WO1998045275A1 - Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, activity - Google Patents
Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, activity Download PDFInfo
- Publication number
- WO1998045275A1 WO1998045275A1 PCT/US1997/021849 US9721849W WO9845275A1 WO 1998045275 A1 WO1998045275 A1 WO 1998045275A1 US 9721849 W US9721849 W US 9721849W WO 9845275 A1 WO9845275 A1 WO 9845275A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- benzoimidazol
- alkyl
- ethyl
- compound
- methyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 367
- 239000000203 mixture Substances 0.000 title claims abstract description 142
- 108060005989 Tryptase Proteins 0.000 title abstract description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 26
- 201000010099 disease Diseases 0.000 title description 23
- 102000001400 Tryptase Human genes 0.000 title description 22
- 230000000694 effects Effects 0.000 title description 10
- 102000012479 Serine Proteases Human genes 0.000 title description 4
- 108010022999 Serine Proteases Proteins 0.000 title description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 127
- 239000001257 hydrogen Substances 0.000 claims abstract description 69
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 69
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 48
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 44
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 39
- 125000001424 substituent group Chemical group 0.000 claims abstract description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 18
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 17
- 125000003943 azolyl group Chemical group 0.000 claims abstract description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 12
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims abstract description 11
- 210000002345 respiratory system Anatomy 0.000 claims abstract description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 5
- 230000000699 topical effect Effects 0.000 claims abstract description 4
- 206010010741 Conjunctivitis Diseases 0.000 claims abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 353
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 166
- -1 amino, carboxy, carbamoyl Chemical group 0.000 claims description 146
- 125000005842 heteroatom Chemical group 0.000 claims description 76
- 125000003118 aryl group Chemical group 0.000 claims description 67
- 239000005711 Benzoic acid Substances 0.000 claims description 60
- 235000010233 benzoic acid Nutrition 0.000 claims description 60
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 41
- 125000002947 alkylene group Chemical group 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 38
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 37
- 125000004429 atom Chemical group 0.000 claims description 37
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 35
- 125000005843 halogen group Chemical group 0.000 claims description 32
- 239000000651 prodrug Substances 0.000 claims description 27
- 229940002612 prodrug Drugs 0.000 claims description 27
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 24
- 125000003282 alkyl amino group Chemical group 0.000 claims description 23
- 125000001931 aliphatic group Chemical group 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 20
- 125000002723 alicyclic group Chemical group 0.000 claims description 17
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 16
- 150000001204 N-oxides Chemical class 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- SKOLWUPSYHWYAM-UHFFFAOYSA-N carbonodithioic O,S-acid Chemical compound SC(S)=O SKOLWUPSYHWYAM-UHFFFAOYSA-N 0.000 claims description 14
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical class N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 claims description 12
- 125000004423 acyloxy group Chemical group 0.000 claims description 12
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
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- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 11
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 9
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
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- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
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- GIHLYBBKNGKPHR-UHFFFAOYSA-N 2-[(5-ethanimidoyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl)methyl]-n-(2-hydroxy-2-naphthalen-1-ylethyl)-3-methylbenzimidazole-5-carboxamide Chemical compound C1=CC=C2C(C(O)CNC(=O)C3=CC=C4N=C(N(C4=C3)C)CC=3NC=4CCN(CC=4N=3)C(=N)C)=CC=CC2=C1 GIHLYBBKNGKPHR-UHFFFAOYSA-N 0.000 claims description 3
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- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 3
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- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- WPYMKLBDIGXBTP-VQEHIDDOSA-N benzoic acid Chemical compound OC(=O)C1=CC=C[13CH]=C1 WPYMKLBDIGXBTP-VQEHIDDOSA-N 0.000 claims 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 claims 6
- 239000000048 adrenergic agonist Substances 0.000 claims 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 1
- XMGODZOTGXEKCX-UHFFFAOYSA-N 2-(5-ethanimidoyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-2-carbonyl)-3-methyl-n-(2-naphthalen-1-ylethyl)benzimidazole-5-carboxamide Chemical compound C1=CC=C2C(CCNC(=O)C3=CC=C4N=C(N(C4=C3)C)C(=O)C=3NC=4CCN(CC=4N=3)C(=N)C)=CC=CC2=C1 XMGODZOTGXEKCX-UHFFFAOYSA-N 0.000 claims 1
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- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
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- 239000011877 solvent mixture Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Chemical group 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- GPTXCAZYUMDUMN-UHFFFAOYSA-N tert-butyl n-(2-hydroxyethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCO GPTXCAZYUMDUMN-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical class NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 201000005539 vernal conjunctivitis Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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
-
- 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
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/20—Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical
-
- 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
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
Definitions
- Tryptase the predominant protease secreted from human mast cells, is thought to be involved in neuropeptide processing and tissue inflammation. Tryptase concentrations are elevated in the bloodstream for several hours following anaphylaxis (Schwartz et al. (1987) N Eng. J. Med. 316:1622-1626), are increased in nasal and lung lavage fluid from atopic subjects following specific antigen challenge (Castells et al. (1988) J. Allerg. Clin. Immunol. 141:563-568) and are elevated in lung lavage fluid of atopic asthmatics after endobronchial allergen challenge.
- Asthma is recognized as an inflammatory disorder (Hood et al. (1984 In: Benjamin-Cummings, ed. Immunology 2nd ed.) and frequently is characterized by progressive development of hyper-responsiveness of the trachea and bronchi to both immunospecific allergens and generalized chemical or physical stimuli.
- the disease involves multiple biochemical mediators in both its acute and chronic stages.
- the hyper-responsiveness of asthmatic bronchiolar tissue is believed to be the result of chronic inflammatory reactions, which irritate and damage the epithelium lining the airway wall and promote pathological thickening of the underlying tissue. Bronchial biopsies in patients with only mild asthma have features of inflammation in the airway wall.
- allergens can activate mast cells and basophils, which are present in the epithelium and underlying smooth muscle tissue by binding IgE located on the cell surface. Activated mast cells release a number of preformed or primary chemical mediators (e.g., histamine) of the inflammatory response and generate numerous other secondary mediators of inflammation
- mast cells e.g., superoxide, lipid derived mediators, etc.
- large molecules e.g., proteoglycans, tryptase, chymase, etc.
- the release of these preformed mediators from mast cells probably accounts for the early bronchiolar constriction in the asthmatic reaction to air borne allergens.
- the early phase of the asthmatic reaction peaks approximately fifteen minutes after exposure to allergen and is generally followed by recovery over the ensuing one to two hours. Twenty five to thirty five percent of the patient population experience a further decline in respiratory function which maximizes six to twelve hours after exposure.
- This late reaction phase is accompanied by a marked increase in the number of inflammatory cells (e.g., eosinophils, neutrophils, lymphocytes, etc.) infiltrating the bronchiolar tissue. The infiltrating cells are attracted to the site by release of mast cell derived chemotactic agents and then become activated during the late reaction phase.
- the late asthmatic response is believed to be a secondary inflammatory reaction mediated in part by the secretory activity of granulocytes.
- Tryptase is implicated in the degradation of vasodilating and bronchorelaxing neuropeptides (Caughey et al. (1988) J.Pharmacol. Exp. Ther. 244:133-137; Franconi et al.
- Tryptase activates prostromelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3, which suggests that tryptase is involved in tissue inflammation and remodeling and joint destruction in rheumatoid arthritis. Further, administration of tryptase inhibitor protects against development of the late and airway hyper-responsive phases in allergen challenged sheep (Clark et al. (1995) Am. J. Respir. Crit. Care MedA52: 2076-2083) and inhibits the immediate cutaneous response to intradermal injection of allergen in allergic sheep (Molinari et al. (1995) Amer. Physiol. Soc. 79(6): 1966- 1970). All of the above-described findings clearly indicate the applicability of tryptase inhibitors as therapeutic agents in treating asthma and other disorders associated with inflammation of the respiratory tract.
- This application relates to a compound of Formula I:
- nl is O or 1, n2 is 0, 1, 2, 3 or 4; n3 is O, 1, 2, 3 or 4;
- C comprises a fused heteropolycyclic radical containing 8 to 18 annular atoms, wherein each ring contains 5 to 7 annular members, each annular atom optionally is a heteroatom, X 4 and X 5 are adjacent annular members of an aromatic ring, X 5 is a heteroatom moiety selected from
- R 6 is hydrogen, a group selected from ( . ⁇ alkyl or hetero(C 2 . ⁇ 2 )alkyl, which group optionally is substituted with one to two substituents independently selected from (C,. 6 )alkylamino, di(C 1.6 )alkylamino, tri(C ⁇ . 6 )alkylammonio, di(C,. 6 )alkylcarbamoyl, (C,. 6 )alkyloxy, (C !.6 )alkyloxycarbonyl, (C,.
- X 3 is -O-, -S-, -S(O)- -S(O) 2 - -C(O)-, -NR 7 - or -CR 7 R 8 -, wherein R 7 is hydrogen, ( . ⁇ alkyl, hetero(C 2 _ ⁇ 2 )alkyl or together with R 6 forms (C 2 . 4 )alkylene or hetero(C 2 . 4 )alkylene and R 8 is hydrogen, (C,. 6 )alkyl or hydroxy or together with R 7 forms (C 2 . 6 )alkylene or
- (C 1-6 )alkylidene wherein any aliphatic or alicyclic moiety comprising R 7 and/or R 8 optionally are substituted with one to three substituents selected from (C,. 6 )alkylamino, di(C,. 6 )alkylamino, tri(C 1.6 )alkylammonio, (Cj. 6 )alkyloxy, (C,. 6 )alkyloxycarbonyl, (C,. 6 )alkanoyloxy, amino, carboxy, carbamoyl, (C,. 6 )alkylcarbamoyl, di(C,.
- R 1 is amino(N 1 . 4 )azolidinyl, amino(N 1 . 4 )azolyl, (N,. 4 )azolidinyl, (N,.
- each R" independently is hydrogen, (C ⁇ alkyl or together with another R u and a carbon atom to which both are attached forms cyclopropyl, wherein any aliphatic or alicyclic moiety comprising R 1 optionally is substituted with one to two substituents independently selected from (C ⁇ alkyloxycarbonyl, (C j ⁇ alkanoyloxy, carboxy, carbamoyl, (C,. 6 )alkylcarbamoyl, di(C,. 6 )alkylcarbamoyl, (C, .6 )alkylsulfonyl and hydroxy; each R 2 independently is (C,. 6 )alkyl, (C,. 6 )alkyloxycarbonyl, (C,. 6 )alkanoyloxy,
- each R 3 independently is (C,. 6 )alkyl, cyano, halo, perhalo(C,.
- R 4 is -R 12 , -OR 12 , -N(R 13 )R 12 , -SR 12 , -S(O)R 12 , -S(O) 2 R 12 , -S(O) 2 O R 12 , -S(O) 2 N(R 13 )R 12 ,
- R 12 is -R 15 or -X 6 -(R 15 ) nl5 , wherein nl5 is 1 or 2, X 6 is (C 0 )alkylene, cyclo(C 3 . 10 )alkylene, hetero(C 2 . 10 )alkylene or heterocyclo(C 3 . 10 )alkylene and each R 15 is independently hydrogen, (C 6 . 14 )aryl, cyclo(C 3 . 14 )alkyl, polycyclo(C 6 . 14 )aryl, heteropolycyclo(C 6 . ]4 )aryl, heterocyclo(C 3 . 14 )alkyl, hetero(C 5 . !4 )aryl or as defined below, R 13 is hydrogen, (C,. 6 )alkyl or hetero(C 2 . 6 )alkyl;
- R 14 is hydrogen, (C[_ 6 )alkyl or together with X 6 and R 15 forms (C 3 . 4 )alkylene; any aliphatic and alicyclic moiety comprising R 4 optionally is substituted with one to five substituents independently selected from (C,. 6 )alkyl, (C,. 6 )alkylamino, di(Cj. 6 )alkylamino, (C,. 6 )alkyloxy, (C j.6 )alkyloxycarbonyl, (C,. 6 )alkysulfinyl, (C,. 6 )alkysulfonyl, (C ⁇ . 6 )alkythio, amino, (C 6 .
- nl is not 0, when n2 is 0 or R 2 is (C ⁇ alkyl or (C,. 6 )alkyloxy, n3 is 0 or R 3 is (C, .6 )alkyl or (C,. 6 )alkyloxy and R 4 is hydrogen, (C 0 )alkyl or (C,. 10 )alkyloxy; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.
- the present invention also provides for pharmaceutical compositions of the compounds of the invention.
- These pharmaceutical compositions can be in a variety of forms including oral dosage forms, inhalable forms, as well as injectable and infusible solutions.
- the compounds of the present invention are used in combination with a pharmaceutically acceptable carrier solution or dry powder which can be converted into aerosol form.
- the compounds of the present invention are used in combination with a pharmaceutically acceptable carrier suitable for such oral administration.
- the compounds of the present invention are used in combination with a non-toxic, pharmaceutically acceptable topical carrier.
- the compounds of the present invention can be used in combination with antiinflammatories or other asthma therapies, such as ⁇ -adrenergic agonists, antiinflammatory corticosteroids, anticholinergics, bronchodilators such as methyl xanthenes and the like.
- the compounds described herein are useful for the prevention and treatment of immunomediated inflammatory disorders, and particularly those associated with the respiratory tract, including asthma, and particularly the hyper-responsiveness phase associated with chronic asthma, and allergic rhinitis.
- the present invention also provides a method for treating immunomediated inflammatory disorders wherein a patient having an immunomediated inflammatory disorder is administered a therapeutically effective dose or amount of a compound of the present invention.
- the compounds described herein are useful for treating syncytial viral infections.
- Figure 1 compares the specific lung resistance of a control (open squares) versus 2-(5-aminomethyl-lH-benzoimidazol-2-ylmethyl)-7V ⁇ -(3-phenylpropyl)-lH-benzoimidazole- 5-carboxamide (Compound 4; closed squares) over time as measured in hours.
- Figure 2 is a bar chart showing the airway hyper-responsiveness (measured as PC400) antigen-challenged sheep treated with Compound 4 by aerosol administration of three 1 mg doses versus sheep treated with a control.
- Alkanoyl means the radical -C(O)R, wherein R is alkyl as defined below, having overall the number of carbon atoms indicated (e.g., includes the radicals formyl, acetyl, propionyl, butyryl, isobutyryl, crotonoyl, isocrotonyl, etc.).
- Alkyl as defined below, having overall the number of carbon atoms indicated (e.g., includes the radicals formyl, acetyl, propionyl, butyryl, isobutyryl, crotonoyl, isocrotonyl, etc.).
- Alicyclic moiety means any saturated or unsaturated, monocyclic or polycyclic hydrocarbon portion of a radical.
- alicyclic moiety refers to cycloalkyl, as defined herein, as well as to alicyclic portions comprising cycloalkylalkyl, cycloalkyloxy, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylcarbamoyl, and the like.
- Aliphatic moiety means any straight or branched, saturated or unsaturated hydrocarbon portion of a radical.
- aliphatic moiety refers to alkyl or heteroalkyl, as defined herein, as well as to aliphatic portions comprising alkyloxy, arylalkyl, heteroarylalkyl, alkylcarbamoyl, alkanoyl, arylalkanoyl, heteroarylalkanoyl, and the like.
- Alkyl for the purposes of this application, means a straight or branched, saturated or unsaturated aliphatic hydrocarbon radical having the number of carbon atoms indicated, and any ketone, thioketone or iminoketone thereof (e.g., (C,.
- alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, 3-oxopentyl, 3-thioxopentyl, 3-iminopentyl, etc.).
- Alkyloxy means the radical -OR, wherein R is alkyl as defined above, having the number of carbon atoms indicated (e.g., (C,. 6 )alkyloxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethynyloxy, 1-propynyloxy, 2-propynyloxy, etc.).
- Alkylsulfinyl mean the radicals -SOR, -S(O) 2 R and -SR, respectively, wherein R is alkyl as defined above, having the number of carbon atoms indicated (e.g., (C 1 .
- alkylsulfonyl includes methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, vinylsulfonyl, allylsulfonyl, 1-propenylsulfonyl, isopropenylsulfonyl, 1-butenylsulfonyl, 2-butenylsulfonyl, 3-butenylsulfonyl, 2-methylallylsulfonyl, ethynylsulfonyl, 1-propynylsulfonyl, 2-propynylsulfonyl, etc.).
- Ammonio means the radical -NH 3 + .
- Ammonio means the radical -C(NH)NH 2 .
- Ammonio means the radical -NH 2 .
- Animal includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, etc.) and non-mammals (e.g., birds, etc.).
- non-human mammals e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, etc.
- non-mammals e.g., birds, etc.
- Aryl means an aromatic monocyclic or fused polycyclic hydrocarbon radical containing the number of carbon atoms indicated, wherein each ring contained therein is comprised of 6 annular members (e.g., (C 6 . 14 )aryl includes phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.).
- Arylsulfonyl mean the radicals -S(O) 2 R, wherein R is aryl as defined above, having the number of carbon atoms indicated (e.g., (C 6 . 10 )arylsulfonyl includes phenylsulfonyl, naptht-1-ylsulfonyl, etc.).
- Aromatic moiety means any aromatic portion of a radical.
- aromatic moiety refers to aryl and heteroaryl, as defined herein, as well as the aromatic portions comprising arylalkyl, heteroarylalkyl, polycycloaryl, heteropolycycloaryl, and the like.
- Azolidinyl means a saturated or unsaturated 5-membered monocyclic radical containing the number of nitrogen atoms indicated.
- (N )azolidinyl includes pyrazolidinyl, pyrrolidinyl, imidazolidinyl, trizolidinyl, tetrazolidinyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl and dihydrotriazolyl.
- Azl means an aromatic 5-membered monocyclic radical containing the number of nitrogen atoms indicated.
- (N I-4 )azolyl includes pyrrolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl.
- Carbamoyl means the radical -C(O)NH 2 .
- Carboxy means the radical -C(O)OH.
- Cyano means the radical -CN.
- Cycloalkyl means a saturated or unsaturated, monocyclic or fused polycyclic hydrocarbon radical containing the number of carbon atoms indicated, wherein each ring contained therein is comprised of 3 to 8 annular members, and any carbocyclic ketone, thioketone and iminoketone derivative thereof (e.g., (C 3 .
- I4 )cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, etc.).
- Cycloalkylene means a saturated or unsaturated, monocyclic or fused polycyclic hydrocarbon divalent radical containing the number of carbon atoms indicated, wherein each ring contained therein is comprised of 3 to 8 annular members, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., (C 3 . 10 )cycloalkylene includes 1 ,2-cyclopropylene, 1 ,2-cyclobutylene, 1,3-cyclobutylene, 1 ,2-cyclopentylene, 1,3-cyclopentylene, 1 ,4-cyclopentylene, 1 ,4-cyclohexylene, 3-cyclohexen-l,2-ylene,
- Deprotecting refers to removing any protective groups present after the selective reaction has been carried out.
- Disease specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition which may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the “side effects” of such therapy.
- “Fused heteropolycyclic radical” includes “fused heterobicyclic radical” and means a heterocyclic radical containing two to three fused rings having the number of annular members indicated, wherein at least two annular members of one ring are common to a second ring (e.g., a heteropolycyclic radical containing from 8 to 18 annular atoms and the carbocyclic ketone and thioketone derivatives thereof includes lH-benzimidazol-2-yl, lH-naphtho[2,3-J]imidazol-2-yl, lH-imidazo[4,5- ]quinolin-2-yl, lH-imidazo[4,5-6]pyridin-2-yl, lH-phenanthro[9,10- ]imidazol-2-yl, lH-imidazo[4,5-g-]quinoxalin-2-yl, 2,6-dioxo- 2,3,6,7-tetrahydro-l
- “Guanidino” means the radical -NHC(NH)NH 2 .
- “Halo” means fluoro, chloro, bromo or iodo.
- Heteroatom means an atom selected from N, O, S and P.
- Heteroalkyl means alkyl, as defined above, except one or more of the carbon atoms indicated is replaced by a heteroatom moiety, as defined in the Detailed Description of the Invention, and any ketone, thioketone or iminoketone derivative thereof (e.g., hetero(C 2 .j 2 )alkyl includes methoxy, ethoxy, ethylthio, 2-(2-methoxyethoxy)ethoxy, 3-methoxymethoxycarbonylmethoxy, 2-(7V-ethyl- ⁇ '-methylamino)ethyl, 2-ethyliminoethyl, ethoxymethoxyphosphoryloxy, etc.).
- Heteroalkylene means alkylene, as defined above, except one or more of the carbon atoms indicated is replaced by a heteroatom moiety, as defined in the Detailed Description of the Invention, or any suitable combination thereof (e.g., -OS(O) 2 -, -S(O) 2 O-, -N(R)S(O) 2 -, -S(O) 2 NR 17 -, -OP(O)(OR 17 )O-, and the like, wherein R 17 is hydrogen or (C,. 6 )alkyl), and any ketone, thioketone or iminoketone derivative thereof (e.g., hetero(C 2 .
- 3-phosphapentamethylene (-CH 2 OP(O)(OH)OCH 2 -), 3-aza-2-oxo-4-carboxyhexamethylene, 4-aza- 1 -oxa-3-oxohexamethylene, 1 -thia-3-oxo-4-azahexamethylene, 1 -thia- 1 , 1 ,3-trioxo- 4-azahexamethylene (-CH 2 CH 2 NHC(O)CH 2 S(O) 2 -), 3-aza-4-oxoheptamethylene, 1 ,4,7-trioxaoctamethylene, 6-aza- 1 -oxa-2,5-dioxooctamethylene (-CH 2 CH 2 NHC(O)CH 2 CH 2 C(O)O-), 3-aza-4-oxodecamethylene, etc.).
- aryl includes thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxaxolyl, indolyl, benzo[6]thienyl, isobenzofuranyl, purinyl, isoquinolyl, pterdinyl, perimidinyl, imidazolyl, pyridyl, pyrazolyl, pyrazinyl, quinolyl, etc.).
- Heterocycloalkyl means cycloalkyl, as defined above, except one or more of the annular carbon atoms indicated are replaced by a heteroatom moiety, as defined in the Detailed Description of the Invention, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., the term heterocyclo(C 5 . 14 )alkyl includes piperidyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, etc.).
- Heterocycloalkylene means cycloalkylene, as defined above, except one or more of the annular carbon atoms indicated is replaced by a heteroatom moiety, as defined in the Detailed Description of the Invention, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., the term heterocyclo(C 3 . 14 )alkylene includes piperidylene, pyrrolidinylene, pyrrolinylene, imidazolidinylene, quinuclidinylene, morpholinylene, etc.).
- Heteropolycycloaryl means polycycloaryl, as defined below, except one or more of the annular carbon atoms indicated are replaced by a heteroatom moiety, as set defined in the Detailed Description of the Invention, and any carbocyclic ketone, thioketone of iminoketone derivative thereof (e.g., heteropolycyclo(C 8 . 10 )alkyl includes 3,4-dihydro-2H-quinolinyl, 5,6,7,8-tetrahydroquinolinyl, 3,4-dihydro-2H-[ 1 ,8]naphthyridinyl,
- Immunomediated inflammatory disorder means those diseases associated with mast cell mediator release and susceptible to treatment with a tryptase inhibitor (e.g., immediated type hypersensitivity diseases such as asthma, allergic rhinitis, urticaria and angioedema, eczematous anaphylaxis, dermatitis such as atopic dermatitis, hyperproliferative skin disease, peptic ulcers, inflammatory bowel disorder, ocular and vernal conjunctivitis, rheumatoid arthritis, inflammatory skin conditions, and the like).
- immediated type hypersensitivity diseases such as asthma, allergic rhinitis, urticaria and angioedema, eczematous anaphylaxis, dermatitis such as atopic dermatitis, hyperproliferative skin disease, peptic ulcers, inflammatory bowel disorder, ocular and vernal conjunctivitis, rheumatoid arthritis, inflammatory skin conditions, and the like).
- “Hyper-responsiveness” means the late phase bronchoconstriction and airway hyperreactivity associated with chronic asthma. Hyper-responsiveness of asthmatic bronchiolar tissue is believed to result from chronic inflammation reactions, which irritate and damage the epithelium lining the airway wall and promote pathological thickening of the underlying tissue.
- Syncytial viral infection means an infection by a virus, such as a respiratory syncytial virus, causing the formation of a cellular protoplasmic mass, i.e. syncytia, via infection.
- “Isomers” mean compounds of Formula I having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space.
- steroisomers that differ in the arrangement of their atoms in space are termed "steroisomers".
- stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes "optical isomers”.
- a carbon atom bonded to four nonidentical substituents is termed a "chiral center”.
- a compound with one chiral center has two enantiomeric forms of opposite chirality is termed a "racemic mixture”.
- a compound that has more than one chiral center has 2" "1 enantiomeric pairs, where n is the number of chiral centers.
- Compounds with more than one chiral center may exist as either an individual diasteromer or as a mixture of diastereomers, termed a "diastereomeric mixture".
- a stereoisomer may be characterized by the absolute configuration of that chiral center.
- Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
- the substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog and the absolute descriptor R or S is cited in parenthesis followed by a hyphen and the chemical name of the compound.
- N-oxide derivatives means a derivatives of compound of Formula I in which nitrogens are in an oxidized state (i.e., O- ⁇ ) and which possess the desired pharmacological activity.
- the N-oxide derivatives of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art.
- “Pathology” of a disease means the essential nature, causes and development of the disease as well as the structural and functional changes that result from the disease processes.
- “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generall safe, non-toxic and neither biologically nor otherwise undesirabale and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
- “Pharmaceutically acceptable salts” means salts of compounds of Formula I which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity.
- Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, -(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benz
- Acceptabale inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydoxide.
- Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
- Polycycloaryl means a fused polycyclic radical containing the number of carbon atoms indicated, wherein at least one, but not all, of the fused rings comprising the radical is aromatic and each ring contained therein is comprised of five to six annular members, and any carbocyclic ketone and thioketone derivative thereof (e.g., polycyclo(C 9 .
- prodrug derivatives means derivatives of compounds of Formula I which are converted in vivo to the corresponding non-derivatized form of a compound of Formula I. Suitable prodrug derivatives include those compounds of Formula I in which one or more nitrogen and/or oxygen atoms with an available free valence are substituted with a group which is readily cleavable by in vivo processes.
- prodrug derivatives of compounds of Formula I may contain one or more /V-substituted amino groups (e.g., -NH 2 (R 18 )) TV-substituted nitrogen atoms incorporated into an aliphatic, alicyclic or aromatic structure (e.g., -N(R 18 )-), JV-substituted imino or amidino groups (e.g., -C(NR 18 )H, -C(NR 18 )NH 2 or -C(NH)NHR 18 ), TV-substituted guanidino groups
- amino groups e.g., -NH 2 (R 18 )
- TV-substituted nitrogen atoms incorporated into an aliphatic, alicyclic or aromatic structure e.g., -N(R 18 )-
- JV-substituted imino or amidino groups e.g., -C(NR 18 )H, -C(NR
- R 18 is (i) -C(O)R 19 or -CH(R 20 )OC(O)R 19 , wherein R 19 is (C 0 )alkyl, (C M0 )alkyloxy, carbamoyl, (C 1 . 10 )alkylcarbamoyl, di(C,. 10 )alkylcarbamoyl, e/s-2-(C M0 )alkanoyloxyphenylvinyl, 3-(C,.
- R 20 is hydrogen or (C 1 . 10 )alkyl; (ii) -X 7 -R 21 , wherein X 7 is (C,. 10 )alkylene and R 21 is carboxy; or (iii) -C(O)OCH(R 22 )OC(O)R 23 , wherein R 22 is hydrogen, (C,. 10 )alkyl or (C 3.10 )cycloalkyl and R 23 is (C,.
- prodrug derivatives of compounds of Formula I may contain one or more TV-hydroxylated imino or amidino groups (e.g., -C(NOR 24 )H, -C(NOR 24 )NH 2 or -C(NH)NHOR 24 ) or N-hydroxylated guanidino groups (e.g., -NHC(NOR 2 )NH 2 , -NHC(NH)NHOR 24 ), in which R 24 is hydrogen, methyl, -C(O)R 25 or
- R 25 is (C,. 10 )alkyl or (C 3 . 10 )cycloalkyl and R 26 is hydrogen or (C, .10 )alkyl;
- TV-substituted hydroxy groups e.g.,-OR 27 ), in which R 27 is -C(O)R 19 or -CH(R 20 )OC(O)R 19 , wherein R 19 and R 20 are as defined above; and/or ester derivatives of carboxylic acids (e.g., -C(O)OR 28 ) wherein R 28 is (C 0 )alkyl or (C 3 . 10 )cycloalkyl.
- Protective group has the meaning conventionally associated with it in synthetic organic chemistry, i.e., a group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site and which can be readily removed after the selective reaction is completed.
- Protected derivatives means derivatives of compounds of Formula I in which a reactive site or sites are blocked with protective groups.
- Protected derivatives of compounds of Formula I are useful in the preparation of compounds of Formula I.
- Suitable protecting groups for reactive nitrogen atoms include tert-butoxycarbonyl, benzyloxycarbonyl and any other suitable amino protective groups (e.g., see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981).
- a suitable protected derivative of Formula I is exemplified by the compound 2-[5-(l,3-dioxo-l, 3-dihydroisoindol-2-ylmethyl)-lH-benzoimidazol-2 -ylmethyl]- 4,5,6,7-tetrahydro-lH-benzoimidazole-5-carboxylic acid.
- “Therapeutically effective amount” means that amount which, when administered to an animal is effective for treating a disease.
- Treatment refers to any administration of a compound of the present invention and includes: (1) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptoms of the disease,
- “Uriedo” means the radical -NHC(O)NH 2 .
- a together with B comprises 5-guanidino-lH-benzoimidazol-2-yl
- C comprises 6-(2-naphth-l-ylethylcarbamoyl)-l -methyl- l//-benzoimidazol-2-yl
- X 3 is -CH 2 - is named 2-(5-guanidino-lH-benzoimidazol-2-ylmethyl)-3-methyl- ⁇ -(2-naphth-l-ylethyl- 3H-benzoimidazole-5-carboxamide;
- a together with B comprises 5-guanidino-lH-benzoimidazol-2-yl
- C comprises 6-[2-(2-carboxyphenyl)ethylcarbamoyl]-l-(3-sulfopropyl-lH-benzoimidazol-2-yl
- X 3 is -CH 2 - is named 2- ⁇ 2-[2-(5-guanidino-lH-benzoimidazol-2-ylmethyl)-3-(3-sulfopropyl)-
- a together with B comprises 5-guanidino-lH-benzoimidazol-2-yl
- C comprises 6-[2-(2-methoxyphenyl)ethylcarbamoyl]-l-(3-sulfopropyl-lH-benzoimidazol-2-yl
- X 3 is -CH 2 - is named 3- ⁇ 2-(5-guanidino-lH-benzoimidazol-2-ylmethyl)- 6-[2-(2-methoxyphenyl)ethylcarbamoyl]benzoimidazol-l-yl ⁇ propane-l-sulfonic acid.
- a preferred aspect of the Invention is a compound of Formula I in which A together with B comprises a fused heterobicyclic radical wherein A contains 5 annular members and B contains 6 annular members and X 4 and X 5 are adjacent members of an oxazol-2-yl, lH-imidazol-2-yl or thiazol-2-yl ring.
- a preferred aspect of the Invention are compounds of Formula II:
- each R 2 independently is (C,_ 6 )alkyl, (C ⁇ _ 6 )alkyloxy, halo or hydroxy
- each R 3 independently is (C 1-6 )alkyl, (C,. 6 )alkyloxy, halo or hydroxy
- X 3 is -C(O)- or -CR 7 R 8 -,
- R 5 is hydrogen or (C,. 4 )alkyl
- R 6 is hydrogen or (C 1-4 )alkyl, which alkyl optionally is substituted with one to two substituents independently selected from (C ⁇ alkyloxy, hydroxy and sulfo,
- R 7 is hydrogen or methyl and
- R 8 is hydrogen, methyl or hydroxy;
- any aliphatic and alicyclic moiety comprising R 4 optionally is substituted with one to five substituents independently selected from (C,. 4 )alkyloxy, (C,. 4 )alkyloxycarbonyl, amino, carbamoyl, carboxy and hydroxy; and any aromatic moiety comprising R 15 optionally is substituted with one to three substituents independently selected from (C 1-4 )alkyl, (C,. 4 )alkyloxy, (C,.
- a preferred aspect of the invention are compounds of Formula I in which:
- a together with B comprises 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridin-2-yl, wherein n2 is 0 and R 1 is -C(NR 9 )R 9 , or A together with B comprises lH-benzoimidazol-2-yl or
- R 1 is aminomethyl or guanidino and each R 2 independently is halo or hydroxy;
- C comprises 4,5,6,7-tetrahydro-l/ -imidazo[4,5-c]pyridin-2-yl or lH-benzoimidazol-2-yl, wherein R 4 is -C(O)X 6 -R' 5 , -C(O)OX 6 -R 15 or -C(O)NHX 6 -R 15 , wherein X 6 is (C,. 4 )alkylene or hetero(C 2 . 4 )alkylene and R 15 is (C 6 . 10 )aryl, (C 6 . 10 )aryloxy, polycyclo(C 6 . 10 )aryl, hetero(C 5 . 10 )aryl, hetero(C 5 .
- a preferred aspect of the invention are compounds of Formula I in which nl is 0 and each R 2 independently is halo or hydroxy, in particular:
- a preferred aspect of the invention are compounds of Formula I in which R 1 is guanidino of aminomethyl, in particular: 2-(5-guanidino- lH-benzoimidazol-2-ylmethyl)-3-methyl-TV-(2-naphth- 1 -ylethyl)-
- a preferred aspect of this invention are compounds of Formula I in which C comprises 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridin-2-yl and R 1 is -C( ⁇ H)R 9 , in particular:
- the compounds of this invention are serine protease inhibitors and, as such, are useful in treating diseases associated with increased serine protease activity.
- the compounds of this invention are tryptase inhibitors and are useful in treating diseases associated with increased tryptase activity.
- In vitro protocols for screening potential inhibitors as to their ability to inhibit tryptase are known in the art. See, e.g., Sturzebecher et al. (1992) Biol. Chem. Hoppe-Seyler 373:1025-1030. Typically, these assays measure the enzyme-induced hydrolysis of peptide-based chromogenic substances. Details of an exemplary procedure for measuring tryptase inhibitory activity are described below.
- the activity of the compounds of the present invention can be evaluated in vivo in one of numerous animal models of asthma. See, Larson, "Experimental Models of Reversible Airway Obstruction", in THE LUNG: SCIENTIFIC FOUNDATIONS, Crystal, West et al., eds., Raven Press, New York, 1991; Warner et al. (1990) Am. Rev. Respir. Dis. 141:253-257.
- An ideal animal model would duplicate the chief clinical and physiological features of human asthma, including: airway hyper-responsiveness to chemical mediators and physical stimuli; reversal of airway obstruction by drugs useful in human asthma ( ⁇ -adrenergics, methylxanthines, corticosteroids, and the like); airway inflammation with infiltration of activated leukocytes; and chronic inflammatory degenerative changes, such as basement membrane thickening, smooth muscle hypertrophy, and epithelial damage.
- Species used as animal models include mice, rats, guinea pigs, rabbits, dogs, and sheep. All have some limitations, and the proper choice of animal model depends upon the question which is to be addressed.
- the initial asthmatic response can be evaluated in guinea pigs, and dogs, and particularly, with a base ⁇ ji-greyhound cross strain which develops nonspecific airway hyper-responsiveness to numerous nonallergenic substances, such as methacholine and citric acid.
- Certain selected sheep exhibit a dual response after antigen challenge with Ascaris proteins.
- the initial asthmatic response (IAR) is followed by a late asthmatic response (LAR) at 6-8 hours post-exposure.
- LAR late asthmatic response
- Hypersensitivity to the cholinergic agonist carbachol increases at 24 hours after antigen challenge in those animals which exhibit LAR.
- the allergic sheep model (see below) was used to evaluate the potential antiasthmatic effects of the compounds of the present invention.
- Administration of compositions comprising the compounds of the present invention to allergic sheep in both oral and inhalant or aerosol formulations, prior to or following exposure to specific allergens demonstrates that such compositions substantially lessen or abolish the late asthmatic response and consequent hyper-responsiveness.
- the compounds of this invention are also useful for the treatment of other immunomediated inflammatory disorders in which tryptase activity contributes to the pathological condition.
- diseases include inflammatory diseases associated with mast cells, such as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflammatory bowel disease, peptic ulcers and various skin conditions.
- the compounds of the present invention can be used to treat syncytial viral infections.
- the efficacy of the compounds of the present invention for the treatment of the vast majority of immunomediated inflammatory disorders can be evaluated by either in vitro or in vivo procedures.
- the anti-inflammatory efficacy of the compounds of the present invention can be demonstrated by assays well known in the art, for example, the Reversed Passive Arthus Reaction (RPAR)-PAW technique (see, e.g., Gangly et al. (1992) U.S. Patent No. 5,126,352).
- Assays for determining the therapeutic value of compounds in the treatment of various skin conditions, such as hyperproliferative skin disease are well known in the art, for example, the Arachidonic Acid Mouse Ear Test (Id.).
- the compounds of the present invention can be evaluated for their antiulcer activity according to the procedures described in Chiu et al. (1984) Archives Internationales de Pharmacodynamie et de Therapie 270:128-140.
- compositions of the present invention are useful for preventing or ameliorating asthma.
- the compounds may be administered prophylactically prior to exposure to allergen or other precipitating factor, or after such exposure.
- the compounds of the present invention are particularly useful in ameliorating the late-phase tissue destruction seen in both seasonal and perennial rhinitis.
- the present invention is directed to the prevention and treatment of other immunomediated inflammatory disorders associated with mast cells such as urticaria and angioedema, and eczematous dermatitis (atopic dermatitis), and anaphylaxis, as well as hyperproliferative skin disease, peptic ulcers, and the like.
- the compounds of the present invention are used to treat syncytial viral infections, particularly infections of respiratory syncytial virus.
- the compositions containing the compounds can be administered for therapeutic and/or prophylactic treatments.
- compositions are administered to a patient already suffering from a disease, as described above, in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as "therapeutically effective amount or dose.” Amounts effective for this use will depend on the severity and course of the disease, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
- compositions containing the compounds of the invention are administered to a patient susceptible to or otherwise at risk of a particular disease in an amount sufficient to prevent or ameliorate the onset of symptoms. Such an amount is defined to be a "prophylactically effective amount or dose.” These can be administered orally or by inhalation.
- a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment can cease.
- a suitable effective dose of the compounds of the present invention will be in the range of 0.05 to 1000 milligram (mg) per recipient per day, preferably in the range of 0.1 to 100 mg per day.
- the desired dosage is preferably presented in one, two, three, four or more subdoses administered at appropriate intervals throughout the day. These subdoses can be administered as unit dosage forms, for example, containing 0.01 to 1000 mg, preferably 0.01 to 100 mg of active ingredient per unit dosage form.
- composition used in these therapies can be in a variety of forms. These include, for example, solid, semi-solid and liquid dosage forms, such as tablets, enteric-coated tablets, pills, powders, liquid solutions or suspensions, liposomes, injectable and infusible solutions. Inhalable preparations, such as aerosols, are also included.
- Preferred formulations are those directed to oral, intranasal, topical and parenteral applications, but it will be appreciated that the preferred form will depend on the particular therapeutic application at hand. Especially preferred formulations are oral or aerosol.
- compositions comprising the compounds of the invention are well known in the art and are described in, for example, REMINGTON'S PHARMACEUTICAL SCIENCES and THE MERCK INDEX 11 th Ed., (Merck & Co. 1989).
- the formulations of the present invention comprise at least one compound described herein in a therapeutically or pharmaceutically effective dose together with a pharmacologically acceptable carrier.
- the pharmaceutical compositions will thus contain the compounds of the present invention in concentrations sufficient to deliver an appropriate dose.
- the concentration of the compound of the invention in the pharmaceutical composition would be 0.05 mg per dose, where one dose per day is used.
- concentration of the compounds of the present invention in the composition will generally depend upon the amount of the dose.
- Typical concentrations of the compounds of the present invention in inhalant or aerosol compositions would be from about 0.01 to about 30 mg/mL.
- the formulation may include other clinically useful compounds, such as ⁇ -adrenergics (e.g., albuterol, terbutaline, formoterol, fenoterol, and prenaline) and corticosteroids (e.g., beclomethasome, triamcinolone, flunisolide, and dexamethasone).
- ⁇ -adrenergics e.g., albuterol, terbutaline, formoterol, fenoterol, and prenaline
- corticosteroids e.g., beclomethasome, triamcinolone, flunisolide, and dexamethasone.
- the compounds of the present invention are synthesized using standard techniques and reagents known to and used by those of skill in the art. It will be noted that the linkages between the various functional groups generally comprise carbon linked to the nitrogen of an amide or carbamate, the oxygen of a carbamate or the carbon of a carbonyl. Those of skill in the art will recognize that methods and reagents for forming these bonds are well known and readily available. See, e.g., March, ADVANCED ORGANIC CHEMISTRY, 4th Ed.
- D together with the vinylene moiety to which it is fused comprises a monocyclic or fused bicyclic divalent radical containing from 5 to 15 annular atoms, wherein each ring contains 5 to 7 annular atoms and each annular atom optionally is a heteroatom, R 29 is
- X 8 is -O-, -NR 6 - or -S- and n2, n3, n4,
- A, B, X 1 , X 2 , X 3 , X 5 , R 1 , R 2 , R 3 , R 4 and R 6 are as defined in the Summary of the Invention.
- Compounds of Formula I in which X 4 and X 5 are adjacent members of an oxazol-2-yl, lH-imidazol-2-yl or thiazol-2-yl ring can be prepared by reacting a compound of Formula 1, or a protected derivative thereof, with a compound of Formula 2, or a protected derivative thereof, and then deprotecting if necessary.
- the reaction between the compounds of Formulae 1 and 2 may be carried out neat, but preferably is carried out in the presence of l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU) or polyphosphoric acid, at 160 to 200°C, preferably 180-190°C, and requires 1 to 5 hours to complete (e.g., see Examples 4(d), 6(h), 8(k), 9(d) and 10(d), infra.).
- Deprotection can be effected by any means which removes the protective group and gives the desired product in reasonable yield (e.g., see Example 2(g), infra.).
- R 30 is -OH, -NHR 5 or -SH
- X 8 is -O-, -NR 6 - or -S- and n2, n3, n4, B, C, X 1 , X 3 , X 4 , X 5 , R 1 , R 2 , R 3 , R 4 and R 6 are as defined in the Summary of the Invention
- Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, high-pressure liquid chromatography (HPLC), or a combination of these procedures.
- suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of course, be used.
- Nuclear magnetic resonance (NMR) spectra were recorded on a General Electric "QE Plus" spectrometer (300 MHz).
- Infrared (IR) spectra were recorded on a Perkin-Elmer 1600 Fourier Transform IR (FTIR).
- Analytical HPLC was performed on a Ultrafast Microprotein Analyzer, Michrom BioResources, Inc. equipped with a PLRP column, lmm x 150mm.
- Preparative HPLC was performed on a Gilson LC using a VYDAC 1x25 cm C 18 reverse phase (RP) column or a Waters Prep LC2000 system using a Vydac 5x25 cm C 18 RP column.
- Mass spectra (MS) were obtained on a Finnigan SSQ 710 with an ESI source by direct infusion or by HPLC MS (Ultrafast Microprotein Analyzer, C 18 column 2mm X 150 mm).
- Compounds of Formula I may be prepared as pharmaceutically acceptable acid addition salts by reacting the free base forms of a compound of Formula I with a pharmaceutically acceptable inorganic or organic acid.
- the pharmaceutically acceptable base addition salts of compounds of Formula I may be prepared by reacting the free acid forms of compounds of Formula I with pharmaceutically acceptable inorganic or organic bases.
- Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula I are set forth in the definitions section of this application.
- the salt forms of the compounds of Formula I may be prepared using salts of the starting materials or intermediates.
- the free acid or free base forms of the compounds of Formula I can be prepared from the corresponding base addition salt or acid addition salt form.
- compounds of Formula I in an acid addition salt form may be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.).
- a suitable base e.g., ammonium hydroxide solution, sodium hydroxide, etc.
- Compounds of Formula I in a base addition salt form may be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
- a suitable acid e.g., hydrochloric acid, etc.
- the N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art.
- TV-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, met -chloroperoxybenzoic acid, etc.) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as methylene chloride) at approximately
- an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, met -chloroperoxybenzoic acid, etc.
- a suitable inert organic solvent e.g., a halogenated hydrocarbon such as methylene chloride
- N-oxides of the compounds of Formula I can be prepared from the TV-oxide of an appropriate starting material.
- Compounds of Formula I in unoxidized form can be prepared from N-oxides of compounds of Formula I by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80°C.
- a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.
- an inert organic solvent e.g., acetonitrile, ethanol, aqueous dioxane, etc.
- Prodrug derivatives of the compounds of Formula I can be prepared by methods known to those of ordinary skill in the art (e.g., see Example 12, infra.). For further details on prodrugs and their preparation see Saulnier et ⁇ /.(1994), Bioorganic and Medicinal Chemistry Letters. 4:1985)..
- Protected derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protective groups and their removal can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.
- Compounds of Formula I can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric comounds, separating the diastereomers and recovering the optically pure enantiomer.
- enantiomers can be carried out using covalent diasteromeric derivatives of compounds of Formula I, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts).
- Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these disimilarities.
- the diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility.
- the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
- an aspect of this Invention is a process for preparing a compound of Formula I, which process comprises: (a) reacting a compound of Formula 1 :
- L is a leaving group
- D together with the vinylene moiety to which it is fused comprises a monocyclic or fused bicyclic divalent radical containing from 5 to 15 annular atoms, wherein each ring contains 5 to 7 annular atoms and each annular atom optionally is a heteroatom
- R 29 is -OH, -NHR 6 or -SH and nl, n2, n3,
- A, B, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 and R 6 are as defined in the Summary of the Invention, and then deprotecting if necessary to give a compound of Formula I in which X 4 and X 5 are adjacent members of an oxazol-2-yl, lH-imidazol-2-yl or thiazol-2-yl, ring; or (b) reacting a compound of Formula 3 :
- R 30 is -OH, -NHR 5 or -SH and nl, n2, n3, B, C, X 3 , X 4 , X s , R 1 , R ⁇ R 3 , R 4 and R 5 are as defined in the Summary of the Invention, and then deprotecting if necessary to give a compound of Formula I in which X 1 and X 2 are adjacent members of an oxazol-2-yl, l/f-imidazol-2-yl or thiazol-2-yl ring;
- the solution was adjusted to pH ⁇ 8 with TV-methylmorpholine and the mixture was allowed to slowly warm to room temperature and then stirred for 20 hours.
- the mixture was transferred to a separatory funnel, diluted with methylene chloride, washed with 0.1 N HCl solution and then saturated NaHCO 3 solution, dried over sodium sulfate, filtered and concentrated.
- N-(4-amino-3-nitrophenyl)guanidine hydrochloride (18.0g, 98% yield); 'H- ⁇ MR (300 MHz, DMSO-d 6 ): 9.7 (s), 7.8 (s), 7.6 (s), 7.5 (s), 7.3 (d), 7.1 (d).
- Example 8 methyl 2-(2- ⁇ 2-[l-(5-fluoro-lH-benzoimidazol-2-yl)ethyl]-3-methyl- 3H-benzoimidazol-5-ylcarbonylamino ⁇ ethoxy )benzoate (Compound 31), MS (Biolon) C 28 H 26 N 5 O 4 F m/e calc 515.54; found 516 (MH + );
- the mixture was cooled at -5°C for 1 hour and allowed to warm to 20 °C and, after 16 hours, concentrated under reduced pressure.
- the residue was suspended in ether and the suspension was washed successively with sodium bicarbonate, sodium chloride, 0.1 M hydrochloric acid and sodium chloride, dried ( ⁇ a 2 SO 4 ), filtered and concentrated under reduced pressure.
- the residue was dissolved in ethanol (320 mL) and the solution was cooled to -5 °C under nitrogen and then sodium ethoxide (21 wt %, 85 mL, 0.22 mol) was added dropwise over 1 hour while the reaction temperature was maintained below 0°C.
- NN-diisopropylethylamine (0.29 mL ), allowed to warm to 20 °C and stirred for 16 hours. The mixture then was cooled to -40 °C, treated with additional EDC (0.080 g) and TV,N-diisopropylethylamine (0.050 mL), stirred for 15 minutes at -40°C and 2 hours at 20°C and concentrated by shortpath distillation. The residue was partitioned between chloroform and sodium bicarbonate and the organic layer was washed with sodium chloride, 0.5 M potassium sulfate and sodium chloride, dried ( ⁇ a 2 SO 4 ), filtered and concentrated under reduced pressure.
- a mixture comprising ethyl 2-(2- ⁇ 2-[l-(4,6,7-trifluoro-lH-benzoimidazol-2-yl)ethyl]- 3-methyl-3H-benzoimidazol-5-carbonylamino ⁇ ethoxy ⁇ benzoate (118 mg, 0.21 mmol), methanol (4 ml) and 2N sodium hydroxide (2.1 ml) was stirred at room temperature for 4 hours, neutralized with 2N hydrochloric acid (2.1 ml) and partitioned between ethyl acetate and saturated ammonium chloride. The aqueous layer was separated and extracted with ethyl acetate (X3).
- Tryptase solution (60g/mL) was prepared by dissolving tryptase purified from human lung or skin tissue preparations or human mast cell line (HMC-1) or obtained from commercial sources, e.g., ICN Biomeidals, Irvine, California, Athens Research & Technology, Athens, Georgia, etc., in a solvent mixture comprising: lOmM 2-TV-morpholinoethane sulfonic acid, 2mM CaCl 2 , 20%) glycerol and 50 g/mL heparin.
- Substrate solution containing 2mM synthetic tripeptide (tosyl-Gly-Pro-Lys-p-nitroanilide) was obtained from Sigma.
- Test Compound solutions were prepared by diluting a stock solution (1 mg of test Compound in 200 ⁇ L of dimethylsulfoxide (DMSO)) by ten- fold into assay buffer (comprising: Tris-HCl (pH 8.2), 50mM; NaCl, lOOmM; 0.05% polyoxyethylenesorbitan monolaurate (Tween-20®); and zinc chloride, 150 ⁇ M) and then making seven additional three-fold dilutions into 10%> DMSO in assay buffer. Aliquots (50 ⁇ L) from each of the eight dilutions of test compound solution were added to separate wells in a 96-well U-bottom microtiter plate.
- assay buffer comprising: Tris-HCl (pH 8.2), 50mM; NaCl, lOOmM; 0.05% polyoxyethylenesorbitan monolaurate (Tween-20®); and zinc chloride, 150 ⁇ M
- Airway hyper-responsiveness is expressed as PC400, the concentration of carbachol that causes a 400%> increase in SRL; therefore, a decrease in PC400 indicates hyper-responsiveness.
- Compound 13 was found to block the onset of hyper-responsiveness. As shown in Figure 2, this compound maintained the PC400 at substantially the baseline value of 15 breath units. The number of breath units fell to 7 for those animals in the control group. Thus, treatment with Compound 13 resulted in a significant improvement in airway function in antigen challenged sheep.
- the present invention provides compounds and compositions that are useful for the prevention and treatment of immunomediated inflammatory disorders, particularly those associated with the respiratory tract, including asthma, and the hyper-responsiveness phase associated with chronic asthma, in addition to allergic rhinitis.
- the present invention is also recognized as providing a method for treating immunomediated inflammatory disorders that are susceptible to treatment with a compound of the present invention.
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- Communicable Diseases (AREA)
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- Pain & Pain Management (AREA)
- Rheumatology (AREA)
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Abstract
Description
Claims
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EEP199900477A EE04055B1 (en) | 1997-04-07 | 1997-12-01 | Compounds and compositions for the treatment of diseases associated with serine protease activity, in particular tryptase activity, and their use |
AU58950/98A AU752064B2 (en) | 1997-04-07 | 1997-12-01 | Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, activity |
NZ500029A NZ500029A (en) | 1997-04-07 | 1997-12-01 | Compounds and compositions of carboxamide derivatives associated with the treatment of rheumatoid arthritis, conjunctivitis and/ or syncytial virus infections |
CA002285454A CA2285454A1 (en) | 1997-04-07 | 1997-12-01 | Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, activity |
SK1367-99A SK136799A3 (en) | 1997-04-07 | 1997-12-01 | Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, activity |
SI9720094A SI20115A (en) | 1997-04-07 | 1997-12-01 | Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, activity |
JP54273998A JP2001519806A (en) | 1997-04-07 | 1997-12-01 | Compounds and compositions for treating diseases associated with serine protease activity, especially tryptase activity |
EP97954520A EP1019382A1 (en) | 1997-04-07 | 1997-12-01 | Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, activity |
HU0001522A HUP0001522A3 (en) | 1997-04-07 | 1997-12-01 | Benzoimidazole derivatives, process for producing them and pharmaceutical compositions containing them |
PL97336233A PL336233A1 (en) | 1997-04-07 | 1997-12-01 | Compounds and agents for treating diseases associated with serinic protease activity, in particular tryptase activity |
NO19994858A NO314183B1 (en) | 1997-04-07 | 1999-10-06 | Benzimidazole derivatives, their use and pharmaceutical preparations containing them |
LVP-99-153A LV12495B (en) | 1997-04-07 | 1999-11-02 | Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, activity |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US83367497A | 1997-04-07 | 1997-04-07 | |
US08/833,674 | 1997-04-07 |
Publications (1)
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WO1998045275A1 true WO1998045275A1 (en) | 1998-10-15 |
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PCT/US1997/021849 WO1998045275A1 (en) | 1997-04-07 | 1997-12-01 | Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, activity |
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Country | Link |
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EP (1) | EP1019382A1 (en) |
JP (1) | JP2001519806A (en) |
KR (1) | KR20010006119A (en) |
CN (1) | CN1251579A (en) |
AU (1) | AU752064B2 (en) |
CA (1) | CA2285454A1 (en) |
EE (1) | EE04055B1 (en) |
HU (1) | HUP0001522A3 (en) |
LT (1) | LT4704B (en) |
LV (1) | LV12495B (en) |
NO (1) | NO314183B1 (en) |
NZ (1) | NZ500029A (en) |
PL (1) | PL336233A1 (en) |
SI (1) | SI20115A (en) |
SK (1) | SK136799A3 (en) |
WO (1) | WO1998045275A1 (en) |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999026933A1 (en) * | 1997-11-26 | 1999-06-03 | Axys Pharmaceuticals, Inc. | Substituted amidinoaryl derivatives and their use as anticoagulants |
WO1999026932A1 (en) * | 1997-11-26 | 1999-06-03 | Axys Pharmaceuticals, Inc. | By amidino group substituted heterocyclic derivatives and their use as anticoagulants |
WO2000020401A1 (en) * | 1998-10-01 | 2000-04-13 | Bayer Aktiengesellschaft | New bis-benzimidazoles |
WO2000020400A1 (en) * | 1998-10-05 | 2000-04-13 | Axys Pharmaceuticals, Inc. | Novel compounds and compositions for treating hepatitis c infections |
WO2000075117A1 (en) * | 1999-06-04 | 2000-12-14 | Elan Pharma International Ltd. | Compositions and methods for inhibiting cell death |
US6221914B1 (en) | 1997-11-10 | 2001-04-24 | Array Biopharma Inc. | Sulfonamide bridging compounds that inhibit tryptase activity |
WO2001052883A1 (en) * | 2000-01-20 | 2001-07-26 | Amgen Inc. | Inhibitors of protease-activated receptor-2 (par-2) as novel asthma therapeutics |
WO2002070491A1 (en) * | 2001-03-01 | 2002-09-12 | Shionogi & Co., Ltd. | Nitrogenous heteroaromatic ring derivative having hiv integrase inhibitory activity |
JP2003513959A (en) * | 1999-11-10 | 2003-04-15 | ベーリンガー インゲルハイム ファルマ コマンディトゲゼルシャフト | Carboxamide-substituted benzimidazole derivatives, methods for their preparation and their use as pharmaceutical compositions |
JP2004502761A (en) * | 2000-07-06 | 2004-01-29 | ベーリンガー インゲルハイム (カナダ) リミテッド | Viral polymerase inhibitor |
DE10048715A1 (en) * | 2000-09-30 | 2004-05-19 | Grünenthal GmbH | Use of amino acid for the treatment of pain |
US20070142403A1 (en) * | 2004-03-19 | 2007-06-21 | Novartis Pharmaceuticala Corporation | Pharmaceutical composition comprising a benzodiazepine derivative and an inhibitor of the rsv fusion protein |
DE102011111991A1 (en) | 2011-08-30 | 2013-02-28 | Lead Discovery Center Gmbh | New cyclosporin derivatives |
US8759535B2 (en) | 2010-02-18 | 2014-06-24 | High Point Pharmaceuticals, Llc | Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof |
US10172840B2 (en) | 2014-12-01 | 2019-01-08 | Vtv Therapeutics Llc | Bach1 inhibitors in combination with Nrf2 activators and pharmaceutical compositions thereof |
US20210169874A1 (en) * | 2011-11-29 | 2021-06-10 | Covis Pharma Gmbh | Anticoagulant reversal agents |
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JP7318009B2 (en) * | 2019-05-21 | 2023-07-31 | 浙江海正薬業股▲ふん▼有限公司 | Macrolide derivative, production method and use thereof |
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1997
- 1997-12-01 WO PCT/US1997/021849 patent/WO1998045275A1/en not_active Application Discontinuation
- 1997-12-01 SK SK1367-99A patent/SK136799A3/en unknown
- 1997-12-01 AU AU58950/98A patent/AU752064B2/en not_active Ceased
- 1997-12-01 HU HU0001522A patent/HUP0001522A3/en unknown
- 1997-12-01 JP JP54273998A patent/JP2001519806A/en active Pending
- 1997-12-01 CA CA002285454A patent/CA2285454A1/en not_active Abandoned
- 1997-12-01 NZ NZ500029A patent/NZ500029A/en unknown
- 1997-12-01 KR KR1019997009197A patent/KR20010006119A/en not_active Application Discontinuation
- 1997-12-01 CN CN97182098A patent/CN1251579A/en active Pending
- 1997-12-01 PL PL97336233A patent/PL336233A1/en unknown
- 1997-12-01 EE EEP199900477A patent/EE04055B1/en not_active IP Right Cessation
- 1997-12-01 SI SI9720094A patent/SI20115A/en unknown
- 1997-12-01 EP EP97954520A patent/EP1019382A1/en not_active Withdrawn
-
1999
- 1999-10-06 NO NO19994858A patent/NO314183B1/en unknown
- 1999-11-02 LV LVP-99-153A patent/LV12495B/en unknown
- 1999-11-05 LT LT99-131A patent/LT4704B/en not_active IP Right Cessation
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US6221914B1 (en) | 1997-11-10 | 2001-04-24 | Array Biopharma Inc. | Sulfonamide bridging compounds that inhibit tryptase activity |
WO1999026932A1 (en) * | 1997-11-26 | 1999-06-03 | Axys Pharmaceuticals, Inc. | By amidino group substituted heterocyclic derivatives and their use as anticoagulants |
WO1999026933A1 (en) * | 1997-11-26 | 1999-06-03 | Axys Pharmaceuticals, Inc. | Substituted amidinoaryl derivatives and their use as anticoagulants |
WO2000020401A1 (en) * | 1998-10-01 | 2000-04-13 | Bayer Aktiengesellschaft | New bis-benzimidazoles |
WO2000020400A1 (en) * | 1998-10-05 | 2000-04-13 | Axys Pharmaceuticals, Inc. | Novel compounds and compositions for treating hepatitis c infections |
WO2000075117A1 (en) * | 1999-06-04 | 2000-12-14 | Elan Pharma International Ltd. | Compositions and methods for inhibiting cell death |
JP2003513959A (en) * | 1999-11-10 | 2003-04-15 | ベーリンガー インゲルハイム ファルマ コマンディトゲゼルシャフト | Carboxamide-substituted benzimidazole derivatives, methods for their preparation and their use as pharmaceutical compositions |
WO2001052883A1 (en) * | 2000-01-20 | 2001-07-26 | Amgen Inc. | Inhibitors of protease-activated receptor-2 (par-2) as novel asthma therapeutics |
JP2004502761A (en) * | 2000-07-06 | 2004-01-29 | ベーリンガー インゲルハイム (カナダ) リミテッド | Viral polymerase inhibitor |
DE10048715A1 (en) * | 2000-09-30 | 2004-05-19 | Grünenthal GmbH | Use of amino acid for the treatment of pain |
WO2002070491A1 (en) * | 2001-03-01 | 2002-09-12 | Shionogi & Co., Ltd. | Nitrogenous heteroaromatic ring derivative having hiv integrase inhibitory activity |
US20070142403A1 (en) * | 2004-03-19 | 2007-06-21 | Novartis Pharmaceuticala Corporation | Pharmaceutical composition comprising a benzodiazepine derivative and an inhibitor of the rsv fusion protein |
US8853204B2 (en) * | 2004-03-19 | 2014-10-07 | Arrow Therapeutics Limited | Pharmaceutical composition comprising a benzodiazepine derivative and an inhibitor of the RSV fusion protein |
US10287284B2 (en) | 2010-02-18 | 2019-05-14 | Vtv Therapeutics Llc | Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof |
US8759535B2 (en) | 2010-02-18 | 2014-06-24 | High Point Pharmaceuticals, Llc | Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof |
US10030011B2 (en) | 2010-02-18 | 2018-07-24 | Vtv Therapeutics Llc | Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof |
US10570126B2 (en) | 2010-02-18 | 2020-02-25 | Vtv Therapeutics Llc | Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof |
US11130753B2 (en) | 2010-02-18 | 2021-09-28 | Vtv Therapeutics Llc | Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof |
US11649230B2 (en) | 2010-02-18 | 2023-05-16 | Vtv Therapeutics Llc | Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof |
WO2013030208A1 (en) | 2011-08-30 | 2013-03-07 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Cyclosporin derivatives |
DE102011111991A1 (en) | 2011-08-30 | 2013-02-28 | Lead Discovery Center Gmbh | New cyclosporin derivatives |
US20210169874A1 (en) * | 2011-11-29 | 2021-06-10 | Covis Pharma Gmbh | Anticoagulant reversal agents |
US10172840B2 (en) | 2014-12-01 | 2019-01-08 | Vtv Therapeutics Llc | Bach1 inhibitors in combination with Nrf2 activators and pharmaceutical compositions thereof |
US10463652B2 (en) | 2014-12-01 | 2019-11-05 | Vtv Therapeutics Llc | Bach1 inhibitors in combination with Nrf2 activators and pharmaceutical compositions thereof |
US10898475B2 (en) | 2014-12-01 | 2021-01-26 | Vtv Therapeutics Llc | Bach1 inhibitors in combination with Nrf2 activators and pharmaceutical compositions thereof |
Also Published As
Publication number | Publication date |
---|---|
HUP0001522A2 (en) | 2001-05-28 |
SI20115A (en) | 2000-06-30 |
SK136799A3 (en) | 2000-07-11 |
EE04055B1 (en) | 2003-06-16 |
EP1019382A1 (en) | 2000-07-19 |
KR20010006119A (en) | 2001-01-26 |
AU5895098A (en) | 1998-10-30 |
CN1251579A (en) | 2000-04-26 |
CA2285454A1 (en) | 1998-10-15 |
NZ500029A (en) | 2001-02-23 |
JP2001519806A (en) | 2001-10-23 |
NO314183B1 (en) | 2003-02-10 |
PL336233A1 (en) | 2000-06-19 |
AU752064B2 (en) | 2002-09-05 |
LV12495B (en) | 2001-01-20 |
LV12495A (en) | 2000-06-20 |
LT4704B (en) | 2000-09-25 |
NO994858D0 (en) | 1999-10-06 |
LT99131A (en) | 2000-04-25 |
HUP0001522A3 (en) | 2001-08-28 |
NO994858L (en) | 1999-12-06 |
EE9900477A (en) | 2000-06-15 |
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