RU2001119160A

RU2001119160A - Phenylglycine derivatives

Info

Publication number: RU2001119160A
Application number: RU2001119160/04A
Authority: RU
Inventors: Жан АККЕРМАНН; Лео АЛИГ; Александер ХУХОЛОВСКИ; Катрин ГРЁБКЕ; Курт ХИЛЬПЕРТ; Хольгер Кюне; Ульрике ОБСТ; Лутц Вебер; Ханс Петер Вессель
Original assignee: Ф.Хоффманн-Ля Рош Аг
Priority date: 1998-12-14
Filing date: 1999-12-06
Publication date: 2004-04-10

Claims

1. Compounds of the formula

where R ¹ denotes hydrogen or a fragment of an ester group that can be cleaved under physiological conditions;

E is hydrogen or hydroxy;

three of the symbols X ¹ -X ⁴ independently from each other represent a group C (R ^a ), C (R ^b ) or C (R ^c ), and the fourth denotes a group C (R ^d ) or N;

R ^a -R ^d are each independently of the other hydrogen, alkenyl, alkenilkarboniloksialkoksi, alkenyloxy, alkynyl, alkynyloxy, alkoxy, alkoxyalkenyl, alkoxyalkoxy, alkoxyalkyl, alkoxyalkyl (alkyl) aminoalkyl, alkoksialkilkarboksamido, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkyl, alkoksikarbonilalkilkarboksamido, alkoksikarbonilarilalkoksi, alkoksikarbonilariloksi , alkoxycarbonylcarboxamido, alkyl, alkyl (alkylcarbonyl) amino, alkylcarbonyl, alkylcarbonylalkoxy, alkylcarbonyloxyalkoxy, alkylcarboxy amido, alkilkarboksamidoalkoksi, alkylsulfanyl, alkilsulfanilalkoksi, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, alkilsulfonilaminoalkoksi, alkylureido, alkylthioureido, amino, aminoalkoxy, aryl, arylalkenyl, arylalkynyl, arylalkoxy, arilalkoksialkoksi, arylalkyl, arylalkylcarboxamide, arilkarbonilalkoksi, arylcarboxamide, arilkarboksamidoalkoksi, aryloxy, ariloksialkoksi, arylsulfonylamino, arylsulfonylaminoalkoxy, carboxy, carboxyalkyl, carboxyalkylcarboxamido, carboxyalkoxy, carboxyarylalkoxy , Karboksiariloksi, karboksikarboksamido, karbamoilalkoksi, cycloalkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylamino, tsikloalkilaminoalkil, tsikloalkilaminokarboniloksi, tsikloalkilkarbamoilalkoksi, tsikloalkilkarboksamido, digidroksialkoksi, halogen, haloalkenyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, gidroksialkoksialkoksi, hydroxyalkyl, gidroksitsikloalkoksi, gidroksitsikloalkilamino, mono- or dialkylamino, mono- or dialkylaminoalkoxy, mono- or dialkylaminoalkyl, mono- or dialkylaminocarbonylalkoxy, 2,2,2-trif toratsetilaminoalkoksi or heterocyclic substituent selected from the group consisting azepanilkarbonilalkoksi, benzoimidazolyl, morfolinilalkoksi, morfolinilalkil, morfoliniloksoalkoksi, piperidinilalkoksi, piperidinylamino, piperidinilaminoalkil, piperidinyloxy, alkilsulfonilpiperidiniloksi, furanilalkoksi, 1,3-dioxo-1,3-digidroizoindolilalkil, imidazolyl, imidazolylalkyl, izatiazoliloksi, dihydroisoxazolyl, piperazinyl, piperazinylalkyl, pyridinylaminoalkyl, bispyridinylalkylamino, pyridinyloxy, pyrimidinylamino-alk ilazepanilidenamino, pyrrolidinyl, pirrolidinilalkoksi, pirrolidinilalkil, pyrrolidinyloxy, pirrolidiniloksoalkoksi, oksopirrolidinilalkoksi, oxadiazolyl, tetragidrofuranilalkoksi, tetrahydrofuranyloxy, tetragidropiranilalkoksi, tetrahydropyranylamino, tetragidrotiopiranilamino, tetrahydropyranyloxy, dioksogeksagidrotiopiranilamino, tiazolilalkoksi and thiophenyl where the heterocyclic substituents being optionally substituted with alkyl, alkoxy, carboxyalkyl, hydroxy, tetrazolilmetoksigruppoy, alkylsulfonyl or al hydroxycarbonylalkyl or two adjacent groups of R ^a -R ^d together form a fragment of a condensed 1,4-dioxane, 1,3-dioxolane, 1-oxane or aryl ring, provided that no more than three of R ^a -R ^d have the same meaning and X ^{1 is} not substituted with aryl, carboxy group or alkoxycarbonyl;

one of the symbols G ¹ and G ² is hydrogen, and the other is hydrogen, alkyl, hydroxy, alkoxy, aroyl or a group COO-R ^e or OCO-R ^e and R ^e is alkyl optionally substituted with halogen, hydroxy, alkoxy, carboxy, alkylcarbonyloxycarbonyl or arylcarbonyloxycarbonyl,

as well as their hydrates or solvates and physiologically acceptable salts.

2. The compounds according to claim 1, where R ^a -R ^d each independently represents hydrogen, alkenyl, alkenylcarbonyloxyalkoxy, alkenyloxy, alkynyl, alkoxy, alkoxyalkenyl, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonylalkoxy, alkoxycarbonylalkyloxy, alkoxycarbonyloxyalkyl, alkylcarboxamidoalkoxy, alkylsulfanylalkoxy, aminoalkoxy, aryl, arylalkenyl, arylalkoxy, arylalkoxyalkoxy, arylalkyl, arylcarbonylalkoxy, arylcarboxamidoalkoxy, aryloxy, aryloxyalkoxy, carbox , Carboxyalkyl, carboxyalkoxyl, karboksiarilalkoksi, karboksiariloksi, karbamoilalkoksi, cycloalkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylamino, tsikloalkilaminoalkil, tsikloalkilaminokarboniloksi, tsikloalkilkarbamoilalkoksi, digidroksialkoksi, halogen, haloalkenyl, haloalkoxy, haloalkyl, hydroxyalkoxy, gidroksialkoksialkoksi, hydroxyalkyl, gidroksitsikloalkoksi, mono- or dialkylaminoalkoxy, mono- or dialkylaminoalkyl, mono- or dialkylaminocarbonylalkoxy or a heterocyclic substituent selected from the group, incl. sistent morfolinilalkoksi, morfolinilalkil, morfoliniloksoalkoksi, piperidinilalkoksi, piperidinyloxy, piridinilaminoalkil, alkilsulfo-nilpiperidiniloksi, furanilalkoksi, imidazolylalkyl, izatiazoliloksi, pyrrolidinyl, pirrolidinilalkoksi, pirrolidinilalkil, pyrrolidinyloxy, pirrolidiniloksoalkoksi, oxadiazolyl, tetragidrofuranilalkoksi, tetrahydrofuranyloxy, tetragidropiranilalkoksi, tetrahydropyranyloxy and tiazolilalkoksi where the heterocyclic substituents being optionally substituted alkyl, alkoxy, tetrazolylmethoxy Rupp, alkylsulphonyl or alkoxycarbonylalkyl or two adjacent groups of R ^a -R ^d taken together to form a fused 1,4-dioxane, 1,3-dioxolane, 1-oksanovogo or aryl ring.

3. The compounds according to claim 2, where R ^a -R ^d each independently represents alkenyl, alkenyloxy, alkynyl, alkoxy, alkoxyalkenyl, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonylarylalkoxy, alkyl, alkylcarbonylalkoxy, alkylsulfanylalkoxy, arylcarboxyloxyalkyloxyalkyloxyalkoxyalkoxy cycloalkylalkoxy, cycloalkylaminocarbonyloxy, cycloalkylcarbamoylalkoxy, dihydroxyalkoxy, halogen, haloalkenyl, haloalkoxy, haloalkyl, hydroxyalkoxy, hydroxyalkoxyalkoxy, hydroxyalkyl, hydroxycycloalkoxy , Mono-or dialkylaminoalkoxy or heterocyclic substituent selected from the group consisting of piperidinyloxy, furanilalkoksi, izotiazoliloksi, morfolinilalkil, piridinilaminoalkil, pirrolidinilalkil, pyrrolidinyloxy, tetrahydrofuranyloxy and tetrahydropyranyloxy, wherein the heterocyclic substituents being optionally substituted with alkyl, alkoxy, tetrazolyl-methoxy, alkylsulphonyl or alkoxycarbonylalkyl.

4. The compounds according to claim 3, where R ^a -R ^d each independently represents hydrogen, alkenyl, alkynyl, alkoxy, alkyl, carbamoylalkoxy, cycloalkoxy, cycloalkylalkoxy, dihydroxyalkoxy, halogen, haloalkoxy, haloalkyl, hydroxyalkoxy, hydroxyalkyl, hydroxycyclo a mono- or dialkylaminoalkoxy or heterocyclic substituent selected from the group consisting of morpholinylalkyl, piperidinyloxy, pyridinylaminoalkyl, pyrrolidinylalkyl, pyrrolidinyloxy and tetrahydropyranyloxy, where heterocyclic substituents are optionally substituted further alkyl, alkoxy, tetrazolylmethoxy, alkylsulfonyl or alkoxycarbonylalkyl.

5. The compound according to claim 4, where R ^a -R ^d each independently represents hydrogen, alkenyl, alkynyl, alkoxy, alkyl, carbamoylalkoxy, halogen, hydroxyalkoxy, hydroxycycloalkoxy, mono- or dialkylaminoalkoxy or a heterocyclic substituent selected from the group including morpholinylalkyl, piperidinyloxy, pyridinylaminoalkyl, pyrrolidinylalkyl and tetrahydropyranyloxy, where the heterocyclic substituents are optionally substituted with alkyl, alkoxy, tetrazolylmethoxy, alkylsulfonyl or alkoxycarbonylalkyl.

6. Compounds according to any one of claims 1 to 5, wherein X ¹ is a group C (R ^a ), X ² is a group C (R ^b ), X ³ is a group C (R ^c ) and X ⁴ is a group C (R ^d )

7. Compounds according to any one of claims 1 to 6, wherein R ^a is hydrogen, carbamoylalkoxy, hydroxyalkoxy or halogen.

8. Compounds according to any one of claims 1 to 7, where R ³ denotes hydrogen.

9. Compounds according to any one of claims 1 to 8, wherein R ^b is hydrogen, alkenyl, alkynyl, alkoxy or alkyl.

10. Compounds according to any one of claims 1 to 9, wherein R ^b is alkoxy.

11. Compounds according to any one of claims 1 to 10, wherein R ^c is hydrogen, alkoxy, mono- or dialkylaminoalkoxy or hydroxyalkoxy.

12. Compounds according to any one of claims 1 to 11, wherein R ^c is hydrogen or alkoxy.

13. Compounds according to any one of claims 1 to 12, wherein R ^d is hydrogen, alkoxy, hydroxycycloalkoxy, mono- or dialkylaminoalkoxy, or a heterocyclic substituent selected from the group consisting of morpholinylalkyl, piperidinyloxy, pyridinylaminoalkyl, pyrrolidinylalkyl or tetrahydro-pyrzyloxyloxy optionally substituted alkyl or alkylsulfonyl.

14. Compounds according to any one of claims ^{1 to 13} , where one of the symbols G ¹ and G ² is hydrogen and the other is hydrogen, alkyl, hydroxy, alkoxy, aroyl or a group COO-R ^e or OCO-R ^e and R ^e denotes alkyl optionally substituted with halogen, hydroxy, alkoxy, carboxy, alkylcarbonyloxycarbonyl or arylcarbonyloxycarbonyl.

15. Compounds according to any one of claims 1 to 14, where one of the symbols G ¹ and G ² is hydrogen or hydroxy, and the other is hydrogen.

16. Compounds according to any one of claims ^{1 to} 15, where the symbols G ¹ and G ² denote hydrogen.

17. Compounds according to any one of claims ^{1 to} 16, where R ¹ denotes hydrogen.

18. Compounds according to any one of claims 1 to 17, where E is hydrogen.

19. Compounds according to any one of claims 1 to 18, selected from the group including:

a) (RS) - (4-carbamimidoylphenylamino) - [4- (2-dimethylaminoethoxy) -3-ethoxyphenyl] acetic acid;

b) (RS) - and (SR) - (4-carbamimidoylphenylamino) - [3-ethoxy-5 - [(1-RS, 2RS) -2-hydroxycyclopentyloxy] phenyl] acetic acid;

c) (RS) - (4-carbamimidoylphenylamino) - (3,5-diethoxy-2-fluorophenyl) acetic acid;

d) (RS) - (4-carbamimidoylphenylamino) - [3-ethoxy-5 - [(1-methylpiperidin-4-yloxy) phenyl] acetic acid;

e) (RS) - and (SR) - (4-carbamimidoylphenylamino) - [3-ethoxy-4 - [(RS) -2-hydroxy-1-methylethoxy] phenyl] acetic acid;

e) (RS) - and (SR) - (4-carbamimidoylphenylamino) - [3-ethoxy-5 - [(1RS, 2RS) -2-hydroxycyclohexyloxy] phenyl] acetic acid;

g) (RS) - (4-carbamimidoylphenylamino) - [3-ethoxy-5- (1-methane-sulfonylpiperidin-4-yloxy) phenyl] acetic acid;

h) (4-carbamimidoylphenylamino) - [3-ethoxy-5- (tetrahydropyran-4-yloxy) phenyl] acetic acid;

i) (RS) - (4-carbamimidoylphenylamino) - (3-ethynyl-5-pyrrolidin-1-ylmethylphenyl) acetic acid;

j) (RS) - (4-carbamimidoylphenylamino) - (3-pyrrolidin-1-ylmethyl-5-vinylphenyl) acetic acid;

k) hydrochloride (RS) - (4-carbamimidoylphenylamino) - (3-ethoxy-4-methoxyphenyl) acetic acid;

m) (RS) - (4-carbamimidoylphenylamino) - (2-fluoro-3,5-dimethoxyphenyl) acetic acid;

m) (RS) - (4-carbamimidoylphenylamino) - [3-ethoxy-5- (pyridin-2-yl-aminomethyl) phenyl] acetic acid;

o) (RS) - (4-carbamimidoylphenylamino) - (3-ethoxy-5-morpholin-4-yl-methylphenyl) acetic acid;

o) (RS) - (4-carbamimidoylphenylamino) - [3-ethoxy-4- (2-hydroxyethoxy) phenyl] acetic acid;

p) (RS) - (4-carbamimidoylphenylamino) - [4,5-diethoxy-2- (2-hydroxyethoxy) phenyl] acetic acid;

c) (RS) - (4-carbamimidoylphenylamino) - [3- (3-dimethylamino-2,2-dimethylpropoxy) -5-ethylphenyl] acetic acid;

t) (RS) - (4-carbamimidoylphenylamino) - [3-ethoxy-4- (2-hydroxyethoxy) phenyl] acetic acid;

y) (RS) - (4-carbamimidoylphenylamino) - [4,5-diethoxy-2- (3-hydroxypropoxy) phenyl] acetic acid; and

f) (RS) - (4-carbamimidoylphenylamino) - (2-carbamoylmethoxy-4,5-diethoxyphenyl) acetic acid.

20. Pharmaceutical compositions containing the compound according to any one of claims 1 to 19 in the form of a galenic form for administration.

21. Compounds according to any one of claims 1 to 19, intended for use as drugs, primarily for inhibiting the formation of coagulation factors Xa, IXa and thrombin induced by factor VIIa and tissue factor, primarily as drugs for treatment or prevention thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis or as an antitumor agent.

22. The use of a compound according to any one of claims 1-19 for the preparation of medicines containing a compound according to any one of claims 1-19, which are intended for the treatment or prevention of thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis or as an antitumor agent.

23. A method of producing compounds according to any one of claims 1 to 19, comprising the conversion of a nitrile group in a compound of formula II

where X ¹ , X ² , X ³ , X ⁴ , R ¹ and E have the meanings specified in claims 1-19, to a carbamimidoyl group or to an N-hydroxycarbamimidoyl group and, if necessary, modifying the reactive group present in the obtained compound of formula I and, if necessary, converting the resulting compound of formula I into a physiologically compatible salt or converting a salt of a compound of formula I into a free acid or base.

24. Compounds according to any one of claims 1 to 19, obtained by the method according to item 23.

25. The compounds of formula II according to claim 23, wherein X ¹ , X ² , X ³ , X ⁴ , R ^1, and E have the meanings indicated in claims 1-19.

26. The invention as presented in the present description.