LV10957B

LV10957B - 16 alpha, 17alpha-acetalsubstituted androstan-17betha-carboxyl acid esters, method of their preparation, intermediates, method of their producing, pharmaceutical compositions

Info

Publication number: LV10957B
Application number: LVP-93-1006A
Authority: LV
Inventors: Andersson Paul Hakan; Andersson Per Ture; Thalen Bror Arne; Trofast Jan William; Axelsson Bengt Ingemar
Original assignee: Draco Ab
Priority date: 1985-04-04
Filing date: 1993-07-30
Publication date: 1996-04-20
Also published as: DE3687239D1; CN1021444C; UA13319A; RU2081879C1; JPS61236794A; CS266581B2; LV10957A; LV10281B; KR930009444B1; DE3689936D1; DK59392D0; DK59392A; DK167574B1; IE61474B1; DK138386D0; FI861275A0; CA1333597C; LTIP1677A; IL78143A0; FI85378B

Description

LV 10957 CJI03KHLIE 3ΦΗΡΕΙ 16, 17-AUETAJIB3AMEIIJEHHOM AHJļPOCTAH-17 b-KAPEOHOBOH KHCJIOTEI, CnOCOE HX nOJiyHEHHH, ΗΧ ΠΟΛΥΠΡΟ^ΥΚΤΕΙ H CnOCOE ΠΟΛΥΗΕΗΜΑ nOCJIEJļHHX, OAPMAIļEBTHHECKHE ΠΡΕΠΑΡΑΤΕΙ

OnHcaHHe

HacTOiimee H3o6peTeHne othochtch k ηοβμμ, Φ3ρμ3κο.πογηη6οκη aKTHBHblM COeūHHeHHūM, Η HX npOMe>KyTOHHbIM npO^KTaM nOJie3HbIM HJlil jieneHHfl οοοτοληηη 3^opoBbH, xapaKTepH3yeMbix BocnojiHTejibHbiM 3a6o-neBaHHeM, ajiepraen, 3a6ojieBaHHH cKejieTHbix Mbimu η κο^κηβιχ 6ojie3Heft. IIpejiMeTOM HacTO^mero H3o6peTeHHa cjivjkht oGecneneHHe γπιοκο-KOpTHKOCTepOHflOM, ObnajīaiOmHM BbICOKOH npOTHBOBOCnaJIH- TeJIbHOH aKTHBHOCTbK) Ha MeCTe npHMeHeHHfl H HH3KHM rJlIOKOKOpTH- KOHHHblM CHCTeMHbIM ^eHCTBHeM. H3BecTHO, hto onpejie^eHHbie nnoKOKOpTHKOCTepOHiibi (ΓΚ(ϋ) mo>kho npHMeHilTb ZIJIH MeCTHOrO JieHeHHfl BOCnOJlHTe.lbHbIX, aJI.neprHHeCKHX hjim HMMyHOJiorH4ecKHX 3a6ojieBaHHH ^bixaTejibHbix πγτείί (HanpHMep acTMa, BocnajiHTejibHoe 3a6ojieBaHHe cjih3hctoh o6ojiohkh Hoca (phhht), kojkho-ro noKpoBa (3K3eMa, ncopHa3), TaioKe κηιιιθηηηκβ (ji3BeHHbiH kojiht, 6o-jie3Hb KpoHa). Πομημο TaKofi μθοτηοη γ,πιοκορτηκοη,ιιηοη TepannH, flocTHratoTc^ κnHHHHecKue npeHMymecTBa npn o6meii TepannH (HanpHMep 3a cneT npHeMa πιιοκοκορτηκοη,ζιημχ Ta6jieT0K), ocoGenHO b OTHOineHHH He»:ejiaTejibHbix πιιοκοκορτΗΚΟΗΰΗΜΧ βο3Λ6ηοτβηη βηθ yna-CTKa 3a6oJieBaHH5L ,ΰ,ΠΗ flOCTHJKeHHfl Τ3ΚΗΧ nOHO)KHTeJlbHbIX KJIHHHHeCKHX npeHMymecTB, Hanp. πρπ τηχθιιμχ 3a6ojreBaHHHx ,nbixaTejibHbix njrefi, TKC hojdkch o6jiaziaTb nojiJieacaiuHM φapMaκoJT0ΓHt^ecκHM προφΗΐτθΜ. Oh flOJDKeH HMeTb BbicoKyK), npncyinyK) eMy co6cTBeHHyio ηποκο-KopTHKOHjļHyio aKTHBHOCTb npn npHMenaHHH, ho Tao^e h 6bidpyK) 2 HHaKTHBauHio nocpezicTBOM, HanpnMep, rn/zpojnm b ueneBOM opraHe hjih nocjie BHe^peHHa b oGmee KpOBOoGpameHHe.

TaK KaK npMCoe^HHeHHe TKC κ γ.πιοκοκορτμκοηχιηομυ ρβηεπτοργ iiBJiaeTca HenpeMeHHbiM npejiBapHTejibHbiM ycjioBHeM rīix τογο, htoGm HMenH μθοτο ero npoTHBOBoenajiHTeabHbie n προτΗΒθ-aruieprHHecKMe jieHCTBHa, to cnoco6HOCTb cTeponaoB cBa3bmaTb OTHOcainneca κ hmm peuenTop hjih peuenTopbi bo3mo>kho Hcnojib30BaTb KaK πρηγολημη cno-co6 onpe^ejieHMa GnojiorHHecKOH βκτηβηοοτη TKC. HenocpeacTBeHHoe cooTHomeHMe Meayiy cpencTBOM TKC κ peuenTOpy h ero nporaBOBoc-nojiHTejibHbiMH nencTBHaMH noKa3aHO nyreM npHMeHeHHa ncnbīTaHHa Ha OTeMHOCTb yxa y Kpbic. (Οοοτηοιηθηηα Me;Kiiy χημηηθοκοη στργκτγροπ, CBittbiBaHHeM c peuenTopoM h c GnojioruMecKOH aKTHBHOCTbio jma HeKO-Topbix ηοβηχ, BbicoKoaKTHBHbix, 16a, 17a - aueTajib3a\iemeHHbix ππιοκο-κορτηκομλοβ cm. E. Dahlberg, I.Thalen, R.Brattsand, 1.A.Gustafsson, U.Johansson, K.Roempke h T.Saantoler Mol. Pharmacol, 25 (1984), 70).

HacToamee H3oGpeTeHHe ocHOBaHo Ha HaGjno^eHHH, hto HeKOTOpbie onpe^ejieHHbie cjio>KHbie οφπρΜ 3-OKco-aH^pocTa- l,4-jiHeH-17^- KapGo-HOBOH KHCJIOTbl oGjianaiOT BbICOKHM CBa3yiOmHM CpēJICTBOM OTHOCHTeJIbHO ΓΠΙΟΚΟΚΟρΤΗΚΟΟΤερΟΗΛΗΟΓΟ peuenTOpa. CoOTHOIIieHHa ΠΟ Η3θ6ρβΤΘΗΗΚ) M05KH0 npHMeHaTb RΪΙΆ ηβΗβΗΗΛ H BOCnperUITCTBOBaHHa pa3BMTHK) BOC-naJ!HTeJlbHbIX COCTOJIHHH.

Coe^HHeHHa H3oGpeTaHHa xapaKTepn3yeTca φορΜγηοίί I: OR3

C = Q

CH3 O

rae: 1, 2 no3Hnna HacbimeHa hjih ημθθτ λβοηηυιο CBa3b; XI BbīGpaH H3 Boaopona η φτορ3; LV 10957 X2 Bbi6paH H3 Bojiopona η φτορ3;

Rl - Bbi6paH H3 Bojiopona hjih C1-C4 ajiKH/ia; R2 - BbīGpaH H3 Boziopojja hjih C1-C5 anKHJia; R3 - BblGpaH H3 0 0

II

II CR4R5OCR6 HJIH CR4R50CYR6 Y 03HaiiaeT O; R4 Bbi6paH H3 Bojjopcma, C1-C5 ajiKHjia, hjih Φθηηιή; R5 BbiSpaH H3 Bonopona hjih MeTHJia; R6 Bbi6paH H3 Boziopojia ιιηηθηηβιχ hjih pa3BeTBjieHHbix, HacbimeHbix hjih HeHacbimeHbix C1-C3 yrjieBOjiopojiHbix iienen, C1-C4 ajiKHjībHoii rpynnbl, 3aMemeHHOH φτΟρΟΜ, φεΗΗΙΙΒΗΟΗ HJIH 6eH3HJIbHOH rpynn, HJIH panHKana φορι^ιΐΜ:

IIpH yCJ10BHH HTO, eCJIH R2 - BOflOpOZl, TO Rl -C1-C4 aJIKHJI. OTjiejibHbie CTepeoH30MeTpHHecKHe κομποηβητβι, npHcyTCTByioiuHe b CMecH CTepoHjja, HMeiomero yKa3aHHyio Bbiuie φopMyJIy (I), mojkho noacHHTb cjiejiyK)mHM o6pa30M: OR3 C=0

HO CH3

---0 --O

/R2 ^Ri CH3

Xi

(II, 3nHMep S) X2 0 4 or3 c=o

OTflejibHbie, CTepeoH30MepHbie κομποηθητβι, npncyTCTyiomHe b CMeCH CTepOH^a CJIO>KHbIX 3φκρ0Β 17β - KapSoHOBOH KHCJIOTbl, HMeiOLUHe φop^ίyJly IV:

O O

II II

St CCr4R50CYR6 (V) o o

II II

St COCR4R5OCR6 (IV) HJTH T^e St 03HaHaeT CTepOH^HblH φρ3ΓΜ6ΗΤ, MOJKHO nOBCHHTb CJieZiyK)lHHM o6pa30M:

O R4O

II I II st coqocR6 1 R5 (VI) O R4 O II I II st coqocR6 R5 (VII) O R4 o 11 1 II st cogocm 1 R 5 O R4 o II I IIst coqocYR6 R5 (VIII) (IX) LV 10957

JlHacTepeoH30Mepbi, no^o6Hbie II, III, VI, VII, VIII η IX pa3JiHMaioTCii ΠΟ ΚΟΗφΗΓγρ3Ι1ΜΜ JlHllIb ΠΟ OflHOIV^ H3 pa3JIHHHbIX aCHMMeTpniieCKHX aTOMOB yrjiepozia. TaKne ,nnacTepeoH30Mepbi ο3Η3Μ3ιοτ anuMepbi.

HacTHbie coeaHHeHRH no H3o6peTeHHio aBJiinomeeca npe,nnoMTHTe.nb-

HblMHI 1) r-3TOKCHKap6oHHjioKCH3TH^ 6a,9a -βΗφτορ-11/?-οκ<:Η-16α,17α-/ (l-MeTHJi-3THJieneH) 6nc(oKCH)/-aH.apocTa-l,4 -.QHeH-3-OH-17^- nap-6oKcnjiaT, annMepHaa CMecb A+Bh annMepa B. 2) r-H3onponoKCHKap6oHHjiOKCM3THji 9α-φτορ-ΙΙβ-οκοΗ-16α, 17α-/(l-MeTHJi3THJiHjieH) 6hc(okch)/- aHļipocTa-1,4- ,nHeH-3-OH -17/3-Kap-SOKCHJiaT, 3ΠΗΜΘΡ B. 3) r-npOnOKCHKap60HHJIOKCH3THJI 6α,9α-ΛΗφτθρ-11/3-ΟΚΟΗ-16α, 17a-/(l-MeTHJi3THjm/aeH) 6hc(okch)/- anpocTa-l,4-^HeH-3-OH-17^- xap-6oKCHJiaT, 3ΠΗΜβρ B. 4) l’-H3onponoKcnKap6oHHjioKCH3THji 6α,9α-ΰΗφτορ-11/3-οκοΗ-16α, 17a-/(I-MeTHji3THjinfleH)6Hc(oKCH)/aHApocTa-l,4-flHeH-3-OH-17/3- Kap-6oKCHj:aT, anuMepHaH CMecb A+Bh annMepa B. 5) r~AueT0KCH3TH^ (20R)-9a^Top-ll/2-OKCn-16a, 17a-nponHJi-MeTHjieHj];oKCHaHpocTa-l,4-flHeH-3-OH-17^-Kap6oKCHJTaT, anniviep B. 6) l’-3TOKCHKap6oHHjioKCH3THji (22R)-9a^TOp-lljS-OKcn-16a, 17a-nponnjiMeTMjieiiHOKCHaHiipocTa-l,4-flHeH-3-OH-17/3-Kap6oKCHjiaT, annMep B. 7) r-H3onpopOKCHKap6oHHjieKCH3THJi (20Κ)-9α-φτορ- 11)8-okch-16a,17a-nponnjiMeTHjieHiiHOKcnaHzipocTa-l,4-iiHeH-3-OH-17/3-Kap6oKc HJiaT, 3ΠΗΜβρ B. 8) l’-3TOKCHKap6oHHji okchsthji (20R)-6a,9a- ΛΗφτορ-ΙΙβ- okch-16a,17a-nponnjiMeTHJieH^HOKCHaHiipocTa-l, 4-^neH- 3-oh-17^- Kap-6oKCHJiaT, ariHMepHaii CMecb A+B n snuiviepa B.

Coe^HHeHHa no H3o6peTeHHio nojiyMaiOT oKCHJieHHeM coeflHHeHHa φορινιγ^ X, XI η XII b cooTBeTCTByiomyio 17/3-Kap6oHOByio κηοποτγ: 6 CH2 - OR7 6

CH2-OR7 c=o

/R2 ^Ri CH2-OR7 C = 0

rae cnnouiHaii mjih npepbiBHCTaa jihhhh osHanaiOT ojļHHapHyio hjih ΛΒΟΗΗΥΚ) CBH3b. LV 10957

Xl, Χ2, Ri h R2 ΗΜΘΚ)Τ yKa3aHHbie Bbirne 3Ha4eHiui, R7 03HaHaeT Bouopoji hjih auHjibHyio rpynny c 1-10 βτομβμμ yniepojia, pacnono- >kch-

HblMH B ϋΗΗΘΗΗΟΗ HJIH pa3BeTBJieHHOH UeiIH. 3aTeM 17/3-Kap6oHOBbie kmcjiotu noziBepraiOT peaKUHH o6pa30BaHMa cjio>KHor() 3φκρ3, Ητο πρηβο,κητ κ coeflHHeHnaM, xapaKTepH3yeMbiM φορ-

MynaMH Ι-ΙΧ, nie------ Χι, Χ2, Ri, R2 h R3 ημθιοτ yKa3aHHbie Bbirne 3ηβηθημλ.

Cnoco6, npe^CMaipHBaiomHH npeBpameHHe coeaHHeHHH φορΜνη X, XI hjih XII b cooTBecTByioinHe 17y3-Kap6oHOBbie khcjiotm, npoBojurr b nojixojiHmeM OKcnreHHpoBaHHOM ymeBoziopoziHOM pacTBopHiejie, tbkom HJIH HH3UIHH aJIKaHOJI, MeTaHOJI H STaHOJI. ĪIpejIHOHTHTeJIbHbl MeTaHOJl H 3TaHOJi, οοο6θηηο nepBbiH. PeaKUHOHHyio CMecb ūobojuit jio cjiaoo-mejion-hoh cpezibi nocpejiCTBOM zio6ajieHH5i nozixo,zuimero cjiaSoro HeopraHHHec-Koro ocHOBaHHa, Tanoro KaK KapSoHaT mejioHHoro MeTa.uia, HanpHMep, KapSoHaT Haipn^i, ιιητηλ h Kajiηλ. IlocjiejiHHH npejinoHTHTejieH. npeBpa-iiieHHe coeziHHeHHa φopMyJIbI X, XI hjih XII b 17£-Kap6oHOByio khcjioij φopMyJIL·I I, II hjih III (R3 = Η) προποχΟΛΗΤ πρπ TeMnepaType OKpy>KaK)iuefi cpejibi, T.e. npH 20-25° C. #jih peaKUHH Heo6xojiHMO npHcyTCTBHe KHCJiopona. Kucjiopon mo>kho nocTaBjiaTb 6ap6oTHpOBaHHeM CTpyn B03nyxa hjih KHCJiopojia b peaKUHOHHyK> CMecb. OKHCJiHTejibHoe pa3pyineHHe 17j3-6okoboh uenn οοθαηηθηηη φopMy-jibi X, XI η XII b cooTBeTCTByioiHHe 17/3-Kap6oHOBbie KHCJiOTbi mojkho ocymecTBjiaTb TaioKe c hohhoh khcjiotoh, γηπο6ρομβτομ HaTpna, hjih BHCMyTaTOM HaTpna. PeaKUHio npoBojuīT b CMēCH bojui c nonxojiamHM OKCHreHHpOBaHHeM yrJieBOJIOpO^HbIM paCTBOpHTeJieM, T3KHM KaK HH3LUHH npocTOH 3φπρ. npennoHTHTejibHbi ziHOKcaH h TeTpBrHjip(^ypaH ocoGeHHo nepBblH. 17)8-Kap6oHOBbie khcjioth coenHHeHHH φopMyJIbI I, II η III (R3 = H) MCUKHO nOJIBepraTb peaKUHH o6pa30BaHHJI CJI05KH0IO 3φπρ3 oGbIHHbIM o6pa30M, mia nojiyMeHHa 17yS-Kap6oKCHJiaTHbix cjio;KHbix 3φπροΒ naHHoro H3o6peTeHHa. HanpHMep, 17£-Kap6oHOByio khcjiott mojkho nonBepraTb peaKUHH c cooTBecTcyiomHM οππρτοΜ h KapOojiHHMHzioM, Hanp. πηηηκπο-reKCHJiKap6ojiHHMHjioM, b nouxouanieM pacTBopHTejieM, tbkom KaK JIH3TMJIOBbIH 3φπρ, TeTparHJipO$ypaH, MeTHJieHXJIOpHJI HJIH nHpHUHH, npeHMymecTBeHHO πρπ TeMnepaType 25-100° C. B KanecTBe βο3μο>κηογο BapnaHTa, co/ib 17y3-Kap6oHOBOH KHCJiOTbi, o6pa30BaHHaa mejiOHHbiM Me- 8

TajiJiOM, HanpHMep JiHTHeM, HaTpneM hjih KajiHeM, hjih cojib, o6pa30BaHHaji HeTBepTHHHbIM ΟΟβΛΗΗΘΗΗΘΜ aMMOHHŪ, HanpHMep TpH3THJI - HJIH TpH6yTHJiaMHHOM, hjih TeTpa6yTHJiaMMOHHeM, MO>KeT no^BepraTbca peaKUHH C ΠΟ^ΧΟ,αίΙίΡΗΜ aJIKHJIHpyiOmHM CpejICTBOM, HanpHMep anHjioKCHajiKHjiranHflOM hjih rajioajiKHji ajiKHJiKap6oHaTOM, npezi-noHTHTejibHO b cpezie nojiapHoro pacTBopnTejia, Tanoro Kan aneTOH, MeTHJI3THJlKeT0H HJIHJIHMeTHJKļH)pMaMH,ZI,JIHMeTHJICyj^()KCHJI, MeTHJieH-xjiophh hjih χποροφορΜ, y^o6HbiM o6pa30M npn TeMnepaType b npejiejiax 25-100° C. PeaKiļHK) bo3mo>kho npoBOjiHTb TaioKe b npHcyTCTBHH Kpoy-Η3φπρ3.

HeOHHmeHHbie CTepOHJIHbie ΟΙΟ>ΚΗ03φΗρΗΒΙ6, npOH3BOZIHbie, o6pa30-BaHHbie nocjie BbmejieHHa, OHHiiiaiOT xpoMaToiļ^HeH Ha nozixoipimeM MaTepnajie, HanpHMep Ha ,,οιπητμχ” nonepenHbiMH cbjhamh rejuix ne-KCTpaHa THna „Sephadex LH” c npHMeHeHHeM ποζιχο^ιιιηχ pacTBopnie-jien b KanecTBe sjnoeHTOB. ĪIpHMepaMH cjiyxaT rajionjiHpoBaHHbie yrjieBOiiopozibi, npocTbie 3φπρΜ, cjioxHbie 3φπρΒΐ - TaKne, KaK arajianeiaT HJIH aueTOHHTpHJI. OTjiejibHbie anHMepbi, o6pa3yiomHeca npn aneTOJiH3aiiHH 16a, 17a-OKcnrpynn hjih npn o6pa30BaHHH cjio>KHbix 3φκροΒ 17/3-Kap6oHOBbix khcjiot, oSjiajiaiOT npaKTHnecKH T(wiecTBeHHbiMH xapaKTepncTHKaMH pac-TBopHMOCTH. CjiejioBaTejibHo, hx CTaHOBHTca HeB03M0»:H0 pa3ziejuiTb h H30jiHp0BaTb H3 anHMepHOH CMecH nocpejicTBOM ο6βιηηογο cnoco6a pa3-JieJieHHH CTepe0H30Mep0B, HanpHMep φρ3ΚηΗ0ΗΗρ0Β3ΗΗ0Η KpHCTajiJiH3auHeH.JlJiJi nojiyHeHHa HHHHBHjiyajiHbix anHMepoB, CTepeoH3o-MepHbie CMecH φopMyJI I, IV η V, nojiCHeHHbix Bbiuie, nojiBepraiOT xpoMa-τοτρ3φΗΗ Ha KOJiOHKe. TaKHM nyTeM pa3jiejiHaioTca annpeMbi II, III, VI, VII, VIII Η IX, BBHJiy pa3JIHHHOH nOHBH^HOCTH Ha CTaUHOHapHOH φ336. Xpo-Μ3ΤΟΓρ3φΗΚ) MO>KHO npOBOJIHTb HanpHMep Ha „CIHHTbIx” nonepeHHbIMH CBa3aMH rejuix aeKCTpaHa THna ,^θφ3ί[6κο LH”, HanpHMep, „Οεφ3ϋ6κο LH-20" b coneTaHHH c nojpcojpimHM opraHHnecKH pacTBopniejieM b Kane-CTBe ajiioeHTa. „Οεφ3Λ6κο LH-20" npoH3BoziHTca φπρΜΟΗ „Pharmacia Fine Chemicals” YnncajiH LIlBenHa. 3το h Me io luh η φορΜ>τ 6ycnHOK rnzīpoKCHnponHJiHpoBaHHbiH HecTpaHOBbin renb, y κοτοροΓΟ nenn jie-KCTpaHa „CLUHTbi” Me^y co6oh, o6pa3ya TpexMepHyio nojiHcaxapHjmyK) pemeTKy. B KanecTBe 3jnoHpyioiiiero areHTa ycneniHO Hcnojib3yeTca ra-jiOHjiHpoBaHHbie yrjieBOjiopojibi, HanpHMep xJIOpoφopM hjih CMecb renTaH- LV 10957 χϋοροφορΜ3Τ3Η(χπ b cooTHomeHHH 0-50: 50-100:10-1, npezinoHTHTejibHO CMecb 20:20:1. B KanecTBe ηοχοαημχ MaTepnanoB ααα ποαυηθηηα οοοαηηθηηη no H3o6peTeHHio πρηΜβΗΑίοτ coe/iHHeHHH φορΜγιι X, XI η XII. Hx nonyMaK)T peaKUHeH οοθαμηθημη, ημθιοιιιηχ φορΜγηγ XIII: ch2 - OR7 c=o

X2 nae crmoiiiHafl hjth npepbiBHCTbie jihhhh Me»my C-l h C-2 03Η3Η3ιοτ npOCT>'K) HAH ΑΒΟΗΗΥΚ) CBA3b; Χΐ, Χ2 m R7 HMeioT yKa3aHHbie Bbirne 3HaHeHHA, c ajībaerHAOM φορ-μυαβι O = CHR2, rae R2 HMeei yKa3aHHoe Bbirne 3HaMeHHe.

AjībAerHAOM cjiy)KnT npe#noHTHTejibHO aiaeTaTeAbAerHA, nponaHaji, 6yTaHOA, H3o6yTaHaji, neHTaHaji, 3-μθτηα 6yTaHaji -2,2- αημθτηα- nponaHaji, reKcaHaji, renTaHaji, OKTaHan, HOHaHaji η αοα6Κ3Η3Α. PeaKiļHio npoBO-Aht π}τθμ αο6οβα6ηηα CTepoRna κ pacTBOpy ajībAernAa cobmcmtho c KHCAOTHbIM Κ3Τ3ΑΗ33Τ0ρ0Μ, Hanp. ΧΑΟρΗΟΗ KHCAOTOH, n-TOAyOACVAb-φΟΚΗΟΑΟΤΟΗ, XJIOpCTOBOAOpOAHOH KHCAOTOH Β Cpefle ΠρΟΟΤΟΓΟ 3φ»ρ3, npeAnoHTHTenbHO AHOKcaHa hjih γ3αοηαηροβαηηβιχ υγαθβοαοροαοβ, npeji-nOHTHTeAbHO - MeTMAeHXJIOpHAa HAH ΧΑθρθφθρΜ3.

CoeAHHeHHA X, XI η XII noAyHaioT TaioKe πγτβΜ TpaHcaneTaAH3aiiHH cooTBecTByK>mnx 16a,17a- aneTOHHAOB XIV: 10 CH2 - OR7

rjie cnjiouiHbie hjih nyHKTHpHaa jihhhh Me>Kay C-l h C-2 03Η3ηβιοτ προπγιο hjih hbohhjto CB^3b; a Χι, Χ2 h R7 hmciot npMBejteHHbie Bbiuie 3HaneHHH, c anbiierH^OM φορΜγπΒΐ: O = CHR2, rae R2 HMeeT Bbirne yKa3aH-Hbie 3HaneHHa.

AjībflernjiOM cjiy>KHT npejinoHTHTejibHo aneTanbjierHu, nponaHaji, 6y-TaHaji, H3o6yTaHaji, neHTaHaji, 3-MeTHJi6yTaHaji; 2,2-jiHMeTHjinponaHaji, reKcaHan, rernaHaji, OKTaHan, HOHaHan h ^eflenaHan. PeaKiļHio npoBojuīT πγτβΜ ao6aBjieHHa creponna κ pacTBopy ajībjiernua b Mecie c chjibhoh HeopraHHHecKoii khcjiotoh b KanecTBe KaTajiH3aiopa, npennoHTHTejibHo XJIOpHOH HJIH XJIOpHCTOBOZIOpOHHOH KHCJIOTOH B Cpejie ΠρΟΟΓΟΓΟ 3φπρ3, npenno^HTHTenbHO nHOKcaHa hjih TeTpamapo<i>ypaHa, rajiojiHpOBaHHoro yrjieBOflopoBa, npejmojiHTHTejibHo MeTHjieHXjiopHjia hjih xjiopocļ)opMa, apoMaTHMecKoro yrjieBOjiopojia, npejmojiHTHTejibHO TOJiyojia, ajinnHKjiHHe-CKoro yrjieBoiiopojia, npeanoziHTHTejibHo rernaHa hjih H300KTaHa, npH^ieM npn nocjiejiHHx ycjioBHax ycTpaHiieTCJi cTajiHH xpOMaτoΓpaφHH hjih nojiy-neHHa sriHMepoB III η XII.

CoeziHHeHH no H3o6peTeHHio mojkho Hcnojib30BaTb aria pa3JiHHHbix BHJIOB MeCTHOrO Η33Η3ΗΘΗ6ΗΗίΓ B 3aBHCHMOCTH OT MeCTOHaXO>K£eHHil yiia-CTKa BocnaneHHa, HapHMep, Ha κοτκθ, napaHTepajībHO hjih JioKajībHoro Η33Η3ΗΘΗΗΗ nOCpeflCTBOM HHraJLHLIHH JUIJI flbIXaTēJIbHbie nyTH.

Ba>KHOH uejibK) npn cocTaBjieHHH penenTvpbi cjiyacHT ziocTH^eHiie OnTHMajībHOH 6HOJIOCTynHOCTH 3ΚΤΗΒΗΟΓΟ CTepOHHHOrO HHrpejļHeHTa. JļjIH peuenTyp, Hcnojib3yeMbix kojkhbim nyTe\i. sto ycneuiHO nocTHraeTca, ecjin CTepOHH C BbICOKOH TepMOHHH3MHH6CKOH aKTHBHOCTbK) paCTBOpaiOT B HOCHTēJie. JIocTHraeTCii sto 3a ciieT npHMeHemifl no,nxo,iyimeH cncieMbi LV 10957 pacTBOpmejieH, BKJHonaiomeH nozixo^HtUHe tjihkojih, TaKHe KaK npOnHJieHrjIHKOJIb HJIH l,3-6yTaHJIHOJI, HJIH KaK TaKOBOH, HJIH COBMeCTHO C BOJIOH.

Mojkho Taoce pacTBopaTb deponē hjih nonHOCTbio, hjih HacTHHHO b JIHm^HJIbHOH φ33θ C ΠΟΜΟΙΙίΜΟ ΠΟΒ6ρΧΗΟ(ΠΉΟ-3ΚΤΗΒΗΟΓΟ BemeCTBa B KanecTBe cpejiCTBa, cnoco6cTByioinero pacTBOpeHHio. Κομπο3ηηηθη jijiji Κ05ΚΗΟΓΟ BBeaeHH^ Μοχςετ 6biTb Ma3b, κρθΜ THna «Bozta b Macjie» hjih JIOCbOH. B 3MyjIbCHOHHbIX HOCHTejIflX HJIH HHepTHbIX CpejiaX CHCTeMbI, COJiep^CameH paCTBOpeHHblH aKTHBHblH ΚΟΜΠΟΗβΗΤ, φ333 ΜΟ/ΚΘΤ 6bITb jīHcnepCHOH hjih HenpepbiBHOH. Crepom MO^ceT TaiūKe npeObmaTb b yKa- 3aHHbIX Bbime K0Mn03HIJHJIX B BHJļē nO,IIBeprHyTOr() MHKpOH3MejIbHeHHK) TBepjioro BemecTBa. JļjiH HHrajiaiiHH nojiocTen pTa h Hoca npeuHasHaneHbi aapoaojiH CTepoHjioB, HaxojiamHecii nojj jiaBjieHHeM. A3po30JibHyio cHcieMy cociaB-juuot TaKHM o6pa30M, ητο6μ Kax;naa BbinycKaeMaa zicm cojepjKana 10-1000 μκγ, npennoHTHTejibHO 20-250 μκγ βκτηβηογο CTeponzia. HanOajiee aKTHBHbie CTepeoHjībi Ha3HaHaioTca jum npneMa b HiDKHeivi npeaejie ηητθρ-Bajia Λ03ΗΡΟΒΚΗ. MHKpOH3MeJIbHeHHbIH CTepeOH^ COCTOHT H3 HaCTHIļ, no cymecTBy μβηβιπηχ 5mkm, cycneHj[HpOBaHHbix b CMecn cpejiCTBa hjw o6pa-30B3H Hfl a3p030JIH ΠρΗ ΠΟΒΜΙΙΙβΗΗΟΜ .HaBJIBHHH C nOMOlIļbK) ^HcneprHpyiomero cpejiCTBa, TaKoro KaK copOHTaH TpnojieaT, ojieHHOBaa KHCJioTa, jieiļHTHH hjih ytae HaipHeBaa cojib zmoKTHjicyj^oaHTapHOH KHCJIOTbl. H3o6peTeHHe iiajiee noacHaeTca cjieayiomHMH, HeorpaHHMHBaiomHMH npHMēpaMH. B npH\iepax, npn npOBejieHHH οπβιτοβ npenapaTHBHOH xpo-Μ3ΤΟΓρ3φΗΗ ηρΗΜΘΗΛΙΟΤ oO^eiV^K) CKOpOCTb HBHJKeHHfl noTOKa 2,5 mji/cm h . Bo Bcex npHMepax MOjieKyjiapHbie Beca onpenejieHbi nocpen-ctbom 3JieKTp0HH0-ynapH0H Macc-cneKTpoMeTpHH. Tohkh njiaBjiemia H3MepeHbi c Hcnojib30BaHH6M MHKpocKona φπρΜΗ „JIeHTiļ Bemnap”. Bce aHajiH3bi HP L C (HP L C= ΒΗθοκο3φφθκτΗΒΗ3ίΐ jKRUKOCTHaa xpoMaior-ρ3φΗΛ> npoBejieHbi c kojiohkoh „Waters μ Bondarak” Cis 300x3,9mm BHyTpeHHHH anaMeTp πρκ ο6τ>θΜΗθίί ckopocth noTOKa 1,0mji/mhh. h CMecbio 3TaH0Jia c βολοη b cooTHomeHHH ot 50:50 λο 60:40 b KanecTBe nOJlBH>KHOft φ33ΒΙ, ΠρΗ OTCJHTCTBHH HHbIX yKa3aHHH. 12 ΠρΗΜβρ 1 JļaHHbiH npHMep M3JiaraeT cnoco6 nojiyHeHHH (22RS)-, (22R)- h (22S)-ll/3-16a-17a-, 21-TeTparnjipoKCHnperHa - 1,4- ziHeH-3,20-jiHOH-16α, 17α aueTajien. npuroTOBJieHne (22RS)-, (22R)- h (22S)-16a, 17a- 6yTHJiHneH- jihok-ch- 6a, 9a -,ζΐΗφτορ-11/3,2l-,aMrHflpoKCHriperHa-l,4-jļHeH-3-,20-jiHOHa. A. K cycneH3HH l,0r 6a, 9α-^Ηφτορ-11/3,16a, 17a, 21-TeTparHjipo-KCHnpreHa-l,4-flHeH-3,20-flHOHa b 500 mji MeTHJieHXJiopHna no6aBJunoT 0,32 mji cBejKeneperHaHHoro H-6yTaHOJia h 2 mji 72%-hoh xjiophoh KHCJIOTbl. PeaKlļHOHHyiO CMeCb OCTaBJIJĪIOT CTOJITb npH KOMHaTHOH TeMne-paType h npH nepeMeuiHBaHHH Ha 24 h. PeaKUHOHHyio CMecb npOMbreaiOT 10%-HbIM BOJIHbIM paCTBOpOM KapGOHaTa KaJIHJI H BOJIOH, BbICyLUHBaK)T HajI cyJIbφaτoM HaTpmi h BbinapHBaiOT. OcTaTOK pacreopiiioT b 3THjiaueTaTe h oca»maiOT neTpojieHHbiM 3φπροΜ. OcTaeTca 883 μγ (22RS)-16a,17a-6yτHJIHJ^eH(αHΓHi^poκcH-6α,9α-JIHφτop-ll^, 21-jinrHjipoKCHnperHa -1,4-jlHeH-3,20-jiHOHa. HP L C -aHajiH3 noKa3biBaeT 99%-hvio HHCTOTy h cooTHomeHHe 16:84 y 22S h 22R-3nHMepoB. MojieKyjmpHbiH Bec : 466. (BbiHHCJieHO 466,4) (22RS) 3nnMepHyio CMecb χροΜ3τοΓρ3φπρνιοτ Ha ko-jiOHKe „€βφ3Λ6κο L H-20” (76 x 6,3 cm) c npHMeHeHneM renTaH: xjiopo-φορΜ: 3TaH0Ji, 20:20:1 b KaHecTBe πολβη>κηοη φ33Μ. OpaKUHii 12315-13425 mji (A) h 13740-15690 mji (B) coGnpaiOT, BbinapHBaiOT, OCT3TOK pacTBopjuoT b MeTHjieHXJiopHiie h oca>K,aaK)T neTpojieHHbiM 3φκροΜ. Φρ3κΐ1ΗΗ (A) ūaeT 62 μγ (22S)- φρ3κιΐΗϋ B 687 μγ (22R)-16a,17a-6yTHJinneHHHOKCH -6α,9α-ιΐΗφτορ ll/3, 21-jiHrHjipoKCHnperHa-l,4-jiHeH-3,20-jiHOHa (22S)-3nHMep: MOjmKyjmpHbiH Bec 466 (BbiHHCJieHO 466,5), T.nji. 196-200°C. (22R)-3nHMep: MOJieKyjuipHbiH Bec 466 (BbiHHCJieHO 466,5), T.nji. 169-172° C. B. K pacTBopy 1,0 r 6α, .9α -βπφτορ- 11β ,21 -jiHrHnpoKCH-16a, 17a-[(l-MeTHJi3THJiHjieH)6Hc(oKCH)] nperHa-l,4-jnieH-3,20-ziHOHa b 500 mji MeTHjieHxjiopHjia aoSobjuiiot 0,30 mji CBeaceneperHaHHoro H-6yTaHOJia h 2mji 72%-hoh xnopHOH KHCJiOTbi. PeaKUHOHHyK) CMecb ocTaBJiHioT cTOiiTb 24h npH 33° C npn nepeMeuiHBaHHH, 3KCTparHpyioT βοιιημμ pacT-BopoM KapSoHaTa Kajina h bojioh, BbicymHBaioT Haji cyJIbφaτoM HaTpna h BbinapHBaioT. OcTaTOK pacTBopjnoT b MeTHjieHXJiopHne h oca>KnaK)T neTpojieHHbiM 3φπροΜ. Bbixon 848 μγ (22RS)-16a, 17a-6yTHjivmeH- ahokch- LV 10957 6α,9«-ΛΗφτορ-11^, flHrH^pOKCHnperHa-l^-iiHeH-S^O-flHOHa. HP L C-aHanM3 noKa3aji 93%-Hyio cieneHb mmctotli h OTHomeHHe 12/88 Me>Kziy 22 S- m 22 R- anHMepaMH. Λ B . K cycneH3HM 4,0 r 6a, 9a -βΗφτορ- 11/3 ,21 -flHrMjļpOKCH-16a, 17a-[(l-MeTMJi3TH^HfleH)6Hc(oKCH)] nperHa-l,4-jineH-3,20-jiHOHa b 100 mji renTaHa ,zio6aBjiiiK>T 1,2 mji CBejKeneperHaHHoro H-6yTaHa h 3,8 mji 72%-HOH XJIOpHOH KHCJlOTbl. PeaKUHOHHyiO CMeCb OCTaBJUIIOT CTOJITb npH KOMHaTHofi TeMnepaType Ha 5 h npH ηητθηοηβηομ nepeMeniHBaHHH, skc-TparnpyK)T BOHHbiM Kap6oHaTOM Kajma η bo^oh, BbicyuiHBaiOT Ha^ cyj^a-tom HaTpua h BbinapHBaiOT. Βηχολ: 4,0 r (22RS)-16a, 17a-6yTHJiHzieH(aHOKCH-6a,9a -ΑΗφτορ-ΙΙβ, 21-flHrH,apoKCHnpreHa-l, 4-ZineH- 3,20-jiHOHa. HP L C -aHajiH3 noKa3aji 98,5%-Hyio hhctoty h otho-meHne Meacjiy 22 S- m 22 R- anHMepaMH 3/97. Flocjie 2 nepeKpncTajuiH3auHH H3 χϋοροφορΜ8 c neTpojieHHbiM 3φπροΜ nojiyMeHO 3,1 r 22R-3nHMepa, cojiep^amero ecero jiHuib 1,1% 22S -ariHMepa h 1,3% ZipyrHx 3arpa3HaiomHx npHMeceft. C. IIoflo6HbiM xce o6pa30M, cjie^ya npoueuype, H3JioxceHHOM b npHMe-pe, npH 3aMeHe 6a, 9a -ΛΗφτορ- 11β, 16a, 17α, 21-TēTparHflpoKCH- nper-Ha-l,4-flneH-3,20-flHOHa 11β, 16a,17a, 21-TeTparH^poKCH- nperHa-l,4-ūHeH-3,20-,iiHOHOM nojiyMatOT 9α-φτορ- η 6a-φτορ-11/3, 16a,17a,21-TeTpaoKCHnperHa-l,4-flHeH-3,20 ληοη hjih cooTBecTcy-K)mHMH 16a,17a,-aueTOHHflaMH t^TOpHpOBaHHbie Η φτθρπρθΒ3ΗΗΒΙ6 HecHMMeTpHHHbie (22RS)-(22R)- h (22S)-llfi, 16α,17α,21-τθτ- parHflpoKCHnperHa-l,4-ziHeH-3,20-flMOH 16a,17a-aueTajiH H3 aueTanb-Zienina, nponaHajiū, 6yTaHajia,H3o6yTaHana, neHTaHajia, 3-MeTHjnoyiaHajia; 2,2-aHMeTHJinponaHajiii, reKcaHana, reirraHajui, OKTaHajia, HOHaHajia η ho-fleKaHana. 14 npmviep 2 A. FIpeflHauHHOJioH 16a, 17a-aueTOHHjj (250 μγ; 0,6 mmojih) pacTBO-pHHDT b 75 mji MeTHJieHXjiopHiia. Jlo6aBji«K)T H-6yxaHajib (130 μγ; 1,8 mmojlh) h 70%-Hyio xjiopHyio KHCJiOTy (0,025 mji). PacTBop nepeMeiuiiBaioT npH 33° C 15 h. TKejiTbifi pacTBop npoMbieaiOT 2x10 mji 10%-ηογο pacT-Bopa KapOoHaTa Kajina h 4x10 mji bohm, BbicyuiHBaiOT h BbinapHBaiOT. Bbixoji: 257 μγ (97,7%). HP L C n0Ka3aji 91,l%-Hyio HHCTOTy. CojjepacaHHe HenpopearHpoBaBiuero aueTOHHjja cocTaBHjio 7,4% 3arpa3HeHHM. Cootho-meHHe mw ariHMepoB 14,6/85,4. B. TpnaMUHHOJiOH 16a, 17a-aueTOHim (0,5 r; 1,1 MMOJib) pacTBopaioT b 150 mji MeTHjieHXJiopnjia. /JoSaBJUiiOT H-6yTaHa;i (260 μγ; 3,6 mmojiji) h 70%-Hyio xjiopHyio KHcjioTy (0,22 mji). CMecb nepeMeuiMBaioT ripu 33° C b TeneHHe 16 nacoB. B jjejiHTejibHyio BopoHKy noMemaiOT MeTHjieHXjiopHH m peaKUHOHHyio KOJi6y npOMbiBaiOT HecKOjibKo pa3 10 mji Kap6oHaia KajiHJi m MeTHJieHxnopHjīOM, cooTBecTBeHHO. 3aieM pacTBop npoMbieaiOT 2x10 mji 10%-ηογο K2CO3 h 4x10 mji BOjibi, BbicymMBaiOT h BbinapHBaiOT. Βμχολ: 438 μγ (84,9%). HP L C noKa3ajia 80,2%-Hyio CTeneHb ηηοτοτμ. Cootho-uieHHe anHMepoB 19/81. C. Ojiioouhhojioh 16a, 17a-aueTOHHn (0,5 r; 1,1 mmojib) pacTBopaiOT b 150 mji MeTHjieHXJiopHjļa. JļoOaBJuiioT H-6yTaHaji (260 μγ; 3,6 mmojuO h 70%-Hyio xnopHyio KHCJioTy (0,22 mji). CMecb nepeMeiiiHBaiOT npw 33o C 24 h. MeTHjieHxjiopHHHyio φa3y nepeHocjrr b ,aejiHTejĪbHyK) BopoHKy. Koji6y jijib npoBeneHHtf peaKLiHM npoMbiBaiOT HecKOjibKo pa3 15 mji 10%-ηογο K2CO3 h MeTHJieHXJiopHjia, cooTBecTBeHHO. PacTBop npoMbieaiOT 2x15mji 10%-ηογο K2CO3 h 4x15 mji βοζιμ, BbicyuiHBaioT h BbinapHBaiOT. Bbixon: 513 μγ (100%). HP L C noKa3ajia 97,4%-Hyio CTeneHb ηηοτοτμ. Cootho-uieHHe jum anHMepa: 8,6/91,4. LV 10957

IlpHMep 3 flaHHbiH npHMep HJUiiocTpHpyeT cnoco6 nojiyHeHHa ll/?-rn,apoKCH-16a,17a-[(l-MeTHJi3THnHiieH)6Hc(oKCH)]- h (20RS), h (20R)-h (20S)-11/9-OKcn-16a, 17a-anKHJiMeTHJieHiiHOKCHaHjipocTa - 1,4- λμθη-3-οη-17/3 Kap6oHOBOH H-4-eH-3-OH-17/3-Kap6oHOBOH khcjiot. FIojiyHeHHe 6α, 9α-,ΐΐΗφτορ-11β-ΓΗ,ιιροκθΗ-16α, 17α-[ (l-MeTHji3THJi-MfleH) 6hC (OKCH)] aHflpOCTa- l,4-JIHeH-3-OH 17/?-Kap60H0B0H KHCJIOTbl. A. K pacTBopy 1,99 r φ^ιοοαΜΗΟιιΟΗ 16α, 17a-aueTOHHna b 120 mji MeTaHOJia jioSaBjiinoT 40mji 20%-ηογο βοζιηογο pacTBopa Kap5oHaTa Kajina. Hepe3 3tot pacTBop 6ap5oTHpyiOT cTpyio B03^yxa npHMepHO 20 nacoB npn nepeMeuiHBaHHH npH κομηετηοη TeMnepaType. MeTaHOJi BbinapHBaiOT h k ocT3TKy floSaBnaioT 200 mji βολβι. PacTBop 3KCTparHpyioT MeTHJieHx-JlOpMJļOM. BojIHyK) φa3y nOaKHCJUIIOT pa36aBJieHHOH XJIOpHCTOBOJIOpOZIHOH KHCJIOTOH. 06pa30BaBUIHeCiI OCa^OK C06npaiOT φρυΐΒΤρ0Β3ΗΗΘΜ H Bbl-cyiiiMBaioT, hto jiaeT 1,34 r 6α, 9a- ΛΗφτορ- 11/3 -rH.apOKCH-16a, 17a -[(l-MeTHJi3THJiM^eH) 6hc (okch)] aH^pocTa- l,4-nHeH-3-OH-17/3-Kap6o-hoboh KHCJIOTbl, Tonna njiaBJieHHJi 264-268°C MOJieKyjmpHbiH Bec 438. CTeneHb MHCTOTbi, onpe^ejieHHaa nocpencTBOM HP L C, cociaBjmei 94,0%. BojiHyK) φa3y 3KdparHpyioT STHjiaueTaTOM. Ilocjie BbicymHBaHHa pacT-BOpHTejib BbinapHBaiOT, hto ocTaejiaeT nonojibHHTejibHO 0,26 r πορηπιο KHCJIOTbl. HHCTOTa: 93,7%. B. MonHyio KHCJiOTy (15, lr) b 16,5 mji bojim jio6aBjuiK)T κ pacTBopy Φ.πκ)οηηηο.ποη 16a, 17a-aueTOHHjia (5,0 r) b 55 mji HHOKcaHa. Pe-aKiļHOHHyio CMecb nepeMeuiHBaiOT πρπ κομηβτηοη TeMnepaType 20 h, HeHTpajiH3yioT HacbimeHHbiM βοληβιμ pacTBOpOM 6nKap6oHaTa HaTpna h BbinapHBaiOT. Oct3tok pacTBopaiOT b 200 mji MeTHjieHXJiopHna h npOMbi-BaioT 8x100 mji 10%-ηογο Kap6oHaTa Kajina. BojiHyio φa3y πολκηοιηιοτ KOHLļ. XJIOpHCTOBOūOpOiIHOii KHCJIOTOH H 3KCTparHpyiOT 6x100 MJI 3THJia-ueTaTa. Ilocjie BbicyuiHBaHHJi pacTBOpHTejib BbinapnBaiOT. Oct3tok pacTBO-paiOT b 400 mji arajiaueTaTa h oca>KaaiOT neTpojiefiHbiM 3φΗροΜ, hto jiaeT 3,96 r 6α, 9a -,ηΗφτορ- 11/3 OKcn-16a, 17a -[(l-MeTHJiamjiHneH) 6hc (okch)] aHnpocTa -l,4-,aHeH-3oH -17b -KapboHOBOft KHCJIOTbl. CTeneHb HHCTOTbi, onpejiejieHHaa HP L C , cocTaBHJia 99,6%. 16

IlpHMep 4 r-3T0KCHKap60HMJI0KCH3TMJĪ 6a, 9a -βΗφτορ-ΙΙ/? -rnapOKCH-16a, 17a-[(l-MeTMJi3TM^HneH) 6hc (oKCH)]aH,apocTa -l,4-nHeH-3-OH-17/?-nap-GoKCHjiaT. A. 6a,9a -,ΰ,Ηφτορ-ΙΙβ -ninpoKCH-16a,17a [(l-MeTHJi3THJinfleH) 6hc (oKCM)]-aH(apocTa-l,4-^HeH-3-OH-17y9 -Kap6oHOByio khcjiott (600 μγ) h 6HKap6oHaT najiHa (684 μγ) pacTBopaioT b 45 mji £HMeTHj^opMaMH,aa. JļoOaBJiaioT l-6poM3raji3THjinap6oHaT (2mji), h peaKLļHOHHyio CMecb nepe-MeuiHBaiOT npn κομη3τηοη TeMnepaType bcio hohb. HoOaBjunoT Boay (200 mji) h CMecb 3KCTparnpyK)Tca MeTHjieHXjiopH,aoM. OOibejiHHeHHbie ancTpan-Tbl npOMLIBaiOT 5%-HbIM BOflHblM 6HKap60HaT0M H ΒΟβΟΗ. OCT3TOK OHHUia-K)T Χρ0Μ3Τ0Γρ3φΗθίί Ha KOJIOHKe „θ6φ3<α6Κ0 LH-20” (72 X 6,3 cm), HCnOJIb3ya ΧϋΟροφορΜ B KaneCTBe nOJIBPDKHOH φ33Η. Co6HpaK)T φρ3ΚΗΗΚ) 1515-2250 mji h BbinapHBaioT, ητο ziaeT 480 μγ l‘-3TOKCHKap6oHMJi-OKCH3THJI 6a, 9a -^Ηφτορ-Ι\β -rHJipOKCH-16a, 17α- [(l-MeTHJI3THJIHJieH) 6hc (okch)] aHjīpocTa -l,4-,nHeH-3-OH -17j3-nap6oncHjiaT. CreneHb HHCTOTbi, onpejjejieHHaa nocpeacTBOM, cocTaBJiaeT 98,1%, a cooTHomeHHe anHMepoB A/B, 48/52. Tonna njiaBJieHHn: 218-27°C [g:]d25=+63,2 (c-0,214; CH2CI2). MojieKyjiapHbiH Bec 554. l‘-3T0KCHKap60HHJI- OKCH3THJ1 6α, 9a -ίΙΗφτθρ-11)3 -OKCH-16a, 17a-[(l-MeTHji3THJiHjieH) 6hc (okch) ] aHjīpocTa -l,4-jiHeH-3 -οη-ΙΊβ -nap-OoKCHJiaT (480 μγ) xpoMaτHΓpaφHpyκ)τ Ha kojiohrc „Οεφ3;ιεκΓ LH-20” (76x6,3) c npHMeHeHHeM renTaH: xJIopoφopbI: 3TaHOJi, 20:20:1 b nanecTBe ΠΟ£ΒΗ>ΚΗΟΗ φ33ΒΙ. Co6HpaiOT φρ3ΚΙΙΗΙΟ 2325-2715 MJI, BbinapHBaiOT H OCT3TOK pacTBopaioT b MeTHjieHXJiopHae, ocaagiaioT nČTpojieHHbiM 3φΜροΜ, ητο jiaeT 200 μγ coejļHHeHHa (A), HMeiomero CTeneHb nncTOTbi 97,3% (onpejiejieHO HP L C-aHajiH30M). Tonna ruiaBJieHHa: 246-250°C. [a]D25= +100,5° (c = 0,214; CH2CI2). MojienyjiapHbiH Bec: 554.

Opanuna 4140-5100 mji najia 250 mji coejiHHeHHa (B), CTeneHb nHCTOTM 99,0%. Tonna ruiaBJieHHa 250-255°C [a]D25= + 28,5° (00,246 CH2CI2). MojienyjiapHbiH Bec: 554. CnrHaji MeTMHa ot οπο>ΚΗθ3φΗρΗθΗ rpynnbi CMemeH 0,13 mjih. jioji. bhh3 nojia η Η - HMP cnempa B no cpaBHeHHio c A, b to BpeMa nan ocTaTonHbie nacTH cnempOB ποητη HjjeH-THnHbi. 3jienTpoHoyziapHbie Macc-cnempLi A η B aBJimoTca HneHTHnHbiMH, Hecnniaa hhtchchbhocth MaccnHKOB. 3th cpenTpocnonHnecnHe pa3JiHnna LV 10957 η cxojicTBa noKa3biBaiOT, hto A η B jibjuhotch snHMepaMH BCJiencTBue XHpajibHoro ueHTpa β αιο>ΚΗ03φΗρΗ0Η rpynne. B. 6α,9a -,Π,Ηφτορ-11/3 -rn,npoKCH-16a,17 a[(l-MeTHji3THjiH,aeH) 6hc (0KCM)]-aHūp0CTa-l,4-flHeH-3-0H-17^ -Kap6oHOByio KncjioTy (200 μγ) pac-ΤΒΟΡΛΙΟΤΒ25 MJI flHMeTHJ^OpMaMHiia.HoGaBJIilIOT l-XJIOp3THJI3THJIKap6o-H3T (IOOmji) m 6nKap6oHaT KajiHa (70 μγ) h 18-KpoyH-6-npocTOH 3φκρ. PeaKUHOHHyio CMecb nepeMeiiiHBaiOT πρκ 80°C 3 h., oxjia>KjiaK)T, nocjie ^o6aBJieHHii 150 mji βολμ 3KCTparHpyiOT MeraneHXJiopH,aoM, BbicymHBaiOT h BbinapHBaiOT. HeoMHmeHHbift nponyKT onHmaioT, KaK yKa3aH0 b npoue-,aype A, npHHeM ocTaeTca 207 μγ r-3TOKCHKap6oHHjioKCH3mri 6a, 9a -ΛΗφτθρ-11/S -rHflpOKCH-16a, 17a-[(l-MeTHJI3THJlHJieH) 6nc (OKCH)] aHfl-pocTa -l,4-jīHeH-3 -οη-ΙΊβ -Kap6oKCHJiaT, a HHCTOTa (HP LC) cocTaBJiaeT 98,4% h cooTHouieHne snuMepoB A/B = 54/46. C. 6α,9α -ζΐΜφτορ-ΙΙβ -rajipOKCH-16a,17a [(l-MeTHji3THJiHjieH) 6hc (0KCH)]-aHflp0CTa-l,4-^HeH-3-0H-17^ -Kap6oHOByio kmcjictit (200 μγ) h l,5-ztHa3a6HUHKjio [5.4.0] yHZieKaH-5 (140 μγ) cycneHjiHpyiOT b 25 mji 6eH30Jia h HarpeBaioT j^JierMauHH. HoOaBjiaioT pacTBop 1-6pom3thji-3THJi-Kap6oHaTa (175 μγ) b 5 mji 6eH30Jia h CMecb HarpeBaioT 2,5 h. c o6paTHbiM xojiojiHjibHHKOM Ilocjie oxjiaxcjieHHa jjo6aBjuuoT 50 mji MeTHJieHXJiopHita h pacTBop npoMbiBaiOT βολοη, BbicyniHBaiOT h ynapHBa-k)t. HeoHHmeHHbift προ^κτ OHHmaiOT, TaKHM >κβ o6pa30M, KaK b npoue-aype A. Βμχολ 207 μγ r-3TOKCHKap6oHHJioKCH3THJi 6α, 9a -χκφτορ-ΙΙβ -rHjipoKCH-16a, 17a-/(l-MeTHJi3THjiHjieH) 6hc (oKCH)/aHjipocTa -1,4-j[HeH-3-OH-17^ -Kap6oKCHJiaTa. HHCTOTa (HP LC) cocTaBjiaeT 96,4%. Co-OTHomeHHe anHMepOB A/B = 44/56. D. K pacTBopy 6α,9a -,ΓίΗφτορ-ΙΙβ -rmipoKCH-16a,17a [(1-msthjisthjiHjļeH) 6hc (oKCH)]-aH,iļpocTa-l,4-flHeH-3-OH-17/? -Kap6oHOBOH KHCJiOTbi (100 μγ) b 25mji aueTOHa ^o6aBJiaioT 175 μγ a-6poMjiH3TMJiKap-6oHaTa h 45 μγ 6e3BonHoro Kap6oHaTa Kajina. CMecb HarpeBaioT 6 ii c oGpaTHbIM XOJIOflHJIbHHKOM. OxJI2DKJieHHyK) peaKIļMOHHyiO CMecb BblJIHBa-K)T B 150 MJI BOflbI H 3KCTparHpyiOT MeTHJieHXJIOpMJļOM. 3KCTpaKT npOMbl-BaiOT ΒΟΛΟίί, BbicyuiHBaiOT Ha^ cyJIbφaτoM HaTpmi h BbinapnBaioT, nojiyHaji 65 ΜΓ TBepflOrO l‘-3T0KCHKap60HHJI0KCH3mn 6α, 9a -βΗφτθρ-11/3 -OKCH-16a, 17a-[(l-MēTHji3THjiHjīeH) 6hc (okch)] aHjjpocTa- l,4-AHeH-3 -oh-17/?- 18

KapfioKCHJiaTa. HncTOTa, onpejiejieHHaa HP LC, cocTaBMjia 97,6% m coot-HomeHHe anHMepOB A/B = 49/51. E. 6a,9a -,Π,ΗφΤΟρ-11/? -rHJIpOKCH-16a,17a-[(l-MeTHJI3THJlimeH) 6hc (0KCH)]-aHjip0CTa-l,4-ziHeH-3-0H-17^ -Kap6oHOByio κηοιοτυ (500 μγ) η KMCJībiii TeTpa6yTMjiaMMOHMM cyj^aT (577 μγ) Ao6aBJiaioT κ 3 mji 1-rnjīpooKCH HaTpMa. JloSaBjiaioT TaK>Ke pacTBop 435 μγ l-6po-M3THji3THjiKap6oHaTa b 50 mji MeTHjieHXjiopHj3a. CMecb HarpeBaiOT c oGpaTHbiM xojiojiHjTbHHKOM b TeHeHMe homh. ΠροΗοχοΛΗτ pa3jiejieHHe Ha 2 cnoa. OpraHHHecKHii cjioh npoMbiBaioT 2x10 mji βολμ, BbicyuiHBaioT h BbinapHBaiOT, „Cbipofi” npOHyKT OHHIIiaiOT Χρ0Μ3Τ0Γρ3φΗ6Η Ha KOJIOHKe „Οεφ3ΐΐθκο LH-20” (72x6,3 cm) c npHMeHeHHeM xJIopoφopMa, b KanecTBe nOflBHJKHOH φ33ΒΙ. Co6HpaiOT φρΒΚΗΜΙΟ 1545-1950 MJI, BbinapHBaiOT H ocTaTOK oca>KiiaioT H3 CMecn M6THJi6Hxjiopn,iia c neTpojieHHbiM 3φπροΜ nOJiynaa 341 ΜΓ l’-3T0KCHKap60HHJI0KCH3THJI 6a, 9a -ϋΗφτορ-11/? -rnnpoKcn-16a, 17a[(l-MeTHji3THJiHjieH) 6hc (oKcn)]aHiipocTa- 1,4-ζιηθη-3-oh- 17^-Kap6oKCHJiaTa. CreneHb hhctotbi, onpeaejieHHaa nocpeziCTBOM HP L C: 99,2%. CooTHomeHHe ariHMepoB A/B = 56/44. F. 6α,9α -,Π,Ηφτορ-ΙΙβ -rnzipoKCH-16a,17a[ (1-MeTHjiHneH) 6hc (0KCH)]-aHap0CTa-l,4-jiHeH-3-0H-17y3 -Kap6oHOByio KHCJioTy (200 μγ) h TpHKanpHjiMeTHjiaMMOHHH xjiopnji (200 μγ) zio6aBjwioT κ 5 mji HacbimeH-ηογο βο^ηογο 6HKap6oHaTa HaTpHa. JI,o6aBjiaioT 100 μγ l-6poM-MeTHji3THJiKap6oHaTa b 10 mji MeTHjieHXjiopHna. Cmccb nepeMeuiHBaioT tipu 45°C b TeneHHe 20 nacoB pa36aBJiai0T 10 mji MeTHJieHXjiopHna, Bbine-jihiot h OHiimaiOT, KaK yKa3aHO b npouejiype E, nojiyMaa 254 μγ 1‘-3T0KCHKap50HHJI0KCH3THJI 6α, 9a -ΛΗφτορ-110 -rHJIpOKCH-16a, 17a [(l-MeTHji3THJiHjieH) 6hc (okch)] aHapocTa-1,4- nneH- 3-oh-17/? -Kap-SoKCHjiaTa. HncTOTa (HP LC): 97,4%. CooTHomeHHe aniiMepoB A/B = 60/40. G. 6α,9α -βΗφτορ-ΙΙβ -rHjipoKCH-16a,17a [(l-MeTHJi3THJinneH) 6hc (oKcn)]-aHjipocTa-l,4-ziHeH-3-OH-17/3 -Kap6oHOByio KHCJioTy (200 μγ), 1-6p0M3THJI3THJIKap60HaT (135 μγ) H TpH3THJiaMHH (275 ΜΓ) paCTBOp^IOT B 20 mji flHMeTHj^opMaMHjia. CMecb nepeMeuiHBaiOT npH 80 °C 3 Mača, pa36aBjunoT 200 mji MeTHJieHXJiopmia, npoMbiBaioT bohoh, BbicymHBaioT h BbinapHBaioT. „CbipoH” npojiyKT OMHinaiOT, KaK \Ka3aH0 b npouejiype A, LV 10957 nOJiyHaiI 69 ΜΓ r-3T0KCHKap60HHJI0KCH3THJI 6α, 9a -ΑΗφτορ-ΙΙ/? -rH^poKCH-16a, 17a-[(l-MeTHJi3THJiHaeH) 6hc (okch)] aHiipocTa- 1,4-nneH -3-OH-17y3-Kap6oKCHjiaTa. HncTOTa (HPLC) 97,8% h cooTHomeHHe anHMepoB A/B = 48/52. rīpMMep 5. r-AueTOKCH3THH 6a, 9a -,αΗφτορ-ΙΙβ -mapoKCH-Ιβα, 17α -[(1-MeTHjiHjm^eH) 6hc (okch) ] aHjīpocTa -1,4-ληθη-3-οη-17/3 -KapSoKCHJiaT 6α, 9a -βΗφτθρ-11β -OKCH-16a,17a -[(l-MeTHJI3THJIHJieH) 6hc (okch)] -aH/ipocTa-l,4-jiHeH-3-OH-17y3 -Kap6oHOByio khcjioty (500 μγ) h 6nKap6o-H3T Kanna (575 μγ) pacTBOpiiiOT b 400 mji nHMeTHJ^opMaMH,na. jļoSaBjiaiOT l-xjiop3THjiaueTaTa (1 mji) h peaKiļHOHHyio CMect nepeMeuiHBaioT npn κομη3τηοη TeMnepaType 40 Mac. PeaKUHOHHyio CMect BbuiHBaiOT b 50 mji BOJIbI H 3KCTparnpyiOT MeTHJieHXJIOpHJIOM. 3KCTpaKT npOMblBaiOT BOJIHblM 6HKap6oHaTOM HaTpna h bohoh, BbicyuiHBaiOT h BbinapHBaioT. OcraTOK xpoMaτHΓpaφHpyκ)τ Ha κοποΗκε ,^3φ3Λβκο LH-20” (72x6,3 cm), npnMe-ηάά χιιοροφορΜ KaK noziBPDKHyio φa3y. OpaKUHH 1755-2025 h 2026-2325 mji coSnpaiOT h BbinapHBaiOT. TBepzibiH npojiyKT H3 φρ3ΚΗΗΗ 1755-2025 mji zionojiHHTejibHO OHHinaioT χροΜ3τοΓρ3φΗεΗ Ha KOJioHKe „€εφ3Λε^ LH-20” (76x6,3 cm - BHyTpeHHHH ΖΙΗ3Μ6Τρ), HCIIOJIb3yH CMCCb Γ6ΠΤ3Η-ΧΙΙθρθφθρΜ-3Τ3ΗΟΙΙ, 20:20:1 b KanecTBe iiojibiūkhoh φ33Μ. OpaKunio 2505-2880 mji coGnpaiOT h BbinapHBaiOT. OcTaTOK pacTBopaioT b MeTHjieHXjiopHjie h ocajKjiaioT πετ-pojiēHHbiM οφπροΜ, nojiyHaa 167 μγ TBepnoro npojiyKTa (A). HncTOTa, onpeflejieHHaji HP L C =99,1%. ToMKa ruiaBjieHHa 238-259° C. ļaļD25 = + 94° (C= 0,192; CH2CI2). MojieKyjmpHbiH Bec = 254. TBepjībiH npo^yKT H3 yKa3aHHOH Bbirne Φρβκηηη 2026-2325 mji jio-nOJIHHTeJIbHO OMHIIiaiOT ΧρθΜ3ΤΟΓρ3φΗβίί TaK >Ke, KaK >'Ka3aHO Bbliue. OpaKUHio 5100-5670 mji coSnpaiOT h BbinapHBaiOT. OciaTOK pacTBOpiiiOT b MeTHJieHXJiopH/ie h oca>KjiaK)T nocpeacTBOM neTpojiefiHoro 3φκρ3, nojiy-Maū 165 μγ TBepnoro npo;iyKTa „B”. HHCTOTa, onpeziejieHHaji nyTeM HP L C, cocTaBJiaeT 99,4%. ToHKa ruiaBJieHHa 261-265°C /a/ d25 = 34° (C = 0,262; CH2CI2). MojieKy-jwpHbiH Bec = 524. H-.HMP cneKTpbi AhB jibjuhotcb πομτηTO?KuecTBeHHbiM, 3a hchjho-

MeHHeM ΤΟΓΟ, ΜΤΟ MeTHHOBblH KBapTeT OT Ο.ΠΟ>ΚΗ03φΗρΗΟΗ Γρ)'ΠΠΜ, ΚΟΤΟ- 20 pbiii ci(BHHyT Ha 0,16 mjih. βοή. b HtDKHioK) oSuacTb COeflHHeHHfl CpaBHCHHH c coeūHHeHHeM A. XapaKTep φρ3ΓΜ6ΗΤ3υΗΗ AhBb 3JieKTpo-y^apoM MaCC-CneKTpe flBJTfllOTCfl H^eHTHMHblMH, ΗΘ ΟΗΗΤΒΛ HHTeHCHBHOCTH Macc-πηκοβ. TaKHe cneKTpocKonnHecKHe xapaKTepHCTHKH A η B noKa3biBaioT, mto ohh ^BJunoTCJi snHMepaMH BCjiejicTBHe xHpanbHoro ueHTpa b cjioaho-3φΜρΗθίί rpynne. FIpHMep 6-88.

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O >> E ο CN I X X Ο X 0J Ε 03 <υ Ο <υ χ Ε Ο Ε Ο 03X ίη 28 ripeMeHaHHfl κ TaGjiHue 1 1) Ha KonoHKe „θ6φ3Λ6Κ0 LH-20” (76x6,3 cm), npHMeHJui xjiopo-φθρΜ-Γ6ΠΤ3Η-3Τ3ΗΟΙΙ (20:20:1), KaK ΠΟ£ΒΗ>ΚΗγΚ) φ33γ. 2) Ha KonoHKe „(^^a,iieKC LH-20” (87,5x2,5 cm), npHMeHHH xjiopo- φθρΜ-ΓΘΠΤ3Η-3Τ3ΗΟΙΙ (20:20:1), KaK nOHBH>KHyK) φ33γ. 3) Ha KonoHKe ,,Οεφααεκΰ LH-20” (85x2,5 cm), npHMeHJUi xjiopo-φορΜ, KaK ΠΟΖΙΒΗ>ΚΗγΐΟ φ33γ. 4) Ha KonoHKe „0θφ3ΛθΚΰ LH-20” (72,6x3 cm), npHMeHjm χπορο- φθρΜ, KaK ΠΟΖΙΒΡϋΚΗγίΟ φ33γ. 5) Ha KOJiOHKe „€εφ3ΛθΚΰ LH-20” (71,5x6,3 cm), npHMeHaa xjiopo- φορΜ, KaK ΠΟΛΒΗίΚΗγΚ) φ33γ. ūpeMeHaHua κ Ta6nHue 2 1) Ha κο,ποηκθ „ϋ6φ3Λεκο LH-20” (72x6,3 cm), npHMeHa^ χπορο-φορΜ, KaK ΠΟΛΒΗΧΗΥΚ) φ33γ. 2) Ha KOJiOHKe „θ6φ3ζΐ6κο LH-20” (83x2,5 cm), npHMeHJUi χιιορο-φορΜ, KaK nOHBH>KHyiO φ33γ. npeMenaHMa κ TaOjiHue 3 1) Ha KOJiOHKe „ϋ6φ3,α6κο LH-20” (76x6,3 cm), npHMeHiLfl rerrraH-χϋοροφορΜ-3Τ3Ηθΐι (20:20:1), KaK ποιιβμ>κηυιο φ33γ. 2) Ha KOJiOHKe „06φ3πεκΰ LH-20” (87,5x2,5 cm), npHMeHjm rerrraH-xJlopoφopM-^τaHOJI (20:20:1), KaK ποζιβη>κηυκ) φ33γ. 3) Ha KOJiOHKe „Οεφ3Α6κ6 LH-20” (72x6,3 cm), πρκΜβΗΛΛ xjiopo-φορΜ, KaK ΠΟΛΒΗ>ΚΗγΐΟ φ33γ. 4) Ha KOJiOHKe „ϋεφ3Λ6κο LH-20” (80x2,5 cm), πρΗΜβΗΛΛ xjiopo-φορΜ, KaK nOJIBH>KHyiO φ33γ. 5) Ha KOJiOHKe „θ6φ3βεκο LH-20” (81,5x2,5 cm), npHMeHaa xnopo-φορΜ, KaK nOJIBH>KHyK) φ33γ. LV 10957 ΠρΗΜερ npeMeHeHna coejļHHeHHH cļ)opMyjibi 1 89.

OapMaueBTHHecKMe peuenTypw

CjienyioiuHe, He orpaHHHeBaiomHe npniviepbi noacHaiOT penemypbi, npeflHa3HaHeHHbie juir pa3JiHHHbix MecTHbix φορΜ BBe^eHHa jieKapcTBa.

KojiHHecTBO aKTHBHoro CTepoHfla b penemypax πολκο^κηογο BBeaeHHa cocTaBjiaeT ο6μηηο 0,001-0,2% (no Becy Ha Bec) npejinoHTHTejibHo 0,01-0,1% (no eecy Ha Bec)

PeqenTypa 1. Ma3b C/repona, MHKpoH3MejibHeHHbift 0,025 r Π3ρ3φΗΗ 10,0 r ΠΒρ3φΗΗ OeJlblH, ΜΗΓΚΗΗ ΛΟ 100,0 r

Peqemypa 2. Ma3b CiepoHzi 0,025 r Π p ο π nu e Hra h koji b 5,0 r Cop6maH cecKBHonaT 5,0 r Π3ρ3φΗΗ 5ΚΗΛΚΗΗ 10,0 r Π3ρ3φΗΗ GeJlblH, ΜΛΓΚΗΗ no 100,0 r

PeqenTypa 3. KpeM Tnna „Macno b Bone” Creponn 0,025 r UeTaHOJi 5,0 r rjmuepnH MOHOCTeapaT 5,0 r Π3ρ3φΗΗ JKHflKHH 10,0 r IļeTOMaKporojib 1000 2,0 r KncjiOTa jiHMOHHaa 0,1 r UnTpaT HaTpna 0,2 r FIponHJieHrjiHKOJib 35,0 r Boabi no 100,0 r 30

PeueriTypa 4. KpeM THna „Macjio b Bozte” CrepOHZt, MHKpOM3MeJIbMeHHbIH 0,025 r īlapacļDHH Oejibin, μλγκηη 15,0 r Π3ρ3φΜΗ ΧΗΖΙΚΗΗ 5,0 r UeiaHOJi 5,0 r Cop6HMaKporojib CTeapaT 2,0 r CopSHTaH MOHocTeapaT 0,5 r KncnoTa copSHHOBaa 0,2 r KHCJIOTa JIHMOHHaa 0,1 r IlmpaT HaTpua 0,2 r Bozta Zto 100 r

Penemypa 5. KpeM THna „BOzta b Macjie” Creponzt 0,025 r Π3ρ3φΗΗ SeJībIH, ΜΗΓΚΗΗ 35,0 r Π3ρ3φΗΗ JKHZtKHH 5,0 r CopGHTaH cecKBHOJieaT 5,0 r KncnoTa copSHHOBaa 0,2 r KncnoTa jiHMOHHaa 0,1 r llHTpaT HaTpna 0,2 r Bozia zio 100,0 r

PenenTypa 6. JIocbOH (npHMOHKa) Creponzt 0,025 r H3onponaHOJi 0,5 mji rioJIHMep Kap6oKCHBHHHJIOBbIH 3 ΜΓ HaTpna rnztpooKHCb CKOJIbKO HyXHO Bozta Zto 0,1 r LV 10957

Peuemypa 7. CycneHCHa ηπη ηηί>6κιιηη CTepOHfl, MHKpOH3MeJIbHeHHbIH HaTpnft Kap6oKCHMeTHjmejiiiK)Jio3a HaTpHM-xjiopn.il nojiHOKCHSTHjieH (20) copOHTaH MOHOojieaT ΦβΗΗΐι- KapOHHOJi Bona, CTepHJībHaji 0,5-10 μγ 7 ΜΓ 7 ΜΓ 0,5 μγ 8 ΜΓ HO 0,1 MJI

Peuemypa 8. Aapoaojib ņjin HHrajinuHH nonocTeH pTa h Hoca

CrepOHn, MHKpOH3MejIbHeHHbIH CopOHTaH TpnojieaT ΤρΗχπορφτορΜετ3Η ^ΗΧη0ρΤβΤρ3φΤ0ρΜβΤ3Η )1ΗΧΠ0ρηΗφΤ0ρΜ6Τ3Η 0,1% Bec/Bec 0,7% Bec/Bec 24,8% Bec/Bec 24,8% Bec/Bec 49,6% Bec/Bec Peuemypa 9. PacTBop nnn MHKpopacnbīneHHfl Creponn nponHJieHniHKOJib Bona 7.0 μγ 5.0 r no 10,0 r PeuenTypa 10. Ποροιιιοκ π,πχ HHrajiHUHH )KejiaTHHOBaa Kancyjia 3anojiHeHa cMecbio: CTeponn, MHKpOH3MeJIbHeHHbIH 0,1 ΜΓ JIaKT03a 20 μγ ΓΊοροιιιοκ BflbixaiOT c noMombio npn6opa fljw HHrajiHUHH. 32

OapMaKOJiorHfl

CpeflCTBO HOBblX CJIOJKHbIX θφπρΟΒ aHZlpOCTaH-n^-KapGOHOBOH KHCJlOTbl no OTHomeHHK) κ peuenTopy πποκοκορτΗΚΟΗ,ιΐΒ

Bce cTepoHflbi cooTBecTByiomne HacToameMy H3o6peTeHHK) abjuiiotcji φΜ3ΗΟϋΟΓΗΗε0ΚΗ-3ΚΤΗΒΗΒΙΜΗ COejtHHeHHflM. CpejJCTBO HOBbIX CJIO>KHbIX 3φηρθΒ aHflpOCTaH- 17/3- KapSOHOBOH KHCJIOTbl K rJHOKOKOpTHKOHJlHOMy peuenTopy ncnojib30BaHHO b KanecTBe Moziejin Aiia onpejiejieHHJi cnoco6-hocth κ npOTHBOcnajiHTejibHOMy ήθηοτβηιο. Hx cpejiCTBa κ peuenTopy cpaBHHBaiOT c 6yjie30HHaoM (/22R/S/-16a, 17a-6yTMJiH,aeHjiHOKCH-ll/3, 21-ΛΗΟΚΟΜΠρ6ΓΗ3-1,4-ΛΗΘΗ-3,20- ilHOHy), rJIK)KOKOpTHKOHJiy nOBbimeH-hoh aKTHBHoera, c GjiaronpHiiTHbiM cooTHomeHneM Me>Kjiy jioKajībHbiM ^encTBHeM, h cncTeMHbiM flencTBHeM othochihhmch κ opraHH3My b uejiOM [Thalen and Brattsand, Arzheim-Forsch. 29, 1687-90 (1979)].

Bo BpeMa Bcex HCCJiejiOBaHHH Hcnojib3yK>T Kpbic-ca\moB „Spraque Dawley” b B03pacTe 1-2 MecaueB. 3o6Hyio xene3y yztajunoT h noMemaioT b φΗ3ΗΟΙΊΟΓΜ460ΚΗΜ paCTBOp nOBapēHHOH COJIM, OXJia»JiaeMbIH JlbJIOM. TKaHb raMoreHH3HpyiOT b roMoremmTope „Potter Elvehjem” b 10 mji 6yφepHOΓO pacTBopa, cojiep>Kamero 20 MMOJib Tpnc, pH 7,4 10% (Bec/o6T>eM) rjinnepHHa, 1 MMOJib 3THJieHanaMHHTeTpayKcycHOM khcjiotm (3JJTA), 20 mmojiL· NaMoŪ4,10 MMOJib MepKamOSTaHOJia. ToMoreHaT KOHU6HTpnpyK)T 15 mhh. npn 20000 x 1 g. llopmiH BepxHero 20000 x 1 g (230 mkji) HHKy6HpyiOT okojio 24 h npn 0°C c 100 mkji Φ0ηη.πμθτη.τ^.πβ-φθΗΗηφτορπΛ3 (ηηγη6ητορ 3CTepa3bi, KOHenHaa KOHiieHTpauHa 0,5 MMOJib), 20 mkji HaMeneHoro - „KOHKypeHTHoro arema" h 50 mkji 3H-μβηθηηογο neKcaMBTa30Ha (KOHeHHaa KOHueHTpauna 3 MMOJib). CBjnaH-hmh h CBo6oflHbiH CTOpOHjībi pa3ji0jmK)T HHKy6npoBaHHeM cmbch c 60 mkji 2,5% (Bec/o6^eM) 3κτηβηροβ3ηηογο ymji h 0,25% (b0c/o6t>0m) cyc-neH3HM ^eKCTpaHa 170 b 20 MMOJib Tpnc. pH 7,4 1 MMOJib 3HTA h 20 MMOJib NaMoŪ4 B ΤΒΗΘΗΗΗ 10 MHH. Πρίΐ 0° C. IlOCJie 3ΤΟΓΟ ^eHTpHφyΓHpyκ)τ npH 500 x g b τοη0ηηη 10 mhh. h 230 mkji BcnjibiBiuero cjiob coHHTbiBaiOT b 10 mji Justa - Gel b cuHHTHJUiaiļHOHHOM οπεκτροφο-TOMeTpe „Packard”. LV 10957

BcruibiBLiiHe cjioh ΗΗκγβπργιοτ c a) [3H] c ολημμ ,neKcaMeTa30H0M, 6)[3H] iteKcaMeTa30H0M BMecTe c 1000-KpaTHbiM μ36βιτκομ HaMēHeHHoro ZieKcaMeTa30Ha h b) [3H] £eKcaMeTa30Ha BMecie c 0,03-300- KpaTHbiM M36biTKOM „KOHKypeHTa”. ΗεοπβΗΗφΗΗεοκγκ) CBH3b onpenejiaioT, Koma 100- KpaTHbiii η36μτοκ η3μθη6ηηογο ^eKcaMeTa30Ha jioSaBJiaioT κ [3H] -μθηθηομυ jieKcaMeTa30Hy. PaziHoaKTHBHocTb, CBH3aHHaa c peuenTopoM b npHcyTCTBHH „KOHKypeHTa”, pa3jiejieHHaa Ha paflHoaKTHBHOCTb, οββ33ηηυκ> c peuenTopoM b otcytctbhh „KOHKypeHTa” h ymHO^ceh Ha.a Ha 100 ziaeT Bbipa5KeHHyio b % οπεαΗφΗΗθοκγκ) CBa3b λπλ μθηθηογο jīeKcaMeTa30Ha. fljia Kaamofi KOHUeHTpaUHH „KOHKypeHTa”, CIiem^HHeCKHCBittaHHaa c paaHOaKTHBHOCTbK), BbIpa>KeHHyiO B %, HaHOCHTCfl Ha Γρ3φΗΚ ΠΟ OTHO-ineHHIO Κ ϋΟΓ3ρπφΜΥ KOHUeHTpaUHH „KOHKypeHTa”. KpHBbie CpaBHHBaiOT npH 50%-HOM γρΟΒΗΘ Cnei^HHeCKOH CBH3H, ΓφΗΗΘΜ CCblJiaiOTCa Ha 6yne-30ΗΗΛ, KOTOpblK OTHOCiīT KaK ejļHHHUa OTHOCHTeJlbHO CpeūCTBO CBH3bIBaHHa ΚΟΤΟρΟΓΟ npHHHMaiOT 3a I. 34

Ta6jinua 4.

Ta6jinua, cyMMHpyioma^ oTHOCHTejibHbie cpe^cTBa CBfl3yeMOCTM (RBA) no OTHomeHMK) κ rjnoKocTepoHjļHOMy peuenTopy una

HeKOTOpbIX HCCJie^OBaHHbIX COeflHHeHHH

CoeiiHHeHHe npHMepa No RBA Byae30HHfl 1 4 3nHMep B 0,30 5 ΒΠΗΜβρ B 0,17 25 0,39 26 0,40 27 0,50 29 0,45 32 0,25 35 0,22 38 0,04 55 0,20 64 0,05 67 0,04 69 0,44 82 0,56 84 1,03 87 0,63 LV 10957 35

HcnbrraHHfl Ha npoTHBOBoenanHTenbHoe nencTBHe BHyTpHTpaxeMHa^ ηηθτηπππηηπ KpbicaM mapHKOB ϋθφ3πθκθ3 πρΗΒΟΛΜτ κ 6ponxnajibHOMy μ aJibBeoji^pHOMy BoenajieHMK). 3το npo-BOUnpyeT HHTepcTHUHanbHbiH cxeK πθγκηχ, κοτορΒίΚ yBenHHHBaeT Bec jierKHX h BocnajieHMe mojkho οηθηηή> KaK yBenHneHHe Beca .πθγκηχ no CpaBHeHHK) C KOHTpOJIbHOH rpynnoR HHCTHJlHpOBaHHOH cpneBbiM paCTBO-poM. 06pa30BaHHe oTeKa πθγκηχ mo>kho npenoTBpaTHTb npenpaBpnTenb-HOH o6pa60TKOH ΓΠΗ3Κ0ρΤΗΚ0ΗΠ3ΜΗ, npennOHTHTeJIbHO npn nOKaJIbHOM ΒΒΘΠΘΗΗΗ B ΒΟΠΘ BHyTpHTpaxeHHOH HHCTHJinnHH HJ1H B ΒΗΠΘ HHraJIfllJHH. B Hiieane, npoTHBOBocnajiHTejibHoe πθηοτβηθ λοπ>κηο HaOnionaTcn TonbKo b ΜΘΘΤΘ HaHecaHHfl rJIIOKOKOpTHKOHJia B ΠΘΓΚΗΧ, a ΗΘ Ha OCTanbHOM ΤΘΠΘ, TaK KaK npH T3KOH ΠΠΗΤΘΠΒΗΟΗ 06pa60bKe M05KHO nOnyMHTb ΠΗΜΗΤΗρ>ΠΟΙ1ίΗΘ Tepannio θηθτθμημθ πο5οηηβιθ οφφθκτΒΐ. ΖΪΗφφθρθΗΗΗΒΗΗΚ) Me>Kny πθηθτβηθμ rnioKOKopTHKOHna β oGnacrn o6pa6oTaHHbix πθγκηχ η βηθ οτογο ynaciKa μο>κηο προβθθτη θ.πθπυιοιπημ o6pa30M. Kpbic urraMMa Spraque Dawley βθθομ no 225 r cnerKa aHe- ΘΤΘ3ΗρθΒ3ΠΗ 3φπρθΜ, Η miOKOKOpTHKOCTepOHnHblH ΤΘΘΤΟΒΒΙΗ npenapaT Β

o6beivie 0,5 μπ/κγ ηηθτηππηροββπη πρπΜΟ β πθβοθ πθγκοθ. Cn>'CT^ 30 μηη)τ cycneH3Hio 0θφ3ΠθΚθ3 (5μγ/κγ) b oObeMe 1μγ/κγ ηηθτη.ππηροβ3πη β Tpaxeio KaK pa3 Han 6Hφypκa^HeH, TaK hto cycneH3Hn nonanana KKa b πθβοθ, TaK η b npaBoe πθγκοθ. Hepe3 20 nacoB Kpbic y\iepmBnanH h ΗΟΘΘΚΒΠΗ ΠΘΒΟΘ H npaBOe ΠΘΓΚΟΘ H B3BeilIHBanH HX OTUenbHO. KOHTpObHOH rpynne ββοπηπη ηοθητθπβ βμθθτο npenapaTa γπκ)κοκορτηκοηπ3 η θοπθβοη pacTBop βμθθτο cycneH3HH Οθφ3βθκο jum onpeneneHHa Beca HeoopaOoTaH-Horo npenapaTOM CTeKa, Bbi3BaHHoro ΟθΦβπθκοομ, h HopManbHoro Beca ΠΘΓΚΟΓΟ.

KaK 6bino yKa3aHO paHee, HneanbHbiH γπιοκοκορτηκοηπηβιη npenapaT ποπ)κθη o6nanaTb ropa3jio 6onee bmcokoh γπιοκοκορτηκοηπηοη 3Κτηβηο- CTbK) B MeCTe ΗΒΗΘΘΘΗΗΗ Β ΠΘΓΚΗΧ, HO HH3KOH aKTHBHOCTblO B OCTanbHbIX ynacTKax. FIo3TOMy Bbi6paHHan μοπθπβ onTHManbHOHoro npenapaTa non-xHa b 3Ha4HTenbHOH θτθπθηη OnoKHpoBaTb οτθκ β noKanbHo npen-BapHTenbHo o6pa6oTaHHOM πθβο,μ πθγκημ, ho o6nanaTb ManoH aKTHBHOCTbio b npaBOM πθγκομ. BancHbiM HBnaeTca noncK hx bmcokoh θτθπθηη pa3neneHHfl Me>Kny noKanbHon aKTHBHOCTbio (npriMep πθβογο πθγκογο) η CHCTeMHOH aKTHBHOCTbto (npHMep npaBoro πθγκογο), a ΗΘ noncK bmcokoh aSconiOTHOH ποτθηηηη (BbicoKaa aKTHBHOCTb Ha μγ npe- 36 napaTa) λπλ αθηοτβηλ Ha JieBoe λθγκοθ. B HcnojiB30BaHHH TecTOBOM npo-TOKOjie Bbi6panH ^03bi, κοτορπθ npHBOHHJiH κ 50% οηη>κθηηκ> CTena BJie-bom JierKOM, h Tenepb Hy>KHbi Obuīn ropa3HO 6ojiee BbicoKHe fl03bi ηθμ απβ bjioKHpoBaHHa onyxjiH npaBoro πθγκογο Ha 50% Bbi6paHHbix #03 napajuiejibHO TecTHpoBajiH 7-9 Kpbic. PaccMHTbiBajiH 3HaneHHa + -5.e.m., h cpaBHHBanH c TecTOM CTbioiieHTa zuia pe3yjibTaTOB οοοτβθοτβ^τοιιιθη Οθφ3-ZieKCOBOM KOHTpojibHoii rpynnbi.

Pe3yjiTaTbi TecTHpoBaHHa ,ζυποκοκορτΗκοοτθροΗ,ηοΒ HacToamero H3o6peTeHHa b cooTBecTBHH c onHcaHHoii paHee μθτοήηκοη πρηβθιιθημ b TaOjiHue 5. B stoh TaSjiHue noKa3aHO, hto HOBbie οοθληηθηηη, κ yAHBJieHHa, oOjia^aiOT HH3KOH ΠΉΟΚΟΚΟρΤΗΚΟΗβΗΟΗ aKTHBHOCTbK) KaK B a6C0JIK)THbIX, TaK Η B OTHOCHTeJIbHbIX ΗΗφρ3Χ. CoejļHHeHHa npHMepOB 25, 27,35, 82 h 84 aaiOT ropa3^o 6onee βμοοκηθ τθρ3πθβτηηθοκηθ οτηοπιθηηϊι (oTHomeHne Me>Kny 37(50 τυπι οηοτθμηοη h JiOKajībHOH βκτηβηοοτη, coot-BecTBeHHo) HexcejiH Te, KOTopbie 3aperHCTpwpOBaHbi nnsi 6yne30HHna. By-neH03H,a He ,naeT ,βηΦΦθρθηηηβηηη Mexc^y JiOKajībHOH h οηοτθμηοη aKTHBHOCTaMH.

TaGnHHa 5

Pa3nejieHHe JiOKajībHOH η οηοτθμηοη γπιοκοκορτηκοη.πηοη aKTHBHOCTeH

CoeflHHeHHe JIoKanbHaa CncTeMHaa TepaneBTHHecKoe npHMepa Ho. riOTeHUHH flJĪH ΠΟΤβΗϋ,ΗΗ ZUIH OTHOineHHe = jieBoro jierKoro npaBoro JierKoro 3/750 npaeoe Jiezme 3Ū50 (μγ/κγ) 3/150 (μγ/κγ) 3/750_/z eeoeji ezme Byzie30HHH 0,15 0,15 1 25 3,4 >10 >3 26 7,6 15 2 27 1,8 10 >8 29 15 >15 1 32 1,5 6 4 35 10 >30 >3 82 1,3 23 18 84 <0,3 10 >33 LV 10957 37 OOPMYJIA H30EPETEHH* 1. Oio>KHbie 3φπρ^ 16 α, 17 α -aueTajib3a\ieineHHOH amipocrraH -17/3 KapGoHOBOH KHCJioTbi, (ļ)opMy;ibi I: OR3

hjih ero CTepeon30MepHoe coeanHeHMe, me 1, 2 Π03ΗΙ1ΗΛ HacbiuueHa hjih n\ieeT λβομηυιο CBA3b;

Xl Bonopon hjih φτορ; X2 ΒΟΛΟΡΟΛ HJIH φτορ;

Rl ΒΟϋορο,α hjih C1-C4 auKMJi; R2 - BOHOpOfl HJIH C1-C5 aJlKH.n; R3 - rpynna: CR4R50C(0)R6 hjih CR4R50C(0)YR6 Y paBeH 0; R4 BOAOpOA C1-C5 aJTKMJI HJIH φθΗΗ^;

R5 Bonopou HJIH MeTHJi; H R6 Bonopoji; jiMnennaji hjih pa3BeiB;ieHHaji, HacbimeHaji hjih nenacbi-LueHaa C1-C3 yrjieBo/K>po,aHaji uenb; C1-C4 a/iKMji, 3aMeiueHHbiii φτοροΜ, φθΗΗΙΙ, 6eH3HJI HJIH pajIHKaJI φθρΜ)7ΙΜ: 38

Ο —CH2 npH yCJ10BHH ΗΤΟ, eCJIH R2 - BOflOpOH, TO Rl -C1-C4 aJIKHJI. LV 10957 ΡΕΦΕΡΑΤ

OnncHBaiOTCH HOBbie coeaHHeHHfl, o6jiauaioniHe npoTHBOBOC-najiHTejibHbiM jieHCTBHeM xapaKTepH3yeMbie φορΜγποπ OR3

hjih ero CTepeoH30MepHbie κομποηθητβι, rne: 1, 2-nojio>KeHe Hacbi-meHO hjih HMeeT λβοηηυιο CBH3b:

Xl - ΒΟΛΟρΟΛ HJIH φτορ; X2 - ΒΟΛΟρΟΛ HJIH φτορ;

Rl - Bojiopozi hjih C1-C4 ajiKHn; R2 - BOflOpOJI HJIH C1-C5 ajIKHJi; R3 - rpynna: CR4R50C(0)R6 hjih CR4R50C(0)YR6 me Y npejjcTaBjiaeT 0; R4 npe^CTaBJiaeT βολοροα C1-C5 ajiKHJi hjih φeHHJI;

R5 - ΒΟΛΟρΟΛ HJIH MeTHJI H R6 - BOnopoA jiHHeftHaji hjih pa3BeTBneHHaa, HacbimeHHaa hjih HeHa-cbimeHHaa C1-C3 yrjieBOnoponHaH uerib; C1-C4 ajiKHJībHaa rpynna, hjih panHKaji φορΜγιΐΒΐ: 40

ο —ch2 πρπ γαιοΒΗΗ hto, ecjiH R2 - Boņopoji, to Ri npe^cTaBJiaeT C1-C4 ajiKHji, nojie3HBie τχχιή jieneHHii BOcnajiHTejibHbix cocto5ihhh.

Claims

LV 10957 PATENTA FORMULA 1. 16a, 17a-Acetālaizvietotas 8ηο1ΐΌ5ί3η-17β-ΙοιΊ3οη8Κ§5θ8 esteri ar formulu I 0R3 C = 0

CR| R2 X2 vai tā stereoizomērs savienojums, kur 1,2 pozīcija ir piesātināta vai ir dubultsaite; X, ir ūdeņradis vai fluors; X2 ir ūdeņradis vai fluors; R, ir ūdeņradis vai C,-C4alkilgrupa; R2 ir ūdeņradis vai Cļ-Csalkilgrupa; R3 ir grupa: CR4Rs0C(0)R6 vai CR4R50C(0)YR6; Y ir O; R4 ir ūdeņradis, C,-C5alkilgrupa vai fenilgrupa; R5 ir ūdeņradis vai metilgrupa; un R6 ir ūdeņradis; nesazarota vai sazarota, piesātināta vai nepiesātināta C^CaOgļūdeņražu virkne; C,-C4alkilgrupa, kas aizvietota ar fluoru, fenilgrupa, benzilgrupa vai radikāls ar formulu: O —CH2 ar noteikumu, ka, ja R2 ir ūdeņradis, tad R, ir C,-C4alkilgrupa