LV10446B - Novel tetrazole derivatives, method for their preparation and pharmaceutical compositions containing them - Google Patents

Novel tetrazole derivatives, method for their preparation and pharmaceutical compositions containing them Download PDF

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Publication number
LV10446B
LV10446B LVP-93-1285A LV931285A LV10446B LV 10446 B LV10446 B LV 10446B LV 931285 A LV931285 A LV 931285A LV 10446 B LV10446 B LV 10446B
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formula
compound
methyl
well
group
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LVP-93-1285A
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LV10446A (lv
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Dieter Dr Binder
Josef Dr Weinberger
Andreas Dr Koch
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Chem Pharm Forsch Gmbh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Description

HOBbIE nPOH3BOflHblE ΤΕΤΡΑ30ΠΑ, CnOCOB ΜΧ ΠΟΠΥΜΕΗΜΡ M OAPMALIEBTMHECKAP Κ0ΜΠ03ΜΜΜ51 HA MX OCHOBE.
OflMCAHME M30čpeTeHne othocmtca κ HOBbiM, TepaneBTunecKM ueHHbiM npon3BOAHbiM TeTpa3ona, CnOCOČy ΜΧ ΠΟΠγΜΘΗΜΛ Μ ΜΧ ΠρΜΜβΗβΗΜΟ. M3 nmepaiypbi yxe H3BecTHO μηοχθοτβο οοθαμηθημμ, KOTopbie MoryT npuMeHATbCfl ΑΠΑ BblCOKOTO ΙφΟΒΗΗΟΓΟ βΗΒΠΘΗΜΛ, Bbl3blBaeMOrO 3ΗΓΜΟΤΘΗ3ΜΗΟΜ I I. H3BecTHbifi aHTaroHMCT peueniopa aHrnoTeH3HHa IΓ, fluP 753 /2*H-6yrnn-4-xnop-5-ΟΚΟΜΜβΤΜΠ-1 -/ /2’-/1 -Η-ΤΘΤρ330Π-5-ΜΠ/-6ΐΐφβΗΜΠ-4-ΜΠ-/ΜΘΤΜΠ/-ΜΜΜΑ330Π/, onncbiBaeTCfl, HanpuMep, b Journal of Pharmacology and Experimental Therapeutics, P.C.Wong u Ap., 1990, t.255, c.211 -217. fluP 753, OAHaKO, npn in vivo πρμμθηθημμ npeBpauiaeica b HeKOHKypeHTHOcnoco6Hbiii MeTačonm, ΕΧΡ 3174, /2-H-6y™n-4-xnop-1-//2'-/IH-TeTpa3on-5-Ķn/-6ΜφθΗΜΠ-4-ΜΠ/ΜΘΤΜΠ/-ΜΜΜΑ330Π-5-Κ3ρ6θΗΟΒνΐΟ KMCnOTy/, KOTOpblii ΑΒΠΑΘΤΟΑ OTBeTCTBeHHbIM GonbīiieM nacTbio 3a AAMTenbHocTb αθμοτβμα fluP 753. HeAoerraTKOM HeKOHKypeHTHocnoco6Hbix aHTaroHMCTOB αβπβθτοα, οαηθκο, to, hto ohm Heo6paTMMo CBfl3biBaraTCfl c peuemopoM n Bbi3blBaiOT Μ3ΜΘΗΘΗΜΑ ΚΠΘΤΟΗΗΟΛ CTpyKTypbl. 3aAanefi HacTOflinero κ3θδρβτΘΗΜΑ, HBnanocb ηβχοχαθημθ hmcto KOHKypeHTHbix aHTaroHMCTOB, KOTopbie ηθ o6pa3yioT ημοκμχ HeKOHKypeHTHOcnoco6Hbix MeiafionuTOB. 3ia 3aAana b HacTomnee BpeMfl μοχθτ pemaTbca HeoxnAaHHbiM o6pa30M c noMOUļbio βθιαθοτβ comacHO n3o6peTeHnto. /1/: 2 ΠρθβΜΘτοΜ Μ3θ6ρβτΘΗΜΗ ποθτομυ πβππιοτοη HOBbie npoM380flHbie TeTpa3ona φορΜγπ^
b κοτοροΜ R-ļ o6o3HaHaeT HacbiineHHbiM μπμ HeHacbimeHHbiM, πμηθμημμ μπμ pa3BeTBn©HHbiii /C-|-C6/-anKMnbHbifi οοτβτοκ, a R2 o6o3HanaeT μθτμπ μπμ θτμπ, aTaioKe mx $apMaueBTMHecKM npneMneMbie conn. B φορΜγηβ 1 R-ļ o6o3Ha4aeT HacbimeHHbiii μπμ HeHacbiiiļeHHbiii, nnHePĪHbifi μπμ pa3BeTBneHHbiii /C-|-C6/-anKMnbHbiM ocTaTOK, KaK, HanpMMep, μθτμπ, θτμπ, προπμπ, μθοπροπμπ, βγΤΜΠ, ΒΤΟρ, -δγΤΜΠ, ΤρΘΤ.-δγΤΜΠ, ΓΘΚΟΜΠ, 3ΤΘΗΜΠ, ΠρΟΠΟΗΜΠ, ΓΘΚΟΜΗΜΠ. RpeflnOHTMTenbHbl οοθβΜΗΘΗΜΠ, β KOTOpbix R-ļ o6o3HanaeT δγτΜΠ, a TaioKe TaKMe, b KOTOpbix R2 o6o3HanaeT ΜΘΤΜΠ.
β κοτοροίί R-ļ o6o3HanaeT HacbimeHHbiM μπμ HeHacbimeHHbifi, πμηθμη^μ μπμ ρ83βθτβπθηηημ /C-ļ -Cg/-anKMnbHbiM οοτβτοκ, a R2 0ā03HaHaeT μθτμπ μπμ θτμπ, a τθκχθ μχ Φ3ρμ314Θβτμηθοκμ
3 LV 10446
b κοτοροΡί R-ļ μμθθτ BbiiueyKa3aHHoe 3HaMeHne v\ R3 o6o3HaHaeT μθτμπ μπμ θτμπ m S 0Č03HaMaeT 3aaļMTHyra rpynny, b μηθρτηομ b ycnoBnax peaKumi opramiHecKOM pacTBopmane n b aTMOc$epe MHepTHoro ra3a bboaat bo B3anMOAePicTBi/ie c coeflMHeHneM $opMynbi /111/: N . θ' Me+ (II!) NH, b κοτοροΡί R2 o6o3HawaeT μθτμπ ριπή stha h Me o6o3HanaeT ΗθτρριΡί nnn KanuPi, c nonyMeHneM coeflMHeHMfl $opMynbi /IV/:
rne R-ļ R2 MMeroT BbiiueyKa3aHHoe 3HaMeHne, m 3aTeM ynanaiOT 3amnTHyto rpynny. (IpeflnaraeMoe cornacHO Μ3θβρβτβΗΜίο B3anMOfleiicTBMe ocyinecTBnneTCfl, TaK, mto cycneH3mo οοθαμηθηριβ φορΜνπω III b ιιηθρτηομ b ycnoBnax peaKUMM, 6θ3βοαηομ opranunecKOM pa36aBMTene, κάκ HanpMMep, b προοτοΜ 3φνιρβ, KaK, HanpuMep, Teiparnflpc^ypaH, fluaTunoBbiii 3φριρ v\m AHOKcaH, b θΤΜΟοφβρβ μηθρτηογο ra3a, KaK, HanpuMep, aproH, reruiPi μπμ a30T, bboaht bo B3anMOfleMCTBne c οοθαμηθημθμ 0opMynbi II pacTBOpeHHbiM b tom >Ke caMOM pa36aBMTene. TeMnepaTypa peaKunn cocTaBnaeT npMMepHO -20°C - +40°C, npeflnoHTMTenbHO, ot-10°C ao +20°C; βρθμβ peaKLļMM, β 3aBncnMocTM ot cooTBeTCTByiou4iix κομποηθητοβ peaKumi m ycnoBnii peaKAMM, οοοτ3βπβθτ npuMepHO 2-40 nacoB, npeflnoHTMTenbHO 2-20 mbcob. B KanecTBe 3amnTHbix rpynn πρκΜβΗΒίοτ, HanpMMep, Tpi^eHMnMeTMnbHbie, 6eH3nnbHbie, n-HMTpo6eH3MnbHbie μπμ 1 -3T0KCH3TMnbHbie rpynnbi. nocneflyiomee oTmenneHne 3amMTHoPt rpynnbi ”S” ot nonyMeHHbix coeflMHeHufi φopMyπbl IV ocyinecTBnaeTca b 3aBMCMMocTH οτ πρΜΜθΗθΗΗοίί 3amMTHoPt rpynnbi, HanpuMep, nyTeM nepeMemHBaHMB b CM9CH HBr /neflaHaa yKcycHaa KHcnoTa β χποροφορΜθ μπμ Tpi^opyKcycHoPi KMcnoTe β χποροφορΜθ npvi κομηβτηοΡΙ TeMnepaType μπμ nymiie nyreM HarpeBaHMB β HM3iueM βΠΜφθΤΜΗβΟΚΟΜ ΟΠΜρΤβ, KaK, ΗΘΠρΜΜβρ, ΜΘΤ3ΗΟΠ ΜΠΜ 3Τ3Η0Π. Οοθαμηθημπ φορΜνπ II h III M3BecTHbi Μ3 nnTepaTypbi fī. Hirots μ AP-, I. Chem. Soc Daiton, 1609,1986; D.l. Carini m AP-, esponePicKMPi naTeHT 0 324 377,1989/.
CoeflMHeHMB φOpMyΠbl I OČblMHblM 0Čpa30M C nOMOLAblO HeOpraHMHeCKMX M 0praHMH6CKMX OCHOBaHMM MO>KHO nep9B0flMTb Β MX φθρΜΘΑΘΒΤΜΗΘΟΚΜ ΠρΜΘΜΠΘΜΜΘ ΟΟΠΜ. Coneo6pa30BaHnn μοχθτ ocymecTBnflTbcn, HanpuMep, τθμ, hto yKa3aHHbie οοθαμηθημπ φopMyπbι I pacTBopaioT β πρμγοαηομ pacTBopMTene, HanpuMep, b BOfle; HM3iueM ΑΠΜφ3ΤΜΗΘ0Κ0Μ CnHpTe; ΠρΟΟΤΟΜ 3φΜρβ, T3KOM, KaK TeτpaΓHflpOφypaH, flHOKCaH AHSTHnOBblH 4 3φΜρ; βΜΜΘΤΜΠφορΜβΜΜΑΘ Μ/1Μ βΜΜΘΤΜΠΟνΠΒφΟΚΟΜΑθ; ΑΟβθΒΠηίΟΤ 3ΚΒΜΒ8ΠΘΗΤΗΟβ ΚΟΠΜΗΘΟΤΒΟ xenaTenbHoro ocHOBaHna, oāecnennBaiOT xopoiuee nepeMetUMBam/ie n no oKOHHaHnn coneoāpa30BaHMH pacTBopnTenb BbinapnsaioT. B cnynae ηθο6χοαμμοοτμ conn, nocne Bbipenenna, μοχηο nepeKpncTannn30BaTb.
OapMaLļeBTMHecKM npneMneMbiMn conaMn nenniOTcn, HanpnMep, conn MeTannOB, b ocočeHHOCTM, conn menoHHbix nnn menoHH03eMenbHbix MeiannoB, KaKconn HaTpna, Kanna, Mamna nnnKanbuna. flpyrnMn φ3ρΜ3ΑβΒτηΗβοκη πρμμθημμμμμ conaMn aBnaiOTca, HanpnMep, πθγκο KpncTannn3Hpyraiuneca aMMOHneebie conn. Ποοπθαημθ aenaiOTca npon3BOflHb/Mn aMMnaKa nnn opraHnnecKnx aMnHOB, HanpnMep, μοηοαη- ηπη τρηβηκηπ-, MHKnoanKnn-, nnn oKcnanKnnaMnHOB., anKnneHAnaMHHOB ηπη οκοηβπκηπ-, apnnanKnn- nnn anKnnaMMOHneebix ocHosaHnn, Kax, HanpnMep, MemnaMnH, nnsTnnaMnH, TpnaTnnaMHH, flniļniaioreKcnn-aMnH, TpnaTaHonaMnH, aTnneHAnaMHH, τρηο-/οκοηΜΘτηπ/-3ΜΜΗθΜθΤ3Η, 6eH3nmpnMeTnnaMMOHnnrnflpoKcnfl n TOMy noflOČHbie.
HoBbie coeAnHeHHH φopMyπbι I n nx conn opanbHO ΘφφβκτηΒΗω n nopaBnaioT cocyflocy>KMBaiomee n noBbimaiomee KpoeaHoe flaeneHne AencTBne aHrnoTeH3MHa 11.
Ha >KHBOTHbix MOAenax coeAnHeHna noKa3biBaioT πρθβοοχοαηοθ cHn>Kaiomee KpoBaHoe AaBnenne AencTBne.
TaK, HanpnMep, /pnc.1/ KpnBaa A03a-AencTBne aHrnoieH3nHa, b pacseie Ha A03y n K0HKypeHTH0CTb, CABHHyra BnpaBO. B cnynae cpasHnTenbHbix onbīTos c JļnP753 /pnc.2/ 0Ka3biBaeTca, hto sto βθιαθοτβο npn in vitro onbiTax/pnc.3/ bhaho npeBpaineHne b aKrnBHbin, HeKOHKypeHTHocnoco6Hbin Meiafionm c 6onee AnmenbHon no cpaBHeHnio c npeAnaraeMbiMn b n3o6peTeHnn'BemecTBaMn npoAonxnTenbHOCTbio AencTBna. McnbrraHna Wong n AP-, 1990,1 PET, Tom 255, c.211-217, noKa3ann, hto θτοτ aKTHBHbin MeTaSonnT ΕΧΡ 3174, HeKOHKypeHTHOcnoco6Hbin, HeoāpaTHMbin aHTaroHncT pepenTopa aHmoTeH3nHa 11, οτΒΘτοτΒβΗβΗ 3a AnnTenbHOCTb AencTBna. npeanaraeMbie b Η3θ6ρβτβΗηη BeipecTBa, HanpoTne: CBa3biBaioTca c pepenTopoM očpaTnMO, TaK hto oh He n3MeHaeTca nnn He pa3pymaeTca. 3to očpaTnMoe CBB3biBaHne npoaBnaeTca b 6onee κότοροη npoAonxnTenbHocTn AencTBna, Snaropapa neMy Taxxe 0Ka3biBaeTca, hto 3Tn BemecTBa AencTByioT 6e3 aicrnBHoro, HeKOHKypeHTHOcnoc6Horo MeTaSonnTa.
Ha ocHOBaHnn 3τηχ φ3ρΜθκοποΓηΗβοκηχ cbohctb HOBbie coeAnHeHna nHAnBnAyanbHO ηπη b CMecn c ppyrnMn aicrnBHbiMn BemecTsaMn β φορΜβ o6biHHbix raneHOBbix KOMno3nunn' MoryT HanTH npnMeHeHne b KanecTBe nene6Hbix cpepcTB pna neneHna BbicoKoro KpoeaHoro paBneHna n ppyrnx cepAeHHO-cocyAncTbix 3a6oneBaHnn. H3o6peTeHne OTHOcnTca, panee, κ neKapcTBeHHbiM cpepcTBaM, KOTopbie HaxopaT npnMeHeHne, HanpnMep, β φορΜβ φ3ρΜ3αβΒτηπβοκηχ npenapaTOB, copepxamnx npepnaraeMbie β Η3θβρβτβΗηη coeAnHeHna φopMyπbl I nnn nx conn b CMecn c oahhm nnn HecKonbKnMn, npnroAHbiMn pna KniuenHoro nnn napeHTepanbHoro πρηΜθΗβΗηη, φ3ρΜ3ΑθΒτηΗβοκηΜη, opraHnnecKnMn nnn HeopraHnnecKnMn ocHoeaMn, KaK HanpnMep, Bopa, 5
1_V JUi+ifO xenaTMHa, ryMMnapa6m<, MonoMHbifi caxap, KpaxManbi, CTeapaT M&vnm, TanbK, pacTmenbHbie Macna, ποπμθπκμπθηγπμκοπμ, Ba3ennHbi nnn TOMy nofloČHbie.
OapMaLieBTunecKue npenapaTbi MOiyr čbiTb b ΤΒβρροίί φορΜθ, HanpuMep, b βμαθ TaSneTOK b ππθηκθ, ppaxe, οβθηθμ, Kancyn, Mm<poKancyn μπμ b χμρκομ φορΜθ, HanpMMep, b BMfle paCTBOpOB, ΜΗΐ>ΘΚΙ4ΜΟΗΗΜΧ paCTBOpOB, CycneH3MM ΜΠΜ 3MynbCMM, ΜΠΜ Β BMfle COCTaBOB c nponoHrupoBaHHbiM BbipeneHMeM 6μοπογμηθοκμ θκτμβηογο BetnecTBa, KaK KOHcepBambi, CTa5nnn3aTopbi μπμ 3MynbraTopbi, conn flnn μθμθηθημπ οομοτμηθοκογο flaBneHMfl μπμ 6yφepbι. B ocočeHHocTM φ3ρΜ3ρΘΒΤΜΗθοκΜθ npenapaTbi Moryr copepxaTb npepnaraeMbie b Μ3θ6ρθΤΘΗΜΜ ΟΟΘΑΜΗΘΗΜΠ B KOMČMHaflMM C flpyrMMM Τθρ3ΠΘΒΤΜΗΘ0ΚΜ LjeHHblMM ΒΘΙΙ1Θ0ΤΒ3ΜΜ. llpennaraeMbie b μ3ο6ρθτθημμ οοθαμηθημπ ΒΜβοτβ c stmmm LjeHHbiMM βθιαθοτβθμμ, aiaioKe c BblLUeyKa3aHHblMM BCnOMOraTenbHbIMM BemeCTBaMM Μ/ΜΠΜ OCHOB3MM ΜΟΧΗΟ φOpMyΠ^1pOBaTb B KOMānHnpoBaHHbie npenapaTbi. npuroflHaa fl03a flnn npneMa HOBbix οοθαμηθημμ cociaBnneT npiiMepHO 4-200 μγ/κγ b fleHb, npeflnommenbHa^ fl03a Ha οαηογο nauneHTa cociaBnneT npuMepHO 60-200 ΜΓ, OflHaKO, B 3aBMCMMOCTM OT COCTOflHMfl Μ3ΠβΗΜΒ3βΜ0Γ0 naiļMeHTa, ΠρΜΗΜΜΒΙΟΤ BO ΒΗΜΜ3ΗΜΘ TaioKe flpyrne fl03bi. HoBbie οοθαμηθημπ μοχηο BBOflMTb b βμαθ HecKonbKMx fl03 opanbHbiM nyTeM.
HoBbie οοθαμηθημπ b npeflnaraeMbix cornacHO μ3ο6ρθτθημιο Φθρμθαθβτμηθοκμχ κομπο3Μ!4μπχ /cocTaBax/ μογ>πγ 6biTb b κοπμηθοτβθ npuMepHO 4-200 μγ Ha Ta6neTKy, npepnoHTMTenbHO npMMepHO 20-50 μγ Ha Ta6neTKy, πρμηθμ ocTanbHoe-3T0 φβρΜθρΘΒΤΜΗβΟΚΜ ΠρΜΘΜΠβΜΝΜ HanonHHTenb. ΠΡ1/ΙΜΕΡ1 5-/4-/2-ByTnn-4-xnop-5/3-MeTnn-1,2,4-OKcaflna3on-5-nn/-1 -μμμα330πμπ-μθτμπ/-6μΦθημπ-2-ΜΠ/-ΜΠ/-1 -ΤρΜφθΗΜΤΜΠ-1 Η-ΤΘΤρ330Π K pacTBopy 0,28 r/0,0038 M0nb/N-0KCM-3TaH-HMMflaMMfla b 20 μπ ačconraTHoro ΤΓΦ 0,09 r /0,0038 Monb/ rMflpMfla Haipna m 3Ty cycneH3Hio HarpeBaioT β τθηθημμ naca Hap MoneKynfipHbiM cmtom β 'βτΜΟοφβρβ a30Ta npH 60°C. CMecb oxnaxflaioT flo 0°C h SbicTpo npMKanbīBaioT pacTBop 2,20 r/0,0032 Monb/ μθτμποβογο 3φΜρ8 1-//2-N-ΤρΜφθΗΜΠΜΘΤΜΠθΤΘΤρ330Π-5-ΜΠ/6ΜφθΗΜΠ-4-ΜΠ/ΜΘΤΜΠ/-2-6/ΓΜΠ-4-ΧΠθρ-1 H-MMMfla30n-KapČOHOBOH KMCnOTbl B 45 ΜΠ aČCOnKDTHOrO ΤΓΦ. CyCneH3HH3 HarpeeaiOT flO Κ0ΜΗ3ΤΗ0Μ TeMnepaTypbi m nepeMeuiMBaioT 18 nacoB. PeaKLļMOHHyio CMecb cm|)MnbTpOBbiBaK)T m φ^tπbτpaτ BbinapMBatoT b BaKyyMe. Οοτβτοκ pacnpepenaraT Mexpy 10 μπ BOflbi m 10 μπ sTMnaiļeiaTa, φa3bl pacpenniOT m BOflHyio φa3y 3KCTpampytoT 3 pa3a no 20 μπ sTMnaLieTaTOM. 06ίϊΘαθηθηημθ opraHunecKHe φa3bι cyujaT Hap cyπbφaτoM Haipnn, oτφnπbτpoBblBa^oτ m padsopmenb ypannioT. OHncTKy npoflyicra ocymecTBnnioT nyTeM κοποηοηηομ χροΜθτοφβφΜΜ /KG60; 30 r; pacTBopuTenb: Tonyon: 3TnnaueTaT=10:1/. npoflyicr nyTeM HacTaHBaHHn β 3φΜρθ ροΒορπτρο KpncTannn3ai4nn. 6
Bbixofl: 1,00 r 6ecu8eTHbix κριιοτβπποΒ /43% οτ Teopnn/ T.nri.: 175-177°C/aueTOH/
ToHKocnoiiHaa χρ0Μ8Τ0Γρ3φΜΛ: pacTBopmenb: τοπγοπ: 3Ttinai4eTaT=10; 1; R/=0,4. MuKpoaneMeHTHbiPi aHanM3: C43H37NSC10 μοπ. Bec=717,28 pacHmaHO, % C 72,01 H 5,20 N 15,62 HafifleHO,% 71,80 5,37 15,68 1 H-RMP/CflC^/: δ/ρριτι-]/: 7,93-7,87/MynbTnrmeT, IH,Bz-H3/; 7,63-7,47/MynbTnnneT, 2H,Bz-H5, * H6,/; 7,41 -7,26/MynbTMnneT IH; BZ-H4/; 7,39-7,28/MynbTnnneT, IOH;Bz-H/; 7,11; 7,07; 6,78; 6,72/ A2B2; 4H; BZ-H2, -Hq μ BZ-H3, -H5/; 6,99-6,89/MynbTnnneT, 6H, Bz-H/; 5,67/ομηγπθτ, 2H, Im-CH2-Bz/; 2,53/TpnnneT, 2H, Bu-ļ-Cl·^/; ομηγπθτ, 3H, -CH3/; 1,63/MynbTnnneT, 2H, BU2-CH2/; 1,22/MynbTnnneT, 2H, BU3-CH2/; 0,84/τρΜΠΠβτ, 3H, Bu-CH3/. 13C-RMP/CflCl3/; 5/ppm/: 166,68; 163,92; 153,06; 141,21,140,94; 134,16;130,72; 130,21; 129,98; 129,83; 128,26; 127,61; 126,22; 125,53; 113,83; 82,87; 48,49; 29,29; 26,94; 22,31; 13,70; 11,51. 5-/4,-/2-EyTMn-4-xnop-5V3-MeTMn-1,2,4-OKcaflMa3on-5-nn/-1-MMMfla3oni'in-MeTMri/6M(})eHMn-2-Mn/- IH-TeTpa3on 0,40 r/0,0006 Monb/ 5-/4’-/2-5γτΜΠ-4-χπορ-5-/3-Μβτνιπ-1,2,4-OKcaflna3on-5-nn/-1-MMMfla3onnn-μθτμπ/-6μΦθημπ-2-μπ/-1-τρμΦθημπ-μ6ΤΜΠ-!Η-τθτρ330Π3 cycneHflnpytOT B 12 ΜΠ MeTaHOna ΙΊ KMnflTaTflBa naca. PacTBopuTenb οτγοηαιοτ, οοτβτοκ HacTanBatoT npn HarpeBaHMM c 3 μπ Kunauļero flusTunoBoro 3φκρ3 m nonyHeHHbie KpucTanbi οτφΜί^τροΒ^Βθκιτ. Cbipofi προργκτ nepeKpncTannn30BbiBaKDT M3 sTunapeTaTa c aicrviBHbiM ymeM.
Bbixofl: 0,10 r 6ecqBeTHbix KpucTannoB /35% οτ τβορml. T. nn.: 178-180°C/3Tnnai4eiaT/
ToHKoenoiiHaa xpoMaτoΓpaφ^1s^: pacTBopmenb: 6eH3on: flMOKcaH: yKcycHaa KMcnoTa= 8:1:1 R/= 0,6
MuKpoaneMeHTapHbiiĪ aHann3: Cgi ^23^^10 μοπ.βθο=474,96 paccnmaHO, % C 60,69 H 4,88 N 23,59
HaiifleHO, % 60,51 4,94 23,29 1 H-RMP/CflCIg/; 5/ppm/: 7,93-7,87/MynbTnnneT, iH,Bz-H3,/; 7,63-7,47/MyribTMnneT, 2H,Bz-H5, -
Hg,/; 7,41 -7,26/MynbTnnneT IH; Βζ-Ηφ/; 7,11; 7,07; 6,92; 6,87/ A2B2; 4H; Bz-H2, *Hg μ BZ-H3, - H5/; 5,67/cnHmeT, 2H, lm-CH2-Bz/; 2,53/TpnnneT, 2H, Bu-ļ-C^/; ομηγπθτ, 3H, -CH3/; 1,63/MyribTnnneT, 2H, BU2-CH2/; 1,22/MynbTnnneT, 2H, BU3-CH2/; 0,84/τρμππθτ, 3H, BU-CH3/ 7 LV 10446 13C-flMP/CflCI3/; 5/ppm/: 166,94; 166,36; 153,01; 140,58,139,30; 135,51; 135,6; 131,38; 130,79; 130,66; 129,60; 128,42; 126,25; 122,89; 113,54; 48,59; 28,56; 26,74; 22,27; 13,66; 11,54. ΠΡ1ΛΜΕΡ2 Αηπίοτθη3μη-Ι l-peuenTop-aHToroHncTvmecKue αθμοτβιίη BemecTBa npuMepa 1 /BemecTBO 1/ no cpaBHeHmo co CTaHnapTHbiM BemecTBOM DuP 753. a/ H3onnpoBaHHaa aopta Kpbicbi.
KyMynaTMBHbie KpuBbie fl03a-fleKcTBne aHrnoTe3MHa 11/10'"* 3-10‘7 Monb/n/ ocyuļecTBnJiiOT M30MSTpnHecKn c ΜΠΜ 6Θ3 npeflBapMTenbHOM očpaSoTKM βθιαθοτβομ H3 npuMepa 1/min DuP 753/ no 10‘8,10-7,10‘8 Monb/n/. n npeflCTaajifliOT b βμαθ npoLiema MaKCMManbHoro coKpameHusi 3a οηθτ HopaApeHannHa/10"8 Monb/n/. 3fl50-3HaMeHMfl μ ρΑ2-3ηβηθημα onpenenaioTCfl pacneTHbiM nyTeM. 6/ HapKOTMsnpOBaHHaii, HopMOTeH3MBHafl Kpbica: ΑΗΓΜΟΤΘΗ3ΜΗ 11 /1ΜΓ/ΚΓ ΒΗγΤρίΙΒΘΗΗΟ/ MH‘beKL4MpytOT flO II B 15-MMHyTHbie MHTepBailbl ΠΟΟΠΘ nHTpapyoAeHanbHoro ββθαθημα eeinecTBa.

Claims (10)

  1. LV 10446 IZGUDROJUMA FORMULA JAUNI TETRAZOLA ATVASINĀJUMI, TO IEGŪŠANAS METODE UN FARMACEITISKAS KOMPOZĪCIJAS UZ TO PAMATA 1. Izgudro jums attiecas uz jauniem tetrazola atvasinājumiem ar formulu (I):
    (I)
    HN-N kurā R1 apzīmē piesātinātu vai nepiesātinātu, taisnu vai sazarotu C^ -Cg-alkilgrupu un Rr, apzīmē metil- vai etilgrupu kā arī uz to farmaceitiski pieņemamiem sāļiem, kuriem piemīt receptora angiotenzīna II antagonistiskas īpašības.
  2. 2. Savienojumi, saskaņā ar 1. punktu, kas atšķiras ar to, ka formulā I, R^ apzīmē butilgrupu.
  3. 3. Savienojums, saskaņā ar 1. punktu, kas atšķiras ar to, ka atbilst formulai 5-/4’- /2-butil-4~hlor-5-/3-me til-1,2,4-oksadiasol-5-il/-1 -imidazolilmetil/-bifenil-2-il/1H-tetrazols.
  4. 4. Savienojumu, kas atbilst formulai I: 2. 2.
    (I), kurā R,j apzīmē piesātinātu vai nepiesātinātu, taisnu vai sazarotu 0^-Cg-alkilgrupu un R2 apzīmē metil- vai etilgrupu, kā arī to farmaceitiski pieņemamu sāļu iegūšanas metode, kas a· t š k i r a s ar to, ka savienojumu ar formulu (II)
    (II), kurā R^ ir tāds, kā norādīts iepriekš, un Rg apzīmē metil- vai etilgrupu, un S apzīmē aizsarggrupu, pakļauj mijiedarbībai ar savienojumu ar formulu (III)
    (III), LV 10446 kurā Rg apzīmē metil- vai etilgrupu un Me apzīmē nātrija vai kālija atomu, organiskā šķīdinātājā, kas ir inerts reakcijas apstākļos, un inertas gāzes atmosfērā, un iegūst savienojumu, kas atbilst formulai (IV) C1
    cm kurā R,j un R2 ir tādi, kā norādīts iepriekš, un pēc tam noņem aizsarggrupu.
  5. 5. Metode, saskaņā ar 4. punktu, kas atšķiras ar to, ka aizsarggrupas atšķelšanu veic apstrādājot savienojumu ar spēcīgām skābēm vai sildot ar zemākajiem alifātiskajiem spirtiem.
  6. 6. Metode, saskaņā ar 4. punktu, kas atšķiras ar to, ka kā aizsarggrupu izmanto trifenilmetilgrupu.
  7. 7. Farmaceitiski preparāti, kas satur savienojumus ar formulu I, saskaņā ar 1. punktu, kā arī to sāļus kombinācijā ar parastām galēniskām palīgvielām un/vai pamatvielām.
  8. 8. Farmaceitiski preparāti, kas satur savienojumus ar formulu I, saskaņā ar 1. punktu, kā arī to sāļus kombinācijā ar citām terapeitiski vērtīgām bioloģiski aktīvām vielām, kā arī ar parastām galēniskām palīgvielām un/vai pamatvielām.
  9. 9. Savienojumi, saskaņā ar 1. punktu, kā arī to sāļi, ko var izmantot kā bioloģiski aktīvas vielas farmaceitiskos preparātos to slimību ārstēšanai, 4 kuru ārstēšanu vai stāvokļa uzlabošanos panāk bloķējot angiotenzīnu li.
  10. 10. Savienojumi, saskaņā ar 1. punktu, ko izmanto kā ārstnieciskas vielas asinsspiediena pazemināšanai.
LVP-93-1285A 1991-01-31 1993-11-30 Novel tetrazole derivatives, method for their preparation and pharmaceutical compositions containing them LV10446B (en)

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AT0020991A AT395853B (de) 1991-01-31 1991-01-31 Neue imidazolderivate, verfahren zu ihrer herstellung und ihre verwendung

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IT1255802B (it) * 1992-08-07 1995-11-16 Luso Farmaco Inst Derivati imidazolici ad attivita' a ii antagonista
GB9507203D0 (en) * 1995-04-07 1995-05-31 Smithkline Beecham Plc Novel compounds
SE9903028D0 (sv) 1999-08-27 1999-08-27 Astra Ab New use
PL379886A1 (pl) * 2003-08-27 2006-11-27 Zentiva, A.S. Sposób usuwania trifenylometanowej grupy zabezpieczającej
US7803940B2 (en) * 2006-11-24 2010-09-28 Takeda Pharmaceutical Company Limited Heteromonocyclic compound or a salt thereof having strong antihypertensive action, insulin sensitizing activity and the like production thereof and use thereof for prophylaxis or treatment of cardiovascular diseases, metabolic diseases and/or central nervous system diseases
AU2008261102B2 (en) 2007-06-04 2013-11-28 Bausch Health Ireland Limited Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
EP2810951B1 (en) 2008-06-04 2017-03-15 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
ES2624828T3 (es) 2008-07-16 2017-07-17 Synergy Pharmaceuticals Inc. Agonistas de la guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
DE102013202306B4 (de) 2013-02-13 2014-12-18 Adidas Ag Sohle für einen Schuh
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
CA2905438A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
USD776410S1 (en) 2013-04-12 2017-01-17 Adidas Ag Shoe
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IE914501A1 (en) 1992-07-29
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US5254574A (en) 1993-10-19
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