diazabicyclo[4.3.1]decan-2-one, and (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(hydroxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-ethyl-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-((dimethylamino)methyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(difluoromethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(fluoromethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(methoxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(ethoxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3-fluorophenyl)sulfonyl)-5-(methoxymethyl)-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((3,5-dibromophenyl)sulfonyl)-5-(methoxymethyl)-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-2-one, 3-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzamide, 3-bromo-5-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzamide, 3-chloro-5-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzamide, N-(2-bromo-4-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)phenyl)acetamide, N-(2-chloro-4-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)phenyl)acetamide, N-(2,6-dichloro-4-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)phenyl)acetamido, methyl 3-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzoate, methyl 3-bromo-5-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzoate, methyl 3-chloro-5-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzoate, 1S,5S,6R)-5-(methoxymethyl)-3-(prop-2-yn-1-yl)-10-(pyridin-3-ylsulfonyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-5-(methoxymethyl)-10-((6-phenylpyridin-3-yl)sulfonyl)-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-5-(methoxymethyl)-3-(prop-2-yn-1-yl)-10-((4-(pyrimidin-2-yl)phenyl)sulfonyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-10-((1H-benzo[d]imidazol-2-yl)sulfonyl)-5-(methoxymethyl)-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-10-((3-fluorophenyl)sulfonyl)-5-(methoxymethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, 1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-10-((3,5-dibromophenyl)-sulfonyl)-5-(methoxymethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, 3-(((1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzamide, 3-(((1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)-5-bromobenzamide, 3-(((1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)-5-chlorobenzamide, N-(4-(((1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)-2-bromophenyl)acetamide, N-(4-(((1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)-2-chlorophenyl)acetamide, N-(4-(((1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)-2,6-dichlorophenyl)acetamide, (1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-10-(pyridin-3-ylsulfonyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-10-((6-phenylpyridin-3-yl)sulfonyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-10-((4-(pyrimidin-2-yl)phenyl)sulfonyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-10-((1H-benzo[d]imidazol-2-yl)sulfonyl)-5-(methoxymethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5R,6R)-10-((3-fluorophenyl)sulfonyl)-5-(methoxymethyl)-3-((1-phenyl-1H-1,2,3-triazol-5-yl)methyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-3-((1-benzyl-1H-1,2,3-triazol-5-yl)methyl)-10-((3-fluorophenyl)-sulfonyl)-5-(methoxymethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, (1S,5S,6R)-3-((1-benzoyl-1H-1,2,3-triazol-5-yl)methyl)-10-((3-fluorophenyl)-sulfonyl)-5-(methoxymethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, and (1S,5S,6R)-10-((3-fluorophenyl)sulfonyl)-5-(methoxymethyl)-3-((1-(phenylsulfonyl)-1H-1,2,3-triazol-5-yl)methyl)-3,10-diazabicyclo[4.3.1]decan-2-one.
5. A method for inhibiting FK506-binding proteins comprising contacting a cell with an effective amount of a compound according to claim 1.
6. The method according to claim 5, wherein the FK506-binding proteins are FK506-binding protein 51 and/or FK506-binding protein 52.
7. A method for stimulating neurite growth comprising administering to a patient in need thereof a dose-effective amount of a compound according to claim 1.
8. Pharmaceutical composition comprising at least one compound according to claim 1 together with at least one pharmaceutically acceptable carrier, solvent or excipient or together with at least one pharmaceutically acceptable carrier, solvent or excipient and at least one active agent selected from the group consisting of an anti-depressant and other psychotropic drugs.
9. Pharmaceutical composition according to claim 8, wherein the anti-depressant is selected from amitriptyline, amioxide clomipramine, doxepine, duloxetine, imipramine trimipramine, mirtazapine, reboxetine, citaloprame, fluoxetine, moclobemide and sertraline.
10. Method for preparation of compound of the general formula (I) comprising the following steps: (a) providing an intermediate compound of formula (I-A1) ##STR00250## wherein R.sup.A has the meanings as defined in claim 1, LG refers to a leaving group, and PG.sub.1 refers to a protecting group for amine; (b) performing a cyclization reaction and deprotecting PG.sub.1 to yield compound of formula (I-B1) ##STR00251## (c) introducing a moiety SO.sub.2R.sup.B to yield compound of formula (I-C) ##STR00252## (d) transforming the vinyl group of compound (I-C) into the substituent R.sup.C to yield compound of the formula (I) ##STR00253## wherein R.sup.A, R.sup.B and R.sup.C have the meanings as defined in claim 1.
11. Method for preparation of compound of the general formula (I) comprising the following steps: (a) providing an intermediate compound of the formula (I-A2) ##STR00254## wherein R.sup.A has the meanings as defined herein, LG refers to a leaving group, and PG.sub.1 and PG.sub.6 refer to protecting groups for amines; (b) performing a cyclization reaction and deprotecting PG.sub.1 to yield compound of the formula (I-B1) ##STR00255## (c) introducing the moiety SO.sub.2R.sup.B to yield compound of the formula (I-B3) ##STR00256## wherein R.sup.B has the meanings as defined herein; (d) deprotecting PG.sub.6 and introducing the moiety R.sup.A to yield compound of the formula (I-C) ##STR00257## (e) transforming the vinyl group of compound (I-C) into the substituent R.sup.C to yield compound of the formula (I) ##STR00258## wherein R.sup.A, R.sup.B and R.sup.C have the meanings as defined herein.
12. Method for preparation of compound of the general formula (I) comprising the following steps: (a) providing an intermediate compound of formula (I-E) ##STR00259## wherein R.sup.A has the meanings as defined in claim 1, PG.sub.2 refers to a protecting group for amine, and PG.sub.3 refers to a protecting group for carboxylic acid; (b) deprotecting PG.sub.2, performing a piperidine ring formation reaction and introducing PG.sub.4 to yield compound of formula (I-F) ##STR00260## wherein PG.sub.4 refers to a protecting group for amine; (c) introducing PG.sub.5, deprotecting PG.sub.3 and performing an amide coupling reaction to yield compound of formula (I-G) ##STR00261## wherein PG.sub.5 refers to a protecting group for hydroxyl group; (d) deprotecting PG.sub.4 and introducing a moiety SO.sub.2R.sup.B to yield compound of formula (I-H) ##STR00262## wherein R.sup.B has the meanings as defined in claim 1; (e) transforming a hydroxyl group obtained by deprotecting PG.sub.5 to yield compound of the formula (I) ##STR00263## wherein R.sup.A, R.sup.B and R.sup.C have the meanings as defined in claim 1; the protecting groups PG.sub.1-PG.sub.4, and PG.sub.6 for amines represent independently of each other carbobenzyloxy, p-methoxybenzyl carbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, 2,2,2-trichlorethoxycarbonyl, trifluoroacetyl, 2-(trimethylsilyl)ethoxycarbonyl, p-methoxy-benzyl or phthalimide; the protecting group PG.sub.3 for carboxylic acid selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, allyl, and benzyl; and the protecting group PG.sub.5 for hydroxyl group is selected from the group consisting of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, allyl, benzyl, tert-butyl, methoxylmethyl, methoxyethyl, tetrahydropyranyl, acetyl, benzoyl and pivalic.
Description
DESCRIPTION OF THE FIGURES
(1)
(2)
EXAMPLES
Abbreviations
(3) AIBN (azobisisobutyronitrile), Boc (tert-butyloxycarbonyl), CAN (ceric ammonium nitrate), CDI (1,1-carbonyldiimidazole), DAST (diethylaminosulfur trifluoride), DCM (dichloromethane), dba (dibenzylideneacetone), DIBAL-H (diisobutylaluminum hydride), DIPEA (N,N-diisopropylethylamine), DMAP (4-dimethyl-aminopyridine), DMF (dimethylformamide), DMM (dimethoxymethane), DMSO (dimethyl sulfoxide), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), EDTA (ethylenediaminetetraacetic acid), EtOAc (ethylacetate), Fmoc (fluorenylmethyloxycarbonyl), HATU (2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), HMDS (hexamethyldisilazane), HOBt (hydroxybenzotriazole), NMO (N-methylmorpholine N-oxide), MOM (methoxymethyl), oNs (2-nitrobenzenesulfonyl), OTf (triflate), oTol (ortho-tolyl), PMB (p-methoxybenzyl), TBAF (tetra-n-butylammonium chloride), tBu (tert-butyl), TEA (triethylamine), TES (triethylsilyl), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TMS (trimethylsilyl).
(4) Synthetic Procedures
(5) The compound of the general formula (I) can be prepared according to the following synthetic procedures.
(6) I. Preparation of Compound A7 as Starting Material
(7) ##STR00072##
Example 1-1: Preparation of N-allyl-2-nitrobenzenesulfonamide A1
(8) ##STR00073##
(9) To a solution of Allylamine (7.63 g, 10 mL, 134 mmol) in CH.sub.2Cl.sub.2 (500 mL) was added 2-nitrobenzene-1-sulfonyl chloride (10.0 g, 45.1 mmol). After 1 h stirring at room temperature saturated aqueous NaCl (100 mL) was added to the reaction and washed with CH.sub.2Cl.sub.2 (3200 mL). The solvent was removed under reduced pressure affording the title compound (10.5 g, 43.3 mmol, 96.1%) as a slightly yellow solid, which was used for the next step without further purification.
(10) R.sub.f: 0.24 (Cyclohexane/EtOAc=4:1)
(11) .sup.1H-NMR (300 MHz, CDCl.sub.3): =3.72-3.79 (m, 2H), 5.09 (d, J=10.5 Hz, 1H), 5.19 (d, J=17.1, 1H), 5.40 (s.sub.br, 1H), 5.65-5.80 (m, 1H), 7.70-7.78 (m, 2H), 7.81-7.88 (m, 1H), 8.08-8.14 (m, 1H).
(12) .sup.13C-NMR (75.5 MHz, CDCl.sub.3): =46.28, 118.0, 125.3, 131.0, 132.5, 132.8, 133.6, 133.9, 147.9.
Example 1-2: Preparation of N-allyl-N-(2-methoxyethyl)-2-nitrobenzenesulfonamide A2
(13) ##STR00074##
(14) To a solution of N-allyl-2-nitrobenzenesulfonamide (100 mg, 0.413 mmol) in DMF (4 mL) were added K.sub.2CO.sub.3 (114 mg, 0.826 mmol) and 1-Bromo-2-methoxyethane (63.1 mg, 43 L, 0.454 mmol). The reaction was heated to 60 C. After two hours the reaction was cooled to room temperature, Et.sub.2O (90 mL) was added and washed with sat. aq. NaCl solution (310 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Flash column chromatography (10-40% EtOAc in Cyclohexane) afforded the title compound (97.0 mg, 0.323 mmol, 78.2%).
(15) R.sub.f: 0.175 (Cyclohexane/EtOAc=4:1)
(16) .sup.1H-NMR (400 MHz, CDCl.sub.3): =3.23 (s, 3H), 3.47-3.48 (m, 4H), 4.02 (dt, J=8.0, 1.6 Hz, 2H), 5.16-5.24 (m, 2H), 5.64-5.74 (m, 1H), 7.26-7.68 (m, 3H), 8.04-8.07 (m, 1H).
(17) .sup.13C-NMR (101 MHz, CDCl.sub.3): =46.18, 51.08, 53.43, 58.71, 70.85, 119.2, 124.1, 130.9, 131.6, 132.7, 133.3, 133.9.
(18) MS (ESI): m/z (%)=301.00 [M+H].sup.+
Example 1-3: Preparation of N-(2-methoxyethyl)-2-nitro-N-(4-(trimethylsilyl)but-2-en-1-yl)benzenesulfonamide A3
(19) ##STR00075##
(20) To a solution of N-allyl-N-(2-methoxyethyl)-2-nitrobenzenesulfonamide (10.0 g, 33.3 mmol) in CH.sub.2Cl.sub.2 (350 mL) were added sequentially Allyltrimethylsilane (38.0 g, 52.9 mL, 333 mmol) and Grubbs Hoveyda II generation catalyst (1.46 g, 2.33 mmol). The reaction was stirred at 60 C. for 4 h. Sat. aq. NaCl solution (100 mL) was added to the reaction and the organic phase was separated. The aqueous phase was extracted with CH.sub.2Cl.sub.2 (3200 mL). The combined organic layers were dried over MgSO.sub.4 and the solvent was removed under reduced pressure. Flash column chromatography over SiO.sub.2 (5-10% EtOAc in Cyclohexane) afforded the title compound (10.1 g, 26.1 mmol, 78.4%).
(21) R.sub.f: 0.37 (Cyclohexane/EtOAc=4:1)
(22) .sup.1H-NMR (300 MHz, CDCl.sub.3) =0.06-0.08 (m, 9H), 1.40-1.53 (m, 2H), 3.16-3.56 (m, 7H), 3.86-4.10 (m, 2H), 5.07-5.21 (m, 1H), 5.56-5.70 (m, 1H), 7.59-7.70 (m, 3H), 8.02-8.09 (m, 1H).
(23) .sup.13C-NMR (75 MHz, CDCl.sub.3) =1.99, 22.91, 45.45, 50.66, 58.69, 70.79, 121.2, 122.0, 124.0, 130.8, 131.4, 133.1, 133.4, 134.2.
Example 1-4: Preparation of N-(2-methoxyethyl)-4-(trimethylsilyl)but-2-en-1-amine A4
(24) ##STR00076##
(25) To a solution of N-(2-methoxyethyl)-2-nitro-N-(4-(trimethylsilyl)but-2-en-1-yl) benzenesulfonamide (10.0 g, 25.9 mmol) in DMF (100 mL) was added K.sub.2CO.sub.3 (10.7 g, 78.0 mmol) and thiophenol (2.85 g, 2.65 mL, 25.9 mmol). After 14 hours stirring at room temperature Et.sub.2O (500 mL) was added to the reaction and washed with sat. aq. NaHCO.sub.3 (3100 mL). The organic phase was dried over MgSO.sub.4 and the solvent was removed under reduced pressure. Column chromatography over SiO.sub.2 (2% TEA and 2% MeOH in EtOAc) afforded the title compound (4.30 g, 21.4 mmol, 82.4%) as a yellow oil. R.sub.f: 0.25 (EtOAc+2% TEA (ESI): m/z (%)=201.92 [M+H].sup.+
Example 1-5: Preparation of (S)N-(2-methoxyethyl)-6-oxo-N-(4-(trimethylsilyl)but-2-en-1-yl)piperidine-2-carboxamide A5.1
(26) ##STR00077##
(27) To a solution of (S)-6-oxopiperidine-2-carboxylic acid (2.70 g, 18.9 mmol) in CH.sub.2Cl.sub.2 (80 mL) were added sequentially HATU (7.89 g, 20.8 mmol), DIPEA (2.68 g, 3.63 mL, 20.8 mmol) and N-(2-methoxyethyl)-4-(trimethylsilyl)but-2-en-1-amine (3.80 g, 18.9 mmol). The reaction was stirred for 4 h and then saturated sat. aq. NH.sub.4Cl solution (25 mL) was added to the reaction and the organic phase was separated. The aqueous phase was extracted with CH.sub.2Cl.sub.2 (3100 mL). The combined organic layers were dried over MgSO.sub.4 and the solvent was removed under reduced pressure. The crude product was used for the next step without further purification.
(28) R.sub.f: 0.44 (EtOAc+3% MeOH+1% TEA)
(29) MS (ESI): m/z (%)=327.17 [M+H].sup.+, 653.02 [2M+H].sup.+, 675.06 [2M+Na].sup.+
Example 1-6: Preparation of (S)-tert-butyl 2-((2-methoxyethyl)(4-(trimethylsilyl)but-2-en-1-yl)carbamoyl)-6-oxopiperidine-1-carboxylate A5.2
(30) ##STR00078##
(31) Crude mixture of A5.1 was dissolved in CH.sub.2Cl.sub.2 (150 mL). TEA (3.82 g, 5.23 mL, 38.0 mmol), Boc.sub.2O (8.29 g, 38 mmol) and DMAP (3.46 g, 28 mmol) were added. After 6 h stirring at room temperature sat. aq. NaCl solution (25 mL) was added to the reaction and the organic phase was separated. The aqueous phase was extracted with CH.sub.2Cl.sub.2 (3100 mL) and the combined organic layers were dried over MgSO.sub.4 and the solvent was removed under reduced pressure. Flash column chromatography (10-40% EtOAc in Cyclohexane) afforded the title compound (4.05 g, 9.40 mmol, 50% over two steps) as a yellow resin. R.sub.f: 0.56 (Cyclohexane/EtOAc=1:1)
(32) MS (ESI): m/z (%)=327.12 [M-Boc+H].sup.+, 875.12 [2M+Na].sup.+
Example 1-6: Preparation of (1S,5R,6R)-3-(2-methoxyethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one A6
(33) ##STR00079##
(34) A solution of (6S)-tert-butyl 2-hydroxy-6-((2-methoxyethyl)(4-(trimethylsilyl)but-2-en-1-yl)carbamoyl)piperidine-1-carboxylate (220 mg, 0.516 mmol) in THF (5 mL) was cooled to 78 C. and then DIBAL-H (1 M solution in CH.sub.2Cl.sub.2, 1.03 mL, 1.03 mmol) was added. After 1 h the solvent was removed under reduced pressure.
(35) The resin resulted from the first step was dissolved in CH.sub.2Cl.sub.2 (25 mL) and cooled to 78 C. HF (70% in pyridine, 1.25 mL) was added and the reaction was stirred for 1 h. Then Sat. aq. NaHCO.sub.3 solution was added. The reaction was extracted three times with CH.sub.2Cl.sub.2, the combined organic layers were dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography (5% MeOH and 2% TEA in EtOAc) afforded the title compound (60.0 mg, 0.251 mmol, 49.1% over two steps) as an orange resin.
(36) .sup.1H-NMR (599 MHz, CDCl.sub.3) =1.56-1.80 (m, 5H), 2.22-2.38 (m, 1H), 2.58-2.76 (m, 1H), 2.79-2.90 (m, 1H), 3.07 (dd, J=13.9, 2.0 Hz, 1H), 3.31 (m, 1H), 3.34 (s, 3H), 3.50-3.56 (m, 3H), 3.65-3.74 (m, 1H), 3.71-3.86 (m, 1H), 4.08 (dd, J=13.9, 10.7 Hz, 1H), 4.94-5.04 (m, 2H), 5.65 (ddd, J=17.0, 10.2, 8.4 Hz, 1H).
(37) .sup.13C-NMR (151 MHz, CDCl.sub.3) =28.04, 29.36, 29.67, 49.61, 51.03, 52.40, 52.57, 57.59, 58.80, 71.32, 114.9, 139.2, 174.2.
(38) MS (ESI): m/z (%)=239.23 [M+H].sup.+, 477.02 [2M+H].sup.+
Example 1-6: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one A7
(39) ##STR00080##
(40) To a solution of (1S,5R,6R)-3-(2-methoxyethyl)-5-vinyl-3,10-diazabicyclo [4.3.1] decan-2-one (600 mg, 2.52 mmol) in CH.sub.2Cl.sub.2 (25 mL) were added 3,5-dichlorobenzene-1-sulfonyl chloride (618 mg, 2.52 mmol), DMAP (308 mg, 2.52 mmol) and DIPEA (0.879 mL, 5.04 mmol) and the reaction was stirred for 24 hours at room temperature. Sat. aq. NaHCO.sub.3 solution (25 mL) was added to the mixture and extracted with CH.sub.2Cl.sub.2 (250 mL). Flash column chromatography on SiO.sub.2 (5-20% EtOAc in Cyclohexane) afforded the title compound (680 mg, 1.52 mmol, 60.3%) as a colorless solid. MS (ESI): m/z (%)=447.17 [M+H].sup.+, 894.44 [2M+H].sup.+
(41) II. Preparation of Compounds B1-B15
(42) ##STR00081##
Example 2-1: Preparation of (1S,5S,6R)-5-acetyl-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one B1 and 2-((1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-5-yl)acetaldehyde B2
(43) ##STR00082##
(44) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (450 mg, 1.01 mmol) in DMF/H.sub.2O (0.571 mL, 7:1) was added PdCl.sub.2 (35.7 mg, 0.201 mmol) and CuCl (100 mg, 1.01 mmol). After three days stirring Et.sub.2O was added to the reaction and extracted three times with saturated Na.sub.2S.sub.2O.sub.3. The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography on SiO.sub.2 (EtOAc/Cyclohexane=1:1) afforded an inseparable mixture of the title compounds (180 mg, 0.388 mmol, 38.6%) as a slightly yellow solid.
(45) R.sub.f: 0.6 (Cyclohexan/EtOAc=15:85)
(46) MS (ESI): m/z (%)=463.13 [M+H].sup.+
Example 2-2: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(2-hydroxypropan-2-yl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one B3
(47) ##STR00083##
(48) A solution of a mixture of 2-((1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-5-yl)acetaldehyde and (5S)-5-acetyl-10-((3, 5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (58.0 mg, 0.125 mmol) in THF (1.5 mL) was cooled to 78 C. CH.sub.3MgBr (3 M in Et.sub.2O, 0.189 mmol, 63.0 L) was added and the reaction was stirred for 1 h. Aq. Sat. NH.sub.4Cl solution (10 mL) was added to the reaction and extracted with CH.sub.2Cl.sub.2 (290 mL). The organic layer was dried over MgSO.sub.4 and the solvent was evaporated under reduced pressure. Normal phase preparative chromatography (10-30% EtOAc in n-Hexane) afforded the title compound (37.0 mg, 0.0772 mmol, 61.8%) as a colorless solid.
(49) .sup.1H-NMR (600 MHz, Chloroform-d) =1.11 (m, 1H), 1.26 (s, 3H), 1.31 (s, 3H), 1.38-1.47 (m, 1H), 1.46-1.57 (m, 3H), 1.65 (d, J=13.4 Hz, 1H), 2.14 (ddd, J=10.3, 6.8, 1.4 Hz, 1H), 2.23 (d, J=13.6 Hz, 1H), 3.27 (dd, J=14.1, 1.6 Hz, 2H), 3.35 (s, 3H), 3.50-3.61 (m, 2H), 3.95 (dd, J=14.3, 10.5 Hz, 1H), 4.06 (ddd, J=14.1, 5.2, 3.6 Hz, 1H), 4.25-4.30 (m, 1H), 4.68 (d, J=5.7 Hz, 1H), 7.56 (t, J=1.8 Hz, 1H), 7.72 (d, J=1.9 Hz, 2H).
(50) .sup.13C-NMR (150 MHz, Chloroform-d) =15.32, 27.10, 27.88, 28.10, 29.72, 49.94, 51.45, 52.01, 53.96, 57.15, 58.80, 71.38, 72.49, 125.0, 132.6, 136.2, 143.9, 169.4.
(51) MS (ESI): m/(%)=479.11 [M+H].sup.+
Example 2-3: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-((R)-1-hydroxyethyl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one B6, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-((S)-1-hydroxyethyl)-3-(2-methoxy ethyl)-3,10-diazabicyclo[4.3.1]decan-2-one B7, and (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(2-hydroxyethyl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one B8
(52) ##STR00084##
(53) To a solution of a mixture of (1S,5S,6R)-5-acetyl-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one and (2-((1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-5-yl)acetaldehyde (60.0 mg, 0.129 mmol) in EtOH/CH.sub.2Cl.sub.2 (2 mL, 3:1) was added NaBH.sub.4 (7.35 mg, 0.194 mmol) and then stirred for 30 minutes at room temperature. Sat. aq. NaCl solution (10 mL) was added to the reaction and extracted with CH.sub.2Cl.sub.2 (350 mL). The organic layer was dried over MgSO.sub.4 and the solvent was evaporated under reduced pressure. Normal phase preparative chromatography on SiO.sub.2 (10-30% EtOAc in n-Hexane) afforded the title compounds (B6: 5.0 mg, 0.011 mmol, B7: 4.2 mg, 0.0090 mmol, B8: 13.0 mg, 0.0279 mmol, 36.9%).
(54) B6
(55) R.sub.f: 0.5 (Cyclohexane/EtOAc=15:85)
(56) .sup.1H-NMR: (600 MHz, CDCl.sub.3) =1.28-1.29 (m, 5H), 1.47-1.58 (m, 4H), 2.06-2.13 (m, 1H), 2.21-2.29 (m, 1H), 3.29-3.33 (m, 2H), 3.34 (s, 3H), 3.49-3.60 (m, 2H), 3.78-3.90 (m, 2H), 3.96-4.02 (m, 1H), 4.12-4.17 (m, 1H), 4.66-4.70 (m, 1H), 7.56 (t, J=1.8 Hz, 1H), 7.71 (d, J=1.8 Hz, 2H).
(57) .sup.13C-NMR: (150 MHz, CDCl.sub.3) =20.92, 28.15, 28.51, 29.66, 48.96, 50.55, 51.33, 52.61, 56.96, 58.83, 68.89, 71.24, 124.9, 124.9, 132.6, 132.6, 136.2, 143.9, 169.6.
(58) MS (ESI): m/z (%)=465.14 [M+H].sup.+
(59) B7
(60) R.sub.f: 0.5 (Cyclohexane/EtOAc=15:85)
(61) .sup.1H-NMR: (600 MHz, CDCl.sub.3) =1.28-1.29 (m, 5H), 1.47-1.58 (m, 4H), 2.06-2.13 (m, 1H), 2.21-2.29 (m, 1H), 3.29-3.33 (m, 2H), 3.34 (s, 3H), 3.49-3.60 (m, 2H), 3.78-3.90 (m, 2H), 3.96-4.02 (m, 1H), 4.12-4.17 (m, 1H), 4.66-4.70 (m, 1H), 7.56 (t, J=1.8 Hz, 1H), 7.71 (d, J=1.8 Hz, 2H).
(62) .sup.13C-NMR: (150 MHz, CDCl.sub.3) =20.92, 28.15, 28.51, 29.66, 48.96, 50.55, 51.33, 52.61, 56.96, 58.83, 68.89, 71.24, 124.9, 124.9, 132.6, 132.6, 136.2, 143.9, 169.6.
(63) MS (ESI): m/z (%)=465.14 [M+H].sup.+
(64) B8
(65) R.sub.f: 0.34 (Cyclohexane/EtOAc=15:85)
(66) .sup.1H-NMR: (600 MHz, CDCl.sub.3) =1.34-1.41 (m, 2H), 1.47-1.69 (m, 3H), 2.22-2.33 (m, 2H), 3.18-3.25 (m, 1H), 3.37 (s, 3H), 3.46-3.55 (m, 2H), 3.65-3.70 (m, 1H), 3.71-3.75 (m, 2H), 3.83-3.89 (m, 1H), 3.94 (dd, J=14.4, 10.5 Hz, 1H), 4.04-4.11 (m, 1H), 4.68 (d, J=5.8 Hz, 1H), 7.56 (t, J=1.8 Hz, 1H), 7.69 (d, J=1.9 Hz, 2H).
(67) .sup.13C-NMR: (150 MHz, CDCl.sub.3) =26.83, 29.66, 35.59, 40.84, 55.79, 56.72, 59.02, 60.09, 72.05, 124.8, 132.6, 136.3, 144.0, 170.0.
(68) MS (ESI): m/z (%)=465.14 [M+H].sup.+
Example 2-4: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decane-5-carbaldehyde B9
(69) ##STR00085##
(70) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (250 mg, 0.559 mmol) in Dioxane/H.sub.2O (5.6 mL, 3:1) was added NaIO.sub.4 (478 mg, 2.23 mmol), OsO.sub.4 (2.5% Solution in tert-Butanol, 0.011 mmol, 140 mL) and 2,6-Lutidine. The solution was stirred for 20 h at room temperature, then Et.sub.2O (90 mL) was added to the reaction and washed with sat. aq. NaCl solution (310 mL). Column chromatography over SiO.sub.2 (EtOAc/Cyclohexane 1:1) afforded the title compound (175 mg, 0.389 mmol, 70.0%) as a slightly yellow solid.
(71) R.sub.f: 0.21 (Cyclohexane/EtOAc=1:1)
(72) .sup.1H-NMR (600 MHz, CDCl.sub.3) 1.21-1.29 (m, 1H), 1.44-1.50 (m, 3H), 1.53-1.59 (m, 1H), 2.29 (dd, J=13.5, 2.1 Hz, 1H), 3.03 (ddd, J=10.5, 7.0, 1.7 Hz, 1H), 3.36 (s, 3H), 3.37-3.42 (m, 1H), 3.50-3.56 (m, 1H), 3.61-3.66 (m, 1H), 3.68-3.72 (m, 1H), 4.01-4.08 (m, 2H), 4.70 (d, J=7.0 Hz, 1H), 4.72 (d, J=5.9 Hz, 1H), 7.57 (t, J=1.9 Hz, 1H), 7.72 (d, J=1.8 Hz, 2H), 9.65 (s, 1H).
(73) .sup.13C-NMR (150 MHz, cdcl.sub.3) =15.20, 28.06, 28.38, 47.66, 48.81, 51.73, 56.97, 57.22, 59.02, 71.53, 124.9, 132.8, 136.4, 143.7, 169.6, 197.7.
(74) MS (ESI): m/z (%)=449.05 [M+H].sup.+
Example 2-5: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decane-5-carboxylic acid B10
(75) ##STR00086##
(76) To a solution of (1S,5S,6R)-5-acetyl-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (25.0 mg, 0.0560 mmol) in CHCl.sub.3/t-BuOH/H.sub.2O (0.9 ml, 6:2:1) were methylbutene (60 L), sodium chlorite (19.5 mg, 0.216 mmol) and sodium dihydrogenphosphate (25.9 mg). After 16 h a room temperature the solvent was removed under reduced pressure and the crude mix loaded directly on SiO.sub.2. Flash column chromatography (20-60% EtOAc in Cyclohexane) afforded the title compound (24.0 mg, 0.0516 mmol, 92.7%) as a white solid.
(77) MS (ESI): m/z (%)=465.07
Example 2-5: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decane-5-carboxamide B11
(78) ##STR00087##
(79) To a solution of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decane-5-carboxylic acid (30.0 mg, 0.0645 mmol) in EtOAc (0.5 ml) was added CDI (15.7 mg, 0.0970 mmol). After one hour stirring at room temperature aqueous ammonia was added (7 M, 184 L, 1.29 mmol) and the reaction was stirred for two hours. Solvent was removed under reduced pressure and flash column chromatography afforded the title compound (12 mg, 0.026 mmol, 41%).
(80) R.sub.f: 0.125 (Cyclohexane/EtOAc=3:7+2% MeOH)
(81) .sup.1H-NMR (600 MHz, Chloroform-d) =1.42 (s, 2H), 1.45-1.52 (m, 2H), 1.52-1.56 (m, 1H), 2.29 (d, J=13.1 Hz, 1H), 2.98 (ddd, J=10.2, 7.3, 1.5 Hz, 1H), 3.20 (ddd, J=14.2, 9.5, 3.1 Hz, 1H), 3.34-3.38 (m, 1H), 3.40 (s, 3H), 3.51-3.56 (m, 1H), 3.70 (td, J=9.7, 2.5 Hz, 1H), 4.12-4.20 (m, 2H), 4.74 (d, J=5.8 Hz, 1H), 4.77-4.81 (m, 1H), 5.90 (s, 1H), 6.14 (s, 1H), 7.56-7.58 (m, 1H), 7.73-7.75 (m, 2H).
(82) .sup.13C-NMR (150 MHz, Chloroform-d) =15.29, 27.82, 28.03, 51.22, 51.23, 51.58, 51.80, 56.88, 59.10, 72.36, 124.9, 132.8, 136.3, 143.7, 169.7, 172.3.
(83) MS (ESI): m/z (%)=464.07 [M+H].sup.+
Example 2-6: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-5-((methylamino)methyl)-3,10-diazabicyclo[4.3.1]decan-2-one B12
(84) ##STR00088##
(85) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decane-5-carbaldehyde (15.0 mg, 0.0330 mmol) in MeOH/AcOH (0.5 mL, 98:2) were added Methanamine Hydrochlorid (6.80 mg, 0.100 mmol) and NaBH(OAc).sub.3 (14.2 mg, 0.0660 mmol) and the reaction was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the crude was loaded directly on SiO.sub.2. Column chromatography over SiO.sub.2 (EtOAc+2% TEA+2% MeOH) afforded the title compound (5.00 mg, 0.0107 mmol, 32.6%).
(86) R.sub.f: 0.16 (EtOAc+2% TEA+2% MeOH)
(87) MS (ESI): m/z (%)=464.36 [M+H].sup.+
Example 2-7: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(hydroxymethyl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one B13
(88) ##STR00089##
(89) To solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decane-5-carbaldehyde (17.0 mg, 0.0378 mmol) in EtOH (1 mL) was added NaBH.sub.4 (2.20 mg, 0.0588 mmol). After 1 h stirring at room temperature sat. aq. NaCl solution (10 mL) was added to the reaction and extracted with CH.sub.2Cl.sub.2 (350 mL). The combined organic phases were dried over MgSO.sub.4 and the solvent was removed under reduced pressure. Column chromatography on SiO.sub.2 (Cyclohexane/EtOAc=1:4) afforded the title compound (11.0 mg, 0.0244 mmol, 64.6%).
(90) R.sub.f: 0.2 (Cyclohexane/EtOAc=1:4)
(91) .sup.1H-NMR (600 MHz, CDCl.sub.3) =1.38-1.44 (m, 2H), 1.50-1.57 (m, 3H), 2.24-2.32 (m, 2H), 3.09-3.14 (m, 1H), 3.30 (dd, J=14.4, 1.7 Hz, 1H), 3.35 (s, 3H), 3.41 (dd, J=14.0, 4.0 Hz, 1H), 3.50-3.54 (m, 1H), 3.57 (dd, J=7.2, 3.9 Hz, 1H), 3.59 (dd, J=7.1, 3.5 Hz, 2H), 3.85-3.97 (m, 3H), 4.69-4.72 (m, 1H), 7.56 (t, J=1.8 Hz, 1H), 7.70 (d, J=1.9 Hz, 2H).
(92) .sup.13C-NMR (150 MHz, CDCl.sub.3) =15.43, 27.98, 29.66, 46.94, 50.23, 51.19, 52.35, 56.99, 58.90, 63.53, 71.21, 124.8, 132.6, 136.2, 144.0, 169.8.
(93) MS (ESI): m/z (%)=451.15 [M+H].sup.+
Example 2-8: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-5-(methoxymethyl)-3,10-diazabicyclo[4.3.1]decan-2-one B14
(94) ##STR00090##
(95) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(hydroxymethyl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (25.0 mg, 0.0554 mmol) in THF (1 mL) was added NaH (60% dispersion in mineral oil, 4.7 mg, 0.12 mmol) and stirred for 20 minutes. CH.sub.3I (16.8 mg, 7.4 L, 0.118 mmol) was added. After 5 h the solvent was removed under reduced pressure and column chromatography over SiO.sub.2 (EtOAc/Cyclohexane=1:1) afforded the title compound (13.0 mg, 0.0279 mmol, 50.4%) as a yellow oil.
(96) .sup.1H-NMR (600 MHz, CDCl.sub.3) =1.27-1.33 (m, 2H), 1.55-1.65 (m, 3H), 2.27 (d, J=13.1 Hz, 1H), 2.30-2.37 (m, 1H), 3.18 (dd, J=14.3, 1.7 Hz, 1H), 3.23-3.34 (m, 2H), 3.34 (s, 3H), 3.35 (s, 3H), 3.40-3.47 (m, 1H), 3.47-3.57 (m, 2H), 3.75 (dd, J=14.3, 10.6 Hz, 1H), 3.79-3.86 (m, 1H), 3.89-3.95 (m, 1H), 4.70 (d, J=5.9 Hz, 1H), 7.55 (t, J=1.8 Hz, 1H), 7.70 (d, J=1.8 Hz, 2H).
(97) .sup.13C-NMR (150 MHz, CDCl.sub.3) 15.45, 22.66, 28.11, 28.16, 29.67, 44.73, 50.31, 51.18, 52.64, 56.99, 70.81, 73.44, 124.9, 132.5, 136.2, 144.0, 169.7.
(98) MS (ESI): m/z (%)=465.12 [M+H].sup.+
Example 2-9: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-ethyl-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one B15
(99) ##STR00091##
(100) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (20.0 mg, 0.0447 mmol) in MeOH (1.0 mL) was added Pd/C (10% wt, 4.76 mg, 4.47 mol) and the reaction was stirred for 1 h at room temperature. The mixture was then filtered through celite and washed with MeOH. CH.sub.2Cl.sub.2 was added to the solution and washed three times with sat. aq. NaCl solution. The organic phase was separated and the solvent was removed under reduced pressure affording the title compound (20.0 mg, 0.0447 mmol, quant.) as a colorless solid.
(101) .sup.1H NMR (600 MHz, CDCl.sub.3) =0.95-0.99 (m, 2H), 1.22-1.26 (m, 3H), 1.30-1.56 (m, 5H), 1.92-1.99 (m, 1H), 2.23 (d, J=13.5 Hz, 1H), 3.07-3.13 (m, 1H), 3.31-3.38 (m, 4H), 3.47-3.56 (m, 2H), 3.79-3.91 (m, 3H), 4.63-4.68 (m, 1H), 7.52-7.56 (m, 1H), 7.67-7.70 (m, 2H).
Example 2-10: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-((S)-2-hydroxypropyl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one B4 and (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-((R)-2-hydroxypropyl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one B5
(102) ##STR00092##
(103) A solution of a mixture of 2-((1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-5-yl)acetaldehyde and (5S)-5-acetyl-10-((3, 5-dichlorophenyl)sulfonyl)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (58.0 mg, 0.125 mmol) in THF (1.5 mL) was cooled to 78 C. CH.sub.3MgBr (3 M in Et.sub.2O, 0.189 mmol, 63.0 L) was added and the reaction was stirred for 1 h. Aq. Sat. NH.sub.4Cl solution (10 mL) was added to the reaction and extracted with CH.sub.2Cl.sub.2 (290 mL). The organic layer was dried over MgSO.sub.4 and the solvent was evaporated under reduced pressure. Normal phase preparative chromatography (10-30% EtOAc in n-Hexane) afforded a mixture of the title compounds (12 mg, 0.0250 mmol, 15%) as a colorless oil.
(104) .sup.1H NMR (600 MHz, Chloroform-d) 1.13-1.20 (m, 1H), 1.31-1.42 (m, 3H), 1.48-1.57 (m, 4H), 2.21-2.27 (m, 2H), 2.30-2.38 (m, 1H), 3.06-3.21 (m, 2H), 3.21-3.26 (m, 1H), 3.29 (dd, J=14.3, 1.7 Hz, 1H), 3.36 (d, J=4.0 Hz, 3H), 3.47-3.53 (m, 1H), 3.60-3.65 (m, 1H), 3.69-3.75 (m, 1H), 3.78 (dt, J=6.7, 3.3 Hz, 1H), 3.96-4.03 (m, 1H), 4.08-4.19 (m, 1H), 4.61-4.70 (m, 1H), 7.53-7.56 (m, 1H), 7.63-7.73 (m, 2H).
(105) MS (ESI): m/z (%)=479.11 [M+H].sup.+
(106) III. Preparation of Compounds C1-C3
Example 3-1: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-hydroxyethyl)-5-(hydroxymethyl)-3,10-diazabicyclo[4.3.1]decan-2-one C1
(107) ##STR00093##
(108) (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-hydroxyethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one in CH.sub.2Cl.sub.2/MeOH (5 mL, 1:1) was cooled to 78 C. N.sub.2 was bubbled trough the solution for 15 minutes. Then O.sub.3 was bubbled through the solution for 5 minutes, until the solution turned blue. The residual O.sub.3 was removed with more N.sub.2 flux. The reaction was allowed to warm to room temperature, quenched with dimethyl sulfide (13 L) and then 3.6 mg of NaBH.sub.4 (0,096 mmol) were added. After 30 minutes solvent was removed under reduced pressure and column chromatography over SiO.sub.2 (ethyl acetate/cyclohexane, 1:1) afforded the title compound (25.0 mg, 0.0569 mmol, 64.9%) as a white solid.
(109) .sup.1H-NMR (600 MHz, Chloroform-d) =1.37 (s, 2H), 1.51-1.54 (m, 3H), 2.25 (d, J=13.2 Hz, 1H), 2.33 (dt, J=10.3, 5.1 Hz, 1H), 3.33 (dd, J=14.4, 1.7 Hz, 1H), 3.39 (d, J=14.4 Hz, 1H), 3.55-3.62 (m, 2H), 3.78-3.82 (m, 2H), 3.86-3.89 (m, 1H), 3.90-3.95 (m, 2H), 4.69 (d, J=5.9 Hz, 1H), 7.56 (t, J=1.8 Hz, 1H), 7.70 (d, J=1.9 Hz, 2H).
(110) .sup.13C-NMR (150 MHz, Chloroform-d) =15.44, 27.71, 29.67, 30.29, 47.10, 50.07, 52.28, 54.08, 57.04, 61.21, 63.17, 124.9, 132.8, 136.3, 143.9, 171.4.
Example 3-2: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(1,2-dihydroxyethyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-3, 10-diazabicyclo[4.3.1]decan-2-one C2/C2b
(111) ##STR00094##
(112) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (30.0 mg, 0.527 mmol) in t-BuOH/H.sub.2O (1 mL, 1:1) was added AD-MIX- (73.8 mg) and the reaction was stirred at room temperature for 24 h. Saturated NaCl was added to the mixture and extracted three times with CH.sub.2Cl.sub.2. The combined organic layers were dried over MgSO.sub.4 and the solvent was removed under reduced pressure. Column chromatography on SiO.sub.2 (Cyclohexane/EtOAc=3:7+1% AcOH) afforded the title compound (24.0 mg, 0.0398 mmol, 75.1%), which were separated by preparative HPLC in pure diastereoisomers.
(113) R.sub.f (C2a): 0.3 (Cyclohexane/EtOAc=3:7+1% AcOH)
(114) R.sub.f (C2b): 0.3 (Cyclohexane/EtOAc=3:7+1% AcOH)
(115) MS (C2a) (ESI): m/z (%)=603.02 [M+H].sup.+; MS (C2b) (ESI): m/z (%)=603.11 [M+H].sup.+
Example 3-3: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(1,2-dihydroxyethyl)-3-(2-ethoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one C3
(116) ##STR00095##
(117) To a solution of ((1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-ethoxyethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (30.0 mg, 0.0650 mmol) in THF/H.sub.2O (1.5 mL, 2:1) were added NMO (30.5 mg, 0,260 mmol) and OsO.sub.4 (2.5% solution in tert-butanol, 2.60 mol, 33 L). After 1 h stirring at room temperature saturated sat. aq. NaCl solution (10 mL) was added to the reaction and extracted with CH.sub.2Cl.sub.2 (340 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography over SiO.sub.2 (1% AcOH in cyclohexane/EtOAc=1:4) afforded the title compound (15.0 mg, 0.0303 mmol, 46.6%). R.sub.f: 0.22 (Cyclohexane/EtOAc=1:4+1% AcOH)
(118) MS (ESI): m/z (%)=495.29 [M+H].sup.+
(119) IV. Preparation of Compounds D1-D8
(120) ##STR00096##
Example 4-1: Preparation of (1S,5S,6R)-5-acetyl-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-3,10-diazabicyclo[4.3.1]decan-2-one D1 and 2-((1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-5-yl)acetaldehyde D2
(121) ##STR00097##
(122) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (25.0 mg, 0.0440 mmol) in DMF/H.sub.2O (0.229 mL, 7:1) was added PdCl.sub.2 (1.57 mg, 8.78 mol) and CuCl (4.35 mg, 0.440 mmol). After 24 h days stirring Et.sub.2O (90 mL) was added to the reaction and washed three times with saturated Na.sub.2S.sub.2O.sub.3 (310 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography on SiO.sub.2 (EtOAc/Cyclohexane=1:1) afforded an inseparable mixture of the title compounds (18.0 mg, 0.0307 mmol, 69.8%) as a white solid.
(123) R.sub.f: 0.36 (EtOAc/Cyclohexane=1:1)
(124) MS D1: (ESI): m/z (%)=585.09 [M+H].sup.+
(125) MS D2: (ESI): m/z (%)=585.10 [M+H].sup.+
Example 4-2: Preparation of (1S,5S,6R)-10-((3, 5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-5-(2-hydroxypropan-2-yl)-3,10-diazabicyclo[4.3.1]decan-2-one D3, (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-5-(2-hydroxypropyl)-3,10-diazabicyclo[4.3.1]decan-2-one D4, and (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-5-(2-hydroxypropyl)-3,10-diazabicyclo[4.3.1]decan-2-one D5
(126) ##STR00098##
(127) A solution of an inseparable mixture of 2-((1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-2-oxo-3, 10-diazabicyclo [4.3.1]decan-5-yl)acetaldehyde and (1S,5S,6R)-5-acetyl-10-((3, 5-dichlorophenyl) sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-3,10-diazabicyclo[4.3.1] decan-2-one (48.0 mg, 0.0820 mmol) in THF (1 mL) was cooled to 78 C. MeMgBr (3 M in Et.sub.2O, 0.123 mmol, 41.0 L) was added and the reaction was stirred for 1 h. Sat. aq. NH.sub.4Cl (15 mL) solution was added to the reaction and extracted with CH.sub.2Cl.sub.2 (390 mL). The organic layer was dried over MgSO.sub.4 and the solvent was evaporated under reduced pressure. Flash column chromatography on SiO.sub.2 (20-50% EtOAc in cyclohexane) afforded the title compound (D3: 23.0 mg, 0.0382 mmol, D4: 6 mg, 0.00998 mmol, D5: 8 mg, 0.0133 mmol, 75.0%).
(128) D3:
(129) .sup.1H-NMR: (600 MHz, Chloroform-d) =1.25 (s, 3H), 1.27 (s, 3H), 1.44-1.52 (m, 2H), 1.57-1.62 (m, 3H), 2.15 (ddd, J=10.5, 6.7, 1.5 Hz, 1H), 2.23 (d, J=13.4 Hz, 1H), 3.41 (dd, J=14.2, 1.4 Hz, 1H), 3.51-3.59 (m, 1H), 3.83 (s, 3H), 3.84 (s, 3H), 3.98-4.07 (m, 2H), 4.13-4.18 (m, 2H), 4.25-4.30 (m, 1H), 4.69 (d, J=5.7 Hz, 1H), 6.40 (dd, J=8.8, 2.8 Hz, 1H), 6.54 (d, J=2.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 7.54 (t, J=1.9 Hz, 1H), 7.72 (d, J=1.9 Hz, 2H).
(130) .sup.13C-NMR: (150 MHz, Chloroform-d) =15.33, 27.42, 27.90, 28.11, 29.68, 50.22, 51.73, 51.96, 54.16, 55.84, 56.40, 57.19, 67.13, 72.50, 100.8, 104.2, 111.9, 125.0, 132.7, 136.3, 143.7, 143.9, 149.8, 153.1, 169.8.
(131) MS (ESI): m/z (%)=601.28 [M+H].sup.+
(132) D4:
(133) .sup.1H-NMR: (600 MHz, Chloroform-d) =1.23-1.29 (m, 5H), 1.49-1.66 (m, 5H), 2.25 (d, J=12.3 Hz, 1H), 2.33-2.41 (m, 1H), 3.31 (dd, J=14.4, 1.7 Hz, 1H), 3.52-3.60 (m, 1H), 3.82-3.87 (m, 7H), 3.93-4.09 (m, 4H), 4.14-4.20 (m, 1H), 4.68 (d, J=5.9 Hz, 1H), 6.42 (dd, J=8.7, 2.8 Hz, 1H), 6.56 (d, J=2.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 7.54 (t, J=1.8 Hz, 1H), 7.69 (d, J=1.9 Hz, 2H).
(134) .sup.13C-NMR: (151 MHz, Chloroform-d) =15.46, 24.98, 29.68, 41.55, 43.10, 51.77, 54.00, 55.58, 55.89, 56.39, 56.91, 65.69, 67.31, 100.8, 104.1, 111.8, 124.8, 132.6, 136.3, 143.8, 144.1, 149.8, 153.0, 170.0.
(135) MS (ESI): m/z (%)=601.28 [M+H].sup.+
(136) D5:
(137) .sup.1H-NMR: (600 MHz, Chloroform-d) =1.21-1.27 (m, 5H), 1.45-1.62 (m, 5H), 2.22-2.29 (m, 1H), 2.35-2.41 (m, 1H), 3.29 (dd, J=14.4, 1.8 Hz, 1H), 3.49-3.56 (m, 1H), 3.81-3.88 (m, 7H), 3.93-4.02 (m, 2H), 4.03-4.08 (m, 1H), 4.13-4.24 (m, 2H), 4.69 (dt, J=6.3, 1.9 Hz, 1H), 6.43 (dd, J=8.7, 2.8 Hz, 1H), 6.57 (d, J=2.8 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 7.54 (t, J=1.8 Hz, 1H), 7.69 (dd, J=1.9, 0.4 Hz, 2H).
(138) .sup.13C-NMR: (150 MHz, Chloroform-d) =15.50, 24.49, 26.71, 26.90, 27.71, 29.68, 40.96, 42.63, 51.73, 52.46, 55.88, 56.38, 56.80, 64.95, 67.97, 100.8, 104.4, 111.9, 124.8, 132.6, 136.3, 143.9, 144.1, 149.9, 153.1, 170.3.
(139) MS (ESI): m/z (%)=601.32 [M+H].sup.+
Example 4-3: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-5-((R)-1-hydroxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one D6, (1S,5S,6R)-10-((3, 5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-5-((R)-1-hydroxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one D7, and (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-5-(2-hydroxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one D8
(140) ##STR00099##
(141) To a solution of an inseparable mixture of 2-((1S,5S,6R)-10-((3,5-dichloro-phenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-2-oxo-3,10 diazabicyclo [4.3.1]decan-5-yl)acetaldehyde and (1S,5S,6R)-5-acetyl-10-((3,5-dichlorophenyl) sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-3,10 diazabicyclo[4.3.1]decan-2-one (90.0 mg, 0.154 mmol) in EtOH (1.5 mL) were added of NaBH.sub.4 (5.82 mg, 0.154 mmol) and then stirred for 15 minutes at room temperature. EtOAc (90 mL) was added to the reaction and washed with sat. aq. NaCl solution (310 mL). The organic layer was dried over MgSO.sub.4 and the solvent was evaporated under reduced pressure. Flash column chromatography on SiO.sub.2 (20-50% EtOAc in cyclohexane) afforded the title compound (D6: 20.0 mg, 0.0340 mmol, D7: 12.0 mg, 0.0204 mmol, D8: 29.0 mg, 0.0494 mmol, 67.7%).
(142) D6:
(143) R.sub.f: 0.53 (Cyclohexane/EtOAc=3:7)
(144) .sup.1H-NMR: (600 MHz, Chloroform-d) =1.29 (s, 3H), 1.37-1.55 (m, 5H), 2.11-2.18 (m, 1H), 2.26 (d, J=13.4 Hz, 1H), 3.45-3.49 (m, 1H), 3.52-3.58 (m, 1H), 3.83 (s, 3H), 3.84 (s, 3H), 3.86-3.91 (m, 1H), 3.95 (dd, J=14.4, 10.6 Hz, 1H), 4.01-4.06 (m, 1H), 4.13-4.17 (m, 3H), 4.70 (d, J=5.7 Hz, 1H), 6.39 (dd, J=8.7, 2.8 Hz, 1H), 6.54 (d, J=2.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 7.53 (t, J=1.9 Hz, 1H), 7.69-7.72 (m, 2H).
(145) .sup.13C-NMR: (150 MHz, Chloroform-d) =15.31, 21.09, 28.19, 28.67, 29.67, 49.68, 50.63, 51.67, 52.48, 55.85, 56.40, 57.00, 67.20, 68.91, 100.6, 103.9, 111.8, 124.9, 132.7, 136.3, 143.7, 143.9, 149.8, 153.1, 169.9.
(146) MS (ESI): m/z (%)=587.16 [M+H].sup.+
(147) D7:
(148) R.sub.f: 0.5 (Cyclohexane/EtOAc=3:7); MS (ESI): m/z (%)=587.16 [M+H].sup.+
(149) .sup.1H-NMR: (600 MHz, Chloroform-d) =1.28 (s, 3H), 1.34-1.54 (m, 5H), 2.21 (s, 1H), 2.26 (d, J=13.7 Hz, 1H), 3.33-3.39 (m, 1H), 3.51-3.58 (m, 1H), 3.83 (s, 3H), 3.85 (s, 3H), 3.84-3.90 (m, 1H), 4.04 (dd, J=14.1, 3.3 Hz, 2H), 4.11-4.20 (m, 3H), 4.70 (d, J=5.7 Hz, 1H), 6.40 (dd, J=8.7, 2.8 Hz, 1H), 6.54 (d, J=2.8 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 7.53 (t, J=1.9 Hz, 1H), 7.71 (d, J=1.8 Hz, 2H).
(150) .sup.13C-NMR: (150 MHz, Chloroform-d) =15.40, 20.25, 28.13, 28.82, 29.68, 50.44, 50.74, 51.56, 51.66, 55.85, 56.41, 57.01, 67.23, 69.12, 100.5, 103.9, 111.9, 124.9, 124.9, 132.7, 136.3, 143.7, 143.9, 149.9, 153.1, 169.9.
(151) D8:
(152) R.sub.f: 0.37 (Cyclohexane/EtOAc=3:7); MS (ESI): m/z (%)=587.15 [M+H].sup.+
(153) .sup.1H-NMR: (600 MHz, Chloroform-d) =1.42-1.56 (m, 7H), 2.26 (d, J=13.6 Hz, 1H), 2.32-2.36 (m, 1H), 3.29 (d, J=12.6 Hz, 1H), 3.50-3.56 (m, 1H), 3.73-3.78 (m, 2H), 3.83 (s, 3H), 3.86 (s, 3H), 3.94 (s, 1H), 4.02-4.08 (m, 1H), 4.13-4.21 (m, 3H), 4.69 (d, J=5.9 Hz, 1H), 6.42 (dd, J=8.8, 2.8 Hz, 1H), 6.55 (d, J=2.8 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 7.55 (t, J=1.8 Hz, 1H), 7.69 (dd, J=1.9, 0.6 Hz, 2H).
(154) .sup.13C-NMR: (75 MHz, Chloroform-d) =15.44, 27.35, 27.84, 29.67, 36.10, 41.09, 51.73, 53.19, 55.42, 55.89, 56.40, 56.85, 59.86, 67.62, 100.7, 104.2, 111.9, 124.8, 132.6, 136.3, 143.8, 144.1, 149.9, 153.1, 170.1.
(155) V. Preparation of Compounds G4-G6
(156) ##STR00100##
(157) ##STR00101##
(158) ##STR00102##
Example 5-1: Preparation of (E)-N-Boc-3-tributylstannyl-2-propen-1-amine E1
(159) ##STR00103##
(160) To a solution of N-Boc-propargylamine (818 mg, 5.27 mmol) in toluene (26 mL) was added AIBN (0.2 M in toluene, 1.32 mL, 2.64.Math.10.sup.5 mol, 0.05 equiv.) and tributyltin hydride (1.56 mL, 5.80 mmol, 1.1 equiv.) and it was stirred for 2.5 h at 120 C. (preheated oil bath). After cooling to room temperature, the solvent was evaporated under reduced pressure. Column chromatography on SiO.sub.2 (cyclohexane/EtOAc 60:1) afforded the title compound (1.48 g, 3.32 mmol, 63%) as colorless liquid.
(161) R.sub.f: 0.42 (Cyclohexane/EtOAc 20:1, KMnO.sub.4)
(162) .sup.1H-NMR (600 MHz, CDCl.sub.3): =0.85-0.90 (m, 15H, 3CH.sub.2, 3CH.sub.3), 1.25-1.33 (m, 6H, 3CH.sub.2), 1.45 (s, 9H, 3CH.sub.3), 1.46-1.51 (m, 6H, 3CH.sub.2), 3.78 (s.sub.br, 1H, CH.sub.2), 4.60 (s.sub.br, 1H, NH), 5.95 (dt, J=19.2, 4.8 Hz, 1H, CH), 6.08 (dt, J=19.2, 1.8 Hz, 1H, CH).
(163) .sup.13C-NMR (150 MHz, CDCl.sub.3): =9.65, 13.90, 27.48, 28.62, 29.27, 46.21, 79.45, 129.3, 144.5, 156.0.
Example 5-2: Preparation of (E)-N-Boc-3-iodo-2-propen-1-amine E2
(164) ##STR00104##
(165) To a solution of E1 (6.96 g, 15.6 mmol) in CH.sub.2Cl.sub.2 (160 mL) was added Iodine (4.16 g, 16.4 mmol, 1.05 equiv.) and the resulting suspension was stirred for 2 h at room temperature. The reaction mixture was washed with 1 M Na.sub.2S.sub.2O.sub.3 solution (150 mL), dried over MgSO.sub.4, filtered and the solvent was evaporated under reduced pressure. Column chromatography on SiO.sub.2 (cyclohexane/EtOAc 10:1) afforded the title compound (4.28 g, 15.1 mmol, 97%) as slightly yellow liquid, which solidified upon cooling to 4 C.
(166) R.sub.f: 0.17 (Cyclohexane/EtOAc 20:1, KMnO.sub.4)
(167) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.44 (s, 9H, 3CH.sub.3), 3.65-3.73 (m, 2H, CH.sub.2), 4.67 (s.sub.br, 1H, NH), 6.27 (dt, J=14.4, 1.6 Hz, 1H, CH), 6.53 (dt, J=14.4, 4.0 Hz, 1H, CH).
(168) .sup.13C-NMR (100 MHz, CDCl.sub.3): =28.56, 44.97, 77.95, 79.99, 142.6, 155.6.
Example 5-3: Preparation of (2S)-tert-Butyl-pyroglutamate F1
(169) ##STR00105##
(170) To a suspension of
(171) R.sub.f: 0.41 (EtOAc, KMnO.sub.4)
(172) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.44 (s, 9H, 3CH.sub.3), 2.12-2.15 (m, 4H, 2CH.sub.2), 4.08-4.16 (m, 1H, CH), 6.11 (s.sub.br, 1H, NH).
(173) .sup.13C-NMR (75.5 MHz, CDCl.sub.3): =25.08, 28.18, 29.58, 56.25, 82.62, 171.2, 177.9.
Example 5-4: Preparation of (2S)N-Cbz-tert-Butyl-pyroglutamate F2
(174) ##STR00106##
(175) To a solution of F1 (2.29 g, 12.4 mmol) in THF (62 mL) was added NaH (60% oil dispersion, 546 mg, 13.6 mmol, 1.1 equiv.) and it was stirred for 30 min at room temperature. Subsequently Benzyl chloroformate (1.94 mL, 13.6 mmol, 1.1 equiv.) was added and stirring was continued for further 20 h. The solvent was evaporated under reduced pressure, sat. aq. NH.sub.4Cl solution (100 mL) was added and extracted with EtOAc (2100 mL). The organic phase was dried over MgSO.sub.4, filtered and the the solvent was evaporated under reduced pressure. Column chromatography on SiO.sub.2 (cyclohexane/EtOAc 3:1) afforded the title compound (3.56 g, 11.1 mmol, 90%) as colorless oil.
(176) R.sub.f: 0.18 (Cyclohexane/EtOAc 3:1, KMnO.sub.4)
(177) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.39 (s, 9H, 3CH.sub.3), 1.97-2.70 (m, 4H, 2CH.sub.2), 4.54 (dd, J=9.3, 2.7 Hz, 1H, CH), 5.27 (dd, J=16.2, 12.3 Hz, 2H, CH.sub.2), 7.27-7.43 (m, 5H, 5ArH).
(178) .sup.13C-NMR (75.5 MHz, CDCl.sub.3): =25.11, 27.12, 31.23, 59.60, 68.43, 82.76, 128.4, 128.6, 128.7, 135.3, 151.1, 170.3, 173.3.
Example 5-5: Preparation of tert-Butyl-(S)-2-(benzyloxycarbonylamino)-5-hydroxypentanoate F3
(179) ##STR00107##
(180) To a suspension of F2 (2.15 g, 6.73 mmol) and KH.sub.2PO.sub.4 (6.87 g, 50.5 mmol, 7.5 equiv.) in MeOH/H.sub.2O (5:1, 67 mL) was added NaBH.sub.4 (1.91 g, 50.5 mmol, 7.5 equiv.) in portions. After stirring for 1 h the mixture was filtered and the solvent was evaporated under reduced pressure. Column chromatography on SiO.sub.2 (cyclohexane/EtOAc 2:1) afforded the title compound (1.43 g, 4.42 mmol, 66%) as colorless oil.
(181) R.sub.f: 0.29 (Cyclohexane/EtOAc 2:1, KMnO.sub.4)
(182) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =1.39 (s, 9H, 3CH.sub.3), 1.41-1.91 (m, 4H, 2CH.sub.2), 3.38 (dd, J=6.3, 1.8 Hz, 2H, CH.sub.2), 3.82-3.92 (m, 1H, CH), 5.04 (d, J=2.4 Hz, 2H, CH.sub.2), 7.28-7.40 (m, 5H, 5ArH), 7.58 (d.sub.br, J=7.8 Hz, 1H, NH).
(183) .sup.13C-NMR (75.5 MHz, DMSO-d.sub.6): =27.62, 28.83, 54.48, 60.10, 65.32, 80.32, 127.7, 127.8, 128.3, 156.1, 171.6.
(184) MS (ESI): m/z (%)=267.9 (16) [M-tBu+H].sup.+, 324.0 (36) [M+H].sup.+, 346.2 (10) [M+Na].sup.+, 646.9 (100) [2M+H].sup.+, 669.0 (28) [2M+Na].sup.+.
Example 5-6: Preparation of tert-Butyl-(S)-2-(benzyloxycarbonylamino)-5-iodopentanoate F4
(185) ##STR00108##
(186) To a suspension of PPh.sub.3 (2.30 g, 8.78 mmol, 2.0 equiv.), I.sub.2 (2.23 g, 8.78 mmol, 2.0 equiv.) and imidazole (897 mg, 13.2 mmol, 3.0 equiv.) in CH.sub.2Cl.sub.2 (44 mL) was added F3 (1.42 g, 4.39 mmol) and it was stirred for 1 h at room temperature. H.sub.2O was added (30 mL), the organic phase separated, washed with aq. 1 M Na.sub.2S.sub.2O.sub.3 solution (30 mL), dried over MgSO.sub.4 and the solvent was evaporated under reduced pressure. Column chromatography on SiO.sub.2 (CH.sub.2Cl.sub.2) afforded the title compound (1.64 g, 3.79 mmol, 86%) as slightly yellow oil, which solidified upon cooling to 4 C.
(187) R.sub.f: 0.35 (Cyclohexane/EtOAc 8:1, KMnO.sub.4)
(188) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.47 (s, 9H, 3CH.sub.3), 1.69-2.00 (m, 4H, 2CH.sub.2), 3.08-3.28 (m, 2H, CH.sub.2), 4.24-4.33 (m, 1H, CH), 5.11 (s, 2H, CH.sub.2), 5.33 (d.sub.br, J=7.5 Hz, 1H, NH), 7.28-7.38 (m, 5H, 5ArH).
(189) .sup.13C-NMR (75.5 MHz, CDCl.sub.3): =5.82, 28.22, 29.20, 34.00, 53.68, 67.18, 82.70, 128.3, 128.4, 128.8, 136.5, 156.0, 171.3.
(190) MS (ESI): m/z (%)=377.8 (74) [M-tBu+H].sup.+, 433.7 (74) [M+H].sup.+, 456.1 (12) [M+Na].sup.+, 810.6 (12) [2M-tBu+H].sup.+, 866.6 (12) [2M+H].sup.+.
Example 5-7: Preparation of (S,E)-tert-Butyl 2-(((benzyloxy)carbonyl)amino)-8-((tert-butoxycarbonyl)amino)oct-6-enoate G1
(191) ##STR00109##
(192) To a suspension of Zn powder (1.57 g, 24.0 mmol, 6.0 equiv.) in DMF (1.8 mL) was added 1,2-Dibromomethane (103 L, 1.20 mmol, 0.3 equiv.) and it was stirred for 0.5 h at 60 C. After cooling to room temperature, TMSCl (30 L, 0.240 mmol, 0.06 equiv.) was added and stirring was continued for further 0.5 h. Then F4 (1.73 g, 4.00 mmol, 1.0 equiv.) was added and the reaction mixture was stirred for 0.5 h. Pd.sub.2(dba).sub.3 (73 mg, 0.080 mmol, 0.02 equiv), P(otol).sub.3 (97 mg, 0.320 mmol, 0.08 equiv.), and E2 (849 mg, 3.00 mmol, 0.75 equiv.) in DMF (1.8 mL), were added and it was stirred for 16 h at room temperature. The resulting green suspension was poured into EtOAc (150 mL) and the organic phase was washed with sat. aq. NaCl solution (350 mL), dried over MgSO.sub.4 and the solvent was evaporated under reduced pressure. Column chromatography on SiO.sub.2 (cyclohexane/EtOAc 8:1.fwdarw.4:1) afforded the title compound (1.25 g, 2.70 mmol, 90%) as yellow oil.
(193) R.sub.f: 0.23 (Cyclohexane/EtOAc 4:1, KMnO.sub.4)
(194) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.44 (s, 9H, 3CH.sub.3), 1.45 (s, 9H, 3CH.sub.3), 1.54-1.86 (m, 4H, 2CH.sub.2), 1.95-2.10 (m, 2H, CH.sub.2), 3.62-3.72 (m, 2H, CH.sub.2), 4.20-4.28 (m.sub.c, 1H, CH), 4.57 (s.sub.br, 1H, NH), 5.10 (s, 2H, CH.sub.2), 5.29 (d.sub.br, J=7.6 Hz, 1H, NH), 5.39-5.48 (m, 1H, CH), 5.49-5.58 (m, 1H, CH), 7.28-7.38 (m, 5H, 5ArH).
(195) .sup.13C-NMR (100 MHz, CDCl.sub.3): =24.67, 28.20, 28.61, 31.80, 32.49, 42.74, 54.34, 67.04, 82.21, 127.4, 128.3, 128.3, 128.7, 128.7, 132.1, 136.6, 155.9, 156.0, 171.7.
(196) MS (ESI): m/z (%)=307.3 (28) [M-Boc-tBu+H].sup.+, 363.2 (100) [M-Boc+H].sup.+, 463.0 (64) [M+H].sup.+, 485.2 (16) [M+Na].sup.+, 825.0 (34) [2M-Boc+H].sup.+.
Example 5-8: Preparation of (S)-tert-Butyl 2-(((benzyloxy)carbonyl)amino)-5-((2S,3S)-3-(((tert-butoxycarbonyl)amino)methyl)oxiran-2-yl)pentanoate G2
(197) ##STR00110##
(198) To a solution of G1 (2.00 g, 4.32 mmol) in DMM/MeCN (60 mL, 2:1) was added buffer (40 mL, 0.05 M solution of Na.sub.2B.sub.4O.sub.7.10H.sub.2O in 4.Math.10.sup.4 M aq. Na.sub.2(EDTA)), nBu.sub.4NHSO.sub.4 (148 mg, 0.432 mmol, 0.1 equiv.) and
(199) R.sub.f: 0.38 (Cyclohexane/EtOAc 2:1, KMnO.sub.4)
(200) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.42 (s, 9H, 3CH.sub.3), 1.45 (s, 9H, 3CH.sub.3), 1.48-1.92 (m, 6H, 3CH.sub.2), 2.70-2.79 (m, 1H, CH.sub.A), 2.79-2.85 (m, 1H, CH.sub.B), 3.17 (ddd, J=14.8, 6.4, 5.2 Hz, 1H, CH), 3.39-3.53 (m, 1H, CH), 4.24 (m.sub.c, 1H, CH), 4.77 (s.sub.br, 1H, NH), 5.09 (s, 2H, CH.sub.2), 5.37 (d.sub.br, J=8.1 Hz, 1H, NH), 7.28-7.38 (m, 5H, 5ArH).
(201) .sup.13C-NMR (75.5 MHz, CDCl.sub.3): =21.78, 28.17, 28.52, 31.18, 32.64, 41.59, 54.39, 56.51, 57.05, 67.05, 79.77, 82.31, 128.3, 128.3, 128.7, 128.7, 136.5, 156.0, 171.6.
(202) MS (ESI): m/z (%)=323.2 (28) [M-Boc-tBu+H].sup.+, 367.1 (58) [M-Boc-tBu-H+2Na].sup.+, 423.0 (100) [M-tBu+H].sup.+, 479.0 (20) [M+H].sup.+, 501.1 (14) [M+Na].sup.+, 957.0 (12) [2M+H].sup.+.
Example 5-9: Preparation of (2S,6R)-1-benzyl 2-tert-butyl 6-((S)-2-((tert-butoxy-carbonyl)amino)-1-hydroxyethyl)piperidine-1,2-dicarboxylate G3
(203) ##STR00111##
(204) A suspension of G2 (1.45 g, 3.03 mmol) and Pd/C (145 mg, 10 wt. %) in EtOH (30 mL) was stirred for 2 h at room temperature under a H.sub.2-atmosphere. The reaction mixture was filtered over Celite, washed with EtOAc and the solvent was evaporated under reduced pressure to give a colorless, crystalline solid.
(205) This solid was dissolved in dioxane/H.sub.2O (30 mL, 2:1), Na.sub.2CO.sub.3 (963 mg, 9.09 mmol, 3.0 equiv.) and benzyl chloroformate (646 L, 4.55 mmol, 1.5 equiv.) were added and it was stirred for 18 h at room temperature. H.sub.2O (50 mL) was added and it was extracted with CH.sub.2Cl.sub.2 (250 mL), dried over MgSO.sub.4, and the solvent was removed under reduced pressure. Column chromatography on SiO.sub.2 (cyclohexane/EtOAc 4:1) afforded the title compound (1.20 g, 2.51 mmol, 83% over 2 steps) as colorless oil.
(206) R.sub.f: 0.50 (Cyclohexane/EtOAc 2:1, KMnO.sub.4)
(207) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =1.35 (s.sub.br, 9H, 3CH.sub.3), 1.37 (s, 9H, 3CH.sub.3), 1.40-1.68 (m, 4H, 2CH.sub.2), 1.96-2.12 (m, 2H, CH.sub.2), 2.82-2.92 (m, 1H, CH.sub.A), 3.28-3.36 (m, 1H, CH.sub.B), 3.55-3.63 (m, 1H, CH), 3.96-4.04 (m, 1H, CH), 4.61-4.67 (m, 1H, CH), 4.76 (d.sub.br, J=5.2 Hz, 1H, OH), 5.03 (d, J=12.4 Hz, 1H, CH.sub.A), 5.15 (d, J=12.4 Hz, 1H, CH.sub.B), 6.13 (s.sub.br, 1H, NH), 7.28-7.40 (m, 5H, 5ArH).
(208) .sup.13C-NMR (100 MHz, DMSO-d.sub.6): =15.76, 22.96, 25.18, 27.35, 28.19, 53.51, 54.87, 66.64, 68.64, 77.53, 81.00, 126.4, 126.6, 127.3, 136.6, 142.5, 155.6, 171.3.
(209) MS (ESI): m/z (%)=323.2 (70) [M-Boc-tBu+H].sup.+, 379.1 (74) [M-Boc+H].sup.+, 478.9 (26) [M+H].sup.+, 501.2 (42) [M+Na].sup.+, 801.0 (92) [2M-Boc-tBu+H].sup.+, 856.9 (100) [2M-Boc+H].sup.+, 956.5 (6) [2M+H].sup.+, 978.8 (36) [2M+Na].sup.+.
Example 5-10: Preparation of (1S,5S,6R)-benzyl 2-oxo-5-((triethylsilyl)oxy)-3,10-diazabicyclo[4.3.1]decane-10-carboxylate G4
(210) ##STR00112##
(211) To a solution of G3 (500 mg, 1.04 mmol) and 2,6-lutidine (1.21 mL, 10.4 mmol, 10 equiv.) in CH.sub.2Cl.sub.2 (20 mL) at 0 C. was added TESOTf (1.17 mL, 5.20 mol, 5.0 equiv.) dropwise. After 30 minutes the cooling bath was removed and the reaction was stirred for 20 h at room temperature. Sat. aq. NH.sub.4Cl solution (20 mL) was added and stirring was continued for 1 h. The organic phase was separated, the aqueous phase was extracted with CH.sub.2Cl.sub.2 (250 mL), the combined organic phases were dried over MgSO.sub.4, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on SiO.sub.2 (CH.sub.2Cl.sub.2/MeOH 20:1 to 10:1).
(212) The obtained amino acid was dissolved in CH.sub.2Cl.sub.2 (25 mL) and the solution was added dropwise at room temperature over 1 h to a solution of HATU (593 mg, 1.56 mmol, 1.5 equiv.) and (iPr).sub.2NEt (400 L, 2.23 mmol, 2.2 equiv.) in CH.sub.2Cl.sub.2 (200 mL). Stirring was continued for further 16 h, following evaporation of the solvent under reduced pressure. The residue was taken up in CH.sub.2Cl.sub.2 (100 mL), washed with CuSO.sub.4 solution (10 wt. %, 3100 mL), dried over MgSO.sub.4, and the solvent was evaporated under reduced pressure. Column chromatography on SiO.sub.2 (cyclohexane/EtOAc 2:1) afforded the title compound (218 mg, 0.521 mmol, 50% over 2 steps) as a slightly yellow oil.
(213) The compound consists of two carbamate rotamers in a 1:0.7 ratio.
(214) R.sub.f: 0.31 (Cyclohexane/EtOAc 1:1, KMnO.sub.4)
(215) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =0.58 (q, J=7.6 Hz, 6H, 3CH.sub.2), 0.90 (t, J=7.6 Hz, 5.4H, 3CH.sub.3), 0.91 (t, J=7.6 Hz, 3.6H, 3CH.sub.3), 1.37-1.70 (m, 5H, 2CH.sub.2, CH), 2.00-2.11 (m, 1H, CH), 2.70-2.79 (m, 1H, CH.sub.A), 2.95-3.07 (m, 1H, CH.sub.B), 3.83-3.93 (m, 1H, CH), 4.24-4.32 (m, 1H, CH), 4.61-4.66 (m, 1H, CH), 5.05 (d, J=12.8 Hz, 0.6H, CH.sub.A), 5.09 (d, J=12.8 Hz, 0.4H, CH.sub.A), 5.17 (d, J=12.8 Hz, 0.4H, CH.sub.B), 5.26 (d, J=12.8 Hz, 0.6H, CH.sub.B), 7.29-7.41 (m, 5H, 3ArH), 7.81-7.86 (m, 0.6H, NH), 7.88-7.93 (m, 0.4H, NH).
(216) .sup.13C-NMR (100 MHz, DMSO-d.sub.6): =4.20 (0.4C), 4.24 (0.6C), 6.62 (0.6C), 6.64 (0.4C), 15.95 (0.4C), 16.01 (0.6C), 26.30, 26.81 (0.4C), 27.14 (0.6C), 44.84 (0.4C), 44.88 (0.6C), 54.64 (0.6C), 54.88 (0.4C), 56.41 (0.4C), 57.27 (0.6C), 66.74 (0.6C), 66.79 (0.4C), 74.45, (0.4C), 74.84 (0.6C), 127.2 (0.6C), 127.4 (0.4C), 127.9 (0.6C), 127.9 (0.4C), 128.3 (0.6C), 128.5 (0.4C), 136.6 (0.6C), 136.7 (0.4C), 155.1 (0.4C), 155.3 (0.6C), 172.2 (0.4C), 172.3 (0.6C).
(217) MS (ESI): m/z (%)=419.2 (34) [M+H].sup.+, 837.1 (100) [2M+H].sup.+.
Example 5-10: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-((triethylsilyl)oxy)-3,10-diazabicyclo[4.3.1]decan-2-one G5
(218) ##STR00113##
(219) A suspension of G4 (500 mg, 1.19 mmol) and Pd/C (50.0 mg, 10 wt. %) in EtOAc (6 mL) was stirred for 3 h at room temperature under a H.sub.2-atmosphere. The reaction mixture was filtered over Celite, washed with EtOAc and the solvent was evaporated under reduced pressure to give a colorless, crystalline solid.
(220) The solid was dissolved in CH.sub.2Cl.sub.2 (6 mL), (iPr).sub.2NEt (624 L, 3.57 mmol, 3.0 equiv.), DMAP (145 mg, 1.19 mmol, 1.0 equiv.) and 3,5-Dichlorobenzenesulfonyl chloride (584 mg, 2.38 mmol, 2.0 equiv.) were added and the solution was stirred for 20 h at room temperature. Sat. aq. NH.sub.4Cl solution was added (25 mL), the aqueous phase was extracted with CH.sub.2Cl.sub.2 (225 mL), dried over MgSO.sub.4, and the solvent evaporated under reduced pressure. Column chromatography on SiO.sub.2 (cyclohexane/EtOAc 3:1) afforded the title compound (420 mg, 0.851 mmol, 72% over 2 steps) as colorless, crystalline solid.
(221) R.sub.f: 0.31 (Cyclohexane/EtOAc 2:1)
(222) .sup.1H-NMR (600 MHz, CDCl.sub.3): =0.61 (q, J=7.8 Hz, 6H, 3CH.sub.2), 0.96 (t, J=7.8 Hz, 9H, 3CH.sub.3), 1.25-1.70 (m, 5H, 2CH.sub.2, CH), 2.16-2.21 (m, 1H, CH), 2.83-2.91 (m, 1H, CH.sub.A), 2.83-2.91 (m, 1H, CH.sub.A), 3.59-3.64 (m, 1H, CH.sub.B), 3.93-3.97 (m, 1H, CH), 4.12-4.15 (m, 1H, CH), 4.64-4.67 (m, 1H, CH), 6.04-6.09 (m, 1H, NH), 7.57 (t, J=1.8 Hz, 1H, ArH), 7.72 (d, J=1.8 Hz, 2H, 2ArH).
(223) .sup.13C-NMR (75.5 MHz, CDCl.sub.3): =4.99, 6.95, 16.26, 26.59, 27.19, 46.88, 56.42, 60.20, 74.89, 125.3, 133.0, 136.5, 144.0, 172.8.
(224) MS (ESI): m/z (%)=493.4 (44) [M+H].sup.+, 987.2 (100) [2M+H].sup.+.
Example 5-10: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-hydroxy-3,10-diazabicyclo[4.3.1]decan-2-one G6
(225) ##STR00114##
(226) To a solution of G5 (400 mg, 0.811 mmol) in THF (4 mL) was added TBAF (1 M in THF, 892 L, 0.892 mmol, 1.1 equiv.) and the solution was stirred for 1.5 h at room temperature. Removal of the solvent under reduced pressure and column chromatography on SiO.sub.2 (CH.sub.2Cl.sub.2/MeOH 20:1) afforded the title compound (294 mg, 0.775 mmol, 96%) as a colorless solid.
(227) R.sub.f: 0.30 (EtOAc)
(228) .sup.1H-NMR (400 MHz, MeOH-d.sub.4): =1.27-1.37 (m, 2H, CH.sub.2), 1.51-1.59 (m, 2H, CH.sub.2), 1.69-1.79 (m, 1H, CH), 2.04-2.11 (m, 1H, CH), 2.99 (dd, J=13.2, 2.8 Hz, 1H, CH.sub.A), 3.58 (dd, J=13.2, 10.4 Hz, 1H, CH.sub.B), 3.94 (ddd, J=10.4, 5.2, 2.8 Hz, 1H, CH), 4.07 (m.sub.c, 1H, CH), 4.66 (dt, J=6.0, 2.0 Hz, 1H, CH), 7.81 (t, J=2.0 Hz, 1H, ArH), 7.89 (d, J=2.0 Hz, 2H, 2ArH).
(229) .sup.13C-NMR (100 MHz, MeOH-d.sub.4): =16.92, 27.51, 27.94, 47.04, 57.80, 60.52, 74.75, 126.5, 134.1, 137.8, 145.7, 175.0.
(230) MS (ESI): m/z (%)=379.0 (100) [M+H].sup.+, 758.7 (52) [2M+H].sup.+.
(231) VI. Preparation of Compounds H1.1-H1.4 and H2.1-H2.3
(232) Further examples for the compound of the general formula (I) are outlined in scheme H1 and scheme H2:
(233) ##STR00115##
(234) ##STR00116##
Example 6-1: Preparation of (1S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3,10-diazabicyclo[4.3.1]decane-2,5-dione H1.1
(235) ##STR00117##
(236) To a solution of G6 (100 mg, 0.264 mmol) in CH.sub.2Cl.sub.2 (6 mL) was added Dess-Martin periodinane (134 mg, 0.317 mmol, 1.2 equiv.) and the solution was stirred for 18 h at room temperature. Removal of the solvent under reduced pressure and column chromatography on SiO.sub.2 (CH.sub.2Cl.sub.2/EtOAc 10:1.fwdarw.5:1) afforded the title compound (100 mg, 0.264 mmol, quant.) as a colorless solid.
(237) R.sub.f: 0.28 (Cyclohexane/EtOAc 2:1)
(238) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.19-1.73 (m, 5H, 2CH.sub.2, CH), 2.20-2.30 (m, 1H, CH), 3.50 (dd, J=13.2, 8.4 Hz, 1H, CH.sub.A), 4.64-4.68 (m, 1H, CH), 4.76 (dd, J=13.2, 1.6 Hz, 1H, CH.sub.B), 4.78-4.81 (m, 1H, CH), 6.36 (d.sub.br, J=8.0 Hz, 1H, NH), 7.63 (d, J=2.0 Hz, 1H, ArH), 7.72 (d, J=2.0 Hz, 1H, 2ArH).
(239) .sup.13C-NMR (100 MHz, CDCl.sub.3): =17.70, 24.74, 27.24, 51.13, 57.14, 62.57, 125.2, 133.7, 137.0, 143.0, 171.5, 205.6.
(240) MS (ESI): m/z (%)=377.0 (100) [M+H].sup.+.
Example 6-2: Preparation of (1S,5R,6R)-5-amino-10-((3,5-dichlorophenyl)sulfonyl)-3,10-diazabicyclo[4.3.1]decan-2-one H1.2
(241) ##STR00118##
(242) To a solution of H1.1 (10.0 mg, 2.65.Math.10.sup.5 mol) in THF (0.5 mL) was added ammonium trifluoroacetate (34.7 mg, 0.264 mmol, 10 equiv.) and NaBH(OAc).sub.3 (16.8 mg, 7.95.Math.10.sup.5 mol, 3.0 equiv.) and the solution was stirred for 10 h at room temperature. 1 M aq. NaOH (15 mL) was added, the aqueous phase was extracted with EtOAc (215 mL), dried over MgSO.sub.4, and the solvent evaporated under reduced pressure. Column chromatography on SiO.sub.2 (cyclohexane/EtOAc 1:2 to 0:1) afforded the title compound (10.0 mg, 2.65.Math.10.sup.5 mol, quant.) as a colorless solid.
(243) R.sub.f: 0.52 (EtOAc)
(244) .sup.1H-NMR (400 MHz, MeOH-d.sub.4): =1.32-1.52 (m, 3H, CH.sub.2, CH), 1.65-1.77 (m, 1H, CH), 2.02-2.12 (m, 1H, CH), 3.28 (dd, J=14.4, 8.0 Hz, 1H, CH.sub.A), 3.47 (dd, J=14.4, 3.6 Hz, 1H, CH.sub.B), 4.14 (m.sub.c, 1H, CH), 4.37 (m.sub.c, 1H, CH), 4.62-4.67 (m, 1H, CH), 7.78 (t, J=1.6 Hz, 1H, ArH), 7.89 (d, J=1.6 Hz, 2H, 2ArH).
(245) MS (ESI): m/z (%)=379.1 (100) [M+H].sup.+. 758.8 (82) [2M+H].sup.+.
Example 6-3: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-methoxy-3-methyl-3,10-diazabicyclo[4.3.1]decan-2-one H1.3
(246) ##STR00119##
(247) To a solution of G6 (40.0 mg, 0.105 mmol) in THF (1 mL) at 0 C. was added NaHMDS (1 M in THF, 126 L, 0.126 mmol, 1.2 equiv.). After 5 min MeI (7.2 L, 0.116 mmol, 1.1 equiv.) was added, the cooling bath was removed and the solution was stirred for 16 h at room temperature. Sat. aq. NH.sub.4Cl solution (20 mL) was added, the aqueous phase was extracted with EtOAc (220 mL), dried over MgSO.sub.4, and the solvent removed under reduced pressure. Column chromatography on SiO.sub.2 (cyclohexane/EtOAc 1:1.fwdarw.1:2) afforded the title compound (11.0 mg, 2.70.Math.10.sup.5 mol, 26%) as a colorless solid.
(248) R.sub.f: 0.34 (Cyclohexane/EtOAc 1:1)
(249) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.12-1.67 (m, 5H, 2CH.sub.2, CH), 2.19-2.26 (m, 1H, CH), 3.11 (s, 3H, NCH.sub.3), 3.15 (dd, J=13.6, 2.4 Hz, 1H, CH.sub.A), 3.43 (s, 3H, OCH.sub.3), 3.49 (ddd, J=10.4, 4.8, 2.4 Hz, 1H, CH), 3.97 (dd, J=13.6, 10.4 Hz, 1H, CH.sub.B), 4.08-4.13 (m, 1H, CH), 4.68 (m.sub.c, 1H, CH), 7.56 (t, J=2.0 Hz, 1H, ArH), 7.70 (t, J=2.0 Hz, 2H, 2ArH).
(250) .sup.13C-NMR (100 MHz, CDCl.sub.3): =16.34, 27.18, 27.50, 50.56, 56.92, 57.08, 58.39, 83.17, 125.3, 133.0, 136.6, 144.1, 170.1.
(251) MS (ESI): m/z (%)=407.0 (100) [M+H].sup.+, 814.7 (8) [2M+H].sup.+.
Example 6-4: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-hydroxy-3,10-diazabicyclo[4.3.1]decan-2-one H1.4
(252) ##STR00120##
(253) To a solution of H1.1 (60.0 mg, 0.159 mmol) in THF (3 mL) at 78 C. was added L-Selectride (1 M in THF, 191 L, 0.191 mmol, 1.2 equiv.) and the solution was stirred for 1 h at 78 C. The cooling bath was removed, H.sub.2O (1 mL) was added and the reaction was allowed to reach room temperature. Sat. aq. NH.sub.4Cl solution (20 mL) was added, the aqueous phase was extracted with EtOAc (220 mL), dried over MgSO.sub.4, and the solvent was evaporated under reduced pressure. Column chromatography on SiO.sub.2 (EtOAc) afforded the title compound (59.0 mg, 0.156 mmol, quant.) as a colorless solid.
(254) R.sub.f: 0.30 (EtOAc)
(255) .sup.1H-NMR (400 MHz, MeOH-d.sub.4): =1.21-1.52 (m, 5H, 2CH.sub.2, CH), 2.02-2.11 (m, 1H, CH), 3.28 (dd, J=14.4, 8.0 Hz, 1H, CH.sub.A), 3.47 (dd, J=14.4, 3.2 Hz, 1H, CH.sub.B), 4.12-4.17 (m, 1H, CH), 4.37 (m.sub.c, 1H, CH), 4.63-4.67 (m, 1H, CH), 7.79 (t, J=2.0 Hz, 1H, ArH), 7.86 (d, J=2.0 Hz, 2H, 2ArH).
(256) .sup.13C-NMR (100 MHz, MeOH-d.sub.4): =19.23, 22.80, 28.42, 46.74, 55.25, 58.59, 71.91, 126.5, 134.0, 137.7, 145.6, 178.1.
(257) MS (ESI): m/z (%)=379.1 (100) [M+H].sup.+, 758.7 (94) [2M+H].sup.+.
Example 6-5: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(2-methoxyethoxy)-3-(2-methoxyethyl)-3,10-diazabicyclo[4.3.1]decan-2-one H2.1
(258) ##STR00121##
(259) To a solution of G6 (10.0 mg, 2.64.Math.10.sup.5 mol) in DMF (0.25 mL), was added NaH (2.6 mg, 6.60.Math.10.sup.5 mol, 2.5 equiv.). After stirring for 5 min, 2-Bromoethyl methyl ether (5.40 L, 5.81.Math.10.sup.5 mol, 2.2 equiv.) was added and the suspension was stirred at 80 C. for 6 h. After cooling to room temperature, H.sub.2O (15 mL) was added and the aqueous phase was extracted with Et.sub.2O (215 mL), dried over MgSO.sub.4, and the solvent was evaporated under reduced pressure. Column chromatography on SiO.sub.2 (cyclohexane/EtOAc 1:1.fwdarw.1:2) afforded the title compound (3.0 mg, 6.06.Math.10.sup.6 mol, 23%) as colorless solid.
(260) R.sub.f: 0.26 (Cyclohexane/EtOAc 1:2)
(261) .sup.1H-NMR (600 MHz, CDCl.sub.3): =1.25-1.60 (m, 5H, CH, 2CH.sub.2), 2.22 (m.sub.c, 1H, CH), 3.25-3.30 (m, 1H, CH). 3.35 (s, 3H, OMe), 3.38 (s, 3H, OMe), 3.49-3.55 (m, 4H, 2CH.sub.2), 3.57-3.65 (m, 2H, CH.sub.2), 3.72-3.77 (m, 2H, CH.sub.2), 3.94 (dd, J=14.4, 10.2 Hz, 1H, CH), 4.01 (dt, J=14.4, 3.6 Hz, 1H, CH), 4.13 (m.sub.c, 1H, CH), 4.67 (m.sub.c, 1H, CH), 7.56 (t, J=1.8 Hz, 1H, ArH), 7.71 (d, J=1.8 Hz, 2H, 2ArH).
(262) MS (ESI): m/z (%)=495.23 (100) [M+H].sup.+, 990.32 (28) [2M+H].sup.+.
Example 6-6: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(methoxymethoxy)-3,10-diazabicyclo[4.3.1]decan-2-one H2.2
(263) ##STR00122##
(264) To a solution of G6 (25.0 mg, 6.59.Math.10.sup.5 mol) in DMF (0.5 mL) was added (iPr).sub.2NEt (138 L, 0.791 mmol, 12 equiv.) and MOMCl (50.0 L, 0.659 mmol, 10 equiv.) and it was stirred at 80 C. for 3 h. After cooling to room temperature, H.sub.2O (15 mL) was added and the aqueous phase was extracted with Et.sub.2O (215 mL), dried over MgSO.sub.4, and the solvent was evaporated under reduced pressure. Column chromatography on SiO.sub.2 (cyclohexane/EtOAc 1:1.fwdarw.1:2) afforded the title compound (11.0 mg, 2.60.Math.10.sup.5 mol, 39%) as colorless solid.
(265) R.sub.f: 0.10 (Cyclohexane/EtOAc 1:1)
(266) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.20-1.75 (m, 5H, 2CH.sub.2, CH), 2.15-2.22 (m, 1H, CH), 3.17 (ddd, J=13.6, 8.8, 2.8 Hz, 1H, CH.sub.A), 3.39 (s, 3H, OCH.sub.3), 3.68-3.76 (m, 1H, CH.sub.B), 3.85 (ddd, J=10.4, 4.8, 2.8 Hz, 1H, CH), 4.22 (m.sub.c, 1H, CH), 4.65 (d, J=7.2 Hz, CH.sub.A), 4.66 (m.sub.c, 1H, CH), 4.69 (d, J=7.2 Hz, CH.sub.B), 6.32 (d.sub.br, J=7.2 Hz, 1H, NH), 7.58 (d, J=2.0 Hz, 1H, ArH), 7.72 (d, J=2.0 Hz, 2H, 2ArH).
(267) .sup.13C-NMR (100 MHz, CDCl.sub.3): =16.19, 26.87, 27.26, 43.99, 56.00, 56.50, 57.85, 80.53, 96.69, 125.3, 133.1, 136.6, 144.0, 172.6.
(268) MS (ESI): m/z (%)=423.0 (100) [M+H].sup.+, 846.8 (94) [2M+H].sup.+.
Example 6-7: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(3,4-dimethoxyphenoxy)ethyl)-5-hydroxy-3,10-diazabicyclo[4.3.1]decan-2-one H2.3
(269) ##STR00123##
(270) To a solution of H2.2 (11.0 mg, 2.60.Math.10.sup.5 mol) in DMF (0.2 mL) was added NaH (1.6 mg, 3.9.Math.10.sup.5 mol, 1.5 equiv.). After stirring for 10 min at room temperature, 4-(2-Bromoethoxy)-1,2-dimethoxy benzene (7.50 mg, 2.86.Math.10.sup.5 mol, 1.1 equiv.) was added and it was stirred at 80 C. for 2 h. After cooling to room temperature, sat aq. NH.sub.4Cl solution (15 mL) was added and the aqueous phase was extracted with Et.sub.2O (215 mL), dried over MgSO.sub.4, and the solvent was evaporated under reduced pressure. Column chromatography on SiO.sub.2 (cyclohexane/EtOAc 2:1.fwdarw.1:1) afforded a colorless solid (6.0 mg, 9.94.Math.10.sup.6 mol, 38%).
(271) This solid was dissolved in EtOH (0.5 mL), conc. aq. HCl (0.1 mL) was added and it was stirred for 2 d at room temperature. Evaporation of the solvent under reduced pressure and column chromatography on SiO.sub.2 (cyclohexane/EtOAc 1:2) afforded the title compound (3.0 mg, 5.36.Math.10.sup.6 mol, 54%) as colorless solid.
(272) R.sub.f: 0.19 (Cyclohexane/EtOAc 1:1)
(273) .sup.1H-NMR (600 MHz, CDCl.sub.3): =1.27-1.67 (m, 5H, CH, 2CH.sub.2), 2.19-2.24 (m, 1H, CH), 3.47 (dd, J=13.8, 2.4 Hz, 1H, CH), 3.60-3.67 (m, 1H, CH), 3.84 (s, 3H, OMe), 3.86 (s, 3H, OMe), 4.01-4.09 (m, 4H, 2CH, CH.sub.2), 4.10-4.17 (m, 2H, CH.sub.2), 4.70 (m.sub.c, 1H, CH), 6.39 (dd, J=9.0, 2.4 Hz, 1H, ArH), 6.51 (d, J=2.4 Hz, 1H, ArH), 6.78 (d, J=9.0 Hz, 1H, ArH), 7.51-7.53 (m, 1H, ArH), 7.69-7.71 (m, 2H, 2ArH).
(274) MS (ESI): m/z (%)=559.0 (100) [M+H].sup.+.
(275) V. Preparation of Compounds J1-J19
(276) ##STR00124##
(277) ##STR00125##
Example 7-1: Preparation of 2-allylisoindoline-1,3-dione I1
(278) ##STR00126##
(279) To a solution of Phthalimide (15.0 g, 102 mmol) in DMF (100 mL) was added Allylbromide (12.3 g, 8.82 mL, 102 mmol). After 3 h stirring at room temperature EtO.sub.2 (300 mL) was added to the reaction and washed with sat. aq. NaCl solution (375 mL). The solvent was removed under reduced pressure affording the title compound (19.0 g, 101 mmol, 99.0%) as a colourless solid, which was used for the next step without further purification.
(280) R.sub.f: 0.43 (Cyclohexane/EtOAc=85:15)
(281) .sup.1H NMR (300 MHz, CDCl.sub.3) =4.29 (dt, J=5.7, 1.5 Hz, 2H), 5.15-5.31 (m, 2H), 5.79-5.97 (m, 1H), 7.68-7.76 (m, 2H), 7.80-7.89 (m, 2H).
(282) .sup.13C-NMR (75.5 MHz, CDCl.sub.3) =40.03, 117.72, 123.27, 131.50, 132.10, 133.94, 167.88.
Example 7-2: Preparation of 2-(4-(trimethylsilyl)but-2-en-1-yl)isoindoline-1,3-dione I2
(283) ##STR00127##
(284) To a solution of 2-allylisoindoline-1,3-dione I1 (13.0 g, 69.4 mmol) in CH.sub.2Cl.sub.2 (500 mL) was added AllylTMS (79.0 g, 110 mL, 694 mmol) and Grubbs I generation catalyst. The reaction was heated to 60 C. and stirred under reflux for 4 h. Tris(hydroxymethyl)phosphine (1 M solution in i-PrOH, 58 mL) was added and stirred under reflux for 12 h, while the color of the reaction turned from black to orange. Sat. aq. NaCl solution (100 mL) was added to the reaction and the organic phase was separated. The aqueous phase was extracted with CH.sub.2Cl.sub.2 (3200 mL). The combined organic layers were dried over MgSO.sub.4 and the solvent was removed under reduced pressure. Column chromatography over SiO.sub.2 (Cyclohexane/EtOAc=85:15) afforded the title compound (15.0 g, 54.9 mmol, 78.9%) as a yellow resin.
(285) R.sub.f: 0.57 (Cyclohexane/EtOAc=85:15)
(286) .sup.1H NMR (300 MHz, CDCl.sub.3) =0.10-0.09 (m, 9H), 1.44 (d, J=8.2 Hz, 1.6H), 1.72 (d, J=8.8 Hz, 0.4H), 4.21 (d, J=6.5 Hz, 1.6H), 4.29 (dd, J=14.5, 5.9 Hz, 0.4H), 5.26-5.47 (m, 0.8H), 5.56-5.70 (m, 0.2H), 5.70-5.87 (m, 0.8H), 5.94-6.09 (m, 0.2H), 7.65-7.74 (m, 2H), 7.79-7.88 (m, 2H).
(287) .sup.13C NMR (75 MHz, cdcl.sub.3) =2.05, 1.83, 1.43, 18.92, 22.73, 34.72, 39.87, 120.51, 121.30, 123.12, 130.78, 132.24, 133.76, 133.90, 167.99.
Example 7-3: Preparation of 4-(trimethylsilyl)but-2-en-1-amine I3
(288) ##STR00128##
(289) To a solution of 2-(4-(trimethylsilyl)but-2-en-1-yl)isoindoline-1,3-dione I2 (150 mg, 0.549 mmol) in MeOH (5 mL) was added Hydrazine (35.2 mg, 0.034 mL, 1.10 mmol) and the reaction was heated to 75 C. and stirred under reflux for 24 h. CH.sub.2Cl.sub.2 (90 mL) was added to the solution and washed with NaOH (1 M solution, 310 mL). The organic layer was dried over MgSO.sub.4 and the solvent was removed under reduced pressure (at room temperature at 150 mbar) affording the title compound as a colourless liquid, which was stored at 20 C.
(290) R.sub.f: 0.24 (EtOAc+2% MeOH+2% TEA)
(291) .sup.1H NMR (300 MHz, CDCl.sub.3) =0.04-0.03 (m, 9H), 1.40-1.50 (m, 2H), 1.69 (s, 2H), 3.14-3.34 (m, 2H), 5.30-5.61 (m, 2H).
(292) .sup.13C NMR (75 MHz, CDCl.sub.3) =2.02, 22.50, 44.36, 127.19, 129.72
Example 7-4: Preparation of N-(4-methoxybenzyl)-4-(trimethylsilyl)but-2-en-1-amine I4
(293) ##STR00129##
(294) To a solution of 4-(trimethylsilyl)but-2-en-1-amine I3 (7.86 g, 54.8 mmol) in EtOH (250 mL) was added 4-methoxybenzaldehyde (7.47 g, 54.8 mL, 1.10 mmol). After 2 h stirring at room temperature NaBH.sub.4 (3.11 g, 82 mmol) was added to the solution, which was stirred until no more gas evolution was observed. NaOH (1 M solution, 100 mL). was added to the reaction and extracted with CH.sub.2Cl.sub.2 (300 mL). The organic layer was dried over MgSO.sub.4 and the solvent was removed under reduced pressure. Column chromatography (EtOAc+2% MeOH+2% TEA) afforded the title compound (11.2 g, 42.5 mmol, 77.6% over 2 steps) as a slightly yellow oil.
(295) R.sub.f: 0.35 (EtOAc+2% MeOH+2% TEA)
(296) MS (ESI): m/z (%)=263.98 [M+H].sup.+, 526.24 [2M+H].sup.+
Example 7-5: Preparation of (S)N-(4-methoxybenzyl)-6-oxo-N-(4-(trimethylsilyl)but-2-en-1-yl)piperidine-2-carboxamide 15.1 and (S)-tert-butyl 2-((4-methoxybenzyl)(4-(trimethylsilyl)but-2-en-1-yl)carbamoyl)-6-oxopiperidine-1-carboxylate I5.2
(297) ##STR00130##
(298) To a solution of (S)-6-oxopiperidine-2-carboxylic acid (1.74 g, 12.15 mmol) in DMF (120 mL) were added N-(4-methoxybenzyl)-4-(trimethylsilyl)but-2-en-1-amine I4 (3.20 g, 12.2 mmol), EDC (2.79 g, 14.6 mmol) and HOBt (2.23 g, 14.6 mmol). After 2 h stirring at room temperature EtO.sub.2 (300 mL) was added to the reaction and washed with sat. aq. NaCl solution (375 mL). The organic layer was dried over MgSO.sub.4 and the solvent was removed under reduced pressure and the crude compound I5.1 was used for the next step without further purification.
(299) MS (ESI): m/z (%)=389.29 [M+H].sup.+, 777.25 [2M+H].sup.+
(300) ##STR00131##
(301) Crude compound I5.1 was dissolved in CH.sub.2Cl.sub.2 (120 mL). DIPEA (3.14 g, 4.24 mL, 24.2 mmol), Boc.sub.2O (7.95 g, 36.4 mmol) and DMAP (1.48 g, 12.2 mmol) were added. After 24 h stirring at room temperature sat. aq. NaCl solution (25 mL) was added to the reaction and the organic phase was separated. The aqueous phase was extracted with CH.sub.2Cl.sub.2 (3100 mL) and the combined organic layers were dried over MgSO.sub.4 and the solvent was removed under reduced pressure. Flash column chromatography (10-30% EtOAc in Cyclohexane) afforded the compound I5.2 (3.50 g, 7.16 mmol, 59% over two steps) as a yellow resin.
(302) R.sub.f: 0.14 (Cyclohexane/EtOAc=1:1)
(303) MS (ESI): m/z (%)=389.15 [M+H-Boc].sup.+, 999.09 [2M+H].sup.+
Example 7-6: Preparation of (1S,5R,6R)-3-(4-methoxybenzyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one I6
(304) ##STR00132##
(305) A solution of (6S)-tert-butyl 2-hydroxy-6-((4-methoxybenzyl)((Z)-4-(trimethylsilyl)but-2-en-1-yl)carbamoyl)piperidine-1-carboxylate (3.5 mg, 7.16 mmol) in THF (75 mL) was cooled to 78 C. and then DIBAL-H (1 M solution in CH.sub.2Cl.sub.2, 10.7 mL, 10.7 mmol) was added. After 15 minutes an excess of Glauber's salt (Na.sub.2SO.sub.4 10H.sub.2O) was added to the reaction. The solution was allowed to warm to room temperature and more Glaubers salt was added and stirred for 15 minutes. The solution was filtered through celite and the solvent was removed under reduced pressure, affording a yellow resin.
(306) The resin resulted from the first step was dissolved in CH.sub.2Cl.sub.2 (300 mL) in a teflon flask and cooled to 78 C. HF (70% in pyridine, 15 mL) was added and the reaction flask was putted in an ice bath at 0 C. After one hour sat. aq. CaCO.sub.3 solution and NaOH (10 M solution) was added to the solution to neutralize the acid and precipitate the fluoride ions as CaF.sub.2. The reaction was extracted three times with CH.sub.2Cl.sub.2, the combined organic layers were dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography (5% MeOH and 2% TEA in EtOAc) afforded the title compound (1.30 g, 4.33 mmol, 60.6% over two steps) as an orange resin.
(307) .sup.1H NMR (400 MHz, Chloroform-d) =1.39-1.55 (m, 2H), 1.60-1.65 (m, 3H), 2.29-2.36 (m, 1H), 2.40-2.50 (m, 1H), 2.76-2.81 (m, 1H), 2.91 (dd, J=13.8, 2.0 Hz, 1H), 3.79 (s, 3H), 3.81-3.85 (m, 1H), 3.89 (dd, J=13.8, 10.8 Hz, 1H), 4.44 (d, J=14.3 Hz, 1H), 4.73 (d, J=14.3 Hz, 1H), 4.77-4.91 (m, 2H), 5.54 (ddd, J=17.0, 10.2, 8.4 Hz, 1H), 6.83-6.88 (m, 2H), 7.19-7.25 (m, 2H).
Example 7-7: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(4-methoxybenzyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one I7
(308) ##STR00133##
(309) To a solution of (1S,5R,6R)-3-(4-methoxybenzyl)-5-vinyl-3, 10-diazabicyclo[4.3.1]decan-2-one (650 mg, 2.16 mmol) in CH.sub.2Cl.sub.2 (20 mL) were added 3,5-dichlorobenzene-1-sulfonyl chloride (1.06 g, 4.33 mmol), DMAP (264 mg, 2.16 mmol) and DIPEA (1.13 mL, 6.49 mmol) and the reaction was stirred for 16 hours at room temperature. Sat. aq. NaHCO.sub.3 solution (25 mL) was added to the mixture and extracted with CH.sub.2Cl.sub.2 (250 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Flash column chromatography on SiO.sub.2 (5-30% EtOAc in Cyclohexane) afforded the title compound (680 mg, 1.33 mmol, 61.7%) as a colorless solid.
(310) .sup.1H NMR (400 MHz, CDCl.sub.3) =1.26 (d, J=7.1 Hz, 2H), 1.46-1.55 (m, 3H), 2.28-2.41 (m, 2H), 2.91 (dd, J=14.3, 1.9 Hz, 1H), 3.80 (s, 3H), 3.90 (dd, J=14.4, 10.9 Hz, 1H), 3.94-3.98 (m, 1H), 4.38 (d, J=14.4 Hz, 1H), 4.77 (dd, J=4.2, 1.8 Hz, 1H), 4.79-4.90 (m, 2H), 5.00 (dd, J=10.1, 1.3 Hz, 1H), 5.66 (ddd, J=17.0, 10.1, 8.9 Hz, 1H), 6.86 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 7.54-7.57 (m, 1H), 7.69-7.72 (m, 2H).
Example 7-8: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one I8
(311) ##STR00134##
(312) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(4-methoxybenzyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (25.0 mg, 0.0491 mmol) in MeCN/H.sub.2O (1.5 mL, 2:1) was added CAN (81.0 mg, 0.147 mmol). After 4 h stirring at room temperature sat. aq. NaCl solution (10 mL) was added to the mixture and extracted with CH.sub.2Cl.sub.2 (90 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Flash column chromatography on SiO.sub.2 (10-40% EtOAc in Cyclohexane) afforded the title compound (17 mg, 0.0437 mmol, 89.0%) as a colorless solid.
(313) .sup.1H NMR (300 MHz, CDCl.sub.3) =1.29-1.36 (m, 2H), 1.54-1.64 (m, 3H), 2.23 (d, J=13.0 Hz, 2H), 2.68 (d, J=7.8 Hz, 1H), 2.90 (d, J=12.5 Hz, 1H), 3.69-3.85 (m, 1H), 4.04 (s, 1H), 4.66 (d, J=5.1 Hz, 1H), 5.06-5.21 (m, 2H), 5.72-5.87 (m, 1H), 7.57 (t, J=1.8 Hz, 1H), 7.70 (d, J=1.8 Hz, 2H).
(314) .sup.13C NMR (75 MHz, CDCl.sub.3) =15.36, 26.48, 26.89, 26.96, 29.67, 45.07, 50.09, 55.47, 117.07, 124.89, 132.75, 136.37, 136.96, 143.97.
Example 7.9
Preparation of (1S,5R,6R)-3-(3-(benzyloxy)propyl)-10-((3,5-dichlorophenyl)sulfonyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one J1
(315) ##STR00135##
(316) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-vinyl-3,10 diazabicyclo [4.3.1] decan-2-one (35.0 mg, 0.0899 mmol) in DMF (1.0 mL) was added NaH (5.39 mg, 0.135 mmol). After 20 minutes ((3-bromopropoxy)methyl)benzene (20.6 mg, 0.0899 mmol) was added, the solution was heated to 80 C. and stirred for 1 h. Et.sub.2O (90 mL) was added to the solution and washed with sat. aq. NaCl solution (310 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography on SiO.sub.2 (Cyclohexane/EtOAc=1:1) afforded the title compound (31.0 mg, 0.0577 mmol, 64.2%) as a colorless solid.
(317) R.sub.f 0.25 (Cyclohexane/EtOAc=7:3)
(318) .sup.1H NMR (600 MHz, CDCl.sub.3) =1.28 (s, 2H), 1.47-1.54 (m, 3H), 1.83-1.92 (m, 2H), 2.23-2.29 (m, 1H), 2.58-2.64 (m, 1H), 2.95-3.00 (m, 1H), 3.49-3.59 (m, 4H), 3.95-4.04 (m, 2H), 4.50 (s, 2H), 4.65 (d, J=6.2 Hz, 1H), 5.09-5.15 (m, 2H), 5.74-5.82 (m, 1H), 7.28 (s, 1H), 7.33 (d, J=1.3 Hz, 4H), 7.56 (s, 1H), 7.69 (d, J=1.8 Hz, 2H).
(319) .sup.13C NMR (150 MHz, CDCl.sub.3) =15.42, 26.29, 26.89, 27.36, 28.14, 29.68, 49.16, 49.53, 51.85, 54.83, 56.84, 67.64, 73.08, 116.8, 124.9, 127.6, 127.7, 128.4, 132.6, 136.3, 137.2, 138.2, 144.1, 169.7.
Example 7.10
Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(3-methoxypropyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one J2
(320) ##STR00136##
(321) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-vinyl-3,10-diazabicyclo [4.3.1]decan-2-one (35.0 mg, 0.0899 mmol) in DMF (1.0 mL) was added NaH (5.39 mg, 0.135 mmol). After 20 minutes 1-bromo-4-methoxypropane (13.8 mg, 0.0102 mL, 0.0899 mmol) was added, the solution was heated to 80 C. and stirred for 1 h. Et.sub.2O (90 mL) was added to the solution and washed with sat. aq. NaCl solution (310 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography on SiO.sub.2 (Cyclohexane/EtOAc=3:7) afforded the title compound (20.0 mg, 0.0433 mmol, 48.2%) as a colorless solid.
(322) R.sub.f: 0.57 (Cyclohexane/EtOAc=1:1)
(323) .sup.1H NMR (600 MHz, CDCl.sub.3) =1.27-1.34 (m, 2H), 1.50-1.56 (m, 3H), 1.83 (q, J=6.9 Hz, 2H), 2.26 (d, J=13.4 Hz, 1H), 2.63 (qd, J=8.3, 4.1 Hz, 1H), 2.94-3.00 (m, 1H), 3.33 (s, 3H), 3.41 (t, J=6.2 Hz, 2H), 3.47-3.59 (m, 2H), 3.96-4.04 (m, 2H), 4.65 (d, J=5.7 Hz, 1H), 5.11 (s, 1H), 5.14 (d, J=6.0 Hz, 1H), 5.79 (dt, J=16.7, 9.4 Hz, 1H), 7.56 (s, 1H), 7.69 (s, 2H).
(324) .sup.13C NMR (150 MHz, CDCl.sub.3) =15.42, 26.29, 27.36, 28.03, 49.21, 49.53, 51.88, 54.83, 56.84, 58.68, 70.04, 116.8, 124.9, 132.6, 136.3, 137.3, 144.1, 169.7.
Example 7.11
Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(4-methoxybutyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one J3
(325) ##STR00137##
(326) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-vinyl-3,10-diazabicyclo [4.3.1] decan-2-one (35.0 mg, 0.0899 mmol) in DMF (1.0 mL) was added NaH (5.39 mg, 0.135 mmol). After 20 minutes 1-bromo-4-methoxybutane (15.0 mg, 0.0118 mL, 0.0899 mmol) was added, the solution was heated to 80 C. and stirred for 1 h. Et.sub.2O (90 mL) was added to the solution and washed with sat. aq. NaCl solution (310 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography on SiO.sub.2 (Cyclohexane/EtOAc=3:7) afforded the title compound (27.8 mg, 0.0584 mmol, 65.1%) as a colorless solid.
(327) R.sub.f: 0.16 (Cyclohexane/EtOAc=1:1)
(328) .sup.1H NMR (600 MHz, CDCl.sub.3) =1.24-1.26 (m, 2H), 1.51-1.55 (m, 3H), 1.55-1.64 (m, 4H), 2.26 (dt, J=14.3, 2.4 Hz, 1H), 2.59-2.65 (m, 1H), 2.90-2.95 (m, 1H), 3.33 (d, J=1.0 Hz, 3H), 3.38-3.42 (m, 2H), 3.42-3.50 (m, 2H), 3.96-4.02 (m, 2H), 4.66 (dt, J=5.8, 1.9 Hz, 1H), 5.11-5.16 (m, 2H), 5.76-5.84 (m, 1H), 7.55-7.57 (m, 1H), 7.68-7.69 (m, 2H).
(329) .sup.13C NMR (150 MHz, CDCl.sub.3) =15.45, 24.43, 26.31, 26.78, 27.39, 29.67, 49.55, 51.18, 51.43, 54.83, 56.86, 58.53, 72.20, 116.8, 124.9, 132.6, 136.3, 137.3, 144.1, 169.6.
Example 7.12
Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one J4
(330) ##STR00138##
(331) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-vinyl-3,10 diazabicyclo [4.3.1] decan-2-one (35.0 mg, 0.0899 mmol) in DMF (1.0 mL) was added NaH (5.39 mg, 0.135 mmol). At the same time 2-(bromomethyl)pyridine-hydrobromide (22.7 mg, 0.0899 mmo) in DMF (1 mL) was neutralized with NaH (2.16 mg, 0.0899 mmol). After 20 minutes the solution were united and heated to 80 C. and stirred for 1 h. Et.sub.2O (90 mL) was added to the solution and washed with sat. aq. NaCl solution (310 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography on SiO.sub.2 (Cyclohexane/EtOAc=1:1) afforded the title compound (43 mg, 0.0899 mmol, 100%) as a colorless solid.
(332) R.sub.f: 0.2 (Cyclohexane/EtOAc=1:1)
(333) .sup.1H NMR (600 MHz, CDCl.sub.3) =1.30-1.39 (m, 2H), 1.52-1.63 (m, 3H), 2.26-2.33 (m, 1H), 2.73 (q, J=8.3, 7.9 Hz, 1H), 3.14 (dd, J=14.3, 2.0 Hz, 1H), 4.00-4.06 (m, 2H), 4.74 (dt, J=6.1, 1.7 Hz, 1H), 4.86 (d, J=15.4 Hz, 1H), 4.90-4.98 (m, 1H), 4.98-5.08 (m, 2H), 5.72 (dddd, J=17.0, 10.0, 8.8, 1.2 Hz, 1H), 7.29 (t, J=6.3 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.57 (td, J=1.8, 1.0 Hz, 1H), 7.70 (dd, J=1.9, 1.0 Hz, 2H), 7.79 (t, J=7.7 Hz, 1H), 8.49-8.61 (m, 1H).
(334) .sup.13C NMR (150 MHz, CDCl.sub.3) =15.46, 26.39, 27.49, 29.67, 49.06, 52.20, 54.89, 55.51, 56.85, 117.02, 122.55, 122.85, 124.84, 132.72, 136.34, 136.93, 143.95, 156.31, 170.56.
Example 7.13: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(hydroxymethyl)-3-(3-hydroxypropyl)-3,10-diazabicyclo[4.3.1]decan-2-one J5
(335) ##STR00139##
(336) To a solution of (1S,5R,6R)-3-(3-(benzyloxy)propyl)-10-((3,5-dichlorophenyl)sulfonyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (31 mg, 0.0576 mmol) in Dioxane/H.sub.2O (0.8 mL, 3:1) was added NaIO.sub.4 (52.3 mg, 0.245 mmol), OsO.sub.4 (2.5% Solution in tert-Butanol, 0.00122 mmol, 0.015 mL) and 2,6-Lutidine (0.014 mL, 0.122 mmol). The solution was stirred for 18 h at room temperature, then Et.sub.2O (90 mL) was added to the reaction and washed with sat. aq. NaCl solution (310 mL). The obtained crude product was dissolved in EtOH (1 mL) and NaBH.sub.4 (3.47 mg, 0.0917 mmol) was added and stirred for 1 h at room temperature. Et.sub.2O (90 mL) was added to the reaction and washed with sat. aq. NaCl solution (310 mL). The solvent was removed under reduced pressure and the crude mixture was dissolved in CH.sub.2Cl.sub.2 (0.5 mL). BCl.sub.3 SMe.sub.2 (2
(337) .sup.1H NMR (600 MHz, CDCl.sub.3) =1.36-1.42 (m, 2H), 1.52-1.58 (m, 3H), 1.71-1.80 (m, 2H), 2.19-2.29 (m, 2H), 2.52-2.61 (m, 2H), 3.20-3.24 (m, 1H), 3.49-3.55 (m, 2H), 3.56-3.64 (m, 3H), 3.73 (s, 1H), 3.84 (dd, J=14.3, 10.7 Hz, 1H), 3.88-3.92 (m, 1H), 4.71 (d, J=6.1 Hz, 1H), 7.57 (s, 1H), 7.69 (d, J=1.9 Hz, 2H).
(338) MS (ESI): m/z (%)=451.14 [M+H].sup.+
Example 7.14: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(hydroxymethyl)-3-(3-methoxypropyl)-3,10-diazabicyclo[4.3.1]decan-2-one J6
(339) ##STR00140##
(340) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(3-methoxypropyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (14 mg, 0.0299 mmol) in Dioxane/H.sub.2O (0.4 mL, 3:1) was added NaIO.sub.4 (26.0 mg, 0.121 mmol), OsO.sub.4 (2.5% Solution in tert-Butanol, 0.00607 mmol, 0.00761 mL) and 2,6-Lutidine (0.00707 mL, 0.061 mmol). The solution was stirred for 24 h at room temperature, then Et.sub.2O (90 mL) was added to the reaction and washed with sat. aq. NaCl solution (310 mL). The obtained crude product was dissolved in EtOH (1 mL) and NaBH.sub.4 (1.72 mg, 0.046 mmol) was added and stirred for 1 h at room temperature. Et.sub.2O (90 mL) was added to the reaction and washed with sat. aq. NaCl solution (310 mL). The solvent was removed under reduced pressure and flash column chromatography over SiO.sub.2 (50-70% EtOAc in Cyclohexane) afforded the title compound (13.0 mg, 0.0279 mmol, 93%) as a colorless solid.
(341) R.sub.f: 0.18 (Cyclohexane/EtOAc=1:4)
(342) MS (ESI): m/z (%)=465.14 [M+H].sup.+
Example 7.15: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(hydroxymethyl)-3-(4-methoxybutyl)-3,10-diazabicyclo[4.3.1]decan-2-one J7
(343) ##STR00141##
(344) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(4-methoxybutyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (24 mg, 0.0499 mmol) in Dioxane/H.sub.2O (0.8 mL, 3:1) was added NaIO.sub.4 (43.2 mg, 0.202 mmol), OsO.sub.4 (2.5% Solution in tert-Butanol, 0.0101 mmol, 0.013 mL) and 2,6-Lutidine (0.012 mL, 0.101 mmol). The solution was stirred for 24 h at room temperature, then Et.sub.2O (90 mL) was added to the reaction and washed with sat. aq. NaCl solution (310 mL). The obtained crude product was dissolved in EtOH (1 mL) and NaBH.sub.4 (2.86 mg, 0.076 mmol) was added and stirred for 1 h at room temperature. Et.sub.2O (90 mL) was added to the reaction and washed with sat. aq. NaCl solution (310 mL). The solvent was removed under reduced pressure and flash column chromatography over SiO.sub.2 (50-90% EtOAc in Cyclohexane) afforded the title compound (17.5 mg, 0.0365 mmol, 73.0%) as a colorless solid.
(345) R.sub.f: 0.18 (Cyclohexane/EtOAc=1:4)
(346) MS (ESI): m/z (%)=479.22 [M+H].sup.+
Example 7-16: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(hydroxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one J8
(347) ##STR00142##
(348) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (43 mg, 0.0891 mmol) in Dioxane/H.sub.2O (0.8 mL, 3:1) was added NaIO.sub.4 (76 mg, 0.357 mmol), OsO.sub.4 (2.5% Solution in tert-Butanol, 0.00178 mmol, 0.022 mL) and 2,6-Lutidine (0.021 mL, 0.178 mmol). The solution was stirred for 24 h at room temperature, then Et.sub.2O (90 mL) was added to the reaction and washed with sat. aq. NaCl solution (310 mL). The obtained crude product was dissolved in EtOH (1 mL) and NaBH.sub.4 (5.00 mg, 0.132 mmol) was added and stirred for 1 h at room temperature. Et.sub.2O (90 mL) was added to the reaction and washed with sat. aq. NaCl solution (310 mL). Flash column chromatography over SiO.sub.2 (30-70% EtOAc in Cyclohexane) afforded the title compound (16 mg, 0.0330 mmol, 37.1%) as a colorless solid.
(349) .sup.1H NMR (600 MHz, CDCl.sub.3) =1.24-1.30 (m, 2H), 1.49-1.58 (m, 3H), 2.25-2.33 (m, 2H), 3.48-3.56 (m, 3H), 3.86 (dd, J=14.4, 10.6 Hz, 1H), 3.92-3.96 (m, 1H), 4.74-4.77 (m, 1H), 4.87 (d, J=7.9 Hz, 2H), 7.29-7.34 (m, 1H), 7.45 (s, 1H), 7.56 (s, 1H), 7.70 (s, 2H), 7.78-7.83 (m, 1H), 8.54 (dt, J=5.2, 0.9 Hz, 1H).
(350) .sup.13C NMR (150 MHz, CDCl.sub.3) =15.51, 27.80, 27.82, 46.93, 49.67, 52.32, 55.22, 57.01, 63.25, 123.10, 123.22, 124.87, 132.71, 136.31, 138.63, 143.91, 147.63, 156.12, 170.54.
Example 7-17: Preparation of ethyl 2-((1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-2-oxo-5-vinyl-3,10-diazabicyclo[4.3.1]decan-3-yl)acetate J9
(351) ##STR00143##
(352) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-vinyl-3,10-diazabicyclo [4.3.1] decan-2-one I8 (120 mg, 0.308 mmol) in DMF (3.0 mL) was added NaH (14.8 mg, 0.370 mmol). After 20 minutes ethyl 2-bromoacetate (51.5 mg, 0.308 mmol) was, added, the solution was heated to 80 C. and stirred for 1 h. Et.sub.2O (90 mL) was added to the solution and washed with sat. aq. NaCl solution (310 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography on SiO.sub.2 (Cyclohexane/EtOAc=8:2) afforded the title compound (78.0 mg, 0.164 mmol, 53.3%) as a colorless solid.
(353) R.sub.f: 0.71 (Cyclohexane/EtOAc=1:1)
(354) .sup.1H NMR (600 MHz, CDCl.sub.3) =1.19-1.26 (m, 3H), 1.57 (d, J=13.2 Hz, 4H), 1.70-1.81 (m, 1H), 2.27 (dd, J=13.6, 3.2 Hz, 1H), 2.88 (dd, J=14.1, 2.0 Hz, 1H), 3.09-3.16 (m, 1H), 3.65 (d, J=17.4 Hz, 1H), 3.99 (t, J=5.8 Hz, 1H), 4.15-4.24 (m, 3H), 4.73 (d, J=17.5 Hz, 2H), 5.11-5.19 (m, 2H), 5.78 (ddd, J=16.9, 10.0, 8.8 Hz, 1H), 7.57 (s, 1H), 7.70 (dt, J=1.8, 0.7 Hz, 2H).
(355) MS (ESI): m/z (%)=475.03 [M+H].sup.+
Example 7-18: Preparation of 2-((1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-2-oxo-5-vinyl-3,10-diazabicyclo[4.3.1]decan-3-yl)acetic acid J10
(356) ##STR00144##
(357) To a solution of ethyl 2-((1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-2-oxo-5-vinyl-3,10-diazabicyclo[4.3.1]decan-3-yl)acetate J9 (70.0 mg, 0.147 mmol) in THF/H.sub.2O (1.5 mL, 2:1) was added aq. NaOH (10 M aq. sol., 0.147 mL). After 20 h the solution was diluted with CH.sub.2Cl.sub.2 (100 mL) and washed with aq. HCl (1 M, 15 mL). The organic phase was dried with MgSO.sub.4 and solvent was removed under reduced pressure affording the title compound (65.0 mg, 0.145 mmol, 98.6%) as a white solid.
(358) .sup.1H NMR (600 MHz, CDCl.sub.3) =1.18-1.36 (m, 3H), 1.49-1.60 (m, 1H), 1.63-1.76 (m, 1H), 2.21-2.32 (m, 1H), 2.91 (dd, J=14.0, 2.0 Hz, 1H), 2.98-3.12 (m, 1H), 3.77 (d, J=17.6 Hz, 1H), 3.95-4.07 (m, 1H), 4.16 (dd, J=14.1, 10.7 Hz, 1H), 4.65-4.76 (m, 2H), 5.09-5.19 (m, 2H), 5.77 (ddd, J=17.0, 10.1, 8.8 Hz, 1H), 7.57 (t, J=1.8 Hz, 1H), 7.70 (d, J=1.8 Hz, 2H).
(359) .sup.13C NMR (150 MHz, CDCl.sub.3) =15.38, 26.23, 27.49, 48.55, 53.17, 53.71, 54.95, 56.68, 117.28, 124.90, 132.78, 136.38, 137.01, 143.91, 171.50, 173.11.
(360) MS (ESI): m/z (%)=447.02 [M+H].sup.+
Example 7-19: Preparation of 2-((1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-2-oxo-5-vinyl-3,10-diazabicyclo[4.3.1]decan-3-yl)acetamide J11
(361) ##STR00145##
(362) To a solution of 2-((1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-2-oxo-5-vinyl-3,10-diazabicyclo[4.3.1]decan-3-yl)acetic acid J10 (57 mg, 0.127 mmol) in EtOAc (1 mL) was added CDI (31.0 mg, 0.191 mmol). After 30 min aq. NH.sub.3 (7 M, 364 mL, 2.55 mmol) was added. After 1 h sat. aq. NH.sub.4Cl solution (15 mL) was added to the solution and extracted with EtOAc (100 mL). The organic phase was dried over MgSO.sub.4 and the solvent was removed under reduced pressure. Column chromatography on SiO.sub.2 (Cyclohexane/EtOAc=3:7) afforded the title compound (43.7 mg, 0.0979 mmol, 77.1%) as a colorless wax.
(363) .sup.1H NMR (600 MHz, CDCl.sub.3) =1.32-1.42 (m, 2H), 1.52-1.58 (m, 1H), 1.60-1.68 (m, 2H), 2.23-2.29 (m, 1H), 2.94-3.00 (m, 1H), 3.05 (dd, J=14.3, 2.0 Hz, 1H), 4.05 (td, J=6.1, 4.9, 2.0 Hz, 1H), 4.08-4.19 (m, 3H), 4.61 (dt, J=6.1, 1.9 Hz, 1H), 5.13-5.21 (m, 2H), 5.52 (s, 1H), 5.78 (ddd, J=17.0, 10.1, 8.8 Hz, 1H), 6.22 (s, 1H), 7.58 (t, J=1.8 Hz, 1H), 7.69 (d, J=1.8 Hz, 2H).
(364) .sup.13C NMR (150 MHz, CDCl.sub.3) =15.38, 26.30, 27.21, 48.47, 53.75, 54.98, 55.18, 56.62, 117.52, 124.88, 132.90, 136.40, 136.65, 143.64, 170.68, 171.40.
(365) MS (ESI): m/z (%)=445.82 [M+H].sup.+
Example 7-20: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(prop-2-yn-1-yl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one J12
(366) ##STR00146##
(367) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-vinyl-3,10-diazabicyclo [4.3.1] decan-2-one I8 (50.0 mg, 0.128 mmol) in DMF (1.0 mL) was added NaH (5.65 mg, 0.128 mmol). After 20 minutes propargylbromide (19.1 mg, 0.014 mL 0.128 mmol) was added, the solution was heated to 80 C. and stirred for 1 h. Et.sub.2O (90 mL) was added to the solution and washed with sat. aq. NaCl solution (310 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography on SiO.sub.2 (Cyclohexane/EtOAc=7:3) afforded the title compound (44.0 mg, 0.103 mmol, 80.4%) as a colorless solid.
(368) R.sub.f: 0.61 (Cyclohexane/EtOAc=3:2)
(369) .sup.1H NMR (600 MHz, CDCl.sub.3) =1.26-1.34 (m, 3H), 1.53-1.57 (m, 2H), 2.22 (tt, J=2.5, 0.7 Hz, 1H), 2.26-2.32 (m, 1H), 2.68-2.75 (m, 1H), 3.18-3.23 (m, 1H), 3.91 (ddt, J=17.2, 2.9, 0.8 Hz, 1H), 3.97-4.03 (m, 2H), 4.66 (ddd, J=17.2, 2.4, 1.0 Hz, 1H), 4.70-4.73 (m, 1H), 5.13-5.19 (m, 2H), 5.82 (dddd, J=17.1, 10.0, 8.8, 1.0 Hz, 1H), 7.57 (dq, J=1.9, 1.0 Hz, 1H), 7.69 (dt, J=1.9, 0.7 Hz, 2H).
(370) .sup.13C NMR (150 MHz, CDCl.sub.3) =15.41, 26.21, 26.90, 27.52, 39.32, 49.32, 50.86, 54.92, 56.86, 71.69, 117.14, 124.88, 132.73, 136.36, 137.03, 143.97, 169.93.
(371) MS (ESI): m/z (%)=427.09 [M+H].sup.+
Example 7-21: Preparation of (1S,5R,6R)-3-((1H-1,2,3-triazol-4-yl)methyl)-10-((3,5-dichlorophenyl)sulfonyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one J13
(372) ##STR00147##
(373) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(prop-2-yn-1-yl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one J12 (25.0 mg, 0.0590 mmol) in DMF/MeOH (0.55 mL, 9:1) were added TMS-azide (10.1 mg, 0.012 mL, 0.0880 mmol) and CuI (0.557 mg, 2.93 mol). After 8 h Et.sub.2O (90 mL) was added to the solution and washed with sat. aq. NaHCO.sub.3 solution (310 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography on SiO.sub.2 (Cyclohexane/EtOAc=6:4) afforded the title compound (14.5 mg, 0.0308 mmol, 52.2%) as a colorless solid.
(374) R.sub.f 0.6 (EtOAc)
(375) .sup.1H NMR (600 MHz, CDCl.sub.3) =1.28-1.40 (m, 3H), 1.44-1.48 (m, 1H), 1.55-1.61 (m, 1H), 2.26 (d, J=13.9 Hz, 1H), 2.53 (q, J=9.2 Hz, 1H), 3.21 (d, J=14.2 Hz, 1H), 3.58-3.75 (m, 2H), 3.98 (q, J=7.0, 6.0 Hz, 1H), 4.07 (dd, J=14.7, 10.5 Hz, 1H), 4.66-4.74 (m, 2H), 5.03-5.11 (m, 2H), 5.74 (dt, J=17.9, 9.3 Hz, 1H), 7.57 (q, J=1.6 Hz, 1H), 7.69 (t, J=1.4 Hz, 2H), 7.90 (d, J=32.0 Hz, 1H).
(376) .sup.13C NMR (150 MHz, CDCl.sub.3) =15.40, 22.67, 26.17, 27.33, 29.68, 45.50, 49.13, 52.25, 54.81, 56.78, 117.31, 124.86, 132.82, 136.38, 136.64, 143.83, 171.11.
(377) MS (ESI): m/z (%)=470.12 [M+H].sup.+
Example 7-22: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(pyrazin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one J14
(378) ##STR00148##
(379) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-vinyl-3,10-diazabicyclo [4.3.1] decan-2-one I8 (35.0 mg, 0.0899 mmol) in DMF (1.0 mL) was added NaH (4.67 mg, 0.117 mmol). After 20 minutes 2-(chloromethyl)pyrazine (23.1 mg, 0.180 mmol) was added, the solution was heated to 80 C. and stirred for 1 h. Et.sub.2O (90 mL) was added to the solution and washed with sat. aq. NaCl solution (310 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography on SiO.sub.2 (Cyclohexane/EtOAc=7:3) afforded the title compound (40.0 mg, 0.0831 mmol, 92.4%) as a colorless solid.
(380) .sup.1H NMR (300 MHz, CDCl.sub.3) =1.26-1.39 (m, 3H), 1.55 (s, 2H), 2.27 (d, J=13.4 Hz, 1H), 2.75 (q, J=8.9 Hz, 1H), 3.08-3.17 (m, 1H), 3.56-3.76 (m, 2H), 4.00 (dd, J=6.8, 4.9 Hz, 1H), 4.59 (d, J=15.5 Hz, 1H), 4.74 (dt, J=6.2, 2.0 Hz, 1H), 4.99-5.09 (m, 2H), 5.67-5.81 (m, 1H), 7.56 (td, J=1.9, 0.5 Hz, 1H), 7.70 (dd, J=1.9, 0.5 Hz, 2H), 8.52 (d, J=1.9 Hz, 2H), 8.62-8.67 (m, 1H).
(381) .sup.13C NMR (75 MHz, CDCl.sub.3) =15.49, 26.31, 27.47, 49.10, 52.59, 54.24, 54.84, 56.83, 70.17, 70.50, 71.26, 72.46, 116.98, 124.89, 132.73, 136.35, 137.06, 143.88, 143.98, 170.61, 170.63.
(382) MS (ESI): m/z (%)=481.28 [M+H].sup.+
Example 7-23: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(pyrimidin-4-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one J15
(383) ##STR00149##
(384) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-vinyl-3,10-diazabicyclo [4.3.1] decan-2-one I8 (35.0 mg, 0.0899 mmol) in DMF (1.0 mL) was added NaH (4.67 mg, 0.117 mmol). After 20 minutes 2-(chloromethyl)pyrimidine (23.1 mg, 0.180 mmol) was added, the solution was heated to 80 C. and stirred for 1 h. Et.sub.2O (90 mL) was added to the solution and washed with sat. aq. NaCl solution (310 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography on SiO.sub.2 (Cyclohexane/EtOAc=7:3) afforded the title compound (4.00 mg, 0.0831 mmol, 9.2%) as a colorless solid.
(385) .sup.1H NMR (300 MHz, CDCl.sub.3) =1.26-1.39 (m, 3H), 1.55 (s, 2H), 2.27 (d, J=13.4 Hz, 1H), 2.75 (q, J=8.9 Hz, 1H), 3.08-3.17 (m, 1H), 3.56-3.76 (m, 2H), 4.00 (dd, J=6.8, 4.9 Hz, 1H), 4.59 (d, J=15.5 Hz, 1H), 4.74 (dt, J=6.2, 2.0 Hz, 1H), 4.99-5.09 (m, 2H), 5.67-5.81 (m, 1H), 7.56 (td, J=1.9, 0.5 Hz, 1H), 7.70 (dd, J=1.9, 0.5 Hz, 2H), 8.52 (d, J=1.9 Hz, 2H), 8.62-8.67 (m, 1H).
(386) .sup.13C NMR (75 MHz, CDCl.sub.3) =15.49, 26.31, 27.47, 49.10, 52.59, 54.24, 54.84, 56.83, 70.17, 70.50, 71.26, 72.46, 116.98, 124.89, 132.73, 136.35, 137.06, 143.88, 143.98, 170.61, 170.63.
(387) MS (ESI): m/z (%)=481.18
Example 7-24: Preparation of 2-((1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-2-oxo-5-vinyl-3,10-diazabicyclo[4.3.1]decan-3-yl)acetonitrile J16
(388) ##STR00150##
(389) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-vinyl-3,10-diazabicyclo [4.3.1] decan-2-one I8 (23.0 mg, 0.0590 mmol) in DMF (1.0 mL) was added NaH (2.84 mg, 0.0710 mmol). After 20 minutes 2-bromoacetonitrile (7.09 mg, 0.004 mL 0.0590 mmol) was added, the solution was heated to 80 C. and stirred for 1 h. Et.sub.2O (90 mL) was added to the solution and washed with sat. aq. NaCl solution (310 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography on SiO.sub.2 (Cyclohexane/EtOAc=7:3) afforded the title compound (12.0 mg, 0.0280 mmol, 47.5%) as a colorless solid.
(390) .sup.1H NMR (600 MHz, CDCl.sub.3) =1.26-1.33 (m, 3H), 1.56-1.59 (m, 2H), 2.24-2.31 (m, 1H), 2.72-2.79 (m, 1H), 3.11 (dd, J=14.3, 2.0 Hz, 1H), 3.94 (d, J=17.2 Hz, 1H), 3.99-4.03 (m, 1H), 4.18 (dd, J=14.3, 10.9 Hz, 1H), 4.73 (dt, J=6.1, 1.9 Hz, 1H), 4.83 (d, J=17.2 Hz, 1H), 5.18-5.25 (m, 2H), 5.81 (ddd, J=17.0, 10.1, 8.8 Hz, 1H), 7.58 (t, J=1.9 Hz, 1H), 7.69 (d, J=1.8 Hz, 2H).
(391) .sup.13C NMR (150 MHz, CDCl.sub.3) =15.35, 25.96, 27.38, 29.68, 38.31, 49.01, 52.45, 54.87, 56.71, 118.10, 124.84, 132.96, 136.21, 136.49, 170.99.
(392) MS (ESI): m/z (%)=428.00
Example 7-25: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(furan-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one J17
(393) ##STR00151##
(394) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-vinyl-3,10-diazabicyclo [4.3.1] decan-2-one I8 (50.0 mg, 0.128 mmol) in DMF (1.0 mL) was added NaH (7.71 mg, 0.193 mmol). After 20 minutes furfurylchloride (29.9 mg, 0.257 mmol) was added, the solution was heated to 80 C. and stirred for 1 h. Et.sub.2O (90 mL) was added to the solution and washed with sat. aq. NaCl solution (310 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography on SiO.sub.2 (Cyclohexane/EtOAc=8:2) afforded the title compound (41.0 mg, 0.0873 mmol, 68.2%) as a colorless solid.
(395) R.sub.f: 0.75 (Cyclohexane/EtOAc=1:1)
(396) .sup.1H NMR (600 MHz, CDCl.sub.3) =1.24-1.34 (m, 3H), 1.48-1.51 (m, 2H), 2.28-2.34 (m, 1H), 2.34-2.42 (m, 1H), 3.07 (dd, J=14.4, 2.0 Hz, 1H), 3.95-4.02 (m, 2H), 4.25 (d, J=15.2 Hz, 1H), 4.73 (dt, J=5.7, 1.8 Hz, 1H), 4.94-5.08 (m, 3H), 5.69-5.77 (m, 1H), 6.27-6.36 (m, 2H), 7.37 (dd, J=2.0, 1.0 Hz, 1H), 7.55-7.58 (m, 1H), 7.69 (t, J=1.5 Hz, 2H).
(397) .sup.13C NMR (150 MHz, CDCl.sub.3) =15.38, 26.35, 27.68, 46.59, 49.33, 50.99, 54.91, 56.92, 108.62, 110.45, 116.91, 124.86, 132.66, 136.31, 137.19, 142.31, 144.01, 150.55, 169.95.
(398) MS (ESI): m/z (%)=469.06 [M+H].sup.+
Example 7-26: Preparation of ((1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(thiophen-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one J18
(399) ##STR00152##
(400) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-vinyl-3,10-diazabicyclo [4.3.1] decan-2-one I8 (25.0 mg, 0.0640 mmol) in DMF (1.0 mL) was added NaH (3.08 mg, 0.0769 mmol). After 20 minutes 2-(chloromethyl)thiophene (25.5 mg, 0.193 mmol) was added, the solution was heated to 80 C. and stirred for 1 h. Et.sub.2O (90 mL) was added to the solution and washed with sat. aq. NaCl solution (310 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography on SiO.sub.2 (Cyclohexane/EtOAc=7:3) afforded the title compound (14.0 mg, 0.0288 mmol, 45.1%) as a colorless solid.
(401) R.sub.f: 0.83 (Cyclohexane/EtOAc=3:2)
(402) .sup.1H NMR (600 MHz, CDCl.sub.3) =1.23-1.31 (m, 3H), 1.49-1.54 (m, 2H), 2.32-2.40 (m, 2H), 3.03 (dd, J=14.3, 2.0 Hz, 1H), 3.94-4.02 (m, 2H), 4.34 (d, J=14.9 Hz, 1H), 4.72-4.75 (m, 1H), 4.90 (dt, J=17.0, 1.0 Hz, 1H), 5.03 (dd, J=10.2, 1.2 Hz, 1H), 5.22 (dd, J=15.0, 1.0 Hz, 1H), 5.69 (ddd, J=17.0, 10.1, 8.8 Hz, 1H), 6.94 (dd, J=5.1, 3.5 Hz, 1H), 6.98-7.00 (m, 1H), 7.24 (dd, J=5.1, 1.2 Hz, 1H), 7.55 (t, J=1.9 Hz, 1H), 7.69 (d, J=1.8 Hz, 2H).
(403) .sup.13C NMR (150 MHz, CDCl.sub.3) =15.48, 26.24, 27.57, 48.98, 49.55, 50.94, 54.88, 56.87, 117.05, 124.88, 125.70, 126.55, 126.90, 132.68, 136.33, 137.09, 139.48, 144.03, 170.02.
(404) MS (ESI): m/z (%)=485.05 [M+H].sup.+
Example 7-27: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(methylamino)ethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one J19
(405) ##STR00153##
(406) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(2-(methylamino)ethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (50.0 mg, 0.116 mmol) in MeOH (1 mL) were added AcOH (0.02 mL) and methanamine (0.058 mL, 0.116 mmol) and the solution was stirred for 1 h at room temperature. Sodiumtriacetoxyborohydride (49.1 mg, 0.232 mmol) was added to the solution. After 1 h sat. aq. NaHCO.sub.3 sol. (5 ml) was added to the mixture and then extracted with CH.sub.2Cl.sub.2 (310 mL). The combined organic layers were dried over MgSO.sub.4 and the solvent was removed under reduced pressure. Column chromatography over SiO.sub.2 (EtOAc+3% TEA) afforded the title compound (20.0 mg, 0.0448 mmol, 39%).
(407) .sup.1H NMR (300 MHz, Chloroform-d) 1.25-1.38 (m, 2H), 1.44-1.60 (m, 3H), 2.14-2.28 (m, 2H), 2.45 (s, 3H), 2.65-2.87 (m, 3H), 2.92-3.00 (m, 1H), 3.47-3.69 (m, 2H), 3.94-4.16 (m, 2H), 4.64 (dt, J=6.1, 1.9 Hz, 1H), 5.05-5.17 (m, 2H), 5.78 (ddd, J=16.9, 10.2, 8.9 Hz, 1H), 7.55 (t, J=1.8 Hz, 1H), 7.68 (d, J=1.8 Hz, 2H).
(408) VI. Preparation of Compounds K1-K29
(409) For the synthesis of examples of different R.sup.B substituents, the synthetic procedure of Scheme I was slightly modified from I3:
(410) ##STR00154##
(411) General Procedure K for the preparation of the sulfonamides K4-K29:
(412) ##STR00155##
(413) To a solution of (1S,5R,6R)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one K3 (25 mg, 0.092 mmol) in CH.sub.2Cl.sub.2 (1 mL) were added sulfonylchloride (R.sup.BSO.sub.2C1, 1.5 Equiv) and DIPEA (0.032 mL) and the reaction was stirred for 16 hours at room temperature. Sat. aq. NaHCO.sub.3 solution (5 mL) was added to the mixture and extracted with CH.sub.2Cl.sub.2 (25 mL). The organic layer was dried over MgSO.sub.4 and the solvent removed under reduced pressure. Column chromatography on SiO.sub.2 afforded the title compounds.
Example 8-1: Preparation of 6-(((1S,5R,6R)-2-oxo-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzo[d]thiazol-2(3H)-one (K4)
(414) ##STR00156##
(415) .sup.1H NMR (600 MHz, CDCl.sub.3) 1.28-1.34 (m, 2H), 1.43-1.55 (m, 3H), 2.26 (d, J=13.4 Hz, 1H), 2.64 (s, 1H), 2.66-2.73 (m, 1H), 3.07-3.12 (m, 1H), 4.00-4.04 (m, 1H), 4.04-4.10 (m, 1H), 4.76-4.87 (m, 3H), 4.96-5.05 (m, 2H), 5.67-5.76 (m, 1H), 7.18-7.23 (m, 2H), 7.31-7.34 (m, 1H), 7.66-7.70 (m, 1H), 7.71-7.74 (m, 1H), 7.89-7.91 (m, 1H), 8.51-8.54 (m, 1H).
(416) .sup.13C NMR (150 MHz, CDCl.sub.3) 15.58, 26.27, 27.42, 29.67, 49.07, 52.13, 54.53, 56.22, 56.74, 111.53, 116.66, 121.38, 122.00, 122.44, 125.17, 136.11, 136.93, 137.34, 138.40, 156.91, 170.54, 170.88.
(417) MS (ESI): m/z (%)=485.19 [M+H].sup.+
Example 8-2: Preparation of (1S,5R,6R)-10-((3-bromophenyl)sulfonyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (K5)
(418) ##STR00157##
(419) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.18-1.36 (m, 3H), 1.46-1.54 (m, 2H), 2.24-2.31 (m, 1H), 2.64-2.73 (m, 1H), 3.09 (dd, J=14.2, 2.0 Hz, 1H), 3.98-4.07 (m, 2H), 4.75-4.87 (m, 3H), 4.95-5.06 (m, 2H), 5.71 (ddd, J=16.9, 10.2, 8.8 Hz, 1H), 7.20 (ddd, J=7.5, 4.9, 1.2 Hz, 1H), 7.33 (d, J=7.9, 1.1 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.66-7.73 (m, 2H), 7.74-7.78 (m, 1H), 7.98 (t, J=1.8 Hz, 1H), 8.51-8.55 (m, 1H).
(420) .sup.13C NMR (100 MHz, CDCl.sub.3) 14.55, 25.23, 26.39, 48.08, 51.05, 53.65, 55.12, 55.78, 115.70, 121.04, 121.45, 122.30, 124.01, 128.46, 129.83, 134.73, 136.06, 136.29, 142.05, 148.02, 155.91, 169.66.
(421) MS (ESI): m/z (%)=490.41 [M+H].sup.+
Example 8-3: Preparation of (1S,5R,6R)-10-((2-methylbenzo[d]thiazol-6-yl)sulfonyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (K6)
(422) ##STR00158##
(423) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.24-1.32 (m, 3H), 1.41-1.50 (m, 2H), 2.19-2.27 (m, 1H), 2.68 (q, J=8.9 Hz, 1H), 2.90 (s, 3H), 3.08 (dd, J=14.2, 1.9 Hz, 1H), 4.01-4.12 (m, 2H), 4.73-4.87 (m, 3H), 4.93-5.05 (m, 2H), 5.72 (ddd, J=17.0, 10.2, 8.8 Hz, 1H), 7.18 (ddd, J=7.5, 4.9, 1.2 Hz, 1H), 7.31 (dt, J=7.9, 1.1 Hz, 1H), 7.66 (td, J=7.7, 1.8 Hz, 1H), 7.86 (dd, J=8.6, 1.9, 0.7 Hz, 1H), 8.04 (dd, J=8.6, 0.6 Hz, 1H), 8.37 (dt, J=1.9, 0.6 Hz, 1H), 8.51 (ddd, J=4.9, 1.8, 0.9 Hz, 1H).
(424) .sup.13C NMR (75 MHz, CDCl.sub.3) 15.56, 20.46, 26.21, 27.35, 29.66, 49.08, 52.08, 54.54, 56.16, 56.76, 116.56, 120.91, 121.99, 122.38, 123.21, 123.91, 136.20, 136.91, 137.42, 137.44, 149.09, 155.74, 157.01, 170.83, 171.54.
(425) MS (ESI): m/z (%)=483.18 [M+H].sup.+
Example 8-4: Preparation of 3-(((1S,5R,6R)-2-oxo-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzonitrile (K7)
(426) ##STR00159##
(427) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.14-1.29 (m, 3H), 1.46-1.58 (m, 2H), 2.26-2.35 (m, 1H), 2.66-2.77 (m, 1H), 3.12 (dd, J=14.3, 2.0 Hz, 1H), 3.97-4.07 (m, 2H), 4.71-4.90 (m, 3H), 4.94-5.08 (m, 2H), 5.71 (ddd, J=17.0, 10.1, 8.8 Hz, 1H), 7.20 (ddd, J=7.6, 4.9, 1.2 Hz, 1H), 7.32 (dt, J=8.0, 1.1 Hz, 1H), 7.65-7.73 (m, 2H), 7.87 (dt, J=7.8, 1.3 Hz, 1H), 8.03-8.09 (m, 1H), 8.09-8.16 (m, 1H), 8.50-8.56 (m, 1H).
(428) .sup.13C NMR (101 MHz, CDCl.sub.3) 14.47, 25.40, 26.58, 48.03, 51.04, 53.87, 55.18, 55.85, 113.01, 115.90, 115.96, 121.07, 121.48, 129.05, 129.44, 134.79, 135.97, 136.09, 141.96, 148.13, 155.83, 169.30.
(429) MS (ESI): m/z (%)=437.21 [M+H].sup.+
Example 8-5: Preparation of (1S,5R,6R)-10-((3,5-dichloro-4-hydroxyphenyl)sulfonyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (K8)
(430) ##STR00160##
(431) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.29-1.35 (m, 1H), 1.48-1.67 (m, 4H), 2.29 (d, J=14.1 Hz, 1H), 2.63-2.72 (m, 1H), 3.09 (dd, J=14.1, 2.0 Hz, 1H), 3.95-4.07 (m, 2H), 4.70-4.75 (m, 1H), 4.81 (s, 2H), 4.92-5.06 (m, 2H), 5.70 (ddd, J=16.9, 10.1, 8.7 Hz, 1H), 7.17-7.22 (m, 1H), 7.28-7.35 (m, 1H), 7.61-7.80 (m, 3H), 8.49-8.55 (m, 1H).
(432) .sup.13C NMR (75 MHz, CDCl.sub.3) 15.55, 26.37, 27.49, 29.66, 49.05, 52.08, 54.69, 56.08, 56.77, 116.76, 122.07, 122.25, 122.50, 126.79, 133.97, 137.11, 137.21, 148.98, 151.86, 156.82, 170.68.
(433) MS (ESI): m/z (%)=496.22 [M+H].sup.+
Example 8-6: Preparation of (1S,5R,6R)-10-(benzo[d]thiazol-6-ylsulfonyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (K9)
(434) ##STR00161##
(435) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.13-1.32 (m, 3H), 1.38-1.51 (m, 2H), 2.17-2.27 (m, 1H), 2.63-2.72 (m, 1H), 3.08 (dd, J=14.2, 2.0 Hz, 1H), 4.01-4.13 (m, 2H), 4.73-4.86 (m, 3H), 4.92-5.04 (m, 2H), 5.71 (ddd, J=17.0, 10.1, 8.8 Hz, 1H), 7.12-7.20 (m, 1H), 7.27-7.33 (m, 1H), 7.61-7.69 (m, 1H), 7.92 (dd, J=8.6, 1.9 Hz, 1H), 8.24 (dd, J=8.6, 0.6 Hz, 1H), 8.46-8.55 (m, 2H), 9.19 (s, 1H).
(436) 13C NMR (100 MHz, CDCl.sub.3) 15.54, 26.26, 27.40, 49.07, 52.09, 54.62, 56.18, 56.79, 116.61, 121.55, 121.99, 122.39, 124.04, 124.62, 134.35, 136.89, 137.38, 138.43, 149.11, 155.43, 156.97, 157.89, 170.75.
(437) MS (ESI): m/z (%)=496.20 [M+H].sup.+
Example 8-7: Preparation of (1S,5R,6R)-10-((3-chloro-4-methoxyphenyl)sulfonyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (K10)
(438) ##STR00162##
(439) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.11-1.26 (m, 3H), 1.39-1.47 (m, 2H), 2.20 (d, J=13.4 Hz, 1H), 2.56-2.64 (m, 1H), 2.96-3.08 (m, 1H), 3.89-4.05 (m, 5H), 4.64-4.82 (m, 3H), 4.85-5.02 (m, 2H), 5.55-5.73 (m, 1H), 6.89-6.98 (m, 1H), 7.08-7.17 (m, 1H), 7.23-7.30 (m, 1H), 7.57-7.71 (m, 2H), 7.72-7.81 (m, 1H), 8.42-8.52 (m, 1H).
(440) MS (ESI): m/z (%)=476.38 [M+H].sup.+
Example 8-8: Preparation of (1S,5R,6R)-10-((3-chlorophenyl)sulfonyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (K11)
(441) ##STR00163##
(442) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.19-1.33 (m, 3H), 1.44-1.53 (m, 2H), 2.22-2.31 (m, 1H), 2.62-2.73 (m, 1H), 3.08 (dd, J=14.3, 2.0 Hz, 1H), 3.97-4.07 (m, 2H), 4.73-4.87 (m, 3H), 4.92-5.04 (m, 2H), 5.70 (ddd, J=16.9, 10.2, 8.8 Hz, 1H), 7.18 (ddd, J=7.6, 4.9, 1.2 Hz, 1H), 7.31 (dt, J=7.9, 1.1 Hz, 1H), 7.41-7.49 (m, 1H), 7.51-7.57 (m, 1H), 7.63-7.73 (m, 2H), 7.81 (t, J=1.9 Hz, 1H), 8.51 (ddd, J=4.9, 1.9, 1.0 Hz, 1H).
(443) .sup.13C NMR (75 MHz, CDCl.sub.3) 15.54, 26.24, 27.40, 49.06, 52.04, 54.65, 56.14, 56.79, 116.66, 122.02, 122.42, 124.59, 126.64, 130.60, 132.79, 135.54, 136.98, 137.30, 142.93, 149.06, 156.94, 170.65.
(444) MS (ESI): m/z (%)=446.20 [M+H].sup.+
Example 8-9: Preparation of (1S,5R,6R)-10-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (K12)
(445) ##STR00164##
(446) .sup.1H NMR (600 MHz, CDCl.sub.3) 1.31-1.40 (m, 1H), 1.51-1.79 (m, 4H), 2.21-2.26 (m, 1H), 2.62-2.69 (m, 1H), 3.05 (dd, J=14.1, 2.0 Hz, 1H), 3.24-3.29 (m, 2H), 3.98-4.03 (m, 1H), 4.04-4.09 (m, 1H), 4.69 (t, J=8.9 Hz, 2H), 4.75 (dt, J=6.0, 1.9 Hz, 1H), 4.80 (s, 2H), 4.93-5.02 (m, 2H), 5.71 (ddd, J=17.0, 10.1, 8.8 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 7.19 (ddd, J=7.5, 4.9, 1.1 Hz, 1H), 7.32 (d, J=7.9, 1.0 Hz, 1H), 7.59-7.63 (m, 1H), 7.65-7.70 (m, 2H), 8.52 (ddd, J=4.9, 1.8, 0.9 Hz, 1H).
(447) .sup.13C NMR (151 MHz, CDCl.sub.3) 15.70, 26.15, 27.28, 29.06, 49.12, 52.09, 54.20, 56.15, 56.60, 72.24, 109.69, 116.37, 121.96, 122.35, 123.94, 128.08, 128.42, 132.87, 136.92, 137.61, 149.07, 157.09, 163.72, 171.17.
(448) MS (ESI): m/z (%)=454.20 [M+H].sup.+
Example 8-10: Preparation of (1S,5R,6R)-10-(phenylsulfonyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (K13)
(449) ##STR00165##
(450) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.23-1.34 (m, 2H), 1.41-1.61 (m, 3H), 2.22 (d, J=13.4 Hz, 1H), 2.61-2.73 (m, 1H), 3.06 (dd, J=14.2, 2.0 Hz, 1H), 3.98-4.07 (m, 2H), 4.72-4.81 (m, 2H), 4.88-5.05 (m, 3H), 5.71 (ddd, J=16.9, 10.2, 8.7 Hz, 1H), 7.22-7.29 (m, 1H), 7.36-7.42 (m, 1H), 7.47-7.61 (m, 3H), 7.72-7.86 (m, 3H), 8.53-8.58 (m, 1H).
(451) .sup.13C NMR (75 MHz, CDCl.sub.3) 15.58, 26.11, 27.22, 49.09, 52.24, 54.40, 55.58, 56.67, 116.62, 122.42, 122.73, 126.52, 129.31, 132.70, 137.31, 138.09, 141.15, 148.06, 156.57, 171.13.
(452) MS (ESI): m/z (%)=412.20 [M+H].sup.+
Example 8-11: Preparation of (1S,5R,6R)-3-(pyridin-2-ylmethyl)-10-(pyridin-2-ylsulfonyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (K14)
(453) ##STR00166##
(454) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.35-1.58 (m, 5H), 2.21-2.30 (m, 1H), 2.63-2.74 (m, 1H), 3.09 (dd, J=14.1, 2.0 Hz, 1H), 4.07-4.15 (m, 2H), 4.80 (d, J=3.3 Hz, 2H), 4.84-4.89 (m, 1H), 4.92-5.01 (m, 2H), 5.72 (ddd, J=16.9, 10.2, 8.8 Hz, 1H), 7.17 (dddd, J=7.6, 4.9, 1.2, 0.6 Hz, 1H), 7.33 (d, J=8.0, 1.6, 0.7 Hz, 1H), 7.48 (dddd, J=7.5, 4.7, 1.3, 0.5 Hz, 1H), 7.62-7.71 (m, 1H), 7.89 (tdd, J=7.8, 1.7, 0.5 Hz, 1H), 7.94-8.01 (m, 1H), 8.51 (ddt, J=5.0, 1.7, 0.7 Hz, 1H), 8.70 (ddt, J=4.7, 1.6, 0.7 Hz, 1H).
(455) .sup.13C NMR (75 MHz, CDCl.sub.3) 15.65, 26.15, 27.37, 49.20, 52.18, 54.87, 56.21, 57.20, 116.44, 122.01, 122.04, 122.35, 126.64, 136.90, 137.48, 138.00, 149.09, 150.23, 157.14, 158.16, 170.97.
(456) MS (ESI): m/z (%)=413.19 [M+H].sup.+
Example 8-12: Preparation of (1S,5R,6R)-10-((3-fluorophenyl)sulfonyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (K15)
(457) ##STR00167##
(458) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.24-1.34 (m, 2H), 1.43-1.63 (m, 3H), 2.26 (d, J=13.3 Hz, 1H), 2.57-2.76 (m, 1H), 3.08 (dd, J=14.2, 2.0 Hz, 1H), 3.95-4.05 (m, 2H), 4.70-4.89 (m, 3H), 4.92-5.06 (m, 2H), 5.70 (ddd, J=17.0, 10.2, 8.8 Hz, 1H), 7.13-7.22 (m, 1H), 7.24-7.34 (m, 2H), 7.44-7.57 (m, 2H), 7.58-7.71 (m, 2H), 8.51 (ddd, J=4.9, 1.8, 0.9 Hz, 1H).
(459) .sup.13C NMR (75 MHz, CDCl.sub.3) 15.55, 26.22, 27.39, 49.06, 52.04, 54.65, 56.18, 56.81, 113.79, 114.11, 116.64, 119.75, 120.03, 122.01, 122.30, 122.34, 122.40, 131.09, 131.19, 136.90, 137.33, 143.20, 143.28, 149.13, 156.99, 164.21, 170.65.
(460) MS (ESI): m/z (%)=430.17 [M+H].sup.+
Example 8-13: Preparation of (1S,5R,6R)-10-((3,5-dibromophenyl)sulfonyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (K16)
(461) ##STR00168##
Example 8-14: Preparation of 3-(((1S,5R,6R)-2-oxo-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzamide (K17)
(462) ##STR00169##
(463) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.09-1.22 (m, 1H), 1.26-1.33 (m, 1H), 1.41-1.62 (m, 3H), 2.23 (d, J=13.4 Hz, 1H), 2.60-2.75 (m, 1H), 3.08 (dd, J=14.2, 2.0 Hz, 1H), 3.96-4.06 (m, 2H), 4.70-4.90 (m, 3H), 4.91-5.04 (m, 2H), 5.70 (ddd, J=17.0, 10.1, 8.8 Hz, 1H), 6.07 (s, 1H), 6.72 (s, 1H), 7.19 (ddd, J=7.6, 4.9, 1.2 Hz, 1H), 7.30 (dt, J=7.9, 1.0 Hz, 1H), 7.55-7.73 (m, 2H), 7.97 (ddd, J=7.9, 1.8, 1.1 Hz, 1H), 8.05-8.14 (m, 1H), 8.31 (td, J=1.8, 0.5 Hz, 1H), 8.52 (ddd, J=4.9, 1.8, 0.9 Hz, 1H).
(464) .sup.13C NMR (100 MHz, CDCl.sub.3) 15.55, 26.23, 27.42, 49.08, 52.17, 54.66, 56.21, 56.79, 116.74, 122.05, 122.50, 125.32, 129.53, 129.89, 131.99, 134.82, 136.97, 137.30, 141.84, 149.22, 156.88, 167.32.
(465) MS (ESI): m/z (%)=455.18 [M+H].sup.+
Example 8-15: Preparation of 3-bromo-5-(((1S,5R,6R)-2-oxo-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzamide (K18)
(466) ##STR00170##
(467) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.26-1.33 (m, 2H), 1.48-1.64 (m, 3H), 2.26 (d, J=13.6 Hz, 1H), 2.67-2.78 (m, 1H), 3.10 (dd, J=14.2, 2.0 Hz, 1H), 3.98-4.07 (m, 2H), 4.70-5.07 (m, 5H), 5.70 (ddd, J=16.9, 10.1, 8.7 Hz, 1H), 6.00 (s, 1H), 6.73 (s, 1H), 7.21 (ddd, J=7.5, 4.9, 1.2 Hz, 1H), 7.30 (dt, J=7.8, 1.1 Hz, 1H), 7.68 (td, J=7.7, 1.8 Hz, 1H), 8.09 (t, J=1.7 Hz, 1H), 8.24 (p, J=1.6 Hz, 2H), 8.53 (ddd, J=5.0, 1.9, 1.0 Hz, 1H).
(468) .sup.13C NMR (100 MHz, CDCl.sub.3) 15.50, 22.70, 26.37, 27.54, 29.37, 29.66, 29.70, 31.93, 49.06, 52.19, 54.89, 56.18, 56.87, 116.93, 122.12, 122.58, 123.73, 123.86, 132.21, 135.11, 136.42, 137.08, 137.13, 143.48, 149.17, 156.72, 165.83.
(469) MS (ESI): m/z (%)=535.09 [M+H].sup.+
Example 8-16: Preparation of 3-chloro-5-(((1S,5R,6R)-2-oxo-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzamide (K19)
(470) ##STR00171##
(471) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.26-1.32 (m, 2H), 1.47-1.63 (m, 3H), 2.23 (dd, J=13.7, 2.9 Hz, 1H), 2.65-2.78 (m, 1H), 3.10 (dd, J=14.2, 2.0 Hz, 1H), 3.99-4.07 (m, 2H), 4.75-4.93 (m, 3H), 4.94-5.07 (m, 2H), 5.70 (ddd, J=16.9, 10.1, 8.7 Hz, 1H), 6.26 (s, 1H), 7.01 (s, 1H), 7.22 (ddd, J=7.5, 5.0, 1.2 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.70 (td, J=7.7, 1.8 Hz, 1H), 7.94 (t, J=1.8 Hz, 1H), 8.07-8.13 (m, 1H), 8.21 (t, J=1.6 Hz, 1H), 8.54 (ddd, J=5.1, 1.7, 0.9 Hz, 1H).
(472) .sup.13C NMR (100 MHz, CDCl.sub.3) 15.47, 26.34, 27.51, 29.70, 49.02, 52.27, 54.86, 56.05, 56.75, 117.00, 122.20, 122.70, 123.31, 129.32, 132.38, 136.28, 136.32, 137.03, 137.34, 143.32, 148.96, 156.51, 163.86, 166.26.
(473) MS (ESI): m/z (%)=489.18 [M+H].sup.+
Example 8-17: Preparation of N-(2-bromo-4-(((1S,5R,6R)-2-oxo-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)phenyl)acetamide (K20)
(474) ##STR00172##
Example 8-18: Preparation of N-(2-chloro-4-(((1S,5R,6R)-2-oxo-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)phenyl)acetamide (K21)
(475) ##STR00173##
Example 8-19: Preparation of N-(2,6-dichloro-4-(((1S,5R,6R)-2-oxo-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)phenyl)acetamide (K22)
(476) ##STR00174##
Example 8-20: Preparation of methyl 3-(((1S,5R,6R)-2-oxo-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzoate (K23)
(477) ##STR00175##
(478) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.13-1.21 (m, 1H), 1.25-1.32 (m, 1H), 1.42-1.65 (m, 3H), 2.25 (d, J=13.5 Hz, 1H), 2.62-2.75 (m, 1H), 3.09 (dd, J=14.2, 2.0 Hz, 1H), 3.96 (s, 3H), 4.01-4.13 (m, 2H), 4.73-5.05 (m, 5H), 5.72 (ddd, J=16.9, 10.1, 8.8 Hz, 1H), 7.19 (ddd, J=7.5, 4.9, 1.2 Hz, 1H), 7.32 (dt, J=7.9, 1.1 Hz, 1H), 7.57-7.71 (m, 2H), 8.01 (ddd, J=7.9, 2.0, 1.2 Hz, 1H), 8.24 (ddd, J=7.8, 1.7, 1.2 Hz, 1H), 8.44-8.49 (m, 1H), 8.52 (ddd, J=4.9, 1.8, 1.0 Hz, 1H).
(479) .sup.13C NMR (75 MHz, CDCl.sub.3) 15.55, 26.23, 27.37, 49.11, 52.10, 52.66, 54.62, 56.15, 56.78, 116.66, 122.03, 122.42, 127.56, 129.59, 130.52, 131.58, 133.51, 136.99, 137.34, 141.93, 149.05, 156.96, 165.31, 170.72.
(480) MS (ESI): m/z (%)=470.18 [M+H].sup.+
Example 8-21: Preparation of methyl 3-bromo-5-(((1S,5R,6R)-2-oxo-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzoate K24)
(481) ##STR00176##
Example 8-22: Preparation of methyl 3-chloro-5-(((1S,5R,6R)-2-oxo-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzoate (K25)
(482) ##STR00177##
Example 8-23: Preparation of (1S,5R,6R)-3-(pyridin-2-ylmethyl)-10-(pyridin-3-ylsulfonyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (K26)
(483) ##STR00178##
(484) .sup.1H NMR (600 MHz, CDCl.sub.3) 1.27-1.34 (m, 2H), 1.46-1.64 (m, 3H), 2.25-2.34 (m, 1H), 2.65-2.75 (m, 1H), 3.12 (dd, J=14.3, 2.0 Hz, 1H), 4.00-4.08 (m, 2H), 4.73-4.89 (m, 3H), 4.96-5.06 (m, 2H), 5.72 (ddd, J=17.0, 10.1, 8.8 Hz, 1H), 7.20 (ddd, J=7.5, 4.9, 1.2 Hz, 1H), 7.32 (dt, J=7.8, 1.1 Hz, 1H), 7.47 (ddd, J=8.0, 4.8, 0.9 Hz, 1H), 7.68 (td, J=7.7, 1.8 Hz, 1H), 8.12 (ddd, J=8.0, 2.4, 1.6 Hz, 1H), 8.53 (ddd, J=4.9, 1.9, 1.0 Hz, 1H), 8.82 (dd, J=4.8, 1.6 Hz, 1H), 9.06 (dd, J=2.4, 0.9 Hz, 1H).
(485) .sup.13C NMR (150 MHz, CDCl.sub.3) 15.54, 26.37, 27.56, 29.68, 49.04, 52.09, 54.70, 56.22, 56.77, 116.79, 122.04, 122.44, 123.84, 134.17, 136.93, 137.20, 137.84, 147.51, 149.16, 153.26, 156.92, 170.46.
(486) MS (ESI): m/z (%)=413.17 [M+H].sup.+
Example 8-24: Preparation of (1S,5R,6R)-10-((6-phenylpyridin-3-yl)sulfonyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (K27)
(487) ##STR00179##
Example 8-25: Preparation of (1S,5R,6R)-3-(pyridin-2-ylmethyl)-10-((4-(pyrimidin-2-yl)phenyl)sulfonyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (K28)
(488) ##STR00180##
(489) .sup.1H NMR (600 MHz, CDCl.sub.3) 1.27-1.35 (m, 2H), 1.43-1.53 (m, 3H), 2.22-2.27 (m, 1H), 2.65-2.72 (m, 1H), 3.09 (dd, J=14.1, 1.9 Hz, 1H), 4.03-4.10 (m, 2H), 4.78-4.90 (m, 3H), 4.96-5.06 (m, 2H), 5.73 (ddd, J=17.0, 10.1, 8.7 Hz, 1H), 7.20-7.23 (m, 1H), 7.29 (t, J=4.8 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.72 (t, J=7.6 Hz, 1H), 7.93-7.99 (m, 2H), 8.52-8.55 (m, 1H), 8.59-8.64 (m, 2H), 8.87 (d, J=4.8 Hz, 2H).
(490) .sup.13C NMR (150 MHz, CDCl.sub.3) 15.51, 25.99, 27.15, 29.59, 49.02, 52.09, 54.44, 55.89, 56.70, 116.54, 119.93, 122.12, 122.45, 126.70, 128.95, 137.30, 141.48, 142.75, 157.35, 162.90, 170.88.
(491) MS (ESI): m/z (%)=490.18 [M+H].sup.+
Example 8-26: Preparation of (1S,5R,6R)-10-((1H-benzo[d]imidazol-2-yl)sulfonyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (K29)
(492) ##STR00181##
VII. Preparation of Compounds M1-M6
(493) From J4 further examples for R.sup.C modifications (M1-M6) were prepared:
(494) ##STR00182##
Example 9-1: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-ethyl-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one M1
(495) ##STR00183##
(496) To a solution of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one (35.0 mg, 0.0730 mmol) in MeOH (1 mL) was added Pd/C (10%, 7.75 mg, 0.00729 mmol) and the solution was saturated with H.sub.2. After 2 h the mixture was filtered through Celite and washed with EtOAc. The solvent was removed under reduced pressure and column chromatography over SiO.sub.2 (Cyclohexane/EtOAc=2:3) afforded the title compound (35.1 mg, 0.0730 mmol, quant.) as a white solid.
(497) R.sub.f: 0.33 (Cyclohexane/EtOAc=2:3)
(498) .sup.1H NMR (300 MHz, CDCl.sub.3) 0.78 (t, J=7.4 Hz, 3H), 1.22-1.37 (m, 4H), 1.42-1.62 (m, 3H), 1.79-1.92 (m, 1H), 2.30 (d, J=13.5 Hz, 1H), 3.11 (dd, J=14.4, 1.8 Hz, 1H), 3.73-3.86 (m, 2H), 4.64 (d, J=15.0 Hz, 1H), 4.71-4.77 (m, 1H), 4.93 (d, J=15.0 Hz, 1H), 7.15-7.21 (m, 1H), 7.28-7.34 (m, 1H), 7.53-7.56 (m, 1H), 7.62-7.71 (m, 3H), 8.49-8.54 (m, 1H).
(499) .sup.13C NMR (75 MHz, CDCl.sub.3) 11.46, 15.62, 26.16, 27.39, 27.62, 45.56, 50.89, 55.54, 56.02, 56.90, 122.16, 122.44, 124.90, 132.57, 136.27, 136.87, 144.17, 149.13, 157.09, 170.39.
(500) MS (ESI): m/z (%)=482.49 [M+H].sup.+
Example 9-2: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-((dimethylamino)methyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one M2
(501) ##STR00184##
(502) To a solution of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-2-oxo-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decane-5-carbaldehyde (35 mg, 0.0730 mmol) in MeOH (1 mL) was added dimethylamine (0.109 mL, 0.218 mmol). After 2 h NaBH.sub.4 to the mixture and stirred for 1 h. The solvent was removed under reduced pressure and the mixture was loaded on SiO.sub.2. Column chromatography over SiO.sub.2 (CH.sub.2Cl.sub.2+MeOH 4%) afforded the title compound (13.0 mg, 0.0254 mmol, 35%).
(503) .sup.1H NMR (600 MHz, CDCl.sub.3) 1.19-1.26 (m, 1H), 1.32-1.41 (m, 1H), 1.44-1.56 (m, 2H), 1.56-1.66 (m, 1H), 2.06 (s, 6H), 2.12-2.19 (m, 1H), 2.22-2.33 (m, 3H), 3.32-3.40 (m, 1H), 3.74-3.89 (m, 2H), 4.64 (d, J=15.2 Hz, 1H), 4.72-4.77 (m, 1H), 4.96 (d, J=15.2 Hz, 1H), 7.18 (dt, J=12.8, 6.2 Hz, 1H), 7.30 (t, J=8.6 Hz, 1H), 7.53-7.56 (m, 1H), 7.63-7.68 (m, 1H), 7.67-7.72 (m, 2H), 8.49-8.53 (m, 1H).
(504) .sup.13C NMR (151 MHz, CDCl.sub.3) 15.69, 28.07, 28.13, 42.25, 45.47, 50.30, 54.35, 56.18, 57.03, 62.45, 122.01, 122.31, 124.87, 132.59, 136.27, 136.81, 144.15, 149.09, 149.15, 157.06, 170.34.
(505) MS (ESI): m/z (%)=511.25 [M+H].sup.+
Example 9-3: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(difluoromethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one M3
(506) ##STR00185##
(507) A solution of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-2-oxo-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decane-5-carbaldehyde (50 mg, 0.104 mmol) in CH.sub.2Cl.sub.2 (1 mL) was cooled to 0 C. and then DAST (0.016 mL, 20.0 mg, 0.124 mmol) was added. After 2 h sat. aq. K.sub.2CO.sub.3 sol. (5 mL) was added to the mixture and extracted with CH.sub.2Cl.sub.2 (325 mL). The collected organic layers were dried over MgSO.sub.4 and the solvent was removed under reduced pressure. Column chromatography over SiO.sub.2 (Cyclohexane/EtOAc=3/7) afforded the title compound (35.0 mg, 0.0693 mmol, 67%).
(508) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.27-1.30 (m, 1H), 1.47-1.59 (m, 4H), 2.27-2.35 (m, 1H), 2.62-2.76 (m, 1H), 3.30-3.37 (m, 1H), 3.90-3.99 (m, 1H), 4.29-4.35 (m, 1H), 4.58 (d, J=15.2 Hz, 1H), 4.75-4.79 (m, 1H), 5.00 (d, J=15.2 Hz, 1H), 5.58-5.86 (m, 1H), 7.17-7.21 (m, 1H), 7.25-7.29 (m, 1H), 7.53-7.57 (m, 1H), 7.64-7.69 (m, 1H), 7.69-7.72 (m, 2H), 8.50-8.53 (m, 1H).
(509) .sup.13C NMR (100 MHz, CDCl.sub.3) 15.16, 28.11, 28.76, 29.66, 48.29, 49.35, 49.37, 56.10, 57.06, 122.15, 122.60, 124.91, 132.90, 136.44, 136.94, 143.61, 149.28, 156.32, 169.86.
(510) MS (ESI): m/z (%)=504.36 [M+H].sup.+
Example 9-4: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(fluoromethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one M4
(511) ##STR00186##
(512) A solution of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(hydroxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (25 mg, 0.0520 mmol) in CH.sub.2Cl.sub.2 (1 mL) was cooled to 0 C. and then DAST (0.016 mL, 20.0 mg, 0.124 mmol) was added. After 2 h sat. aq. K.sub.2CO.sub.3 sol. (5 mL) was added to the mixture and extracted with CH.sub.2Cl.sub.2 (325 mL). The collected organic layers were dried over MgSO.sub.4 and the solvent was removed under reduced pressure. Column chromatography over SiO.sub.2 (Cyclohexane/EtOAc=3/7) afforded the title compound (13 mg, 0.0268 mmol, 52%).
(513) R.sub.f: 0.29 (Cyclohexane/EtOAc=3:7)
(514) .sup.1H NMR (600 MHz, CDCl.sub.3) 1.40-1.46 (m, 2H), 1.50-1.59 (m, 3H), 2.33 (d, J=13.3 Hz, 1H), 2.49-2.57 (m, 1H), 3.29 (dd, J=14.4, 2.0 Hz, 1H), 3.88 (dd, J=14.3, 10.7 Hz, 1H), 3.99 (t, J=5.7 Hz, 1H), 4.24-4.35 (m, 2H), 4.71 (d, J=152 Hz, 1H), 4.77-4.80 (m, 1H), 4.90 (d, J=15.2 Hz, 1H), 7.17-7.22 (m, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.56-7.58 (m, 1H), 7.67-7.72 (m, 3H), 8.53 (d, J=5.0 Hz, 1H).
(515) .sup.13C NMR (150 MHz, CDCl.sub.3) 15.41, 27.90, 28.02, 29.67, 45.01, 45.12, 48.56, 48.60, 51.28, 51.33, 56.14, 57.02, 80.72, 82.46, 83.61, 122.04, 122.51, 123.12, 124.89, 132.78, 133.76, 136.37, 136.91, 143.81, 149.28, 156.63, 170.12.
(516) MS (ESI): m/z (%)=486.28 [M+H].sup.+
Example 9-5: Preparation of (1S,5R,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(methoxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one M5
(517) ##STR00187##
(518) A solution of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(hydroxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (14.0 mg, 0.0290 mmol) in DMF (1 mL) was cooled to 0 C. and then NaH (60% dispersion in mineral oil, 2.3 mg, 0.058 mmol) was added and stirred for 20 minutes. CH.sub.3I (8.20 mg, 3.6 L, 0.0.058 mmol) was added. After 16 h at room temperature the solvent was removed under reduced pressure and column chromatography over SiO.sub.2 (Cyclohexane/EtOAc=3/7) afforded the title compound (8.5 mg, 0.0171 mmol, 59%) as a yellow oil.
(519) R.sub.f: 0.2 (Cyclohexane/EtOAc=3:7)
(520) .sup.1H-NMR (600 MHz, CDCl.sub.3) =1.46 (dt, J=13.3, 5.0 Hz, 1H), 1.52-1.64 (m, 4H), 2.27-2.33 (m, 1H), 2.37 (dtd, J=13.1, 8.6, 7.6, 5.8 Hz, 1H), 2.88 (s, 1H), 2.95 (s, 1H), 3.22-3.31 (m, 5H), 3.76 (dd, J=14.4, 10.8 Hz, 1H), 4.00 (td, J=5.0, 2.4 Hz, 1H), 4.75 (dt, J=6.2, 1.8 Hz, 1H), 4.82 (d, J=15.7 Hz, 1H), 7.39 (s, 1H), 7.45-7.51 (m, 1H), 7.56 (d, J=1.9 Hz, 1H), 7.70 (d, J=1.8 Hz, 2H), 7.90 (t, J=7.5 Hz, 1H), 8.57 (d, J=5.0 Hz, 1H).
(521) .sup.13C-NMR (150 MHz, CDCl.sub.3) =1.00, 15.50, 27.94, 28.09, 29.63, 29.66, 36.45, 44.59, 49.94, 52.68, 56.96, 59.00, 73.17, 123.17, 123.26, 124.91, 132.70, 136.27, 143.85, 170.74.
(522) MS (ESI): m/z (%)=498.46 [M+H].sup.+
Example 9-6: Preparation of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(ethoxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one M6
(523) ##STR00188##
(524) A solution of (1S,5S,6R)-10-((3,5-dichlorophenyl)sulfonyl)-5-(hydroxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (25.0 mg, 0.0520 mmol) in THF (1 mL) was cooled to 0 C. and then NaH (60% dispersion in mineral oil, 2.3 mg, 0.058 mmol) was added and stirred for 20 minutes. Iodoethane (8.20 mg, 3.6 L, 0.0.058 mmol) was added. After 2 h at room temperature the solvent was removed under reduced pressure and column chromatography over SiO.sub.2 (Cyclohexane/EtOAc=3/7) afforded the title compound (13.0 mg, 0.0254 mmol, 50%) as a yellow oil.
(525) R.sub.f: 0.5 (EtOAc)
(526) .sup.1H NMR (600 MHz, CDCl.sub.3) 1.10-1.14 (m, 3H), 1.41-1.43 (m, 1H), 1.51-1.65 (m, 4H), 2.27-2.34 (m, 2H), 3.20-3.28 (m, 3H), 3.35-3.41 (m, 2H), 3.73 (dd, J=14.2, 10.9 Hz, 1H), 3.91-3.95 (m, 1H), 4.73-4.82 (m, 3H), 7.16-7.20 (m, 1H), 7.27 (d, J=7.9 Hz, 1H), 7.53-7.56 (m, 1H), 7.64-7.71 (m, 3H), 8.52 (d, J=4.8 Hz, 1H).
(527) .sup.13C NMR (151 MHz, CDCl.sub.3) 14.95, 15.59, 27.98, 44.57, 49.55, 52.72, 56.14, 57.03, 66.58, 71.06, 121.89, 122.38, 124.94, 132.61, 136.23, 136.94, 144.00, 149.16, 156.92, 170.36.
(528) MS (ESI): m/z (%)=512.24 [M+H].sup.+
(529) VIII. Preparation of Compounds N1-N32
(530) further examples for R.sup.B modifications (N1-N32) are prepared from I6 according to the following synthesis procedure (Scheme N)
(531) ##STR00189##
Example 10-1: Preparation of (1S,5S,6R)-5-(methoxymethyl)-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-2-one (N1.5)
(532) ##STR00190##
Example 10-2: Preparation of (1S,5S,6R)-10-((3-fluorophenyl)sulfonyl)-5-(methoxymethyl)-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-2-one (N2)
(533) ##STR00191##
Example 10-3: Preparation of (1S,5S,6R)-10-((3,5-dibromophenyl)sulfonyl)-5-(methoxymethyl)-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-2-one (N3)
(534) ##STR00192##
Example 10-4: Preparation of 3-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzamide (N4)
(535) ##STR00193##
Example 10-5: Preparation of 3-bromo-5-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzamide (N5)
(536) ##STR00194##
Example 10-6: Preparation of 3-chloro-5-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzamide (N6)
(537) ##STR00195##
Example 10-7: Prep. of N-(2-bromo-4-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)phenyl)acetamide (N7)
(538) ##STR00196##
Example 10-8: Prep. of N-(2-chloro-4-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)phenyl)acetamide (N8)
(539) ##STR00197##
Example 10-9: Preparation of N-(2,6-dichloro-4-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)phenyl)acetamide (N9)
(540) ##STR00198##
Example 10-10: Preparation of methyl 3-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzoate (N10)
(541) ##STR00199##
Example 10-11: Preparation of methyl 3-bromo-5-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzoate (N11)
(542) ##STR00200##
Example 10-12: Preparation of methyl 3-chloro-5-(((1S,5S,6R)-5-(methoxymethyl)-2-oxo-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzoate (N12)
(543) ##STR00201##
Example 10-13: Preparation of (1S,5S,6R)-5-(methoxymethyl)-3-(prop-2-yn-1-yl)-10-(pyridin-3-ylsulfonyl)-3, 10-diazabicyclo[4.3.1]decan-2-one (N13)
(544) ##STR00202##
Example 10-14: Preparation of (1S,5S,6R)-5-(methoxymethyl)-10-((6-phenylpyridin-3-yl)sulfonyl)-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-2-one (N14)
(545) ##STR00203##
Example 10-15: Preparation of (1S,5S,6R)-5-(methoxymethyl)-3-(prop-2-yn-1-yl)-10-((4-(pyrimidin-2-yl)phenyl)sulfonyl)-3,10-diazabicyclo[4.3.1]decan-2-one (N15)
(546) ##STR00204##
Example 10-16: Preparation of (1S,5S,6R)-10-((1H-benzo[d]imidazol-2-yl)sulfonyl)-5-(methoxymethyl)-3-(prop-2-yn-1-yl)-3,10-diazabicyclo[4.3.1]decan-2-one (N16)
(547) ##STR00205##
Example 10-17: Preparation of (1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-10-((3-fluorophenyl)sulfonyl)-5-(methoxymethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (N17)
(548) ##STR00206##
Example 10-18: Preparation of (1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-10-((3,5-dibromophenyl)sulfonyl)-5-(methoxymethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (N18)
(549) ##STR00207##
Example 10-19: Preparation of 3-(((1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)benzamide (N19)
(550) ##STR00208##
Example 10-20: Preparation of 3-(((1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)-5-bromobenzamide (N20)
(551) ##STR00209##
Example 10-21: Preparation of 3-(((1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)-5-chlorobenzamide (N21)
(552) ##STR00210##
Example 10-22: Preparation of N-(4-(((1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)-2-bromophenyl)acetamide (N22)
(553) ##STR00211##
Example 10-23: Preparation of N-(4-(((1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)-2-chlorophenyl)acetamide (N23)
(554) ##STR00212##
Example 10-24: Preparation of N-(4-(((1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-2-oxo-3,10-diazabicyclo[4.3.1]decan-10-yl)sulfonyl)-2,6-dichlorophenyl)acetamide (N24)
(555) ##STR00213##
Example 10-25: Preparation of (1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-10-(pyridin-3-ylsulfonyl)-3,10-diazabicyclo[4.3.1]decan-2-one (N25)
(556) ##STR00214##
Example 10-26: Preparation of (1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-10-((6-phenylpyridin-3-yl)sulfonyl)-3,10-diazabicyclo[4.3.1]decan-2-one (N26)
(557) ##STR00215##
Example 10-27: Preparation of (1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-5-(methoxymethyl)-10-((4-(pyrimidin-2-yl)phenyl)sulfonyl)-3,10-diazabicyclo[4.3.1]decan-2-one (N27)
(558) ##STR00216##
Example 10-28: Preparation of (1S,5S,6R)-3-((1H-1,2,3-triazol-5-yl)methyl)-10-((1H-benzo[d]imidazol-2-yl)sulfonyl)-5-(methoxymethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (N28)
(559) ##STR00217##
Example 10-29: Preparation of (1S,5R,6R)-10-((3-fluorophenyl)sulfonyl)-5-(methoxymethyl)-3-((1-phenyl-1H-1,2,3-triazol-5-yl)methyl)-3,10-diazabicyclo[4.3.1]decan-2-one (N29)
(560) ##STR00218##
Example 10-30: Preparation of (1S,5S,6R)-3-((1-benzyl-1H-1,2,3-triazol-5-yl)methyl)-10-((3-fluorophenyl)sulfonyl)-5-(methoxymethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (N30)
(561) ##STR00219##
Example 10-12: Preparation of (1S,5S,6R)-3-((1-benzoyl-1H-1,2,3-triazol-5-yl)methyl)-10-((3-fluorophenyl)sulfonyl)-5-(methoxymethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (N31)
(562) ##STR00220##
Example 10-12: Preparation of (1S,5S,6R)-10-((3-fluorophenyl)sulfonyl)-5-(methoxymethyl)-3-((1-(phenylsulfonyl)-1H-1,2,3-triazol-5-yl)methyl)-3,10-diazabicyclo[4.3.1]decan-2-one (N32)
(563) ##STR00221##
Example 11: Fluorescence Polarization (FP) Assays
(564) In-vitro fluorescence polarization assays were performed to determine the binding affinities for FKBP51 and 52 according to a literature procedure (Kozany, C.; Marz, A.; Kress, C.; Hausch, F., Fluorescent probes to characterise FK506-binding proteins. Chembiochem 2009, 10, (8), 1402-10).
(565) For fluorescence polarization assays the fluorescent ligand 2b was dissolved in HEPES (20 mm, pH 8), Triton-X100 (0.01%), at double the concentration required for the final sample. The target protein was also diluted in this assay buffer at double the highest concentration required for the final sample. This protein stock was used for a 1:1 serial dilution.
(566) The fluorescent ligand 2b was diluted in assay buffer to a concentration double the final concentration (20 nM 2b). The inventive compound was dissolved in DMSO to reach a 100-times concentrated stock solution. This was used for a 1:1 serial dilution in DMSO. Every sample of this serial dilution was diluted by a factor of 50 in assay buffer supplemented with ligand 2b to achieve a 2 concentrated mixture of ligand 2b and the inventive compound. To this competitive ligand double the protein concentration for 2b assay: FKBP51FK1 560 nM (2280 nM) or FKBP52FK1 800 nM (2400 nM) diluted in assay buffer was added.
(567) The samples were transferred to black 384-well assay plates (No.: 3575; Corning Life Sciences). After incubation at room temperature for 30 min the fluorescence anisotropy was measured (GENios Pro, Tecan, Mnnedorf, Switzerland) by using an excitation filters of 485/20 nm and emission filters of 535/25 nm. The binding assays were performed in duplicates in the plate format.
(568) The competition curves were analyzed by using SigmaPlot9. Data were fitted to a four parameter logistic curve to deduce the IC.sub.50 values. For the analysis of K.sub.1 values, data were fitted to the following equation (Z. X. Wang, FEBS Lett. 1995, 360, 111-114).
A=(A.sub.maxA.sub.min)/[L].sub.t(([L].sub.t((2((K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t[R].sub.t)^23(K.sub.comp([L].sub.t[R].sub.t)+K.sub.lig([I].sub.t[R].sub.t)+K.sub.ligK.sub.comp))^0.5COS(ARCCOS((2(K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t[R].sub.t)^3+9(K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t[R].sub.t)(K.sub.comp([L].sub.t[R].sub.t)+K.sub.lig([I].sub.t[R].sub.t)+K.sub.ligK.sub.comp)27(1K.sub.ligK.sub.comp[R].sub.t))/(2((((K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t[R].sub.t)^23(K.sub.comp([L].sub.t[R].sub.t)+K.sub.lig([I].sub.t[R].sub.t)+K.sub.ligK.sub.comp))^3)^0.5)))/3))(K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t[R].sub.t)))/((3K.sub.lig)+((2((K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t[R].sub.t)^23(K.sub.comp([L].sub.t[R].sub.t)+K.sub.lig([I].sub.t[R].sub.t)+K.sub.ligK.sub.comp))^0.5COS(ARCCOS((2(K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t[R].sub.t)^3+9(K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t[R].sub.t)(K.sub.comp([L].sub.t[R].sub.t)+K.sub.lig([I].sub.t[R].sub.t)+K.sub.ligK.sub.comp)27(1K.sub.ligK.sub.comp[R].sub.t))/(2((((K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t[R].sub.t)^23(K.sub.comp([L].sub.t[R].sub.t)+K.sub.lig([I].sub.t[R].sub.t)+K.sub.ligK.sub.comp))^3)^0.5)))/3))(K.sub.lig+K.sub.comp+[L].sub.t+[I].sub.t[R].sub.t)))+A.sub.min
(569) In this equation K.sub.lig and K.sub.comp stand for the K.sub.d values of the used tracer or competing inhibitor, [I].sub.t is referring to the total concentration of the titrated inhibitor.
(570) ##STR00222##
(571) These assays revealed that substitutents R.sup.C significantly increased the affinity to FKBP51/52 compared to known FKBP51 ligands (Ref.1-Ref.4). Table 1 summarize the binding data of exemplary compounds.
(572) The compounds B3-N32 and Ref. 1-Ref. 4 are FKBP51/52 inhibitors of which Ki values are:
(573) TABLE-US-00002 K.sub.i 0.1 M ++++ 0.1 M < K.sub.i 0.5 M +++ 0.5 M < K.sub.i 1 M ++ 1 M < K.sub.i 5 M + 5 M < K.sub.i
(574) TABLE-US-00003 TABLE 1 Chemical compounds according to formula (I) tested for binding to the FK506-binding domain of FKBP51/52 using fluorescence polarization assay (Kozany et al, ChemBioChem 2009, 10, 1402) FKBP51 FKBP52 Compound K.sub.i [M] K.sub.i [M] B3 ++++ ++++ B4&B5 +++ ++++ B6 ++++ ++++ B7 ++++ ++++ B8 +++ +++ B9 +++ +++ B11 +++ +++ B12 +++ +++ B13 ++++ +++ B14 ++++ +++ B15 ++++ ++++ C1 ++++ ++++ C2(C2a/b) ++++ ++++ C3 +++ +++ D3 ++++ ++++ D4 ++++ ++++ D5 ++++ ++++ D6 ++++ ++++ D7 ++++ ++++ D8 ++++ ++++ G6 ++ +++ H1.2 + + H1.3 ++ ++ H1.4 + + H2.1 +++ +++ H2.2 ++ ++ H2.3 ++++ +++ I8 ++ ++ J1 +++ +++ J2 ++ ++ J3 ++ ++ J4 +++ +++ J5 ++ ++ J6 +++ ++ J7 ++ ++ J8 ++++ ++++ J9 +++ +++ J10 +++ +++ J11 +++ +++ J12 +++ +++ J13 ++++ ++++ J14 +++ +++ J15 +++ +++ J16 +++ +++ J17 + + J19 +++ +++ K4 ++++ ++++ K5 ++++ ++++ K6 ++++ ++++ K7 +++ +++ K8 +++ +++ K9 +++ +++ K10 +++ +++ K11 +++ +++ K12 ++ ++ K13 ++ ++ K15 +++ +++ K16 ++++ ++++ K17 +++ +++ K18 +++ +++ K19 +++ +++ K20 +++ +++ K21 +++ +++ K22 ++++ ++++ K23 ++ ++ K24 ++++ ++++ K25 ++++ ++++ K26 +++ +++ K27 +++ +++ K28 ++++ ++++ K29 ++++ ++++ M1 ++++ ++++ M2 ++++ ++++ M3 ++++ ++++ M4 ++++ ++++ M5 ++++ ++++ M6 ++++ ++++ N2 +++ +++ N3 +++ +++ N4 +++ +++ N5 +++ +++ N6 +++ +++ N7 +++ +++ N8 +++ +++ N9 +++ +++ N10 +++ +++ N11 +++ +++ N12 +++ +++ N13 ++ ++ N14 +++ +++ N15 +++ +++ N16 +++ +++ N17 ++++ ++++ N18 ++++ ++++ N19 ++++ ++++ N20 ++++ ++++ N21 ++++ ++++ N22 ++++ ++++ N23 ++++ ++++ N24 ++++ ++++ N25 ++++ ++++ N26 ++++ ++++ N27 ++++ ++++ N28 ++++ ++++ N29 +++ +++ N30 +++ +++ N31 +++ +++ N32 +++ +++ Ref. 1 + + Ref. 2 + + Ref. 3 + + Ref. 4
(575) Reference compounds Ref.1-Ref. 4 and FK506 have the following structures:
(576) TABLE-US-00004 Compound Structure Ref. 1
Example 12: N2a Cellular Assay
(577) At day one N2a cells were plated into 24-well plates with cover slips (pretreated with polylysine) at a density of 35,000 cells/well and cultured with DMEM (incl. FCS 10% and Pen/Strep 1%) for 24 h. Next, cells were transfected with 80 ng expression plasmids encoding Venus as well as 720 ng pRK5 (mock transfection) in a total volume of 500 l starvation media containing different concentrations of compounds or DMSO for 36 h (media without FCS; induction of neurite outgrowth). Therefore media was removed and replaced by 400 l DMEM (empty). Next an equivalent volume of plasmids were given to 50 l OPTIMEM and incubated for 5 min at RT. Additionally 1.5 l Lipofectamine 2000 was separately dissolved in 50 l OPTIMEM. After 5 min both solutions (plasmids and Lipofectamine 2000 containing media) were combined and incubated again for another 20 min. After that 100 l of this mixture was given to 400 l media per well. (See also protocol of the providerLife Technologies).
(578) On the next day cells were washed with PBS and incubated for 30 min with 300 l PFA (4%) and sucrose (5%) to fix cells. After fixation cells were washed three times, mounted onto microscope slides using 4 l Vectashield (mounting media) and analyzed by fluorescence microscopy. Each bar represents the mean of the neurite length of 30-50 cells after the indicated treatment (
(579) FK506 was included (see