LV10949B - Substituted 4-phenyl-4-piperidinecarboxamides with both local anaesthetic and analgesic effect as well as processes for their preparation - Google Patents

Substituted 4-phenyl-4-piperidinecarboxamides with both local anaesthetic and analgesic effect as well as processes for their preparation Download PDF

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Publication number
LV10949B
LV10949B LVP-93-1042A LV931042A LV10949B LV 10949 B LV10949 B LV 10949B LV 931042 A LV931042 A LV 931042A LV 10949 B LV10949 B LV 10949B
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formula
compound
preparation
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compounds
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LVP-93-1042A
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LV10949A (lv
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Anna-Lena Ask
Rune Verner Sandberg
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Astra Ab
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C07D211/64Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Cosmetics (AREA)

Description

LV 10949 3ΑΜΕΉΕΗΗΜΕ4-ΦΕΗΗΛ-4-ΠΗΠΕΡΗβΗΗΚΑΡΕΟΚεΑΜΗβΒΙ, CIIOCOE ΗΧ ΠΟϋΥΗΕΗΗΗ Η ΦΑΡΜΑΙίΕΒΤΗΗΕεΚΑΗ Κ0ΜΠ03ΗΙ1Η5Ι
OnHcaHHe 06jracTb Hcnojib30BaHna H3o6peTeHHa flaHHoe H3o6peTeHHe nanpaBJieHO Ha HOBbie coejmHeHHa, o6jiaaaiomMe KaK MecTHbiM aHecTe3HpyiomHM, TaK m aHanbreTHHecKHM fleftcTBHeM, Ha hx Hcnojib30BaHHe b npoH3BojicTBe φΒρΜΒΗεΒΤΜΗβοκΗΧ npenapaTOB h Ha cnoco6 HX nOJiyHeHHB. IIpeflnocbmKH κ co3,aaHHio H3o6peieHHa ΠετΗ^ΗΗ aBJiaeTca nacTo Hcnojib3yeMbiM aHanbreraKOM. Oh o6jiaaaeT Taoce cjiaSbiM MecTHbiM aHacTaTHnecKHM aeiicTBHeM. AHacTeTHHec-Koe/aHajībreTHHecKoe fleftcTBHe neTHHHHa nocjie criHHajībHoro BBeneHna HaCTO HBJiaeTCa He^OCTaTOHHblM B ΟΤΗΟΙΗβΗΗΗ 3ΤΗΧ ^Byx B03JieHCTBHH. BMe-cto 3Toro o6biHHO Hcnojib3yioTca coHeTaHHa 6ynHBaKaHHa η Φθητ3ηη;ί3 hjih ΜορφΗΗ3. HapKOTHnecKHe aHajībreTHKH ΗΜβιοτ pm cepbe3Hbix HejtocraTKOB, Τ3ΚΗΧ KaK, HanpHMep, pa3BHTHe TOJiepaHTHOCTH, HapKOMaHHH, pHCK >THe-τβΗΗΗ flbixaHHa. TaKHM o6pa30M, cymecTByeT Heo6xoflHMOCTb b areHTax, flaioiuHx MecTHyio aHecTe3Hio c ocrraTOHHbiM aHajībreTHHecKHM jieHCTBHeM. TaKHe areHTbi flOJDKHbi Hcnojib30BaTbca nocjie cnHHajibHbix hjih 3nmiypajib-Hbix ΗΗΈβκΗΗΗ b KanecTBe MecTHbK aHecTe3HpyiomHx cpe^cTB. ITocjie 3τογο -2- coeflHHeHHfl ο6μμηο flaiOT xopomee nocjieonepauHOHHoe oGjieneHHe hjih cmmie Gojieft.
npefluiecTBjToiuHe aHajiorH
Hardy D.G. c coTpyiiH. onncbiBaioT b T.Med.Chem. 8 trip. 847-851 (1965) B3aHMOCBa3b Me7Kjxy CTpyKTypofi h aKTHBHOCTbio ΗεκοτορΒίχ aHanoroB nemaHHa, KOTopbie 0Ka3biBai0T aHajībreTHHecKoe fleficTBHe.
UlBeflCKHH naTeHT 96980 onncbiBaeT l-MeTHJi-l^eHHJi-nHnepHjiHH-4-Kap6oHOByio KHCjiOTy h jtea ee aMnaa. B ,πβηηομ jioKjnvieHTe He naeTca HHKaKOrO KOHKpeTHOrO φ3ρΜ3Ι1βΒΤΗΜ60ΚΟΓΟ fleHCTBHJI, a TOJIbKO yKa3aHHe, MTO COeflHHeHHH MOiyr 6bITb HCn0Jlb30BaHbI npH npOH3BO^CTBe H0BbIX JieKap-CTBeHHbK cpejicTB. H3 naTeHTa FR 2156470 H3Becrabi npon3BO,aHbie 1-(3,3-ΛΗφεΗΗΙΙΠρ0ΠΗ;ΐ)-ΠΗΠ6ρΗΛΗΗ3, KOTOpbie 6jiarOJiapJI CBOeH BbICOKOH JIHIIOUHOH paCTBOpHMOCTH MOiyT 6bITb aKTHBHbIMH TOJIbKO B K3HeCTBe aHaJIb-reTHKOB ho He b KanecTBe MecTHbix aHecreTHKOB. B pa6oTe Acta Pol. Pharm 1979,36(4), οτρ. 439-4, (Chemical Abstracts 93 (1980) 7970 V) onncbmaioTca HeKOTopbie aMHjībi noxoxce oSjiaaaioT aHajībreTHHecKHM, ho He MecrabiM aHecTeTHHecKHM jieHCTBHeM.
OnHcaHHe Η3ο6ρετεΗΗ3 06HapyxceHO hto coejiHHeHHa, cooTBecTByiomHe φοριν^ε IV hjih hx φ3ρΜ3ΗεΒΤΗΗεοκΗ npneMJieBbie cojih, ziaioT He tojibko HeojKHnaHHO χοροπίΗΗ 3φφεκτ b KanecTBe cnHHajibHbix h 3nnjiypajibHbix aHecTeTHKOB, ho Taoce OKa3biBaiOT jionojiHHTejibHoe aHaribreTHHecKoe jiencTBHe, κοτοροε npoaojDKaeTca b TeneHHe juiHTejibHoro BpeMeHH nocjie τογο, KaK CHHJKaeica aHadeTHHecKHH οφφεκτ. TaKHM o6pa30M, HeT Heo6xojjHMOCTH b coHeTaHHH aKTHBHbix coejiHHeHHH h, cjiejioBaTejibHO, mo>kho H36e»:aTb ynoM3HyToro Bbirne pncKa. CoejjHHeHHa, cooTBecTByiomHe H3o6peTeHHio, onpejiejunoTca cjiejoromen φορΜ>τιθΗ IV:
CON(R2)R3 -3- LV 10949 b κοτοροίί Ri «BJiHeica ajiKHjībHoii rpynnoH c 2-6, yrjiepo;iHbiMH βτομβμη hjih anKOKCHāJiKHjībHOH rpynnofi R40-(CH2)m-, rae R4 npe^cTaBJiiieT co6oii ajiKHjii>Hyio rpynny c 1-4 yrjiepoflHi>iMH 3τομβμη, a m paBHo 2-4 h R3 h R2 aBJiaiOTca οληηβκοββιμη hjih pa3JiHMHBiMH h Ka^cjībiH HBJiaeTca ajiKHjībHOfi rpynnoH, coziep^cameH jio 6 yrjiepojiHbix aTOMOB, hjih R2 h R3 BMecrre o6pa3yiOT uenb (CH2)n, me n paBHo 4-6, hjih ojihh H3 R2 h R3 HBJiaeTca ΒΟΛΟρΟΛΟΜ, a JIPJTOH - npJIMOH HJIH pa3BeTBJieHHOH aJIKHJIbHOH ΓργΠΠΟΗ C 1-6 JTJiepOJIHbIMH 3ΤΟΜ3ΜΗ, a TaiOKe HX φ3ρΜ3ΙΙ6ΒΤΗΗ60ΚΗ npHeMJieMbie COJIH. npejinOHTHTeJIbHbIMH COejtHHeHHBMH B COOTBeCTBHH c H3o6peTeHHeM 3BJIHI0TCH TaKHe, B KOTOpbK Rl, R2 H R3 BBJMIOTCa aJIKHJIbHblMH rpynnaMH.
OcoSeHHO npejinoHTHTejibHbiM aBJiaeTca coejiHHeHHe, b κοτοροΜ rpynna Rl HBjiaeTca reKCHJiOM, R2 smmeTca MeranoM hjih sthjiom, a R3 aBjiaeTca 3THJIOM. ripennOHTHTeJIbHblMH COJUIMH B COOTBeCTBHH C H306peTeHHeM HBJHH0TC3 φΒρΜΒΙΙβΒΤΗΗβΰΚΗ ΓφΗΘΜΙΙβΜΜ COJIH. Oco6eHHO Ιφθ,ΖΙΠΟΗΤΗΤβΙΙΒΗΜΜ 3BJI3-K)Tca nmpoxjiopHji. riojiyHeHHe
CoeziHHeHHa φopMyJIbI IV, npHBejieHHOH Bbirne, nojiyHajiHCb cjiejuromHM o6pa30M:
-4-
rzie A, Ri, R2 h R3 HMeioT onpeneneHHbie Bbirne 3HaHeHHa.
Coe^HHeHH^ φορΜγ.πι>ι I, b κοτοροΜ A ABjiaeTca rpynnoH CN hjih -CO2C2H5, a Ri HMeeT onpejjejieHHbie Bbiuie 3HaHeHKa, nojiyHajincb H3 cooTBeTCTByiomero βτορηηηογο aMHHa (Ri = H), 3a HCKjHoneHHeM co-ejļHHeHna, b κοτοροΜ Ri ^BJiaeTca rpynnon CH3, a A -rpynnon CO2C2H5, κοτοροβ HBjiHeTCii KOMMepnecKH λοοτ>ήηβιμ coeztHHeHneM πθτηαμη. Co-eiiHHeHH^ φop^ίyJlbI II nojiyHaK)Tca HenocpejicTBeHHO H3 coejiHHeHHJi I, b κοτοροΜ A aBJiaeTca rpynnoH -CO2C2H5 (cm. ĪIpHMep I) B3anMOjieHCTBHeM c ajiKHJiaMHHOM hjih nojiyHaiOTca TaKHM >Ke o6pa30M, KaK coeflHHeHna φορ-Myjibi IV. Ohh nojiyHaioTca npe>Kiie Bcero npe>Kne Bcero rHnpojiH30M co-ΘΛΗΗβΗΗΗ φopMyJIbI I C IIOJiyHeHHeM Kap60H0BbIX KHCJIOT φopMyJIbI III, KOTopbie 3aTeM nojiBepraiOTca B3aMMOueMCTBMK) c OKcajiHjuūiopmiOM h coot-BeCTBJTOHIHM 3MHHOM, HaBaH ΟΟβϋΗΗβΗΗβ φορ^ϋΒΙ IV.
JleTajībHoe onncaHHe npouecca npuroTOBJieHHa IIpHMepbi, o6o3HaHeHbi 11-16 onncbiBaioT npoMe/KjroHHbie coejiHHeHiia npH nnrOTOBJieHHH COejJHHeHHH φθρΜ}ΓϋΒΙ IV. -5- LV 10949 COEflHHEH m 1 npHMep 11 3thji l-reKCHjM-ļieHHjM-nHnepH.ziHH KapGOKCHJiaT ΓΗ,αροχπίορΗΛ
HeopneTHiiHH (23.5 r, 0.10 moji), reKCHJiHftonim (23.5 r, 0.11 moji), 6e3BOflHtiH Na2C03 (11.7 r, 0.11 moji) h aueTOHHTpHji (250 mji) HarpeBajiHct c oGpaTHMM χο;ίοληιιβηηκομ h nepeMeiiiHBajiHCb b τθηβηηθ 1.5 nacoB. CMecb φιυΐΒτροΒ3ΐΐ3(;Β h pacTBopHTejib ynaji5mcfl. OcTaTOK pacTBopajica b CH2CI2, pacTBop npoMbiBajicii 100 mji 1 N pacTBopa NaCH, 3aTeM Bonofi h HaKOHeu BbicyuiHBajica (K2CO3). 3aTeM jioGaBji^jica κ pacTBopy HC1 (r) b jihsthjiobom οφπρε, nocjie Mēro pacTBopirrejiH yjx2jwjmcb, a ocTaTOK nepeKpHCTajuiH30-BbiBajica H3 3THjiaueTaTa. Ββιχολ cocTaBHJi 22.5 r rMnpoxjiopH,na c t. nji. 156-158° C. T. rui. b cooTBecTBHH c T.Med.Chem. 8 CTp. 847-851 (1965) cocrraBjmeT 158°C. ΠρΗΜερ I2
3thji l-[4-3TOKCH6ymji]-4^eHHji-4-iiHnepHjiHH KapGoKcmiaT rHJIpOXJIOpHŪ
HeopnerajiHH (15,63 r, 67 mmoji), 4-3TOKcn6yTHjixjiopH,n (10,67 r, 70mmoji), Na2C03 (7,77 r, 73 mmoji), K1 (0,6 r) h aiieTOHHTpHji (150 mji) HarpeBaJIHCb C o6paTHbIM XOJIO,aHJIbHHKOM npH nepeMeUIHBaHHH B TeMeHHe 72 nacoB. CMecb φπιΐΒτροΒ3ϋ30Β h pacTBopHTejib ynajuuicH. OcTaTOK pacT-BOpHJICH B HH3THJIOBOM 3φΗρβ, pCTBOp npOMblBajlCB BOJIOH H BblCJTIIHBaJICB (MgS04). neperoHKa najia 17,9 r ocHOBaHua, Knroimero npH 160-163° C (0,05 mm Hg . Τ.κηπ. b cooTBecTBHH c T.Chem. Soc. 3062 (1958) ocTCBJiaeT 180° C) 1 mm Hg. T.rui. rejūpoxnopmia 143-145° C. -6- ΠρΜΜερI3
l-(2-3TOKCH3THJl)-4-UHaHO-4^eHHJI-nHnepHJIHH YKa3aHHoe b 3arjiaBHH coe^HHeHHe nojiyHajiocb KaK onncaHo b FIpHMepe I 2 H3 4-UHaHO-4-cļ)eHMJinHnepimHHa H 2-6pOM3THJI STHJlOBOrO 3φπρ3, HCKniona^ KI. Bpeivw peaKUHH npH KHruiHeHHe c očpaTHtiM xojio,HHjibHHKOM 6 nacoB. Coe^HHeHHe KHnejio npH 130-132°/0,005 mm Hg.
COEHHHEHHfl II
l-reKCHji-4-(ļ)eHH.ji-4-nHnepH,aHHKap6oKCH.ribHOH KHCJIOTbī γη flp0XJ10pH,H CMeCb 3ΤΗΙΙΟΒΟΓΟ 3φΗρ3 (22,5 Γ, 64 MMOJl), 20% COJUIHOH KHCJIOTbī (225mji) h yKcycHOH KHCJIOTbī (70 mji) HarpeBajiacb b TeHeHHe 30 nacoB c o6paTHbiM xojio,aHjTbHHKOM. Ilocjie oxjia>KiieHH5i CMecb BbiJiHBajiacb b 200 mji JieiPIHOH BOHbl, KHCJlOTa ΟΤφ/1ΒΤρθΒΜΒ3ϋ30Β H BbICyUIHBaJIHCb Ha B03nyxe. Bbixoji - 12,9 r. <3>HJibTpaT BbinapHBajica, a Ha ocTaTOK neiiCTBOBajiH aue-tohhtphjiom, nojiyHaa eme 4 r khcjiotbi. nepeKpHCTajuiH3auHa H3 aue-TOHHTpnjia ziajia 16,9 r c T.nji. 193-195° C. KncjioTa cojļepjKHT pacTBopHTeiib KpHCTaJUlH3aUHH.
IlpHMep I 5
l-[4-3T0KCH6yTHJl]-4^eHHJĪ-4-riHnepHIIHHKap60KCHJlbH0H KHCJIOTbī rHJipOXJIOpHH CMecb STHjioBoro 3φπρ3 (17,9 r, 53,7 mmoji), 2N NaCH (55 mji) h STaHOjia (6 mji) HarpeBajiacb npn nepeMeuiHBaHHH c oOparabiM xojionHjibHHKOM b TeneHHe 24 HacoB. PacTBop SKCTparnjipoBajica nH3THjioBbiM 3φπροΜ h 3aTeM nojiKHCJiHjica pa36aBjieHHOH cojuihoh khcjiotoh. PacTBophtcjib yjiajuuicfl, a OCT3TOK SKCTparHJīpOBajICH aueTOHOM. AlieTOHOBblH paCTBOp OTφHJIbTpOBbI- -7- LV 10949
Bariem h pacTBopHTejib BtinapHBanca. KpHCTajuiHHecKHM ocTaTOK cymHJica Haa CaCl2 b B3KyyMHOM SKCHKaTOpe h nepeKpHCTajuiH30BbiBajicji H3 cMecH ΤΓΦ - sranaueTaT. Ββιχολ npojiyKTa 11,7 r c T.nji. 131-133° C. ĪIpHMep I 6 1-(2-3τθΚ0Η3ΤΗΚ)-4-φ6ΗΗ;ΐ-4-ΠΗΠ6ρΗΛΗΗ Kap60KCHJlbH0H KHCJlOTbl riinpoxjiopnji CMecb iļHaHHiia b cootbcctbhh c npHMepoM I 3 (5,6 r), KOH (5,6 r), STaHOJia (39 mji) h bojim (17 mji) HarpeBajiacb b TeneHHe 6 nacoB b aBTOKjiaBe npH 140° C. PeaKiļHOHan CMecb no,aKHCjmjiacb KOHueHTpHpoBaHHoft cojishoK KHCJĪOTOH, BbinaBUiaH B OCaflOK COJIb ΟΤφHJIbTpOBblBaJiaCb, H φΐ!ΓΊΒΤρ3Τ Bbl-napHBajica. OcTaTOK BLimenanHBajica γορημημ aueTOHOM. M3 aqTeoHOBbix SKCTpaKTOB 6 biji o nojryHeHO 4,2 ryKa3aHHoro b 3arojioBKe coejjHHBHna. T.nji. 150-155° C.
COEJJHHEHKfl III npHMep 1 Ν-Ε5<ΤΗ;ΐ-1-Μ6ΤΒυΐ-4-φ6ΗΗΙΙ-4-ΠΗΠ6ρΗϋΗΗΚΒρ6θΚΟΒΜΗ5 ΠετΗΛΗΗ ΓΗίΐροχπορΗΛ (2,56 r, 9 mmoji) η 6yTHjiaMHH (5 mji) b TeneHHe 3 ΛΗβΗ HarpeBajiHCb b aBTOKjiaBe npH 180° C. PeaKijHOHHaH CMecb pa3Aejifl-jiacb BCTpaxHBaHHeM Mexmy 10 mji IN NaOH η ληθτιιποββιμ 3φΗροΜ, η 3φκρΗΒΐ6 3KCTpaKTbi cyuiHJiHCb (MgSŪ4)· PacTBopHTejib Hcnapajica, a ocra-tok xpoMaτoΓpaφHpOBaJICJ^ Ha okhch ajiiOMHHHH c Hcnojib30BaHHeM b Kane-CTBe 3JiioeHTa STHJiaueTaTa. KpHCTajiJiHHecKHH προ^κτ (1,0 r) nepeKpHCTajiJiH30BbiBajica H3 H-renTaHa c b bixo.no m 0,59 r nponyKTa c T.nji. 73-76,5° C. -8- īlpHMep 3 Ν-3τΜΙΙ-1-Γ6Κ0ΗΙΙ-4-φθΗΗΙΙ-4-ΠΗΠ6ρΜ^ΗΗΚ3ρ6θΚΟ3ΜΜ^ 3το coeaHHeHHe nojiyHajiocb, KaK onncaHO Bbiiue, H3 sthji l-reKcnji-4-φ6ΗΗϋ-4-ΠΗΠθρΗΛΗΗΚ3ρ6θΚ0ΗΙΙ3Τ rHflpOXJIOpHJia (3,54 Γ, 10 MMOJl) H 3THJiaMHHa (2,25 r, 50 mmoji). BpeMa peaKUHH - 2 jx hb. HeoHHmeHbifi προ^γκτ (1,0 r) nepeKpHCTajuiH3HBbiBajica H3 jiHH3onponHJioBoro 3φηρ3, ūaBaa 0,81 r nponyKTa c T.nji. 92-94° C. Γ *mpoxnopHn hmbst t.iiji. 221-223° C (h3 2%-ro βοληογο aueTOHa). COEJļHHEHH^ ΓΥ OSiiihh ΜβτοΛ nojiyMeHna. OKcajiHjixjiopH^ (4 mji) zioOaBjiajTca no KannaM npn nepeMeuiHBaHHH κ pacTBopy nHnepHjtHHKapOoHOBOH khcjiotbi (CoejiHHeHHH III) (5-6 mmoji) b CH2CI2 (20 mji). PeaKitHOHHaa CMecb nepeMeuiHBajracb b TeHemin 2 nacoB npn 50° C. PacTBopuTejib yaajuuicji, no6aBjmjiocb HecKOJibKO mji TOJiyojia, 3aTeM pacTBopHTejib chob3 ynajiajicji. OcTaTOK pacTBOpjmca b CH2CI2 (10 mji), h pacTBop no KanjiaM npn nepeMeiuHBaHHH jjoOaBJuuica κ pacTBopy cootbct-CTByiomero aMHHa (35-42 mmoji) b CH2CI2 (20 mji), oxjia^ajica b jiejpiHOH BO,ae. 3aTeM peaKUHOHHaa CMecb b TeneHHe HecKOJibKHx nacoB nepeMeimīBa-jiacb npn κομηητηοη TeMnepaType. 3aTeM OHa BCTpaxHBajiacb c 1 HopM. NaOH (20 mji), ohhh pa3 c bojioh. BbicyinHBanacb (K2CO3) n pacTBopHTejib BbinapHBajica. īlepeji npeBpameHneM b rtmpoxjiopmi HeoMnmeHHoe ocHOBaHne b ηθ-cKOJibKHX cjiyHaax nojjBeprajiocb jionojiHHTejibHOH onncTKe, HanpnMēp, xpo-Μ3ΤΟΓρ3φΗΗβΟΚΗ. B cjiezoTomen Ta6jinue 1 ziaioTca HeKOTopbie οοθλμηθηηλ, cooTBecTBv-lomne H3o6peTeHHK). -9- LV 10949
TaSjiHua 1
CoenHH. Ri R2 Γκζφοχ/ιορΗ,α R3 τ.ηπ. °C 1 ch3 H C4H9 73-76.5 2 C6Hi3 H ch2 252-254 3 C6Hi3 H C2H5 221-223 4 C6Hi3 H CH(CH3)2 145-148 5 C6Hi3 ch3 CH3 155.5-158.5 6 C6Hi3 ch3 c2h5 137-141 7 C6Hi3 C2H5 C2H5 151-154 8 C6Hl3 (CH 2)s 217-219 9 c2h5o(ch2)4 CH3 ch3 125-128 10 C2H50(CH2)4 ch3 C2H5 115-117 11 C2H50(CH2)4 (CH2)5 130-132 12 c2h5och2-ch2 c2h5 C2H5 142-144 -10- <I>apMaueBTHHecKHe npenapara Jļria npMroTOBjieHRa (ļ)apMaueBTHHecKHx npenapaTOB HOBoe coennHeHHe pacTBopaeTca b ^cmukom pa36aBHTene, κοτορΒίΗ aBjiaeTca πολχοζιηιιιημ jxjlh HHi>eKijHH. Hcnojib3yeMbie npenapaTbi npencTaBjiaiOT co6oh BOHHbie pacTBO-pbi, KOTopbie conep>KaT 2,5 no 40,0 μγ/mji 3κτηβηογό coenHHeHHa b paeneie
Ha rHHpOXJIOpHHHyīO COJlb.
BnojiorHHecKHe HccjienoBaHHa
CnHHajībHaa 3ηθοτθ3ηα
CoenHHeHna, cooTBecTByK>mne H3o6peTeHHio, HcnbīTbiBajincb Ha cnHHajibHyK> aHecTe3Hio Ha Mbimax. B Kaagjon rpynne ηοπβιτ3ηηκ> nonBep-rajiHCb rnecTb >κηβοτηβιχ. B KanecTBe KOHTpojibHbix coēnHHēHHH ncnbīTbiBaji-ca neTHjļHH, HcxonHbie MaTepnajībi .nna coenHHeHHM 2)-8), a ημθηηο, sthji l-reKCHji-4-(ļ>eHHJi-4-nHriepH,nHHKap6oKCHJiaT ΓΗηροχπορπη (ΠρΗΜερ I 1), h zuia coenHHeHHa 9) h 10) -sthji l-[4-3TOKCH6yTHji]-4-cļ)eHHji-4-nHnepHHHHKapOoKCHjiaT ΓΗηροχπορπη (IlpHMep I 2), H3BecTHbie H3 ynoivia-h>toh Bbime padora T.Med. Chem. Pe3yjibTaTbi npencTaBjieHbi b cjienjTomeii TaSjiHiie 2. -11- LV 10949
Ta6jiHiia 2
CpeflRJLH JUIHTeJIbHOCTb (MHH) flBHraTenbHOrO TOpMOKeHHH H nOJIHOH 3HecTe3HH (na^eHHe XBOCTa) y Mbiuiefi nocne cy6apaxHOH#HOH HH-beKunn 5-th mkji HcnbiTyeMoro pacTBopa. fljiHTejibHocTH oTCHHTbiBaiOTca c MOMema BB6H6HKH ΗΗΈεΚΙΙΗΗ.
CoeaHH. KoHiieHTpauHH % IIpo,zioji>KHTe.ribHOCTb flBHraTe/ibHoro TOpMO>KeHHH MHH. riajieHHe xBOCTa MHH. 3 1 4 14 35 5 14 20 6 20 40 7 27 50 8 19 40 9 3 10 10 6 10 11 6 10 12 3 10 11 15 40 12 5 25 3 2 22 30 4 24 30 5 21 25 6 36 55 7 48 85 81 49 >120 -12-
CoeziHH. KoHiteHTpauHH % IIpoiion>KHTenbHOCTb ztBnraTenbHoro TOpMO>KeHHH MHH. riajieHHe xB0CTa MHH. 9 6 10 10 7 10 11 12 35 12 6 10 12 10 15 Pethidine 4 15 I 4 17 20 Pethidine 10 25 1 5KnB0THt>ie 6buiH pa3apa>KMTe^bHbi, nncKajībHbi JļHCKyCCHŪ
KaK mo^cho BtmeTb H3 Ta6jiHm>i 2, coenHHeHHH, cooTBecTBjTomne H3o6-peTeHHio, naioT jiyMuiHH jioKajībHbiH aHecTeTHHecKHH 3φφεκτ, neM H3BecT-Hbifi aHajībreraK neTenHH. B cbh3h c TeM, mto aHecreTHHecKoe aencTBue coMeTaeTca c χοροιπΗΜ aHanbreTHHecKHM θφφεκτοΜ, coenHHeHHa H3o6pe-TeHHa aBJiaioTca 6ojiee LiēHHbiMH, neM πθτηληη. Ohh Moryr Taoce 3aMeuHTb KOMGnHauHH οληογο aHanbreTMHecKoro η οληογο aHecTHHecKoro areHTa - c χοροιπΗΜ pe3yjibTaT0M.
Kan bhhho H3 npencTaBJieHHoro, jt^iuihm o6pa3uoM ocymecTBjieHna H3o6peTeHHa aBjiaioTca Hcnojib30BaHHe coenHHeHHa 6 hjih 7. LV 10949 -13- ΦΟΡΜΥΠΑ ΡΪ30ΒΡΕΤΕΗΡ1Η
1. CoenHHeHH* 4>opMyjibi IV
b κοτοροκ Ri npencTaBjiaeT reKcmi, R2 h R3 aBJiaioTca οληηηκοββιμη mjim pa3JiHMHbiMH, h icaa<nbifi npencrraBjmeT coGom ajiKHJibHyio rpynny, conepara-myio ΛΟ 6 jTJieponHbK 3tomob, hjih R2 h R3 BMecre o6pa3yioT uenb (CH2)n, B KOTOpOH n paBHO 4-6, HJTH OflHH H3 R2 HJIH R3 ABJUieTCfl ΒΟϋΟρΟΛΟΜ, a upjTOH npencTaBjmeT co6oh npaMyio hjih pa3BeTBjieByio ajiKHJibHyio rpynny c 1-6 yrjieponHbiMH 3τομ3μη, - a Taoce h hx cļiapMaiieBTHHecKH npneMJieMbie COJIH. 2. CoenHHeHHe no π. 1, b κοτοροΜ R2 h R3 hbjuhotch ajiKHjībHbiMH rpynnaMH. 3. CoenHHeHHe no n. 2, b κοτοροΜ R2 HBjuieTca MeTHjioM, a R3 npencraB- JIHeT ΟΟβΟΗ 3THJ1. -14- 4. CoenHHeHHe no π. 2, b κοτοροΜ R2 h R3 o6a aBjunoTca othjiom. 5. OapMaueBTHMecKHH npenapaT jum peryJiHpoBaHna GjiOKanbi πγτβΜ BBeneHHa β οπμηηομο3γοβοη KaHaji, coaepJKamHH coenHHeHHe no π. 1. 6. OapMaueBTHnecKHH npenapaT min aHecTe3HH h aHani>re3HH, conepaca-men coenHHeHHe no π. 1. 7. ΠρΗΜβΗΘΗΗΘ COeflHHeHHfl ΠΟ Π. 1 JUia npOH3BO^CTBa φ3ρΜ3-ueBTHHecKHx npenapaTOB c aHecTeTHHecKHM h aHajībreTHHecKHM jiencTBneM. 8. Cnoco6 nojiyMeHiw coenHHeHna φορινιγηΜ IV, onpenejieHHoro β π. 1, oTJiHnaeTca TeM, hto
a) 3φηρ HJTH HHTpHJl φορΜγπΒΙ I nWpOJIH3yiOTOI B COOTBeCTByK)myiO KHCJiOTy φορΜγιη.ι III, κοτοργιο 3aTeM nonBepraiOT B3aHMoneHCTBHK> c 1) OKCaJlHJKJlOpHflOM H 2) COOTBeCTByK)mHM aMHHOM C 06pa30BaHHeM KOHeH-Horo npojiyKTa φορΜγΛΗ IV
III LV 10949 -15- LV 10949 -15-
1) (C0C1)2 2) R3(R2)NH b κοτοροίί Ri, R2 h R3 ημθιοτ 3HaHeHiw, onpenejieHHbie Bbime b nyHKTe 1, a A npencTaBjiaeT co6oh -CN hjih -CO2C2H5; hjih b) coejīHHeHHe φορΜγιΐΜ I, b κοτοροΜ A npencTaBjmeT co6oft -CO2C2H5, nonBepraiOT B3aHMOneftcTBHK) c βμηηομ R2NH2 c o6pa30BaHHeM co-emmenm cļ}opMyjii>i II, b κοτοροΜ Ρι η P2 hm66iot onpe^ejieHHbie Btiiue 3HaHeHHfl, HO eCTb COeHHHeHRH φορΜγΐΊΗ IV, B ΚΟΤΟρΟΜ Pl HJTH P2 HBJiaeTCH BOHOpOHOM.
II -16- αΡΑΒΗΜΤΕΠΒΗΗΕ ΗΟΊΒΙΤΑΗΗϋ
KoHiieHT- Προ- flOJlJKHTejIb- naueHiie CoenHHeHHH pauHH HOCTb xB0CTa (%) HBHraTejib- MHH. ΗΟΓΟ TOp-MO>KeHHH MHH.
10 15 8 15
9 -17- LV 10949 ΡΕΦΕΡΑΤ
OnHCblBaiOTC^ COejIHHeHHa φορΜγ,ΠΒΙ (IV) JUTB HCn0Jlb30BaHHB B KaHeCTBe MecTHbix aHecTeTMKOB h aHajībreraKOB, a TaioKe cnoco6 hx nojiyHeHHfl, hx φ3ρΜ3Ι1βΒΤΗι16ΟΚΗ0 npenapaTbl Η ΗΧ ΓφΗΜΘΗΘΗΗΘ.

Claims (8)

  1. LV 10949 PATENTA FORMULA 1. Savienojumi ar formulu IV
    kurā: R, ir heksilgrupa, 15 R2 un R3 ir vienādi vai dažādi un katrs ir C^-alkilgrupa vai R2 un R3 kopā veido virkni (CH2)n, kurā n ir 4-6, vai arī viens no R2 un R3 ir ūdeņradis, bet otrs ir lineāra vai sazarota C^-alkilgrupa, kā ari to farmaceitiski saderīgi sāļi.
  2. 2. Savienojums pēc 1. punkta, kurā R2 un R3 ir alkilgrupas.
  3. 3. Savienojums pēc 2. punkta, kurā R2 ir metilgrupa un R3 ir etilgrupa.
  4. 4. Savienojums pēc 2. punkta, kurā R2 un R3 abi ir etilgrupa. 25
  5. 5. Farmaceitisks preparāts, kas paredzēts ievadīšanai mugurkaulāja dobumā, lai regulētu blokādi, un satur savienojumu pēc 1. punkta.
  6. 6. Farmaceitisks preparāts, kas paredzēts anestēzijai un analgēzijai un satur 30 savienojumu pēc 1. punkta.
  7. 7. Savienojuma pēc 1. punkta pielietojums tādu farmaceitisku preparātu ražošanai, kam piemīt anestētiska un analgētiska darbība.
  8. 8. Paņēmiens savienojumu ar formulu IV pēc 1. punkta iegūšanai, kas atšķiras ar to, ka 2 a) esteri vai nitrilu ar formulu I hidrolizē par atbilstošo skābi ar formulu III, kuru pēc tam apstrādā ar 1) oksalilhlorīdu un 2) piemērotu aminu, veidojot galaproduktu ar formulu IV 2
    kurā R1( R2 un R3 nozīmes ir 1. punktā dotās, bet A ir -CN vai -C02C2H5; 25 vai b) savienojumu ar formulu I, kurā A ir -C02C2H5 apstrādā ar amīnu R2NH2, veidojot savienojumu ar formulu II, kurā R, un R2 ir ar jau minētām nozīmēm, proti, savienojumu IV, kurā R, un R2 ir ūdeņradis.
    II
LVP-93-1042A 1989-12-21 1993-08-27 Substituted 4-phenyl-4-piperidinecarboxamides with both local anaesthetic and analgesic effect as well as processes for their preparation LV10949B (en)

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LV960262A LV5766B4 (lv) 1989-12-21 1996-07-17 Aizvietoti 4-fenil-4-piperidinkarboksamidi ar lokalu anestezejosu un analgetisku daribu ka ari to iegusanas metodes

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FI100881B (fi) 1998-03-13
IL96636A0 (en) 1991-09-16
LT4005B (en) 1996-07-25
FI922806A0 (fi) 1992-06-17
PL288409A1 (en) 1991-12-02
FI922806A (fi) 1992-06-17
SK278283B6 (en) 1996-08-07
PL163591B1 (pl) 1994-04-29
SI9012346A (sl) 1998-08-31
IE904534A1 (en) 1991-07-03
ES2087280T3 (es) 1996-07-16
DE69027221T2 (de) 1996-10-10
IS1664B (is) 1997-07-04
HK22997A (en) 1997-02-27
RU2039043C1 (ru) 1995-07-09
JP2656152B2 (ja) 1997-09-24
HU9202044D0 (en) 1992-09-28
ATE138650T1 (de) 1996-06-15
UA26403A (uk) 1999-08-30
SK658190A3 (en) 1996-08-07

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