EP1073624A1 - Derives d'ester aminomethyl benzoique utilises comme inhibiteurs de la tryptase - Google Patents

Derives d'ester aminomethyl benzoique utilises comme inhibiteurs de la tryptase

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Publication number
EP1073624A1
EP1073624A1 EP99918168A EP99918168A EP1073624A1 EP 1073624 A1 EP1073624 A1 EP 1073624A1 EP 99918168 A EP99918168 A EP 99918168A EP 99918168 A EP99918168 A EP 99918168A EP 1073624 A1 EP1073624 A1 EP 1073624A1
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EP
European Patent Office
Prior art keywords
gradient
tfa
acetonitrile
water
hplc
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP99918168A
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German (de)
English (en)
Inventor
Bohdan Waszkowycz
Sarah Elizabeth Lively
Martin James Harrison
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tularik Ltd
Original Assignee
Proteus Molecular Design Ltd
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Publication date
Priority claimed from GBGB9808813.1A external-priority patent/GB9808813D0/en
Priority claimed from GBGB9822432.2A external-priority patent/GB9822432D0/en
Application filed by Proteus Molecular Design Ltd filed Critical Proteus Molecular Design Ltd
Publication of EP1073624A1 publication Critical patent/EP1073624A1/fr
Withdrawn legal-status Critical Current

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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C235/52—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
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    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
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    • C07D295/182—Radicals derived from carboxylic acids
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Definitions

  • the invention relates to compounds for use m the treatment of mast cell mediated diseases such as asthma and other allergic and inflammatory conditions and to pharmaceutical compositions thereof and their use m the 5 treatment of the human or animal body, and m particular to compounds which are tryptase inhibitors.
  • asthma is a complex disease frequently characterised by progressive developments of hyper- responsiveness of the trachea and bronchi as a result of - 2 - chronic inflammation reactions which irritate the epithelium lining the airway and cause pathological thickening of the underlying tissues.
  • Leukocytes and mast cells are present in the epithelium and smooth muscle tissue of the bronchi where they are activated initially by binding of specific inhaled antigens to IgE receptors. Activated mast cells release a number of preformed or primary chemical mediators of the inflammatory response in asthma as well as enzymes. Moreover, secondary mediators of inflammation are generated by enzymatic reactions of activated mast cells and a number of large molecules are released by degranulation of mast cells.
  • bronchodilator drugs which causes airways to expand.
  • the most effective bronchodilators are the (3-adrenergic agonists which mimic the actions of adrenalin. These are widely used and are simply administered to the lungs by inhalers.
  • bronchoconstrictor drugs are primarily of use in short term symptomatic relief, and do not prevent asthma attacks nor deterioration of lung function over the long term.
  • Anti -inflammatory drugs such as cromoglycate and the corticosteroids are also widely used in asthma therapy.
  • Cromoglycate has anti -inflammatory activity and has been found to be extremely safe. Although such cromolyns have minimal side effects and are currently preferred for initial preventive therapy in children, it is well known that they are of limited efficacy.
  • corticosteroids in asthma therapy was a major advance since they are very effective anti- inflammatory agents, however, steroids are very powerful, broad spectrum anti -inflammatory agents and their potency and non-specificity means that they are seriously limited by adverse side effects. Localising steroid treatment to the lungs using inhaler technology has reduced side effects but the reduced systemic exposure following inhalation still results in some undesirable effects. Hence, there is a reluctance to use steroids early in the course of the disease. There therefore still remains a need for an alternative asthma therapy which is a safe, effective, anti -inflammatory or immunomodulatory agent which can be taken to treat chronic asthma.
  • Tryptase is the major secretory protease of human mast cells and is proposed to be involved in neuropeptide processing and tissue inflammation. Tryptase is one of a large number of serine protease enzymes which play a central role in the regulation of a wide variety of physiological processes including coagulation, fibrinolysis , fertilization, development, malignancy, neuromuscular patterning and inflammation. Although a large number of serine proteases have been widely investigated, tryptase still remains relatively unexplored.
  • Mature human tryptase is a glycosylated, heparin- - 4 - associated tetramer of catalytically active subunits. Its amino-acid structure appears to have no close counterpart among the other serine proteases which have been characterised. Tryptase is stored in mast cell secretory granules and after mast cell activation, human tryptase can be measured readily in a variety of biological fluids. For example, after anaphylaxis, tryptase appears in the blood stream where it is readily detectable for several hours. Tryptase also appears in samples of nasal and lung lavage fluid from atopic subjects challenged with specific antigen.
  • Tryptase has been implicated in a variety of biological processes, including degradation of vaso- dilating and bronchorelaxing neuropeptides thereby destroying potent bronchodilatory action and modulation of bronchial responsiveness to histamine. Accordingly, mast cell tryptase may increase bronchoconstriction in asthma by destroying bronchodilating peptides. Moreover, the ability of tryptase to activate prostromelysin and procollagenase suggests that tryptase also may be involved in tissue inflammation. Accordingly, tryptase has been proposed as a potentially important mediator in the development of inflammatory response in asthma and other inflammatory diseases.
  • tryptase inhibition may be of great value in the propylaxis and treatment of a variety of mast cell mediated conditions, such as asthma, particularly in the treatment of chronic, late stage inflammatory asthma .
  • mast cell mediated conditions such as asthma
  • tryptase inhibition may be of great value in the propylaxis and treatment of a variety of mast cell mediated conditions, such as asthma, particularly in the treatment of chronic, late stage inflammatory asthma .
  • a variety of peptide based compounds are suggested as potential inhibitors of the mast cell protease tryptase.
  • a tryptase inhibitor is provided by a polypeptide obtainable from the leech hirudo medi cinalis .
  • secretory leukocyte protease inhibitor (SLPI) and active fragments thereof have been found to inhibit the proteolytic activity of - 5 - tryptase .
  • Aminomethyl-benzoic ester derivatives have previously been employed in a variety of fields. In US 5,628,803 aminomethyl-benzoic ester derivatives have been used as fuel additives. In EP 0048433, FR 2500825 and 2500826 a number of aminomethyl-benzoic ester derivatives are suggested as being useful in anti- complement compositions. The compounds are also said to have strong anti-trypsin, anti-plasmin and anti- kallikrein activity. In Japanese Abstract No. 57095908. aminomethyl-benzoic ester derivatives are disclosed as potential anti -allergic compounds and in Acta. Pharm. Nord. 3(1) 31-40 (1991) water-soluble aminoalkylbenzoate esters are suggested as prodrugs .
  • ester derivatives are generally poorly stable in biological systems, leading to a very limited duration of action in a therapeutic drug, stability to chemical and enzymatic hydrolysis can be enhanced by modification of the nature of the ester and/or by addition of stabilising chemical moieties.
  • the aminomethyl-benzoic ester derivatives of the present invention may be substituted by a range of polar, in particular acidic, moieties that may yield a large increase in plasma stability.
  • the compound of the invention will be useful not only in the treatment and prophylaxis of asthma but also of other allergic and inflammatory conditions mediated by tryptase such as allergic rhinitis, skin conditions such as eczema, atopic dermatitis and urticaria, rheumtoid arthritis, conjunctivitis and inflammatory bowel disease.
  • tryptase such as allergic rhinitis, skin conditions such as eczema, atopic dermatitis and urticaria, rheumtoid arthritis, conjunctivitis and inflammatory bowel disease.
  • the invention provides the use of a tryptase inhibitor of formula I
  • R represents hydrogen, alkyl, alkenyl, hydroxy, alkoxy, aminoalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, amino, halo, cyano, nitro, thiol, alkylthio, haloalkoxy or haloalkyl;
  • Ar represents an optionally substituted carbocyclic or heterocyclic aryl group with the proviso that when Ar represents a naphthyl moiety it is not substituted by amidino or guanidine;
  • Y represents a hydrogen atom or alkyl group; or a physiologically tolerable salt thereof, e.g. a halide, phosphate, sulphate, or trifluoroacetate salt or salt with ammonium or an organic amine such as ethylamine or meglumine; in the manufacture of a medicament for use in a method of treatment of the human or non-human animal body to combat a condition responsive to said inhibitor.
  • carbocyclic aryl groups preferably contain 5 to - 7 -
  • Heterocyclic aryl groups preferably contain 5 to 10 ring atoms including 1, 2 or 3 ring heteroatoms selected from oxygen, nitrogen and sulphur.
  • Alkyl or alkenyl groups preferably contain up to 10 carbon atoms, most preferably, up to 6 carbon atoms.
  • the substituent R is preferably a short chain alkyl, e.g. Cj_ 3 alkyl such as methyl but most preferably R represents hydrogen.
  • the substituent Y is preferably a short chain alkyl, e.g. C 1-3 alkyl such as methyl but most preferably Y represents hydrogen.
  • Ar groups include optionally substituted phenyl , optionally substituted naphthyl, optionally substituted pyridyl, optionally substituted quinolyl, and optionally substituted isoquinolyl. These groups should preferably carry at least one polar, especially acidic or protected acidic substituent.
  • the substituent on the carbocyclic or heterocyclic aryl group should not be strongly basic, i.e. ArH must be less basic than benzylamine. This ensures that the compounds of the invention bind more efficiently in the tryptase active site, thus maintaining selectivity.
  • Ar represents a phenyl derivative
  • the phenyl may be substituted by one or more substituents selected from: halo, for example fluoro, chloro, bromo or iodo, methylenedioxy, -R 1 , -NR ⁇ OR 2 , C 2 _ 6 -alkenyl , -(CH 2 ) w -OR 1 ,
  • R 1 and/or R 2 are also optionally substituted with -(CH 2 ) compassion- C00R 1 , - (CH 2 ) w -CH(NHC0R 1 ) -C00R 2 , - (CH 2 ) W -CH (NR*R 2 ) -C00R 1 , - (CH 2 ) w -CONH-S0 2 -R ⁇ - (CH ⁇ -SCANHCO-R 1 , - (CH 2 ) w -tetrazole, - (CH 2 ) W -S (0) r -R 1 , or - (CH 2 ) w -P(0) 2 .
  • the substituent will comprise an electron withdrawing group and/or at least one polar moiety, most preferably an acidic or a protected form of an acidic moiety.
  • Preferred electron withdrawing groups include cyano, nitro, carboxamido, alkylsulfenyl , alkylsulfonyl , alkylaminosulfonyl , sulphonylaminoalkyl , trifluoromethyl , or halogen, and most preferably where the substituent is an electron withdrawing group the substituent will be on the 2 or 4 -position of the phenyl group .
  • the presence of at least one polar moiety provides enhanced biological stability.
  • Preferred acidic groups include alkyl or aryl carboxylic acids and esters, acyl sulphonamide, sulphonylamidocarboxyalkyl , carboxyamidosulphonylalkyl , tetrazole, sulphonic acid or phosphonic acid each bonded to the Ar ring directly or via an alkyl, sulphonamidoalkyl or carboxamidoalkyl linkage, the linkage itself being optionally substituted by small polar or apolar groups such as Cj_ 4 alkyl, NH 2 , CN, N0 2 , NHCO-alkyl, or halogen.
  • the acidic subsitutent will preferably be on the para position of the phenyl ring. In another preferred embodiment an acidic substituent is present on the ortho position of the pheny
  • Ar represents a naphthyl derivative
  • the naphthyl may be substituted by one or more substituents selected from the same group as those as listed for phenyl above.
  • substituents are cyano, nitro, carboxamido, alkyla inosulfonyl , alkylsulfonyl , alkylsulfenyl, sulphonylaminoalkyl or trifluoromethyl or as for phenyl above naphthyl may be substituted by at least one polar moiety, most preferably an acidic or a protected form of an acidic moiety, such as alkyl or aryl carboxylic acids and esters, acyl sulphonamide, sulphonylamidocarboxyalkyl , carboxyamidosulphonylalkyl , tetrazole, sulphonic acid or phosphonic acid each bonded to the Ar ring directly or via an alkyl, sulphonamido
  • aromatic heterocyclic groups include pyridyl, quinolyl, isoquinolyl, imidazolyl, indolinyl, pyrazolinyl, pyrrolidinyl, imidazolidinyl , isoindolinyl , pyrazolidinyl, furyl , pyrolyl, pyrazinyl, benzothienyl , thienyl and benzofuryl .
  • Particularly prefered heterocyclic groups are quinolyl, especially, 6 -quinolyl and pyridyl, especially 3 -pyridyl.
  • Suitable Ar groups therefore include (for convenience hydrogen atoms have been missed out) :
  • the salt is preferably a hydrochloride or other physiologically tolerated salt.
  • R and Y are as hereinbefore defined; and Z represents a phenyl group substituted by methylenedioxy, -NR x COR 2 , C 2 . 6 -alkenyl , -(CH 2 ) w -OR 1 , - (CA 6 ) -perfluoroalkyl, -(CH 2 ) W CN, -(CH 2 ) w N0 2 , -(CH 2 ) W CF 3 , -
  • R 1 and/or R 2 are also optionally substituted with -(CH 2 ) W - COOR 1 , - (CH 2 ) w -CH(NHCOR 1 ) -COOR 2 , - (CH 2 ) W -CH (NR X R 2 ) -COOR 1 , - (CH 2 ) w -CONH-S0 2 -R 1 , - (CH 2 ) w -S0 2 -NHCO-R 1 , - (CH 2 ) w -tetrazole, - (CH 2 ) w -S(0) r -R 1 , or - (CH 2 ) W -P (0) z ⁇ -R 1 ; where R 3 is an oligomer comprising 1-4 aminoacid monomers, such as the natural aminoacids
  • Z represents a naphthyl group substituted by halo, - 13 - for example fluoro, chloro, bromo or iodo, methylenedioxy, -R 1 , -NR ⁇ OR 2 , C 2 . 6 -alkenyl , -(CH 2 ) w -OR 1 ,
  • R 1 and R 2 independently represent H, C ⁇ g alkyl, C 3-7 cycloalkyl, or -(CH 2 ) W -Ph, or R 1 and R 2 are optionally connected by a bond to form a 5- 8 atom cyclic structure (eg.
  • ZH should be less basic than benzylamine. This ensures that the compounds of the invention bind more efficiently in the tryptase active site.
  • R is preferably a short chain alkyl, e.g. C 1-3 alkyl such as methyl but most preferably R represents hydrogen.
  • Y is preferably a short chain alkyl, e.g. C,_ 3 alkyl such as methyl but most preferably Y represents hydrogen and wherever possible Z represents a preferred substituent Ar as defined above.
  • the invention provides a tryptase inhibitor of formula (II) for use in combatting a condition responsive to said inhibitor.
  • a pharmaceutical composition comprising a compound of formula (II) , together with at least one pharmaceutically acceptable excipient .
  • the compounds of the invention may be prepared by conventional chemical synthetic routes, e.g. by ester bond formation to couple the Ar-OH compound to the aminomethylbenzoic acid derivative.
  • the readily available starting material 4- aminomethyl-benzoic acid can be utilised. Prior to esterification the amino group should be protected by any appropriate protecting group e.g. Boc, Z, Fmoc or Bpoc .
  • protecting groups e.g. Boc, Z, Fmoc or Bpoc .
  • the use of protecting groups is described in McOmie, "Protective Groups in Organic Chemistry", Plenum, 1973 and Greene, "Protective Groups in Organic Synthesis", Wiley Interscience, 1981.
  • the protected aminomethyl-benzoic acid can be simply coupled to a suitable Ar-OH derivative by conventional esterification techniques before deprotection is effected.
  • the protected aminomethyl-benzoic acid derivative can be activated by converison to its corresponding anhydride or acyl chloride, using conventional reagents, to facilitate esterification. If the aminomethyl-benzoic acid compound is to carry phenyl substituents these can be conveniently introduced prior to the esterification or protection step using conventional aromatic substitution chemistry.
  • a starting material could be employed which already carries the substituent R and the aminomethyl functionality introduced for example by reduction of a cyano group.
  • the Ar-OH alcohols are all readily available or prepared by the skilled chemist.
  • the compounds of the invention may be administered by any conventional route e.g. into the gastrointestinal - 15 - tract (e.g. rectally or orally), the nose, lungs, musculature or vasculature or transdermally .
  • the compounds may be administered by inhalation, orally, intravenously or topically to the skin or to the eye.
  • the compounds may be administered in any convenient administrative form e.g. tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g.
  • the composition will be suitable for inhalation via a nebulizer or inhalable spray, e.g. a metered dose inhaler or dry powder inhaler for the treatment of lung conditions such as asthma.
  • a nebulizer or inhalable spray e.g. a metered dose inhaler or dry powder inhaler for the treatment of lung conditions such as asthma.
  • the composition will be suitable for application to the skin or mucous membranes formulated as a cream, ointment or solution. Such compositions form a further aspect of the invention.
  • the dosage of the inhibitor compound of the invention will depend upon the nature and severity of the condition being treated, the administration route and the size and species of the patient. However, in general, quantities to be administered are from 0A to 1000 mgs per day, preferably, 1 to 100 mgs per day. Conveniently, a suitable dosage, e.g 20mgs, can be admnistered by inhalation three times daily.
  • the invention provides a method of treatment of human or non-human animal body (e.g. mammalian, avian or reptilian body) to combat a condition responsive to a tryptase inhibitor, said method comprising administering to said body an effective amount of a tryptase inhibitor according to the invention.
  • human or non-human animal body e.g. mammalian, avian or reptilian body
  • the tryptase inhibitors of the invention can be administered along with other - 16 - active ingredients suitable for use in treating asthma, for example beta-adrenoceptor agonists such as salbutamol or anti-inflammatory agents such as cortiosteroids e.g. beclamethasone or cromolyns. It is envisaged that the tryptase inhibitors of the invention and the other active ingredient may act synergistically together.
  • the compounds of the invention are administered in conjunction with corticosteroids to reduce the dose of the steriod hence minimising steriod associated side effects.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) , together with one or more anti-asthma agents together with at least one pharmaceutically acceptable excipient.
  • the compounds of the invention will be of use in combating mast cell mediated diseases such as asthma, allergic rhinitis, skin conditions such as eczema, atopic dermatitis and urticaria, rheumatoid arthritis, conjunctivitis and inflammatory bowel disease.
  • mast cell mediated diseases such as asthma, allergic rhinitis, skin conditions such as eczema, atopic dermatitis and urticaria, rheumatoid arthritis, conjunctivitis and inflammatory bowel disease.
  • a tryptase inhibitor will be primarily administered chronically as prophylaxis to prevent or diminish exacerbations of the disease. However, for some diseases a more acute relief of symptoms may also be achievable .
  • Flash column chromotography 1 was carried out using Merck silica gel Si60 (40-63mm, 230-400 mesh) .
  • H nmr (d 6 DMSO) 8.58 (3H, bs, NH 3 + ) ; 8.31-7.95 (4H, m, Ar) ; 7.85-7.30 (4H, m, Ar) ; 4.08 (2H, m, 4-CH 2 ).
  • M.S.TOF 273 (M+l) + .
  • Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 12.2 min.
  • Hplc Symmetry C8 , Gradient 2, water/acetonitrile/TFA) rt 9.9 min.
  • Example 5 4' -Chlorophenyl 4- (aminomethyl) benzoate hydrochloride salt l H nmr (d 6 DMSO) 8.59 (3H, bs, NH 3 + ) ; 8.25 (2H, m, 2-H, 6- H) ; 7.80 (2H, m, 3 ' -H, 5 ' -H) ; 7.59 (2H, m, 3-H, 5-H) ; 7.40 (2H, m, 2'-H, 6 ' -H) ; 4.20 (2H, bs , 4-CH 2 ).
  • Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 14.8 min.
  • Hplc (Symmetry C8 , Gradient 2, water/acetonitrile/TFA) rt 10.2 min.
  • Hplc Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 18.28min.
  • Hplc SymmetryC ⁇ , Gradient 2, - 20 - water/acetonitrile/TFA) rt 10.88min.
  • M.S. TOF 263 (M+l) + .
  • Hplc (Jupiter5 C18, Gradient 1, Water/acetonitrile/TFA) rt 14.71 min.
  • Hplc SymmetryC ⁇ Gradient 2, Water/acetonitrile/TFA) rt 11.29 min.
  • Hplc Jupiter5 Cl ⁇ , Gradient 1, water/acetonitrile/TFA) rt 17.64min.
  • Hplc SymmetryC ⁇ , Gradient 2, water/acetonitrile/TFA rt 10.75min.
  • Hplc (Jupiter5 Cl ⁇ , Gradient 1, water/acetonitrile/TFA) rt 17.6 min.
  • Hplc (Symmetry C ⁇ , Gradient 2, water/acetonitrile/TFA) rt 10.6 min.
  • Hplc (Jupiter5 C18, Gradient 1, Water/acetonitrile/TFA) rt 12.75 min.
  • Hplc (SymmetryC ⁇ Gradient 2, Water/acetonitrile/TFA) rt 10.00 min.
  • Hplc Jupiter5 Cl ⁇ , Gradient 1, water/acetonitrile/TFA) rt 15.57min.
  • Hplc SymmetryC ⁇ , Gradient 5, water/acetonitrile/TFA rt 8.65min
  • Hplc Jupiter5 Cl ⁇ , Gradient 1, water/acetonitrile/TFA) rt 16.82min.
  • Hplc SymmetryC ⁇ , Gradient 2, water/acetonitrile/TFA rt 10.4 ⁇ min.
  • Hplc Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 4.3min.
  • Hplc Symmetry C ⁇ , Gradient 3, water/acetonitrile/TFA rt 7.5 min.
  • Hplc Jupiter5 Cl ⁇ , Gradient 1, water/acetonitrile/TFA) rt 4.97min.
  • Hplc SymmetryC ⁇ , Gradient 5, water/acetonitrile/TFA rt 7.66min.
  • Hplc Jupiter5 Cl ⁇ , Gradient 1, water/acetonitrile/TFA) rt 3.77min.
  • Hplc SymmetryC ⁇ , Gradient 5, water/acetonitrile/TFA
  • Hplc Jupiter5 Cl ⁇ , Gradient 1, water/acetonitrile/TFA) rt 5.93min.
  • Hplc SymmetryC ⁇ , Gradient 5, water/acetonitrile/TFA rt 7.71min.
  • Example 55 O- [Methyl N-acetyl-L_tyrosinyl] 4- (aminomethyl) benzoate trifluoroacetate salt l n nmr (d 4 methanol) 8.22 (2H, d) ; 7.63 (2H, d) ; 7.31 (2H, d) ; 7.20 (2H, d) ; 4.72 (IH, m) ; 4.27 (2H, s) ; 3.69 (3H, S) ; 3.21 (3H, s) ; 3.21 (IH, dd) ; 3.01 (IH, dd) ; 2.92 (3H, s) .
  • H nmr (d 4 methanol) 8.28 (2H, d) ; 8.14 (2H, d) ; 7.69 (2H, d) ; 7.38 (2H, d) ; 4.27 (2H, s) .
  • Hplc Magneticellan C8, Gradient 5, Water/acetonitrile/TFA
  • LC-MS Magneticellan C18, Gradient 6, water/acetonitrile/TFA
  • Hplc Magneticellan C8, Gradient 5, Water/acetonitrile/TFA
  • LC-MS Magneticellan C18, Gradient 6, water/acetonitrile/TFA rt 2.07 min, 426 (M+l) + .
  • H nmr (d 4 methanol) 8.2 ⁇ (2H, d) ; 8.02 (2H, d) ; 7.68 (2H, d) ; 7.46 (2H, d) ; 4.27 (2H, s) .
  • Hplc Magneticellan C8, Gradient 5, Water/acetonitrile/TFA) rt ⁇ .70 min.
  • LC/MS Magneticellan Cl ⁇ Gradient 6, water/acetonitrile/TFA
  • H nmr (d 4 methanol) 8.29 (2H, d) ; 8.21 (2H, d) ; 7.96 (2H, d) ; 7.70 (2H, d) ; 7.58 (2H, d) ; 7.52 (2H, d) ; 4.29 (2H, s) ; 4.22 (2H, s) .
  • Hplc Magneticellan C8, Gradient 5, Water/acetonitrile/TFA
  • H nmr (d 4 methanol) 8.29 (2H, d) ; 7.69 (2H, d) ; 7.43 (IH, t) ; 7.24 (IH, d) ; 7.17-7.11 (2H, m) ; 4.73 (IH, dd) ; 4.29 (2H, s) ; 3.31 (IH, dd) ; 3.04 (IH, dd) ; 1.96 (3H, s) .
  • Hplc Magnellan C8, Gradient 5
  • H nmr (d 4 methanol) 8.30 (2H, d) ; 7.68 (2H, d) ; 7.51- 7.39 (2H, m) ; 7.36-7.26 (2H, m) ; 4.27 (2H, s) ; 3.82 (2H, s) ; 3.65 (2H, s) .
  • Hplc Magneticellan C8, Gradient 5, Water/acetonitrile/TFA) rt 6.42 min.
  • LC/MS Magneticellan Cl ⁇ Gradient 6, water/acetonitrile/TFA
  • H nmr (d 4 methanol) 8.29 (2H, d) ; 7.84 (IH, d) ; 7.68- 7.61 (3H, m) ; 7.39 (IH, d) ; 4.57 (IH, t); 4.27 (2H, s) ; 3.92 (IH, dd) ; 3.84 (IH, dd) .
  • Hplc Magneticellan C ⁇ ,
  • Tryptase assays were carried out at room temperature in 0.1 M phosphate buffer, 0.5 mg/ml heparin, pH 7.4 according to a method of Tapparelli et - 48 - al. (1993) J. Biol . Chem . 268., 4734-4741.
  • Purified human lung tryptase was purchased from Dr Andrew Walls, Immunopharmacology Group, Southampton General Hospital, Southampton, UK.
  • the chromogenic substrate for tryptase, S-2366 was purchased from Quadratech, Epsom, Surrey, UK.
  • K-nitroaniline was quantified by absorption at 405nm in 96 well microplates using a Dynatech MR 5000 reader (Dynex Ltd, Billingshurst , UK) .
  • K-, and Ki were calculated using SAS software.
  • a K-, value of 216 ⁇ M was determined for tryptase/S-2366.
  • Inhibitor stock solutions were prepared at 40 mM in Me 2 S0 and tested within the range lOOmM-lnM. Accuracy of K ⁇ measurements was confirmed by comparison with K values of a known inhibitor of tryptase. In agreement with published data, benzamidine inhibited tryptase with a K x value of 30 ⁇ M.
  • the tryptase pKi ' s of a number of the compounds of the invention are illustrated in Table 1 below. Also quoted are the trypsin pKi ' s of the compounds.
  • R and Y represent hydrogen in formula (I) .
  • the stability of compounds on incubation in human plasma 49 can be used to demonstrate the hydrolytic stability of the ester moiety towards the range of esterases and proteases normally present in plasma.
  • this assay is an informative measure of metabolic stability in the whole animal for compounds where ester hydrolysis is a major metabolic pathway.
  • R and Y represent hydrogen in formula (I) .

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Abstract

La présente invention concerne l'utilisation de composés de formule (I): dans laquelle R représente un hydrogène, un alkyle, un alkényle, un hydroxy, un alcoxy, un aminoalkyle, un hydroxyalkyle, un carboxyalkyle, un alcoxyalkyle, un amino, un halo, un cyano, un nitro, un thiol, un alkylthio, un haloalcoxy ou un haloalkyle; Ar représente un groupe carboxylique ou aryle hétérocyclique facultativement substitué à condition que lorsque Ar représente un fragment naphtyle, il ne soit pas substitué par un amidino ou une guanidine; et Y représente un atome d'hydrogène ou un groupe alkyle; ou de sels physiologiquement tolérables de ces composés, ces composés et leurs sels étant utilisés comme inhibiteurs de la tryptase.
EP99918168A 1998-04-24 1999-04-23 Derives d'ester aminomethyl benzoique utilises comme inhibiteurs de la tryptase Withdrawn EP1073624A1 (fr)

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GBGB9808813.1A GB9808813D0 (en) 1998-04-24 1998-04-24 Compounds
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GBGB9822432.2A GB9822432D0 (en) 1998-10-14 1998-10-14 Compounds
GB9822432 1998-10-14
PCT/GB1999/001263 WO1999055661A1 (fr) 1998-04-24 1999-04-23 Derives d'ester aminomethyl benzoique utilises comme inhibiteurs de la tryptase

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US7074934B2 (en) 2000-06-13 2006-07-11 Tularik Limited Serine protease inhibitors
GB0114185D0 (en) * 2001-06-12 2001-08-01 Protherics Molecular Design Lt Compounds
AR037097A1 (es) 2001-10-05 2004-10-20 Novartis Ag Compuestos acilsulfonamidas, composiciones farmaceuticas y el uso de dichos compuestos para la preparacion de un medicamento
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AU527371B2 (en) * 1980-09-16 1983-03-03 Torii & Co., Ltd. Amidine
JPS5795908A (en) * 1980-12-05 1982-06-15 Dai Ichi Seiyaku Co Ltd Antiallergic agent
US4490388A (en) * 1981-02-27 1984-12-25 Torii & Co., Ltd. Amidine compound and anticomplement agent comprising same
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