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 PDFInfo
- 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
- Authority
- LV
- Latvia
- Prior art keywords
- formula
- compound
- preparation
- hjih
- compounds
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract 3
- 238000002360 preparation method Methods 0.000 title claims abstract 3
- 230000003444 anaesthetic effect Effects 0.000 title claims 2
- 230000000202 analgesic effect Effects 0.000 title claims 2
- 230000008569 process Effects 0.000 title claims 2
- JPUKONSIEHCAQA-UHFFFAOYSA-N 4-phenylpiperidine-4-carboxamide Chemical class C=1C=CC=CC=1C1(C(=O)N)CCNCC1 JPUKONSIEHCAQA-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract 4
- 230000036592 analgesia Effects 0.000 claims abstract 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 150000001412 amines Chemical class 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 206010002091 Anaesthesia Diseases 0.000 claims 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 230000037005 anaesthesia Effects 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 239000012467 final product Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 210000000278 spinal cord Anatomy 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 238000002690 local anesthesia Methods 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000203 mixture Substances 0.000 description 3
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229960000482 pethidine Drugs 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 101150095510 TMEM35A gene Proteins 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic 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
- C07D211/36—Heterocyclic 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon 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
- C07D211/64—Carbon 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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]
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Public Health (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (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)
- Cosmetics (AREA)
- Nitrogen Condensed Heterocyclic Rings (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)
- LV 10949 PATENTA FORMULA 1. Savienojumi ar formulu IVkurā: 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. Savienojums pēc 1. punkta, kurā R2 un R3 ir alkilgrupas.
- 3. Savienojums pēc 2. punkta, kurā R2 ir metilgrupa un R3 ir etilgrupa.
- 4. Savienojums pēc 2. punkta, kurā R2 un R3 abi ir etilgrupa. 25
- 5. Farmaceitisks preparāts, kas paredzēts ievadīšanai mugurkaulāja dobumā, lai regulētu blokādi, un satur savienojumu pēc 1. punkta.
- 6. Farmaceitisks preparāts, kas paredzēts anestēzijai un analgēzijai un satur 30 savienojumu pēc 1. punkta.
- 7. Savienojuma pēc 1. punkta pielietojums tādu farmaceitisku preparātu ražošanai, kam piemīt anestētiska un analgētiska darbība.
- 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 2kurā 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
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8904298A SE8904298D0 (sv) | 1989-12-21 | 1989-12-21 | New compounds |
| PCT/SE1990/000818 WO1991009845A1 (en) | 1989-12-21 | 1990-12-17 | Substituted 4-phenyl-4-piperidinecarboxamides with both local anaesthetic and analgesic effect as well as processes for their preparation |
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| Publication Number | Publication Date |
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| LV10949A LV10949A (lv) | 1995-12-20 |
| LV10949B true LV10949B (en) | 1996-06-20 |
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| Application Number | Title | Priority Date | Filing Date |
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| LVP-93-1042A LV10949B (en) | 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 |
| 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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| Application Number | Title | Priority Date | Filing Date |
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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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| JP3916092B2 (ja) * | 1993-09-17 | 2007-05-16 | 杏林製薬株式会社 | イミダゾリジノン誘導体とその酸付加塩及び老年性痴呆症の治療薬 |
| SE9400447D0 (sv) * | 1994-02-11 | 1994-02-11 | Astra Ab | New compounds |
| SE9404438D0 (sv) * | 1994-12-21 | 1994-12-21 | Astra Ab | New process |
| US5931809A (en) | 1995-07-14 | 1999-08-03 | Depotech Corporation | Epidural administration of therapeutic compounds with sustained rate of release |
| US7799337B2 (en) | 1997-07-21 | 2010-09-21 | Levin Bruce H | Method for directed intranasal administration of a composition |
| US20020102291A1 (en) * | 1997-12-15 | 2002-08-01 | Noven Pharmaceuticals, Inc. | Compositions and method for treatment of attention deficit disorder and attention deficit/hyperactivity disorder with methylphenidate |
| CA2443672C (en) * | 2001-04-12 | 2011-03-29 | Pharmacopeia, Inc. | Aryl and biaryl piperidines used as mch antagonists |
| MXPA05006354A (es) * | 2002-12-13 | 2005-08-26 | Smithkline Beecham Corp | Antagonistas ccr5 como agentes terapeuticos. |
| AR063275A1 (es) * | 2006-10-12 | 2009-01-14 | Epix Delaware Inc | Compuestos de carboxamida, una composicion farmaceutica que los comprende y su uso en la preparacion de un medicamento para el tratamiento de enfermedades mediadas por la activacion de ccr2. |
| WO2009076512A1 (en) | 2007-12-11 | 2009-06-18 | Epix Delaware, Inc. | Carboxamidξ compounds and their use as chemokine receptor agonists |
| US8473062B2 (en) | 2008-05-01 | 2013-06-25 | Autonomic Technologies, Inc. | Method and device for the treatment of headache |
| US8412336B2 (en) | 2008-12-29 | 2013-04-02 | Autonomic Technologies, Inc. | Integrated delivery and visualization tool for a neuromodulation system |
| US9320908B2 (en) | 2009-01-15 | 2016-04-26 | Autonomic Technologies, Inc. | Approval per use implanted neurostimulator |
| US8494641B2 (en) | 2009-04-22 | 2013-07-23 | Autonomic Technologies, Inc. | Implantable neurostimulator with integral hermetic electronic enclosure, circuit substrate, monolithic feed-through, lead assembly and anchoring mechanism |
| US20220096452A1 (en) | 2019-01-22 | 2022-03-31 | Icm (Institut Du Cerveau Et De La Moelle Épinière) | Local anesthetic for the treatment of neurological symptoms resulting from brain dysfunctions |
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| US2486796A (en) * | 1943-06-25 | 1949-11-01 | Ciba Pharm Prod Inc | Esters of 1-alkyl-4-hydroxyphenylpiperidyl-4-ketones |
| US3334106A (en) * | 1964-10-20 | 1967-08-01 | Aldrich Chem Co Inc | N(aryl)n(hydrocarbyl)-omega-(4-phenyl-4-piperidinocarbonylheteroamine) alkanoamide |
| US3539580A (en) * | 1967-06-26 | 1970-11-10 | Janssen Pharm | 4-aryl-4-aminoalkoxy-piperidines |
| CH498836A (de) * | 1968-12-20 | 1970-11-15 | Geigy Ag J R | Verfahren zur Herstellung von neuen Piperidinderivaten |
| US3737538A (en) * | 1968-12-30 | 1973-06-05 | Ciba Geigy Corp | Antitussive compositions and method with isonipecotic acid derivatives |
| FR2156470A2 (en) * | 1971-10-21 | 1973-06-01 | Synthelabo | 1-(3,3-diphenyl-1-propyl)-4-aryl-piperidines - as analgesics spasmolytic and anti-tussive agents |
| ZA899436B (en) * | 1988-12-12 | 1990-08-29 | Ciba Geigy | Piperidine derivatives |
| US5100903A (en) * | 1989-05-12 | 1992-03-31 | Anaquest, Inc. | N-aryl-n-(1-substituted-3-alkoxy-4-piperidinyl)amides and pharmaceutical compositions and methods employing such compounds |
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1989
- 1989-12-21 SE SE8904298A patent/SE8904298D0/xx unknown
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1990
- 1990-11-30 NZ NZ236293A patent/NZ236293A/xx unknown
- 1990-12-10 ZA ZA909903A patent/ZA909903B/xx unknown
- 1990-12-11 IL IL9663690A patent/IL96636A/en not_active IP Right Cessation
- 1990-12-12 DZ DZ900223A patent/DZ1468A1/xx active
- 1990-12-12 YU YU234690A patent/YU48086B/sh unknown
- 1990-12-12 SI SI9012346A patent/SI9012346B/sl not_active IP Right Cessation
- 1990-12-17 SG SG1996004491A patent/SG46413A1/en unknown
- 1990-12-17 KR KR1019920701484A patent/KR0179382B1/ko not_active IP Right Cessation
- 1990-12-17 HU HU9202044A patent/HU213110B/hu unknown
- 1990-12-17 JP JP3501896A patent/JP2656152B2/ja not_active Expired - Fee Related
- 1990-12-17 IS IS3659A patent/IS1664B/is unknown
- 1990-12-17 DE DE69027221T patent/DE69027221T2/de not_active Expired - Fee Related
- 1990-12-17 IE IE453490A patent/IE74855B1/en not_active IP Right Cessation
- 1990-12-17 AU AU69783/91A patent/AU647068B2/en not_active Ceased
- 1990-12-17 DK DK91901571.9T patent/DK0506778T3/da active
- 1990-12-17 RO RO92-0832A patent/RO112864B1/ro unknown
- 1990-12-17 CA CA002069608A patent/CA2069608C/en not_active Expired - Fee Related
- 1990-12-17 ES ES91901571T patent/ES2087280T3/es not_active Expired - Lifetime
- 1990-12-17 WO PCT/SE1990/000818 patent/WO1991009845A1/en active IP Right Grant
- 1990-12-17 EP EP91901571A patent/EP0506778B1/en not_active Expired - Lifetime
- 1990-12-17 UA UA5052485A patent/UA26403A/uk unknown
- 1990-12-17 AT AT91901571T patent/ATE138650T1/de not_active IP Right Cessation
- 1990-12-20 PT PT96303A patent/PT96303B/pt active IP Right Grant
- 1990-12-20 EG EG74690A patent/EG19361A/xx active
- 1990-12-21 PL PL90288409A patent/PL163591B1/pl not_active IP Right Cessation
- 1990-12-21 CZ CS906581A patent/CZ278035B6/cs not_active IP Right Cessation
- 1990-12-21 US US07/633,246 patent/US5227389A/en not_active Expired - Lifetime
- 1990-12-21 SK SK6581-90A patent/SK658190A3/sk unknown
- 1990-12-21 CN CN90106009A patent/CN1037841C/zh not_active Expired - Fee Related
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1991
- 1991-01-09 SA SA91110209A patent/SA91110209B1/ar unknown
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1992
- 1992-06-17 FI FI922806A patent/FI100881B/fi not_active IP Right Cessation
- 1992-06-17 NO NO922380A patent/NO178858C/no unknown
- 1992-06-19 RU SU925052485A patent/RU2039043C1/ru not_active IP Right Cessation
- 1992-06-19 BG BG96513A patent/BG60912B1/bg unknown
- 1992-09-29 HR HRP-2346/90A patent/HRP920591B1/xx not_active IP Right Cessation
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1993
- 1993-07-12 US US08/090,416 patent/US5360805A/en not_active Expired - Lifetime
- 1993-08-27 LV LVP-93-1042A patent/LV10949B/lv unknown
- 1993-12-30 LT LTIP1731A patent/LT4005B/lt not_active IP Right Cessation
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1996
- 1996-07-17 LV LV960262A patent/LV5766B4/lv unknown
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1997
- 1997-02-27 HK HK22997A patent/HK22997A/xx not_active IP Right Cessation
- 1997-04-30 BR BR1100379-0A patent/BR1100379A/pt active IP Right Grant
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