Classifications

• • 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
• • 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
• • 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
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/14—Decongestants or antiallergics
• • 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
  • 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
  • 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
  • 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

Definitions

• This invention relates to novel bis-benzimidazoles, processes for their preparation and their use for the prophylaxis and treatment of diseases associated with tryptase activity, in particular for the treatment of asthma and allergic rhinitis.
• Elevated levels of tryptase have been detected in a number of diseases, including asthma, allergic conjunctivitis, allergic rhinitis, rheumatoid athritis, multiple sclerosis, and interstitial cystitis (Drugs of the Future 1996, 21, 811).
• diseases including asthma, allergic conjunctivitis, allergic rhinitis, rheumatoid athritis, multiple sclerosis, and interstitial cystitis (Drugs of the Future 1996, 21, 811).
• Unlike other protease associated with mast cells such as chymase, carboxypeptidase A, and cathepsin tryptase is present in virtually all mast cells including those in gut mucosa, alveolar interstitium, and dermis (Immunol. Res. 1989, 8, 130).
• Tryptase is the major secretory proteinase in both the MC CT and MC T mast cell lines, which contain approximately 35pg and llpg of the enzyme, respectively, per cell. This quantity of tryptase may represent up to 25% of the total protein content of the mast cell (J. Immunol. 1987, 138, 2611). Cloning and sequencing efforts have revealed that tryptase is comprised of a family of several highly conserved enzymes which share 90-98% sequence homology. The crystal structure of ⁇ -tryptase complexed with 4-amidinophenyl pyruvic acid has recently been reported (Nature 1998, 392, 306), which sheds significant light on the structure and unique biochemical properties of human tryptase.
• the active tetramer consists of a flat and nearly square assembly of monomers held together through hydrophobic surface contact interactions and heparin association.
• Each of the four monomer active sites faces the interior of an oval central cavity with the corresponding distances between adjacent active sites in the range of 20- 40 A.
• the size of this central cavity and proximity of adjacent monomers limits accessibility of large protein substrates and inhibitors, making tryptase structurally well-suited for the task of selective neuropeptide and protein processing.
• the scope of biochemical functions and the corresponding physiological consequences of tryptase proteolytic activity in vivo is defined by its substrate specificity, regulation, and by the complex distribution of mast cells throughout the body.
• the immediate consequence of mast cell stimulation and degranulation is the release of active ⁇ - tryptase along with other mediators, which then initiates the proteolytic cleavage of specific peptide and protein substrates.
• These substrates can by classified into three general types: neuropeptides, active daughter enzymes and zymogen proteins, and cell surface receptors, each of which may have complex biochemical and physiological significance.
• the crystal structure of ⁇ -tryptase provides insight into the enzyme's unique substrate specificity and resistance to endogenous inhibitors.
• the central cavity of tryptase which contains the active site domain, has limited accessibility due to the proximity and arrangement of adjacent monomers. This structural feature limits the substrate family to small, conformationally flexible peptides and to proteins which can project cleavable surface loops into the active site cavity and provides a rationale for the limited number of physiologically relevant tryptase substrates and inhibitors which have been identified.
• VIP vasoactive intestinal peptide
• PLM calcitonin gene-related peptide
• CGRP calcitonin gene-related peptide
• pro-MMP 3 pro-matrix metalloprotease 3
• bradykinin from high and low molecular weight kininogen
• IL-8 interleukin-8
• Type IV collagen is proposed to link major elements of the extracellular matrix and is associated in particular with connective tissues.
• the degradation of type IV collagen may be of significance in certain pathological conditions involving the degradation and chronic inflammation of connective tissue and skin, such as arthritis, atopic dermatitis and psoriasis.
• Another pathway by which tryptase may indirectly initiate extracellular matrix degradation is through the activation of matrix metalloproteinases (Exp. Opb. Invest. Drugs 1997, 6, 811).
• the cascade is likely initiated through the cleavage of prostromelysin or pro- matrix metalloproteinase 3 (proMMP-3) by tryptase.
• proMMP-3 pro- matrix metalloproteinase 3
• MMP-3 can degrade proteoglycans, fibronectin and laminin as well as type IV and type IX collagen.
• Synovial procollagenase is activated by tryptase in vitro, and this activity is entirely dependent upon the enzymatic activation of MMP-3 (J. Clin. Invest. 1989, 84, 1657; J. Immunol.
• tryptase may function in a number of pathological conditions where MMP activity and cartilage degradation is involved, as well as at sites of collagen deposit in diseases such as arthritis, chronic peridontitis, rheumatiod synovium and sclerosis. More recent studies demonstrated a potential connection between tryptase activation of pro-matrix metalloproteinase-8 and bronchiectasis, a chronic lung disorder characterized by degradation of airway and lung tissue extracellular matrix (Eur. Respir. J. 1997, 10, 2788 .
• u-PA Single-chain urinary type plasminogen activator
• Tryptase has been shown to act as a mitogen for cultured human endothelial cells in vitro and may function in this context in the process of neovascularization (J. Allergy Clin. Immunol. 1998, 101, SllO). Thus, tryptase activity may be at the center of several physiological pathways that modulate cell growth and pathological conditions associated with hyperplasia.
• a number of further diseases or conditions are thought to be mediated by tryptase activity. These include: metastasis of tumor cells (Drugs of the Future 1996, 21, 811), anaphylaxis, mastocytosis, scleroderma, skin diseases such as urticaria, atopic dermatitis, bullous pemphigoid, psoriasis (Exp. Opin. Invest.
• Drugs 1997, 6, 811 pulmonary fibrosis, interstitial pneumonia, nephritis, hepatic fibrosis, hepatitis, hepatic cirrhosis, Crohn's disease, ulcerative colitis, nasal allergy, peptic ulcers, gastric disease induced by non-steroidal inflammatory agents, cardiac infarction, disseminated intravascular coagulation, pancreatitis, multi organ failure (WO 9737969), interstitial lung diseases, gingivitis, peridontitis, virus infections (e.g.
• Tryptase inhibitors have been described in WO 9737969, WO 9609297 and WO 9420527.
• the new bis-benzimidazoles are tryptase inhibitors which interact with the catalytic Ser and His residues through the intermediacy of divalent zinc as described by Katz et al. (Nature 1998, 391, 608). Even low concentrations of ambient zinc will enhance the potency of these inhibitors substantially in vitro (Angew. Chem. 1998, 110, 1939).
• the invention relates to novel bis-benzimidazoles, processes for their preparation and their use for the prophylaxis and treatment of diseases associated with tryptase activity, including allergic, inflammatory and related immunological diseases, in particular for the treatment of asthma, allergic rhinitis, allergic conjunctivitis and allergic dermatitis.
• the invention relates to compounds of the general formula (I) and their tautomeric and stereoisomeric forms
• R 1 , R 2 , R 3 and R" are identical or different and represent hydrogen, hydroxy or halogen
• R 5 and R 8 are identical or different and represent hydrogen, or straight-chain or branched (C r )
• R 6 and R 7 are identical or different and represent hydrogen, straight-chain or branched
• R 9 , R 10 and R 11 are identical or different and represent hydrogen, halogen, nitro, cyano or trifluoromethyl, and
• A represents a residue of a formula
• R 12 and R 13 are identical or different and denote hydrogen, halogen, nitro, cyano, straight-chain or branched ( - C 6 )-alkyl or (C, - C 6 )-alkoxy, or hydroxy, or
• A represents a non-aromatic 5- to 7-membered N-heterocycle which is bound over the nitrogen atom and which optionally contains an oxygen atom or a residue -NR 14 or -CH-R 15 , wherein R 14 and R 15 are identical or different and denote hydrogen, (C 3 - C 8 )- cycloalkyl, or denotes straight-chain or branched (C, - C 4 )-alkyl, which is optionally substituted by (C 6 - C, 0 )-aryl, or denote (C 6 - C 10 )-aryl or a 5- or 6-membered aromatic or non-aromatic heterocycle having up to 3 heteroatoms from the series comprising N, S and/or O, and which, in the case of the non-aromatic heterocycle, is optionally bound over a nitrogen atom and wherein the aryl and the heterocycle are optionally mono- to tri-substituted by identical or different substitutents from the series comprising hal
• R 16 and R' 7 are identical or different and denote hydrogen, straight-chain or branched
• R M denotes a residue of the formula -S0 2 -R 18 , in which
• R 18 denotes (C 6 - C 10 )-aryl, or straight-chain or branched (C ! - GJ-alkyl, or A represents a residue of the formula -NR 19 R 20 , in which
• R 19 denotes hydrogen, straight-chain or branched ( - C,)-alkyl
• R 20 denotes a residue of a formula -D-E-R 21 , in which
• D denotes a straight-chain or branched (C t - C 6 )-alkyl chain
• E denotes an oxygen atom or a bond
• R 21 denotes (C 6 - C ⁇ 0 )-aryl or a 5- or 6-membered aromatic heterocycle having up to 3 heteroatoms from the series comprising N, S and/or O, which are optionally mono- to tri-substituted by nitro, cyano, halogen, tetrazolyl or by a residue of the formula -NR 22 R 23 , in which
• R 22 and R 23 are identical or different and denote hydrogen, straight-chain or branched
• the new bis-benzimidazoles according to the invention can also be present in the form of their salts.
• salts with organic or inorganic bases or acids may be mentioned here.
• Physiologically acceptable salts are preferred in the context of the present invention.
• Physiologically acceptable salts can also be salts of the compounds according to the invention with inorganic or organic acids.
• Preferred salts here are those with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, ethanesulphonic acid, berzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
• the compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers).
• the invention relates both to the antipodes and to the racemate forms, as well as the diastereomer mixtures.
• the racemate forms like the diastereomers, can be separated into the stereoisomerically uniform constitutents in a known manner.
• a non-aromatic 5- to 7-membered heterocycle in general represents morpholinyl, piperidinyl, piperazinyl or 1,4-diazacycloheptyl.
• piperidinyl piperazinyl or 1,4- diazacycloheptyl.
• Heterocycle in general represents a 5- to 7-membered aromatic or non-aromatic, preferably 5- to 6- membered, saturated or unsaturated ring which can contain up to 3 oxygen, sulphur and/or nitrogen atoms as heteroatoms.
• Preferred compounds of the general formula (I) are those, in which R 1 , R 2 , R 3 and R'are identical or different and represent hydrogen, hydroxy or fluorine, wherein at least one of the above mentioned substituents R 1 , R 2 , R 3 or R 4 is different from hydrogen, R 5 and R 8 are identical or different and represent hydrogen, methyl, ethyl or isopropyl, R 6 and R 7 are identical or different and represent hydrogen, straight-chain or branched (C,-C 4 )- alkyl, hydroxy, or fluorine,
• R 9 , R 10 and R n are identical or different and represent hydrogen, fluorine, chlorine or cyano, and A represents a residue of the formula wherein
• R 12 and R 13 are identical or different and denote hydrogen, fluorine, chlorine or cyano,
• R 14 , R 14' and R 15 are identical or different and denote hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or denote straight-chain or branched
• (C) - C 3 )-alkyl which is optionally substituted by phenyl, or denote phenyl, pyrimidyl, pyridyl or piperidinyl which are optionally substituted by fluorine, chlorine, nitro, cyano or a residue of the formula -NR 16 R 17 , in which
• R 16 and R 17 are identical or different and denote hydrogen, straight-chain or branched
• R 14' denotes a residue of the formula -S0 2 -R 18 , in which
• R 18 denotes phenyl, or straight-chain or branched (Cj - C 3 )-alkyl, or
• A represents a residue of the formula -NR ⁇ R 20 , in which
• R 19 denotes hydrogen, or straight-chain or branched ( - C 3 )-alkyl
• R 20 denotes a residue of the formula D-E-R 21 , in which D denotes a straight-chain or branched (C, - C 5 )-alkyl chain,
• E denotes an oxygen atom or a bond
• R 21 denotes phenyl or pyridyl, which are optionally monosubstituted or disubstituted by nitro, cyano, fluorine, chlorine, tetrazolyl or by a residue of the formula -NR ⁇ R 23 , in which
• R 22 and R 23 are identical or different and denote hydrogen, straight-chain or branched
• Particularly preferred compounds of the general formula (I) are those, in which
• R 1 , R 2 , R 3 and R 4 are identical or different and represent hydrogen, hydroxy or fluorine, wherein two or three of the above mentioned substituents R 1 , R 2 , R 3 or R 4 are different from hydrogen,
• R 5 and R 8 are identical or different and represent hydrogen, methyl or isopropyl
• R 6 and R 7 are identical or different and represent hydrogen, straight-chain or branched (Ci - C 3 )- alkyl, hydroxy, or fluorine,
• R 9 , R 10 and R 11 are identical or different and represent hydrogen or fluorine
• A represents a residue of the formula
• R 12 and R 13 are identical or different and denote hydrogen or fluorine and R 14 , R 14' and R 15 are identical or different and denote hydrogen, cyclopentyl, cyclohexyl, cycloheptyl, or denote straight-chain or branched (C, - C 3 )-alkyl, which is optionally substituted by phenyl, or denote phenyl, pyrimidyl, pyridyl or piperidinyl, which are optionally substituted by fluorine, nitro, cyano or a residue of the formula -
• R 16 and R 17 are identical or different and denote hydrogen, straight-chain or branched
• R 14' denotes a residue of the formula -S0 2 -R 18 , in which
• R 18 denotes phenyl or methyl
• A represents a residue of the formula -NR ( 19 RD ⁇ , in which
• R 19 denotes hydrogen or methyl
• R 20 denotes a residue of the formula -D-E-R 21 , in which
• D denotes a straight-chain or branched ( - C,)-alkyl chain
• E denotes an oxygen atom or a bond
• R 21 denotes phenyl or pyridyl, which are optionally monosubstituted or disubstituted by nitro, cyano, fluorine, tetrazolyl or by a residue of the formula - NR ⁇ R 23 , in which
• R 22 and R 23 are identical or different and denote hydrogen, straight-chain or branched (C, - C 3 )-acyl, or R 22 denotes hydrogen and R 23 denotes a residue -S0 2 -CF 3 .
• Very particularly preferred compounds of the general formula (I) are those, in which R 1 , R 2 , R 3 and R are identical or different and represent hydrogen or fluorine, wherein two or three of the above mentioned substitutents R 1 , R 2 , R 3 or R 4 are different from hydrogen, R 5 denotes hydrogen and R 8 denotes methyl,
• R 6 and R 7 are identical or different and represent hydrogen, methyl or fluorine,
• R 9 , R 10 and R 11 are hydrogen
• A represents a residue of the formula
• R 14' denotes phenyl, which is optionally substituted by fluorine, cyano or a residue -NHS0 2 CF 3 ⁇
• A represents a residue of the formula -NR l9 R 20 , in which
• R 19 denotes hydrogen
• R 20 denotes a residue of the formula -D-E-R 21 , in which
• D denotes (CH 2 ) 2 -group
• E denotes an oxygen atom
• R 21 denotes phenyl, which is optionally monosubstituted or disubstituted by fluorine or cyano.
• R 1 , R ⁇ R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R" have the above mentioned meaning, or their reactive derivatives on the carboxyl radical are reacted with compounds of the general formula (III)
• A has the above mentioned meaning, in inert solvents, if appropriate in the presence of a base and/or in the presence of auxiliary reagents, or
• R 1 , R 2 , R 3 , R 4 , R 5 , R ⁇ and R 7 have the above mentioned meaning, and R 24 denotes straight-chain or branched (C, - C 6 )-alkyl- are reacted with compounds of the general formula (V)
• R 8 , R 9 , R 10 , R 11 and A have the above mentioned meaning, in inert solvents, if appropriate in the presence of a base and/or in the presence of auxiliary
• R 1 , R 2 , R 3 and R 4 have the above mentioned meaning, with the above mentioned system and finally with acetic acid, or
• inert solvents such as water and tetrahydrofuran
• Suitable solvents are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofuran, acetone, dimethyl sulfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as dichlormethane, trichloromethane or tetrachloromethane. Dichloromethane and dimethylformamide are preferred.
• Suitable bases are generally inorganic or organic bases. These preferably include alkali metal hydroxides such as, for example, sodium hydroxide, sodium hydrogencarbonate or potassium hydroxide, alkaline earth metal hydroxides such as, for example, barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkaline metal or organic amines (trialkyl (C ] - C 6 )amines) such as triethylamine, or N-methyl- or ethylmorpholine, or heterocycles such as 1,4- diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or amides such as sodium amides, lithium butyl amide or butyllithium, pyridine or methylpiperidine. Triethylamine, N-methylmorpholine or N-ethylmorph
• the process is in general carried out in a temperature range from -30 °C to +100 °C, preferably from -10 °C to +50 °C.
• the process is generally carried out at normal pressure. However, it is also possible to carry out it at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
• the base is employed in an amount from 1 mol to 10 mol, preferably from 1.0 mol to 4 mol, relative to 1 mol of the compounds of the general formula (II) or (III).
• Suitable solvents are generally customary organic solvents which do not change under the reaction conditions. These include ethers such di-n-butyl ether, dimethyl sulfoxide, dimethylformamide or DMPU or DMEU (N, N-dimethylethyleneurea) or high-boiling aromatic carbocyclic or heterocyclic compounds such as mesitylene. Preferred are DMPU and dimethylformamide.
• the process is in general carried out in a temperature range from 30 °C to 300 °C, preferably from 100 °C to 250 °C.
• the process is generally carried out at normal pressure. However, it is also possible to carry it out at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
• Suitable solvents are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofuran, acetone, dimethyl sulfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as dichlormethane, trichloromethane or tetrachloromethane. Dichloromethane is preferred.
• Suitable bases are generally inorganic or organic bases. These preferably include alkali metal hydroxides such as, for example, sodium hydroxide, sodium hydrogencarbonate or potassium hydroxide, alkaline earth metal hydroxides such as, for example, barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkaline metal or organic amines (trialkyl (Cj- ) amines) such as triethylamine, or N-methyl- or N-ethylmorpholine, or heterocycles such as 1,4- diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or amides such as sodium amides, lithium butyl amide or butyllithium, pyridine or methylpiperidine. Triethylamine, N-methylmorpholine or N-ethylmorpholine
• the process is in general carried out in a temperature range from -30°C to +100°C, preferably from -10 °C to +50 °C.
• the process is generally carried out at normal pressure. However, it is also possible to carry it out at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
• the base is employed in an amount from 1 mol to 10 mol, preferably from 1 mol to 4 mol, relative to 1 mol of the compounds of the general formula (Vila) or (Vllb).
• Suitable solvents are generally customary organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, dioxane or tetrahydrofuran acetone, dimethyl sulfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as dichlormethane, trichloromethane or tetrachloromethane. Dichloromethane is preferred.
• Suitable bases are generally inorganic or organic bases. These preferably include alkali metal hydroxides such as, for example, sodium hydroxide, sodium hydrogen carbonate or potassium hydroxide, alkaline earth metal hydroxides such as, for example, barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkaline metal or organic amines (trialkyl ( - ) amines) such as triethylamine, or N-methyl- or N-ethylmorpholine, or heterocycles such as 1,4- diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or amides such as sodium amides, lithium butyl amide or butyllithium, pyridine or methylpiperidine. Triethylamine, N-methylmorpholine or N-ethylmorpholine are
• the process is in general carried out in a temperature range from -30°C to +100°C, preferably from -10°C to +50°C.
• the process is generally carried out at normal pressure. However, it is also possible to carry it out at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
• the base is employed in an amount from 1 mol to 10 mol, preferably from 1.0 mol to 4 mol, relative to 1 mol of the compounds of the general formula (II) or (IX).
• R 8 , R 9 , R 10 , and R 11 have the above mentioned meaning, in presence of one of the above mentioned solvents, preferably dimethylformamide and DMPU at 190°C.
• D, E and R 21 have the above mentioned meaning, with compounds of the general formula (XI) in the system PyBOP, HOBt, NMM and DMF.
• the process is in general carried out in a temperature range from -30°C to +100°C, preferably from -10°C to +50°C.
• the process is generally carried out at normal pressure. However, it is also possible to carry it out at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
• 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).
• RPAR Reversed Passive Arthus Reaction
• 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.
• the efficacy of the compounds of the present invention in blocking cell fusion caused by a syncytial virus infection can be evaluated by the methods generally set forth in Tidwell, et al., J. Med. Chem. 26.. 294- 298 (1983).
• Inhibitory activities of the compounds of the invention against human tryptase may be determined as described below.
• the inhibitory activity against human tryptase was determined according to WO 9822619.
• Tryptase solution 60 g/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: 10 mM 2-N-morpholinoethane sulfonic acid, 2 mM CaCl 2 , 20% glycerol and 50 g/mL heparin.
• Substrate solution containing 2 mM synthetic tripeptide was obtained from Sigma.
• Test Compound solutions were prepared by diluting a stock solution (1 mg of test Compound in 200 ⁇ L of dimethyl sulfoxide (DMSO) by ten-fold into assay buffer (comprising: Tris-HCI (pH 8.2), 50 mM; NaCl, 100 mM; 0.05% polyoxyethylenesorbitan monolaurate O7ween-20: trade name); and zinc chloride, 150 ⁇ M) and then making seven additional three-fold dilutions into 10% DMSO in assay buffer.
• DMSO dimethyl sulfoxide
• the assay protocol for determination of inhibition in the absence of zinc is conducted under essentially equivalent assay conditions that described above, with the exception that the assay medium does not contain zinc chloride and is modified to 1 mM EDTA. Following these assay conditions none of the compounds of the invention showed inhibitory activity with Ki' values lower than 10 ⁇ M.
• the compounds of the invention were also tested for their inhibitory activity toward plasmin, trypsin and thrombin in the presence of 150 ⁇ M zinc chloride. Following these assay conditions the compounds of the invention showed inhibitory activities, which were at least 10 2 , typically 10 3 to 10 5 times greater than the inhibitory activity toward tryptase.
• One aspect of the model is that following an inhaled antigen challenge (Ascaris suum extract), there is an acute bronchoconstriction which peaks after 2-3 minutes and generally resolves within 60 minutes. 24 Hours later the primate airways have become hyperresponsive. This is measured by assessing the responsiveness of the lungs to an inhaled methacholine challenge. Furthermore, a bronchoalveolar lavage carried out at this time will show evidence of a large cellular influx, the predominant cell being the eosinophil.
• the treatments are administered prior to the antigen challenge, the route of administration and dosing regime will vary according to the type of compound being studied. Potential therapeutic compounds can be tested in this model to see whether they can prevent or reduce the increase in lung resistance, airway hyperresponsiveness and inflammatory cell influx into the airways.
• mice Male cynomolgus monkeys (Macaca fascicularis) were used in the development of this model. The animals were maintained at constant temperature and humidity, with a twelve hour light cycle. They were fed twice daily, except on an experimental day when food was withheld the night before the procedure. Water was available ad lib at all times.
• the endotracheal tube was connected to a Harvard Ventilator adjusted to deliver 30-35 breaths per minute. Airflow was measured by a Fleisch pneumotachograph and thoracic pressure was measured by a validyne pressure transducer (as the difference between the pressure at the distal end of the tube and room pressure). The pneumotachograph and validyne were connected to a pre-amplifier and then into an MI 2 respiratory analyzer. Using the primary signals of flow and pressure the analyzer computed airway resistance and compliance (as well as a number of other respiratory parameters). An initial measurement of 5-6 minutes was carried out to ensure the signals were steady and that the values for resistance and compliance were within recognized limits.
• Ascaris challenge Following this an inhalation challenge with Ascaris suum was carried out.
• the aerosol was delivered with a pressure driven Rainbow drop nebuliser (puritan- Bennett) connected to a Bird mark 7A respirator, set to deliver 15 breaths per minute.
• 30 Breaths of antigen were administered after which the acute bronchoconstriction was monitored for 15 min.
• the normal dose of antigen nebulised was a solution containing 1000 ⁇ g/ml of ascaris extract. However this dose of antigen could be titrated such that the increase in resistance should be in the range of 100-200% above baseline. If the bronchoconstriction is much higher then the inflammation induced may be too great to treat.
• Bronchoalveolar lavage A bronchoalveolar lavage was carried out both before the antigen challenge (giving a baseline reading) and again following the methacholine dose response curve 24 hours later.
• the distal end of a paediatric fibreoptic bronchoscope was liberally coated with xylocaine gel, and inserted down the endotracheal tube.
• the bronchoscope was guided past the carina into one side of the lung and onward into the distal lung until the tip of the bronchoscope was wedged in the bronchoalveolar region. Then 15 ml of normal saline at room temperature was instilled slowly down one channel of the bronchoscope followed by 2 - 3 ml of air to ensure complete emptying of the bronchoscope channel.
• the fluid was then slowly aspirated back into the syringe using gentle pressure and gentle movement of the tip of the bronchoscope.
• recovery volumes were greater than 60% of the instilled volume.
• the recovered volume was measured and put into a 15 ml falcon tube and stored on ice for subsequent treatment.
• the lavage fluid was centrifuged at 1100 rpm for 10 min at 4°C.
• the supernatant was pipetted off and frozen at -20°C for later analysis.
• the cell pellet was resuspended in Hanks Balanced Salt Solution (HBSS; calcium and magnesium-free) and aliquots were used for total cell counts (Coulter counter) and cell differential counts (Cytospin preparations).
• HBSS Hanks Balanced Salt Solution
• Methacholine dose response curves were carried out to assess the airway hyperresponsiveness. In the acute model, the hyperresponsiveness was assessed at +24 hour and compared to the responsiveness 7 days before treatment.
• An aerosol of phosphate buffered saline (PBS) was delivered using a nebuliser as above. The aerosol was administered for 15 breaths and then lung resistance was monitored for ten minutes. Methacholine (0.1 mg.ml' 1 , 15 breaths) was administered followed by another ten minutes monitoring. Successive doses of methacholine were administered with the dose increasing by a half-log at each step until either the lung resistance had doubled or the maximum dose of methacholine (100 mg.ml '1 ) had been administered. The baseline (zero%) resistance was taken as the resistance achieved following the PBS administration. The increase in lung resistance (%) and the methacholine doses were entered into a spreadsheet and the PC 10 o was calculated from a graph of dose against resistance.
• PBS phosphate buffered
• Results Acute bronchoconstriction; The peak increase in lung resistance in the 15 minutes following antigen challenge is compared for treatment versus control studies.
• Total cell count The total cell count (cells per ml of BAL fluid) at 0 hours is subtracted from the total cell count at +24 hr, to give a value representing cell influx following antigen challenge. This value is compared for the treatment study versus the control study.
• Total Eosinophils From a cytospin preparation the percentage of eosinophils in the lavage fluid can be measured. From this value and the total cell count we calculate the total eosinophil count. As for total cells, the difference between the 24 hr count and the time 0 hour count gives a measure of the eosinophil influx, and this influx is compared for the treatment study versus the control study.
• Each sheep serves as its own control. Body weights for these animals ranged from 20- 50 kilograms.
• the treatments are administered prior to the antigen challenge, the route of administration and dosing regime will vary according to the type of compound being studied.
• Airway hyper-responsiveness is expressed as PC W , the concentration of carbachol that causes a 400% increase in SRL; therefore, a decrease in PC 00 indicates hyperresponsiveness.
• tryptase inhibitors e.g. the preferred compound cis-1, 5-cyclooctylene bis[4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxylate] in WO 9609297
• tryptase inhibitors showed a poor bioavailability in rat, dog and other species after oral administration. Therefore, these compounds had been inappropriate for an oral treatment.
• the compounds of the invention surprisingly showed improved oral bioavailability in rats, dogs and primates. Pharmacokinetic Investigations Rat and Dog and Monkey
• Plasma proteins were precipitated with acetonitrile and a sample was centrifuged at 14000 rpm for 10 min. The supernatant was withdrawn and evaporated to dryness under a gentle stream of nitrogen in a 40°C water bath. The residue was dissolved acetonitrile: ammonium acetate buffer 1:1.
• Calibration samples Known amounts of the compounds were added to plasma from untreated animals and the samples were treated in the same way. Plasma concentrations were determined via LC/MS with Turbo Ion Spray.
• the invention provides compounds and compositions that are useful for the prevention and treatment of immunomediated inflammatory disorders in mammals such as human, farm animal or domestic pet, in particular those associated with the respiratory tract, including asthma and allergic rhinitis.
• the invention also relates to a method of treating a mammal such as a human, a farm animal, or a domestic pet, to achieve an effect, in which the effect is: prevention and treatment of diseases or pathological conditions including allergic conjunctivitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other athritic conditions, multiple sclerosis, interstitial cystitis, chronic obstructive pulmonary disease including chronic bronchitis and emphysema, skin diseases such as urticaria, allergic dermatitis, atopic dermatitis, bullous pemphigoid, psoriasis, and scleroderma; pulmonary fibrosis, interstitial pneumonia, nephritis, hepatic fibrosis, hepatitis, hepatic cirrhosis, Crohn's disease, ulcerative colitis, nasal allergy, peptic ulcers
• Influenza virus Sendai virus, human immunodefidiency virus, syncytial virus), ocular allergy (including atopic, vernal and giant papillary keratoconjunctivitis, contact blepharoconjunctivitis), inflammatory bowel disease, allergic contact dermatitis, emphysema, adult respiratory distress syndrome, bladder diseases, wound healing, bronchiectasis, pathological conditions associated with hype ⁇ lasia; angina, fibrotic diseases such as fibrotic lung disease, artherosclerosis, and cardiomyopathic disorders; diseases in which matrix metalloproteases are activated such as: chronic obstructive pulmonary disease including chronic bronchitis and emphysema; cystic fibrosis; bronchiectasis; adult respiratory distress syndrome (ARDS); allergic respiratory disease including allergic rhinitis; diseases linked to TNF ⁇ production including acute pulmonary fibrotic diseases, pulmonary sarcoidosis, silicosis, coal worker'
• enterotoxin A resulting from Staphylococcus infection, meningococcal infection, Borrelia burgdorferi infections, Treponema pallidum infections, cytomegalovirus infections, Influenza virus infections, Sendai virus infections, Theiler's encephalomyelitis, and human immunodeficiency virus infections; retardation of tumor metastasis; retardation of tumor growth or angiogenesis associated with tumor growth; retardation of degenerative cartilage loss following traumatic joint injury; reduction of pain; reduction of coronary thrombosis from atherosclerotic plaque rupture; improved birth control; or improved wound repair including that due to bums; the method comprising administering an amount of a compound of the invention as described above, and in more detail in the detailed description below, which is effective to inhibit the activity of at least one matrix metalloprotease, resulting in achievement of the desired effect.
• compositions containing the compounds of the invention can be administered for therapeutic and or prophylactic treatments.
• the 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.
• an amount is defined to be a "prophylactically effective amount of dose.”
• prophylactically effective amount of dose can be administered orally or by inhalation. In this use, the precise amounts again depend on the patient's state of health, weight, and the like.
• 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. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of the disease symptoms.
• a suitable effective dose of the compounds of the 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, REMINTON'S PHARMACEUTICAL SCIENSE AND THE MERCK INDEX 11th Ed., (Merck & Co. 1989).
• HOBt 1-hydroxy-benzotriazole
• example 4A (42.2g; 254mmol) and DMPU (l,3-dimethyltetrahydro-2(iH)- pyrimidone; 150ml) was stirred under- vacuum at 50°C for lh to remove residual gases and heated to 200°C (bath temperature) for 2h under argon in a distillation apparatus to remove the reaction water.
• the DMPU was evaporated in vacuo and the warm residue was dissolved in dichloromethane ' . After addition of water (500ml) the product crystallized and was collected by filtration. Further purification was achieved by heating a suspension of the crude product in refluxing dichloromethane/methanol (1:1, 1000ml) and filtration after cooling to room temperature, followed by heating of a product suspension in T ⁇ F/methanol (1:1,
• Cesium carbonate (61.1g; 187.4mmol) was added under argon to a solution of 4-fiuorophenol (10.5g; 93.7mmol) in DMF (150ml). After stirring for 15min a solution of l-bromo-2-(iV- rert-butyioxycarbonylamino)ethane (J. Org. Chem.53, 1988, 2226; 21. Og; 93.7mmol) in DMF (50ml was added dropwise at room temperature and stirring was. continued for 18h. Cesium carbonate was removed by filtration and the solvent was removed in vacuo.
• Example 27A 2-[(5-Benzyloxy-6-fluoro-lH-benzimidazol-2-yl)difluoromethyl]-N-[2-(4- fluorophenoxy)e yl]-3-me yl-3 ⁇ -ber ⁇ zi-- dazole-5-carboxamide.
• Tri-(o-tolyl)phosphine (0.1 lg; 0.36mmol) was added at room temperature under argon to a stirred suspension of tris-(dibenzylidenacetone)-dipalladium(0) (0.33g; 0.36mmol) in toluene
• Triethylamine(0.56 mL, 4.02 mmol) was added to a solution of /ert-butyloxypiperazine (500 mg, 2.68 mmol) in 3 mL of dichlorqmethane, then it was cooled to 0 °C.
• Benzenesulfonylchlor.de (0.39 mL, 3.22 mmol) was added to the solution and stirred for 3 hours. The solvent was evaporated in vacuo and the residue was washed with ether. The resulting white solid was filtrated and dried.
• Diethyl azodicarboxylate (0.883 mL, 5.609 mmol) and azidotrimethylsilane (0.744 mL, 5.609 mmol) were added, alternating 10 drops at a t ime, starting with diethyl azodicarboxylate.
• the mixture was warmed to 40 °C, stirred for 1 hour, and stirred at room temperature overnight
• the mixture was partitioned between ethyl, acetate and water, and the separated aqueous phase was extracted with ethyl acetate.
• the combined organic extracts were washed successively with saturated sodium bicarbonate, water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo.
• N-( / ⁇ .rt-butoxycarbonyl)-2-[2-[l-(2-cyanoethyl)-lH-tetrazol-5-yl]phenoxy]ethyIamine (0.976 g) was dissolved in 1,4-dioxane (2.0 mL), and treated with 4N HCI in 1,4-dioxane (5.0 mL).
• example 58A To a solution of example 58A (306 mg) in 1,4-dioxane (4 mL) was added 4N-hydrochloric acid in 1,4-dioxane (4 mL) at room temperature. The mixture was stirred at ambient temperature for 1 hour. A large volume of diethyl ether was poured into the reaction mixture until a white precipitate was observed. The precipitate was collected by filtration, washed with diethyl ether and dried. Yield 115 mg (26% yield in 2 steps from example 56 A), white solid
• Example 77A a-Methyl-Z ⁇ . ⁇ .y-trifluoro-IH-benzimidazol ⁇ -yl-rnethy -SH-benzimidazole-S- carboxylic acid
• example 10A (0.75g; 2.91 mmol), example 4A (0.51 g; 3.05mmol) and DMPU (1,3-dimethyltetrahydro-2( ⁇ H)-pyrimidone; 2.5ml) was stirred under vacuum at 50°C for 2h to remove residual gases and heated to 200°C (bath temperature) for 1h under argon in a distillation apparatus to remove the reaction water.
• the DMPU was evaporated in vacuo and the warm residue was taken up in dichloromethane and stirred at room temperature for 2h. The product was collected by filtration and dried in vacuo. Yield: LOOg (96% of theory); grey crystalline solid
• Example 5 2-[(6-Fluoro-5-hydroxy-lH-be ⁇ -zimidazol-2-yl)difluoromethyl]-N-[2-(4- fluorophenoxy)ethyl]-3-me yl-3H-be ⁇ - 2 imidazol-5-carboxamide.
• example 11A (0.70g; 1.87mmol) in dichloromethane (20ml) was added under Argon at -10°C triethylamine (0.38g; 3.74mmol), l-(4-fluorophenyl)pi ⁇ erazine (0.34g; 1.87mmol) andN-(3-dimemylammopropyl)-N'-ethylcarbodiimide hydrochloride (0.39g; 2.06mmol). The mixture was allowed to warm to room temperature and stirring was continued for 15h. The mixture was diluted with dichloromethane and washed with water (50ml), sat. aq. NaHCO j solution (2 x 50ml), water (50ml), dried over Na 2 SO 4 , and evaporated in vacuo. The residue was purified as described above in method A. Yield: 0.67g (67% of theory), white crystals
• Example 12 5.[4-(2-cyanophenyl)piperazin-l-ylcarbonyl]-3-methyl-2-[l-(4,5,7-trifluoro-lH- benzimidazol-2-yl)ethyl]-3H-benzimidazole
• Example 20 5-.[4 ⁇ 4-Fl uor ophenyl)pipe-a----n-l-ylcarbonyl]-3-isopropyl-2-[l-(4,5,7-trifluoro-lH- ben-dmidazol-2-yl)ethyl-3H-ben-ri ⁇ udazole
• example 8A (1.00 g, 3.67 mmol) and example 37A (1.38 g, 3.67 mmol) and DMPU (2 mL) was stirred ' under vacuum at 50°C for lh to remove residual gases and heated to 190 °C for 16 hours. After cooled to room temperature, the mixture was diluted with ca.150 mL of ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried, and concentrated. Silica gel column chromatography (ethyl acetate eluent) followed by crystallization from chloroform / diisopropyl ether to afford a white solid, that was recrystallized from chloroform/n-hexane. Yield 520 mg (24% of theory), colorless solid.

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