LV10959B - Novel 16,17-acetalsubstitute derivatives of pregnane-21-acid, method for their preparation, medicinal preparations of thereof - Google Patents
Novel 16,17-acetalsubstitute derivatives of pregnane-21-acid, method for their preparation, medicinal preparations of thereof Download PDFInfo
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- LV10959B LV10959B LVP-93-1046A LV931046A LV10959B LV 10959 B LV10959 B LV 10959B LV 931046 A LV931046 A LV 931046A LV 10959 B LV10959 B LV 10959B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
- C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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)
- LV 10959 PATENTA FORMULA 1. Jauni 16,17-acetālaizvietotas pregnān-21 -skābes atvasinājumi ar kopējo formulu (I) COORivai to stereoizomēri, kur R1 ir lineāra vai sazarota ogļūdeņraža virkne ar 1-4 oglekļa atomiem.
- 2. Savienojums saskaņa ar 1. punktu, kas atšķiras ar to, ka R, ir metilgrupa.
- 3. Savienojums saskaņā ar 1. punktu, kas atšķiras ar to, ka R, ir etilgrupa.
- 4. Savienojums saskaņā ar 1. punktu, kas atšķiras ar to, ka R, ir n-propilgrupa.
- 5. Savienojums saskaņā ar 1. punktu, kas atšķiras ar to, ka Rļ ir izopropilgrupa.
- 6. Savienojums saskaņā ar 1. punktu, kas atšķiras ar to, ka R, ir n-butilgrupa.
- 7. Paņēmiens savienojuma ar formulu (I) 2 2 COORiH 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 CHOvai 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 AO-'sp-'H --0" sCH2CH2CH3F 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 formului F c) esterificē karbonskabi ar formulu COORi\ s CH2CH2CH3 COOH--CKr^H --0'^ vCH2CH2CH3F 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 vCH2CH2CH3I 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. Paņēmiens saskaņā ar 7. punktu, kas atšķiras ar to, ka iegūst savienojumu saskaņā ar jebkuru no 2.-6. punktiem. 5 LV 10959
- 9. Farmaceitisks preparāts, kas atšķiras ar to, ka satur kā aktīvo vielu savienojumu saskaņā ar jebkuru no 1 .-6. punktiem.
- 10. Farmaceitiskais preparāts saskaņā ar 9. punktu dozētas individuālas 5 formas veidā.
- 11. Farmaceitiskais preparāts saskaņā ar 9. vai 10. punktu, kas atšķiras ar to, ka tas satur aktīvo vielu kopā ar farmaceitiski pieņemamu nesēju.
- 12. Savienojuma saskaņā ar jebkuru no 1 .-6. punktiem efektīva daudzuma izmantošana iekaisuma, alerģisku vai dermatoloģisku slimību ārstēšanai un profilaksei zīdītājiem, ieskaitot cilvēku.
- 13. Savienojums saskaņā ar jebkuru no 1.-6. punktiem, ko paredzēts 15 izmantot kā zā|u preparātu iekaisuma, alerģisku un dermatoloģisku slimību ārstēšanai.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE8506015A SE8506015D0 (sv) | 1985-12-19 | 1985-12-19 | Novel 16,17-acetalsubstituted pregnane 21-oic acid derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
LV10959A LV10959A (lv) | 1995-12-20 |
LV10959B true LV10959B (en) | 1996-06-20 |
Family
ID=20362521
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
LVP-93-1046A LV10959B (en) | 1985-12-19 | 1993-08-27 | Novel 16,17-acetalsubstitute derivatives of pregnane-21-acid, method for their preparation, medicinal preparations of thereof |
Country Status (31)
Country | Link |
---|---|
EP (1) | EP0232690B1 (lv) |
JP (1) | JPH0780900B2 (lv) |
KR (1) | KR940004067B1 (lv) |
CN (1) | CN1016508B (lv) |
AR (1) | AR242797A1 (lv) |
AT (1) | ATE57935T1 (lv) |
AU (1) | AU591950B2 (lv) |
CA (1) | CA1318664C (lv) |
CS (1) | CS266597B2 (lv) |
DD (1) | DD256703A5 (lv) |
DE (1) | DE3675378D1 (lv) |
DK (1) | DK168601B1 (lv) |
ES (1) | ES2018656B3 (lv) |
FI (1) | FI84488C (lv) |
GR (1) | GR3001052T3 (lv) |
HU (1) | HU196831B (lv) |
IE (1) | IE59241B1 (lv) |
IL (1) | IL80679A (lv) |
IS (1) | IS1559B (lv) |
JO (1) | JO1499B1 (lv) |
LT (1) | LT3912B (lv) |
LV (1) | LV10959B (lv) |
MY (1) | MY100750A (lv) |
NO (1) | NO164243C (lv) |
NZ (1) | NZ218614A (lv) |
PH (1) | PH23237A (lv) |
PL (1) | PL151627B1 (lv) |
PT (1) | PT83984B (lv) |
RU (1) | RU1839673C (lv) |
SE (1) | SE8506015D0 (lv) |
ZA (1) | ZA868750B (lv) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU203769B (en) * | 1989-03-09 | 1991-09-30 | Richter Gedeon Vegyeszet | Process for producing new steroide derivatives and pharmaceutical compositions containing them |
US5643602A (en) * | 1989-11-22 | 1997-07-01 | Astra Aktiebolag | Oral composition for the treatment of inflammatory bowel disease |
SE8903914D0 (sv) | 1989-11-22 | 1989-11-22 | Draco Ab | Oral composition for the treatment of inflammatory bowel diseases |
US6166024A (en) * | 1995-03-30 | 2000-12-26 | Mayo Foundation For Medical Education And Research | Use of topical azathioprine and thioguanine to treat colorectal adenomas |
CA2936741C (en) | 2014-10-31 | 2018-11-06 | Purdue Pharma | Methods and compositions particularly for treatment of attention deficit disorder |
US10722473B2 (en) | 2018-11-19 | 2020-07-28 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1387911A (en) * | 1971-10-04 | 1975-03-19 | Schering Ag | Pregnane acid derivatives |
DE2150268C3 (de) * | 1971-10-04 | 1980-11-06 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Pregnansäure-Derivate, Verfahren zu ihrer Herstellung sowie diese enthaltende Arzneimittel |
DE2204360C2 (de) * | 1972-01-27 | 1982-11-04 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Neue Pregnansäure-Derivate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Präparate |
SE378109B (lv) * | 1972-05-19 | 1975-08-18 | Bofors Ab | |
DE2264003C2 (de) * | 1972-12-22 | 1982-11-04 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Neue Pregnansäure-Derivate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Präparate |
IE38659B1 (en) * | 1972-12-22 | 1978-05-10 | Schering Ag | New pregnane acid derivatives |
SE8403905D0 (sv) * | 1984-07-30 | 1984-07-30 | Draco Ab | Liposomes and steroid esters |
-
1985
- 1985-12-19 SE SE8506015A patent/SE8506015D0/xx unknown
-
1986
- 1986-11-18 ZA ZA868750A patent/ZA868750B/xx unknown
- 1986-11-18 IL IL80679A patent/IL80679A/xx not_active IP Right Cessation
- 1986-12-11 IE IE324586A patent/IE59241B1/en not_active IP Right Cessation
- 1986-12-11 NO NO865004A patent/NO164243C/no unknown
- 1986-12-12 DE DE8686850436T patent/DE3675378D1/de not_active Expired - Lifetime
- 1986-12-12 NZ NZ218614A patent/NZ218614A/xx unknown
- 1986-12-12 EP EP86850436A patent/EP0232690B1/en not_active Expired - Lifetime
- 1986-12-12 AU AU66448/86A patent/AU591950B2/en not_active Ceased
- 1986-12-12 ES ES86850436T patent/ES2018656B3/es not_active Expired - Lifetime
- 1986-12-12 AT AT86850436T patent/ATE57935T1/de not_active IP Right Cessation
- 1986-12-15 JO JO19861499A patent/JO1499B1/en active
- 1986-12-15 PH PH34590A patent/PH23237A/en unknown
- 1986-12-16 FI FI865128A patent/FI84488C/fi not_active IP Right Cessation
- 1986-12-16 DK DK605186A patent/DK168601B1/da not_active IP Right Cessation
- 1986-12-17 MY MYPI86000221A patent/MY100750A/en unknown
- 1986-12-17 PL PL1986263041A patent/PL151627B1/pl unknown
- 1986-12-18 RU SU864028689A patent/RU1839673C/ru active
- 1986-12-18 AR AR86306261A patent/AR242797A1/es active
- 1986-12-18 CA CA000525677A patent/CA1318664C/en not_active Expired - Fee Related
- 1986-12-18 DD DD86297902A patent/DD256703A5/de unknown
- 1986-12-18 JP JP61300242A patent/JPH0780900B2/ja not_active Expired - Lifetime
- 1986-12-18 KR KR1019860010870A patent/KR940004067B1/ko not_active IP Right Cessation
- 1986-12-18 HU HU865302A patent/HU196831B/hu not_active IP Right Cessation
- 1986-12-19 IS IS3179A patent/IS1559B/is unknown
- 1986-12-19 CN CN86108634A patent/CN1016508B/zh not_active Expired
- 1986-12-19 PT PT83984A patent/PT83984B/pt not_active IP Right Cessation
- 1986-12-19 CS CS869604A patent/CS266597B2/cs unknown
-
1990
- 1990-11-06 GR GR90400871T patent/GR3001052T3/el unknown
-
1993
- 1993-08-27 LV LVP-93-1046A patent/LV10959B/lv unknown
- 1993-12-28 LT LTIP1682A patent/LT3912B/lt not_active IP Right Cessation
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