Electrophilic peptide analogs as inhibitors of trypsin-like enzymes

US 6,060,462 A
Filed: 08/01/1997
Issued: 05/09/2000
Est. Priority Date: 10/20/1993
Status: Expired due to Fees

First Claim

Patent Images

1. A compound of formula (I) ##STR526## or a pharmaceutically acceptable salt thereof, wherein:

R¹ isa) --(C₁ -C₁₂ alkyl)--X, ab) --(C₁ -C₁₂ alkenyl)--X, or ##STR527## x is a) halogen,b) --CN,c) --NO₂,d) --CF₃,e) --NH₂,f) --NHOR²,g) --NHC(═

NH)R²,h) --NHC(═

NH)NHOH,i) --NHC(═

NH)NHNH₂,j) --NHC(═

NH)NHCN,k) --NHC(═

NH)NHR²,l) --NHC(═

NH)NHCOR²,m) --C(═

NH)NHR²,n) --C(═

NH)NHCOR²,o) --C(═

O)NHR²,p) --CO₂ R²,q) --OR²,r) --OCF₃,s) --S(O)_r R²,t) --SC(═

NH)NHR², oru) --SC(═

NH)NHC(═

O)R² ;

R² isa) hydrogen, orb) C₁ -C₄ alkyl;

R³ isa) --C(═

O)--(CH₂)_p --CR⁶ R⁷ --(CH₂)_q -aryl,b) --C(═

O)--W--CR⁸ R⁹ -aryl, with the proviso that W cannot be a bivalent oxygen atom,c) --C(═

O)--CR⁸ R⁹ --W--(CH₂)_r -aryl, with the proviso that W cannot be --NR⁴ -- or --NC(═

O)R⁴ --,d) --C(═

O)--W--CR⁸ R⁹ -heteroaryl,e) --C(═

O)--CR⁸ R⁹ --W--(CH₂)_r -heteroaryl, with the proviso that W cannot be --NR⁴ -- or --NC(═

O)R⁴ --,f) --C(═

O)--W--CR⁸ R⁹ -heterocycle,g) --C(═

O)--CR⁸ R⁹ --W--(CH₂)_r -heterocycle, with the proviso that W cannot be --NR⁴ -- or --NCOR⁴ --,h) --C(═

O)--(CH₂)_t --W--(C₅ -C₇ cycloalkyl), ##STR528## wherein aryl is limited to phenyl, ##STR529## wherein aryl is limited to phenyl, ##STR530## with the proviso that R¹³ cannot be --N(C₁ -C₄ alkyl)₂ when A is --C(═

O)R¹⁴, ##STR531## wherein aryl is limited to phenyl,t) --C(═

O)--(CR⁸ R⁹)--NHS(O)_r R⁸, ##STR532## R⁴ and R⁵ are independently selected at each occurrence from the group consisting of;

a) hydrogen,b) C₁ -C₄ alkyl,c) --(C₁ -C₄ alkyl)-aryl, ord) C₅ -C₇ cycloalkyl;

R⁸ and R⁹ are independently selected at each occurrence from the group consisting of;

a) hydrogen,b) C₁ -C₄ alkyl,c) C₁ -C₄ alkoxy,d) aryl,e) --(C₁ -C₄ alkyl)-aryl,f) --(C₁ -C₄ alkyl)-heterocycle,g) --O-aryl,h) --(CH₂)_p --CO₂ R⁴,i) R⁸ and R⁹ can be taken together to form a (C₂ -C₇) alkyl;

R¹⁰ is;

phenyl, wherein phenyl is optionally substituted with one to three substituents selected from the group consisting of halogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₇ -C₁₅ alkylaryl, C₇ -C₁₅ alkoxyaryl, methylenedioxy, --NO₂, --CF₃, --SH, --S(O)_r --(C₁ -C₄ alkyl), CN, --OH, --NH₂, --NH(C₁ -C₄ alkyl), --N(C₁ -C₄ alkyl)₂, --NHCOR⁴, --(CH₂)_p --CO₂ R⁴ ;

R¹¹ is;

a) --OR⁴,b) --NR¹⁵ R¹⁶,c) --NC(═

O)R¹⁵ R¹⁶,d) --NR¹⁵ C(═

O)OR⁴,e) aryl,f) --(C₁ -C₄ alkyl)-aryl,g) heteroaryl,h) --(C₁ -C₄ alkyl)-heteroaryl,i) --(C₁ -C₄ alkyl)--CO₂ R⁴,j) heterocycle,k) --(C₁ -C₄ alkyl)heterocycle, ##STR533## R³ and R¹¹, when taken together to form a ring bonded to the nitrogen;

##STR534## R¹³ is independently selected at each occurrence from the group consisting of;

a) hydrogenb) halogen,c) C₁ -C₄ alkyl,d) C₁ -C₄ alkoxy,e) methylenedioxy,f) --NO₂,g) --CF₃,h) --SH,i) --S(O)_r --(C₁ -C₄ alkyl),j) --CN,k) --OH,l) --NH₂,m) --NH(C₁ -C₄ alkyl),n) --N(C₁ -C₄ alkyl)₂,o) --NHC(═

O)R⁴, orp) --(CH₂)_p --CO₂ R⁴ ;

R¹⁴ is;

a) --CF₃,b) --CHF₂,c) --CH₂ F,d) --CH₂ Cl,e) --C(═

O)OR⁴,f) --C(═

O)NR¹⁵ R¹⁶,g) --C(═

O)R⁴,h) --C(═

O)COOR⁴,i) --C(═

O)C(═

O)NR¹⁵ R¹⁶,j) --C(═

O)C(═

O)R⁴,k) --CY³ Y⁴ COOR⁴,l) --CY³ Y⁴ C(═

O)NR¹⁵ R¹⁶, orm) --CY³ Y⁴ C(═

O)R⁴ ;

R¹⁵ and R¹⁶ are independently selected at each occurrence from the group consisting of;

a) hydrogen,b) C₁ -C₄ alkyl,c) --(C₁ -C₄ alkyl)-aryl,d) C₅ -C₇ cycloalkyl, ore) phenyl, unsubstituted or substituted by R¹³ ;

R¹⁵ and R¹⁶ taken together to form a ring can also include;

##STR535## R¹⁷ is;

a) hydrogen,b) C₁ -C₄ alkyl,c) aryl,d) --(C₁ -C₄ alkyl)-aryl, ore) C₅ -C₇ cycloalkyl;

R¹⁸ is;

a) hydrogen,b) --(C₁ -C₅) alkyl, orc) --(C₁ -C₅) haloalkyl,d) --(C₁ -C₅) alkoxy;

R¹⁹ is;

a) hydrogen,b) --(C₁ -C₅) alkyl,c) halo, ord) --(C₁ -C₅) haloalkyl,e) --NO₂,f) --NR⁴ R⁵,g) --CN,h) --(C₁ -C₅) alkoxy;

A is;

--BY¹ Y² ;

W isa) --O--,b) --S(O)_r --,c) --NR⁴ --, ord) --NC(═

O)R⁴ --;

Y¹ and Y² area) --OH,b) --F,c) --NR⁴ R⁵,d) C₁ -C₈ alkoxy, or when taken together Y¹ and Y² form;

e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O;

Y³ and Y⁴ area) --OH orb) --F;

n is 0 or 1;

p is 0 to 3;

q is 0 to 4;

r is 0 to 2;

t is 1 to 3;

v is 1 to 17;

wherein aryl is defined as phenyl, fluorenyl, biphenyl and naphthyl, which may be unsubstituted or include optional substitution with one to three substituents;

heteroaryl is 2-, or 3-, or 4-pyridyl;

2- or 3-furyl;

2- or 3-benzofuranyl;

2-, or 3-thiophenyl;

2- or 3-benzo[b]thiophenyl;

2-, or 3-, or 4-quinolinyl;

1-, or 3-, or 4-isoquinolinyl;

2- or 3-pyrrolyl;

1- or 2- or 3-indolyl;

2-, or 4-, or 5-oxazolyl;

2-benzoxazolyl;

2- or 4- or 5-imidazolyl;

1- or 2-benzimidazolyl;

2- or 4- or 5-thiazolyl;

2-benzothiazolyl;

3- or 4- or 5-isoxazolyl;

3- or 4- or 5-pyrazolyl;

3- or 4-or 5-isothiazolyl;

3- or 4-pyridazinyl;

2- or 4- or 5-pyrimidinyl;

2-pyrazinyl;

2-triazinyl;

3- or 4-cinnolinyl;

1-phthalazinyl;

2- or 4-quinazolinyl;

or 2-quinoxalinyl ring;

said ring(s) may be unsubstituted or include optional substitution with one to three substituents;

heterocycle is tetrahydroisoquinoline, tetrahydroquinoline, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholino;

said ring(s) may be unsubstituted or include optional substitution with one to three substituents;

the substituents that may be attached to the aryl, heteroaryl and heterocycle ring(s) may be independently selected at each occurrence from the group consisting of;

halogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, methylenedioxy, --NO₂, --CF₃, --SH, --S(O)_r --(C₁ -C₄ alkyl)--CN, --OH, --NH₂, --NH(C₁ -C₄ alkyl) --N(C₁ -C₄ alkyl)₂, --NHC(═

O)R⁴, --(CH₂)_p --CO₂ R⁴, phenyl which may be unsubstituted or substituted with R¹³.

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Abstract

This invention relates to electrophilic dipeptide analogs conjugated to an N,N-disubstituted α-amino acid as inhibitors of trypsin-like serine protease enzymes.

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12 Claims

1. A compound of formula (I) ##STR526## or a pharmaceutically acceptable salt thereof, wherein:
- R¹ isa) --(C₁ -C₁₂ alkyl)--X, ab) --(C₁ -C₁₂ alkenyl)--X, or ##STR527## x is a) halogen,b) --CN,c) --NO₂,d) --CF₃,e) --NH₂,f) --NHOR²,g) --NHC(═
  
  NH)R²,h) --NHC(═
  
  NH)NHOH,i) --NHC(═
  
  NH)NHNH₂,j) --NHC(═
  
  NH)NHCN,k) --NHC(═
  
  NH)NHR²,l) --NHC(═
  
  NH)NHCOR²,m) --C(═
  
  NH)NHR²,n) --C(═
  
  NH)NHCOR²,o) --C(═
  
  O)NHR²,p) --CO₂ R²,q) --OR²,r) --OCF₃,s) --S(O)_r R²,t) --SC(═
  
  NH)NHR², oru) --SC(═
  
  NH)NHC(═
  
  O)R² ;
  
  R² isa) hydrogen, orb) C₁ -C₄ alkyl;
  
  R³ isa) --C(═
  
  O)--(CH₂)_p --CR⁶ R⁷ --(CH₂)_q -aryl,b) --C(═
  
  O)--W--CR⁸ R⁹ -aryl, with the proviso that W cannot be a bivalent oxygen atom,c) --C(═
  
  O)--CR⁸ R⁹ --W--(CH₂)_r -aryl, with the proviso that W cannot be --NR⁴ -- or --NC(═
  
  O)R⁴ --,d) --C(═
  
  O)--W--CR⁸ R⁹ -heteroaryl,e) --C(═
  
  O)--CR⁸ R⁹ --W--(CH₂)_r -heteroaryl, with the proviso that W cannot be --NR⁴ -- or --NC(═
  
  O)R⁴ --,f) --C(═
  
  O)--W--CR⁸ R⁹ -heterocycle,g) --C(═
  
  O)--CR⁸ R⁹ --W--(CH₂)_r -heterocycle, with the proviso that W cannot be --NR⁴ -- or --NCOR⁴ --,h) --C(═
  
  O)--(CH₂)_t --W--(C₅ -C₇ cycloalkyl), ##STR528## wherein aryl is limited to phenyl, ##STR529## wherein aryl is limited to phenyl, ##STR530## with the proviso that R¹³ cannot be --N(C₁ -C₄ alkyl)₂ when A is --C(═
  
  O)R¹⁴, ##STR531## wherein aryl is limited to phenyl,t) --C(═
  
  O)--(CR⁸ R⁹)--NHS(O)_r R⁸, ##STR532## R⁴ and R⁵ are independently selected at each occurrence from the group consisting of;
  
  a) hydrogen,b) C₁ -C₄ alkyl,c) --(C₁ -C₄ alkyl)-aryl, ord) C₅ -C₇ cycloalkyl;
  
  R⁸ and R⁹ are independently selected at each occurrence from the group consisting of;
  
  a) hydrogen,b) C₁ -C₄ alkyl,c) C₁ -C₄ alkoxy,d) aryl,e) --(C₁ -C₄ alkyl)-aryl,f) --(C₁ -C₄ alkyl)-heterocycle,g) --O-aryl,h) --(CH₂)_p --CO₂ R⁴,i) R⁸ and R⁹ can be taken together to form a (C₂ -C₇) alkyl;
  
  R¹⁰ is;
  
  phenyl, wherein phenyl is optionally substituted with one to three substituents selected from the group consisting of halogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₇ -C₁₅ alkylaryl, C₇ -C₁₅ alkoxyaryl, methylenedioxy, --NO₂, --CF₃, --SH, --S(O)_r --(C₁ -C₄ alkyl), CN, --OH, --NH₂, --NH(C₁ -C₄ alkyl), --N(C₁ -C₄ alkyl)₂, --NHCOR⁴, --(CH₂)_p --CO₂ R⁴ ;
  
  R¹¹ is;
  
  a) --OR⁴,b) --NR¹⁵ R¹⁶,c) --NC(═
  
  O)R¹⁵ R¹⁶,d) --NR¹⁵ C(═
  
  O)OR⁴,e) aryl,f) --(C₁ -C₄ alkyl)-aryl,g) heteroaryl,h) --(C₁ -C₄ alkyl)-heteroaryl,i) --(C₁ -C₄ alkyl)--CO₂ R⁴,j) heterocycle,k) --(C₁ -C₄ alkyl)heterocycle, ##STR533## R³ and R¹¹, when taken together to form a ring bonded to the nitrogen;
  
  ##STR534## R¹³ is independently selected at each occurrence from the group consisting of;
  
  a) hydrogenb) halogen,c) C₁ -C₄ alkyl,d) C₁ -C₄ alkoxy,e) methylenedioxy,f) --NO₂,g) --CF₃,h) --SH,i) --S(O)_r --(C₁ -C₄ alkyl),j) --CN,k) --OH,l) --NH₂,m) --NH(C₁ -C₄ alkyl),n) --N(C₁ -C₄ alkyl)₂,o) --NHC(═
  
  O)R⁴, orp) --(CH₂)_p --CO₂ R⁴ ;
  
  R¹⁴ is;
  
  a) --CF₃,b) --CHF₂,c) --CH₂ F,d) --CH₂ Cl,e) --C(═
  
  O)OR⁴,f) --C(═
  
  O)NR¹⁵ R¹⁶,g) --C(═
  
  O)R⁴,h) --C(═
  
  O)COOR⁴,i) --C(═
  
  O)C(═
  
  O)NR¹⁵ R¹⁶,j) --C(═
  
  O)C(═
  
  O)R⁴,k) --CY³ Y⁴ COOR⁴,l) --CY³ Y⁴ C(═
  
  O)NR¹⁵ R¹⁶, orm) --CY³ Y⁴ C(═
  
  O)R⁴ ;
  
  R¹⁵ and R¹⁶ are independently selected at each occurrence from the group consisting of;
  
  a) hydrogen,b) C₁ -C₄ alkyl,c) --(C₁ -C₄ alkyl)-aryl,d) C₅ -C₇ cycloalkyl, ore) phenyl, unsubstituted or substituted by R¹³ ;
  
  R¹⁵ and R¹⁶ taken together to form a ring can also include;
  
  ##STR535## R¹⁷ is;
  
  a) hydrogen,b) C₁ -C₄ alkyl,c) aryl,d) --(C₁ -C₄ alkyl)-aryl, ore) C₅ -C₇ cycloalkyl;
  
  R¹⁸ is;
  
  a) hydrogen,b) --(C₁ -C₅) alkyl, orc) --(C₁ -C₅) haloalkyl,d) --(C₁ -C₅) alkoxy;
  
  R¹⁹ is;
  
  a) hydrogen,b) --(C₁ -C₅) alkyl,c) halo, ord) --(C₁ -C₅) haloalkyl,e) --NO₂,f) --NR⁴ R⁵,g) --CN,h) --(C₁ -C₅) alkoxy;
  
  A is;
  
  --BY¹ Y² ;
  
  W isa) --O--,b) --S(O)_r --,c) --NR⁴ --, ord) --NC(═
  
  O)R⁴ --;
  
  Y¹ and Y² area) --OH,b) --F,c) --NR⁴ R⁵,d) C₁ -C₈ alkoxy, or when taken together Y¹ and Y² form;
  
  e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O;
  
  Y³ and Y⁴ area) --OH orb) --F;
  
  n is 0 or 1;
  
  p is 0 to 3;
  
  q is 0 to 4;
  
  r is 0 to 2;
  
  t is 1 to 3;
  
  v is 1 to 17;
  
  wherein aryl is defined as phenyl, fluorenyl, biphenyl and naphthyl, which may be unsubstituted or include optional substitution with one to three substituents;
  
  heteroaryl is 2-, or 3-, or 4-pyridyl;
  
  2- or 3-furyl;
  
  2- or 3-benzofuranyl;
  
  2-, or 3-thiophenyl;
  
  2- or 3-benzo[b]thiophenyl;
  
  2-, or 3-, or 4-quinolinyl;
  
  1-, or 3-, or 4-isoquinolinyl;
  
  2- or 3-pyrrolyl;
  
  1- or 2- or 3-indolyl;
  
  2-, or 4-, or 5-oxazolyl;
  
  2-benzoxazolyl;
  
  2- or 4- or 5-imidazolyl;
  
  1- or 2-benzimidazolyl;
  
  2- or 4- or 5-thiazolyl;
  
  2-benzothiazolyl;
  
  3- or 4- or 5-isoxazolyl;
  
  3- or 4- or 5-pyrazolyl;
  
  3- or 4-or 5-isothiazolyl;
  
  3- or 4-pyridazinyl;
  
  2- or 4- or 5-pyrimidinyl;
  
  2-pyrazinyl;
  
  2-triazinyl;
  
  3- or 4-cinnolinyl;
  
  1-phthalazinyl;
  
  2- or 4-quinazolinyl;
  
  or 2-quinoxalinyl ring;
  
  said ring(s) may be unsubstituted or include optional substitution with one to three substituents;
  
  heterocycle is tetrahydroisoquinoline, tetrahydroquinoline, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholino;
  
  said ring(s) may be unsubstituted or include optional substitution with one to three substituents;
  
  the substituents that may be attached to the aryl, heteroaryl and heterocycle ring(s) may be independently selected at each occurrence from the group consisting of;
  
  halogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, methylenedioxy, --NO₂, --CF₃, --SH, --S(O)_r --(C₁ -C₄ alkyl)--CN, --OH, --NH₂, --NH(C₁ -C₄ alkyl) --N(C₁ -C₄ alkyl)₂, --NHC(═
  
  O)R⁴, --(CH₂)_p --CO₂ R⁴, phenyl which may be unsubstituted or substituted with R¹³.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)
- - 2. A compound of claim 1 whereinheteroaryl is 2-, 3-, or 4-pyridyl;
    - 2-, or 3-furyl;
      
      2-, or 3-thiophenyl;
      
      2-, 3-, or 4-quinolinyl;
      
      or 1-, 3-, or 4-isoquinolinyl which may be unsubstitued or include optional substitution with one to three substituents; and
      
      heterocycle is 1-, 3-, or 4-tetrahydroisoquinolinyl, 2- or 3-pyrrolidinyl, and 2-, 3- or 4-piperidinyl which may be unsubstituted or include optional substitution with one to three substituents.
  - 3. A compound of claim 2 whereinR³ isa) --C(═
    - O)--(CH₂)_p --CR⁶ R⁷ --(CH₂)_q -aryl, ##STR536## wherein aryl is limited to phenyl;
      
      ##STR537## wherein aryl is limited to phenyl;
      
      or ##STR538##
  - 4. A compound of claim 3 wherein R³ is hydrocinnamoyl and R¹¹ is ##STR539##
  - 5. A compound of claim 4 wherein R⁴ and R⁵ are both H.
  - 6. A compound of claim 1 selected from the group consisting of:
    - Hydrocinnamoyl-[N-(Phenethyl)-Gly]-boroOrn-C10H16 HClHydrocinnamoyl-[N-(Phenethyl)-Gly]-boroOrn(CH═
      
      NH)-C10H16 HClHydrocinnamoyl-[N-(Phenethyl)-Gly]-boroOrn(CH═
      
      NH)--OH HClHydrocinnamoyl-[N-(Phenethyl)-Gly]-boroArg(CH3)-C10H16 HClHydrocinnamoyl-[N-(N(CH3)₂)-Gly]-boroLys-C10H16 HClHydrocinnamoyl-[N-(N(CH3)₂)-Gly]-boroLys--OH HClHydrocinnamoyl-[N-(N(CH3)₂)-Gly]-boroOrn-C10H16 HClHydrocinnamoyl-[N-(N(CH3)₂)-Gly]-boroOrn(CH═
      
      NH)-C10H16 HClMethanesulfonyl-Gly-[N-(Phenethyl)-Gly]-boroLys-C10H16 HClHydrocinnamoyl-[N-(3-(Trifluoromethyl)-Phenethyl)-Gly]-boroLys-C10H16 HClHydrocinnamoyl-[N-(3-(Trifluoromethyl)-Phenethyl)-Gly]-boroLys--OH HClHydrocinnamoyl-[N-(3-(Methyl)-Phenethyl)-Gly]-boroLys-C10H16 HClHydrocinnamoyl-[N-(3-(Methyl)-Phenethyl)-Gly]-boroLys--OH HClSuccinyl-[N-(3-(Methyl)-Phenethyl)-Gly]-boroLys-C10H16 HClHydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroLys--OH HClHydrocinnamoyl-[N-(2-(Cyclopropyl)-Phenethyl)-Gly]-boroLys-C10H16 HClHydrocinnamoyl-[N-(2-(Cyclopropyl)-Phenethyl)-Gly]-boroLys--OH HClHydrocinnamoyl-[N-(2-(Cyclopropyl)-Phenethyl)-Gly]-boroOrn(CH═
      
      NH)--OH HClHydrocinnamoyl-[N-(2,2-(Diethyl)-Phenethyl)-Gly]-boroLys-C10H16 HClAcetyl-Gly[N-(2-(Benzyl)-Benzyl)]-boroLys-C10H16 HClPinanediol N-{N-methyl-N-[2-(pyrrol-1-ylmethyl)-Benzyl]glycyl}-1-amido-5-aminopentaneboronate, hydrochloride saltPhenoxyacetyl-[N-(Cyclopropyl)-Gly]-boroLys-C10H16 HClThiophenacetyl-[N-(Cyclopropyl)-Gly]-boroLys-C10H16 HClPhenoxyacetyl-[N-(Cyclopropyl)-Gly]-boroLys--OH HClThiophenacetyl-[N-(Cyclopropyl)-Gly]-boroLys--OH HClGlutaryl-[N-(Phenethyl)-Gly]-boroLys--OH HClGlutaryl(3,3-Dimethyl)-[N-(Phenethyl)-Gly]-boroLys-C10H16Methyl Glutaryl(3,3-Dimethyl)-[N-(Phenethyl)-Gly]-boroLys-C10H16 HClGlutaryl(3,3-Dimethyl)-[N-(Phenethyl)-Gly]-boroLys--OHMethyl Glutaryl(3,3-Dimethyl)-[N-(Phenethyl)-Gly]-boroLys--OH HClBoc-Asp-[N-(Phenethyl)-Gly]-boroLys-C10H16Boc-Glu-[N-(Phenethyl)-Gly]-boroLys-C10H16Boc-Glu(OCH3)-[N-(Phenethyl)-Gly]-boroLys-C10H16 HClBoc-Glu-[N-(Phenethyl-Gly]-boroLys--OHMethanesylfonyl-Gly-[N-(N-(Methyl)-Benzyl)-Gly]-boroLys-C10H16 HClMethanesulfonyl-Gly-[N-(N-(Methyl)-Benzyl)-Gly]-boroLys--OH HClSuccinyl-[N-(Phenethyl)-Gly]-boroLys--OHMethyl Succinyl-[N-(Phenethyl)-Gly]-boroLys--OH HClGlutaryl-[N-(Phenethyl)-Gly]-boroLys-C10H16Methyl Glutaryl-[N-(Phenethyl)-Gly]-boroLys-C10H16 HClMethyl Glutaryl-[N-(Phenethyl)-Gly]-boroLys--OH HCl.
  - 7. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 1.
  - 8. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 2.
  - 9. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 6.
  - 10. A method of treating a physiological disorder in a warm blooded animal catalyzed by trypsin-like enzymes comprising administering to an animal in need such treatment an effective amount of a compound of claim 1.
  - 11. A method of treating a physiological disorder in a warm blooded animal catalyzed by trypsin-like enzymes comprising administering to an animal in need such treatment an effective amount of a compound of claim 2.
  - 12. A method of treating a physiological disorder in a warm blooded animal catalyzed by trypsin-like enzymes comprising administering to an animal in need such treatment an effective amount of a compound of claim 6.

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Current Assignee
Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
Original Assignee
DuPont Performance Elastomers L (Bristol-Myers Squibb Company)
Inventors
Weber, Patricia Carol, Knabb, Robert Madara, Pacofsky, Gregory James, Amparo, Eugene Cruz, Cacciola, Joseph, Miller, William Henry, Fevig, John Matthew, Galemmo, Robert Anthony Jr., Abelman, Matthew Mark
Primary Examiner(s)
AMBROSE, MICHAEL GEORGE

Application Number

US08/904,881
Time in Patent Office

1,012 Days
Field of Search

514/64, 546/13, 548/110, 549/4, 558/5, 558/288, 558/298, 562/7
US Class Current

514/64
CPC Class Codes

A61K 38/00   Medicinal preparations cont...

C07F 5/025   Boronic and borinic acid co...

C07F 9/5325   Aromatic phosphine oxides o...

C07K 5/06191   containing heteroatoms diff...

C07K 7/02   Linear peptides containing ...

Electrophilic peptide analogs as inhibitors of trypsin-like enzymes

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Abstract

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Electrophilic peptide analogs as inhibitors of trypsin-like enzymes

First Claim

2 Assignments

Subscription Required

Subscription Required

0 Petitions

Subscription Required

Accused Products

Subscription Required

Abstract

27 Citations

12 Claims

Specification

Subscription Required

Use Cases

Quick Links

Others