Claims (15)
1. Spoj formule II
[image]
naznačen time da
M je CH2 ili NH;
R1 je H ili hidroksi;
R2 je H, CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2OH, -CH2OCH3, -CH(OH)CH3, -CH2SCH3, ili -CH2CH2SCH3;
ili njegova farmaceutski prihvatljiva sol, za upotrebu u profilaksi ili liječenju opće kolestaze.1. Compound of formula II
[image]
indicated that
M is CH2 or NH;
R 1 is H or hydroxy;
R2 is H, CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2OH, -CH2OCH3, -CH(OH)CH3, - CH2SCH3, or -CH2CH2SCH3;
or a pharmaceutically acceptable salt thereof, for use in the prophylaxis or treatment of generalized cholestasis.
2. Spoj za upotrebu prema zahtjevu 1, naznačen time da spoj formule II je odabran iz grupe koja se sastoji od:
1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N-(karboksimetil)karbamoil] benzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin;
1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N’-((S)-1-karboksietil)karbamoil]benzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,5-benzotiazepin;
1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N-((S)-1-karboksipropil) karbamoil]benzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin;
1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N-((R)-1-karboksi-2-metiltioetil)karbamoil]benzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin;
1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N-((S)-1-karboksipropil) karbamoil]-4-hidroksibenzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin;
1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N-((R)-1-karboksi-2-metiltio-etil)karbamoil]-4-hidroksibenzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin;
1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N-((S)-1-karboksi-2-methilpropil)karbamoil]benzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin;
1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N-((S)-1-karboksi-2-(R)-hidroksipropil)karbamoil]-4-hidroksibenzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin;
1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N-((S)-1-karboksibutil) karbamoil]-4-hidroksibenzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin;
1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N-((S)-1-karboksietil) karbamoil]benzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin;
1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N’-((S)-1-karboksipropil) karbamoil]-4-hidroksbenzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,5-benzotiazepin;
1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N-((S)-1-karboksietil)karbamoil]-4-hidroksibenzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin;
1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N-((S)-1-karboksi-2-metilpropil)karbamoil]-4-hidroksibenzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin; i
1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-1’-fenil-1’-[N’-(karboksimetil) karbamoil]metil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,5-benzotiazepin,
ili njihove farmaceutski prihvatljive soli.2. Compound for use according to claim 1, characterized in that the compound of formula II is selected from the group consisting of:
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl] benzyl}carbamoylmethoxy)-2,3,4 ,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy )-2,3,4,5-tetrahydro-1,5-benzothiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthioethyl)carbamoyl] benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl) carbamoyl]-4-hydroxybenzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl] benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)- hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxybutyl) carbamoyl]-4-hydroxybenzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-((S)-1-carboxypropyl) carbamoyl]-4- hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl }carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl] -4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; and
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy )-2,3,4,5-tetrahydro-1,5-benzothiazepine,
or pharmaceutically acceptable salts thereof.
3. Spoj za upotrebu prema zahtjevu 1 ili 2, naznačen time da spoj formule II je 1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N-((S)-1-karboksipropil)karbamoil]-4-hidroksibenzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin, ili njegova farmaceutski prihvatljiva sol.3. Compound for use according to claim 1 or 2, characterized in that the compound of formula II is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α- [N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, or a pharmaceutically acceptable salt thereof.
4. Spoj za upotrebu prema zahtjevu 1 ili 2, naznačen time da spoj formule II je 1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-1’-fenil-1’-[N’-(karboksimetil)-karbamoil]metil}karbamoilmetoksi-2,3,4,5-tetrahidro-1,5-benzotiazepin, ili njegova farmaceutski prihvatljiva sol.4. Compound for use according to claim 1 or 2, characterized in that the compound of formula II is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1' -phenyl-1'-[N'-(carboxymethyl)-carbamoyl]methyl}carbamoylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine, or a pharmaceutically acceptable salt thereof.
5. Spoj 1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N-((S)-1-karboksipropil)klarbamoil]-4-hidroksibenzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,2,5-benzohiadiazepin, ili njegova farmaceutski prihvatljiva sol za upotrebu u profilaksi ili liječenju opće kolestaze.5. Compound 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)clarbamoyl]- 4-Hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzohiadiazepine, or a pharmaceutically acceptable salt thereof for use in the prophylaxis or treatment of generalized cholestasis.
6. Spoj 1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-1’-fenil-1’-[N’-(karboksimetil)karbamoil] metil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,5-benzotiazepin, ili njegova farmaceutski prihvatljiva sol, za upotrebu u profilaksi ili liječenju opće kolestaze.6. Compound 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)carbamoyl] methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine, or a pharmaceutically acceptable salt thereof, for use in the prophylaxis or treatment of generalized cholestasis.
7. Spoj za upotrebu prema bilo kojem od zahtjeva 1 do 6, naznačen time da opća kolestaza je intra- ili ekstrahepatična kolestaza.7. Compound for use according to any one of claims 1 to 6, characterized in that the general cholestasis is intra- or extrahepatic cholestasis.
8. Spoj za upotrebu prema bilo kojem od zahtjeva 1 do 6, naznačen time da opća kolestaza je žutica zbog lijekova ili žutica tijekom trudnoće.8. The compound for use according to any one of claims 1 to 6, characterized in that the general cholestasis is jaundice due to drugs or jaundice during pregnancy.
9. Farmaceutski pripravaka koji sadrži spoj formule (II)
[image]
naznačen time da
M je CH2 ili NH;
R1 je H ili hidroksi;
R2 je H, CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2OH, -CH2OCH3, -CH(OH)CH3, -CH2SCH3, ili -CH2CH2SCH3;
ili njegova farmaceutski prihvatljiva sol, za upotrebu u profilaksi ili liječenju opće kolestaze.9. Pharmaceutical preparations containing the compound of formula (II)
[image]
indicated that
M is CH2 or NH;
R 1 is H or hydroxy;
R2 is H, CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2OH, -CH2OCH3, -CH(OH)CH3, - CH2SCH3, or -CH2CH2SCH3;
or a pharmaceutically acceptable salt thereof, for use in the prophylaxis or treatment of generalized cholestasis.
10. Farmaceutski pripravak za upotrebu prema zahtjevu 9, naznačen time da spoj formule II je 1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N-((S)-1-karboksipropil)karbamoil]-4-hidroksibenzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin, ili njegova farmaceutski prihvatljiva sol.10. Pharmaceutical preparation for use according to claim 9, characterized in that the compound of formula II is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[ N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, or a pharmaceutically acceptable salt thereof.
11. Farmaceutski pripravak za upotrebu prema zahtjevu 9, naznačen time da spoj formule II je 1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-1’-fenil-1’-[N’-(karboksimetil)karbamoil]metil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,5-benzotiazepin, ili njegova farmaceutski prihvatljiva sol.11. Pharmaceutical preparation for use according to claim 9, characterized in that the compound of formula II is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'- phenyl-1'-[N'-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine, or a pharmaceutically acceptable salt thereof.
12. Farmaceutska kombinacija za istovremenu ili sekvencijalnu primjenu, koja sadrži spoj formule II
[image]
naznačena time da
M je CH2 ili NH;
R1 je H ili hidroksi;
R2 je H, CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2OH, -CH2OCH3, -CH(OH)CH3, -CH2SCH3, ili -CH2CH2SCH3;
ili njegova farmaceutski prihvatljiva sol, i ursodeoksiholična kiselina, za upotrebu u profilaksi ili liječenju opće kolestaze.12. A pharmaceutical combination for simultaneous or sequential administration, containing a compound of formula II
[image]
indicated that
M is CH2 or NH;
R 1 is H or hydroxy;
R2 is H, CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2OH, -CH2OCH3, -CH(OH)CH3, - CH2SCH3, or -CH2CH2SCH3;
or a pharmaceutically acceptable salt thereof, and ursodeoxycholic acid, for use in the prophylaxis or treatment of generalized cholestasis.
13. Farmaceutska kombinacija za istovremenu ili sekvencijalnu primjenu, koja sadrži spoj formule II
[image]
naznačen time da
M je CH2 ili NH;
R1 je H ili hidroksi;
R2 je H, CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2OH, -CH2OCH3, -CH(OH)CH3, -CH2SCH3, or -CH2CH2SCH3;
ili njegova farmaceutski prihvatljiva sol, i nor-ursodeoksiholična kiselina, za upotrebu u profilaksi ili liječenju opće kolestaze.13. A pharmaceutical combination for simultaneous or sequential administration, containing a compound of formula II
[image]
indicated that
M is CH2 or NH;
R 1 is H or hydroxy;
R2 is H, CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2OH, -CH2OCH3, -CH(OH)CH3, - CH2SCH3, or -CH2CH2SCH3;
or a pharmaceutically acceptable salt thereof, and nor-ursodeoxycholic acid, for use in the prophylaxis or treatment of generalized cholestasis.
14. Farmaceutska kombinacija za upotrebu prema zahtjevu 12, naznačena time da spoj formule II je 1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-α-[N-((S)-1-karboksipropil)karbamoil]-4-hidroksibenzil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,2,5-benzotiadiazepin, ili njegova farmaceutski prihvatljiva sol.14. Pharmaceutical combination for use according to claim 12, characterized in that the compound of formula II is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[ N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, or a pharmaceutically acceptable salt thereof.
15. Farmaceutska kombinacija za upotrebu prema zahtjevu 12, naznačena time da spoj formule II je 1,1-diokso-3,3-dibutil-5-fenil-7-metiltio-8-(N-{(R)-1’-fenil-1’-[N’-(karboksimetil)karbamoil]metil}karbamoilmetoksi)-2,3,4,5-tetrahidro-1,5-benzotiazepin, ili njegova farmaceutski prihvatljiva sol.15. Pharmaceutical combination for use according to claim 12, characterized in that the compound of formula II is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'- phenyl-1'-[N'-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine, or a pharmaceutically acceptable salt thereof.