LV10860B - Method for producing of phenylalkylamines - Google Patents
Method for producing of phenylalkylamines Download PDFInfo
- Publication number
- LV10860B LV10860B LVP-93-650A LV930650A LV10860B LV 10860 B LV10860 B LV 10860B LV 930650 A LV930650 A LV 930650A LV 10860 B LV10860 B LV 10860B
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- LV
- Latvia
- Prior art keywords
- carbon atoms
- general formula
- phenyl
- alkyl
- formula
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract 21
- 125000000217 alkyl group Chemical group 0.000 claims abstract 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract 6
- 150000001875 compounds Chemical class 0.000 claims abstract 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract 5
- 125000005843 halogen group Chemical group 0.000 claims abstract 4
- 238000000034 method Methods 0.000 claims abstract 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims abstract 2
- 150000001412 amines Chemical class 0.000 claims 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 239000011230 binding agent Substances 0.000 claims 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- 230000003993 interaction Effects 0.000 claims 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 150000007530 organic bases Chemical class 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 125000002130 sulfonic acid ester group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract 3
- 230000014759 maintenance of location Effects 0.000 abstract 2
- 208000024827 Alzheimer disease Diseases 0.000 abstract 1
- 239000004480 active ingredient Substances 0.000 abstract 1
- 150000003943 catecholamines Chemical class 0.000 abstract 1
- 230000006735 deficit Effects 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 239000003368 psychostimulant agent Substances 0.000 abstract 1
- 238000001228 spectrum Methods 0.000 abstract 1
- 239000000021 stimulant Substances 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- 239000011800 void material Substances 0.000 abstract 1
- 101150115538 nero gene Proteins 0.000 description 2
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- 241001669680 Dormitator maculatus Species 0.000 description 1
- 101150096418 Mepe gene Proteins 0.000 description 1
- 101100066898 Mus musculus Flna gene Proteins 0.000 description 1
- 101100366940 Mus musculus Stom gene Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- 244000240602 cacao Species 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61P25/24—Antidepressants
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- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- External Artificial Organs (AREA)
Description
LV 10860
CnOCOE ΠΟΠΥΗΕΗΜΛ ΦΕΗΜ/ΙΑΠΚΜίΙΑΜΜΗΟΒ
OnncaHMe
Hacrofliuee Μ3θ6ρβτβΗΜβ othocmtch κ o6nac™ opraHMHecKoro ομητθ3β m KacaeTcn nonyMeHMfl hobwx Φθημπ3Πκμπ3Μηηοβ , o6naaanmHX 6M©nonmecKoii aKTMBHOCTbto m ncnonb3yeMwx b KanecTBe atcTMBHO-ne^cTByiotuero Hanana b 4)apMaueBTvmecKWx npenapaiax, cTMMynnpyiomMx i4eHTpam>Hyio HepBHyro cvicTeMy. HOBbie φθΗΜηβΠΚΜΠΒΜΜΗΜ Η30ΤΟΛ111βΓΟ Η3θ6ρβΤΘΗΜΛ ΠΡΟΒΒΠΒΙΟΤ CBOB peHCTBHe Ha opraHMdM rnaBHUM o6pa30M 3a cseT MHrn6npoBaHMH ΗΒΜΡΟΗΗΟΓΟ ΠΟΓΠΟΙ^βΗΜΛ βΜΟΓΘΗΗΜΧ aMMHOB. M3BBCTHO, ΜΤΟ ΗΒΗΰΟΠΘβ BcUKHUM 3aBMCJUIļMM ΟΤ fl03W 3φφβΚΤ TaK Ha3WBaeMbtX OKa3WBa(OUļMX ΗΘΠρΒΜΟβ fleŪCTBMe CMMnaTOMM ΜΘΤΜ ΗΘΟΚΗΧ aMMHOB, ormocaujMxcfl χμμμηβοκμ k xnaccy Φθημϊκιπκμπβμμηοβ (HanpMMep, 3HflOreHHWX φθΗΜΠ3ΤΜΠ3ΜΜΗ3 (Φ9Α) M TMpaMMHa), 33ΚΠΚ>Μ3ΘΤΟΛ B Bblfle/ieHHM Κ3Τβχο/ΐ3Μhhob (b nepeyio onepepb HopappeHanMHa) H3 nna3MamMecKHX 3anacoe HenpoHOB. AHanonHHUMM cBOHcnsaMM o6naflaioT flpyme ΗΘ3ΗΑρθΓΘΗΗΜΘ φβΗΜΠΒΠΚΜΠΒΜΜΗΜ (HanpMMep, 3ΜφβΤ3ΜΗΗ Μ ΜβΤβΜφβΤβΜΗΗ).
Eonee τογο 3φφβκτ BupeneHHH Hopappet+aroiHa μ (β 3&βμομμοοτμ οτ po3u) 3φφβκτ qpyrvix nepepaTOMHb»x aMMHOB (HanpMMep, cepoTOHMHa) no ΜβΤβδΟΠΜΗβΟΚΗΜ ΠρΜΜΜΗ3Μ ΒΒΠΗβΤΟΗ CMHbHMM M ponro fleHCTBytOtLļMM. ΜβτθΜφβτβΜΗΗ TaioKe b 3aMerHOH creneHM MHrvi6npyeT HeiipoHHoe nomoujeHMe 3HfjoreHHbix ομμπβτομημθτμμθοκμχ ημμηοβ ηθπρλμογο λθμοτβμλ, OPHaKO, 3ΤΟΤ 3φφβΚΤ Β ΜΗ BMBO yCHOBMBX ΠΟΠΗΟΟΤΒΙΟ ΠΟρβΒΠΛβΤΟΑ βμρθπθημβμ HopappeHanMHa.
Cyu4ecTB0 Hacro&mero Μ3ο6ρθτθημη ocHoeaHo Ha tom φβκτβ, hto b KJiacce φβΗΜηβηκΜηβΜΜΗΟΒ npneMneMa μοαμΦμιώιιμη χμμμηβοκομ cTpytcrypw CnOCOGna nOflHOCTblO yCTpaHBTb M3BeCTHW© XapaKrepMCTMKM M flOMHHaHTHblfl 3φφβκτ yKa3aHHOM rpynnw coenMHeHM*, a μμβηηο, 3φφβκτ WHflyqHpOBaHMB orroKa nepepaTOMHbix βμμηοβ, m, c npyroū cropoHu, sto cnoco6Ho ycwiHBan nOJJHHHeHHblfi flO HaCTOBUļefO ΒρβΜβΗΜ 3φφβΚΤ ynOMBHyTOM rpynnbI COepMHeHM5)( a ΜΜβΗΗΟ, ΜΗΓΜβΜρΟΒΒΗΜβ ΗβϋρΟΗΗΟΓΟ ΠΟΓΠΟΙ^βΗΜΛ ΟΜΜΠβΤΟΜΗΜβΤΜΗβΟΚΗΧ aMMHOB) CenetCTMBHbtM ΠγτβΜ. TaKMM 06pa30M MOryT 6wTb nonyHeHM cTMMynHTopbi, xapaKTepM3ytou4necfl ηοθμμ οπβκτροΜ peMCTBMH. B COOTB6TCTBMM C HaCT05UpMM Μ3θ6ρβΤΘΗΜΘΜ npeflnaraeTCH ΠΟΠγΗβΗΜβ ČHOnOrHHeCKU aKTHBHb4X φβΗΗΠΗΠΚΗΠΒΜΜΗΟΒ ΰδίΜΘΜ φορΜγΠΜ I Μ ΜΧ ΟΟΠβΗ. 2
R R rpe: papm<anbi: R1 μ R2 μμθιοτ cnepyK>mne 3HaweHnn: R1 o6o3HanaeT anKnn c npnMotf κηκ pa3B6TBneHHoii κθπμο, copep)KamMii or 2 po 3 ymepoflHbix aTOMoe; (peHM/ianKM/i, copepx<amnft ot 7 po 10 ymepopHb»x aTOMoe; φβΗΜΠ wnn MMKJioanKnn, copepKaīpMH ot 3 po 5 ymepopHbtx aTOMoe; φβΗΜπ ΜΠΜ UHKJToa/iKMn, copepacaipuM οτ 3 po 5 ymepopHWX aTOMOB; R2 o6o3HanaeT anxnn c npnMofl nnn pa3BeTBneHHoii uenwo, copepjKaujMŪ ot 1 po 8 ymepopHbix aTOMOB, 3aMeujeHHbiM btomom ranoreHa, mppoKCM/iOM, anxoKoirpynnoMt copepacaujeii ot 1 po 4 ymepopHbtx stomob; anKMfi, copepacaipHM 3 aTOMa yrnepopa h 3aMeujeHHbiM Φθημπομ; wnn UUKnoanKnn, copepx<auļtiM ot 3 po 8 yrnepopHbix aTOMOB, npn ycnoenn, hto R1 m R2 BMecre copepxaT Π5τη> yrnepopHwx aTOMoe; μ πρΜΗβΜ ecnn R1 - 3τκπ, το R2 - η© M3o6yTnn.
ComacHO νΐ3θ6ρβτβΗΜΐο φβΗΜΠ3ΠΚΜΠ3ΜΜΗΒΐ nony4aiOT ΤβΜ, ΜΤΟ Ββορητ no Β33ΜΜοπβΜ<ττΒΜθ aMMH οδιρβϋ φορΜγπω ΙΙ|
R
(II) C ΟΟβρΜΗΘΗΜβΜ ΟδίρβΜ φορΜγΠΜ III: (III)
X “ CH 4 R Χ-aTOM ranoreHa ηπμ ακ»κΗ03φΜρΗ3Η rpynna cyπbφoHOBOH κκαιοτω; LV 10860 R3 -ūtom eopopopa nnn anKnn Ct-C4, κοτορωή Μ0>κβτ 6wTb 3aMeujeH ranoreHOM, rappoKCunoM, anKOKCvi-rpynnoti c 1-4 aTOMaMu yrnepopa nnn ορΗοή min f|ByMii φβΗΜΠΒΗΜΜΜ rpynnaMn; R4 - aTOM BOflopopa; nnn R3 n R4 MoryT BMecre o6pa3oeaTb LļUKnoanKHnbHoe Konbuo c 3-8 aTOMaMM yrnepopa, nocne nero, ecnn JKenaTenbHo, coepnHeHM* οδιρβίί φορΜγηω I noflBepratoT npeBpaipeHHKJ b cohm, o6pa3yeMbie c opraHMsecKOH nnn MHHepanbHoPi kmcdotom, n/nnn BbipennioT coepMHeHHfl οδιρβΑ φορΜγηω H3
ΟΟΠθίί B CBOČOflHOM COCTOBHHH, Μ, βΟΙΜ JKenaTenbHO, C HCnonb30BaHHeM coepMHeHMM očmen φopMyπbl I v\m nx conefi γοτοβλτ no ΜβτορβΜ, κοτορωβ caMvi no ce6e n3BecTHbi, φαρΜΕΐ^ββΤΜΜβοκΜβ npenapaTbi. yKa3aHHyto peaKumo anKnnnpoBaHnn npepnoMTMTenbHee npoBopmrb b npncyTCTBMM CBB3biBaK>mero KMcnoTy areHTa. C stom uenbīo mojkho MCnonb30BaTb M36blT0K ΗΟΧΟΡΗΟΓΟ ΒΜΜΗΟΒΟΓΟ COeflMHeHMa ΜΠΜ )Ke opraHunecKoe nnn HeopraHvmecKoe ocHoeaHue (HanpnMep, Tpn3TnnaMHH nnn KapčoHaT Kanna); mojkho τβιοκβ ncnonb3oeaTb ocHOBHy»o μοηοο6μθηηυκ> cMony.
CoeflMHeHna οδιρβή φορΜγπω i, nonyneHHbje no cnoco6y HacToaujero Μ3θ6ρβτβΗΜΒ, npepcTaBnaioT cočoū b φορΜβ cbo6ophwx ocHOBaHMii nnnonppacTBopnMbte MacnonopoČHbie eeipecTBa, κοτορωβ npn xenaHnn mo)kho noflBepmyTb KOHBepcnn ece KpncrannnHecKne BopopacTBopnMbie conn. flpoiiecc nonyHeHMa conn mojkho npoBopuTb c ncnonb30BaHneM φ3ρΜ3146ΒΤΜΗ60ΚΜ ΠρΜβΜηβΜΒΙΧ ΗβθρΓ3ΗΜΜβΟΚΜΧ 1ΛΠ1Λ θρΓ3ΗΜΜβΟΚΜΧ KMCHOT, nanpnMep, conaHon ΚΜοποτω, δροΜΜοτοβορορορΗοίί κκαιοτω, cepHon κκοποτω, φΟΟφορΗΟΜ KMCflOTbl, MypaBbHHOM KMCnOTbl, yKCyCHOH KMCJTOTbJ, īpaBeneBOM KMcnoTbi, ManenHoeon kmchotu m TOMy nopočHoro). CoeflnHeHnn očipett φορΜγπΜ i mokho Bbtpenmb M3 κμοποτμ appyKTOB no očhhhhm MeTopaM.
CoennHeHna očiueū φορΜγηω I μ μχ čnonorMHecKM npneMneMbie Kncnbje appyKTW Moryr 6wTb Mcnonb3oeaHbi b KasecTBe aicniBHopeHCTByiou|Hx BeipecTB npn npnroToeneHHM φ3ρΜ3ΐ4βΒΤΜΗβοκιιχ κομπο3μμμμ pn* Μβποββκβ. yxa3aHHbie φΡρΜβΙΙβΒΤΜΗβΟΚΜβ K0Mn03HqWH Ha OCHOBe HOBblX coepMHeHMM Moryr 6b)Tb npnroTOBneHbi no H3B6Cthum b φαρΜαΜββτΗΗβοκοή npoMb/ujneHHocTn MeTopaM. AKTHBHopeHCTByKJ(pee eeipecTBO mojkho ncnonb3oeaTb β ο6βιμημχ po3npoeaHHbix φορΜ3Χ (HanpnMep, β φορΜβ Ta6neTOK, nnnionb, ppajKe, Kancyn, npenapaTOB pnn ΜΗΒβκρΜίί m TOMy ποβοδΗΟΓο). YKa3aHHue (ļiapMaueaTviHecKMe κομπο3μι4«μ μογ/τ BtcnionaTb β ce6a ο6μηημθ HocMTenu, poČaBKM, CMa3biBatomne BeujecTBa, ηβποπημτθγιη, BcnoMoraTenbHue areHTbi h TOMy ποροόΗΟβ.
CoeflMHeHMfl o6(lļeŪ φΟρΜγΠΝ I 33ΜβΤΗΟ ΜΗΓΜδΜργΚΤΓ ΜΗΗΐρίΜργβΜΟβ TvtpaMMHOM BbipeneHne HopappeHannHa M3 nna3MaTvmecKnx πορ ΗβκροΗοβ 3a cneT MHniCMpoBaHMfl npouecca πογποιμθημλ TMpaMMHa. B npoTMBonono)KHOCTb M3BeCTHblM φβΗΙΛΠΒΠΚΙΛΠΒΜΜΗΒΜ ΟΟβρίΛΗβΗΜΒ o6Uļeft φορΜγΠΜ I Ηβ ΠρΟΗΒΠΒΙΟΤ 3φφβκτΒ BbtAeneHvm HopaapeHanviHa. ΟρΗΟΒρβΜβΗΗΟ c sthm coepMHeHMst φορΜγπω I cMJībHo nonaBnaioT ηθμροηηοθ ποτηοιμβΗΜβ HopappeHanMHa m ponaMMHa, 3HaHHTenbHo ycMHMBa5i KaTexonaMMHeprMM6CKoe pencrBMe, ho b ΟΤΠΗΗΜΘ OT 3ΜφθΤ3ΜΗΜΗ3 Μ ΜΘΤΗΜφθΤβΜΜΗΒ ΗΘ OKa3biBatOT ΒΠΜΗΗΜΑ Ha ceporoHeprMMecKoe ρθμοτβμθ pa>Ke npw ΒββρβΗΜΜ b opraHnaM β 6οπμιιμχ qo3ax.
CoepMHeHHfl οδιιιβϋ φορΜγπω αβπαιοτοα crMMyrorropaMM neHTpanbHoft HepBHOM CHCTeMbl, KOTOpafl ΠρΟΒΒΠΒβΤ (ΓΓΜΜγΠΜργίΟΙΜΜΗ 3φφβΚΤ Β φΒρΜΒΚΟΠΟΠΙΗβΟΚΜΧ Μ0ΠΜΤ3ΗΜΗΧ Ha ΟδγΗβΗΜΘ Η aHTMJļ6np6CCMBH0CTb, mitUb Β γΜβρβΗΗΟΗ ΟΤΘΠΘΗΜ yCVU1HBa6T ΠΟβΒΜΧΗΟΟΠ» Η ΜΘΤ3δθΠΜ3Μ, Ηβ fleMOHCTpH py Κ)Τ 3ΒΜ6ΤΗ0Γ0 aHOpeKTanbHOrO 3φφβΚΤβ M TOnbKO Β enaČOM ΟΤΘΠβΗΜ TOKCMHHbJ. Β npOTMBOnonO)KHOCTb OCHOBHOH φγΠΠβ H3BeCTHbiX ΠΟΗΧΟβΗβρΓβ-ΤΜΜβΡΚΜΧ areHTOB ΟΟβΠΜΗΘΗΜΜ 0δΐ11βΜ φορΜγΠΜ I Ηβ ΟδΠβΒββΤ ΑβΗΟΤΒΜβΜ, ΜΗΓΜδΜργίΟΙΜΜΜ MOHOaMHHO-OKCMfla3y (ΜΑΟ). ΕθΠΜ paCCMaTpMBaTb ΜΘΧ3ΗΗ3Μ ΙΊΧ fleMCTBMfl Η ΧΜΜΜΜβΟΚΟβ ΟΤρΟΘΗΜΘ, ΟΗΜ SHaHMTeilbHO OTTOlHaJOTCfl OT H386CTHbJX ΤρΜφΙΚΠΜΜβΟΚΜΧ aHTHflenpeCCaHTOB. OCHOBUBa^Cb Ha ΒΗ11ίθΗ3ΠΟΧβΗΗΟΜ, MOX(HO YTBepX(naTb, hto φθΗΗΠβΠΚΜΙΚΙΜΜΗΜ OČUjeM φορΜγίΙΜ I COCTaBflHIOT ΠΟΗΧΟφβρΜΒΚΟΗΟΒγίΟ rpynny c HOBHM Μ6Χ3ΗΗ3ΜΟΜ ββΜΟΤΒΜΒ, ΠρΗβΜΠΘΜΜΜ Pfm nOBMUJeHHB nCMXMHeCKOM aKTMBHOCTVi ΟδγΜΘΗΗβ, ΟΟΧρβΗβΗΗβ ΠΒΜΒΤΜ) Η ΡΠΛ ΜθβΗρΜΗΟΚΟΓΟ ΠΘΗβΗΜΒ ΚΠΗΗΗΗβΟΚΜΧ ΜΟρβΠβΗ ρβΠρβΟΟΗΜ, Λ ΤβΙΟΚβ 3a6oneBaHMM, COnpOBO)KnaiOtHMXCfl SaMeTHblMM ρβφβΚΤβΜΜ CnOCo6HOCTM Κ οδγΜΘΗΗΚ) Μ aanoMMHaHMio, πορροδΗΟ δοπβ3ΗΜ AjibLireiiMepa, npepnono)KVfrenbHo δβ3 ΠρΟΑΒΠβΗΜΑ ΠΟβΟΗΗωΧ 3φφβΚΤ0Βρ CBOŪCTBeHHWX Μ3ΒβΟΤΗΒΙΜ ΟΤΜΜγΠίΤΤΟρβΜ, κοτορωθ Bb<3biBaioT ΒωρβπβΗΜβ KaTexonaMHHa. B COOTBeTCTBHH C aKTMBHOCTbK) ΟΟβΑΜΗβΗΜΜ HaCTOflUļerO Μ3θδρβΤβΗΜΒ cnoco6 πθηθημβ npepycMaTpHBaeT πθηθημ© 3ροροβωχ mjim 6οπβημχ πιορβϋ LV 10860 <)}apMaLieBTMsecKOM κομπο3μμμθΑ, coflep)«aiueA 3φφβκτνΐΒΗθβ κο/ιμηθοτβο ΟΟββΜΗβΗΜΑ ΟδίμβΜ φορΜγηΜ I ΜΠΜ βθ φβρΜ314ΘΒΤΙ4ΗβΟ(Μ ΠρΜΘΜΠΘΜΟΓΟ KMcnoro afloyKTa. npepnOMTMTenbHbie β*βρΗΘΒΗΙ>»β fl03W COCTaBnaiOT ΠρΗ6ηΐ13ΜΤΘΠΒΗΟ ot 10 ρο 150 ΜΓ, B M3CTH0CTM, ΠρΜΜβρΗΟ 30 ΜΓ. TaKMB φ3ρΜ311βΒΤΜΗβ€ΚΜβ κομπο3ΜΙ4μμ πρβρποΗτνιτβπΒΗββ BBopuTb b opraHM3M nepopanbHo, napeHTepanbHo mv\ cy6nMHrBanbHO.
Enarofjapn cBoeii HH3Kofi tokcmhhoctvi coeflMHemifl o6meii φορΜγπω I mokho TaiOKe ncnonb30BaTb pna πθηθημλ «θτθμ b οοοτβθτοτβυκιιμμμ oāpa30M nepecHMTaHHovi po3npoBKe. ΠρΜβΜπβΜβΛ eeTepMHapHaa qo3a cocTaenneT 2-3 μγ/κγ.
CoeflMHeHM$< οδιμβΰ φορΜγπΜ IV o6paaytoT noprpynny coepMHeHMii oGuieft φορΜγπω I, Koropas nenneTcn oco6©hho 6naronpnflTHOū. R5 ‘ (,V) (Qļ-CH2 - CH - nh - ch2 - ch2 - ch3 rfle R5 - amatu, coflepacaufMft 2-4 aTOMa ymepopa.
Hhjk© npMBepeHbi npMMepw, kotophmm h© orpaHHHMeaioTcn paMKM h 06b©M ΠρΜΤ£33ΗΜΜ. flpHMep .1 16,3 r (0,1 MOJifl) 1-φβΗΗη-2-neHTMn-aMMHa pacrBopnioT b 130 μπ aTM/iaiieTara m poāaBnflfOT 30 r K2C03, nocne nero b CMecb npnKanwBajoT 12,3 r (0,1 m) H3onponnn6poMHļjū. CMecb ΚΗΠΗΤΗΤ c OCpaTHUM XOnOfļHITbHHKOM B ΤβΗΘΗΜΘ 3 M3C0B. ΟτφΜΠΒΤρΟΒΜΒΒΙΟΤ HBOpraHMM6CKyiO COnb m OHHUļaioT φΜΓ^τρβτ aKTMBMpoeaHHbiM ymeM. 3aTew φκτη>τρ3τ BwnapnBatoT m OCT3TOK pacTBopaioT b connHOKMcnoM dTaHone, a nonyMeHHMM pacTBop BbmapMsaioT cHoea. nocne KpMcrannM3ai4MM W3 cm©cm aranona h θτμγιοβογο 3φΜρβ nonyMa»OT 17,5 r (72 ) N-M3onponnn-1 -φβΗΗΠ-2-πβΗΤΗΠ3ΜΜΗΓ>ιρροχηορΗρ c TeMnepaTypoM nnaeneHMsi 13Θ-139 °C. ripHMepbL2-14 ΠβρθΗΜοπβΗΗωβ ημχθ b TaCnnue coeflHHeHnn nonyHann aHanorviHHo npnM©py 1. χ s i 3 P i α 5 Ο H- P š 3 2- CL Φ
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Jf I Jf ^ ® _? 2 Χο>ΧΧΧχΧχ O^OOOOOC? α Φ 2 x α c cj 00 ^ m (O n 00 O) ° CM n rf LV 10860 ļļpHMep 15
16,3 r (0,14 Morifl) 1 -0eHnn-2-āyTnnaMHH pacTBopatoT b 70 μπ 6eH3ona m poāaensitoT no KannflM 2,96 r (0,01 μοπλ) 3Tvin-napa-Tonyon-cynb(tīOHaTa, pacTBopeHHoro e 20 μπ 6eH3ona (τ.π. 34 °C). PeaKUMOHHyio CMecb κμππτπτ ipn naca m KOHLļeHTpnpyjoT. OcTaTOK pacTBopafOT b 6eH3one m 3KCTparwpy»oT ruppooKMCbra HaTpua m 3aTeM Bopoii (xa)Kflbin pa3 pBaJKflbi). 5eH3onbHbie 3KCTpaTU Bbicyujtf BatOT Μ KOHljeHTpM py KDT. H36b(TOK MCXOflHblX BeUļeCTB ypanaioT pacuM/inaMMeM b BaKyyMe npn 122-124 °C (/p10). OcrraTOK pacTBopaioT b 3TaHO/ie m poOaenaioT conaHyio KMcnory b STaHone c o6pa3oeaHneM οοππηοκμογιομ convi. ripu oca^peHvni pnaTvinoBbtM 3φν»ροΜ nonyMaiOT 15,4 r Ν-3ΤΜΠ-1 -φβΗΜΠ-1 -6yTMnaMMH-rMppoxnopMpa. T. nn. 145-147°C. II. Εμοπογμηφοκμβ πρΜΜβρω IIZL. OiipeflefleHHe_ 3φφβκτ8_ BbmeneHHfl HopappeHannaa hh bmho Ha κοιιικζχ CocTonHMe MMraTenbHoft nepenoHKM nopBepmyTOM aHecrre3MM koujkh nocTOJiHHo perncTpnpyeTcn c noMouļbto ayKcoTOHMHecKoro caMonwujymero KHMorpa0a. BbipeneHne HopappeHannHa MHMijMMpyeT OKame MuraTenbHOM nepenoHKM b 3aBMCMMOCTM ot floabi BeuļecTBa. BHyTpM6piowMHHoe ββθρ©ημθ 1 μγ/κγ Φ3Α MHMi4MnpyeT coKpameHMe MHraTenbHofl nepenoHKM. flo3a 1 μγ/κγ 3ΜφβΤ3ΜΜΗ3 Μ Μ6Τ3ΜφβΤ3ΜΜΗ3 Bbl3blBaeT Τ3Κ0Θ COKpailļeHMe Β ΤΘΗβΗΜβ flnmenbHoro nepnopa ΒρβΜβΗΜ. Β xope προΒβρθΗΜΑ BbiuiyKa3aHHoro McnbuaHMB coeflMHeHMSi οβιρβΜ φopMynω ( ηθ BU3biBa>0T ημκβκογο coKpameHMB nepenoHKM (Μβτορ J. Knoll, Monoamin Oxidase and 1th inhibition /Eds Wolstenholme and Khight), Elsevier, 1976 r., <rrp. 131). ll/2. OnpeneneHMe ncMXocTMMynMpyioLiiero 3φφβκτ3 Ha Kpbicax a) ΜορΗφΜΜΜροΒΑΗΗΟβ npuKKOBoe McnbīTaHMe (J. Knoit and B. Knoil Arch, Int. Pharmacodyn 148, 200, 1964 r).
B xope npoBepeHMB paHHoro McnbrraHMH HečonbUJMe po3w 3Μφβτ3ΜΜΗ3 (po 1-2 μγ/κγ) ynyMUiaioT, Torpa KaK ποβωωβΗΗΜβ po3bi 8ΜφβΤ3ΜΜΗ3 (6onee 3 ΜΓ/ΚΓ) yxyplliatOT CnOCOČHOCTb K 0<5yHeHMt0 M 33ΠΟΜΜΗ3ΗΜΚ) B 3aBMCMMOCTM ot κοΗκρβτΗΟΜ po3w. ΟοβρΜΗβΗΜΑ οβιρβΜ φopMyπbι I ynymjjaiOT xapa«TepMCTMKM Β ρθ3ΜρθΒΚβ 0,5-15 ΜΓ/ΚΓ B 3aBMCMMOCTM OT ΚΟΗΚρβΤΗΟΜ fl03bl. TaKMM o6pa30M, HOBbie coepMHeHMa CBoGopHbi ot yxypiuaiotnero 3φφβκτ3, κοτορωΐί χαρακτβρβπ B āonblliMX P03ax ρππ 3ΜφβΤ3ΜΜΗ3 BCnepCTBMe 3KTMB3L|MM οβροτοΗβρΓΜΗβοκοϋ cncTeMbi. flo3bi, npeebuuaiouļHe 10 μγ/κγ, paccMaipuBatoTCfl KaK oneHb čonboine. b) HcnbīTaHMe c ηθπηοηηομ KaMepoū ( Μβτορ: B. Knoll, J. Knoll, Po J. Pharmacol. Pharm., 54, 17-2 , 19 π). B οοοτββτοτβΜΜ c paHHoii ΜβτορΜΚΟή
McnbiTaHviq e>KeflHeBHoe BBejqeHne b opraHH3M po3bi b 1 μγ/κγ πορκωκΗΟ 3Μφβτ3ΜΜΗ3 Bbi3biBaeT 3HaHHTenbHoe ycnneHne acenaHHfl b BbipaSoTKe ycnoBHoro ρθφ/ieKca n ero coxpaHeHnfl b τθηθημθ πλτμ flHeii m6ntoļļema. OffHūKo ycHneHne cnocočHocnt conpoBOjKffaerca Heecrecrβθηηο cunbHOM peaKpneii Ha npoMex<yTOHHbie cnrHanbī. 3φφβκτ čonee βμοοκμχ po3 3Μφβτ3ΜiiHa (5-10 μγ/κγ) paxe ηθβο3ΜΟ)κηο openHTb b μ6Πηοηηομ KaMepe BcnepcTBue βοβημκηοβθημα aeneHaa ηοοκοημτθπβηο bucokoh očtueM ΠΟΡΒ H)KHOCTH. Ε)ΚΘΠΗβΒΗΟβ ΒΒβρβΗΜΘ B 0praHM3M 0,5 ΜΓ/ΚΓ COeflMHeHM» B C00TB6TCTBMM C ΠρΜΜβρΟΜ 4 Π03Β0η«βΤ 3HaMMTenbH0 nOBbICHTb CnOCOāHOCTb ΠΟ CpaBHBHMfO C KOHTpODbHblM 3ΚΟΠβρΜΜΘΗΤΟΜ 6β3 ΠρΜ3Η3Κ0Β yCMJTeHHfl o6iqen noflBkDKHOCTM.
CoeflMHeHne b οοοτβθτοτβημ c npuMepoM 2 ycnnnBario cnocoČHocTb κ o6yHeHMto n coxpaHeHirito HaBbiKoe c caMoro nepaoro pna μ b τβπβΗΜβ scero nepnopa McnbuaHUfl pa*e npn BBepeHnn b opraHH3M KpatfHe bncokom ΘΧβΡΗβΒΗΟΜ fl03bl B 15 ΜΓ/ΚΓ. B TO Χβ ΒρβΜΑ KaK CnOCOČHOCTb ΠΟΡΟΠΜΤΗΒΙΧ >KHBOTHblX OKa3blBaeTC51 Heo6biHHO BbJCOKOH, γΟΜΠβΗΜΘ ρβφηβΚ03 Ha npoMe>KyTOMHbie cnrHanbī mokho paccMaTpii BaTb KaK yMepeHHoe, ecnn npHHMMaTb BO ΒΗΗΜΒΗΜβ MCKTIIOMMT©nbHyiO BblCOKyiO CnOCOGHOCTb K 06yHeHMt0. >KMBOTHbie, KOTOpbIM ΟΟβρΜΗβΗΜβ B COOTBSTCT3MM C ΠρίΙΜβρΟΜ 2 SSCffUnH 3 OpraHH3M B fl03e 15 ΜΓ/ΚΓ, nOHHOCTblO COXpaHi1IOT CnOCOČHOCTb flOCTMrHyryiO no 3aBepujeHHio opHOHepenbHoro nepnopa o6yseHHfl, paxe cnycrrfl 6 Hepenb nocne 3aBepuieHnB Kypca BBepeHna neKapcTBa. B cooTBeTCTBnn c pe3ynbTaTaMn γποΜΗΗγτωχ ncnbrraHnii coepHHeHMii Hacroaipero ΜβοβρβτβΗΗΛ Π03Β0ΠΒΙ0Τ P0CTHHb MCKniOHMTenbHOrO ΡΘ3ΚΟΓΟ 3φφβΚΤ3 ycnneHMB cnocofiHocrn κ o6yseHMK3, πρηΜβΜ, yKa3aHHbm 3φφβκτ HBnaeTCii oneHb cnnbHbiM n ιυηροκΜΜ, He pocTnraeTCH no ppyroMy MexaHH3My b cpaBHeHnn c MeXaHH3MOM ffeāCTBUP 3ΜφβΤ3ΜΜΗ3. LV 10860 II/3. ΟπρβΡβπβΗΜβ aHTaroHH3Ma κ cenpeccHH. Bbi3BaHHOH ρθμοτβμθμ TeTpačeHa3HHa. b xofle HcnbīTaHHH no oāyMeHMK) Kpbic a) npbDKKoeoe McnbrraHMe. Μβτορ: J. Knoll, B.Knoll, Azznoimittll Forschung 8, , 1958 r., 9,6 , 1959 r. 3aKpenneHHbivi ycnoBHbi»i ρβφπβκο, pocTviraeMbtvi b xope npbi>KKOBbix McnbrraHMM, Ηβ μοχθτ 6brn» MHrvi6MpoBaH οοθαμηθημαμμ οβιρβΛ φορΜγπω I paace b 6onbiuMX fl03ax (HanpMMep, b poae 15 μγ/κγ οοθαμηθημ?? β COOTBeTCTBMH C ΠρΜΜβρΟΜ 7). TaKOfi ρβφπβκο ΜΟ>ΚβΤ 6blTb nonHOCTbro nopaeneH TonbKo čonbīuMMM po3aMM T©Tpa6eHa3MHa (5 μγ/κγ) Toma kūk penpeccnBHOMy θφφβκπγ TeTpa6eHa3MHa μοκθτ 3φφβκτΗΒΗ0 npoTHBopeHCTBoeaTb coepHHeHMe b cootbotctbmm c npMMepoM 7 β fl03e 15 μγ/κγ. b) McnbrraHMe μ©πηομηομ KaMepoft. Μβτορ: B Knoll, J. Knoll, Po1, J. Pharmocol, Pharm. 34, 17-23, 1982 r. B cootbbtctbhk c p©3ynbTaTaMM paHHoro McnbrraHMM flenpeccMM, Bbl3BaHHOM TeTpa6©Ha3MHOM, MO)KHO npOTMBOCTOiTTb C nOMOlflbSC CCeflMHeHMM οδιηβπ φopMyπbt l. B Ta6nnue 3 npvtBepeHbi HMcnoBb»© aHaHeHMs, nonyseHHbje b pape HcnuTaHHM, npoBepeHHbix c Mcnonb30BaHMeM coeflMHeHHii b COOTBeTCTBMH C ΠρΜΜβρΟΜ 7. AHanorMHHbie pe3ynbTaTU nonyHatOT npM πρμμθηθημμ οοθαμηθημμ b COOTBeTCTBMH C ΠρΜΜβρΒΜΜ 2 M 12._Tafowua_3 06yneHMe F+ /+ /- IR _PeaKUMfl Ha CTHMynguMto_ 51,67 18,67 3,25 ±6,62 ±7,96 ±2,39 31.25 59,17 10,25 +9,20 +11.68 +2.45 49,80 16,40 10,50 ±7,08 ±10,18 ±2,05 25.25 21,42 11,00 ±6,01 ±10,84 ±2,51 30,75 60,75 8,33 ±9,81 ±11,81 ±2,34 21,00 16,80 14,70 ±7,17 ±11,45 ±5,27 31,17 10,58 13,83 ±8,35 +6,46 ±4,00 15,83 72,75 4,67 1 flenb 2 fleHb 3 fleHb
C T V c T 29,67 +6,31 9,58 +3.74 34,60 +7,00 53,33 ±9,87 8,50 ±3.68 62,20 ±11,39 58,25 ±10,43 11,42
V V ±11,10 ±1,23 21.00 21,30 ±12,51 ±7,50 5,17 i O OC W|bW ±4,09 ±5,80 73,08 4,50 ±10,63 ±1,31 17,40 14,30 ±11,66 ±5,06 4,52 12,83 ±3,60 ±4,06 69,75 6,92 ±11,64 ±1,90 15,40 16,80 ±10,31 ±5,78 ±4.94 ±6,14 69,20 9.80 ±11,65 ±3,17 66,00 28,83 ±8,97 ±8,14 9,80 17,83 ±4.02 ±6,81 64,90 17,70 ±10,92 ±5,21 72,25 23,33 ±7,60 ±6,62 17,67 12,58 ±8.10 ±4,03 76,10 8,50 ±11,29 ±2,33 4 fleHb 5 fleHb
T
V c
T
V C - KOHTpO/lbHbIM ΘΚΟΠβρΜΜβΗΤ (φΜ3ΜΗβΟΚΜΜ paCTBOp ΧΠΟρΜΟΤΟΓΟ ΗΒΤρΜΗ β/ΚβρΗΘΒΗΟ, nOflKO)KHO, N = 12); T - 0,5 μγ/κγ T6Tpa6eHa3MHa πορκακΗΟ β>κβρΗβΒΗθ, N = 12; V - 0,5 μγ/κγ T6Tpa6eHa3MHa + 10 μγ/κγ coepMHeHMfl b cooTBeTCTBMM c npUMepOM 7 nOflKO)KHO ΘΧβρΗβΒΗΟ, N = 12; F+ = )KMBOTHblX, ΠρΟΗΒΠΑΚίίρΜΧ ycnoBHbiii ρβφπβκο /+ = >KMBOTHbix, peampy>ou|MX Ha HecTaHpapTHbiM pa3qpax<MTenb /- = )kmbothwx, κοτορωΒ He pearnpytoT qaxe Ha HecraHpapTHbtii pasppattMTenb IR = HHcno peaKUMii Ha npoMexcyTOHHbiii CMman.
11/4. OnpepeneHHe 3φφβκτα. oKa3biBaeMoro Ha noPBH)KHQCTb KpbLC HcnblTaHHfl npOBOfiflT B ΗβΠΗΟΗΗΟΗ KaMepe 6β3 nopaHH TOKa H CBeTa. PerncTpnpytoT m cyMMnpytOT b noMoīpb npn6opa sncno caMonpon3BonbHbix ΠβρβΜθίμθΗΜΗ OT OPHOH CT6HKM KaMepbl flO ppyroti B ΤβΜβΗΜΘ MHH. flaHHO© McnbīTaHM© προβορητ c rpynnoM χμβοτηβιχ, KOTopaji ΒκηιοΜβθτ b ce6a 112 Kpbic pacbi cry o6omx ποποβ secoM no 160-200 r KzoKnaa* Πβρβρ HananoM MCnblTaHMfl nOflKOXCHO JKMBOTHbIM BBOflHT MCnWTyeM06 C06flMH6HMe οδίρβίί φopMyΠbl I COBMeCTHO COOTB6TCTB6HHO C TeTpa6eHa3MHOM M pecMeTMnMMMnpaMHHOM (flMM), ncnonb3yeMbiM b KasecTBe cpaBHMTenbHoro COepMHeHMfl. LV 10860 B cooTBeTCTBUM c pe3ynbTaTaMM paHHoro McnbrraHMa, θοθρμηθημη npuMepoe 2 m 7 ηθ npeebiujaioT nopeM)KHocTb b po3e 10 μγ/κγ, rorpa KaK οοθρμηθημη πρΜΜβροΒ 2, 6 m 12 b onpepeneHHOM οτθπθημ noebiiuaioT nopBM)KHOCTb. ΒφφθΙΟγ ΠΟΒωΐϋθΗΜΛ flOPBMJKHOCTM, Bbl3BaHHOMy 1 ΜΓ/ΚΓ
TeTpaāeHa3MHa, 33μθτήο προτμβοθτομτ οοθρμηθημθ npMMepa 7 b po3e 2,5 μγ/κγ h nonHOCTbto npoTMBopeiicTByeT οοθρμηθημθ npMMepa 2 yx© b ρο3β 1 μγ/κγ. B xope paHHbix McnbrraHMM flMM προΗΒΠΗθτ cKopee μηγμ6μρυκ>ιρμμ caM Γ.0 cs6s 3φφβΚΤ, ΜΘΜ aHTarOHMCTMMeCKOe peŪCTBMe B ΟΤΗΟΙϋθΗΜΜ penpeccviM nOflBH^HOCTM, BU3BaHHOH TeTpa6eHa3MHOM. ll/5^0npeneneHHe βγιμμημβ. OKa3biBaeMorQ Ha MeTa6onn3M y Kpbic Μβτορ: B (SSekutz, B.lssekutz, Jr., Naymyn, Shiedebero 2 Arch Pharmac 106, 1942 r. B xone npoeeoeHMij naHHoro μοπηπήημα οοθρμηθημ* οβιρβΜ φορΜγπΜ I ycKop«KjT o6mbh seipecTB b 3HaMwrer!bHO μθημρθμ οτθπθημ b τθμθημθ 6onee ΚΟΡΟΤΚΟΓΟ nepMOpa ΒρθΜΘΗΜ, ΜΘΜ 3ΜφθΤ3ΜΜΗ, ΠΜ6θ 1 -ρβΠρβΗΜΠ. H/6. ΟπρβΡθπβΗΜβ βπμαημα Ha ποτρβδηβΗΜθ πμιιιη y κρωο Ββθρθημθ nepopanbHO μπμ πορκο>κηο cwtwm χμβοτημμ ηρκ χοροιιιβΜ ΜΧ ΚΟρΜΠΘΗΜΜ ΟΟΘΡΜΗΘΗΜΗ B ΟΟΟΤΒΘΤΟΤΒΜΜ C ΓφΜΜΘΡΟΜ 7 Β Ρ03β 15 ΜΓ/ΚΓ Ηθ Μ3ΜΘΗΑΘΤ ΚΟΠΜΗΘΟΤΒΘ ΠΟΤρθδΠΒΘΜΟΗ ΜΜΜ ΠΜΙ14Μ (ΒΜφθΤΒΜΜΗ ΠρΟΒΒΠΒΘΤ βηορθκτμμθοκμμ 3φφβκτ yxe β ρο3β 1 μγ/κγ). Ππμ θηθπογμμηομ ρο3β οη ηθ 0Ka3blBaeT ΒΠΜΛΗΜΒ Ha ΚΟΠΗΜΘΟΤΒΟ ΠΟΤρββΠΛΘΜΟΜ ΠΜΙ11Μ KpbJCaMM, κοτορωΜ ηθ pasa/JH ecrb β τθμθημθ 96 μ, y κοτορωχ nyBCTBo ronopa ποπηοοτβιο ΠΟρβΒΠΛΘΤΟΛ ΒΜφβΤΒΜΜΗΟΜ Β ΤΘΜΘΗΜΘ 3-4 Μ ΓφΜ Ρ03Θ 2-5 ΜΓ/ΚΓ. fl03a Β 5 ΜΓ/ΚΓ ΡΟΘΡΜΗΘΗΜΜ β ΟΟΟΤΒΘΤΟΤΒΜΜ C ΠρΜΜθρθΜΜ 2 Μ 12 Bb<3b<eaeT 3φφβκτ nopaeneHHB MyecTBa ronopa, κοτορωπ πρμ6πμ3μτθπβηο ΜΡΘΗΤΜΗΘΗ 3φφθκτγ, Bbi3biBaeMOMy ΘΜφθΤΘΜΜΗΟΜ Β Ρ03Θ 0,5 ΜΓ/ΚΓ Β τθμθημθ πβρβοΓο Mača.
\\Π. ΟηρθΡΘΠβΗΜΘ ΜΗ ΒΜΒΟ ΠΟΓΠΟΙΙΙΘΗΜΑ Ή-HOpaiipeHanMHa HeDOCTaTOMHbIM οποθμ KopTeKca Kpbic (in vivo) Κορτθκο roMoreHM3MpyiOT β 0, 2 M pacTBope caxapo3bi c noMOīpbio ΤθφΠΘΗΟΒΟΓΟ ropilJOMKa, flflpa ΚΠΘΤΟΚ COPMMeHTMpytOT ΜΘΗΤρΜφγΓΜρ0Β3ΗΜΘΜ npM TeMnepaType 0 °C β τθμθημθ 20 mmh 8 κοπμμθοτβθ 1000 r. flna ncnbiTaHUH Hcncnb3yioT BbipeneHHbiii τβκμμ o6pa30M HepocapoHHbiH cnow. ripouecc nornouļeHMfl προβορΒτ b pacTBope Kpeāca-XeūH3eneiiTa,
HaCbUpeHHOM KapčOreHOM, B ΚΟΗΘΗΗΟΜ οδ^βΜβ 1 ΜΠ ΠρΜ KOHLļeHTpaUMM 3H-HopappeHannHa 5,10'3 μοπ. Onepapna npepHHKy6Hpo8aHHa m HHKyCHpoBaHHB npoBOfljrr npn TeMnepaType 37 °C b τθηθημθ 5 mmh KaxpyKD. PeaKpHio npeKpaipaKDT po6aeneHHeM 4 μπ oxna>KpeHHoro nbflOM pacTBopa Kpe6ca h TKaHb οτρβπΒΚ)τ ΟΓ/B-0nnbTpoBaHMeM. OTHOcmenbHoe nornoīpeHHe onpepenatoT c Mcnonb30BaHneM 10’4 Μ m pacTBopa HH30KC6THHa npn TeMnepaīype 37°C. PapHoaKTHBHocTb cr/B-0nnbTpoBanbHOM 5yMarn ΟΠρβρβΠΒ»ΟΤ Η3ΜβρβΗΗβΜ ΟΠΗΗΤΗΠΠΒΜΗΗ ΧΗρΚΟΟΤΗ B CMBCM ΤΟΠγΟΠ-ΡΤΟ- POPOP-nponyicT 'τρηποη\ ΠοπγΗβΗΗωβ pe3ynbTaTbi ceepeHbi b TačnHpe 4.
TaCnHLia 4
CoepHHeHHe Uc50 (M) JUMU 10'J - 5 X 10'y CoepHHeHHe B COOTBeTCTBHH c npHMepOM 2 5 x ισ7 CoepHHeHHe B COOTBeTCTBHH c ΓφΗΜβρΟΜ 7 5 x 10*7 CoepHHeHHe Β COOTBeTCTBHH c npHMepOM 12 1 x 10'7 l-penpeHHn 7 x 10‘6 ΟπρβΡβπβΗΜβ 3φψβκτΒ ycHneHHfl ponaMHHepHHOBoro peHCTBHfl Ha H3onnpoBaHHbix xpb!CHHbix GTpnaTyMHbix npenapaiax MeTOfl: Kerecsen h pp., Chromotography, the State of the Art., (Eds. Kalasz, Ettre) Akadimial Kiado Budapest, 1985 r., crp. 195-203. B xope npoeepeHMB 3Kc bhho HcnbrraHHH Ha >khbothwx mm bbopbt πορκο>κΗθ b opraHM3M οοθρηηθηηβ b τβΜβΗΜβ 3 Hepenb, a CnyCTfl 2 H nocjie 3aKJiK)HMTenbHoii MH-beKUMH opraH ypan«ioT. f1onyMeHHbie pe3ynbTaTbi cBepeHbi b Ta6n. 5 h 6. LV 10860
Ta6nnna 5 H3MeHeHMe KOHueHTpaLļUM flonaMMHa (flA) n flOPAC b 6aHe c opraHOM, c na6opaTopHbix ycnoBM«x (μοπ η.γ'1 mmh'1
HcnbīTaeMoe flo3a flA POPAC coeflMHeHne KoHTponbHbiū - 91 258 SKcnepMMeHT flpuMep 7 0,3 214* 172* 1,0 366* 190 3,0 290 331* 10,0 477* 537*
Ta6nnua 6 H3MeH©Hne KOHneHTpannM ponaMMHa (flA) h OPAC b 6aHe c opraHOM, c ncnbnaHM5ix μη βμβο(μοπ η.γ'1 mmh'1
McnbrraeMoe E^eflHeBHafl flA OPAC coeflMHeHMe po3a KOHTpODbHblM - 91 258 SKcnepMMeHT ΠρΜΜβρ 7 0,25 257* 222 5,0 189* 223 * 3tWM 3H3HK0M ΟΤΜβΗβΗΜ craTMHecKM© pe3ym>TaTbi. ii/8 OCTDafl TOKCMHHOCTb 3 (Ha K0b(cax) nonyHeHHbie pe3ynbTarbi ceepeHbi b TaGnMue 7. HcribiTbiBaeMoe ΒΗγτρΜΒβΗΗΟ flepopanbHo coepMHeHMe 50 μγ/κγ 2 27 50 270 1 - 135 - 3 50 >200(0%) -
Ta6nMua 7 4 - 75(0%)* - 5 - 140 - 6 - >150(0%) - 7 40 140 300 8 - >200(20%) - 9 46 195 - 10 - 160 - 11 18 175 - 12 - 110 - 13 16 >25* - 14 - >50 (0%)* - * 6onee KOHqeHTpvipoBaHHWM pacreop πρηγοτοβμτβ H6bo3Mokho 11/9. MHrMgMpoBaHMe 3φφ©κτ8 BbmeneHMM HopaapeHanHHa nop oeflcrrBHeM TupaMMHa Ha KponnKax. neroMHbift apTepnanbHbiM npenapaT (b na6opaTopHbix ycflQBMflX) Μβτορ: J. Knoll, J. Neure, Tramsn. 43, 177, 1976 r. npoqepypa McnbrraHMB βκγήομ©θτ b ce6$« cnepyiou)Me crapMM: 1) ΠοστρΟβΗΜβ KOHTpOnbHOrO φβφΜΚβ ΠΠΛ TMpaMMHa Β γΟΊΟΒΜΒΧ ΚγΜγΠίΓΓΜΒΗΟΓΟ β03Μρθβ©ΗΜ& (fl03W TMpaMMHa: 1, 3, 8, 18 ΜΓ/ΚΓ, 2) Ποοπβ npOMbiBKM Β ΤβΜβΗΜΘ 20 MMH ΠΟΒΤΟρΗΟβ ΠΟΟφΟβΗΜβ Γραφνιι^ ρπβ TMpaMMHa. 3) ypaBHOBeuiM8aHMe c Mcnonb30BaHneM θρμημηηομ qo3bt HcnbīTbiBaeMoro οοορμηθημμ ofiujeti φορΜγπω I β τθηθημθ 30 mmh. 4) ΠοΟφΟβΗΜ© φβφΜΚΒ flHfl TMpaMMHa B npHCyTCTBMM ΜΟΠΜΤΜΒβθΜΜΧ coepMHeHMM τβκ, KaK 3T0 Μ3ΠΟ)κθηο b paanene 1). 5) flocne ΠρΟΜΜΒΚΜ Β ΤβΗβΗΜβ 20 MMH ΠΟΒΤΟρΗΟβ ΠΟΟφΟβΗΜβ φ3φΜΚ3 ΠΠΒ TMpaMMHa. Ποπγ ΜβΗΗΜ© p©3ynbTaTM ceeneHbi 8 Ta6n. 8 LV 10860
TaānHua 8
HcnbīTbiBaeMoe HHrn6wpyioiuai? coeflMHeHne KOHLieHTpauMa 2 npuMepoB IC50 (M) 1 1,22 x 10'e 0,77 2 7,47 x 10 ® 0,78 3 3,68 x 10'7 0,77 4 7,47 x 10 ® 0,80 5 4,80 X 10'7 0,81 7 8,46 X 10'7 0,61 8 5,75 x 10‘7 0,94 9 1,89 x 1C6 0,7 LV 10860
ΦΟΡΜΥΠΑ H30EPETEHMR
1. Cnocoč ΠΟηγΗβΗΜΛ φθΗΜΠΗΠΚΜΠαΜΜΗΟΒ ΟβίΙΙΘΜ φορΜγπω I 2
R R (0 R1 o6o3HaMaeT anKnn c πρηΜοίί nnn pa3BeTBneHHoti peribio, coflep)KauiMM ot 1 flo 8 ymepoflHWX aTOMoe; Φθημ^ιικμπ, cppepiKaiUMM ot 7 flo 10 ymepoflHUX aTOMoe; φβΗΗη mjih umcnoanKHn, copeparauiHM ot 3 yrnepoflHwx aTOMoe; R2 o6o3HaMaeT a/ικΜΠ c npnMoii μπη paaeeTBneHHOM uenwo, copepacamnH ot 1 no 8 ymepopHbix aTOMoe; anKnn, coflepxamMM ot 1 no 8 ymepopHux θτομοβ, 3aMemeHHbift btomom ranoreHa, rwnpoKcwnoM, anKOKCnrpynnoū, coftepKaujeft ot 1 no 4 yrnepoflHux aTOMoe, a/τκΜΠ copepKauļiift 3 aTOMa ymepopa m 3aMeujeHHbift φβΗκποΜ, mjim LjMKnoanKMn, copepxau4MH ot 3 no 8 ymepopHbix βτομοβ, npM ycnoBMM, hto rpynnw R1 h R2 cobmbctho οορβρχ&τ no MeHbiueft Mepe 5 ymepopHux aTOMa, m b tom cnyHae, Korpa R1 o6o3HanaeT stvot, R2 ηθ μοχθτ o6o3HasaTb H3o6yTvui, hjim coneīi 3Tmx οοθρμηθημμ, oTntmaioiiļMftcft τβΜ, mto ocymecTBnniOT peaKMMio aMMHa o6ujeM φορΜγπΜ II:
R
(II) C ΟΟβρΜΗΘΗΜΘΜ θ6ΐ1|ΘΜ φορΜγΠΜ III: me R1 ΜΜββτ 3HaweHMn, yKa3aHHbie Bbiuie, X o6o3HanaeT aTOM ranoreHa μπμ ocraTOK οποχηογο 3φπρβ 0γΜ>φθΗΟΒΟΜ KMCnOTbi, R3 - aTOM BOflopofla v\m a/iKM/i C^C?, κοτορωΛ μοχθτ 6bm» 3aMeujeH raroreHOM, γμαροκομπομ, anKOKCH-rpynnoM c 1-4 aTOMaMM ymepopa μπμ oflHoii nrin pByMii φβΗΜΠΒΗΜΜΗ rpynnaMH, R4 -- aTOM Bopopofla μπμ R3 m R4 BMecre MoryT o6pa30Ba*rb MMKnoanKunbHoe KonbLļo b 3-8 aroMaMM ymepoqa.
2. CnocoC no n. 1, oTnMHaioiuMMCJi τθμ, hto ocymecTsn«ioT peaKumo aMMHa oCineM
<JwpMynbi I! c οοβΑΜΗθΗΜθΜ o6ujeft φopMyπbι III (III)
X - CH me: X, R3 M R4 MMOIOT BHUJeyKa3aHHbie 3HaMeHMH, C MCnonb30BaHMeM cBfl3biBaioii|ero ΚΜοηοτγ areHTa, npeflnoMTvrrenbHo μ36μτοηηογο κο/τμηθοτββ aMMHa, opraHMnecKoro μπμ HeopraHunecKoro οοηοβθηηλ μπμ uienoHHoro M0HOO6MBHHMKa.
3. CnocoC no n. 1, OTntmaiouļMHCfl τθμ, hto nonyHa»OT coepMHeHMe očmeM 0opMy/iw IV
CHo - CH - NH - CH0 - CHo - CH, me: R5 - anKMnbHaa rpynna c 2-4 aTOMOB ymepopa. (IV) LV 10860 - 23 - OOJTBBHV BOBU φβΗΛΚΒ! asat o&nmāBBpB diomonvoRofi ik*
Bipņam awnpaaMyD aepny» «ww^ Hbb» tanmon Β8βΤ0η1ΒΓ0 M»wļWTBIUm qQR8S8DV 6809 ΧβαΟΧΒΒ HS OpļVUBM lUfift* bisi odpasou sa eie» «nd^posana* aeflpoBHoro norogenM teea»
Claims (3)
- LV 10860 IZGUDROJUMA FORMULA 1. Fenilalkilamīna ar vispārēju formulu ICH2—CH — NH R1 R2 formula I kur R1 apzīmē alkilgrupu ar lineāru vai sazarotu virkni, kura satur 1 līdz 8 oglekļa atomiem; fenilalkilgrupu, kura satur no 7 līdz 10 ogleļa atomiem; feilgrupu vai cikloalkilgrupu, kura satur no 3 līdz 8 oglekļa atomiem; R2 apzīmē alkilgrupu ar lineāru vai sazarotu virkni, kura satur no 1 līdz 8 oglekļa atomiem; alkilgrupu, kura satur no 1 līdz 8 oglekļa atomiem, aizvietotu ar halogēna atomu, hidroksilgrupu, alkoksigrupu, kura satur no 1 līdz 4 oglekļa atomiem, alkilgrupu, kura satur 3 oglekļa atomus un ir aizvietota ar fenilgrupu, vai cikloalkilgrupu, kura satur no 3 līdz 8 oglekļa atomiem, ar noteikumu, ka R1 un R2 grupas kopā satur vismaz 5 oglekļa atomus un gadījumā, kad R1 apzīmē etilgrupu, R2 nevar būt izobutilgrupa, vai šī savienojuma sāļu iegūšanas paņēmiens, kas a t -šķiras ar to, ka nodrošina amīna ar vispārējo formulu IIformula II mijiedarbību ar savienojumu III ar vispārējo formuluformula III kur R1 ir tāds, kā norādīts iepriekš, ' X apzīmē halogēna atomu vai sulfonskābes ēstera atlikumu, R3 apzīmē ūdeņraža atomu vai C1-C7 alkilgrupu, kura var būt aizvietota ar halogēna atomu, hidroksilgrupu, alkoksilgrupu ar 1-4 oglekļa atomiem vai vienu, vai divām fenilgrupām, R4 apzīmē ūdeņraža atomu vai R3 un R4 kopā var veidot cikloalkila gredzenu ar 3 - 8 oglekļa atomiem. 2
- 2. Paņēmiens pec 1. p-ta, kas atšķiras ar to, ka nodrošina amīna ar vispārējo formulu II mijiedarbību ar savienojumu ar vispārējo formulu (III) 2 X — CH /\ R3 R4 formula III kur: X, R3 un R4 ir tādi, kā norādīts iepriekš, izmantojot skābi saistošu aģentu, vēlams amīna, organiskas vai neorganiskas bāzes pārākums vai sārmaina jonu apmainītāja klātbūtne.
- 3. Paņēmiens pēc 1. p-ta, kas atšķiras ar to, ka iegūst savienojumu ar vispārējo formulu IVformula IV kur R5 - alkilgrupa ar 2-4 oglekļa atomiem.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU864101A HU207280B (en) | 1986-09-25 | 1986-09-25 | Process for producing new phenyl-alkyl-amines and pharmaceutical compositions containing them |
| PCT/HU1987/000040 WO1988002254A1 (en) | 1986-09-25 | 1987-09-25 | New psychostimulant agent |
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| Publication Number | Publication Date |
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| LV10860A LV10860A (lv) | 1995-10-20 |
| LV10860B true LV10860B (en) | 1996-04-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LVP-93-651A LV10709B (en) | 1986-09-25 | 1993-06-22 | Method for preparation of phenylalkylamines |
| LVP-93-650A LV10860B (en) | 1986-09-25 | 1993-06-22 | Method for producing of phenylalkylamines |
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| Application Number | Title | Priority Date | Filing Date |
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| LVP-93-651A LV10709B (en) | 1986-09-25 | 1993-06-22 | Method for preparation of phenylalkylamines |
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| US (1) | US5075338A (lv) |
| EP (1) | EP0284621B1 (lv) |
| KR (1) | KR880701545A (lv) |
| AT (1) | ATE117204T1 (lv) |
| CS (1) | CS277418B6 (lv) |
| DD (1) | DD262226A5 (lv) |
| DE (1) | DE3751006T2 (lv) |
| DK (1) | DK282488A (lv) |
| ES (1) | ES2007411A6 (lv) |
| FI (1) | FI882474A (lv) |
| GE (1) | GEP19960656B (lv) |
| HU (1) | HU207280B (lv) |
| IL (1) | IL83905A (lv) |
| LT (2) | LT3530B (lv) |
| LV (2) | LV10709B (lv) |
| PL (1) | PL151642B1 (lv) |
| PT (1) | PT85799B (lv) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5430044A (en) * | 1987-02-06 | 1995-07-04 | Fisons Corporation | Arylalkyl-amines and -amides having anticonvulsant and neuroprotective properties |
| ATE135206T1 (de) * | 1988-08-12 | 1996-03-15 | Astra Ab | Arylalkylamine und -amide mit krampflösender und nervenschützender wirkung |
| HUT58270A (en) * | 1989-06-02 | 1992-02-28 | Wyeth John & Brother Ltd | Process for producing amine derivatives and pharmaceutical compositions containing them |
| US6011068A (en) * | 1991-08-23 | 2000-01-04 | Nps Pharmaceuticals, Inc. | Calcium receptor-active molecules |
| US6001884A (en) * | 1991-08-23 | 1999-12-14 | Nps Pharmaceuticals, Inc. | Calcium receptor-active molecules |
| US6313146B1 (en) | 1991-08-23 | 2001-11-06 | Nps Pharmaceuticals, Inc. | Calcium receptor-active molecules |
| HUT63579A (en) * | 1991-12-20 | 1993-09-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing double-phase pharmaceutical compositions suitable for treating diseases occurring during neurodegenerative processes |
| RU2195446C2 (ru) | 1994-12-08 | 2002-12-27 | Эн-Пи-Эс Фармасьютикалз, Инк. | Соединения, обладающие активностью в отношении рецептора кальция (варианты), фармацевтическая композиция и способы лечения (варианты) |
| US6299901B1 (en) | 1995-01-13 | 2001-10-09 | Somerset Pharmaceuticals, Inc. | Methods and pharmaceutical compositions employing desmethylselegiline |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US485926A (en) | 1892-11-08 | Field | ||
| DE767263C (de) * | 1937-10-03 | 1952-03-31 | Theodor H Temmler | Verfahren zur Herstellung von ª-Aralkylaminen |
| DE893341C (de) * | 1950-08-23 | 1953-10-15 | Troponwerke Dinklage & Co | Verfahren zur Herstellung von N-Aralkyl-ª-phenyl-isopropylaminen |
| US2797242A (en) * | 1953-08-11 | 1957-06-25 | Parke Davis & Co | Substituted alpha-benzylphenethylamines and methods for producing the same |
| DE227447C (lv) | 1955-03-23 | 1910-10-21 | ||
| DE1210873B (de) * | 1959-03-18 | 1966-02-17 | Hoffmann La Roche | Verfahren zur Herstellung von Halogenalkylaminen |
| US3044932A (en) * | 1960-02-24 | 1962-07-17 | Upjohn Co | Appetite suppressant drugs |
| DE1133395B (de) * | 1960-11-12 | 1962-07-19 | Hoechst Ag | Verfahren zur Herstellung von herz- und kreislaufwirksamen Phenylalkylaminen |
| DE1227447B (de) * | 1962-03-30 | 1966-10-27 | Chinoin Gyogyszer Es Vegyeszet | Verfahren zur Herstellung von Phenylisopropylaminen |
| GB1031425A (en) * | 1962-03-30 | 1966-06-02 | Chinoin Gyogyszer Es Vegyeszet | New aralkylamines and their preparation |
| FR1478311A (fr) * | 1963-10-18 | 1967-04-28 | Koninklijke Pharma Fab Nv | Procédé de préparation d'aminoalcanes et produits en résultant |
| GB1218135A (en) * | 1967-07-28 | 1971-01-06 | Abbott Lab | Substituted phenethylamine derivatives |
| DE2143204C3 (de) * | 1971-08-28 | 1979-09-27 | Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler, 6000 Frankfurt | N-Fluoralkyl-phenylisopropylamin-Derivate und deren Salze, Verfahren zu deren Herstellung und Arzneimittel auf deren Basis |
| US4025624A (en) * | 1975-11-18 | 1977-05-24 | A. H. Robins Company, Incorporated | Phenylalkylamines and phenylalkylureas in combinations to suppress gastric bleeding in aspirin therapy |
| US4404222A (en) * | 1980-08-25 | 1983-09-13 | American Cyanamid Company | Phenylethanolamine derivatives and acid addition salts thereof for enhancing the growth rate of meat-producing animals and improving the efficiency of feed utilization thereby |
| DD145599A1 (de) * | 1979-08-23 | 1980-12-24 | Roswitha Toepfer | Mittel zur regulierung des pflanzenwachstums |
-
1986
- 1986-09-25 HU HU864101A patent/HU207280B/hu not_active IP Right Cessation
-
1987
- 1987-09-15 IL IL83905A patent/IL83905A/xx not_active IP Right Cessation
- 1987-09-21 DD DD87307094A patent/DD262226A5/de not_active IP Right Cessation
- 1987-09-23 ES ES8702717A patent/ES2007411A6/es not_active Expired
- 1987-09-25 PT PT85799A patent/PT85799B/pt not_active IP Right Cessation
- 1987-09-25 UA UA4742460A patent/UA19171A/uk unknown
- 1987-09-25 EP EP87906316A patent/EP0284621B1/en not_active Expired - Lifetime
- 1987-09-25 AT AT87906316T patent/ATE117204T1/de not_active IP Right Cessation
- 1987-09-25 PL PL1987267913A patent/PL151642B1/pl unknown
- 1987-09-25 CS CS876898A patent/CS277418B6/cs unknown
- 1987-09-25 DE DE3751006T patent/DE3751006T2/de not_active Expired - Fee Related
- 1987-09-25 WO PCT/HU1987/000040 patent/WO1988002254A1/en active IP Right Grant
- 1987-09-25 UA UA4355858A patent/UA11100A/uk unknown
-
1988
- 1988-05-24 KR KR1019880700574A patent/KR880701545A/ko not_active Application Discontinuation
- 1988-05-24 DK DK282488A patent/DK282488A/da not_active Application Discontinuation
- 1988-05-24 SU SU884355858A patent/SU1746882A3/ru active
- 1988-05-25 FI FI882474A patent/FI882474A/fi not_active IP Right Cessation
-
1989
- 1989-10-11 US US07/420,058 patent/US5075338A/en not_active Expired - Fee Related
- 1989-11-23 RU SU894742460A patent/RU2007384C1/ru active
-
1990
- 1990-09-10 UA UA4830945A patent/UA19808A/uk unknown
-
1993
- 1993-06-22 LV LVP-93-651A patent/LV10709B/lv unknown
- 1993-06-22 LV LVP-93-650A patent/LV10860B/lv unknown
- 1993-08-12 GE GEAP19931393A patent/GEP19960656B/en unknown
- 1993-08-19 LT LTIP878A patent/LT3530B/lt not_active IP Right Cessation
- 1993-08-19 LT LTIP879A patent/LT3531B/lt not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CS277418B6 (en) | 1993-03-17 |
| RU2007384C1 (ru) | 1994-02-15 |
| DK282488D0 (da) | 1988-05-24 |
| GEP19960656B (en) | 1996-12-24 |
| UA11100A (uk) | 1996-12-25 |
| WO1988002254A1 (en) | 1988-04-07 |
| LT3530B (en) | 1995-11-27 |
| PL267913A1 (en) | 1989-03-06 |
| DE3751006D1 (de) | 1995-03-02 |
| SU1746882A3 (ru) | 1992-07-07 |
| DK282488A (da) | 1988-05-24 |
| LT3531B (en) | 1995-11-27 |
| DD262226A5 (de) | 1988-11-23 |
| US5075338A (en) | 1991-12-24 |
| FI882474A0 (fi) | 1988-05-25 |
| LV10860A (lv) | 1995-10-20 |
| LV10709B (en) | 1995-12-20 |
| ES2007411A6 (es) | 1989-06-16 |
| LV10709A (lv) | 1995-06-20 |
| CS689887A3 (en) | 1992-08-12 |
| LTIP879A (en) | 1995-03-27 |
| ATE117204T1 (de) | 1995-02-15 |
| EP0284621A1 (en) | 1988-10-05 |
| HUT45962A (en) | 1988-09-28 |
| UA19808A (uk) | 1997-12-25 |
| KR880701545A (ko) | 1988-11-03 |
| EP0284621B1 (en) | 1995-01-18 |
| IL83905A (en) | 1993-07-08 |
| HU207280B (en) | 1993-03-29 |
| DE3751006T2 (de) | 1995-05-24 |
| PT85799A (en) | 1987-10-01 |
| FI882474A (fi) | 1988-05-25 |
| PL151642B1 (en) | 1990-09-28 |
| LTIP878A (en) | 1995-03-27 |
| UA19171A (uk) | 1997-12-25 |
| PT85799B (pt) | 1990-08-31 |
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