Sulfonamides as cell adhesion inhibitors

US 6,221,888 B1
Filed: 11/29/1999
Issued: 04/24/2001
Est. Priority Date: 05/29/1997
Status: Expired due to Fees

First Claim

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1. A compound having the formula Ia:

or a pharmaceutically acceptable salt thereof, whereinR²is

     1) hydrogen, or2) C_1-6alkyl;

one of R³and R⁴is hydrogen and the other is1) aryl, 2) heteroaryl, 3) aryl-C_1-10alkyl, 4) heteroaryl-C_1-10alkyl, or 5) C_1-10alkyl, wherein aryl and heteroaryl are each optionally substituted with one to four substituents selected from R^b; and

alkyl is optionally substituted with one to four substituents independently selected from R^a;

orR³, R⁴and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N, O and S;

one of R⁶and R⁷is hydrogen and the other is1) aryl, 2) aryl-C_1-10alkyl, or 3) C_1-10alkyl, wherein aryl is optionally substituted with one to four substituents independently selected from R^y, and alkyl is optionally substituted with one to four substituents selected from R^x; and

R^ais

     1) Cy, or2) a group selected from R^x;

wherein Cy is optionally substituted with one to four substituents independently selected from R^c;

R^bis

     1) a group selected from R^a,2) C_1-0alkyl, 3) C_2-10alkenyl, 4) C_2-10alkynyl, 5) aryl C_1-10alkyl, 6) heteroaryl C_1-10alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from R^c;

R^cis

     1) halogen,2) amino, 3) carboxy, 4) C_1-4alkyl, 5) C_1-4alkoxy, 6) aryl, 7) aryl C_1-4alkyl, or 8) aryloxy;

R^dand R^eare independently selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, Cy and Cy C_1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy is optionally substituted with one to four substituents independently selected from R^c;

or R^dand R^etogether with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;

R^fand R^gare independently selected from hydrogen, C_1-10alkyl, Cy and Cy C_1-10alkyl;

or R^fand R^gtogether with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;

R^xis

     1) —

OR^d,2) —

NO₂, 3) halogen 4) —

S(O)_mR^d, 5) —

SR^d, 6) —

S(O)₂OR^d, 7) —

S(O)_mNR^dR^e, 8) —

NR^dR^e, 9) —

O(CR^fR^g)_nNR^dR^e, 10) —

C(O)R^d, 11) —

CO₂R^d, 12) —

CO₂(CR^fR^g)_nCONR^dR^e, 13) —

OC(O)R^d, 14) —

CN, 15) —

C(O)NR^dR^e, 16) —

NR^dC(O)R^e, 17) —

OC(O)NR^dR^e, 18) —

NR^dC(O)OR^e, 19) —

NR^dC(O)NR^dR^e, 20) —

CR^d(N—

OR^e), or 21) —

CF₃;

R^yis

     1) a group selected from R^x,2) C_1-10alkyl, 3) C_2-10alkenyl, 4) C_2-10alkynyl, 5) aryl C_1-10alkyl, 6) heteroaryl C_1-10alkyl, 7) cycloalkyl, 8) heterocyclyl;

wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R^x;

Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;

m is an integer from 1 to 2; and

n is an integer from 1 to 10.

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Abstract

Compounds of Formula I are antagonists of VLA-4 and/or α₄β₇, and as such are useful in the inhibition or prevention of cell adhesion and cell-adhesion mediated pathologies. These compounds may be formulated into pharmaceutical compositions and are suitable for use in the treatment of asthma, allergies, inflammation, multiple sclerosis, and other inflammatory and autoimmune disorders.

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10 Claims

1. A compound having the formula Ia:
- or a pharmaceutically acceptable salt thereof, whereinR²is
  
       1) hydrogen, or2) C_1-6alkyl;
  
  one of R³and R⁴is hydrogen and the other is1) aryl, 2) heteroaryl, 3) aryl-C_1-10alkyl, 4) heteroaryl-C_1-10alkyl, or 5) C_1-10alkyl, wherein aryl and heteroaryl are each optionally substituted with one to four substituents selected from R^b; and
  
  alkyl is optionally substituted with one to four substituents independently selected from R^a;
  
  orR³, R⁴and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N, O and S;
  
  one of R⁶and R⁷is hydrogen and the other is1) aryl, 2) aryl-C_1-10alkyl, or 3) C_1-10alkyl, wherein aryl is optionally substituted with one to four substituents independently selected from R^y, and alkyl is optionally substituted with one to four substituents selected from R^x; and
  
  R^ais
  
       1) Cy, or2) a group selected from R^x;
  
  wherein Cy is optionally substituted with one to four substituents independently selected from R^c;
  
  R^bis
  
       1) a group selected from R^a,2) C_1-0alkyl, 3) C_2-10alkenyl, 4) C_2-10alkynyl, 5) aryl C_1-10alkyl, 6) heteroaryl C_1-10alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from R^c;
  
  R^cis
  
       1) halogen,2) amino, 3) carboxy, 4) C_1-4alkyl, 5) C_1-4alkoxy, 6) aryl, 7) aryl C_1-4alkyl, or 8) aryloxy;
  
  R^dand R^eare independently selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, Cy and Cy C_1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy is optionally substituted with one to four substituents independently selected from R^c;
  
  or R^dand R^etogether with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
  
  R^fand R^gare independently selected from hydrogen, C_1-10alkyl, Cy and Cy C_1-10alkyl;
  
  or R^fand R^gtogether with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
  
  R^xis
  
       1) —
  
  OR^d,2) —
  
  NO₂, 3) halogen 4) —
  
  S(O)_mR^d, 5) —
  
  SR^d, 6) —
  
  S(O)₂OR^d, 7) —
  
  S(O)_mNR^dR^e, 8) —
  
  NR^dR^e, 9) —
  
  O(CR^fR^g)_nNR^dR^e, 10) —
  
  C(O)R^d, 11) —
  
  CO₂R^d, 12) —
  
  CO₂(CR^fR^g)_nCONR^dR^e, 13) —
  
  OC(O)R^d, 14) —
  
  CN, 15) —
  
  C(O)NR^dR^e, 16) —
  
  NR^dC(O)R^e, 17) —
  
  OC(O)NR^dR^e, 18) —
  
  NR^dC(O)OR^e, 19) —
  
  NR^dC(O)NR^dR^e, 20) —
  
  CR^d(N—
  
  OR^e), or 21) —
  
  CF₃;
  
  R^yis
  
       1) a group selected from R^x,2) C_1-10alkyl, 3) C_2-10alkenyl, 4) C_2-10alkynyl, 5) aryl C_1-10alkyl, 6) heteroaryl C_1-10alkyl, 7) cycloalkyl, 8) heterocyclyl;
  
  wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R^x;
  
  Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
  
  m is an integer from 1 to 2; and
  
  n is an integer from 1 to 10.
- View Dependent Claims (2, 4, 8, 9)
- - 2. A compound of claim 1 wherein R^bis selected from C_1-10alkoxy, halogen, cyano, and trifluoromethyl;
    - R²is H or methyl;
      
      one of R³and R⁴is hydrogen and the other is phenyl, Cy-C_1-3alkyl (wherein Cy is thienyl, pyridyl or phenyl optionally substituted with one or two groups selected from phenyl, hydroxy, halogen, cyano, and nitro);
      
      or C_1-6alkyl optionally substituted with CO₂H or CONH₂;
      
      one of R⁶and R⁷is hydrogen and the other is aryl-C_1-2alkyl, wherein aryl is optionally substituted with one to two substituents independently selected from halogen; and
      
      R^yis as defined in claim 1.
  - 4. A pharmaceutical composition which comprises a compound of claim 1 and a pharmaceutically acceptable carrier thereof.
  - 8. A method for the treatment of diseases or disorders, mediated by cell adhesion in a mammal which comprises administering to said mammal an effective amount of a compound of claim 1.
  - 9. A method for the treatment of asthma, allergic rhinitis, multiple sclerosis, atherosclerosis inflammatory bowel disorder, or inflammation in a mammal which comprises administering to said mammal an effective amount of a compound of claim 1.

3. A compound selected from the group consisting of:
- N-(3,4dimethoxybenzenesulfonyl)-(L)-3-(2-thienyl)alanyl-norleucine;
  
  N-(3,4-dimethoxybenzenesulfonyl)-(L)-3,3-diphenylalanyl-(L)-norleucine;
  
  N-3,4-dimethoxybenzenesulfonyl)-(L)-aspartyl-(L)-norleucine;
  
  N-(3,4-dimethoxybenzenesulfonyl)(L)-3-(3-pyridyl)alanyl-(L)-norleucine;
  
  N-(3,4-dimethoxybenzenesulfonyl)-(L)-alanyl-(L)-norleucine;
  
  N-(3,4-dimethoxybenzenesulfonyl)-(L)-homophenylalanyl-(L)-norleucine;
  
  N-(3,4-dimethoxybenzenesulfonyl)-L)-valyl-(L)-3-(2-naphthyl)alanine;
  
  N-(3,4-dimethoxybenzenesulfonyl)-(L)-asparagyl-(L)-norleucine;
  
  N-(3,4-dimethoxybenzenesulfonyl)-(L)-isoleucyl-(L)-3-(2-naphthyl)alanine;
  
  N-(3,4-dimethoxybenzenesulfonyl)-(L)-3-(4biphenyl)alanyl-(L)-norleucine;
  
  N-(3,5-dichlorobenzenesulfonyl)(L-N-methylvalyl-(L)-3-(2-naphthyl)alanine;
  
  N-(3,5-di(trifluoromethyl)-benzenesulfonyl)-(L)-N-methylvalyl-(L)-3-(2-naphthyl)alanine;
  
  N-(3,5-dichlorobenzenesulfonyl)-2(S)-aminobutyryl-(L-3-(2-naphthyl)alanine;
  
  N-(3,4-dimethoxybenzenesulfonyl)-(L)-N-methylisoleucyl-(L)-3-(2-naphthyl)alanine;
  
  N-(3,4-dimethoxybenzenesulfonyl)-(L)-N-methylvalyl-(L)-3-(2-naphthyl)alanine;
  
  N-(3,4-dimethoxybenzenesulfonyl)-(L)-sarcosinyl-(L)-3-(2-naphthyl)alanine;
  
  N-(3,4-dimethoxybenzenesulfonyl)-(L)-phenylalanyl-(L)norleucine;
  
  N-(3,4-dimethoxybenzenesulfonyl)-(L)-N-methylphenylalanyl-(L)-norleucine;
  
  N-(3,4-dimethoxybenzenesulfonyl)-(L)-a-phenylglycyl-(L)-norleucine;
  
  N-(3,4-dimethoxybenzenesulfonyl)-(L)-N-methylalanyl-(L)-norleucine;
  
  N-(3,5-dichlorobenzenesulfonyl)-(L)-tyrosyl-(L)-4-fluorophenylalanine;
  
  N-(3,5-dichlorobenzenesulfonyl)-(L-3-(4-pyridyl)alanine4L)-4-fluorophenylalanine;
  
  N-(3,5-dichlorobenzenesulfonyl)(L)-phenylalanyl-(L)4-fluorophenylalanine;
  
  N-(3,5-ichlorobenzenesulfony1S(L)4-fluorophenylalanyl-(L)-4-fluorophenylalanine;
  
  N-(3,5dichlorobenzenesulfonyl)-(L-3,5fluorophenylalanyl-(L)4-fluorophenylalanine;
  
  N-(3,5-dichlorobenzenesulfonyl)-(L-N-methylaspartyl-(L)-2-naphthylalanine;
  
  N-(3,5-dichlorobenzenesulfonyl)(L)-3-(2pyridyl)alanyl-(L)4-fluorophenylalanine;
  
  N-(3,5-dichlorobenzenesulfonyl)-(L)-N-methylvalyl-(L)-3-(2-naphthyl)alanine;
  
  N-(3-fluorobenzenesulfonyl)(L-N-methylvalyl-(L)-3-(2-naphthyl)alanine;
  
  N-(3,5-dichlorobenzenesulfonyl)-(L-4-chlorophenylalanyl-(L)-4-fluorophenylalanine;
  
  N-(3,5-dichlorobenzenesulfonyl)-(L)4-cyanophenylalanyl-(L)-4-fluorophenylalanine;
  
  N-(3,5-dichlorobenzenesulfonyl)(L)-4-nitrophenylalanyl-(L)-4-fluorophenylalanine;
  
  N-(3,5-dichlorobenzenesulfonyl)-(L)aspartyl-(L)-4-fluorophenylalanine;
  
  N-(3,5-dichlorobenzenesulfonyl)-L)-3(3-pyridyl)alanyl-(L)-4-fluorophenylalanine; and
  
  N-(3,5-dichlorobenzenesulfonyl)-(D)-N-methylvalyl-(L)-4-fluorophenylalanine;
  
  N-(3,5-dichlorobenzenesulfonyl)4L)-N-methylvalyl-(L)- 3-(2-naphthyl)alanine;
  
  N-(3-chlorobenzenesulfonyl)-2-amino-indan-2-carbonyl-(L-4-fluorophenylalanine;
  
  N43-fluorobenzenesulfonyl)(L)-2-phenylglycyl-(L)-4-fluorophenylalanine; and
  
  N43,5-dichlorobenzenesulfonyl)(L)-leucyl4L)-aspartic acid.

5. A method for the treatment of diseases or disorders mediated by cell adhesion in a mammal which comprises administering to said mammal an effective amount of a compound of Formula I:
- or a pharmaceutically acceptable salt thereof wherein;
  
  R¹is
  
       1) C_1-10alkyl,2) C_2-10alkenyl, 3) C_2-10alkynyl, 4) Cy, 5) Cy-C_1-10alkyl, 6) Cy-C_2-10alkenyl, 7) Cy-C_2-10alkynyl, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from R^a; and
  
  Cy is optionally substituted with one to four substituents independently selected from R^b;
  
  R²and R³are independently selected from1) hydrogen, or 2) a group selected from R¹;
  
  R₄is
  
       1) hydrogen,2) C_1-10alkyl, 3) C_2-10alkenyl, 4) C_2-10alkynyl, 5) aryl, 6) aryl-C_1--10alkyl, 7) heteroaryl, 8) heteroaryl-C_1-10alkyl, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from R^a; and
  
  aryl and heteroaryl optionally substituted with one to four substituents independently selected from R^b;
  
  orR³, R⁴and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N, O and S;
  
  R⁵is
  
       1) hydrogen,2) C_1-10alkyl, 3) Cy, or 4) Cy-C_1-10alkyl, wherein alkyl is optionally substituted with one to four substituents independently selected from R^a; and
  
  Cy is optionally substituted with one to four substituents independently selected from R^b;
  
  R⁶is
  
       1) hydrogen,2) C_1-10alkyl, 3) C_2-10alkenyl, 4) C_2-10alkynyl, 5) Cy, 6) Cy-C_1-10alkyl, 7) Cy-C_2-10alkenyl, 8) Cy-C_2-10alkynyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from R^x, and Cy is optionally substituted with one to four substituents independently selected from R^y;
  
  R⁷is
  
       1) hydrogen,2) C_1-10alkyl, 3) C_2-10alkenyl, 4) C_2-10alkynyl, 5) aryl, 6) aryl-C_1-10alkyl, 7) heteroaryl, 8) heteroaryl-C_1-10alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Rx, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from R^y;
  
  orR⁶, R⁷together with the atoms to which they are attached form a 3-7 membered ring containing 0-2 heteroatoms selected from N, O and S;
  
  R^ais
  
       1) Cy, or 2) a group selected from Rx;
  
  wherein Cy is optionally substituted with one to four substituents independently selected from R^c;
  
  R^bis
  
       1) a group selected from R^a, 2) C_1-10alkyl, 3) C_2-10alkenyl, 4) C_2-10alkynyl, 5) aryl C_1-10alkyl, 6) heteroaryl C_1-10alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from R^c;
  
  R^cis
  
       1) halogen,2) amino, 3) carboxy, 4) C_1-4alkyl, 5) C_1-4alkoxy, 6) aryl, 7) aryl C_1-4alkyl, or 8) aryloxy;
  
  R^dand R^eare independently selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, Cy and Cy C_1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy is optionally substituted with one to four substituents independently selected from R^c;
  
  orR^dand R^etogether with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
  
  R^fand R^gare independently selected from hydrogen, C_1-10alkyl, Cy and Cy C_1-10alkyl;
  
  orR^fand R^gtogether with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
  
  R^his
  
       1) hydrogen, 2) C_1-10alkyl, 3) C_2-10alkenyl, 4) C_2-10alkynyl, 5) cyano, 6) aryl, 7) aryl C_1-10alkyl, 8) heteroaryl, 9) heteroaryl C_1-10alkyl, or 10) —
  
  SO₂Rⁱ;
  
  wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from R^a; and
  
  aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R^b;
  
  Rⁱis
  
       1) C_1-10alkyl,2) C_2-10alkenyl, 3) C_2-10alkynyl, or 4) aryl;
  
  wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R^c;
  
  R^xis
  
       1) —
  
  OR^d,2) —
  
  NO₂, 3) halogen 4) —
  
  S(O)_mR^d, 5) —
  
  SR^d, 6) —
  
  S(O)₂OR^d, 7) —
  
  S(O)_mNR^dR^e, 8) —
  
  NR^dR^e, 9) —
  
  O(CR^fR^g)_nNR^dR^e, 10) —
  
  C(O)R^d, 11) —
  
  CO₂R^d, 12) —
  
  CO₂(CR^fR^g)_nCONR^dR^e, 13) —
  
  OC(O)R^d, 14) —
  
  CN, 15) —
  
  C(O)NR^dR^e, 16) —
  
  NR^dC(O)R^e, 17) —
  
  OC(O)NR^dR^e, 18) —
  
  NR^dC(O)OR^e, 19) —
  
  NR^dC(O)NR^dR^e, 20) —
  
  CR^d(N—
  
  OR^e), or 21) —
  
  CF₃;
  
  R^yis
  
       1) a group selected from R^x,2) C_1-10alkyl, 3) C_2-10alkenyl, 4) C_2-10alkynyl, 5) aryl C_1-10alkyl, 6) heteroaryl C_1-10alkyl, 7) cycloalkyl, 8) heterocyclyl;
  
  wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R^x;
  
  Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
  
  m is an integer from 1 to 2;
  
  n is an integer from 1 to 10;
  
  X is
  
       1) —
  
  C(O)OR^d,2) —
  
  P(O)₂OR^d, 3) —
  
  S(O)_mOR^d, 4) —
  
  C(O)NR^dR^h, or 5) -5-tetrazolyl.
- View Dependent Claims (6, 7, 10)
- - 6. A method of claim 5 wherein said disease is selected from asthma, allergic rhinitis, multiple sclerosis, inflammation, inflammatory bowel disease and atherosclerosis.
  - 7. A method of claim 5 wherein said cell adhesion is mediated by VLA-4(very later antigen-4).
  - 10. A method of claim 5 wherein in compounds of Formula I

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Current Assignee
Merck & Co., Inc.
Original Assignee
Merck & Co., Inc.
Inventors
Maccoss, Malcolm, Mills, Sander G., Durette, Philippe L., Hagmann, William K., Mumford, Richard A.
Primary Examiner(s)
McKane, Joseph K.
Assistant Examiner(s)
Solola, Taofiq A.

Application Number

US09/424,823
Time in Patent Office

512 Days
Field of Search

514/604, 514/357, 514/438, 546/336, 546/337, 549/76, 549/77, 564/91, 564/97, 564/99
US Class Current

514/357
CPC Class Codes

A61K 38/05   Dipeptides

C07K 5/06026   the side chain containing 0...

C07K 5/06034   the side chain containing 2...

C07K 5/06052   Val-amino acid

C07K 5/06078   and aromatic or cycloaliphatic

C07K 5/06113   Asp- or Asn-amino acid

C07K 5/06139   with the first amino acid b...

C07K 5/06191   containing heteroatoms diff...

Sulfonamides as cell adhesion inhibitors

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Sulfonamides as cell adhesion inhibitors

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