WO2007072041A1 - Therapeutic compounds - Google Patents
Therapeutic compounds Download PDFInfo
- Publication number
- WO2007072041A1 WO2007072041A1 PCT/GB2006/004897 GB2006004897W WO2007072041A1 WO 2007072041 A1 WO2007072041 A1 WO 2007072041A1 GB 2006004897 W GB2006004897 W GB 2006004897W WO 2007072041 A1 WO2007072041 A1 WO 2007072041A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- aryl
- optionally substituted
- amino
- methyl
- Prior art date
Links
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- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
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- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—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
- C07C235/44—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
- C07C235/56—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 a carbon atom of a six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—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
- C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—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
- 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
- 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
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—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
- C07D295/22—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 with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/914—Hydrolases (3)
- G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
- G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
- G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
- G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
- G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
- G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
- G01N2333/96433—Serine endopeptidases (3.4.21)
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
Definitions
- This invention relates to therapeutic compounds which are inhibitors of serine proteases, to pharmaceutical compositions thereof and to their use in the treatment of the human or animal body.
- the present invention also relates to trypsin-like serine protease pharmacophores, and in particular to compounds which bind to and inhibit such proteases and methods of obtaining such compounds using the pharmacophores.
- the present invention further relates to compositions, methods and uses of the compounds and pharmacophores.
- Proteases or proteolytic enzymes are essential in organisms, from bacteria and viruses to mammals. Proteases digest and degrade proteins by hydrolyzing peptide bonds. Serine proteases (EC. 3.4.21) have common features in the active site, primarily an active serine residue. There are two main types of serine proteases; the chymotrypsin/trypsin/elastase-like and subtilisin-like, which have an identical spatial arrangement of catalytic His, Asp, and Ser but in quite different protein scaffolds. However, over twenty families (S1-S27) of serine proteases have been identified that are grouped into 6 clans on the basis of structural similarity and other functional evidence, SA, SB, SC, SE, SF & SG.
- the family of chymotrypsin/trypsin/elastase-like serine proteases have been subdivided into two classes.
- the "large” class (ca 230 residues) includes mostly mammalian enzymes such as trypsin, chymotrypsin, elastase, kallikrein, and thrombin.
- the "small” class (ca 190 residues) includes the bacterial enzymes.
- the catalytic His, Asp and Ser are flanked by substrate amino acid side chain residue binding pockets termed Sl', S2', S3' etc on the C-terminal or 'prime' side of the substrate and Sl, S2, S3 etc on the N-terminal side.
- This nomenclature is as described in Structure and Mechanism in Protein Science: A Guide to Enzyme Catalysis and Protein Folding, Alan Fersht, 1999 (W.H. Freeman and Company) pages 40-43 and Brik et al, Org. Biomol. Chem., 2003, 1, 5-14.
- the chymotrypsin/trypsin/elastase-like serine proteases can also be further subdivided by the residues present in the Sl pocket as described in Introduction to Protein Structure, Carl Branden and John Tooze, 1991 (Garland Publishing Inc) pages 231-241.
- the subdivisions are chymotrypsin-like (Gly-226, Ser-189 and Gly-216 in Sl pocket), trypsin-like (Gly-226, Asp-189 and Gly-216 in Sl) and elastase-like (Val-226 and Thr-216 in Sl) where the residues numbering is taken from the standard chymotrypsin numbering.
- trypsin-like serine proteases prefer substrates which place either Lys or Arg in the Sl pocket.
- the principal eukaryotic trypsin-like serine proteases are listed below according to their SwissProt code, their common name (where relevant) and the residue they possess at position 190 (in the chymotrypsin numbering):
- Thrombin and Factor Xa have been extensively studied in an attempt to identify drugs useful in treating cardiovascular disease, and more recently Factors Vila and Factor IXa are also being studied for the same application.
- Urokinase has been studied in an attempt to identify inhibitors that might be useful in treating human cancers and for other therapeutic uses.
- Beta-Tryptase inhibitors may be useful in the treatment of asthma and inflammatory diseases.
- Trypsin-like serine proteases can be further categorised by the residue at position 190 (chymotrypsin numbering).
- the residue at this position is Ala.
- Urokinase, Factor Vila, FactorIXa and beta-Tryptase the residue at this position is Ser. This has an important consequence to the properties of the key Sl specificity pocket.
- the AIa-190 enzymes have a more lipophilic Sl pocket than the Ser-190 enzymes, and although both types of protein still recognise Arg, the AIa-190 enzymes can be inhibited by peptidomimetics or small molecule inhibitors that contain neutral (non-basic) resides that do not directly mimic Arg, e.g. see Hies et al, Expert Opinion in Therapeutic Patents, 2002, 1181-1214.
- those enzymes that have Ser-190 in the Sl pocket are usually only inhibited by molecules that contain a strongly basic group that occupies the Sl pocket, binding to Asp-189 and to Ser-190.
- Factor Vila is a key serine protease involved in the initiation of the coagulation cascade. It is a glycosylated disulfide-linked heterodimer comprised of an ammo-terminal D-carboxyglutamic acid-rich (GIa) domain and two epidermal growth factor (EGF)-like domains in the light chain, and a trypsin-like serine protease domain in the heavy chain.
- FVIIa requires tissue factor (TF), a membrane bound protein, as an essential cofactor for maximal activity towards its biological substrates Factor X, Factor IX and Factor VII (FVII).
- TF'FVHa activity may prevent the formation of fibrin clots and thus be useful in the management of thrombotic disease.
- the development of TF'FVIIa inhibitors to validate this target has been of great interest.
- a wide array of strategic approaches to inhibiting the biochemical and biological functions of the TF'FVIIa complex has been pursued. This has been greatly aided from our understanding of the structures for TF, FV ⁇ , FVIIa, and the TF'FVTIa complex. These approaches have resulted in inhibitors directed specifically towards either FVIIa or TF.
- Antagonists include active site inhibited FVIIa, TF mutants, anti-TF antibodies, anti-FVII/FVIIa antibodies, naturally-occurring protein inhibitors, peptide exosite inhibitors, and protein and small molecule active site inhibitors. These antagonists can inhibit catalysis directly at the active site as well as impair function by binding to exosites that may interfere with substrate, membrane, or cofactor binding.
- FVIIa active site inhibited FVIIa
- TF mutants anti-TF antibodies
- anti-FVII/FVIIa antibodies naturally-occurring protein inhibitors
- peptide exosite inhibitors peptide exosite inhibitors
- protein and small molecule active site inhibitors proteins and small molecule active site inhibitors.
- Tryptase (EC 3.4.21.59) is a homotetrameric, trypsin-like serine protease that constitutes 20-25% of the total protein of human mast cells. Since it is stored in a catalytically active form (rather than as a 2ymogen) within the secretory granules and released on stimulation, this enzyme is highly relevant to mast cell dependent inflammatory conditions. Tryptase has been directly implicated in the pathology of asthma.
- tryptase inhibitors have therapeutic potential for treating allergic or inflammatory disorders such as asthma, vascular injury, inflammatory bowel disease, and psoriasis.
- allergic or inflammatory disorders such as asthma, vascular injury, inflammatory bowel disease, and psoriasis.
- tryptase inhibitors - review of the recent patent literature. IDrugs (2002), 5(7), 682-688.
- the serine proteases have a common catalytic mechanism characterized by a particularly reactive Ser residue at position 195 using the chymotrypsin numbering system.
- serine proteases are descrribed above and include trypsin, tryptase, chymotrypsin, elastase, thrombin, plasmin, kallikrein, Complement Cl, acrosomal protease, lysosomal protease, cocoonase, ⁇ -lytic protease, protease A, protease B, serine carboxypeptidase ⁇ , subtilisin, urokinase (uPA), Factor
- Processes involving serine proteases include coagulation, fibrinolysis, fertilization, development, malignancy, neuromuscular patterning and inflammation. It is well known that these compounds inhibit a variety of circulating proteases as well as proteases that are activated or released in tissue. It is also known that serine protease inhibitors inhibit critical cellular processes, such as adhesion, migration, free radical production and apoptosis. La addition, animal experiments indicate that intravenously administered serine protease inhibitors, variants or cells expressing serine protease inhibitors, provide protection against tissue damage.
- Serine protease inhibitors have also been predicted to have potential beneficial uses in the treatment of disease in a wide variety of clinical areas such as oncology, neurology, haematology, pulmonary medicine, immunology, inflammation and infectious disease. Serine protease inhibitors may also be beneficial in the treatment of thrombotic diseases, asthma, emphysema, cirrhosis, arthritis, carcinoma, melanoma, restenosis, atheroma, trauma, shock and reperfusion injury. A useful review is found in Expert Opin. Ther. Patents (2002), 12(8).
- the conventional method of treatment of cancers involves chemotherapy, often administered at high levels with severe side effects. Recent advances have made progress in improving patient longevity and improving the quality of life for those undergoing treatment. Nevertheless, chemotherapy still has disadvantages. Most pharmaceutical interventions to treat cancer have common side effects, including nausea, vomiting, bone-marrow suppression, alopecia and impaired reproductive function. Even after apparently successful treatment, dormant cancer cells may lead to relapse many years into the future.
- the uPA system plays a major role in metastasis and primary tumor growth.
- the uPA system is an extra-cellular protease enzyme system which is over-expressed on, for example, aggressive metastasizing solid tumors.
- the uP A system consists of:
- uPA - urokinase
- PAI-I physiological inhibitor
- uPA-receptor uPA-receptor
- Proteases or proteolytic enzymes are essential in organisms, from bacteria and viruses to mammals. Proteases digest and degrade proteins by hydrolyzing peptide bonds. Serine proteases (EC. 3.4.21) are one type that have an active serine residue. There are two main types of serine proteases; the trypsin-like and subtilisin-like, which have an identical spatial arrangement of catalytic His, Asp, and Ser but in quite different protein scaffolds. uPA is a member of the trypsin-like serine protease family.
- the uPA system triggers proteolytic processes through which tumor cells are enabled to degrade their surrounding tissue (the extracellular matrix or ECM), to invade into healthy tissue and blood vessels and thus to migrate and form new tumors at distant sites.
- ECM extracellular matrix
- the uPA-system interacts with other molecular-biological systems, and thus promotes primary tumor growth.
- uPA converts the zymogen plasminogen to plasmin, an enzyme which degrades fibrin and numerous other components of the extracellular matrix, such as type IV collagen, fibronectin and laminin. This likely enables tumor cells to migrate through tissue barriers
- ECM Error-associated mammase originating from epithelial cells
- uPA and plasminogen may activate other families of protein-cleaving enzymes such as metalloproteinases (MMPs), which along with uPA promote tumor cell invasion and angiogenesis.
- MMPs metalloproteinases
- the enzymatic activity of uPA is controlled by a number of inhibitors.
- One of these inhibitors, PAI-I inhibits uPA when it is bound to its cell surface receptor uPAR.
- PAI-I binds to the uPA/uPAR complex, the cell internalizes all three molecules.
- uPA and PAI-I are degraded and uPAR is recycled to the cell surface ready to bind another uPA molecule.
- uPA The binding of uPA to uPAR transduces growth promoting signals in tumor cells, events which are separate from its enzymatic activity.
- uPAR interacts with vitronectin and integrins, which are involved in cell adhesion and signal transduction.
- tumor cells acquire growth and survival advantages by overexpressing the uPA system, which promotes the growth, invasion, and metastatic spread of tumor cells via multiple mechanisms.
- Such agents could benefit by acting at multiple points of the tumour growth and metastatic process.
- uPA and PAI-I have been qualified as new prognostic markers of breast cancer with the highest level of evidence (LOE-I) by the European Organization for Research and Treatment of Cancer (EORTC).
- uPA inhibitors are known (e.g. Wilex compounds WX-UKl and WX-671), and at least one is currently in clinical trials. Further and preferably improved uPA inhibitors are desired to offer additional options for treatment of cancer with reduced toxicity-related side effects.
- uPA is also implicated in diseases associated with angiogenesis. These include but are not limited to angiogenesis-based retinopathies, arthritis, skin disease including inflammatory skin disease for example psoriasis, asthma, chronic respiratory disease including chronic obstructive pulmonary disease (COPD), osteoarthritis, HIV and multiple sclerosis. For these conditions too there is a need for further and preferably improved uPA inhibitors. uPA inhibitors are also found to have contraceptive activity - again, provision of further and preferably better inhibitors is desired.
- Angiogenesis is generally used to describe the development of new or replacement blood vessels, or neovascularisation. It is a necessary and physiological normal process by which the vasculature is established in the embryo. Angiogenesis does not occur, in general, in most normal adult tissues, exceptions being sites of ovulation, menses and wound healing. Many diseases, however, are characterized by persistent and unregulated angiogenesis.
- angiogenesis occurs in many stages and attempts are underway to discover and develop compounds that work to block angiogenesis at these various stages.
- FVTIa Factor Vila
- GIa ammo-terminal ⁇ -carboxyglutamic acid-rich
- EGF epidermal growth factor
- FVIIa requires tissue factor (TF), a membrane bound protein, as an essential cofactor for maximal activity towards its biological substrates Factor X, Factor IX and Factor VEt (FVTT).
- TF-FVIIa activity may prevent the formation of fibrin clots and thus be useful in the management of thrombotic disease.
- TFrFVHa inhibitors to validate this target has been of great interest.
- a wide array of strategic approaches to inhibiting the biochemical and biological functions of the TFrFVIIa complex has been pursued. This has been greatly aided from our understanding of the structures for TF, FV ⁇ , FVIIa, and the TFrFVIIa complex. These approaches have resulted in inhibitors directed specifically towards either FVIIa or TF.
- Antagonists include active site inhibited FVIIa, TF mutants, anti-TF antibodies, anti-FVII/FVIIa antibodies, naturally-occurring protein inhibitors, peptide exosite inhibitors, and protein and small molecule active site inhibitors. These antagonists can inhibit catalysis directly at the active site as well as impair function by binding to exosites that may interfere with substrate, membrane, or cofactor binding.
- FVIIa active site inhibited FVIIa
- TF mutants anti-TF antibodies
- anti-FVII/FVIIa antibodies naturally-occurring protein inhibitors
- peptide exosite inhibitors peptide exosite inhibitors
- protein and small molecule active site inhibitors proteins and small molecule active site inhibitors.
- Tryptase (EC 3.4.21.59) is a homotetrameric, trypsin-like serine protease that constitutes 20-25% of the total protein of human mast cells. Since it is stored in a catalytically active form (rather than as a zymogen) within the secretory granules and released on stimulation, this enzyme is highly relevant to mast cell dependent inflammatory conditions. Tryptase has been directly implicated in the pathology of asthma. Thus, tryptase inhibitors have therapeutic potential for treating allergic or inflammatory disorders such as asthma, vascular injury, inflammatory bowel disease, and psoriasis. For a review see Bradley, Tryptase inhibitors - review of the recent patent literature. IDrugs
- uPA inhibitors are described in US 6504031, US 2001/0049374 and WO 01/81314, based around substituted naphthamidine compounds.
- a series of substituted benzanilides, including benzamides, are known as modulators of the CCR5 receptor, and described in WO 98/50343, WO 98/50346, WO2004/010943 and WO 2004/011427.
- the compounds are broadly defined and there is no mention therein of use to inhibit serine proteases.
- EP 0638553 discloses a class of amides having a terminal carboxylic acid group as anti-thrombotic compounds. On page 37 of this document, there is described the preparation of the compound 4-[[4-(2-aminoethoxy)benzoyl]amino]-benzenepropanoic acid.
- JP 11236369 discloses a class of sulphonamide compounds that are useful as matrix metalloproteinase inhibitors.
- a compound specifically described in this document is N-[[4- [[4-(2-aminoethoxy)benzoyl]amino]phenyl]sulphonyl]-N-(2-methylpropyl)-glycine.
- Serine protease inhibitors are disclosed in US published patent applications US 2003/0100089 and 2004/0180371 and in US patents 6,784,182, 6,656,911, 6,656,910, 6,608,175, 6,534,495 and 6,472,393.
- inhibitors of serine proteases offers additional therapies against the aforementioned disease states and a need thus exists for compounds that are potent and selective serine protease inhibitors, as alternatives to the existing inhibitors and preferably which possess greater bioavailability and/or fewer side-effects and/or improved potency that than known serine protease inhibitors.
- HSV herpesvirus
- HCMV human cytomegalovirus
- HCV hepatitis C virus
- septic shock septic shock.
- V is selected from
- Ci- 2 alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S- methyl;
- Ci- 2 alkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S-methyl;
- di-Ci- 2 alkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S-methyl;
- W, X and Y are independently selected from
- Ci- 6 alkyl optionally substituted by R a ;
- Ci-C ⁇ alkoxy optionally substituted by R a ;
- Z-aryl or Z-heteroaryl optionally substituted by R a , wherein Z is selected from C 1-4 alkyl, CH 2 NH, S, O, S(O), S(O 2 ), S(O 2 )NH, NHS(O 2 ), CH 2 NH, NHCH 2 , CH 2 O 5 OCH 2 , CH 2 CH 2 ,
- aryl or heteroaryl optionally substituted by R a .
- R m , R n , R p , R q are selected from
- Ci- 2 alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S- methyl; 3. propyl,
- R m and R n , R p and R q , or R m and R q form a cyclopropane ring.
- L is selected from 1) a covalent bond
- cycloalkyl or heterocyclyl optionally fixsed to A, e.g. via R 1 or R 5 , 45) aryl or heteroaryl, optionally fused to A, e.g. via R 1 or R 5 ' and
- R L is selected from
- R M and R N are independently selected from
- Ci -6 alkyl optionally substituted by R a ,
- n is 0 to 4
- t is 0 to 2
- R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from 1. H, halogen, CN, NH 2 , OH, COOH, CH 2 OH, SO 2 H, trifluoromethyl; and
- R 1 , R 2 , R 3 , R 4 and R 5 together with the ring to which they are attached form part of a fused bicyclic or tricyclic ring system in which the first ring is a benzene ring, optionally substituted as defined herein, and the second and, if present, third rings are independently selected from aryl, heteroaryl and saturated or unsaturated carbocyclic and heterocyclic rings, optionally substituted by R a .
- bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, indoline, isoindoline, indazole, and benzodioxole groups.
- bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, benzodioxan, benzoxazine, benzodiazine, quinoxaline, quinazoline, phthalazine, naphthalene, and cinnoline groups.
- R 1 , R 2 , R 3 , R 4 and R 5 together with the ring to which they are attached can form part of a ring to create a bicyclic aryl or heteroaryl ring system, optionally substituted by R a , or two or more of R 1 , R 2 , R 3 , R 4 and R 5 together with the ring to which they are attached can form part of a ring to create an bicyclic ring system in which the second ring is not aromatic, optionally substituted by R a , or two or more of R 1 , R 2 , R 3 , R 4 and R 5 together with the ring to which they are attached can form part of a ring to create a tricyclic ring system, optionally substituted by R a .
- polycyclic aryl and heteroaryl groups containing an aromatic ring and a non-aromatic ring include such ring systems as tetrahydro-naphthalene, indoline, indene, indane, dihydro- isoindole, dihydro-benzofuran, tetrahydro-quinoline, tetrahydro-isoquinoline, dihydro-quinazoline, 5-phenyl-2,3-dihydro-lH-benzo[e][l,4]diazepine, and 5-phenyl-2,3,4,5-tetrahydro-lH- benzo[e][l,4]diazepine.
- ring systems as tetrahydro-naphthalene, indoline, indene, indane, dihydro- isoindole, dihydro-benzofuran, tetrahydro-quinoline, tetrahydro-isoquinoline, di
- R 1 , R 2 , R 3 , R 4 and R 5 are each other than trifluoromethyl.
- the invention uses a compound of the formula (I 0 ):
- Formula I 0 or a salt, solvate, hydrate, N-oxide or ester thereof; wherein R m , R n , R p , R q , V, W, X, Y, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in repect of formula (I).
- the invention provides a compound of formulae I or I 0 , or a solvate, hydrate, ester or pharmaceutically acceptable salt thereof, as defined herein for use as an inhibitor of a serine 190 protease.
- the invention also provides a compound of formulae I or I 0 , or a solvate, hydrate, ester or pharmaceutically acceptable salt thereof, as defined herein for use as an inhibitor of uPA.
- the present invention provides the use of compounds of formulae I or I 0 , or a solvate, hydrate, ester or pharmaceutically acceptable salt thereof, as defined herein for the manufacture of a medicament for inhibition of a serine 190 protease.
- the invention further provides the use of compounds of formulae I or I 0 , or a solvate, hydrate or pharmaceutically acceptable salt thereof, as defined herein for the manufacture of a medicament for inhibition of uPA.
- methods of inhibiting or treating aberrant serine protease activity in a mammal methods treating or ameliorating diseases reponsive to a serine protease inhibitor, methods of contraception, anti-coagulant methods and uses and methods for treating aberrant cell proliferation, tumours, cancer, angiogenesis, angiogenesis-based retinopathies, autoimmune disease, inflammation, skin disease, arthritis, rheutmatoid arthritis, asthma, osteoarthritis, HTV, multiple sclerosis an dother diseases and conditions as referred to herein by administering to a patient an effective amount of a compound of the invention.
- the invention is of application to a wide range of serine 190 proteases, including but not limited to trypsin, tryptase, chymotrypsin, elastase, thrombin, plasmin, kallikrein, Complement Cl, acrosomal protease, lysosomal protease, cocoonase, ⁇ -lytic protease, protease A, protease B, serine carboxypeptidase II, subtilisin, urokinase (uPA), Factor Vila, Factor IXa, and Factor Xa.
- trypsin tryptase
- chymotrypsin elastase
- thrombin plasmin
- kallikrein Complement Cl
- acrosomal protease lysosomal protease
- cocoonase ⁇ -lytic protease
- protease A protease
- the invention provides methods of treatment using the compounds of the invention as inhibitors of uPA.
- methods of inhibiting or treating aberrant uPA activity in a mammal methods of contraception, anti-coagulant methods and uses and methods for treating aberrant cell proliferation, tumours, cancer, angiogenesis, angiogenesis-based retinopathies, autoimmune disease, inflammation, skin disease, arthritis, rheutmatoid arthritis, asthma, osteoarthritis, HIV and multiple sclerosis by administering to a patient an effective amount of a compound of the invention.
- the invention provides novel compounds per se wherein the novel compounds are compounds of the formulae I or I 0 , but excluding (a-i) 4-(2-aminoethoxy)-N-[4-methyl-3-[[4- (3-pyridmyl)-2-pvrirddinyl]amino]phenyl-benzamide and salts thereof; (a-ii) N-[[4-[[4-(2- aminoethoxy)benzoyl]amino]phenyl]sulphonyl]-N-(2-methylpropyl)-glycine and salts thereof; and (a-iii) 4-[[4-(2-arnmoethoxy)benzoyl]amino]-benzenepropanoic acid and salts and N-protected forms thereof.
- the present invention also provides, as compounds of the invention, the compounds of formulae I and I 0 and solvates, hydrates and pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the same, generally in combination with a pharmaceutically acceptable carrier, especially for administration to a human, but excluding pharmaceutical compositions containing (a-i) 4-(2-ammoethoxy)-N-[4-methyl-3-[[4-(3-pyridmyl)-2-pyrirrddmyl]aniino]phenyl- benzamide and salts thereof; (a-ii) N-[[4-[[4-(2-aminoethoxy)benzoyl]amino]phenyl]sulphonyl]-N- (2-methylpropyl)-glycine and salts thereof; and (a-iii) 4-[[4-(2-arninoethoxy)benzoyl]amino]- benzenepropanoic acid and salts and N-protected forms thereof.
- exclusions (a-i) to (a-iii) may optionally apply also in relation to each of the therapeutic uses of the compounds of the formulae I or I 0 described herein.
- the compound may be other than a compound containing an optionally substituted pyrimidin-2-ylaminophenyl group.
- R 3 may be other than an alkanoic acid (e.g. acetic acid or propanoic acid) residue.
- R 3 may be other than a group containing an alkanoic acid (e.g. formic acid, acetic acid or propanoic acid) residue.
- alkanoic acid e.g. formic acid, acetic acid or propanoic acid
- the compound may be other than a compound containing a substituted benzenesulphonamide group wherein the nitrogen atom of the benzenesulphonamide forms part of a non-cyclic disubstituted amino group.
- the compound may be other than a compound containing a carboxylic acid group.
- alkyl used on its own or as part of another group refers to both straight and branched chain radicals of up to 6 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl.
- the alkyl chain is 1 to 3 carbon atoms in length.
- alkenyl is used to indicate a straight or branched chain radical of 2-6 carbon atoms, with a double bond between 2 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl, and the like.
- the alkenyl chain is 2 to 4 carbon atoms in length.
- alkynyl is used to mean a straight or branched chain radical of 2-6 carbon atoms wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1 -propylene, 2-propylene, and the like.
- the alkynyl chain is 2 to 4 carbon atoms in length.
- the unsaturated linkage i.e., the vinylene or acetylene linkage is preferably not directly attached to a nitrogen, oxygen or sulfur moiety.
- - alkoxy is used herein to mean a straight or branched chain radical of 1 to 6 carbon atoms, linked to an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy and isopropoxy.
- the alkoxy chain is 1 to 4, more preferably 1 to 3 carbon atoms in length.
- - aryl by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 5 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.
- heteroaryl refers to groups having 5 to 14 ring atoms; 6, 10 or 14 pi electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms.
- heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H- indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, iso
- Ci -6 alkyl groups as discussed above having an aryl substituent, for example benzyl, phenylethyl or 2-naphthylmethyl.
- - cycloalkyl or carbocyclic by itself or as part of another group refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms and preferably refers to mono-cycloalkyl groups containing 3 to 9, more preferably 3 to 7, carbon atoms.
- Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.
- halogen or "halo" by itself or as part of another group refers to chlorine, bromine, fluorine or iodine, preferably chlorine unless otherwise stated.
- dialkylamine or “dialkylamino” by itself or as part of another group refers to an amino group which is substituted with two alkyl groups, each having from 1 to 6 carbon atoms.
- - hydroxyalkyl means any of the above alkyl groups substituted by one or more hydroxyl moieties.
- - carboxyalkyl refers to any of the above alkyl groups substituted by one or more carboxylic acid moieties.
- heterocyclic or heterocyclyl means a saturated or wholly or partially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
- rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms are rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms.
- heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl,
- tricyclic indicates any tricyclic ring, including saturated and wholly and partially unsaturated rings, optionally containing one or more heteroatoms, optionally aryl or cycloalkyl, generally having 13, 14 or 15 members.
- the tricyclic ring which can be formed by R 1 , R 2 , R 3 , R 4 and R 5 it refers to any such ring in which one ring is the optionally substituted benzene ring of formula I.
- heteroatom means an oxygen atom ("O"), a sulfur atom (“S”) or a nitrogen atom (“N”).
- O oxygen atom
- S sulfur atom
- N nitrogen atom
- the heteroatom when it is nitrogen, it can form an NR y R z moiety, wherein R y and R z are, independently, hydrogen or C 1-6 alkyl, or form together with the nitrogen to which they are bound a saturated or unsaturated 5, 6, or 7 membered ring.
- - alkoxy refers to any of the above alkyl groups linked to an oxygen atom.
- - aryloxy refers to any of the above aryl groups linked to an oxygen atom.
- - cycloalkyoxy refers to any of the above cycloalkyl groups linked to an oxygen atom.
- heteroaryloxy means any of the above heteroaryl groups linked to an oxygen atom.
- - aralkyloxy or arylalkyloxy means any of the above aralkyl or arylalkyl groups linked to an oxygen atom.
- V is selected from
- CVCaalkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S- methyl;
- Ci-C 2 alkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S-methyl;
- V is selected from
- Ci-C 2 alkyl optionally substituted by fluoro
- V enhanced protease inhibition
- V is selected from Me, CH 2 F, CHF 2 , CF 3 , Et, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 OH, CH 2 OMe, CH 2 SMe, Cl, Br, I, OMe, OCHF 2 , OCH 2 F OCF 3 , OEt, CN, NH 2 , NHMe, NHMe 2 or OH, especially when selected from Me, CH 2 F, CHF 2 , CF 3, or Cl especially improved inhibitory activity is obtained.
- V is selected from Me, CH 2 F, CHF 2 , CF 3 , Et, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 OH, CH 2 OMe, CH 2 SMe, Cl, Br, I, OMe, OCHF 2 , OCH 2 F OCF 3 , OEt, CN, NH 2 , NHMe, NHMe 2 or OH
- W, X and Y may be independently selected from
- d- ⁇ alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
- Ci- ⁇ alkenyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
- Ci- 6 alkynyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
- NR 6 R 7 wherein R 6 and R 7 are each independently selected from H, amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl; 10. hydroxyl;
- carboxyCi- ⁇ alkyl optionally substituted by H, amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl; 14. carboxyamino;
- C ⁇ cycloalkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl , S-methyl, C 1-6 alkyl and Ci -6 alkoxy; 18.
- aryl or heteroaryl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl , S-methyl, Ci -6 alkyl and Ci -6 alkoxy.
- W, X and Y may each be independently selected from the substituents listed in subsections 2 to 19 in the immediately preceding section; i.e. W, X and Y may each be other than hydrogen.
- W is selected from
- di-Ci -6 alkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
- carboxyCi- ⁇ alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
- aryl or heteroaryl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl , S-methyl, Ci -6 alkyl, C 1-6 alkoxy and R a .
- W may be selected from the substituents listed in subsections 2 to 17 in the immediately preceding section; i.e. W may be other than hydrogen.
- W can generally be more broadly defined than V.
- good protease inhibition e.g. good uPA inhibition
- W is a 1, 2 or 3 membered alkyl group optionally substituted as set out above, or comprises an amino group linked to a 1, 2 or 3 membered alkyl group, again, optionally substituted as set out above, or comprises an amino group linked to an acetate group or a 1, 2 or 3 membered alkyl group, optionally substituted and linked to an aryl group, again optionally substituted.
- W is selected from
- Q-galkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
- Ci-C 6 alkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
- W is selected from
- carboxyC 1-3 alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
- protease inhibitory activity can be affected by particular combinations of values for V and W.
- a first combination is that both V and W are not H. More preferred combinations are those in which any sub class of values of V is combined with any sub class of values for W. More specifically, combinations of V and W are (i) both are methyl, (ii) one is methyl and one is chloro, (iii) one is methyl and one is amino, and (iv) both are chloro.
- X and Y are suitably selected from H; optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl; Ci -6 alkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl; and halo.
- Specific compounds show good activity when both X and Y are H.
- V is as defined above, including its preferred definitions and W
- R m , R n , R p and R q are suitably selected from H, Me, CH 2 F, CHF 2 , CF 3 , Et, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , n Pr, CH 2 OMe and CH 2 SMe.
- R m and R n or R p and R q or R m and R q can optionally form a cyclopropane ring, and should preferably be H, or methyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S-methyl.
- one of R m and R n is methyl, forming preferably the R isomer, and the other is H.
- both of R p and R q are preferably H. Most preferably, all of R m , R n , R p and R q are H.
- R 1 , R 2 , R 3 , R 4 and R 5 are found to be widely variable, and compounds have been prepared and tested and shown to have good protease inhibitory activity (e.g. good uPA inhibitory activity) when these groups have many widely differing values. Accordingly it is believed that protease inhibition will also be achieved with values across the ranges as set out herein in the definitions for R 1 , R 2 , R 3 , R 4 and R 5 .
- the compounds made and tested enable extrapolation of inhibitory activity across the range. Nevertheless, certain sub-classes of these groups can be identified, and in one such group R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from
- Ci -6 alkyl b. C 2-6 alkenyl, c. C 3 . 12 cycloaU.yl, d. C 5- i O aryl, e. Cs-i ⁇ heteroaryl f. Ci -6 alkyloxy, g. C 3- I 2 CyClOaIlSyIoXy, h. C 5- i 0 aryloxy, i. C 5- i 4 heteroaryloxy j. Ci -6 alkyl-C 5- i O aryl, k. C 5-10 arylC 1-6 alkyloxy. 1.
- R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from
- Ci -6 alkyl b) C 2-6 allcenyl, c) C 3- i 2 cycloalkyl, d) C 5- ioaryl, e) C 5- i 4 heteroaryl f) C 1-6 alkyloxy, g) C 3-12 CyClOaIlJyIoXy, h) C 5-10 aryloxy, i) Cs- ⁇ eteroaryloxy j) Ci -6 alkyl-C 5- ioaryl, k) Cs-ioarylCi- ⁇ alkyloxy.
- R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from
- Compounds of the invention can also, through combination of the groups for R 1 , R 2 , R 3 , R 4 and R 5 form cyclic, bicyclic and tricylic ring structures together with the aromatic ring atoms to which they are attached, wherein the first ring is aromatic, and heterocyclic versions of such.
- the rings are preferably formed between R 3 and R 4 or R 4 and R 5 and wherein, respectively, R 1 , R 2 , and R 5 or R 1 , R 2 and R 5 are H.
- R 1 , R 2 , R 3 , R 4 and R 5 together with the ring to which they are attached can thus form part of a ring to create a bicyclic aryl or heteroaryl ring system, optionally substituted by R a .
- ring systems are naphthalene, indole, isoindole, phthalirnide, benzofuran, benzothiophene, indazole, benzimidazole, benzthiazole, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, and quinoxaline.
- R 1 , R 2 , R 3 , R 4 and R 5 together with the ring to which they are attached can form part of a ring to create a bicyclic ring system in which the second ring is not aromatic, optionally substituted by R a .
- ring systems examples include tetrahydro-naphthalene, indoline, indene, indane, dihydro-isoindole, dihydro-benzofuran, tetrahydro-quinoline, tetrahydro-isoquinoline, dihydro-quinazoline, 5-Phenyl-2,3-dihydro-lH-benzo[e][l,4]diazepine, and 5-Phenyl-2,3,4,5- tetrahydro-lH-benzo[e][l,4]diazepine.
- R 1 , R 2 , R 3 , R 4 and R 5 together with the ring to which they are attached can also form part of a ring to create a tricyclic ring system, optionally substituted by R a .
- ring systems are carbazole, fluorine, dibenzofuran, acridine, phenazine, phenothiazine, and phenoxazine
- L is preferably selected from: 1. a covalent bond
- cycloakyl or heterocyclyl optionally fused to A, e.g. via R 1 or R 5 ,
- aryl or heteroaryl optionally fused to A, e.g. via R 1 or R 5 ' and 32.
- R L , R M and R N may further be independently selected from
- aryl optionally substituted by R a
- arylalkyl optionally substituted by R a
- Cs-scycloalkylCi- ⁇ alkyl, optionally substituted by R a , m can be from 1 to 5, n from 0 to 2, and t from 0 to 2.
- linker L may separately be defined as follows. L may be selected from:
- Ci -6 alkyl optionally substituted by R a ,
- R a cycloalkyl, optionally substituted by R a , wherein P and R are independently selected from NH, O, S, C(O), C(O)NH, NHC(O) and S(O) 2 , Q and S are independently selected from CH 2 , CHR 6 and CR 6 R 7 , wherein R 6 and R 7 are independently selected from H, halo, amino, hydroxy, methyl, methyl substituted by halo and sulphydryl, d is O to 6, fis O to ⁇ , c is O or 1, e is O or 1, provided that not all of c, d, e and f are O and that d + e ⁇ 6.
- the linker is an amide linker, i.e. is C(O)NH, and hence the compounds are compounds of the formula (I 0 ) and sub-groups thereof as defined herein.
- the linker is not an amide linker, i.e. is not C(O)NH.
- Q and S are independently selected from CH 2 , CHR 6 and CR 6 R 7 , wherein R 6 and R 7 are independently selected from H, halo, amino, hydroxy, methyl, methyl substituted by halo and sulphydryl, 0 d is O to 4, fis 0 to 4, c is O or 1, and e is O or 1, provided that not all of c, d, e and f are O and that d + e ⁇ 4,
- L is cycloakyl or heterocyclyl, optionally fused to A, e.g. via R 1 or R 5 , or aryl or heteroaryl, optionally fused to A, e.g. via R 1 or R 5
- L fused to A forms a bicyclic or tricyclic O ring, more preferably a bicyclic ring and further preferred that L is C 5-6 cycloakyl, C 5-6 heterocyclyl C 5-6 aryl or C 5 . 6 heteroaryl, forming when fused to A a bicyclic ring.
- compounds of the invention have been made using a range of different substituent groups at the R a and R b/c position.
- R b and R c are independently selected from H or C 1-6 alkyl, more preferably H, methyl or ethyl, especially H.
- the invention also provides compounds, uses and methods as set out herein using any combination of preferred values and definitions of sub classes of values for all groups in formula I 5 each such combination forming a separate embodiment of the invention.
- the invention further provides:-
- a method for the prophylaxis or treatment of a disease state or condition mediated by a serine protease comprises administering to a subject in need thereof a compound of the formula (I), formula (I 0 ) or any sub-group or embodiment thereof as defined herein.
- a method for treating a disease or condition comprising or arising from abnormal cell growth or abnormally arrested cell death in a mammal comprising administering to the mammal a compound of the formula (I), formula (f) or any sub-group or embodiment thereof as defined herein in an amount effective to inhibit serine protease activity, such as uPA activity.
- a method of inhibiting a serine protease, such as uPA comprises contacting the serine protease (e.g. uPA) with a serine protease inhibiting compound (e.g. uPA inhibiting compound) of the formula (J), formula (I 0 ) or any sub-group or embodiment thereof as defined herein,
- a method for treating a disease or condition comprising or arising from abnormal cell growth or abnormally arrested cell death in a mammal comprises administering to the mammal a compound of the formula (I), formula (f) or any sub-group or embodiment thereof as defined herein in an amount effective in inhibiting abnormal cell growth.
- a method for alleviating or reducing the incidence of a disease or condition comprising or arising from abnormal cell growth or abnormally arrested cell death in a mammal comprises administering to the mammal a compound of the formula (I), formula (I 0 ) or any sub- group or embodiment thereof as defined herein in an amount effective in inhibiting abnormal cell growth.
- a method for the treatment or prophylaxis of any one of the disease states or conditions disclosed herein comprises administering to a patient (e.g. a patient in need thereof) a compound (e.g. a therapeutically effective amount) of the formula (T), formula (I 0 ) or any sub- group or embodiment thereof as defined herein.
- a patient e.g. a patient in need thereof
- a compound e.g. a therapeutically effective amount
- T formula (T), formula (I 0 ) or any sub- group or embodiment thereof as defined herein.
- a method for alleviating or reducing the incidence of a disease state or condition disclosed herein comprises administering to a patient (e.g. a patient in need thereof) a compound (e.g. a therapeutically effective amount) of the formula (I), formula (I 0 ) or any subgroup or embodiment thereof as defined herein.
- a patient e.g. a patient in need thereof
- a compound e.g. a therapeutically effective amount of the formula (I), formula (I 0 ) or any subgroup or embodiment thereof as defined herein.
- a method for the diagnosis and treatment of a disease state or condition mediated by a serine protease, such as uPA comprises (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against the serine protease (e.g. uPA); and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient a compound of the formula (I), formula (I 0 ) or any sub- group or embodiment thereof as defined herein.
- a serine protease such as uPA
- a pharmaceutical composition comprising a novel compound of the formula (I), formula (I 0 ) or any sub-group or embodiment thereof as defined herein and a pharmaceutically acceptable carrier.
- the linker is not an amide linker, i.e. is not C(O)NH.
- the linker is an amide linker, i.e. is C(O)NH.
- the invention is of application not only to uPA, but also to a wide range of serine proteases, including but not limited to trypsin, tryptase, chymotrypsin, elastase, thrombin, plasmin, kallikrein, Complement Cl, acrosomal protease, lysosomal protease, cocoonase, ⁇ -lytic protease, protease A, protease B, serine carboxypeptidase ⁇ , subtilisin, urokinase (uPA), Factor Vila, Factor IXa, and Factor Xa.
- the invention is of application to trypsin, thrombin, plasmin, urokinase (uPA), Factor Vila, Factor IXa, and Factor Xa.
- the compounds of the invention will be useful in the treatment or prophylaxis of any one more cancers selected from: adenomas, carcinomas, leukaemias, lymphomas, melanomas, sarcomas and teratomas.
- cancers which may be inhibited include, but are not limited to, a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g. colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermal, liver, lung, for example adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, oesophagus, gall bladder, ovary, pancreas e.g.
- a carcinoma for example a carcinoma of the bladder, breast, colon (e.g. colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermal, liver, lung, for example adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, oesophagus, gall bladder, ovary, pancreas e.g.
- exocrine pancreatic carcinoma, stomach, cervix, thyroid, prostate, or skin for example squamous cell carcinoma
- a hematopoietic tumour of lymphoid lineage for example leukaemia, acute lymphocytic leukaemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma
- a hematopoietic tumour of myeloid lineage for example acute and chronic myelogenous leukaemias, myelodysplastic syndrome, or promyelocytic leukaemia
- thyroid follicular cancer a tumour of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma
- a tumour of the central or peripheral nervous system for example astrocytoma, neuroblastoma, glioma or schwannoma;
- One subset of cancers treatable according to the invention includes any one or more cancers selected from: breast cancer, ovarian cancer, colon cancer, prostate cancer, oesophageal cancer, squamous cancer and non-small cell lung carcinomas.
- conditions ameliorated by the inhibition of serine proteases are discussed throughout, and include, but are not limited to the said conditions. More particularly, the conditions can be selected from:-
- inflammatory and arthritic diseases and conditions such as Reiter's syndrome, acute synovitis, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis;
- chronic inflammatory lung diseases such as emphysema, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome and acute respiratory distress syndrome (ARDS);
- COPD chronic obstructive pulmonary disease
- ARDS acute respiratory distress syndrome
- lung diseases and conditions such as tuberculosis, silicosis, pulmonary sarcoidosis, pulmonary fibrosis and bacterial pneumonia;
- diseases and conditions selected from atherosclerosis; muscle degeneration; gout; cerebral malaria; bone resorption diseases; fever and myalgias due to infection, such as influenza; cachexia, in particular cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS); AK)S; ARC (AIDS related complex); keloid formation; scar tissue formation; pyresis and asthma.
- the invention provides a method for the prophylaxis or treatment of a disease state or condition of the type hereinbefore defined, which method comprises administering to a subject (e.g. a human subject) in need thereof a compound of the formula (I) as defined herein.
- a subject e.g. a human subject
- the invention also provides a compound of the formula (T) as defined herein for use in the prophylaxis or treatment of a disease state or condition mediated by a serine protease or its receptor.
- compounds of the invention are as serine protease inhibitors for anticoagulant use either embedded in or physically linked to devices, especially medical devices and materials used to make such devices used for example in collecting blood, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents.
- references to compounds of the formula (I) or formula (I 0 ) include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic mixtures) or two or more optical isomers, unless the context requires otherwise.
- optical isomers may be characterised and identified by their optical activity (i.e. as + and - isomers, or d and 1 isomers) or they may be characterised in terms of their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl, 1966, 5, 385-415.
- Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art.
- the compound of the formula (T) is present as a single optical isomer (e.g. enantiomer or diastereoisomer). In one general embodiment, 99% or more (e.g. substantially all) of the total amount of the compound of the formula (J) may be present as a single optical isomer (e.g. enantiomer or diastereoisomer).
- formula (I) and formula (I 0 ) are any polymorphic forms of the compounds, solvates (e.g. hydrates), complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds.
- the compounds of Formula I or formula (I 0 ) may also be solvated, especially hydrated. Hydration may occur during manufacturing of the compounds or compositions comprising the compounds, or the hydration may occur over time due to the hygroscopic nature of the compounds.
- N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
- N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
- MCPBA m-chloroperoxybenzoic acid
- prodrugs Certain compounds within the scope of Formula I or formula (I 0 ) are derivatives referred to as prodrugs.
- prodrug denotes a derivative of a known direct acting drug, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process; see Notari, R.
- the pharmaceutically acceptable acid addition salts those salts in which the anion does not contribute significantly to toxicity or pharmacological activity of the organic cation, are preferred.
- the acid addition salts are obtained either by reaction of an organic base of Formula
- organic or inorganic acid preferably by contact in solution, or by any of the standard methods detailed in the literature available to any practitioner skilled in the art.
- useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, cyclamic acid, pivalic acid and the like;
- useful inorganic acids are hydrohalide acids such as HCl, HBr, HI; sulfuric acid; phosphoric acid and the like.
- Preferred acids for forming acid addition salts include HCl and acetic acid.
- the compounds of the present invention represent a novel class of potent inhibitors of serine proteases, as exemplified by their inhibition of uPA in specific examples set out in more detail below.
- a specific end use application of the compounds that inhibit uPA is in treatment of tumours, especially solid tumours and cancers.
- the potency and other biochemical parameters of the en2yme-irihibiting characteristics of the compounds of the present invention is readily ascertained by standard biochemical techniques well known in the art.
- Actual dose ranges for their specific end-use application will, of course, depend upon the nature and severity of the disease state of the patient or animal to be treated, as determined by the attending diagnostician. It is expected that a useful dose range will be about 100 pg to 100 mg per kg per day, preferably from 10 ng to 10 mg per kg per day, more preferably from 1 ⁇ g to 10 mg per kg per day, for an effective therapeutic effect.
- Compounds of the present invention that inhibit serine proteases, including uPA or plasminogen activator, are potentially useful in treating excessive cell growth disease state.
- compounds of the present invention may also be useful in the treatment of benign prostatic hypertrophy and prostatic carcinoma, the treatment of psoriasis, and as abortifacients.
- the potency and other biochemical parameters of the enzyme inhibiting characteristics of compounds of the present invention are readily ascertained by standard biochemical techniques well known in the art. Actual dose ranges for this application will depend upon the nature and severity of the disease state of the patient or animal to be treated as determined by the attending diagnostician.
- a useful dose range will be about 100 pg to 100 mg per kg per day, preferably from 10 ng to 10 mg per kg per day, more preferably from 1 ⁇ g to 10 mg per kg per day, for an effective therapeutic effect.
- the pharmaceutical compositions of the invention can be administered to any animal that can experience the beneficial effects of the compounds of the invention. Foremost among such animals are humans, although the invention is not intended to be so limited.
- compositions of the present invention can be administered by any means that achieve their intended purpose.
- administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular routes.
- administration can be by the oral route.
- the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
- the new pharmaceutical reparations can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
- compositions of the present invention are manufactured in a manner that is, itself, known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
- pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
- Suitable excipients are, in particular, fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as, starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
- fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as, starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacan
- disintegrating agents can be added, such as, the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as, sodium alginate.
- Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as, magnesium stearate or calcium stearate, and/or polyethylene glycol.
- Dragee cores are provided with suitable coatings that, if desired, are resistant to gastric juices.
- concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
- suitable cellulose preparations such as, acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used.
- Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
- Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as, glycerol or sorbitol.
- the push-fit capsules can contain the active compounds in the form of granules that may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
- the active compounds are preferably dissolved or suspended in suitable liquids, such as, fatty oils or liquid paraffin.
- stabilizers may be added.
- Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, alkaline solutions and cyclodextrin inclusion complexes.
- Especially preferred salts are hydrochloride and acetate salts.
- One or more modified or unmodified cyclodextrins can be employed to stabilize and increase the water solubility of compounds of the present invention. Useful cyclodextrins for this purpose are disclosed in U.S. Pat. Nos. 4,727,064, 4,764,604, and 5,024,998.
- suspensions of the active compounds as appropriate oily injection suspensions can be administered.
- suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
- Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
- the suspension may also contain stabilizers.
- uronium-based coupling agents such as O- (7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and phosphonium-based coupling agents such as l-benzo-triazolyloxytris-(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (Castro et al, Tetrahedron Letters, 1990, 31, 205).
- Carbodiimide- based coupling agents are advantageously used in combination with l-hydroxy-7-azabenzotriazole (HOAt) (L. A. Carpino, /. Amer.
- Preferred coupling reagents include EDC (EDAC) and DCC in combination with HOAt or HOBt.
- the coupling reaction is typically carried out in a non-aqueous, non-protic solvent such as acetonitrile, dioxane, dimethylsulphoxide, dichloromethane, dimethylformamide or ⁇ - methylpyrrolidine, or in an aqueous solvent optionally together with one or more miscible co- solvents.
- a non-aqueous, non-protic solvent such as acetonitrile, dioxane, dimethylsulphoxide, dichloromethane, dimethylformamide or ⁇ - methylpyrrolidine
- an aqueous solvent optionally together with one or more miscible co- solvents.
- the reaction can be carried out at room temperature or, where the reactants are less reactive (for example in the case of electron-poor anilines bearing electron withdrawing groups such as sulphonamide groups) at an appropriately elevated temperature.
- the reaction may be carried out in the presence of a non-interfering base, for example a tertiary amine such as tri
- a tert-butyl-carbonyl protecting group must be removed from the primary amine to give the final product.
- This is conveniently carried out using dry hydrogen chloride gas in a range of organic solvents, for example, dioxane, ethyl acetate or methanol, or a combination of solvents, such as dioxane and methanol. Protection of one or more groups to prevent reaction from taking place at an undesirable location on the molecule is commonly carried out in organic synthesis. Examples of protecting groups, and methods of protecting and deprotecting functional groups, can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
- Scheme 2 illustrates the process for synthesis of Intermediate A, used in the preparation of examples of this invention. Alkylation of the commercially available phenol with N-(2- bromoethyl) phthalimide, followed by removal of the phthalimide protecting group and exchange for the tert-butyl carbamate (BOC) protecting group, and finally saponification to the acid gives A.
- Scheme 3 illustrates the process for production of intermediate B, used in the preparation of examples of this invention.
- the key transformations are the Friedel Crafts acylation of 2- methylanisole; the bromoform reaction to covert the ketone intermediate into the carboxylic acid; chlorination of 4-hydroxy-3-methyl-benzoic acid methyl ester; and Mitsunobu alkylation of the hindered phenol to form 4-(2-tert-butoxycarbonylamino-ethoxy)-3-chloro-5-methyl-benzoic acid methyl ester.
- the Friedel Crafts reaction is described below and similar conditions are outlined by Hauser et al, Journal of Organic Chemistry (2000), 65(6), 1842-1849.
- Mitsunobu chemistry can be carried out between a primary or secondary alcohol and an acidic compound such as a carboxylic acids, phenols, sulfonamides and certain classes of heterocycles.
- the Mitsunobu coupling reaction is typically carried out using diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and triphenylphosphine as the coupling agent in a polar solvent such as THF.
- DEAD diethylazodicarboxylate
- DIAD diisopropylazodicarboxylate
- THF triphenylphosphine
- Scheme 5 describes the synthesis of intermediate D. Nitration of 4-hydroxy-3-methyl-benzoic acid methyl ester was carried out according to standard procedures, e.g. from Advanced Organic Chemistry, by Jerry March, 4 th edition, 119, Wiley Interscience, New York; Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2), and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471- 31192-8). The remainder of the synthesis is similar to procedures outlined above.
- compounds of the invention can accordingly be prepared by coupling a protected compound of formula Ha to a compound of formula lib, followed by deprotecting, to yield a compound of formula I.
- compounds of formula Ha are selected from intermediates A, B, C, D and E.
- Intermediate F was prepared from intermediate A according to Scheme 7.
- the synthesis requires the use of a silyl protected alcohol intermediate as a masked function group (see Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
- Deprotection using TBAF revealed the alcohol, which was then oxidised under standard conditions, for example as outlined in Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8).
- This aldehyde intermediate was used to prepare a range of amine derivatives by reductive amination chemistry.
- Reductive amination is a very common reaction to allow a broad range of amines to be coupled to an aldehyde intermediate, and can often be used in the synthesis of combinatorial libraries.
- An example for the synthesis of a small library of compounds by a related method is Burns, et al, Bioorganic & Medicinal Chemistry Letters (2002), 12(9), 1263-1267.
- Scheme 8 illustrates the general process where compounds of this invention can be prepared by a reductive amination reaction.
- Formula IJJ Formula IV In further methods of preparing compounds of the invention, a protected compound of formula HI is converted to a compound of formula IV by reductive amination, and then deprotected, yielding a compound of formula I.
- the compound of formula III can be, by way of a specific example, intermediate F.
- aniline compounds are described below for use in this invention.
- Many anilines and amino heterocycles are commercially available or are easily prepared by functional group inter- conversion for example from aromatic nitro-compounds by reduction, or from benzoic acid compounds by use of the Curtius rearrangement.
- Functional group interconversions and reagents and conditions for carrying out such conversions can be found in, for example, Advanced Organic Chemistry, by Jerry March, 4 th edition, 119, Wiley Interscience, New York; Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2); and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471- 31192-8).
- anilines are useful for this invention that are produced from aromatic nitro compounds using nucleophilic aromatic substitution reactions in which a halogen is displaced by an amine.
- piperidine can be used to displace a fluorine or chlorine atom on an aromatic nitro compound to form a nitrophenyl piperidine derivative. Reduction of the nitro group then gives the aniline useful for this invention.
- SNAr chemistry is well know to those skilled in the art, and, for example is described by Tempest et al, Tetrahedron Letters (2003), 44(9), 1947-1950 and Greizerstein, Journal of the American Chemical Society (1962), 84 1032-6.
- biphenyl amines are useful for synthesis of compounds in this invention.
- Such compounds, and heterocyclic modifications of biphenyl compounds are readily prepared by palladium mediated coupling chemistries between aromatic bromo or iodo compounds and aromatic boronic acids or stannane derivatives.
- Suzuki coupling chemistry is broadly applicable to synthesis of aryl-aryl compounds.
- the Suzuki reaction can be carried out under typical conditions in the presence of a palladium catalyst such as bis(tri-t-butylphosphine)palladium and a base (e.g. a carbonate such as potassium carbonate).
- the reaction may be carried out in an aqueous solvent system, for example aqueous ethanol, and the reaction mixture is typically subjected to heating, for example to a temperature in excess of 100 0 C.
- aqueous solvent system for example aqueous ethanol
- heating for example to a temperature in excess of 100 0 C.
- Many boronates suitable for use in preparing compounds of the invention are commercially available, for example from Boron Molecular Limited of Noble Park, Australia, or from Combi-Blocks Inc, of San Diego, USA. Where the boronates are not commercially available, they can be prepared by methods known in the art, for example as described in the review article by N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457.
- boronates can be prepared by reacting the corresponding bromo-compound with an alkyl lithium such as butyl lithium and then reacting with a borate ester.
- the resulting boronate ester derivative can, if desired, be hydrolysed to give the corresponding boronic acid.
- Suitable reagents would be, for example, sulfonyl chlorides and amines or ureas, isocyanates and amines, carboxylic acids or acid chlorides with amines, Wittig reagents with aldehydes, aromatic boronic acids, alkynes, vinyl halides or organotin reagents with aryl halides, and the like.
- Olefins, formed by Wittig chemistry or Palladium mediated cross coupling reactions can be further elaborated to cyclopropanes using, for example, methods outlined in US6504031. These types of coupling chemistries are described in
- L is a heterocyclic linker, such as a 5-ring heterocycle or a bicyclic system
- a benzimidazole can be formed from a 1,2-dianiline by amide bond formation to a carboxylic acid, followed by ring closure by heating.
- an oxadiazole ring can be formed by peptide coupling of an amidoxime containing compound to a carboxylic acid, and the intermediate cyclised by heating.
- the compounds prepared were characterised by liquid chromatography and mass spectroscopy (LC/MS) using the system and operating conditions set out below. Where chlorine is present, the mass quoted for the compound is for 35 Cl. Where bromide is present the mass quoted for the compound is 79 Br.
- LC/MS liquid chromatography and mass spectroscopy
- PS-A2 Platform System - acidic analytical conditions PS-A3 Platform System - acidic analytical conditions 3
- LC-MS is a standard and effective method used for the purification of small organic molecules such as the compounds described herein.
- the methods for the liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide better separation of the crude materials and improved detection of the samples by MS.
- Optimisation of the preparative gradient LC method will involve varying columns, volatile eluents and modifiers, and gradients. Methods are well known in the art for optimising preparative LC-MS methods and then using them to purify compounds.
- Solvent A H 2 O + 10 mM NH 4 HCO 3 + NH4OH, pH 9.5
- Solvent B CH 3 CN
- Preparative LC-MS can thus be used to purify compounds of the invention.
- 5-nitroisophthalic acid methyl ester was refluxed for 1.5hr in thionyl chloride (20ml) under nitrogen. The mixture was cooled and the solvent removed in vacuo. The residues were dissolved in toluene and the solvent was again removed in vacuo. The resulting acid chloride was a white solid. This material was dissolved in DCM (5ml) and cooled in ice under nitrogen. A solution of piperidine (10ml) in DCM (10ml) was added very cautiously dropwise over 30mins. The mixture was then allowed to warm to room temperature and stirred for 18hrs. 2N HCl (100ml) and DCM (100ml) were added and the mixture extracted, the organic layer separated and then dried over MgSO 4 .
- the Boc-protected derivative was dissolved in a saturated solution of hydrogen chloride in ether (2-5ml) and stirred for 4-24 hours until the reaction was complete. Where the Boc-compound was poorly soluble in ether a 4M solution of hydrogen chloride in dioxane (2-5ml) was substituted. If the material still remained insoluble an equal volume of methanol was added. Once the reaction was complete (3-24hrs) the solvents were removed in vacuo to yield the target compound as its mono or di-hydrochloride salt, hi some cases the final products were triturated with ether, or rarely required further purification by preparative HPLC/MS.
- the compounds prepared are set out in a table at the end of the examples section.
- Example 16 From 3-(isopropoxy)aniline.
- 1 H NMR (MeOH-d 4 ) 7.90 (IH, s), 7.80 (IH, s), 7.40 (IH, s), 7.25 (2H, s), 6.70 (IH, m), 4.60 (IH, m), 4.25 (2H, t), 3.45 (2H, t), 2.45 (3H, s), 1.35 (6H, d).
- Example 42 From S-amino-S-Cpiperidine-l-carbony ⁇ -N-propyl-benzamide.
- 1 H NMR (MeOH-(I 4 ) 8.20 (IH, s), 8.00 (IH, s), 7.71 (2H, s), 7.54 (IH, s), 4.10 (2H, t), 3.75 (2H, bs), 3.33-3.48 (6H, m), 2.41 (6H, s), 1.58-1.80 (8H, m), 1.01 (3H, t).
- Example 48 From 3-(isopropyloxy)aniline.
- 1 H NMR (DMSO-d 6 ) 10.05 (IH, s), 8.80 (3H, br s), 7.42 (IH, s), 7.31 (3H, m), 7.21 (IH, t), 6.63 (IH, d), 4.54 (IH, m), 4.04 (2H 3 1), 3.28 (2H, m), 2.32 (3H, s), 1.27 (6H, d).
- Example 50 From 6-amino-2-(tert-butyloxycarbonyl)-l,2,3,4-tetrahydroisoquinoline.
- 1 H NMR (DMSO-d 6 ) 10.18 (IH, s), 9.50 (2H, br s), 8.41 (3H, br s), 7.69 (3H, s), 7.62 (IH, d), 7.18 (IH, d), 4.21 (2H, m), 3.89 (2H, m), 3.62 (IH, m), 3.38 (2H, m), 3.02 (2H, t), 2.32 (6H, s), 1.38 (3H, d).
- Example 58 From 2-allyl-4-ethyl-l,2,3,4-tetrahydroisoquinolin-6-ylamine. (Ref. J. Med. Chem. (2004), 47 (2), 303-324).
- 1 H NMR (MeOH-d 4 ) 7.85 (IH, s), 7.72 (2H, s), 7.61 (IH 5 d), 7.25 (IH, d), 4.35 (2H 5 s), 3.95 (2H, m), 3.82 (IH, m), 3.62 (IH 5 m),3.34 (IH, m), 3.22 (IH 5 m) 5 2.41 (6H 5 s), 2.05 (IH, m), 1.85 (IH, m) 5 1.52 (3H, d), 1.05 (3H, t).
- the reaction mixture was diluted with DCM (20ml) and water (20ml) and extracted. The organic layer was separated and dried over MgSO 4 .
- the solvents were evaporated and the crude reaction mixture purified using a 1Og silica SPE cartridge, eluting with ether and then ether/methanol.
- the major product was an oil (43mg) and half of the material was dissolved in methanol (ImI) and treated with a saturated solution of hydrogen chloride in ether (ImI). The solvents were removed to give the product as a HCl salt (22mg as a solid).
- Example 68 ⁇ 3-f4-(2-Amino-ethoxy)-3.5-dimethylbenzoylaminol-5-isopropoxy-phenoxy>-acetic acid
- a solution of ⁇ 3-[4-(2-Amino-ethoxy)-3,5-dimethyl-benzoylamino]-5-isopropoxy-phenoxy ⁇ -acetic acid methyl ester hydrochloride (50 mg, 0.107 mmol), lithium hydroxide (5.1 mg, 0.214 mmol) in THF (2 ml) and water (1 ml) were stirred at room temperature for 12 h. The solvent was removed in vacuo and the residue submitted to preparative HPLC/MS to afford the product as a white solid (15 mg, 37%).
- Example 72 3 '-[4-(2-Amino-ethoxyV3,5-dimethyl-benzoylamino1-biphenyl-2-yloxyl -acetic acid Prepared from ⁇ 3 ' -[4-(2-Amino-ethoxy)-3 ,5 -dimethyl-benzoylamino] -biphenyl-2-yloxy ⁇ -acetic acid methyl ester hydrochloride by the saponification method described above to afford, after purification (preparative HPLC) the product as a white solid (80 mg, 64%).
- N-(2-bromoethyl)phthalimide (1.1 equivalents) was then added and the reaction allowed to stir at 13O 0 C for 12 hours. Progress of the reaction was followed by tic (1:4 EtO Ac/petrol). Potassium carbonate (1.1 equivalents was then added and the reaction allowed to stir at 13O 0 C for a further 6 hours. The reaction was then cooled, reduced in vacuo and partitioned between EtOAc and sodium hydroxide (0.5M)(aq) and the organics washed with H 2 O. Material dried over magnesium sulfate, reduced in vacuo and purified by column chromatography eluting with 1:9 EtOAc/petrol to give the title compound as a colourless crystalline solid (155mg).
- Method 1 Activity of uPA was measured using the peptide Z-Gly-Gly- Arg-AMC from Bachem as substrate 1.
- Compounds were incubated with uPA and 25 ⁇ M peptide substrate 1 in 50 mM Tris, pH 7.5, 0.1 % PEG, 2 % DMSO in 96-well black, flat bottomed Cliniplates in a final assay volume of 50 ⁇ l.
- the reaction rate was monitored at room temperature on a Gemini XS (Molecular Devices) platereader with excitation and emission wavelengths of 365nm and 460nm respectively.
- Initial reaction rates were measured and ICsos were calculated from replicate curves using GraphPad Prism software.
- the present invention thus provides compounds for use as serine protease inhibitors and novel therapies based thereon.
- the present invention also provides a pharmacophore that enables design of compounds that bind to Ser-190 Trypsin-like serine proteases, most preferably Urokinase (uPA), Factor Vila, Factor DCa, and beta - Tryptase, which can preferably act as therapeutically useful inhibitors, and interact with the protein or proteins by binding to the Sl pocket and also preferably to adjacent sub-pockets in the active site region, according to specified pharmacophoric interactions described in this invention.
- uPA Urokinase
- Factor Vila Factor Vila
- Factor DCa Factor DCa
- beta - Tryptase which can preferably act as therapeutically useful inhibitors, and interact with the protein or proteins by binding to the Sl pocket and also preferably to adjacent sub-pockets in the active site region, according to specified pharmacophoric interactions described in this invention.
- amidine, benzamidine or, in particular, a naphthamidine moiety of the type known in existing serine 190 Trypsin-like serine protease inhibitors, can be replaced with a non-amidine moiety.
- amidine, benzamidine and naphthamidine containing compounds are disclosed in the prior art as inhibitors of Ser-190 Trypsin-like serine proteases, such as uPA, Factor Vila, Factor IXa, and beta -Tryptase.
- Compounds of some embodiments of the invention may not have biological activity in an enzyme assay, but are useful as starting points for structure guided optimisation in order to derive larger, more functionalised compounds that are enzyme inhibitors, useful ligands, and therapeutically useful agents.
- the present invention provides a pharmacophore comprising a motif that binds to the Sl pocket of Ser-190 Trypsin-like serine proteases, typically containing an amino group with a pKa of ⁇ 9.0.
- the invention provides inhibitors of Ser-190 Trypsin-like serine proteases and enables design of further inhibitors of Ser-190 Trypsin-like serine proteases, preferably with better pharmaceutical properties, especially orally bioavailable drugs.
- Mexiletine is a representative of the pharmacophore claimed. Mexiletine is a known drug, a class Ib antiarrhythmic agent; with bioavailability of about 90%; and weakly bound to plasma proteins (70%). Its volume of distribution is large and varies from 5 to 9 L/kg in healthy individuals. Mexiletine is eliminated slowly in humans (with an elimination half-life of 10 h).
- the invention is based on the observation that Mexiletine can bind to the Sl specificity pocket of Ser-190 serine proteases, as indicated by X-ray structural determination in the enzyme Urokinase.
- the pharmacophore scheme illustrated in Formula A represents compounds of a first aspect of the invention, and can be used to design therapeutically useful inhibitors of Trypsin-like serine proteases.
- the compounds of the invention preferably have a primary amino functionality with a pka value in the range 7-9.5.
- two carbons link the primary amine to an oxygen, which is linked to an aromatic scaffold.
- a benzene ring can be attached to the oxygen atom.
- a heterocyclic ring system is used as a replacement.
- A, B, and C are amino acid residues in the protease and are described below, cl, c2 and c3 form part of a ring such as a 5- or 6 membered aromatic (e.g. aryl or heteroaryl) or heterocyclic ring.
- the pharmacophore is represented by Formula 1 (as described in Part I of this application), where T is a linker group, designed using the principles of structure-based drug design described below, and knowledge of the binding site of the Trypsin-like serine protease of interest.
- T could be for example a halogen, sulphonamide, or a heterocyclic group or a similar polar group, from which further groups are appended to bind to the active site.
- uPA Trypsin-like serine protease Urokinase
- the present invention hence provides a compound which is capable of binding a trypsin-like serine protease and comprises a pharmacophore of Formula 1-X as hereinbefore defined.
- Particular compounds within formula I are those wherein:
- V is selected from methyl, chlorine, bromine or a similar lipophilic group or is defined according to formulas 2b, 3b and 4b below,
- W is selected from methyl, chlorine, bromine or a similar lipophilic group or can be a heteroatom, such as N, S or O, for example an amino group, or is defined according to formulas 2b, 3b and 4b below,
- R m , R n , R p and R q are selected from 4. H; 5. Me or R m and R n , R p and R q , or R m and R q form a cyclopropane ring, or are defined according to formulae 2b, 3b and 4b below.
- V 5 W, X, Y and/or T is carbon
- the carbon atom may be sp3, sp2 or sp hybridised and hence attached to any group by a single, double or triple bond.
- the invention further includes compounds where V, W, X, Y and/or T may be carbon or a heteroatom such as N, O or S, attached to hydrogen, any functional group or molecular scaffold.
- the Rn-q groups and the group V sit against the hydrophobic phase of the Sl pocket, forming van der Waals contacts.
- the group W sits against a di-sulphide bridge (e.g. Cys 193-Cys 221 in Urokinase), again forming van der Waals contacts and additionally can pick up additional interactions in the Sl -beta pocket.
- the nature of the interactions in the Sl beta pocket can vary, depending on the particular residues present in the Trypsin-like serine protease of interest. For example, in Urokinase, a H-bond with Lys 141 can be targeted.
- the choice of W will be defined using structure-based drug design principles, depending on the residues present in this region in the Trypsin-like serine protease of interest.
- the pharmacophore of the invention enables design of useful molecules with therapeutic activity.
- compounds are designed with activity in inhibiting uPA, as an example of a Ser-190 Trypsin-like serine protease
- Slbeta adjacent to the Sl pocket of Urokinase other binding pockets are present termed Slbeta, S2, S4 and Sl'. These pockets have side-chain preferences, which introduce specificity for the substrates of the proteases, and preferably compounds identified herein interact with one or more of these pockets.
- the amino acid residues in the different binding pockets of the Trypsin-like serine protease Urokinase are recited in Table 2.
- the present invention hence provides compounds that match the pharmacophore described above, and additionally are designed, using structure-based drug design approaches (described below) and a knowledge of the Trypsin-like serine protease of interest, that present functional groups that are suitable for binding in the Sl, Sl ⁇ . S2, S4 and/or Sl' pockets.
- pharmacophore points are used to define the type of functionality preferred for each S' or S pocket in Urokinase. They are described as weighted average positions in three-dimensional space. The distances between each pharmacophore point and the C- ⁇ atom of selected protein residues are reported in Table 3. Table 3. Pharmacophore points (residue numbering taken from lowk * )
- the present invention provides a method of identifying compounds which are modulators, such as inhibitors, of a Trypsin-like serine protease, the method comprising:
- a candidate modulator e.g. an inhibitor using the pharmacophore represented by Formula A or 1-X or a compound as defined herein;
- the present invention provides a method of identifying compounds which are modulators, such as inhibitors, of a Trypsin-like serine protease, the method comprising:
- a candidate modulator e.g. an inhibitor using the pharmacophore represented by Formula A or 1 -X or a compound as defined herein by replacing the amidine, benzamidine, or especially a naphthamidine group with the moiety from the pharmacophore of this invention; (c) optionally modifying the compound based on the result of the fitting step; and
- steps (a)-(c) are carried out in silico, e.g. using computer modelling as discussed in more details below.
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Abstract
This invention relates to a novel class of substituted amino-ethoxy benzene derivatives of formula (I) which are inhibitors of serine proteases and to their use in treating aberrant serine protease activity in a mammal, contraception, anti-coagulant methods and methods for treating aberrant cell proliferation, tumours, cancer, angiogenesis, angiogenesis-based retinopathies, autoimmummune disease, inflammation, skin disease, arthritis, rheutmatoid arthritis, asthma, osteoarthritis and multiple sclerosis. (I), Wherein Rm, Rn, Rp, Rq, V, W, X, Y and R8 are as defined in the claims.
Description
THERAPEUTIC COMPOUNDS
This invention relates to therapeutic compounds which are inhibitors of serine proteases, to pharmaceutical compositions thereof and to their use in the treatment of the human or animal body. The present invention also relates to trypsin-like serine protease pharmacophores, and in particular to compounds which bind to and inhibit such proteases and methods of obtaining such compounds using the pharmacophores. The present invention further relates to compositions, methods and uses of the compounds and pharmacophores.
Background Of The Invention
Proteases or proteolytic enzymes are essential in organisms, from bacteria and viruses to mammals. Proteases digest and degrade proteins by hydrolyzing peptide bonds. Serine proteases (EC. 3.4.21) have common features in the active site, primarily an active serine residue. There are two main types of serine proteases; the chymotrypsin/trypsin/elastase-like and subtilisin-like, which have an identical spatial arrangement of catalytic His, Asp, and Ser but in quite different protein scaffolds. However, over twenty families (S1-S27) of serine proteases have been identified that are grouped into 6 clans on the basis of structural similarity and other functional evidence, SA, SB, SC, SE, SF & SG. The family of chymotrypsin/trypsin/elastase-like serine proteases have been subdivided into two classes. The "large" class (ca 230 residues) includes mostly mammalian enzymes such as trypsin, chymotrypsin, elastase, kallikrein, and thrombin. The "small" class (ca 190 residues) includes the bacterial enzymes.
The catalytic His, Asp and Ser are flanked by substrate amino acid side chain residue binding pockets termed Sl', S2', S3' etc on the C-terminal or 'prime' side of the substrate and Sl, S2, S3 etc on the N-terminal side. This nomenclature is as described in Structure and Mechanism in Protein Science: A Guide to Enzyme Catalysis and Protein Folding, Alan Fersht, 1999 (W.H. Freeman and Company) pages 40-43 and Brik et al, Org. Biomol. Chem., 2003, 1, 5-14. The chymotrypsin/trypsin/elastase-like serine proteases can also be further subdivided by the residues present in the Sl pocket as described in Introduction to Protein Structure, Carl Branden and John Tooze, 1991 (Garland Publishing Inc) pages 231-241. The subdivisions are chymotrypsin-like (Gly-226, Ser-189 and Gly-216 in Sl pocket), trypsin-like (Gly-226, Asp-189 and Gly-216 in Sl) and elastase-like (Val-226 and Thr-216 in Sl) where the residues numbering is taken from the standard chymotrypsin numbering. The trypsin-like serine proteases prefer substrates which place either Lys or Arg in the Sl pocket.
The principal eukaryotic trypsin-like serine proteases are listed below according to their SwissProt code, their common name (where relevant) and the residue they possess at position 190 (in the chymotrypsin numbering):
SwissProt Code Common Name Residue at 190
ACRO JHUMAN T
KLK8 JHUMAN T
TMS4 JHUMAN T
APOAJHUMAN S
C1S_HUMAN complement CIS S
CFADJHUMAN S
CORI_HUMAN S
ENTK_HUMAN S
FA7_HUMAN factor VHa S
FA9JΪUMAN factor IX S
GRAA_HUMAN S
GRAK_HUMAN S
KLK4JHUMAN S
KLK5_HUMAN S
KLK6_HUMAN S
KLKB_HUMAN S
KLKD_HUMAN S
KLKE_HUMAN S
MAS2_HUMAN S
NETRJHUMAN neurotrypsin S
PLMN_HUMAN plasmin S
ST14_HUMAN matriptase S
TMS2_HUMAN S
TMS3_HUMAN S
TRB1_HUMAN tryptase betal S
TRB2_HUMAN tryptase beta2 S
TRY1_HUMAN trypsin I S
TRY2JHUMAN trypsin π S
TRY3_HUMAN trypsin m S
TRY4 HUMAN S
TRYD_HUMAN tryptase delta S
UROKJHUMAN urokinase S
BSS4_HUMAN A
ClRJHUMAN complement ClR A CFAI_HUMAN complement factor 1 A
CRARJffUMAN A
DES1_HUMAN A
FA10_HUMAN factor X A
FA11_HUMAN A
FA12JHUMAN A
HATT_HUMAN A
HEPS_HUMAN hepsin A
HGFA_HUMAN A
KAL_HUMAN A
KLKCJΪUMAN A
MPN_HUMAN A
PRTC_HUMAN A
PSS8_HUMAN A
TEST_HUMAN A
THRB_HUMAN thrombin A
TMS5_HUMAN A
TPAJIUMAN A
TRYGJHUMAN tryptase gamma A
Many of the above enzymes are of therapeutic interest for a broad range of diseases. In particular, Thrombin and Factor Xa have been extensively studied in an attempt to identify drugs useful in treating cardiovascular disease, and more recently Factors Vila and Factor IXa are also being studied for the same application. Urokinase has been studied in an attempt to identify inhibitors that might be useful in treating human cancers and for other therapeutic uses. Beta-Tryptase inhibitors may be useful in the treatment of asthma and inflammatory diseases. For a discussion of the therapeutic potential of inhibitors of trypsin-like serine proteases see, Dies et al, Expert Opinion in Therapeutic Patents, 2002, 1181-1214.
Trypsin-like serine proteases can be further categorised by the residue at position 190 (chymotrypsin numbering). In some of the family members, for example thrombin and Factor Xa, the residue at this position is Ala. In others, for example Urokinase, Factor Vila, FactorIXa and beta-Tryptase, the residue at this position is Ser. This has an important consequence to the properties of the key Sl specificity pocket. The AIa-190 enzymes have a more lipophilic Sl pocket than the Ser-190 enzymes, and although both types of protein still recognise Arg, the AIa-190 enzymes can be inhibited by peptidomimetics or small molecule inhibitors that contain neutral (non-basic) resides that do not directly mimic Arg, e.g. see Hies et al, Expert Opinion in Therapeutic Patents, 2002, 1181-1214. However, those enzymes that have Ser-190 in the Sl pocket are usually only inhibited by molecules that contain a strongly basic group that occupies the Sl pocket, binding to Asp-189 and to Ser-190. Despite many years of research little progress has been made to identify less-basic compounds that are useful inhibitors for Ser-190 enzymes; i.e. basic groups with a pKa of <9. Indeed, most inhibitors of Ser-190 enzymes contain an amidine or benzamidine group and it is well known that such a group imparts poor pharmaceutical properties to the compound, especially in terms of very low oral bioavailability.
Factor Vila (FVIIa) is a key serine protease involved in the initiation of the coagulation cascade. It is a glycosylated disulfide-linked heterodimer comprised of an ammo-terminal D-carboxyglutamic acid-rich (GIa) domain and two epidermal growth factor (EGF)-like domains in the light chain, and a trypsin-like serine protease domain in the heavy chain. FVIIa requires tissue factor (TF), a membrane bound protein, as an essential cofactor for maximal activity towards its biological substrates Factor X, Factor IX and Factor VII (FVII). Inhibition of TF'FVHa activity may prevent the formation of fibrin clots and thus be useful in the management of thrombotic disease. The development of TF'FVIIa inhibitors to validate this target has been of great interest. A wide array of strategic approaches to inhibiting the biochemical and biological functions of the TF'FVIIa complex has been pursued. This has been greatly aided from our understanding of the structures for TF, FVπ, FVIIa, and the TF'FVTIa complex. These approaches have resulted in inhibitors directed specifically towards either FVIIa or TF. Antagonists include active site inhibited FVIIa, TF mutants, anti-TF antibodies, anti-FVII/FVIIa antibodies, naturally-occurring protein inhibitors, peptide exosite inhibitors, and protein and small molecule active site inhibitors. These antagonists can inhibit catalysis directly at the active site as well as impair function by binding to exosites that may interfere with substrate, membrane, or cofactor binding. For a review see Lazarus et al, Current Medicinal Chemistry, 2004, 11, 2275-2290.
A recent paper describes inhibitors of factor IXa as anti-coagulation agents; Batt, et al, Bioorganic & Medicinal Chemistry Letters (2004), 14(21), 5269-5273.
Tryptase (EC 3.4.21.59) is a homotetrameric, trypsin-like serine protease that constitutes 20-25% of the total protein of human mast cells. Since it is stored in a catalytically active form (rather than as a 2ymogen) within the secretory granules and released on stimulation, this enzyme is highly relevant to mast cell dependent inflammatory conditions. Tryptase has been directly implicated in the pathology of asthma. Thus, tryptase inhibitors have therapeutic potential for treating allergic or inflammatory disorders such as asthma, vascular injury, inflammatory bowel disease, and psoriasis. For a review see Bradley, Tryptase inhibitors - review of the recent patent literature. IDrugs (2002), 5(7), 682-688.
The serine proteases have a common catalytic mechanism characterized by a particularly reactive Ser residue at position 195 using the chymotrypsin numbering system. Examples of serine proteases are descrribed above and include trypsin, tryptase, chymotrypsin, elastase, thrombin, plasmin, kallikrein, Complement Cl, acrosomal protease, lysosomal protease, cocoonase, α-lytic protease, protease A, protease B, serine carboxypeptidase π, subtilisin, urokinase (uPA), Factor
Vila, Factor IXa, and Factor Xa. The serine proteases have been investigated extensively for many years and are a major focus of research as a drug target due to their role in regulating a wide variety of physiological processes.
Processes involving serine proteases include coagulation, fibrinolysis, fertilization, development, malignancy, neuromuscular patterning and inflammation. It is well known that these compounds inhibit a variety of circulating proteases as well as proteases that are activated or released in tissue. It is also known that serine protease inhibitors inhibit critical cellular processes, such as adhesion, migration, free radical production and apoptosis. La addition, animal experiments indicate that intravenously administered serine protease inhibitors, variants or cells expressing serine protease inhibitors, provide protection against tissue damage.
Serine protease inhibitors have also been predicted to have potential beneficial uses in the treatment of disease in a wide variety of clinical areas such as oncology, neurology, haematology, pulmonary medicine, immunology, inflammation and infectious disease. Serine protease inhibitors may also be beneficial in the treatment of thrombotic diseases, asthma, emphysema, cirrhosis, arthritis, carcinoma, melanoma, restenosis, atheroma, trauma, shock and reperfusion injury. A useful review is found in Expert Opin. Ther. Patents (2002), 12(8).
The conventional method of treatment of cancers involves chemotherapy, often administered at high levels with severe side effects. Recent advances have made progress in improving patient longevity and improving the quality of life for those undergoing treatment. Nevertheless, chemotherapy still has disadvantages. Most pharmaceutical interventions to treat cancer have
common side effects, including nausea, vomiting, bone-marrow suppression, alopecia and impaired reproductive function. Even after apparently successful treatment, dormant cancer cells may lead to relapse many years into the future.
Most cancer deaths are not caused by the growth of the primary tumor but result from its invasive spread to secondary sites (metastases). Although the underlying biochemical processes for metastasis are still not fully understood, a large body of research has shown that the uPA system plays a major role in metastasis and primary tumor growth. The uPA system is an extra-cellular protease enzyme system which is over-expressed on, for example, aggressive metastasizing solid tumors.
The uP A system consists of:
- urokinase (or uPA);
- its physiological inhibitor (PAI-I);
- and the uPA-receptor (uPAR) which is over-expressed on tumor cells.
Proteases or proteolytic enzymes are essential in organisms, from bacteria and viruses to mammals. Proteases digest and degrade proteins by hydrolyzing peptide bonds. Serine proteases (EC. 3.4.21) are one type that have an active serine residue. There are two main types of serine proteases; the trypsin-like and subtilisin-like, which have an identical spatial arrangement of catalytic His, Asp, and Ser but in quite different protein scaffolds. uPA is a member of the trypsin-like serine protease family.
The uPA system triggers proteolytic processes through which tumor cells are enabled to degrade their surrounding tissue (the extracellular matrix or ECM), to invade into healthy tissue and blood vessels and thus to migrate and form new tumors at distant sites. In addition, the uPA-system interacts with other molecular-biological systems, and thus promotes primary tumor growth.
Through the binding of uPA to the uPA receptor (uPAR), uPA converts the zymogen plasminogen to plasmin, an enzyme which degrades fibrin and numerous other components of the extracellular matrix, such as type IV collagen, fibronectin and laminin. This likely enables tumor cells to migrate through tissue barriers
Degradation of ECM helps tumor cells to invade into adjacent tissues and, eventually, into the blood circulation. It also promotes the release of various growth factors such as EGF, bFGF, and HGF/SC that are otherwise sequestrated by intact ECM. Furthermore, uPA and plasminogen may activate other families of protein-cleaving enzymes such as metalloproteinases (MMPs), which along with uPA promote tumor cell invasion and angiogenesis. Several studies provided evidence
that the expression of active uPA by malignant cells correlates with their invasive potential - see review by Keleg, S. et al, "Invasion and metastasis in pancreatic cancer" in Molecular Cancer 2003, 2:14.
The enzymatic activity of uPA is controlled by a number of inhibitors. One of these inhibitors, PAI-I, inhibits uPA when it is bound to its cell surface receptor uPAR. After PAI-I binds to the uPA/uPAR complex, the cell internalizes all three molecules. uPA and PAI-I are degraded and uPAR is recycled to the cell surface ready to bind another uPA molecule. Thus, there is a positive correlation between high PAI-I expression and tumor metastasis.
The binding of uPA to uPAR transduces growth promoting signals in tumor cells, events which are separate from its enzymatic activity. In addition, uPAR interacts with vitronectin and integrins, which are involved in cell adhesion and signal transduction.
Thus, tumor cells acquire growth and survival advantages by overexpressing the uPA system, which promotes the growth, invasion, and metastatic spread of tumor cells via multiple mechanisms. This makes the uPA system an attractive target for the development of cancer drugs. Such agents could benefit by acting at multiple points of the tumour growth and metastatic process.
Over the last decade, substantial scientific evidence has demonstrated that components of the uPA system play a key role in metastasis. The clinical significance of these components was supported by numerous publications. Examination of human cancers led to the discovery of uPA over- expression in a wide range of tumor types including breast, gastric and ovarian cancer. In a number of different cancers, high levels of uPA and PAI-I have been shown to be associated with unfavorable disease progression, whereas low levels of uPA and PAI-I are associated with a more favorable prognosis. Both uPA and PAI-I have a strong prognostic impact on disease-free survival and overall survival. Patients with high levels of both uPA and PAI-I expressions have a significantly shorter disease-free survival and overall survival than those with low levels. uPA and PAI-I have been qualified as new prognostic markers of breast cancer with the highest level of evidence (LOE-I) by the European Organization for Research and Treatment of Cancer (EORTC).
uPA inhibitors are known (e.g. Wilex compounds WX-UKl and WX-671), and at least one is currently in clinical trials. Further and preferably improved uPA inhibitors are desired to offer additional options for treatment of cancer with reduced toxicity-related side effects.
uPA is also implicated in diseases associated with angiogenesis. These include but are not limited to angiogenesis-based retinopathies, arthritis, skin disease including inflammatory skin disease for example psoriasis, asthma, chronic respiratory disease including chronic obstructive pulmonary
disease (COPD), osteoarthritis, HIV and multiple sclerosis. For these conditions too there is a need for further and preferably improved uPA inhibitors. uPA inhibitors are also found to have contraceptive activity - again, provision of further and preferably better inhibitors is desired. Specifically, aberrant uPA activity is described by Mondino, Anna; Blasi, Francesco, "uPA and uPAR in fibrinolysis, immunity and pathology", Trends in Immunology (2004), 25(8), 450-455; by Kucharewicz, Iwona; Kowal, Krzysztof; Buczko, Wlodzimierz; Bodzenta-Lukaszyk, Anna, "The plasmin system in airway remodeling", Thrombosis Research (2003), Volume Date 2004, 112(1-2), 1-7; by Degryse, Bernard, "Is uPAR the centre of a sensing system involved in the regulation of inflammation?", Current Medicinal Chemistry: Anti-Inflammatory & Anti-Allergy Agents (2003), 2(3), 237-259; and Alfano, Massimo; Sidenius, Nicolai; Blasi, Francesco; and by PoIi, Guido, "The role of urokinase-type plasminogen activator (uPA)/uPA receptor in HIV-I infection", Journal of Leukocyte Biology (2003), 74(5), 750-756.
Angiogenesis is generally used to describe the development of new or replacement blood vessels, or neovascularisation. It is a necessary and physiological normal process by which the vasculature is established in the embryo. Angiogenesis does not occur, in general, in most normal adult tissues, exceptions being sites of ovulation, menses and wound healing. Many diseases, however, are characterized by persistent and unregulated angiogenesis.
In arthritis, new capillary blood vessels invade the joint and destroy cartilage (Colville-Nash and Scott, Ann. Rhum. Dis., 51, 919 (1992)). In diabetes (and in many different eye diseases), new vessels invade the macula or retina or other ocular structures, and may cause blindness (Brooks, et al , Cell, 79, 1157 (1994)). The process of atherosclerosis has been linked to angiogenesis (Kahlon, et al, Can. J. Cardiol, 8, 60 (1992)). Tumor growth and metastasis have been found to be angiogenesis-dependent (Folkman, Cancer Biol, 3, 65 (1992); Denekamp, Br. J. Rad., 66,181 (1993); Fidler and ElUs, Cell, 79,185 (1994)).
In addition, chronic proliferative diseases are often accompanied by profound angiogenesis, which can contribute to or maintain an inflammatory and/or proliferative state, or which leads to tissue destruction through the invasive proliferation of blood vessels. (Folkman, EXS, 79, 1-81 (1997); Folkman, Nature Medicine, 1, 27-31 (1995); Folkman and Shing, J. Biol. Chem., 267, 10931 (1992)).
The recognition of the involvement of angiogenesis in major diseases has been accompanied by research to identify and develop inhibitors of angiogenesis. These inhibitors are generally classified in response to discrete targets in the angiogenesis cascade, such as activation of endothelial cells by an angiogenic signal; synthesis and release of degradative enzymes; endothelial cell migration;
proliferation of endothelial cells; and formation of capillary tubules. Therefore, angiogenesis occurs in many stages and attempts are underway to discover and develop compounds that work to block angiogenesis at these various stages.
There are publications that teach that inhibitors of angiogenesis, working by diverse mechanisms, are beneficial in diseases such as cancer and metastasis (O'Reilly, et al, Cell, 19, 315 (1994); Ingber, et al, Nature, 348, 555 (1990)), ocular diseases (Friedlander, et al, Science, 270,1500 (1995)), arthritis (Peacock, et al, J. Exp. Med., 175, 1135 (1992); Peacock et al, Cell. Immun., 160,178 (1995)) and hemangioma (Taraboletti, et al, J. Natl. Cancer Inst, 87, 293 (1995)).
Various serine proteases, including urokinase, are known to be implicated in angiogenesis - see "Urokinase-dependent angiogenesis in vitro and diacylglycerol production are blocked by antisense oligonucleotides against the urokinase receptor", Fibbi, Gabriella; Caldini, Riccardo; Chevanne, Marta; Pucci, Marco; Schiavone, Nicola; Morbidelli, Lucia; Parenti, Astrid; Granger, Harris J.; Del Rosso, Mario; Ziche, Marina; Istituto di Patologia Generale, Universita' di Firenze, Viale Morgagni, Florence, Italy; Laboratory Investigation (1998), 78(9), 1109-1119.
Gveric, D. et al, in "Implications for the inflammatory response and axonal damage" Brain, Vol. 124, No. 10, 1978-1988, October 2001 have described plasminogen activators in multiple sclerosis lesions. Components of the plasminogen activator (PA) and matrix metalloprotease (MMP) cascade have been characterized in multiple sclerosis lesions by immunohistochemistry, enzyme-linked immunosorbent assay and enzyme activity assays in order to establish a functional role for the enzyme sequence in lesion development. Highly significant quantitative increases in uPA, urokinase receptor (uPAR) and plasminogen activator inhibitor- 1 were detected in acute multiple sclerosis lesions.
Factor Vila (FVTIa) is a key serine protease involved in the initiation of the coagulation cascade. It is a glycosylated disulfide-linked heterodimer comprised of an ammo-terminal γ-carboxyglutamic acid-rich (GIa) domain and two epidermal growth factor (EGF)-like domains in the light chain, and a chymotrypsin-like serine protease domain in the heavy chain. FVIIa requires tissue factor (TF), a membrane bound protein, as an essential cofactor for maximal activity towards its biological substrates Factor X, Factor IX and Factor VEt (FVTT). Inhibition of TF-FVIIa activity may prevent the formation of fibrin clots and thus be useful in the management of thrombotic disease. The development of TFrFVHa inhibitors to validate this target has been of great interest. A wide array of strategic approaches to inhibiting the biochemical and biological functions of the TFrFVIIa complex has been pursued. This has been greatly aided from our understanding of the structures for TF, FVπ, FVIIa, and the TFrFVIIa complex. These approaches have resulted in inhibitors directed
specifically towards either FVIIa or TF. Antagonists include active site inhibited FVIIa, TF mutants, anti-TF antibodies, anti-FVII/FVIIa antibodies, naturally-occurring protein inhibitors, peptide exosite inhibitors, and protein and small molecule active site inhibitors. These antagonists can inhibit catalysis directly at the active site as well as impair function by binding to exosites that may interfere with substrate, membrane, or cofactor binding. For a review see Lazarus et al, Current Medicinal Chemistry, 2004, 11, 2275-2290.
A recent paper describes inhibitors of factor IXa as anti-coagulation agents; Batt, et al, Bioorganic & Medicinal Chemistry Letters (2004), 14(21), 5269-5273.
Tryptase (EC 3.4.21.59) is a homotetrameric, trypsin-like serine protease that constitutes 20-25% of the total protein of human mast cells. Since it is stored in a catalytically active form (rather than as a zymogen) within the secretory granules and released on stimulation, this enzyme is highly relevant to mast cell dependent inflammatory conditions. Tryptase has been directly implicated in the pathology of asthma. Thus, tryptase inhibitors have therapeutic potential for treating allergic or inflammatory disorders such as asthma, vascular injury, inflammatory bowel disease, and psoriasis. For a review see Bradley, Tryptase inhibitors - review of the recent patent literature. IDrugs
(2002), 5(7), 682-688.
uPA inhibitors are described in US 6504031, US 2001/0049374 and WO 01/81314, based around substituted naphthamidine compounds.
A series of substituted benzanilides, including benzamides, are known as modulators of the CCR5 receptor, and described in WO 98/50343, WO 98/50346, WO2004/010943 and WO 2004/011427. The compounds are broadly defined and there is no mention therein of use to inhibit serine proteases.
US 2004/0224967 (Chen) discloses a class of pyrirnidin-2-ylaminophenyl compounds as tyrosine kinase inhibitors. Example 1 in this document describes the preparation of the compound 4-(2- ammoethoxy)-N-[4-methyl-3-[[4-(3-pyridmyl)-2-pyrimidmyl]arnmo]phenyl-benzamide.
EP 0638553 (Dr Karl Thomae) discloses a class of amides having a terminal carboxylic acid group as anti-thrombotic compounds. On page 37 of this document, there is described the preparation of the compound 4-[[4-(2-aminoethoxy)benzoyl]amino]-benzenepropanoic acid.
JP 11236369 (Kotobuki Sieyaku) discloses a class of sulphonamide compounds that are useful as matrix metalloproteinase inhibitors. A compound specifically described in this document is N-[[4- [[4-(2-aminoethoxy)benzoyl]amino]phenyl]sulphonyl]-N-(2-methylpropyl)-glycine.
Serine protease inhibitors are disclosed in US published patent applications US 2003/0100089 and 2004/0180371 and in US patents 6,784,182, 6,656,911, 6,656,910, 6,608,175, 6,534,495 and 6,472,393.
Hence, the provision of inhibitors of serine proteases offers additional therapies against the aforementioned disease states and a need thus exists for compounds that are potent and selective serine protease inhibitors, as alternatives to the existing inhibitors and preferably which possess greater bioavailability and/or fewer side-effects and/or improved potency that than known serine protease inhibitors.
It is an object of the present invention to provide uses of compounds for therapies based upon inhibition of serine proteases, for contraception and anti-coagulant use and for treatment of various diseases, including aberrant cell proliferation, tumours, cancer, angiogenesis, angiogenesis-based retinopathies, autoimmune disease, inflammation, skin disease, arthritis, rheutmatoid arthritis, asthma, osteoarthritis, HIV, multiple sclerosis, thrombotic disease, emphysema, asthma, herpesvirus (HSV), human cytomegalovirus (HCMV), hepatitis C virus (HCV) and septic shock. A further object is to provide novel compounds and pharmaceutical compositions containing these compounds.
PART I.
Summary Of The Invention
The invention provides and uses compounds of formula I:
Formula I wherein
V is selected from
1. H;
2. Ci-2alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S- methyl;
3. ethenyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S- methyl;
4. ethynyl;
5. Ci-2alkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S-methyl;
6. nitro;
7. halo;
8. CN;
9. amino; 10. mono-Ci-2alkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S-methyl;
11. di-Ci-2alkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S-methyl;
12. hydroxyl; and 13. carboxy
W, X and Y are independently selected from
1. H;
2. Ci-6alkyl optionally substituted by Ra;
3. C1 -βalkenyl optionally substituted by Ra; 4. Crβalkynyl optionally substituted by Ra;
5. Ci-Cβalkoxy optionally substituted by Ra;
6. nitro;
7. halo;
8. CN; 9. NR6R7, wherein R6 and R7 are each independently selected from Ra;
10. hydroxyl;
11. carboxy;
12. Ci-6alkyloxyCi-6alkyl;
16. NH(C=O)OC1-6alkyl;
17. C3-6cycloalkyl optionally substituted by Ra;
18. Z-aryl or Z-heteroaryl, optionally substituted by Ra , wherein Z is selected from C1-4alkyl, CH2NH, S, O, S(O), S(O2), S(O2)NH, NHS(O2), CH2NH, NHCH2, CH2O5 OCH2, CH2CH2,
NH(C=O), (C=O)NH and NH(C=O)NH, 0(C=O)NH, NH(C=O)O; and
19. aryl or heteroaryl, optionally substituted by Ra.
Rm, Rn, Rp, Rq are selected from
1. H; 2. Ci-2alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S- methyl; 3. propyl,
or Rm and Rn, Rp and Rq , or Rm and Rq form a cyclopropane ring.
L is selected from 1) a covalent bond,
2) (CH2)m,
3) NRL,
4) NRMC(O)NRN,
5) NRMC(S)NRN, 6) C(S),
7) C(O),
8) NRMC(S),
9) NRMC(O),
10) C(S)NRM, 11) C(O)NRM,
12) CH=CH,
13) C≡C, 14) 0, 15) S(OX
16) C=C-C(CH2)nNRMC(O),
17) C=C-C(CH2)nNRMC(S),
18) C(S)NRM(CH2)nC≡C-C,
19) C(O)NRM(CH2)nC≡C-C, 20) (CH2)nNSO2,
21) NRMSO2(CH2)nC≡C,
22) C≡C-C(CH2)nNRMSO2NRN,
23) NRMSO2NRN(CH2)nC≡C,
24) SO2NRM, 25) NRMSO2,
26) NRMSO2NRN,
27) N=N,
28) C(S)N(ORM),
29) C(O)N(ORM), 30) N(ORM)C(S),
3 I) N(ORM)C(O),
32) HC=CH(CH2)nNRMC(S),
33) HC=CH(CH2)nNRMC(O),
34) (CH2)nNRMC(S)CH=CH, 35) (CH2)nNRMC(O)CH=CH,
36) CH=CH(CH2)nNSO2,
37) NRMSO2(CH2)nCH=CH,
38) (CH2)nNRMSO2NRN,
39) NRMSO2NRN(CH2)nCH=CH, 40) NRMC(O)O,
41) OC(O)NRM,
42) CH=NO,
43) ON=CH,
44) cycloalkyl or heterocyclyl, optionally fixsed to A, e.g. via R1 or R5, 45) aryl or heteroaryl, optionally fused to A, e.g. via R1 or R5' and
46)
W2
in which W2 is selected from
1. O,
2. S,
3. NRL, and 4. (CH2)m,
RL is selected from
1. H,
2. an N-protecting group,
3. C1-6alkyl, optionally substituted by Ra 4. C2-6alkenyl, optionally substituted by Ra,
5. C2-6alkynyl, optionally substituted by Ra
6. aryl, optionally substituted by Ra
7. arylalkyl, optionally substituted by Ra
8. C3-8cycloalkyl, optionally substituted by Ra ,and 9. C3-8cycloalkylCi-6alkyl, optionally substituted by Ra
RM and RN are independently selected from
1. H,
2. Ci-6alkyl, optionally substituted by Ra,
3. C2-6alkenyl, optionally substituted by Ra 4. C2-6alkynyl, optionally substituted by Ra,
5. aryl, optionally substituted by Ra
6. arylalkyl, optionally substituted by Ra,
7. C3-8cycloalkyl, optionally substituted by Ra ,and
8. C3-8cycloalkylCi-6alkyl, optionally substituted by Ra,
m is from 1 to 5, n is 0 to 4, t is 0 to 2,
R1, R2, R3, R4 and R5 are independently selected from 1. H, halogen, CN, NH2, OH, COOH, CH2OH, SO2H, trifluoromethyl; and
2. C1-6alkyl-Ra, C2-6alkenyl-Ra, Cs-izcycloalkyl-R3, C5-ioaryl-Ra, C5-i4heteroaryl-Ra, Q- 6alkyloxy-Ra, OCi-6alkyl-Ra, OCi-6alkylC(O)OH, C3-12cycloalkyloxy-Ra, OC3-12CyClOaIlSyI- Ra, C5-i0aryloxy-Ra, OC5-i0aryl-Ra,
OCi- 6alkylC5-i0heteroaryl-Ra, OCLβalkylCs-ioaryl-R3 , C5-i4heteroaryloxy-Ra, Ra, Cs-ioheterocyclyl-R3,
C(=O)Ci-6alkyl-Ra, CC=O)OC1-
6alkyl-Ra,
S(=O)NHCi-6alkyl-Ra, S(=O)N(Ci-6alkyl-Ra)2, SO2Ci-6alkyl-Ra, S02lNEHCi-6alkyl-R3, SO2N(C1-6alkyl-Ra)2, NH(C1-6alkyl)-R3, N(Ci-6alkyl-Ra)2,
C5-6aryl-Ra, OC5-6aryl-Ra, C(=O)C5.6aryl-Ra, C(=O)OC5.6aryl-Ra, C(=O)NHC5-6aryl-Ra, C(=0)N(C5- 6aryl-Ra)2, S(=O)C5-6aryl-Ra, S(=O)NHC5-6aryl-Ra, S(=O)N(C5.6aryl-Ra)2, SO2C5-6aryl-R3,
SO2NHC5-6aryl-Ra, SO2N(C5-6aryl-Ra)2 NH(C5-6aryl)-Ra, N(C5-6aryl)2-Ra, NC(=O)C5-6aryl, C5-6heterocyclyl-Ra, OC5-6heterocyclyl-Ra, C(=O)C5-6heterocyclyl-Ra, C(=0)0C5- 6heterocyclyl-Ra, C(=O)NHC5-6heterocycryl-Ra, C(=O)N(C5-6heterocyclyl-Ra)2, S(=O)C5- 6heterocyclyl-Ra, S(=O)NHC5-6heterocyclyl-Ra, S(=O)N(C5-6heterocyclyl-Ra)2, SO2C5- gheterocyclyl-R3, SO2NHC5-6heterocyclyl-Ra, SO2N(C5-6heterocyclyl-Ra)2, NH(C5- 6heterocyclyl)-Ra, N(C5-6heterocyclyl-Ra)2, NC(=O)C5.6heterocyclyl, SO2R3, S(=O)Ra, N(Ci-6alkyl-Ra)(C1-6aryl-Ra), N(C1_6alkyl-Ra)(C1-6heteroaryl-Ra), N(C1-6aryl-Ra)(C1- 6heteroaryl-Ra), C(-O)(Ci-6alkyl-Ra)(Ci-6aryl-Ra), C(=O)(C1-6allcyl-R3)(C1-6lieteroaryl-Ra), C(=O)(Ci.6aryl-R3)(C1-6heteroaryl-Ra), C(=O)O(C1-6all<yl-Ra)(Ci-6aryl-Ra), C(=O)O(Ci. 6alkyl-Ra)(Ci-6heteroaryl-Ra), C(=0)O(Ci-6aryl-Ra)(C1-6lieteroaryl-R3), S(=O)(Ci-6alkyl-
R3)(C1-6aryl-R3), S(=O)(Ci-6alkyl-Ra)(C1-6heteroaryl-R3), S(=O)(C1-6aryl-Ra)(Ci-6heteroaryl- R3), SO2(C1-6alkyl-R3)(Ci-6aryl-R3), SO2(C1-6alkyl-Ra)(C1-6heteroaryl-Ra), SO2C5- 6heterocyclyl-Ra) and S02(C1.6aryl-Ra)(Ci-6heteroaryl-Ra),
or two or more of R1, R2, R3, R4 and R5 together with the ring to which they are attached form part of a fused bicyclic or tricyclic ring system in which the first ring is a benzene ring, optionally substituted as defined herein, and the second and, if present, third rings are independently selected from aryl, heteroaryl and saturated or unsaturated carbocyclic and heterocyclic rings, optionally substituted by Ra.
Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, indoline, isoindoline, indazole, and benzodioxole groups.
Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, benzodioxan, benzoxazine, benzodiazine, quinoxaline, quinazoline, phthalazine, naphthalene, and cinnoline groups.
Compounds as thus defined can be substituted by one or more Ra groups, and reference to substitution by Ra throughout refers to substitution by one or more such groups, on each occasion independently selected from:-
H, halogen, nitro, amino, CN, hydroxyl, CH2OH, carboxy, Ci-6alkyl, trifluoromethyl, C3- ecycloalkyl, Cr6alkenyl, Cr6alkynyl, C(=O)C1-6alkyl, C5-i0aryl, OCi-6alkylRb, OC1- 6alkylC(=O)ORb, C(=O)OC1-6alkyl, C(=O)NH2, C(=O)NHCi-6alkyl, C(=O)N(C1-6alkyl)2, SC1- βalkyl, SOCi-6alkyl, SONHCi-6alkyl, SON(Ci.6alkyl)2j SO2Ci-6alkyl, SO2NHC1-6alkyl, SO2N(Ci- 6alkyl)2, NH(Ci-6alkyl), N(C1-6alkyl)2, NC^C^alkyl, C5-6aryl0C5-6aryl, Ci-6alkoxyC5.6aryl, C(=O)C5-6aryl5 C(=O)OC5-6aryl, C(=O)NH2, C(=O)NHC5-6aryl, C(=O)N(C5-6aryl)2, SO2C5-6aryl, SO2NHC5-6aryl, SO2N(C5-6aryl)2, NH(C5-6aryl), N(C5.6aryl)2, NC(=O)C5-6aryl, C5-6heterocyclyl, OC5-6heterocyclyl, C(=O)C5-6heterocyclyl, C(=O)OC5-6heterocyclyl, C(=0)NH2, C(=0)NHC5- eheterocyclyl, C(=O)N(C5-6heterocyclyl)2, S(=O)C5-6heterocyclyl, S(=O)NHC5-6heterocyclyl, S(=O)N(C5-6heterocyclyl)2, SOaNHCs-βheterocyclyl, SO2N(C5-6heterocyclyl)2, NH(C5.
6heterocyclyl), N(C5-6heterocyclyl)2, NC(=O)C5-6heterocyclyl, C(=O)NHCi-6alkylC5-6aryl, NRbRc, C(=0)Rb, C(=O)NRbR°, C02NRbRc, S(=O)Rb, S(=O)NRbR° , S(O)2OH, S(O)2C1-6alkyl and SO2NRbR°. and Rb and Rc are each independently selected from H, Ci-6alkyl, C3.6cycloalkyl, C5^aTyI, or C5- 6heterocyclyl.
Two or more of R1, R2, R3, R4 and R5 together with the ring to which they are attached can form part of a ring to create a bicyclic aryl or heteroaryl ring system, optionally substituted by Ra, or two or more of R1, R2, R3, R4 and R5 together with the ring to which they are attached can form part of a ring to create an bicyclic ring system in which the second ring is not aromatic, optionally substituted by Ra, or two or more of R1, R2, R3, R4 and R5 together with the ring to which they are attached can form part of a ring to create a tricyclic ring system, optionally substituted by Ra.
Examples of polycyclic aryl and heteroaryl groups containing an aromatic ring and a non-aromatic ring include such ring systems as tetrahydro-naphthalene, indoline, indene, indane, dihydro- isoindole, dihydro-benzofuran, tetrahydro-quinoline, tetrahydro-isoquinoline, dihydro-quinazoline, 5-phenyl-2,3-dihydro-lH-benzo[e][l,4]diazepine, and 5-phenyl-2,3,4,5-tetrahydro-lH- benzo[e][l,4]diazepine.
In one embodiment, R1, R2, R3, R4 and R5 are each other than trifluoromethyl.
Formula I0 or a salt, solvate, hydrate, N-oxide or ester thereof; wherein Rm, Rn, Rp, Rq, V, W, X, Y, R1, R2, R3, R4 and R5 are as defined in repect of formula (I).
Accordingly, in a first aspect, the invention provides a compound of formulae I or I0, or a solvate, hydrate, ester or pharmaceutically acceptable salt thereof, as defined herein for use as an inhibitor of a serine 190 protease.
The invention also provides a compound of formulae I or I0, or a solvate, hydrate, ester or pharmaceutically acceptable salt thereof, as defined herein for use as an inhibitor of uPA.
The present invention provides the use of compounds of formulae I or I0, or a solvate, hydrate, ester or pharmaceutically acceptable salt thereof, as defined herein for the manufacture of a medicament for inhibition of a serine 190 protease.
The invention further provides the use of compounds of formulae I or I0, or a solvate, hydrate or pharmaceutically acceptable salt thereof, as defined herein for the manufacture of a medicament for inhibition of uPA.
Also provided by the invention are methods of treatment using the compounds of the invention as inhibitors of serine 190 proteases. Thus, also provided are methods of inhibiting or treating aberrant serine protease activity in a mammal, methods treating or ameliorating diseases reponsive to a serine protease inhibitor, methods of contraception, anti-coagulant methods and uses and methods for treating aberrant cell proliferation, tumours, cancer, angiogenesis, angiogenesis-based retinopathies, autoimmune disease, inflammation, skin disease, arthritis, rheutmatoid arthritis, asthma, osteoarthritis, HTV, multiple sclerosis an dother diseases and conditions as referred to herein by administering to a patient an effective amount of a compound of the invention.
The invention is of application to a wide range of serine 190 proteases, including but not limited to trypsin, tryptase, chymotrypsin, elastase, thrombin, plasmin, kallikrein, Complement Cl, acrosomal protease, lysosomal protease, cocoonase, α-lytic protease, protease A, protease B, serine carboxypeptidase II, subtilisin, urokinase (uPA), Factor Vila, Factor IXa, and Factor Xa.
In one embodiment, the invention provides methods of treatment using the compounds of the invention as inhibitors of uPA. Thus, also provided are methods of inhibiting or treating aberrant uPA activity in a mammal, methods of contraception, anti-coagulant methods and uses and methods for treating aberrant cell proliferation, tumours, cancer, angiogenesis, angiogenesis-based retinopathies, autoimmune disease, inflammation, skin disease, arthritis, rheutmatoid arthritis, asthma, osteoarthritis, HIV and multiple sclerosis by administering to a patient an effective amount of a compound of the invention.
In a further aspect, the invention provides novel compounds per se wherein the novel compounds are compounds of the formulae I or I0, but excluding (a-i) 4-(2-aminoethoxy)-N-[4-methyl-3-[[4- (3-pyridmyl)-2-pvrirddinyl]amino]phenyl-benzamide and salts thereof; (a-ii) N-[[4-[[4-(2- aminoethoxy)benzoyl]amino]phenyl]sulphonyl]-N-(2-methylpropyl)-glycine and salts thereof; and (a-iii) 4-[[4-(2-arnmoethoxy)benzoyl]amino]-benzenepropanoic acid and salts and N-protected forms thereof.
The present invention also provides, as compounds of the invention, the compounds of formulae I and I0 and solvates, hydrates and pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the same, generally in combination with a pharmaceutically acceptable carrier, especially for administration to a human, but excluding pharmaceutical compositions containing (a-i) 4-(2-ammoethoxy)-N-[4-methyl-3-[[4-(3-pyridmyl)-2-pyrirrddmyl]aniino]phenyl- benzamide and salts thereof; (a-ii) N-[[4-[[4-(2-aminoethoxy)benzoyl]amino]phenyl]sulphonyl]-N- (2-methylpropyl)-glycine and salts thereof; and (a-iii) 4-[[4-(2-arninoethoxy)benzoyl]amino]- benzenepropanoic acid and salts and N-protected forms thereof.
The exclusions (a-i) to (a-iii) may optionally apply also in relation to each of the therapeutic uses of the compounds of the formulae I or I0 described herein.
Any one or more (in any combination) of the following optional provisos may also apply to formulae I or f, either in relation to the definitions of the compounds per se or to their therapeutic uses and pharmaceutical compositions containing them:
(b-i) The compound may be other than a compound containing an optionally substituted pyrimidin-2-ylaminophenyl group.
(b-ii) R3 may be other than an alkanoic acid (e.g. acetic acid or propanoic acid) residue.
(b-iii) R3 may be other than a group containing an alkanoic acid (e.g. formic acid, acetic acid or propanoic acid) residue.
(b-iv) The compound may be other than a compound containing a substituted benzenesulphonamide group wherein the nitrogen atom of the benzenesulphonamide forms part of a non-cyclic disubstituted amino group.
(b-v) The compound may be other than a compound containing a carboxylic acid group.
General Preferences And Definitions
The following terms and derivatives thereof are used in this application with the following meaning, unless the context requires otherwise.
- alkyl used on its own or as part of another group refers to both straight and branched chain radicals of up to 6 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl. Unless otherwise stated, preferably, the alkyl chain is 1 to 3 carbon atoms in length.
- alkenyl is used to indicate a straight or branched chain radical of 2-6 carbon atoms, with a double bond between 2 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl, and the like. Preferably, the alkenyl chain is 2 to 4 carbon atoms in length.
- alkynyl is used to mean a straight or branched chain radical of 2-6 carbon atoms wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1 -propylene, 2-propylene, and the like. Preferably, the alkynyl chain is 2 to 4 carbon atoms in length.
In all instances herein where there is an alkenyl or alkynyl moiety as a substituent group, the unsaturated linkage, i.e., the vinylene or acetylene linkage is preferably not directly attached to a nitrogen, oxygen or sulfur moiety.
- alkoxy is used herein to mean a straight or branched chain radical of 1 to 6 carbon atoms, linked to an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy and isopropoxy. Preferably the alkoxy chain is 1 to 4, more preferably 1 to 3 carbon atoms in length.
- aryl by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 5 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.
- heteroaryl refers to groups having 5 to 14 ring atoms; 6, 10 or 14 pi electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms. Examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H- indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4.alpha.H-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl groups.
- aralkyl or arylalkyl by itself or as part of another group refers to Ci-6 alkyl groups as discussed above having an aryl substituent, for example benzyl, phenylethyl or 2-naphthylmethyl.
- cycloalkyl or carbocyclic by itself or as part of another group refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms and preferably refers to mono-cycloalkyl groups containing 3 to 9, more preferably 3 to 7, carbon atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.
- halo
"halogen" or "halo" by itself or as part of another group refers to chlorine, bromine, fluorine or iodine, preferably chlorine unless otherwise stated.
- mono / di akylamino
"monoalkylamine" or "mono-alkyl amino" by itself or as part of another group refers to an amino group which is substituted with one alkyl group having from 1 to 6 carbon atoms.
"dialkylamine" or "dialkylamino" by itself or as part of another group refers to an amino group which is substituted with two alkyl groups, each having from 1 to 6 carbon atoms.
- hydroxyalkyl means any of the above alkyl groups substituted by one or more hydroxyl moieties.
- carboxyalkyl refers to any of the above alkyl groups substituted by one or more carboxylic acid moieties.
- heterocyclic or heterocyclyl means a saturated or wholly or partially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Especially useful are rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. Examples of such heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
- tricyclic indicates any tricyclic ring, including saturated and wholly and partially unsaturated rings, optionally containing one or more heteroatoms, optionally aryl or cycloalkyl, generally having 13, 14 or 15 members. In relation to the tricyclic ring which can be formed by R1, R2, R3, R4 and R5 it refers to any such ring in which one ring is the optionally substituted benzene ring of formula I.
- heteroatom
means an oxygen atom ("O"), a sulfur atom ("S") or a nitrogen atom ("N"). When the heteroatom is nitrogen, it can form an NRy Rz moiety, wherein Ry and Rz are, independently, hydrogen or C1-6 alkyl, or form together with the nitrogen to which they are bound a saturated or unsaturated 5, 6, or 7 membered ring.
- alkoxy refers to any of the above alkyl groups linked to an oxygen atom.
- aryloxy refers to any of the above aryl groups linked to an oxygen atom.
- cycloalkyoxy refers to any of the above cycloalkyl groups linked to an oxygen atom.
- heteroaryloxy means any of the above heteroaryl groups linked to an oxygen atom.
- aralkyloxy or arylalkyloxy means any of the above aralkyl or arylalkyl groups linked to an oxygen atom.
Preferred Embodiments
In a series of preferred embodiments of the invention, V is selected from
1. CVCaalkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S- methyl;
2. ethenyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S- methyl;
3. ethynyl;
4. Ci-C2alkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S-methyl;
5. halo; 6. amino;
7. mono-CVCzalkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S-methyl;
8. hydroxyl; and
9. carboxy
Preferably, V is selected from
1. Ci-C2alkyl optionally substituted by fluoro,
2. CrC2alkoxy optionally substituted by fluoro, and
3. halo.
We have found in compounds of the invention, that enhanced protease inhibition (e.g. enhanced uPA inhibition) is generally shown for this preferred definition of V, and when V is selected from Me, CH2F, CHF2, CF3, Et, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH2OMe, CH2SMe, Cl, Br, I, OMe, OCHF2, OCH2F OCF3, OEt, CN, NH2, NHMe, NHMe2 or OH, especially when selected from Me, CH2F, CHF2, CF3, or Cl especially improved inhibitory activity is obtained.
W, X and Y may be independently selected from
1. H;
2. d-βalkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
3. Ci-βalkenyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
4. Ci-6alkynyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
5. CrCβalkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl; 6. nitro;
7. halo;
8. CN;
9. NR6R7, wherein R6 and R7 are each independently selected from H, amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl; 10. hydroxyl;
11. carboxy;
12. Ci-6alkyloxyCi-6alkyl;
13. carboxyCi-βalkyl optionally substituted by H, amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl; 14. carboxyamino;
15. NH(C=O)C1-6alkyl;
16. NH(C=O)OC1-6alJcyl;
17. C^cycloalkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl , S-methyl, C1-6alkyl and Ci-6alkoxy;
18. Z-aryl or Z-heteroaryl, optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl , S-methyl, Ci-6alkyl and Ci-6alkoxy, wherein Z is selected from C1-4alkyl, CH2NH, S, O, S(O), S(O2), S(O2)NH, NHS(O2), CH2NH, NHCH2, CH2O, OCH2, CH2CH2, NH(C=O), (C=O)NH and NH(C=O)NH, 0(C=O)NH, NH(C=O)O; 19. aryl or heteroaryl, optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl , S-methyl, Ci-6alkyl and Ci-6alkoxy.
In another embodiment, W, X and Y may each be independently selected from the substituents listed in subsections 2 to 19 in the immediately preceding section; i.e. W, X and Y may each be other than hydrogen.
In a further series of preferred embodiments, W is selected from
1. H;
2. Cr6alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
3. Cr6alkenyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
4. CrQalkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
5. halo;
6. amino; 7. mono-Ci-βalkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
8. di-Ci-6alkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
9. hydroxyl; 10. carboxy;
11. Ci-6alkyloxyCi-6alkyl;
12. carboxyCi-βalkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
13. carboxyamino; 14. NH(C=O)C1-6alkyl;
15. NH(C=O)OCi-6alkyl;
16. Z-aryl or Z-heteroaryl, wherein Z is selected from CH2, NH, S, O, S(O), S(O2), S(O2)NH, NHS(O2), CH2NH, NHCH2, CH2O, OCH2, CH2CH2, NH(C=O), (C=O)NH and
NH(C=O)NH, 0(C=O)NH5 NH(C=O)O, optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl , S-methyl, Ci-6alkyl, C1-6alkoxy and Ra ; 17. aryl or heteroaryl, optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl , S-methyl, Ci-6alkyl, C1-6alkoxy and Ra .
Ih another embodiment, W may be selected from the substituents listed in subsections 2 to 17 in the immediately preceding section; i.e. W may be other than hydrogen.
Thus, W can generally be more broadly defined than V. In specific compounds, good protease inhibition (e.g. good uPA inhibition) is obtained when W is a 1, 2 or 3 membered alkyl group optionally substituted as set out above, or comprises an amino group linked to a 1, 2 or 3 membered alkyl group, again, optionally substituted as set out above, or comprises an amino group linked to an acetate group or a 1, 2 or 3 membered alkyl group, optionally substituted and linked to an aryl group, again optionally substituted. In one class of such compounds, W is selected from
1. Q-galkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl; 2. Ci-C6alkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
3. halo;
4. mono-Ci-βalkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl; 5. di-Ci-6alkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
6. Ci-6alkyloxyCi-6alkyl;
7. carboxyCi-6alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl; 8. NH(C=O)C1-6alkyl;
9. NH(C=O)OC1-6alkyl;
In a further sub-class of such compounds, W is selected from
1. optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl; 2. C!-C4alkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
3. halo;
4. mono-Chalky! amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
5. Ci-3alkyloxyCi-3alkyl;
6. carboxyC1-3alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
7. NH(C=O)C1-4alkyl; 8. NH(C=O)OCi-4alkyl;
Li particularly preferred embodiments W is selected from
1. C1 -C2alkyl optionally substituted by fluoro,
2. CVC2alkoxy optionally substituted by fluoro,
3. NHC(O)OH, and 4. halo.
It is also found that protease inhibitory activity (e.g. uPA inhibitory activity) can be affected by particular combinations of values for V and W. A first combination is that both V and W are not H. More preferred combinations are those in which any sub class of values of V is combined with any sub class of values for W. More specifically, combinations of V and W are (i) both are methyl, (ii) one is methyl and one is chloro, (iii) one is methyl and one is amino, and (iv) both are chloro.
In preparation and use of compounds of the invention it is also found that there are preferred values for other substituents on the core benzene or benzamide ring (i.e. the ring bearing the groups X, Y, V and W). Accordingly, X and Y are suitably selected from H;
optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl; Ci-6alkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl; and halo. Specific compounds show good activity when both X and Y are H.
In a further subclass of compounds of the invention, V is as defined above, including its preferred definitions and W, X and Y are selected from H, Me, CH2F, CHF2, CF3, Et, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH2OMe, CH2SMe, CH2OH, CH2NH2, F, Cl, Br, I, Et, OMe, OCF3, OC2-6alkyl, CN, NH2, OH, COOH, C(=0)Me, C(=0)NH2, NHCi-6alkyl,
NH(C=O)OCi- 6alkyl, Ci-6alkyl,
It is believed, though the inventors do not wish to be bound by any such theory, that the Rm, Rn, Rp and Rq groups on the left hand, primary amine side of the compounds bind in use to a relatively tightly defined pocket or groove in a protease target such as uPA, resulting in the inhibitory activity of these compounds. Rm, Rn, Rp and Rq are suitably selected from H, Me, CH2F, CHF2, CF3, Et, CH2CH2F, CH2CHF2, CH2CF3, nPr, CH2OMe and CH2SMe. Rm and Rn or Rp and Rq or Rm and Rq can optionally form a cyclopropane ring, and should preferably be H, or methyl optionally
substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S-methyl. In one series of compounds of the invention, one of Rm and Rn is methyl, forming preferably the R isomer, and the other is H.
Compounds of this series in which R8 is C(O)NH-A may be represented by formula Ia:-
and illustrates the R isomer, preferred also for compounds of the invention with different choices of R8; a chiral centre in the compound is indicated by a.
Separately, both of Rp and Rq are preferably H. Most preferably, all of Rm, Rn, Rp and Rq are H.
The values for R1, R2, R3, R4 and R5 are found to be widely variable, and compounds have been prepared and tested and shown to have good protease inhibitory activity (e.g. good uPA inhibitory activity) when these groups have many widely differing values. Accordingly it is believed that protease inhibition will also be achieved with values across the ranges as set out herein in the definitions for R1, R2, R3, R4 and R5. The compounds made and tested enable extrapolation of inhibitory activity across the range. Nevertheless, certain sub-classes of these groups can be identified, and in one such group R1, R2, R3, R4 and R5 are independently selected from
1. H,
2. halogen, and 3. a. Ci-6alkyl, b. C2-6alkenyl, c. C3.12cycloaU.yl, d. C5-iOaryl, e. Cs-iφheteroaryl f. Ci-6alkyloxy, g. C3-I2CyClOaIlSyIoXy, h. C5-i0aryloxy,
i. C5-i4heteroaryloxy j. Ci-6alkyl-C5-iOaryl, k. C5-10arylC1-6alkyloxy. 1. Cs-ioheterocyclyl, wherein each of 3a-l are optionally substituted by halogen, CN, NH2, OH, COOH, Ci-6alkoxy, C1- ealkyl, CH2OH, SO2H, S(=0), C1-6alkyl-Ra, OC1-6alkyl-Ra, C(=O)Ci-6alkyl-Ra, C(=O)OC1-6alkyl- Ra, C(=0)NH2) C(=O)NHC1-6alkyl-Ra, C(=O)N(C1-6alkyl-Ra)2, S(=O)C1-6alkyl-Ra, SC=O)NHC1- 6alkyl-Ra, S(=O)N(C1.6alkyl-Ra)2, SO2C1-6alkyl-Ra, SO2NHC1-6alkyl-Ra, SO2N(Ci-6alkyl-Ra)2, NH(C1-6alkyl)-Ra, N(C1-6alkyl-Ra)2> NHC(=O)C1-6alkyl, C5-6aryl-Ra, OC5-6aryl-Ra, C(=O)C5.6aryl- Ra, C(=O)OC5-6aryl-Ra, C(=O)NHC5-6aryl-Ra, C(=O)N(C5-6aryl-Ra)2, S(=O)C5-6aryl-Ra, S(=O)NHC5-6aryl-Ra, S(=O)N(C5-6aryl-Ra)2, SO2C5-6aryl-Ra, SO2NHC5-6aryl-Ra, SO2N(C5-6aryl- Ra)2 NH(C5.6aryl)-Ra, N(C5-6aryl)2-Ra, NC(=O)C5-6aryl, C5-6heterocyclyl-Ra, OC5-6heterocyclyl-Ra, C(=O)C5-6heterocyclyl-Ra, C(=O)OC5-6heterocyclyl-Ra, C(=O)NHC5-6heterocyclyl-Ra, C(=O)N(C5- 6heterocyclyl-Ra)2, S(=O)C5-6heterocyclyl-Ra, S(=O)NHC5-6heterocyclyl-Ra, S(O)N(C5- 6heterocyclyl-Ra)2, SO2C5-6heterocyclyl-Ra, SO2NHC5-6heterocyclyl-Ra, SO2N(C5-6heterocyclyl- Ra)2, NH(C5-6heterocyclyl)-Ra, N(C5-6heterocyclyl-Ra)2, NC(=O)C5-6heterocyclyl, SO2R3, S(=O)Ra, N(Ci-6alkyl-Ra)(C1-6aryl-Ra), N(C1-6alkyl-Ra)(C1-6heteroaryl-Ra), N(Ci-6aryl-Ra)(Cj.6heteroaryl-Ra), C(=O)(C1-6alkyl-Ra)(C1-6aryl-Ra), C(=O)(C1-6alkyl-Ra)(C1-6heteroaryl-Ra), C(=O)(C1-6aryl-Ra)(Ci- 6heteroaryl-Ra), C(=O)O(Ci-6alkyl-Ra)(Ci-6aryl-Ra), C(=O)O(C1-6alkyl-Ra)(C1-6heteroaryl-Ra), C(=O)O(Ci-6aryl-Ra)(Ci-6heteroaryl-Ra), S(=O)(C1-6alkyl-Ra)(C1-6aryl-Ra), S(=O)(C1-6alkyl-Ra)(Ci- 6heteroaryl-Ra), S(=O)(Ci-6aryl-Ra)(C1-6heteroaryl-Ra), SO2(Ci-6alkyl-Ra)(Ci-6aryl-Ra), SO2(C1- 6alkyl-Ra)(Ci-6heteroaryl-Ra) and SO2(C1-6aryl-Ra)(Ci.6heteroaryl-Ra),
In a further subclass of compounds R1, R2, R3, R4 and R5 are independently selected from
1. H, 2. halogen, and
3. a) Ci-6alkyl, b) C2-6allcenyl, c) C3-i2cycloalkyl, d) C5-ioaryl, e) C5-i4heteroaryl f) C1-6alkyloxy, g) C3-12CyClOaIlJyIoXy, h) C5-10aryloxy, i) Cs-^eteroaryloxy
j) Ci-6alkyl-C5-ioaryl, k) Cs-ioarylCi-βalkyloxy. 1) Cs-ioheterocyclyl, wherein each of 3a-l are optionally substituted by halogen, CN, NH2, OH, COOH, C(=O)Alkyl, C1-6alkoxy, C1-6alkyl, CH2OH, SO2H and S(=O)Me.
In one embodiment, each of 3a-l are optionally substituted by halogen, CN, NH2, OH, COOH, Ci- 6alkoxy, Ci-6alkyl, CH2OH, SO2H and S(=O).
In a still further subclass of compounds, R1, R2, R3, R4 and R5 are independently selected from
1. halogen, and 2. , a) Ci-6alkyl, b) Ci-6alkyloxy, c) C3-i2cycloalkyloxy, d) C5-10heterocyclyl, wherein each of 2a-d are optionally substituted by halogen, CN, NH2, OH, COOH, C(=O)Oalkyl, Ci-6alkoxy, Ci.6alkyl, CH2OH, SO2H, and S(=O)Me, and more preferably optionally substituted by OH.
Compounds of the invention can also, through combination of the groups for R1, R2, R3, R4 and R5 form cyclic, bicyclic and tricylic ring structures together with the aromatic ring atoms to which they are attached, wherein the first ring is aromatic, and heterocyclic versions of such. The rings are preferably formed between R3 and R4 or R4 and R5 and wherein, respectively, R1, R2, and R5 or R1, R2 and R5 are H.
Two or more of R1, R2, R3, R4 and R5 together with the ring to which they are attached can thus form part of a ring to create a bicyclic aryl or heteroaryl ring system, optionally substituted by Ra. Examples of such ring systems are naphthalene, indole, isoindole, phthalirnide, benzofuran, benzothiophene, indazole, benzimidazole, benzthiazole, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, and quinoxaline.
Two or more of R1, R2, R3, R4 and R5 together with the ring to which they are attached can form part of a ring to create a bicyclic ring system in which the second ring is not aromatic, optionally substituted by Ra. Examples of such ring systems are tetrahydro-naphthalene, indoline, indene, indane, dihydro-isoindole, dihydro-benzofuran, tetrahydro-quinoline, tetrahydro-isoquinoline,
dihydro-quinazoline, 5-Phenyl-2,3-dihydro-lH-benzo[e][l,4]diazepine, and 5-Phenyl-2,3,4,5- tetrahydro-lH-benzo[e][l,4]diazepine.
Two or more of R1, R2, R3, R4 and R5 together with the ring to which they are attached can also form part of a ring to create a tricyclic ring system, optionally substituted by Ra. Examples of such ring systems are carbazole, fluorine, dibenzofuran, acridine, phenazine, phenothiazine, and phenoxazine
Again, a wide variety of different such ring-containing compounds have been prepared and tested, and shown to have acceptable protease inhibitory activity.
In particular compounds of the invention within formula I, L is preferably selected from: 1. a covalent bond,
2. (CH2)m,
3. NRL,
4. NRMC(O)NRN,
8. C(O)NRM,
9. CH=CH,
10. O, 11. S(OX
12. C=C-C(CH2)nNRMC(O),
15. NRMSO2, 16. NRMSO2NRN,
17. N=N,
18. C(O)N(ORM),
19. N(ORM)C(O),
20. HC=CH(CH2)nNRMC(O), 21. (CH2)nNRMC(O)CH=CH,
22. CH=CH(CH2)nNSO2,
23. NRMSO2(CH2)nCH=CH,
24. (CH2)nNRMSO2NRN,
25. NRMSO2NRN(CH2)nCH=CH,
26. NRMC(O)O,
27. OC(O)NRM,
28. CH=NO,
29. ON=CH,
30. cycloakyl or heterocyclyl, optionally fused to A, e.g. via R1 or R5,
31. aryl or heteroaryl, optionally fused to A, e.g. via R1 or R5' and 32.
in which W2 is selected from
1) O,
2) S,
3) NRL, and
4) (CH2)m.
RL, RM and RN may further be independently selected from
1. H,
2. optionally substituted by Ra
3. C2-4alkenyl, optionally substituted by Ra
4. aryl, optionally substituted by Ra 5. arylalkyl, optionally substituted by Ra,
6. C3-gcycloalliyl, optionally substituted by Ra ,and
7. Cs-scycloalkylCi-βalkyl, optionally substituted by Ra, m can be from 1 to 5, n from 0 to 2, and t from 0 to 2.
In further embodiments of the invention the linker L may separately be defined as follows. L may be selected from:
1) (P)c-(Q)d-(R)e-(S)f,
2) Ci-6alkyl, optionally substituted by Ra,
3) C2-6alkenyl, optionally substituted by Ra,
4) C1-6alkoxy, optionally substituted by Ra, 5) aryl, optionally substituted by Ra, or
6) cycloalkyl, optionally substituted by Ra, wherein
P and R are independently selected from NH, O, S, C(O), C(O)NH, NHC(O) and S(O)2, Q and S are independently selected from CH2, CHR6 and CR6R7, wherein R6 and R7 are independently selected from H, halo, amino, hydroxy, methyl, methyl substituted by halo and sulphydryl, d is O to 6, fis O to β, c is O or 1, e is O or 1, provided that not all of c, d, e and f are O and that d + e < 6.
In one series of compounds, the linker is an amide linker, i.e. is C(O)NH, and hence the compounds are compounds of the formula (I0) and sub-groups thereof as defined herein.
In one series of compounds, the linker is not an amide linker, i.e. is not C(O)NH.
In another series of compounds the linker is restricted in length, and hence preferably L =
1. -(P)c-(Q)d-(R)e-(S)f-, or 2. d^alkyl, optionally substituted by Ra' wherein P and P are independently selected from NH, O, S, C(O), C(O)NH, and NHC(O),
Q and S are independently selected from CH2, CHR6 and CR6R7, wherein R6 and R7 are independently selected from H, halo, amino, hydroxy, methyl, methyl substituted by halo and sulphydryl, 0 d is O to 4, fis 0 to 4, c is O or 1, and e is O or 1, provided that not all of c, d, e and f are O and that d + e < 4,
5 In specific embodiments of the invention described and tested in examples set out in more detail below, inhibition of serine proteases has been obtained using linkers that are further restricted in length, such that c + d + e + f = 1, 2 or 3, more preferably c + d + e + f = 2.
Where L is cycloakyl or heterocyclyl, optionally fused to A, e.g. via R1 or R5, or aryl or heteroaryl, optionally fused to A, e.g. via R1 or R5, it is preferred that L fused to A forms a bicyclic or tricyclic O ring, more preferably a bicyclic ring and further preferred that L is C5-6cycloakyl, C5-6heterocyclyl C5-6aryl or C5.6heteroaryl, forming when fused to A a bicyclic ring.
Lastly, compounds of the invention have been made using a range of different substituent groups at the Ra and Rb/c position. In preferred embodiments of the invention, Rb and Rc are independently selected from H or C1-6alkyl, more preferably H, methyl or ethyl, especially H. Separately, Ra is preferably selected from H, C(=O)C1-6alkyl, C(=O)OCi-6alkyl, C(=O)NH2, C(=O)NHC1-6alkyl, C(=O)N(C1-6alkyl)2, NH(Ci-6alkyl), N(C1-6alkyl)2, NC(=O)C1-6alkyl, C5-6aryl, OC5-6aryl, C(O)C5- 6aryl, C(=O)OC5-6aryl, C(=O)NH2, C(=O)NHC5-6aryl, C(=O)N(C5-6aryl)2, NH(C5.6aryl)5 N(C5- 6aryl)2, NC(=O)C5-6aryl, C5-6heterocyclyl, OC5-6heterocyclyl, C(=0)C5.6heterocyclyl, C(=O)OC5- eheterocyclyl, C(O)NH2, C(=O)NHC5-6heterocyclyl, C(=O)N(C5-6heterocyclyl)2, NH(C5- eheterocyclyl), N(C5-6heterocyclyl)2, NC(=O)C5-6heterocyclyl, C(=O)NHCi-6alkylC5-6aryl, NRbRc, C(=O)Rb, C(=O)NRbRc, CO2NRbRc, S(=O)Rb, S(=O)NRbRc and SO2NRbRc.
For the avoidance of doubt, the invention also provides compounds, uses and methods as set out herein using any combination of preferred values and definitions of sub classes of values for all groups in formula I5 each such combination forming a separate embodiment of the invention.
The invention further provides:-
- A compound per se of the formula (I), formula (I0) or any other sub-group or embodiment of the formula (I) as defined herein.
- A compound of the formula (I), formula (f) or any sub-group or embodiment thereof as defined herein for use in the prophylaxis or treatment of a disease state or condition mediated by a serine protease, such as uPA.
- A compound of the formula (I), formula (I0) or any sub-group or embodiment thereof as defined herein for use in medicine.
- The use of a compound of formula (I), formula (I0) or any sub-group or embodiment thereof as defined herein for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition mediated by a serine protease, such as uPA.
- The use of a compound of the formula (Q, formula (I0) or any sub-group or embodiment thereof as defined herein for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition in a patient.
- The use of a compound of the formula (I), formula (I0) or any sub-group or embodiment thereof as defined herein for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition arising from abnormal cell growth or abnormally arrested cell death.
- The use of a compound of the formula (I), formula (I0) or any sub-group or embodiment thereof as defined herein for the manufacture of a medicament for the prophylaxis or treatment of any one of the disease states or conditions disclosed herein.
- A method for the prophylaxis or treatment of a disease state or condition mediated by a serine protease, which method comprises administering to a subject in need thereof a compound of the formula (I), formula (I0) or any sub-group or embodiment thereof as defined herein.
- A method for treating a disease or condition comprising or arising from abnormal cell growth or abnormally arrested cell death in a mammal, the method comprising administering to the mammal a compound of the formula (I), formula (f) or any sub-group or embodiment thereof as defined herein in an amount effective to inhibit serine protease activity, such as uPA activity.
- A method of inhibiting a serine protease, such as uPA, which method comprises contacting the serine protease (e.g. uPA) with a serine protease inhibiting compound (e.g. uPA inhibiting compound) of the formula (J), formula (I0) or any sub-group or embodiment thereof as defined herein,
- A method of modulating a cellular process by inhibiting the activity of a serine protease, such as uPA, using a compound of the formula (I), formula (I0) or any sub-group or embodiment thereof as defined herein.
- A method for treating a disease or condition comprising or arising from abnormal cell growth or abnormally arrested cell death in a mammal, which method comprises administering to the mammal a compound of the formula (I), formula (f) or any sub-group or embodiment thereof as defined herein in an amount effective in inhibiting abnormal cell growth.
- A method for alleviating or reducing the incidence of a disease or condition comprising or arising from abnormal cell growth or abnormally arrested cell death in a mammal, which method comprises administering to the mammal a compound of the formula (I), formula (I0) or any sub- group or embodiment thereof as defined herein in an amount effective in inhibiting abnormal cell growth.
- A method for the treatment or prophylaxis of any one of the disease states or conditions disclosed herein, which method comprises administering to a patient (e.g. a patient in need thereof) a compound (e.g. a therapeutically effective amount) of the formula (T), formula (I0) or any sub- group or embodiment thereof as defined herein.
- A method for alleviating or reducing the incidence of a disease state or condition disclosed
herein, which method comprises administering to a patient (e.g. a patient in need thereof) a compound (e.g. a therapeutically effective amount) of the formula (I), formula (I0) or any subgroup or embodiment thereof as defined herein.
- A method for the diagnosis and treatment of a disease state or condition mediated by a serine protease, such as uPA, which method comprises (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against the serine protease (e.g. uPA); and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient a compound of the formula (I), formula (I0) or any sub- group or embodiment thereof as defined herein.
- A pharmaceutical composition comprising a novel compound of the formula (I), formula (I0) or any sub-group or embodiment thereof as defined herein and a pharmaceutically acceptable carrier. In one series of compounds, the linker is not an amide linker, i.e. is not C(O)NH. In another series of compounds, the linker is an amide linker, i.e. is C(O)NH.
In these respects, the invention is of application not only to uPA, but also to a wide range of serine proteases, including but not limited to trypsin, tryptase, chymotrypsin, elastase, thrombin, plasmin, kallikrein, Complement Cl, acrosomal protease, lysosomal protease, cocoonase, α-lytic protease, protease A, protease B, serine carboxypeptidase π, subtilisin, urokinase (uPA), Factor Vila, Factor IXa, and Factor Xa. Preferably the invention is of application to trypsin, thrombin, plasmin, urokinase (uPA), Factor Vila, Factor IXa, and Factor Xa.
Biological Properties and Uses
It is envisaged that the compounds of the invention will be useful in the treatment or prophylaxis of any one more cancers selected from: adenomas, carcinomas, leukaemias, lymphomas, melanomas, sarcomas and teratomas.
Particular examples of cancers which may be inhibited include, but are not limited to, a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g. colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermal, liver, lung, for example adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, oesophagus, gall bladder, ovary, pancreas e.g. exocrine pancreatic carcinoma, stomach, cervix, thyroid, prostate, or skin, for example squamous cell carcinoma; a hematopoietic tumour of lymphoid lineage, for example leukaemia, acute lymphocytic leukaemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a
hematopoietic tumour of myeloid lineage, for example acute and chronic myelogenous leukaemias, myelodysplastic syndrome, or promyelocytic leukaemia; thyroid follicular cancer; a tumour of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma; a tumour of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xenoderoma pigmentosum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.
One subset of cancers treatable according to the invention includes any one or more cancers selected from: breast cancer, ovarian cancer, colon cancer, prostate cancer, oesophageal cancer, squamous cancer and non-small cell lung carcinomas.
Examples of other conditions ameliorated by the inhibition of serine proteases are discussed throughout, and include, but are not limited to the said conditions. More particularly, the conditions can be selected from:-
(i) inflammatory and arthritic diseases and conditions such as Reiter's syndrome, acute synovitis, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis;
(ii) chronic inflammatory lung diseases such as emphysema, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome and acute respiratory distress syndrome (ARDS);
(iii) lung diseases and conditions such as tuberculosis, silicosis, pulmonary sarcoidosis, pulmonary fibrosis and bacterial pneumonia;
(iv) inflammatory diseases and conditions of the enteric tract such as inflammatory bowel disease, Crohn's disease and ulcerative colitis;
(v) toxic shock syndrome and related diseases and conditions such as sepsis, septic shock, endotoxic shock, gram negative sepsis and the inflammatory reaction induced by endotoxin;
(vi) reperfusion injury; and
(vii) acquired immune deficiency syndrome (AIDS); and
(viii) diseases and conditions selected from atherosclerosis; muscle degeneration; gout; cerebral malaria; bone resorption diseases; fever and myalgias due to infection, such as influenza; cachexia, in particular cachexia secondary to infection or malignancy, cachexia secondary to acquired
immune deficiency syndrome (AIDS); AK)S; ARC (AIDS related complex); keloid formation; scar tissue formation; pyresis and asthma.
In another aspect, the invention provides a method for the prophylaxis or treatment of a disease state or condition of the type hereinbefore defined, which method comprises administering to a subject (e.g. a human subject) in need thereof a compound of the formula (I) as defined herein. Accordingly, the invention also provides a compound of the formula (T) as defined herein for use in the prophylaxis or treatment of a disease state or condition mediated by a serine protease or its receptor.
Other uses of compounds of the invention are as serine protease inhibitors for anticoagulant use either embedded in or physically linked to devices, especially medical devices and materials used to make such devices used for example in collecting blood, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents.
Salts. Isomers, Polymorphs. Tautomers. N-oxides. esters and Pro-drugs
Where compounds of the formula (I) or formula (I0) contain one or more chiral centres, and can exist in the form of two or more optical isomers, references to compounds of the formula (I) or formula (I0) include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic mixtures) or two or more optical isomers, unless the context requires otherwise.
The optical isomers may be characterised and identified by their optical activity (i.e. as + and - isomers, or d and 1 isomers) or they may be characterised in terms of their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl, 1966, 5, 385-415.
Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art.
Where compounds of the formula (I) or formula (I0) exist as two or more optical isomeric forms, one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers, or only one of a plurality of
diastereoisomers. Accordingly, the invention provides compositions containing a compound of the formula (I) having one or more chiral centres, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of the formula (T) is present as a single optical isomer (e.g. enantiomer or diastereoisomer). In one general embodiment, 99% or more (e.g. substantially all) of the total amount of the compound of the formula (J) may be present as a single optical isomer (e.g. enantiomer or diastereoisomer).
Also encompassed by formula (I) and formula (I0) are any polymorphic forms of the compounds, solvates (e.g. hydrates), complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds.
The compounds of Formula I or formula (I0) may also be solvated, especially hydrated. Hydration may occur during manufacturing of the compounds or compositions comprising the compounds, or the hydration may occur over time due to the hygroscopic nature of the compounds.
Compounds of the formula (I) or formula (f) containing an amine function may also form N- oxides. A reference herein to a compound of the formula (I) that contains an amine function also includes the N-oxide.
Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
Certain compounds within the scope of Formula I or formula (I0) are derivatives referred to as prodrugs. The expression "prodrug" denotes a derivative of a known direct acting drug, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process; see Notari, R. E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology, 112:309-323 (1985); Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future, 6(3): 165-182 (1981); and Bundgaard, H., "Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, New York (1985).
Examples of useful prodrugs are set out e.g. in U.S. Pat. No. 5,466,811 and Saulnier et al, Bioorg. Med. Chem. Lett. 4:1985-1990 (1994).
For medicinal use, the pharmaceutically acceptable acid addition salts, those salts in which the anion does not contribute significantly to toxicity or pharmacological activity of the organic cation, are preferred. The acid addition salts are obtained either by reaction of an organic base of Formula
I with an organic or inorganic acid, preferably by contact in solution, or by any of the standard methods detailed in the literature available to any practitioner skilled in the art. Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, cyclamic acid, pivalic acid and the like; useful inorganic acids are hydrohalide acids such as HCl, HBr, HI; sulfuric acid; phosphoric acid and the like. Preferred acids for forming acid addition salts include HCl and acetic acid.
The compounds of the present invention represent a novel class of potent inhibitors of serine proteases, as exemplified by their inhibition of uPA in specific examples set out in more detail below. A specific end use application of the compounds that inhibit uPA is in treatment of tumours, especially solid tumours and cancers. For their end-use application, the potency and other biochemical parameters of the en2yme-irihibiting characteristics of the compounds of the present invention is readily ascertained by standard biochemical techniques well known in the art. Actual dose ranges for their specific end-use application will, of course, depend upon the nature and severity of the disease state of the patient or animal to be treated, as determined by the attending diagnostician. It is expected that a useful dose range will be about 100 pg to 100 mg per kg per day, preferably from 10 ng to 10 mg per kg per day, more preferably from 1 μg to 10 mg per kg per day, for an effective therapeutic effect.
Compounds of the present invention that inhibit serine proteases, including uPA or plasminogen activator, are potentially useful in treating excessive cell growth disease state. As such compounds of the present invention may also be useful in the treatment of benign prostatic hypertrophy and prostatic carcinoma, the treatment of psoriasis, and as abortifacients. For their end-use application, the potency and other biochemical parameters of the enzyme inhibiting characteristics of compounds of the present invention are readily ascertained by standard biochemical techniques well known in the art. Actual dose ranges for this application will depend upon the nature and severity of the disease state of the patient or animal to be treated as determined by the attending diagnostician. It is expected that a useful dose range will be about 100 pg to 100 mg per kg per day, preferably from 10 ng to 10 mg per kg per day, more preferably from 1 μg to 10 mg per kg per day, for an effective therapeutic effect.
The pharmaceutical compositions of the invention can be administered to any animal that can experience the beneficial effects of the compounds of the invention. Foremost among such animals are humans, although the invention is not intended to be so limited.
The pharmaceutical compositions of the present invention can be administered by any means that achieve their intended purpose. For example, administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular routes. Alternatively, or concurrently, administration can be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
Pharmaceutical Formulations
In addition to the pharmacologically active compounds, the new pharmaceutical reparations can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
The pharmaceutical preparations of the present invention are manufactured in a manner that is, itself, known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as, starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents can be added, such as, the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as, sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as, magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings that, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as, acetylcellulose phthalate or
hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as, glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules that may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as, fatty oils or liquid paraffin. In addition, stabilizers may be added.
Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, alkaline solutions and cyclodextrin inclusion complexes. Especially preferred salts are hydrochloride and acetate salts. One or more modified or unmodified cyclodextrins can be employed to stabilize and increase the water solubility of compounds of the present invention. Useful cyclodextrins for this purpose are disclosed in U.S. Pat. Nos. 4,727,064, 4,764,604, and 5,024,998.
In addition, suspensions of the active compounds as appropriate oily injection suspensions can be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.
Methods for the Preparation of Compounds of the formula (D and (1°)
The preparation of compounds of the invention is now described. The procedures described below and used in this synthesis are well known to those skilled in the art, and examples of alkylations, acylations, functional group interconversions and reagents and conditions for carrying out . such conversions can be found in, for example, Advanced Organic Chemistry, by Jerry March, 4th edition, 119, Wiley Interscience, New York; Fiesers' Reagents for Organic Synthesis, Volumes 1-
17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2); and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8).
A number of key intermediates were synthesised (intermediates A-E outlined below) that allow many examples of this invention to be prepared from anilines by an amide coupling reaction
(Scheme 1). Many anilines and amino-heterocyclic compounds are commercially available and can be coupled using procedures commonly employed in the synthesis of peptides. Examples of such reagents include 1,3-dicyclohexylcarbodiimide (DCC) (Sheehan et al, J. Amer. Chem Soc. 1955, 77, 1067), l-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (referred to herein either as EDC or EDAC) (Sheehan et al, J. Org. Chem., 1961, 26, 2525), uronium-based coupling agents such as O- (7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and phosphonium-based coupling agents such as l-benzo-triazolyloxytris-(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (Castro et al, Tetrahedron Letters, 1990, 31, 205). Carbodiimide- based coupling agents are advantageously used in combination with l-hydroxy-7-azabenzotriazole (HOAt) (L. A. Carpino, /. Amer. Chem. Soc, 1993, 115, 4397) or 1-hydroxybenzotriazole (HOBt) (Konig et al, Chem. Ber., 1970, 103, 2024-2033). Preferred coupling reagents include EDC (EDAC) and DCC in combination with HOAt or HOBt.
The coupling reaction is typically carried out in a non-aqueous, non-protic solvent such as acetonitrile, dioxane, dimethylsulphoxide, dichloromethane, dimethylformamide or Ν- methylpyrrolidine, or in an aqueous solvent optionally together with one or more miscible co- solvents. The reaction can be carried out at room temperature or, where the reactants are less reactive (for example in the case of electron-poor anilines bearing electron withdrawing groups such as sulphonamide groups) at an appropriately elevated temperature. The reaction may be carried out in the presence of a non-interfering base, for example a tertiary amine such as triethylamine or N,N-diisopropylethylamine.
In each case, after amide coupling, starting from intermediates A-E, a tert-butyl-carbonyl protecting group must be removed from the primary amine to give the final product. This is conveniently carried out using dry hydrogen chloride gas in a range of organic solvents, for example, dioxane, ethyl acetate or methanol, or a combination of solvents, such as dioxane and methanol. Protection of one or more groups to prevent reaction from taking place at an undesirable location on the molecule is commonly carried out in organic synthesis. Examples of protecting groups, and methods of protecting and deprotecting functional groups, can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
The two step process of coupling intermediates A-E with amines, anilines or amino-heterocyclic compounds, followed by removal of the protecting group, is straightforward and is suitable for the synthesis of large combinatorial libraries of molecules, useful for this invention. Examples of combinatorial libraries are described in Solid-Phase Synthesis and Combinatorial Technologies By Pierfausto Seneci. Wiley-Interscience, New York. 2000. xii + 637 pp. ISBN 0471331953).
Scheme 1
Formula Ha Formula lib Formula I
Scheme 2 illustrates the process for synthesis of Intermediate A, used in the preparation of examples of this invention. Alkylation of the commercially available phenol with N-(2- bromoethyl) phthalimide, followed by removal of the phthalimide protecting group and exchange for the tert-butyl carbamate (BOC) protecting group, and finally saponification to the acid gives A.
Scheme 3
Scheme 3 illustrates the process for production of intermediate B, used in the preparation of examples of this invention. The key transformations are the Friedel Crafts acylation of 2- methylanisole; the bromoform reaction to covert the ketone intermediate into the carboxylic acid; chlorination of 4-hydroxy-3-methyl-benzoic acid methyl ester; and Mitsunobu alkylation of the hindered phenol to form 4-(2-tert-butoxycarbonylamino-ethoxy)-3-chloro-5-methyl-benzoic acid methyl ester. The Friedel Crafts reaction is described below and similar conditions are outlined by Hauser et al, Journal of Organic Chemistry (2000), 65(6), 1842-1849. The bromoform transformation is described below and a similar reaction is described by Kajigaeshi et al, Synthesis (1985), (6-7), 674-5. The chlorination reaction is described below and a similar transformation is described by Bugnet et al, Tetrahedron Letters (2003), 44(29), 5491-5494. The Mitsunobu reaction with (2-hydroxyethyl)-carbamic acid tert-butyl ester is described below and similar reactions are described by Ding et al, Journal of Organic Chemistry (2001), 66(24), 8273-8276 and Falkiewicz et al, Tetrahedron (2001), 57(37), 7909-7917. In general Mitsunobu chemistry can be carried out between a primary or secondary alcohol and an acidic compound such as a carboxylic acids, phenols, sulfonamides and certain classes of heterocycles. The Mitsunobu coupling reaction is typically carried out using diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and triphenylphosphine as the coupling agent in a polar solvent such as THF.
Intermediate C
Intermediate C was synthesised according to Scheme 4. N-(fert-butyloxycarbonyl)-0-(4- methylphenylsulphonyl)ethanolarnine was prepared as described below and is also described, for example, by Canne et al, Tetrahedron Letters (1997), 38(19), 3361-3364. Alkylation afforded the ester intermediate, which was saponified to give intermediate C.
Scheme 5
From Scheme 2
Intermediate D
Scheme 5 describes the synthesis of intermediate D. Nitration of 4-hydroxy-3-methyl-benzoic acid methyl ester was carried out according to standard procedures, e.g. from Advanced Organic Chemistry, by Jerry March, 4th edition, 119, Wiley Interscience, New York; Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2), and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471- 31192-8). The remainder of the synthesis is similar to procedures outlined above.
Intermediate E
Intermediate E was synthesised according to Scheme 6. (2?>N-(tert-butyloxycarbonyl)-0-(4- methylphenylsulphonyl)-2-aminopropanol was prepared as described below and is also described, for example, by Lin et al, PCT Int. Appl. (2001), 131 pp. WO 2001/056991. Alkylation afforded the ester intermediate, which was saponified to give intermediate E.
Compounds of the invention can accordingly be prepared by coupling a protected compound of formula Ha to a compound of formula lib, followed by deprotecting, to yield a compound of formula I. In specific embodiments of the invention, compounds of formula Ha are selected from intermediates A, B, C, D and E.
Scheme 7
Intermediate F was prepared from intermediate A according to Scheme 7. The synthesis requires the use of a silyl protected alcohol intermediate as a masked function group (see Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999). Deprotection using TBAF revealed the alcohol, which was then oxidised under standard conditions, for example as outlined in Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8). This aldehyde intermediate was used to prepare a range of amine derivatives by reductive amination chemistry. Reductive amination is a very common reaction to allow a broad range of amines to be coupled to an aldehyde intermediate, and can often be used in the synthesis of combinatorial libraries. An example for the synthesis of a small library of compounds by a related method is Burns, et al, Bioorganic & Medicinal Chemistry Letters (2002), 12(9), 1263-1267. Scheme 8 illustrates the general process where compounds of this invention can be prepared by a reductive amination reaction.
Scheme 8
Reductive amination methods
Formula IJJ Formula IV
In further methods of preparing compounds of the invention, a protected compound of formula HI is converted to a compound of formula IV by reductive amination, and then deprotected, yielding a compound of formula I. The compound of formula III can be, by way of a specific example, intermediate F.
In these preparative methods, the definitions of Rm, Rn, Rp, Rq, Ra, Rb, Rc, V, W, X, Y and R1"5 are as described for the various embodiments of the invention disclosed elsewhere herein, and P indicates a protecting group.
A range of aniline compounds are described below for use in this invention. Many anilines and amino heterocycles are commercially available or are easily prepared by functional group inter- conversion for example from aromatic nitro-compounds by reduction, or from benzoic acid compounds by use of the Curtius rearrangement. Functional group interconversions and reagents and conditions for carrying out such conversions can be found in, for example, Advanced Organic Chemistry, by Jerry March, 4th edition, 119, Wiley Interscience, New York; Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2); and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471- 31192-8).
Further anilines are useful for this invention that are produced from aromatic nitro compounds using nucleophilic aromatic substitution reactions in which a halogen is displaced by an amine. For example piperidine can be used to displace a fluorine or chlorine atom on an aromatic nitro compound to form a nitrophenyl piperidine derivative. Reduction of the nitro group then gives the aniline useful for this invention. Such SNAr chemistry is well know to those skilled in the art, and, for example is described by Tempest et al, Tetrahedron Letters (2003), 44(9), 1947-1950 and Greizerstein, Journal of the American Chemical Society (1962), 84 1032-6.
Certain amino-tetrahydroisoquinoline heterocyclic compounds are described below and are useful for synthesis of compounds in this invention. Some are simply available by function group inter- conversion from commercial compounds as described above. Others, useful for preparation of compounds for this invention are described in Wendt et al, Journal of Medicinal Chemistry (2004), 47(2), 303-324 and Geyer, et al, U.S. (2001), 91 pp., Cont.-in-part of U.S. 6,258,822. US 6284796.
Certain biphenyl amines are useful for synthesis of compounds in this invention. Such compounds, and heterocyclic modifications of biphenyl compounds, are readily prepared by palladium mediated coupling chemistries between aromatic bromo or iodo compounds and aromatic boronic
acids or stannane derivatives. In particular, Suzuki coupling chemistry is broadly applicable to synthesis of aryl-aryl compounds. The Suzuki reaction can be carried out under typical conditions in the presence of a palladium catalyst such as bis(tri-t-butylphosphine)palladium and a base (e.g. a carbonate such as potassium carbonate). The reaction may be carried out in an aqueous solvent system, for example aqueous ethanol, and the reaction mixture is typically subjected to heating, for example to a temperature in excess of 1000C. Many boronates suitable for use in preparing compounds of the invention are commercially available, for example from Boron Molecular Limited of Noble Park, Australia, or from Combi-Blocks Inc, of San Diego, USA. Where the boronates are not commercially available, they can be prepared by methods known in the art, for example as described in the review article by N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457. Thus, boronates can be prepared by reacting the corresponding bromo-compound with an alkyl lithium such as butyl lithium and then reacting with a borate ester. The resulting boronate ester derivative can, if desired, be hydrolysed to give the corresponding boronic acid.
Many transformations involving coupling together building blocks to form compounds of formula 1 require combining suitable pairs of reactive intermediates to form the linker group L. This will be well understood by someone skilled in the art of organic synthesis. Suitable reagents would be, for example, sulfonyl chlorides and amines or ureas, isocyanates and amines, carboxylic acids or acid chlorides with amines, Wittig reagents with aldehydes, aromatic boronic acids, alkynes, vinyl halides or organotin reagents with aryl halides, and the like. Olefins, formed by Wittig chemistry or Palladium mediated cross coupling reactions can be further elaborated to cyclopropanes using, for example, methods outlined in US6504031. These types of coupling chemistries are described in
Advanced Organic Chemistry, by Jerry March, 4th edition, 119, Wiley Interscience, New York;
Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN:
0-471-58283-2); and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8).
Where L is a heterocyclic linker, such as a 5-ring heterocycle or a bicyclic system, many methods are described in the chemical literature for the synthesis of these types of rings. For example, a benzimidazole can be formed from a 1,2-dianiline by amide bond formation to a carboxylic acid, followed by ring closure by heating. Similarly, an oxadiazole ring can be formed by peptide coupling of an amidoxime containing compound to a carboxylic acid, and the intermediate cyclised by heating. Again, such general methods can be found in Advanced Organic Chemistry, by Jerry March, 4th edition, 119, Wiley Interscience, New York; Fiesers1 Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2); and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8).
EXAMPLES
The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following procedures and examples in which compounds of the invention have been prepared and tested for activity in inhibiting uPA (as a representative example of a serine protease).
The starting materials for each of the procedures described below are commercially available unless otherwise specified.
Proton magnetic resonance (1H NMR) spectra were recorded on a Bruker AV400 instrument operating at 400.13MHz, in MeOH-d4, DMSO-d6 or CDCl3 (as indicated) at 27 0C, unless otherwise stated and are reported as follows: chemical shift δ/ppm (number of protons, multiplicity where s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad). The residual protic solvent was used as the internal reference.
In the examples, the compounds prepared were characterised by liquid chromatography and mass spectroscopy (LC/MS) using the system and operating conditions set out below. Where chlorine is present, the mass quoted for the compound is for 35Cl. Where bromide is present the mass quoted for the compound is 79Br. The two systems were equipped with identical chromatography columns and were set up to run under the same operating conditions. The operating conditions used are also described below.
Platform System HPLC System: Waters 2795
Mass Spec Detector: Micromass Platform LC
PDA Detector: Waters 2996 PDA
Acidic Analytical conditions 1:
Eluent A: H2O (0.1% Formic Acid) Eluent B: CH3CN (0.1% Formic Acid)
Gradient: 5-95% eluent B over 3.5 minutes
Flow: 0.8 ml/min
Column: Phenomenex Synergi 4μ Hydro-RP 80A5 2.0 x 50 mm
Acidic Analytical conditions 2: Eluent A: H2O (0.1% Formic Acid)
Eluent B: CH3CN (0.1% Formic Acid)
Gradient: 5-95% eluent B over 3.5 minutes
Flow: 0.8 ml/min
Column: Phenomenex Synergi 4μ MAX-RP 8OA, 2.0 x 50 mm
Acidic Analytical conditions 3:
Eluent A: H2O (0.1% Formic Acid) Eluent B: CH3CN (0.1% Formic Acid)
Gradient: 5-95% eluent B over 15 minutes
Flow: 0.4 ml/min
Column: Phenomenex Synergi 4μ MAX-RP 8OA, 2.0 x 150 mm
Basic Analytical conditions 1: Eluent A: H2O (1OmM NH4HCO3 buffer adjusted to pH=9.5 WItIiNH4OH)
Eluent B: CH3CN
Gradient: 05-95% eluent B over 3.5 minutes
Flow: 0.8 ml/min
Column: Phenomenex Luna Cl 8(2) 5μm 2.0 x 50 mm Basic Analytical conditions 2:
Eluent A: H2O (1 OmM NH4HCO3 buffer adjusted to pH=9.5 with NH4OH)
Eluent B: CH3CN
Gradient: 05-95% eluent B over 15 minutes
Flow: 0.8 ml/min Column: Phenomenex Luna Cl 8(2) 5μm 2.0 x 50 mm
MS conditions:
Capillary voltage: 3.5 kV
Cone voltage: 30 V
Source Temperature: 120 0C Scan Range: 165-700 amu
Ionisation Mode: ElectroSpray Negative, Positive or Positive & Negative
In the examples below, the following key is used to identify the LCMS conditions used: PS-Al Platform System- acidic analytical conditions 1
PS-A2 Platform System - acidic analytical conditions 2 PS-A3 Platform System - acidic analytical conditions 3
PS-B 1 Platform System - basic analytical conditions 1
PS-B2 Platform System - basic analytical conditions 2
Mass Directed Purification LC-MS System
Preparative LC-MS is a standard and effective method used for the purification of small organic molecules such as the compounds described herein. The methods for the liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide better separation of the crude materials and improved detection of the samples by MS. Optimisation of the preparative gradient LC method will involve varying columns, volatile eluents and modifiers, and gradients. Methods are well known in the art for optimising preparative LC-MS methods and then using them to purify compounds. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC/MS; J Comb Chem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C, Development of a custom high-throughput preparative liquid chromatography/mass spectrometer platform for the preparative purification and analytical analysis of compound libraries; J Comb Chem.; 2003; 5(3); 322-9.
One such system for purifying compounds via preparative LC-MS is described below although a person skilled in the art will appreciate that alternative systems and methods to those described could be used. In particular, normal phase preparative LC based methods might be used in place of the reverse phase methods described here. Most preparative LC-MS systems utilise reverse phase LC and volatile acidic modifiers, since the approach is very effective for the purification of small molecules and because the eluents are compatible with positive ion electrospray mass spectrometry. Employing other chromatographic solutions e.g. normal phase LC, alternatively buffered mobile phase, basic modifiers etc as outlined in the analytical methods described above could alternatively be used to purify the compounds.
• Hardware:
Waters Fractionlynx system: 2767 Dual Autosampler/Fraction Collector 2525 preparative pump CFO (column fluidic organiser) for column selection RMA (Waters reagent manager) as make up pump Waters ZQ Mass Spectrometer Waters 2996 Photo Diode Array detector
• Software: Masslynx 4.0
• Columns:
1. Low pH chromatography:
Phenomenex Synergy MAX-RP, lOμ, 150 x 15mm
(alternatively used same column type with 100 x 21.2mm dimensions).
2. High pH chromatography: Phenomenex Luna Cl 8 (2), 10μ, 100 x 21.2mm (alternatively used Thermo Hypersil Keystone BetaBasic C18, 5D, 100 x 21.2mm)
• Eluents:
1. Low pH chromatography: Solvent A: H2O + 0.1% Formic Acid, pH 1.5 Solvent B: CH3CN + 0.1% Formic Acid
2. High pH chromatography:
Solvent A: H2O + 10 mM NH4HCO3 + NH4OH, pH 9.5 Solvent B: CH3CN
3. Make up solvent: MeOH + 0.1% Formic Acid (for both chromatography type)
• Methods:
According to the analytical trace the most appropriate preparative chromatography type was chosen. A typical routine was to run an analytical LC-MS using the type of chromatography (low or high pH) most suited for compound structure. Once the analytical trace showed good chromatography a suitable preparative method of the same type was chosen. Typical running condition for both low and high pH chromatography methods were:
Flow rate: 24 ml/min
Gradient: Generally all gradients had an initial 0.4 min step with 95% A + 5% B. Then according to analytical trace a 3.6 min gradient was chosen in order to achieve good separation (e.g. from 5% to 50% B for early retaining compounds; from 35% to 80% B for middle retaining compounds and so on)
Wash: 1 minute wash step was performed at the end of the gradient
Re-equilibration: 2.1 minute re-equilibration step was ran to prepare the system for the next run Make Up flow rate: 1 ml/min
• Solvent:
All compounds were usually dissolved in 100% MeOH or 100% DMSO
• MS running conditions:
Capillary voltage: 3.2 kV
Cone voltage: 25 V
Source Temperature: 12O 0C
Multiplier: 500 V
Scan Range: 125-800 amu
IonisationMode: ElectroSpray Positive
Preparative LC-MS can thus be used to purify compounds of the invention.
Synthesis of Intermediates
Intermediate A
3,5-Dichloro-4-[2-('l,3-dioxo-l,3-dihvdro-isoindol-2-ylVethoxyl-benzoic acid ethyl ester
A stirred solution of ethyl-3,5-dichloro-4-hydroxybenzoate (15 g, 63.75 mmol) and potassium carbonate (10.5 g, 76.5 mmol) in NN-dimethylformamide (50 ml) and acetonitrile (50 ml) at 120° C was treated with N-(2-bromoethyl) phthalimide (24.3 g, 95.62 mmol) in small portions over a period of 1 h. The mixture was stirred at 120° C overnight, cooled and water added (100 ml). The resulting mixture was extracted with dichloromethane, the organic layer dried over magnesium sulfate and evaporated to dryness in vacuo to afford the crude product as a white solid (26 g, 100%). This material was used in the following step without any further purification. 1H ΝMR (MeOH-(I4) 7.95 (2H5 s), 7.9 (2H, m), 7.85 (2H, m), 4.35 (4H, m), 4.15 (2H, t), 1.35 (3H51).
4-(2-Amino-ethoxy)-3,5-dichloro-benzoic acid ethyl ester
To a stirred solution of 355-dichloro-4-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-ethoxy]-benzoic acid ethyl ester (26 g, 63.75 mmol) in ethanol (100 ml) at room temperature was added dropwise hydrazine monohydrate (3.09 ml, 63.75 mmol). The mixture was stirred at 100° C for 3 h, cooled and the resulting precipitate removed by filtration and the residue evaporated to dryness in vacuo . The residue was triturated with dichloromethane (100 ml) to afford the crude product as a pale yellow solid (12.3 g, 70%). This material was used in the following step without any further purification. 1H ΝMR (MeOH-(I4) 7.90 (2H, s), 4.25 (2H5 q), 4.05 (2H51), 2.95 (2H51), 1.25 (3H, t).
4-(2-fert-Butoxycarbonyl amino-ethoxyV3.5-dlchloro-benzoic acid ethyl ester
To a stirred solution of 4-(2-amino-ethoxy)-3,5-dichloro-benzoic acid ethyl ester (12.3 g, 44.4 mmol) in dichloromethane (100 ml) at room temperature was added portionwise, di-tøt-butyl dicarbonate (9.69 g, 44.4 mmol). The mixture was stirred for 2 h, water (100 ml) added and the organic layer separated, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo . Purification by column chromatography on silica eluting with 30% ethyl acetate in petroleum ether afforded the product as a white solid (13.5 g, 810Zo)-1H NMR (MeOH-^) 7.85 (2H, s), 4.25 (2H, q), 4.00 (2H, t), 3.40 (2H, t), 1.40 (9H, s), 1.25 (3H, t).
4-(2-fer^-Butoxycarbonylamino-ethoxy)-3,5-dicnloro-benzoic acid
To a stirred solution of 4-(2-ter£-butoxycarbonyl amino-ethoxy)-3,5-dichloro-benzoic acid ethyl ester (13.5 g, 35.8 mmol) in THF (100 ml) and water (30 ml) at room temperature was added portionwise, lithium hydroxide (1.70 g, 71.6 mmol). The mixture was stirred for 3 h, the THF was removed in vacuo and the resulting basic aqueous solution was acidified by the addition of 1 M hydrochloric acid. The white precipitate was filtered off under suction, washed with water and dried in a vacuum oven to afford the product as a white solid (11.04 g, 88%). 1H NMR (MeOH-d4) 8.00 (2H, s), 4.15 (2H, q), 3.50 (2H, t), 1.45 (9H, s). LC/MS: (PS-A2) Rt 3.05 [M-H]+ 348.
Intermediate B
AlCl3 (474 g) under cooling (0-5° C) was added to 1,2-dichloroethane (2 L). To this mixture acetyl chloride (211 g) was added dropwise over a period of 30 min at RT. The reaction mixture was stirred for 10 min. Then, 2-methylanisole (250 g) dissolved in 1,2-dichloroethane (100 ml) was added dropwise to the above mixture and stirred over a period of 1 h. The progress of the reaction was monitored by TLC (20% EtOAc/n-hexane, product Rf ~ 0.4). On completion, reaction mixture was poured in to cold water (500 ml) and cone. HCl (30 ml) was added to the reaction mixture. The 1,2-dichloroethanelayer was separated and the solvent was removed under reduced pressure to give the product (21Og).
4-Methoxy-3-methyl-benzoic acid
NaOH (19.5 g) was added to water (160 ml) and 2 ml of dioxane under cooling condition. Then, l-(4-methoxy-3-methyl-phenyl)-ethanone (8 g) and bromine (23.3 g) were added dropwise to the above reaction mixture over a period of 30 min at RT. The reaction mixture was stirred for 12 h. The progress of the reaction was monitored by TLC (20% EtOAc/n-hexane, product Rf - 0.3). On completion, reaction mixture was acidified with cone. HCl solution. The obtained residue was filtered under suction to give the product (4g).
4-Hvdroxy-3-methyl-benzoic acid
A mixture of acetic acid (50 ml) and 48% hydro bromic acid (50 ml) was added to 4-methoxy-3- methyl-benzoic acid (6 g). The reaction mixture was refluxed for 24 h at 120° C. The progress of the reaction was monitored by TLC (10% MeOHZCHCl3, product Rf ~ 0.1). On completion, the reaction mixture was poured in ice water (0-5° C, 150 ml) and extracted with ethyl acetate (3x75 ml). The combined organic extracts were dried over sodium sulfate. Then, ethyl acetate was removed under reduced pressure to give the product (3g).
4-Hvdroxy-3-methyl-benzoic acid methyl ester
A mixture of methanol (40 ml) and sulfuric acid (2 ml) was added to 4-hydroxy-3-methyl-benzoic acid (3 g). The reaction mixture was refluxed over a period of 5 h. The progress of the reaction was monitored by TLC (10% MeOH/CHCl3, product Rf ~ 0.7). On completion, methanol was removed under reduced pressure and EtOAc (30 ml) was added to it. Then, the compound was extracted with aqueous 5% NaHCO2 (20 ml). The obtained organic layer was separated and dried. The solvent was removed under reduced pressure to give the product (2.5g).
3-Chloro-4-hvdroxy-5-methyl-benzoic acid methyl ester
Sulfuryl chloride (1.29 ml) was added to the solution of 4-hydroxy-3 -methyl-benzoic acid methyl ester (0.5 g) in 1,2-dichloroethane (15 ml), AlCl3 (0.5 g) and stirred for 10 min. The reaction mixture was refluxed for Ih. The progress of the reaction was monitored by TLC (20% EtOAc/n- hexane, product Rf ~ 0.7). On completion, the reaction mixture was washed with water (15 ml). 1,2-dichloroethane layer was separated and dried over sodium sulfate. The solvent was removed under reduced pressure to give the product (solid) (0.5g)
(2-Hydroxy-ethyD-carbamic acid tert-butyl ester
To the mixture of ethanol amine (10 g) and THF (80 ml) was added (Boc)2O (39.2 g) and TEA (34 ml). The reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC (50% EtOAc/n-hexane, product Rf ~ 0.3). On completion, THF was removed under reduced pressure and ice water (100 ml) was added to it. The reaction mixture was extracted with EtOAc (2x50 ml). The obtained EtOAc layer was separated and dried over sodium sulfate. The solvent was removed under reduced pressure to give the product, which was further purified by column chromatography (SiO2, 3% MeOH/CHCl3) to give 19g of product.
4-(2-tert-Butoxycarbonylamino-ethoxy)-3-chloro-5-methyl-benzoic acid methyl ester
To a mixture of S-chloro^-hydroxy-S-methyl-benzoic acid methyl ester (1 g) in dry THF (20 ml) was added triphenylphosphine (3.082 g) and (2-hydroxy-ethyl)-carbamic acid tert-butyl ester
(0.915 g). The reaction mixture was stirred at 0-5° C. To this, DEAD (3.274 g) was added over a period of 10 min. The reaction mixture was stirred at RT for 12 h. The progress of the reaction was monitored by TLC (20% EtOAc/n-hexane, product Rf ~ 0.5). On completion, the THF was removed under reduced pressure. The reaction mixture was extracted with EtOAc (3x150 ml) and given 5% NaOH (2x75 ml). The EtOAc layer was separated and dried over sodium sulfate. The solvent was removed under reduced pressure to get the low melting, pale yellow, solid (0.45g).
4-(2-tert-Butoxycarbonylamino-ethoxy)-3-chloro-5-methyl-benzoic acid
To a solution of 4-(2-tert-Butoxycarbonylamino-ethoxy)-3-chloro-5-methyl-benzoic acid methyl ester (2g) in THF:MeOH:H2O 2.5:1:1 (45mL) was added LiOH (2 equivalents) and the reaction allowed to stir at RT for 4 hours. Reaction was followed by tic (1:1 EtOAc/petrol) and on completion the reaction was neutralised with IN HCl and reduced in vacuo. Material taken up in hot ethanol and purified by filtration to give a yellow oil which was triturated with petrol 40:60 to give the title compound as a pale yellow solid (2.14g). 1H NMR (MeOH-d4) 7.8 (IH, s), 7.7 (IH, s), 4.0 (2H, t), 3.5 (2H, t), 2.35 (3H, s), 1.5 (9H, s).
Intermediate C
Methyl 4-hvdroxy-3 ,5 -dimethylbenzoate
4-Hydroxy-3, 5 -dimethyl benzoic acid (10.94 g, 65.9 mmol) was stirred in a 2% solution of dry hydrogen chloride in methanol (100 ml) and held at reflux for 3 h. Evaporation of the solvent in vacuo afforded the product as a white solid (11.8 g, 99%). 1H NMR (DMSO-d6) 9.13 (IH, s), 7.58 (2H, s), 3.78 (3H, s), 2.19 (6H, s). LC/MS: (PS-A2) Rt 2.68 [M+H]+ 181.
N-(fert-ButyloxycarbonylVO-(4-methylphenylsulphonyl)ethaαolamitie
A stirred solution of N-(tert-butyloxycarbonyl)ethanolamine (16.1 g, 0.10 mol) in pyridine (50 ml) at 0° C was treated with 4-methylphenylsulphonyl chloride (19.1 g, 0.10 mol) and the mixture stirred and allowed to warm to room temperature overnight. Pyridine was removed in vacuo at room temperature and the residue partitioned between 2 M hydrochloric acid and dichloromethane. The organic layer was separated and the solvent removed in vacuo to afford the crude product as a pale yellow oil (23.0 g, 73%). 1H NMR (DMSO-d6) 7.78 (2H, d), 7.49 (2H, d), 7.01 (IH, t), 3.96 (2H, t), 3.12 (2H, m), 2.41 (3H, s), 1.31 (9H, s).
Methyl 4-(2-(fer^butyloxycarbonylamino)ethoxy-3 ,5 -dimethylbenzoate
A stirred solution of methyl 4-hydroxy-3,5-dimethylbenzoate (8.65 g, 48.06 mmol) and caesium carbonate (23.5 g, 72.08 mmol) in N^V-dimethylformamide (50 ml) at 50° C was treated with N- (tert-butyloxycarbonyl)-O-(4-methylphenylsulphonyl)-ethanolamine (23.0 g, 0.73 mmol) in small portions over a period of 8 h. The mixture was stirred at 50° C overnight and the solvent removed in vacuo. The residues were partitioned between 2 M sodium hydroxide and dichloromethane, the organic layer separated and evaporated to dryness in vacuo to afford the crude product as a brown oil. Purification by column chromatography on silica eluting with 5-20% ethyl acetate in petroleum ether afforded the product as a colorless solid (13.4 g, 86%). 1H ΝMR (DMSOd6) 7.65 (2H5 s), 7.09 (IH, t), 3.82 (3H, s), 3.78 (2H, m), 3.30 (2H, m), 2.26 (6H, s), 1.40 (9H, s). LC/MS: (PS-A2) Rt 3.38 [M+H]+ 324.
4-('2-(tert-Butyloxycarbonylamino')ethoxy)-3.5-dimethylbenzoic acid A stirred solution of methyl 4-(2-(terr-butyloxycarbonylamino)ethoxy)-3,5-dimethylbenzoate (9.69 g, 30.0 mmol) in methanol (120 ml) at 50° C was treated with a solution of potassium hydroxide (5.6 g, 0.10 mol) in water (40 ml) and the mixture stirred at 50° C for 3 h. The methanol was removed in vacuo and the resulting basic aqueous solution was acidified by the addition of 2 M hydrochloric acid. The white precipitate was filtered off under suction, washed with water and dried in a vacuum oven to afford the product as a colorless solid (9.0 g, 97%). 1H ΝMR (DMSO- d6) 12.70 (IH, br s), 7.62 (2H, s), 7.08 (IH, t), 3.82 (3H, s), 3.79 (2H, m), 3.30 (2H, m), 2.26 (6H, s), 1.38 (9H, s). LC/MS: (PS-A2) Rt 2.89 [M-H]+ 308.
Inteπnediate D
4-Hvdroxy-3-methyl-5-nitro-benzoic acid methyl ester
4-Hydroxy-3-methyl-benzoic acid methyl ester (prepared as in the preparation of Intermediate B) (20 g) taken in water (100 ml) was added to acetic acid (100 ml). Then, to this mixture fuming nitric acid (12 g) was added dropwise at 0° C. The reaction mixture was stirred at RT over a period of 1 h and heated at 60° C for 1 h. The progress of the reaction was monitored by TLC
(30% EtOAc/n-hexane, product Rf ~ 0.6). On completion, ice cold water (200 ml) was added to the reaction mixture and solid precipitate was formed which was filtered washed with water and dried. Then, obtained solid compound was dissolved in EtOAc (500 ml) and EtOAc layer removed under reduced pressure to give the product (22g).
4-(2-tert-Butoxycarbonylaminoethoxy)-3-methyl-5-m'tro-benzoic acid methyl ester 4-Hydroxy-3-methyl-5-nitro-benzoic acid methyl ester (0.5 g) in dry THF (5 ml) was added to (2- hydroxy-ethyl)-carbamic acid tert-butyl ester (0.4 g). Then, triphenyl phosphine (1.8 g) was added to the above mixture and kept at 0-5° C in ice. To this reaction mixture DEAD (1.6 g) in dry THF (5 ml) was added dropwise over a period of 15 min. The reaction mixture was stirred at RT over a period of 6 h. The progress of the reaction was monitored by TLC (30% EtOAc/n-hexane, product Rf ~ 0.3). On completion, THF was removed under reduced pressure, which gave the crude product, which was further subjected to column chromatography (Siθ2, 1% MeOH/CHCl3) and checked TLC (3% EtOAc/n-hexane). Again it was further purified by column chromatography (SiO2, 5-10% EtOAc/n-hexane) (0.3g).
3-Amino-4-(2-tert-butoxycarbonylamino-ethoxy)-5-methyl-benzoic acid methyl ester 4-(2-tert-Butoxycarbonylamino-ethoxy)-3-methyl-5-nitro-benzoic acid methyl ester (6.2 g) dissolved in methanol (50 ml) was added to 5% Pd/C (2.5 g) with methanol (20 ml). The reaction mixture was kept for hydrogenation over a period of 16 h at 60 psi. The progress of the reaction was monitored by TLC (30% EtOAc/n-hexane, product Rf ~ 0.2). On completion, the reaction mixture was filtered over a pad of celite with methanol. The obtained filtrate was removed under reduced pressure, which gave the product, which was subjected to column chromatography (SiO2, 19% EtOAc/n-hexane) to yield 3.1 g of the product as a viscous liquid.
Potassium 3-Amino-4-(2-tert-butoxycarbonylamino-ethoxyV5-methyl-benzoate 3-Amino-4-(2-tert-butoxycarbonylamino-ethoxy)-5-methyl-benzoic acid methyl ester (1.62 g) in methanol (40 ml) at 50° C was treated with a solution of potassium hydroxide (280 mg) in water (10 ml) and the mixture was held at 50° C for 16 h. The mixture was evaporated in vacuo to afford the product as a pale pink solid (1.6 g, 92%). 1H NMR (DMSO-d6) 7.03 (IH, s), 6.86 (IH, s), 3.67 (2H, t), 3.22 (2H, t), 2.11 (3H, s), 1.37 (9H, s).
Intermediate E
A stirred solution of N-(tert-butyloxycarbonyl)-2-aminopropanol (7.0 g, 40.0 mmol) in pyridine (30 ml) at 0° C was treated with 4-methylphenylsulphonyl chloride (7.62 g, 40.0 mol) and the mixture stirred and allowed to warm to room temperature overnight. Pyridine was removed in vacuo at room temperature and the residue partitioned between 2 M hydrochloric acid and dichloromethane. The organic layer was separated and the solvent removed in vacuo to afford the crude product as a pale yellow oil (12.4 g, 94%). 1H ΝMR (DMSOd6) 7.78 (2H, d), 7.48 (2H, d), 6.86 (IH, d), 3.85 (2H, m), 3.68 (IH, m), 3.12 (2H, m), 2.42 (3H, s), 1.34 (9H, s), 0.97 (3H, d).
Methyl ^?)-4-(2-(fert-butyloxycarbonylamino)propyloxy)-3 ,5 -dimethylbenzoate
A stirred solution of methyl 4-hydroxy-3,5-dimethylbenzoate (5.4 g, 30.0 mmol) and caesium carbonate (14.67 g, 45.0 mmol) in N^/V-dimethylformamide (30 ml) at 50° C was treated with (2?> N-(ter^bu1yloxycarbonyl)-O-(4-methylphenylsulphonyl)-2-aminopropanol (12.4 g, 37.6 mmol) in small portions over a period of 8 h. The mixture was stirred at 50° C overnight and the solvent removed in vacuo. The residues were partitioned between 2 M sodium hydroxide and dichloromethane, the organic layer separated and evaporated to dryness in vacuo to afford the crude product as a brown oil. Purification by column chromatography on silica eluting with 5-20% ethyl acetate in petroleum ether afforded the product as a colorless solid (4.2 g, 42%). 1H ΝMR (DMSOd6) 7.62 (2H, s), 6.92 (IH, d), 3.81 (4H, m), 3.68 (2H, m), 3.30 (2H, m), 2.24 (6H, s), 1.38 (9H, s), 1.20 (3H, d). LC/MS: (PS-A2) Rt 3.55 [M+H]+ 338.
^)-4-(2-(te^Butyloxycarbonylamino>)ρropyloxy)-3,5-dimethylbenzoic acid
A stirred solution of methyl 4-(2-(?e^butyloxycarbonylarnino)propyloxy)-3,5-dimetlαylbenzoate (4.2 g, 12.46 mmol) in methanol (60 ml) at 50° C was treated with a solution of potassium hydroxide (2.8 g, 50.0 mmol) in water (20 ml) and the mixture stirred at 50° C for 3 h. The methanol was removed in vacuo and the resulting basic aqueous solution was acidified by the addition of 2 M hydrochloric acid. The white precipitate was filtered off under suction, washed with water and dried in a vacuum oven to afford the product as a colorless solid (3.6 g, 90%). 1H NMR (DMSO-d6) 12.70 (IH, br s), 7.60 (2H, s), 6.93 (IH, d), 3.82 (IH, m), 3.79 (2H, m), 3.68 (2H, m), 2.24 (6H, s), 1.38 (9H, s), 1.18 (3H, d). LC/MS: (PS-A2) Rt 3.05 [M+H]+ 324.
Intermediate F
(2-{4-[4-(tert-Butyl-dimethyl-silanyloxymethylVphenylcarbamoylV2,6-dichloro-phenoxy)-ethyl)- carbamic acid tert-butyl ester
4-(2-tert-Butoxycarbonylamino-ethoxy)-3,5-dichloro-benzoic acid (prepared as in the preparation of Intermediate A) (2.78 g) taken in THF (35 ml) was added 4-(tert-Butyl-dimethyl- silanyloxymethyl)-phenylamine. Then, to this mixture was added EDAC (1.1 equivalents), HOAt
(1.1 equivalents) and Et3N (2 equivalents) and the RM allowed to stir at RT for 12 hours. The progress of the reaction was monitored by LC-MS. On completion, the reaction mixture was diluted with EtOAc and washed with sat. bicarbonate and brine. The material was triturated with petrol 40-60 to give the title compound as an off-white solid (3.16g). 1H NMR (MeOD) 7.9 (2H, s),
7.5 (2H, d), 7.2 (2H, d), 4.6 (2H, s), 4.0 (2H, t), 3.4 (2H, t), 1.35 (9H, s), 0.8 (9H, s), 0.00 (6H, s).
{2-[2,6-Dichloro-4-r4-hvdroxymethyl-phenylcaramoyD-phenoxy1-ethyl} -carbamic acid tert-butyl ester
To a solution (2-{4-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-phenylcarbamoyl]-2,6-dichloro- phenoxy}-ethyl)-carbamic acid tert-butyl ester (3.16g) in THF (3OmL) was added TBAF (l.OM in THF) (5.5mL) and the reaction allowed to stir at RT for 3 hours. The progress of the reaction was followed by tic (EtOAc). On completion the reaction mixture was partitioned between organic solvent (Et20, EtOAc, DCM) and brine. Organics dried over magnesium sulfate, reduced in vacuo and purified by column chromatography eluting with 1:4 EtO Ac/petrol and flushing with EtOAc to
give the title compound as an off-white solid (1.4g). 1H NMR (MeOD) 8.0 (2H, s), 7.65 (2H, d), 7.4 (2H, d), 4.6 (2H, s), 4.15 (2H, t), 3.5 (2H, t), 1.5 (9H, s).
{2-[2,6-Dichloro-4-(4-formyl-phenylcarbamoyl)-phenoxy]-ethyU-carbamic acid tert-butyl ester To a solution of {2-[2,6-Dichloro-4-(4-hydroxymethyl-phenylcaramoyl)-phenoxy]-ethyl}- carbamic acid tert-butyl ester (740mg) in THF (2OmL) was added manganese dioxide (10 equivalents) and the reaction allowed to stir at RT. The progress of the reaction was monitored by tic (1:2 EtOAc/petrol) and further equivalents of manganese dioxide were added as required. On completion the reaction was filtered to give the title compound as a beige solid (818mg). 1H NMR (MeOH-(I4) 9.93 (IH, s), 8.05 (2H, s), 7.95 (4H, m), 4.16 (2H, t), 3.15 (2H, t), 1.49 (9H, s).
Preparation of aniline intermediates
3,5-Di-(isopropyloxy)benzoic acid
A mixture of methyl 3,5-dihydroxybenzoate (3.36 g, 20.0 mmol), potassium carbonate (8.28 g, 60.0 mmol) and isopropyl iodide (8 ml) in N,N,dimethylformamide (25 ml) was stirred at 80 C for 16 h. The solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was separated and the solvent removed in vacuo to afford a pale yellow liquid. Methanol (60 ml) and potassium hydroxide (3.0 g) in water (20 ml) were added and the mixture stirred and held at reflux for Ih. The methanol was removed in vacuo and the aqueous solution acidified with 2 M hydrochloric acid. The white precipitate was removed by suction filtration, washed with water and dried overnight in a vacuum oven to afford the product as a colourless solid (3.8 g, 80%). 1H ΝMR (DMSO-d6) 12.92 (IH, br s), 6.99 (2H, s), 6.68 (IH, s), 4.63 (2H, m), 1.27 (12H, d).
3.5-Di-(isopropyloxy)aniline hydrochloride
A stirred solution of 3,5-di-(isopropyloxy)benzoic acid (1.19 g, 5.0 mmol) in toluene (30 ml) was treated with diphenylphosphoryl azide (1075 μl, 5.0 mmol) and triethylamine (835 μl, 6.0 mmol) and the mixture stirred at room temperature for 2 h. The solvent was removed in vacuo at room temperature and the residue partitioned between 1 M hydrochloric acid and dichloromethane. The organic layer was separated and the solvent removed in vacuo at room temperature to afford the crude acyl azide as a pale yellow oil. Toluene (20 ml) and tert-butanol (1.0 g) were added, the mixture was stirred and held at reflux for 16 h, the solvent was removed in vacuo and the residue was purified by column chromatography on silica. Elution with 5% ethyl acetate in petroleum ether afforded the N-tert-butyloxycarbonyl derivative as a colourless solid. 1H ΝMR (DMSO-dβ) 9.17 (IH, s), 6.64 (2H, d), 6.04 (IH, s), 4.48 (2H, m), 1.47 (9H, s), 1.24 (12H, d). LC/MS: (PS- A2) Rt 3.76 [M+H]+ 310. 4M Hydrogen chloride in dioxan (8 ml) was added and the mixture was stirred at room temperature for 3 h. Removal of the solvent in vacuo afforded the crude product which was triturated with 5:1 v/v petroleum ether and diethyl ether. The solid was collected by suction filtration and dried overnight in a vacuum oven to afford the product as a pale tan solid (460 mg, 44%). 1H ΝMR (DMSOd6) 9.90 (3H, br s), 6.41 (3H, s), 4.56 (2H, m), 1.27 (12H, d). LC/MS: (PS-A2) Rt 2.52 [M+H]+ 210.
3-Fluoro-5-(moφholin-4-yl')aniline dihvdrochloride
A stirred solution of 3-fluoro-5-(morpholin-4-yl)benzoic acid [Prepared according to Frederickson, et al, PCT Int. Appl. (2003),75 pp. WO 2003087087] (450 mg, 2.0 mmol) in toluene (10 ml) was treated with diphenylphosphoryl azide (430 μl, 2.0 mmol) and triethylamine (335 μl, 2.4 mmol) and the mixture stirred at room temperature for 3 h. The solvent was removed in vacuo at room temperature and the residue partitioned between 1 M hydrochloric acid and dichloromethane. The organic layer was separated and the solvent removed in vacuo at room temperature to afford the crude acyl azide as a pale yellow oil. Toluene (10 ml) and tert-butanol (0.5 g) were added, the mixture was stirred and held at reflux for 16 h, the solvent was removed in vacuo and the residue was purified by column chromatography on silica. Elution with 25-50% ethyl acetate in petroleum ether afforded the N-tert-butyloxycarbonyl derivative as a colourless solid. 1H ΝMR (DMSO-d6) 9.37 (IH, s), 6.88 (IH, s), 6.26 (IH, d), 6.39 (IH, d), 3.71 (4H, m), 3.04 (4H, m), 1.46 (9H, s). 4M
Hydrogen chloride in dioxan (8 ml) and methanol (5 ml) were added and the mixture was stirred at room temperature for 2 h. Removal of the solvent in vacuo afforded the crude product as a pale tan solid (230 mg, 43%). 1H NMR (DMSO-d6) 6.72 (IH, d), 6.64 (IH, s), 6.50 (IH, s), 3.72 (4H, m), 3.13 (4H, m).
1 -(3 -Chloro-5 -nitro-phenylVpiperidine
3,5-dichloro-nitro-benzene (1.27g) was mixed with piperidine (ImI) and DMSO (3ml) and potassium carbonate added (l.lg). The mixture was heated to 12O0C and stirred under nitrogen for 3 hours. The mixture was cooled, poured into ethyl acetate (50ml) and extracted with 5% aqueous citric acid solution (50ml). The organic layer was separated and dried over MgSO4. The solvents were evaporated and the crude reaction mixture purified using a 2Og silica SPE cartridge, eluting with pet ether and then 10% ether in pet ether. The purified product was a red gum (0.28g). LC/MS: (PS-A2) Rt 3.84 [M+H]+ 241.
3-Chloro-5-piperidin-l-yl-phenylamine l-(3-Chloro-5-nitro-phenyl)-piperidine (0.28g) was dissolved in ethanol (20ml) and stannous chloride dihydrate added (1.2g). The mixture was refluxed under nitrogen for 3 hours. The mixture was cooled, poured into ethyl acetate (50ml) and extracted with IN sodium hydroxide solution (50ml). The organic layer was separated and dried over MgSO4. The solvents were evaporated and the product (0.235g) was a red oil that was sufficiently pure for use without purification. LC/MS: (PS-A2) Rt 1.78 [M+H]+ 211.
1 -(3 -Chloro-5 -nitro-ρhenylVpiperidin-3 -ol
3,5-dichloro-nitro-benzene (Ig) was mixed with 3-hydroxy-piperidine (ImI) and DMSO (3ml) and potassium carbonate added (Ig). The mixture was heated to 12O0C and stirred under nitrogen for 5 hours. The mixture was cooled, poured directly onto a 2Og silica SPE cartridge and washed through
with ether (250ml). The solvents were evaporated and the crude reaction mixture purified using a 2Og silica SPE cartridge, eluting sequentially with 1/1 pet ether / ether, ether and then 10% methanol in ether. The purified product was an amber gum (0.43g). LC/MS: (PS-A2) Rt 3.01 [M+H]+ 257.
1 -(3 -Amino-5 -chloro-phenyr)-piperidin-3 -ol l-(3-Chloro-5-nitro-phenyl)-piperidin-3-ol (0.43g) was dissolved in ethanol (40ml) and stannous chloride dihydrate added (1.7g). The mixture was refluxed under nitrogen for 3 hours. The mixture was cooled, poured into ethyl acetate (50ml) and extracted with IN sodium hydroxide solution (50ml). The organic layer was separated and dried over MgSO4. The solvents were evaporated and the product (0.3g) was a red oil that was sufficiently pure for use without purification. LC/MS: (PS-A2) R1 1.85 [M+H]+ 227.
3-Bromo-2-methyl-5-piperidin-l-yl-phenylamine
3-Bromo-2-methyl-5-piperidin-l-yl-phenylamine was prepared in an analogues manner to the synthesis described immediately above, from 2-bromo-4-fluoro-6-nitrotoluene. LC/MS: (PS-A2) Rt
6-Trifluoroacetamido-l .2,3,4-tetrahydroisoquinoline hydrochloride
A stirred solution of 6-amino-l,2,3,4-tetrahydroisoquinoline hydrochloride (620 mg, 2.5 mmol) and triethylamine (725 μl, 5.5 mmol) in dichloromethane (10 ml) was treated dropwise with trifluoroacetic anhydride (382 μl, 2.75 mmol) and the mixture stirred at room temperature for 1 h.
The reaction was quenched by the addition of water, the organic layer was separated and the solvent removed in vacuo at room temperature to afford the crude 6-trifluoroacetamido derivative as a pale yellow oil. 1H NMR (DMSO-d6) 11.18 (IH, br s), 7.50 (IH, s), 7.43 (IH, d), 7.21 (IH, d), 4.48 (2H, s), 3.55 (2H, t), 2.78 (2H, t), 1.43 (9H, s). 4 M Hydrogen chloride in dioxan (20 ml) was added and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo to afford the product as a pale tan solid (680 mg, 97%). 1H NMR (DMSO-d6) 6.72 (IH, d), 6.64 (IH, s), 6.50 (IH, s), 3.72 (4H, m), 3.13 (4H, m). LC/MS: (PS-A2) R13.32 [M+H]+ 245.
6-Amino-2-methyl- 1,2.3 ,4-tetrahvdroisoquinoline
A solution of 6-trifluoroacetamido-l,2,3,4-tetrahydroisoquinoline hydrochloride (280 mg, 1.0 mmol) and 37% aqueous formaldehyde (525 μl, 6.0 mmol) in methanol (5 ml) was striked at room temperature for 4 h and then treated with sodium borohydride (400 mg) and the mixture stirred at room temperature for 16 h. The solvent was removed in vacuo, the residue partitioned between water and dichloromethane, the organic layer separated and evaporated in vacuo to afford the crude N-methyl derivative. LC/MS: (PS-Bl) R4 2.56 [M+H]+ 259. Methanol (8 ml) and potassium hydroxide (224 mg, 4.0 mmol) were added and the mixture stirred and held at reflux for 5 h. The solvent was removed in vacuo, the residue partitioned between water and dichloromethane, the organic layer separated and evaporated in vacuo to afford the product as a yellow oil (112 mg, 69%). LC/MS: (PS-Bl) R12.01 [M+H]+ 163.
7-Arnmo-2-Ν-(fert-butyloxycarbonyr) -1 ,2.3.4-tetrahydroisoquinolme
To a stirred solution of 7-amino- 1,2,3,4-tetrahydroisoquinoline hydrochloride (200 mg, 0.9 mmol) in dichloromethane (5 ml) at room temperature was added triethylamine (0.126 ml, 0.9 mmol) and di-tøt-butyl dicarbonate (196 mg, 0.9 mmol). The mixture was stirred at room temperature for 30 mins, then N,N,dimethylformamide (1 ml) was added and the reaction stirred at 50° C for 3 h. Water (20 ml) was added and the mixture extracted with dichloromethane, the organic layer separated, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo . The material was used in the next step without any further purification. 1H ΝMR (CDCl3) 6.85 (IH, d), 6.55 (IH, d), 6.45 (IH, s), 4.4 (2H, s), 3.55 (2H, br, s), 2.65 (2H, t), 1.4 (9H, s). LC/MS: (PS-A2) Rt 2.08 [M+H]+ 349.
2 ' -Methoxybiphenyl-3 -ylamine
To a degassed solution of 3-bromoaniline (0.42 g, 2.45 mmol), in toluene (1.5 ml) was added bis(tri-tert-butylphosphine)palladium(0), (5 mg) followed by 2-methoxyphenylboronic acid (0.56 g, 3.68 mmol) as a solution in ethanol (1.5 ml). Potassium carbonate (0.68 g, 4.9 mmol) was then added as a solution in H2O (3 ml) followed by methanol (1.5 ml). The reaction was heated to 1350C for 35 minutes in the microwave. The mixture was cooled to room temperature and the solvent removed in vacuo. The resulting material was partitioned between dichloromethane and water, dried over MgSO4 and evaporated to dryness to yield a light brown oil, which was used without further purification. (0.48 g, 100%). 1H NMR (CDCl3) 7.35 (4H, m), 7.20 (2H, d), 7.00 (3H, m),
3.80 (3H, s). LC/MS: (PS-Bl) Rt 2.84 [M+H]+ 200.
2 ' -Benzyloxy-biphenyl-3 -ylamine
Prepared from 2-benzyloxybromobenzene and 3-aminobenzeneboronic acid using the Suzuki coupling method described above to afford the product, after purification (column chromatography using 15% EtOAc in petrol as eluent) as a brown oil (0.56 g, 32%). 1H NMR (CDCl3) 7.30 (13H, m), 5.10 (2H, s). LC/MS: (PS-Bl) Rt 3.41 [M+H]+ 276.
3-Hydroxy-5-isopropoxy-benzoic acid methyl ester
A mixture of methyl 3,5-dihydroxybenzoate (3.0 g, 17.84 mmol), potassium carbonate (2.71 g, 19.63 mmol) and isopropyl iodide (1.96 ml, 19.63 mmol) in N^V,dimethylformamide (20 ml) was stirred at 500C for 3 h. The solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was separated and the solvent removed in vacuo to afford a brown oil. Purification by column chromatography on silica eluting with 20% ethyl acetate in petroleum ether afforded the product as a yellow oil (1.45 g, 39%). 1H ΝMR (CDCl3) 7.15 (IH, s), 7.10 (IH, s), 6.60 (IH, s), 4.60 (IH, m), 3.90 (2H, s), 1.35 (6H, d). LC/MS: (PS-Bl) Rt 2.66 [M-H]+ 209.
3-Benzyloxy-5-isopropoxy-benzoic acid
A mixture of 3-hydroxy-5-isopropoxy-benzoic acid methyl ester (1.45 g, 6.9 mmol), potassium carbonate (1.9 g, 13.8 mmol) and benzyl bromide (1.64 ml, 13.8 mmol) mN,N,dimethylformamide (20 ml) was stirred at 5O0C for 2 h. The solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was separated and the solvent removed in vacuo to afford a brown oil which was used in the next step without further purification. 1H ΝMR (CDCl3) 7.40 (6H, m), 7.20 (IH, s), 6.70 (IH, s), 4.60 (IH, m), 3.90 (3H, s), 1.35 (6H, d). LC/MS: (PS-Bl) R1 3.68 [M+H]+ 301. This residue was redissolved in THF (20 ml) and sodium hydroxide (0.55 g, 13.8 mmol) in water (50 ml) was added and the mixture stirred at 50° for 12h. The THF was removed in vacuo and the aqueous solution acidified with 2 M hydrochloric acid. The white precipitate was removed by suction filtration, washed with water and dried overnight in a vacuum oven to afford the product as a colourless solid (1.95 g, 98%). 1H ΝMR (DMSOd6) 7.40 (5H, m),
7.10 (IH5 s), 7.05 (IH, s), 6.80 (IH, s), 5.15 (2H, s), 4.65 (IH, m), 1.25 (6H, d). LC/MS: (PS-Bl) Rt 2.27 [M-H]+ 285.
O-Benzyloxy-S-isopropoxy-phenylVcarbamic acid-fert-butyl ester
A stirred solution of 3-benzyloxy-5-isopropoxy-benzoic acid (1.95 g, 6.9 mmol) in toluene (20 ml) was treated with diphenylphosphoryl azide (1.56 ml, 7.24 mmol) and triethylamine (1.09 ml, 8.28 mmol) and the mixture stirred at room temperature for 3 h. The solvent was removed in vacuo at room temperature and the residue partitioned between 1 M hydrochloric acid and dichloromethane. The organic layer was separated and the solvent removed in vacuo at room temperature to afford the crude acyl azide as a pale yellow oil. Toluene (20 ml) and føt-butanol (10 ml) were added, the mixture was stirred and held at reflux for 12 h, the solvent was removed in vacuo and the residue was purified by column chromatography on silica. Elution with 5% ethyl acetate in petroleum ether afforded the title compound as a colourless oil (1.14 g, 46%). 1H NMR (CDCl3) 7.90 (5H, m), 7.20 (IH, s), 7.05 (IH, s), 6.90 (IH, s), 6.75 (IH, s), 5.50 (2H, m), 5.00 (IH, m), 2.00 (9H, s), 1.80 (6H, d).
3-(BenzyloxyV5-(isopropoxy^aniline hydrochloride
To a stirred solution of (S-benzyloxy-S-isopropoxy-pheny^-carbamic acid-tøt-butyl ester (1.14 g, 3.19 mmol) in MeOH (3 ml) was added 4 M Hydrogen chloride in dioxane (8 ml) and the mixture was stirred at room temperature for 3 h. Removal of the solvent in vacuo afforded the crude product which was triturated with diethyl ether. The solid was collected by suction filtration and dried overnight in a vacuum oven to afford the product as a cream solid (0.93 g, 100%). 1H NMR (DMSO-d6) 7.40 (5H, m), 6.35 (3H, m), 5.10 (2H, s), 4.55 (IH, m), 4.00 (2H, br, s), 1.25 (6H, d). LC/MS: (PS-Al) Rt 3.17 [M+H]+ 258.
3 -(C yclopentyloxyϊphenylamine To a solution of cyclopentanol (0.55mL) in THF (3OmL) was added 3-aminophenol (1.5 equivalents), DEAD (1.5 equivalents) and triphenylphosphine (1.5 equivalents) and the reaction allowed to stir at RT for 12 hours. Progress of the reaction was followed by tic (EtOAc). On completion the reaction mixture was reduced in vacuo and triturated with diethylether. The filtrate was purified by column chromatography eluting with 1 :9 EtO Ac/petrol to 1 :4 EtOAc/petrol to give the title compound as a pale orange oil (810mg). 1H NMR (MeOH-d4) 9.96 (IH, t), 6.30 (2H, m), 6.24 (IH, dd), 4.75 (IH, m), 1.90 (2H, m), 1.80 (4H, m), 1.65 (2H, m).
4-(tert-Butyl-dinietliyl-silanyloxymethyπphenylamine
To a solution of 4-aminobenzyl alcohol (3g) in DMF (10OmL) was added tert-butyldimethylsilyl chloride (1 equivalent) and imidazole (1 equivalent) and the reaction allowed to stir at RT for 12 hours. The reaction was reduced in vacuo and partitioned between DCM and H2O and the organics dried over magnesium sulfate and reduced in vacuo. Material purified by column chromatography eluting with 1:9 EtO Ac/petrol to 1:4 EtO Ac/petrol to give the title compound as a pale yellow oil (1.89g). 1HNMR (MeOH-d4) 7.98 (2H, d), 6.60 (2H, d), 4.50 (2H, s), 0.85 (9H, m), 0.00 (6H, m).
S-Nitro-S-fpiperidine-l-carbonylVbenzoic acid methyl ester
5-nitroisophthalic acid methyl ester (5g) was refluxed for 1.5hr in thionyl chloride (20ml) under nitrogen. The mixture was cooled and the solvent removed in vacuo. The residues were dissolved in toluene and the solvent was again removed in vacuo. The resulting acid chloride was a white solid. This material was dissolved in DCM (5ml) and cooled in ice under nitrogen. A solution of piperidine (10ml) in DCM (10ml) was added very cautiously dropwise over 30mins. The mixture was then allowed to warm to room temperature and stirred for 18hrs. 2N HCl (100ml) and DCM (100ml) were added and the mixture extracted, the organic layer separated and then dried over MgSO4. The solvent was removed under vacuum and the residues triturated with ether / pet. ether, decanting off the solvent. The resulting product was a white solid (6.25g). LC/MS: (PS-A2) Rt 3.05 [M+H]+ 293.
3-Nitro-5-(piρeridine-l -carbonvD-benzoic acid
3-Nitro-5-(piperidine-l-carbonyl)-benzoic acid methyl ester (5g) was treated with potassium hydroxide (1.8g) in methanol (40ml) and the mixture stirred for lhr at room temperature. The solvent was evaporated and the residues extracted with IN HCl (100ml) and 2XlOOmI of DCM. The organic layer was dried (MgSO4) and evaporated in vacuo to give a white solid (4.76g). LC/MS: (PS-A2) Rt 2.68 [M+H]+ 279.
3-Ni1xo-5-(piperidine-l-carbonylVN-propyl-benzamide
3-Mtro-5-(piperidine-l-carbonyl)-benzoic acid (Ig) was dissolved in DCM (10ml) and N-ethyl-N'- (3-dimethylaminopropyl)carbodiimide hydrochloride (1.4g), 1-hydroxybenzotriazole (0.5g) and propylamine (ImI) were added and the mixture was stirred at room temperature for 3hrs. The mixture was then extracted with 2N HCl (30ml) and 2N NaOH (30ml) from DCM (50ml). The organic layer was dried (MgSO4) and evaporated in vacuo to give a gum (1.08g). LC/MS: (PS-A2) Rt 2.92 [M+H]+ 320.
S-Amino-S-Cpiperidine-l-carbonylVN-propyl-benzamide 3-Nitro-5-(piperidine-l-carbonyl)-N-propyl-benzamide (Ig) was dissolved in ethanol (50ml) and stannous chloride dihydrate added (2.8g). The mixture was refluxed under nitrogen for 3 hours. The mixture was cooled and the solvent was then evaporated in vacuo. The residues were dissolved in ethyl acetate (50ml) and extracted with IN sodium hydroxide solution (50ml). The organic layer was separated and dried over MgSO4. The solvents were evaporated and the product (Ig) was a white solid that was sufficiently pure for use without purification. LC/MS: (PS-A2) R4 2.38 [M+H]+ 290.
1 -Chloro-2-ethoxy-5 -fluoro-3 -nitrobenzene
A mixture of 2-chloro-4-fluoro-6-nitrophenol (prepared from 2-chloro-4-fluorophenol according to WO 00/13508) (7.30 g, 38.12 mmol), potassium carbonate (7.89 g, 57.18 mmol) and ethyl iodide (10 ml) in N,N,-dimethylformamide (60 ml) was stirred at 60 0C for 60 h. The solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was separated and the solvent removed in vacuo to afford the product as a dark yellow liquid (8.0 g, 96%). 1H ΝMR (DMSOd6) 7.98 (2H, d), 4.13 (2H, q), 1.33 (3H, t).
1 -Chloro-2-ethoxy-3-nitro-5-(l -piperidinyPbenzene
A stirred solution of l-chloro-2-ethoxy-5-fluoro-3 -nitrobenzene (2.19 g, 10.0 mmol), potassium carbonate (3.45 g, 25.0 mmol) and piperidine (2.13 g, 25.0 mmol) in dimethylsulphoxide (5 ml) was stirred at 120 0C for 3 h. Upon cooling the mixture was diluted with diethyl ether and the organics extracted with water and then twice with 5% citric acid. The organic layer was separated and the solvent removed in vacuo to afford the crude product as an orange oil (1.53 g, 54%). H ΝMR (DMSO-d6) 7.32 (2H, s), 4.04 (2H, q), 3.41 (4H, m), 1.56 (6H, m), 1.30 (3H, t). LC/MS: (PS-A2) Rt 3.95 [M+H]+ 285.
3-CMoro-2-ethoxy-5-(l-piperidmyl)aniline
A stirred solution of l-chloro-2-ethoxy-3-nitro-5-(l-piperidinyl)benzene (1.53 g, 5.39 mmol), and tin (E) chloride dihydrate (5.6 g, 24.24 mmol) in ethanol (50 ml) was stirred and held at reflux for 16 h. Upon cooling the solvent was removed in vacuo and the residue partitioned between dichloromethane and 2 M sodium hydroxide. The organic layer was separated, the solvent removed in vacuo and the residues subjected to column chromatography on silica. Elution with petroleum ether and ethyl acetate (4:1 v/v) afforded the product as a pale orange oil(300 mg, 22%). 1H ΝMR (DMSOd6) 6.22 (IH, d), 6.12 (IH, d), 4.92 (2H, br s), 3.82 (2H, q), 3.00 (4H, m), 1.55 (4H, m), 1.50 (2H, m), 1.31 (3H, t). LC/MS: (PS-B2) R13.45 [M+H]+ 255.
SYNTHESIS OF TEST COMPOUNDS
General Methods;
Method 1. Amide Coupling Reaction
The following general method was used to form amide coupling products with intermediates A, B, C, D, and E, typically on 0.5-lmmol scale.
The acid (A, B, C, D, or E) (1 equivalent), aniline (1 equivalent) starting material, N-ethyl-N'-(3- dimetnylaminopropyl)carbodiirnide hydrochloride (1.1-2.0 equivalents), l-hydroxy-7- azabenzotriazole or 1-hydroxybenzotriazole (1 equivalent) in DMF (1-5 mL) was stirred at room
temperature, or, if no reaction occurred, heated at 50-650C for 24 hours. In some cases triethylamine (0.2ml) was also added to aid solubility. The mixture was cooled, dilute hydrochloric acid (20-40 mL) and DCM or ethyl acetate (20-40 mL) were added, and the organic layer separated. The organic layer was washed with dilute sodium hydroxide and then dried with MgSO4, filtered and evaporated to dryness. The residue was purified by column chromatography or preparative HPLC/MS to yield the target compound as its Boc-protected derivative, in moderate to good yields in most cases.
Method 2. Amide Coupling Reaction via Acid Fluoride
The acid (A, B, C, D or E) (1 equivalent), cyanuric fluoride (5 equivalents), pyridine (1 equivalent) in DCM (~5mL) were stirred at -100C for ~ 1 hour. The reaction was followed by tic and upon completion quenched with ice, extracted with DCM and concentrated in vacuo (at RT) to give the acid fluoride in DCM (~ 5mL).
The aniline (1 equivalent) starting material in H2O (~5mL), sodium hydrogen carbonate (2 equivalents) and acid fluoride solution (1 equivalent) added drop-wise, in DCM and the reaction stirred vigorously for 12 hours. The reaction mixture was cooled, DCM and sat. bicarbonate soln (aq), dried over MgSO4, filtered and reduced in vacuo. Material purified by SCX.
Method 3. Boc-deprotection
The following general method was used to remove the Boc-protecting group from the amide coupled products, typically on 0.5-lmmol scale.
The Boc-protected derivative was dissolved in a saturated solution of hydrogen chloride in ether (2-5ml) and stirred for 4-24 hours until the reaction was complete. Where the Boc-compound was poorly soluble in ether a 4M solution of hydrogen chloride in dioxane (2-5ml) was substituted. If the material still remained insoluble an equal volume of methanol was added. Once the reaction was complete (3-24hrs) the solvents were removed in vacuo to yield the target compound as its mono or di-hydrochloride salt, hi some cases the final products were triturated with ether, or rarely required further purification by preparative HPLC/MS.
Method 4. Methyl carbamate formation
The following general method was used to prepare methyl carbamates from primary amines on 0.1- lmmol scale.
A stirred solution of the primary amine derivative in anhydrous pyridine (l-2ml) was treated dropwisewith methyl chloroformate (10 fold excess) and stirred for 4-24 hours until the reaction was judged to be complete by LC/MS. The mixture was evaporated in vacuo and the residue partitioned between aqueous copper sulphate and dichloromethane. The organic layer was separated and evaporated in vacuo to afford the methyl carbamate product which which typically did not require any further purification.
Method 5. Allyl Deprotection
To a solution of the 2-allyl-4-ethyl-l,2,3,4-tetrahydroisoquinolin-6-ylamide in DCM (~3ml) was added tetraMs(triphenylphosphine)palladium(0) (catalytic) and N,N'-dimethylbarbituric acid (3 equivalents) and the reaction heated to 350C for 3 hours. The progress of the reaction was monitored by LC-MS. On completion, the reaction was diluted with DCM and washed with sat. sodium carbonate and brine. The organics were dried over magnesium sulfate and purified by SCX (1Og).
Method 6. Reductive Animation
To a solution of {2-[2,6-Dichloro-4-(4-formyl-phenylcarbamoyl)-phenoxy]-ethyl}-carbamic acid tert-butyl ester (0.33mmol) in DCM (5mL) was added amine (1 equivalent) , triethylamine (3 equivalents) and 4A molecular sieves followed by sodium triacetoxyborohydride (4 equivalents). The reaction was allowed to stir at RT for 12 hours and the progress of the reaction was followed by LC-MS. Further sodium triacetoxyborohydride was added as required. On completion the reaction was filtered and the filtrate washed with sat. bicarbonate, dried over magnesium sulfate and purified by column chromatography.
The compounds prepared are set out in a table at the end of the examples section.
The following compounds were prepared from Intermediate A using methods 1 and 3 outlined above.
EXAMPLE 1
From 3-Isopropoxyaniline and purified by prep HPLC. 1H NMR (MeOH-d4) 8.42 (IH, s), 8.05 (2H, s), 7.40 (IH, s), 7.25 (2H, m), 6.75 (IH, dd), 4.60 (IH, m), 4.35 (2H, t), 3.45 (2H, t), 1.35 (6H, d). LC/MS: (PS-A2) Rt 2.27 [M+H]+ 383.
EXAMPLE 2 From aniline. 1H NMR (MeOH-(I4) 8.35 (IH, s), 8.05 (2H, s), 7.70 (2H, d), 7.35 (2H, t), 7.15 (IH, t), 4.35 (2H, t), 3.45 (2H, t). LC/MS: (PS-A3) R46.75 [M+H]+ 325.
EXAMPLE 3
From 2-methoxyaniline. 1H NMR (MeOH-(I4) 8.45 (IH, s), 8.00 (2H, s), 7.85 (IH, d), 7.21 (IH, t), 7.12 (IH, d), 7.00 (IH, t), 4.35 (2H, t), 3.90 (3H, s), 3.45 (2H, t). LC/MS: (PS-A3) Rt 6.91 [M+H]+ 355.
EXAMPLE 4
From 2-allyl-4-ethyl-l,2,3,4-tetrahydroisoquinolin-6-ylamine. (Ref. J. Med. Chem. (2004), 47 (2), 303-324). 1H NMR (DMSO-d6) 10.42 (IH, s), 8.31 (2H, br s), 8.15 (2H, s), 7.81 (IH, s), 7.70 (IH, d), 7.20 (IH, d), 6.15 (IH, m), 5.50-5.60 (2H, m), 4.20-4.40 (4H, m), 3.85 (2H, m), 3.30 (2H, t), 3.00-3.05 (3H, br m), 1.70-2.05 (2H, br m), 1.00 (3H, m). LC/MS: (PS-Bl) R13.46 [M+H]+ 448.
EXAMPLE 5
From m-phenetidine. 1H NMR (MeOH-d4) 8.52 (IH, s), 8.06 (2H, s), 7.40 (IH, s), 7.25 (2H, m), 6.75 (IH, dd), 4.46 (2H, t), 4.05 (2H, q), 3.45 (2H, t), 1.42 (3H, t). LC/MS: (PS-A3) Rt 7.48
EXAMPLE 6 From 3-(Cyclopentyloxy)phenylamine. 1H NMR (MeOH-d4) 8.54 (IH, s), 8.06 (2H, s), 7.38 (IH, s), 7.21 (2H, m), 6.72 (IH, dd), 4.82 (IH, m), 4.35 (2H, t), 3 45 (2H, t), 1.95 (2H, m), 1.85 (4H, m), 1.66 (2H, m). LC/MS: (PS-A2) Rt 2.50 [M+H]+ 409.
EXAMPLE 7
From 6-amino-2-N-(tert-butyloxycarbonyl) -1,2,3,4-tetrahydroisoquinoline. 1H NMR (DMSO-d6) 10.51 (IH, s), 9.50 (2H, s), 8.32 (2H, s), 8.15 (2H, s), 7.65 (IH, s), 7.61 (IH, d), 7.22 (IH, d), 4.33 (2H, t), 4.25 (2H, s), 3.41 (2H, d), 3.32 (2H, d), 3.00 (2H, t). LC/MS: (PS-A3) R1 0.68 [M+H]+ 380.
EXAMPLE 8
From 5-amino-2-N-(tert-butyloxycarbonyl) -1,2,3,4-tetrahydroisoquinoline. 1H NMR (DMSO-dβ) 10.31 (IH, s), 9.52 (2H, s), 8.33 (2H, s), 8.15 (2H, s), 7.32 (2H, m), 7.15 (IH, d), 4.31 (4H, m), 3.32 (4H, m), 2.91 (2H, t). LC/MS: (PS-A3) R10.68 [M+H]+ 380.
EXAMPLE 9
From 7-amino-2-N-(tert-butyloxycarbonyl) -1,2,3,4-tetrahydroisoquinoline. 1H NMR (DMSO-dβ) 10.50 (IH, s), 9.51 (2H5 s), 8.30 (2H, s), 8.15 (2H, s), 7.72 (IH, s), 7.61 (IH, d), 7.22 (IH, d), 4.30 (4H, m), 3.35 (2H, d), 3.30 (2H, d), 3.00 (2H, t). LC/MS: (PS-A3) Rt 0.69 [M+H]+ 380.
EXAMPLE 10
From 6-amino-2-methyl-l,2,3,4-tetrahydroisoquinoline. 1H NMR (DMSO-(I6) 10.81 (IH, s), 10.52 (IH, s), 8.30 (2H, s), 8.15 (2H, s), 7.71 (IH, s), 7.65 (IH, d), 7.20 (IH, d), 4.45 (IH, d), 4.25 (3H, m), 3.65 (IH, m), 3.30 (4H, m), 3.05 (IH, d), 2.90 (3H, s). LC/MS: (PS-A3) R10.69 [M+H]+ 394.
EXAMPLE Il From 3-phenoxyaniline. 1H NMR (DMSOd6) 10.40 (IH, s), 8.15 (2H, s), 8.10 (2H, s), 7.55 (IH, d), 7.45 (IH, s), 7.40 (3H, m), 7.15 (IH, t), 7.05 (2H, d), 6.80 (IH, d), 4.25 (2H, t), 3.25 (2H, m). LC/MS: (PS-B2) R19.15 [M+H]+ 417.
The following compounds were prepared from Intermediate A using methods 1, 5 and 3 outlined above:
EXAMPLE 12
From 2-allyl-4-ethyl-l,2,3,4-tetrahydroisoquinolin-6-ylamine. 1H NMR (MeOH-d4) 8.12 (2H, s), 7.75 (IH, s), 7.61 (IH, d), 7.25 (IH, d), 4.35 (4H, m), 3.62 (IH, dd), 3.51 (3H, m), 3.15 (IH, m), 2.15 (IH, m), 1.82 (IH, m), 1.11 (3H, t). LC/MS: (PS-B2) Rt 6.34 [M+H]+ 408.
The following compounds were prepared from Intermediate A using methods 2 and 3 outlined above :
EXAMPLE 13
From 2,6-difluroaniline. 1H NMR (MeOH-d^ 8.55 (IH, br s), 8.12 (2H, s), 7.41 (IH, m), 7.10
(2H, t), 4.35 (2H, t), 3.45 (2H, t). LC/MS: (PS-A2) Rt 1.99 [M+H]+ 361.
Example 14
From 2-chloro-5-methoxyaniline. 1H NMR (MeOH-d4) 8.05 (2H, s), 7.42 (IH, d), 7.35 (IH, d), 6.91 (IH, dd), 4.40 (2H, t), 3.85 (3H, s), 3.51 (2H, t). LC/MS: (PS-A2) Rt 2.09 [M+H]+ 389.
Example 15 From 3-methoxy-5-(trifluromethyl)aniline. 1H NMR (MeOH-d^ 8.55 (IH, br s), 8.11 (2H, s), 7.72 (IH, s), 7.61 (IH, s), 7.00 (IH, s), 4.35 (2H, t), 3.94 (3H, s), 3.45 (2H, t). LC/MS: (PS-A2) R1 2.37 [MH-H]+ 423.
The following compounds were prepared from Intermediate B using methods 1 and 3 outlined above :
Example 16
From 3-(isopropoxy)aniline. 1H NMR (MeOH-d4) 7.90 (IH, s), 7.80 (IH, s), 7.40 (IH, s), 7.25 (2H, s), 6.70 (IH, m), 4.60 (IH, m), 4.25 (2H, t), 3.45 (2H, t), 2.45 (3H, s), 1.35 (6H, d). LC/MS: (PS-A3) Rt 6.66 [M+H]+ 363.
Example 17
From 6-amino-2-N-(tert-butyloxycarbonyl) -1,2,3,4-tetrahydroisoquinoline. 1H NMR (DMSO-dβ) 10.35 (IH, s), 9.45 (2H, s), 8.35 (2H, s), 7.95 (IH, s), 7.85 (IH, s), 7.65 (IH, s), 7.6 (IH, d), 7.2 (IH, d), 4.2 (2H, s), 4.15 (2H, t), 3.4 (2H, d), 3.3 (2H, d), 3.0 (2H, t), 2.4 (3H, s). LC/MS: (PS-A3) Rt 0.70 [M+H]+ 360.
Example 18
From 2-allyl-4-ethyl4,2,3,4-tetrahydroisoqumolin-6-ylamine. 1H NMR (MeOH-d4) 7.9 (3H, m), 7.65 (IH, d), 7.25 (IH, d), 6.11 (IH, m), 5.70 (2H, m), 4.30-4.50 (2H, br s), 4.25 (2H, t), 4.00 (2H, d), 3.50 (2H, t), 2.50 (3H, s), 2.00-2.15 (IH, br s), 1.80-1.90 (IH, m), 1.00 (3H, br m). LC/MS: (PS-A3) Rt 4.86 [M+H]+ 428.
Example 19
From 5-amino-2-Boc-amrno-indane. 1HNMR (MeOH-d4) 7.91 (IH, s), 7.83 (IH, s), 7.73 (IH, s), 7.48 (IH, d), 7.31 (IH, d), 4.26 (2H, t), 4.14 (IH, m), 3.45 (2H, t), 3.5-3.4 (2H, m), 3.05 (2H, m), 2.48 (3H, s). LC/MS: (PS-A2) Rt 1.45 [M+H]+ 360.
Example 20
From 3,5-di-(isopropyloxy)aniline. 1H NMR (DMSOd6) 10.14 (IH, s), 8.29 (3H, br s), 7.92 (IH, s), 7.83 (IH, s), 7.00 (2H, s), 6.19 (IH, s), 4.52 (2H, m), 4.17 (2H, t), 3.28 (2H, m), 2.40 (3H, s), 1.28 (12H, d). LC/MS: (PS-A2) Rt 2.45 [M+H]+ 421.
Example 21
From S-chloro-S-piperidin-l-yl-phenylamine. 1H NMR (MeOH-dO 8.36 (IH, s), 7.97 (IH, s), 7.88 (2H, s), 7.62 (IH, s), 4.26 (2H, t), 3.69 (4H, m), 3.47 (2H, t), 2.48 (3H, s), 2.08 (4H, m), 1.84 (2H, m). LC/MS: (PS-A2) Rt 2.34 [M+H]+ 422.
Example 22
From 3-Amino-9-ethylcarbazole. 1H NMR (MeOH-d4) 8.45 (IH, s), 8.12 (IH, d), 7.97 (IH, s), 7.91 (IH, s), 7.73 (IH, d), 7.55 (2H, d), 7.52 (IH, m), 7.21 (IH, t), 4.45 (2H, q), 4.25 (2H, t), 3.45 (2H, t), 2.52 (3H, s), 1.45 (3H, t). LC/MS: (PS-B2) R18.73 [M+H]+ 422.
Example 23
From 5-Amino-isophthalic acid dimethyl ester. 1H NMR (MeOH-d4) 8.55 (2H, s), 8.32 (IH, s), 7.94 (IH, s), 7.81 (IH, s), 4.25 (2H, m), 3.95 (6H, s), 3.51 (2H, m), 2.45 (3H, s). LC/MS: (PS-B2) Rt 7.34 [M+H]+ 421.
Example 24
From 3-(l-pyrrolidinylsulfonyl)aniline. 1H NMR (MeOH-d4) 8.35 (IH, s), 7.95 (IH, m), 7.92 (IH, s), 7.85 (IH, s), 7.6 (2H, m), 4.25 (2H, t), 3.45 (3H, t), 3.28 (4H, m), 2.45 (3H, s), 1.75 (4H, m). LC/MS: (PS-B2) Rt 7.05 [M+H]+ 438.
The following compound was prepared from Intermediate B using methods 1, 5 and 3 outlined above :
Example 25 From 2-allyl-4-ethyl-l,2,3,44etrahydroisoquinolin-6-ylamine. (Ref. J. Med. Chem. (2004), 47 (2), 303-324). 1H NMR (MeOH-d4) 7.9 (IH, s), 7.85 (2H, s), 7.65 (IH, d), 7.25 (IH, d), 4.35 (2H, s), 4.25 (2H, t), 3.61 (IH, dd), 3.52 (2H, t), 3.30 (IH, m), 3.22 (IH, m), 2.45 (3H, s), 2.05(1H, m), 1.85 (IH, m), 1.05 (3H, t). LC/MS: (PS-A3) Rt 4.36 [M+H]+ 388.
The following compounds were prepared from Intermediate C using methods 1 and 3 outlined above :
Example 26
From 3-(isopropoxy)aniline. 1H NMR (DMSO-d6) 10.05 (IH, s), 8.23 (2H, s), 7.65 (2H, s), 7.45 (IH, s), 7.37 (IH, d), 7.22 (IH, t), 6.65 (IH, d), 4.55 (IH, m), 4.00 (2H, t), 3.31 (2H, m), 2.35 (6H, s), 1.33 (6H, d). LC/MS: (PS-A3) Rt 7.7 [M+H]+ 343.
Example 27
From 6-amino-2-N-(tøt-butyloxycarbonyl) -1,2,3,4-tetrahydroisoquinoline. 1H NMR (DMSO-d6) 10.15 (IH, s), 9.15 (2H, s), 8.15 (2H, s), 7.65 (3H, s), 7.62 (IH, d), 7.21 (IH, d), 4.25 (2H, s), 4.00 (2H, t), 3.43 (2H, t), 3.25 (2H, m), 3.02 (2H, t), 2.33 (6H, s). LC/MS: (PS-A3) Rt 1.29 [M+H]+ 340.
Example 28
From 6-amino-2-metliyl-l,2,3,4-tetrahydroisoquinoline. 1H NMR (DMSO-(I6) 10.85 (IH, s), 10.21
(IH, s), 8.31 (2H, s), 7.72 (IH, s), 7.65 (2H, s), 7.64 (IH5 d), 7.15 (IH, d), 4.45 (IH, d), 4.21 (IH, dd), 4.00 (2H, t), 3.62 (IH, m), 3.25 (4H, m), 3.02 (IH, d), 2.87 (3H, s), 2.35 (6H, s). LC/MS: (PS-
Example 29
From 7-amino-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepine (prepared as patent US 3144439). 1H
NMR (MeOH-d4) 7.72 (6H, m), 7.55 (2H, s), 7.45 (IH, s), 7.05 (IH, d), 4.12 (4H, m), 3.85 (2H, t),
3.43 (2H, t), 2.35 (6H, s). LC/MS: (PS-B2) Rt 6.07 [M+H]+ 429.
Example 30
From 3,5-di-(isopropyloxy)aniline. 1H NMR (DMSO-d6) 10.02 (IH, s), 8.30 (3H, br s), 7.65 (2H, s), 7.02 (2H, s), 6.18 (IH, s), 4.52 (2H, m), 3.99 (2H, t), 3.25 (2H, m), 2.33 (6H, s), 1.27 (12H, d).
LC/MS: (PS-A2) Rt 2.45 [M+H]+ 401.
Example 31
From 6-aminoindazole. 1H NMR (DMSO-d6) 10.28 (IH, s), 8.3 (3H, br, s), 8.25 (IH, s), 8.0 (IH, s), 7.7 (2H, s), 7.68 (IH, s), 7.35 (IH, d), 4.0 (2H, t), 3.25 (2H, m), 2.35 (6H, s). LC/MS: (PS-B2)
Rt 5.05 [M+H]+ 325.
Example 32
From 3-bromoaniline. 1H NMR (DMSO-d6) 10.28 (IH, s), 8.15 (2H, s), 8.05 (IH, s), 7.75 (IH, d), 7.68 (2H, s), 7.32 (2H, m), 4.01 (2H, t), 3.25 (2H, t), 2.32 (6H, s). LC/MS: (PS-B2) R4 7.53 [M+H]+ 363.
Example 33
From 2'-methoxy-biphenyl-3-ylamine. 1H NMR (DMSO-dβ) 10.52 (IH, s), 8.15 (2H, s), 7.85 (IH, s), 7.75 (IH, d), 7.71 (2H, s), 7.35 (2H, t), 7.32 (IH, d), 7.24 (IH, d), 7.15 (IH, d), 7.05 (IH, t), 4.02 (2H, t), 3.75 (3H, s), 3.25 (2H, m), 2.32 (6H, s). LC/MS: (PS-B2) Rt 8.19 [M+H]+ 391.
Example 34
From 3-(ben2yloxy)-5-(isoρropoxy)aniline hydrochloride. 1H NMR (DMSO-d6) 10.02 (IH, s), 8.15 (2H, s), 7.65 (IH, s), 7.44 (5H, m), 7.10 (IH, s), 7.03 (IH5 s), 6.28 (IH, s), 5.75 (IH, s), 5.07 (2H, s), 4.52 (IH, m), 3.95 (2H, t), 3.25 (2H, m), 2.35 (6H, s), 1.25 (6H, d). LC/MS: (PS-B2) Rt 9.14 [M+Hf 449.
Example 35
From 3-(cyclopentyloxy)phenylamine. 1H NMR (MeOH-(I4) 7.69 (2H, s), 7.41 (IH, s), 7.22 (2H, m), 6.68 (IH, d), 4.85 (IH, m), 4.12 (2H, t), 3.45 (2H, t), 2.40 (6H, s), 1.95 (2H, m), 1.85 (4H, m), 1.70 (2H, m). LC/MS: (PS-B2) Rt 8.26 [M+H]+ 369.
Example 36
From 3-fluoro-5-(morpholin-4-yl)aniline. 1H NMR (DMSO-d6) 10.16 (IH, s), 8.31 (3H, br s), 7.68 (2H, s), 7.23 (IH, d), 7.19 (IH, s), 6.53 (IH, d), 4.00 (2H, m), 3.73 (4H, m), 3.25 (2H, m), 3.13 (4H, m), 2.32 (6H, s). LC/MS: (PS-Bl) Rt 2.79 [M+H]+ 388.
Example 37
From l-(3-amino-5-chloro-phenyl)-piperidin-3-ol. 1H NMR (MeOH-dt) 8.23 (IH, s), 7.82 (IH, s), 7.72 (2H, s), 7.50 (IH, s), 4.21 (IH, m), 4.11 (2H, t), 3.73 (2H, m), 3.52 (2H, m), 3.43 (2H, t), 2.42 (6H, s), 2.37 (IH, m), 1.96 (2H, m), 1.84 (IH, m). LC/MS: (PS-A2) Rt 2.14 [M+H]+ 418.
Example 38
From 2,5-diethoxyaniline. 1H NMR (DMSOd6) 9.15 (IH, s), 8.32 (3H, s), 7.65 (2H, s), 7.55 (IH, d), 7.03 (IH, d), 6.71 (IH, dd), 4.00 (6H, m), 3.25 (2H, m), 2.35 (6H, s), 1.32 (6H, m). LC/MS: (PS-A3) Rt 8.19 [M+H]+ 373.
Example 39
From 3-(2-methyl-l,3-thiazol-4-yl)aniline. 1H NMR (MeOH-d4) 8.3 (IH, s), 8.05 (IH, s), 7.75 (3H, s), 7.6 (2H, m), 4.1 (2H, t), 4.1 (2H, t), 3.45 (2H, t), 3.05 (3H, s), 2.45 (6H, s). LC/MS: (PS- A3) Rt 7.62 [M+H]+ 382.
Example 40
From 3-Chloro-5-piperidin-l-yl-plienylamine. 1H NMR (MeOH-d^ 8.25 (IH, s), 7.85 (IH, s), 7.75 (2H, s), 7.55 (IH, s), 4.1 (2H, t), 3.65 (4H, t), 3.45 (2H, t), 2.4 (6H, s), 2.1 (4H, t), 1.85 (2H, m). LC/MS: (PS-A3) Rt 8.19 [MfH]+ 402.
Example 41
From 4-methoxy[l,l'-biphenyl]-2-amine. 1H NMR (MeOH-d4) 7.4 (6H, m), 7.35 (3H, m), 6.95 (IH, dd), 4.05 (2H, t), 3.85 (3H, s), 3.4 (2H, t), 2.3 (6H5 s). LC/MS: (PS-B2) Rt 8.06 [M+H]+ 391.
Example 42
From S-amino-S-Cpiperidine-l-carbony^-N-propyl-benzamide. 1H NMR (MeOH-(I4) 8.20 (IH, s), 8.00 (IH, s), 7.71 (2H, s), 7.54 (IH, s), 4.10 (2H, t), 3.75 (2H, bs), 3.33-3.48 (6H, m), 2.41 (6H, s), 1.58-1.80 (8H, m), 1.01 (3H, t). LC/MS: (PS-A2) Rt 2.10 [M+H]+ 481.
Example 43
From 2-amino-3-methyl phenol. 1H NMR (MeOH-d,) 7.75 (2H, s), 7.06 (IH, t), 6.78 (2H, br d),
4.10 (2H, t), 3.43 (2H, t), 2.40 (6H, s), 2.25 (3H, s). LC/MS: (PS-A2) R12.00 [M+H]+ 315.
Example 44 From 3,4,5-trimethoxyaniline. 1H NMR (MeOH-d4) 7.68 (2H, s), 7.12 (2H, s), 4.10 (2H, t), 3.87 (6H, s), 3.77 (3H, s), 3.43 (2H, t), 2.40 (6H, s). LC/MS: (PS-A2) Rt 2.12 [M+H]+ 375.
Example 45
From S-chloro^-ethoxy-S-piperidm-l-yl-plienylamine. 1H NMR MeOH-d^ 8.43 (IH, d), 7.72 (2H, s), 7.29 (IH, d), 4.20 (2H, q), 4.12 (2H, t), 3.68 (4H, t), 3.44 (2H, t), 2.42 (6H, s), 2.06 (4H, m), 1.82 (2H, m), 1.47 (3H, t). LC/MS: (PS-Bl) Rt 3.81 [M+H]+ 446.
Example 46
From 3-bromo-2-methyl-5-piperidin-l-yl-phenylamine. 1H NMR (MeOH-d4) 8.00 (IH, d), 7.88 (IH, d), 7.77 (2H, s), 4.13 (2H, t), 3.68 (4H, m), 3.45 (2H, t), 2.43 (3H, s), 2.41 (6H, s), 2.09 (4H, br t), 1.82 (2H, m). LC/MS: (PS-A2) Rt 2.15 [M+H]+ 460/462.
The following compounds were prepared from Intermediate C using methods 1, 5 and 3 outlined above :
Example 47
From 2-allyl-4-ethyl-l,2,3,4-tetrahydroisoquinolm-6-ylamine. (Ref. J. Med. Chem. (2004), 47 (2),
303-324). 1H NMR (MeOH-d4) 7.85 (IH, s), 7.72 (2H, s), 7.65 (IH, d), 7.25 (IH, d), 4.35 (2H, s),
4.11 (2H9 1), 3.65 (IH, dd), 3.45 (2H, t), 3.35 (IH, m), 3.22 (IH, m), 2.37 (6H, s), 2.05 (IH, m), 1.85 (IH, m), 1.05 (3H, t). LC/MS: (PS-B3) Rt 6.06 [M+H]+ 368.
The following compounds were prepared from Intermediate D using methods 1 and 3 or methods 1, 4 and 3 (as appropriate) as outlined above :
Example 48
From 3-(isopropyloxy)aniline. 1H NMR (DMSO-d6) 10.05 (IH, s), 8.80 (3H, br s), 7.42 (IH, s), 7.31 (3H, m), 7.21 (IH, t), 6.63 (IH, d), 4.54 (IH, m), 4.04 (2H31), 3.28 (2H, m), 2.32 (3H, s), 1.27 (6H, d). LC/MS: (PS-A2) Rt 2.15 [M+H]+ 344.
Example 49
From 3-(isopropyloxy)aniline. 1H NMR (DMSO-d6) 10.10 (IH, s), 9.06 (IH, s), 8.25 (3H, br s), 8.21 (IH, s), 7.57 (IH, s), 7.41 (IH, s), 7.31 (IH, d), 7.21 (IH, t), 6.65 (IH, d), 4.58 (IH, m), 4.01 (2H, t), 3.72 (3H, s), 3.28 (2H, m), 2.34 (3H, s), 1.30 (6H, d). LC/MS: (PS-A2) Rt 2.22 [M+H]+ 402.
The following compounds were prepared from Intermediate E using methods 1 and 3 outlined above :
Example 50 From 6-amino-2-(tert-butyloxycarbonyl)-l,2,3,4-tetrahydroisoquinoline. 1H NMR (DMSO-d6) 10.18 (IH, s), 9.50 (2H, br s), 8.41 (3H, br s), 7.69 (3H, s), 7.62 (IH, d), 7.18 (IH, d), 4.21 (2H, m), 3.89 (2H, m), 3.62 (IH, m), 3.38 (2H, m), 3.02 (2H, t), 2.32 (6H, s), 1.38 (3H, d). LC/MS: (PS-Bl) Rt 2.86 [M+Hf 354.
Example 51
From 6-amino-2-methyl-l,2,3,4-tetrahydroisoquinoline. 1H NMR (DMSO-d6) 10.94 (IH, br s), 10.21 (IH, s), 8.38 (3H, br s), 8.72 (3H, m), 7.65 (IH, d), 7.18 (IH, d), 4.43 (IH, d), 4.25 (IH, m), 3.91 (2H, m), 3.65 (IH, m), 3.37 (2H, m), 3.03 (IH, d), 2.91 (3H, s), 2.36 (6H, s), 1.39 (3H, d). LC/MS: (PS-Bl) Rt 2.86 [M+H]+ 368.
Example 52
From 3-(isopropyloxy)aniline. 1H NMR (DMSO-d6) 10.08 (IH, s), 8.32 (3H, br s), 7.67 (2H, s), 7.43 (IH, s), 7.31 (IH, d), 7.22 (IH, t), 6.64 (IH, d), 4.55 (IH, m), 3.90 (2H, m), 3.62 (IH, m), 2.33 (6H, s), 1.36 (3H, d), 1.29 (6H, d). LC/MS: (PS-A2) Rt 2.31 [M+H]+ 357.
Example 53
From 3,5-di-(isopropyloxy)aniline. 1H NMR (DMSO-d6) 10.02 (IH, s), 8.32 (3H, br s), 7.65 (2H, s), 7.02 (2H, s), 6.18 (IH, s), 4.52 (2H, m), 3.92 (2H, m), 3.60 (IH, m), 2.34 (6H, s), 1.35 (3H, d), 1.27 (12H, d). LC/MS: (PS-A2) Rt 2.45 [M+H]+ 415.
Example 54
From 3-(cyclopentyloxy)aniline. 1H NMR (DMSO-d6) 10.04 (IH, s), 8.32 (3H, br s), 7.66 (2H, s), 7.42 (IH, s), 7.32 (IH, d), 7.22 (IH, t), 6.61 (IH, d), 4.77 (IH, m), 3.86 (2H, m), 3.62 (IH, m), 2.35 (6H, s), 1.90 (2H, m), 1.72 (4H, m), 1.60 (2H, m), 1.37 (3H, s). LC/MS: (PS-A2) Rt 2.60 [M+H]+ 383.
Example 55
From 3-fluoro-5-(morpholin-4-yl)aniline. 1H NMR (DMSO-d6) 10.17 (IH, s), 8.40 (3H, br s), 7.68 (2H, s), 7.25 (IH, d), 7.20 (IH, s), 6.52 (IH, d), 3.90 (2H, m), 3.75 (4H, m), 3.62 (IH, m), 3.13 (4H, m), 2.34 (6H, s), 1.37 (3H, d). LC/MS: (PS-Bl) Rt 3.00 [M+H]+ 402.
Example 56
From 3-chloro-5-(piperidin-l-yl)aniline. 1H NMR (DMSOd6) 10.22 (IH, s), 8.38 (3H, br s), 7.71 (2H, s), 7.54 (2H, s), 6.95 (IH, s), 3.90 (2H, m), 3.63 (IH5 m), 3.27 (4H, m), 2.36 (6H, s), 1.72 (4H, m), 1.60 (2H, m), 1.37 (3H, d). LC/MS: (PS-Bl) Rt 3.75 [M+H]+ 416.
Example 57
From 2-ethoxy-3-chloro-5-(ρiperidin-l-yl)aniline. 1H NMR (DMSO) 9.72 (IH, br s), 8.33 (2H, br s), 7.70 (2H, s), 4.00 (2H, q), 3.90 (2H, m), 3.62 (IH, m), 3.30 (4H, m), 2.34 (6H, s), 1.78 (4H, m), 1.58 (2H, m), 1.34 (3H, d), 1.27 (3H51). LC/MS: (PS-A2) Rt 2.37 |M+H]+ 460.
The following compounds were prepared from Intermediate E using methods 1,5 and 3 outlined above :
Example 58 From 2-allyl-4-ethyl-l,2,3,4-tetrahydroisoquinolin-6-ylamine. (Ref. J. Med. Chem. (2004), 47 (2), 303-324). 1H NMR (MeOH-d4) 7.85 (IH, s), 7.72 (2H, s), 7.61 (IH5 d), 7.25 (IH, d), 4.35 (2H5 s), 3.95 (2H, m), 3.82 (IH, m), 3.62 (IH5 m),3.34 (IH, m), 3.22 (IH5 m)5 2.41 (6H5 s), 2.05 (IH, m), 1.85 (IH, m)5 1.52 (3H, d), 1.05 (3H, t). LC/MS: (PS-A3) Rt 4.93 [M+H]+ 382.
The following compounds were prepared from Intermediate F using methods 6 and 3 outlined above :
Example 59
From methylamine. 1H NMR (MeOH-(I4) 8.11 (2H, s), 7.85 (2H5 d), 7.52 (2H, d), 4.35 (2H, t), 4.21 (2H5 s)5 3.53 (2H5 1), 2.75 (3H, s). LC/MS: (PS-Bl) Rt 2.81 [M+Hf 368.
Example 60
From cyclopropanemethylamine. 1H NMR (MeOH-d4) 8.10 (2H, s), 7.85 (2H, d), 7.48 (2H, d), 4.35 (2H, t), 4.19 (2H, s), 3.50 (2H, t), 3.03 (2H, d), 1.15 (IH, m), 0.75 (2H, m), 0.45 (2H, m). LC/MS: (PS-A3) Rt 4.84 [M+H]+ 408
Example 61
From dimethylamine. 1H NMR (MeOH-(I4) 8.11 (2H, s), 7.85 (2H, d), 7.62 (2H, d), 4.35 (4H5 m),
3.53 (2H, m), 3.50 (2H, t), 2.90 (6H, s). LC/MS: (PS-B2) Rt 6.43 [M+H]+ 337.
Example 62
From ethylamine. 1H NMR (MeOH-(I4) 8.11 (2H, s), 7.85 (2H, d), 7.51 (2H, d), 4.35 (2H, t), 4.22 (2H, s), 3.46 (2H, t), 3.15 (2H, q), 1.35 (3H, t). LC/MS: (PS-B2) Rt 5.63 [M+H]+ 337.
Other examples
Example 63 3,5-Dichloro-2,4-difluoro-N-(3-isopropoxv-T3henvl)-benzamide
2,4-difluoro-3,5-dichlorobenzoyl fluoride (1.82g) was mixed with a solution of 3- isopropoxyaniline (1.2g) in DCM (10ml) and triethylamine (2ml). The mixture was stirred under
nitrogen for 3 hours. Water (25ml) was added and the mixture extracted into DCM (25ml added). The organic layer was separated and dried over MgSO4. The solid product was washed with pet ether and then dried in vacuo to give product (2.7g). LC/MS: (PS-A2) Rt 3.75 [M+H]+ 360.
3,5-Dichloro-4-fluoro-N-('3-isopropoxy-phenylV2-methoxy-benzamide
3,5-Dichloro-2,4-difluoro-N-(3-isopropoxy-phenyl)-benzamide (0.54g) was dissolved in methanol (10ml) and sodium methoxide powder added (0.09Ig). The mixture was heated to 5O0C and stirred for 1 /4 hours under nitrogen, when more sodium methoxide was added (0.125g). The mixture was heated for a further 2 hours. The solvent was evaporated in vacuo and water added (15ml). The mixture was extracted with DCM (25ml), the organic layer dried over MgSO4 and the solvent evoprated in vacuo to give a wax (0.54g). LC/MS: (PS-A2) Rt 3.73 and 3.86 (1:2.7 isomeric mixture) [M+H]+ 372.
4-(2-Amino-ethoxyV3.5-dichloro-N-('3-isopropoxy-phenyl)-2-methoxy-benzamide Ethanolamine (O.lg) in dry THF (2ml) was treated with 60% sodium hydride in oil (0.7Ig) under nitrogen and the mixture stirred for 5 minutes. The resulting solution was added to 3,5-Dichloro-4- fluoro-N-(3-isopropoxy-phenyl)-2-methoxy-benzamide (0.18g) in a microwave vessel and the mixture was heated in a CEM microwave at 12O0C for 4 minutes (ramping to 12O0C over 4 mins).
The reaction mixture was diluted with DCM (20ml) and water (20ml) and extracted. The organic layer was separated and dried over MgSO4. The solvents were evaporated and the crude reaction mixture purified using a 1Og silica SPE cartridge, eluting with ether and then ether/methanol. The major product was an oil (43mg) and half of the material was dissolved in methanol (ImI) and treated with a saturated solution of hydrogen chloride in ether (ImI). The solvents were removed to give the product as a HCl salt (22mg as a solid). LC/MS: (PS-A2) Rt 2.30 [M+H]+ 413. 1H NMR (MeOH-d4) 7.79 (IH, s), 7.49 (IH, s), 7.26 (IH, t), 7.17 (IH, d), 6.75 (IH, d), 4.62 (IH, quin), 4.35
(2H, t), 3.96 (3H, s), 3.47 (2H, t), 1.34 (6H, s).
Example 64
4-(2-Amino-ethoxy)-3.5-dimethyl-N-('5-phenyl-2.3.4.5-tetrahvdro-lH-benzo[el [1.41 diazepin-7- yl) benzamide
To a solution of 4-(2-amino-ethoxy)-3,5-dimethyl-N-(5-phenyl-2,3-dihydro-lH-benzo[e] [1,4] diazepin-7-yl) benzamide hydrochloride (40 mg, 0.086 mmol), acetic acid (1 ml) and acetonitrile (3 ml) was added sodium cyanoborohydride (24 mg, 0.39 mmol) and the mixture stirred at room temperature for 12 h. The solvent was removed in vacuo, the residue partitioned between water and dichloromethane, the organic layer separated and evaporated in vacuo. The residue was purified by ion-exchange chromatography (Strata SCX) to yield the product as a cream solid (7 mg 20%). 1H NMR (MeOHKl4) 7.41 (8H, m), 7.02 (IH, s), 6.91 (IH, d), 5.62 (IH, s), 3.95 (2H, t), 3.85 (2H, t), 3.25 (7H, m), 2.23 (6H, s). LC/MS: (PS-Bl) R12.51 [M+H]+ 431.
Example 65
4-(2-Amino-ethoxy)-N-(3-hvdroxy-5-isopropoxy-phenyl')-3,5-dimethyl-benzamide hydrochloride
To a stirred solution of {2-[4-(3-Benzyloxy-5-isopropoxy-phenylcarbamoyl)-2,6-dimethyl- phenoxy]-ethyl}-carbamic acid-tert-butyl ester (0.88 g, 1.82 mmol) in EtOH (20 ml) was added 10% palladium on carbon (10 mg) and the reaction was purged with hydrogen for 15 minutes and then stirred for a further 24 h under a hydrogen atmosphere (1 atm). The hydrogen atmosphere was then removed in vacuo and the resulting mixture filtered through a pad of celite, eluting with EtOAc (50 ml). The solvent was removed under reduced pressure to yield {2-[4-(3-hydroxy-5- isopropoxy-phenyl carbamoyl)-2,6-dimethyl-phenoxy]-ethyl}-carbamic acid-tert-butyl ester as a yellow oil. (0.39 g, 47%). 1H NMR (CDCl3) 8.25 (IH, s), 7.51 (2H, s), 6.88 (IH, s), 6.75 (IH, s), 6.17 (IH, s), 5.19 (IH, s), 4.47 (IH, m), 3.78 (2H, t), 3.50 (2H, br, s), 2.25 (6H, s), 1.45 (9H, s), 1.31 (6H, d). The above compound was deprotected using method 3 to afford the product as a cream foam. 1H NMR (MeOH-(I4) 9.81 (IH, s), 7.65 (2H, s), 6.85 (IH, s), 6.81 (IH, s), 6.15 (IH, s), 4.55 (IH, m), 4.12 (2H, t), 3.45 (2H, t), 2.41 (6H, s), 1.32 (6H, d). LC/MS: (PS-B2) Rt 6.12 [MH-H]+ 359.
Example 66
{3-r4-(2-Amino-ethoxy)-3,5-dimethyl-benzoylaminol-5-isopropoxy-phenoxy)--acetic acid methyl ester hydrochloride A mixture of {2-[4-(3-hydroxy-5-isopropoxy-phenyl carbamoyl)-2,6-dimethyl-phenoxy]-ethyl}- carbamic acid-tert-butyl ester (100 mg, 0.218 mmol), potassium carbonate (45 mg, 0.328 mmol) and methyl bromoacetate (52 μl, 0.55 mmol) in NN,dimethylformamide (3 ml) was stirred at 50° C for 24 h. The solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was separated and the solvent removed in vacuo to afford a yellow oil. 1H ΝMR (CDCl3) 7.85 (IH, s), 7.45 (2H, s), 6.90 (IH, s), 6.81 (IH, s), 6.17 (IH, s), 4.55 (2H, s), 4.45 (IH, m), 3.75 (2H t), 3.70 (3H, s), 3.45 (2H, t), 2.25 (6H, s), 1.42 (9H, s), 1.25 (6H, d). The above compound was deprotected using method 3 to afford the product as a cream foam. 1H ΝMR (MeOH-d4) 7.65 (2H, s), 7.01 (IH, s), 6.95 (IH, s), 6.28 (IH, s), 4.67 (2H, s), 4.58 (IH, m), 4.10 (2H, t), 3.82 (3H, s), 3.45 (2H, t), 2.41 (6H, s), 1.32 (6H, s). LC/MS: (PS- B2) Rt 7.41 [M+H]+ 431.
Examole 67
4-('2-Amino-ethoxyN)-N-r3-isoproρoxy-5-r4-methanes\ilfonyl-benzyloxy')-phenyll-3,5- dimethylbenzamide hydrochloride
Prepared using the method above using 4-methylsulfonylbenzyl bromide and {2-[4-(3-hydroxy-5- isopropoxy-phenyl carbamoyl)-2,6-dimethyl-phenoxy] -ethyl} -carbamic acid-ført-butyl ester, followed by method 3 to afford the title compound as a white solid (20 mg, 16%). 1H NMR (MeOEkI4) 9.91 (IH, s), 8.02 (2H, d), 7.75 (2H, d), 7.65 (2H, s), 7.08 (IH, s), 6.95 (IH, s), 6.35 (IH, s), 5.25 (2H, s), 4.56 (IH, m), 4.10 (2H, m), 3.42 (2H, m), 3.15 (3H, s), 2.38 (6H, s), 1.28 (6H, d). LC/MS: (PS-B2) Rt 8.12 [M+H]+ 527.
Example 68 {3-f4-(2-Amino-ethoxy)-3.5-dimethylbenzoylaminol-5-isopropoxy-phenoxy>-acetic acid A solution of {3-[4-(2-Amino-ethoxy)-3,5-dimethyl-benzoylamino]-5-isopropoxy-phenoxy}-acetic acid methyl ester hydrochloride (50 mg, 0.107 mmol), lithium hydroxide (5.1 mg, 0.214 mmol) in THF (2 ml) and water (1 ml) were stirred at room temperature for 12 h. The solvent was removed in vacuo and the residue submitted to preparative HPLC/MS to afford the product as a white solid (15 mg, 37%). 1HNMR (DMSO^6) 9.91 (IH, s), 8.28 (IH, s), 7.55 (2H, s), 7.01 (IH, s), 6.85 (IH, s), 6.12 (IH, s), 4.52 (IH, m), 4.21 (2H, s), 3.85 (2H, t), 3.12 (2H, t), 2.32 (6H, s), 1.25 (6H, d). LC/MS: (PS-B2) Rt 4.38 [M+H]+ 417.
Example 69
4-(2-Amino-ethoxyVN-(2'-benzyloxy-biphenyl-3-yl)-3,5-dimethylbenzamide hydrochloride Prepared by the coupling of intermediate C and 2'-benzyloxy-biphenyl-3-ylamine using method 1 to afford {2-[4-(2'-benzyloxy-biphenyl-3-ylcarbamoyl)-2,6-dimethyl-phenoxy]-ethyl}-carbamic acid-føt-butyl ester (0.89 g, 77%). 1H NMR (MeOH-d4) 7.71 (IH, s), 7.65 (3H, m), 7.30 (9H, m), 7.15 (IH, d), 7.05 (IH, t), 4.90 (2H, s), 3.85 (2H, t), 3.45 (2H, t), 2.35 (6H, s), 1.51 (9H, s). LC/MS: (PS-Bl) Rt 4.01 [M+H]+ 567. The above compound was deprotected using method 3 to afford the product as a light brown solid (90 mg, 100%). 1H NMR (DMSOd6) 10.15 (IH, s), 8.25 (2H, s), 8.02 (IH, s), 7.75 (IH, d), 7.71 (2H, s), 7.35 (9H, m), 7.22 (IH, d), 7.05 (IH, t), 5.15 (2H, s), 3.98 (2H, t), 3.25 (2H, m), 2.35 (6H, s). LC/MS: (PS-B2) Rt 9.73 [M+H]+ 467.
Example 70
4-(2-Amino-ethoxyVN-(2'-hvdroxy-biphenyl-3-ylV3,5-dimethylbenzamide hydrochloride Prepared from 2-[4-(2'-benzyloxy-biphenyl-3-ylcarbamoyl)-2,6-dimethyl-phenoxy]-ethyl}- carbamic acid-tert-butyl ester by the hydrogenation method described above to afford {2-[4-(2'- hydroxy-biphenyl-S-ylcarbamoy^^^-dimethyl-phenoxyl-ethylJ-carbamic acid-fert-butyl ester as a white foam (0.54 g, 82%). 1H NMR (CDCl3) 8.21 (IH, s), 7.73 (2H, s), 7.51 (2H, s), 7.38 (IH, t), 7.25 (2H, m), 6.95 (2H, m), 3.82 (2H, t), 3.51 (2H, br, s), 2.25 (6H, s), 1.48 (9H, s). LC/MS: (PS- Bl) R1 4.01 [M+H]+ 567. The above compound was deprotected using method 3 to afford the product as a white foam (85 mg, 100%). 1H NMR (DMSOd6) 10.15 (IH, s), 9.55 (IH, s), 8.30
(2H, s), 7.91 (IH, s), 7.75 (IH, d), 7.72 (2H, s), 7.35 (IH, t), 7.25 (2H, t), 7.15 (IH, t), 6.95 (IH, d), 6.88 (IH, t), 4.01 (2H, t), 3.25 (2H, d), 2.35 (6H, s). LC/MS: (PS-B2) R17.07 [M+Hf 377.
Example 71
(3 '-[4-(2-Amino-ethoxyV3.5-dimethyl-benzoylamino]-biphenyl-2-yloxyl -acetic acid methyl ester hydrochloride
Prepared from {2-[4-(2 ' -hydroxy-biphenyl-3 -ylcarbamoyl)-2,6-dimethyl-phenoxy] -ethyl} - carbamic acid-tert-butyl ester and methyl bromoacetate using the alkylation method described above to afford, after purification (column chromatography using 30% EtOAc in petrol as eluent) {3'-[4-(2-ter^butoxycarbonylammoethoxy)-3,5-dimethyl-benzoylamino]-biphenyl-2-yloxy}-acetic acid methyl ester as a white solid (0.287 g, 71%). 1H NMR (CDCl3) 7.91 (IH, s), 7.85 (2H, m), 7.58 (2H, s), 7.40 (3H, m), 7.10 (IH, t), 6.90 (IH, d), 4.65 (2H, s), 3.89 (2H, t), 3.55 (2H, t), 2.35 (6H, s), 1.51 (9H, s). LC/MS: (PS-Bl) Rt 3.59 [M+H]+ 549. The above compound was deprotected using method 3 to afford the product as a white foam (250 mg, 100%). 1H NMR (DMSOd6) 10.15 (IH, s), 8.10 (2H, s), 7.89 (IH, s), 7.75 (IH, d), 7.71 (2H, s), 7.35 (4H, m), 7.10 (IH, t), 7.02 (IH, d), 4.85 (2H, s), 4.01 (2H, t), 3.25 (2H, m), 2.35 (6H, s). LC/MS: (PS-B2) Rt 8.10 [M+H]+ 449.
Example 72
3 '-[4-(2-Amino-ethoxyV3,5-dimethyl-benzoylamino1-biphenyl-2-yloxyl -acetic acid Prepared from {3 ' -[4-(2-Amino-ethoxy)-3 ,5 -dimethyl-benzoylamino] -biphenyl-2-yloxy} -acetic acid methyl ester hydrochloride by the saponification method described above to afford, after purification (preparative HPLC) the product as a white solid (80 mg, 64%). 1H NMR (DMSO-d6) 10.10 (IH, s), 7.75 (IH, d), 7.65 (2H, s), 7.35 (2H, m), 7.25 (2H, m), 6.95 (IH, t), 6.90 (IH, d), 4.35 (2H, s), 3.80 (2H, t), 3.11 (2H, t), 2.30 (6H, s). LCMS: (PS-Bl) Rt 2.41 [M+H]+ 435.
Example 73 4-(2-Amino-ethoxy)-N-[3-chloro-5-(3-ethoxy-piperidin-l-yl)-phenyll-3.5-dimethyl-benzamide
To a mixture of ethyl iodide (50mg) and 4-(2-BOC-amino-ethoxy)-N-[3-chloro-5-(3-hydroxy- piperidin-l-yl)-phenyl]-3,5-dimethyl-benzamide (155mg) in dry THF (2.5ml) at -7O0C was added sodium hexamethyldisilazide (0.15ml of a 2N solution in THF) under nitrogen. The mixture was allowed to slowly warm to room temperature. More ethyl iodide was then added (50mg). After stirring for 18hrs the reaction was quenched with dilute aq HCl (30ml) and extracted with DCM (30ml). The organic layer was washed with 2N NaOH solution (30ml), dried (MgSO4) and evaporated in vacuo. The crude product was treated with 4N HCl in dioxane (3ml) and methanol (ImI), stirring under nitrogen for 6 hours. The solvents were evaporated and the product purified by prep HPLC to give pure product, which was reformulated as its di-HCl salt by treatment with 4N HCl in dioxane, followed by evaporation. The product was a gum (32mg). 1H NMR (MeOH-d4) 7.79 (IH, s), 7.53 (IH, s), 7.48 (IH5 s), 7.08 (2H, s), 4.21 (IH, m), 4.00 (4H, m), 3.53 (2H, m), 3.43 (IH, m), 3.32 (3H, m), 3.25 (IH, m), 2.23 (6H, s), 1.98 (2H, m), 1.78 (IH, m), 1.23 (3H, t). LC/MS: (PS-A2) R12.18 [M+H]+ 446.
Example 74
{4-(3,5-Dichloro-4-hydroxy-benzoylamino')-benzyll-carbamic acid tert-butyl ester To a solution of 3,5-Dichloro-4-hydroxybenzoic acid (466mg)in DCM (2OmL) was added 4[(N- Boc)aminomethyl] aniline (1 equivalents), EDAC (1.1 equivalent), HOAt (1.1 equivalents) and triethylamine (3 equivalents) and the reaction allowed to stir at RT for 12 hours. Reaction was followed by tic (EtOAc) and on completion the reaction was diluted with DCM and washed with 5% citric acid, sat. bicarbonate(aq) and brine. Material dried over magnesium sulfate, reduced in vacuo and purified by column chromatography eluting with 1 :4 EtOAc/petrol to 1 :2 EtO Ac/petrol. The material was then triturated with petrol to give the title compound as a yellow solid (336mg).
(4-{3,5-Dichloro-4-[2-(l,3-dioxo-l,3-dihvdro-isoindol-2-yl)-ethoxy1-benzoylamino>-benzylV carbamic acid tert-butyl ester To a stirred solution of {4-(3, 5 -Dichloro-4-hydroxy-benzoylamino)-benzyl] -carbamic acid tert- butyl ester (200mg) in DMF (3mL) was added sodium carbonate (1.1 equivalents) and the reaction heated to 13O0C. N-(2-bromoethyl)phthalimide (1.1 equivalents) was then added and the reaction allowed to stir at 13O0C for 12 hours. Progress of the reaction was followed by tic (1:4 EtO Ac/petrol). Potassium carbonate (1.1 equivalents was then added and the reaction allowed to stir at 13O0C for a further 6 hours. The reaction was then cooled, reduced in vacuo and partitioned between EtOAc and sodium hydroxide (0.5M)(aq) and the organics washed with H2O. Material
dried over magnesium sulfate, reduced in vacuo and purified by column chromatography eluting with 1:9 EtOAc/petrol to give the title compound as a colourless crystalline solid (155mg).
{4-[4-(2-Arnmo-ethoxyV3.5-dichlorobenzoylaminol-benzvU-carbamic acid tert-butyl ester To a stirred suspension of (4-{3,5-Dichloro-4-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-ethoxy]- benzoylamino}-benzyl)-carbamic acid tert-butyl ester (176mg) in EtOH (1OmL) was added excess hydrazine monohydrate and the reaction heated to refux for 90 minutes. The reaction was allowed to cool, the precipitate filtered and the filtrate purified by SCX to give the title compound as a colourless solid (93mg).
4-(2-Ammo-ethoxy)-N-(4-ammomethyl-phenylV3-5-dichloro-benzamide
To a solution of {4-[4-(2-Ammo-ethoxy)-3,5-dicMorobenzoylamino]-benzyl}-carbamic acid tert- butyl ester (93mg) in MeOH (4mL) was added sat. HCl in EtOAc (5mL) and the reaction allowed at RT for 1 hour. Reaction reduced in vacuo to give the title compound as a yellow solid (76mg). 1H NMR (MeOH-d4) 8.08 (2H, s), 7.82 (2H, d), 7.50 (2H, d), 4.38 (2H, t), 4.15 (2H, s), 3.47 (2H, t). LC/MS: (PS-Bl) Rt 2.26 [MH-H]+ 356.
Example 75
(2-{2-Chloro-4-['4-('l,3-dioxol,3-dihvdro-isoindol-2-ylmethyl')-plienylcarbamoyll-6-methyl- phenoxy}-ethvD-carbamic acid tert-butyl ester
To a solution of 4-(2-tert-butoxycarbonylamino-ethoxy)-3-chloro-5-methyl-benzoic acid [intermediate B] (800mg) in DMF (2OmL) was added 2-(4-amino-benzyl)isoindole-l,3-dione (lequivalent), (Ref: patent WO 2004/007459), EDAC (1.1 equivalents), HOAt (1.1 equivalents) and triethylamine (3 equivalents) and the reaction heated to 5O0C for 12 hours. Reaction was followed by LC-MS and on completion was reduced in vacuo and partitioned between EtOAc and sat. bicarbonate (aq) and brine. Material dried over magnesium sulfate, reduced in vacuo and purified by column chromatography eluting with a gradient of 20% EtOAc/petrol to 70% EtOAc/petrol and the column flushed with a gradient elution of EtOAc to 5% MeOH/EtOAc to give the title compound as a yellow solid (748mg). 1H NMR (DMSO) 10.25 (IH, s), 7.9 (5H, m), 7.8 (IH, s), 7.7 (2H, d), 7.3 (2H, d), 7.1 (IH, t), 4.75 (2H, s), 3.95 (2H, t), 3.3 (2H, m, partially overlaps with solvent) 2.3 (3H, s), 1.4 (9H, s).
{2- {4-(4-Aminomethyl-phenylcarbamoylV2-chloro-6-metliyl-phenoxy1 -ethyll -carbamic acid tert- butyl ester
To a suspension of (2-{2-Chloro-4-[4-(l,3-dioxol,3-dihydro-isoindol-2-ylmethyl)- phenylcarbamoylj-θ-methyl-phenoxyl-ethy^-carbamic acid tert-butyl ester (748mg) in EtOH (3OmL) was added hydrazine monohydrate (5 equivalents) and the reaction heated to reflux for 2.5 hours. The reaction mixture was filtered, reduced in vacuo, partitioned between DCM and NaOH (0.5M). Material dried over magnesium sulfate and reduced in vacuo to give the title compound as a yellow solid (442mg). 1HNMR (DMSO) 10.2 (IH, s), 7.9 (IH, s), 7.8 (IH, s), 7.65 (2H, d), 7.3 (2H, d), 7.1 (IH, t), 3.95 (2H, t), 3.7 (2H, s), 3.3 (2H, m, overlaps with solvent) 2.3 (3H, s), 1.4 (9H, s).
r2-(2-Chloro-6-methyl-4-{4-methyl-pentanoylamino)methyl1-phenylcarbamovU-phenoxy)ethyl]- carbamic acid tert-butyl ester To a solution of {2-{4-(4-Aminomethyl-phenylcarbamoyl)-2-chloro-6-methyl-phenoxy]-ethyl}- carbamic acid tert-butyl ester (196mg) in DMF (5mL) was added 4-methylvaleric acid (1 equivalent), EDAC (1.1 equivalents), HOAt (1.1 equivalents) and triethylamine (3 equivalents) and the reaction heated to 5O0C for 12 hours. Reaction was followed by LC-MS and on completion was reduced in vacuo and partitioned between EtOAc and 5% citric acid. Organic were washed with sat. bicarbonate (aq) and brine. Material dried over magnesium sulfate and purified by column chromatography eluting with a gradient of 40% EtO Ac/petrol to 100% EtOAc to give the title compound as an off-white solid (106mg). 1H NMR (MeOD) 7.9 (IH, s), 7.8 (IH, s), 7.65 (2H, d), 7.3 (2H, d), 4.4 (2H, s), 4.05 (2H, t), 3.5 (2H, t) 2.4 (3H5 s), 2.3 (2H, t), 1.6 (3H, m), 1.5 (9H, s), 0.95 (6H, d).
4-(2-Anamo-ethoxy-3-cMoro-5-methyl-N-{4-r(4-methyl-pentanoylamino)-methyll-ρhenvU- benzamide
To a suspension of [2-(2-Chloro-6-methyl-4-{4-methyl-pentanoylamino)methyl]- phenylcarbamoyl}-phenoxy)ethyl]-carbamic acid tert-butyl ester (106mg) in MeOH (2mL) was added sat. HCl in diethylether (2mL) and the reaction allowed to stir at RT for 12 hours. Reaction reduced in vacuo to give the title compound as a yellow oil (94mg). 1H NMR (MeOH-d4) 7.9 (IH, s), 7.8 (IH, s), 7.7 (2H, d), 7.3 (2H, d), 4.5 (2H, s), 4.25 (2H, t), 3.45 (3H, t), 2.4 (3H, s), 2.35 (2H, t), 1.55 (3H, m), 0.9 (6H d). LC/MS: (PS-A3) R47.16 [M+H]+ 432.
Example 76 4-f2-Amino-ethoxyVN-(4-aminometliyl-phenyl)-3-chloro-5-nietliyl-benzaniide
To a solution of {2-{4-(4-Aminomethyl-phenylcarbamoyl)-2-chloro-6-meth.yl-phenoxy]-ethyl}- carbamic acid tert-butyl ester (50mg) in MeOH (2mL) was added sat. HCl in diethylether (2mL) and the reaction allowed to stir at RT for 4 hours. RM reduced in vacuo and suspended in MeOH (2mL) and 4M HCl in dioxan (ImL) added and the RM allowed to stir at RT for a further 2 hours. RM reduced in vacuo to give the title compound as a yellow solid (40mg). 1H NMR (MeOH-d4) 7.9 (IH, s), 7.8 (3H, m), 7.5 (2H, d), 4.25 (2H, t), 4.1 (2H, s), 3.45 (2H, t), 2.5 (3H, s). LC/MS: (PS-B2) Rt5.22 [M-HH]+ 334.
Example 77
Assay of uPA Inhibitory Activity
The following methods were used for assaying uPA inhibitory activity.
Method 1 Activity of uPA was measured using the peptide Z-Gly-Gly- Arg-AMC from Bachem as substrate 1. Compounds were incubated with uPA and 25 μM peptide substrate 1 in 50 mM Tris, pH 7.5, 0.1 % PEG, 2 % DMSO in 96-well black, flat bottomed Cliniplates in a final assay volume of 50 μl. The reaction rate was monitored at room temperature on a Gemini XS (Molecular Devices) platereader with excitation and emission wavelengths of 365nm and 460nm respectively. Initial reaction rates were measured and ICsos were calculated from replicate curves using GraphPad Prism software.
Method 2
Compounds that fluoresced under the conditions described above were assayed in an alternative assay. Compounds were incubated with uPA and 70 μM peptide substrate 2 (Z-Val-Gly-Arg-pNA from Calbiochem) in 5OmM Tris, pH 7.5, 2 % DMSO in 96-well clear, flat bottomed V2 area Costar plates in a final assay volume of 50 μl. The reaction rate was monitored at room temperature on a SpectraMax platereader (Molecular Devices) with absorbance 405nm. Initial reaction rates were measured and used to calculate IC50S as described above.
Using the methods described, all compounds were assayed and all found to inhibit uPA with IC50 <40μM indicating strong uPA inhibition. A sub-group inhibited uPa with IC50 <1 μM, as indicated in the table.
Table 1 - Compounds of the invention
4-(2-Amino-ethoxy)-N-(lH- indazol-6-yl)-3,5-dimethyl- < 40.0 benzamide
The present invention thus provides compounds for use as serine protease inhibitors and novel therapies based thereon.
PART Π.
Pharmacophore for Compounds that Bind to Ser-190 Trypsin-like Proteases
In addition to the novel compounds disclosed in Part I of this application, the present invention also provides a pharmacophore that enables design of compounds that bind to Ser-190 Trypsin-like serine proteases, most preferably Urokinase (uPA), Factor Vila, Factor DCa, and beta - Tryptase, which can preferably act as therapeutically useful inhibitors, and interact with the protein or proteins by binding to the Sl pocket and also preferably to adjacent sub-pockets in the active site region, according to specified pharmacophoric interactions described in this invention.
- I ll -
Use of this pharmacophore enables the design of compounds in which an amidine, benzamidine or, in particular, a naphthamidine moiety, of the type known in existing serine 190 Trypsin-like serine protease inhibitors, can be replaced with a non-amidine moiety. Such amidine, benzamidine and naphthamidine containing compounds are disclosed in the prior art as inhibitors of Ser-190 Trypsin-like serine proteases, such as uPA, Factor Vila, Factor IXa, and beta -Tryptase.
Compounds of some embodiments of the invention may not have biological activity in an enzyme assay, but are useful as starting points for structure guided optimisation in order to derive larger, more functionalised compounds that are enzyme inhibitors, useful ligands, and therapeutically useful agents.
The present invention provides a pharmacophore comprising a motif that binds to the Sl pocket of Ser-190 Trypsin-like serine proteases, typically containing an amino group with a pKa of <9.0. The invention provides inhibitors of Ser-190 Trypsin-like serine proteases and enables design of further inhibitors of Ser-190 Trypsin-like serine proteases, preferably with better pharmaceutical properties, especially orally bioavailable drugs.
Mexiletine is a representative of the pharmacophore claimed. Mexiletine is a known drug, a class Ib antiarrhythmic agent; with bioavailability of about 90%; and weakly bound to plasma proteins (70%). Its volume of distribution is large and varies from 5 to 9 L/kg in healthy individuals. Mexiletine is eliminated slowly in humans (with an elimination half-life of 10 h).
The invention is based on the observation that Mexiletine can bind to the Sl specificity pocket of Ser-190 serine proteases, as indicated by X-ray structural determination in the enzyme Urokinase.
The pharmacophore scheme illustrated in Formula A represents compounds of a first aspect of the invention, and can be used to design therapeutically useful inhibitors of Trypsin-like serine proteases.
Formula A
The compounds of the invention preferably have a primary amino functionality with a pka value in the range 7-9.5.
Referring to the formula, two carbons link the primary amine to an oxygen, which is linked to an aromatic scaffold. In Formula A a benzene ring can be attached to the oxygen atom. In some embodiments a heterocyclic ring system is used as a replacement. A, B, and C are amino acid residues in the protease and are described below, cl, c2 and c3 form part of a ring such as a 5- or 6 membered aromatic (e.g. aryl or heteroaryl) or heterocyclic ring.
Formula 1-X
In another embodiment, the pharmacophore is represented by Formula 1 (as described in Part I of this application), where T is a linker group, designed using the principles of structure-based drug design described below, and knowledge of the binding site of the Trypsin-like serine protease of interest. For example, T could be for example a halogen, sulphonamide, or a heterocyclic group or a similar polar group, from which further groups are appended to bind to the active site. An illustration of how groups T can be designed against the Trypsin-like serine protease Urokinase (uPA) is described below as exemplification of the approach to compound design using the pharmacophore of this invention.
The present invention hence provides a compound which is capable of binding a trypsin-like serine protease and comprises a pharmacophore of Formula 1-X as hereinbefore defined. Particular compounds within formula I are those wherein:
V is selected from methyl, chlorine, bromine or a similar lipophilic group or is defined according to formulas 2b, 3b and 4b below,
W is selected from methyl, chlorine, bromine or a similar lipophilic group or can be a heteroatom, such as N, S or O, for example an amino group, or is defined according to formulas 2b, 3b and 4b below,
X, Y and T are defined according to formulas 2b, 3b and 4b below, Rm, Rn, Rp and Rq are selected from 4. H; 5. Me or Rm and Rn, Rp and Rq , or Rm and Rq form a cyclopropane ring, or are defined according to formulae 2b, 3b and 4b below.
Where V5 W, X, Y and/or T is carbon, the carbon atom may be sp3, sp2 or sp hybridised and hence attached to any group by a single, double or triple bond.
The invention further includes compounds where V, W, X, Y and/or T may be carbon or a heteroatom such as N, O or S, attached to hydrogen, any functional group or molecular scaffold.
The arrangement of atoms described in Formula 1-X constrains the molecules in a particular conformation, which allows the primary amine to form a network of hydrogen bonds with three residues present in the Sl pocket of Trypsin-like serine proteases. Table 1 gives the residue numbers for these important residues in representative Trypsin-like serine proteases using the residue numbering scheme for the serine protease from the specified PDB codes. The
corresponding chymotrypsin numbering for the A, B and C residues in this table is 189, 190 and 219. Unless otherwise stated all subsequent references to residue numbers in Urokinase refer to the residue numbering for Urokinase in PDB code, lowk. The Rn-q groups and the group V sit against the hydrophobic phase of the Sl pocket, forming van der Waals contacts. The group W sits against a di-sulphide bridge (e.g. Cys 193-Cys 221 in Urokinase), again forming van der Waals contacts and additionally can pick up additional interactions in the Sl -beta pocket. The nature of the interactions in the Sl beta pocket can vary, depending on the particular residues present in the Trypsin-like serine protease of interest. For example, in Urokinase, a H-bond with Lys 141 can be targeted. The choice of W will be defined using structure-based drug design principles, depending on the residues present in this region in the Trypsin-like serine protease of interest.
S2 region
Formula 1-X - bind mode
Table 1. Residues involved in hydrogen bond formation with the primary amine described in the pharmacophore.
The pharmacophore of the invention enables design of useful molecules with therapeutic activity. In embodiments of the invention set out in more detail in the examples below, compounds are designed with activity in inhibiting uPA, as an example of a Ser-190 Trypsin-like serine protease
Specifically, adjacent to the Sl pocket of Urokinase other binding pockets are present termed Slbeta, S2, S4 and Sl'. These pockets have side-chain preferences, which introduce specificity for the substrates of the proteases, and preferably compounds identified herein interact with one or more of these pockets. The amino acid residues in the different binding pockets of the Trypsin-like serine protease Urokinase are recited in Table 2.
Table 2. Binding site information (residue numbering taken from lowk)
The present invention hence provides compounds that match the pharmacophore described above, and additionally are designed, using structure-based drug design approaches (described below) and a knowledge of the Trypsin-like serine protease of interest, that present functional groups that are suitable for binding in the Sl, Slβ. S2, S4 and/or Sl' pockets.
Six pharmacophore points, one for each binding site, are used to define the type of functionality preferred for each S' or S pocket in Urokinase. They are described as weighted average positions in three-dimensional space. The distances between each pharmacophore point and the C-α atom of selected protein residues are reported in Table 3.
Table 3. Pharmacophore points (residue numbering taken from lowk*)
The types of substituent preferred in each pharmacophore point and their distances from different groups (see Formula 1-X) are reported in Table 4. The distances to the pharmacophore point are measured from the first atom of the specified group.
Table 4. Preferred types of substituents for each pharmacophore point and its distance from the different groups described in Formula Ib.
In a further aspect, the present invention provides a method of identifying compounds which are modulators, such as inhibitors, of a Trypsin-like serine protease, the method comprising:
(a) designing and/or selecting a candidate modulator e.g. an inhibitor using the pharmacophore represented by Formula A or 1-X or a compound as defined herein;
(b) fitting one or more candidate modulators to determine the probability of the candidate modulator interacting with the Trypsin-like serine protease; (c) optionally modifying the compound based on the result of the fitting step; and
(d) optionally identifying compounds or candidate modulators which are capable of binding or modulating the Trypsin-like serine protease.
In a further aspect, the present invention provides a method of identifying compounds which are modulators, such as inhibitors, of a Trypsin-like serine protease, the method comprising:
(a) selecting a known inhibitor that contains a strongly basic group, such as an amidine, benzamidine, or especially a naphthamidine group that is known to bind in the Sl specificity pocket
(b) designing and/or selecting a candidate modulator e.g. an inhibitor using the pharmacophore represented by Formula A or 1 -X or a compound as defined herein by replacing the amidine, benzamidine, or especially a naphthamidine group with the moiety from the pharmacophore of this invention; (c) optionally modifying the compound based on the result of the fitting step; and
(d) optionally identifying compounds or candidate modulators which are capable of binding or modulating the Trypsin-like serine protease.
In some embodiments of the invention, one or more of steps (a)-(c) are carried out in silico, e.g. using computer modelling as discussed in more details below.
In this way, comparisons of the chemical structures of compounds claimed as inhibitors of Ser-190 Trypsin-like serine proteases containing naphthamidine, amidinoquinolines, amidinoisoquinolines, amidinoquinazolines, 5 or 6-amidinoindole, 5-amidinobenzimidazole, 5 or 6-amidinobenzthiazole, 5 or 6-amidinobenzothiophene, 5 or 6-amidinobenzoxazole and other similar amidine-containing formulas can be made to derive new compounds that contain an ethanolamine motif attached to the corresponding phenyl or heterocycle. By way of example, patents in which such comparisons can be made to derive new formula, covered by the pharmacophore of this invention, and in which inhibitors of Ser-190 Trypsin-like serine proteases could be derived, are as follows: US 2004122073, EP 1312602, US 6504031, US 6495562, WO 2001081314, US 6284796, US 6258822, WO 2000066545, WO 9905096, EP 568289, JP 55072145, WO 2004094372, WO 2004062661, US 2004138233, WO 2004050637, WO 2004048335, WO 2004002405, WO 2004002406, US 2004006065, WO 2004000310, WO 2003101281, US 6653316, WO 2003076391, WO 2003068756, WO 2003066588, WO 2003042187, WO 2003029224, WO 2003015715, WO 2003006011, WO 2003006670, EP 1270551, WO 2002074756, WO 2002074765, WO 2002070471, WO 2002062829, US 6432922, CN 1298869, WO 2002042272, WO 2002034711, EP 1193248, US 2002037857, WO 2002022575, WO 2002014274, WO 2002014307, WO 2002010145, WO 2002010127, WO 2002008177, WO 2002006269, WO 2001097794, WO 2001096286, EP 1162194, WO 2001087854, WO 2001087852, WO 2001087851, WO 2001087842, WO 2001079155, WO 2001068605, US 6291514, WO 2001044172, WO 2001042199, EP 1059302, WO 2000047578, WO 2000047207, WO
2000041531, WO 2000035858, WO 2000035886, WO 2000017158, EP 987274, CH 689611, WO 2000005245, WO 2000004954, WO 9950254, WO 9950263, US 5952307, WO 9941231, WO 9940088, EP 921116, WO 9911658, WO 9748706, WO 9612499, JP 05279315, JP 63238051, EP 217286, the contents of all of which are incorporated herein by reference.
Using the pharmacophore of this invention, and the naphthamidine-based compounds described as inhibitors of Urokinase in US 6495562 and also in WO 2001081314, and taking the formula for compounds of that invention below (Formula 2a), then serine 190 Trypsin-like serine protease inhibitors are suitably designed that are represented by Formula 2b.
Formula 2a
Formula 2b
Hence, a further aspect of the present invention provides compounds of formula 2b, wherein R1, R 2 and R ,3 are as defined in US 6495562, the contents of which are incorporated herein by reference, R1 being preferably H. It is understood that R2 is equivalent to W as described above and V, X and Y are as defined herein.
Using the pharmacophore of this invention, and the naphthamidine-based compounds described as inhibitors of Urokinase in US 6284796, and taking the formula for compounds of that invention below (Formula 3a), then serine 190 Trypsin-like serine protease inhibitors are suitably designed that are represented by Formula 3b.
Formula 3a
Formula 3b
Thus, another aspect of the invention provides compounds of formula 3b, wherein z and Z are as defined in US 6284796, the contents of which are incorporated herein by reference, Z4 being preferably H; C is equivalent to W as defined herein; B is equivalent to Y as defined herein; A is equivalent to T as defined herein; and V is as defined herein.
Using the pharmacophore of this invention, and the benzimidazole-based compounds described as inhibitors of Urokinase in, for example, WO 2004050637, and taking the formula for compounds of that invention below (Formula 4a), then serine-190 Trypsin-like serine protease inhibitors are suitably designed that are represented by Formula 4b.
Formula 4a
Formula 4b
Another aspect of the present invention is hence provided by compounds of formula 4b, in which R13, X1, X4, R, R1, R2 and R3 are as defined in WO 2004050637, the contents of which are incorporated herein by reference, R13 being preferably H. It is understood that X4 is equivalent to V described above. It is also understood that X1 should preferably be substituted in formula 4b to best fulfil the pharmacophore of this invention.
Ih the above embodiments and aspects of this invention, comparisons of the amidine-based inhibitors described in the prior art with the pharmacophore of this invention are facilitated by use of the protein-ligand complexes of representative inhibitors. Not meaning to limit the scope ύf the use of the pharmacophore of this invention, examples of protein-ligand complexes available to help
design new types of inhibitor for, for example, Urokinase are available using the following PDB codes: 1C5Y, 1C5W, 1GI7, 1GI8, 1G19, 1GJ4, 1GJ5, 1GJ7, 1GJ8, 1GJ9, IGJB, IGJC, 1O3P, 1C5Z, 1F5K, 1F92, IGJA, IGJD, 1SC8, 1VJ9, IVJA, IEJN, 1F5L, 10WD, 10WE, 10WH, 1OWI, 1OWJ, 1OWK, ISQA, ISQO, ISQT, 1FV9.
The present invention provides a method of modulating Trypsin-like serine protease activity in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or derivative thereof.
In a further aspect, the present invention provides a method of treating a condition mediated by Trypsin-like serine protease activity in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or derivative thereof.
In a further aspect, the present invention provides a method of identifying compounds which are modulators, such as inhibitors, of a Trypsin-like serine protease, the method comprising:
(a) designing and/or selecting a candidate modulator e.g. an inhibitor using the pharmacophore represented by Formula A, 1-X, 2b, 3b, or 4b, or a compound as otherwise defined herein;
(b) fitting one or more candidate modulators to determine the probability of the candidate modulator interacting with the Trypsin-like serine protease;
(c) optionally modifying the compound based on the result of the fitting step; and (d) optionally identifying compounds or candidate modulators which are capable of binding or modulating the Trypsin-like serine protease.
In a further aspect, the present invention provides a method of identifying compounds which are modulators, such as inhibitors, of a Trypsin-like serine protease, the method comprising:
(a) selecting a known inhibitor that contains a strongly basic group, such as an amidine, benzamidine, or especially a naphthamidine group that is known to bind in the Sl specificity pocket
(b) designing and/or selecting a candidate modulator e.g. an inhibitor using the pharmacophore represented by Formula A, 1-X, 2b, 3b or 4b or a compound as otherwise defined herein by replacing the amidine, benzamidine, or especially a naphthamidine group with the moiety from the pharmacophore of this invention ;
(c) optionally modifying the compound based on the result of the fitting step; and
(d) optionally identifying compounds or candidate modulators which are capable of binding or modulating the Trypsin-like serine protease.
Li a further aspect, the present invention provides a method of identifying compounds which are modulators, such as inhibitors, of a Trypsin-like serine protease, the method comprising:
(a) selecting a known inhibitor that contains an amidine, indole-amidine or benzimidazole- amidine group that is known to bind in the Sl specificity pocket (b) designing and/or selecting a candidate modulator e.g. an inhibitor using the pharmacophore represented by Formula A, 1-X, 2b, 3b or 4b or a compound as otherwise defined herein by replacing the naphthamidine group with the moiety from the pharmacophore of this invention ;
(c) optionally modifying the compound based on the result of the fitting step; and (d) optionally identifying compounds or candidate modulators which are capable of binding or modulating the Trypsin-like serine protease.
In a further aspect, the present invention provides a method of identifying compounds which are modulators, such as inhibitors, of a Trypsin-like serine protease, the method comprising:
(a) selecting a known inhibitor that contains a naphthamidine group that is known to bind in the Sl specificity pocket
(b) designing and/or selecting a candidate modulator e.g. an inhibitor using the pharmacophore represented by Formula A, 1-X, 2b, 3b or 4b or a compound as otherwise defined herein by replacing the naphthamidine group with the moiety from the pharmacophore of this invention; (c) optionally modifying the compound based on the result of the fitting step; and
(d) optionally identifying compounds or candidate modulators which are capable of binding or modulating the Trypsin-like serine protease.
Li particular methods of the invention there are provided:-
- a method of identifying compounds which are modulators of a serine 190 Trypsin-like serine protease, the method comprising:
(a) designing and/or selecting a candidate modulator containing the pharmacophore represented by Formula A, 1-X, 2b, 3b, 4b or as otherwise defined herein,
(b) contacting a serine protease with the candidate modulator to be tested under conditions such that the candidate modulator can interact with the serine protease; (c) detecting the binding and/or modulation of the candidate modulator to the serine protease; and
(d) identifying compound(s) which are capable of binding or modulating the serine protease;
- a method of identifying compounds which are modulators of a serine protease, the method
compπsing:
(a) designing and/or selecting a candidate modulator using the pharmacophore represented by Formula A, 1-X, 2b, 3b, 4b or as otherwise defined herein:
(b) fitting one or more candidate modulators to determine the probability of the candidate modulator interacting with said serine protease; and
(c) optionally modifying said candidate modulator based on the result of the fitting step; thus identifying compounds or candidate modulators which are capable of binding to or modulating said serine protease, and
- compounds identified thereby.
In specific embodiments of the invention, of application to pharmacophores of formula 1-X, 2b, 3b and 4b, both V and W are not H. More preferred combinations are those in which any sub-class of values of V is combined with any sub class of values for W. More specific combinations of V and W are (i) both are methyl, (ii) one is methyl and one is chloro, (iii) one is methyl and one is amino, and (iv) both are chloro.
It is believed, though the inventors do not wish to be bound by any such theory, that the Rm, Rn, Rp and Rq groups on the left hand, primary amine side of the compounds bind in use to a relatively tightly defined pocket or groove in the protease target, resulting in the inhibitory activity of these compounds. Rm, Rn, Rp and Rq are preferably H or Me. Rm and Rn or Rp and Rq or Rm and Rq can optionally form a cyclopropane ring, and should preferably be H, or methyl. In one preferred series of pharmacophores and compounds of the invention, one of Rm and Rn is methyl, forming preferably the R isomer, and the other is H and Rp and Rq are H.
These groups are typical of those suitable in compounds and pharmacophores of the invention. Particularly preferred pharmacophores are those in which V and W are Me or Cl, and all of Rm, Rn, Rp and Rq are H.
The present invention provides the use of compounds of formula A, 1-X, 2b, 3b and 4b or a solvate, hydrate, ester or pharmaceutically acceptable salt thereof, as defined herein for the manufacture of a medicament for inhibition of a serine 190 Trypsin-like serine protease.
The present invention also provides, as compounds of the invention, the compounds of formula A, 1-X, 2b, 3b and 4b and solvates, hydrates and pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the same, generally in combination with a pharmaceutically acceptable carrier, especially for administration to a human.
Also provided by the invention are methods of treatment using the compounds of the invention as inhibitors of serine 190 Trypsin-like serine proteases. Thus, also provided are methods of inhibiting or treating aberrant serine protease activity in a mammal, methods treating or ameliorating diseases responsive to a serine protease inhibitor, methods of contraception, anti-coagulant methods and uses and methods for treating aberrant cell proliferation, tumours, cancer, angiogenesis, angiogenesis-based retinopathies, autoimmune disease, inflammation, skin disease, arthritis, rheutmatoid arthritis, asthma, osteoarthritis, HTV, multiple sclerosis and other diseases and conditions as referred to herein by administering to a patient an effective amount of a compound of the invention.
The invention is of application to a wide range of serine 190 Trypsin-like serine proteases, including but not limited to trypsin, tryptase, plasmin, urokinase (uPA), Factor Vila, and Factor IXa.
For the avoidance of doubt, the invention also provides compounds, uses and methods as set out herein using any combination of preferred values and definitions of sub classes of values for all groups in formula 1-X, each such combination forming a separate embodiment of the invention.
The invention thus provides:-
- a compound per se of the formula A, 1-X, 2b, 3b or 4b, or as otherwise defined herein,
- a compound of the formula A, 1-X, 2b, 3b or 4b or as otherwise defined herein for use in the prophylaxis or treatment of a disease state or condition mediated by a serine 190 Trypsin-like serine protease,
- the use of a compound of formula A, 1-X, 2b, 3b or 4b or as otherwise defined herein for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition mediated by a serine 190 Trypsin-like serine protease,
- a method for the prophylaxis or treatment of a disease state or condition mediated by a serine protease, which method comprises administering to a subject in need thereof a compound of the formula A, 1-X, 2b, 3b or 4b or as otherwise defined herein.
a method for treating a disease or condition comprising or arising from abnormal cell growth or abnormally arrested cell death in a mammal, the method comprising administering to the mammal a compound of the formula A, 1-X, 2b, 3b or 4b or as otherwise defined herein in an amount effective to inhibit serine 190 Trypsin-like serine protease,
- a method of inhibiting serine 190 Trypsin-like serine protease, which method comprises contacting the protease with a protease inhibiting compound of the formula A, 1-X, 2b, 3b or 4b or as otherwise defined herein,
- a method of modulating a cellular process by inhibiting the activity of a serine 190 Trypsin-like serine protease using a compound of the formula A, 1-X, 2b, 3b or 4b or as otherwise defined herein,
- the use of a compound of the formula A, 1-X, 2b, 3b or 4b or as otherwise defined herein for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition arising from abnormal cell growth or abnormally arrested cell death,
- a method for treating a disease or condition comprising or arising from abnormal cell growth or abnormally arrested cell death in a mammal, which method comprises administering to the mammal a compound of the formula A5 1-X, 2b, 3b or 4b or as otherwise defined herein in an amount effective in inhibiting abnormal cell growth,
- a method for alleviating or reducing the incidence of a disease or condition comprising or arising from abnormal cell growth or abnormally arrested cell death in a mammal, which method comprises administering to the mammal a compound of the formula A, 1-X, 2b, 3b or 4b or as otherwise defined herein in an amount effective in inhibiting abnormal cell growth,
- a pharmaceutical composition comprising a novel compound of the formula A, 1-X, 2b, 3b or 4b or as otherwise defined herein and a pharmaceutically acceptable carrier,
- a compound of the formula A, 1, 2b, 3b or 4b or as otherwise defined herein for use in medicine,
- the use of a compound of the formula A, 1-X, 2b, 3b or 4b or as otherwise defined herein for the manufacture of a medicament for the prophylaxis or treatment of any one of the disease states or conditions disclosed herein,
- a method for the treatment or prophylaxis of any one of the disease states or conditions disclosed herein, which method comprises administering to a patient (e.g. a patient in need thereof) a compound (e.g. a therapeutically effective amount) of the formula A, 1-X, 2b, 3b or 4b or as otherwise defined herein,
- a method for alleviating or reducing the incidence of a disease state or condition disclosed herein, which method comprises administering to a patient (e.g. a patient in need thereof) a compound (e.g. a therapeutically effective amount) of the formula A, 1-X, 2b, 3b or 4b or as
otherwise defined herein,
- a method for the diagnosis and treatment of a disease state or condition mediated by a serine protease, which method comprises (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against the serine protease; and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient a compound of the formula A, 1-X, 2b, 3b or 4b or as otherwise defined herein, and
- the use of a compound of the formula A, 1-X, 2b, 3b or 4b or as otherwise defined herein for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition in a patient.
In another aspect, the invention provides a method for the prophylaxis or treatment of a disease state or condition of the type hereinbefore defined, which method comprises administering to a subject (e.g. a human subject) in need thereof a compound of the formula A, 1, 2b, 3b or 4b or as otherwise defined herein. Accordingly, the invention also provides a compound of the formula 1- X, 2b, 3b or 4b or as otherwise defined herein for use in the prophylaxis or treatment of a disease state or condition mediated by a serine protease or its receptor.
Where compounds of the formula A, 1-X, 2b, 3b or 4b or as otherwise defined herein contain one or more chiral centres, e.g. positions indicated as a and b in the formula, and can exist in the form of two or more optical isomers, references to such compounds include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic mixtures) or two or more optical isomers, unless the context requires otherwise.
Further Definitions
In describing this invention, by "binding site" or "binding cavity" we mean a site (such as an atom, a functional group of an amino acid residue or a plurality of such atoms and/or groups) in a Trypsin-like serine protease binding cavity, which may bind to an agent compound such as a candidate inhibitor. Depending on the particular molecule in the cavity, sites may exhibit attractive or repulsive binding interactions, brought about by charge, and/or steric considerations and the like.
Binding sites are sites within a macromolecule such as a Trypsin-like serine protease, or on its surface, at which ligands can bind. Examples are the catalytic or active site of an enzyme (the site
on an enzyme at which the amino acid residues involved in catalysing the enzymatic reaction are located), allosteric binding sites (ligand binding sites distinct from the catalytic site, but which can modulate enzymatic activity upon ligand binding), cofactor binding sites (sites involved in binding/coordinating cofactors e.g. metal ions), or substrate binding sites (the ligand binding sites on a protein at which the substrates for the enzymatic reaction bind). There are also sites of protein-protein interaction. More particularly the binding site of Urokinase is defined as including the pockets and associated residues specified in Table 2, and one skilled in the art would be able to establish the binding sites of other Trypsin-like serine proteases through the use of sequence and/or structural alignment of a specified trypsin-like serine protease onto Urokinase.
In the following by "active site" we mean a site (such as an atom, a functional group of an amino acid residue or a plurality of such atoms and/or groups) in a Trypsin-like serine protease binding cavity, which is involved in catalysis.
The term "hydrogen bond" refers to a favourable interaction that occurs whenever a suitable donor atom, Qx, bearing a proton, H, and a suitable acceptor atom, Qγ, have a separation of < 3.5 A and where the angle Qx-H-Qγ is greater than 90 degrees. Sometimes, a single acceptor atom Qγ may form a plurality of hydrogen bonds with a plurality of protons on suitable donor atoms, Qx. Sometimes, a single proton on a donor atom Qx may form hydrogen bonds with a plurality of suitable acceptor atoms, Qγ. For example, the proton on a -NH-group may form a separate hydrogen bond with each of the two oxygen atoms in a carboxylate anion. Suitable donor and acceptor atoms are well understood in medicinal chemistry (G.C. Pimentel and A.L. McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R. Taylor and O. Kennard, Hydrogen Bond Geometry in Organic Crystals, Accounts of Chemical Research, 17, pp. 320-326 (1984)).
The term "hydrogen bonding moiety" refers to a chemical structure containing one or more suitable hydrogen bond donor moieties or hydrogen bond acceptor moieties.
The term "hydrogen bonding donor moiety" refers to a chemical structure containing a suitable hydrogen bond donor atom bearing one or more protons. Examples of donor atoms having one proton are -OH, -SH and -NH-. Examples of donor atoms having more than one proton are -NH2, -
The term hydrogen bonding acceptor moiety refers to a chemical structure containing a suitable hydrogen bond acceptor atom. Examples of acceptor atoms include fluorine, oxygen, sulfur and nitrogen.
The term salt bridge refers to the non-covalent attractive interaction between a positively charged moiety (P) and a negatively charged moiety (N) when the distance between the centers of mass of P and N is between 2 and 6 Angstroms. The term center of mass refers to a point in three- dimensional space that represents a weighted average position of the masses that make up an object, thus in calculating the center of mass, atoms which may contain a formal charge and atoms immediately adjacent to these are included. For example, a salt bridge may be formed between the positively charged guanidinium side chain of an arginine residue and the negatively charged carboxylate side chain of a glutamate residue. Salt bridges are well known in medicinal chemistry (L. Stryer, Biochemistry , Freeman, San Francisco, (1975); K. A. Dill, Dominant Forces in Protein Folding, Biochemistry, 29, No. 31, pp. 7133- 7155, (1990)).
The term "lipophilic" or "hydrophobic" refers to a non-polar moiety that tends not to dissolve in water and is fat-soluble. Hydrophobic moieties include, but are not limited to, hydrocarbons, such as alkanes, alkenes, alkynes, cycloalkanes, ethers, cycloalkenes, cycloalkynes and aromatic compounds, such as aryls, certain saturated and unsaturated heterocycles, and moieties that are substantially similar to the side chains of lipophilic natural and unnatural amino acids, including valine, leucine, isoleucine, methionine, phenylanine, α-amino isobutyric acid, alloisoleucine, tyrosine, and tryptophan. Lipophilic interactions can be modeled using a variety of means. For example the ChemScore function (Eldridge M D; Murray C W; Auton T R; Paolini G V; Mee R P Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes, Journal of computer-aided molecular design (1997 Sep), 11(5), 425-45) assigns protein and ligand atoms as hydrophobic or polar, and a favorable energy term is specified for the interaction between two hydrophobic atoms. Other methods of assessing the hydrophobic contributions to ligand binding are available and these would be known to one skilled in the art.
"Polar" refers to compounds having one or more polar bonds in which the electron density of the bond lies closer to one atom than the other as one of the atoms is more electronegative than the other. This means that one of the atoms develops a degree of positive charge while the other some degree of negative charge. Compounds having polar bonds generally have dipole moments. In contrast, covalent bonds between atoms having the same electronegativity are symmetric.
"Acidic" refers to the tendency of compounds to donate a proton (H+) or accept an electron pair into an empty orbital (Lewis Theory of Acids and Bases). "Basic" refers to the tendency of compounds to accept a proton (H+) (Bronsted-Lowry Theory) or donate an electron pair.
By "fitting", is meant determining by automatic, or semi-automatic means, interactions between one or more atoms of a candidate molecule and at least one atom of a Trypsin-like serine protease structure e.g. Urokinase, and calculating the extent to which such interactions are stable. Interactions include attraction and repulsion, brought about by charge, and/or steric considerations and the like. Interactions of this type can be modeled computationally. An example of such computation would be via a force field such as Amber (Cornell et al A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules, Journal of the American Chemical Society, (1995), 117(19), 5179-97) which would assign partial charges to atoms on the protein and ligand and evaluate the electrostatic interaction energy between a protein and ligand atom using the Coulomb potential. The Amber force field would also assign van der Waals energy terms to assess the attractive and repulsive steric interactions between two atoms. Other methods of assessing interactions are available and would be known to one skilled in the art of designing molecules consistent with specified pharmacophores. Various computer-based methods for fitting are described further herein.
Molecular fragments or molecular scaffolds are typically compounds with a molecular weight between 100 and 300 Da. They typically will have simple functional groups, for example those involving only carbon, nitrogen, oxygen, sulfur and halogens, and be more soluble than larger molecules. They are discussed in more detail in the following references Carr, R; et al.; Drug Discov. Today, 2002, 7(9):522-527; Bemis GW, et al; J Med Chem. 1996, 39(15):2887-93; Bemis GW, et al.; J Med Chem. 1999;42(25):5095-9; Fejzo J, et al; Chem Biol. 1999; 6(10):755-69; Ajay, et al; J Med Chem. 1999;42(24):4942-51.
A functional group is a particular group of atoms in a molecule. They are submolecular structural motifs, characterized by specific elemental composition and connectivity, that confer reactivity upon the molecule that contains them. Just as elements have distinctive properties, functional groups have characteristic chemistries. Types of functional groups are discussed in standard chemistry textbooks such as March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure by Michael Smith and Jerry March (John Wiley & Sons Inc) 1992 and 2001; Organic Chemistry by McMurry (Brooks Cole), Foundations of Organic Chemistry, Stephen G. Davies (Foreword), M. Hornby and Josephine Peach (Oxford Chemistry Primers, Oxford University Press) 1993 etc.
The term "modulator" is a compound that will modulate the Trypsin-like serine protease activity i.e. increase or decrease the activity of the Trypsin-like serine protease. Modulators of Trypsin-like serine proteases may be inhibitors of the enzyme or compounds which affect their specificity or activity in relation to their respective substrates in other ways. The invention is particularly
suitable for the design, selection and development of Trypsin-like serine protease inhibitor components e.g. Trypsin-like serine protease inhibitor compounds. The present invention therefore particularly pertains to modulators that decrease the activity of the Trypsin-like serine protease i.e. that the modulators are Trypsin-like serine protease inhibitors.
The term "pharmaceutical composition" is used herein to define a solid or liquid composition in a form, concentration and level of purity suitable for administration to a patient (e.g. a human or animal patient) upon which administration it can elicit the desired physiological changes.
By a "computer system" we mean the hardware means, software means and data storage means used to analyse atomic coordinate data. The minimum hardware means or device of the computer- based systems of the present invention typically comprises a central processing unit (CPU), input means or device, output means or device and data storage means or device. Desirably a monitor is provided to visualise structure data. The data storage means or device may be RAM or means or device for accessing computer readable media of the invention. Examples of such systems are microcomputer workstations available from Silicon Graphics Incorporated and Sun Microsystems running Unix based, Windows NT or IBM OS/2 operating systems.
By "computer readable media" we mean any medium or media, which can be read and accessed directly by a computer e.g. so that the media is suitable for use in the above-mentioned computer system. Such media include, but are not limited to: magnetic storage media such as floppy discs, hard disc storage medium and magnetic tape; optical storage media such as optical discs or CD- ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media.
By "optimising the structure" we mean e.g. adding molecular scaffolding, adding or varying functional groups, or connecting the molecule with other molecules (e.g. using a fragment linking approach) such that the chemical structure of the modulator molecule is changed while its original modulating functionality is maintained or enhanced. Such optimisation is regularly undertaken during drug development programmes to e.g. enhance potency, promote pharmacological acceptability, increase chemical stability etc. of lead compounds.
Structure-based Drug Design
The process of using the pharmacophore claimed here and the structural information available for the Trypsin-like serine protease of interest to design a therapeutically active compound is usually called structure-based drug design. Determination of the Trypsin-like serine protease pharmacophore can greatly assist the process of rational drug design. This information may be
used for rational design of Trypsin-like serine protease inhibitors, e.g. by computational techniques which identify possible binding ligands for the binding sites, by linked-fragment approaches to drug design, and by structure-based design based on the location of bound ligand. These techniques are discussed in more detail below.
Greer et al. (J. of Medicinal Chemistry, Vol. 37, (1994), 1035-1054) describes an iterative approach to ligand design based on repeated sequences of computer modelling, protein-ligand complex formation and X-ray crystallographic or NMR spectroscopic analysis. Thus novel thymidylate synthase inhibitor series were designed de novo by Greer et al, and Trypsin-like serine protease inhibitors may also be designed in the this way. More specifically, using e.g. GRID on the solved 3D structure of the Trypsin-like serine protease, a ligand (e.g. a potential inhibitor) for the Trypsin-like serine protease may be designed that complements the functionalities of the Trypsin-like serine protease binding sites. The ligand can then be synthesised, formed into a complex with the Trypsin-like serine protease, and the complex then analysed by X-ray crystallography to identify the actual position of the bound ligand. The structure and/or functional groups of the ligand can then be adjusted, if necessary, in view of the results of the X-ray analysis, and the synthesis and analysis sequence repeated until an optimised ligand is obtained. Related approaches to structure-based drug design are also discussed in Bohacek et al, Medicinal Research Reviews, Vol.16, (1996), 3-50.
The fragment-linking approach involves determining (computationally or experimentally) the binding locations of plural ligands to a target molecule, and then constructing a molecular scaffold to connect the ligands together in such a way that their relative binding positions are preserved. The ligands may be provided computationally and modelled in a computer system, or provided in an experimental setting, wherein crystals are provided and a plurality of ligands soaked separately or in mixed pools into the crystal prior to X-ray analysis and determination of their location.
The binding site of two or more ligands are determined and may be connected to form a potential lead compound that can be further refined using e.g. the iterative technique of Greer et al. For a virtual linked-fragment approach see Verlinde et al., J. of * Computer-Aided Molecular Design, 6, (1992), 131-147, and for NMR and X-ray approaches see Shuker et al., Science, 274, (1996), 1531- 1534 and Stout et al., Structure, 6, (1998), 839-848. The use of these approaches with the pharmacophore of the invention can be used to design Trypsin-like serine protease inhibitors.
Many of the techniques and approaches to structure-based drug design described above rely at some stage on X-ray analysis to identify the binding position of a ligand in a ligand-protein complex. A common way of doing this is to perform X-ray crystallography on the complex,
produce a difference Fourier electron density map, and associate a particular pattern of electron density with the ligand. However, in order to produce the map (as explained e.g. by Blundell, TL and Johnson, LN, in Protein Crystallography, Academic Press, New York, London and San Francisco, (1976)) it is necessary to know beforehand the protein 3D structure (or at least the protein structure factors).
The provision of the pharmacophore of the invention will also allow the development of compounds which interact with the binding pocket regions of a Trypsin-like serine protease based on a fragment linking or fragment growing approaches.
For example, molecular fragments and scaffolds herein can provide a starting point for medicinal chemistry to optimize the interactions using a structure-based approach. The fragments can be combined onto a template or used as the starting point for 'growing out' an inhibitor into other pockets of the protein (Blundell TL, Jhoti H, Abell C, Nature Reviews Drug Discovery, 1, 45 - 54,
2002, Carr, R; Jhoti, H; Drug Discov. Today, 2002, 7(9), 522-527). The fragments can be positioned in the binding pockets of Trypsin-like serine proteases and then 'grown' to fill the space available, exploring the electrostatic, van der Waals or hydrogen-bonding interactions that are involved in molecular recognition. The potency of the original weakly binding fragment thus can be rapidly improved using iterative structure-based chemical synthesis.
At one or more stages in the fragment growing approach, the compound may be synthesized and tested in a biological system for its activity. This can be used to guide the further growing out of the fragment.
Where two fragment-binding regions are identified, a linked fragment approach may be based upon attempting to link the two fragments directly, or growing one or both fragments in the manner described above in order to obtain a larger, linked structure, which may have the desired properties.
Uses of the Pharmacophore of the Invention in in silico analysis and design
Current computational techniques provide a powerful alternative to the need to generate crystals and generate and analyse diffraction data. Accordingly, a particularly preferred aspect of the invention relates to in silico methods directed to the analysis and development of compounds, containing the pharmacophoric feature of the present invention, or derived or designed from the molecular fragments herein.
The approaches to structure-based drug design described below all require initial identification of possible compounds for interaction with the target bio-molecule (in this case Trypsin-like serine
proteases). Sometimes these compounds are known e.g. from the research literature. However, when they are not, or when novel compounds are wanted, a first stage of the drug design program may involve computer-based in silico screening of compound databases (such as the Cambridge Structural Database or the Available Chemical Directory (ACD)(MDL Information Systems, San Leandro, CA, USA) with the aim of identifying compounds which interact with the binding site or sites of the target bio-molecule. Screening selection criteria may be based on pharmacokinetic properties such as metabolic stability and toxicity or the pharmacophore of the invention. The pharmacophore can thus be used as selection criteria or filter for database screening.
Thus as a result of the determination of the Trypsin-like serine protease pharmacophore more purely computational techniques for rational drug design may also be used to design Trypsin-like serine protease inhibitors (for an overview of these techniques see e.g. Walters et al, Drug
Discovery Today, Vol.3, No.4, (1998), 160-178; Abagyan, R.; Totrov, M. Curr. Opin. Chem. Biol.
2001, 5, 375-382). For example, automated ligand-receptor docking programs (discussed e.g. by
Jones et al. in Current Opinion in Biotechnology, Vol.6, (1995), 652-656 and Halperin, I; Ma, B.; Wolfson, H.; Nussinov, R. Proteins 2002, 47, 409-443), can be used to design potential aspartic proteinase inhibitors on the basis of the pharmacophore of the invention.
The determination of the pharmacophore for Trypsin-like serine proteases provides a basis for the design of new and specific ligands for Trypsin-like serine proteases. For example, computer modelling programs may be used to design different molecules expected to interact with binding cavities or other structural or functional features of Trypsin-like serine proteases. Examples of this are discussed in Schneider, G.; Bohm, H. J. Drug Discov. Today 2002, 7, 64-70.
More specifically, the interaction of a compound with Trypsin-like serine proteases can be examined through the use of computer modelling using a docking program such as GOLD (Jones et al., J. MoI. Biol, 245, 43-53 (1995), Jones et al., J. MoI. Biol, 267, 727-748 (1997)), GRAMM (Vakser, I.A., Proteins , SuppL, 1:226-230 (1997)), DOCK (Kuntz et al, JMol.Biol 1982 , 161, 269-288, Makino et al, J.Comput.Chem. 1997, 18, 1812-1825), AUTODOCK (Goodsell et al, Proteins 1990, 8, 195-202, Morris et al, J.Comput.Chem. 1998, 19, 1639-1662.), FlexX, (Rarey et al, JMoLBiol 1996, 261, 470-489) or ICM (Abagyan et al, J.Comput.Chem. 1994, 75, 488-506). This procedure can include computer fitting of compounds to Trypsin-like serine proteases to ascertain how well the shape and the chemical structure of the compound will bind to the Trypsin- like serine proteases.
Also, computer-assisted, manual examination of the binding site structure of Trypsin-like serine proteases may be performed. The use of programs such as GRID (Goodford, J. Med. Chem., 28,
(1985), 849-857) - a program that determines probable interaction sites between molecules with various functional groups and an enzyme surface - may also be used to analyse the binding cavity or cavities to predict partial structures of inhibiting compounds.
Computer programs (e.g. molecular simulation methods such as Tounge and Reynolds, J. Med. Chem., 46, (2003), 2074-2082) can be employed to estimate the attraction, repulsion, and steric hindrance of the two binding partners (i.e. the Trypsin-like serine proteases and a candidate modulator). Generally the tighter the fit, the fewer the steric hindrances, and the greater the attractive forces, the more potent the potential modulator since these properties are consistent with a tighter binding constant. Furthermore, the more specificity in the design of a potential drug, the more likely it is that the drug will not interact with other proteins as well. This will tend to minimise potential side-effects due to unwanted interactions with other proteins.
A plurality (for example two, three or four) of (typically spaced) Trypsin-like serine proteases binding sites may be characterised and a plurality of respective compounds designed or selected. The agent compound may then be formed by linking the respective compounds into a larger compound which preferably maintains the relative positions and orientations of the respective compounds at the binding sites. The larger compound may be formed as a real molecule or by computer modelling.
In one embodiment a plurality of candidate agent compounds are screened or interrogated for interaction with the binding sites. In one example, this involves providing the structures of the candidate agent compounds, each of which is then fitted to computationally screen a database of compounds (such as the Cambridge Structural Database or ACD) for interaction with the binding sites, i.e. the candidate agent compound may be selected by computationally screening a database of compounds for interaction with the binding sites and containing the pharmacophore of the invention (see Martin, J. Med. Chem., vol 35, 2145-2154 (1992)). In another example, a 3-D descriptor for the agent compound is derived where the descriptor includes the pharmacophoric feature(s) of the invention. The descriptor may then be used to interrogate the compound database, the identified agent compound being the compound which matches with the features of the descriptor.
Detailed information either structural or activity data can be obtained about the binding of the compound to Trypsin-like serine proteases, and in the light of this information adjustments can be made to the structure or functionality of the compound, e.g. to improve its interaction with Trypsin-like serine proteases. The above steps may be repeated and re-repeated as necessary.
Uses of the Pharmacophore of the Invention in coniuction with X-ray crystallography
Complexes of Trypsin-like serine proteases and compound can be crystallized and analyzed using X-ray diffraction methods, e.g. according to the approach described by Greer et al., J. of Medicinal Chemistry, Vol. 37, (1994), 1035-1054, and difference Fourier electron density maps can be calculated based on X-ray diffraction patterns of soaked crystals of Trypsin-like serine proteases or co-crystallized Trypsin-like serine proteases and the solved structure of uncomplexed Trypsin-like serine proteases. These maps can then be analyzed e.g. to determine whether and where a particular compound binds to the Trypsin-like serine proteases and/or changes the conformation of the Trypsin-like serine proteases.
Electron density maps can be calculated using programs such as those from the CCP4 computing package (Collaborative Computational Project 4. The CCP4 Suite: Programs for Protein Crystallography, Acta Crystallographica, D50, (1994), 760-763.). For map visualization and model building programs such as "O" (Jones et al., Acta Crystallographica, A47, (1991), 110-119) or "QUANTA" (1994, San Diego, CA: Molecular Simulations) can be used.
The crystal structures of a series of complexes may then be solved by molecular replacement and compared with that of the Trypsin-like serine protease in the PDB file. Potential sites for modification within the various binding sites of the enzyme may thus be identified. This information provides an additional tool for determining the most efficient binding interactions, for example, increased hydrophobic interactions, between Trypsin-like serine proteases and a chemical entity or compound.
All of the complexes referred to above may be studied using well-known X-ray diffraction techniques and may be refined against 1.5 to 3.5 A resolution X-ray data to an R value of about 0.30 or less using computer software, such as CNX (Brunger et al., Current Opinion in Structural Biology, Vol. 8, Issue 5, October 1998, 606-611, and commercially available from Accelerys, San Diego, CA), X-PLOR (Yale University, ©1992, distributed by Accelerys), as described by Blundell et al, (1976) and Methods in Enzymology, vol. 114 & 115, H. W. Wyckoff et al., eds., Academic Press (1985).
This information may thus be used to optimize known classes of Trypsin-like serine protease substrates or inhibitors, and more importantly, to design and synthesize novel classes of Trypsin- like serine protease modulators.
Analysing the complex by X-ray crystallography will determine the ability of the candidate compound to interact with the Trypsin-like serine proteases. Analysis of the co-complexes of the
Trypsin-like serine proteases may involve e.g. phasing, molecular replacement or calculating a Fourier difference map of the complex as discussed above.
Thus, in a further aspect, the invention provides a method for determining the structure of a compound bound to the Trypsin-like serine protease, said method comprising: (a) providing a crystal of the Trypsin-like serine protease according to the invention; (b) soaking the crystal with said compounds; and (c) determining the structure of said Trypsin-like serine proteases compound complex.
Alternatively, the Trypsin-like serine proteases and compound may be co-crystallized. Thus the invention provides a method for determining the structure of a compound bound to the Trypsin-like serine proteases, said method comprising; mixing the protein with the compound(s), crystallizing the protein-compound^) complex; and determining the structure of said Trypsin-like serine protease -compound(s) complex.
A mixture of compounds may be soaked or co-crystallized with the crystal, wherein only one or some of the compounds may be expected to bind to the Trypsin-like serine protease. As well as the structure of the complex, the identity of the complexing compound(s) is/are then determined.
hi either case, substrate or a substrate analogue thereof may optionally be present.
The analysis of such structures may employ (i) X-ray crystallographic diffraction data from the complex and (ii) a three-dimensional structure of the Trypsin-like serine protease, or at least selected coordinates thereof, to generate a difference Fourier electron density map of the complex. The difference Fourier electron density map may then be analysed, to identify the binding mode of the modulator.
EXAMPLES
The invention will now be described with reference to specific Examples. These are merely exemplary and for illustrative purposes only. They are not intended to be limiting in any way to the scope of the invention described. Example II-4 exemplifies that it is possible to design groups T to fit the active site region of a particular protease, in this case Urokinase, using the pharmacophore of this invention. Numbering below is with reference to PDB code lowk.
The invention is further illustrated by the Examples 1 to 77 in Part I of this application. The starting materials for each of the procedures described below are commercially available unless otherwise specified.
Proton magnetic resonance (1H NMR) spectra were recorded on a Bruker AV400 instrument operating at 400.13MHz, in MeOH-d4, DMSO-d6 or CDCl3 (as indicated) at 27 0C, unless otherwise stated and are reported as follows: chemical shift δ/ppm (number of protons, multiplicity where s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad). The residual protic solvent was used as the internal reference.
Examples II- 1 and II-2, included herein as illustrative of the pharmacophore, are commercially available materials
EXAMPLE π-1
Mexiletine; 2-(2,6-dimethyl-phenoxy)-l -methyl-ethylamine
EXAMPLE π-2 2-(4-Bromo-2,6-dimethyl-phenoxy)-ethylamine
The other examples were prepared according to the following procedures.
EXAMPLE H-3
4-(2-Amino-ethoxyV3,5-dichloro-benzoic acid ethyl ester
SJ-Dichloro^-p-d^-dioxo-l^-dihydro-isoindol^-vD-ethoxyi-benzoic acid ethyl ester
A stirred solution of ethyl-3,5-dichloro-4-hydroxybenzoate (15 g, 63.75 mmol) and potassium carbonate (10.5 g, 76.5 mmol) in NJV-dimethylformamide (50 ml) and acetonitrile (50 ml) at 120° C was treated with N-(2-bromoethyl) phthalimide (24.3 g, 95.62 mmol) in small portions over a period of 1 h. The mixture was stirred at 120° C overnight, cooled and water added (100 ml). The resulting mixture was extracted with dichloromethane, the organic layer dried over magnesium sulfate and evaporated to dryness in vacuo to afford the crude product as a white solid (26 g, 100%). This material was used in the following step without any further purification. 1H ΝMR (MeOH-dO 7.95 (2H, s), 7.9 (2H, m), 7.85 (2H, m), 4.35 (4H, m), 4.15 (2H, t), 1.35 (3H, t).
4-("2-Amino-ethoxyV3.5-dichloro-benzoic acid ethyl ester To a stirred solution of 3,5-dichloro-4-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-ethoxy]-benzoic acid ethyl ester (26 g, 63.75 mmol) in ethanol (100 ml) at room temperature was added dropwise hydrazine monohydrate (3.09 ml, 63.75 mmol). The mixture was stirred at 100° C for 3 h, cooled and the resulting precipitate removed by filtration and the residue evaporated to dryness in vacuo . The residue was triturated with dichloromethane (100 ml) to afford the product as a pale yellow solid (12.3 g, 70%). 1H ΝMR (MeOH-d4) 7.90 (2H, s), 4.25 (2H, q), 4.05 (2H, t), 2.95 (2H, t), 1.25 (3H, t).
EXAMPLE π-4
4-(2-Amino-ethoxy)3 ,5 -dichloro-benzoic acid
To a solution of 4-(2-Amino-ethoxy)-3,5-dichloro-benzoic acid ethyl ester (70mg) in THF/MeOH/H2O (1:1:2.5) (4.5mL) was added LiOILH2O (1.5 equivalents) and the reaction allowed to stir at RT for 3 hours. The reaction was followed by tic (20% MeOH/DCM) and on completion neutralised with 2M HCl and reduced in vacuo. Material triturated with hot EtOH and purified by prep LC-MS to give the title compound as an off-white solid (16mg). 1H ΝMR (MeOH-dt) 8.0 (2H, s), 4.3 (2H, t), 4.45 (2H, t).
EXAMPLE π-5
2-r2-Methyl-6-(2-pyridin-4-yl-ethyl)-phenoxy1-ethylamine
2-r2-(l.,3-Dioxo-1.3-dihvdro-isoindol-2-ylVethoxy1-3-methyl-benzaldehvde A mixture of 2-hydroxy-3-methylbenzaldehyde (1.59 g, 10.0 mmol), N-(2-bromoethyl)phthalimide (2.54 g, 10.0 mmol), potassium carbonate (2.0 g, 14.5 mmol) in NN-dimethylformamide (40 ml) was stirred and held at 100 0C for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo and the residues partitioned between dichloromethane and water. The organic layer was separated, reduced to dryness in vacuo and the residues subjected to column chromatography on silica. Elution with 15% v/v ethyl acetate in petroleum ether afforded the product as a pale yellow solid (575 mg, 19%). 1H ΝMR (DMSO-d6) 10.21 (IH, s), 7.92 (2H, m), 7.87 (2H, m), 7.58 (IH, d), 7.52 (IH, d), 7.19 (IH, t), 4.18 (2H, t), 4.05 (2H, t), 2.15 (3H, s).
2-[2-Met3iyl-6-('2-pyridin-4-yl-ethyl)-phenoxyl-ethylamine
A suspension of (4-pyridylmethyl)tτiphenylphosphorrium chloride hydrochloride (142 mg, 0.33 mmol) in tetrahydrofuran (5 ml) was treated with potassium tert-butoxide (90 mg, 0.8 mmol) and the mixture was stirred at room temperature for 15 minutes. 2-[2-(l,3-dioxo-l,3-dihydro-isoindol- 2-yl)-ethoxy]-3-methyl-benzaldehyde (103 mg, 0.33 mol) was added and mixture stirred and held at reflux for 2 hours. Upon cooling the solvent was removed in vacuo and the residue dissolved in methanol (5 ml). 10% Palladium on carbon (70 mg) was added and the mixture stirred under a hydrogen atmosphere for 16 hours. The mixture was filtered and the methanolic solution was applied to an SCX cartridge. Elution with 2 M ammonia in methanol and evaporation of the solvent in vacuo afforded a colourless oil which was dissolved in ethanol (8 ml). Hydrazine hydrate (0.5 ml) was added and the mixture stirred and held at reflux for 2 hours. Upon cooling the solvent was removed in vacuo and the residues partitioned between dichloromethane and water. The organic layer was separated and reduced to dryness in vacuo to afford the product as a pale yellow oil (50 mg, 59%). 1H KMR (DMSOd6) 8.44 (2H, m), 7.28 (2H, m), 7.05 (2H, t), 6.93 (IH, t), 3.70 (2H, t), 2.88 (6H, m), 2.22 (3H, s).
EXAMPLE π-6
nPA Inhibitory Activity
Using the methods described in Example 77 of Part I of this specification, 4-(2-amino-ethoxy)-3,5- dichloro-benzoic acid was assayed and found to inhibit uPA with IC50 <40μM, indicating strong uPA inhibition.
The invention thus provides serine 190 Trypsin-like serine protease pharmacophores and compounds based thereon for inhibition of serine 190 Trypsin-like serine proteases and methods and uses based, thereon.
Claims
1. A compound for use as as an inhibitor of a serine 190 protease such as uPA, wherein the compound is of the formula I, or a solvate, salt, hydrate, N-oxide or ester thereof,
Formula I
wherein
R8 = -L-A, in which L is a linker as defined below,
A =
V is selected from
1. H;
2. Ci-2alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S- methyl;
3. ethenyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S- methyl;
4. ethynyl;
5. Ci-2alkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S-methyl;
6. nitro;
7. halo;
8. CN;
9. amino; 10. mono-Cr2alkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S-methyl;
11. di-Cr2alkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S-methyl;
12. hydroxyl; and 13. carboxy
W, X and Y are independently selected from
1. H;
2. Ci-6alkyl optionally substituted by Ra; 3. Cj-βalkenyl optionally substituted by Ra;
4. Ci-βalkynyl optionally substituted by Ra;
5. Ci-Cealkoxy optionally substituted by Ra;
6. nitro;
7. halo; 8. CN;
9. NR6R7, wherein R6 and R7 are each independently selected from Ra;
10. hydroxyl;
11. carboxy;
12. Ci-6alkyloxyCi-6alkyl; 13. carboxyCi-6alkyl optionally substituted by Ra;
14. carboxyamino;
15. NH(C=O)C1-6alkyl;
16. NH(C=O)OCi-6alkyl;
17. C3.6cycloall.yl optionally substituted by Ra; 18. Z-aryl or Z-heteroaryl, optionally substituted by Ra , wherein Z is selected from C1-4alkyl,
CH2NH, S, O, S(O), S(O2), S(O2)NH, NHS(O2), CH2NH, NHCH2, CH2O, OCH2, CH2CH2, NH(C=O), (C=O)NH and NH(C=O)NH, 0(C=O)NH, NH(C=O)O; and 19. aryl or heteroaryl, optionally substituted by Ra.
Rm, Rn, Rp, Rq are selected from 1. H;
2. Ci-2alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S- methyl;
3. propyl,
or Rm, Rn or Rp, Rq form a cyclopropane ring,
L is selected from
1) a covalent bond,
2) (CH2)m, 3) NRL,
4) NRMC(O)NRN,
5) NRMC(S)NRN,
6) C(S), V) C(O), 8) NRMC(S),
9) NRMC(O),
10) C(S)NRM, 11) C(O)NRM, 12) CH=CH, 13) C≡C,
14) O5
15) S(O),
16) C=C-C(CH2)nNRMC(O),
17) C=C-C(CH2)nNRMC(S), 18) C(S)NRM(CH2)nC≡C-C,
19) C(O)NRM(CH2)nC≡C-C,
20) (CH2)nNSO2,
21) NRMSO2(CH2)nC≡C,
22) C≡C-C(CH2)nNRMSO2NRN, 23) NRMSO2NRN(CH2)nC≡C,
24) SO2NRM,
25) NRMSO2,
26) NRMSO2NRN,
27) N=N, 28) C(S)N(ORM),
29) C(O)N(ORM),
30) N(ORM)C(S),
31) N(ORM)C(O),
32) HC=CH(CH2)nNRMC(S),
33) HC=CH(CH2)nNRMC(O), 34) (CH2)nNRMC(S)CH=CH,
35) (CH2)nNRMC(O)CH=CH,
36) CH=CH(CHz)nNSO2,
37) NRMSO2(CH2)nCH=CH,
38) (CH2)nNRMSO2NRN, 39) NRMSO2NRN(CH2)nCH=CH,
40) NRMC(O)O,
41) OC(O)NRM,
42) CH=NO,
43) ON=CH, 44) cycloakyl or heterocyclyl, optionally fused to A, e.g. via R1 or R5,
45) aryl or heteroaryl, optionally fused to A, e.g. via R1 or R5' and
in which W2 is selected from
1. O,
2. S,
3. NRL, and
4. (CH2)m,
RL is selected from
1. H,
2. an N-protecting group,
3. Ci-βalkyl, optionally substituted by Ra 4. C2-6alkenyl, optionally substituted by Ra ;
.5. C2-6alkynyl, optionally substituted by Ra
6. aryl, optionally substituted by Ra
7. arylalkyl, optionally substituted by Ra
8. C3-8cycloalkyl, optionally substituted by Ra ,and
9. C3-8cycloalkylCi-6alkyl, optionally substituted by Ra,
RM and RN are independently selected from
1. H, 2. Ci-6alkyl, optionally substituted by Ra
3. C2-6alkenyl, optionally substituted by Ra
4. C2-6alkynyl, optionally substituted by Ra
5. aryl, optionally substituted by Ra
6. arylalkyl, optionally substituted by Ra, 7. C3-8cycloalkyl, optionally substituted by Ra ,and
8. C3-8cycloalkylCi.6alkyl, optionally substituted by Ra
R1, R2, R3, R4 and R5 are independently selected from
1. H, halogen, CN, NH2, OH, COOH, CH2OH, SO2H; and
2. C1-6alkyl-Ra, C2-6alkenyl-Ra, C3-i2cycloalkyl-Ra, C5-i0aryl-Ra, C5-i4heteroaryl-Ra, C1- 6alkyloxy-Ra, OCi-6alkyl-Ra, OCi-6alkylC(O)OH, C3-i2cycloalkyloxy-Ra, OC3-i2cycloalkyl-
Ra, C5-i0aryloxy-Ra, OC5-i0aryl-Ra, CLgalkylCs-ioaryl-R8, CLsalkylCj-ioheteroaryl-R3, OC1- 6alkylC5-10lieteroaryl-Ra, OC1-6alkylC5-1oaryl-Ra , C5-14lieteroaryloxy-Ra, OC5-i4heteroaryl- Ra, C5-1olieterocyclyl-Ra, Ci-6alkylC5-10lieterocyclyl-Ra, C(=O)C1-6alkyl-Ra, C(=O)OCi. 6alkyl-Ra, C(=O)NH2, C(=O)NHCi-6alkyl-Ra, C(=O)N(C1-6alkyl-Ra)2, S(=O)C1-6alkyl-Ra, S(=O)NHCi-6alkyl-Ra, S(=O)N(Ci-5alkyl-Ra)2, SO2Ci-6alkyl-Ra, SO2NHC1-6alkyl-Ra,
SO2N(C1-6alkyl-Ra)2, NH(C1-6alkyl)-Ra, N(Ci-6alkyl-Ra)2; NHC(=O)C1-6alkyl, C5-6aryl-Ra, OC5-6aryl-Ra, C(=O)C5.6aryl-Ra, C(=O)OC5-6aryl-Ra, C(=O)NHC5-6aryl-Ra, C(=O)N(C5- 6aryl-Ra)2, S(=O)C5-6aryl-Ra, S(=O)NHC5:6aryl-Ra, S(=O)N(C5-6aryl-Ra)2, SO2C5-6aryl-Ra, SO2NHC5-6aryl-Ra, SO2N(C5-6aryl-Ra)2 NH(C5-6aryl)-Ra, N(C5-6aryl)2-Ra, NC(=O)C5-6aryl, C5-6heterocyclyl-Ra, OCs^heterocyclyl-R3, C(=O)C5-6heterocyclyl-Ra, C(=O)OC5- 6heterocyclyl-Ra, C(=0)NHC5-6lieterocyclyl-Ra, C(=O)N(C5-6heterocyclyl-Ra)2, S(=O)C5- 6heterocyclyl-Ra, S(=O)NHC5.6heterocyclyl-Ra, S(=O)N(C5-6lieterocyclyl-Ra)2, SO2C5- βheterocyclyl-R3, SO2NHC5-6heterocyclyl-Ra, SO2N(C5.6heterocyclyl-Ra)2, NH(C5- 6heterocyclyl)-Ra, N(C5-6heterocyclyl-Ra)2, NC(=O)C5-6heterocyclyl, SO2R3, S(=O)Ra, N(C1-6all<yl-Ra)(C1-6aryl-Ra), N(Ci-6alkyl-Ra)(C1-6heteroaryl-Ra),
6heteroaryl-Ra), C(=O)(C1-6alkyl-Ra)(C1-6aryl-Ra), C(==O)(Ci-6alkyl-Ra)(C1.6lieteroaryl-Ra),
C(=O)(C1-6aryl-Ra)(C1-6heteroaryl-Ra), C(=O)O(C1-6alkyl-Ra)(Ci-6aryl-Ra), CC=O)O(C1- 6alkyl-Ra)(Ci-6lieteroaryl-Ra), C(=O)O(C1.6aryl-Ra)(C1.6heteroaryl-Ra),
Ra)(Ci-6aryl-Ra), S(=O)(C1-6alkyl-Ra)(Ci-6heteroaryl-Ra), S(=O)(C1-6aryl-Ra)(C1- 6heteroaryl-Ra), SO2(C1-6alkyl-Ra)(C1-6aryl-Ra), SO2(Ci-6alkyl-Ra)(C1-6heteroaryl-Ra), SO2C5-6heterocyclyl-Ra) and SO2(C1.6aryl-Ra)(C1-6heteroaryl-Ra),
or two or more of R1, R2, R3, R4 and R5 together with the ring to which they are attached form part of a fused bicyclic or tricyclic ring system in which the first ring is a benzene ring, optionally substituted as defined herein, and the second and, if present, third rings are independently selected from aryl, heteroaryl and saturated or unsaturated carbocyclic and heterocyclic rings, optionally substituted by Ra,
each of the one or more Ra substituents, when present, is independently from
H, halogen, nitro, amino, CN, hydroxyl, CH2OH, carboxy,
trifluoromethyl, C3.. ecycloalkyl, d-6alkenyl, Ci-6alkynyl, C(=O)C1-6aliyl, C5-i0aryl, OCi.6alkylRb, OC1-
6alkylC(=O)ORb, C(=O)OCi-6alkyl, C(=0)NH2, C(=O)NHCi-6alkyl, C(=O)N(Ci-6alkyl)2, SQ- 6alkyl5 SOCi-6alkyl, SONHCi-6alkyl, SON(Ci-6alkyl)2, SO2Ci-6alkyl, SO2NHCi-6alkyl, SO2N(C1- 6alkyl)2, NH(Ci-6alkyl), N(C1-6alkyl)2, NC(=O)Ci.6alkyl, Cs-βarylOCs-earyl, Ci-6alkoxyC5-6aryl, C(=O)C5-6aryl, C(=O)OC5-6aryl, C(=O)NH2, C(=O)NHC5-6aryl, C(=O)N(C5-6aryl)2, SO2C5-6aryl, SO2NHC5-6aryl, SO2N(C5-6aryl)2, NH(C5-6aryl), N(C5-6aryl)2, NC(=O)C5-6aryl, C5-6heterocyclyl, OCs-eheterocyclyl, C(=O)C5-6heterocyclyl, C(=O)OC5-6heterocyclyl, C(=0)NH2, C(=0)NHC5- eheterocyclyl, C(=O)N(C5-6heterocyclyl)2, S(=O)C5-6heterocyclyl, S(=O)NHC5-6heterocyclyl, S(=O)N(C5-6heterocyclyl)2> S02NHC5-6heterocyclyl, SO2N(C5.6heterocyclyl)2, NH(C5- 6heterocyclyl), N(C5-6heterocyclyl)2, NC(=O)C5-6heterocyclyl, C(=O)NHC1-6alkylC5-6aryl, NR1H0, C(=0)Rb, C(=0)NRbRc, C02NRbR°, S(=O)Rb, S(=O)NRbR° , S(O)2OH, S(O)2Ci-6alkyl and SO2NRbR°,
and
Rb and Rc are each independently selected from H, Ci.6alkyl, Ci-βalkyl, C3-6cycloalkyl, C5-6aryl, or Cs-βheterocyclyl.
Formula I0 or a salt, solvate, hydrate, N-oxide or ester thereof; wherein Rm, Rn, Rp, Rq, V, W, X, Y, R1, R2, R3, R4 and R5 are as defined in claim 1.
3. A compound per se having the formula I or I0 as defined in claim 1 but excluding (a-i) 4-(2- ammoethoxy)-N-[4-methyl-3-[[4-(3-pyridmyl)-2-pyrirnidmyl]ammo]phenyl-benza^ and salts thereof; (a-ii) N-[[4-[[4-(2-aminoethoxy)benzoyl]amino]phenyl]sulphonyl]-N-(2-methylpropyl)- glycine and salts thereof; and (a-iii) 4-[[4-(2-arninoethoxy)benzoyl]arnino]-benzenepropanoic acid and salts and N-protected forms thereof.
4. A compound according to any one of claims 1 to 3 , wherein V is selected from
1. Cj-Caalkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S- methyl;
2. ethenyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S- methyl;
3. ethynyl;
4. Ci-C2alkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S-methyl;
5. halo;
6. amino;
7. mono-CrCaalkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S-methyl; 8. hydroxyl; and
9. carboxy
5. A compound, according to Claim 4, wherein V is selected from
1. Ci-C2alkyl optionally substituted by fluoro,
2. CrC2alkoxy optionally substituted by fluoro, and
3. halo.
6. A compound according to Claim 5, wherein V is selected from Me, CH2F, CHF2, CF3, and Cl.
7. A compound according to any of claims 1 to 6, wherein W is selected from
1. Ci-6alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
2. Crβalkenyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
3. Ci-Cβalkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl; 4. halo;
5. amino;
6. mono-Ci-6alkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
7. di-Ci-6alkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
8. hydroxyl;
9. carboxy;
10. C1-6alkyloxyCi-6alkyl;
11. carboxyCi.galkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
12. carboxyamino;
13. NH(C=O)C1-6alkyl;
14. NH(C=O)OC1-6alkyl;
15. Z-aryl or Z-heteroaryl, wherein Z is selected from CH2NH, S, O, S(O), S(O2), S(O2)NH, NHS(O2), CH2NH, NHCH2, CH2O, OCH2, CH2CH2, NH(C=O), (C=O)NH and
NH(C=O)NH, 0(C=O)NH, NH(C=O)O, optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl , S-methyl, Chalky!, C^alkoxy and Ra ;
8. A compound according to claim 7, wherein W is selected from 1. Ci-6alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
2. Ci-C6alkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
3. halo;
4. mono-Ci-6alkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
5. di-Ci-βalkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
6. Ci-6alkyloxyC1-6alkyl;
7. carboxyCi-6alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
8. NH(C=O)Ci-6alkyl;
9. NH(C=O)OC1-6alkyl;
9. A compound according to claim 8, wherein W is selected from 1. C1-4alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
2. Ci-C4alkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
3. halo; 4. mono-Ci.4alkyl amino optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
5. Ci-3alkyloxyC1-3alkyl;
10. A compound according to claim 9, wherein W is selected from 1. Ci-C2alkyl optionally substituted by halo, 2. Ci -C2alkoxy optionally substituted by halo,
3. NHC(O)OH, and
4. halo.
11. A compound according to any of claims 1 to 10, wherein X and Y are selected from 1. H;
2. Ci-6alkyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl;
3. Ci-6alkoxy optionally substituted by amino, halo, hydroxy, nitro, carboxy, trifluoromethyl, cyano, sulphydryl or S-methyl; 4. halo.
12. A compound according to any of claims 1 to 11 , wherein Rm, Rn, Rp and Rq are
1. H, or
2. methyl optionally substituted by amino, halo, hydroxy, nitro, carboxy, sulphydryl or S- methyl
13. A compound according to any of claims 1 to 12, wherein Rp and Rqare H.
14. A compound according to any of claims 1 to 13, wherein Rm and Rn are methyl or H.
15. A compound according to any previous claim, wherein R1, R2, R3, R4 and R5 are independently selected from
1. H,
2. halogen, and 3. a. Ci-6alkyl, b. C2-6alkenyl, c. C3-i2cycloalkyl, d. C5-iOaryl,
f. C1-6alkyloxy, g. Cs-^cycloalkyloxy, h. C5-i0aryloxy, i. C5-i4heteroaryloxy, j. Cwalkyl-Cs-ioaryl, k. C5-i0arylC1-6alkyloxy. 1. Cs-ioheterocyclyl, wherein each of 3a-l are optionally substituted by halogen, CN, NH2, OH, COOH, d-6alkoxy, Q- 6alkyl, CH2OH, SO2H and S(=O).
16. A compound according to any previous claim, wherein two or more of R1, R , R3, R and R together with the ring to which they are attached form part of a ring to create a bicyclic aryl or heteroaryl ring system, optionally substituted by Ra.
17. A compound according to any previous claim, wherein two or more of R1, R , R3, R and R together with the ring to which they are attached form part of a ring to create an bicyclic ring system in which the second ring is not aromatic, optionally substituted by Ra.
18. A compound according to any previous claim, wherein two or more of R , R , R , R and R together with the ring to which they are attached can also form part of a ring to create a tricyclic ring system, optionally substituted by Ra.
19. A compound according to any previous claim, wherein Ra is selected from
H, C(=O)Ci-6alkyl, C(=O)OC1-6alkyl, C(=O)NH2, C(=O)NHC1-6alkyl, C(=O)N(Ci-6alkyl)2, NH(Ci- 6alkyl), N(C1-6alkyl)2, NC(=O)C1-6alkyl, C^aryl, OC5-6aryl, C(=O)C5-6aryl, C(=O)OC5-6aryl,
C(=O)NH2, C(=O)NHC5-6aryl, C(=O)N(C5.6aryl)2, NH(C5-6aryl), N(C5-6aryl)2, NC(=O)C5-6aryl, C5-
6heterocyclyl, OC5-6heterocyclyl, C(=O)C5-6heterocyclyl, C(=O)OC5-6heterocyclyl, C(=O)NH2,
C(=O)NHC5-6heterocyclyl, C(=O)N(C5-6heterocyclyl)2, NH(C5-6heterocyclyl), N(C5-6heterocyclyl)2,
NC(=O)C5-6heterocyclyl, C(=O)NHC1-6alkylC5-6aryl, NRbRc, C(=O)Rb, C(=O)NRbR°, CO2NR13R0, S(=O)Rb, S(=O)NRbR° and SO2NRbRc;
20. A compound according to any previous claim, wherein Rb and R° are H.
21. A compound according to any previous claim, wherein R1, R2, R3, R4 and R5 are independently selected from
1. H,
2. halogen, and 3. a. C1-6alkyl, b. C2-6alkenyl, c. C3-12cycloalkyl,
e. C5-i4heteroaryl f. Ci-6alkyloxy, g. C3-12CyClOaIlCyIoXy, h. C5-i0aryloxy,
i. C5-14heteroaryloxy j. Ci-SaUCyI-C5-IOaTyI, k. C5-10arylC1-6alkyloxy. 1. Cs-ioheterocyclyl, wherein each of 3a-l are optionally substituted by halogen, CN, NH2, OH, COOH, Ci-6alkoxy, C1. 6alkyl, CH2OH, SO2H, S(=0), d.6alkyl-Ra, OC1-6alkyl-Ra, C(=O)Ci-6alkyl-Ra, C(=O)OCi-6alkyl- Ra,
6alkyl-Ra, S(=O)N(C1-6alkyl-Ra)2, SO2C1-6alkyl-Ra, SO2NHCi-6alkyl-Ra, SO2N(C1-6alkyl-Ra)2, NH(C1-6alkyl)-Ra, N(C1-6alkyl-Ra)2, NHC(=O)C1-6alkyl, C5-6aryl-Ra, OC5-6aryl-Ra, C(=O)C5-6aryl- Ra, C(=O)OC5-6aryl-Ra, C(=O)NHC5-6aryl-Ra, C(=O)N(C5-6aryl-Ra)2, S(=O)C5-6aryl-Ra, S(=O)NHC5-6aryl-Ra, S(=O)N(C5-6aryl-Ra)2, SO2C5-6aryl-Ra, SO2NHC5-6aryl-Ra, SO2N(C5-6aryl- Ra)2 NH(C5.6aryl)-Ra, N(C5-6aryl)2-Ra, NC(=O)C5-6aryl, Cj-eheterocyclyl-R", OC5-6heterocyclyl-Ra, C(=O)C5-6heterocyclyl-Ra, C(=O)OC5-6heterocyclyl-Ra, C(=O)NHC5-6heterocyclyl-Ra, C(=O)N(C5- 6heterocyclyl-Ra)2, S(=O)C5-6heterocyclyl-Ra, S(=O)NHC5-6heterocyGlyl-Ra, , S(=O)N(C5- 6heterocyclyl-Ra)2, S02C5-6heterocyclyl-Ra, SO2NHC5-6heterocyclyl-Ra, SO2N(C5-6heterocyclyl- Ra)2, NH(C5-6heterocyclyl)-Ra, N(C5-6heterocyGlyl-Ra)2, NC(=O)C5-6heterocyclyl, SO2Ra, S(=O)Ra, N(C1-6alkyl-Ra)(Ci-6aryl-Ra), N(Ci-6alkyl-Ra)(Ci-6heteroaryl-Ra), N(C1-6aryl-Ra)(Ci-6heteroaryl-Ra), C(=O)(Ci-6alkyl-Ra)(C1-6aryl-Ra), C(=O)(C1-6alkyl-Ra)(C1-6heteroaryl-Ra),
6heteroaryl-Ra), C(=O)O(C1-6alkyl-Ra)(Ci-6aryl-Ra), C(=O)O(Ci-6alkyl-Ra)(C1-6heteroaryl-Ra), C(=O)O(C1-6aryl-Ra)(Ci-6heteroaryl-Ra), S(=O)(C1-6alkyl-Ra)(C1-6aryl-Ra), S(=O)(C1-6alkyl-Ra)(C1- gheteroaryl-R3), S(=O)(C1-6aryl-Ra)(Ci-6heteroaryl-Ra), SO2(Ci-6alkyl-Ra)(Ci-6aryl-Ra), SO2(C1- 6alkyl-Ra)(C1-6heteroaryl-Ra) and SO2(C1-6aryl-Ra)(C1-6heteroaryl-Ra).
22. A compound according to any previous claim, wherein L is not C(O)NH.
23. A compound according to any previous claim, wherein L is selected from:
1. (P)c-(Q)d-(R)e-(S)f,
2. Ci-6alkyl, optionally substituted by Ra,
3. C2-6alkenyl, optionally substituted by Ra, 4. Ci-6alkoxy, optionally substituted by Ra,
5. aryl, optionally substituted by Ra, and
6. cycloalkyl, optionally substituted by Ra, wherein
P and R are independently selected from NH, O, S, C(O), C(O)NH, NHC(O) and S(O)2,
Q and S are independently selected from CH2, CHR6 and CR6R7, wherein R6 and R7 are independently selected from H, halo, amino, hydroxy, methyl, methyl substituted by halo and sulphydryl, d is 0 to 6, fis O to β, c is 0 or 1, and e is O or 1, provided that not all of c, d, e and f are 0 and that d + e < 6.
24. A compound according to claim 22, wherein c + d+ e + f= l, 2 or 3
25. A method of inhibiting a serine protease, comprising contacting said serine protease with an effective amount of a compound as defined in any of claims 1 to 24.
26. A method of treatment or prophylaxis of a disease responsive to an inhibitor of a serine protease or of providing a therapy achievable by inhibition of serine protease, comprising administering to a patient an effective amount of a compound as defined in any of claims 1 to 24.
27. A method of treatment or prophylaxis of a disease responsive to an inhibitor of a serine protease selected from tumour growth, cancer, angiogenesis, angiogenesis-based retinopathies, arthritis, multiple sclerosis and inflammation, comprising administering to a patient an effective amount of a compound as defined in any of claims 1 to 24.
28. A method according to any of claims 25 to 27, wherein the disease is responsive to a serine protease other than uPA.
29. A method according to any of claims 25 to 27, for treatment or prophylaxis of a disease by inhibtion of a serine protease other than uPA.
30. A pharmaceutical composition comprising a compound of formula I as defined in any of claims 1 to 24 for use in treatment or prophylaxis of a disease responsive to a serine protease inhibitor.
31. A pharmaceutical composition according to claim 30, wherein the serine protease is selected from trypsin, tryptase, chymotrypsin, elastase, thrombin, plasmin, kallikrein, Complement Cl, acrosomal protease, lysosomal protease, cocoonase, α-lytic protease, protease A, protease B, serine carboxypeptidase π, subtilisin, urokinase (uPA), Factor Vila, Factor Ka, and Factor Xa.
32. A pharmaceutical composition according to claim 30, wherein L is not C(O)NH.
33. Use of a compound of formula I according to any of claims 1 to 24, in inhibiting a serine protease.
34. Use of a compound of formula I according to any of claims 1 to 24, for manufacture of a compound for inhibiting a serine protease.
35. Use of a compound of formula I according to any of claims 1 to 24, for manufacture of a compound for use in medicine.
36. A compound capable of binding to a serine 190 Trypsin-like serine protease and comprising a pharmacophore of Formula A:
A
Formula A wherein
V is selected from methyl, chlorine, bromine or a similar lipophilic group or is defined according to formulas 2b, 3b and 4b herein and below,
W is selected from methyl, chlorine, bromine or a similar lipophilic group or can be a heteroatom, such as N, S or O; for example an amino group; or is defined according to formulas 2b, 3b and 4b herein and below, Ci, C2 and C3 form part of an aromatic ring,
Rm is selected from
1. H;
2. Me or forms a cyclopropane ring with its adjacent carbon, or is defined according to formulas 2b, 3b and 4b herein and below.
37. A compound capable of binding to a serine 190 Trypsin-like serine protease and comprising a pharmacophore of Formula 1-X:
Formula 1-X
Where V is selected from methyl, chlorine, bromine or a similar lipophilic group or are defined according to formulas 2b, 3b and 4b herein and below,
W is selected from methyl, chlorine, bromine or a similar lipophilic group or can be a heteroatom, such as N, S or O; for example an amino group; or are defined according to formulas 2b, 3b and 4b herein and below, X, Y and T are defined according to formulas 2b, 3b and 4b herein and below,
Rm, Rn, Rp and Rq are selected from
1. H;
2. Me or Rm and Rn, Rp and Rq , or Rm and Rq form a cyclopropane ring, or are defined according to formulas 2b, 3b and 4b herein and below.
38. The compound of claim 37, wherein V is selected from methyl, chlorine and bromine or is a small lipophilic group.
39. The compound of claim 37, wherein W is selected from methyl, chlorine and bromine or is a similar lipophilic group or a heteroatom, such as N, S or O.
40. The compound of claim 36, wherein Rm is H.
41. The compound of claim 37, wherein Rm, Rn, Rp and Rq are H.
42. A method of identifying compounds which are modulators of a serine 190 Trypsin-like serine protease, the method comprising: (a) designing and/or selecting a candidate modulator containing the pharmacophore represented by Formula 1 -X:
(b) contacting a serine protease with the candidate modulator to be tested under conditions such that the candidate modulator can interact with the serine protease;
(c) detecting the binding and/or modulation of the candidate modulator to and/or of the serine protease; and
(d) identifying compound(s) which are capable of binding or modulating the serine protease.
43. The method of claim 42, wherein V is selected from methyl, chlorine and bromine.
44. The method of claim 42, wherein W is selected from methyl, chlorine and bromine or is a similar lipophilic group or a heteroatom, such as N, S or O.
45. The method of claim 42, wherein Rm, Rn, Rp and Rq are H.
46. The method of claim 42, comprising identifying a compound which is an inhibitor of a serine protease.
47. The method of claim 42, wherein said serine protease is selected from tryptase, plasmin, urokinase (uPA), Factor Vila, and Factor DCa.
48. The method of claim 42, wherein said compound contains an amino group with a pKa of <9.5 and >7.
49. The method of claim 42, wherein the compound binds to the Sl pocket of a serine 190 Trypsin- like serine protease.
50. The method of claim 43, wherein said compound further interacts with a binding pocket adjacent the active site of the serine protease.
51. The method of claim 49, wherein said binding pocket is one or more of S lbeta, S2, S4 and S 1 ' binding pocket(s).
52. The method of claim 49, wherein said binding pocket(s) comprise one or more of the amino acids as set out in Table 2 for uPA, or one or more corresponding amino acids of a further serine protease.
53. The method of claim 49, wherein the binding pocket comprises amino acids Aspl91, Serl92, Gly220, Val215, Tyr230 and Gly228.
54. The method of claim 49, wherein the binding pocket comprises amino acids Cys221, Cysl93, Glnl94, Gly220, Serl44 and Lysl41.
55. The method of claim 49, wherein the binding pocket comprises amino acids His93, His45, Ala88, Tyr86, ϋe48, Asp49 and Ser216.
56. The method of claim 49, wherein the binding pocket comprises amino acids Trp217, Gly218, Arg219, Gly220, Leu91 and Thr90.
57. The method of claim 49, wherein the binding pocket comprises amino acids Glyl95, Asp 196, Serl 97, Val29, Cys30 and Cys46.
58. A compound identified according to the method of claim 42.
59. A pharmaceutical composition comprising the compound of claim 58.
60. A method of identifying compounds which are modulators of a serine 190 Trypsin-like serine protease, the method comprising:
(a) designing and/or selecting a candidate modulator containing the pharmacophore represented by Formula 2b, 3b or 4b, wherein
V is selected from methyl, chlorine and bromine or is a similar lipophilic group or is defined according to formulas 2b, 3b and 4b below,
W is selected from methyl, chlorine and bromine or is a similar lipophilic group or a heteroatom, such as N, S or O; for example an amino group; or is defined according to formulas 2b, 3b and 4b below,
X, Y and T are defined according to formulas 2b, 3b and 4b below, Rm, Rn, Rp and Rq are selected from
1. H;
2. Me or Rm and Rn, Rp and Rq , or Rm and Rq form a cyclopropane ring, or are defined according to formulas 2b, 3b and 4b below,
wherein for compounds of formula 2b, R1, R2 and R3 are as defined in US 6495562,
wherein for compounds of formula 3b, z and Z4 are as defined in US 6284796, C is W as defined above, B is Y as defined above, A is T as defined above, and optionally B and A form a ring, with 3-12 ring members, the ring being optionally aryl, heteroaryl, cycloalkyl or heterocycloalkyl and, further, optionally substituted,
wherein for compounds of formula 4b, R13, X1, X4, R, R1, R2 and R3 are as defined in WO 2004050637,
(b) contacting a serine protease with a compound to be tested under conditions such that the compound can interact with the serine protease;
(c) detecting the binding and/or modulation of the compound to the serine protease; and (d) identifying compound(s) which are capable of binding or modulating the serine protease.
61. A compound identified by the method of claim 60 which inhibits a serine 190 Trypsin-like serine protease.
62. A pharmaceutical composition containing the compound of claim 60.
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