Classifications

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  • C07D213/00—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
  • C07D213/02—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
  • 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
  • C07D213/72—Nitrogen atoms
  • C07D213/73—Unsubstituted amino or imino radicals
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
  • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
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  • C07—ORGANIC CHEMISTRY
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  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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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
  • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/34—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by 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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  • 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
  • C07D211/40—Oxygen atoms
  • C07D211/44—Oxygen atoms attached in position 4
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  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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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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  • C07D213/02—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
  • 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
  • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/56—Amides
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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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  • C07D277/38—Nitrogen atoms
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  • C07D277/38—Nitrogen atoms
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  • C07D277/62—Benzothiazoles
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  • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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  • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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Definitions

• This invention relates to compounds which are inhibitors of the serine protease, tryptase, to pharmaceutical compositions thereof and to their use in the treatment of the human or animal body. More particularly it relates to compounds for use in the treatment of mast cell mediated diseases such as asthma and other allergic and inflammatory conditions, to pharmaceutical compositions thereof and to their use in the treatment of the human or animal body.
• bronchoconstriction i.e. the narrowing of the airways in the lungs
• inflammation in the lungs is an integral part of the development of the disease.
• asthma The inhalation of an allergen by an asthmatic generates a strong immune system response which triggers release of ' various inflammatory mediators, including histamine and leukotrienes from inflammatory cells.
• various inflammatory mediators including histamine and leukotrienes from inflammatory cells.
• These increase the permeability of the blood vessel walls, attract inflammatory cells into the tissues and contract the smooth muscle around the airways. As a result, fluid leaks from the blood and the tissues swell, further narrowing the airways.
• the inflammatory cells cause damage to the epithelial cells lining the airways exposing nerve endings which stimulates secretion of mucous as well as augmenting the inflammation by causing the release of neurokinins .
• asthma is a complex disease frequently characterised by progressive developments of hyper-responsiveness of the trachea and bronchi as a result of 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 drug which causes airways to expand.
• the most effective bronchodilators are the ⁇ - 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.
• 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- 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 where activation and degranulation of mast cells occur. Accordingly, mast cell tryptase inhibition may be of great value in the prophylaxis and treatment of a variety of mast cell mediated conditions.
• Mast cells can degranulate by both IgE-dependent and independent mechanisms thereby implicating tryptase in both atopic and non-atopic inflammatory conditions.
• Tryptase can activate proteases such as pro-urokinase and pro-MMP3 (pro-matrix metalloprotease 3, pro-stromelysin) , thereby indicating a pathological role in tissue inflammation and remodelling.
• tryptase can activate certain G-protein coupled receptors (eg PAR2) and induce neurogenic inflammation points to a broader physiological role, for example in modulating pain mechanisms.
• G-protein coupled receptors eg PAR2
• tryptase inhibitors may be beneficial in a broad range of diseases.
• asthma chronic obstructive pulmonary disease
• COPD chronic obstructive pulmonary disease
• pulmonary fibrotic diseases rhinitis; psoriasis; urticaria; dermatitis; arthritis; Crohn' s disease; colitis; angiogenesis; atherosclerosis; multiple sclerosis; interstitial cystitis; migraine headache; neurogenic inflammation and pain mechanisms; wound healing; cirrhosis of the liver; Kimura' s disease; pre-eclampsia; bleeding problems associated with menstruation and the menopause; cancer (particularly melanoma and tumour metastasis); pancreatitis; and certain viral infections (Yong, Exp.
• WO96/09297, W095/32945, WO94/20527 and US 5,525,623 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 medicinalis .
• secretory leukocyte protease inhibitor (SLPI) and active fragments thereof have been found to inhibit the proteolytic activity of tryptase.
• the compounds 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, psoriasis, atopic dermatitis and urticaria, rheumatoid arthritis, conjunctivitis, inflammatory bowel disease, neurogenic inflammation, atherosclerosis and cancer.
• tryptase such as allergic rhinitis, skin conditions such as eczema, psoriasis, atopic dermatitis and urticaria, rheumatoid arthritis, conjunctivitis, inflammatory bowel disease, neurogenic inflammation, atherosclerosis and cancer.
• the invention provides a tryptase inhibitor compound of formula (I)
• R 5 represents amino, hydroxy, aminomethyl, hydroxymethyl or hydrogen
• R Sa represents hydrogen or methyl
• R la represents hydrogen, (1-6C) alkyl or phenyl (1-6C) alkyl ;
• L is CO or CONR ld (CH 2 ) m in which m is 0 or 1 and R ld is hydrogen, (1-6C) alkyl or phenyl (1-6C) alkyl ;
• Cy represents cycloalkyl, piperidinyl, 3,4- methylenedioxyphenyl , furyl , thienyl , imidazolyl , oxazolyl , thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, naphthyl, indolyl , indanyl, 3 , 4-dihydrobenzofuryl, benzofuryl or benzo [b] thienyl group, optionally substituted by R 3a or R 3i X in which X A is a bond, O, NH, CH 2/ CO, CONH, NHCO
• R 5 preferably represents amino or hydrogen, more preferably hydrogen.
• R 6a preferably represents hydrogen.
• the alpha atom (*) preferably has the conformation that would result from construction from a D- ⁇ -aminoacid NH 2 - CH (Cy) -COOH where the NH 2 represents part of X-X.
• aryl groups preferably contain 5 to 10 ring atoms optionally including 1, 2 or 3 heteroatoms selected from O, ⁇ and S; alkyl, alkenyl or alkynyl groups or alkylene moieties preferably contain up to 6 carbons, e.g. C x _ 6 or C x _ 3 ; cyclic groups preferably have ring sizes of 3 to 8 atoms; and fused multicyclic groups preferably contain 8 to 16 ring atoms.
• R la is preferably hydrogen.
• the X moiety nearest to the alpha atom is an NH or 0 atom, most preferably an NH group.
• the X moiety alpha to the aromatic ring is preferably a carbon based group such as CH 2 or CO, preferably CO.
• a particularly preferred linker X-X is -CONH- .
• R ld hydrogen; for (1-6C) alkyl: methyl or ethyl; and for phenyl (1-6C) alkyl : benzyl or phenylethyl .
• R ld is preferably hydrogen.
• L examples of particular values for L are CO, CONH, CON(CH 3 ) and CONHCH 2 , more preferably CO, CONH or CON(CH 3 ) . It will be appreciated by those skilled in the art that a diverse range of organic groups are lipophilic, and that it is therefore impractical to define with precision each and every structure that may be incorporated into a serine protease inhibitor according to the invention.
• R le is preferably a hydrogen atom.
• the lipophilic group comprises an alkyl group
• this may be, for example, a (1-3C) alkyl group, such as methyl, ethyl or propyl .
• an alkyl group is unsubstituted.
• the lipophilic group comprises a carbocyclic group, this may be, for example, a non-aromatic or aromatic, mono or polycyclic hydrocarbon group containing up to 25, more preferably up to 10 carbon atoms.
• the carbocyclic group may thus be, for example, a cycloalkyl, polycycloalkyl, phenyl or naphthyl group, or a cycloalkyl group fused with a phenyl group .
• Examples of particular values for a cycloalkyl group are (3-6C) cycloalkyl groups, such as cyclopentyl and cyclohexyl .
• a cycloalkyl group is preferably unsubstituted or substituted by one group R 3 , preferably an amino or alkyl group.
• Examples of particular values for a polycycloalkyl group are (6-10C) polycycloalkyl groups, such as bicycloalkyl, for example decalinyl or norbornyl .
• a polycycloalkyl group is preferably unsubstituted or substituted by one, two or three R 3 groups, for example alkyl such as methyl.
• An example of a polycycloalkyl group substituted by alkyl is isopinocampheyl .
• a phenyl group is preferably unsubstituted or substituted by one or two R 3 groups .
• a naphthyl group is preferably unsubstituted or substituted by one R 3 group.
• Examples of a cycloalkyl or cycloalkenyl group fused with a phenyl group are indanyl and tetrahydronaphthyl .
• This group is preferably unsubstituted or substituted by oxo or one or two R 3 groups.
• Examples of groups substituted by oxo are 1- oxoindan-5-yl, 1-oxo-l, 2 , 3 , 4-tetrahydronaphth-7-yl and 1-oxo- 1,2,3, 4-tetrahydro-naphth-6-yl .
• the lipophilic group comprises a heterocyclic group
• this may be, for example, a non-aromatic or aromatic, mono or polycyclic group containing one or two oxygen, nitrogen or sulfur atoms in the ring system, and in total up to 25, more preferably up to 10 ring system atoms.
• Examples of a heterocyclic group when it is a non- aromatic monocyclic group are azacycloalkyl groups, such as pyrrolidinyl and piperidinyl ; azacycloalkenyl groups, such as pyrrolinyl; diazacycloalkyl groups, such as piperazinyl; oxacycloalkyl groups, such as tetrahydropyranyl ; oxaazacycloalkyl groups, such as morpholino; and thiacycloalkyl groups, such as tetrahydrothiopyranyl .
• a non- aromatic monocyclic group preferably contains 5, 6 or 7 ring atoms and is preferably unsubstituted or substituted by one group R 3 .
• heterocyclic group when it is a non- aromatic polycyclic group are bicyclic groups, such as azacycloalkyl fused with phenyl, for example dihydroindolyl , dihydroisoindolyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl ; azacycloalkyl fused with cycloalkyl, such as decahydroisoquinolinyl ; and thienyl fused with cycloalkyl, such as tetrahydrobenzo [b] thienyl or 4H- cyclopenta (b) thienyl .
• bicyclic groups such as azacycloalkyl fused with phenyl, for example dihydroindolyl , dihydroisoindolyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl ; azacycloalkyl
• Examples of thienyl fused with cycloalkyl are 4H-cyclohepta (b) thienyl and tetrahydro-4, 7- methanobenzo (b) thiophenyl .
• Further examples of bicyclic groups are thienyl fused with a heteracycloalkyl group, such as 4 , 5-dihydro-5H-thieno [2 , 3-c] pyranyl, 4 , 5-dihydro-5H- thieno [2 , 3-c] thiopyranyl and 4, 5, 6, 7-tetrahydrothieno [2 , 3- b] pyridinyl .
• heterocyclic group when it is an aromatic monocyclic group are furyl , pyrrolyl, thienyl, imidazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl , pyrazinyl and triazinyl, preferably unsubstituted or substituted by one or two R 3 groups .
• heterocyclic group when it is an aromatic polycyclic group examples include bicyclic groups such as benzofuryl, quinolinyl, isoquinolinyl, benzothienyl , indolyl and benzothiazolyl .
• Lp comprises a combination of at least two groups, it preferably comprises a combination of two or three such groups.
• R 3 are : - for an amino acid residue: N-acetylalaninoyl , serinoyl, threoninoyl, aspartoyl or glutamoyl; for N- (1-6C) alkylaminocarbonyl : ⁇ - (1, 3 -dimethyl) butylamino- carbonyl ; for ⁇ , ⁇ -di (1-6C) alkylaminocarbonyl : N-methyl-N- ethylaminocarbonyl ; for N- (1-6C) alkylamino (1-6C) alkanoyl : N-methylacetyl ; for N- (1-6C) alkanoylamino (1-6C) alkanonyl : 2 -
• R 3 Further examples of particular values for R 3 are : - for N- (1-6C) alkylaminocarbonyl : N-methylaminocarbonyl or N- isobutylaminocarbonyl; and for N,N-di (1-6C) alkylaminocarbonyl : N,N-dimethylaminocarbonyl or N,N-diethylaminocarbonyl .
• the lipophilic group is selected from
• R 3 is as hereinbefore defined; and X represents CH or N.
• L represents
• R 3 preferably represents hydrogen, hydroxyl or (1-6C) alkylaminocarbonyl.
• Lp in this sub-group examples include pyrrolidin-1-yl , piperidin-1-yl, N-methyl, N- ethylaminocarbonylpiperidin-1-yl, decahydroisoquinolin-2-yl and 2 , 3-dihydroindol-l-yl .
• L represents CONR ld (such as CONH or CONCH 3 ) and Lp represents
• each R 3 is preferably selected independently from hydrogen, amino, hydroxy, (1-6C) alkyl, (1- 6C) alkanoyl, (1-6C) alkanoyloxy, (1-5C) alkoxycarbonyl (1- 6C) alkyl, amino (1-6C) alkyl or cyano.
• values for R 3 in this group include hydrogen, amino, hydroxy, alkyl or aminoalkyl.
• L represents C0NR ld (such as CONH or C0NCH 3 ) and Lp represents
• R 3 is (1-6C) alkylaminocarbonyl , N- (1-6C) alkylamino (1-
• 6C)alkanoyl N- (1-6C) alkanoylamino (1-6C) alkanonyl , C- hydroxyamino (1-6C) alkanoyl, hydrogen, (1-6C) alkoxy, (1-
• 6C) alkyl amino (1-6C) alkyl, aminocarbonyl, hydroxy (1-6C) alkyl, (1-6C) alkoxy (1-6C) alkyl, (1-6C) alkoxycarbonyl, (1-
• the phenyl group is unsubstituted or substituted by one or two R 3 groups.
• R 3 groups are phenyl, 3-cyano-4- methylphenyl , 3 -aminocarbonylphenyl, 4-aminocarbonylphenyl, 4- chloro-3-aminocarbonylphenyl, 4-chlorophenyl, 3,5- dichlorophenyl , 3-aminomethylphenyl , 4-methyl-3- acetylaminophenyl, 4- (1-hydroxethyl) phenyl and 4- isopropylphenyl .
• L represents CONR ld (such as CONH or CONCH 3 ) and Lp represents
• the heterocyclic group is preferably substituted by one or two R 3 groups.
• Each R 3 group is preferably selected from hydrogen, halogen such as chlorine, (1-6C) alkyl, such as methyl, and (1-6C) alkoxy, such as methoxy.
• examples of particular values for Lp are: benzothiazol-2-yl, 4-chlorobenzothiazol-2-yl , 4-methylbenzo- thiazol-2-yl , 6-methylbenzothiazol-2-yl, 4-methoxybenzo- thiazol-2-yl and 5 , 6-dimethylbenzothiazol-2-yl .
• L represents CONR ld (such as CONH or C0NCH 3 ) and Lp represents
• R 3x represents R 3 or a group of formula
• R j represents a carbocyclic or heterocyclic group, optionally substituted by R 3 .
• R 3x represents R 3 or a group of formula -(CO) p -(G 1 )-R j
• G 1 represents (1-3C) alkanediyl or, when p is 1, a bond.
• Lp represents a group as described above, it corresponds to a group in which Lp is a combination of a heterocyclic group (2 , 3-dihydroindolyl) , a carbocyclic or heterocyclic group (R j ) and optionally an alkyl
• R j examples of particular values for R j are the examples given above for a carbocyclic or heterocyclic group forming part of Lp .
• G 1 examples of values for G 1 are a bond, -CH 2 -, CH 2 CH 2 a.nd.
• the 2 , 3-dihydroindolyl group in the above formula is preferably a 2 , 3-dihydroindol-5-yl or -6-yl group, especially a 2, 3-dihydroindol-6-yl group.
• example is ethyl.
• examples of particular values for Lp are: 1- (N-methylaminoacetyl) -2 , 3-dihydroindol-6-yl ; 1- (N- acetylaminoacetyl) -2, 3-dihydroindol-6-yl; 1- (N- acetylaminopropanoyl) -2 , 3-dihydroindol-6-yl; 1-N- (2- methylpropanoyl) aminoacetyl) -2 , 3-dihydroindol-6-yl ; 1- (N- acetylalaninoyl) -2, 3-dihydroindol-6-yl ; 1- (serinoyl) -2,3- dihydroindol-6-yl; 1- (threoninoyl) -2 , 3-dihydroindol-6-yl ; 1- (aspartoyl) -2 , 3-dihydrool
• R 3 is a substituent on a cyclohexyl, phenyl, naphthyl, thiazolyl, imidazolyl, pyridyl or quinolinyl group, it is preferably hydrogen, hydroxy, amino, alkanoylamino, alkyl, aminoalkyl or alkanoylaminoalkyl . Examples of particular values are hydrogen, hydroxy, amino, formylamino, isopropyl, aminomethyl and acetylaminomethyl .
• Lp further examples of particular values for Lp are: 2 , 3-dihydroindol-5-yl, 1- (2-aminocyclohexyl) -carbonyl- 2, 3-dihydroindol-6-yl, 1- (4-aminocyclohexyl) -acetyl-2, 3- dihydroindol-6-yl, 1-prolinoyl-2 , 3-dihydroindol-6-yl , 1- pyrrolidin-2-ylacetyl-2, 3-dihydroindol-6-yl, l-piperidin-3 - ylcarbonyl-2, 3-dihydroindol-6-yl, l-piperidin-3 -ylacetyl-2 , 3- dihydroindol-6-yl, l-phenylacetyl-2 , 3-dihydroindol-6-yl, l-(2- hydroxy)phenylacetyl-2,
• R 3y represents R 3 or a group of formula
• Lp represents a group as described above, it corresponds to a group in which Lp is a combination of a heterocyclic group (tetrahydrobenzothienyl) , a carbocyclic or heterocyclic group (R k ) and optionally an
• alkyl group (G 2 ) which groups are linked by a single bond, or a CO, OCO, COO or NHCO group.
• R k examples of particular values for R k are the examples given above for a carbocyclic or heterocyclic group forming part of Lp.
• diazacycloalkyl such as piperazin-1-yl ; furyl, such as fur-2- yl; thienyl, such as thien-2-yl; pyrrolidin-1-yl and pyrid-2 - yl.
• G 2 examples of values for G 2 are a bond, -CH 2 -, and CH 2 CH 2 .
• R 3 is present as a substituent on the 1-position of a piperazinyl group, it is preferably hydrogen, (1-6C) alkanoyl, such as formyl , or (1-6C) alkoxycarbonyl, such as ethoxycarbonyl .
• R 3 is present as a substituent on a piperidin-1-yl group, it is preferably at the 3- or 4-position and is preferably hydrogen, (1-6C) alkyl, such as methyl; amido or (1- 6C) alkoxycarbonyl, such as ethoxycarbonyl.
• R 3 When R 3 is present as a substituent at the 3 -position of a 4, 5, 6, 7-tetrahydrobenzothiophene group, it preferably represents a carboxy group; a (1-6C) alkoxycarbonyl group, such as methoxycarbonyl or ethoxycarbonyl; or a (1- 6C) alkylaminocarbonyl group, such as N-1, 3- dimethylbutylaminocarbonyl .
• Other examples of values for a (1-6C) alkylamincarbonyl group are methylaminocarbonyl and isobutylaminocarbonyl .
• examples of particular values for Lp are: 3- carboxy-4, 5,6, 7-tetrahydrobenzothien-2-yl, 3-ethoxy-carbonyl- 4, 5, 6, 7-tetrahydrobenzothien-2-yl and 3-N-(2,3- dimethylbutylaminocarbonyl-4, 5,6, 7-tetrahydrobenzothien-2-yl .
• Further examples are 3-N-methylaminocarbonyl-4 , 5 , 6 , 7- tetrahydrobenzothien-2-yl and 3-N-isobutylaminocarbonyl- 4,5,6, 7-tetrahydrobenzothien-2-yl .
• R 3 when it is present as a substituent at the 3-position of a , 5, 6, 7-tetrahydrobenzothiophene group are N,N-dialkylaminocarbonyl , such as dimethylaminocarbonyl or diethylaminocarbonyl; amido; (1-6C) alkoxycarbonyl, such a s methoxycarbonyl or ethoxycarbonyl; cyano and (1- 6C) alkylsulfonyl, such as methylsulfonyl .
• Lp are 3-N,N- dimethylaminocarbonyl-4, 5,6, 7-tetrahydrobenzothien-2-yl, 3- N,N-diethylaminocarbonyl-4, 5,6, 7-tetrahydrobenzothien-2-yl , 3- ethoxycarbonyl-4 ,5,6, 7-tetrahydrobenzothien-2-yl , 3 -amido- 4,5,6, 7-tetrahydrobenzothien-2-yl, 3-methylsulfonyl-4 , 5,6,7- tetrahydrobenzothien-2-yl, 3-cyano-4 , 5 , 6, 7- tetrahydrobenzothien-2-yl and 3-ethoxycarbonyl-4H- cyclopenta (b) thienyl .
• R 3 is present as a substituent on a phenyl or pyridyl group, it is preferably a hydrogen atom.
• Lp examples of particular values for Lp are: 3- benzyloxycarbonyl-4, 5,6, 7-tetrahydrobenzothien-2-yl, 3- benzylaminocarbonyl-4, 5, 6, 7-tetrahydrobenzothien-2-yl , 3- (3- pyridyl)methylaminocarbonyl-4, 5, 6, 7-tetrahydro-benzothien-2- yl , 3-cyclopropylmethylaminocarbonyl-4 ,5,6,7- tetrahydrobenzothien-2-yl, 3-morpholinocarbonyl-4, 5, 6, 7- tetrahydrobenzothien-2-yl and 3-piperidinocarbonyl-4 , 5, 6 , 7- tetrahydrobenzothien-2-yl .
• R 3 is present as a substituent at the 4,5,6 and/or 7 position of a 4 , 5, 6, 7-tetrahydrobenzothien-2-yl group or the 4,5 and/or 6 position of a 4H-cyclopenta) b) thienyl group, it is preferably a hydrogen atom or a (1-6C) alkyl group, such as methyl .
• Examples of particlar values for Lp are accordingly 3- ethoxycarbonyl-4-methyl-4 ,5,6, 7-tetrahydrobenzothien-2-yl , 3- ethoxycarbonyl-5-methyl-4 ,5,6, 7-tetrahydrobenzothien-2-yl and 3 -ethoxycarbonyl-6-methyl-4, 5,6, 7-tetrahydrobenzothien-2-yl .
• L represents CONR ld (such as CONH or CONCH 3 ) and Lp represents
• R 3y is as defined hereinabove
• X z is 0, S or NR Z in which R z is independently selected from one of the values for R 3y
• X za is CH 2 or is as defined for X z .
• R 3y examples of particular values for R 3y are (1- 6C) alkoxycarbonyl, such as ethoxycarbonyl, N,N- dialkylaminocarbonyl, such as N,N-dimethylaminocarbonyl, and cyano .
• R 3 is preferably hydrogen.
• R z is preferably hydrogen, (1-6C) alkanoyl, amino (1- 6C) alkanoyl or benzyloxycarbonyl .
• Examples of particular values for R z are hydrogen, acetyl, aminoacetyl and benzyloxycarbonyl .
• examples of particular values for Lp are: 3-ethoxycarbonyl-tetrahydro-4H-cyclohepta (b) thien-2-yl , 3- ethoxycarbonyl-4, 5-dihydro-5H-thieno [2, 3-c] pyranyl, 3- ethoxycarbonyl-4 , 5-dihydro-5H-thieno [2 , 3-c] thiopyranyl, 3- dimethylamido-6-benzyloxycarbonyltetrahydrothieno [2,3- b]pyridin-2-yl, 3 -dimethylamido-tetrahydrothieno [2 , 3- b] pyridin-2-yl, 3-dimethylamido-6-acetyltetrahydrothieno [2,3- b]pyridin-2-yl, 3 -dimethylamido-6-aminoacetyltetrahydrothieno- [2 , 3-b]
• the cyclic group attached to the alpha carbon is preferably cyclohexyl, piperidin-4-yl , 3 , 4-methylenedioxy- phenyl , fur-2-yl, thien-2-yl, thien-3-yl, imidazol-4-yl , oxazol-4-yl, oxazol-5-yl, thiazol-4-yl, thiazol-5-yl, pyrid-2- yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-2-yl , pyrimidin-4-yl , pyrimidin-5-yl, pyrazin-2-yl , pyrazin-3-yl , naphth-1-yl, naphth-2-yl, indol-5-yl, indan-5-yl, 3 , 4-dihydrobenzofur-5-yl, benzofur-2-yl or benzo [b]
• R3 a examples of particular values for R3 a are : - hydrogen; hydroxyl; for (1- ⁇ C) alkoxy : methoxy, ethoxy or isopropoxy; for (1- ⁇ C) alkyl: methyl, ethyl or isopropyl; for: (1-6C) alkanoyl: acetyl, propanoyl or isopropanoyl, for (1-6C) alkylaminoalkyl: methylartiinomethyl or dimethyla inomethyl ; for (1- ⁇ C) hydroxyalkyl: hydroxymethyl carboxy; for (1- ⁇ C) alkoxyalkyl: methoxymethyl; for (1-6C) alkoxycarbonyl: methoxycarbonyl or ethoxycarbonyl; for (1- ⁇ C) alkylaminocarbonyl: methylaminocarbonyl or dimethylaminocarbonyl ; for (1- ⁇ C) aminoalkyl: aminomethyl;
• 6C) alkylaminoacetyl such as methylaminoacetyl; for di (1-6C) alkylamino (1-6C) alkanoylamino: dimethyla inoacetylamino; for (1-6C) alkoxycarbonylamino: methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino; amino ; for halo: fluoro or chloro; cyano ; nitro; thiol; for (1- ⁇ C) alkylthio: methylthio; for (1-6C) alkylsulphonyl: methylsulphonyl or ethylsulphonyl; for (1-6C) alkylsulphenyl: methylsulphenyl; for imidazolyl: imidazol-4-yl; hydrazido; for (1- ⁇ C) alkylimidazolyl : 2-methylimidazol-4-yl; for
• R 3i is phenyl.
• 3i Xi is phenyl, phenoxy, phenylamino and benzyl .
• Cy is preferably unsubstituted or substituted by one or two R3 a groups.
• R3 a is hydrogen, hydroxyl, methyl, ethyl, isopropyl, acetyl, propanoyl, isopropanoyl, isopropoxy, amino, aminomethyl, hydroxymethyl, carboxy, amido, formylamino, acetylamino, aminoacetyl or carboxy.
• Cy examples of particular values for Cy are cyclohexyl, piperidin-4-yl, l-acetylpiperidin-4-yl, 1-propanoylpiperidin- 4-yl, l-isobutyrylpiperidin-4-yl, l-aminoacetylpiperidin-4-yl , 5-methylfur-2 -yl, imidazol-4-yl, 2-methylthiazol-4-yl , 2- aminothiazol-4-yl, 2-formylaminothiazol-4-yl , 2-aminothiazol- 5-yl, 2-formylaminothiazol-5-yl, 2-phenylthiazol-4-yl , 4- aminopyrid-3-yl, 6-methylpyrid-2-yl , 3-amino-pyrid-4-yl , naphth-1-yl, naphth-2-yl, benzofur-2-yl or 3-methylbenzothien- 2-yl.
• Cy 6- aminopyrid-3-yl, 2-ethylthiazol-4-yl , 2-benzylthiazol-4-yl , 2- methylsulfonamidothiazol-4-yl , 2-chloropyrid-3-yl , 2- hydroxyacetylaminothiazol-4-yl, 2-N,N-dimethylaminoacetyl- aminothiazol-4-yl, indol-5-yl, indan-5-yl and 3,4- dihydrobenzofur-2-yl .
• the cyclic group attached to the alpha carbon is cycloalkyl (such as cyclohexyl) , piperidinyl (such as piperidin-4-yl) , 3 , 4-methylenedioxy- phenyl, furyl (such as fur-2-yl) , thienyl (such as thien-2-yl or thien-3-yl) , imidazolyl (such as imidazol-4-yl) , thiazolyl (such as thiazol-4-yl or thiazol-5-yl) , pyridyl (such as pyrid-2-yl, pyrid-3-yl or pyrid-4-yl) , naphthyl (such as naphth-1-yl or naphth-2-yl) , benzofuryl (such as benzofur-2- yl) , benzo [b] thienyl (such as benzo [b] thieny
• examples of values for R 3a are hydrogen; hydroxyl; methoxy; ethoxy; isopropoxy; methyl; ethyl; isopropyl; acetyl; propanoyl; isopropanoyl; methylaminomethyl; dimethylartiinomethyl; hydroxymethyl ; carboxy; methoxymethyl; methoxycarbonyl; ethoxycarbonyl; methylaminocarbonyl; dimethylaminocarbonyl; aminomethyl;
• Cy in this group examples are cyclohexyl, piperidin-4-yl , l-acetylpiperidin-4-yl , 1- propanoylpiperidin-4-yl, l-isobutyrylpiperidin-4-yl, 1- aminoacetylpiperidin-4-yl, 3 , -methylenedioxyphenyl, 5- methylfur-2 -yl, imidazol-4-yl, 2-methylthiazol-4-yl, 2- aminothiazol-4-yl, 2-formylaminothiazol-4-yl , 2-aminothiazol- 5-yl, 2-formylaminothiazol-5-yl, 2-phenylthiazol-4-yl, 4- aminopyrid-3-yl , 6-methylpyrid-2-yl , 3-aminopyrid-4-yl , naphth-1-yl, naphth-2-yl, benzofur-2-yl and 3- methylbenzo
• the cyclic group attached to the alpha carbon is an optionally R 3a substituted cycloalkyl (such as cyclohexyl) , piperidinyl (such as piperidin-4-yl) , thienyl (such as thien-2-yl or thien-3-yl) , thiazolyl (such as thiazol-4-yl or thiazol-5-yl) , pyridyl (such as pyrid-3-yl or pyrid-4-yl) or naphthyl (such as naphth-1-yl) group and each R 3a independently is hydrogen, hydroxyl, (1-6C) alkoxy, (1-6C) alkyl, (1-6C) alkylaminoalkyl, hydroxy (1-6C) alkyl, (1-6C) alkoxyalkyl, (1-6C) alkoxycarbonyl, (1-6C) alkylaminocarbonyl, amino (1-6C) alkyl, piperid
• examples of values for R 3a are hydrogen, hydroxyl, methoxy, ethoxy, methyl, ethyl, methylaminomethyl , dimethylaminomethyl, hydroxymethyl, methoxymethyl, methylaminocarbonyl, dimethylaminocarbonyl, aminomethyl, C0NH 2 , CH 2 CONH 2 , aminoacetyl, formylamino, acetylamino, methoxycarbonylamino, ethoxycarbonyla ino, t- butoxycarbonylamino, amino, fluoro, chloro, cyano, nitro, thiol, methylthio, methylsulphenyl, imidazol-4-yl, hydrazido, 2-methylimidazol-4-yl, methylsulphonylamido, ethylsulphonyl- amido, methylaminosulphonyl, ethylaminosulphonyl, amino- sul
• Cy in this group examples include cyclohexyl, piperidin-4-yl, 2-aminothiazol-4-yl, 2- formylaminothiazol-4-yl, 2-aminothiazol-5-yl, 2- formylaminothiazol-5-yl, 4-aminopyrid-3-yl, 3-aminopyrid-4-yl and naphth-1-yl.
• a group of compounds of particular interest is that in which Cy is a group of formula
• X a is S or NH and X b is N. Particular mention may be made of compounds in which X a is S and X b is N.
• R 3s is hydrogen.
• R 3r is hydrogen, (1-6C) alkyl, amino, (1- 6C) alkanoylamino, hydroxy (1-6C) alkanoylamino, N,N-di(l-
• Another group of compounds in which good bioavailability has been found are compounds of formula I in which Cy is pyrid-2-yl, pyrimidin-2-yl , pyrimidin-4-yl, pyrazin-2-yl , pyrazin-3-yl or oxazol-4-yl, optionally substituted by R 3a or
• the compounds of the invention may be prepared by conventional chemical synthetic routes, e.g. by amide bond formation to couple the aromatic function to the alpha atom and to couple the lipophilic function to the alpha atom.
• the cyclic group-alpha atom combination may conveniently derive from an alpha amino acid (preferably of D configuration) with the aromatic deriving from for example an acid derivative of a compound based on R 2 , e.g. an aminomethylbenzoic acid (which is readily available) .
• Amide formation from such reagents in which any amino or hydroxyl function (especially in an aminomethyl group) may if desired be protected during some or all of the synthesis steps) yields a compound of formula (V) .
• PG e.g. Boc, Z, Fmoc or Bpoc .
• protecting groups are described in McOmie, “Protective Groups in Organic Chemistry", Plenum, 1973 and Greene, “Protective Groups in Organic Synthesis", Wiley Interscience, 1981.
• the present invention provides a compound of formula
• PG' represents hydrogen or an amino protecting group (PG) and R Sa and R 6a are as defined hereinabove, or a salt thereof .
• the lipophilic group may then conveniently be introduced by reaction of a compound of formula (V) (or another analogous carboxylic acid) optionally after transformation into an activated form, e.g. an acid chloride or active ester, with a lipophilic group carrying or containing an amine group to produce a compound with the linkage of -CO- or -CO-NR ld (CH 2 ) ra - from the alpha atom to the lipophilic group.
• the protecting group, PG is then removed.
• a compound of formula V or another analogous carboxylic acid may be transformed into an alcohol by reaction with isobutylchloroformate and reduction with sodium borohydride.
• R 2 - CONH - CH(Cy)CH 2 OH (VI) can be reacted to introduce the lipophilic group by reactions such as : oxidation of the alcohol to form a corresponding aldehyde (e.g. by oxidation with manganese dioxide or DMSO/oxalyl chloride or DMSO/S0 3 or Dess-Martin reagent) which may be reacted to introduce the lipophilic group by reactions such as : reaction with an organometallic, eg a Grignard reagent, optionally followed by oxidation of the resulting hydroxyl group (e.g. with Mn0 2 , DMSO/oxalyl chloride or Dess-Martin reagent .
• organometallic eg a Grignard reagent
• PG Protecting group The protecting group may then be removed before coupling of the 3-aminomethylbenzoic acid (optionally protected) .
• carboxy protecting groups include C ⁇ -C 6 alkyl groups such as methyl, ethyl, t-butyl and t-amyl; aryl(C ⁇ - C 4 ) alkyl groups such as benzyl, 4-nitrobenzyl, 4-methoxybenzyl, 3, 4-dimethoxybenzyl, 2, 4-dimethoxybenzyl, 2,4,6- trimethoxybenzyl, 2, 4 , 6-trimethylbenzyl, benzhydryl and trityl; silyl groups such as trimethylsilyl and t- butyldi ethylsilyl; and allyl groups such as allyl and 1- (trimethylsilylmethyl) prop-l-en-3-yl.
• C ⁇ -C 6 alkyl groups such as methyl, ethyl, t-butyl and t-amyl
• aryl(C ⁇ - C 4 ) alkyl groups such as benzyl, 4-nitrobenzyl,
• amine protecting groups include acyl groups, such as groups of formula RCO in which R represents C ⁇ _ 6 alkyl, C 3 _ ⁇ o cycloalkyl, phenyl C ⁇ _ 6 alkyl, phenyl, C ⁇ -6 alkoxy, phenyl C ⁇ - 6 alkoxy, or a C 3 - ⁇ 0 cycloalkoxy, wherein a phenyl group may be optionally substituted, for example by one or two of halogen, C ⁇ -C alkyl and C ⁇ -C 4 alkoxy.
• Preferred amino protecting groups include t-butoxycarbonyl (Boc) and benzyl.
• ⁇ -Amino acids of formula (VII) which are not commercially available can be synthesized by methods known in the art, for example as described in "Synthesis of Optically Active ⁇ -Amino Acids” by Robert M. Williams (Perga on Press, 1989) and " symmetric Synthesis of ArylGlycines” , Chem. Rev. 1992, 889- 917.
• the invention provides a process for the preparation of a compound according to the invention which process comprises coupling a lipophilic group to a compound of formula (VIII)
• the compounds of formula I may alternatively be prepared by a process in which the group R 2 is introduced in the final process step.
• the invention provides a process for the preparation of a compound according to the invention which process comprises reacting a compound of formula (IX)
• a compound of formula (IX) in which Z 2 is H 2 N may be reacted with a compounds of formula (X) in which Z3 is COOH or a reactive derivative thereof, such as an acyl halide or an anhydride, for example as described in the Examples herein.
• the invention relates to a process for preparing a compound of formula I comprising deprotecting a compound of formula (I') :
• R 2 '-X-X-CH(Cy') -L-Lp (I 1 ) wherein R 2 ' is R 2 (as hereinabove defined) or protected R 2 , Cy' is Cy (as hereinabove defined) or protected Cy and Lp ' is Lp (as hereinabove defined) or protected Lp; providing at least one protecting group is present.
• physiologically tolerable salts can be formed using methods known in the art .
• the lipophilic group Lp comprises more than one group
• it may generally be formed by coupling these groups together at an appropriate stage in the preparation of the compound of formula I using conventional methods or as described in the Examples.
• the compounds of the invention may be administered by any convenient route, e.g. into the gastrointestinal tract (e.g. rectally or orally) , the nose, lungs, musculature or vasculature or transdermally.
• 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.
• compositions will be sterile and in a solution or suspension form suitable for injection or infusion. Such compositions form a further aspect of the invention.
• Hard gelatin capsules are prepared using the following ingredients :
• the above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
• Tablets each containing 60 mg of active ingredient are made as follows :
• the active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
• the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No . 14 mesh U.S. sieve.
• the granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve.
• the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a serine protease (tryptase) inhibitor according to the invention together with at least one pharmaceutically acceptable carrier or excipient.
• a serine protease tryptase
• the pharmaceutical composition may also optionally comprise at least one further anti-inflammatory agent.
• the invention provides the use of a tryptase inhibitor according to the invention for the manufacture of a medicament for use in a method of treatment of the human or non-human animal body (e.g. a mammalian, avian or reptilian body) to combat (i.e. treat or prevent) a condition responsive to said inhibitor, which comprises administering an effective amount of a compound according to the invention.
• a human or non-human animal body e.g. a mammalian, avian or reptilian body
• combat i.e. treat or prevent
• the invention provides a method of treatment of the human or non-human animal body (e.g. a mammalian, avian or reptilian body) to combat a condition responsive to a tryptase inhibitor.
• 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 of from 0.01 to 100 ⁇ mol/kg bodyweight will be administered. All publications referred to herein are hereby incorporated by reference.
• Flash column chromatography was carried out using Merck silica gel Si60 (40-63 ⁇ m, 230-400 mesh) . Purification of final products was by crystallisation, flash column chromatography or gradient reverse phase HPLC on a Waters Deltaprep 4000 at a flow rate of 50 mL/minute using a Deltapak C18 radial compression column (40 mm x 210 mm, 10-15 mm particle size) .
• Eluant A consisted of aqueous trifluoroacetic acid (0.1 %) and eluant B 90% acetonitrile in aqueous trifluoroacetic acid (0.1 %) with gradient elution (Gradient, 0 minutes 5 % B for 1 minutes, then 5 % B to 20 % B over 4 minutes, then 20 % B to 60 % B over 32 minutes) . Fractions were analysed by analytical HPLC and LC/MS before pooling those with >95 % purity for lyophilisation . Analysis :
• LC/MS were performed on a PESCIEX single quadrupole API-150EX instrument, equipped with a Luna 2 C18 column (3 ⁇ , 30 mm x 4.6 mm) eluting with 20 % to 100 % acetonitrile in water over five minutes (gradient 4) .
• 2-Amino-6-nitrobenzothiazole 500 mg, 2.56 mmol was dissolved in methanol (20 mL) and 10 % palladium on carbon (50 mg) was added as a slurry in methanol (1 L) . The atmosphere was replaced with hydrogen and the suspension was stirred overnight. The catalyst was removed by suction filtration and the solvent evaporated to afford 2, 6-diaminobenzothiazole (420 mg, 99 %) as a pale yellow solid.
• N-BOC-D-Phenylglycine 2-aminobenzothiazol-6-amide N-BOC-D-Phenylglycine (250 mg, 1.0 mmol), l-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (190 mg, 1.0 mmol) and 7-aza-l-hydroxybenzotriazole (140 mg, 1.0 mmol) were stirred in dimethylformamide (3 mL) for ten minutes. 2, 6-Diaminobenzothiazole (160 mg, 1.0 mmol) was then added and the solution was stirred overnight at room temperature.
• N-BOC-3-aminomethylbenzoic acid 250 mg, 1.0 mmol
• l-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 190 mg, 1.0 mmol
• 7-aza-l-hydroxybenzotriazole 140 mg, 1.0 mmol
• D-Phenylglycine 2-aminobenzothiazol-6-amide trifluoroacetate salt 350 mg, 0.85 mmol was then added and the mixture was stirred overnight.
• Examples 1 - 5 were synthesised in the same way as the compound of Method 1 using the indicated amino acid in place of phenylglycine and the indicated amine in place of 2,6- diaminobenzothiazole.
• N-Formyl-5-aminoindane To a solution of 5-aminoindane (7.53 g, 56.5 mmol) in DMF (100 mL) was added formic acid (2.2 mL, 58.3 mmol), l-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (10.94 g, 57 mmol) and diisopropylethylamine (19.7 mL, 0.11 mol). The resulting solution was stirred overnight and then partitioned between saturated aqueous citric acid (100 mL) and ethyl acetate (200 mL) .
• the aqueous layer was extracted with dichloromethane (2 x 50 mL) and the combined organic extracts then washed with brine (200 mL) , dried over magnesium sulphate and concentrated under reduced pressure.
• the crude oil was purified by vacuum distillation to give the product as a clear oil which solidified at low temperature (7.8 g, 72 %) ; bp. 100-105°C (0.05mBar) .
• the purple oily residue was taken up in methanol (2 L) and purified by SCX acid ion- exchange chromatography, eluting with methanol and then 5% - 10 % 2 N NH 3 /methanol in dichloromethane, to afford 3- (aminomethyl) benzoyl-D/L-4-methylphenylglycine indan-5-amide as its free base.
• This was taken up in acetonitrile (5 mL) and water (10 L) was added, followed by 5 % HCI (aq.) to afford a pale yellow solution.
• Examples 6 - 11 were synthesised in the same way as the compound of method 2 using the indicated aldehyde.
• This compound was prepared in an analogous fashion to 3- (N- BOC-aminomethyl) benzoyl-D/L- (N-BOC-piperidin-4-yl ) glycine indan-5-amide, an intermediate in the synthesis of Example 3, except that 3- (W-Z-aminomethyl) benzoic acid was used in the final coupling reaction.
• Examples 18 - 20 were prepared in a manner analogous to Example 17, except that the indicated carboxylic acid derivative was used to form the amide of the piperidine nitrogen, under appropriate conditions.
• Example 22 3- (Aminomethyl)benzoyl-D/L-6-amino-3-pyridylglycine indan-5- amide bis (hydrochloride) salt.
• N-t-butyloxycarbonyl-D/L-2- ethylthiazol-4-ylglycine ethyl ester 824 mg, ) as a golden oil.
• the oil was dissolved in methanol (25 mL) and aqueous sodium hydroxide (2 M, 5 mL) was added. After stirring at room temperature for 2 hours, the solution was concentrated, water (30 mL) was added, and the solution extracted with ethyl acetate (30 L) .
• Example 29 3- (Aminomethyl) benzoyl-D/L-2-methylthiazol-4-ylglycine 2,3- dihydroindol-6-amide bis (trifluoroacetate) salt.
• Example 30 3- (Aminomethyl) benzoyl-D/L-2- (dimethylamino- acetylamino) thiazol-4-ylglycine indan-5-amide bis (trifluoroacetate) salt.
• the dimethylformamide was evaporated under reduced pressure, and the resulting oil partitioned between water (50 L) and ethyl acetate (50 mL) .
• the ethyl acetate layer was washed with 5% hydrochloric acid (10 mL) , saturated sodium bicarbonate solution (10 mL) , dried (MgS0 4 ) and evaporated under reduced pressure to give a brown foam (1.0 g) .
• the foam was dissolved up in acetic acid (27 mL) , and to this stirred solution was added 30% HBr/acetic acid (13.5 mL) , then heated at 60°C for 4 hours.
• the dimethylformamide was evaporated under reduced pressure, and the resulting oil partitioned between water (50 mL) and ethyl acetate (50 mL) .
• the ethyl acetate layer was washed with 5% hydrochloric acid (10 mL) , and NaHC0 3 (sat. aq., 10 mL) , dried (MgS0 4 ) and evaporated under reduced pressure.
• the residue was absorbed onto silica and purified by column chromatography, eluting with 30 - 50% ethyl acetate / hexane. The desired fractions were combined and evaporated to give the amine as a light brown foam (270 mg) .
• Examples 31 and 32 were synthesised in the same way as example 30 but using the indicated reagent in place of N,N- dimethylglycine .
• Example 31 3- (Aminomethyl) benzoyl-D/L-2- (hydroxyacetylamino) thiazol-4- ylglycine indan-5-amide.

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