SI9210098B - Benzimidazoli, zdravila, ki te spojine vsebujejo, in postopek za njihovo pripravo - Google Patents

Benzimidazoli, zdravila, ki te spojine vsebujejo, in postopek za njihovo pripravo Download PDF

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SI9210098B
SI9210098B SI9210098A SI9210098A SI9210098B SI 9210098 B SI9210098 B SI 9210098B SI 9210098 A SI9210098 A SI 9210098A SI 9210098 A SI9210098 A SI 9210098A SI 9210098 B SI9210098 B SI 9210098B
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methyl
imidazo
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carbon atoms
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Norbert Hauel
Berthold Narr
Uwe Ries
Meel Jacques Van
Wolfgang Wienen
Michael Entzeroth
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Dr. Karl Thomae
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Claims (9)

1 PATENTNI ZAHTEVKI 1. Benzimidazoli s splošno formulo
v kateri pomenijo Ri atom fluora, klora ali broma, alkilno, cikloalkilno, fluormetilno, difluormetilno ali trifluormetilno skupino, R2 po izbiri z eno ali dvema alkilna skupinama ali s tetrametilensko ali pentametilensko skupino substituirano 5-, 6- ali 7-člensko alkilenimino- ali alkenilenimino skupino, v kateri je metilenska skupina nadomeščena s karbonilno ali sulfonilno skupino, po izbiri z alkilno ali fenilno skupino mono- ali disubstituirano imido skupino maleinske kisline, pri čemer so lahko substituenti enaki ali različni, po izbiri v položaju 1 z alkilno skupino z 1 do 6 atomi ogljika ali cikloalkilno skupino substituirano benzimidazol-2-ilno ali 4,5,6,7-tetrahidro-benzimidazol-2-ilno skupino, pri čemer je lahko fenilno jedro ene od predhodno navedenih benzimidazolnih skupin dodatno substituirano z atomom fluora, metilno ali trifluormetilno skupino, imidazo[2. l-b]tiazol-6-ilno imidazo[1.2-a]piridin-2-ilno, 5,6,7,8-tetrahidro-imidazo[ 1.2-a]piridin-2-ilno, imidazo-[ 1.2-a]pirimidin-2-ilno, imdazo[4.5-b]piridin-2-ilno, imidazo[4.5-c]piridin-2-ilno, imidazo[1.2-c]pirimidin-2-ilno, imidazo[1.2-a]pirazin-2-ilno, imidazo[1.2-b]piridazin-2-ilno, purin-8-ilno, imdazo[4.5-b]pirazin-2-ilno, imidazo[4.5-c]piridazin-2-ilno ali imidazo[4.5-d]piridazin-2-ilno skupino, piridilno skupino, ali 2 po izbiri v položaju 1 z alkilno ali benzilno skupino preko atoma ogljika vezano imidazolilno skupino, ki je lahko dodatno v ogljikovem ogrodju substituirana z alkilno skupino, R3 alkilno skupino z 1 do 5 atomi ogljika ali cikloalkilno skupino s 3 do 5 atomi ogljika, in R4 karboksi ali lH-tetrazolilno skupino, in njihove soli z anorganskimi ali organskimi kislinami ali bazami, pri čemer, če ni drugače navedeno, lahko predhodno navedeni alkilni del vsebuje vsakokrat 1 do 3 atome ogljika, predhodno navedeni cikloalkilni del pa vsakokrat 3 do 7 atomov ogljika.
2. Benzimidazoli s splošno formulo I po zahtevku 1 v kateri pomenijo Ri atom klora, alkilno skupino z 1 do 3 atomi ogljika ali trifluormetilno skupino R2 5-, 6- ali 7-člensko alkilenimino skupino, v kateri je lahko metilenska skupina nadomeščena s karbonilno ali sulfonilno skupino, po izbiri z alkilno skupino z 1 do 3 atomi ogljika ali s fenilno skupino mono- ali di-substituirano imido skupina maleinske kisline, pri čemer so lahko substituenti enaki ali različni, po izbiri v položaju 1 z alkilno skupino z 1 do 6 atomi ogljika ali cikloalkilno skupino substituirano bezimidazol-2-ilno ali 4,5,6,7-tetrahidro-benzimidazol-2-ilno skupino, pri čemer je lahko fenilno jedro ene od predhodno navedenih benzimidazolnih skupin dodatno substituirano z atomom fluora, metilno ali trifluormetilno skupino, imidazo[2. l-b]tiazol-6-ilno, imidazo[1.2-a]piridin-2-ilno, 5,6,7,8- tetrahidroimidazo[ 1,2-a]piridin-2-ilno, imidazo[ 1.2-a]pirimidin-2-ilno, imidazo[4.5-b]piridin-2-ilno, imidazo[4.5-c]piridin-2-ilno, imidazo[l .2-c]pirimidin-2-ilno, imidazo[1.2-a]pirazin-2-ilno, imidazo[1.2-b]piridazin-2-ilno, purin-8-ilno, imidazo[4.5-b]pirazin-2-ilno, imidazo[4.5-c]piridazin-2-ilno ali imidazo[4.5-d]piridazin-2-ilno skupino, piridilno skupino, ali v položaju 1 z alkilno skupino z 1 do 3 atomi ogljika ali z benzilno skupino substituirano imidazol-4-ilno skupino, ki je lahko dodatno v ogljikovem ogrodju substituirana z alkilno skupino z 1 do 3 atomi ogljika, 3 R3 alkilno skupino z 1 do 5 atomi ogljika ali cikloalkilno skupino s 3 do 5 atomi ogljika, in R4 karboksilno ali ΙΗ-tetrazolilno skupino, in njihove soli z anorganskimi ali organskimi kislinami ali bazami.
3. Benzimidazoli s splošno formulo I po zahtevku 1, v kateri pomenijo Ri merilno skupino ali atom klora, R2 5-, 6- ali 7-člensko alkilenimino skupino, v kateri je lahko metilenska skupina nadomeščena s karbonilno ali sulfonilno skupino, po izbiri z alkilno skupino z 1 do 3 atomi ogljika ali s fenilno skupino mono- ali di-substituirano imido skupino maleinske kisline, pri čemer so lahko substituenti enaki ali različni, po izbiri v položaju 1 z alkilno skupino z 1 do 3 atomi ogljika substituirano benzimidazol-2-ilno ali 4,5,6,7-tetrahidrobenzimidazol-2-ilno skupino, pri čemer je lahko fenilno jedro ene od predhodno navedenih benzimidazolnih skupin dodatno substituirano z atomom fluora, imdazo[1.2-a]piridin-2-ilno, 5,6,7,8-tetrahidro-imidazo[1.2-a]piridin-2-ilno, imidazo[1.2-a]pirimidin-2-ilno ali imidazo[2. l-b]tiazol-6-ilno skupino, ali v položaju 1 z alkilno skupino z 1 do 3 atomi ogljika substituirano imidazol-4-ilno skupino, R3 alkilno skupino z 1 do 5 atomi ogljika ali cikloalkilno skupino s 3 do 5 atomi ogljika, in R4 karboksilno ali ΙΗ-tetrazolilno skupino, in njihove soli z anorganskimi ali organskimi kislinami ali bazami.
4. Naslednji benzimidazoli s splošno formulo I po zahtevku 1: (a) 4'-[[2-n-propil-4-metil-6-(l-metilbenzimidazol-2-il)-benzimidazol-l-il]metil]bifenil-2-karboksilna kislina (b) 4'-[[2-n-propil-4-metil-6-( l-metilbenzimidazol-2-il)-benzimidazol- l-il]metil]-2-(1 H-tetrazol-5-il)bifenil (c) 4'-[[2-n-propil-4-meril-6-(butansultam-l-il)-benzimidazol-l-il]metil]-2-(1 H-tetrazol-5-il)bifenil 4 (e) 4'-[(2-ciklopropil-4-metil-6-(l-metilbenzimidazol-2-il)benzimidazol-1 -il)-metil]biefnil-2-karboksilna kislina (f) 4’-[(2-n-propil-4-metil-6-( lmetil-5-fluor-benzimidazol-2-il)benzi-midazol- l-il)metil]bifenil-2-karboksilna kislina (g) 4'-[(2-n-propil-4-metil-6-(imidazo[1.2-a]pirimidin-2-il)benzimidazol-l-il)metil]-2-(1 H-tetrazol-5-il)bifenil (h) 4'-[(2-n-propil-4-metil-6-(5,6,7,8-tetrahidro-iniidazo[ 1,2-a]-piridin-2-il)benzimidazol- l-il)metil]bifenil-2-karboksilna kislina (i) 4'-[(2-n-propil-4-metil-6-(5,6,7,8-tetrahidro-imidazo[ 1,2-a]-piridin-2-il)benzimidazol- l-il)metil]-2-( lH-tetrazol-5-il)bifenil (j) 4'-[(2-n-propil-4-klor-6-(l-metilbenzimidazol-2-il)benzimidazol-l-il)metil]-2-(lH-tetrazol-5-il)bifenil (k) 4'-[[2-n-propil-4-metil-6-(imidazo[2. l-b]tiazol-6-il)benzimidazol-l-il]metil]bifenil-2-karboksilna kislina (l) 4'-[[2-etil-4-metil-6-(butansultam-l-il)benzimidazol- l-il]metil]-2-( 1H-tetrazol-5-il)bifenil (m) 4'-[[2-n-butil-4-metil-6-(l-metilbenzimidazol-2-il)benzimidazol-l-il]metil]-2-(lH-tetrazol-5 -il)bifenil (n) 4'-[[2-n-propil-4-metil-6-(imidazo[ 1 2-a]piridin-2-il)benzimidazol- 1- il]metil]bifenil-2-karboksilna kislina (o) 4'-[[2-n-propil-4-metil-6-(imidazo[ 1.2-a]piridin-2-il)benzimidazol- l-il]metil]- 2- ( lH-tetrazol-5-il)bifenil (P) 4'-[[2-n-propil-4-metil-6-(imidazo[2. l-b]tiazol-6-il)benzimidazol- l-il]metil]-2-( 1 H-tetrazol-5-il)bifenil (q) 4'-[[2-n-propil-4-metil-6-(l-metil-6-fluor-benzimidazol-2-il)benzimidazol- 1- il)metil]bifenil-2-karboksilna kislina, in njihove soli z anorganskimi ali organskimi kislinami ali bazami.
5. 4'-[ [2-n-propil-4-metil-6-( 1 -metilbenzimidazol-2-il)benzimidazol-1 -il]metil]bifenil- 2- karboksilna kislina in njene soli z anorganskimi ali organskimi kislinami ali bazami. 5
6. Fiziološko prenesljive soli spojin po vsaj enem od zahtevkov 1 do 5 z anorganskimi ali organskimi kislinami ali bazami.
7. Zdravilo, ki vsebuje spojino po vsaj enem od zahtevkov 1 do 5 ali fiziološko prenesljivo sol po zahtevku 6 poleg po izbiri enega ali več inertnih nosilcev in/ali razredčil.
8. Uporaba spojine po vsaj enem od zahtevkov 1 do 6 za pripravo zdravila z angiotenzinskim antagonističnim učinkom.
9. Postopek za pripravo zdravila po zahtevku 7, označen s tem, da na nekemični način vdelamo spojino po vsaj enem od zahtevkov 1 do 6 v enega ali več inertnih nosilcev in/ali razredčil.
10. Postopek za pripravo benzimidazolov po zahtevkih 1 do 6, označen s tem, da a) cikliziramo spojino s splošno formulo
(II) , v kateri sta Ri in R2, kot je definirano v zahtevkih 1 do 5, eden od ostankov Xi ali Yi pomeni skupino s splošno formulo,
6 drugi od ostankov X! ali Yi pa skupino s splošno formulo, 6
Z 2 R3 pri čemer sta R3 in R4, kot je definirano v zahtevkih 1 do 5, Rg je atom vodika ali R3CO-skupina, pri čemer je R3, kot je definirano predhodno, Zi in Z2, ki sta lahko enaka ah različna, pomenita po izbiri substituirane amino skupine ah po izbiri z nižjimi alkilnimi skupinami substituirane hidroksi ah merkapto skupine, ah Zi in Z2 skupaj pomenita atom kisika ah žvepla, po izbiri z alkilno skupino z 1 do 3 atomi ogljika substituirano imino skupino, alkilendioksi ah alkilenditio skupino z vsakokrat 2 ah 3 atomi ogljika, pri čemer mora eden od ostankov Xi ah Yi pomeniti skupino s splošno formulo ah
in po izbiri tako dobljeni ustrezni N-oksid reduciramo, ah b) benzimidazol s splošno formulo (III),
7 R
H v kateri so Ri do R3, kot je definirano v zahtevkih 1 do 5, presnovimo z bifenilno spojino s splošno formulo
/ (IV) , v kateri je Rt, kot je definirano v zahtevkih 1 do 5 in Z3 pomeni nukleofilno izstopno skupino, ali c) za pripravo spojine s splošno formulo I, v kateri R4 pomeni karboksi skupino, spojino s splošno formulo R
(V) , v kateri so Ri do R3, kot je definirano v zahtevkih 1 do 5, in je
8 RV skupina, ki se da prevesti v karboksi skupino s hidrolizo, termolizo ali hidrogenolizo, presnovimo v ustrezno karboksi spojino, ali d) za pripravo spojine s splošno formulo I, v kateri R4 pomeni lH-tetrazolilno skupino, odcepimo zaščitni ostanek spojine s splošno formulo
(vi) . v kateri so Ri, R2 in R3, kot je definirano v zahtevkih 1 do 5 in R4" pomeni lH-tetrazolilno skupino, zaščiteno v 1- ali 3-položaju z zaščitnim ostankom, ali e) za pripravo spojine s splošno formulo I, v kateri R4 pomeni lH-tetrazolilno skupino, spojino s splošno formulo
CN (VII), v kateri so Ri do R3, kot je definirano v zahtevkih 1 do 5, presnovimo z dušikvodikovo kislino ali njenimi solmi, ali 9 f) za pripravo spojin s splošno formulo I, v kateri R2 pomeni eno od skupin: imidazol[1.2-a]piridin-2-ilno, imidazol[ 1.2-a]pirimidin-2-ilno, imidazol[1.2-c]pirimidin-2-ilno, imidazo[1.2-a]pirazin-2-ilno, imidazo[1.2-b]piridazin-2-ilno ali imidazo[2.1-b]tiazol-6-ilno, navedenih v zahtevkih 1 do 5, presnovimo spojino s splošno formulo
9 B N (VIII), S) nh2 v kateri pomenijo eden od ostankov A, B, C ali D po izbiri z merilno skupino substituirano metinsko skupino ali atom dušika, in drugi ostanki A, B, C ali D metinske skupine, ali A in B vsakokrat metinsko skupino, in -C=D-skupina atom žvepla, s spojino s splošno formulo
(IX) , v kateri so Ri, R.3 in R4, kot je definirano v zahtevkih 1 do 5 in Z4 pomeni nukleofilno izstopno skupino, kot je atom halogena, npr. atom klora ali broma, ali g) za pripravo spojin s splošno formulo I, v kateri R2 pomeni eno od skupin: benzimidazol-2-ilno, imidazo[4.5-b]piridin-2-ilno, imidazo[4.5-c]piridin-2-ilno, 10 imidazo[4.5-b]pirazin-2-ilno, imidazo[4.5-c]piridazin-2-ilno, imidazo[4.5-d]piridazin-2-ilno ali purin-8-ilno, navedenih v zahtevkih 1 do 5, cikliziramo spojino s splošno formulo 10
C (X) ,
v kateri pomenijo nobeden, eden ali dva od ostankov Ai, Bb Q ali Di atom dušika in drugi ostanki od ostankov Ai, Bi, Ci ali Di metinske skupine kot tudi Ri j atom vodika ali fluora, metilno ali trifluormetilno skupino, eden od ostankov X2 ali Y2 pomeni Ri3-NH-skupino in drugi od ostankov X2 ali Y2 skupino s splošno formulo
pri čemer so Rj, R3 in R4, kot je definirano v zahtevkih 1 do 5, eden od ostankov Ri3 ali R14 pomeni atom vodika in drugi od ostankov Ri3 ali Ru atom vodika, alkilno skupino z 1 do 6 atomi ogljika ali cikloalkilno skupino s 3 do 7 atomi ogljika, Z5 in Zg, ki sta lahko enaka ali različna, pomenita po izbiri substituirane amino skupine ali po izbiri z nižjimi alkilnimi skupinami substituirane hidroksi ali merkapto skupine, ali Z5 in Z6 pomenita skupaj atom kisika ali žvepla, po izbiri z alkilno skupino z 1 do 3 atomi ogljika substituirano imino skupino, alkilendioksi ali alkilenditio skupino z 11 vsakokrat 2 ali 3 atomi ogljika, in po izbiri tako dobljeni ustrezni N-oksid reduciramo in tako dobljeno spojino po izbiri nato hidroliziramo in po potrebi odcepimo zaščitni ostanek, uporabljen za zaščito reaktivnih skupin pri presnovah a) do g), in/ali po potrebi tako dobljeno izomemo zmes ločimo v njene izomere in/ali tako dobljeno spojino s splošno formulo I prevedemo v njeno sol, zlasti za farmacevtsko uporabo v njeno fiziološko prenesljivo sol z anorganskimi ali organskimi kislinami ali bazami. Za Dr. KARL THOMAE Gesellschaft mit beschrankter Haftung:
SI9210098A 1991-02-06 1992-01-30 Benzimidazoli, zdravila, ki te spojine vsebujejo, in postopek za njihovo pripravo SI9210098B (sl)

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DE4137812A DE4137812A1 (de) 1991-02-06 1991-11-16 Benzimidazole, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung
YU9892A YU48849B (sh) 1991-02-06 1992-01-30 Benzimidazoli, njihove 1-,3-izomerne smeše i njihove soli kao i postupak za njihovo dobijanje

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FI920486A (fi) 1992-08-07
EP0502314B1 (de) 1998-05-20
DK0502314T3 (da) 1999-03-29
CA2060624C (en) 1999-12-21
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AU1070792A (en) 1992-08-13
NO2002011I2 (no) 2008-03-03
FI105547B (fi) 2000-09-15
HU217084B (hu) 1999-11-29
BG62309B2 (bg) 1999-07-30
FI920486A0 (fi) 1992-02-05
NO920476D0 (no) 1992-02-05
NL990007I2 (nl) 1999-07-01
DE10299029I2 (de) 2006-06-29
IE920373A1 (en) 1992-08-12
HUT60493A (en) 1992-09-28
SI9210098A (en) 1994-12-31
MX9200509A (es) 1992-08-01
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HRP940752B1 (en) 2001-02-28
IE81111B1 (en) 2000-03-08
JPH04346978A (ja) 1992-12-02
HK1011145A1 (en) 1999-07-02
ATE166346T1 (de) 1998-06-15
PL293387A1 (en) 1993-01-25
EP0502314A1 (de) 1992-09-09
LU91802I2 (fr) 2011-05-30
LU90372I2 (fr) 1999-05-12
NL990007I1 (nl) 1999-06-01
NL300095I2 (nl) 2002-11-01
SG50481A1 (en) 1998-07-20
JP2709225B2 (ja) 1998-02-04
AU655794B2 (en) 1995-01-12
SK279261B6 (sk) 1998-08-05
LU90950I2 (fr) 2002-10-30
PL169675B1 (pl) 1996-08-30
DE10299029I1 (de) 2003-01-23
CS30692A3 (en) 1992-08-12
NL300095I1 (nl) 2002-09-02
NO2011005I1 (no) 2011-05-16
DE59209330D1 (de) 1998-06-25
HRP940752A2 (en) 1997-04-30
HU211524A9 (en) 1995-11-28
NO301585B1 (no) 1997-11-17
RU2053229C1 (ru) 1996-01-27
HU9200355D0 (en) 1992-04-28
DE59209330C5 (de) 2013-10-31
CZ287607B6 (cs) 2001-01-17
ES2118095T4 (es) 2011-04-07
CH0502314H1 (sl) 2012-03-15
NO920476L (no) 1992-08-07
IL100864A (en) 1996-01-19
IL100864A0 (en) 1992-11-15
CA2060624A1 (en) 1992-08-07

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