Use of non-peptide bradykinin antagonists for the treatment or prevention of Alzheimer's disease

• US 5,952,346 A
• Filed: 10/14/1997
• Issued: 09/14/1999
• Est. Priority Date: 10/14/1996
• Status: Expired due to Term

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Hoechst Marion Roussel Deutschland GmbH (Sanofi )
• Inventors: Wirth, Klaus, Heitsch, Holger, Wiemer, Gabriele
• Primary Examiner(s): Criares, Theodore J.
• Application Number:
  US08/949,495
• Time in Patent Office: 700 Days
• Field of Search: 514/311, 514/314, 514/367, 514/299, 514/300, 514/247, 514/259, 514/396, 514/379, 514/415, 514/395
• US Class Current: 514/311
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Abstract

The invention relates to the use of non-peptide bradykinin antagonists for the production of pharmaceuticals for the prevention and treatment of Alzheimer'"'"'s disease. Suitable Compounds are non-peptide bradykinin antagonists which inhibit the actions of the Alzheimer'"'"'s protein amyloid (β/A4) in isolated endothelial cells, such as for example, fused heterobicyclic fluoroalkyl derivatives.

Claims

1. A method for the treatment or prevention of Alzheimer'"'"'s disease comprising the step of administering to a host in recognized need of such treatment an amount of a non-peptide bradykinin antagonist, or a physiologically tolerable salt thereof, effective to achieve said treatment.

2. The method as claimed in claim 1, wherein said non-peptide bradykinin antagonist is a compound of the formula (I):

##STR177## in which the symbols have the following meanings;

D is

     1) a radical of the formula (II) ##STR178## or

     2) a radical of the formulae (III) to (VI) ##STR179## E is

     1) a radical of the formula (VII) ##STR180## or

     2) hydrogen, halogen, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkylthio or (C₁ -C₄)-alkoxy, where in the last 3 radicals 1 or more hydrogen atoms can be replaced by fluorine;

X¹ is nitrogen or C--R⁴ ;

X² is nitrogen or C--R⁵ ;

X³ is nitrogen or C--R⁶ ;

X⁴ is independently oxygen, sulfur, nitrogen or N--R⁷ ;

R¹ and R² are identical or different and are hydrogen, halogen, (C₁ -C₄)-alkyl or (C₁ -C₄)-alkoxy;

R³ is independently hydrogen, halogen, (C₁ -C₆)-alkyl, (C₆ -C₁₂)-aryl, (C₁ -C₃)-alkyl-(C₆ -C₁₂)-aryl, (C₁ -C₅)-alkenyl, (C₁ -C₄)-alkoxy or CO₂ R¹¹ ;

R⁴ is hydrogen, halogen, (C₁ -C₄)-alkyl, hydroxyl, ( C₁ -C₄)-alkylthio, amino, (C₁ -C₄)-alkylamino, (C₁ -C₄)-dialkylamino, (C₁ -C₄)-alkoxy, in which the alkyl part of any of the preceding substituents is optionally substituted by hydroxyl, (C₁ -C₄)-alkoxy, amino and (C₁ -C₄)-alkylamino, or (C₆ -C₁₂)-aryl, optionally substituted by (C₁ -C₄)-alkyl or CO₂ R¹¹ ;

R⁵ is

     1) hydrogen, (C₁ -C₄)-alkyl or ##STR181## R⁶ is

     1) hydrogen, halogen, (C₁ -C₄)-alkyl, hydroxyl, (C₁ -C₄)-alkylthio, amino, (C₁ -C₄)-alkylamino, (C₁ -C₄)-dialkylamino, (C₁ -C₄)-alkoxy, in which the alkyl part of any of the preceding substituents is optionally substituted by hydroxyl, (C₁ -C₄)-alkoxy, amino and (C₁ -C₄)-alkylamino, or (C₆ -C₁₂)-aryl, optionally substituted by (C₁ -C₄)-alkyl or CO₂ R¹¹ ;

or

2) a radical of the formula (VIII) ##STR182## R⁷ is independently (C₁ -C₄)-alkyl, (C₆ -C₁₂)-aryl or (C₁ -C₃)-alkyl-(C₆ -C₁₂)-aryl;

R⁸ and R⁹ are identical or different and are hydrogen, halogen, (C₁ -C₃)-alkyl or (C₁ -C₃)-alkoxy;

A is (C₁ -C₃)-alkanediyl;

Q is O or NR¹¹ ;

R¹⁰ is a radical of the formula (IX) ##STR183## wherein W is oxo or sulfur;

R¹¹ is independently hydrogen or (C₁ -C₄)-alkyl;

R¹⁴ is independently hydrogen or (C₁ -C₄)-alkyl;

G is oxo or 2 single-bonded hydrogen atoms;

R¹² is, if G is oxo, hydrogen and if G is 2 single-bonded hydrogen atoms, hydrogen or R¹⁶ CO;

R¹³ is (C₁ -C₄)-alkyl, (C₃ -C₇)-cycloalkyl, --(CH₂)_m -(C₃ -C₇)-cycloalkyl, --(CH₂)_m -CON(R¹¹)₂, or ##STR184## m and n are, identically or differently, a number from 0-6;

AA is an amino acid such as methionine, alanine, phenylalanine, 2-chlorophenylalanine, 3-chlorophenylalanine, 4-chlorophenyl-alanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, tyrosine, o-methyltyrosine, β

-(2-thienyl)-alanine, glycine, cyclohexylalanine, leucine, isoleucine, valine, norleucine, phenylglycine, serine, cysteine, aminopropionic acid or aminobutyric acid;

Y is

1) (C₂ -C₅)-alkenediyl,

2) (C₁ -C₈)-alkanediyl,

3) (C₃ -C₁₀)-cycloalkanediyl or

4) -(CH₂)_p -T_o --(CH₂)_q -,

where

     1) to

     4) can optionally be substituted by one or more identical or different radicals such as O--R⁸, NO₂, CN, CO₂ R¹¹, SO₃ R¹⁸, NR²⁰ R²¹, SO₂ NR²⁰ R²¹, CONR²⁰ R²¹ ;

T is O, NR²¹ or S;

o is a number O or 1;

p and q are identical or different and denote a number from 0 to 6;

R¹⁵ independently is

1) hydrogen,

2) (C₁ -C₅)-alkyl,

3) (C₆ -C₁₀)-aryl or

4) (C₁ -C₉)-heteroaryl,

where

     3) and

     4) can optionally be substituted by one or more identical or different groups, such as halogen, CN, NO₂, (C₁ -C₅)-alkylthio, NR²⁰ R²¹, CO₂ R¹⁹, SO₃ R¹⁸, SO₂ NR²⁰ R²¹, SO₂ R¹⁸, O--R¹⁸, NR²⁰ CO--R¹⁵, (C₁ -C₆)-alkyl, (C₆ -C₁₀)-aryl, (C₂ -C₅)-alkenyl or (C₁ -C₅)-alkoxy, where the last four radicals can optionally be partly or completely substituted by halogen;

R¹⁶ is independently hydrogen, (C₁ -C₄)-alkyl, (C₆ -C₁₂)-aryl, (C₁ -C₄)-alkyl-(C₆ -C₁₂)-aryl or perfluoro-(C₁ -C₄)-alkyl;

R¹⁷ is hydrogen, halogen, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy, perfluoro-(C₁ -C₄)-alkyl, NO₂, OH, NH₂, CON(R¹⁶)₂ or NR¹⁶ CON(R¹⁶)₂ ;

R¹⁸, R¹⁹ and R²⁰ are each identical or different and are hydrogen, (C₁ -C₅)-alkyl, (C₃ -C₅)-alkenyl, (C₆ -C₁₂)-aryl-(C₁ -C₃)-alkyl, (C₃ -C₁₀)-cycloalkyl, (C₃ -C₁₀)-cycloalkyl-(C₁ -C₃)-alkyl, C(O)--O--(C₁ -C₅)-alkyl or C(O)--NH--(C₁ -C₅)-alkyl;

R²¹ is independently hydrogen, C(O)--O--(C₁ -C₅)-alkyl or C(O)--O--(C₁ -C₃)-alkyl-(C₆ -C₁₀)-aryl;

Z is --N(R;

¹⁴)(R²²);

R²² is ##STR185## R²³ is (C₁ -C₄)-alkyl, ##STR186## or a physiologically tolerable salt thereof.

3. The method as claimed in claim 2, in which said non-peptide bradykinin antagonist of the formula (I), wherein:

D is

1) a radical of the formula (Xa) ##STR187##

     2) a radical of the formula (Xb) ##STR188## E is

     1) a radical of the formula (XI) ##STR189##

     2) hydrogen, (C₁ -C₄)-alkyl or (C₁ -C₄)-alkoxy;

R¹ and R² are identical or different, and are hydrogen, halogen or (C₁ -C₄)-alkyl;

R⁴ is hydrogen, (C₁ -C₄)-alkyl, phenyl or methoxy;

R⁵ is

     1) hydrogen, (C₁ -C₄)-alkyl or ##STR190## R⁶ is

     1) hydrogen, (C₁ -C₄)-alkyl or

2) a radical of the formula (VIII) ##STR191## R⁸ and R⁹ are identical or different and are hydrogen, halogen, (C₁ -C₃)-alkyl or (C₁ -C₃)-alkoxy;

A is --CH₂ - or --CH₂ -CH₂ -;

R¹⁰ is a radical of the formula (IX);

##STR192## wherein W is oxo or sulfur;

R¹¹ is, identically or differently, hydrogen, methyl or ethyl;

R¹⁴ is, identically or differently, hydrogen, methyl or ethyl;

G is oxo or 2 single-bonded hydrogen atoms;

R¹² is, if G is O, hydrogen and if G is 2 single-bonded hydrogen atoms, hydrogen or R¹⁶ CO;

R¹³ is (C₁ -C₄)-alkyl, cyclopentyl, cyclohexyl, --(CH₂)_m CON(R¹¹)₂, or ##STR193## m and n are, identically or differently, a number from 0-2;

AA is the aminocarboxylic acid glycine or alanine;

Y is

1) (C₂ -C₅)-alkenediyl,

2) (C₂ -C₄)-alkanediyl,

3) (C₃ -C₆)-cycloalkanediyl or

4) --(CH₂)_p --T₀ --(CH₂)_q -;

T is O or S;

o is a number 0 or 1;

p and q are identical or different, and are a number from 0-2;

R¹⁵ is

1) hydrogen,

2) (C₁ -C₅)-alkyl,

3) phenyl or

4) (C₅ -C₉)-heteroaryl,

where

     3) and

     4) can optionally be substituted by one, two or three identical or different groups, such as halogen, NO₂, (C₁ -C₃)-alkylthio, NR²⁰ R²¹, NR²⁰ CO--(C₁ -C₅)-alkyl and NR²⁰ CO-pyridyl, (C₁ -C₃)-alkyl or (C₁ -C₃)-alkoxy, in which, if appropriate, the hydrogen atoms of the alkyl or alkoxy group can be partly or completely replaced by halogen;

R¹⁶ is hydrogen, (C₁ -C₄)-alkyl or phenyl;

R¹⁷ is hydrogen, halogen, (C₁ -C₄)-alkyl, NO₂ or NH₂ ;

R²⁰ is independently hydrogen, (C₁ -C₄)-alkyl or benzyl;

R²¹ is independently hydrogen or C(O)--O--(C₁ -C₄)-alkyl;

Z is --N(R¹⁴)(R²²);

R²² is ##STR194## R²³ is (CO₁ -C₄)-alkyl, ##STR195## or a physiologically tolerable salt thereof.

4. The method as claimed in claim 2, in which said non-peptide bradykinin antagonist of the formula (I), wherein:

D is

1) a radical of the formula (Xa) ##STR196##

     2) a radical of the formula (Xb) ##STR197## E is a radical of the formula (XI) ##STR198## R¹ and R² are identical or different, and are hydrogen, halogen or (C₁ -C₄)-alkyl;

R⁴ is hydrogen or (C₁ -C₄)-alkyl;

R⁵ is hydrogen;

R⁶ is hydrogen;

R⁸ and R⁹ are identical or different, and are hydrogen, chlorine, methyl or methoxy;

A is --CH₂ - or --CH₂ -CH₂ -;

R¹⁰ is a radical of the formula (IX) ##STR199## W is oxo;

R¹⁴ is hydrogen, methyl or ethyl;

AA is the aminocarboxylic acid glycine;

Y is

1) (C₂ -C₅)-alkenediyl,

2) (C₂ -C₄)-alkanediyl,

3) (C₃ -C₆)-cycloalkanediyl or

4) --(CH₂)_p --T_o --(CH₂)_q -;

T is O or S;

o is a number 0 or 1;

p and q are identical or different, and are a number from 0-2;

R¹⁵ is

1) is hydrogen

2) (C₁ -C₃)-alkyl,

3) phenyl or

4) (C₅ -C₉)-heteroaryl, where

     3) and

     4) can optionally be substituted by one, two or three identical or different groups, such as halogen, NO₂, NR²⁰ R²¹, NR²⁰ CO--(C₁ -C₃)-alkyl and NR²⁰ CO-pyridyl, (C₁ -C₃)-alkyl or (C₁ -C₃)-alkoxy, in which, if appropriate, the hydrogen atoms of the alkyl or alkoxy group are partly or completely replaced by halogen;

R²⁰ is independently hydrogen, (C₁ -C₄)-alkyl or benzyl;

R²¹ is hydrogen or C(O)--O--(C₁ -C₅)-alkyl;

or a physiologically tolerable salt thereof.

5. The method as claimed in claim 1, wherein said non-peptide bradykinin antagonist is:

N-{1-{4-(1,1-dimethylethyl)phenyl}methyl4-piperidinyl}-8-methoxy-4-{{4-{{{1-(phenylmethyl)4-piperidinyl}amino}carbonyl}phenylamino}3-quinolinecarboxamide;

N-{1 -{(3-chlorophenyl}methyl-4-piperidinyl}-8-methoxy-4-{{4-{{{1-(phenylmethyl)-4-piperidinyl}amino}carbonyl}phenylamino}3-quinolinecarboxamide;

8-methoxy-N-{1-(phenyl}methyl-4-piperidinyl-{4-{{4-{{{1-(phenylmethyl)-4-piperidinyl}amino}carbonyl}phenylamino}-3-quinolinecarboxamide;

N-{2-(dimethylamino)ethyl}8-methoxy-4-{{4-{{{1-(phenylmethyl)4-piperidinyl}amino}carbonyl}phenylamino}-3-quinolinecarboxamide trifluoroacetate;

N-2-(dimethylamino)ethyl}-N-ethyl-8-methoxy-4-{{4-{{{1-(phenylmethyl)4-piperidinyl}amino}carbonyl}phenylamino}3-quinolinecarboxamide;

4-{{4-{{(3-cyclopentyl-1-oxopropyl)-{1-{6-(diethylamino)-6-oxo-hexyl-4-piperidinylamino}methylphenyl}amino}-8-methoxy-N-{1-(phenylmethyl)4-piperidinyl}-3-quinolinecarboxamide;

4-(4-{{(1-butyl4-piperidinylamino}methyl}phenylamino}-8-methoxy-N-1-(phenylmethyl)4-piperidinyl}-3-quinolinecarboxamide;

N-(1-butyl4-piperidinyl)-8-methoxy-{{4-{{{1-(phenylmethyl)-4-piperidinyl}amino}carbonyl}phenyl}amino-3-quinolinecarboxamide;

N-1-6-(diethylamino)-6-oxohexyl-4-piperidinyl-8-methoxy-4-{{4-{{{1-(phenylmethyl)-4-piperidinyl}amino}carbonyl}phenyl}amino}3-quinolinecarboxamide;

4-{{4-{{(1-butyl-4-piperidinyl)-(1-oxobutyl)amino}methyl}phenyl}amino-3-methoxy-N-{1-(phenylmethyl)-4-piperidinyl}-3-quinolinecarboxamide;

N-{1-{4-{(diethylamino)carbonyl}phenyl4-piperidinyl-8-methoxy-4-{{4-{{{1-(phenylmethyl)-4-piperidinyl}amino}carbonyl}phenyl}amino-3-quinolinecarboxamide;

N-{1-(2-phenylethyl)4-piperidinyl}-8-methoxy-4-{{4-{{{1-(phenylmethyl)-4-piperidinyl}amino}carbonyl}phenyl}amino}-3-quinolinecarboxamide;

4-{{4-{{(1-butyl4-piperidinyl)amino}carbonyl}phenyl}amino}-8-methoxy-N-{1-(phenylmethyl)4-piperidinyl}-3-quinolinecarboxamide;

8-methoxy-N-(1-methyl-4-piperidinyl)-4-{{4-{{{1-(phenylmethyl)-4-piperidinyl}amino}carbonyl}phenyl}amino}-3-quinolinecarboxamide;

N-1-{(3-methoxyphenyl)methyl}4-piperidinyl-8-methoxy-4-{{4-{{{1-(phenylmethyl)-4-piperidinyl}amino}carbonyl}phenyl}-amino-3-quinolinecarboxamide;

8-methoxy-4-{{4-{{{1-(phenylmethyl)4-piperidinyl}amino}carbonyl}phenyl}-amino}-1-{{3-(trifluoromethyl)phenyl}methyl}-4-piperidinyl)-3-quinolinecarboxamide;

7-chloro-N-{1-(phenylmethyl)-4-piperidinyl}-4-{{4-{{{1-(phenylmethyl)-4-piperidinyl}amino}carbonyl}phenyl}amino-3-quinolinecarboxamide;

or a physiologically tolerable salt thereof.