SI8010622A8 - Process for preparation of guanidine thiazole compounds - Google Patents

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CAMAHOUCHI PHARKACEW2ICAL CO.IttD. JAPAH

10571/LJVAS "POSTDPAA ZA DOBIJAHJE GVAHIDIHTIAZOIBIH JEDINJEHJA" Oblast tehniko u ka.lu spada, pmnalazak

Ovaj pronalazak oe odnosi na postupak za dobijanje gvanidintiazolnih jedinjenja, Prana medjunarodnoj klasifikaciji patenata pronalazak bi e· mogao svrstati u ki. C 07D 277/38 i A 61 E J1/A25.

Tehnldki problem ovim pronalaskon rcSava se tehni&ci problen dobijanja gvanidintia-zolnih jedinjenja ko ja lmaju primenu kao inhibitor! lučenjaželu-da&na ki soline.

Pole reSenjfl tehničkpg problema

Prema ovo» pronalasku dobijaju se novi gvanidintiazolna jedinjenja predstavljena opStom forsmlom I

R-NH

C

V

Ϊ r (CH^ - A gde R predstavlja atom vodonika ili nižu slkll grupu, Y predstavlja atom nuapora ili motilen ert$u, n i n predetavljaju cco broj 1-2* A predstavlja grupa prikazanu en

ili - COHH - (gde predstavlja atom vodonika 2 cijeno grupu, karbomoil grupu, ureido grupu, hidroksil grupu, nižu alkoksi grupu, nižu acil grupu, acilamino grupu, arilsulfa-mil (-HH-Si^-aril) grupu, arilalkil grupu, karboksimetil grupu ili grupu prikazanu sa - SO^-R^ J^gde R^ predstavlja nižu alkil grupu, halogeno-nižu alkil grupu, nesupstituisanu ili supstitu-iaanu aril grupu, amino grupu, mno-ili di-nižu alkilamino grupu, arilamino grupu, aril alkil amino grupu), Rg predstavlja atom Vodenika , nižu alkil grupu, nižu alkenil grupu, nižu alkinil grupu cijano grupu ili nižu acilgrupu, a predstavlja atom vodonika, nižu alkil grupu, hidroksil grupu ili sulfamol grupu/ i kisele aditivne soli gvanidintiazolnih jedinjenja koja se mogu koristiti u medicinske svrhe.

Sem toga, prema drugim izvod jen jima ovog pronalaska, dati su postupak za dobijanje novih gvanidintiazolnih jedinjenja opšte formule I i medicinskih sastava koji sadrže nova gvanidintiazol jedinjenja.

Izraz’"niži" u tumadenju gore pomenute opšte formule znaši pravi ili razgranati ugljenični lanac koji ima 1-5 atoma ugljenika. Stoga, kao niža alkil grupa po9toje metil grupa, etil grupa, izo-propil grupa, butil grupa, itd; kao niže alkenil grupe poštoje vinil grupa, alil grupa, izopropinil grupa itd·; kao niža alkinil grupa poštoji etinil grupa, propinil grupa, butinil grupa itd.; a kao acilamino grupa, poštoje niža acilamino grupa kao što je acetilamino grupa, propionilamino grupa itd.; a kao arilkarbonilamino grupa takva kao što je benzoilamino grupa itd.; kao arilalkil grupa poštoje benžCL grupa, fenetil grupa itd; a kao arilsulfamil grupa poštoje fenilsulfamil grupa, naftil-sulfamil grupa itd.Šta vise, aril grupa može imati supsticent (d) kao sto su halogeni atom, hiiroksil grupa, amino grupa, al-koksi grupa itd.

Sem toga, jedinjenja napred navedene opšte formule I lako obrazu ju svoje kisele aditivne soli i takodje poštoje tautomeri ovih jedinjenja u položaju - C ^ 1 . Otuda, pronalazak tako- \ kh-r2 dje uključuje ove aditivne kisele soli i tautomere jedinjenja opšte formule 1.

Kako je gore pomenuto, gvanidintiazolna jedinjenja iz ovog pronalaska lako obrazu ju kisele aditivne soli ko^je se mogu koristiti u medicinske svrhe. Od ovih soli poštoje soli gvani-dintiazolnih jedinjenja sa neorganskim ili organskim kiselinama. Primeri neorganskih kiselih soli su hidrohloridi, hidrobromidi i sulfati itd. Takodje, primeri posebno korisnih organskih kiselih soli su soli sa alifatskim karbonskim kiselinama kao što je sircetna kiselina, maleinska kiselina, furnama kiselina, itd.

Prva karakteristika ovog pronalaska je da jedinjenja dobljena ovim pronalaskom imaju inhibitorsko dejstvo na želudačnu kise-linu a ovo dejstvo nije izazvano antiholinergičnim dejstvom. Pošto standardni na tržištu raspoloživi inhibitori lučenja sto-mačne kiseline najčešče baziraju na antiholinergičnom dejstvu 4 i pokazuju neželjene sporedne efekte izazvane antiholinergičnim dejstvom, jedinjenja prema ovom pronalasku su korisna kao novi tip inhibitora lučenja želudačne kiseline. J5ruga karakteristika ovog pronalaska je ta da su neka od jedi-njenja prema pronalasku aktivna kod inhibiranja lučenja želudačne kiseline prema histamin H2- receptora. Predlagano je da se receptori histalina klasifikuju u - reeeptore i ne-H^-re-ceptore ili H2- reeeptore od strane Ash i Schild-a:”Brit.J.of Pharmacol. Chemother", 27 . 427 (1966) i Black-a i karadnici ; "Nature”, 236« 385 (1972). Efekti histamina na lučenje želudačne kiseline i srčani ritam kod izolovane pretkomore kod morskog praseta se postiže pomocu H2- receptora i ovi efekti histamina nisu inhibirani standardnim antihistaainima kao št o su mepiramini ali im se suprostavljaju sredstva za blokadu H2- receptora kao sto je metilamid.

Pošto agens za blokadu H2- receptora deluje inhibiraju6e na osnovno lučenje želudacne kiseline i lučenje želudačne kiseline izazvano gastrinom ili hranom, on se može koristiti za lečenje čira u stomaku i dvanaestopalačnom crevu izazvanim prevelikim lučenjem želudačne kiseline.

Sem toga, kao materijali koji imaju karakteristike kao kod jedinjenja iz ovog pronalaska, jedinjenja u belgijskim paten-tima br. 804,145; 866,156; 867,105; 867.594; ameriČkom patentu br. 3,950,335 itd. Su poznati ali su jedinjenja iz ovog pronalaska sva nova jedinjenja koja imaju različite strukture i bolje 5 farmakološke efekte ta poredjenju sa onima kod poznatih Zedinjenja.

Jedinjenja iz ovog pronalaska mogu se davati oralno ili parentiral· no ali je bolje oralno davanje. Jedinjenja iz ovog pronalaska ko-riste se kao slobodne baze ili njihove farmakološki prihvatljive soli i ona se načelno, koriste kao medicinski ili farmaceutski sastavi sa nosačima ili razredjivačima koji se mogu načelno koristiti za pripremu medikamenata. V slučaju oralnog davanja, naj-podesnije je koristiti medicinske sastave iz ovog pronalaska u obliku kapsula ili tableta ali se mogu koristiti kao preparati sa pcpdaženim delovanjem. Sem toga, sastavi se mogu koristiti kao šecerom .obloženi preparati ili sirupi. Njihove doze pri oralnem davanju su 50 do 800 mg. dnevno i propisano je da se lek daje podeljen u 1 do 4 doze.

Jedinjenja iz ovog pronalaska prikazana opštom formulom I su inhibitori lučenja stomačne kiseline izazvanog histaminom, što ce se dokazati sledečim testovima. (i) lučenje želudačne kiseline kod anesteziranih pasa:

Psima mešovite pasmine teškim 8 do 15 kg. uskladjivana je hrana ΡΛ časa i anestezirani su intravenozno petobarbitolom (30 mg/kg). Kanila od nerdjajučeg Čelika uvedena je kroz trbužni zid stomaka posle podvezivanja pilorusa i ezofagusa (S. Ovklfeve i snradnici: Japan, J.Phamacol. 2£, 17-22, 1977)· Želudačni sok je snkupljan iz želudačne kanile gravitacionora dreriaAom svakih 15 minute. Ispj.tna jedinjenja davana su intravenozno posle 6 želudačnog lučenja izazvanog kontinualnom intravenozno® infuzijo® histamina (160 Mg/kgh) ne dostigne stacionarno stanje. Kiselost želudačnog soka mereno je titracijom sa 0,05 N NaOH koristeci autoiaatski titrator ( Kyoto Electronics ilanufacturing Co, AT-107). Procenat inhibicije želudačnog lučenja svakom dozom lekova izračunat je iz razlike izmedju iznosa kiseline pre da-vanja leka i minimalnog iznosa kiseline koji se obično dobija u okviru 45 minuta posle davanja leka. Doza koja daje 50% inhibicij iznosa kiseline dobijena je iz krive doza-feakcija kod koje je inhibicija ucrtana semilogaritamski prema dozi. Podaci su prikazani u tabeli I, u koloni označenoj sa (A). (ii) Luženje stomačne kiseline kod pacova sa podvezanim pilorusom:

Mužjaci Vistar pacova težine oko 200 gr. lišavani gu hrane 24 časa ali im je dopusten Slobodan pristup vodi pre eksperimenata u po-jedinačnim kavezima. Pilorus je povezan pod anestezijom pomoču etra prema metodu Shay-a i saradnika (Gastroenteral. £, 45-61, 1945). Probna jedinjenja bila su data intradaodenalno odmah nakon podvezivanja pilornsa. Životinje su žrtvovane 4 časa posle da-vnnja leka i sakupljeni su stomačni sadržaji. Kiselost želudačnog soka merena je titracijom sa 0,05N NaOH koristeci automatski titrator (kyota Electronics Manufacturing Co, AT-107). Procenat inhibicije želudačnog lučenja svakom dozom lekova izračunat je iz iznosa kiseline kontrolnih i tretiranih grupa. Vrednost ED^Q odredjene su podesnora metodom. Podaci su prikazani u tabeli 1, u koloni označenoj sa (B). 7. (iii) Akutna toksičnost kod miševa lekovi su ubrizgovani intravenozno muž^acina ICP miževa. težine 35 g., brzinom od 0 1 tal/ 10 mg/lO sec. i životinje su posmatrane tokom 7 dana. Vrednosti LP^q odredjivane su metodom gore-dole koristeci 10 životinja Podaci su prikazani u tabeli 1, u koloni označenoj sa (C). belgijskog patenta br. 866.156) % »i e-t Cj hj 3 S s t, 1 1 ra O P P P P ra ro M P· P- C' H· t’ H’ P* H· H- P P P P μ· P* P* P P ra ra ra CD P (D ro Cj. CJ. P P P P Cj. S 0 ra ra © H· H· P P vn vO ro ro P c_i. Cj. CJ. Cj. • • vn ro Cj. 0) ra ra • • P N* rN H· P· H P· σ' /•N X X σ' P σ' σ' P P P N P P P P fo ra P N N N N P v_J P P H* H· SJ v» VJ < < σ' σ' 4* ·· δ P M P ΓΟ CJ- ti P 1 oi ra 1 VJ VJ P- o < H« H· Ρ S. CJ. P ra H Ο P P Η· CJ. O d V ra H· N 1 a 1 p \ \ H N< 0 fe IV) a o t* ra P «* 1 Tfi ct vn vn h ct /N H· v» vn M M o c WH ro •d H vn vn 03 σ> vO 03 p./~N ro < t p 1 » « • « • * - /TV P > l P o H* d· ra a ro vn vn -P H» nJ S* 0<vj * P σ' o H K Cj. P S v 1+ 1+ 1+ l+ 1+ 1+ ;n o d P 1 (V) 4* o o ro o H* o ro 1 « ro • • • * CR P P C*3 θ' fO • NJ CD (D vn • (X B < P N • o h· ra P ja • ·. d CJ. d -P •«4 Cj. P H· v» 1 v>-ra P· .« P it v£> ra p vn ct v/ o H· o «ra M ct v» • H· v* vn *d M vn 1 ct «ra ti' P H* B o O m E H· o B P- M H O o M < (D P vO ro vn Γ0 * « a h· ft o N « • « • O Co vn *d Μ O V» <n 03 -o vi o h· ra Η o H» \ «4 H· /“v s-\ P c> ω ct o M ro ro S3 0) vn O m 4*d vj \c O H’ VJ cn M • • • • P CJ. 0 • * ro o 00 vn P* ra P- N O ra o o • 1 » CO RQ<< O P· d· » 1 (O ro ro 1 • 0 ra M H· H· vO 0) cn σ> O H H· N p H vn vn • • » • « P O CJ. ct « « CD -o 03 vO p, 5 et ra H· vn vn VJ VJ VJ Ό • ti' H· p O w VJ VJ vj 0 •d CJ. \ H· ra ra o< ct d ca H· O ra H* V Cj. *d I?» fc» <D P X*vn P* o o o P* P- P P. J~N p P P* H H H ro M 0 CJ. Cj. P* $ vn -P vO vn -P 0 m p· (D ra p· Γ0 CJ) -o ro £ p P « • 9 4 * • me (γθ CJ. P CD vn ~vj CO H -P ro en vj ra P fN < » et P H· P· ct H* * P •d N< H· • H· cx BK P ct o

Farmakološka dejstva sredstava za EP - blokiranje

Gvanidintiazol jedinjenja iz ovog pronalaska prikazana opštom forraulom I mogu se dobiti sledečim postupcima:

Proizvodni postupak 1:

N-E

K-NH

K ~(CHp)m-Y-(CHp)-C '\C=N * i

1

0-B ’

III I 2 1 U gornjoj formuli, E’ predstavlja nižu alkil grupu, a R,B^,R2,Y» min imaju isto značenje kao gore.

Ovaj postupak se izvodi bilo reagovanjem polaznog jedinjenja formule 11^ i reaktivne količine amina formule III^, ili reagovanjem polaznog jedinjenja formule i reaktivne količine amina formule III2. Amini prikazani formulama III^ ili IIIp koriščeni u postup-ku su oni koji su sposobni da daju željeni proizvod 1^ reagovanjem polaznog materijala jedinjenja 11^ ili Up·

Primeri amina prikazani formulom III^ su nmonijak (amonijurahlorid) ni£i alkil-amin kao što je metilamin, dimetilamin, etilamin, 10 izopropilamin, itd.; niši alkenilamin kao što je alilamin, 2-butenilamin, itd.; niži alkinilamin kao što je propargilamin, pentihilamin itd. i sl. Primeri amina prikazani formulom III2 su amonijak (amonijumHorid); cijanamid; urea; hidroksilamin; e- nizi alkilhidroksiamin kao što jeO-metilhidroksilamin, o-butil-hidroksilamin itd.; niži acilamin kao što je acetilamid itd; acilhidrazin kao što je acetilhidrazin, benzoilhidrazin, itd·; benzolsulfohidrazin; semikarbazid* arilalkilamin kao što je benzilamin, fenetilamin, itd«; niži alkilsulfamid kao što je metilsuflamid, etilsulfamid itd; niži halogeno alkilsitifamidi kao što je trifluormetil sulfamid itd.; supstituisani ili ne-supstituisani arilsulfamidi kao što je benzolsulfamid, P-hlor-benzolsulfamid, P-aminobenzolsulfamid itd.} sulfamid ; niži alkilsulfamid kao što je metilsulfamid, dietilsulfamid itd.; arilsulfamid kao što je fenilsulfamid, naftilsulfamid itd·; arilalkilsulfamid kao što je benzilsulmid lfc itd; glicin; i sl.

Reakcija se obišno izvodi u rastvarašu i podesni rastvaraši ukljuČuju napr. organske rastvarače kao što su metanol, etanol, izopropanol, hloroform, etar, tetrahidrofuran, benzol, itd. Najbolje je da ovi rastvaraši ne sadrže vodu. Ne poštoje posebna ograniŠenja u pogledu temperature reakcije ali se reakcija najbolje izvodi na sobnoj temperaturi ili uz zagrevanje. Takodje je poželjno da reakcionš sistem bude neutralan do bazan.

Proizvodni postupak 2: 11 Proizvodni postupak 2s

0-R’

O

II 3

III 3 0

U gornjim formulama R, R1 ,R^,T,m i n imaju isto znamenje kao gore. Ovaj postupak se izvodi reagovanjem polaznog jedinjenja formule

jedinjenja formule II^ dobljen je hidrolizom na standardni način polaznog materijala jedinjenja formule 11^ ili II2 gde je R^ ili R2 atom vodonika. Primeiri amina prikazanih formulom IIIj su araonijak; niši alkilamin kao Sto je metilamin, etilamin izopropil-aoin itd; hidroksilamin; i slično. Uslovi reakcije kao sto su reakcionirastvarač, reakciona temperatura itd. su isti kao oni u proizvodnom postupku 1.

Osim toga, kao drugi postupci dobijanja željenog proizvoda iz ovog pronalaska, poštoji nekoliko postupaka kao Što je postupak uza-jamnog pretvaranja ili željenog proizvoda I i slično. Naprimer, poštoje sledeči postupci. (i) žel jeni proizvod formiSLe I (u slučaju da A predstavlja grupu

N—R

prikazanu sa -C r' 1 ) gde je R^ karbamoil grupa, dobijen je 12 plolaženjem suvog gasovitog hlor vodonika kroz alkohol k o ji sa-drži jedinjenje formule I gde je R^ cijano grupa, uz hladjenje ili tretiranje navedenog jedinjenja koncentrovanom hlorovodoničnom kiselinom. tli) želojni proizvod formule I ( u slučaju da A predstavlja grupu prikazanu sa -C ) gde R, i R0 predstavi ja ju istu "" NH-Rg 1 d ni?,u acil grupu, dobi ja se reagovanjem nižeg aoilhalogenida i jedinjenja formule I gde i i Hg predstavljaju atom vodonika. (iii) željeni .proizvod formule (I)(u slučaju da A predstavlja

O grupu prikazanu sa -C^' ) gde R* predstavlja -SOpNHP, "HH-R^ dobija se hidrolizom jedinjenja formule I u slučaju da A predsta- B Ό vija grupu prikazanu sa -C 1 ) gde R« predstavlja sul- HH-Rg * famil grupu a Rg predstavlja atom vodonika.

Zatim, postupci iz ovog pronalaska dalje ce biti objašnjeni kroz sledeče primere. U primerima su mp, Anal, NMR i Mass. skracenice za tačku topljenja, vrednosti elementarne analize, spektar nuklearne magnetne rezonance i maseni spektar.

Primer 1 H2N h2n C-N-

N

CH2SCH2CH2C ^>NOH «h2 U 35 ml metanola rastvoreno je 4,?2 g. metil 3-/(2-gvanidintiazol--4-il)metiltio/ propionimidat a zatim je u rastvor dodato 23 ml. 13 metanolnog rastvora sl obodno p; hidroksilamina dobijenog tretiranjem 1,2 g. hidroksilamin hlorhidrata sa 0,93 g. natrijommetoksida.

Posle 2 časa mešanja smeae na sobnoj temparaturi, rastvarač je predestilisan pod sniženim pritiskom a dobljeni ostatak je prečiščen putem hroraatografije na koloni koristeci mešoviti rastvarač od hloroforma i metanola kao razvojni rastvarač i rekristalisan iz metanola-acetona da bi se dobilo 1,3 g. 3-/(2-gvanidintiazol-4—il) metiltio/propionamidoksim. Proizvod ili sledeče fizičko-mehaničke osobine: (i) Tačka topljenja: 177-179°C (razloženo) (ii) elementarna analiza za c8hwh6°s2 '1/4 h20

CER izračunato: 34-,46% 5,24% 30,14$ nadjeno; 34,78% 5,23% 30,06% mi

Uz to, metil 3-/A (2-gvanidintiazol-4-il)metiltio/propionj6at korišcen kao sirovina u ovom primem dobljen je na sledeči način.

ch2sch2ch2cn n smeši od 4-90 ml. vode i 320 ml. etanol rastvoreno je 98,1 G-S-(2-aminotiazol-4— ilmetil)izotiourea 2-hlorhidrata (vidi"d.Amer. Chem. Soc." 68, 2155-2159 (1946) u struji azota i posle dodavanja u nju 37,o g. hlorpropionitrila, smeša je hladjena na 0-10°C i rastvor od 4-5,1 g. natrijumhidroksida u 4-50 ml. vode dodavan je u sraešn ukapavanjem. Posle toga, smeša je mešana u toku jednog časa na 0-10°C i još jedan čas na sobnoj temperaturi i nastali 14. proizvod je ekstrahovan 4 puta sa po 600 ml. hloroforma.

Sobi jeni hloroformni sloj bio je pran vodom i sušen bezfcodnia magnezijumsulfatom. Zatim je rastvarač koncentrovan pod smanje-nim pritiskom istaloženi kristali su sakupljani filtriranjem da bi se dobilo 47,2 g. 3-(2-aminotiazol-4-ilmetiltio) propionitril koji pokazuje tačku topljenja od 104»106°C (b)

S ___ CHgSCHgCHgCH {/ \ COKHCNH—l/ |! W \ U 500 ml. acetona rastvoreno je 50 g. S-(2-amino-tiazol-4-il-metiltio) pripionitril i posle dodavanja ovome 45 g. benzddlizo-cijanata, pmeša se zagreva uz refluks u toku 5 časova. Posle toga, rastvarač je koncentrisan pod smanjenim pritiskom a istaloženi kristali su sakupljani filtriranjem da bi se dobilo 79,4 g. igličastih kristala 3-/2-(3-benzoiltioureido)tiazol-4-ilmetiltio/ propionitril koji pokazuje tačku topljenja od 158-160°C. (e) S‘ J/ 0

, CH^SCHjjCH^CN U smeši od 1400 ml. acetona i 350 m. metanola rastvoreno je 80g. il 3-/2-( 3-benzoiltioureide)-tiazol~4-i(fcetiltio/ propionitrila i posle dodavanja na to rastvora od 20 g. kalijumkarbonata u 300 ml. vode, smeša je mešana u toku 5 časova na 50°C. Onda su rastvaraŠi koncentrisani pod smanjenim pritiskom, nastali ostatak je dodat 15 u 2000 ml. ledene vode Sto je praceno mešanjem u toku 24 5asa i istalozeni kristali su sakupljani filtradjom da bi se dobilo 55»3 g· 3-(2-tio~ureidotiazol-4-ilmetiltio)propionitril koji pokazuje tačku topljenja od 135-137°C·

SCH

<d) U 200 ml. etanola rastvoreno je 15 g. (3-(2-tioureidoiia2ol-4-ilmetiltio)propionitrila i posle dodavanja na to 12,4 g. metil-jodida, smesa je zagrevana uz refluk u toku jednog časa. Zatim se rastvarač koncentriše, pod smanjenim pritiskom a istaloženi kristali su sakupljani filtriranjem da bi se dobilo 20,9 g, 3-/2-(S-metilizotioureido)tiazol-4-ilaetiltio/propionitriljod-hidrat koji ima tačku topljenja od 148-149°C (razložen) (e)

U 200 ml. metanola koji sadrži 17*0 g. (1,0 mol) amonijaka rastvoreno je 20 g. (0,05 mola) 3-/2-(S-raetilizotiourado)tiazol 4-ilmetiltio/propionitril jodhidrata i 2,68 g. (0,05 mola) amo-nijumhlorida i rastvor je zagrevan u zaptivenoj cevi na 80-90°C u toku 15 časova. 16.

Posle hladjenja reakcione smeše, rastvarač je otdestilovan pod smanjenim pritiskom. U dobijeni ostatak dodato je 200 ml. vode i smeša je alkalisana dodatkom zasičenog vodenog rastvora kali-» jumkarbonata. Onda je istaloženi smedji talog sakupljan filtrači jom, sušen vazduhom i rekristalisan iz acetona da bi se dobilo 6,2 g. 3-(2-gvanidintiazol-4-ilmetiltio) propionitril koji pokazuje tačku topljenja od 132°C.

CH2SCH2CH2

SH 0CH5 U smeši od 60 ml bezvodnog metanola i 120 ml. bezvodnog hlorforma rastvoreno je 10 g. 3-(2-gvanidintiazol-4-ilmetiltio) propionitri-la i posle hladjenja rastvora na 0-10°B u struji azota i provodje-nja kroz njega suvog gasovitog hlorovodonika u toku 3 šaša, ras-tvor je ostavljen da stoji u zatvorenom sudu na 0-4°C u toku 20 časova.

Zatim su rastvarači otdestilisani pod sni ženim pritiskom i kon-centrisani ostatak je iziubven u 200 ml. ledene vode ko ja sadrži 30 g. kalcijumkarbonata i rastvor smeše je ekstrahovan triputa sa 130 ml. hloroforma koji sadrži 20% metilakholoha.

Organski sloj je sušen preko bezvodnog magnezijumsulfata i rastvarač je otdestilisan pod smanjenim pritiskom da bi se dobilo 10,3 g· metil -3-/(2-gyanidintiazol-4~il)metiltio/propioni-midata. 17. PRIMER 2

Prema postupku iz primera 1, dobijeno je sledeče jedinjenje H2»

S C»N-\ E CH2SCH2CH2C t NOCHj nh2

. CHCOOH lf .!

^ CHCOOH o-metil-3/(2-gvanidintiazol-4-il)metiltio/propionamidoksii»aleat ·

Amin upotrebljen u reakci jiiH^NOCH^

Fizičko-hemijske karakteristike proizvoda: (i) tačka topljenja: 16lA-164°C (ii) Elementarna analiza za C14H21°6N6S2^2°! izračunato nadjeno C H 38,0036 5,01% 38,o4% 4,94% N 18,99% 19,31% PRIMER 5 V\ NH. , N .... CH2SCH2CH2C ^ Mil2

NCR h2n

Na 1,9 E« etil 3v{2-gvanidintiazol-4-il)metiltio/-propionimidate 18 dodato je 10 ml. etanolnog rastvora 0,28 g. cijamida i smeša je ostavljena da stoji preko noči na sobnoj temperaturi. Zatim je rastvarač otdestilisan iz reakcione smeše pod smanjeniro pritiskom i dobijeni ostatak je prečičen u hromatografskoj koloni sa sili-kagelom koristeci smešu rastvaraČa od hloroforma i metanola kao razvojni rastvarač da bi se dobilo 1,35 6· N-cijano-3-/(2-gvani-dintiazol-4-il)metiltio/propionamidin. Proizvod pokazuje sledeče fizičko-hemijske osobine: (i) tačka topljenja: 102,5 - 104°C (rekristalisan iz metanola» etra) C9H13N7S2 : (ii) Elementarna analiza za

C H K izračuna to nadjeno 38,15/6 4,62% 34,60% 37,84% 4,59% 34,26% PEIMEBI 4-8

Prema postupku kao u primeru 3, dobijena su sledeča jedinjenja.

Primer 4: IUN * \=2» 7

CmB-

N____CH0SCBLCH0ί J

^m2 c' * ^NCR2CzCH N»( 2-propinil)-3-/ ( 2-gvanidintiazol~4-il)metiltio/-propionamidin. 19

Amin koriščen u reakciji: HSNCE^C zz CH fizičko hemijske osobine proizvoda: (i) Maseni spektar: m/e 296 (M+ ) (ii) Spektri nuklearne mahnetne rezonance (DMSO -dg +CD^OD) J' : 2,50 (2H, tl 2,70 (2H, tj B0H2CH2), 2,83 (IH, t,CH2C ===== CH) 3,60 (2H, S \-CE^~)t 3.7ο (2H, d, NCH^C^CH). 6.48 (IH, S, ^

S H

PfilKER 5:HA

CH^CHgCHgC HH,

HgN / \

Kca2

N-benzil -3- (2 -gvanidintiazol -4-il) metiltio propionamidine,

Amin upotrebljen u reakciji: HgNCH,, -^ ^

Fizičko hemijske osobine proizvoda: (i) Masen! spektar: m/e 241 (M-HH2CH2C6H^) (ii) spektri nukleatne magnetne rezonance (DMS0-d&): : 2,58 (2 H, tj 2,75 (2 H, t SCH2(CH2), 3,60 (2 H, S (^6- * j ' 4,17 (2 H, S, NCH2 6.45 (1H,S,

H H

PfilMER 6: HH, 2ο

H^R HgN / /N. ,ch9sch-celc 2 2 2 %

SH . fiCl 3 f( 2. gvanidinti a zo 1 - 4 - il) oetiltio j propionaaidin hlorhidrat.

Amin koriščen u rekkciji : NH^Cl.

Fizičko hemijske osobine proizvoda:

(i) tačka topljenja: lo9 - 112°C (ii) Elementarna analiza za Izračunato: ' C 32,59% E 5,15* Nadjeno: 32,33% 5,ol*

N 28,51% 28,28% “a PRIMES 7* H2» C - H —

H CBgBCH^g C N-benzoil -3 |(2-gvanidintiazol —-4~il) metiltio] propionamidrazon Anin koriščen u reakciji: H^HRHCO - (f ^

Fizičko - hemijske osobine proizvoda: (i) tačka topljenja: lo3 - 106°C. (ii) Elementarna analiza za C15H19N7OS2:

Izračunato: c H N 47.73% 5-ol% 25.97%

Nadjeno: 47,43% 5*oo% 25,72% PRIMER 6

21. Primer 8: V

NE

N C - E—/· (f

CH2SCH2CH2C N-NHCOCE, Λ ·>'·>· propion- N-acetil — 3 — Γ ( 2-gyanidintiazol - 4 - il)metiltio amidrazon.

Anin koriSčen za reakciju: HgNNHCOCHj FiziČko kemijske oeobine proizvoda:

(i) Tačka topljenjas 163 - 166°C (ii) Elementarna analiza za CloH17VS2 !

Izračunato: Nadjenoe PfiMER 9j CHS 38,0» 5,4» 31,o» 37,8» 5,6» 30,7»

U smeši od 13 ni etanola i 10 ml. kloroforma rastvoreno Je 0,5 g N-ciJano - 3 j( 2-gvanidintiazol -4-il)-metilti<Tj propionaaidin i posle provodjenja kroz rastvor euvog gasovitog hlorovodonika u ta toku 1,3 časa uz bladjenje ledeno» vodom, reakciona enega Je koncentrieana pod smanjenim pritiskom. Ostatku Je dodato lo ml etanola, smeša Je ponovo koncentrieana pod smanjenim pritiskom . Stvoreni ostatak Je rastvoren u maloJ količini etanola i posle dodavanja etra u njega i odlešavanja smeše preko noči, istaloSeni kristali su sakupljeni filtriranjem da 22. bi se dobilo 0*55 g 8- karbamil -31 (2-gvanidintiazol - 4 - il) metiltio Γ propionamidin.di-hlorhidrata. Proizvod pokazuje sledeče fizičko-hemijske karakteristike:

(i) tačka topljenca: 171 - 173°C (ii) elementarna analiza za CpH-^NoSpOClp :

Izračunato: nad^eno: C H 28*88% 4.58% 28*73% 4.64% N 26.19% 25.78% PRIMER 10:

H

HH, U 3o ml etanola rastvoreno je 6*4 g aetil -(2-metilgvanidin-tiazol-4-±lmetiltio)propionimidat i posle dodavanja na to 0*9 g* cijanamida i mešanca smeše u toku 2 časa na sobnoj temperaturi, rastvarač je otdestiliean pod sniženim pritiskom. Onda je dobijeni oatatak prečiSčavan na hromatografskoj koloni kori steči smešu kloroforma i metanola kao razvojni rastvarač i prekristalisan iz etanola da bi ee dobilo 2,0 g. K-cijano -3-(2- metlgvanidintiazol -4-ilmetiltio ) propionamidin koji pokazuje tačku topljenja od 144 - 145°C. Elementarna analiza za

0 H N

Izračunato: 4o,39% 5 »o 8% 32,97% nadjeno: 4o,13% 5*oo% 32,68% 23- PRIMER 11 23- EH,

N

X

NCOEB. ch2soh2ch2

S .2HC3 'ΧΚΗ, U smeši 2o ml etanola, 3o.«l hloroforma IjL lo ml. metanola rastvoreno je 1.0 g N-cijano - 3- (2-metilgvanidintiazola -4- ilmetiltio) propionamidina i posle hladjenja rastvora na O - 5°C i prevod;) en j a gasovitog hlorovodonika u toka jednog šaša, rastvarači su otdeatilovani pod amanjenim pritiskom. Zatim je nastali oetatak rekristaliaan iz etanola da bi se dobilo 1,2 g H- karbomil -3~(2-metilgvanidin-tiazol - 4 - il metiltio)propionamidin.di hlorhidrat koji pokazuje tačku topljenja 180 - 182^ C. 1

Elementarna analizač *· CloHllVS2C12· i H2°s

Izračunate t Eadjeno: PRIMER 12: H 5,o7% 5,οβ% C 3o,23%3o,$2% H 24,68% 24,41%

HJS S \ __^ C - E H2N '

XJ

X CHgSCHgCHgC^ NKHSO„

EH, U 49 ml oetan.ola rastvoreno je 2.0 g. metil 3-(2-gvanidin-tiazol - 4- ilmetiltio) propinnimidata i 1,21 benzolsulfo-hidrazina i posle mešanja rastvara u toku 24 Šaša na sobnoj temperaturi, rastvor je otdestilisan pod sniženim pritiskom·

Zatira se nastali ostatak precišcava na hromatografskoj koloni koristeči smešu hloroforma i metanola kao razvojen rastvarač da bi se dobilo 1,2 g. N-benzolsulfo -3- (2-gvanidintiazol -4 - ilmetil - tio) propion amidrazon koji pokazuje tačku topljenja od 159*5 - 161°C .

Elementarna analiza za C14Vt°^:

C H N

Izračunato: nadjeno: 4o,66% 4.635¾ 23.59% 4o.3o% 4.54% 23.46% PHIHBR 13

»ch2cooh 2 U 20 ral. metanola suspendovano je 2 g metil 3~(2-gvanidin-tiazol -4-ilmetiltio) propionimidata i onda je u suspenziju dodat rastvor od 0.5 g. glicina u 5 ml. vode. Posle mešanja smese u toku 24 časa na sobnoj temperaturi, rastvarač je otde-stilisan pod sniženim pritiskom i nastali ostatak je prekrista-lisan iz mešavine vode i acetona da bi se dobio l,o g. 5- (2-gvanidintiazol -4 - ilmetiltio) propioanamidinoglicin koji pokazuje tačku topljenja od 14o - 141°C ( razložen).

Elementarna analiza za °loll16N6°2S2- ?«H20:

C

H

Izračunato: nadjeno: 35.65% 33.82% 5-79% 5.43% n 23.55% 23,65% 25. PRIMER 14. 25. H2N'

C

CH2SCH2CH20 . »CK ✓

NHCH U 55 ®1 metanola rastvoreno je 5»1 E metil 5 - (2 - gvanidin-tiazol-4-oetiltio) propion imidata i posle dodavanja 0,9 g. «χ$ηοηίκ cijanamida rastvoru i mešanja smeš e u toku 24 časa na sobnoJ temperaturi, rastvaraČ Je otdestilisan pod sniženim pritiskom. Zatim Je nastali ostatak prečiščen na hromatografskoj koloni koristeci emešu kloroforma i metanola kao razvojni rastvarač d£ bi se dobilo 4.8 g N-ciJano - 3-(2-gvanidintiazol-4-ilmetiltio)- propion amidin i 0,¾ M,N* - dicijano - 5 (2 -gvanidinotiazol -4-il) metiltiopropionamidina koji pokazuje tačku topljenja od 223 - 224°C (razložen) HMR (dgRMSO):

Mas.spekt.(PD metod); m/e 3<>9 (M* + 1) NMR (dgDMSO): J 2.5-2.8(4H,m, “SCHgCHg-), 3.75(2H,s -0^8-) 7.1o(lH,s, S_H)Ji 8.1o(4H,bs, C-N-) PRIMER 15

C *N

W2c A? H hAcohh, \ NH,

Rastvoru od 246,6 mg. kalijumtercijernog bitoksida u lo ml. bezvodnog metanola dodato Je 245,5 semikarbazidhlorhidrata uz hladjenje ledom i posle mešanja smeše lo minuta na sobnoj 26 temperaturi, smeši je dodat rastvor od 54o mg metil 3-1 (2-gvanidintiazol -4-il)tiometi i - propionimidat.. Posle mešanja srneše u toku 2 dana na sobnoj temperaturi, rastvarač je otdesti-lisan pod sniženim pritiskom i nastali ostatak je prečiščen na hromatografskoj koloni ea silikagelom kori steči smešu hioroforma i metanola da bi se dobilo 0,4 g« h- karbamoilamina -3-(2-gvanidintiazol -4-il) metiltio^ -propionamidin. Proizvod je rastvoren u 3 ml metanola i posle dodavanja 0,4 g maleinske kiseline rastvoru i mešanja srneše u toku lo minuta rastvarač je otdestilisan, ostatku je dodato 2o. ml. acetona i nerastvome materije su otfiltrirane da bi se dobilo 0,3 g. N-karboilamino-3“j (2gvanidintiazola-4-il) - metiltioj propion amidin.dima-leat mono -hidrat koji pokazuje tačku topljenja od lo9-lll°C. Elementarna analiza za ci7H26N8S2^: izraČunato: nadjeni: H 4-59% 4.55% C 36.o4% 36.ol% H19-79%19-55% 113o%11,57% PRIMES 16 *y> H — Η^ϊ

X

NCN

N

CHgSCHgCH^C \ KHCH.

Na 5,2 metil N - cijano ~3~ (2-gvanidintiazol~4-il-)metiltio j propionimidat dodato je 5o ml.metanolnog rastvora 40% metil- arnlna i posle odhšavanja smese u toku 2o časova na eobnoj temperaturi rastvarač je otdestilisan pod sniženim pritiskom. Nastali ostatak je prečiščen u hromatografskoj koloni koristeči smešu liloroforma i metanola kao razvojni rastvarač, 27. tako da prečiščen proizvod preveden je u maleat u acetonu i rekristalisan iz metanola da bi se dobio 1 g. & - cijano -i'>t-3-(2-rivanidintiazol - 4 - ilmetiltio) propionamidina ko ji pokazuje tačku topljenja od 159 - 161°C.

Elementarna analiza za C 16U2lV6B2 · %

HgO:

Izracunato: liad jeno: C39.99% H 4.61% K 20.40% 20.24% 59.89% 4.69%C Γ Pored toga, metil | H-cijano -3-j (2-gvanidintiazol-4-il) - I metiltio.; propionimidate koriščen u ovom primeru kao sirovina dobljen je prema sledečem metodu. U smešu od 9o ml. osušenog hloroforma m 40 ml osušenog metanola rastvoreno je 7,5 g 3 - (2-gvanidintiazol - 4—Ilmetiltio) propionittcbla .i posle hlad j en ja raetvora na 0 10 C u struji azota i provodjenja kroz rastvor 25 G gasovitog hlorovodonika, rastvor je ostavljen 48 časova na 0 - 10°C. Zatim .je rastvarač otdestilisan pod sniženim pritiskom i nastali ostatak je rastvoren u 5° ®1- osušenog metanola i posle dodavanja 1,3 G· cijanamida, smeša je mešana u toku 3,5 Časa na sobnoj temperaturi. Posle toga, rastvarač je koncentrisan pod složenim pritiskom i posle dodatka 5o ®1 ledene vode u kojoj je rastvoreno 12 g. kalijumkarbonata nastalem rastvoru proizvod je ekstrahovan tri puta sa po 5o ml. hloroforma. Dobljeni ekstrakt je sušen bezvodnim magnezijumsulfafcom i onda je rastvarač otdestilisan pod sniženim pritiskom.

PfllHKR 17 C s k

HgK ..

X j},.. 0H2SCH2C

miG0GH3 CHCOOH 1 . * 2 i' KCGCLL· CliCOOH D 28 U 10 ml. dimetilformalida rastvoreno je 1,2 g. 3 -i 2-gvanidin-tiazol - 4 - ilmetiltio propionamidina i posle dodatka 0,4 g. trietilamina rastvoru i hladjenja smeše iepod 15°C, rastvor cd 1,4 g. acetilhlorida u 3 ml· kloroforma ukapavan je u smešu. Posle toga, smeša je mešana 3° minuta na sobnoj temperaturi, a zatim je rastvarac otdestilisan. Nastalom ostatku dodat je rastvor od 0.8 g kalijumkarbonata u 2 ml. vode. Posle otdesti-lovanja vode, ostatak je podvrgnut preciščavanju u hromatografskot koloni sa silikagelom i proizvod je razvijen smešom hloroforma i metanola. Zatim je ispirač otdestilisan da bi se dobilo 0,3 E· N, H’- diacetil - 3 “(2- gvanidintiazol - 4 - ilmetiltio) propionamidin. Proizvod je dodat rastvoru od 0.2 g maleinske kiseline u lo ml. acetona prač eno mešanjem u toku 3o minuta na sobnoj temperaturi. Nastali talozm su sakupljeni filtracijom da bi se dobilo 0,2 g N,N’-diacetil -3-(2-gvanidin~ tiazol - 4 - ilmetiltio)- propionamidin. 1/2 maleata. H^O koji pokazuje tačku topljenja od 180 - 181°C.

Elementarna analiza za ci4H22N6S205:

Izračunato: nadjeno: C 4o.l9% 39-91% S H 4.52% Po.oo% 4.53% 2o.ol% 8 15.5015.2?% PRIMER 18

H2N HgN h^'\CH28CH2CH20 ^

O •HC1 'NHCH. U 3° ml. metanolnog rastvora 40% metilamina rastvoreno je 3 g« metil 3 - ( 2- gvanidintiazol-4-ilmetil-tio) propionat i posle spajanja rastvora u toku 24 časa na sobnoj temperaturi, rastvarac se otdestiliše pod sniženim pritiskom. Nastali ostatak je prečiščavan na hromatografskoj koloni koristeči 29 smešu kloroforma i metanola kao rastvarač za razvijanje, tako nastali proizvod preveden je u hlorhidrat tretiranjem sa hlorovodoničnom kiselinom i rekristalisan iz smeše izopropanol i etilacetata da bi se dobilo 1,5 g· N - metil - J - (2-gvanidintiazol - 4 ~ ilmetiltio)—propionamidhlorhidrat koji pokaži) je tačlcu topljenja od 126 - 127°C.

Elementarna analiza za C9B16E50ii2C1 c(%) H(%) Izračunate: 34..89 5.20 22.60 Nadjenoi 34.51 5.19 22.55

Gem toga, metil 3-(2-gvanidintiazol - ilmetil -tio) propionat upotrebljen k ovem primeru kao sirovina, debijen je na slede6i nači U smeši od 6o ml. metanola i 12o ml hloroforma rastvoreno je lo g 3-(2-gvanidintiazol - 4 - ilmetiltio) propionitrila m posle hladjenja rastvora na 0 -10°C i propuštanja kroz njega Jo g gasovitog hlorovodonika, rastvor je ostavljen da odleži 20 časova na 0 - 10°C. U reakcionu emešu dodato je 0,7 ml. vode i posle stajanja smeše u toku 2o časova na sobno j temperaturi, reakciona smeša je dodata u 25o ml. ledene vode ko ja sadrži 12o g. kalijumkarbonata i ekstrahovana 4 puta sa pc loo φΐ. hloroforma koji sadrži 20% metanola. Dobijeni ekstrakt koneentrisan je pod smanjenim pritiskom i ostatak je prečišcavan na hromatografskoj koloni koristeci smešu hloroforma i metanola kao rastvarač za razvijanje da bi se dobilo 5,0 g. metil J -(2- gvanidintiazol - 4 - ilmetil-tio) propionat koji pokazuje tačku topljenja od Ιοβ -lo7°C.

PlUMEit 19

S.

0 ClipoCHpCIipC / / MHOH 3ο

Prema istom postupku kao u primeru 18t medjutim, koristeči hidr silamin umesto metilamina, dobijena je 5 - (gvanidintiazol-4- iloetiltio) propionhidroksamska kiselina.

Proizvod ima sledeče fizičko-hemijske osobine: (i) tačka topljenja : 155-156°C <ii) MIR (DMSO - d&)

C O O : 2.24 (2H, t, -¾ - 0^ ) 2.66 (2H, t, -SCH2CH2 - ) 3.58 (2H, t, -CH2S - ) 6.48 (IH, s,

H (iii) tlaaeni epektar (FD metod) m/e 276 (M+ + 1) PRIMER 20

ch2sch2ch2c

O \

HH 2 U smeši od 3° ni· etanola i 3° ml. vode rastvoreno je 5»° metil 3 - (2 gvanidintiazol - 4 - ilmetiltio) propionimidata i posle stajanja rastvora u toku 2o časova na 40°0, rastvarač £ je otdestilisan jiod smanjenim pritiskom. Nastali ostatak je prečiščen hromatografijom na kolonu uz koriščenje smeše hloroforma i metanola i rekristalisan iz metanola da bi se dobilo 3,2 g. 3 - (2- gvanidintiazol - 4 - ilmetiltio) propionamida koji pokazuje tačku topljenja od 193 “ 194°C ' (razložen).

Elementarna analiza za C^H^N 50S2: C H N Izračunato: 37.05% 5.o5» 27,oo% Nadjeno: 36.97% 5.06» 26.84% 31 ffRIttEB 21 HdH 2 'Χ h2h

S o CH2SCH2CH2C ^10180^2 .HC1 U 5o ol 1 N 1IC1 rastvoreno je 2,5 K· N-sulfamoil - 3“ (2-gvanidintiazol - 4- ilmetiltio) propionamidina i posle mešanja rastvora u toku 2 časa na 40°C, netaloženi kristali sakupljani su filtracijo® i rekristalisani iz smeše metanola i etil-acetata da bi se dobilo 1,65 g 3 - (2-gyanidintiazol-4- il~ metiltio) propionilsulfamid hlorhidrata koji pokazuje tačku topljenja od 166 - 167°C.

Elementarna analiza za .Η20ί C H N Izračunato: 24.46% 4.36% 21.39% Nadjeno: 24.78% 4.23% 21.61% PBIfiER 22 /V ° C «N — ^ CH2SCH2CH2C ^ .HC1 H2N'/ \ EHS02»H2 U 3o ml. metanola rastvoreno je 4,o9 g. metil 3 -j (2-gvanidintiazol -4-il) metiltio ! propionimidata a zatira, je u rastvor dodato 15 ml. metanolnog rastvora 2,88 g. sulfamida uz deflegmaciju. Posle deflegmacije u toku oko 3 časa, rastvarač je oddestilisan pod soanjenim pritiskom i ostatak je prečiščen na hromatografskoj koloni sa silikagelom koristeci smešu hloroforma i metanola (20 : 1 --- 10 : 1) kao razvojni rastvarač da bi se dobilo 3,26 g. K -sulfamoil -3 i ( 2- gvanidintiazol - 4 - il) metiltio j propionamidin. ?2

Proizvod, pokazuje sledeče fizičko-hemijske osobine:

(i) tačka topljenja: 163 - 164° C (i.i) elementarna analiza za :

C H K

Izračunato : nadjeno: 28.48% 28..37% 4.48% 4.48% 29,oo%28,97% O (iii) Spektri nuklearne magnetne rezonance (DMSO - dr) A: O v' 2.50 (2H, m, - SCH2CH2 -), 2.65 (2H, m, -SCHgGH^), 3,6o (2Ht s,

Ajh2s - S. H ), 6.45 (3J1, (iv) Ha s eni spektar : (FI) metod), m/e 338. PRIMER 23

V

K

S HSO-CH, HCCOOH A 'i n n^A'--CH2SCH2CH2C -HHg. HCCOOH a) U lo ml. metanola rastvoreno je 1,27 E· metil 3“ ; (2- gvanidintiazol - 4 - il) metiltio j propionimidata i 0,86 g metansulfamida i posle reagovanja u toku 48 Časova na eobnoj temperaturi, rastvarac je otdestilovan pod smanjenitii pritiskom. Žetim je nastali ostatak prečiščavan poooču bromatografslce kolone sa sililca gelom kori steci smešu hloroforma i metanola (20 : 1 ->10 : 1 ) da bi se dobilo 1,44 g. amorfnog U - r ! metansulfonil - 3 - ( 2 - gvanidintiazol - 4 - il) metiltio : propionamidina. Proizvod pokazujc sledeče fizičko hcmijske osobine: 3 (i) Spektri nuklearne magnetne rezonance

Cod5od)(\ . 2*58 (2H, d, - SCH2CH2 - ), 2.78 (2H, d, - S0HoCH- - ), —2 2 n 2.91 (3H, s - CH ), 5,67 (2H, s, A CH s - ), 6*5o (IH,

H ch2s“ ii) Maseni spektar (El metod): m/e 536. b) Ovako dobljeni N-metansulfo 3- f (2-gvanidintiazol - 4 -il) metiltio j propionamidin rastvoren je u acetonu a zatim je rastvoru dodavan u kapima acetonski rastvor 0,5 g. maleinske kiseline, pri čemu se talože kristali. Kristali su sakupljani filtracijom da bi se dobilo N - metansulfo -3- J" (2 - gvanidin-tiazol - 4- il) metiltio [ propionamidinmaleat. Proizvod pokazuje sledeče fizičko hemijske osobine:

i) Tačka topljenja : 195 - 197°C ii) Elementarna analiza za ^3^20^6^6^3

C H N

Izračunato: 34,51% 4.45% 18.57%

Nadjeno: 54.64% 4.49% 18.12% PRIMER 24

H 8 ml. metanola rastvoreno je 800 ml. metil 3-|( 2-gvanidin- tiazol-4-il)metiltio! propionimidata i 59o mg benzolsulfamida

J i posle reagovanja u toku 24 časa na sobnoj temperaturi rastvarač je otdestilisan pod 9manjenim pritiskom. Nastali ostatak je prečiščen na hromatografskoj koloni sa silikagelom koristeč.i cmošu hloroforma i metanola (20 : 1 —& 10 : 1 ) 34 da bi se dobilo 833 mg amorfnog H - benzolsulfo -3 - ( 2 gvanidin tiazol - 4 - il) metiltio propionamida. Proizvod pokazuje sledede fizičko hemijske osobine: 1) Spektri nuklearne magnetne rezonance (DMSO - d^)ό : 2.60 (4H , m, -5 - CHgCHgCf 3-55 (2H ’ E’ AcHgS- ), 6.40 (IH, 8« ), 7.50 (3H, m, so2-Q-h ), Hv-T 7.8o (2H, m, “2-0 ), ii) naseni spektar (PD metod): m/e 398 PRIMER 25

h2n

ch2sch2ch2c U lo ml. metanola rastvoren je 1 g. metil -3“J(2 -gvanidintiazol-4-il) metiltio! propion-imidata i 0,38 g metansulfamida i posle reagovanja n toku 48 šasova na sobno j temperaturi» rastvarač je otdestilisan pod smanjenim pritiskom. Zatim je nastali ostatak rastvoren u J ml etanola i rastvor ostavljen da se ohladi, pri čemu se talože beli kristali. Kristali su sakupljani filtracijom i sušeni da bi se dobilo 0,7 g N-metansulfo - 3 “ !(-gvanidintiazol - 4 - il) metiltio! -propionamidina. Proizvod

L pokazuje sledeče fizicko hemijske osobine: i) Tačka topljenja: 117 - 118° C. ii) Spektri nuklearne magnetne rezonance (CD^OD) h : 35 2.6o (2H, m, - SCHgCHgC 2.8o (2H, m, - sch2ch2c 2.92 (3H, s, so2ch3 3*66 (2H, s, S II 6.50 (IH, 6, CHgS ) ),), PRIMER 26

HgN

Xn/^CH2SCH2CE2° ^S02-

X KH,

U lo tal etanola rastvoreno je 1 g. metil 3~ j(2-gvanidintiazol- -a:« ' — 4-il)metiltio | propionimidata i Ot69 g p-aminobenzolsulfamida i posle reagovanja u toku 46 časova na sobnoj temperaturi« rastvarač je otdestilisan pod sman j enim pritiskom. Z.atim je nastali ostatak prečiščen na hromatografskoj koloni sa silika-gelom koristeči smešu hloroforma i metanola (20 : 1 - ·> 10 : 1 ) da bi se dobio 1, 2 g. araorfnog N - p-aminobenzolsulfo)^- (2-gvanidintiazolar^-il) metiltiopropionamidina. Proizvod pokazuje sledeče JTizičko kemijske osobine:

Spektri nuklearne magnetne rezonance (DMSO - dg),^: 2.50 (2H, m, - SCH2CH2C ^ ), 2.64 (2H, m, - SCHoCHo0 ^ “c t s ), 3*56 (2H, ^ Ci^S ), 5*68 (2H, s, - »h2 ), 36. 6.40 (IH,

H H 6.54

).), 6.80 (4H, s, BH2 \g «N - ), m2 7.44 (2H, d, ), 7.74/8.58 (2H, s, -PRIMERI 27 - 28 //KSo2 hh2

Prema istim postupcima kao u primeru 26, dobijena su sledeča jedinjenjas PRIMER 27: CH,N&-_ 3 H2» /KSV~2 JSH,

N CH2SCH2CH2Cn NH, N-sulfamoil - 3 -J (2-R-metilgvanidintiazol -4-il)metiltioj propionamidin .

Amin upotrebljen u reakciji: HgNSOj^NHg fizičko hemijske odobine proizvoda: i) Tačka topljenja: 163 - 164°C(rekristaliBan iz metanola). ii) Elementarna analiza za 37 C H N Izračunato: 3o.76% 4.88% 27.9o% Nadjeno: 3o.47% 4.84% 27.6o% ΓΗΙΙΐΕΒ 28: η2ν /C = Ν< Ν

·· S

^IiS02WH2

CH2SCH20H2CH2C m z K-BulXamoil -4- ;(2~gvanidintiazol-4“il)nietiltio - butiramidin. Amin upotrebljen u reakciji: HgNSO^i^

PiziČko hetaijeke osobine proizvoda: i) Tačka topljenja: 159-161°C (rekristalizovano iz etanola). PEIMEk 2-KZ a)

Sledeči postupak iz primera 23, dobijena su sledeča jedinjenja:S. C «N* H0N c

N CH2SCH2CH2C : ^ nso^jugh^/' \\ 11H_ ii) Elementarna analiza za C C H N Izračunato: 3o.76% 4.88% 27.9o% Nadjeno: 3o.39% 4.86% 27. ol ΓΒΙΓιΕΚΙ 29 - 32 N-benzilsulgamil - J- 1 (2-gvanidintiazol-4-il)metiltio j propionamidin.. b) Njegov maleat.

Amin koriščen u reakciji: Η^ΊδΟ^ΛΙΟ^ - ..... V· '

FiziČko hemijske osobine proizvoda: a) i) Spektri nuklearne resonance (DMSO - d&): 358- 358- ψο < :sh, SCH0CH0C^ 2-2 ^ ) 2.64 (ΞΗ, m , SCHgCHgC^ ), 3-60 (2H, 8 ^^ch2s - ), 4.o2 (2H, d * ^2-0 6.46 (IH, s H » Ϊ ch2s" ), 6.82 (4B, S, H;,* £ \c «H - ), 7-18 (ih, %, so2hhch2 ),

H H 7.24 (5H, s,

‘H 1¾ 7.5ο, 8,3ο (2H, s -C^ b)

i) Tačka topljenja: 160-162°C ii) Elementarna analiza za °19W6S3 :

C H N

Izračunat o: Fronadjeno: 41.98% 4.64% 18.04% 41.79% 4.64% 17.90% PRIMER 30 ^ CH HJ*\ d y> C =N S' ' CH2SCH2CH2Cn^ NS0oK \ d CH N HH„ -il-)metiltio) H-dimetilsulfamil -3- j (2gvanidintiazol-‘ propionamidin. b) Njegov maleat. ^ / 3

Amin koriščen u reakciji: H^NSC^N 3 m \

Fizicko hemijske osobine proizvoda: a) i) Spektri nuklearne magnetne rezonance C /CB, 0 : 2*59 (6Ht d,r 5 ), nCH, 3 2.5-2.8 (4H, m, SCH2CH2 ), 3.64 (2H, s, Si /\CH2S ), 6.50 (IH, s, ^ S _ H ) N 6.84 (4H, s, H_N ;0 . M - ), h2n b) i) Tačka topljenj a : 183 - 186°C ii) Elementarna analiza za ^4^23^7^6^3 C H Izračunato: 34.92% 4.81% Pronadjeno: 34.82% 4.76% (DI1SO - d6):

N 2o.3o% 19-96% 4ο ΡΚΙΙ-1ΕΚ 31 Η2Ν χ

CH2SCH2CH2C NS0.CP, 2 3 ΚΗ

2 < ,CHC0QH

CHCOOH N-trifluormetansulfo -3- |(2-gyanidintiazol-4~ix)_metixti0'j propionamidindimaleat·

Amin korišcen. u rekaci ji : H^iSO-jCP^ i) Tačka topljenja : 168 - 170°C (rekristaliaan iz metil etilketona). ii) Elementarna analiza za ^x<t®21I,6^1oS3^3 *

Izračunato: Nadjeno: PRIMER 32 a) h2n h2n- C H 32.80% 3-4-0% N 13,50 32.?o* 3..46% lij, 00% / o N S' ; ch2sch2ch2c <;

N ^-NSOgNHCH^ (2-gvanidintiazol-4-il)metiltio N- metilsulfamil -5-propi onamidin· b) Njegov maleat.

Amin upotrebljen u reakciji: H^SOgNHCR^

Pizičko kemijske .osobine proizvoda: a) 2.45 (2H, d, NHCH, ) 2.55 (2H, SCH_CIU - C Z 2r-2. 2.7O (21, m, SCH2CH2 - C\ i; Spektri nuklearne magnetne rezonance (DMso -d ) n 6 V^1 O tL^ (O H Λ 18ΗΓ.Η ^ 41 41 / "i. 3.60 (2H, s, > N " ch2s )

/e v s 6.46 (lil, s, N ), 6.46 (H, 6·8ο (4H, e S0oNHCH-, ) 2 — 3

HpN v C = N - ) h2n 7.48, 8.26 (2H, s, - C^' )

b) i) Tačka topljenja : 181 - 184°C ii) Elementarna analiza: za : C13H21H7°6S5:

C H K

Izračunato : 33-4o % 4.53 % 2o.97%

Nadjeno: 33-36% 4.43 % 2o.68 % PRIMER 33

Medicinski saetav ---- tablete za oralno davanje. Sastav za looo tableta: aktivna komponenta 26o g škrob 37 g mlečni šečer 5o g raagnezijum stearat 3 6

Goro navedene komponente granulisane su na uobičajen način koristeci skrobnu pastu kao vezivno sredstvo a zatim presuju u kalupima u tablete prečnika 9i5 mmj?. . •v 42. PRIMES 54

Medicinski sastav — formulacija za injekcije.

Sastav za 2 ml injekcije: aktivna komponenta 26o ml destilovana voda za injekciju da čini 2 ml

Destilovana voda za injekcije dodata je aktivnoj komponenti i aktivna komponenta je rastvorena pri provodjenju gasovitog azota da bi se dobio rastvor koncentracije 13% (koncentracija od 10% kao baza). Posle filtriranja rastvora pomoču bakterijekog filtra po 2,2 ml rastvora sipano je u ampulu od 2 ml pod sterilnim uslovima i posle ispunjavanja prostora u ampuli gasovitim azotom, ampula se zatvara.

RCH PRIMER 35

V \ / \// \J

N (CH2)4 C / \ m OCH. V, NH, D lo ml. metanolnog rastvora 2,5 S metil - 5-(2- gvanidin-tiazol-4-il) pentanimidata dodato je 0,6 g. cijanatnida, i tastvor je mešan na sobnoj temperaturi 1,5 čas. Kastvarač je otdestilisan a na ostatak je dodato lo ml. acetona. Istaloženi kristali su otfiltrirani i proizvod je prečiščen koristeči dimetil formamidnu vodu. Prečiščeni proizvod je rastvoren u smeši od 0,7 ml sirčetne kiseline, 8 ml. etanola i 16 ml vode i rastvoru je dodato 11,6 ml fl-NaOH rastvora. Istaloženi kristali su sakupljeni filtracijom da bi se dobilo 1.9 g. / 43-

N-cijano-5-(2 gvanidintiazol-4-il) pentanamidina i) Tačka topljea: 195 - 196°C ii) Elementarna analiza za Hj3nS

C

H

Izračunato :

Hadjeno: 45.27 % 5-7o % 56.95 % 45-13 % 5-82 % 36.62 %

Uz to metil 5 - (2-gvanidintiazol-4-pentanimidat koriščen kao sirovina u ovom primeru dobijen je prema sledečem metodu. (a) C1 (CH2)4C0C1-C1(0H2)4000H2C1 u 3oo ml etarskog rastvora diazometana dobijenog iz 43 g p-tozil-H-metil N-nitrozoacetamida dodato je uz mešanje 3o ml etarekog

i rastvor je ostavljen da stoji na istoj temperaturi 2 časa. Gasoviti hlorovodonik provodjen je kroz reakcioni rastvor na 0°C i rastvor je ostavljen da stoji na istoj temperaturi 0,5 časova.. Sadtavu je dodato loo ml vode i etarski sloj je razdvojen. Vodeni sloj je dalje ekstrahovan dvaputa sa po loo ml etra. Etarski slojevi su sakupljani i dobijeni etarski rastvor je sušen iznad bezvodnog magnezijumsulfata i rastvor je otdestilovan a ostatak destilovan pod smanjenim pritiskom da bi se dobilo 8,2 g 1,6 - dihlor -2 - heksanona koji ima tačku ključanja 120 do 125°c (14 mm Hg). b)

. HC1 U 2oo ml acetonskog rastvora 23,5 K lt6-dihlora-2-heksanona dodato je 16,4 g gvaniltioures i rastvor mešan dva dana. 44.

Kastvarač je oddestilovan a ostatak prečiščen na hromatografskoj koloni sa silikagelora koristeci smešu hlorofoma i metanola kao razvojni rastirarač da bi se dobio 2-gvanidin~4~(4-hlorobutil) tiazolhlorhidrat (ovaj proizvod pokazuje tačku. topljenja od 113 do 114°C posle rekristalizacije iz smeše etanola i etra). Ovaj hlcrhidrat je rastvoren u 3oo ml. vode i u rastvortf je dodato loo ml vodenog rastvora 17 »4 6 kalijum karbonata.

Dobljeni rastvor je ekstrahovan triputa sa po 5oo ml.f 2oo ml i 2oo ral hloroforma. kkstrahovani rastvor je sakupljan i sušen iznad bezvodnog kalijumkarbonata a rastvarač je otdesti-lican. Dobljeni kristali su rekristalisani iz smeše etra i n-heksana da bi se dobilo 2o g 2~gvanidin~4-(4-hlorbutil) tiazola. Tačke topljenja 83 do 84°C. c) <CHAC1 h2n C « -v /

//"N/ (°V

ϋ 24 ral dimetilsulfcksida dodato jo 4.9 g natrijumcijanida i dobijena sraeša jo zagrevana na 7U°C. Uz mešanje ra stvoru na . je dodato/?o do 75^* 19.5 E- 2-gvanidin-4-(4-hlorbutil) tiazola, i rastvor je na istoj temperaturi mešan 3 časa. Keak-cioni rastvor jo ohladjen i rastvoru je dodato loo mi. hloroforma Posle filtriranja'nerastvorenog materijala, ostatak je prečiščen poraccu liromatografske kolone sa silikagelom koristeci smešu hloroforma i metanola kao razvojni rastvarač da bi se dobilo 15 g 2-gvanidin-4-(4-cijanobutil) tiazola. Proizvod pokazuje 45 / Λ tadku topljenja 1ο4 - lo5 C posle rekristalizacije iz eaeše etilaeetata i n- h «lesena, d) m

lo g» 2-gvanidin-4-(4-cijanobutil)tiazola suspendovano je u saeši 60 al, metanola i llo al hloroforaa 1 gasovtti hloro-vodonik propuštan je kroz rastvor uz mešanje na - 5 do 5°C u toku 2 časa. Hastal^ rastror ostavljen je da odet o ji na 5°C 2 Anttm i rastvarač je otdestiloran. Ostatak je suapendovan u saeši hloroforaa i metanola, i suspenzija izliven* u ledenu rodu koja sadrži 6o g kalijuakarbonata. Hloroforeni sloj je odvojen a vodeni sloj je dalje akstrahovan triputa sa po 150 al hloroforaa. Ekstrakti su sakupljeni i sušeni iznad bezvodnog kalijuakarbonata. Raatvarač je otdestilovan da bi ae dobilo lig aetil 5~(2gvanidintiaeol-4-il) pentanoiaidata tačke topljenja 14J ~145°C. PRIMER 36

HgH H2»

«a2)4

1 g N-ci jano-5 ( 2-gvanidintiazola-4-il)pentanamidina suspendovano je u saeši od 2o al. metanola i 3o ni« hloroforaa

Kroz suspenziju je propuštan gasoviti hlorovodonik u toku 1,5 časova na - 5 do 5°C i reakcioni rastvor je koncentrisan pod smanjenim pritiskom. Uljasti ostatak je rekristalisan iz smeše metanola etra koja sadrži malu količinu vode da bi se dobio 1,1 g H-karbamoil-5-(2-gvanidintiazol-4-il) pentanoamidin-dihlorhidrat monohidrata tačke topljenja 148 - 150°C.

Elementarna analiza za .2HC1.H^O

\C«N

S ch2)4 c NSOgNHg ΈΗ, C H N Izračunate: 32.o9 5.65 26.2o Nadjeno: 32.1ο 5.65 26,06 PRIMER 37 1.5 metil 5-(2-gyanidintiazol~4-*il)pentanimidata i 1,1 g sulfamida rastvorenog u 4,3 ml.metanola, i rastvor je ostavljen da stoji preko noči na sobnoj temperaturi. Rastvarač je otdestilisan pod smanjenim pritiskom i ostatak je prečiščen na hromatografskoj koloni sa silikagelom koristeči smešu acetona i metanola kao razvoni rastvarač. Robljeni kristali su rastvoreni u smeši 0,4 ml sirčetne kiseline, 4 ml etanola i 8 ml vode, i tretirani aktivnim ugljem. Filtratu je dodato 6.6 ml Ιϊ- NaOIl i istaloženi kristali su sakupljeni filtracijom da bi se dobilo 0,70 g. N -sulfamoil - 5 - (2- gvanidintiazol-4-il) pentanoamidina tačke topljenja 156 -157°C.

Elementarna analiza za H 5,36 5*4-5 N 3o,7o 3o,24

Izračunato: Nadjeno:

C 33,84 33,55 47

Sledeči tok reakcije kao u gornje» primeru, dobijen je N - propilsulfamil -5-(2-gvanidintiazol - 4 - il) pentano-emidin tačke topljenja 173 “ 175°C (reaktant: H^NSO^H(CH^)2^Η 47 temperatura reakcije, vreme i uslovi reakcije: refluks uz zagr nje, 5 časova.) /Jnso2nech2oh2ch3

H.N

HjH < ) N\ /Ccii2)^c' M.

Elementarna analiza za ^12^23^7^2^2

C H ' N 39,87 6.41 27.12 4o.o9 6.48 26.87 N / X NH (ch2)4 c ^ \ez . HC1 S

\Q«H

Izračunate: Nadjeno: PHIHER 36

V U 5 il metanolnog raetvora 0,64 g metil 5 -(2-gvanidintiazol- 4-il) pentanoimidata dodato je 0,084.g amonijumhlorida i rastvor je mešan preko noči na sobnoj temperaturi u reakcino rastvor dodato je 5 ml. acetona i istaloženi kristali sakupljani su riltracijom. Dobijeni kristali su rekristali- sani iz vodenog etanola da bi se dobilo 0,37 E- 5~(2~gvanidin tiazol-4-il) pentanamidinhlorhidrata.

Elementarna analiza za . HC1 9 16 6

Izračunato: Nadjeno: H 6.19 6.3o

C 39.06 39,16

N 3o.36 3o.l7 48, HOMER 39

=N hs°2 (CH2)4C / "^ΜΗ2

^CH-COOH "CH-COOH

R 5 ml metanola dodato je 0,64 g metil - 5~(2~gvanidintiazol* 4-il) pentanimidata i 0,27 g· p-aminobenzolsulfamida, i rastvor je zagrevan uz refluk 5 časova. Rastvarač je otdestilisan pod smanjenim pritiskom, ostatak je prečiščen pomoču hromatografske kolone sa silikagelom koristeči hloroform-metanol kao razvojni rastvarač. Dobljeni proizvod rastvoren je u acetonu i u nastali rastvor dodat je acetonski rastvor 0,4. maleinske kis©line.

Istaloženi kristali rekristalisani su iz metanola-etra da bi se dobilo 0,51 g K- 4-amino-benzolsulfo) - 5-(2-gvanidintiazol - 4 -il)pentanoamidinmaleat tačke topljenja 145 - 146°C.

Elementarna analiza za ^19^25¾¾¾ C H H Izračunato: 44.61 4.93 19.17 Nadjeno: 44.89 4.96 18.67

Sledeči tok reakcije kao u gornjem primeru (reaktant: 'f 'V- SOpNHg), dobi jena je so H-benzolsulfo -5-(2-gvanidin~ tiazol-4-il) pentanamidin maleinske kiseline tačke topljenja 162 - 164°C. K- "2"Hg» if x (Cfl2)4c

HH2

CH-COOH L CH-COOH 49.

Elementarna analiza za 49. Oslu toga sledeči gornji tok reakcije (reaktant: H^SOgMH-4>j* dobi jena je so N-cikloheksilsulfamin - 5-

V_ „ (2-gvanidintiazol/-il) pentanamidin naleinake kiseline tačke topljenja 1J0 - 131°C. M V'

'C«N <v

'HH,

Cfl-COOH Hh-cooh C H H Izračunato: 45.96 4.87 16.92 Nadjeno: 45.67 4.92 16.81

Elementarna analiza za 0 H N 44.o9 6.o4 18.94 44.05 6.oo 18.66

Izračunato:

Kadjeno: PRIMER 40 ϋ 5 «1 »etanola rastvoreno je 0*64 g metil -5-(2-gvanidin-tiazol-4-il) pentaninidata i raetvoru je dodato 0*09 g propargilamina poale čega je sastvor ostavljen da stoji preko noči na sobnoj temperaturi. Raetvor je otdestiliean a ostatak prečiščen na hromatografskoj koloni ea silikagelom kori steči hloroforta-aetanol-trie ti lamin kao razvojni raetvarač. Robljeni uljaeti proizvod raatvoren je u aoetonu i u rastvor je dodat acetonski raetvor 0*4 g maleinske kiseline. Istaloženi kristali sakupljani su filtracijom, rekristalisani 5ο. iz etanola da bi se dobilo 0.14 g. N-propargil-5(2-gyanidin-tiazol-4-il) pentanamidinmaleata.

Elementarna analiza za C2oH26H6°8S

Izračunato: Kadjeno: H 5.15 5.2o

C 4?.o5 46.75

N 16.46 16.54

Sledeči tok reakcije kao u gornjem primeru (reaktant: /7 Τ' - >y , dobijen je -N-benzil-^-CS-gvanidintiazol -4- il) pentanoamidin dimaleat tačke topljenja 92 - 94°C. *=-«

r«,,. rf'"· O *2'4 u\ MH.

N^N

CH-COOH2 ii CH-COOH

Elementarna analiza za C24H5oW6°8S

Izračunato: Nadjeno: PRIMER 41 ‘H 5-37 5-35 51..24 50.76 N 14.94 14.82 v*.

N •C*N - ^CH2>4° F°2°& NH_ S' h2n U 5 ml metanola dodato je 0.17 g etansulfamida i 0.64 g metil-5-(2-gvanidintiazol-4-il) pentanimidata, i rastvor je zagrevan uz relluks 5 čaeova. Rastvarač je otdestilovan pod smanjenim pritiskom i ostatak je prečiščen na hromatografskoj koloni ea silikagelom koristeci bloroform-metanol kao razvojni rastuarač da bi se dobilo 0,56 g N-etilsul:Conil-5-(2-gvanidin“ tj azol-4-;il) pentanamidina tačke topljenja 115-116°C. Elementarna analiza za C-^i^NgOgSg 0 H N Izračunate: 39-74 6.o6 25-28 Nadjeno s 39.7ο 6.o7 25-12 PRIMER 42 S H~N, \ . ^ ' 0 = E~ . NNHCOCH^ (ch2vc f s nh2 U 5 ®1 metanola rastvoreno je 0.64 g metil 5-(2-gvanidintiazol-4—il) pentanimidata i rastvoru je dodato 0.27 g acetilhidrazina. Rekacioni rastvor mešan je na eobnoj temperaturi preko noči i istalošeni kristali su sakupljani filtracijom. Dobijen proizvod je opran etanolom-etrom da bi se dobilo 0,27 g N-aeetil - 5“(2-gvanidintiazol-4-il) pentanamidrazona tačke topljenja 157 - 159°.

Elementarna analiza za 011*νΜ» C H H Izračunato: 44.45 6.44 32-97 Nadjenoi 44.06 6-57 52.6 o bledeči tok reakcije kao u gornjem primeru (reaktant: H^NlUibO^ j ),. dobijen je li-benzolsulionil-^-OHivanidin- tiazol-4-il) pentanamidrazona tačke topljenja 2o6~2o7°C. 52H/. V'

n c «n_// N (ch2)^c

Elementarna analiza za °15Η21Ϊ7°232 σ H N Izračunate: 45-55 5.35 24.79 Nadjeno: 45.53 5.38 24.79 PRIMER 43 (CH2)4CONHC3H5 H H’

d » N h2n

Na 0,27 mtiletar 5”(2-gvanidintiazol-4-il) propionske kiseline dodato je 1 ml 40 % metanovog rastvora metilamina, i raetvor je ostavljen da stoji na sobnoj temperaturi 2 dana. Ietaloženi kristali sakupljeni su filtracijo» i oprani metanolom a zatim etrom, da bi se dobilo 0,21g N-metil 5~(2-gvanidintiazol-4-il) amida valerijanske kiseline. Ovaj proizvod je rekristalisan iz vodenog metanola da bi se dobio prečiščeni proizvod tačke topljenja 228-232°C.

Elementarna analiza za °loH17ii5OS C H N Izračunato: 47.04 6.71 27-43 Nadjeno: 46.86 6.54 27.68

Oem toga etil estar 5”(2-gvanidintiazol-4-il) valerijanske kiseline koriščen u ovom primeru, dobijen je po sledečem metodu. 53a) m

(ch2)4c OCH2CH5 2 {5. 2 -gvanidin-4~(4-cijanobutil)tiazol suspendovan je u smeši 15 ml etanola i 25 ml hloroforma i kroz rastvor je provodjen gasoviti hlorovodonik uz mešanje na - 5 do 5°C u toku 2 časa. Nastali rastvor ostavljen je da stoji na 5°C 4 dana i rastvarač je otdestilisan $od smanjenim pritiskom. Ostatak je suspendovan u etanolu i suepenzija je sipana u ledenu vodu koja sadrži 15 6· kalijumkarbonata. Istaloženi kristali sakupljani su filtracijom, oprani vodom i etrom da bi se dobio 2,1 g etil 5~(2-gvanidintiazol-4-il) pantanimidata tačke topljenja 158 - 159°C·

Na i,2 etil-5-(2-6Vanidintiazol-^-il) pentanimidata dodato je 3o ml etanola i 3 ml vode. Pobijeni rastvor je jako zakišeljen sirčetnom hlorovodoničnom kiselinom i zagrevan na cjC°C lo minuta. Posle hladjenja, 3o ml hloroforma i 3^ ml vode dodato je reakcionom rastvoru. Rastvor je alkalisan kalijumkarbonatom i hloroformni sloj je odvojen. Vodeni sloj je dalje ekstrahovan dva tri puta sa po 20 ml hloroforma. Hloroformni slojevi su sakupljani i sušeni iznad bezvodnog magnezijurasulfata. Rastvarač je otdestilovan pod smanjenim pritiskom i ostatak je prečiščen na hromatografskoj koloni koristeci hloroform-metanol kao razvojni rastvarač da bi se dobilo 2.o g etil estra 5~(2-gvanidintiazol-il) valeri-janske kiseline. Ovaj proizvod je rekristalisan iz etanola da bi se dobio prečiščeni proizvod tačke topljenja lo9 - 110°C. PRIMER 44

CV4Ct

N OH 2 0*15 g hidroksilamihhlorhidrata i 0,117 6 natrijumhidroksida rastvoreno je u 5 ni metilalkohola. Posle dodavanja 0,64 g metil (2-gvanidintiazol-4-il) pentanimidata, reakciona smeša ostavljena je da stoji na sobnoj temperaturi tri dana« Eastvor iz reakcione smeše je otdestiliean i ostatak kristalisan dodavanjem etilalkobola i vode. Dobljeni kristali su rastvoreni u 0,4 ml sirčetne kiseline, 4 ml etil alkohola i 8 ml vode i tretiran je aktivnim ugljem. Filtratu je dodato 6,6 ml IN natrijumhidroksida i istaloŽeni kristali su sakupljeni filtriranjem da se dobije 0,24 g 5~(2-gvanidintiazol-4-il) pentanamidoksima tačke topljenja 167 " 168°C.

C

H

N

Izračunato: 42.17 6.29 32.79

Nadjeno 42.24 6.39 32.47

Havodpri javioca o najboljem načinu za privrednu upotrebu pronalaska

Kao najbolji prijaviocu poznat primer za upotrebu pri j avl j eno g pronalaska navodi se sledeči:

HgN ^CH2 sch2 oh2 o ^ MH hhso2 nh2 •HC1 U 30 ml metanola rastvqreno je 4,09 g- metil 3- [ (2-gwanidinti-azol-4~il) metiltio propionimidata a zatim je n rastvor doda-to 15 m. metanolnog rastvora 2,88 g. sulfamida uz deflegmaciju. Posle deflegmacije u toku oko 3 časa, rastvarač je oddestilisan pod smanjenim pritiskom i ostatak je prečičen na hromatografskoj koloni sa silikagelom koristeči smeSu kloroforma i metanola (20 : 1 ——— do : 1) kao razvojni rastvarač da bi se dobilo 3»26 g. N-sulfamoil - 3 [_ (2- gvanidintiazol - 4 - il) metiltio] propionamidin.

Proizvod pokazuje sledeče fi z ičko-hemi j ske osobine:

(i) tačka topljenja: 163 - 164°C (ii) elementarna analiza za ^:

C H H

Izračunato: 28.48% 4.4®» 29 »00%

Kadjeno: 28.37% 4.48% 28,97% (iii) Spektri nuklearne magnetne rezonance (DMSO - d^) % :

ο

CAMAHOUCHI PHARKACEW2ICAL CO.IttD. JAPAH

10571 / LJVAS " ACHIEVED FOR THE OBTAINING GVAHIDIHTIAZOIBIH UNITS " The field of technique in ka.lu belongs, pmnalazak

This invention relates to a process for the preparation of guanidinthiazole compounds, the Prana of the International Patent Classification, the invention could be categorized into. C 07D 277/38 and A 61 E J1 / A25.

The technical problem with this invention is that it is technically possible to obtain guanidine-zonal compounds that are administered as an inhibitor! lucifer-yes & salt pans.

Pole reSenjfl technical problem

According to this invention, new guanidinthiazole compounds are provided by opStom for Formula I

R-NH

C

V

Where r represents a hydrogen atom or a lower slkll group, Y represents a atom of a nuapor or a motilene ert $ u, nin predominate cco number 1-2 * A represents the group shown in

or -COHH- (wherein the hydrogen atom is a 2-membered group, a carbonyl group, an ureido group, a hydroxyl group, a lower alkoxy group, a lower acyl group, an acylamino group, an arylsulfa-mil (-HH-Si2 -aryl) group, an arylalkyl group, a carboxymethyl group or a group represented by -SO 2 -R 6 R 9 wherein R 5 represents a lower alkyl group, a halogeno-lower alkyl group, an unsubstituted or substituted-aryl aryl group, an amino group, a multi-di-lower alkylamino group, an arylamino group , an aryl alkyl amino group), Rg represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cyano group or a lower acyl group, and represents a hydrogen atom, a lower alkyl group, a hydroxyl group or a sulfamol group and an acid addition salt of guanidinthiazole compounds which can be used for medical purposes.

In addition, according to another embodiment of the present invention, a method is provided for the preparation of novel guanidinthiazole compounds of general formula I and of medical compositions containing a novel guanidinthiazole compound.

The term " lower " in the interpretation of the general formula mentioned above means a straight or branched carbon chain having 1-5 carbon atoms. Therefore, as a lower alkyl group, the methyl group, ethyl group, iso-propyl group, butyl group, etc .; as a lower alkenyl group, a vinyl group, an allyl group, an isopropynyl group, and the like; as a lower alkynyl group, it is understood that ethynyl group, propynyl group, butynyl group, etc .; and as an acylamino group, a lower acylamino group such as an acetylamino group, a propionylamino group, etc .; arylcarbonylamino group such as a benzoylamino group, etc .; such as an arylalkyl group, a benzyl group, a phenethyl group, and the like; and as an arylsulfamyl group, there are phenylsulfamyl groups, naphthylsulfamyl groups, etc. What is more, the aryl group may have a substituent (d) such as a halogen atom, a hyiroxyl group, an amino group, an alcoxy group, etc.

Additionally, the compounds of the aforementioned general formula I easily form their acidic additive salts and also tautomers of these compounds are in the position of - C ^ 1. Thus, the invention also includes those additive acid salts and tautomers of compounds of general formula 1.

As noted above, the guanidinthiazole compounds of the present invention easily form acid addition salts which can be used for medical purposes. Of these salts salts of guanidine-dithiazole compounds with inorganic or organic acids are observed. Examples of inorganic acid salts are hydrochlorides, hydrobromides and sulphates, etc. Also, examples of particularly useful organic acid salts are salts with aliphatic carboxylic acids such as acetic acid, maleic acid, acid furnace, etc.

A first feature of the present invention is that the compounds obtained by the present invention have an inhibitory effect on gastric acid and this effect is not caused by an anticholinergic effect. Since the standard on-market inhibitors of stocharic acid are most often based on anticholinergic activity 4 and show undesired side effects due to anticholinergic effects, the compounds of this invention are useful as a new type of gastric acid secretion inhibitor. Another feature of the present invention is that one of the compounds of the invention is active in inhibiting the secretion of gastric acid to the histamine H2 receptor. It has been suggested that histamine receptors classify u - reeeptors and non-H? -Receptors or H2-reseptors by Ash and Schild: "Brit.J.of Pharmacol. Chemother ", 27. 427 (1966) and Black and Karadjani; " Nature ", 236 " 385 (1972). The effects of histamine on the secretion of gastric acid and cardiac rhythm in isolated pacemaker atrium are achieved by the H2 receptor and these effects of histamine are not inhibited by standard antihistasins such as mepiramines but are opposed to blocking agents for the H2 receptor such as methylamide.

Since the blocking agent of the H2 receptor acts to inhibit the primary secretion of stomach acid and the secretion of gastric or food gastric acid, it can be used to treat stomach ulcer and duodenal ulcer caused by excessive secretion of gastric acid.

In addition, as materials having characteristics such as those of the compounds of the present invention, compounds in the Belgian patent number no. 804,145; 866,156; 867,105; 867,594; U.S. Pat. 3,950,335 etc. The compounds of the present invention are known to be all of the novel compounds having different structures and better 5 pharmacological effects compared to those of the known compounds.

The compounds of the present invention can be administered orally or parentally, but a better oral administration is preferred. The compounds of the present invention are used as free bases or pharmacologically acceptable salts thereof, and they are, in principle, used as medical or pharmaceutical compositions with carriers or diluents that can be used in principle for the preparation of medicaments. In the case of oral administration, it is most advantageous to use the medical compositions of the present invention in the form of capsules or tablets, but can be used as preparations with effective action. In addition, the assemblies can be used as a sugar-coated preparations or syrups. Their oral doses are 50 to 800 mg. daily and it is prescribed that the medicine is given in 1 to 4 doses.

The compounds of the present invention represented by the general formula I are inhibitors of the secretion of stomach acid caused by histamine, which will be demonstrated by the following assays. (i) secretion of gastric acid in anesthetized dogs:

Dogs of mixed breeds weighing between 8 and 15 kg. the food was ΡL time adjusted and anesthetized with intravenous petobarbitol (30 mg / kg). Stainless Steel Cannula was introduced through the stomach wall of the stomach after the binding of the pilorus and the esophagus (S. Ovklfeva and the donors: Japan, J.Phamacol 2 £, 17-22, 1977) · Stomach juice is saccharine from the dreriaAom gallbladder cannula every 15 minutes . The following compounds were administered intravenously after 6 gastric secretions caused by continual intravenous infusion histamine (160 Mg / kgh) did not reach the stationary state. The acidity of gastric juice was measured by titrating with 0.05 N NaOH using the autoantic titrator (Kyoto Electronics ilanufacturing Co., AT-107). The percentage of inhibition of gastric lavage with each dose of drugs was calculated from the difference between the amount of acid before the drug was given and the minimum amount of acid that is usually obtained within 45 minutes after administration of the drug. A dose that yields 50% acid inhibition is derived from a dose-fection curve in which the inhibition is plotted semilogarithamically to the dose. The data are shown in Table I, in the column marked with (A). (ii) Lupus erythematosus in rat pylori rats:

Male Vistar rats weigh about 200 gr. They are deprived of food for 24 hours but are allowed Free access to water before experiments in single cages. Pilorus is associated with Anesthesia with the help of the ether according to the method of Shay and associates (Gastroenter., 45-61, 1945). The test compounds were given intradodenally immediately after the binding of the pylori. Animals were sacrificed 4 hours after the onset of the drug and stomach contents were collected. The acidity of gastric juice was measured by titration with 0.05N NaOH using an automatic titrator (kyota Electronics Manufacturing Co., AT-107). The percentage of inhibition of gastric secretion by each dose of drugs was calculated from the amount of acid of the control and treated groups. The values of ED ^ Q are determined by the method by the method. The data are shown in Table 1, in the column marked with (B). 7. (iii) Acute toxicity in mice drugs is injected intravenous male ICP muscle cells. weight 35 g, at a rate of 0 1 tall / 10 mg / lO sec. and animals were observed for 7 days. The values of LP ^ q were determined using the method up and down using 10 animals. The data are shown in Table 1, in the column labeled with (C). Belgian patent no. 866.156)% »and et Cj hj 3 S st, 1 1 ra OPPPP ra ro MP · P-C 'H · t' H 'P * H · H- PPPP μ · P * P * PP ra ra ra CD P ( D ro Cj. CJ. PPPP Cj. S 0 ra ra © H · H · PP vn vO ro ro P c_i Cj. CJ. Cj • • vn ro Cj. 0) ra • • PN * rN H · P · HP · σ '/ • NXX σ' P σ 'σ' PPPNPPPP fo ra PNNNNP v_J PPH * H · SJ v »VJ &lt;&lt; σ 'σ' 4 * ·· δ PMP ΓΟ CJ- ti P 1 oi ra 1 VJ VJ P-o &lt; H «H · P. S. CJ. P ra H Ο PP Η · CJ. O d V ra H · N 1 a 1 p \ \ H N &lt; 0 fe IV) aot * ra P «* 1 Tfi ct vn vn h ct / NH · v» vn MM oc WH ro • d H vn vn 03 σ &gt; vO 03 p./~N ro &lt; tp 1 »« • «• * - / TV P &gt; l P o H * d · ra a ro vn vn -PH »nJ S * 0 &lt; vj * P σ 'o HK Cj. PS v 1+ 1+ 1+ l + 1+ 1+; nod P 1 (V) 4 * oo ro o H * o ro 1 «ro • • • * CR PPC * 3 θ 'fO • NJ CD (D vn • (XB &lt; PN &lt; / RTI &gt; • ohr ra P &lt; - &gt; C d. &Lt; / RTI &gt; o H · o «ra M ct v» • H · v * vn * d M vn 1 ct «ra ti 'PH * B o O m EH · o B P- MHO o M &lt; (DP vO ro vn Γ0 * «Ah · ft o N« • «• O Co vn * d M OV» &lt; n 03 -o vi oh · ra H o H »\« 4 H · / "v s- \ P c &gt; ω ct o M ro ro S3 0) vn O m 4 * d vj \ c OH 'VJ cn M • • • • P CJ. 0 • * roo 00 vn P * ra P- NO ra oo • 1 »CO RQ &lt;&lt; OP · D · »1 (O ro ro 1 • 0 ra MH · H · vO 0) cn σ> OHH · N p H vn vn • • • •« PO CJ. Ct «« CD-o 03 vO p, 5 et ra H · vn vn VJ VJ VJ ô • ti 'H · p O w VJ VJ vj 0 • d CJ. \ H ra ra o <ct d ca H · O ra H * V Cj. * d I? »fc »&Lt; DPX * vn P * ooo P * P- P P. J ~ N p PP * HHH ro M 0 CJ. Cj. P * $ vn -P vO vn -P 0 mp · (D ra p · Γ0 CJ ) -o ro £ p P «• 9 4 * • me (γθ CJ .P CD vn ~ vj CO H -P ro n v i ra P fN &lt; »et PH · P · ct H * * P • d N <H • • H · cx BK P ct o

Pharmacological effects of EP blocking agents

The guanidinthiazole compounds of the present invention represented by the general forwards I can be obtained by the following methods:

Production process 1:

NO

K-NH

K ~ (CHp) mY- (CHp) -C '\ C = N * i

1

0-B '

III I 2 1 In the above formula, E 'represents a lower alkyl group, and R, B 2, R 2, Y "min have the same meaning as above.

This process is carried out by either reacting a starting compound of formula &lt; RTI ID = 0.0 &gt; 11 &lt; / RTI &gt; and a reactive amount of an amine of formula III, or reacting a starting compound of formula and reactive amount of an amine of formula III2. The amines represented by the formulas III or IIIp used in the process are those capable of delivering the desired product 1 by reacting the starting material of compound 11 ^ or Up ·

Examples of the amine represented by the formula IIIa are monmonium (ammonium chloride) lower alkyl amine such as methylamine, dimethylamine, ethylamine, 10 isopropylamine, etc .; niche alkenylamine such as allylamine, 2-butenylamine, etc .; lower alkynylamine, such as propargylamine, pentihylamine, etc. and the like. Examples of the amine represented by the formula III2 are ammonia (ammonium chloride); cyanamide; urea; hydroxylamine; e.g. alkyl hydroxyamines such as O-methylhydroxylamine, o-butyl-hydroxylamine, etc .; lower acylamine such as acetylamide etc.; acylhydrazine such as acetylhydrazine, benzoylhydrazine, etc. ·; benzolsulfohydrazine; semicarbazide * arylalkylamine such as benzylamine, phenethylamine, etc. "; lower alkyl sulfamide such as methylsulfamide, ethylsulfamide, etc .; lower halogeno alkylsilynamides such as trifluoromethyl sulfamide, etc .; substituted or unsubstituted arylsulfamides such as benzenesulfamide, P-chlorobenzenesulfamide, P-aminobenzenesulfamide, etc.} sulfamide; lower alkyl sulfamide such as methylsulphamide, diethylsulfamide, etc .; arylsulfamide such as phenylsulfamide, naphthylsulfamide etc.; arylalkylsulfamide such as benzylsulmide lfc etc .; glycine; and the like.

The reaction is conveniently carried out in a solvent and suitable solvents include, e.g. organic solvents such as methanol, ethanol, isopropanol, chloroform, ether, tetrahydrofuran, benzol, etc. It is best that these solvents do not contain water. No special limitations are observed regarding the reaction temperature, but the reaction is best performed at room temperature or with heating. It is also desirable that the reaction system be neutral to the basin.

Production process 2: 11 Production process 2s

0-R '

O

II 3

III 3 0

In the above formulas, R, R1, R4, T, min have the same mark as above. This process is carried out by reacting the starting compound of the formula

compounds of formula II &lt; 2 &gt; are obtained by hydrolysis to the standard manner of the starting material of the compound of formula 11 or II2 wherein R1 or R2 is a hydrogen atom. The amines of the amines of formula IIIj are arachniac; lower alkylamine such as methylamine, ethylamine isopropyl-aoin, etc.; hydroxylamine; and the like. Reaction conditions such as reacting the solvent, reaction temperature, etc. are the same as those in the production process 1.

In addition, as other methods of obtaining the desired product of the present invention, there are several procedures such as the method of mutual converting or the desired product I and the like. For example, follow these steps. (i) the desired product is a form I (in case A represents a group

N-R

represented by -C1-1) wherein R1 is a carbamoyl group, is obtained by placing a dry gaseous hydrogen chloride through an alcohol containing the compound of formula I wherein R is a cyano group, in the cooling or treatment of said compound with concentrated hydrochloric acid. gt;) the desired product of formula I (in the case that A represents a group represented by -C) wherein R, and R &lt; 0 &gt; represent the same &quot; NH-Rg 1 d yl, in the acyl group, is obtained by reacting a lower aoylhalogenide and a compound of formula I wherein ii Hg represents a hydrogen atom. (iii) the desired product of formula (I) (in case A represents

O group represented by -C1-4) wherein R1 represents -SOpNHP, &quot; HH-R1 &apos; is obtained by hydrolysis of a compound of formula I in the case that A represents a group represented by -C1) The HH-Rg * famil group and Rg represents a hydrogen atom.

The methods of the present invention will then be further explained by the following examples. Examples are mp, Anal, NMR and Mass. abbreviations for the melting point, the values of elemental analysis, the nuclear magnetic resonance spectrum, and the mass spectrum.

Example 1 H2N h2n CN-

N

CH2SCH2CH2C2NH2OH2 To 35 ml of methanol was dissolved 4, [delta] 2 g. methyl 3 - [(2-guanidinthiazol-4-yl) methylthio / propionimidate and then 23 ml was added to the solution. 13 methanol solution sl circumferential p; hydroxylamine obtained by treatment with 1.2 g. hydroxylamine hydrochloride with 0,93 g. sodium methoxide.

After 2 hours of stirring the mixture at room temperature, the solvent was distilled off under reduced pressure and the residue obtained was purified by column chromatography using a mixed solvent of chloroform and methanol as a development solvent and recrystallized from methanol-acetone to give 1.3 g. 3 - [(2-guanidinthiazol-4-yl) methylthio / propionamidoxime. The product or the following physical-mechanical properties: (i) Melting point: 177-179 ° C (Explained) (ii) Elemental analysis for c8hwh6 ° s2 '1/4 h20

CER calculated: 34-, 46% 5.24% 30.14 $ found; 34.78% 5.23% 30.06% mi

In addition, methyl 3- [A (2-guanidinthiazol-4-yl) methylthio] propionate, used as raw material in this example was obtained as follows.

ch2sch2ch2cn n is mixed with 4-90 ml. water and 320 ml. ethanol 98.1 GS- (2-aminothiazol-4-ylmethyl) isothiourea of 2-chlorohydrate is dissolved (see "Am. Chem. Soc.", 68, 2155-2159 (1946) in the nitrogen stream and after adding it to it 37, about chlorpropionitrile, the mixture was cooled to 0-10 [deg.] C. and a solution of 4-5.1 g of sodium hydroxide in 4-50 ml of water was added dropwise, after which the mixture was stirred for one hour at 0-10 [deg.] C. for one hour at room temperature and the resulting product 14 was extracted 4 times with 600 ml of chloroform.

The combined chloroform layer was washed with water and dried without magnesium magnesium sulfate. Then the solvent was concentrated under reduced pressure, precipitated crystals were collected by filtration to give 47.2 g. 3- (2-aminothiazol-4-ylmethylthio) propionitrile which showed a melting point of 104 ° C 106 ° C (b)

S ___ CHgSCHgCHgCH {/ \ COKHCNH-l / | W \ U 500 ml. acetone is dissolved 50 g. S- (2-amino-thiazol-4-yl-methylthio) prionitrile and after adding 45 g. benzddlizo-cyanate, the mixture was heated at reflux for 5 hours. Subsequently, the solvent was concentrated under reduced pressure and the precipitated crystals were collected by filtration to give 79.4 g. needle crystals of 3- [2- (3-benzoylthioureido) thiazol-4-ylmethylthio / propionitrile showing a melting point of 158-160 ° C. (s) S 'J / 0

, CH2CH2CH2CH2CN To a mixture of 1400 ml. acetone and 350 m. methanol was dissolved 80 g. yl 3- (2- (3-benzoylthioureide) -thiazol-4-yl (phenylthio) propionitrile and after addition to this solution of 20 g of potassium carbonate in 300 ml of water, the mixture was stirred for 5 hours at 50 ° C. Then the solvents were concentrated under reduced pressure, the resulting residue was added 15 in 2000 ml of ice water. This was followed by stirring for 24 hours and the precipitated crystals were collected by filtration to give 55 [mu] g of 3- (2-thio ~ ureidoothiazole -4-ylmethylthio) propionitrile which shows a melting point of 135-137 ° C ·

SCH

&lt; d) In 200 ml. ethanol was dissolved 15 g. (3- (2-thioureidoidin-4-ylmethylthio) propionitrile and after adding 12.4 g of methyl iodide, the mixture was heated to reflux for one hour. filtered to give 20.9 g of 3- (2- (S-methylisothioureido) thiazol-4-ylethylthio) propionitrile hydrate having a melting point of 148-149 ° C (unbound) (e)

In 200 ml. methanol containing 17 * 0 g. (1.0 mol) of ammonia was dissolved 20 g. (0.05 mol) of 3- [2- (S-raethylisothiourado) thiazol 4-ylmethylthio / propionitrile iodide and 2.68 g. (0.05 mol) of amonium chloride and the solution was heated in a sealed tube at 80-90 [deg.] C. for 15 hours. 16.

After cooling the reaction mixture, the solvent was distilled under reduced pressure. To the obtained residue was added 200 ml. water and the mixture is alkalized by the addition of a saturated aqueous solution of kalium carbonate. Then the precipitated brown solid was collected by filtration, dried with air, and recrystallized from acetone to give 6.2 g. 3- (2-guanidinthiazol-4-ylmethylthio) propionitrile which showed a melting point of 132 ° C.

CH2SCH2CH2

SH 0CH5 To a mixture of 60 ml of anhydrous methanol and 120 ml. anhydrous chloroform was dissolved 10 g. 3- (2-guanidinthiazol-4-ylmethylthio) propionitrile and after cooling the solution at 0-10 ° B in nitrogen stream and conducting it through dry dry gas chloride during 3 times, the solution was allowed to stand indoors at 0-4 ° C for 20 hours.

The solvents were subsequently depressurized under reduced pressure and the concentrated residue was washed in 200 ml. ice water that contains 30 g. calcium carbonate and a solution of the mixture was extracted three times with 130 ml. chloroform containing 20% of methyl alcohol.

The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 10.3 g of methyl -3 - [(2-gyanidinthiazol-4-yl) methylthio / propionate. EXAMPLE 2

According to the method of Example 1, the following compound H2 &quot;

SC »N- \ E CH2SCH2CH2C t NOCHj nh2

. CHCOOH lf.!

^ CHCOOH o-methyl-3 ((2-guanidinthiazol-4-yl) methylthio] propionamidoxy} aleat

The amine used in the reaction is H ^ NOCH ^

Physical-chemical properties of the product: (i) Melting point: 16lA-164 ° C (ii) Elemental analysis for C14H21 ° 6N6S2 ^ 2 °! calculated found CH 38.0036 5.01% 38, o4% 4.94% N 18.99% 19.31% EXAMPLE 5 V \ NH. , N .... CH2SCH2CH2C2H2O2

NCR h2n

To 1.9 E, ethyl 3V {2-guanidinthiazol-4-yl) methylthio] -propionimidate 18, 10 ml was added. ethanolic solution 0.28 g. cumin and the mixture was allowed to stand overnight at room temperature. Then, the solvent was distilled off from the reaction mixture under reduced pressure and the residue obtained was quenched in a silica cage chromatography column using a mixture of chloroform and methanol solvent mixture as a development solvent to give 1.35 6 N-cyano-3- [ -guanine-dithiazol-4-yl) methylthio / propionamidine. The product exhibits the following physico-chemical properties: (i) melting point: 102.5 - 104 ° C (recrystallized from methanol "ether") C9H13N7S2: (ii) Elemental analysis for

CHK calculates that found 38,15 / 6 4,62% 34,60% 37,84% 4,59% 34,26% PEIMEBI 4-8

Following the procedure as in Example 3, the following compounds were obtained.

Example 4: IUN * \ = 2 &quot; 7

CmB-

N ____ CH0SCBLCH0 J

^ m2 c '* ^ NCR2CzCH N' (2-propynyl) -3- (2-guanidinthiazol-4-yl) methylthio] -propionamidine. 19

Amin used in the reaction: HSNCE ^ Czz CH Physical chemical properties of the product: (i) Mass spectrum: m / e 296 (M +) (ii) Nuclear magnetic resonance spectra (DMSO-dg + CD3 OD) J ': 2.50 (2H, t) 2.70 (2H, t, B0H2CH2), 2.83 (1H, t, CH2C = CH) 3.60 (2H, S) -CH2 ~~ 3.7O (2H, d , NCH2C (CH2) 6, 6.48 (1H, S, J)

SH

PfilKER 5: HA

CH 2 CH 2 CH 2 CH 2 HH,

HgN / \

Kca2

N-benzyl-3- (2-guanidinthiazol-4-yl) methylthio propionamidine,

The amine used in the reaction: HgNCH ,, -

Physical chemical properties of the product: (i) Massen! Spectrum: m / e 241 (M-HH2CH2C6H4) (ii) nuclear magnetic resonance spectra (DMS0-d &amp;): 2.58 (2H, i.e. 2.75 (2H, t SCH2 (CH2) 60 (2H, S (.delta. - .dbd. 4.17 (2H, s, NCH2 6.45 (1H, S,

HH

PfilMER 6: HH, 2ο

H ^ R HgN / / N. , ch9sch-celc 2 2 2%

SH. fiCl 3 f (2nd guanidine and z-1-yl) oethylthio propionyidine chlorhydrate.

Amin used in the reaction: NH ^ Cl.

Physical chemical properties of the product:

(i) melting point: lo9 - 112 ° C (ii) Elemental analysis for Calculated: 'C 32.59% E 5.15 * Found: 32.33% 5, ol *

N 28.51% 28.28% "a PRIMES 7 * H2" C - H -

H CBgBCH2 g C N -benzoyl-3 (2-guanidinthiazol-4-yl) methylthio] propionamidrazone Anin used in the reaction: H ^ HRHCO- (f ^

Physico - chemical properties of the product: (i) melting point: lo3 - 106 ° C. (ii) Elemental analysis for C15H19N7OS2:

Calculated: c HN 47.73% 5-ol% 25.97%

Found: 47.43% 5 * oo% 25.72% EXAMPLE 6

21. Example 8: V

NO

NC - E- / · (f

CH2SCH2CH2C N-NHCOCE, Λ ·> · · propion-N-acetyl-3-Γ (2-gyanidinthiazol-4-yl) methylthio amidrazone.

Anin used for the reaction: HgNNHCOCHj Physical chemical ooobines products:

(i) Melting point 163 - 166 ° C (ii) Elemental analysis for CloH17VS2!

Calculated: Paid PfiMER 9j CHS 38.0 »5.4» 31, »37.8» 5.6 »30.7»

In a mixture of 13 ethanol and 10 ml. Chloroform dissolved. It is 0.5 g of N-cyano-3 (2-guanidinthiazol-4-yl) -methylthieno propionate and after conducting through a solution of e.g. gaseous hydrogen chloride during this time for 1.3 hours with ice-water, It is concentrated under reduced pressure. To the residue Lo ml of ethanol was added, the mixture was again concentrated under reduced pressure. The resulting residue was dissolved in a small amount of ethanol and after the addition of ether to it and the deposition of the mixture overnight, the same crystals were collected by filtration to obtain 0 * 55 g of 8-carbamyl-31 (2-guanidinyl-4-yl) methylthio Γ propionamidine di-chlorohydrate. The product shows the following physical-chemical characteristics:

(i) melting point: 171-173 ° C (ii) elemental analysis for CpH- ^ NoSpOClp:

Calculated: above CH 28 * 88% 4.58% 28 * 73% 4.64% N 26.19% 25.78% EXAMPLE 10:

H

HH, U 3 ml of ethanol, 6 * 4 g of acetyl- (2-methylguanidin-thiazol-4-ylmethylthio) propionimide were dissolved and after addition of 0 * 9 g * cyanamide and a mixture of the mixture for 2 hours at room temperature, it was depressed under reduced pressure. Then the obtained honeycomb is stirred on a chromatographic column of corium to obtain a mixture of chloroform and methanol as a development solvent and recrystallized from ethanol to give 2.0 g. K-cyano-3- (2-methylguanidinthiazol-4-ylmethylthio) propionamidine which showed a melting point of 144-145 ° C. Elementary analysis for

0 HN

Calculated: 4o, 39% 5 »o 8% 32.97% found: 4o, 13% 5 * oo% 32.68% 23- EXAMPLE 11 23- EH,

N

X

NCOEB. ch2soh2ch2

S .2HC3 'ΧΚΗ, To a mixture of 2 mL of ethanol, 3 [mu] l of chloroform IIL lo ml. methanol was dissolved 1.0 g of N-cyano-3- (2-methylguanidinthiazol-4-ylmethylthio) propionamidine and after cooling the solution to O-5 DEG C. and the translation of gas chloride into a stream of a single slurry, the solvents were attenuated at reduced pressure . Thereafter, the resulting rice was recrystallized from ethanol to give 1.2 g of H-carbonyl -3- (2-methylguanidin-thiazol-4-ylmethylthio) propionamidine dihydrochloride which showed a melting point of 180-182C.

Elementary analyzer * · CloHllVS2C12 · and H2 ° s

Calculated t Same: EXAMPLE 12: H 5, o7% 5, οβ% C 3o, 23% 3o, $ 2% H 24.68% 24.41%

HJS S \ __ ^ C - E H2N '

XJ

X CHgSCHgCHgC ^ NKHSO "

EH, To 49 ml of oethanol, 2.0 g was dissolved. methyl 3- (2-guanidin-thiazol-4-ylmethylthio) propinimidate and 1,21 benzolsulfo-hydrazine and after stirring it dissolve for 24 hours at room temperature, the solution was depopulated under reduced pressure.

The resulting residue was purified on a chromatographic column using a mixture of chloroform and methanol as a developing solvent to give 1.2 g. N-benzenesulpho -3- (2-guanidinthiazol-4-ylmethyl-thio) propionamidrazone showing a melting point of 159 * -5 - 161 ° C.

Elementary analysis for C14Vt °:

CHN

Calculated: found: 4o, 66% 4.635¾ 23.59% 4o.3o% 4.54% 23.46% PHIHBR 13

»Ch2cooh 2 U 20 ral. methanol was suspended 2 g of methyl 3 ~ (2-guanidin-thiazol-4-ylmethylthio) propionimide and then a solution of 0.5 g was added to the suspension. glycine in 5 ml. water. After stirring the mixture for 24 hours at room temperature, the solvent was re-styled under reduced pressure and the resultant residue was recrystallized from a mixture of water and acetone to give 1, g. 5- (2-guanidinthiazol-4-ylmethylthio) propionamidinoglycine indicating a melting point of 14 ° - 141 ° C (unloaded).

Elemental analysis for ° loll16N6 ° 2S2-? H20:

C

H

Calculated: found: 35.65% 33.82% 5-79% 5.43% n 23.55% 23.65% 25. EXAMPLE 14. 25. H2N '

C

CH2SCH2CH2O. »CK ✓

NHCH U 55? 1 methanol 5? 1 E methyl 5 - (2-guanidin-thiazol-4-ethylthio) propionimidate was dissolved and after 0.9 g. "Χ $ ηοηίκ cyanamide solution and stirring was mixed for 24 hours at room temperature, solvent. It was dried under reduced pressure. Then, the resulting residue was purified on a chromatographic column using a chloroform and methanol emulsion as the developing solvent dE to give 4.8 g of N-cyano-3- (2-guanidinylthiazol-4-ylmethylthio) propionamidine and 0, dicyano-5 (2-guanidinothiazol-4-yl) methylthiopropionamidine showing a melting point of 223-224 [deg.] C. (unbranched) HMR (dgRMSO):

Mas.spect. (PD method); m / e 3 &lt; 9 (M * + 1) NMR (d6 DMSO): J 2.5-2.8 (4H, m, &lt; , S_H), 8.1 (4H, bs, CN-). EXAMPLE 15

C * N

W2c A? H hAcohh, \ NH,

A solution of 246.6 mg. potassium tertiary bisoxide in lo ml. anhydrous methanol was added 245.5 g of semicarbazide hydrochloride under ice-cooling and after stirring the mixture at room temperature for 26 minutes, a solution of 54 mg of methyl 3-1 (2-guanidinthiazol-4-yl) thiomethane and propionimidate was added to the mixture. After stirring rolled for 2 days at room temperature, the solvent was removed under reduced pressure and the resulting residue was purified on a chromatographic column ea with silica gel using a mixture of the haloform and methanol to give 0.4 g of a carbamoylamine-3- (2 -guanidinthiazol-4-yl) methylthio] -propionamidine. The product was dissolved in 3 ml of methanol and after 0.4 g of maleic acid was added to the solution and mixing of deer during the course of a minute, the solvent was distilled, the residue was added 2 °. ml. acetone and insoluble matter were filtered to give 0.3 g. N-carboylamino-3 "(2guanidinthiazol-4-yl) -methylthio propionamidine-dimethyl mono -hydrate indicating a melting point of lo9-1 [deg.] C. Elemental analysis for cy7H26N8S2: calculated: found: H 4-59% 4.55% C 36.o4% 36.ol% H19-79% 19-55% 113o% 11.57% PRIMES 16 * y &gt; H - Η ^ ι

X

NCN

N

CHgSCHgCH ^ C \ KHCH.

To 5,2 methyl N-cyano-3- (2-guanidinthiazol-4-yl) methylthio] propionimidate was added 5 ml of a ml of methanol solution of 40% methylarnone and after leaving the mixture at 2 hours at ambient temperature, the solvent was depopulated under reduced pressure. The resulting residue was purified in a chromatographic column using a mixture of lloroform and methanol as a development solvent, 27. so the purified product was converted to maleate in acetone and recrystallized from methanol to give 1 g. &amp; cyano-1 't-3- (2-guanidinylthiazol-4-ylmethylthio) propionamidine which shows it a melting point of 159-161 ° C.

Elemental analysis for C 16U2lV6B2 ·%

HgO:

Calculated: liaded: C39.99% H 4.61% K 20.40% 20.24% 59.89% 4.69% C Γ In addition, methyl | H-cyano-3-yl (2-guanidinthiazol-4-yl) -1-methylthio; The propionimidate used in this example as the raw material was obtained according to the following method. To a mixture of 9 ml. dried chloroform m 40 ml of dried methanol was dissolved 7.5 g of 3- (2-guanidinthiazol-4-ylmethylthio) propionic acid and after cooling the raison at 0 ° C in nitrogen stream and conducting through a solution of 25 g of gaseous hydrogen chloride, was left for 48 hours at 0-10 ° C. Then, the solvent was distilled off under reduced pressure and the resultant residue was dissolved in 5 [mu] L of dried methanol and after adding 1.3 g of cyanamide, the mixture was stirred for 3.5 hours at room temperature. Subsequently, the solvent is concentrated under a complex pressure and after the addition of 5 [mu] l of ice water in which 12 g is dissolved. potassium carbonate to the resulting solution, the product was extracted three times with 5 [mu] ml. chloroform. The extract obtained is dried with anhydrous magnesium sulfur and then the solvent is depopulated under reduced pressure.

PfllHKR 17 C sk

HgK ..

X j}, .. 0H2SCH2C

miG0GH3 CHCOOH 1. * 2 and 'KCGCLL · CliCOOH D 28 U 10 ml. dimethylformalide was dissolved 1.2 g. 3-yl-2-guanidin-thiazol-4-ylmethylthio propionamidine and after addition of 0.4 g. triethylamine solution and cooling mixture iepod 15 [deg.] C., solution of 1.4 g. acetyl chloride in 3 ml of chloroform was added dropwise to the mixture. Thereafter, the mixture was stirred for 3 minutes at room temperature and then the solvent was distilled off. To the resulting residue was added a solution of 0.8 g of potassium carbonate in 2 ml. water. After removing water, the residue was subjected to an aging in the chromatography column with silica gel and the product was developed with a mixture of chloroform and methanol. The wash was then sublimated to give 0.3 E · N, H'-diacetyl-3 "(2-guanidinthiazol-4-ylmethylthio) propionamidine. The product was added to a solution of 0.2 g of maleic acid in lo ml. acetone by stirring for one minute at room temperature for 3 minutes. The resulting talog was collected by filtration to give 0.2 g of N, N'-diacetyl-3- (2-guanidin-thiazol-4-ylmethylthio) -propionamidine. 1/2 maleate. H ^ O indicating a melting point of 180-181 ° C.

Elemental analysis for c14H22N6S2O5:

Calculated: found: C 4o.l9% 39-91% SH 4.52% Po.oo% 4.53% 2o.ol% 8 15.5015.2%% EXAMPLE 18

H2N HgN h ^ 1 \ CH28CH2CH2O2

O HCl NHCH. In 3 ° ml. methanol solution of 40% methylamine was dissolved 3 g of methyl 3 - (2-guanidinthiazol-4-ylmethyl-thio) propionate and after the solution was coupled for 24 h at room temperature, the solvent was distilled off under reduced pressure. The resulting residue was purified on a chromatographic column using 29 mixture of chloroform and methanol as a solvent for development, the resulting product was converted to chlorohydrate by treatment with hydrochloric acid and recrystallised from a mixture of isopropanol and ethyl acetate to give 1.5 g of N - methyl - J - (2-guanidinthiazol-4-ylmethylthio) -propionamide hydrochloride which show) is a melting point of 126 - 127 ° C.

Elemental analysis for C9B16E50ii2C1 c (%) H (%) Calculated: 34..89 5.20 22.60 Estimated 34.51 5.19 22.55

Gem toe, methyl 3- (2-guanidinthiazol-ylmethyl-thio) propionate, used as the raw material in this example, was bred in the following manner. A mixture of 6 ml. methanol and 12 ml of chloroform, lo g of 3- (2-guanidinthiazol-4-ylmethylthio) propionitrile m was dissolved after cooling the solution to 0-10 ° C and leaching through it to a gaseous hydrogen chloride, the solution was left to leave 20 hours at 0 - 10 ° C. 0.7 ml was added to the reaction mixture. water and after standing the mixture for 2 hours at room temperature, the reaction mixture was added to 25 ml. ice water that contains 12 g. potassium carbonate and extracted 4 times with pc loo φ. chloroform containing 20% methanol. The resulting extract was concentrated under reduced pressure and the residue was purified on a chromatographic column using a mixture of chloroform and methanol as a solvent to evolve to give 5.0 g. methyl J- (2-guanidinthiazol-4-ylmethyl-thio) propionate indicating a melting point of IOβ-10 [deg.] C.

PlumEit 19

S.

0 ClipoCHpCIipC / / MHOH 3ο

By the same procedure as in Example 18t, using hydr silamine instead of methylamine, 5 - (guanidinthiazol-4-yloethylthio) propionhydroxamic acid was obtained.

The product has the following physico-chemical properties: (i) melting point: 155-156 ° C &lt; ii) MIR (DMSO-d &amp;)

COO: 2.24 (2H, t, -2-0.0) 2.66 (2H, t, -SCH2CH2-) 3.58 (2H, t, -CH2S-) 6.48 (1H,

H (iii) pressed ejector (FD method) m / e 276 (M + + 1) EXAMPLE 20

ch2sch2ch2c

O \

HH 2 To a mixture of 3 ° N · ethanol and 3 ° ml. water is dissolved 5 &quot; of methyl 3 - (2 guanidinthiazol-4-ylmethylthio) propionimide and after standing the solution for 2 hours at 40 [deg.] 0, the solvent is depopulated with reduced pressure. The resulting residue was purified by column chromatography using a mixture of chloroform and methanol and recrystallized from methanol to give 3.2 g. 3- (2-guanidinthiazol-4-ylmethylthio) propionamide showing a melting point of 193 "194 ° C (unbound).

Elementary analysis for C ^ H ^ N 50S2: CHN Calculated: 37.05% 5.o5 »27, oo% Found: 36.97% 5.06» 26.84% 31 ffRIttEB 21 HdH 2 'X h2h

S, CH2SCH2CH2C10 10180-2 .HC1. To 5 o ol 1 N 1IC1 was dissolved 2.5 K · N-sulfamoyl-3 "(2-guanidinthiazol-4-ylmethylthio) propionamidine and after stirring the solution for 2 hours at 40 ° C , the precipitated crystals were collected by filtration ® and recrystallized from a mixture of methanol and ethyl acetate to give 1.65 g of 3 - (2-gyanidinthiazol-4-ylmethylthio) propionylsulfamide chlorhydrate showing a melting point of 166-167 ° C.

Elementary analysis for .H20 CHN Calculated: 24.46% 4.36% 21.39% Found: 24.78% 4.23% 21.61% PBIfiER 22 / V ° C «N- ^ CH2SCH2CH2C ^ .HC1 H2N '/ \ EHS02» H2 U3O ml. methanol was dissolved 4, o9 g. methyl 3 - [(2-guanidinthiazol-4-yl) methylthio] propionimidate and backing, 15 ml was added to the solution. methanolic solution of 2.88 g. sulfamide with deflagration. After deflation for about 3 hours, the solvent was distilled off under dried pressure and the residue was purified on a chromatographic column with silica gel using a mixture of chloroform and methanol (20: 1 --- 10: 1) as a development solvent to give 3.26 g . K-sulfamoyl-3 and (2-guanidin-thiazol-4-yl) methylthio] propionamidine. ? 2

The product shows the following physico-chemical properties:

(i) melting point: 163 - 164 ° C (ii) elemental analysis for:

CHK

Calculated: found: 28.48% 28..37% 4.48% 4.48% 29, oo% 28.97% O (iii) Nuclear magnetic resonance spectra (DMSO - dr) A: O v '2.50 (2H, m, - SCH2CH2 - ), 2.65 (2H, m, -SCHgGH2), 3.6o (2Ht,

AH2S3SH), 6.45 (3J1, (iv) Ha with one spectrum: (FI) method), m / e 338. EXAMPLE 23

V

K

S HSO-CH, HCCOOH A 'inn ^ A' - CH2SCH2CH2C-HHg. HCCOOH a) U lo ml. methanol was dissolved 1.27 E · methyl 3 "; (2-guanidinthiazol-4-yl) methylthio propionimidate and 0.86 g of methanesulfamide and after reaction for 48 hours at e.g., the solvent was distilled under reduced pressure. The resulting residue was purified by purification of the bromide column using silica gel using a mixture of chloroform and methanol (20: 1 - &gt; 10: 1) to give 1.44 g. amorphous U - r! Methanesulfonyl-3- (2-guanidinthiazol-4-yl) methylthio: propionamidine. The product exhibits the following physical properties: 3 (i) Nuclear magnetic resonance spectra

(2H, d, -S0HoCH-), -2-2 n 2.91 (3H, s-CH), 5.67 (2H, s) , A CH s -), 6 * 5 (1H,

H ch2s &quot; ii) Mass spectrum (El method): m / e 536. b) The resulting N-methanesulfonyl 3- (2-guanidinthiazol-4-yl) methylthio propionamidine was dissolved in acetone and then the solution was added dropwise acetone solution 0.5 g. maleic acid, in which crystals are deposited. The crystals were collected by filtration to give N-methanesulfon-3-J &quot; (2-guanidin-thiazol-4-yl) methylthio [propionamidine maleate. The product exhibits the following physical chemical properties:

i) Melting point: 195 - 197 ° C ii) Elemental analysis for ^ 3 ^ 20 ^ 6 ^ 6 ^ 3

CHN

Calculated: 34.51% 4.45% 18.57%

Found: 54.64% 4.49% 18.12% EXAMPLE 24

H 8 ml. methanol was dissolved in 800 ml. methyl 3- (2-guanidin-thiazol-4-yl) methylthio] propionimidate and 590 mg of benzolsulfamide

After reaction at room temperature for 24 hours, the solvent was attenuated at a reduced pressure. The resultant residue was purified on a chromatographic column with silica gel using a slurry of chloroform and methanol (20: 1 -? 10: 1) 34 to give 833 mg of amorphous H-benzenesulfonyl 3- (2guanidinthiazol-4-yl) methylthio propionamide. The product exhibits the following physical chemical properties: 1) Nuclear magnetic resonance spectra (DMSO-d6): 2.60 (4H, m, -5-CH2CH2CF 3-55 (2H, E 'AcHgS-), 6.40 (1H, , 7.50 (3H, m, SO2-Qh), Hv-T 7.8o (2H, m, 2-0), ii) nasal spectrum (PD method): m / e 398 EXAMPLE 25

h2n

ch2sch2ch2c U lo ml. methanol was dissolved 1 g. methyl-3 &apos; J (2-guanidinthiazol-4-yl) methylthio] propion-imidate and 0.38 g of methanesulfamide and after reaction of 48 chips at room temperature, the solvent was depopulated under reduced pressure. The resulting residue is then dissolved in J ml of ethanol and the solution allowed to cool, while white crystals are deposited. The crystals were collected by filtration and dried to give 0.7 g of N-methanesulfonyl-3 "(guanidinthiazol-4-yl) methylthio] -propionamidine. Product

L shows the following physical chemical properties: i) Melting point: 117 - 118 ° C. ii) Nuclear magnetic resonance spectra (CDCl3) h: 35 2.6o (2H, m, - SCHgCHgC 2.8o (2H, m, - sch2ch2c 2.92 (3H, s, SO2CH3 3 * 66 (2H, s, S II 6.50 (1H, 6, CHgS)), EXAMPLE 26

HgN

Xn / ^ CH2SCH2CE2O ^ S02-

X KH,

1 g of solution was dissolved in ethyl alcohol. methyl 3 ~ (2-guanidin-thiazol-1'-yl-4-yl) methylthio propionimide and Ot69 g of p-aminobenzenesulfamide and after reaction at 46 hours at room temperature, the solvent was depopulated under reduced pressure. Z.atim the resulting residue purified on a silica gel chromatography column using a mixture of chloroform and methanol (20: 1 -> 10: 1) to give 1, 2 g. araorphic N-p-aminobenzenesulfonyl- (2-guanidinthiazolar-2-yl) methylthiopropionamidine. The product shows the following JT chemical properties:

Nuclear Magnetic Resonance Spectrum (DMSO-dg), 2: 2.50 (2H, m, - SCH2CH2C2), 2.64 (2H, m, - SCHoCHoO2Cc), 3 * 56 (2H, 68 (2H, s, - H2), 36. 6.40 (1H,

HH 6.54

).), 6.80 (4H, s, BH2 &lt; / RTI &gt; g of N-), m2 7.44 (2H, d,), 7.74 / 8.58 (2H, s, -PRIMERS 27-28HCo2 hh2

According to the same procedures as Example 26, the following compound was prepared EXAMPLE 27: CH, N &amp; 3 H2 &quot; KSV ~ 2 JSH,

N CH2SCH2CH2Cn NH, N-sulfamoyl-3-J (2-R-methylguanidinthiazol-4-yl) methylthio propionamidine.

Amine used in the reaction: HgNSOj ^ NHg Physical chemicals of the product: i) Melting point: 163-164 ° C (recrystallizedBan from methanol). ii) Elementary analysis for 37 CHN Calculated: 3o.76% 4.88% 27.9o% Found: 3o.47% 4.84% 27.6o% ΓΗΙΙΐΕΒ 28: η2ν / C = Ν &lt; Ν

·· S

^ IiS02WH2

CH2SCH2OH2CH2C mz K-Bulxamoyl -4-; (2 ~ guanidinthiazol-4 "yl) niethylthio-butyramidine. Amin used in the reaction: HgNSO ^ i ^

The pesticide hetaic properties of the product: i) Melting point: 159-161 ° C (recrystallized from ethanol). PEIMEk 2-KZ a)

Following the procedure of Example 23, the following compounds were obtained: S. C «N * H0N c

N CH2SCH2CH2C: ^ nso ^ jugh ^ / '\\ 11H_ ii) Elemental analysis for CCHN Calculated: 3o.76% 4.88% 27.9o% Found: 3o.39% 4.86% 27. ol ΓΒΙΓιΕΚΙ 29-32 N-benzylsulphamyl- - 1 (2-guanidinthiazol-4-yl) methylthio] propionamidine .. b) Its maleate.

The amine is taken in the reaction: H ^^^^^^^ V ^

Physical chemical properties of the product: a) i) Nuclear resonance spectra (DMSO - d &amp;): 358- 358- ψο &lt; : sh, SCH0CH0C2-2-2) 2.64 (ΞΗ, m, SCHgCHgCl3), 3-60 (2H, s), 2.30 (2H, d) H), 6.82 (4B, S, H;, * £ \ c «H -), 7-18 (ih,%, so2hhch2),

H H 7.24 (5H, s,

'H 1¾ 7.5O, 8.3 (2H, s -C ^ b)

i) Melting point: 160-162 ° C ii) Elemental analysis for ° 19W6S3:

CHN

Calculated on: Froned: 41.98% 4.64% 18.04% 41.79% 4.64% 17.90% EXAMPLE 30 ^ CH HJ * \ d y &gt; C = NS '' CH2SCH2CH2Cn ^ NS0oK \ d CHNHH-yl-) methylthio) H-dimethylsulfanyl-3-yl (2guanidinthiazol-propionamidine b) Its maleate. ^ / 3

Amin used in the reaction: H ^ NSC ^ N 3 m \

Physical properties of the product: a) i) Nuclear magnetic resonance spectra C / CB, 0: 2 * 59 (6Ht, r 5), nCH, 3 2.5-2.8 (4H, m, SCH2CH2), 3.64 (2H, Si / \ CH2S), 6.50 (1H, s, JS) H 6.84 (4H, s, H_N; 0 M-), h2n b) i) Melting point a: 183- 186 ° C ii) Elemental analysis for ^ 4 ^ 23 ^ 7 ^ 6 ^ 3 CH Calculated: 34.92% 4.81% Found: 34.82% 4.76% (DI1SO-d6):

N 2o.3o% 19-96% 4o ΡΚΙΙ-1ΕΚ 31 Η2Ν χ

CH2SCH2CH2C NS0.CP, 2 3 ΚΗ

2 &lt; , CHCOQH

CHCOOH N-trifluoromethanesulfonyl-3- (2-gyanidinthiazol-4-yl) methylthiophene-propionamideindile

Amin used. in the reaction: H2SO3-jCP2 i) Melting point: 168-170 ° C (recrystallian from methyl ethyl ketone). ii) Elemental analysis for ^ x &lt; t®21I, 6 ^ 1oS3 ^ 3 *

Calculated: Found: EXAMPLE 32 a) h2n h2n-CH 32.80% 3-4-0% N 13.50 32.? Oo 3..46% fw, 00% / o NS '; ch2sch2ch2c &lt;;

N-NSOgNHCH2 (2-guanidinthiazol-4-yl) methylthio N-methylsulfanyl-5-propionamidine · b) Its maleate.

Amin used in the reaction: H ^ SOgNHCR ^

The chemical properties of the product are: a) 2.45 (2H, d, NHCH,) 2.55 (2H, SCH_CIU-CZ 2r-2 2.7O (21, m, SCH2CH2-CIi; Nuclear magnetic resonance spectra (DMso-d) n 6 V ^ 1 O tL ^ (OH Λ 18ΗΓ.Η ^ 41 41 / "3.60 (2H, s, &gt;N" ch2s)

(ev, 6.46 (H, 6.86 (4H, e S0oNHCH-,) 2 - 3

HpN in C = N-) h2n 7.48, 8.26 (2H, s, -C &apos;)

b) i) Melting point: 181 - 184 ° C ii) Elemental analysis: for: C13H21H7 ° 6S5:

CHK

Calculated: 33-4o% 4.53% 2o.97%

Found: 33-36% 4.43% 2o.68% EXAMPLE 33

Medicinal Complex ---- tablets for oral administration. Looo tablet composition: active ingredient 26o g starch 37 g milk sugar 5o g ragnesium stearate 3 6

Goro said components are granulated in a conventional manner using a starch paste as a binding agent and then compressed into molds in tablets of diameter 9.5 mm &lt; 5 &gt;. . • in 42. PRIMES 54

Medical composition - a formulation for injection.

Composition for 2 ml injections: active component 26o ml distilled water for injection to make 2 ml

Distilled water for injections was added to the active component and the active component was dissolved in gas nitrogen conduction to obtain a solution concentration of 13% (concentration of 10% as a base). After filtering the solution, using a 2.2 ml bacterial filter solution was poured into the ampoule of 2 ml under sterile conditions and after ampoule amplitude filled with gaseous nitrogen, the ampoule is closed.

RCH PRIMER 35

V \ / \ // \ J

N (CH2) 4 C / 1 OCH. V, NH, D lo ml. methanolic solution of 2.5 S methyl-5- (2-guanidin-thiazol-4-yl) pentanylate, 0.6 g was added. cyanate, and the taste was stirred at room temperature for 1.5 hours. The castvar was absent and lo ml was added to the residue. acetone. The precipitated crystals were filtered off and the product was purified using dimethylformamide water. The purified product was dissolved in a mixture of 0.7 ml of acetic acid, 8 ml. ethanol and 16 ml of water, and 11.6 ml of a fl-NaOH solution was added to the solution. The precipitated crystals were collected by filtration to give 1.9 g. / 43-

N-cyano-5- (2 guanidinthiazol-4-yl) pentanamidine i) Melting point: 195 - 196 ° C ii) Elemental analysis for Hj3nS

C

H

Calculated:

Hadeno: 45.27% 5-7% 56.95% 45-13% 5-82% 36.62%

In addition, the methyl 5 - (2-guanidinthiazole-4-pentanamidate used as the feedstock in this example was prepared according to the following method: (a) C1 (CH2) 4C0Cl-C1 (0H2) 4000H2Cl in a 3 ml ml of a diazomethane obtained from 43 gp -tosyl-H-methyl N-nitrozoacetamide was added with stirring of 3 [mu] l of etheric

and the solution was allowed to stand at the same temperature for 2 hours. Gaseous hydrogen chloride was carried out through the reaction solution at 0 [deg.] C. and the solution was allowed to stand at the same temperature for 0.5 hours. Saduve was added loo ml of water and the ether layer was separated. The aqueous layer was further extracted twice with a loo ml of ether. Ether layers were collected and the resulting ether solution was dried over anhydrous magnesium sulfate and the solution was distilled off and the residue distilled under reduced pressure to give 8.2 g of 1,6-dichloro-2-hexanone having a boiling point of 120 to 125 ° C ( 14 mmHg). b)

. HCl To a 2oo ml acetone solution of 23.5 K of l6-dichloro-2-hexanone was added 16.4 g of guanythioures and the solution was mixed for two days. 44.

The castrate was distilled off and the residue purified on a silica gel column chromatography using a mixture of chlorophene and methanol as a development raster to give 2-guanidine 4- (4-chlorobutyl) thiazolechlorohydrate (this product showed a melting point of 113 to 114 ° C after recrystallization from a mixture of ethanol and ether). This hydrochloride is dissolved in 3 ml of ml. water and in solution was added loo ml aqueous solution of 17.46 potassium carbonates.

The resulting solution was extracted three times with 5 &lt; RTI ID = 0.0 &gt; ml &lt; / RTI &gt; 2oo ml and 2oo ral chloroform. the quenched solution was collected and dried over anhydrous potassium carbonate, and the solvent was distilled off. The resulting crystals were recrystallized from a mixture of ether and n-hexane to give 2 g of 2-guanidine 4- (4-chlorobutyl) thiazole. Melting point 83 to 84 ° C. c) &lt; CHAC1 h2n C &apos; -v /

// &quot; N / (° V

Twenty-four dimethylsulfaxide was added 4.9 g of sodium cyanide and the resulting crude was heated at 7 [deg.] C. With the mixing of the creature on. 75% * 19.5 e-2-guanidine-4- (4-chlorobutyl) thiazole was added, and the solution was stirred at the same temperature for 3 hours. The keak-cioni solution was cooled and the solution was added to the loo. Chloroform After filtering the uncoated material, the residue was purified by the silica gel column chromatography column using a mixture of chloroform and methanol as a development solvent to give 15 g of 2-guanidine-4- (4-cyanobutyl) thiazole. The product shows 45 / Λ melting point 1O4 - lo5 C after recrystallization from ethyl acetate and n - h «wooden, d) m

lo g of 2-guanidine-4- (4-cyanobutyl) thiazole was suspended in sauce of 60 [mu] l, methanol and llo [alpha] chloroform 1 gas chloride hydrogen was passed through the solution with stirring at -5 to 5 ° C for 2 hours. The hastal &lt; 3 &gt; fragment was left to wash off at 5 [deg.] C. 2 Anttm and the solvent was odious. The residue is succinct in chloroform and methanol sauce, and the suspension is poured into an ice cell containing 6 g of potassium carbonate. The chlorophoric layer was separated and the aqueous layer was further truncated with triplets of 150 alpha chloroform. The extracts were collected and dried over anhydrous potassium carbonate. The prodrug was absent to give a leucine of aetiol 5 ~ (2guanidinteol-4-yl) pentanoate melt point 14 [deg.] ~ 145 [deg.] C. EXAMPLE 36

HgH H2 »

«A2) 4

1 g of N-cyano-5 (2-guanidinthiazol-4-yl) pentanamidine was suspended in a sauce of 2 [alpha] methanol and 3o of ni chloroform

A gas chloride gas is passed through the suspension for 1.5 hours at-5 to 5 ° C and the reaction solution is concentrated under reduced pressure. The oily residue was recrystallized from a mixture of ethanol methanol containing a small amount of water to give 1.1 g of H-carbamoyl-5- (2-guanidinthiazol-4-yl) pentanoamidine dihydrochloride monohydrate at a melting point of 148-150 ° C.

Elemental analysis for .2HC1.H2O

\ C «N

S ch2) 4 c NSOgNHg ΈΗ, CHN Calculated: 32.o9 5.65 26.2o Found: 32.1 DEG 5.65 26.06 EXAMPLE 37 1.5 methyl 5- (2-guyanidinthiazol-4-yl) pentanylidate and 1.1 g of sulfamide dissolved in 4.3 ml of methanol, and the solution was allowed to stand overnight at room temperature. The solvent was evaporated under reduced pressure and the residue was purified on a silica gel column chromatography using a mixture of acetone and methanol as a solvent diluent. The crude crystals were dissolved in a mixture of 0.4 ml of acetic acid, 4 ml of ethanol and 8 ml of water, and treated with activated carbon. To the filtrate was added 6.6 ml of I-NaOH1 and the precipitated crystals were collected by filtration to give 0.70 g. N-sulfamoyl-5- (2-guanidinthiazol-4-yl) pentanoamidine melting point 156 -157 ° C.

Elementary analysis for H 5.36 5 * 4-5 N 3o, 7o 3o, 24

Calculated: Found:

C 33.84 33.55 47

The following reaction stream as in the above example was obtained: N-propylsulfanyl-5- (2-guanidin-thiol-4-yl) pentano-emidine melting points 173 DEG -178 DEG C. (reactant: H2SO3 H (CH2) Η 47 reaction temperature, reaction time and conditions: reflux with warming, 5 hours.) / Jnso2nech2oh2ch3

HN

HjH &lt; ) N \ / Ccii2) ^ c 'M.

Elementary analysis for ^ 12 ^ 23 ^ 7 ^ 2 ^ 2

CH 'N 39.87 6.41 27.12 4o.o9 6.48 26.87 N / X NH (ch2) 4 c ^ \ ez. HC1 S

\ Q «H

Calculated: Found: PHIHER 36

VU of 5-yl methanolic ramure 0,64 g of methyl 5 - (2-guanidinthiazol-4-yl) pentanoimidate is added 0.084 g of ammonium chloride and the solution is stirred overnight at room temperature to a reaction solution of 5 ml. acetone and precipitated crystals were collected by riltration. The resulting crystals were recrystallized from aqueous ethanol to give 0.37 g of 5- (2-guanidin-thiazol-4-yl) pentanamidine chloride.

Elementary analysis for. HC1 9 16 6

Calculated: Found: H 6.19 6.3o

C 39.06 39.16

N 3o.36 3o.l7 48, HOMER 39

= N hs ° 2 (CH2) 4C / "^ MH2

CH-COOH &quot; CH-COOH

R 5 ml of methanol was added 0.64 g of methyl 5- (2-guanidinthiazol-4-yl) pentanylidate and 0.27 g of p-aminobenzenesulfamide, and the solution was heated at reflux for 5 hours. The solvent was evaporated under reduced pressure, the residue was purified by aid of a chromatographic column with silica gel using chloroform-methanol as a development solvent. The resulting product was dissolved in acetone and the resulting solution was added with an acetone solution of 0.4. maleic acid © line.

The precipitated crystals were recrystallized from methanol-ether to give 0.51 g of K-4-amino-benzenesulfonyl-5- (2-guanidinthiazol-4-yl) pentanoamidine moleate melting point 145-146 ° C.

Elemental analysis for ^ 19 ^ 25¾¾ CHH Calculated: 44.61 4.93 19.17 Found: 44.89 4.96 18.67

The following reaction stream as in the example above (reactant: 'f' V-SOpNHg) was obtained with H-benzenesulfonyl- (2-guanidin-thiazol-4-yl) pentanamidine maleic acid at a melting point of 162-164 ° C. K- &quot; 2 &quot; Hg &quot; if x (Cfl2) 4c

HH2

CH-COOH L CH-COOH 49.

Elementary analysis for 49. In addition, the following upper course of the reaction (reactant: H ^ SOgMH-4 &gt; * was obtained with N-cyclohexylsulfamine-5-

V_ "(2-guanidinthiazol-yl) pentanamidine naaleic acid of the melting point 1J0-131 ° C. M V '

'C' N &lt; v

'HH,

Cfl-COOH Hh-cooh CHH Calculated: 45.96 4.87 16.92 Found: 45.67 4.92 16.81

Elementary analysis for 0 HN 44.o9 6.o4 18.94 44.05 6.oo 18.66

Calculated:

Fired: EXAMPLE 40 5, 1 &gt; of ethanol, 0 * 64 g of methyl -5- (2-guanidin-thiazol-4-yl) pentaninidate was dissolved, and 0 * 09 g of propargylamine was added to the rack and the composition was allowed to stand overnight at room temperature. The aquarium was distilled and the residue purified on a chromatographic column ea silica gel using crude chloroform-aethanol-triethylamine as a development processor. The oiled product was quenched in aoetone and a solution of 0 * 4 g of maleic acid was added to the solution. The precipitated crystals were collected by filtration, recrystallized by 5u. from ethanol to give 0.14 g. N-propargyl-5 (2-gyanidin-thiazol-4-yl) pentanamidine maleate.

Elemental analysis for C20H26H6 8S

Calculated: Fired: H 5.15 5.2o

C 4? .O5 46.75

N 16.46 16.54

The following reaction stream as in the example above (reactant: / 7 Τ '-> y, gave N-benzyl-β-CS-guanidinthiazol-4-yl) pentanoamidine dimaleate melting point 92-94 ° C. * = - «

r «,,. rf '&quot; · O * 2'4 in \ MH.

N ^ N

CH-COOH2 and CH-COOH

Elemental analysis for C24H5oW6 ° 8S

Calculated: Found: EXAMPLE 41 'H 5-37 5-35 51..24 50.76 N 14.94 14.82 v *.

N • C * N ->CH2> 4 ° F ° 2 ° &amp; NH.sub.S.H2n. To 5 ml of methanol, 0.17 g of ethanesulfamide and 0.64 g of methyl-5- (2-guanidinylthiazol-4-yl) pentanylidate were added and the solution was heated at 5 rs. The solvent was distilled under reduced pressure and the residue was purified on a silica gel column chromatography using bloroform-methanol as a developmental extender to give 0.56 g of N-ethylsul: Conil-5- (2-guanidine &lt; / RTI &gt; ) pentanamidine melting point 115-116 ° C. Elementary analysis for C- ^ i ^ NgOgSg 0 HN Calculated: 39-74 6.o6 25-28 Found with 39.70 6.o7 25-12 EXAMPLE 42 SH ~ N, \. ^ '0 = E ~. NNHCOCH2 (ch2vc fs nh2 U 5? 1 methanol was dissolved 0.64 g of methyl 5- (2-guanidinthiazol-4-yl) pentanylidate and 0.27 g of acetylhydrazine was added to the solution.The solution solution was stirred at ambient temperature overnight and the melt crystals were collected The obtained product was washed with ethanol-ether to give 0.27 g of N-acetyl-5 "(2-guanidinthiazol-4-yl) pentanamidrazone melting point 157-159 [deg.].

Elementary analysis for 011 * νΜ »CHH Calculated: 44.45 6.44 32-97 Observed 44.06 6-57 52.6 on the pale flow of the reaction as in the example above (reactant: H ^ NlUibO ^ j). Li-benzolsulionyl-4-OHivanidin-thiazol-4-yl) pentanamidrazone was obtained at a melting point of 2 ° 6 ~ 2 ° C. 52H /. V '

nc «n _ // N (ch2) ^ c

Elementary analysis for ° 15H21N7 ° 232 HN Calculated: 45-55 5.35 24.79 Found: 45.53 5.38 24.79 EXAMPLE 43 (CH2) 4CONHC3H5HH '

d »N h2n

To 0.27 mL of 5 &quot; (2-guanidinthiazol-4-yl) propionic acid was added 1 ml of 40% methane methanamine solution, and the racture was allowed to stand at room temperature for 2 days. The ethylated crystals were collected by filtration and washed with methanol followed by ether to give 0.21 g of N-methyl 5 ~ (2-guanidinylthiol-4-yl) amide of valeric acid. This product was recrystallized from aqueous methanol to give the purified product of the melting point 228-232 ° C.

Elemental analysis for ° loH17ii5OS CHN Calculated: 47.04 6.71 27-43 Found: 46.86 6.54 27.68

Accordingly, the 5 &quot; (2-guanidinthiazol-4-yl) valeric acid ethyl ester used in this example was obtained by the following method. 53a) m

(ch2) 4c OCH2CH5 2 {5. 2-guanidin-4- (4-cyanobutyl) thiazole was suspended in a mixture of 15 ml of ethanol and 25 ml of chloroform and a solution of gaseous hydrogen chloride was added to the solution with stirring at -5 to 5 ° C for 2 hours. The resulting solution was allowed to stand at 5 [deg.] C. for 4 days and the solvent was depreciated from reduced pressure. The residue was suspended in ethanol and the syepenis was poured into ice water containing 15 6 · potassium carbonate. The precipitated crystals were collected by filtration, washed with water and ether to give 2.1 g of ethyl 5 ~ (2-guanidinylthiol-4-yl) pantanimidate melting point 158-159 [deg.] C

Na, 2 ethyl-5- (2-6Vidin-thiazol-2-yl) pentanylidate was added 3 ml of ethanol and 3 ml of water. The cracked solution is strongly acidified with acetic acid and heated to CcC for 1 minute. After cooling, 3 ml of chloroform and 3 ml of water were added to the reaction solution. The solution was alkaliated with potassium carbonate and the chloroform layer was separated. The aqueous layer was further extracted two times with 20 ml of chloroform. The chloroform layers were collected and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified on a chromatographic column using chloroform-methanol as a development solvent to give the 2 g of 5 ~ (2-guanidinylthiazol-yl) valeric acid ethyl ester. This product is recrystallized from ethanol to give the purified product of the melting point lo9 - 110 ° C. EXAMPLE 44

CV4Ct

N OH 2 0 * 15 g of hydroxylamine hydrochloride and 0,117 6 sodium hydroxide was dissolved in 5 non-methyl alcohol. After the addition of 0.64 g of methyl (2-guanidinthiazol-4-yl) pentanylidate, the reaction mixture was allowed to stand at room temperature for three days. The Eastvor from the reaction mixture was distilled and the residue was crystallized by the addition of ethyl alcohol and water. The resulting crystals were dissolved in 0.4 ml of acetic acid, 4 ml of ethyl alcohol and 8 ml of water and treated with activated carbon. 6.6 ml of IN and sodium hydroxide were added to the filtrate and the resulting crystals were collected by filtration to give 0.24 g of 5 ~ (2-guanidinthiazol-4-yl) pentanamido oxime melting point 167 &quot; 168 [deg.] C.

C

H

N

Calculated: 42.17 6.29 32.79

Found 42.24 6.39 32.47

The story of the best way for the commercial use of the invention

As the best applicator, a well-known example for use in the invention of the invention is as follows:

HgN ^ CH2 sch2 oh2O ^ MH hhso2 nh2 • HCl In 30 ml of methanol, 4.09 g of methyl 3 - [(2-guanidinyl-azol-4-yl) methylthio propionimide was dissolved and then n solution was added to 15 m . methanolic solution of 2.88 g. sulfamide with deflagration. After deflation for about 3 hours, the solvent was distilled off under reduced pressure and the residue was quenched on a silica gel column chromatography using a mixture of chloroform and methanol (20: 1 --- to: 1) as a development solvent to give 3 &quot; 26 g . N-sulfamoyl-3 [(2-guanidin-thiazol-4-yl) methylthio] propionamidine.

The product shows the following fi lco-chemical properties:

(i) melting point: 163 - 164 ° C (ii) elemental analysis for ^:

CHH

Calculated: 28.48% 4.4® »29» 00%

Fired: 28.37% 4.48% 28.97% (iii) Nuclear magnetic resonance spectra (DMSO - d ^)%:

Claims (1)

_ζ(&amp; P1ISBIHI ZAHTEVI • Postopek sa dobijacnje gvanidlntlasolnlh jedlmjenja formule B-HH H \ Orfr-^_z (&amp; P1 &lt; RTI ID = 0.0 &gt; REQUIREMENTS) &lt; / RTI &gt; The process of obtaining a guanidine derivative of formula B-HH H &lt; Orfr- «(OHg),, -A Ode H predstavlja atom Vodenika ili nižu alkil grupu, T predstavlja atom sumpora 111 motilen grupu, m i m su ceo broj 1,2 111 3 a A 11-¾ oznadava - C \ grnpu 111 HM, COHH - grupu u kojoj jo vodonik, oljarno grupa* kartamo 11 grupa, ureido grupa, hidrokallna grupa, niža alkoksi grupa, »12a Oj. acil grupa, acllamino grupa, fenilaulfanoil grupa, ίekil^Š^^SŠiitgr'^^a ili - EOg - Ej grupa, gda je B^ niža alkil grapa, niža 0^ halogenalkll grupa, u datom eludaju supstituisana fenil grupa, «arino grupa, aono - ili dl - niža alkileaino grupa, fanti srnino grupa ili fenil alkil arnlno grupa, Rg jo vodonik, niža alkil grupa, niža alkenil grupa, niža alkinll gr^a, cijano grupa 111 niža aoil grupa, a B^ je vodonik, niža alkil grupa, hidrokailna grupa ili sulfaaoil grupa i njene soli, nesnažen time, Sto obuhvata reakciju jedinjenja formule * &quot; &quot;“C.,- Βλ gde je/niža °χ^ alkll grugpa^ X predstavlja vodonlk, H-fc^ ili B-®g a B, B^f Bgf X9 a i n iaajti isto ssnaSenje kao u ebmjoj fonrali* sa «dno« opita formule Βχ * HHg» Bg -¾¾ 111 B^ -BHg gia Bj* Bg 1 imaju «naSanja kao u gornjo j fonrali pri časa ea reakcija isvodi u teavodno* organsko« rastvaraču kao Sto ja «etanol, atakoi, laopropanol« hloroform» at ar* tetrahidrofuran ili toenzol9 na temperaturi od sobne temperature do temperature refluksa* TAMAHOUCHI JESABIttOEOSIGAL Co. Itd. Zaetupniki 9DSSBOZATOD(OHg) ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, a group in which hydrogen, an oil group * maps 11 groups, an ureido group, a hydrocarbon group, a lower alkoxy group, "12a O. an acyl group, an acylamino group, a phenyl sulfonyl group, a hydroxyl group, or a - EOg -Ej group, wherein B is a lower alkyl grape, a lower O halogenalkyl group, in a given substituted phenyl group, an "aryl group , a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkyl group, a lower alkyl group, a lower alkyl group, a lower alkyl group, a lower alkyl group or a phenyl alkyl group, a lower alkyl group, a hydrocyl group or a sulfamoyl group and its salts, unsaturated with time, comprising reacting a compound of formula &quot; "C., - Bλ where / lower ° χ ^ alkll grugpa ^ X represents water, H-fc ^ or B-®ga B, B ^ f Bgf X9 and also the same equation as in the background * with the bottom "Experiments of the formula Βχ * HHg" Bg-¾ 111 B ^ -BHg gia Bj * Bg 1 have "finds as in the upper j of the phonon at ea reaction time into a trivial" organic "solvent such as" ethanol, ataco, laopropanol "chloroform »At ar * tetrahydrofuran or toenzol 9 at a temperature from room temperature to reflux temperature * TAMAHOUCHI JESABIttOEOSIGAL Co. Etc. Circuits 9DSSBOZATOD