2-saccharinylmethyl aryl and arloxy acetates useful as proteolytic enzyme inhibitors and compositions and method of use thereof

• US 5,783,589 A
• Filed: 05/24/1995
• Issued: 07/21/1998
• Est. Priority Date: 12/30/1991
• Status: Expired due to Fees

• Current Assignee: Sanofi
• Original Assignee: Sanofi
• Inventors: Dunlap, Richard Paul, Latimer, Lee Hamilton
• Primary Examiner(s): Dees, Jose G.
• Assistant Examiner(s): LUTZ, LAURA REBEKAH
• Application Number:
  US08/449,641
• Time in Patent Office: 1,154 Days
• Field of Search: 514/373, 514/233.8, 514/253, 514/321, 548/210, 546/198, 544/135, 544/368
• US Class Current: 514/373
• CPC Class Codes: A61K 31/425 Thiazoles
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 275/06 with hetero atoms directly attached to the ring sulfur atom
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

4-R⁴ -R⁵ -2-Saccharinylmethyl aryl and aryloxy acetates, useful in the treatment of degenerative diseases, are prepared by reacting a 4-R⁴ -R⁵ -2-halomethylsaccharin with an aryl or aryloxyacetic acid in the presence of an acid-acceptor.

Claims

1. A compound having the formula:

##STR20## wherein;

m is zero, n is one;

R¹ is hydrogen or lower-alkyl;

R² is hydrogen or lower-alkyl;

R³ is phenyl or phenyl substituted by from one to three, the same or different, members of the group consisting of lower-alkyl, perfluorolower-alkyl, lower-alkoxy and halogen;

R⁴ is halogen, perfluorolower-alkyl, perchlorolower-alkyl, lower-alkenyl, lower-alkynyl, cyano, carboxamido, amino, lower-alkylamino, dilower-alkylamino, lower-alkoxy, benzyloxy, lower-alkoxycarbonyl, hydroxy or phenyl; and

R⁵ is hydrogen or from one to two substituents in any of the 5-, 6- or 7-positions selected from halogen, cyano, nitro, N═

B, lower-alkyl-2-pyrrolyl, lower-alkylsulfonyl-amino, polyfluorolower-alkylsulfonylamino, polychlorolower-alkylsulfonylamino, aminosulfonyl, lower-alkyl, polyfluoro-lower-alkyl, polychlorolower-alkyl, cycloalkyl, lower-alkoxy, hydroxy, carboxy, carboxamido, hydroxylower-alkyl, methylenedioxy, cycloalkyloxy, formyl, aminomethyl, polyfluorolower-alkylsulfonyl, polychlorolower-alkylsulfonyl, lower-alkylsulfonylaminosulfonyl, di(lower-alkyl)phosphonoxy, lower-alkoxypoly-lower-alkyleneoxy, hydroxy-lower-alkoxy, polyhydroxy-alkoxy, or acetal or ketal thereof, polyalkoxy-alkoxy, --SR, --SOR, --SO₂ R, --OCOR, --O--(C₁ -C₁₀ alkylene)-COOR, --O--(C₂ -C₁₀ alkylene)-N═

B where R is lower-alkyl, phenyl, benzyl or naphthyl, or phenyl or naphthyl substituted by from one to two substituents selected from lower-alkyl, lower-alkoxy or halogen and where N═

B in each instance is amino, lower-alkylamino, dilower-alkylamino, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl, 4-lower-alkyl-1-piperazinyl, 4-benzyl-1-piperazinyl, 1-imidazolyl or (carboxylower-alkyl)amino, or R⁵ is a 5- or 6-membered saturated ring fused to the saccharin ring at the 5,6 or 6,7 positions, said ring containing two heteroatoms chosen from the group consisting of nitrogen, oxygen and sulfur or a methylated derivative of said ring;

or

R⁴ is hydrogen, or lower-alkyl; and

R⁵ is from one to two substituents in any of the 5-, 6- or 7-positions selected from halogen, cyano, nitro, N═

B, lower-alkyl-2-pyrrolyl, lower-alkylsfonyl-amino, polyfluorolower-alkylsulfonylamino, polychlorolower-alkylsulfonylamino, aminosulfonyl, lower-alkyl polyfluoro-lower-alkyl, polychlorolower-alkyl, cycloalkyl, hydroxy, carboxy, carboxamido, hydroxylower-alkyl, methylenedioxy, cycloalkyloxy, formyl, aminomethyl, polyfluorolower-alkylsulfonyl, polychlorolower-alkylsulfonyl, lower-alkylsulfonylaminosulfonyl, di(lower-alkyl)phosphonoxy, lower-alkoxypoly-lower-alkyleneoxy, hydroxy-lower-alkoxy, polyhydroxy-alkoxy, or acetal or ketal thereof, --SR, --SOR, --SO₂ R, --OCOR, --O--(C₁ -C₁₀ alkylene-COOR, --O--(C₂ -C₁₀ alkylene)-N═

B where R is lower-alkyl, phenyl, benzyl or naphthyl, or phenyl or naphthyl substituted by from one to two substituents selected from lower-alkyl, lower-alkoxy or halogen and where N═

B in each instance is amino, lower-alkylamino, dilower-alkylamino, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl, 4-lower-alkyl-1-piperazinyl, 4-benzyl-1-piperazinyl, 1-imidazolyl or (carboxylower-alkyl)amino;

or R⁵ is a 5- or 6-membered saturated ring fused to the saccharin ring at the 5,6 or 6,7 positions, said ring containing two heteroatoms chosen from the group consisting of nitrogen, oxygen and sulfur or a methylated derivative of said ring;

or acid-addition salts of basic members thereof or base-addition salts of acidic members thereof.

2. A composition for the treatment of degenerative diseases which comprises a pharmaceutical carrier and an effective proteolytic enzyme-inhibiting amount of a compound having the formula:

##STR21## wherein;

m is zero, n is one;

R¹ is hydrogen or lower-alkyl;

R² is hydrogen or lower-alkyl;

R³ is phenyl or phenyl substituted by from one to three, the same or different, members of the group consisting of lower-alkyl, perfluorolower-alkyl, lower-alkoxy and halogen;

R⁴ is halogen, perfluorolower-alkyl, perchlorolower-alkyl, lower-alkenyl, lower-alkynyl, cyano, carboxamido, amino, lower-alkylamino, dilower-alkylamino, lower-alkoxy, benzyloxy, lower-alkoxycarbonyl, hydroxy or phenyl; and

R⁵ is hydrogen or from one to two substituents in any of the 5-, 6- or 7-positions selected from halogen, cyano, nitro, N═

B, lower-alkyl-2-pyrrolyl, lower-alkylsulfonyl-amino, polyfluorolower-alkylsulfonylamino, polychlorolower-alkylsulfonylamino, aminosulfonyl, lower-alkyl, polyfluoro-lower-alkyl, polychlorolower-alkyl, cycloalkyl, lower-alkoxy, hydroxy, carboxy, carboxamido, hydroxylower-alkyl, methylenedioxy, cycloalkyloxy, formyl, aminomethyl, polyfluorolower-alkylsulfonyl, polychlorolower-alkylsulfonyl, lower-alkylsulfonylaminosulfonyl, di(lower-alkyl)phosphonoxy, lower-alkoxypoly-lower-alkyleneoxy, hydroxy-lower-alkoxy, polyhydroxy-alkoxy, or acetal or ketal thereof, polyalkoxy-alkoxy, --SR, --SOR, --SO₂ R, --OCOR, --O--(C₁ -C₁₀ alkylene)-COOR, --O--(C₂ -C₁₀ alkylene)-N═

B where R is lower-alkyl, phenyl, benzyl or naphthyl, or phenyl or naphthyl substituted by from one to two substituents selected from lower-alkyl, lower-alkoxy or halogen and where N═

B in each instance is amino, lower-alkylamino, dilower-alkylamino, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl, 4-lower-alkyl-1-piperazinyl, 4-benzyl-1-piperazinyl, 1-imidazolyl or (carboxylower-alkyl)amino;

or R⁵ is a 5- or 6-membered saturated ring fused to the saccharin ring at the 5,6 or 6,7 positions, said ring containing two heteroatoms chosen from the group consisting of nitrogen, oxygen and sulfur or a methylated derivative of said ring;

or

R⁴ is hydrogen, or lower-alkyl, and

R⁵ is from one to two substituents in any of the 5-, 6- or 7-positions selected from halogen, cyano, nitro, N═

B, lower-alkyl-2-pyrrolyl, lower-alkylsulfonyl-amino, polyfluorolower-alkylsulfonylamino, polychlorolower-alkylsulfonylamino, aminosulfonyl, lower-alkyl, polyfluoro-lower-alkyl, polychlorolower-alkyl, cycloalkyl, hydroxy, carboxy, carboxamido, hydroxylower-alkyl, methylenedioxy, cycloalkyloxy, formyl, aminomethyl, polyfluorolower-alkylsulfonyl, polychlorolower-alkylsulfonyl, lower-alkylsulfonylaminosulfonyl, di(lower-alkyl)phosphonoxy, lower-alkoxypoly-lower-alkyleneoxy, hydroxy-lower-alkoxy, polyhydroxy-alkoxy, or acetal or ketal thereof, --SR, --SOR, --SO₂ R, --OCOR, --O--(C₁ -C₁₀ alkylene)-COOR, --O--(C₂ -C₁₀ alkylene)-N═

B where R is lower-alkyl, phenyl, benzyl or naphthyl, or phenyl or naphthyl substituted by from one to two substituents selected from lower-alkyl, lower-alkoxy or halogen and where N═

B in each instance is amino, lower-alkylamino, dilower-alkylamino, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl, 4-lower-alkyl-1-piperazinyl, 4-benzyl-1-pipierazinyl, 1-imidazolyl or (carboxylower-alkyl)amino;

or R⁵ is a 5- or 6-membered saturated ring fused to the saccharin ring at the 5,6 or 6,7 positions, said ring containing two heteroatoms chosen from the group consisting of nitrogen, oxygen and sulfur or a methylated derivative of said ring;

or acid-addition salts of basic members thereof or base-addition salts of acidic members thereof.

3. A composition according to claim 2 wherein R¹ is hydrogen or methyl, R² is hydrogen or methyl, R³ is phenyl or substituted phenyl, R⁴ is hydrogen, or lower-alkyl, and R⁵ is hydrogen, lower-alkoxy, or polyalkoxy-alkoxy.

4. A method for the treatment of degenerative diseases which comprises administering to a patient in need of such treatment a medicament containing an effective proteolytic enzyme-inhibiting amount of a compound having the formula:

##STR22## wherein;

m is zero n is one,

R¹ is hydrogen or lower-alkyl;

R² is hydrogen or lower-alkyl;

R³ is phenyl or phenyl substituted by from one to three, the same or different, members of the group consisting of lower-alkyl, perfluorolower-alkyl, lower-alkoxy and halogen,

R⁴ is halogen, perfluorolower-alkyl, perchlorolower-alkyl, lower-alkenyl, lower-alkynyl, cyano, carboxamido, amino, lower-alkylamino, dilower-alkylamino, lower-alkoxy, benzyloxy, lower-alkoxycarbonyl, hydroxy or phenyl; and

R⁵ is hydrogen or from one to two substituents in any of the 5-, 6- or 7-positions selected from halogen, cyano, nitro, N═

B, lower-alkyl-2-pyrrolyl, lower-alkylsulfonyl-amino, polyfluorolower-alkylsulfonylamino, polychlorolower-alkylsulfonylamino, aminosulfonyl, lower-alkyl, polyfluoro-lower-alkyl, polychlorolower-alkyl, cycloalkyl, lower-alkoxy, hydroxy, carboxy, carboxamido, hydroxylower-alkyl, methylenedioxy, cycloalkyloxy, formyl, aminomethyl, polyfluorolower-alkylsulfonyl, polychlorolower-alkylsulfonyl, lower-alkylsulfonylaminosulfonyl, di(lower-alkyl)phosphonoxy, lower-alkoxypoly-lower-alkyleneoxy, hydroxy-lower-alkoxy, polyhydroxy-alkoxy, or acetal or ketal thereof, polyalkoxy-alkoxy, --SR, --SOR, --SO₂ R, --OCOR, --O--(C₁ -C₁₀ alkylene)-COOR, --O--(C₂ -C₁₀ alkylene)-N═

B where R is lower-alkyl, phenyl, benzyl or naphthyl, or phenyl or naphthyl substituted by from one to two substituents selected from lower-alkyl, lower-alkoxy or halogen and where N═

B in each instance is amino, lower-alkylamino, dilower-alkylamino, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl, 4-lower-alkyl-1-piperazinyl, 4-benzyl-1-piperazinyl, 1-imidazolyl or (carboxylower-alkyl)amino, or R⁵ is a 5- or 6-membered saturated ring fused to the saccharin ring at the 5,6 or 6,7 positions, said ring containing two heteroatoms chosen from the group consisting of nitrogen, oxygen and sulfur or a methylated derivative of said ring;

or

R⁴ is hydrogen or lower-alkyl; and

R⁵ is from one to two substituents in any of the 5-, 6- or 7-positions selected from halogen, cyano, nitro, N═

B, lower-alkyl-2-pyrrolyl, lower-alkylsulfonyl-amino, polyfluorolower-alkylsulfonylamino, polychlorolower-alkylsulfonylamino, aminosulfonyl, lower-alkyl, polyfluoro-lower-alkyl, polychlorolower-alkyl, cycloalkyl, hydroxy, carboxy, carboxamido, hydroxylower-alkyl, methylenedioxy, cycloalkyloxy, formyl, aminomethyl, polyfluorolower-alkylsulfonyl, polychlorolower-alkylsulfonyl, lower-alkylsulfonylaminosulfonyl, di(lower-alkyl)phosphonoxy, lower-alkoxypoly-lower-alkyleneoxy, hydroxy-lower-alkoxy, polyhydroxy-alkoxy or acetal or ketal thereof, --SR, --SOR, --SO₂ R, --OCOR, --O--(C₁ -C₁₀ alkylene)-COOR, --O--(C₂ -C₁₀ alkylene)-N═

B where R is lower-alkyl, phenyl, benzyl, or naphthyl, phenyl or naphthyl substituted by from one to two substituents selected from lower-alkyl, lower-alkoxy or halogen and where N═

B in each instance is amino, lower-alkylamino, dilower-alkylamino, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl, 4-lower-alkyl-1-piperazinyl, 4-benzyl-1-piperazinyl, 1-imidazolyl or (carboxylower-alkyl)amino;

or R⁵ is a 5- or 6-membered saturated ring fused to the saccharin ring at the 5,6 or 6,7 positions said ring containing two heteroatoms chosen from the group consisting of nitrogen, oxygen, and sulfur or a methylated derivative of said ring;

or acid-addition salts of basic members thereof or base-addition salts of acidic members thereof.

5. A method according to claim 4 wherein R¹ is hydrogen or methyl, R² is hydrogen or methyl, R³ is phenyl or substituted phenyl, R⁴ is hydrogen, or lower-alkyl, and R⁵ is hydrogen, lower-alkoxy, or polyalkoxy-alkoxy.

6. A process for preparing a compound of formula ##STR23## wherein:

m is zero or one, n is zero or one, and the sum of m+n is zero or one;

R¹ is hydrogen or lower-alkyl;

R² is hydrogen or lower-alkyl;

R³ is phenyl or phenyl substituted by from one to three, the same or different, members of the group consisting of lower-alkyl, perfluorolower-alkyl, lower-alkoxy and halogen;

R⁴ is hydrogen, halogen, lower-alkyl, perfluorolower-alkyl, perchlorolower-alkyl, lower-alkenyl, lower-alkynyl, cyano, carboxamido, amino, lower-alkylamino, dilower-alkylamino, lower-alkoxy, benzyloxy, lower-alkoxycarbonyl, hydroxy or phenyl; and

R⁵ is hydrogen or from one to two substituents in any of the 5-, 6- or 7-positions selected from halogen, cyano, nitro, N═

B, lower-alkyl-2-pyrrolyl, lower-alkylsulfonyl-amino, polyfluorolower-alkylsulfonylamino, polychlorolower-alkylsulfonylamino, aminosulfonyl, lower-alkyl, polyfluoro-lower-alkyl, polychlorolower-alkyl, cycloalkyl, lower-alkoxy, hydroxy, carboxy, carboxamido, hydroxylower-alkyl, methylenedioxy, cycloalkyloxy, formyl, aminomethyl, polyfluorolower-alkylsulfonyl, polychlorolower-alkylsulfonyl, lower-alkylsulfonylaminosulfonyl, di(lower-alkyl)phosphonoxy, lower-alkoxypoly-lower-alkyleneoxy, hydroxy-lower-alkoxy, polyhydroxy-alkoxy, or acetal or ketal thereof, polyalkoxy-alkoxy, --SR, --SOR, --SO₂ R, --OCOR, --O--(C₁ -C₁₀ alkylene)-COOR, --O--(C₂ -C₁₀ alkylene)-N═

B where R is lower-alkyl, phenyl, benzyl or naphthyl, or phenyl or naphthyl substituted by from one to two substituents selected from lower-alkyl, lower-alkoxy or halogen and where N═

B in each instance is amino, lower-alkylamino, dilower-alkylamino, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl, 4-lower-alkyl-1-piperazinyl, 4-benzyl-1-piperazinyl, 1-imidazolyl or (carboxylower-alkyl)amino;

or R⁵ is a 5- or 6-membered saturated ring fused to the saccharin ring at the 5,6 or 6,7 positions, said ring containing two heteroatoms chosen from the group consisting of nitrogen, oxygen and sulfur or a methylated derivative of said ring;

which comprises reacting a compound of formula ##STR24## where X'"'"' is Cl, Br or I with a compound of formula ##STR25## in the presence of an acid acceptor.

7. A process according to claim 6 wherein R¹ is hydrogen or methyl, R² is hydrogen or methyl, R³ is phenyl or substituted phenyl, R⁴ is hydrogen, or lower-alkyl, and R⁵ is hydrogen, lower-alkoxy, or polyalkoxy-alkoxy.