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Details for Patent: 5,401,766

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Details for Patent: 5,401,766

Title: Aminoacid derivatives, a process for their preparation, agents containing these compounds, and the use thereof
Abstract:Aminoacid derivatives of the formula I ##STR1## A , n, R.sup.1, R.sup.2 and R.sup.3 have the meanings given, and salts thereof, a process for their preparation, pharmaceutical preparations based on these compounds, and their use as medicaments.
Inventor(s): Geiger; Rolf (Frankfurt am Main, DE), Teetz; Volker (Hofheim am Taunus, DE), Urbach; Hansjorg (Kronberg/Taunus, DE), Scholkens; Bernward (Kelkheim, DE), Henning; Rainer (Giessen, DE)
Assignee: Hoechst Aktiengesellschaft (Frankfurt am Main, DE)
Filing Date:Mar 09, 1994
Application Number:08/208,443
Claims:1. A compound of the formula ##STR715## or physiologically tolerated salt thereof, wherein COOR.sub.3 is a) carboxyl,

b) carboxyl ester and

R.sub.1 is

a) alkyl or alkenyl having up to 6 C atoms,

b) alkyl or alkenyl having up to 6 C atoms substituted by

1) (C.sub.5 -C.sub.7)-cycloalkyl,

2) (C.sub.5 -C.sub.7)-cycloalkenyl,

3) hydroxy,

4) (C.sub.1 -C.sub.2)-alkoxy,

5) phenoxy,

6phenoxy substituted by

6.1) halogen,

6.2) (C.sub.1 -C.sub.2)-alkyl, or

6.3) (C.sub.1 -C.sub.2)-alkoxy,

7) naphthyloxy,

8) monoalkylamino having up to 7 C atoms,

9) monoalkylamino having up to 7 C atoms substituted in the alkyl part by

9.1) hydroxy,

9.2) carboxy,

9.3) carboxamido,

9.4) carboethoxy,

9.5) amino,

9.6) alkylamino,

9.7) dialkylamino,

9.8) piperidino, or

9.9) morpholino,

10) dialkylamino having up to 7 C atoms,

11) dialkylamino having up to 7 C atoms substituted as defined in b) 9.1-9.9,

12) monocycloalkylamino having up to 7 C atoms,

13) dicycloalkylamino having up to 7 C atoms,

14) alkyloxycarbonylamino,

15) phenoxycarbonylamino,

16) phenoxycarbonylamino substituted as defined in b) 6.1-6.3,

17) naphthyloxycarbonylamino,

18) benzyloxycarbonylamino or phenethyloxycarbonylamino,

19) benzyloxycarbonylamino or phenethyloxycarbonylamino each substituted in the aryl part by

19.1) halogen,

19.2) nitro,

19.3) (C.sub.1 -C.sub.2)-alkyl, or

19.4) (c.sub.1 -C.sub.2)-alkoxy.

20) alkylureido,

21) phenylureido,

22) phenylureido substituted as defined in b) 6.1-6.3,

23) naphthylureido,

24) benzylureido or phenethylureido,

25) benzylureido or phenethylureido each substituted as defined in b) 19.1-19.4,

26) formyl,

27) alkanoylamino,

28) benzoylamino,

29) benzoylamino substituted as defined in b) 6.1-6.3,

30) naphthoylamino,

31) phenylamino or naphthylamino,

32) phenylamino or naphthylamino each mono- or di-substituted by

32.1) (C.sub.1 -C.sub.2)-alkyl,

32.2) (C.sub.1 -C.sub.2)-alkoxy,

32.3) methylenedioxy,

32.4) amino,

32.5) hydroxy,

32.6) acetoxy,

32.7) carboxy,

32.8) carboxamido,

32.9) carboethoxy,

32.10) halogen, or

32.11) nitro,

33) benzylamino or phenethylamino,

34) benzylamino or phenethyl amino each mono- or di-substituted in the aryl part as defined in b) 32.1-32.11,

35) (C.sub.1 -C.sub.7)-alkylmercapto, (C.sub.1 -C.sub.7)-alkylsulfinyl, or (C.sub.1 -C.sub.7)-alkylsulfonyl

36) (C.sub.1 -C.sub.7)-alkylmercapto, (C.sub.1 -C.sub.7)-alkylsulfinyl, or (C.sub.1 -C.sub.7)-alkylsulfonyl each substituted by

36.1) methoxy,

36. 2) ethoxy,

36.3) hydroxy,

36.4) carboxy,

36.5) carboxamido,

36.6) carboethoxy,

36.7) amino, or

36.8) alkylamino,

37) phenylmercapto or naphthylmercapto, phenylsulfinyl or naphthylsulfinyl, or phenylsulfonyl or nephthylsulfonyl,

38) phenylmercapto or naphthylmercapto, phenylsulfinyl or naphthylsulfinyl, or phenylsulfonyl or naphthylsulfonyl each substituted

38.1) as defined in b) 36.1-36.8 or substituted by

38.2) halogen,

38.3) nitro, or

38.4) sulfonamido,

39) benzylmercapto, benzylsulfinyl, or benzylsulfonyl,

40) benzylmercapto, benzylsulfinyl, or benzylsulfonyl each substituted

40.1) in the alkyl part as defined in b) 36.1-36.8 or

40. 2) in the aryl part as defined in b) 38.1-38.4,

41) carboxy,

42) carboethoxy,

43) carboxamido,

44) alkylaminocarbonyl having up to 6 C atoms,

45) cycloalkylaminocarbonyl having up to 6 C atoms,

46) cycloalkyleneaminocarbonyl having up to 6 C atoms,

47) dialkylaminocarbonyl having up to 6 C atoms,

48) phenylaminocarbonyl,

49) phenylaminocarbonyl substituted as defined in b) 6.1-6.3,

50) naphthylaminocarbonyl,

51) benzylaminocarbonyl or phenethylaminocarbonyl,

52) benzylaminocarbonyl or phenethylaminocarbonyl each substituted as defined in b) 19.1-19.4,

53) guanido,

54) phenyl,

55) phenyl substituted by

55. 1) halogen

55.2) hydroxy,

55.3) acetoxy,

55.4) carboxy,

55.5) carboxamido,

55.6) sulfonamido,

55.7) nitro,

55.8) methyl,

55.9) ethyl,

55.10) methoxy, or

55.11) ethoxy,

56) naphthyl, dihydronaphthyl, or tetrahydronaphthyl,

57) naphthyl, dihydronaphthyl, or tetrahydronaphthyl, each substituted as defined in b) 55.1-55.11,

58) imidazol-4-ethyl, or

59) indolemethyl,

c) (C.sub.5 -C.sub.7)-cycloalkyl or (C.sub.5 -C.sub.7)-cycloalkenyl,

d) phenyl,

e) naphthyl, dihydronaphthyl, or tetrahydronaphthyl,

f) imidazol-4-ethyl,

g) indolemethyl, or

h) the side-chain of a naturally occurring L-amino acid,

R.sub.2 is

a) alkyl or alkenyl having up to 6 C atoms,

b) alkyl or alkenyl having up to 6 C atoms, substituted by

1) (C.sub.5 -C.sub.7)-cycloalkyl,

2) (C.sub.5 -C.sub.7)-cycloalkenyl,

3) hydroxy,

4) (C.sub.1 -C.sub.2)-alkoxy,

5) phenoxy,

6) phenoxy substituted by

6.1) halogen

6.2) (C.sub.1 -C.sub.2)-alkyl,

6.3) (C.sub.1 -C.sub.2)-alkoxy,

6.4) nitro, or

7) naphthyloxy,

8) benzyloxy,

9) benzyloxy substituted in the aryl part by

9.1) methoxy,

9.2) carboxamido,

9.3) amino,

9.4) halogen,

9.5) nitro, or

10) monoalkylamino having up to 7 C atoms,

11) monoalkylamino having up to 7 C atoms, substituted in the alkyl part by

11.1) hydroxy,

11.2) carboxy,

11.3) carboxamido,

11.4) carboethoxy,

11.5) amino,

11.6) alkylamino,

11.7) dialkylamino,

11.8) piperidino, or

11.9) morpholino,

12) dialkylamino having up to a total of 7 C atoms,

13) dialkylamino having up to a total of 7 C atoms substituted as defined in b) 11.1-11.9,

14) monocycloalkylamino having up to 7 C atoms,

15) dicycloalkylamino having up to 7 C atoms,

16) alkoxycarbonylamino,

17) phenoxycarbonylamino,

18) phenoxycarbonylamino substituted as defined in b) 6.1-6.3,

19) nephthyloxycarbonylamino,

20) benzyloxycarbonylamino or phenethyloxycarbonylamino,

21) benzyloxycarbonylamino or phenethyloxycarbonylamino each substituted in the aryl part by

21.1) halogen,

21.2) nitro,

21.3) (C.sub.1 -C.sub.2)-alkyl, or

21.4) (C.sub.1 -C.sub.2)-alkoxy,

22) (C.sub.1 -C.sub.10)-alkylureido,

23) phenylureido,

24) phenylureido substituted as defined in b) 6.1, 6.2, 6.3 or by nitro,

25) naphthylureido,

26) benzylureido or phenethylureido,

27) benzylureido or phenethylureido each substituted as defined in b) 21.1-21.4,

28) formyl,

29) alkanoylamino,

30) benzoylamino,

31) benzoylamino mono- to di-substituted by

31.1) halogen,

31.2) (C.sub.1 -C.sub.2)-alkyl,

31.3) (C.sub.1 -C.sub.2)-alkoxy,

31. 4) hydroxy,

31.5) carboxy,

31.6) nitro, or

31.7) amino,

32) naphthoylamino,

33) phenylamino or naphthylamino,

34) phenylamino or naphthylamino each mono- or di-substituted by

34.1) (C.sub.1 -C.sub.2)-alkyl,

34.2) (C.sub.1 -C.sub.2)-alkoxy,

34.3) methylenedixoy,

34.4) amino,

34.5) hydroxy,

34.6) acetoxy,

34.7) carboxy,

34.8) carboxamido,

34.9) carboethoxy,

34.10) halogen, or

34.11) nitro,

35) benzylamino or phenethylamino,

36) benzylamino or phenethylamino each mono- or di-substituted in the aryl part as defined in b) 34.1-34.11,

37) (C.sub.1 -C.sub.7)-alkylmercapto, (C.sub.1 -C.sub.7)-alkylsulfinyl, or (C.sub.1 -C.sub.7)-alkylsulfonyl,

38) (C.sub.1 -C.sub.7 )-alkylmercapto, (C.sub.1 -C.sub.7)-alkylsulfinyl, or (C.sub.1 -C.sub.7)-alkylsulfonyl each substituted by

38.1) methoxy,

38.2) ethoxy,

38.3) hydroxy,

38.4) carboxy,

38.5) carboxamido,

38.6) carboethoxy,

38.7) amino, or

38.8) alkylamino

39) phenylmercapto or naphthylmercapto, phenylsulfinyl or naphthylsulfinyl, or phenylsulfonyl or naphthylsulfonyl,

40) phenylmercapto or naphthylmercapto, phenylsulfinyl or naphthylsulfinyl, or phenylsulfonyl or naphathylsulfonyl each substituted

40.1) as defined in b) 38.1-38.8, or substituted by

40.2) halogen,

40.3) nitro,

40.4) sulfonamido, or

41) benzylmercapto, benzylsulfinyl, or benzylsulfonyl,

42) benzylmercapto, benzylsulfinyl, or benzylsulfonyl each substituted

42.1) in the alkyl part as defined in b) 38.1-38.8 or

42.2) in the aryl part as defined in b) 40.1-40.4,

43) carboxy,

44) alkylaminocarbonyl having up to 6 C atoms,

45) cycloalkylaminocarbonyl having up to 6 C atoms,

46) cycloalkyleneaminocarbonyl having up to 6 C atoms,

47) dialkylaminocarbonyl having up to 6 C atoms,

48) phenylaminocarbonyl,

49) phenylaminocarbonyl mono- to di-substituted by

49.1) halogen,

49.2) (C.sub.1 -C.sub.2)-alkyl,

49.3) (C.sub.1 -C.sub.2)-alkoxy,

49.4) carboxyl,

49.5) carboxyamido,

49.6) hydroxy, or

49.7) nitro,

50) naphthylaminocarbonyl,

51) benzylaminocarbonyl or phenethylaminocarbonyl,

52) benzylaminocarbonyl or phenethylaminocarbonyl each substituted as defined in b) 21.1-21.4,

53) guanido,

54) naphthyl, dihydronaphthyl, or tetrahydronaphthyl,

55) naphthyl, dihydronaphthyl, or tetrahydronaphthyl, each substituted by

55.1) halogen,

55.2) hydroxy,

55.3) acetoxy,

55.4) carboxy,

55.5) carboxamido,

55.6) sulfonamido,

55.7) nitro,

55.8) methyl,

55.9) ethyl,

55.10) methoxy, or

55.11) ethoxy,

56) a 5-membered or 6-membered monocyclic heterocyclic structure, the hetero atoms of which are

56. 1) 1 or 2 S atoms or 1 O atom and 0 or 1 N atom or

56.2) up to 4N atoms

57) a heterocycle as defined in b) 56 substituted by

57.1) halogen,

51.2) oxo,

57.3) S-oxo,

57.4) hydroxy,

57.5) carboxy,

57.6) carboxamido,

57.7) sulfonamido,

57.8) nitro,

57.9) (C.sub.1 -C.sub.9)-alkyl,

57.10) benzyl or phenethyl,

57.11) methoxy,

57.12) ethoxy, or

58) a 9-membered or 10-membered bicyclic heterocyclic structure, the hetero atoms of which are 2 O atoms or 1 or 2 N atoms or

59) a heterocycle as defined in b) 58 substituted as defined in b) 57.1-57.12,

60) phenyl or

61) phenyl mono- to di-substituted by

61.1) halogen,

61.2) hydroxy,

61.3) acetoxy,

61.4) carboxy,

61.5) carboxamido,

61.6) sulfonamido,

61.7) nitro,

61.8) methyl,

61.9) ethyl,

61.10) methoxy,

61.11) ethoxy, or

c) (C.sub.5 -C.sub.7)-cycloalkyl- or cycloalkenyl,

d) naphthyl, dihydronaphthyl, or tetrahydronaphthyl,

e) a 5-membered or 6-membered monocyclic heterocyclic structure, the hetero atoms of which are

1) 1 or 2 S atoms or 1O atom and 0 or 1 N atom or

2) up to 4 N atoms,

f) a heterocycle as defined in e) substituted by

1) halogen,

2) oxo,

3) S oxo,

4) hydroxy,

5) carboxy,

6) carboxamido,

7) sulfonamido,

8) nitro,

9) (C.sub.1 -C.sub.9)-alkyl,

10) benzyl or phenethyl,

11) methoxy, or

12) ethoxy,

g) a 9-membered or 10-membered bicyclic heterocyclic structure, the hetero atoms of which are 2 O atoms or 1 or 2 N atoms or

h) a heterocycle as defined in g) substituted as defined in f) 1-12,

i) phenyl.

2. A compound as in claim 1 wherein R.sub.2 is

a) alkyl having up to 6 C atoms,

b) alkyl having up to 6 C atoms substituted by

1) (C.sub.5 -C.sub.7)-cycloalkyl,

2) (C.sub.1 -C.sub.2)-alkoxy,

3) (C.sub.1 -C.sub.2)-alkoxy substituted by

3.1) Alkylamino

4) phenoxy,

5) phenoxy substituted by

5.1) halogen

5. 2) (C.sub.1 -C.sub.2)-alkyl, or

5.3) (C.sub.1 -C.sub.2)-alkoxy,

6) benzyloxy,

7) benzyloxy substituted in the aryl part by

7.1) methoxy,

7.2) carbo amido,

7.3) amino,

7.4) halogen, or

7.5) nitro,

8) monoalkylamino having up to 7 C atoms,

9) monoalkylamino having up to 7 C atoms substituted in the alkyl part by

9.1) carboxamido,

9.2) carboethoxy,

9.3) dialkylamino,

10) dialkylamino having up to 7 C atoms,

11) alkoxycarbonylamino,

12) benzyloxycarbonylamino,

13) (C.sub.1 -C.sub.10)-alkylureido,

14) phenylureido,

15) phenylureido substituted by

15.1) halogen,

15.2) nitro,

15.3) (C.sub.1 -C.sub.2)-alkyl, or

15. 4) (C.sub.1 -C.sub.2)-alkoxy,

16) alkanoylamino,

17) benzoylamino,

18) benzoylamino mono- or di-substituted by

18.1) halogen,

18.2) (C.sub.1 -C.sub.2)-alkyl,

18.3) (C.sub.1 -C.sub.2)-alkoxy,

18.4) hydroxy,

18.5) carboxy,

18.6) nitro, or

18.7) amino,

19) phenylamino,

20) phenylamino substituted by

20.1) (C.sub.1 -C.sub.2)-alkyl,

20.2) (C.sub.1 -C.sub.2)-alkoxy,

20.3) methylenedioxy,

20.4) amino,

20.5) hydroxy,

20.6) acetoxy,

20.7) carboxamido,

20.8) carboethoxy,

20.9) halogen, or

20.10) nitro,

21) (C.sub.1 -C.sub.7)-alkylmercapto, (C.sub.1 -C.sub.7)-alkylsulfinyl, or (C.sub.1 -C.sub.7)-alkylsulfonyl,

22) (C.sub.1 -C.sub.7)-alkylmercapto, (C.sub.1 -C.sub.7)-alkylsulfinyl, or (C.sub.1 -C.sub.7)-alkylsulfonyl substituted by

22.1) ethoxy,

22.2) carboxamido,

22.3) carboethoxy, or

23) phenylmercapto, phenylsulfinyl, or phenylsulfonyl,

24) phenylmercapto, phenylsulfinyl, or phenylsulfonyl substituted by

24.1) methoxy,

24.2) carboxy,

24.3) carboxamido,

24.4) amino,

24.5) nitro,

24.6) halogen, or

24.7) sulfonamido,

25) benzylmercapto, benzylsulfinyl, or benzylsulfonyl,

26) carboxy,

27) cycloalkylaminocarbonyl up to 6 C atoms,

28) dialkylaminocarbonyl up to 6 C atoms,

29) phenylaminocarbonyl,

30) phenylcarbonyl substituted by

30.1) halogen,

30. 2) (C.sub.1 -C.sub.2)-alkyl,

30.3) carboxy,

30.4) carboxamido,

30.5) carboethoxy,

30.6) hydroxy, or

30.7) nitro,

31) phenyl,

32) phenyl mon- or di-substituted by

32.1) halogen,

32.2) hydroxy,

32.3) carboxy,

32.4) carboxamido,

32.5) nitro,

32.6) methyl, or

32.7) methoxy,

33) naphthyl,

34) a 5-membered or 6-membered monocyclic heterocyclic structure, the hetero atoms of which are

34.1) 1 or 2 S atoms or 1 O atoms and 0 or 1 N atom or

34.2) up to 4 N atoms,

35) a heterocycle as defined in b) 35 substituted by

35.1) halogen,

35. 2) oxo,

35.3) (C.sub.1 -C.sub.9)-alkyl, or

35.4) methoxy,

36) a 9-membered or 10-membered bicyclic heterocyclic structure, the hetero atoms of which are 2 O atoms or 1 or 2 N atoms

c) (C.sub.5 -C.sub.7)-cycloalkenyl, or

d) a 5-membered or 6-membered monocyclic heterocyclic structure, the hetero atoms of which are

1) 1 or 2 S atoms or 1 O atom and 0 or 1 N atom or

2) 1, 2 or 4 N atoms.

3. A compound as in claim 1 wherein R.sub.1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary-butyl, linear or branched pentyl or hexyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, benzyl, phenethyl, p-fluorophenethyl, o-methylphenethyl, p-methoxyphenethyl, 2,4-dichlorophenethyl, or cyclohexylethyl.

4. A compound as in claim 1 wherein R.sub.2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary-butyl, linear or branched pentyl or hexyl, cyclopoentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, benzyl, phenethyl, p-fluorophenethyl, o-methylphenethyl, p-methoxyphenethyl, 2,4-dichlorophenethyl, or cyclohexylethyl.

5. A compound as in claim 1 wherein R.sub.1 is the side-chain of a naturally occuring L-amino acid.

6. A compound as in claim 1 wherein R.sub.1 is methyl, isobutyl, methylthioethyl, carboxymethyl, carboxyethyl, amino-n-butyl, guanido-n-propyl, imidazol-4-ethyl, benzyl, 4-hydroxybenzyl, or 3-indolemethyl.

7. A compound as in claim 1 wherein R.sub.1 is

(C.sub.1 -C.sub.6)-alkyl,

(C.sub.1 -C.sub.6)-alkyl, substituted by

hydroxy,

amino,

phenylmercapto,

guanido,

phenyl,

imidazol-4-ethyl, or

indolemethyl.

8. A compound as in claim 1 which is N-[1-S-carboethoxy-3-(4-fluorophenyl)-propyl]-S-alanyl-1,2,3,4-tetrahydroi soquinoline-3-S-carboxylic acid.

9. A compound as in claim 1 which is N-[1-S-carboethoxy-2-(3-indolyl)-ethyl]-S-alanyl-1,2,3,4-tetrahydrodroisoq uinoline-3-S-carboxylic acid.

10. A compound as in claim 1 which is N-(1-S-carboxy-3-phenyl-propyl)-S-(lysyl-1,2,3,4-tetrahydroisoquinoline-3- S-carboxylic acid.

11. A compound as in claim 1 which is N-(1-S-carboxy-2-cyclohexyl-ethyl)-S-isoleucyl-1,2,3,4-tetrahydroisoquiino line-3-S-carboxylic acid.

12. A pharmaceutical preparation for the treatment of hypertension, said preparation comprising a hypotensively effective amount of a compound or salt as in claim 1 and a pharmaceutically acceptable carrier therefor.

13. A method for treating hypertension in a patient suffering therefrom, which method comprises orally, intravenously, or subcutaneously administering to said patient a hypotensively effective amount of a compound as in claim 1.
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