PL144549B1 - Method of obtaining novel heterocyclic oxazepin derivative - Google Patents

Method of obtaining novel heterocyclic oxazepin derivative Download PDF

Info

Publication number
PL144549B1
PL144549B1 PL1983254628A PL25462883A PL144549B1 PL 144549 B1 PL144549 B1 PL 144549B1 PL 1983254628 A PL1983254628 A PL 1983254628A PL 25462883 A PL25462883 A PL 25462883A PL 144549 B1 PL144549 B1 PL 144549B1
Authority
PL
Poland
Prior art keywords
derivative
formula
oxazepin
novel heterocyclic
obtaining novel
Prior art date
Application number
PL1983254628A
Other languages
Polish (pl)
Other versions
PL254628A1 (en
Original Assignee
Ah *Robins Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ah *Robins Company filed Critical Ah *Robins Company
Publication of PL254628A1 publication Critical patent/PL254628A1/en
Publication of PL144549B1 publication Critical patent/PL144549B1/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Hydrogenated Pyridines (AREA)

Description

Opis patentowy opublikowano: 89 08 31•osouuAzo fezsz^Mod aoAofefnzB^M Mo^zfeiMz B[p Sm g op 3 po sissj^bz m 3is DIDS9IIU 9izp3q fefsojop £qoso Bjp B[MBp Buzoajmjs oz 'feftuaSns iiu£MouiiuBisiq -A\TD9ZJ(I llUB^pi IUlXuUI IUlXuM9(I Z TlIUBUMCJOd M ipi^SJOm IJD^UTMS BU 9UZ0lgoiO[BUUBJ BIUBpBq 3iui9§o *bzjbu£j3Pm qrq bzjb:pi uiajozpBu pod 'iiu^uzoApaui iiuBpBSBz iuiX;5fXzjd z oiupoSz aUBJSaJ^O 9TDSTMXzDO fep3q 3UU9lZp I3JMBp Z9TUMCJ 3[Bf 'SUJBnpiMApUI l[MBp 9{SpS •BIUBMO^fMBp fepBjsod fe}3f£zjd z 3is BfBzpB§z Buzo9}tv[s B^MBp BiupaiModpo £qB 'Azdbuz o; 'fóuzo^n^s psoji m |BMod3jsXM AuuKzd ^lupBpis XqB 'o^l ;sof oup5qz9i^sj ti5[zbibuXm Srqp3M uioqosods qoAuBzi -bm;Aa\ Mc^zfeiMz biubmo[a\bp pBjsod qoXu;sXzjoi XpBp[Xzjd feiMOUBis T^jdozo i i^nduiB 4i[tnsdB[ 'l^JP^B} SUB^pjMOd *P|PiqBX '^O^UUAZD MC^IUpBpjS I)[MBp fouOJS9.D[0 BIUSZOJBJSOp Op Xztl{S B)[A\Bp B5JB} Bp?B5[ 9fZp§ 'ipKMO^JSOUpSf 5J3MBp pBJSOd M fes SUBZJBMJAm 91 3foXzoduiO| 3TU;sXzJO)J •n^zsojd oJfoipns pBjsod av qnj Azoop fsuBiAdzoa m l 3ZJ0ZM O tl[ZfelAVZ I^ZDSJsfeZD 9JBUI OxfoDfefBJ3IMBZ tl|OZOJ9B an\ I^UB^Ujd DBJSOd 09TUI fe§OUI ipZJ[SO njBzsqo qnj BjpJBg 'bsou op BiuBMBpod op pjpoje "np^iaoiiS oqjB o83mob[b[ b|sbui pBf^Azjd BU 'B5jd0ZD BZOflDOd Z ZTS CBpBp(S 9ZOUI 5JTUSOU OZ0IU}£qpOOp BIUBMBpod Op aOBfoAzoduiO^ ^ •qoB^[|nduiB m sjjbmbz XMopiqoBiB h\o qrq BpoM [Bf foi^Bj pB{[Xzjd bu 'Azoap OMojipfBzod faujBZDzsndop 'fdujAjdis oz sis DBpBpjs azoui ^pjBpop qrq [iusou oMojipfBzod BiuBMBpod bjq •uopij -ojidoj^uiMijod i nzauSBiu ubtu^jb^s 'Xmoui9zj5[ i XmouXjb9;s sbm^ 'BuAjBpz '^b; 'BUBizpAjn^n^ I BUBZDBIUUI9IZ BiqOJ[S 'BZO^B] lfeZ3|BU BIUBMO}[PiqBl Op MC^Bpop qDIUp3lMOdpO OQ 'fcuZOAl -naoBUUBj 30juqo3i m submosojs 9|[Xmz p[iusou qoXofefBJ3iMBz 'ppiqBa qoKuozD3jMod qtq pp|qBi '[9|nsdB[ 'Mcjis^ip OBjsod OBMOUifAzjd pBp[Xzjd bu feSoiu aiujsnop BiuBMBpod op ofo^zoduio^ •bsou op qnj 9iu{/(zop 'oMouM^zj^opcjs 'oMOiussiuiop '3iuJ9jspod cOMo;xpfBzod 'ozDiu^qpoop ^TU^StlOp BIUBMBpod Op 5lS UlXofefBpBU UlXuZ0X;tl3DBUIJBJ tl[pOJS M OBMOd^S/CM 3ZOUI U31 (9ZfelMZ •ui3iiiBpop qrq iust^iusou uiKujBzozsndop 9iuzoXjn9DBuiJBj z zbjm \ ozjozm o ^szfeiMz 3uuXzo D[IUpBp|S 0[Bf UlXDfefBJ9TMBZ 'UI^DfeKz UIOUIZTUBgjO BIUBMBpod Op qDAuZD^n9DBUIJBJ qDBfoXz -Odui05[ M BIUBMOSO^S Op fes 3UOZ0BUZ9Zjd n^ZBJBU^M 8iqp3M UI3qOSOdS OUBZJBM^M T[ZfelMZ •9MOUIUIB}SiqMp9Zjd 3TUB{BIZp qOT BU UpZjSzM 9Z 9U;sXzjO[ 9IUI9§3Z0ZS fes J 3ZJOZM O I)|ZfeTMZ '/09ad/ ^feZJSIMZ %QC fepJSTUIS p3Zid fóofefBZD9ldzoqBZ I^MBp OSO^piM DIJSOJ^O BUZOUI S3{MBp feuBpod bu ifo^BSj qoXMAzj^ 3iMB;spod b^ 'psoj! fóuiBS te\ m oS uiaiuBMBpod z feupj^uo^ 5q9ad ZSZid 9UBMOJOJ;U03( ;S9f STUBJBIZp 0§9f 'BpOM ZIU XUUT ^S9f ll5[ZfelMZ O§0UBpBq KUBMOSOJS [IUSOU ijssf 'fsMouiuiB^s^Mpszjd psouuAzo p9Mop imoub;s uizpoS pi zszjd qoijsjoui (3Uims spAz^zjj 766aix3 = /83(/8ui 2'| 90MBp m 3uiuiB;sTq zis 9fn5[XzjisM feuzsn 5^Az feufBj^s m fóiuz9d ;nuiui 0£ M. H^TUSOU UITUpSIMOdpO M 039UBM0^0SXzjd tl5|ZfelMZ OxfoUBpBq S5[/8ui Q£ OMOUM3ZJ^OpOJS 5lS afn^AzjisM i^mzs £ od qoBdnj8 m uio^zjstmz BiuBpBq mup yw 'uszotubjSo zsq 5poM fefB;sop 3is3j[o uiA; m ^uxzpo8 ^-81 z^zjcI auozpofS fes qoB5(;Bi5i q3Xu|BnpiAvXpui m subuiKzji 3ijsjoui i[ui/wq •9fnd5;sBu 5jBfB83iq9zjd i /pL6\ '0LZ~V9Z 'P/P "I°A 'suoipy Pu^ siu^gy/ !uu!! !zzol HBsido fejBf 'Kjnpsoojd 5|bBiTjXpoui tmoubjs BiUBpBq q9Sods *qDi^sjoui qoB5[uiMs bu uBpBq n[oi m 3ubzbjXm 3Mou;uiBisiqMp3zjd 3iuBjBizp fefnzB5[XM u[zb|buXm SnjpsM ui3qosods 9ubzjbm;Xm i^zfeiMz #|cs feuBpfezod 3is 3fnUlXzj^O I UI3SBM[ UI^UBSldO fOZKM Z lfD[B9J 5lS 9fBppOd Aq9ZJ^od 9IZBJ M STUd^SBU fej9^ 'ZpBSBZ feujOM DfefnUlAzJ^O 'BZS^BZ T ZTS XZS11S feuZDTUB§JO Sm^SJB^ 'KpBSBZ J9AYIZOJ XupOM AuOZOU^pZOJ b uuojojoiqo }(Bf i(Bi ^uzoiubSjo 5jiu[Bzozsndzoj lupsiModpo Xzp3iuiod 5is ipizpii jcs * \ szjozm o n^zfeiMz faupCoAppB qos foupMop z XpBSBz [bujoM biubuiAzj^o npo av '^P^sbz foujoM op 3iup5i§zM 'qos fóuui op oS aiuazpBMOjdazjd ^ssf suBpfezod zs\ Xzo 'qos fouiBzozsndop 9iuzoX;n90BuiJBj pBJSOd M Zllf ^S9f l 9ZJOZM O 5pzfelMZ XZD 'og^ pO pSOUZSJBZ M ^MO^JUIUBM ^S9f igrijp dBjg #9izpB||yCzjd m ouBSido 5(Bf 'ciuq3jpo£M oS buzoui uiAzo od 'UIST^BIUOUIB I UI^pOS Z ifD^BSJ rt[luXM M UOUldSZBS^O ^UOIMB^SpodSlU-^ IUp^TMOdpO M 5lS BZpBM -ojdazjd B| azjozM o uouid9ZBS5[0|Xzu9q-^ ii^zbibuKm Snjp^M nqosods 3idBp uiXzsMj9id a^ n[ZBi -buAm SnjpoM M9^zfeiMz biubzjbm^Km q9sods sftuisniT n^unsAj bu AuoiMB^spazjd ^Bui3qos : 19S feujBzozsndop 9IUZDX;n9DBUJJBJ ^S 9friUlXzj;0 UI^ZO ^Zjd ^MOpZZJOyBMZD 9JOS UlAofezjOM} UI9UBZ0JBIS qnj UI3I| -U33ojBq OqjB UI^ i'M[ UlXujBZDZStldop 9IUZ0Xltl90BUIJBJ Z ifo^BSJ STS 9fBppod 9lU|BmU9M3 'fozKMOd \144 549 3 W oparciu o dane uzyskane na zwierzetach przewiduje sie dawki jednostkowe zawierajace zwiazek wytwarzany sposobem wedlug wynalazku w ilosci odpowiadajacej od okolo 0,03 do 0,10 mg substancji czynnej na kg wagi ciala. Dla ludzi przewiduje sie dawki dzienne w ilosci od okolo 0,2 do 0,6 mg/kg wagi ciala, przy czym oczywiscie jednorazowo mozna podawac kilka mniejszych dawek jednostkowych. Ponizszy przyklad ilustruje sposób wedlug wynalazku.Przyklad. Wytwarzanie 2-[2-/dimetyloaminoAetylo]-2,3- dihydropirydo [3,2-f] [1,4] oksazepin -5/4H/onu.Roztwór 3,0 g /0,006 mola/ hemihydratu szczawianu 2-[2-/dimetyloamino/-etylo]-2,3- dihydro -4-fenylometylopirydo [3,2-f] [1,4] oksazepin -5/4H/-onu w okolo 50 ml wody zalkalizo- wano rozcienczonym wodnym roztworem wodorotlenku sodowego i nastepnie ekstrahowano trzema porcjami po 50 ml benzenu. Polaczone ekstrakty benzenowe wysuszono nad siarczanem sodowym i zatezono przez odparowanie na wyparce obrotowej/ laznia parowa/. Pozostalosc wysuszono nastepnie przez powtarzana 2 razy azeotropowa destylacje z okolo 50 ml suchego benzenu, z odparowaniem kazdorazowo do sucha. Koncowa pozostalosc rozpuszczono w 40 ml cieklego amoniaku i dodawano male kulki sodu przy stalym mieszaniu do tego roztworu az do wystapienia niebieskiego zabarwienia, utrzymujacego sie przez 20 minut /czas dodawania okolo 1 godziny/. Nastepnie powoli dodano 3 g chlorku amonowego i pozostawiono do odparowania amoniaku. Pozostalosc zawieszono w chloroformie i mieszanine odsaczono. Przesacz zatezono, a pozostalosc chromatografowano wykorzystujac preparatywna cisnieniowa chromatografie cie¬ czowa, z zastosowaniem kolumny z zelem krzemionkowym i eluujac mieszanine 75% octanu etylu /25%/ dimetyloformamidu. Otrzymano 0,1 g /!%/ produktu.Badanie na spektrometrze masowym przy zastosowaniu jonizacji chemicznej wykazalo pik przy 236, odpowiadajacy masie czasteczkowej 235. Widmo 1 H NMR przedmiotowego zwiazku otrzymano w CDCI3 zawierajacym 1% tetrametylosilanu /TMS/ i jest ono zgodne z proponowana budowa, z uwzglednieniem niewielkich ilosci zanieczyszczen w postaci dimetyloformamidu /DMF/ i oleju mineralnego. Ponizej podano zestawienie przesuniec chemicznych, multipletowosci i przyporzadkowan dla badanego zwiazku.Przesuniecia chemiczne Przyporzadkowania 8,45/multiplet/ H/8/ i H/6/ 8,00/singlet/ C-H /DMF/ 7,85 /rozszerzony singlet/ N-H 7,20 /dublet dubletów/ H/7/ 4,65/pentet/ H/2/ 4,05 /rozszerzony singlet/ nieznane zanieczyszczenie 3,50Ariplet/ H2/3/ 2,95 /singlet/ CH3/DMF/ 2,90 /singlet/ CH3/DMF/ 2,60 Ariplet/ H2-a-azot grupy amino 2,25 /singlet/ N/CH3/2 2,05 /multiplet/ H2-/3-azot grupy amino 0,7-1,7/multiplet/ olej mineralny PLThe patent description was published: 89 08 31 • osouuAzo fezsz ^ Mod aoAofefnzB ^ M Mo ^ zfeiMz B [p Sm g op 3 after sissj ^ bz m 3is DIDS9IIU 9izp3q fefsojop £ qoso Bjp £ [MBp Buzoajmjs oz 'feftuaSiu \ iBiui TD9ZJ (I Lor ^ pi IUlXuUI IUlXuM9 (MA TlIUBUMCJOd pi ^ M ^ Sjoman IJD UMTS BU 9UZ0lgoiO [BUUBJ BIUBpBq 3iui9§o * £ bzjbu j3Pm qrq bzjb pi uiajozpBu the 'IIU ^ uzoApaui iiuBpBSBz iuiX; 5fXzjd of oiupoSz aUBJSaJ ^ O 9TDSTMXzDO fep3q 3UU9lZp I3JMBp Z9TUMCJ 3 [Bf 'SUJBnpiMApUI l [MBp 9 {SpS • BIUBMO ^ fMBp fepBjsod fe} 3f £ zjd z 3is BfBzpB§z Buzo9} tv [s B ^ MBp ^upai nModpobuz o ^' AModpobuz o ^ 'nModpobuz o ^' AModpobuz o ^ s psoji m | BMod3jsXM AuuKzd ^ lupBpis XqB 'o ^ l; sof oup5qz9i ^ sj ti5 [zbibuXm Srqp3M uioqosods qoAuBzi -bm; Aa \ Mc ^ zfeiMz biubmo [a \ bp pBjsodjsodpzoXu; nduiB 4i [tnsdB ['l ^ JP ^ B} SUB ^ pjMOd * P | PiqBX' ^ O ^ UUAZD MC ^ IUpBpjS I) [MBp fouOJS9.D [0 BIUSZOJBJSOp Op Xztl {SB) [A \ Bp B5JB} Bp? B5 [9fZp§ 'ipKMO ^ JSOUpSf 5J3MBp pBJSO from M fes SUBZJBMJAm 91 3foXzoduiO | 3TU; sXzJO) J • n ^ zsojd oJfoipns pBjsod av qnj Azoop fsuBiAdzoa ml 3ZJ0ZM O tl [ZfelAVZ I ^ ZDSJsfeZD 9JBUI OxfoDfefBJ3IMBZ tl | OZOJ9B an \ ndBsoujojo bnjdbj9b an \ nI ^ UBoujo BiuBMBpod op pjpoje "eg ^ iaoiiS oqjB o83mob [b [b | sbui pBf ^ Asiand BU 'B5jd0ZD BZOflDOd ZTS CBpBp (S 9ZOUI 5JTUSOU OZ0IU} £ qpOOp BIUBiUiU} £ qpOOp BIUBi ^MBpod Op aOBzfo | qrq BpoM [Bf foi ^ Bj pB {[Xzjd bu 'Azoap OMojipfBzod faujBZDzsndop' fdujAjdis oz sis DBpBpjs azoui ^ pjBpop qrq [iusou oMojipfBzod BiuBMBi9m ^ pod BiuBMBxj ^ ui-sbouxj ^ ui-sbouxj ^ ui-sbouxj ^ ui-sbouxj ^ sbm ^ 'BuAjBpz' ^ b; 'BUBizpAjn ^ n ^ I BUBZDBIUUI9IZ BiqOJ [S' BZO ^ B] lfeZ3 | BU BIUBMO} [PiqBl Op MC ^ Bpop qDIUp3lMOdpO OQ 'fcuZOAl -naoBU3ij 30ij 30 qoXofefBJ3iMBz 'ppiqBa qoKuozD3jMod qtq pp | qBi' [9 | nsdB ['Mcjis ^ ip OBjsod OBMOUifAzjd pBp [Xzjd bu feSoiu aiujsnop BiuBMBpod op ^o ^ o ^ zoduiopiun (o ^ o' o ^ zoduiopiun 3iuJ9jspod como; xpfBzod 'ozDiu ^ qpoop ^ TU ^ StlOp BIUBMBpod Op 5LS UlXofefBpBU UlXuZ0X; tl3DBUIJBJ tl [pOJS M OBMOd ^ S / CM 3ZOUI U31 (9ZfelMZ • ui3iiiBpop qrq iust ^ iusou uiKujBzozsndop 9iuzoXjn9DBuiJBj of zbjm \ ozjozm o ^ szfeiMz 3uuXzo D [IUpBp | S 0 [Bf UlXDfefBJ9TMBZ ' UI ^ DfeKz UIOUIZTUBgjO BIUBMBpod Op qDAuZD n9DBUIJBJ qDBfoXz -Odui05 ^ [S ^ M BIUBMOSO Op fes 3UOZ0BUZ9Zjd n ^ M ^ ZBJBU 8iqp3M UI3qOSOdS OUBZJBM MT ^ [ZfelMZ • 9MOUIUIB SiqMp9Zjd 3TUB} {BU BIZp qOT UpZjSzM 9Z 9U; sXzjO [9IUI9§3Z0ZS fes J 3ZJOZM OI) | ZfeTMZ '/ 09ad / ^ feZJSIMZ% QC fepJSTUIS p3Zid fóofefBZD9ldzoqBZ I ^ MBp OSO ^ piM DIJSOJ ^ O BUZOUI S3 {MBp feuBpod bu ifo ^ BSj qoXMAzj! b ^ 3' psoXMAzj! fóuiBS te \ m oS uiaiuBMBpod with feupj ^ uo ^ 5q9ad ZSZid 9UBMOJOJ; U03 (; S9f STUBJBIZp 0§9f 'BpOM ZIU XUUT ^ S9f ll5 [ZfelMZ O§0UBpBouss KUBMOSO ^ souopjpjpjBOSOJS [IpjpjBUSOU i moubiuf' fsOJS [IpjpjBUSOU] uizpoS pi zszjd qoijsjoui (3Uims spAz ^ zjj 766aix3 = / 83 (/ 8ui 2 '| 90MBp m 3uiuiB; sTq zis 9fn5 [XzjisM feuzsn 5 ^ Az feufBj ^ sm fóiuz9d; nuiuiSIMOUt ^ PUSD0MU ^ PUSd0MUt ^ TpUt ^ TpUt ^ TpUt tl5 | ZfelMZ OxfoUBpBq S5 [/ 8ui Q £ OMOUM3ZJ ^ OpOJS 5lS afn ^ AsiisM i ^ mzs £ from qoBdnj8 m uio ^ zjstmz BiuBpBq mup yw 'otubjSo zsq 5poM fefB ^ sop 3isi3j [sop 3isi3j; zjcI auozpofS fes qoB5 (; Bi5i q3Xu | BnpiAvXpui m subuiKzyj 3ijsjoui i [ui / wq • 9fnd5; sBu 5jBfB83iq9zjd i / pL6 \ '0LZ ~ V9Z' P / P / Pip ^ "I ° A 'suu! !! zzol HBsido fejBf 'Kjnpsoojd 5 | bBiTjXpoui tmoubjs BiUBpBq q9Sods * QDI ^ sjoui qoB5 [uiMs bu uBpBq n [o and m 3ubzbjXm 3Mou; uiBisiqMp3zjd 3iuBjBizp fefnzB5 [XM u [ZB | buXm SnjpsM ui3qosods 9ubzjbm; Xm and ^ zfeiMz # | cs feuBpfezod 3is 3fnUlXzj ^ OI UI3SBM [UI ^ UBSldO fOZKM Z lfD [B9J 5lS 9fBppO from Aq9ZJ ^ from 9IZBJ M STUd ^ SBU f ej9 ^ 'ZpBSBZ feujOM DfefnUlAzJ ^ O' BZS ^ BZ T ZTS XZS11S feuZDTUB§JO Sm ^ SJB ^ 'KpBSBZ J9AYIZOJ XupOM AuOZOU ^ pZOJ b uuojispoojoiqo} (Bf i (Bfji \ uzoiuojSjSj 5jo ^ uzoiuojoiqz 5 * on ^ zfeiMz faupCoAppB qos foupMop with XpBSBz [bujoM biubuiAzj ^ o npo av '^ P ^ sbz foujoM op 3iup5i§zM' qos fóuui op oS aiuazpBMOjdazjd ^ ssfSuBiullll ljdjd ^ ssf suBpfezzos nf ^ pjdazjd ^ ssf suBpfezod zs9 O 5pzfelMZ XZD 'og ^ pO pSOUZSJBZ M ^ MO ^ JUIUBM ^ S9f igrijp dBjg # 9izpB || yCzjd m ouBSido 5 (Bf' ciuq3jpo £ M oS buzoui uiAzo from 'UIST ^ BIUOJOSIB I if UIST ^ BSUOJOSIB I if UIST ^ BSUOUOSIB I if UI ^ M UOUldSZBS ^ O ^ UOIMB ^ SpodSlU- ^ IUp ^ TMOdpO M 5lS BZpBM -ojdazjd B | asiatic o uouid9ZBS5 [0 | Xzu9q- ^ ii ^ zbibuKm Snjp ^ M nqosods 3idBp uiXzsMj9id a ^ n [ZBi -buAm SnjpoM M9 ^ zfeiMz biubzjbm ^ Km q9sods sftuisjosJsBu ^ ftuisjosjd n ^ feiUjosjdjn ^ ftuisjosjdn 19 ^ feujosjds n ^ feujosjdjn: S 9friUlXzj; 0 UI ^ ZO ^ Zjd ^ MOpZZJOyBMZD 9JOS UlAofezjOM} UI9UBZ0JBIS qnj UI3I | -U33ojBq OqjB UI ^ i'M [UlXujBZDZStldop 9IUZ0Xltl90BUIJBJ Z ifo ^ BSJ STS 9fBppod 9lU | BmU9M3 'fozKMOd \ 144 549 3 Based on the data obtained on animals, unit doses of the invention are expected in the amount of about 0 compound 03 to 0.10 mg of active ingredient per kg of body weight. For humans, daily doses of about 0.2 to 0.6 mg / kg body weight are envisaged, but of course several smaller unit doses may be administered at once. The following example illustrates the method of the invention. Preparation of 2- [2- (dimethylaminoAethyl] -2,3-dihydropyridine [3,2-f] [1,4] oxazepine -5 / 4H / one. Solution 3.0 g (0.006 mol) of 2- [2 oxalate hemihydrate - (dimethylamino) -ethyl] -2,3-dihydro-4-phenylmethylpyridine [3,2-f] [1,4] oxazepine -5 (4H) -one in about 50 ml of water made alkaline with dilute aqueous sodium hydroxide solution and then extracted with three 50 ml portions of benzene. The combined benzene extracts were dried over sodium sulfate and concentrated by rotary evaporation (steam bath). The residue was then dried by repeated 2 times azeotropic distillation from about 50 ml of dry benzene, evaporating to dryness in each case. The final residue was dissolved in 40 ml of liquid ammonia and little spheres of sodium were added with constant stirring to this solution until a blue color was present for 20 minutes (addition time about 1 hour). Then 3 g of ammonium chloride was slowly added and the ammonia was allowed to evaporate. The residue was suspended in chloroform and the mixture was filtered. The filtrate was concentrated and the residue was chromatographed by preparative pressure liquid chromatography, using a silica gel column, eluting with 75% ethyl acetate / 25% dimethylformamide. Yield 0.1 g (µ%) of the product. Chemical ionization mass spectrometer analysis showed a peak at 236 corresponding to a molecular mass of 235. The 1 H NMR spectrum of the compound of interest was obtained in CDCl3 containing 1% tetramethylsilane (TMS) and is in agreement with the proposed structure, taking into account small amounts of impurities in the form of dimethylformamide / DMF / and mineral oil. The following is a summary of the chemical shifts, multiplicities, and assignments for the test compound. Chemical shifts Assignments 8.45 / multiplet / H / 8 / and H / 6 / 8.00 / singlet / CH / DMF / 7.85 / extended singlet / NH 7 20 / doublet of doublets / H / 7 / 4.65 / pentet / H / 2 / 4.05 / extended singlet / unknown impurity 3.50 Ariplet / H2 / 3 / 2.95 / singlet / CH3 / DMF / 2.90 / singlet / CH3 / DMF / 2.60 Ariplet / H2-a-nitrogen of the amino group 2.25 / singlet / N / CH3 / 2 2.05 / multiplet / H2- / 3-nitrogen of the amino group 0.7-1, 7 / multiplet / mineral oil PL

Claims (1)

1. Zastrzezenie patentowe Sposób wytwarzania nowej heterocyklicznej pochodnej oksazepiny o wzorze 1, w którym A oznacza pierscien pirydyny posiadajacy dwa atomy wegla wspólne z reszta oksazepiny, E oznacza atom tlenu, Z oznacza grupe-N/CH3/2 oraz jej farmaceutycznie dopuszczalnych soli, znamienny tym, ze benzylozwiazek o wzorze la, w którym A, E i Z maja wyzej podane znaczenie, poddaje sie reakcji z sodem i amoniakiem, a nastepnie otrzymany zwiazek o wzorze 1, w którym A, E i Z maja wyzej podane znaczenie, ewentualnie poddaje sie reakcji z farmaceutycznie dopuszczalnym kwa¬ sem albo halogenkiem lub siarczanem tworzacym sole czwartorzedowe.144 549 M I O CO r N I- < UJ X o co N "cni ID UD O er o N Pracownia Poligraficzna UP PRL. Naklad 100 egz Cena 400 zl PLClaim 1. A process for the preparation of a new heterocyclic oxazepine derivative of formula I, in which A is a pyridine ring having two carbon atoms in common with the rest of the oxazepine, E is oxygen, Z is the group N / CH3 / 2 and pharmaceutically acceptable salts thereof, characterized by that the benzyl compound of formula Ia, in which A, E and Z are as defined above, is reacted with sodium and ammonia, and then the obtained compound of formula I, in which A, E and Z are as defined above, is optionally subjected to Reaction with a pharmaceutically acceptable acid or a halide or sulphate forming quaternary salts 144 549 MIO CO r N I- <UJ X o co N "cni ID UD O er o N Printing Workshop UP PRL. Volume 100 copies Price PLN 400 PL
PL1983254628A 1982-09-30 1983-09-29 Method of obtaining novel heterocyclic oxazepin derivative PL144549B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US43150082A 1982-09-30 1982-09-30
US52755983A 1983-08-29 1983-08-29

Publications (2)

Publication Number Publication Date
PL254628A1 PL254628A1 (en) 1986-06-17
PL144549B1 true PL144549B1 (en) 1988-06-30

Family

ID=27029064

Family Applications (6)

Application Number Title Priority Date Filing Date
PL1983243953A PL144480B1 (en) 1982-09-30 1983-09-26 Method of obtaining cyclic or heterocyclic oxazepins or thiazepins
PL1983254627A PL145530B1 (en) 1982-09-30 1983-09-29 Method of obtaining novel aromatic or heterocyclic oxazepins or thiazepins
PL25462683A PL254626A1 (en) 1982-09-30 1983-09-29 Method of obtaining aromatic or heterocyclic oxazepins or thiazepins
PL1983254630A PL143324B1 (en) 1982-09-30 1983-09-29 Method of obtaining novel heterocyclic exazepin derivative
PL1983254629A PL144550B1 (en) 1982-09-30 1983-09-29 Method of obtaining novel aromatic or heterocyclic oxazepins or thiazepins
PL1983254628A PL144549B1 (en) 1982-09-30 1983-09-29 Method of obtaining novel heterocyclic oxazepin derivative

Family Applications Before (5)

Application Number Title Priority Date Filing Date
PL1983243953A PL144480B1 (en) 1982-09-30 1983-09-26 Method of obtaining cyclic or heterocyclic oxazepins or thiazepins
PL1983254627A PL145530B1 (en) 1982-09-30 1983-09-29 Method of obtaining novel aromatic or heterocyclic oxazepins or thiazepins
PL25462683A PL254626A1 (en) 1982-09-30 1983-09-29 Method of obtaining aromatic or heterocyclic oxazepins or thiazepins
PL1983254630A PL143324B1 (en) 1982-09-30 1983-09-29 Method of obtaining novel heterocyclic exazepin derivative
PL1983254629A PL144550B1 (en) 1982-09-30 1983-09-29 Method of obtaining novel aromatic or heterocyclic oxazepins or thiazepins

Country Status (13)

Country Link
KR (1) KR890002093B1 (en)
DK (1) DK450683A (en)
EG (1) EG17485A (en)
ES (3) ES8607956A1 (en)
FI (1) FI78102C (en)
GR (1) GR81284B (en)
HU (2) HU195649B (en)
IL (1) IL69760A (en)
NO (1) NO833297L (en)
NZ (1) NZ205813A (en)
PL (6) PL144480B1 (en)
PT (1) PT77431B (en)
YU (1) YU45891B (en)

Also Published As

Publication number Publication date
FI78102C (en) 1989-06-12
NZ205813A (en) 1987-01-23
PL254627A1 (en) 1986-06-17
YU45891B (en) 1992-09-07
PT77431A (en) 1983-10-01
IL69760A (en) 1988-05-31
EG17485A (en) 1990-12-30
PL144480B1 (en) 1988-05-31
IL69760A0 (en) 1983-12-30
PL143324B1 (en) 1988-02-29
ES551422A0 (en) 1987-06-01
PL254628A1 (en) 1986-06-17
PT77431B (en) 1986-11-24
DK450683A (en) 1984-03-31
KR840006253A (en) 1984-11-22
FI833319A (en) 1984-03-31
HU195649B (en) 1988-06-28
KR890002093B1 (en) 1989-06-18
PL254630A1 (en) 1986-06-17
PL144550B1 (en) 1988-06-30
FI833319A0 (en) 1983-09-16
NO833297L (en) 1984-04-02
HU199811B (en) 1990-03-28
PL145530B1 (en) 1988-09-30
PL243953A1 (en) 1985-12-03
PL254629A1 (en) 1986-06-17
YU195183A (en) 1986-10-31
ES526086A0 (en) 1986-06-01
GR81284B (en) 1984-12-11
ES543661A0 (en) 1986-12-01
ES8607956A1 (en) 1986-06-01
FI78102B (en) 1989-02-28
ES8802574A1 (en) 1987-06-01
ES8802304A1 (en) 1986-12-01
HUT47089A (en) 1989-01-30
DK450683D0 (en) 1983-09-29
PL254626A1 (en) 1986-06-17

Similar Documents

Publication Publication Date Title
US3888877A (en) Macrocyclic compounds and complexes thereof
GB2079270A (en) Imidazo-rifamycin derivatives
PL108024B1 (en) METHOD OF PRODUCING PYROLIDINE DERIVATIVES METHOD OF PRODUCING DERIVATIVES OF PYRROLIDINE
US4299834A (en) 8-Phenyl-purines and pharmaceutical compositions containing same
HU223439B1 (en) A process for the preparation of tetraazamacrocycles
LV12207B (en) Tricyclic compounds having activity specific for integrins, particularly av©3 integrins, method for preparing same, intermediates therefor, use of said compounds as drugs, and pharmaceutical compositions containing same
FR2645153A1 (en) THIENO-TRIAZOLO-DIAZEPINE DERIVATIVES AND METHOD FOR PREPARING THE SAME
SU1342415A3 (en) Method of producing derivatives of pyridazine
PL144549B1 (en) Method of obtaining novel heterocyclic oxazepin derivative
US4865765A (en) Ursodeoxycholic acid derivatives and their inorganic and organic salts having therapeutic activity, and process for preparing the same
WO1988008843A2 (en) New imidazols
ES2247107T3 (en) NEW POLYCLY INDANILIMIDAZOLS WITH ADRENERGIC ACTIVITY.
AU593679B2 (en) Alpha-methylene ketones
US3920687A (en) 2,3,6,7-tetrahydro-6-phenyl-5h-imidazo(1,2-d)+8 1,4)benzodiazepin-5-ones and diazepines
EP0030749A1 (en) Carboximidamide derivatives, a process for preparing them and pharmaceutical preparations containing same
US4746665A (en) Nitro derivatives of vinblastine-type bisindoles, and pharmaceutical compositions containing them
US4610986A (en) Aminonaphthacene derivatives and their production
PL83620B1 (en)
PL92579B1 (en) Bis piperazino-androstanes - as muscle relaxants[FR2194434A1]
FI64596C (en) PROCEDURE FOR FRAMSTATION OF AV 9- (2,6-DIHALOGENBENYL) ADENIN VAESENTLIGEN FRI FRAON 3-ISOMEREN
PL94079B1 (en) Manufacture of novel naphthyridine derivative [jp57150693a] [jp1194027c]
Moriwake et al. TOTAL SYNTHESIS OF KUKOAMINE A USING 2‐METHYL‐5, 6‐DIHYDRO‐4H‐1, 3‐OXAZINE AS A CARBOXAMIDE BUILDING BLOCK
SU1189348A3 (en) Method of producing esters of alkoxyvincaminic acid and/or esters of alkoxyapovincaminic acid or their epimers,racemates,optically active isomers or their acid physiologically acceptable salts
CA1137473A (en) Halogenated 15-hydroxy-e-homoeburnane derivatives and a process for the preparation thereof
KR790001254B1 (en) Process for preparing imizole