EP0938477A4 - BENZOTHIAZOLO AND RELATED HETEROCYCLIC GROUPS CONTAINING CYSTEIN AND SERINE PROTEASE INHIBITORS - Google Patents

BENZOTHIAZOLO AND RELATED HETEROCYCLIC GROUPS CONTAINING CYSTEIN AND SERINE PROTEASE INHIBITORS

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Publication number
EP0938477A4
EP0938477A4 EP97949430A EP97949430A EP0938477A4 EP 0938477 A4 EP0938477 A4 EP 0938477A4 EP 97949430 A EP97949430 A EP 97949430A EP 97949430 A EP97949430 A EP 97949430A EP 0938477 A4 EP0938477 A4 EP 0938477A4
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Prior art keywords
compound
alkyl
optionally substituted
carbons
groups
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EP97949430A
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German (de)
English (en)
French (fr)
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EP0938477A1 (en
Inventor
Ron Bihovsky
Gregory J Wells
Ming Tao
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Cephalon LLC
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Cephalon LLC
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Priority claimed from US08/968,035 external-priority patent/US5952328A/en
Application filed by Cephalon LLC filed Critical Cephalon LLC
Publication of EP0938477A1 publication Critical patent/EP0938477A1/en
Publication of EP0938477A4 publication Critical patent/EP0938477A4/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • C07D327/06—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6544—Six-membered rings
    • C07F9/6547—Six-membered rings condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • Novel benzothiazo and related heterocyclic group- containing inhibitors of cysteine or serine proteases methods for making these novel compounds, and methods for using the same are disclosed.
  • cysteine and serine proteases Numerous cysteine and serine proteases have been identified in human tissues.
  • a "protease” is an enzyme which degrades proteins into smaller components (peptides) .
  • the terms "cysteine protease” and “serine protease” refer to proteases which are distinguished by the presence therein of a cysteine or serine residue which plays a critical role in the catalytic process.
  • Mammalian systems, including humans normally degrade and process proteins via a variety of enzymes including cysteine and serine proteases. However, when present at elevated levels or when abnormally activated, cysteine and serine proteases may be involved in pathophysiological processes.
  • calpains calcium-activated neutral proteases
  • cysteine proteases which are ubiquitously expressed in mammalian tissues.
  • Two major calpains have been identified; calpain I and calpain II. While calpain II is the predominant form in many tissues, calpain I is thought to be the predominant form in pathological conditions of nerve tissues.
  • the calpain family of cysteine proteases has been implicated in many diseases and disorders, including neurodegeneration, stroke, Alzheimer's, amyotrophy, motor neuron damage, acute central nervous system injury, muscular dystrophy, bone resorption, platelet aggregation, cataracts and inflammation.
  • Calpain I has been implicated in excitatory amino-acid induced neurotoxicity disorders including ischemia, hypoglycemia, Huntington' s Disease, and epilepsy.
  • the lysosomal cysteine protease cathepsin B has been implicated in the following disorders: arthritis, inflammation, myocardial infarction, tumor metastasis, and muscular dystrophy.
  • Other lysosomal cysteine proteases include cathepsins C, H, L and S.
  • Interleukin-l ⁇ converting enzyme (“ICE") is a cysteine protease which catalyzes the formation of interleukin-l ⁇ .
  • Interleukin-l ⁇ is an immunoregulatory protein implicated in the following disorders: inflammation, diabetes, septic shock, rheumatoid arthritis, and Alzheimer's disease.
  • ICE has also been linked to apoptotic cell death of neurons, which is implicated in a variety of neurodegenerative disorders including Parkinson's disease, ischemia, and amyotrophic lateral sclerosis (ALS) .
  • ALS amyotrophic lateral sclerosis
  • Cysteine proteases are also produced by various pathogens.
  • the cysteine protease clostripain is produced by Clostridium histolyticum .
  • Other proteases are produced by Trypanosoma cruzi , malaria parasites Plasmodiu falciparum and P . vinckei and Streptococcus .
  • Hepatitis A viral protease HAV C3 is a cysteine protease essential for processing of picornavirus structural proteins and enzymes.
  • Exemplary serine proteases implicated in degenerative disorders include thrombin, human leukocyte elastase, pancreatic elastase, chymase and cathepsin G.
  • thrombin is produced in the blood coagulation cascade, cleaves fibrinogen to form fibrin and activates Factor VIII; thrombin is implicated in thrombophlebitis, thrombosis and asthma.
  • Human leukocyte elastase is implicated in tissue degenerative disorders such as rheumatoid arthritis, osteoarthritis , atherosclerosis, bronchitis, cystic fibrosis, and emphysema.
  • Pancreatic elastase is implicated in pancreatitis.
  • Chymase an enzyme important in angiotensin synthesis, is implicated in hypertension, myocardial infarction, and coronary heart disease.
  • Cathepsin G is implicated in abnormal connective tissue degradation, particularly in the lung.
  • the present invention is directed to novel cysteine and serine protease inhibitors which contain a benzoheterocyclic group.
  • Exemplary compounds are represented by the following Formula I :
  • A-B represents one, two, or three carbon atoms or nitrogen atoms, optionally connected by single bonds or one double bond, optionally substituted with one or more groups selected from R 3 , R 4 , OR 3 , OR 4 , R 4a , and 0R 4a , with the proviso that the number of nitrogen atoms is 0, 1 or 2 ;
  • R 1 and R 2 are each independently hydrogen, alkyl having from one to about 14 carbons, cycloalkyl having from 3 to about 10 carbons, aryl having from about 6 to about 14 carbons, heteroaryl having from about 6 to about 14 ring atoms, aralkyl having from about 7 to about 15 carbons, heteroaralkyl , or an optionally protected natural or unnatural side chain of an amino acid, said alkyl, cycloalkyl, aryl, and heteroaryl groups being optionally substituted with one or more K groups;
  • R 3 , R 4 and R 4a are each independently hydrogen, lower alkyl, or a natural or unnatural side chain of an optionally protected amino acid, said alkyl groups being optionally substituted with an aryl or heteroaryl group;
  • R 5 , R 6 , R 7 and R 8 are each independently hydrogen, alkyl having from one to about 14 carbons wherein said alkyl groups are optionally substituted with one or more K groups, alkoxy having from one to about 10 carbons, halogen, alkoxycarbonyl, carboxyl, hydroxyl , heterocyclic, or amino optionally substituted with 1 to 3 aryl or lower alkyl groups; or any two adjacent R 5 , R ⁇ , R 7 and R 8 groups taken together with any intervening atoms of the benzene ring to which they are attached form an alicyclic, aromatic, heterocyclic, or heteroaryl ring having 5 to 8 ring atoms; K is halogen, lower alkyl, lower alkenyl, aryl, heterocyclic, guanidino, nitro, alkoxycarbonyl, alkoxy, hydroxyl, carboxyl, arylaminosulfonyl , heteroarylaminosulfonyl, alkylami
  • Y is O, NH, NR 9 or CHR 9 ;
  • R 9 is hydrogen, alkyl having from one to about 10 carbons, said alkyl groups being optionally substituted with one or more K groups, aryl having from about 6 to about 14 carbons, or aralkyl having from about 7 to about 15 carbons;
  • R 10 is aryloxy, heteroaryloxy, L, halogen, or has the formula O-M, wherein M has the structure:
  • R is N or CR 11 ;
  • W is a double bond or a single bond
  • E and F are independently R 12 , R 13 , or J; or E and F taken together comprise a joined moiety, said joined moiety being an aliphatic carbocyclic ring optionally substituted with J and having from 5 to 7 carbons, an aromatic carbocyclic ring optionally substituted with J and having from 5 to 7 carbons, an aliphatic heterocyclic ring optionally substituted with J and having from 5 to 7 atoms, or an aromatic heterocyclic ring optionally substituted with J and having from 5 to 7 atoms, said aliphatic heterocyclic ring or said aromatic heterocyclic ring each having from 1 to 4 heteroatoms;
  • R 11 , R 12 , and R 13 are independently H, alkyl having from 1 to 10 carbons, heteroaryl having from 1 to 10 carbons, alkanoyl having from 1 to 10 carbons, or aroyl, wherein said alkyl, heteroaryl, alkanoyl and aroyl groups are optionally substituted with J;
  • R 14 and R 15 are independently H, alkyl having from 1 to 10 carbons, aryl, or heteroaryl, wherein said alkyl, aryl and heteroaryl groups are optionally substituted with K;
  • L is a phosphorus-containing enzyme reactive group having the formula:
  • the compounds of the invention are useful for the inhibition of cysteine and serine proteases. Beneficially, the compounds find utility in a variety of settings.
  • the claimed compounds can be used, for example, as standards to screen for natural and synthetic cysteine protease and serine protease inhibitors which have the same or similar functional characteristics as the disclosed compounds.
  • the compounds of the present invention can be used to alleviate, mediate, reduce and/or prevent disorders which are associated with abnormal and/or aberrant activity of cysteine proteases and/or serine proteases.
  • methods for using the subject compounds such as methods for inhibiting serine proteases or cysteine proteases comprising contacting said proteases with an inhibitory amount of a compound of the invention are disclosed.
  • Methodologies for making the benzothiazine group-containing inhibitors are also disclosed.
  • A-B represents one, two, or three carbon atoms or nitrogen atoms, optionally connected by single bonds or one double bond, optionally substituted with one or more groups selected from R 3 , R 4 , OR 3 , OR 4 , R 4a , and OR 4a , with the proviso that the number of nitrogen atoms is 0, 1 or 2 ;
  • R 1 and R 2 are each independently hydrogen, alkyl having from one to about 14 carbons, cycloalkyl having from 3 to about 10 carbons, aryl having from about 6 to about 14 carbons, heteroaryl having from about 6 to about 14 ring atoms, aralkyl having from about 7 to about 15 carbons, heteroaralkyl, or an optionally protected natural or unnatural side chain of an amino acid, said alkyl, cycloalkyl, aryl, and heteroaryl groups being optionally substituted with one or more K groups;
  • R 3 , R 4 and R 4a are each independently hydrogen, lower alkyl, or a natural or unnatural side chain of an optionally protected amino acid, said alkyl groups being optionally substituted with an aryl or heteroaryl group;
  • R 5 , R 6 , R 7 and R 8 are each independently hydrogen, alkyl having from one to about 14 carbons wherein said alkyl groups are optionally substituted with one or more K groups, alkoxy having from one to about 10 carbons, halogen, alkoxycarbonyl, carboxyl, hydroxyl, heterocyclic, or amino optionally substituted with 1 to 3 aryl or lower alkyl groups; or any two adjacent R 5 , R 6 , R 7 and R 8 groups taken together with any intervening atoms of the benzene ring to which they are attached form an alicyclic, aromatic, heterocyclic, or heteroaryl ring having 5 to 8 ring atoms; K is halogen, lower alkyl, lower alkenyl , aryl, heterocyclic, guanidino, nitro, alkoxycarbonyl, alkoxy, hydroxyl, carboxyl, arylaminosulfonyl, heteroarylaminosulfonyl , alkylaminos
  • R 9 is hydrogen, alkyl having from one to about 10 carbons, said alkyl groups being optionally substituted with one or more K groups, aryl having from about 6 to about 14 carbons, or aralkyl having from about 7 to about 15 carbons;
  • R 10 is aryloxy, heteroaryloxy, L, halogen, or has the formula 0-M, wherein M has the structure:
  • R is N or CR 11 ;
  • W is a double bond or a single bond
  • E and F are independently R 12 , R 13 , or J; or E and F taken together comprise a joined moiety, said joined moiety being an aliphatic carbocyclic ring optionally substituted with J and having from 5 to 7 carbons, an aromatic carbocyclic ring optionally substituted with J and having from 5 to 7 carbons, an aliphatic heterocyclic ring optionally substituted with J and having from 5 to 7 atoms, or an aromatic heterocyclic ring optionally substituted with J and having from 5 to 7 atoms, said aliphatic heterocyclic ring or said aromatic heterocyclic ring each having from 1 to 4 heteroatoms;
  • R 11 , R 12 , and R 13 are independently H, alkyl having from 1 to 10 carbons, heteroaryl having from 1 to 10 carbons, alkanoyl having from 1 to 10 carbons, or aroyl, wherein said alkyl, heteroaryl, alkanoyl and aroyl groups are optionally substituted with J;
  • J is
  • R 14 and R 15 are independently H, alkyl having from 1 to 10 carbons, aryl, or heteroaryl, wherein said alkyl, aryl and heteroaryl groups are optionally substituted with K;
  • L is a phosphorus-containing enzyme reactive group having the formula :
  • m, n, and b are each independently 0 or 1 ;
  • R 2 , R 5 and R 8 are each H.
  • R 1 is alkyl or aralkyl, preferably i- butyl or benzyl .
  • R 6 and R 7 are independently H, alkoxy, halogen, or heterocyclic, or R 6 and R 7 taken together form -0-CH 2 -CH 2 - O- .
  • R 6 and R 7 are independently H, -OCH 3 , F, Cl, or morpholin-4-yl , or R 6 and R 7 taken together form -0-CH 2 -CH 2 -0- .
  • Y is 0, NH, NR 9 or CHR 9 , where R 9 is alkyl or aralkyl.
  • Y is NR 9 or CHR 9 , where R 9 is methyl ethyl, i-propyl, i-butyl or benzyl .
  • R 2 , R 5 and R 8 are each H;
  • R 1 is alkyl or aralkyl, with i-butyl or benzyl being preferred;
  • R 6 and R 7 are independently H, alkoxy, halogen, or heterocyclic, or R 6 and R 7 taken together form -0-CH 2 -CH 2 - 0-;
  • Y is O, NH, NR 9 or CHR 9
  • R 6 and R 7 are preferably independently H, -0CH 3 , F, Cl, or morpholin-4-yl , or R 6 and R 7 taken together form -0-CH 2 -CH 2 - O- , and Y is preferably NR 9 or CHR 9 , where R 9 is methyl ethyl, i-propyl, i-butyl or benzyl.
  • A-B is -CH 2 -CH-; Z is S0 2 ; R 2 , R 5 and R 8 are each H; and
  • R 1 is alkyl, alkyl substituted with K, or aralkyl, with i-butyl, benzyl, or alkyl substituted with phenylsulfonyl -amino being preferred;
  • R 6 and R 7 are independently H, alkoxy, halogen, or heterocyclic, with H, OCH 3 , F, Cl , or morpholin-4-yl being preferred, or preferably R 6 and R 7 taken together form -0-CH 2 -CH 2 -0-;
  • A-B is -CH 2 - CH-; Z is S0 2 ; R 2 , R 5 and R 8 are each H; and R 1 , R 6 , R 7 , Y and Q have the values shown in Table II, infra .
  • A-B is -CH 2 -CH- ;
  • Z is S0 2 ;
  • R 2 , R 5 and R 8 are each H;
  • R 6 and R 7 taken together form -0-CH 2 -CH 2 -0- ;
  • R 1 is benzyl;
  • Y is N-H or N-ethyl;
  • A-B is -CH 2 - CH-; Z is S0 2 ; R 2 , R 5 and R 8 are each H; R 6 and R 7 taken together form -0-CH 2 -CH 2 -0- ; R 1 is benzyl; and Y and Q have the values shown in Table III, infra .
  • Z is S0 2 ;
  • R 2 , R 5 and R 8 are each H;
  • R 1 is benzyl;
  • R 6 and R 7 are independently H or halogen, or R 6 and R 7 taken together form -0-CH 2 -CH 2 -0- ;
  • R 4 is H, alkoxy with methoxy being preferred, or hydroxy;
  • Z is S0 2 ;
  • R 2 , R 5 and R 8 are each H; and
  • R 1 , R 6 , R 7 , R 4 , Y and Q have the values shown in Table IV, infra .
  • A-B is -N(R 4 )-CH-; Z is S0 2 ; R 2 , R 5 and R 8 are each H; R 1 is benzyl; R 6 and R 7 are each H; Y is N-R 9 ; and R 4 , R 9 and Q have the values shown in Table V, infra .
  • Z is S0 2 ;
  • Y is NH;
  • R 2 , R 5 and R 8 are each H;
  • R 1 is benzyl and
  • R 6 and R 7 are each H, or R 6 and R 7 taken together form -0-CH 2 -CH 2 -0- ;
  • Z is S0 2 ;
  • Y is NH;
  • R 2 , R 5 and R 8 are each H;
  • R 1 is benzyl and
  • R 6 , R 7 and Q have the values shown in Table VI, infra .
  • compounds of the invention have the formula:
  • the invention includes the bisulfite addition products of the aldehydes of Formula I, as exemplified in Example 187, infra .
  • alkyl is meant to include straight -chain, branched and cyclic hydrocarbon groups such as, for example, ethyl, isopropyl and cyclopropyl groups. Preferred alkyl groups have 1 to about 10 carbon atoms. "Cycloalkyl” groups are cyclic alkyl groups. "Aryl” groups are aromatic cyclic compounds including but not limited to phenyl , naphthyl, anthracyl, phenanthryl, and pyrenyl . Also included within the definition of "aryl” are ring systems having two aromatic rings connected by a bond, such as biphenyl . Preferred aryl groups include phenyl and naphthyl.
  • Carbocyclic refers to cyclic groups in which the ring portion is composed solely of carbon atoms.
  • hetero denotes the presence of one or more noncarbon atoms.
  • heterocyclic refers to cyclic groups in which the ring portion includes at least one heteroatom such as 0, N or S .
  • Heteroalkyl groups are heterocycles containing solely single bonds within their ring portions, i.e. saturated heteroatomic ring systems.
  • the term “lower alkyl” refers to alkyl groups of 1-4 carbon atoms.
  • halogen refers to F, Cl, Br, and I atoms.
  • aralkyl denotes alkyl groups which bear aryl groups, for example, benzyl groups.
  • heteroaryl denotes aryl groups having one or more heteroatoms (e.g., 0, N, or S) contained within an aromatic ring.
  • heteroarylkyl groups are aralkyl groups which have one or more heteroatoms in their aromatic ring portion. Also included within the definition of “heteroaryl” are ring systems having two aromatic rings connected by a bond, where at least one of the rings contains a hetero atom.
  • alkoxy groups are alkyl groups linked through an oxygen atom. Examples of alkoxy groups include methoxy (-OCH 3 ) and ethoxy (-OCH 2 CH 3 ) groups.
  • Alkoxycarbonyl groups are carbonyl groups which contain an alkoxy substituent, i.e., groups of general formula
  • aroyl analogously denotes an aryl group attached through a carbonyl group.
  • alkenyl is intended to include straight-chain or branched hydrocarbon chains having at least one carbon-carbon double bond. Examples of alkenyl groups include ethenyl groups and propenyl groups.
  • amino acid denotes a molecule containing both an amino group and a carboxyl group.
  • L-amino acid denotes an ⁇ -amino acid having the L configuration around the a>- carbon, that is, a carboxylic acid of general formula CH(COOH) (NH 2 ) - (sidechain) , having the L-configuration.
  • Nonnaturally occurring amino acid sidechains are moieties that are used in place of naturally occurring amino acid sidechains in, for example, amino acid analogs. See, for example, Lehninger,
  • Formula I may contain blocking groups .
  • Blocking groups are known per se as chemical functional groups that can be selectively appended to functionalities, such as hydroxyl groups, amino groups, thio groups and carboxyl groups.
  • Protecting groups are blocking groups that can be readily removed from functionalities. These groups are present in a chemical compound to render such functionality inert to chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups may be employed with the present invention.
  • One such protecting group is the benzyloxycarbonyl (Cbz; Z) group.
  • Other protecting groups include toluenesulfonyl , t-butoxycarbonyl , methyl ester and benzyl ether groups.
  • Other preferred protecting groups according to the invention may be found in Greene, T.W.
  • Further blocking groups useful in the compounds of the present invention include the phthalimido group, arylcarbonyls , alkylcarbonyls , alkoxycarbonyls, aryloxycarbonyls , aralkyloxycarbonyls, alkyl- and aralkylsulfonyls, and arylsulfonyl groups such as those which have the following formulas:
  • benzothiazo and related heterocyclic grou -containing components of the invention inhibit cysteine proteases and serine proteases, they can be used in both research and therapeutic settings.
  • preferred compounds having defined attributes can be used to screen for natural and synthetic compounds which evidence similar characteristics in inhibiting protease activity.
  • the compounds can also be used in the refinement of in vi tro and in vivo models for determining the effects of inhibition of particular proteases on particular cell types or biological conditions.
  • compounds of the invention can be utilized to alleviate, mediate, reduce and/or prevent disorders which are associated with abnormal and/or aberrant activity of cysteine proteases and/or serine proteases .
  • compositions are provided for inhibiting a serine protease or a cysteine protease comprising a compound of the invention.
  • methods are provided for inhibiting serine proteases or cysteine proteases comprising contacting a protease selected from the group consisting of serine proteases and cysteine proteases with an inhibitory amount of a compound of the invention.
  • the disclosed compounds of the invention are useful for the inhibition of cysteine proteases and serine proteases.
  • the terms “inhibit” and “inhibition” mean having an adverse effect on enzymatic activity.
  • An inhibitory amount is an amount of a compound of the invention effective to inhibit a cysteine and/or serine protease .
  • compositions as disclosed herein.
  • pharmaceutically acceptable salts as used herein means an inorganic acid addition salt such as hydrochloride, sulfate, and phosphate, or an organic acid addition salt such as acetate, maleate, fumarate, tartrate, and citrate.
  • pharmaceutically acceptable metal salts are alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt.
  • pharmaceutically acceptable organic amine addition salts are salts with morpholine and piperidine .
  • pharmaceutically acceptable amino acid addition salts are salts with lysine, glycine, and phenylalanine .
  • compositions can be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable nontoxic excipients and carriers.
  • compositions may be prepared for use in parenteral administration, particularly in the form of liquid solutions or suspensions; or oral administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, nasal drops, or aerosols; or dermally, via, for example, transdermal patches; or prepared in other suitable fashions for these and other forms of administration as will be apparent to those skilled in the art .
  • compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington ' s Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980) .
  • Formulations for parenteral administration may contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils and vegetable origin, hydrogenated naphthalenes and the like.
  • biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds .
  • parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation administration contain as excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate , or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
  • Formulations for parenteral administration may also include glycocholate for buccal administration, a salicylate for rectal administration, or citric acid for vaginal administration.
  • Formulations for transdermal patches are preferably lipophilic emulsions.
  • the materials for this invention can be employed as the sole active agent in a pharmaceutical or can be used in combination with other active ingredients which could facilitate inhibition of cysteine and serine proteases in diseases or disorders.
  • concentrations of the compounds described herein in a therapeutic composition will vary depending upon a number of factors, including the dosage of the drug to be administered, the chemical characteristics (e.g., hydrophobicity) of the compounds employed, and the route of administration.
  • the compounds of this invention may be provided in effective inhibitory amounts in an aqueous physiological buffer solution containing about 0.1 to 10% w/v compound for parenteral administration. Typical dose ranges are from about l ⁇ g/kg to about 1 g/kg of body weight per day; a preferred dose range is from about 0.01 mg/kg to 100 mg/kg of body weight per day.
  • Such formulations typically provide inhibitory amounts of the compound of the invention.
  • the preferred dosage of drug to be administered is likely, however, to depend on such variables as the type or extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, and formulation of the compound excipient, and its route of administration.
  • contacting means directly or indirectly causing at least two moieties to come into physical association with each other. Contacting thus includes physical acts such as placing the moieties together in a container, or administering moieties to a patient.
  • administering for example administering a compound of the invention to a human patient evidencing a disease or disorder associated with abnormal and/or aberrant activity of such proteases falls within the scope of the definition of the term "contacting".
  • 2 , 3-dihydrobenzothiazole-3 -carboxylates may be prepared by treating N-alkylbenzenesulfonamides with a strong base such as butyllithium followed by glyoxylic ester by a modification of the method of robel and Dietrich, supra .
  • 2- (aminosulfonyl) henyl- propanoic acid described by P. Catsoulacos and C. Camoutsis (J. Heterocycl . Chem . 1976, 13 , 1309 - 1314, incorporated by reference herein in its entirety)
  • This compound was prepared according to General Procedure B. From 21 (2.5 g, 10.7 mmol) in neat chlorosulfonic acid (-10 ml) at 150°C for 1.5 hours, 3.3 g (89%) of the title compound was obtained as a yellow powder which was isolated by dropwise addition of the dark reaction mixture (cooled to ambient temperature) to a vigorously stirred slurry of ice-water (-100 g) , suction filtration of the precipitate and washing with cold water and drying to constant weight in vacuo to give analytically pure material; Anal. Calc'd for C 9 H 7 C1 4 N0 3 S : C, 30.80; H, 2.01; N, 3.99; S, 9.12; Found: C, 30.47; H, 1.92; N, 3.38; S, 9.29.
  • This compound was prepared according to General Procedure B. To a dry flask equipped with a magnetic stirrer, rubber septum and drying tube was added compound 2n (5.0 g, 25.0 mmol) . Chlorosulfonic acid (17 ml) was added with stirring over 5-10 minutes at ambient temperature. An appreciable exotherm was observed along with gas evolution (HCl) that persisted for 10-15 minutes following completion of the addition. After being allowed to stir for an additional one hour, the mixture was heated to 100°C for one hour, cooled to ambient temperature, and added dropwise with vigorous stirring to an ice-water slurry ( ⁇ 500g) .
  • This compound was prepared according to General Procedure C. However, the reaction was performed using concentrated aqueous ammonium hydroxide. From compound 4r (2.4 g, 7.1 mmol) and cone. NH 4 0H (50 ml) the title compound (0.87 g, 44%) was obtained following flash chromatography on silica gel (25% ethyl acetate/hexane to ethyl acetate); MS: 283 (M-H)-.
  • This compound was prepared according to General Procedure F using acidic conditions (refluxing 4 N aqueous HCl in 1,4 -dioxane) rather than basic conditions. From 6k (1.0 g, 3.87 mmol) the title compound (0.43 g, 43%) was obtained following recrystallization (ether/hexanes) ; MS: 258 m/z (M-H) " ; Anal. Calc'd for C 10 H 10 FNO 4 S : C, 47.57; H, 4.55; N, 5.04; S, 11.52; F, 6.84; Found: C, 47.81; H, 4.28; N, 5.36; S, 11.62; F, 7.29.
  • Procedure F acidic conditions using refluxing 4N aqueous HCl in 1,4 -dioxane. From 61 (200 mg, 0.65 mmol) the title compound (200 mg, 100%) was obtained following lyophillization of the reaction mixture; NMR (DMSO-d 6 ) ⁇ 2.64 (s, 3H) , 3.13-3.37 (m, 2H) , 4.72-4.77 (m, IH) , 7.87 (s, IH) , 7.98 (s, IH) . MS: 308, 310, 312 m/z (M+H) + (Cl 2 pattern) .
  • This compound was prepared according to General Procedure G. From 8s (70 mg, 0.23 mmol) and L-N e - (benzenesulfonyl) lysinol trifluoroacetic acid salt (117 mg, 0.30 mmol) crude product (144 mg) was obtained as a mixture of diastereomers. Separation was effected by preparative tic on silica gel (5% MeOH/CH 2 Cl 2 ) :
  • N- (methanesulfonyl) aminoethanamine was prepared from (JV- ( -butoxycarbonyl) amino) ethanamine and methanesulfonyl chloride according to the procudure of
  • This compound was prepared according to General Procedure G. From 8s (prepared from L-DOPA, 30 mg, 0.10 mmol) and 3-amino-3 - (S) -benzyl-2- (R, S) -hydroxy-N- (3 - (4- nitrobenzenesulfonylamino) propyl) propanamide hydrochloride (59 mg, 0.12 mmol) the title compound (32 mg, 55%) was obtained following flash chromatography on silica gel (75% ethyl acetate/hexanes); MS: 732 m/z (M+H) + .
  • This compound was prepared according to General Procedure G. From 8s (prepared from L-DOPA, 30 mg, 0.10 mmol) and 3-amino-3- (S) -benzyl-2- (R, S) -hydroxy-N- (2- (3 , 4- dichlorobenzenesulfonylamino) ethyl) propanamide hydrochloride (60 mg, 0.12 mmol) the title compound (58 mg, 97%) was obtained following flash chromatography on silica gel (75% ethyl acetate/hexanes); MS: 741, 743, 745 m/z (M+H) + .
  • Procedure G From 8s (prepared from L-DOPA, 35 mg, 0.11 mmol) and 3 -amino-3- (S) -benzyl-2- (R, S) -hydroxy-iV- (2- (benzenesulfonylamino) ethyl) propanamide hydrochloride (60 mg, 0.15 mmol) the title compound (62 mg, 83%) was obtained following trituration with ether; MS: 673 m/z (M+H) + .
  • This compound was prepared according to General Procedure G. From 8s (prepared from L-DOPA, 30 mg, 0.10 mmol) and 3-amino-3 - (S) -benzyl-2- (R, S) -hydroxy-lV- (3 - (4 - fluorobenzenesulfonylamino) propyl) propanamide hydrochloride (43 mg, 0.12 mmol) the title compound (40 mg, 59%) was obtained following preparative tic on silica gel (ethyl acetate); MS: 705 m/z (M+H) + .
  • Compound 7r was prepared from compound 19 according to the procedure described for synthesis of 8s.
  • Compound HAD was prepared according to General Procedure G. From compound 7r (22 mg, 0.077 mmol) and JV-butyl 2- (R, S) -hydroxy- 3 - (S) -benzyl-3-aminopropanamide, HCl salt (27.6 mg, 1.25 eq) (Harbeson, S. L., et al . ; J " . Med . Chem . , 1994, 37, 2918- 2929) the title compound (20.0 mg, 50%) was obtained; MS: 518 (M+H) + .
  • the reaction was cooled to - 5 °C and 43 ml (10 eq) of Et 3 N, 733 mg (0.3 eq) of DMAP in CHC1 3 (50 ml) was added. The mixture was stirred overnight ( ⁇ 14hr) while the temperature was warmed to room temperature and then the reaction mixture was refluxed for 3 hours. After that, the reaction mixture was poured into 500 ml of ice-water and separated. The aqueous layer was extracted with CH 2 C1 2 (3x100 ml) . The combined organic layers were washed with water, 3% HCl, 5% of NaHC0 3 , brine and dried.
  • Example 159 Also isolated was 118 mg (27%) of a diastereomeric mixture.
  • Example 159 Also isolated was 118 mg (27%) of a diastereomeric mixture.
  • This compound was prepared according to General Procedure I (in this case, isobutyl chloroformate was used in place of HOBt/BOP) . From compound 40a (25 mg, 0.11 mmol) and 3- amino- 3 - (S) -benzyl -2 -oxo-JV-butylpropanamide hydrochloride (35 mg, 0.12 mmol) the title compound (9 mg, 18%) was obtained as an off-white solid following trituration of the crude (33 mg) product with ether; MS: 455 m/z (M-H) " .
  • JV-Benzoyl-1, 2,3, 4-tetrahydro-3-isoquinolinecarboxylic acid This compound was prepared according to Hein et . al . , J “ . Amer. Chem . Soc . ; 1962, 84 , 4487-4494, incorporated by reference herein in its entirety.
  • a slurry of 1,2,3, 4-tetrahydro-3-isoquinolinecarboxylic acid hydrochloride (20.3 g, 95 mmol) in 2N NaOH (150 ml) was treated with benzoyl chloride (13.4 ml, 114 mmol) dropwise over 30 minutes.
  • This compound was prepared according to Maeda et . al . , Chem . Phar . Bull . ; 1988, 36, 190-201, incorporated by reference herein in its entirety.
  • a solution of compound 44 (15.4 g, 54.7 mmol) and potassium carbonate (7.6 g, 54.7 mmol) in water (450 ml) was treated portionwise with potassium permanganate (17.3 g, 109.5 mmol) over 10 minutes.
  • the mixture was stirred for two hours, quenched with sodium bisulfite (6.5 g) and stirred for 5-10 minutes, and filtered through a bed of Celite 0 .
  • the filtrate was acidified to pH 2-3 and the resulting gummy precipitate was extracted with ethyl acetate.
  • assay buffer i.e., 50mM Tris, 50mM NaCl, ImM EDTA, ImM EGTA, and 5mM-mercaptoethanol , pH 7.5 including 0.2mM Succ-Leu-Tyr-MNA (Enzyme Systems Products, Dublin, CA) and 175 mL aliquoted into the same wells containing the independent inhibitor stocks as well as to positive control wells containing 5 mL DMSO, but no compound.
  • assay buffer i.e., 50mM Tris, 50mM NaCl, ImM EDTA, ImM EGTA, and 5mM-mercaptoethanol , pH 7.5 including 0.2mM Succ-Leu-Tyr-MNA (Enzyme Systems Products, Dublin, CA) and 175 mL aliquoted into the same wells containing the independent inhibitor stocks as well as to positive control wells containing 5 mL DMSO, but no compound.
  • Inhibition of calpain I activity was calculated as the percent decrease in the rate of substrate hydrolysis in the presence of inhibitor relative to the rate in its absence. Comparison between the inhibited and control rates was made within the linear range for substrate hydrolysis. For screening, compounds were tested at 10 mM. Compounds having 50% inhibition at 10 mM were considered active. The IC50s of inhibitors (concentration yielding 50% inhibition) were determined from the percent decrease in the rates of substrate hydrolysis in the presence of five to seven different concentrations of the test compound. The results were plotted as percent inhibition versus log inhibitor concentration, and the IC50 was calculated from linear regression of the data. Results are presented in Tables II- VII and in Example 187.

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US6150378A (en) * 1997-10-07 2000-11-21 Cephalon, Inc. Peptidyl-containing α-ketoamide cysteine and serine protease inhibitors
AU2594799A (en) 1998-02-11 1999-08-30 Du Pont Pharmaceuticals Company Novel cyclic sulfonamide derivatives as metalloproteinase inhibitors
CA2319551A1 (en) * 1998-03-31 1999-10-07 Warner-Lambert Company Benzoxazinones/benzothiazinones as serine protease inhibitors
AU3731400A (en) 1999-03-05 2000-09-21 Trustees Of University Technology Corporation, The Methods and compositions useful in inhibiting apoptosis
FR2818641B1 (fr) * 2000-12-21 2004-03-05 Servier Lab Nouveaux derives de 1,1-dioxo-2h-1,2-benzothiazine 3-carboxamides, leur procede de preparation et les compositions pharmaceutiques que les contiennent
PL2520654T3 (pl) 2003-08-26 2017-08-31 The Regents Of The University Of Colorado, A Body Corporate Inhibitory aktywności proteazy serynowej i ich zastosowanie w sposobach i kompozycjach do leczenia zakażeń bakteryjnych
BRPI0508183B8 (pt) 2004-04-02 2021-05-25 Prana Biotechnology Ltd compostos neurologicamente ativos, seus usos, composição farmacêutica ou veterinária e processos para preparação dos mesmos
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