LV10959B - Novel 16,17-acetalsubstitute derivatives of pregnane-21-acid, method for their preparation, medicinal preparations of thereof - Google Patents

Description

LV 10959

HOBblE IlPOH3BOjļHbIE 16,17-AUETAJIb3AMEUļEHHOfl ΠΡΕΓΗAH-21-ΟΒΟΪΪ KHCJIOTbl, CnOCOB ΗΧ ΠΟΛΥΗΕΗΗΗ, «DAPMALļEBTHHECKHft ΠΡΕΠΑΡΑΤ HA HX OCHOBE

OmicaHHe

06jiacTb H3o6peTeHHH ΠρβίίΜβτοΜ HacToamero Η3ο6ρβτεΗΗΛ hbjwk>tch HOBbie (frapMa-ueBTHHēCKH aKTHBHbie coeflHHeHmj h cnoco6 hx nojīy4eHna. ΠρβΛΜβτοΜ 3ΤΟΓΟ M306peTeHHi[ TaiOKe flBJlflKJTCH φΒρΜΗαθΒΤΚΗβΟΚΗΘ COCTaBbl, BKJHOMa-lomne 3th coe^HHeHM^, h cnoco6bi jie4eHna BocnajiMTejibHbix, aji-jieprHwecKHx min ^epMaTo^ornMecKnx 3a6oiieBaHHH c noMombio 3thx COeflHHeHHH.

IiejibK) 3τογο H3o6peieHH^ BB.ifleTca co3naHne nmoKOKopTeKocTe-ponaa, očnaaaiomero GojibiuoM npoTMBOBocnajiHTejibHOM aKTHBHocTbK) Ha

MeCTe npHMeHeHUH Η HH3KOft Γ/ΙΙΟΚΟΚΟρΤΗΚΟΗαΗΟίί CHCTeMHOH aKTHBHO-CTblO. ΠρΟΤΟΤΗΠ r^K)KOKOpTHKOCTeponabi /GCS/ HBjunoTCfl HaH6o;iee ueHHbiMH jieKap-CTBeHHbiMH npenapaTaMH, npe;ma3Ha4eHHbiMH ann jieneHHa acTMbi w pMHHTa. LUnpOKO ΠρΜ3Η3ΗΟ, HTO niK)KOKOpTHKOCTepOHJlbI OK33bIBaK)T npoTMBOBocnajiHTejibHoe η προτμβο3Η3Φμ.π3κτη46οκο0 aeftcTBHe b ,abixa-TejibHbix nyTHX h jiero4Hbix τκβηλχ. /ļjiniejibHOMy npneMy πιιοκοκορτΗκοο τεροπαοΒ 4epe3 ροτ b 3Ha4HTejibHOH cTeneHH nperurrcTBjTOT cepbe3Hbie no6o4Hbie 3φφβκτΗ b opraHH3Me. Πο3τομυ b nacToamee BpeM* 04eHb ne-Cojibiuaa 4acTb 6ojibHbix acTMoii hjw phhhtom npoxonaT Kypc jie4eHH^ rjiiOKOKopTMKocTepoHaaMH. Eojibum 6e3onacHOCTb aocTHraeTCfl npn BBe- 2 ΛβΗΗΗ ΓΛίοκοκορτΗκοοτεροπΛΟΒ rijreM HHrammHH a3po30JibHbix npenapa-tob. O^HaKo, TaioKe coo6majiocb o cn/ibHoxieHCTByK)mHx γ/ιιοκοκορτηκοο Teponaax, Hcnojib3yeMbix b HacToamee Bpeisia, a HMeHHO c 17 a, 21-flHnponHOHaTe 6eKJi0MeTa30Ha h 6yflecoHHjie, KOTopbie o6^aflaiOT ao-BOJibHo y3KHMM rpaHHuaMH 6e3onacHOCTH h Bbi3biBaiOT He>KejiaTejibHbie aBjieHna, npHcymHe r^ioKOKopTHKocTeponaaM, b CHCTeMe o6mero κροΒοοβ-pameHM^, npHHeM peKOMenE[yeMbie ^03bi 3thx npenapaTOB λβλλιοτολ ca-MbiMH 6o/ibiiiHMH jum HHrajuuHM /K,H>k. JI(^aajī, T. Me^CTpaKIl h H. CBenMMp, Eur. I. Respir. Dis. Suppl. 136.65 /1984 r./; CA. ĒxaHCOH, K.E. AnaepcoH, P. EpaTcaaa, E. TpyBCTaii η Π. Xe^Hep, Eur. I. Clin. Pharmacol. 22 /1982 r./, 523; Z1>k. Η. Tyrya, ZI>k. K. BacKepenjuie, E. JļaceHHHHrc, H.M. Ήεφκοε h CA. ĒraHCOH. I. Allerg. Clin. Immanol. 70 /1982/ 288/. 3το mo->κετ 6biTb oraeceHo 3a cneT τογο, hto TaKHe coeaHHeHmi nocjie nomo-meHMfl xapaKTepn3yK)Tca nepucmoM nojiypacnaaa njra3Mbi ^ 2 wacoB, h hx HHaKTHBauna npoHcxojiMT rnaBHbiM o6pa30M b neneHH /P. Li.ayBe.nc η M. B3H nep CrpsTeH, Eur. I. Respir. Dis. Supp. 122,63 /1982 r./, 83; A. ΡπρφβϋΒΛτ, Π. AHaepcoH, C. 3nc6aKep, M. TeHHecoH, R. Hsbhc η P. riay-3jic, Eur. I. Respir. Dis. Suppl. 122,63 /1982 r./, 86/. B cooTBeTCTBHh c 3thm 6ynecoHnn xapaKTepH3yeTca hh3koh H36HpaTejibHOCTbK) npH nprnvie-HeHHH b flbixaTenbHbix nyrcix b MojiejiHpyiomeH cncreMe /P. EpaTcana, Jl. KajiCTpēM, Y. ĒxaHCOH μ M. JLanGaK, «BocnanHTenbHaa h 6poHXHanbHan rnnappeaKTHBHOcTb ΓηκϊκοκορτΗκοστεροΗηοΒ», non penaKuneR jļ^.K. Xor-ra, P. 3ηηΗ6η-ΜΗΚ3ηβφ3, P. EpaTcaaaa, H3naTenbCTBO «3Kceprrra Menmca», 1985 r„ AMCTep^aM, CTp. 150-153/. B 3KcnepwMeHTajibHbix cncTeMax He-flaBHO onHCbmaJiHCb niiOKOKopTHKOCTepOKābi, HMeiomne flpyrne XHMHHeCKHe CTpyKTypbI, HanpHMep, φτθρΚθρΤΗΗ6)ΓΗηθΒΒΜ 3φπρ /FCB/ //Εκ.Φ. Kann, X. Kom, M. TēnepT, X£*. Keccnep η E. repxapnc, Arzneim-Forsch. 27 /1977 r./, 2230/. 3th coenHHeHna Moryr MHaKTHBMpoBaTbca b pe3yjibTaie 6HOTpaFKxļ)opMauHn nyTe\i rnaponH3a BHe neneHu, ho b coot-BeTCTBHH c MccjienoBaHHeM Mtcmena /Arzneim-Forsch. 27 /1977 r./, 3 LV 10959 2191/ φτορκορτΗΗδγτΗϋΟΒΒΐίί 3φνφ xapaKTepH3yeTCH τ3κημ προ-jiojdkmtsτιbHbiμ nepnozioM no/iypacnaaa β njia3Me, ητο η 6yjiecoHna. Bc^e^CTBHe 6onee ΗΗ3ΚΟΗ aKTHBHOCTH ψΤ0ρΚ0ρΤΗΗβ>ΤΗ;ΐΟΒΒΙΗ 3φπρ Heo6- χολημο Hcnojib30BaTb β ropa3,ao 6ojibLUHx ao3ax neM 6y,aecoHHA h/ih BDP /n.C. EepzpK, 3φτΗΜΗ0, M. TēpHep-BopBHH h FI.TJ1>k. Heziviec, Clinical Allergy 12 /1982 r./, 523/. Ο/ΐΗοίί uenbīo 3τογο n3o6peTeHna aBjiaeTca onncaHHe HOBbix ππιοκο-KopTMKOCTepoM^bix coeziHHeHHM, npe^Ha3HaHeHHbix zirm Hcno;ib30BaHHH nyTēM HHrajiaiļHH. Ohh xapaKTepH3yK)Tca o6ocHOBaHHoii npoTHBOBOc-na^HTe^bHOfl Η ΠρθΤΗΒ03Η3φϋΠ3ΚΤΗΗ60Κθ8 3KTHBHOCTbK) ΠρΗ npHMe-HeHHH B JlbIXaTe^bHbIX ΓΤγΤίΙΧ, H B H3CTHOCTH OHH OTJIHHaiOTCH 33MeTHO JīyHUieH B33HMOCBH3bK) Me>KHy nOTeHUHefi H aKTHBHOCTbK), BbI3bIBaK)meii jjeftcTBHe rjiK)KOKopTHKOCTeponaoB 3a npeaejiaMH o6pa6aTbiBaeMoro ynacT-na.

PacKpbiTHe cjtuhocth H3o6peTeHHH

HacToamee H3o6peTeHHe ocHOBaHo Ha tom Ha6juo,aeHHH, hto onpejie-neHHbie cjTOJKHbie 3φΗρΜ nperHaHOBoii KHCJiOTbi oBjiaziaioT bmcokoE npOTHBOBOCnaJIHTeJlbHOH Η Πρ0ΤΗΒ03Η3φΗ.Π3ΚΤΗ46ΰΚ0Η aKTHBHOCTbK) B

MecTe npuMeHeHna πρπ η£ήηηηη eecbMa He3Ha4HTejibHbix πιιόκο-KOpTHKOH£HbIX CHCTeMHbtX ΟφφθΚΤΟΒ. ΟοθΛΗΗβΗΗΛ ΠΟ 3TOMy H3o6pe-T6HHK) MOryT HCn0JIb30BaTbC3 zum JieneHH^ Η ΠροφΗ,ΙΉΚΤΗΚΗ BocnajiHTejibHbix, ajmeprH4ecKHx hjih HMMyHOJiorH4ecKHx 3a6ojieBaHHft AbIXaTe^bHbIX nyTeH, KO>KH, CyCT3B0B HJIH KHUieHHHKa.

CoeziHHeHHfl no 3TOMy H3o6peTeHHK) xapaKTepH3yiOTCfl φορι^/ιοπ 4 COORi

hjih npe^CTaBJunoT eē CTepeoH30MepHbiH κοΜποΗβΗτ, h b 3toK (ļ)opMyjie 3JieMeHT Ri BBjmeTca npHMOJiHHeiiHOH hjih pa3BeTBJieHHOft yr^eBo^o-ροϋΗοίι uentK), BKJiiOHafomeH 1-4 aTovia yniepozia.

OcoSeHHO npennoHTHTejibHbiMM 3aMecTMTejwMM Ri aBJiaiOTCH mcthji, 3THJ1, H-nponmi, M30np0nHJl, H-6yTMJI, H306yTHJI H BTOp-6yTHJI. OTjjejibHbie CTepeoH30MepHbie κομποηβητη, npHcyTCTByiomHe b c\iecH creponna, MMeiomero BbiLueyKa3aHHyK) φορινίγπγ /1/, mojkho oxa-paKTepH30BaTb cjie^yTomnM o6pa30M: COORi

i I F (S) 5 LV 10959 COORi

CH2CH2CH3 *s. F (R) ĪIpejinoHTHTejibHbiM ariHMepoM HBjmeTca 22 R - H30Mep.

Cnoco6 nojiyMeHHJi A. OKHCJieHHe anb^ernaa φορΜγ^Η

CHO

H X. CH2CH2CH3 (II) ero rHApaTa hjth no^yaueTajm b npHcyTCTBHM hohob unaHuaa h cnupTa φορΜΥΛΜ

Rl-OH 6 β κοτοροΚ Ri HMeeT yKa3aHHoe Bbiiue 3HaHeHHe.

Flpouecc B COOTBeTCTBHH C 3THM CnOCOČOM OnHCbIBaeTCa HkūKe COBMe-ctho c npefliuecTByiomeii CTa^neH, Ηβοβχο,αΗΜΟΗ λπλ πο/τυμθηηλ co-eZIHHeHRH φορΜΥΛΜ II. B npefliuecTByioineM cTannn 21-oKCHCTepOHH φορΜγτΐΜ

CH2OH

H'''‘CH2CH2CH3 (III)

F KOHBepTHpyeTca c Hcnojib30BaHHeM KMCJiopona /hjih B03iiyxa/ h Ka-TajiH3aTopa, TaKoro KaK cojib Menn β οπηρτοβομ pacreope, b crepoHaHbiH a^b^erpta φορΜγ/ΐΜ II. FIpHeMjieMbiMH cojmMH Menn /11/ jum 3toh peaKUHH aBJiaioTca boho-pacTBOpHMbie cojih HeopraHHHecKnx h opraHHHecKHx khcjiot. IlpHeivtneMbie COJIH MeflH /11/ BKJliOMaFOT, HO He OrpaHHHHBaiOTCa φθρΜΗ3ΤΟΜ ΜΘΛΗ /11/, aueTaTOM Mejin /11/, nponnoHaTOM Menn /11/ hjih 6yTMpaTOM Mejin /11/.

CnnpTaMH, HCnOJlb3yeMbIMH B nepBOfi CTaAHH peaKUHH, bbjihiotcji cnupTbi o6meH φορΜγ-ΠΜ RiOH, β κοτοροίί Ri HMeeT TaKue ace 3HaiieHHa hto η β φορΜγ,πβ I. OcoSeHHo npennoHTHTeJibHbiMH crmpTaMH aBJiaioTca MeTaHOJi, STaHOji, nponaHon, M3onponaHOJi, 6yTaH0Ji, H3o6yTaHOJi hjih BTop-6yTaHO^. npe^uiecTByK>maa crajiHa peaKUHH npejinoHTHTejibHO ocymecTBJiaeTca npH TeMnepaiype peaKUHH ot 0°C ro 40°C. BpeMa peaKUHH b 33bhchmocth 7 LV 10959 οτ TeMnepaTypbi peaKUHH cocraBjmeT 5-60 mhh>t, npezinoHTHTejibHO 40 ΜΗΗγτ npM KOMHaTHoii TeMnepaType. B 3aBHCHMOCTH OT HCn0Jlb30BaHHJl JUU1 peaKUHH BOflHbK HJIH 6e3BOJ[-Hbix cnnpTOM b npouecce 3toh peaKUHH o6pa3yioTCii cooTBeTCTByiomHe ruapaTbi, nonyaueiajiH hjih hx CMecn. XapaKTep nojiyHeHHoro npoityKTa HMeeT BaxHoe 3HaneHHe b oTHOujeHHH nocnejoTomeii peaKUHH. Πρε,α-nOHTHTeJlbHO HCn0JIb30BaTb TOT xe CnnpT, HTO Η BO BTOpOft CT3JIHH peaKUHH.

AueiaJieBbie hjih nojiyaueTajieBbie npo3BOūHbie ajībaenma φορΜγ^Μ II MOiyr npeo6pa30BbiBaTbca HenocpejiCTBeHHO b oio)KHbie οφπρΜ npemaHO-BOH KHCJlOTbl o6mefi φορΜγ^Η I ΠγΤβΜ OKHCJieHHH. Ha CTa^HH aue-TaJlHpOBaHH^ JIOJDKeH HCnOJIb30BaTbCH CnnpT, COOTBeTCTBJTOLUHH CJTO>KHOMy 3φπργ, κοτορΜΗ Heo6xoiiHMO nojiyHHTb. OKHCJieHHe ocymecTBjweTCii c nOMOLUbfO XJIOpHOBaTHCTOH KHCJlOTbl, 06pa3yeM0H H3 ΓΗΠΟΧϋΟρΗΤψ^ΟΗ- ηογο MeTamia, HanpnMep, rnnoxjiopHTa ηβτρηλ hjih Kajiua, h kmcjiotu, npejinoHTHTejibHo yKcycHoii KHCJlOTbl, npn TeMnepaType 0-25°C, ripe/i-nOHTHTeJIbHO npH 0°C. IlpHeMJieMblMH paCTBOpHTeJLHMH ilBJUUOTCJI KeTOHbl, HanpHMep, aUeTOH, MeTHJI3THJIKeTOH H CnnpTbl. ΗεοβχΟΛΗΜΟ HCn0Jlb30BaTb tot >Ke cnnpT, KOTopbifi >KejiaTejibHo HMeTb b KanecTBe nacTH οιο>κηογο 3φπρ3 Kap60HOBOH KHCJlOTbl.

KoHBepcHJi CTepouaHoro ajīb^eruaa φορΜγιΐΜ II b cjio>KHbie οφπρ^ nperHaHOBOil KHCJlOTbl oGmen φopMyJlbI I MO?KeT OC>TUeCTBJlBTbCil c nOMOLUbK) pa3H006pa3HbIX OKHCJIHTejieH.

HanpHMep, mo>kho npeo6pa30BbiBaTb coejiHHeHHe II hjih ero npojiyK-Tbl npHCOeAHHeHRH B CJlOJKHbie 3φπρΜ nperHaHOBOH KHCJlOTbl C nOMOLUbK) cnnpTOB hjih opraHHHecKHx OKHCJIHTejieH, t3khx KaK πepcyJlbφaτ 3μμοηηλ, N-6pOMCyKUHHHMHH, 5,6-HHXJ10p- 2,3-JlHUHaH06eH30XHH0H HJIH XJ10pHCTblii TpHφeHHJlTeτpa30JI.

TaioKe mohcho OKHCJiaTb CTepoHjļHbiH ajībjļerna II okhcjuiioluhmh okhcICih MeTajuiOB hjih cojlhmh MēTajuiOB, τβκημη KaK OKHCb MapraHua, 8 oKHCb cepečpa, xpoMOBaa KHCJioTa, nepMaHraHaT h noao6Hbie BemecTBa, b npHCJTCTBHH ΟΠΜρΤΟΒ Η Β3ρΗ3ΗΤΗΟ KHCJIOT. CrepOHJlHblH aJlbiierHjl II TaK->Ke ΜΟ?ΚβΤ B3aHMOiieHCTBOBaTb C 3ΤΜΟθφβρΗΒΙΜ KHCJlOpOflOM B npHCJTCTBHH ennpTa H HOHOB UHaHHJia. ΠΡΗ nOJiyMeHHH 20-ΚεΤΟ-21-ΟΒΟΗ KHCJIOTbl B COOTBCTCTBHH c npoueccoM A KHCJioTa koh BepTHpyeTCfl b cno>KHbiH 3<φπρ <ļ>opMyjibi I, HanpHMep, no cnoco(5y C.

Han6ojiee 6bicTpaa peaKumi h HauSojibiune Bbixoabi aocTHraiOTCii npn

HCF10Jlb30BaHHH OKHCJLHK)LHHX OKHCJIOB TiDKējIbLX ΜβΤΒΛΠΟΒ B npHCyTCTBHH cnnpTa h hohob unaHHaa. Biopaji CTanna npouecca aojuKHa ocymecTBjmTb-ch c ncnojib30BaHHeM cnnpTa, npeaHa3HaHeHHoro juīn o6pa30BaHmi nacTH ΟΠΟ>ΚΗΟΓΟ 3φΗρ3 H HCnOJlb30BaHHOĪO B nepBOR CTaaHH peaKUHH. ΠρΗ Mcnonb30BaHHH b nepBon ct3jimh peaKUHH apyroro cnnpTa 6yaeT no;iyHeH cjio^KHbiH 3φπρ c 3THM cnHpTOM, npeacTaBJiaiOLUHM npHMecb b προ,αγκτε peaKUHH KOHBepCHH H3 ajlbaerniia II B CJlOJKHblH 3φπρ I, TaK KaK 3Τ0Τ αιπρτ BBOjiHTca bo BTopyK) cTajiHK) peaKUHH nojTyaueTajieM ajībaerHna. H3-6biTOK cnnpTa TaiOKe mo>kho OūHOBpeMeHHO ncnojibaoBaTb b KanecTBe pacT-BOpHTejlfl peaKUHH, ΧΟΠΙ TaK MO/KHO BBOJlHTb HHepTHbie pacTBopHTejlΗ Β peaKUHOHHyio CMecb nonojiHHTejibHo κ cnnpTaM. ilpneMjieMbie HHepTHbie pacTBOpHTejiH BKjnonaiOT, ho He orpaHHHHBaioTca yrjieBO,nopo,aaMH, HanpHMep, 6eH30ji, UHKjioreKcaH, hjih TOJiyoji; xjiopHpoBaHHbiMH ynneBoao-pojiaMH, HanpHMep, MeTHJieHXJiopn.il, χ/ιοροφορΜ hjih TeTpaxjiop3TaH; npo-CTblMH 3φΗρ3ΜΗ, HanpHMep, npOCTOH HH3THJIOBbIH 3φηρ, npOCTOH JlHH30np0nHJ10BbIH 3φπρ, npOCTOH iw6yTHJI0BbIH 3φπρ, npOCTOH zmMeTHjioBbift 3φΗρ nnHKOjm, anoKcaH hjih τeτpaΓHIIpoφypaH; annojmp-HbiMH anpoTOHHbiMH pacTBOpHTejuiMH, HanpHMep, ΙΙΗΜεΤΚΠφορΜΒΜΗ,ΙΙ, N-MeTHjiaueTaMHa hjih N-MeTHjinHppojiHaoH h tji.

Bo Βτοροίί CTanHH peaKUHH npneMjieMbie okhch BīcniOHaiOT, ho He OrpaHHHHBaiOTCil OKHCJIMH CepeGpa, OKHCbK) CBHHUa /IV/, CBHHUOBbIM cypHKOM /Pb304/, OKHCbK) Banaana /V/ hjih oKucbio MapraHua /IV/. Ka- 9 LV 10959

TajiH3aTOp, npHMeHHeMbin b stoh ctbamh peaKUHH, npezicTaB/meT hohbi UHaHHfla, npeiļnoHTHTejibHo nojiyHeHHbie M3 UHaHHflOB mejiOHHbix MeTaji-jiob, HanpMMep, UHaHHua HaTpun hjih Kajina. npH Hcnojib30BaHHH UHaHHflOB mejiOHHbK MeTajuioB b KanecTBe peareHTOB, cjiy5KamHx zum o6pa-30Β3ΗΗΗ HOHOB UHaHHfla, 3Ta peaKUHH OCyUļeCTBJlHeTCH ITjnreM ZZOGaBJieHHB κ peaKUHOHHofi cMecH HeHTpajiH3yioiuero mejioHHoro MeTajuia KOJiMnecrea KMCJiOTbi, HanpMMep, HeopraHHHecKoii KHCJiOTbi, TaKoft KaK cepHaa, φοο φθρΗ3Λ HJIH XJ10pHCT0B0Zl0p0ZlHaa KHCJIOTa; Cyj^OKHCJIOTbI, TaKOfi KaK napa-TOjiyojicyj^OKHCJioTa, hjih KapOoHOBOH κηοζίοτμ, TaKoii KaK My-paBbHHan hjih yKcycHafl KHCJIOTa, zum coxpaHeHna noKa3aTejm pH b MHTep-Bajie ot 2,0 zio 6,0. 3ia peaKUHH ocymecTBJiHeTCH npn TeMnepaType peaKUHH ot 0°C zio + 50°C, npezinoHTHTejibHO πρπ κομηατηοΡι TeMnepaType. BpeMH peaKUHH b 3aBHCHMOCTH ot TeMnepaTypbi peaKUHH cocTaBjmeT ot 15 zio 120 mhhjt, npezinoHTHTejibHo 50 μηητγ npH κομηβτηοη TeMnepaType.

Ecjih onHcaHHan Bbime peaKUHH 6yzieT npoziojoKaTbcn b TeneHHe npo-ziojuKHTejibHoro nepHOfla BpeMeHH, HanpMMep, 6onee 48 HacoB, οοηοβημμ npOflyKTOM 6yjieT CJIO>KHbIH 3φπρ 20-OKCH-21-Kap6OHOBOft KHCJIOTbl, HMe-k)luhh φopMyJīy, yKa3aHHyio b πρμβολμμομ HMH<e cnoco6e B.

B. OKHCJieHHe 20-rHflpoKCHJibHOH rpynnbi coeziMHeHRH φopMyJ^bI COORi

CH2CH2CH3

F 10 20-niapoKCHJibHafl rpynna Μωκετ HaxoaHTbCii b a - hjih β - nono-2ΚΘΗΗΗ, Η 3TOT npOUeCC 0CymeCTBJUieTCH B HHepTHOM paCTBOpHTeJie c Mcnoiib30BaHMeM OKHCjmiomeH okhch MeTa/uia hjih cojih MeTaruia. ripouecc ΠΟ 3TOMy Η3θ6ρβΤ6ΗΗΚ) B COOTBeTCTBHH CO CnoeoOoM B MO->κετ ocymecTBjWTbCii β ΗΗβρτΗΟΜ pacTBopHTejie. ripHeMjieMbiMH pacrr-BOpHTen^MH HBJunoTca yrjieBoaoponbi, HanpHMep, UHKjioreKcaH, 6eH30Ji, TOJiyon h kchjioji; xjiopHpoBaHHbie ^jieBOjiopojibi, HanpHMep, μθτμ/ιθηχ-jiopna, χηοροφορΜ, TeipaxjiopMeTaH; npocTbie οφπρΜ, HanpHMep, προοτοΗ flH3THJIOBBIH 3φΗρ, npOCTOH JIHH30nponHJ10BbIH 3φπρ, npOCTOH XlH6yTHJ10-BblH 3φΗρ, Τετρ3ΓΗ/ΐρθφνρ3Η, JIMOKCaH, npOCTOH JIHMeTHJIOBblH 3φπρ r/iHKOJia: KeTOHbi, HanpHMep, aueroH, MeTHji3THjiKeT0H, MemnH3o6ymnKe-toh; h cnHpTbi, HanpHMep, MeiaHOJi, aiaHOJi, H3onponaHOJi h TpeT6yTaHOJi; a TaioKe cMecn 3thx pacTBopHTejieii. OKHcneHHe b cootb6tctbhh co cnoco6oM B MO^eT ocymecTBJWTbca npH HCn0JIb30BaHHH OKMCH MSpraHUa /IV/, OKHCH CBHHlia /IV/ HJIH aueTa-Ta CBHHua /IV/. C uejibio λοοτη>κ6ηηλ βμοοκηχ ββιχολοβ b 3tom npouecce npeanoHTHTejibHo Hcnojib30BaTb aKTHBHyio OKHCb MapraHua /IV/. OKHC/ieHHe npejinoHTHTejibHO ocymecTBjmeTC3 npH TeMnepaType peaKUHH ot 0°C h 150°C. TaKHM o6pa30M, mojkho npoH3BO^HTb OKHCJieHHe b cooTBeTCTBHH co cnocoOoM B npn KOMHaTHOH TeMnepaType hjih πρπ τεΜ-nepaType κππεΗΗΛ Hcnojib3yeMoro pacTBopHTejm. ΚθΗφΗΓ7ρ3ηΗϋ 20-rHHpOKCHJlbHOH rpynnbl ΗΟΧΟΛΗΟΓΟ εΟβΛΗΗβΗΗΛ He npejjcTaBjmeT 3HaHeHH3 npH ocymecTBJieHHH cnocoGa no 3TOMy H3o6pe-TeHHio. Ilo3TOMy b npoH3BOHHbie nperHaHOBoft κηοιοτμ o6men φopMynbl I mojkho OKHCJurrb anHMepbi c 20α - h 20 β- rnapoKCHJībHbiMH rpynnaMH, a TaiOKe hx cMecn. C. 3iepHUHKauHa KapOoHOBoii KHCJioTbi φορΜ>7ΐΜ 11 LV 10959

COOH !c=o HO

^ CH2CH2CH3

F

O

F (IV) HJTH ee φγΗΚίΙΗΟΗΒϋΒΗΟ SKBHBajieHTHOCTbK) Πρ0Η3Β0ϋΗ0Γ0 npH nOMOlUH coeiiMHeHHB φορνίγ.τπ>ι

Ri-OH HJIH ee φγΗΚ11ΗΟΗ3ϋΒΗΟ SKBHBaJieHTHOrO ΠρθΗ3ΒΟΛΗΟΓΟ, B KOTOpOM R1 HMeeT yKa3aHHbie Bbiuie 3HaHeHHfl.

Coe^HHeHHH φορΜγπΜ IV nojryHaioT πγτεΜ oKncneHna aJībaerHaa II. rnapaTa hjih nojiyaueTajm npn noMomn OKHCJiHTejia. 20-KeTO-21-OBbie KncjioTbi, Hcnojib3yeMbie b npouecce no 3tomy H306peTeHHK) B COOTBeTCTBHH CO Cn0C060M C, MOJKHO nOJiyHHTb nyreM ΟΚΗΟΓΙβΗΗΛ ΟΟβΛΗΗβΗΗΛ OČlUeft φορΜΥ^Η II npH ΠΟΜΟΙΙΙΗ OKHCJUnomeH okhch MeTajuia, npejinoHTHTejibHO okhch cepe6pa, ποιτυηθηηοΚ H3 HHTpaTa cepe6pa, η γηλροοκηοη menoHHoro MeTa/uia, HanpHMep, γηλροοκηοη HaTpna hjih Kajins b bojihom pacTBOpe. ZlpyrHe npneMJieivibie OKncjunomne peareHTbi BKinonaiOT nepMaHraHaT TeTpa6yTHJiaMMOHHa, KOMnneKCbi cepe6-pa /11/, χηορκτ h nono6Hbie BemecTBa. 12

AjībTepHaTHBHO, npoH3BOziHbie unaHorHnpHHa φορΜγ^Μ II mo>kho oKHcnarb c noMombK) MeTunenoBOH cmhm hjih OKHceft MēTajuioB, τβκηχ KaK OKMCb MapraHua hjih OKHCb cepe6pa. 20-KeTO-21-OBbie KHCJioTbi Tarace mo>kho nonyMHTb nyreM oMbi-JieHRH 21-CJlO)KHbIX 3φπρ0Β φορΜγ^Μ I/Rl = aJIKHJl/. OMbIJieHHe MO/KeT ocymecTBjLHTbca H3BecTHbiMH cnocoCaMH, HanpHMep, nyTeM OMbiJieHna CJIO>KHbIX 3φπρθΒ B BOJie HJIH BOHHOM ΟΠΗρΤβ B npHCJHTCTBHH KHCJIOTHOIO KaTajiH3aTopa, HanpHMep, χπορΗοτοΒο,αοροΛΗοΑ κηοποτμ, cepHOH κηοποτμ HJIH Π8ρ3-Τθπ>Ό;ΐθγΛΒφθΚΗθ;ΐΟΤΒΙ HJIH B npHCJTCTBHH OCHOBHOrO KaTanH3a-

Topa, HanpHMep, GHKapGonaT Kajinn, KapGonaT Kanna, rnjipooKHCb narpna hjih Kanna. 3τερΗφΗΚ3ΐ4ΗΗ CBo6ojiHbix khcjiot φορΜγηπ IV BbinojiHaeTca c nOMOLUblO H3BeCTHbIX MeTOJļOB. TaK, CBoCojlHbie KHCJlOTbl MOiyr Β33ΗΜΟ~ ZieftCTBOBaTb c ΟΠΗφαΤΗΜεΟΚΗΜ C1-C4 JlH330C0ejlMHeHHeM, ΖΙΗ330ΜΘΤ3Η0Μ HJIH J[Ha303TaH0M, o6pa3ya COOTBeTCTByK)LUHH CJIOXCHblft MeTHJlOBblH H STHJiOBbift 3φΗρ. OčbiHHO npHMeHaeMbiM cnoco6oM HBJiaeTca B3anMo-ZieftCTBHe CBOČOflHbK KHCJIOT CO CnnpTOM B npHCJTCTBHH, N, Ν’- Kap-60HMJWHHMHiia30Jia, JIHUHKJIOreKCHJIKapGoAHHMHAa, aHH0H006MeHHb!X cmoji, 3aiuHineHHoro nojiHMepoM AICI3, cojien nnpHjiHHa, H3BO3-H2SO4, Et20, MOJieKyjiapHbix cht - H2SO4, 1,1 - /Kap6oHHjmHOKCH/ jiHGeH-30TpHa30Jia, 6-xjiop-I-napa-xjiop5eH30Jicyj^OHH.aoKCH6eH30TpHa3ona, aHrHiipHJia ΤρΗφτορ>'^ΟΗθίί KHCJlOTbl, Κ3Τ3/ΙΗ33Τ0ρ0Β C nepeHOCOM φ33, TpHMeTHjmiopCHjiaHa, xjiopaHrHnpHjia, N, N’-6Hc/2-oKco-3-oKca-3ojihjihhhji/φοοφορζΐΗΕΜΗΛΟΒΟΗ KHCJlOTbl h jipyrnx aHajiorHHHbix Be-mecTB. KncjiOTbi TaioKe MOiyr 6bm> npečpa30BaHbi b CMemaHHbiH aHTKapna, HanpHMep, H3o6yTHjixjiopKap6oHaT, a 3aTeM noziBeprHyTbi B3aHMoaeHCTBHio c BbīGpaHHbiM cnnpTOM hjih cojiaMH cepeGpa, npnneM nocjiejiHee BemecTBO B3aHMoaeiiCTByeT c ajiKHJiranoreHHjioM. AūTepHaTHBHO, COJlb 20-KeTO-21-OBOH KHCJlOTbl c mejlOMHbIM Me-

TajuiOM, HanpHMep, jumteM, naipneM hjih Kainesi; cojib aMHHa, HanpHMep, 13 LV 10959

TpH3THJl-MJlH TpH6yTMJiaMHHa, COJlb ČHLļHKJIHHeCKOrO aMHJlHHa, HanpHMep, l,5-HHa3o6HUHKJio/5,5,0/ yaaeueH-5 /DBU/, cojib ΗβτΒερτΗΗΗΟΓΟ aM-MOHHeBoro 0CH0BaHP«, TaKaa KaK cojib TeTpa6yTHJiaMMOHHH hjih TpMKanpHJlMeTHJiaMMOHKa, MO>KeT B3aHMO,aeHCTBOBaTb C COOTBeTCTByiOLLIΗ M ajiKHjinpyiomHM areHTOM, HanpHMep, rajioimajiKHjioM hjih jiHajiKHjicyj^a-tom, HanpHMep, - flHMeTHJi-HJiH jiH3THJicy.r^aTOM, npeAnoHTHTenbHO b cpeae ποληρηογο pacTBOpHTejm, Tanoro KaK aueTOH, MeTHJi3THjiKeT0H, ΛΗΜβΤΗϋφθρΜ3ΜΗΛ, ΛHMeTHJ^CyJlbφ0KCH1^, ΜβΤΗϋβΗΧϋΟρΗΛ HJIH XJIOpO- φορΜ, oSbiHHo npn TeMnepaType b HHTepeajie 25-100°C. 3Ta peaKumi TaK-5Ke Μο>κβτ ocymecTBJWTbCfl b πρηοτιότβηη npocToro 3φπρ3. ,ϋργτΗΜ cnoco6oM nojiyHeHHii cjiojkhoio 3φπρ3 φop^ίyJlbI I «BJLaeTCii npeo6pa30BaHHe CBo6onHbix khcjiot b cooTBeTCTByiomHe ajiKHJiaue-ΤΒ/η^ΗΜβΤΗϋφορΜΒΜΗΛΒ. CBOGojlHbie KHCJlOTbl TaiOKe ΜΟΓ>Τ B3aHMO/ieHCT-BOBHTb B npHCyTCTBHH CHJlbHOrO KHCJlOTHOrO KaTajlH3aTOpa, HanpHMep, KnopOBO^OpOfla, CepHOft KHCJlOTbl, XJ10pH0H KHCJlOTbl, τρΗφτορMeTHJlC>’Jlb-φοΚΗΟ/ΙΟΤΜ HJIH napa - TOJTy0.riCyj^OKHCJ[OTbI, CO ennpTOM HJIH CJIOJKHblM οφπροΜ HH3mero aJiKaHa h KapGoHOBoii KHCJiOTbi BbīGpaHHoro cnnpTa. CBo6ojiHbie Kap6oHOBbie KHCJlOTbl TaioKe \ioryr 6biTb npeo6pa30BaHbi b XJIOpaHrHJipHJlbI HJIH 3HrHJIpHI|bI H B3aHMOHeHCTBOBaTb C Bbl6paHHbIMH CnnpTaMH B npHCJTCTBHH OCHOBHbIX Κ3Τ3ϋΗ33Τ0ρ0Β.

Ο.Τρ3Η03τερΗφΗΚ3ηιΐΗ cjiokhoto 3φπρ3 φopMy;IbI COOR2 c=o

CH2CH2CH3

F 14 β κοτοροft R2 npeacTaejuieT Memn hjih sthji, co οππρτοΜ φορΜγ;π>ι

Ri-OH β κοτοροΜ Ri HMeeT yKa3aHHbie Bbime 3HaHeHRa. Τρ3Η03τερΜφΗΚ3αΗΐο npejinoHTHTejibHO ocymecTBJiaK)T b npHCyTCTBHH KHCJIOTHOrO HJIH ochobhoio KaTajiH3aTOpa. npouecc no 3TOMy H3o6peTeHMio b cootbctctbηh co cnocoāoM D ocy-mecTBjmeTca nyTeM B3aHMOjieHCTBHs cjio?KHbix οφπροΒ npHBezieHHOH Bbime φop^ίyJIbI c >KejiaeMbiM cnnpTOM φορ\οτΐΜ RiOH b npHcyTCTBHH npeji-noHTHTenbHO KHCJiOTHoro hjih 6e3BOflHoro οοηοβηογο KaTanH3aT0pa. npeanoHTHTejibHbiMH kstojiH33TopaMh ochobhoto xapaKTepa BBJIBIOT-cji anKorojiaTbi mejiOHHbix MeTajuioe, meji0MH0-3ēMejibHbix MeTajuioe h ajnoMHHHR, a npeiinoHTHTejibHbiM KHCJiOTHbiM KaTariH3aTopoM HBjmeTCii napa-TOJiyojicyj^oKHCJiOTa. 3Ta peaKuna npezinoHTHTejibHO ocymecTBjm-eTca npH TeMnepaType ot 0°C ao 180°C. B npouecce stoh peaKUHH cnupT ΠρΗΜβΗΛΘΤΟΛ B H36bITKe. CnHpT TaiOKe MOJKCT 6bITb pa36aBJieH HHepTHbIM pacTBOpHTejieM. ripneMJieMbiMn pacTBopHTCiuiMH hbjuhotcji npocTbie οφπρΜ, HanpHMep, npocToii jiH-H-6yTHJiOBbiR 3φπρ, τeτpaΓHi^poφypaH, JIHOKCaH H npOCTOH JIHMeTHJIOBblH 3φπρ rjlHKOJIfl; hjih jiHnojmpHbie anpo-TOHHbie paCTBOpHTeJIH, HanpHMep, ΛΗΜεΤΗΙΐφθρΜ3ΜΗϋ,- MēTHJiaueTaMHŪ, ZiHMeTHJicyj^OKCHji, -MemnnHppojiHūOH h aueTOHHTpHJi. B KanecTBe cno>KHbix 3φπροΒ npHBezieHHoft Bbime φopMyJIbI, ncnojib-3yeMbix jum ocymecTBJieHmi npouecca no cnoco6y, npezinoHTeHHe OTjiaeTCfl CJlOJKHblM ΗΗ31ΙΙΗΜ aJlKHJIOBblM 3φπρ3Μ, HanpHMep, CJIO>KHOMy MeTHJIOBO-My HJIH 3THJI0B0My ^φHpy nperHaHOBOfi KHCJlOTbl. 06lhhm zum cnoco6oB A - ABjmeTca το, ητο b jik>6om npouecce β Kane-CTBe HcxoziHoro MaTepnajia ΜΟ/κετ Hcnojib30BaTbCH C-22 anHMepHaji CMecb, KOTopaji, npH jKejiaHHH, nocjie 3aBepmeHHH βτογο npouecca pa3aejmeTCfl Ha R h S H30Mepbi /C-22/. AnbTepHaTHBHo, jiio6oh npouecc A- Μο>κετ ocy- 15 LV 10959 mecTBjiHTbCii πγτβΜ Hcnojib30BaHna b KaMecTBe ncxoaHoro MaTepnajia R hjih S n30Mepa, npHMeM b 3tom cjiynae npouecc 3aBepuiaeTca nojiyHeHHeM KOHeHHbK ΠρΟΛΥΚΤΟΒ B BHJie R HJIH S H30Mepa.

OapMaueeTHHecKHe npenapaTbi

CoejiHHeHHJi no 3TOMy H3o6peTeHHK) Moryr Hcnojib30BaTbca rjv\ pa3JIHMHbIX peJKHMOB ΜβΟΤΗΟΓΟ ΠρΗΜβΗβΗΗΗ B 3aBHCHMOCTH OT yHaCTKa BocnajieHHJi, HanpHMep, ποακο>κΗθ, nap3HTepajibH0, hjih oji* MecTHoro ΠρΗΜΘΗβΗΗΛ B abDOTeJlbHOM Π>ΤΜ nOCpeaCTBOM MHraJLHlļHH. Ba>KHoii uejibio cocTaBa iiBjuieTca αοατϋκεΗηε onTHMajībHOH 6ho3kthbhocth aKTHBHoro CTepORaHoro HHrpejiHeHTa. Jļnsi nojiKO>KHbix cocTaBOB 3Ta ueiib jiyHLue Bcero aocTnraeTca, ecjin crepona pacTBopMeTca b HocHTeae c Bbico-koh TepMOHHHaMHHecKOM aKTHBHOCTbio. 3to ziocTHraeTCJi b pe3yjibiaTe Hcnojifa30BaHna cooTBeTCTByioineft CHCTeMbi hjih pacTBopHTejien, Bicmona-iomHx npneMJieMbie rjiHKOJin, Tanne KaK nponnjieH-rjiHKOJib hjih l,3-6y- T3JIHOH B OTfleJIbHOCTH HJIH BMeCTe C BOJIOH.

Crepona TaiūKe mojkho pacreopaTb nojiHOCTbio hjih ηβοτηηηο b jiHno(ļ)HJibHOH φ33ε c noMombio noBepxHocTHO-aKTHBHoro BeiuecTBa, npencTaBjunomero cojiio6HjiH3aTop. rioaKoacHbie cocTaBbi MOiyr npeacraB-jiaTb Ma3b, 3MyjibCHio Tnna «Macjio b Boae», 3MyjibCHio THna «Boaa b Macjie» HJIH npHMOHKH. B 3MyjlbCHOHHbLX HOCHTeJUIX CHCTeM3, BKJIIOHaiOmaJI paCT-

BopeHHbiH aKTHBHbiii κομποηθητ, Μοκετ o6pa30BbiBaTb aHcnepcHyio φa3y, a TaioKe HenpepbiBHyio φa3y. CTepona Tāme Μ05κετ HaxoanTbca b yKa3aH-Hbix Bbiuje cocTaBax b Bnae TOHKow3MejibHeHHoro TBepaoro BemecTBa.

HaxooJHUHecH ποα aaBjieHnevi a3po30JiH, coaepacamne creponabi, npeaHa3Ha4eHbi juvi HHrajiauHH nepe3 ροτ vum hoc. A3po30JibHaii CHCTeMa cKOHCTpyHpOBaHa τβκημ o6pa30M, hto KcDKaaa noaaBaeMaa ao3a coaep>KHT 10-1000 μκγ, npeanoHTHTejibHo 20-250 μκγ 8κτηβηογο oreponaa. HanGo-jiee aKTMBHbie CTeponabi BBoaaTca b ημ^κηθη μβοτη anana30Ha ao3bi. To-HKOH3MeabHeHHbiH CTepona npeacTaBjmeT nacTnubi MeHee 5 mhkpoh, 16 KOTOpbie cycneHHHpyK)TCfl b aaposojibHOH CMecH c noMouibio TaKoro ^HcnepraTopa, KaK TpHOJieaT, ojieHHOBaa KHCJioTa, jieuHTHH hjim cojib HaTpHH flHOKTHJlCyjlb(ļ)OflHTapHOίί KHCJlOTbl. TOHKOH3MejTbHeHHblfi CTepOHJl T3K5Ke MO>KHO CMeiUHBaTb C T3KHM HOCHTejieM, KaK /iaKT03a hjih r/iK>K03a. nopouiKoo6pa3Haa CMecb flHcneprHpyeTca b acecTKne >KenaTHHOBbie Kancyxibi, Kaxaaa H3 KOTopbix co-jiepjKHT Tpe6yeMyio ao3y crepomia. B npouecce Hcnojib30BaHKH 3iy Kancy-jiy noMemaioT b MHrajiaTop, h j[03a nopoiiJKa B.abixaeTca b iibixaTejibHbie nyTH.

PaSonne npHMepbi 3to H3o6peTeHne aajiee HjijnocTpnpyeTca cjieziyK)mnMH Heor-paHHHHBaioiUHMH npHMepaMH. B npHBeaeHHbDc npHMepax b npena-paTHBHbK ΧρθΜ3ΤΟΓρ3φΗΜεθΚΗΧ HCCJieūOBaHRflX ΠρΗΜβΗΛβΤΟΛ CKOpOCTb noTOKa, paBHa^ 2,5 mji/cm2 x wac , Mo;ieKyjurpHbie eeca bo ecex npHMepax oripeziejiaiOTca ripu πομοπιη ajiēKTpoHHOH yaapHOH Macc-cneKTpoMeTpun, a TeMnepaTypbi njiaejieHRH onpezie/unoTCii ripu πομοιιιη MMKpocKona zum onpeziejieHH* TeMnepaTypbi ruiaBjieHHa Leitz Wetzlar. Bce aHajiH3bi bmcoko-3φφ€ΚΤΗΒΗθίί >KHZlKOCTHOH Χρ0Μ3Τ0Γρ3φΗΗ BbinOJlHflJlHCb Ha KOHOHKe

Waters Bondapak Ci8 /300x3,9 mm zma BHyTpeHHoro zinaMeTpa/ co cKopo-CTbio noTOKa 1,0 mji/mmk m cooTHomeHneM 3TaHOjia h boziu 50:50 h 60:40 b KanecTBe noABH^cHofi φ33Μ, ecjiM HeT cneunajībHoro yKa3aHna.

IlpHMep 1

PacTBop 0,18 r aueTaTa MeziH /11/ b 100 mji MeTaHOjia floSaBjunoT κ pacTBOpy 0,825 r /22R/ -16a, 17a -6ymnnneHziH0Kcn -6a , 9 α-ΛΗφτορ-11>3 ,21-ziHOKCHnperHaH- l,4-,aHeH-3,20-;iHOHa b 50 mji MeTaHo^a. Bo3nyx 6ap6aTHpyeT Mepe3 peaKUHOHHyio CMecb b TeieHne 40 mhh>t πρκ κομηβτ-hoh Te\inepaType. BojibmyK) nacTb MeTaHOjia yziajuuoT, a oct3tok pacTBopa-k>t b 150 mji MeTHjieHXjiopHaa, npoMbiBaioT 10% βοληβιμ pacTBopoM 17 LV 10959 JCnOpMCTOrO 3MMOHHH H ΒΟΛΟΗ, a 38ΤΘΜ CyLUaT. OCT3TOK riOCJie Bbl-napHBaHmi ocaxuaiOT M3 CMecn MeTHjieHxnopmia h neiūieiiHoro 3(ļ)Hpa, b pe3yjibTaTe nero nojry4aK)T 0,837 r /22R/-16a ,17 a-6ymnHaenaHOKCH-6a, 9a-aHc£Top-llč-oKCH-3,20-,nHOKconperHaH-l,4 -UHeH-21-aji-MeTHJinojiya-ueTajLa. HncTOTa, onpeueJieHHaa nocpeucTBOM ΒΜΟοκοθφφθκτΗΒΗΟίί 5KHUKOCTHOH Χρ0Μ3Τ0Γρ3φΗΗ, paBHa 98,5%. 100 μγ 3ΤΟΓΌ ajībjiernua pacTBopaioT b 1,25 mji aMMeraj^opMaMnaa. K 3TOMy pacTBopy uoSaBJunoT UHaHHCTbiH Kajinn /13μγ/, OKHCb MapraHua /IV/ /Ι75μγ/, MeTaHOJi /0,5 mji/ h KOHueHTpnpoBaHHyio yKcycHyio κπαιοτγ /0,1 mji/, nocjie nero peaKunoHHyio CMecb nepeMeuiHBaiOT b Te-neHHe 50 μηη>τ πρπ κομη3τηοΚ TeMnepaType. OKHCb MapraHua /IV/ yaa-JUUOT φHJΊbTpOBaHHeM Η K φΗϋΒΤρ3Τ)' UOSaBJDUOT 25 ΜΓ MemneHXJ10pH.ua. 3tot pacTBop npOMbiBaioT 6%-BOUHbiM pacTBopoM KapGoHaTa Kajma h bo-jioh. Ilocue BbicynjHBaHna pacTBopHTeuH BbinapHBaiOT h ocTaTOK peKpHCTajuiH3yioT H3 CMecH aueTOHa h boum c BbixoaoM 66 μγ Memji-/22R/ -16a ,17a- 6yTHJinaeHaHOKCH- 6a,9a- Λπφτορ- 11/3- okch- 3, 20-UHOKconperHaH -l,4-uHeH-21-oaTa. HncTOTa, onpeuejieHHau npH πομοιιιμ ΒΜ0ΟΚΟ3φφβΚΤΗΒΗΟΗ JKHJļKOCTHOfl ΧρθΜ3ΤΟΓρ3φΗΗ, pOBH3 94,7%. ΤβΜΠβ- paiypa ruiaBjieHHu: 225-36°C. (a]D25= +72,0°/ c =0,400; CH2CI2/. Mo-jieKyjmpHbiH eec paeeH 494. IIpHMep 2

AueiaT Meuu /11/ /0,5r/ uo6aBjunoT κ pacTBOpy 1 r /22R/-16a,17a-6)ΓΗ;ΐΗΛ6ΗϋΗθκθΗ-6α,9α-ϋΗφτορ-11/3,21-HHOKCHnperHaH- l,4-jiMeH-3,20-UHOHa b 100 mji MeTaHOJia. 3Ty CMecb nepeMeuiMBaioT b TeneHHe 3-x uhch npw KOMHaTHoft TeMnepaType. B TeneHHe 3-x nacoB ββολλτ khcjiopou, nocne Hero 3Ty CMecb nepeMeuiHBaioT eme Ha προπυκβΗΗΗ 8 ΛΗβίί. PacT-BopHTejib BbinapHBaioT h ocraTOK pacrBopjnoT b 300 mji MemjieHxjiopH,aa, npoMbiBaKJT 4x25 mji 10% pacTBopoM ruapooKMCM βμμοηηη, 2x25 mji bo-Ubi, cymaT h BbinapnBaiOT. OciaTOK onumaioT nocpeucTBOM χροΜΒτοΓρΒφΗΗ 18

Ha KOJioHKe H3 οεφΒΛβκοβ LH-20 /72x6,3 cm/ c ncno3b30B3HneM xjiopo-φορΜ3 b KanecTBe πο3βη>κηοη φ33Μ. OpaKUHH 2550-3000 mji /A/ h 3150-3825 mji /B/ co6HpaK)T h BbinapHBatoT. H3 φρ3κΐ1ΗΗ A nojiyHaiOT 102 μγ TBep^oro Beinetrrea, Η36ητηΦηηηροβ3ηηογο KaK MeTnn-/22R/-16 α,17α-6γΤΜ^ΗΑ6Η(αΜΟΚςΗ-6α,9α-(αΗφτθρ-11^-ΟΚΟΗ-3,20-ΛΗΟΚΟΟΠρ6ΓΗ3Η-1,4-AHeH-21-oaT, m H3 φρΒκυκΗ B nojiyHaiOT 586 μγ MeTHJi-/22R/-16 α,17α-6yTHJinaemiHOKCH- 6a,9a- 3Ηφτορ- 1Ιβ,20- 3hokch- 3- OKconperHaH- 1,4-jiHeH -21-oaTa. K pacTBopy 100 μγ nocjieūHero coeziHHeHMfl 3o6aBjuiK)T 20 μγ okhch MapraHua /IV/ h peaKUMOHHyio CMecb nepeMeujHBaioT b TeneHHe 16 nacoB npH KOMHaTHOH TeMneparype. flByoKncb MapraHua /IV/ yjtaji?noT φιυΐΒτρο-B3HneM nepe3 ue/iHT h pacTBopmejib BbinapHBaiOT. Oct3tok pacTBopaioT b ΧίΙΟροφορΜΘ H OMVimaiOT Χρ0Μ3Τ0Γρ2φΗρ0Β3ΗΜ6Μ Ha KOJIOHKe H3 Οεφ^αβΚ-ca LH-20 /72x6,3 cm/ c Hcnojib30BaHneM xjiopc^opMa b KanecTBe ΠΟΛΒΗΑΗΟίί φ33Μ. Φρ3Κ11ΗΚ) 2190-2560 MJI COOHpaiOT, BbinapHBaiOT Η ΠΟΒ-TOpHO OHHmaiOT Χρ0Μ3Τ0Γρ3φΗρ0Β3ΗΗ6Μ Ha KOJIOHKe H3 ΟβφβΑβΙΚΉ LH-20 /72x6,3 cm/ c ncnojib30BaHneM CMecH renTaHa: xjiopc^opMa: 3TaHOJia c cooTHOLiieHHeM 20:20:1 b KanecTBe πο3βη;κηοη φ33Μ. OpaKiļHio 5130-5745 mji co6HpaiOT h BbinapHBaiOT c Bbixo30M 35 μγ Memn-/22R/ -16a, 17α-6>τνυΐΗ3εΗ3Ηθΐ«:Η-6α,9α-3Ηφτορ-11β- OKCH-3,20-3HOKConperHaH -l,4-3HeH-21-oaTa. HHCTOTy onpene^eioT nocpeacTBOM bmcokc^-φεκτΗΒΗοίί >kh3KOcthoh χροΜ3τοΓρ8φΗΜ η 0Ha poBHa 95,5%. TeMnepaiypa ruiaBJieHHa 223-35°C. MojieKyjmpHbiH Bec paBeH 494.

IlpHMep 3

PacTBOp 0,45 r aueTaTa Me3n /11/ b 100 mji aOcojnoTHoro 3TaHOjia 30-6aBJWioT κ pacTBOpy 2,0 r /22R/ -16a,17a-6ymnn3eH3HOKCH-6a,9a-3κφτορ-11/3,2 l-3HOKCHnperHaH-l,4-3neH-3,20-3HOHa b 300 mji a6co3ioTnoro 3TaH03a h noABepraioT B3anM03eiiCTBHio, noc3e liero Bbme-jlhhdt o6pa30BaBiunRc^ npo3yKT TaK, Kax onncaHo b npriMepe I, h Bbixo3 co- 19 LV 10959 craBimeT 2,0 r /22Κ/-16α,17α-6γτΗΐΐΜΛ6ΗΛΗθκεΜ-6α,9α-ΛΜφτορ-11^ -OKcn-3,20-^HOKConperHaH-l,4-^HeH-21-aji-3TH^no^yaueTajw. 3tot ajībflerna noasepraiOT β33μμολ6ηοτβηιο b ycjioBHiix, onHcaHHbix b npHMepe 1, 3aMeHHB MeTaHOJi 3TaH0Ji0M. Bbixo.a: 1,77 r HeoMmueHHoro npo^yKTa, κοτορΜπ oHHmaioT Ha KonoHKe H3 06φ3Λ6Κ03 LH-20 /76,5x6,3 cm/ c Hcnojib30BaHneM CMecH renTaHa: χϋοροφορΜ3: STaHOJia c cootho-uieHHēM 20:20:1 b KanecTBe ποβΒΐυκΗοϊί φ33Βΐ. OpaKUHio 2655-3150 mji co6npafOT h BbinapHBaioT. Flocjie peKpHCTajuiH3auHH ocTaTKa M3 STaHo/ia nojiyHaioT 1,03 r 3τπ;ι-/22Κ/-16α,17α-6}ττυΐΗ,α6ΗΐΐΗθΐ^Η-6α,9α-,ηΗφτορ-11^3-OKCH-3,20-jinoKconperHaH-l,4-jiHeH-21-oaTa. HncTOTa, onpeneneHHaji ΒΜΟοκοθφφβκτΗΒΗΟΗ jkhukocthoh χροΜΒτο^φπβΗ, poBHa 97%. TeMnepa-iypa njiaBJieHH^: 227-235°C. [a]25=+67,2 /c = 0,180; CH2CI2/. MojieKy-jiapHbiH Bec paeeH 503..

IlpHMep 4

PacTBop 0,35 r aueTaia μθλη /11/ b 150 mji nponaHOJia jio6aBjunoT κ pacTBOpy 0,80 r /22R/-16a,17a-6yTHJiH;ieH.nHOKCH-6a,9a-;n^Top-ll/l,21-jiHOKCHnperHaH- l,4-^HeH-3,20-^HOHa b 100 mji nponaHOJia h noziBepraioT B3aHMOflefiCTBMK). OGpaaoBaBiiiHiica npoxiyKT BbmejmiOT TaK, Kan onHcaHO b npHMepe I, npw stom Bbixoū cocraBjmeT 0,95 r /22 R/- 16a, 17a-6yTHJiHfleHaHOKCH-6a,9a-,ai^TC>p-ll/?-OKCH-3,20-.aMOKconperHaH-l,4-ΛΗβΗ -21-aji-nponHjmojTyaueTajui. 3tot ajībflerna nonBepraiOT B3aHMOj36HCTBHio b ycjiOBnax, onHcaHHbix b npHMepe 1, 33MeHHB MeTaHOJi nponaHOJioM. HeoHHmeHHbitt προι^κτ 04MLuaK)T Ha KOjiOHKe H3 06φ3Λεκ03 LH-20 /76,5x6,3 cm/ c ncnojib3o-B3HHeM renTaHa: χϋοροφορΜ3: 3TaH0Jia c cooTHomeHHeM 20:20:1 b KanecT-ee nojiBH>KHOH φ33Μ. OpaKiļHK) 3450-3990 mji coGnpaiOT h BbinapHBaiOT. OcTaTOK ocaagjaiOT H3 CMecH MeTHjieHXJiopnaa m neTpojiefiHoro 3φπρ3 c Bbixo;ioM 0,38 r H-nponHji-/22R/-16a,17a-6yTHjimieHjuiOKCH-6a,9a- ΛΗφτορ-l 1/3-okch- 3,20-^HOKConperHaH-l,4-jiHeK-21-oaTa. HHCTOTa, 20

Onpe^eJieHHaH nOCpejlCTBOM ΒΜΟΟΚΟΒφφβΚΤΜΒΗΟΗ >khakocthom XpOMaTOr- ρ3φΗΗ, poBHa 98,9%. TeMnepaTypa ruiaBJieHHa: 192-195°C. [a]D25= +66,4° /c = 0,256; CH2CI2/. MojieKyjmpHbift Bec 522. IIpHMep 5

PacTBOp 0,45 aueTaTa MeziH /11/ b 150 mji MeTaHOJia AoāaBJtaiOT κ pac-TBopy 1,0 r /22Κ/-16α,17α-6>τκπΜΛβΗΛΗθκοΗ-6α,9α-φτορ-11^,21-^HOKCHnperHaH- l,4-<aHeH-3,20-.aMOHa b 150 mji MeTaHOJia h noABepraioT BaaHMojieRcTBHio. 06pa30BaBuiHHca προζ^κτ BbiaejuuoT Tan, KaK onncaHo b npMMepe I. 3τοτ προζ^κτ pacTBopaiOT b 15 mji H3onponaHOjia m BbinapHBa-kdt. 3τγ npoueziypy ποΒτορΒίοτ ABajKAbi, b pe3yjibTaie 4ero nonyHaiOT 1,2 r /22Κ/-16α,17α-6)ΤΓΗϋΗΛ6ΗΠΗθκοΜ-6α,9α-ΛΜφτορ-11/3-οκθΗ-3,20-ΛΗθκςο-npemaH- l,4-j[HeH-21 -an-nponnjinojiyaueTajm. 3tot a^biiermi noziBepraiOT B3anMozieMCTBMK) b ycjioBHax, onHcaHHbix b npMMepe 1, 3aMeHHB MeTaHon M3onponaHonoM. HeoiMiueHHbiH προζ^κτ OHHmaioT Ha KOJioHKe m ςεφΒΛεκοΒ LH-20 /71,5x6,3 cm/ c Mcnojib3o-Β3ΗΜΘΜ Χ/1θρθφθρΜ3 B K3lieCTBe ΠΟΖΙΒΜ;>ΚΗΟΜ φ33Μ. Φρ3Κ14ΗΚ) 1845-2100 mji coGupaioT m BbinapHB3K)T c o6pa30BaHneM 0,42 r TBepaoro BemecTBa, κοτοροβ ocaacaaioT h3 cMecn MeTHJieHXjiopnaa h neTpojieHHoro 3φΗρ3. BbixoA cocTaBJueT 0,41 r H3onponMji-/22R/-16(2,17i2-6yTHJiHzieHOKCn-6α,9a -ΛΗφτορ-1 1/3-okch- 3,20-ūMOKconperHaH-l,4-ziMeH-21-oaTa. Hhcto-Ta, onpeziejieHHaji nocpezicTBOM ΒΜαζκοΒφφβκτΗΒΗοίί jkhūkocthoK χροΜ3τοΓρ3φΗΗ 96,5%. TeMnepaTypa njiaBjieHHa: 198-210°C. [a]D25=s +62,0° /<57292; CH2CI2/. MojieKyjmpHbiH eec paBeH 522. IIpHMep 6

PacTBop 55 μγ aueTaTa MeziH /11/ b 25 mji MeTaHOJia zioGaBjuuoT κ pac-TBopy 200 μγ /22Κ/-16α,17α-6>ΓΗτΐΗϋ6καΜθκαΗ-6<2,9α-ζΐΗφτορ-11/9,21-ZiHOKCMnperHaH- l,4-AHen-3,20-HMOHa b 25 mji MeTaHOJia u nozuīepraioT B3aHMOACMCTBHK). 06pa30BaBiunHCii npoziyKT BbiAeAJUOT Tax, KaK onHcaHo b 21 LV 10959 npHMepe I, npH 3τομ βμχολ 250 mji /22R/-16a,17a-6ymnnaeHaHOKCH-6a,9a-zu«i)Top-ll/5-OKCH-3,20-.aHOKConperHaH-l,4-,aHeH-21-aji- MēTHJino-jīyaueTajm. 3tot ajībiienm no^BepraioT B3aHMoaeiiCTBHjo b υοιοβηλχ, oriHcaHHbix b npHMepe 1, 33MeHMB MeTaHOJi 6yTaHOjiOM. HeonHmeHHbiH προΛγκτ OHHinaHDT Ha KOJiOHKe H3 LH-20 /87,5x2,5 cm/ c Hcnojib3o-

BaHHeM CMecH renTaHa: χϋοροφορΜ3: 3TaH0Jia c cooTHomeHHeM 20:20:1 b KanecTBe noflBiūKHofi φ33Μ. OpaKUHio 610-674 mji co6HpaioT, BbinapnBaioT h oca>KjiaK)T H3 cMecu MemneHxjiopnaa h neTpojieiiHoro 3φηρ3 c o6pa30-BaHHeM 76 μγ 6yTHJi^22R/-16a,17a-6yTMJiKaeiiaHOKCH-6a,9a-(iUKļ)TOp-ll/3-oKCH-3,20-ziHOKConperHaH-l,4-flHeH-21-oaTa. HHCTOTa, onpeflejieHHafl nOCpejICTBOM ΒΜ0ΟΚΟ3φφεΚΤΗΒΗθίί JKKflKOCTHOH ΧρθΜ3ΤΟΓρ8φΗΗ, 97,0%. TeMnepaTypa njiaBjieHMa: 185-188°C. [«]d25=+63,3 /c = 0,300; CH2CI2/. MojieKyjwpHbiH Bec paBeH 536.

IlpHMep 7 K pacTBopy 185 μγ /22Κ/-16α,17α-β>ΓΓΗ;ΐΗίΐ6Η(ιΐΗθκοΗ-6α,9α-ΛΗφτορ-ll^-OKCH-3,20-flMOKconperHaH-l,4-jiHeH-21-aji-MeTMJinojiyaueTaJui b 10 MJI ΛΗΜεΤΓϋϊφορΜΒΜΚΙΙΒ JloGaBJDHOT 40 ΜΓ UHaHHCTOrO KaJIHJI H 0,2 MJI Jie-AHHoft yKcycHoft khcjiotm. Ilocjie nepeMeuiHBaHHa b TeneHHe 15 μηηυτ ho-6aBJunoT 0,5 r okhch MapraHua /IV/. 3ry peaKUHOHHyio cMecb nepeMeuiHBaiOT πρπ komh3thoh TeMnepaType b TeneHHe eme 2-x nacoB. OttHCb MapraHLia /IV/ yjX2JlSUOJ φΚΠΒΤρ0Β3ΗΗθΜ H OCTaTOK BblJIHBaiOT b 50 mji Bojibi h TiuaTejibHo 3KCTparHpyioT STHJiaueTaTOM. BOHHOHI paCTBOp nOJIKMCJUUOT XJIOpHCTOBO^OpO^HOH KHCJIOTOH H 3KC-TparHpyiOT STHjiaueTaTOM. 3KcrpaKT cyuiaT h BbinapHBaioT. Oct3tok OHHUjaiOT nOCpejlCTBOM ΧρθΜ3ΤΟΓρ3φΗΜ Ha KOJiOHKe H3 0εφ3Λ6Κ03 LH-20 /88x2,5 cm/ c Hcnojib30BaHHeM CMecH xJIopoφopMa: 3TaHOJia: jiejiaHOH yK-cycHOH KHCJiOTbi c cooTHOiueHHeM 95:5:0,25 b KanecrBe πολβηχηοη φ33Μ. OpaKLuiK) 985-1125 mji coGnpaioT m BbinapHBaiOT c BbixojiOM 60 μγ /22R/- 22 16α,17α-6>ΤΗ;ΐΗΛβΗΛΗθΚ0Η-6α,9α-ΛΗφτορ-1 1/?-okch-3,20- aHOKeonper-HaH-l,4-uHeH-21- oBoft kmcjiotm. HwcTOTa, onpeziejieHHaji nocpencTBOM ΒΜ0ΟΚΟ3φφ6ΚΤΜΒΗΟΗ JKHflKOCTHOH Χρ0Μ3Τ0Γρ3φΗΗ, 99,0%. MaCC-CnēKTp/ XHMHMecKaii HOHH3aun*/: 481 /MH + /, 460 /MH + -HP/, 409 /MH+ -/CO2/2O/.

IlpHMep 8 K 680 μγ AgN03, pacTBOpeHHoro b 1,2 mji βολμ, jiočaBjunoT 4 mji 2 M pacTBopa rmīpooKHCH HaTpn* npn nepeMeuiHBaHHH. BcnjibrcaiomHM cjioh ίίβΗτρΜφγτΗργιοτ Hepe3 15 μηηυτ, a pacTBopHTejib ,aeKaHTHpy}OT. 06pa3o-BaBuiyioc« Ag20 cycnenaHpyK)T b 3 mji 0,01 M pacTBopa ruapooKHCH Harpna h aoāaBJuuoT 185 μγ /22R/-16a,17a- 6ymnHHeHQH0KCH-6a,9a-ΛΗφτορ-11/3-οκοΗ-3,20-ΛΜθκοοπρ6ΓΗ3Η-1,4-^6^21-311- MeTHjmojTyaue-τ3ιιλ. 3τγ cycneH3HK) nepeMeujHBafOT πρπ κομη3τηομ TeMnepaType b TeneHHe 1 naca, α6ΗτρΗφ>τΗρ)τοτ h BcruibiBaiomHM cjioh cycneH,aHpyioT b 3 mji 0,01 M pacreopa ruapooKHCH HaTpHH h τρίϋΚΛΜ L^eHτpHφyΓHpy^oτ. CoejiMHeHHbie mejioHHbie φ33Μ 3KCTparHpyiOT MeTHJieHXJ10pHilOM, ΓΙΟ,ίίΚΗΟΠίΠΟΤ 2M paCTBOpOM XJ!OpHCTOBOHOpOJlHOH KHCJIOTbl H 3KC-TparMpyK)T STHjiaueTaTOM. PacTBopHTejib BbinapnBaioT h oct3tok OHHinaioT nOCpeHCTBOM ΧρθΜ3ΤΟΓρ3φΜΜ Ha KOJIOHKe H3 06φ3Λ6Κ03 LH-20 /88x2,5 cm/ c Hcno/ib30BaHHeM cMecH xjiopc^opMa: STaHOJia: jiejiHHOH yKcycHOH KHCJiOTbi c cooTHomeHMeM 95:5:0,25 b KanecTBe πολβιόκηοη φ33Μ. OpaKUHK) 900-1010 mji coGHpaiOT π BbinapnBaiOT c βμχολομ 85 μγ /22R/-16a,17a-6ymnnaeHūHOKCH-6a,9a-j^Top-ll/?-OKCH-3,20- aHOKConperHaH -l,4-;iHeH-21- ioboR KHCJiOTbi.

IlpHMep 9 K pacTBopy 130 μγ /22R/-16α,17α-6yτHJIHJ^e^ļ^HoκcH-6α,9α-,^Hφτop-11/3-okch-3,20- ;iHOKConperHaH-l,4-flHeH-21-aji-MeTHJinojiyaueTajui b 1,5 Mji aueTOHa jio6aBjunoT 3 mji 0,1 Μ βοληογο pacTBopa Na3PŪ4 h 1 μγ 23 LV 10959 UHaHHCToro Kanna. PeaKunoHHyio cMecb nepeMeuiHBaiOT npn KOMHaTHofi TeMnepaiype b TeneHHe 30 μηη>τ. MeTnneHOByio cnHb /1% b Bone/ aoOaB-jihk)t no Karuiavi ιχο τβχ nop, noKa UBeT He coxpaHaeTca. PeaKunoHHyio CMecb nepeMeujHBaiOT b TeHeHne eme 30 mhhjt, κοΗαβΗτρηργιοτ no -2 mji n ^o6aBJwioT 25 mji HacbimeHHoro βοληογο pacTBopa NaHC03. 3iy CMecb npoMbiBaioT MeTHjienxjiopnnoM, noAKHejuuoT 2M pacreopoM xjiophctobo-ΛοροΛΗΟΗ KHCJiOTbi h 3KCTparnpyioT 3TMjiaueTaTOM. 3KCTpaKT cymaT n Bbi-napHBaioT, a οοτβτοκ OHHmaiOT nocpejiCTBOM xpoMaTOiļ^nn Ha KOJioHKe H3 0θφ3ΛβΚ03 LH-20 /88x2,5 cm/ c Hcnonb30BaHHeM cmcch χ;ιοροφορΜ3: 3TaH0Jia: nenunoPi yKcycHon KHcnoTbi c cooTHouieHHeM 95:5:0,25 b KanecT-Be nonBMJKHOH φ33Μ. OpaKLļMK) 900-1005 MJI COejlHHJllOT H BbinapHBaiOT c Bbixo,aoM 27 μγ /22R/-16a,17a-6yTHJiHaeHflHOKCH-6a,9a-n^Top-ll/3-OKCH-3,20-^HOKCOnperHaH-l,4-flHeH-21- OBOft KHCJlOTbl. ripHMep 10 K pacTBopy 100 μγ /22R/-16a,17a-6yTHjiH.aeH,aH0KCH-6a,9a-ji^T0p-11^-okch-3,20- AHOKConperHaH-l,4-aHeH-21- oboh khcjiotm h 35 μγ 6nKap6oHaTa Kanna b 10 mji ηηΜβτη/ιφορΜηΜΗϋη aoOaBJiniOT 285 μγ no^ncToro MeTnjia. 3Ty peaKLMOHHyio CMecb b TeneHne hohh nepeMeuiHBa-k)t npn KOMHaTHoii TeMnepaType, noGaBJiaioT 50 mji bojim n 3Ty CMecb skc-TparnpyioT MeraneHxjiopHnoM. OpraHnHecKyio φa3y otucjuiiot, npoMbieaiOT 10 mji HacbimeHHoro βοληογο pacTBopa τHocynbφaτa HaTpna, 2x10 mji bo-λμ, cyuiaT n BbinapnBaioT. Oct3tok onnuiaiOT nocpejiCTBOM χροΜ3τοΓρ3φηη Ha KOJioHKe n3 οεφααεκοΒ LH-20 /72x6,3 cm/ c ncnonb30BaHneM xjiopo-φορΜ3 b KanecTBe ποΛΒηχαιοίί φ33Μ. OpaKunio 2115-2550 mji coGnpaioT n BbinapnBaioT. Oct3tok pacTBopaiOT b MeTHJieHXjiopHne n ocajKnaioT npn noMomn neTpojieitHoro 3φηρ3 /TeMnepaTypa KnneHna 40-60°C/ c Bbixo-ΛΟΜ 88 μγ MeτnJI-/22R/-16α,17α-6yτnJmαeHΛHOKcn-6α,9α-J^nφτop-ll/3-OKcn-3,20-jmoKConperHaH-l,4-flneH-21-oaTa. HncTOTa, onpejiejieHHaa 24 nOCpe,HCTBOM BbIC0K03(ļ)(ļ)eKTHBH0H 5KHHKOCTHOK Χρ0Μ3Τ0Γρ8φΗΗ 96,2%.

TeMnepaTypa miaBJieHHJi: 227-235°C. Mo/ieKy;uipHbiH Bec paeeH 494. ΠρΗΜβρ 11

KpacTBOpy 100 mji /22R/-16a,17a-6yTHjHtaeiļaHOKCH-6a,9a-,a^Top-11/5-okch-3,20- jLHOKConperHaH-l,4-^HeH-21- oboh κηοιοτμ b 10 mji flHMeTHJ^opMaMHna ,ao6aB;uuoT 0,2 mji TpnaTHJiaMHHa h 0,5 mji mo^hctoto MeTHjia. 3iy peaKUMOHHyio CMecb nepeMeiiiHBaioT ripu TeMnepaiype 45°C b TeneHHe 4 nacoB, oxjia*maioT no κομη3τηοη TeMnepaTypbi, pa36aBjunoT 50 mji MeTMjieHXJiopH.ua, npoMbieaioT bojioh, cyiuaT h BbinapHBaioT. Oct3tok OHHmaiOT nOCpeilCTBOM χρθΜ3ΤΟΓρ3φΜΜ Ha KOJIOHKe H3 οεφαζιει^ LH-20 /88x2,5 cm/ c Hcnojib30BaHMeM CMecH χϋοροφορΜ3: 3TaHOJia: jiejumoft yx-cyCHOH KHCJiOTbi c cooTHOiueHHeM 95:5:0,25 b KanecTBe πολβηχ<ηοη φ83Μ. OpaKLiHio 265-320 mji co6npaK)T h BbinapHBaioT, a oct3tok ocaacjiaioT H3 CMecH MemneHXJiopH.ua h neTponenHoro 3φπρη /TeMnepaTypa κμπθηηλ 40-60°C/ c Bbixo,aoM 89 μγ MeTHji-/22R/-16a,17a-6yTHjiH.aeHjaHOKCH-6a,9a -ϋπφτορ-Ι l)3-OKCH-3,20-^HOKConperHaH-l,4-^HeH-21-oaTa. Hhcto-Ta, onpeaejieHHafl nocpejicTBOM ΒΜα)κο3φφβκτΗΒΗθΗ jkhjikocthoh χροΜ3τοτρ3φΗΗ, paBmuiacb 98,8%. TeMnepaT>pa ruiaBneHua: 231-236°C. MojieKyjLapHbift eec paeeH 494. ΠρΗΜβρ 12 K pacTBopy 100 μγ /22R/-16a,17a-6yTHjiM,AeH,AHOKCH-6a,9a-,at^TC)p-11/S-okch-3,20- flHOKConperHaH-l,4-/iHeH-21- oBofi kmcjiotu b 15 mji 6eH30Jia ao6aBJWK>T 65 mji l,5-iiHa3a6HUHKjio-[5,4,0]-yH^eueHa-5 h 0.5 mji HOiiHCToro MeTHJTa. PeaKUHOHHyro CMecb nepeMeuiHBaioT npn TeMnepaType 50°C b TeneHHe 4 nacoB, pa36aBJUHOT no 50 mji MeTHJieHXJiopRaa, npOMbi-B3K)T ΒΟΛΟΗ, CyiiiaT H BbinapHBaiOT. OcTaTOK OHHLIiaiOT Ha KOJIOHKe H3 ΰβφ3- aeKca LH-20 /88x2,5 cm/ c Hcnojib30BaHHeM CMecH χϋοροφορΜΒ: 3TaH0.na: nejviHoti yKcycHoii κηοιοτμ c cooTHomeHHeM 95:5:0,25 b KawecT- 25 LV 10959

Be πο£βη)κηοΚ (})a3bi. OpaKUHio 295-385 mji co6HpaioT h BbinapHBaiOT. OcTaTOK pacTBop^ioT b MemneHXJiopnae h ocaacnaioT npn noMomu πβτρο-jiefiHoro 3φπρ3 /TeMnepaTypa KMneHna 40-60°C/ c o6pa30BaHHeM 93 μγ MeTHji-/22R/-16a,17a-6ymnHneHnHOKCM-6a,9a-ni^Top -11£-okcm-3,20-flHOKConperHaH-l,4-flHeH-21-oaTa. HHCTOTa onpenejieHHaa nocpencTBOM ΒΒΐοοκο3φφ6κτΗΒΗθίι >KHaKOCTHoii χροΜ3τοΓρ8φΗΗ 98,9%. TeMnepaTypa ruiaBJieHna: 231-236°C. MojieKyjiflpHbiH Bec paBeH 494. ĪIpHMep 13 /22R/-16a,17a-6yTHjiHneHnHOKCM-6a,9a-ni«j)Top-ll£-OKCH-3,20-flHOKConperHaH-l,4-nHeH-21- oByio KHCJioTy /100 μγ/ h 6Hcyj^aT TeTpa6yTHJiaMMOHna /100 μγ/ noOaBjmioT κ 0,5 mji 1M pacTBopa rHnpo-OKMCHHaTpH^. /loSaBJunoT pacTBop 0,5 mjt μοληοτογο MeTHJia b 10 mji

MeTHJieHXJ10pH^a. 3Ty CMeCb ΚΜΠΗΤΗΤ C OČpaTHbIM XOJ10nHJIbHHKOM npH nepeMeniHBaHtm b TeneHHe hohh. riocjie oxjia>KneHHJi noOaBjunoT eme 20 mji MeTHJieHXJiopHaa. JļBa cjioh pa3nejunoT. OpraHHnecKHH cjioh npoMbiBa-K)T 2x10 mji Boabi, cyuiaT h BbinapHBaioT. HeoHHineHHbifi nponyKT onnma-k)t nocpencTBOM χροΜ3τοΓρ3φΗΗ Ha KOJiOHKe H3 οεφοϋεκοΒ LH-20 /72x6,3 cm/ C HCn0Jlb30BaHHeM XJ10poφopMa B KaneCTB? nOABH>KHOH φ33Μ.

OpaKUHio 2130-2550 mji co6HpaiOT h BbinapHBaioT, a oct3tok oca^KnaioT H3 CMecH MeTHJieHXJiopnaa h neTpojieHHoro 3φ«ρ3 /TeMnepaTypa KHneHHJi 40-60°C/ c bbixo.nom 106 μγ Memn-/22R/-16a,17a-6yTMjiH.aeHnHOKCM-6α,9α-ηΜφτορ-1 l/?-oKCH-3,20-nnoKConperHaH- 1.4-nHeH-21-oaTa. HncTOTa onpenejieHHan nyreM ΒΒίοοκοοφφεκτΗΒΗοίί jkhūkocthom χρομβτογρβΦκη 93,8%. TēMnepaTypa ruiaBJiemm: 225-235°C. MojieKyjmpHbifi Bec paeeH 494.

IlpHMep 14 /22Κ/-16α,17α-6>τρυΐΗηβΗηΗθκοΗ-6α,9α-ηΜφτορ-11^-οκθΗ-3,20-nnoKConperHaH-l,4-nneH-21-. OByio KncJiOTy /100 μγ/ m 80 μγ 26 xjiopHCToro TpHKanpmiMeTHjiaMMOHHa /οπηκβ3τ 336/ .aoGaBJunoT κ 2,5 mji HacbimeHHoro βοληογο pacTBopa NaHC03. ZloGaBjuuoT 0,5 mji ηοληοόγο MeTHJia b 10 mji MeTHjienxjiopmia. 3τγ CMecb nepeMeLUHBaiOT npw TCMnepa-Type 45°C b TeneHHe 20 nacoB, oxjia>KjiaK>T h pa36aBjmiOT 20 mji MeTHJiCH-xjiopnaa. flea cnoa pa3,aeJLHK)T. OpraHHHecKHH cjioft npoMbieaioT 3x5 mji Bojibi, cyiuaT h BbinapHBaioT. HeoHHmeHHbiii προζιγκτ OHnmaioT nocpe/iCT-bom χροΜ3τοΓρ3φΗΗ Ha KOJioHKe H3 ΰβφααβ^ LH-20 /88x2,5 cm/ c Hcnojib30BaHHeM CMēCH χ3ΐοροφορΜ3: 3TaHOJia: jie;wHOM yKcycHoft KHCJiOTbi c cooTHOiueHHeM 95:5:0,25 b KanecTBe πολβη^ηομ φ33Μ. <Ī>paKuwo 300-350 mji coGnpaiOT h BbinapHBaiOT, a ocraTOK ocaagiaiOT M3 CMecH MemneHXJiopmia m neTpojieiiHoro 3φπρ3 /TeMnepaTypa KnneHna 40-60°C/ c Bbixo,aoM 28 μγ MeTHji-/22R/-16a,17a-6yTHJiH,aeftaMOKCH-6α,9α-ΛΗφτορ-11^-οκθΜ-3,20-ΛΜθκοοπρ6ΓΗ3Η- l,4-,aHeH-21-oaTa. Hhcto-Ta, OnpejieJieHHaJl ΒΜΰΟΚ03φφ6ΚΤΜΒΗΟΗ >KHHKOCTHOH Χρ0Μ3Τ0Γρ3φΜθΗ, paBRajiacb 98,7%. TeMnepaTypa njiaBjieHna: 231-236°C. MojieKyjiapHbiM Bec paeeH 494.

IlpHMep 15 /22Κ/-16α,17α-6>τιυΐΜΛ6ΗΛΜθκαΜ-6α,9α-ΛΜφτορ-11/3-οκθΗ-3>20-flHOKConpemaH-l,4-AMeH-21- objto khcjiott /100 μγ/ pacTBopaioT b 5 mji MeTHJieHXjiopnaa h cMcmHBafOT c 5 mji 3Φηρηογο pacTBopa ziHa30MeTa-Ha. Hepe3 10 mhhtt no KanjmM aoSaBJunoT yKcycHyio khcjiott λο Mciie3HO-ΒβΗΜΛ ncejvroft OKpacKM. 3Ty CMecb BbinapMBaioT, a ocraroK pacTBopjnoT b MemneHXJiopmie h oca>KaaK)T H3 neTpojieiiHoro 3φπρ3 /TeMnepaTypa κππβΗΗΛ 40-60°C/ c BbixojjOM 76 μγ Mēma-/22R/-16a, 17a-β^Η,πΗΛεΗαΗο^Η-όα^α-,αΗφτορ-ΙΙβ-οκΰΗ^^Ο-,αΗΟ^οπρβΓ^Η- 1,4-jiHeH-21-oaTa. MHCTOTa onpeziejieHHafl nocpejiCTBOM ΒΒΐοοκο3φφβκτΗΒΗθΗ jkhjikocthoh χροΜ3τοΓρ3φΗΗ 96,7%. TeMnepairypa njiaBjieHna: 228-235°C. MojieKyjwpHbifi Bec paBeH 494. 27 LV 10959 IIpHMep 16 K pacTBOpy 82 μγ /22R/-16a,17a-6ymnKaeKiiHOKCH-6a,9a-(ai^Tc>p-11£-okch-3,20- xiMOKConperHaH-l,4-iiMeH-21-aji-MeTHjinoJTyaueTaji^ b 25 mji MeTaHOJia, oxjia>KjeHHoro b BaHHe co JibjiOM, jio6aBJunoT 0,06 mji jiejia-hoh yKcycHOH KucjiOTbi, a 3aieM MejuieHHo bbo;wt 0,5 mji 2M βο^ηογο pac-TBopa rHnoxjiopHTa HaTpmi ripu nepeMeniHBaHHH. PeaKUHOHHyio CMecb nepeMeuiMBaioT eme b TeneHHe οζιηογο naca. HoOaBjmiOT MeTHjieHXjiopn,q /150 mji/, nocjie nero pacTBOp npoMbmaiOT 10% βολημμ pacTBopoM Kap-6oHaTa Kajina h HacbimeHHbiM xjiopncTbiM HaipneM. OpraHHHecKyio φa3y BbICyiIIHBaK)T H BbinapHBaiOT. OeTaTOK paCTBOpHIOT B MeTHJieHXJ10pHJie M ocajKjiaioT c noMombio neTpojieiiHoro 3φκρ3 /TeMneparypa KHneHHa 40-60°C/ c Bbixo^OM 9 μγ MeTHJi-/22R/-16a,17a-6yTHjiHaeHjiHOKCH-6a,9a-ίΐΗφτορ-l l^-OKCH-3,20-jiHOKConperHaH- l,4-(aHeH-21-oaTa. HHCTOTa onpejiejieHHaa nocpencTBOM βμοοκοβΦΦθκτηβηοϊι >khhkocthoh xpoMaior-ρ3φΜΜ 93,8%. TeMnepaTypa njiaBjieHna: 225-235°C. MojieKyjiapHbiH eec paeeH 494. IIpHMep 17 K pacTBopy 100 μγ MeTHji-/22R/-16a,17a-6yTHJiH^eH^MOKCH-6a,9a-ίΐιιφτορ-Ι 1/3-okcm- 3,20-jinoKconperHaH-l,4-aHeH-21-oaTa h 12 mji h-nponaHOJia jioBaBjmioT 20 μγ TpeT- 6yTHjiaTa Kajimi. PeaKUHOHHyio CMecb κηπλτλτ c oGpaTHbiM xojiojiHJibHHKOM πολ cjioeM aproHa b TeneHMe 1 Mača, oxjia>KjiaiOT, BbiJiHBaioT b 25 mji JiejiflHofi bojim h 3KCTparnpyiOT MeTHjieHX-jiopHAOM. 3KcrpaKT npoMbieaiOT HacbimeHHbiM bohhmm pacTBopoM 6nKap-SoHaTa Harptia, cymaT h BbinapuBaioT, b pe3yjibTaTe nero nojiyHaioT 28 μγ nponHJĪ-/22R/-16a,17a-6yTHJiHiieHiiHOKCH-6a,9a-,EwinOp-ll/S-oKCH-3,20-ziHOKConperHaH-l,4-^HeH-21-oaTa. HHCTOTa onpejiejieHHaJi nocpencTBOM ΒΜςοκο3φφ6κτΗΒΗ0Η jkhūkocthoh χροΜ3τοΓρ3φΗΗ 99,2%. TeMnepaTypa ruiaBjieHmi: 262-270°C. MojieKyjmpHbiH Bec paeeH 566. 28 ΠρπΜβρ 18.4>apMaiieBTHHecKHe npenapaTbi

Cne£cyK>mne HeorpaHHMHBaiomne npMMepbi HJuiK>cTpnpyK)T cocTaBbi, npeHHa3HaHeHHbie ΛΠΛ pa3JlHHHbIX J10Ka/lbHbIX ΒΜΛΟΒ ΓφΗΜβΗβΗΗΗ. Ko^HHecTBO aKTHBHoro CTeponaa b no,nKO?KHbix cocTaBax ο6μηηο cocraB/LH-ετ 0,001-0,2% /BecoBbie npoueHTbi/, npe,anoMTHTejibHO 0,01-0,1% /Beco-Bbie npoueHTbi/.

Cocrae 1, Ma3b CTepOHfl, TOHKOH3MeJlbHeHHbIH ^(παΚΗβ ΠβρΒφΗΗ Bejlblfi ΜΗΓΚΜΗ Π3ρ3φΗΗ 0,025 r 10,0 r ,αο 100,0 r

CocraB 2, Ma3b Crepomi 0,025 r nponM^eHr^HKOjib 5,0 r CecKBnojieaT copOHTa 5,0 r }ΚΗΛΚΗΗ ΠΒρΒφΗΗ 10,0 r EeJIblH ΜΗΓΚΗΗ Π3ρ3φΗΗ jxo 100,0 r CocTae 3, 3MyjicHH THna «Macjio b Bo^e» Creponji 0,025 r UeTaHOJi 5,0 r MoHOCTeapaT niHuepHHa 5,0 r )KHHKHH Π3ρ3φΗΗ 10,0 r neTOMaKporo/i 1000 2,0 r JlHMOHHaiī KHCJ10T3 0,1 r llHTpaT HaTpua 0,2 r FIporiHJieHrjlHKOJlb 35,0 r Bo^a ΛΟ 100,0 r 29 LV 10959

CocraB 4, 3MyjibCHH Tnna «Macjio b BO,ae» CTepOHtt, TOHKOH3MeJĪbMeHHblii 0,025 r BeJlblH ΜΗΓΚΗίί Π3ρ3φΜΗ 15,0 r )KhūKMH Π3ρ3φΗΗ 5,0 r UeTaHOJi 5,0 r CTeapaT cop6HMaKporojia 2,0 r MoHocTeapaT cop6nTa 0,5 r CopČHHOBaa KHCjiOTa 0,2 r JlHMOHHaa KHCjiOTa 0,1 r UHTpaT HaTpna 0,2 r Bona ro 100,0 r

CocraB 5, 3MyjibCHH Tnna «eo^a b Macne»

Crepona 0,025 r

BejibiH μλγκηη napacļ)HH 35,0 r >ΚΗϋΚΗΗ Π3ρ3φΗΗ 5,0 Γ

CecKBHOJieaT copOnTa 5,0 r

CopčHHOBaa KHCjiOTa 0,2 r

JlHMOHHafl KHCJIOTa 0,1 Γ UHTpaT HaTpRH 0,2 r

Bona jio 100,0 r

CocTae 6, npHMOHKa 0,25 μγ 0,5 mji 3 ΜΓ ΠΟ nOTpeāHOCTH ΆΟ 1,0 r

Crepomi H3onponaHOJi

Kap60KCHBHHHJ10BbIH nojiHMep

NaOH

Bozia 30

CocraB 7, cycneH3HH ajib HHbeKumi Οτεροκα, TOHKOH3MejlbHeHHblfi 0,05-10 ΜΓ

HaTpneBaa Kap6oKCHMeTmmejuiiojio3a 7 μγ

NaCl 7 μγ

MoHOOJieaT nojinoKCH3TnneH /20/ copČHTa 0,5 μγ EeH3HJioBbiii cnwpT 8 μγ

Boaa, CTepunbHaa ao 1,0 mji

CocraB 8, a3po30Jib λπλ HHrajumHH nepe3 ροτ h hoc 0,1 BecoBO^· % 0,7 BecoBt>ix % 24.8 BecoBbix % 24.8 BecoBbix % 49,6 BecoBbix % 7.0 μγ 5.0 r Λo 10,0 r

Crepottn, TOHKOM3MejlbMeHHbIH TpHOJieaT copOHTa ΤρΜΧΠΟρφΤΟρΜεΤΒΗ /ΐΗΧΠ0ρΤβΤρ3φΤ0ρΜ6Τ3Η /1ΗΧί1θρΛΗφτθρΜβΤ3Η

CocTae 9, pacTBop jum pacnbuieHHa

Crepomi nponmieHrjiHKOJib

Bozia

CocraB 10, nopouiOK ajib HHrajiauHH )Ke/iaTHHOBaH Kancy;ia, 3anojiHeHHaa CMecbio cTeponaa, TOHKOH3MejibHeHHoro 0,1 μγ

JlaKT03a 20 μγ lĪHrajiĀUM nopouiKa npoH3BO,nnTCfl nocpe^cTBOM HHrajiaTopa. 31 LV 10959

OapMaKOjiorHH

IlpOTHBOBOCnaJlHTeJIbHblH 3φφ6ΚΤ H36HpaTeJlbHOCTb B OTHOllieHHH npOTHBOBOCnaJIHTeJlbHOrO ΛβΗΟΤΒΗΛ Ha MecTe npHMeHeHHa b /ierKHx 6bi/io Hccne/iOBaHo b MO,ae^HpyKimeft CHCTeMe y Kpbicbi nocjie BHyTpH6poHXMajibHoro BBejjeHna rjnoKOKopTHKocrepoHaa. BBēHeHHē UiapMKOM 0βφ3ΛβΚ03 B nerKMe KpbICbl npOBOflMT K 6poHXHajibHOMy h ajibBeojwpHOMy BocnajieHHio. 3to Bbi3biBaeT HHTepcTHUHajībHbifi οτεκ jierKnx, KOTOpbiH yBejiHHHBaeT Bec Jienora, no3TOMy BocnaneHHe mojkho H3MepaTb b bmjic yBejiHHeHHa eeca jierKnx no cpaBHeHHio c KOHTpojibHoii rpynnoft, κοτοροη 6biJio np0H3Be,aeH0 BJiHBaHne HOCHTejia. 06pa30BaHHK> OTena jienara mo>kho npoTHBo^eHCTBOBaTb nyreM npeiiBapHTejibHoro jieneHHa rmoKOKopTHKOCTepomiaMH, npeanoHTHTejibHO b pe3yjibTaie BHyTpH6poHXHajibHoro BBeaeHRH hjih HHrajiaiļHH. B HaeajībHOM cjīyHae npoTMBOBOcnajiHTejibHoe AencTBne jiojokho 6biTb αοοτμγητγο TOJibKO b MecTe npHMeHeHna rjnoKOKopTHKocTeponaa b jierKnx, a He 3a npe^enaMH 3τογο ynacTKa, TaK Kan sto npw npojiojDKHTejibHOM jieHeHHH Μωκετ npHBēCTH κ orpaHHMHBaiomnM jieneHHe cncTeMHbiM no6oMHbiM aBJieHnaM. ΑΗφφΒρεΗη^αΗΛ Me>K£y .aencTBHeM rjnoKOKopTHKOCTepoiina b o6pa6oTaHHOM ynacTKe jierKoro h 3a npejie/iaMH 3τογο ynacTKa 6bura oxapaKTepH30BaHa b cjiezoTomeM npoTOKone HcnbrraHHH. Kpbic - Sprague Dawley /225 r/ cnerKa aHacTe3HpoBajiH προσπ>ΐΜ 3φηροΜ, nocne nero hm bbohhjim HSibiTyeMbiH npenapaT niFOKOKopTHKOCTepoH/ia b oObevie 0,5 μγ/κγ TOjibKo b jieByļo Λοιικ) JierKoro. 3to ,aocTnrajiocb nyreM BBe,aeHHa τοηκογο h H3orHyToro CTajībHoro KaTeTepa nepe3 ροτ h Tpaxeto b jieByio flojiio JierKoro / Bbi6op 3τογο peauiMa BBejzeHna TOJibKo b jieByio aojiio 6biJi nO^TBep>KHeH OTaejlbHblMH 3KCnepHMeHT3MH C HCn0nb30BaHHeM CHHH 3eaHca, b pe3yjibTaīe βμπο,πηβημλ KOTopbix Gbuio o6Hapy>KeHO, hto >95% BBeaeHHoro BeuiecTBa Haxo^Mjiocb b jieBoii aojih h <5% - b npaBon ^ojih 32

jrerKoro/. Hepe3 TpmmaTb μηηυτ bbohhjih cycneH3Hio οεφαπεκοΒ /5 μγ/ κγ b o6^eMe 1 mji/κγ b TpaxeK) HenocpejicTBeHHO Haa 6i^ypKauneft, TaK hto cycneH3wi flocrama KaK jicboh, TaK h npaBoft αοιιθη jierKHx. Hepe3 ziBaauaTb nacoB Kpbic y6HBajiH, noc/ie nero y hhx OTceKajin jieBoe h npaBoe nerKoe m B3B6LUHBajiH oTūenbHO. TaioKe perncTpnpoBajiH eec TMMyca. KOHTpOJIbHbIM rpynnaM ΒΒΟΛΜΙΙΜ HOCHTeJIb BMeCTO rjiioKOKopTMKOCTepomiHoro npenapaTa μ Φρπηολογηηθοκηη pacTBop BMecTO cycneH3HH οεφΒϋεκοΒ ajlh onpe^ejieHMa eeca, He 3amHmeHHoro npenapaTOM oreKa ncm «aeiicTBHeM οεφααε^, h eeca HopMajībHoro jierKoro. Jļjia Kaacaoro rjuoKOKopTHKOCTeponnHoro npenapaTa HcnbīTbiBajiH, no KpafiHeft Mepe, 3 Λ03Η b AHana30He 0,01-10 μγ/κγ h b OTHomeHHH Ka^aoH> 6 naparuiejiefi / ,ao3y. ΓjifOKOKopTHKocTeponabi cycneHaHpoBajiM b HOCHTene CMC-Na 0,75%, TBHHe 80 0,04% m 0,7% NaCl jiočaBjmeMon ūo 100%. Πρη cTporo jioKajībHOM npoTHBOBOcnajiHTejibHOM aeiicTBHH b cjiyHae 3a6ojīeBaHHW flbixaTeJTbHbix nyTefi HaeanbHbiM προφΗ/ιβΜ coe^HHeHHa ΛΒ/iaeTca τ3κοη προφΗ/ib, KOTopbiii ūo/dkch npoTHBoaeficTBOBaTb BocnajieHHK) b noflBepraeMoft jiOKanbHOMy jieHeHHio jieBoft aojih JierKoro, a He b npaBOM iiojin JierKoro, Ky^a CHanana nonaaaeT ΓΛιοκοκορτηκοοτθροΗϋ no 6ojibmoMy Kpyry KpoBooOpameHHa / nocne nomomeHHa H3 JieBoro jierKoro/. CooTHOiueHHe Me>Kny Tpe5yeMOH cpe^Heii 3φφ0κτΗΒΗοη Λ030ίί /^03bi, yMeHbmaK)mMe οτεκ Ha 50%/ b npaBofi n jieBoft ao;mx JierKoro Μ0>κβτ Hcnojib30BaTb b KanecTBe napaMeTpa zum oueHKH H36HpaTenbHon aKTHBHOCTH Ha MecTe npHMeHeHRH. nneaJībHoro rniOKOKopTMKocTepoHjia 3TO cooTHomeHMe H36MpaTejibHOCTH hojukho 6biTb BbICOKHM.

Pe3yjibTaTbi BbinonHeHHbix HcnbīTaHHii npHBe/ieHbi b TaOziHue I, rae b BepXHeR nacTM npeacTaBJieHbi ^eHCTBna, flocTHraeMbie paHee H3BecTHbiMn THnaMH rjiioKOKopTHKOCTepoM^OB. 5y/ļecoHH^ He oGecnenHBaeT KaKoR -jim6o H36HpaTe;ibHOCTH zum MecTa npuMeHeHRH b zierKOM, TaK KaK Tpe6yeMaii cpeziHzm 3φφθκτΗΒΗ^ zi03a zum zieBoii m npaBofl ziojien JierKoro 33 LV 10959 6bUia flOBOJlbHO OflHHaKOBOM / COOTHOUJeHHe H36HpaTeJIbHOCTH —1,5/. B cjiynae caMofi bmcokoh HcribiTaHHOH λο3μ /0,5 μγ/κγ/ 6yzieHOCna yMeHbiuaeT Bec THMyca Ha 22% /p<0,01/. PaHee H3BecTHbi rjifOKOKOpTHKocTeponn FCB aocTHraeT ηθκοτοροΚ H36HpaTe;ibH0CTH, TaK Kan yMeHbiueHHe OTena npaBoīi ,αο,πΗ jierKoro Tpe6yeT b 2-3 pa3a OojibiueH A03bi no cpaBHeHHio c Heo6xo6HMOM Λ030ίί zum TopMO^ceHna OTeKa JieBoro JierKoro.

HoBbie οοβΛΗΗβΗΗΛ no 3TOMy n3o6peTeHHio xapaKTepH3yiOTC^ ropa3,ao JiyHllieft H36HpaTeJIbHOCTbIO B OTHOlIieHHH aKTHBHOCTH, CBiī3aHHOH c ποΛΒβρΓΗΤτοη MecTHOMy ζιβΗβΗΜΚ) jieBOH ziojih jierKoro /TaO^Hua I/. CooTHomeHHe H36HpaTe;ibH0CTH aocTHraeT 6 hjih ^a^e 6ojibiuero nncna

Be/IHHHH. C nOMOLUbK) 3ΤΗΧ COejlHHeHHH MO>KHO nperiflTCTBOBaTb pa3BHTMK) OTena JieBoro /ιθγκογο, no MeHbineH Mepe Ha 60% 6e3 KaKoro-jTH6o 3HaMHTeJlbHOrO BJ1UHHHH Ha ΟΤβΚ npaBOH JļOJTH ΖΐβΓΚΟΓΟ. ΠρΗ Λ03β 10 μγ/κγ coezjHHeHUH β cootb6tctbhh c npHMepaMH 1 h 5 BOo6me He bjihjuot Ha Bec THMyca, β το BpeM* KaK coeziHHeHHe no npMMepy 3 πρΗ το£ί >κβ zi03e Bbi3biBaeT He3HaHHTenbHoe yMeHbineHHe eeca TMMyca /Ha 15%, p<0,05/.

HoBbie coejiHHēHH^ oOjiaaaioT 6o/iee bmcokoh npOTHBOBOCnaJIHTenbHOfi aKTHBHOCTbK) Ha MeCTe ΠρΗΜβΗβΗΗΛ / 3HaneHHe cpenHen οφφεκτΗΒΗοίί ao3bi b jieBoft Aone JierKoro <5 μγ/κγ/ no CpaBHeHHK) C HH3KOfl aKTHBHOCTbK), npOAeMOHCTpHpOBaHHOft ΛΠΛ npenapaTa FCB /10 μγ/κγ/. 34

Ta6jiHua 1 iJefiCTBHfl HCnbITaHHbIX rūK)KOKOpTHKOCTepOH£OB B MO^ejie 0βφ3Λ6Κ03. Pe3yjibTaTbi npHBeaeHbi no OTHOiueHHio κ cooTBeTCTBjTomeH koht-pojibHOii rpynne, κοτορο& bbohhjicji ce(J)aaeKc.

CoCAHHeHHe no npHMepy CpeAHJM 3φφβκ-THBHaa A03a(x) Jleeaa aojih jierKoro μγ/κγ CooTHouieHHe H36HpaTejib-HOCTH cpeuHaa ϊφφεκτΗΒ^Η A03a&) npaeoe JierKoe THMyc % HHBOJ1IOUHH /A03a μγ/κγ/ cpenHaa 3φφεκτΜΒΗ3« A03a(x) jieeoe JierKoe ByaecoHna 0,2 1,4 22/0,3/ FCB 10 2,5 6/10/ 1 2,5 6,0 -3/10/ 3 1,7 5,9 15/10/ 5 5 10,0 -1/10/ 4 1 10 6/10/ x/ CpejiHioi 3φφβκτΗΒΗ3Λ fl03a - Tpe6yeMafl £03a πποκοκορτΜΚοετε-ponna, Heo6xoflHMaH mm yMeHbweHRH oTeKa Ha 50%. 35 LV 10959

ΦΟΡΜΥΛΑ H30EPETEHHH 1. HoBbie npoH3BOAHbie 16,17 - aueTanb 3aMemeHHOH nperHaH-21-oboh KMCjiOTbi oāmeii <ļ>opMyjibi: COORi

H ^nCH2CH2CH3 (I)

F hjih hx CTepeoH30MepHbie KOMnoHeHTbi, b KOTopbix ajieMeHT Ri npeacTaB-jiaeT npHMOjiHHeiiHyio hjih pa3BeTBjieHHyio yr^eBO^opoaHyio uenb, bkjuo-naiomjTo 1-4 aTOMa yniepo.ua. 2. CoejiHHeHMe no nyHKTy 1, OTjiHHaiomeecfl TeM, hto Ri npencTaBJiaeT MeTHJibHyK) rpynny. 3. Coe^MHeHHe no nyHKTy 1, OTjiHHaiomeeca TeM, hto Ri npeacTaBJiaeT 3THJibHyio rpynny. 4. CoeflHHēHHe no nyHKry 1, OT/innafoineeca τθμ, hto Ri npe^cTaBJiaeT H-nponMjibHyio rpynny. 5. CoeflHHeHHe no nyHKTy 1, OTjiHHaiomeecH τθμ, hto Ri npeflCTaBJiaeT H3onponHjibHyio rpynny. 6. CoeziHHeHHe no nyHKTy 1, OTJiHHaiomeeca τθμ, hto Ri npeACTaBJiaeT H-6ymnbHyio rpynny. 36 7. Cnoco6 nojiyHeHHfl coeflHHeHRa φορινιγιΐΜ 36 COORi

F

H ^xCH2CH2CH3 hjih ero CTepeoH30MepHoro κομποηθητη, b κοτορι>ιχ ajieMēHT Ri npezicTaB-jiaeT npflMOJiHHeiiHyK) hjim pa3BeTB/ieHHyK) yrjieBOnopoiiHyK) uerib, bkjiio-HaK>myio 1-4 aTOMa yrjiepona; oTJiHHaiomHMca TeM, mto npoH3BO,aMTca a1/ OKHCJieHHe ajib,nenma 4)opMyjibi

CHO

Osc.H CH2CH2CH3 F 37 LV 10959 ero nmpaTa hjih nojryaueTajieH b πρηοτοτβηη hohob unaHuaa h cnnpTa φορΜγ/ΐΜ

Ri-OH b κοτοροίί Ri ΗΜβετ yKa3aHHoe Bbiuie 3HaMeHne, hjih a2/ OKHCJieHHe coeAHHeHna φορΜγ^Μ

A

0^r^H v CH2CH2CH3

O

F

b κοτοροΗ A npeacTaBJUieT aueTajibHyio nacTb - CH/OR1/2 hjih nojiyaue-TajibHyio nacTb - CH/OH/ORi, npHneM b 3thx φορΜγ^Βχ 3JieMeHT Ri HMecT yKa3aHHoe Bbiiue 3HaMeHHe, ocymecTBjweMbiM c noMombio xjiop-HOBaTHCTOH KHCJlOTbl, HJIH 6/ OKHCJieHHe 20-niapoKCHjibHOH rpynnbi coejiHHeHHJi φορι^/ΐΗ 38 COORi

V s CH2CH2CH3

F b/ 3TepH^HKaUKH KapČOHOBOH KHC/IOTbl (ļ)OpMyJlbl

COOH

v CH2CH2CH3

F HJ1H ee φγΗΚΙΙΗΟΗΟΠΒΗΟ 3ΚΒΗΒ3ϋεΗΤΗΟΓΟ Πρ0Η3Β0ΛΗ0Γ0 ΓφΗ ΠΟΜΟΙΙ1Η CO-εΛΜΗβΗΜΛ φορΜγ/ΊΒΙ

RlOH HJ1H ero φγΉΚΙΙΗΟΗ3ϋΒΗΟ 3KBHBaJieHTHOrO Πρ0Μ3Β0ΛΗ0Γ0, ΓφΗΗβΜ B 3TOH φορΜγιιβ Ri ΗΜβετ yKa3aHHoe Bbirne 3HaHeHHe, πρπ πομοιιιη ūMa3oco-ejiHHeHna φορΜγ,πΜ 39 LV 10959

Rl-CH2 = N2 b κοτοροίί Ri npe^CTaBjmeT npHMOJiHHefiHyK) hjih pa3BeTBJieHHyio ynieBO-ΛοροΛΗγκ) uenb, BKJiK)HaK)myio 1-3 aTOMa yrviepo,aa; hjih Γ/ TpaHC3TepH(ļ)HKaUH* ΟΙΟ>ΚΗΟΓΟ 3φπρ3 φορΜΥ^Η COOR2

C'H ^ v CH2CH2CH3

f B KOTOpOfi R2 «BJUieTCa ΜΘΤΗΠΟΜ HJIH 3THJI0M, npH ΠΟΜΟΙΙΙΗ CnHpTa φορ-Myjlbl

Rl-OH b κοτοροίί Ri HMeeT yKa3aHHoe Bbime 3HaneHHe, nocjie nero, ecjin nojiy-HCHHoe t3khm o6pa30M coeziHHeHHe npeacTaBjuieT 3nMMepH>To CMecb, h ^ejiaTejibHO nojiyHHTb MHCTbiii anHMep, npoH3Bonnrca pa3nejieHHe 3τοίί CMecH Ha CTepeoH30MepHbie κομποηθητη. 8. Cnoco6 no nyHKTy 7, OTJiHMaK>mHHca Tevi, hto nojiyHaK)T co-eflHHeHHe no jno6oMy H3 πυηκτοβ 2-6. 9. 4>apMaueBTHHecKHH npenapaT, oTjiHHaioiuHHca τθμ, hto oh BKjnona-ετ b KanecTBe βκτηβηογο HHrpejiHeHTa coeaHHeHHe no jno6o\iy H3 nyHKTOB 1-6. 40 10. «^apvtaueBTHMecKHH npenapaT no nyHKTy 9 b BHae ao3Hpo-

BaHHOH HHflHBHflyaibHOH φορΜΜ. 11. OapMaueBTHHecKHH npenapaT no nynKTy 9 hjih 10, otjihma-K)IHHHCH TeM, 4T0 OH BKJHOHaeT aKTHBHblH HHrpeaneHT COBMeCTHO c φapMa^eBTH^ecκH npHevuevibiM HOCHTe/ieM. 12. Hcno;ib30BaHHe εφφεκτΗΒΗΟΓο KOJiHHecTBa coeaHHeHHii no JIK)60My H3 nyHKTOB 1-6 ΛΠΗ JieMeHHH Η ΠρθφϋΠ3ΚΤΗΚΗ BOcnariHTe.ribHbix, ajuieprHHecKHx hjih aepMaTOJiorHMeckhx 3a6o;reBaHHH y MjieKO-nHTaiomHx, BKjnoHaa we;ioBeKa. 13. CoeflHHeHne no ;no6oMy H3 πυηκτοβ 1-6, npeaHa3HaMeHHoe juia Hcnojib30BaHHH b KanecTBe neKapcTBeHHoro npenapaTa προτΗΒ Bocna-jiHTejibHbix, ajuieprHMecKHX h jiepMaTOJiorHMecKHx 3a6o;ieBaHHH. 41 LV 10959 AHHOTAIļHfl ΠρββΜβτοΜ 3τογο H3o6peTeHiw hbjwk)tc^ coejtHHeHH3, xapaKTepH3y-KmjHecii aKTHBHOCTbio προτΗΒ BOcnajiHTejibHtK, ajuieprHMecKHx h jiepMa-TOJiorHHecKHx 3a6ojieBaHHH. 3th coe^HHeHHa ΜΜβιοτ φορινιγπγ COORi

<Xr^H cr ^ v CH2CH2CH3

F hjih BKjiiOHaiOT ee CTepeH30MepHbiH KOMnoHeHT, npuneM b 3toh φορΜγιΐθ sjieMeHT Ri npeflCTaBjiaeT npHMOJiHHefiHjTo hjih pa3BeTBjieHHyio yrjieBojjo-poflHyio uerib, HMeK>myio 1-4 aTOMa yrjiepoaa. ūpejiMeTOM 3Toro H3o6peTeHHa Taioce HBjmiOTca cnoco6bi nojiyHeHHa 3thx coenHHeHHH, φ3ρΜ3ΐ16ΒΤΗΗθ0ΚΗε npenapaTbi, conepacamne οληο H3 3ΤΗΧ COeflHHeHHH.

Claims (13)

1. LV 10959 PATENTA FORMULA 1. Jauni 16,17-acetālaizvietotas pregnān-21 -skābes atvasinājumi ar kopējo formulu (I) COORi

   vai to stereoizomēri, kur R1 ir lineāra vai sazarota ogļūdeņraža virkne ar 1-4 oglekļa atomiem.
2. 2. Savienojums saskaņa ar 1. punktu, kas atšķiras ar to, ka R, ir metilgrupa.
3. 3. Savienojums saskaņā ar 1. punktu, kas atšķiras ar to, ka R, ir etilgrupa.
4. 4. Savienojums saskaņā ar 1. punktu, kas atšķiras ar to, ka R, ir n-propilgrupa.
5. 5. Savienojums saskaņā ar 1. punktu, kas atšķiras ar to, ka Rļ ir izopropilgrupa.
6. 6. Savienojums saskaņā ar 1. punktu, kas atšķiras ar to, ka R, ir n-butilgrupa.
7. 7. Paņēmiens savienojuma ar formulu (I) 2 2 COORi

   H VvCH2CH2CH3 f kur Rļ ir lineāra vai sazarota ogļūdeņraža virkne ar 1-4 oglekļa atomiem, vai tā stereoizomēra iegūšanai, kas atšķiras ar to, ka a1) oksidē aldehīdu ar formulu CHO

   vai tā hidrātu, vai pusacetalus cianīda jona un spirta ar formulu RrOH , kur R, ir iepriekš dota nozīme, klātbūtnē vai a2) oksidē ar hlorapskabi savienojumu ar formulu 3 LV 10959 A

   O-'sp-'H --0" sCH2CH2CH3

   F kur A ir acetala -CH(OR1)2 grupējums vai pusacetāla -CHiOHjOR, grupējums, pie kam šajās formulās R, ir iepriekš dotā nozīme, vai b) oksidē 20-oksigrupu savienojumā ar formulu

   i F c) esterificē karbonskabi ar formulu COORi

   \ s CH2CH2CH3 COOH

   --CKr^H --0'^ vCH2CH2CH3

   F 4 vai tas funkcionāli ekvivalentu atvasinājumu ar savienojumu ar formulu RrOH vai tā funkcionāli ekvivalentu atvasinājumu, pie kam R, ir iepriekš dotā nozīme, vai ar diazosavienojumu ar formulu R/-CH2=N2, kur R,' ir lineāra vai sazarota ogļūdeņražu virkne ar 1-3 oglekļa atomiem, vai d) pāresterificē esteri ar formulu coor2

   --Ovr^H vCH2CH2CH3

   I F kur R2 ir metilgrupa vai etilgrupa, ar spirtu ar formulu RrOH , kur Rļ ir iepriekš dotā nozīme, un pēc tam, ja šādi iegūtais savienojums ir epimēru maisījums un vēlams iegūt tīru epimēru, veic maisījuma sadalīšanu stereoizomērajos komponentos.
8. 8. Paņēmiens saskaņā ar 7. punktu, kas atšķiras ar to, ka iegūst savienojumu saskaņā ar jebkuru no 2.-6. punktiem. 5 LV 10959
9. 9. Farmaceitisks preparāts, kas atšķiras ar to, ka satur kā aktīvo vielu savienojumu saskaņā ar jebkuru no 1 .-6. punktiem.
10. 10. Farmaceitiskais preparāts saskaņā ar 9. punktu dozētas individuālas 5 formas veidā.
11. 11. Farmaceitiskais preparāts saskaņā ar 9. vai 10. punktu, kas atšķiras ar to, ka tas satur aktīvo vielu kopā ar farmaceitiski pieņemamu nesēju.
12. 12. Savienojuma saskaņā ar jebkuru no 1 .-6. punktiem efektīva daudzuma izmantošana iekaisuma, alerģisku vai dermatoloģisku slimību ārstēšanai un profilaksei zīdītājiem, ieskaitot cilvēku.
13. 13. Savienojums saskaņā ar jebkuru no 1.-6. punktiem, ko paredzēts 15 izmantot kā zā|u preparātu iekaisuma, alerģisku un dermatoloģisku slimību ārstēšanai.