EP1015454A1 - Procede d'inhibition d'enzymes serine proteases - Google Patents

Procede d'inhibition d'enzymes serine proteases

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Publication number
EP1015454A1
EP1015454A1 EP98948907A EP98948907A EP1015454A1 EP 1015454 A1 EP1015454 A1 EP 1015454A1 EP 98948907 A EP98948907 A EP 98948907A EP 98948907 A EP98948907 A EP 98948907A EP 1015454 A1 EP1015454 A1 EP 1015454A1
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EP
European Patent Office
Prior art keywords
inhibitor
enzyme
compound
alkyl
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP98948907A
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German (de)
English (en)
Inventor
Alan David Glaxo Wellcome plc BORTHWICK
Steven John Glaxo Wellcome plc COOTE
Michael Dennis Glaxo Wellcome plc DOWLE
Anne Marjorie Glaxo Wellcome plc EXALL
Harry Glaxo Wellcome Plc Finch
Michael Menteith Glaxo Wellcome plc HANN
Henry Anderson Glaxo Wellcome plc KELLY
Simon John Fawcett Glaxo Wellcome plc MACDONALD
Andrew McMurtrie Glaxo Wellcome plc MASON
Neil Anthony Glaxo Wellcome plc PEGG
Andrew Michael Kenneth Pennell
Nigel Grahame Glaxo Wellcome plc RAMSDEN
Nigel Stephen Glaxo Wellcome plc WATSON
Gordon Gad Glaxo Wellcome plc WEINGARTEN
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Glaxo Group Ltd
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Glaxo Group Ltd
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Publication of EP1015454A1 publication Critical patent/EP1015454A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical

Definitions

  • This invention relates to a new class of chemical compounds and their use as inhibitors of serine protease enzymes. These compounds are useful as pharmaceuticals and we provide processes for preparing them and formulations containing them.
  • Serine proteases are a class of proteolytic enzymes characterised by having at the active site a serine residue which interacts with the carbonyl carbon of a peptide bond to cleave the peptide bond via an acyl enzyme intermediate.
  • the active site serine is generally numbered Ser-195.
  • Most members of the family of serine proteases have a histidine and an aspartic acid residue in the active site (numbered His-57 and Asp-102 based on chymotrypsin) which activate the serine hydroxyl group to attack the scissile peptide carbonyl.
  • the mechanism of hydrolysis of peptide bonds by serine proteases is believed to be similar for all enzymes in the family, it is well known that their substrate specificities differ dramatically.
  • specificity is shown for peptide bonds which have a particular moiety ⁇ to the scissile peptide carbonyl which in conventional nomenclature is said to be in the P- t position and to occupy the S ⁇ specificity subsite (see Schlecter and Berger (1967) Biochem Biophys Res Common 27 157).
  • the preferred substrate for thrombin is a peptide containing a basic residue (e.g. arginine i.e.
  • Serine proteases are widespread in the human body and abnormal or excessive activity of serine proteases is implicated in a diverse range of diseases and conditions (see “Proteinase Inhibitors", Barrett and Salveson (1986), Elsevier, p56; Drugs Future (1996), 21(8), 811-816; Exp. Opin. Ther. Patents (1997) 7(1) 17-28).
  • Neutrophil elastase is found in neutrophil azurophilic granules associated with tissue inflammation and is associated with a number of inflammatory diseases including emphysema, chronic bronchitis and adult respiratory distress syndrome (ARDS).
  • ARDS adult respiratory distress syndrome
  • thrombin Members of the blood coagulation cascade (e.g. thrombin, Factor Vila, Factor Xa, Factor Xla, Factor Xlla) and members of the fibrinolytic cascade (e.g. tissue plasminogen activator and plasmin) are potential targets for treatment of diseases of the vascular system.
  • thrombin is a potential target for the treatment of thrombosis.
  • Tissue plasminogen activator and plasmin may also be implicated in tumour metastasis.
  • Tryptase is present in mast cells and inhibitors of tryptase have shown efficacy in models of asthma.
  • Pancreatic elastase, trypsin and chymotrypsin are associated with digestive disorders such as pancreatitis.
  • Cathepsin G is associated with emphysema.
  • Serine proteases are also widespread in human pathogens especially viruses and these provide an attractive target for the treatment of pathogenic diseases and conditions.
  • Herpes viruses encode a serine protease which is crucial for viral replication and is therefore a target for the treatment of conditions caused by these viruses.
  • Herpes family of viruses is responsible for a wide range of human infectious diseases including chicken pox and shingles (varicella and Herpes zoster viruses, respectively), cold sores and genital herpes (herpes simplex virus), retinitis, pneumonitis and keratitis (human cytomegalovirus, hCMV), as well as diseases caused by Epstein Barr Virus (EBV), human herpes virus 6 (HHV 6),
  • EBV Epstein Barr Virus
  • HHV 6 human herpes virus 6
  • Hepatitis C virus also encodes a serine protease (known as the NS3 serine protease) which is a target for treatment of Hepatitis C virus infection and associated hepatic damage.
  • NS3 serine protease a serine protease
  • inhibitors of serine protease enzymes which are substituted derivatives of trans- hexahydropyrrolo[3,2-b]pyrrol-2-one (save that we exclude the compounds of formula IA and IB as defined in Annex 1).
  • this invention relates to inhibitors of serine protease enzymes which are compounds of formula I:
  • R 1 is a moiety adapted to fit in the S specificity subsite of the enzyme
  • R 2 is a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and enzyme kinetic properties of the inhibitor
  • R 3 is a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and physicochemical properties of the inhibitor
  • physiologically acceptable salts and solvates thereof save that we exclude compounds of formula IA and IB (as defined in Annex 1).
  • translactam template of formula I is highly complementary to the active site of serine proteases and the lactam carbonyl mimics the peptide carbonyl of the enzyme's natural substrate.
  • Inhibition of serine proteases by compounds of the invention has been found to be either competitive (reversible) or time-dependent (acylating) depending on the precise enzyme and particular substitution pattern on the translactam template.
  • Time-dependent (acylating) inhibition is believed to occur when attack of the enzyme active site serine on the translactam carbonyl causes opening of the strained lactam ring generating an enzyme acylated at the serine sidechain.
  • the advantages of our invention reside inter alia in that (a) the trans- hexahydropyrrolo[3,2-b]pyrrol-2-one template is completely new and therefore highly desirable in a medicament especially for the treatment of pathogenic conditions which are prone to drug resistance, (b) the trans- hexahydropyrrolo[3,2-b]pyrrol-2-one template may be highly functionalised and is therefore ideal for the specific and selective inhibition of a wide range of different enzymes, (c) the trans-hexahydropyrrolo[3,2-b]pyrrol-2-one template may potentially be functionalised to give (i) high or low metabolic stability and (ii) competitive or time-dependent inhibition as desired.
  • the determination of the optimum substitution of the derivatives of trans- hexahydropyrrolo[3,2-b]pyrrol-2-one, especially regarding selection of groups R 1 , R 2 and R 3 for a particular serine protease enzyme can be made in a conventional manner, namely: (a) by preparation of a number of compounds having sufficient diversity especially in groups R 1 , R 2 and R 3 , (b) treatment of a sample of the enzyme in question with a sample of each of the compounds so prepared and (c) determining the extent to which inhibition of the enzyme has occurred.
  • Suitable R 1 groups will fit appropriately in the S ! specificity subsite of the target enzyme.
  • Choice of group R 1 may be made having regard to the known substrate specificity preferences of the target enzyme, crystallographic information concerning the geometry of the S 1 specificity subsite of the target enzyme and/or empirical determination based on screening data (see for example "Proteinase Inhibitors” Barrett and Salveson (1986), Elsevier, p9 and p59).
  • the group R 1 is preferably small and hydrophobic, e.g. C 2-4 alkyl or C 2-4 alkenyl, especially propyl or isopropyl, particularly isopropyl.
  • the group R 1 is preferably large and hydrophobic, e.g. (CH 2 ) 1-2 Ph, (CH 2 ) 0-2 cyclohexyl, t-butyl.
  • Ph represents phenyl or substituted phenyl (e.g. phenyl substituted by C 1-6 alkyl, halogen).
  • Planar aromatic sidechains e.g. benzyl are especially preferred.
  • group R 1 is preferably methyl.
  • R 2 will be a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and enzyme kinetic properties of the serine protease inhibitor.
  • R 2 will be lactam activating moiety.
  • Suitable activating groups include electron withdrawing groups which may typically (but not exclusively) comprise a SO 2 or CO moiety attached to the lactam nitrogen.
  • R 2 may represent CHO or SO 2 C 1-6 alkyl and is preferably a group -SO 2 Me.
  • R 2 is preferably a group CONH(CH 2 ) 1-4 Ph, SO 2 (CH 2 ) 0-1 Ph, -COOC 1-4 alkyl (e.g. -COOMe), CONH 2 or -CONHC 1-4 alkyl (e.g. -CONHMe). These may also be the preferred R 2 for other trypsin-like enzymes.
  • R 2 is preferably -COC 1-6 alkyl (e.g - CO-cyclopropyl).
  • an electron wwiitthhddrraawwiiing heteroaryl group e.g. 2- benzothiazolyl
  • R 2 may also be preferred.
  • R 2 comprises an SO 2 moiety attached to the lactam nitrogen
  • the inhibitor is generally time-dependent (acylating).
  • R 2 comprises a CO moiety attached to the lactam nitrogen
  • the inhibitor may be time-dependent (acylating) or not depending on the exact nature of R 2 .
  • R 2 represents COOC 1-4 alkyl it is more likely to be time-dependent (acylating) than when R 2 represents
  • R 3 will be a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and physicochemical properties of the serine protease inhibitor. It may also be adapted to optimise other pharmacological properties such as water solubility and oral activity (if desired).
  • R 3 can vary quite widely and a person skilled in the art would be able to determine from suitable testing if a given R 3 is suitable for the aforementioned purposes or not.
  • R 3 comprises a CO, SO 2 or CO.O (especially a CO or SO 2 ) moiety attached directly to the pyrrolidine nitrogen and is, for example, a group of formula R 30 CO, R 30 SO 2 or R 30 OCO (especially R 30 CO or R 30 SO 2 ).
  • R 30 will also be a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and physicochemical properties of the serine protease inhibitor and may represent, for example, alkyl (e.g. C 1-8 alkyl), alkenyl (e.g. C 1-8 alkenyl), aryl, alkylaryl (e.g. C 1-8 alkyiaryl), or alkenylaryl (e.g. C-,_ 8 alkenylaryl).
  • alkyl e.g. C 1-8 alkyl
  • alkenyl e.g. C 1-8 alkenyl
  • aryl e.g. C 1-8 alkyiaryl
  • alkenylaryl e.g. C-,_ 8 alkenylaryl
  • alkyl includes branched and cyclic alkyl.
  • Alkenyl includes branched and cyclic alkenyl.
  • Aryl includes mono and bicyclic aromatic rings optionally containing heteroatoms, e.g. O, N and S atoms (for example 1 to 4 heteroatoms) and biaryl.
  • Alkyl, alkenyl, aryl, alkylaryl and alkenylaryl groups may be optionally substituted, e.g. by amine and halogen and optionally interrupted by a heteroatom (e.g. nitrogen or oxygen) or otherwise functionalised.
  • a heteroatom e.g. nitrogen or oxygen
  • Amine groups include primary, secondary and tertiary amine groups including cyclic amine.
  • the extent to which inhibition has occurred may be determined by conventional assay techniques including (but not limited to) chromogenic assays, fluorogenic assays, HPLC and scintillation proximity assays.
  • a library comprising a plurality of substituted derivatives of trans-hexahydropyrrolo[3,2-b]pyrrolo-2- one will be prepared.
  • the library will comprise a plurality of compounds of formula I
  • R 1 is a moiety adapted to fit in the S 1 specificity subsite of the enzyme
  • R 2 is a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and enzyme kinetic properties of the inhibitor
  • R 3 is a moiety adapted to optimise the potency, pharmacokinetics, pharmacodynamics, selectivity and physicochemical properties of the inhibitor; and physiologically acceptable salts and solvates thereof.
  • the library will, ideally comprise at least 10 (e.g. 10, 100, 1000 or more) different compounds.
  • a library of compounds of formula I wherein R 1 represents a small and hydrophobic group e.g. C 2-4 alkyl or C -4 alkenyl, especially propyl or isopropyl, particularly isopropyl may be particularly useful for screening for an inhibitor of elastase-like enzymes e.g. neutrophil elastase.
  • a library of compounds of formula I wherein R 1 represents methyl may be especially useful for screening for an inhibitor of Herpes virus proteases.
  • a trypsin-like enzyme e.g. thrombin or tryptase
  • a library of compounds of formula I wherein R 1 represents a large and hydrophobic group e.g. (CH 2 ) 1-2 Ph, (CH 2 ) 0-2 cyclohexyl or t-butyl may be useful for screening for an inhibitor of a chymotrypsin-like enzyme e.g. chymotrypsin or cathepsin G.
  • Library technology will be known to a person skilled in the art and is reviewed in Drug Discovery Today (1996) 1(4) 134-144 and Annual Reports in Combinatorial Chemistry and Molecular Diversity 1. Ed. Moos Walter H, Pavia Michael R, Kay Brian K, Ellington Andy D.
  • the library may be a solid phase or a solution phase library. It may be a discrete library or a pooled library.
  • We also provide a method of treatment of a disease in which serine protease activity is implicated which comprises administering to a patient an effective amount of compound of the invention; and use of a compound of the invention in the manufacture of a medicament for the treatment of a disease in which serine protease activity is implicated.
  • references herein to treatment extend to prophylaxis as well as the treatment of established conditions.
  • a particularly preferred embodiment of the invention relates to the application of compounds of the invention in the inhibition of neutrophil elastase, thrombin, herpes virus proteases and tryptase.
  • R 1 is a moiety adapted to fit in the S 1 specificity subsite of the enzyme; or a protected derivative thereof, by sequential reaction to introduce the desired R 2 and R 3 substituent.
  • base e.g. NaOH
  • This conversion may be performed on treatment with ammonium bicarbonate in the presence of a suitable solvent such as pyridine/DMF and in the presence of
  • This reaction may be performed by treatment with RX where RX is a compound (e.g. Mel, benzyliodide or Me 2 S0 4 ) capable of converting sulphur in the SMe moiety to sulphonium in a suitable solvent, e.g. propanone or acetonitrile.
  • RX is a compound (e.g. Mel, benzyliodide or Me 2 S0 4 ) capable of converting sulphur in the SMe moiety to sulphonium in a suitable solvent, e.g. propanone or acetonitrile.
  • R will represent alkyl or aralkyl and X will represent halide, especially iodide, or sulphate. Protection of the amide is convenient, although not essential, for this reaction.
  • Step (e) This ring closure reaction may be performed by treatment with Dowex 2 x 8 400 mesh OH " resin in a suitable solvent, e.g. MeCN.
  • a suitable solvent e.g. MeCN.
  • the ring closure may be performed by treatment with potassium carbonate in a suitable solvent e.g. MeCN.
  • Deprotection may be performed in a conventional manner, for example, a BOC protecting group may be removed by treatment with HCI, e.g. in dioxan.
  • This reaction may be performed by treatment with a trifluoroacetic acid alkyl ester (e.g. the methyl ester) or anhydride in the presence of a suitable base e.g. N-methylmorpholine.
  • a trifluoroacetic acid alkyl ester e.g. the methyl ester
  • anhydride e.g. N-methylmorpholine.
  • This conversion will take place on treating the compound of formula (IX) with a reducing agent eg sodium borohydride, followed by treatment with concentrated sulphuric acid in the presence of an alkyl alcohol e.g. ethanol solvent.
  • a reducing agent eg sodium borohydride
  • concentrated sulphuric acid in the presence of an alkyl alcohol e.g. ethanol solvent.
  • the reaction of compounds of formula (X) and (XI) takes place in the presence of a Lewis acid and an inert solvent.
  • the group "alkyl” in Oalkyl and OSi(alkyl) 3 generally represents C 1-6 alkyl.
  • suitable alkyl groups in the silyl alkyl moiety include methyl, isopropyl and t-butyl.
  • the preferred Oalkyl is OEt and the preferred OSi(alkyl) 3 is OSi(i-Pr) 3 or OSi(Me) 2 (t- Bu).
  • the use of variants of compounds of formula (XI) in which Oalkyl is replaced by OSi(alkyl) 3 is also envisaged.
  • the relative proportions of the rel-(2S,3R,1S) and rel-(2S,3R,1R) diastereoisomers can be varied.
  • Use of boron trifluoride dietherate in DCM or preferably MeCN leads primarily to the rel-(2S,3R,1S) diastereoisomer.
  • Use of TMSOTf in DCM leads primarily to the rel-(2S,3R,1 R) diastereoisomer.
  • Compounds of formula (XI) may be prepared by treatment of the corresponding carboxylic acid ester (R 1 CH 2 COOEt or another alkyl ester, which compounds are either known or may be prepared by known methods) with a strong base (eg LHMDS) followed by a trialkylsilylchloride (such as trimethylsilylchloride) or a trialkylsilyltriflate.
  • a strong base eg LHMDS
  • a trialkylsilylchloride such as trimethylsilylchloride
  • a trialkylsilyltriflate Typically the reaction will be performed at low temperature (less than 0°C) in an inert solvent (such as THF) in the presence of DMPU.
  • This ring closure reaction may be performed on treatment with an alkyl Grignard reagent (e.g. t-butylmagnesium chloride) in an inert solvent such as THF in the presence of tetramethylethylenediamine at a temperature of -20°C to 25°C.
  • an alkyl Grignard reagent e.g. t-butylmagnesium chloride
  • an inert solvent such as THF
  • Ring closure of the rel-(2S,3R,1S) diastereoisomer of the compound of formula (XIII) should lead to the rel-(3S,3aS,6aR) diastereoisomer of the compound of formula (XIV).
  • Ring closure of the rel-(2S,3R,1 R) diastereoisomer of the compound of formula (XIII) should lead to the rel-(3R,3aS,6aR) diastereoisomer of the compound of formula (XIV).
  • the protecting group can be removed by catalytic hydrogenation, e.g. hydrogen over Pd/C. in a suitable solvent (e.g. ethanol) optionally in the presence of acid (e.g. acetic acid).
  • a suitable solvent e.g. ethanol
  • acid e.g. acetic acid
  • the reaction will proceed under standard conditions for forming alkyl esters, for example by treatment with an alcohol eg methanol in the presence of SOCI 2 .
  • R 13 is suitably a C 1-6 alkyl group, preferably methyl.
  • the TFA protected amine is formed by treating the compound of formula (XVII) with methyl trifluoroacetate in a polar protic solvent, eg MeOH.
  • Suitable protecting groups P. include CBZ.
  • the compound of formula (XVIII) may be treated with a strong base such as LHMDS or nBuLi in an inert solvent such as THF, followed by treatment with CBZ-CI.
  • the compounds of formula (XIX) are either known compounds or may be made in analogous manner to known compounds.
  • P 1 is a N-protecting group, preferably CBZ (benzyloxycarbonyl).
  • Step (a) is a further N-protection reaction.
  • P 2 in formula (XX) is a different N-protecting group, preferably BOC (t-butyloxy carbonyl). When P 2 is BOC, the reaction is suitably carried out using BOC 2 0.
  • reaction is carried out in the presence of a base such as triethylamine or 4-dimethylaminopyridine in a solvent such as ethyl acetate, at a temperature of suitably 0°-25° C.
  • a base such as triethylamine or 4-dimethylaminopyridine
  • a solvent such as ethyl acetate
  • a 2- phenylsulfinyl acetic acid ester PhSOCH 2 CO 2 R 13
  • piperidine a solvent such as acetonitrile
  • R 13 is suitably a C 1-6 alkyl group, preferably methyl.
  • N-deprotection and re-protection two reactions occur: N-deprotection and re-protection.
  • the phthalimido group is removed suitably with hydrazine hydrate in a solvent such as ethanol at a temperature between 0°C and reflux.
  • Protecting group P 3 is incorporated in a conventional manner. When P 3 is BOC, this is suitably achieved with BOC 2 O.
  • the R 1 side chain may be introduced by alkylation, using as reactant R Y, wherein Y is a reactive group such as bromo or iodo.
  • R Y is a reactive group such as bromo or iodo.
  • the reaction is carried out using a base, preferably a strong base such as LHMDS.
  • LHMDS suitably a cosolvent DMPU in THF is used.
  • Suitable reaction temperatures are -78° to 50°C. Under these conditions the reaction generally takes place with good stereochemical control preferably producing the isomer as illustrated.
  • Other R 1 side chains may be introduced by conventional processes.
  • the former is carried out in a conventional manner, for example by using KOH in aqueous ethanol, at a temperature of suitably 25°-80°C .
  • the latter is carried out in a conventional manner, for example by using HCI in dioxan, at a temperature of suitably 0°-50°C if the protecting group is BOC. If the protecting group is trifluoroacetate, this may be achieved by treatment with base.
  • Step (j) This is a cyclocondensation reaction, suitably carried out in the presence of a cyclising agent such as diphenylphosphorylazide or 2-chloro-1- methylpyridinium iodide and a suitable base such as triethylamine or N, N- diisopropyl ethylamine in a solvent such as dichloromethane, at a temperature of suitably O°C-reflux.
  • a cyclising agent such as diphenylphosphorylazide or 2-chloro-1- methylpyridinium iodide
  • a suitable base such as triethylamine or N, N- diisopropyl ethylamine
  • a solvent such as dichloromethane
  • the compounds of formula (XXIX) are either known compounds or may be prepared in analogous manner to known compounds.
  • P 3 is a protecting group as discussed above, and is suitably BOC.
  • the reaction is suitably carried out using PIFA (phenyl iodosylbis(trifluoroacetate) and a base such as pyridine in an aqueous solvent, such as aqueous THF, dioxan or acetonitrile. This is the method of Stansfield, CF. Organic Preparations and Procedures Int., 1990, 22(5), 593-603.
  • Step (b) P. is a protecting group eg CBZ.
  • This protection reaction may be carried out in a conventional manner. For instance it is suitably carried out in a water miscible solvent such as THF, DMF or dioxan using N- (benzyloxycarbonyloxy)succinamide, benzyloxycarbonyl chloride, or any suitable source of the benzyloxycarbonyl group, with pH adjustment to alkaline with sodium carbonate.
  • the compound of formula (XXXI) can be prepared in conventional manner from diaminobutyric acid.
  • This reaction is suitably carried out in two stages.
  • the first stage involves reacting the compound of formula (XXXI) at reduced temperature with N- methylmorpholine and then an alkyl chloroformate such as ethyl chloroformate, in an organic solvent such as DCM, dioxan or THF.
  • an alkyl chloroformate such as ethyl chloroformate
  • the product is reduced, suitably with sodium borohydride at reduced temperature, such as -20° to 10°C, in a solvent such as THF.
  • This oxidation reaction may be carried out in any suitable manner, for instance using oxalyl chloride in DMSO and methylene dichloride under nitrogen at reduced temperature, such as -30° to -70°C, followed by triethylamine.
  • the intermediate (XXXIII) suitably is not isolated.
  • a phosphonate in a Wadsworth-Emmons reaction.
  • R 13 is suitably C 1-6 alkyl, preferably ethyl.
  • This Michael addition reaction is suitably carried out using LHMDS or other suitable strong base in a suitable organic solvent such as THF, ether or toluene, and preferably a complexing agent such as TMEDA is also present.
  • a suitable organic solvent such as THF, ether or toluene, and preferably a complexing agent such as TMEDA is also present.
  • step (d) is an alkylation it may be performed by treating with a base (e.g. LHMDS) and then with a compound R 1 Y wherein Y is a leaving group such as halogen.
  • a base e.g. LHMDS
  • R 1 Y wherein Y is a leaving group such as halogen.
  • Other R 1 may be introduced by conventional processes.
  • Step (e) may be performed under conditions analogous to Scheme 1 , step (I).
  • Schemes 1 , 2, 3, 4 and 5 may be modified to produce homochiral products by using homochiral starting materials (e.g. S-methionine in Scheme 1 or S-diaminobutyric acid in Scheme 4) or by performing an additional chiral resolution step.
  • homochiral starting materials e.g. S-methionine in Scheme 1 or S-diaminobutyric acid in Scheme 4
  • Both enantiomers of the compound of formula (VIII) may also be produced from a synthesis based on S-methionine or R-methionine following similar procedures.
  • Compounds of formula (I) may also be prepared from another compound of formula (I) following one or more conventional chemical transformations.
  • R 1 when R 1 contains an amidine moiety, it may be preferred to introduce substituent R 1 (e.g. as in Scheme 1 or 3) as the oxadiazolinone derivative. This may be suitably O or N protected in subsequent chemical processes. Treatment of this derivative with hydrogen over Pd/C yields the free amidine.
  • the invention embraces compounds of the invention in racemic form as well as in a form in which one enantiomer predominates or is present exclusively. Generally, we prefer to provide a compound of formula (I) in diastereoisomerically and enantiomerically pure form.
  • Enantiomers having the absolute stereochemistry shown in formula (la) are especially preferred.
  • Suitable physiologically acceptable salts include inorganic base salts such as alkali metal salts (for example sodium and potassium salts) and ammonium salts and organic base salts.
  • Suitable organic base salts include amine salts such as trialkylamine (e.g. triethylamine), dialkylamine (e.g. dicyclohexylamine), optionally substituted benzylamine (e.g. phenylbenzylamine or p-bromobenzylamine), procaine, ethanolamine, diethanolamine, N-methylglucosamine and tri(hydroxymethyl)methylamine salts and amino acid salts (e.g. lysine and arginine salts).
  • Suitable inorganic and organic acid salts include the hydrochloride, trifluoroacetate and tartrate.
  • the compounds of the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions for use in therapy, comprising a compound of the invention or a physiologically acceptable salt or solvate thereof in admixture with one or more physiologically acceptable diluents or carriers.
  • the compounds of the invention may, for example, be formulated for oral, buccal, parenteral, topical or rectal administration.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p_- hydroxybenzoates or sorbic acid.
  • the preparations may also contain buffer salts, flavouring, colouring and/or sweeten
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds of the invention may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre- filled syringes, or in multi-dose containers with an added preservative.
  • the compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or toxicity adjusting agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.
  • topical administration as used herein, we include administration by insufflation and inhalation.
  • preparation for topical administration include ointments, creams, lotions, powders, pessaries, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (e.g. eye or nose drops).
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or solvents.
  • bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil or a solvent such as a polyethylene glycol.
  • Thickening agents which may be used include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, microcrystalline wax and beeswax.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.
  • Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch.
  • Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents or suspending agents.
  • Spray compositions may be formulated, for example, as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, 1 ,1 ,1 ,2- tetrafluorethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, 1 ,1 ,1 ,2- tetrafluorethane, carbon dioxide or other suitable gas.
  • Capsules and cartridges for use in an inhaler or insufflator, of for example gelatin may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • Compounds of the invention may also be used in purification and diagnostic applications involving serine protease enzymes.
  • an immobilised compound of the invention may allow a serine protease capable of binding that compound to be isolated.
  • a tagged compound of the invention may enable a serine protease capable of binding that compound to be identified.
  • enzyme activity is generally determined at a 15 minute timepoint. Enzyme kinetics may be investigated by determining enzyme activity at other timepoints (e.g. 0, 30 minutes). Assay Example 1
  • Suitable concentrations of compound under test diluted with water from a 10mM stock solution in dimethylsulphoxide are final concentrations after the addition of substrate solution (see below).
  • Compounds of the invention may be tested for their thrombin inhibitory activity as determined in vitro by their ability to inhibit human ⁇ -thrombin in a chromogenic assay, using N-p-tosyl-Gly-Pro-Lys p-nitroanilide as the chromogenic substrate. All dilutions were made in a buffer consisting of: 50mM HEPES, 150 mM NaCl, 5mM CaCI 2 , 0.1% PEG and at pH7.4. Briefly, the substrate (final cone, of 100 ⁇ M) was added to thrombin (final cone, of 1 nM) and the reaction monitored for 10mins at 405nm using a Biotek EL340 plate reader; the assay was performed at room temperature.
  • IC 50 values the data were analysed using Kineticalc ® with a 4-parameter curve fitting procedure to obtain the IC 50 value.
  • the compounds were preincubated with thrombin for these times prior to adding the chromogenic substrate.
  • hCMV serine protease used is a mutant of the 30K protease lacking the internal cleavage site (Ala142/Ala143) and which has been cloned in E.coli to produce active enzyme (hCMV ⁇ Ala protease).
  • IC 50 data for test compounds are determined after preincubation of the enzyme with test inhibitor compound for 15 minutes. Test compounds are dissolved in DMSO, serially diluted and added at a range of concentrations (from 100 ⁇ M - 0.195 ⁇ M) to a reaction containing
  • Compounds of the invention may be tested for their tryptase inhibitory activity as determined in vitro by their ability to inhibit human lung mast cell tryptase in a chromogenic assay, using N-p-Tosyl-Gly-Pro-Lys-p-nitroanilide as the chromogenic substrate.
  • Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 10mM Tris- HCI, 120mM NaCl, pH 7.4.
  • the substrate final cone, of 400 ⁇ M
  • tryptase final cone, of 0.1 I ⁇ g.ml "1
  • the reaction monitored for 30 minutes at 405nm using a Molecular Devices Thermomax microplate reader; the assay was performed at room temperature.
  • IC 50 values the data were analyzed using curve fitting software.
  • the compounds were preincubated with tryptase for this time prior to addition of the chromogenic substrate.
  • Compounds of the invention may be tested for their trypsin inhibitory activity as determined in vitro by their ability to inhibit bovine trypsin in a chromogenic assay, using N-Benzoyl-lle-Glu-Gly-Arg-p-nitroanilide as the chromogenic substrate.
  • Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 50mM Tris- HCI, 15mM CaCI 2 , pH 8.4.
  • the substrate final cone, of 160 ⁇ M
  • trypsin final cone, of 25ng.ml "1
  • compound at appropriate concentrations incubated for 15 minutes and the reaction monitored for 10 minutes at 405nm using a BioTek EL340 plate reader; the assay was performed at 37°C.
  • IC 50 values the data were analyzed using Kineticalc ® with a 4-parameter curve-fitting procedure.
  • In vitro assay for inhibition of Factor Xa Compounds of the invention may be tested for their Factor Xa inhibitory activity as determined in vitro by their ability to inhibit human Factor Xa in a chromogenic assay, using N- ⁇ -Benzyloxycarbonyl-D-Arg-Gly-Arg-p-nitroanilide as the chromogenic substrate. Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 50mM Tris-HCI, 150mM NaCl, 5mM CaCI 2 , pH 7.4.
  • the substrate final cone, of 200 ⁇ M
  • Factor Xa final cone, of 0.02 U.ml "1
  • compound at appropriate concentrations incubated for 15 minutes and the reaction monitored for 10 minutes at 405nm using a BioTek EL340 plate reader; the assay was performed at 37°C.
  • IC 50 values the data were analyzed using Kineticalc ® with a 4-parameter curve fitting procedure.
  • Compounds of the invention may be tested for their Factor Xla inhibitory activity as determined in vitro by their ability to inhibit human Factor Xla in a chromogenic assay, using L-Pyroglutamyl-Pro-Arg-p-nitroanilide as the chromogenic substrate.
  • Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 8.1mM NaH 2 P0 4 , 147mM KH 2 PO 4 , 2.7mM KCI, 137mM NaCl, pH 7.2.
  • the substrate final cone, of 400 ⁇ M
  • Factor Xla final cone, of 0.25 ⁇ g.ml "1
  • compound at appropriate concentrations incubated for 15 minutes and the reaction monitored for 10 minutes at 405nm using a BioTek EL340 plate reader; the assay was performed at 25°C.
  • IC 50 values the data were analyzed using Kineticalc ® with a 4-parameter curve fitting procedure.
  • In vitro assay for inhibition of Factor Xlla Compounds of the invention may be tested for their Factor Xlla inhibitory activity as determined in vitro by their ability to inhibit human Factor Xlla in a chromogenic assay, using H-D-Pro-Phe-Arg-p-nitroanilide as the chromogenic substrate. Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 28mM NaBarbitone, 125mM NaCl, 1mM EDTA, pH 7.35.
  • the substrate final cone, of 200 ⁇ M
  • Factor Xlla final cone, of 1.25 ⁇ g.ml "1
  • compound at appropriate concentrations incubated for 15 minutes and the reaction monitored for 10 minutes at 405nm using a BioTek EL340 plate reader; the assay was performed at 25°C.
  • Compounds of the invention may be tested for their tissue plasminogen activator inhibitory activity as determined in vitro by their ability to inhibit human tissue plasminogen activator in a chromogenic assay, using MeSO 2 -D-CHT-Gly-Arg-p- nitroanilide as the chromogenic substrate.
  • Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 50mM Tris-HCI, 150mM NaCl, pH 8.4.
  • the substrate final cone, of 750 ⁇ M
  • tissue plasminogen activator final cone, of I .O ⁇ g.ml "1
  • compound at appropriate concentrations incubated for 15 minutes and the reaction monitored for 10 minutes at 405nm using a BioTek EL340 plate reader; the assay was performed at 30°C.
  • IC 50 values the data were analyzed using Kineticalc ® with a 4-parameter curve-fitting procedure.
  • In vitro assay for inhibition of plasmin Compounds of the invention may be tested for their plasmin inhibitory activity as determined in vitro by their ability to inhibit human plasmin in a chromogenic assay, using H-D-Val-Leu-Lys-p-nitroanilide as the chromogenic substrate. Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 50mM Tris-HCI, 150mM NaCl, 5mM CaCI 2 , pH 7.4.
  • the substrate final cone, of 363 ⁇ M
  • plasmin final cone, of 0.02 U.ml "1
  • compound at appropriate concentrations incubated for 15 minutes and the reaction monitored for 10 minutes at 405nm using a BioTek EL340 plate reader; the assay was performed at 37°C.
  • IC 50 values the data were analyzed using Kineticalc ® with a 4-parameter curve fitting procedure.
  • Compounds of the invention may be tested for their Factor Vila inhibitory activity as determined in vitro by their ability to inhibit human Factor Vila in a chromogenic assay, using H-D-lle-Pro-Arg-p-nitroanilide as the chromogenic substrate.
  • Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 20mM Tris- HCI, 150mM NaCl, 5mM CaCI 2 , 0.1% bovine serum albumin, pH 7.5.
  • Compounds of the invention may be tested for their chymotrypsin inhibitory activity as determined in-vitro by their ability to inhibit human pancreatic chymotrypsin in a chromogenic assay, using MeO-Succ-Arg-Pro-Tyr-pNA hydrochloride as the chromogenic substrate.
  • Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of 50mM Tris-HCI, 150mM NaCl, 25mM CaCI 2 , pH 8.4.
  • the substrate final cone, of 178 ⁇ M
  • chymotrypsin final cone, of 0.2 ⁇ g/mL
  • compound at appropriate concentrations
  • the reaction monitored for 10 minutes at 405nm using a BioTek EL340 plate reader: the assay was performed at 30°C.
  • IC 50 values the data were analysed using Kineticalc ® with a 4-parameter curve fitting procedure.
  • the compounds were preincubated with chymotrypsin for these times prior to addition of the chromogenic substrate.
  • Compounds of the invention may be tested for their Cathepsin G inhibitory activity as determined in vitro by their ability to inhibit human neutrophil Cathepsin G in a chromogenic assay, using N-succinyl-Ala-Ala-Pro-Phe-p- nitroanilide as the chromogenic substrate.
  • Compounds were diluted from a 10mM stock solution in dimethylsulphoxide. All dilutions were made in a buffer consisting of: 100mM HEPES, 300mM NaCl, pH 7.2. Briefly, the enzyme (1.25ug/mL final ), buffer and compound at appropriate concentrations were incubated for 15 mins at 30°C.
  • Reverse phase high performance liquid chromatography was used to quantify compounds at each time point.
  • Half-lives for the compounds were calculated from the time-course data by log-linear regression. Compounds were considered to be unstable if the half life was less than 10 minutes.
  • the mechanism of binding of the compounds was determined using biophysical techniques such as mass spectrometry and X-ray crystallography. Briefly, crystal structures were prepared in complex with thrombin by soaking and co- crystallisation. X-ray data was collected using a FAST area detector system and difference fourier analysis identified the binding modes of the inhibitors. The bound conformations for each inhibitor were obtained after subsequent refinement cycles which often identified an acylation event.
  • step (a) The product of step (a), (1g), water (70ml) and Dowex 2x8-400 mesh (16.4ml) were stirred for 1h. The resin was then filtered and the filtrate concentrated in vacuo to give the title compound as a white solid (0.40g), T.l.c silica (18:3 ethyl acetate: methanol) Rf 0.07.
  • step (c) To the product of step (c) (3.5g) and tetrahydrofuran (100ml) at -70°C was added lithium hexamethyldisilazide (20ml). After I ⁇ h, benzyl chloroformate (2.8ml) was added. The mixture was warmed to room temperature for 1 h and 1M hydrochloric acid (25ml) added. After extraction with ethyl acetate (3x25ml), the combined extracts were washed with 2% ammonia solution, 2M hydrochloric acid and brine, then dried (MgSO 4 ). After solvent removal, the white solid was recrystallised from ethyl acetate: hexane 5:1 to give the title compound (4.2g). T.l.c. (18:2 ethyl acetate: methanol) Rf 0.7
  • step (d) To the product of step (d) (34g) in ethanol (1070ml) at -5°C was added sodium borohydride (9.86g). A solution of 4M hydrogen chloride in 1 ,4-dioxan (20ml) was then added dropwise. Periodically further portions of 4M hydrogen chloride in 1 ,4-dioxan (2x5ml, 1x10ml) and sodium borohydride (2g) were added. After 3h, concentrated sulphuric acid (11ml) was added and the mixture warmed to room temperature for 2h. Saturated aqueous sodium bicarbonate (300ml) was then added and the ethanol and dioxan removed in vacuo.
  • step (f) trans-2-(1-Ethoxycarbonyl-2-methyl-propyl)-3-(2,2,2-trifluoro-acetylamino)- pyrrolidine-1 -carboxylic acid benzyl ester
  • step (e) ethyl trimethylsilyl isopropylketene acetal (11ml) and dichloromethane (250ml) were cooled to 5°C and boron trifiuoride dietherate (17ml) added over h. After 1h, further boron trifiuoride dietherate (3.4ml) and ketene acetal (11ml) were added.
  • step (f) 31g
  • potassium carbonate (71g) water (930ml)
  • ethanol (930ml) were warmed at 60°C for 3h.
  • the ethanol was removed in vacuo and the aqueous residue extracted with ethyl acetate (3x300ml).
  • the combined extracts were washed with brine and dried (MgSO 4 ) and concentrated in vacuo to give the title compound as a brown oil (17.5g).
  • step (h) rel-(3R,3aR,6aS)-6-lsopropyl-5-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1- carboxylic acid benzyl ester
  • the product of step (g) (17.5g) in tetrahydrofuran (1,800ml) was cooled to -5°C and 1M t-butylmagnesium chloride in tetrahydrofuran(204ml) was added over Vah.
  • 1 M hydrochloric acid (250ml) and brine (300ml) were added and then extracted with ethyl acetate (250ml).
  • ethyl acetate 250ml
  • the extracts were washed with brine and dried (MgS0 4 ). Solvent removal in vacuo followed by trituration with diethyl ether
  • step (i) A suspension of the product of step (i) (13.63g) in ethyl acetate (900ml) was added to 20% palladium hydroxide (moist) on carbon (3.16g) and the resulting black suspension stirred vigorously under hydrogen at room temperature for 90 min. The mixture was then filtered through Harborlite J2 and concentrated in vacuo to give the title compound as a fine white powder (8.63g).
  • step G The product of step G) (0.04g), piperidinepropanoic acid (0.028g), di- isopropylethylamine (0.085ml), bromo-tris-pyrrolidine-phosphonium hexafluorophosphate (0.083g) and dichloromethane (3ml) were mixed for 4h. The mixture was diluted with ethyl acetate and washed with water and brine and dried (MgS0 4 ). Solvent removal in vacuo followed by flash chromatography on silica 9385 eluting with ethyl acetate: methanol gave an oil (41 mg).
  • step (b) rel-(3R,3aR,6aS)-3-lsopropyl-1-methanesulfonyl-4- ⁇ 4-[(methyl-propyl- amino)-methyl]-benzoyl ⁇ -hexahydro-pyrrolo[3,2-b]pyrrol-2-one hydrochloride
  • a solution of the product of step (a) (30mg) in dry dichloromethane (3ml) was stirred with N-methylpropylamine (9.8 ⁇ l).
  • Sodium triacetoxyborohydride (25.2mg) was added and the reaction was stirred for 48 hours.
  • NaHCO 3 solution (1ml) and water (2ml) was added to the reaction before stirring vigorously for 10 mins.
  • the product was isolated from the organic phase by pipetting it equally onto two varian silica cartridges (500mgSi) which had DCM filtered through them until the solvent reached the top of the silica. Each pair of columns were then filtered under vacuum to remove the load volume of solvent, before eluting the following solvent quantities into collection tubes by vacuum filtration; dichloromethane (2xcol.vol), chloroform (2xcol.vol), ether (2xcol.vol), ethyl acetate (2xcol.vol), acetonitrile (2xcol.vol), methanol (4xcol vol) (each col.vol. being ⁇ 2.5ml). The product containing fractions were combined and the solvent removed in vacuo to give the free base.
  • Triethylamine (53.7ml) was added dropwise over 10 minutes followed by the immediate addition of the Wittig reagent (19.3g). The cooling bath was removed and the internal temperature allowed to rise to 17°C. The reaction mixture was poured into ether (400ml) and brine (400ml). The organic phase was separated and the aqueous phase extracted with ether (2x100ml). The combined organic phases were dried (MgSO4) and evaporated under reduced pressure to give a tan oil (36.22g). This was purified by flash column chromatography (Merck 9385 silica eluting with 40% ethyl acetate in cyclohexane) to give the product (15.71g) as an oil:
  • step (b) The product of step (b) (12.2g) was suspended in dry toluene (175ml) with stirring under N2. Tetramethylethylenediamine (1.1ml) was added followed by lithium bis-(trimethylsilyl)amide (1.0M in hexanes, 7.6ml). On completion of the addition a solution had formed. The reaction mixture was stirred for 15 minutes and then poured into ethyl acetate (300ml) and saturated aqueous ammonium chloride (300ml). The organic phase was separated and the aqueous phase extracted with ethyl acetate (2x50ml).
  • step (c) To the product of step (c) 246.6gm, 1eq, 0.607mol was added trifluoroacetic acid (25eq, 15.18mol, 1731gm, 1169ml) at room temperature. After stirring for one hour the solution was evaporated and the residue azeotroped twice with toluene (300ml). The resulting oil was dissolved in ethyl acetate (2500ml) and washed with 2M sodium hydroxide (1x800ml + 3x300ml), water and brine, dried (MgS0 4 ) and evaporated to give the title compound as a golden oil, 168.9gm, after high vacuum. Mass spec 613 [2M+H] + , 307 [MHf.
  • step (f) To the product of step (f)(52.9gm, 173mmol) in tetrahydrofuran (550ml) in an ice-salt bath was added a solution of tert butyl magnesium chloride (554ml of a 1M solution in tetrahydrofuran, 554mmol), keeping the temperature ⁇ 1°C.
  • the mixture was warmed to room temperature over 1 hr 15min, then quenched with saturated ammonium chloride whilst cooling in an ice bath.
  • the phases were separated and the aqueous phase extracted with ethyl acetate.
  • the combined organics were washed with water and brine, dried (MgSO 4 ) and evaporated and to give the title compound as a cream solid, 43.5gm.
  • step (g) To the product of step (g) (43.2gm, 166mmol) in tetrahydrofuran (1200ml) at - 72°C under a nitrogen blanket was added lithium bis (trimethylsilyl)amide (216ml of a 1 M solution in tetrahydrofuran, 216mmol) dropwise, keeping the temperature ⁇ -71°C. After ten minutes a solution of di-tert-butyldicarbonate (54.3 gm, 249mmol) in tetrahydrofuran (350ml) was added, keeping the temperature ⁇ -71°C. The reaction was stirred at -73°C for two and a half hours and then quenched with saturated ammonium chloride.
  • step (h) The product of step (h) (606mg, 1eq, 1.68mmol) was dissolved in tetrahydrofuran (6ml) and cooled, under nitrogen, to -75°C. Lithium hexamethyldisilazide (1.3 eq, 2.2ml of a 1 M solution in tetrahydrofuran) was added, keeping the temperature below -70°C. After 10 minutes methyl iodide was added (17eq, 28.9mmol, 1.8ml). After stirring for a further 45 minutes the reaction was quenched with saturated aqueous ammonium chloride and then allowed to warm to room temperature.
  • Lithium hexamethyldisilazide 1.3 eq, 2.2ml of a 1 M solution in tetrahydrofuran
  • step (i) To the product of step (i) (486mg, 1eq, 1.3mmol) was added trifluoroacetic acid
  • step (k) (3aS,6S,6aR)-4-Cyclopropanecarbonyl-6-methyl-5-oxo-hexahydro- pyrrolo[3,2-b]pyrrole-1 -carboxylic acid benzyl ester
  • step (j) 992mg, 1eq, 2.75mmol
  • dry THF (7ml) 7ml
  • lithium hexamethyldisilazide 3.3ml of a 1 M solution in tetrahydrofuran, 1.2eq, 3.3mmol
  • step (k) A solution of the product of step (k) (330mg, 0.96mmol) in isopropanol (30ml) was added to the catalyst (119mg, 10% palladium on activated carbon with 50% water, Degussa type E101 NE/W) under nitrogen and the resulting mixture stirred vigorously under an atmosphere of hydrogen for 2.75hours.
  • the catalyst was filtered off under an atmosphere of nitrogen and a 1M solution of hydrogen chloride in diethyl ether (1ml, 1eq, 1mmol) was added to the filtrate. Evaporation of the solvent gave the title compound as a colourless gum, 175mg.
  • step (I) the product of step (I) (racemic) (0.152g,0.62mmol,1 eq.) in DMF (0.5mL) and diisopropylethylamine (0.215mL,1.23 mmol, 2 eq.) were added.
  • the reaction mixture was allowed to stir at room temperature for 16 hours and was then diluted with dichloromethane (15mL) and water (15mL).
  • the aqueous layer was re-extracted with dichloromethane (15mL) and the combined organic extracts were then washed with 2N HCI (15mL) , water (15mL) and sat. NaHCO 3 solution (15mL). After drying over MgSO the solvent was evaporated in vacuo to give an orange oil.
  • step (m) The product of step (m) (0.893g,2.03mmol) was added to the catalyst (0.419g, 10% palladium on activated carbon with 50% water, Degussa type E101 NE/W) as a solution in isopropanol (160mL). Warming was required for all material to dissolve. A 1.0M solution of HCI in ether (2.3mL,2.3mmol) was also added. The reaction mixture was stirred vigorously under an atmosphere of hydrogen for 5 hours with further catalyst (0.4g) added after 1.5 hours to complete the reaction. The catalyst was filtered off and a 1.0M solution of HCI in ether (0.2 mL) was added to the filtrate. Evaporation of the filtrate in vacuo afforded the title compound, as a white foam (0.721 g). It was used in step (o) without further purification.
  • step (n) The product of step (n) (57mg,233 ⁇ mol,1eq.) was dissolved in MeCN (4 mL). To the clear solution was added triethylamine (80mL,574 ⁇ mol,2.5eq.) and a solution of dansyl chloride (69mg,256 ⁇ mol,1.1eq.) in MeCN (1mL). The reaction mixture was stirred at room temperature for 1.5 hours. Isopropanol (10mL, 128 ⁇ mol) was added and the solution was evaporated to dryness. The residue was purified by flash column chromatography silica gel (Merck 9385) and eluted with cyclohexane:ethyl acetate to give the title compound as a yellow/ green foam (15.4mg).
  • step (a) To the product of step (a) (8.61g, 31.1 mmol) in dry dichloromethane (20mL) was added trifluoroacetic acid (20mL, 260mmol, 8 eq.). The solution was stirred at room temperature for 2 hours. The solvents were then evaporated and the resulting brown gum was azeotroped with toluene (4X 50 mL). The title compound , was obtained in quantitative yield as a brown gum which was used in the next reaction without further purification. Mass Spec: 141 [MH] + parent amine.
  • step (b) (12.01g, 31.1 mmol of trans-lactam + 57 mmol TFA) and triethylamine (11.2 mL, 80.43 mmol, 2.6 eq. w.r.t. trans-lactam) were dissolved in water (40mL).
  • MOZ-ON 2-(4-methoxybenzyloxycarbonyloxyimino)-2- phenylacetonitrile
  • step (d) (3aS,6S,6aR)-4-Benzothiazol-2-yl-6-methyl-5-oxo-hexahydro-pyrrolo[3,2- b]pyrrole-1 -carboxylic acid 4-methoxy-benzyl ester
  • 2- bromobenzothiazole 1 (1.17g,5.47mmol,1.6eq.
  • potassium carbonate 0.768g,5.56 mmol, 1.6 eq.
  • copper (I) chloride 0.45g,3.49mmol,1eq.
  • TDA-1 0.330mL,1.03 mmol,0.3eq.
  • xylene xylene
  • step (d) To the product of step (d) (850mg, 2.194mmol) was added trifluoroacetic acid (20mL) at room temperature. After 20 minutes the solvent was evaporated in vacuo to give, after trituration under diethyl ether, the title compound as a tan solid, (643 mg). Mass spec 274 [MH] + .
  • step (f) To the product of step (f) (64mg, 136 ⁇ mol) was added trifluoroacetic acid
  • step (a) A solution of the product of step (a) (3.198g) in tetrahydrofuran (44ml, dry) was cooled to -10°C under nitrogen, 4-methylmorpholine (1.0ml) was added followed by ethylchloroformate (0.868ml). After stirring for 8 mins sodium borohydride (1 03g) was added in one portion followed by methanol (88ml) over a period of
  • Triethylamine (53.7ml) was added dropwise over 10 minutes followed by the immediate addition of the Wittig reagent (19.3g). The cooling bath was removed and the internal temperature allowed to rise to 17°C. The reaction mixture was poured into ether (400ml) and brine (400ml). The organic phase was separated and the aqueous phase extracted with ether (2x100ml). The combined organic phases were dried (MgSO4) and evaporated under reduced pressure to give a tan oil (36.22g). This was purified by flash column chromatography (Merck 9385 silica eluting with 40% ethyl acetate in cyclohexane) to give the product (15.71g) as an oil:
  • step (c) The product of step (c) (12.2g) was suspended in dry toluene (175ml) with stirring under N2- Tetramethylethylenediamine (1.1ml) was added followed by lithium bis-(trimethylsilyl)amide (1.0M in hexanes, 7.6ml). On completion of the addition a solution had formed. The reaction mixture was stirred for 15 minutes and then poured into ethyl acetate (300ml) and saturated aqueous ammonium chloride (300ml). The organic phase was separated and the aqueous phase extracted with ethyl acetate (2x50ml).
  • step (f) (2.31 g) in THF/HMPA (10ml/21ml) was added over 10 min and the resultant solution was maintained at -70°C for 1h.
  • step (h) trans-3-Amino-2-[1-ethoxycarbonyl-5-(5-oxo-4,5-dihydro-[1 ,2,4]oxadiazol-3- yl)-pentyl]-pyrrolidine-1 -carboxylic acid benzyl ester trifluoroacetate
  • the product of step (g) (2.77g) was dissolved in trifluoroacetic acid (11ml) and dichloromethane (100ml). After 2h, the solvents were removed under reduced pressure to give the title compound (2.8g) as a yellow oil.
  • Triethylamine (0.1ml) was added to a stirred solution of the product of step (j) (0.1g) and di-tert-butylcarbonate (0.109g) in dry DMF (5ml) at room temperature. After 18h, further di-tert-butylcarbonate (0.055g) was added and stirring continued for 8h. The solution was poured into phosphate buffer (pH6.5) and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (sodium sulfate) and concentrated under reduced pressure. The residue was triturated with ethyl acetate: hexane (1 :11) to give the title compound (0.094g) as a colourless gum. T.l.c. Silica (ethyl acetate) Rf 0.45
  • step (k) A solution of the product of step (k) (0.093g) in DMF (5ml) was added to sodium hydride (0.018g, 60% dispersion in oil) at room temperature. After 30 min, methyl chloroformate (0.043ml) was added and stirring continued for 18h. Further sodium hydride (0.018g) followed by methyl chloroformate (0.043ml) was added and stirring continued for 24h. The mixture was poured into phosphate buffer (pH6.5) and extracted with ethyl acetate. The combined, dried (sodium sulfate) organic extracts were concentrated under reduced pressure and the residue was treated with dichloromethane (5ml) and trifluoroacetic acid (1ml).
  • Preparative high performance liquid chromatography (h.p.l.c.) was carried out using a Dynamax 60A C18 8 ⁇ M 25cm x 41.4mm i.d. column eluted with a mixture of solvents (i) 0.1% trifluoroacetic acid in water and (ii) 0.05% trifluoroacetic acid in acetonitrile, at a flow rate of 45ml/minute.
  • Analytical h.p.l.c. was carried out using a Dynamax 60A C18 8 ⁇ M 25cm x 4.6mm i.d. column using eluants as for preparative h.p.l.c. at a flow rate of 1 ml/minute.
  • step (b) rel-(3aS,6R,6aR)-4-Methylcarbamoyl-6- ⁇ 4-[4-(2-nitro-benzyl)-5-oxo-4,5- dihydro-[1 ,2,4]oxadiazol-3-yl]-butyl ⁇ -5-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1- carboxylic acid benzyl ester
  • a mixture of the product of step (a) (5g), sodium hydride (1.9g, 60% dispersion in oil) and methyl isocyanate (2.7ml) in THF (500ml) was stirred at room temperature for 64h.
  • step (c) A mixture the product of step (c) (0.22g), trifluoroacetic acid (0.110ml), and 10% palladium on carbon (0.24g) in ethyl acetate (11ml) was hydrogenated at atmospheric pressure for 16h. The reaction mixture was filtered through
  • step (k) (0.250g) in THF (5ml) was added to sodium hydride (0.060g, 60% dispersion in oil) at room temperature. After 10 min, benzenesulfonyl chloride (0.195ml) was added and stirring continued for 24h. Further sodium hydride (0.060g) followed by benzenesulfonyl chloride (0.195ml) was added and stirring continued for 24h. The mixture was poured into phosphate buffer (pH6.5) and extracted with ethyl acetate.
  • phosphate buffer pH6.5
  • step (b) rel-(3R,3aR,6aS)-5-(1-Benzenesulfonyl-2-oxo-octahydro-pyrrolo[3,2-b]pyrrol- 3-yl)-pentanamidine trifluoroacetate
  • step (a) 0.060g
  • 10% palladium on carbon 0.060g
  • ethyl acetate 60ml
  • R 1 represents C 2- alkyl, C 2-4 alkylthio
  • R 2a represents C 1-6 alkyl; - heteroaryl, which aryl or heteroaryl are mono-ring, gs one of which may be saturated, and which aryl and heteroaryl groups may be substituted by one or more C 1-4 alkyl, halo, -NR 7 R 8 , -SO 2 NR 7 R 8 , -CONR 7 R 8 , -C 1-6 alkyl ester, -CN, -CH 2 OH, -O-C 1-6 alkyl, -CF 3 , or nitro groups; aryl-C 1-4 alkyl, aryl-C 1-4 alkyl-NH- or
  • R 4 and R 5 independently represent hydrogen, C 1- alkyl, C 1-4 alkoxy, -(CH ⁇ CONR ⁇ R ⁇ , -CO-C 1-4 alkyl or phenyl optionally substituted by one or more C 1-4 alkyl or halogen groups or R 4 and R 5 may be joined such that NR 4 R 5 represents a mono, bi- or tri-cyclic ring system containing 4-15 ring carbon atoms, wherein one or more rings may be optionally interrupted by one or more heteroatoms selected from O, N and S and wherein one or more ring carbon atoms may have carbonyl functionality; or -(CH 2 ) n -NR 4 R 5 may represent a group of formula 1 a:
  • R 6 is hydrogen or a carboxy C 1-6 alkyl ester, n 1 is 0-6 and a and b independently represent an integer 0-3 provided a+b is in the range 3-5;
  • R 7 , R 8 , R 9 , R 10 , R 11 R 12 independently represent hydrogen or C 1-4 alkyl; m represents an integer 0 to 8; n represents an integer 1 to 9; and salts and solvates thereof.
  • Compounds of formula IB (which are not compounds of the invention) are defined as follows:
  • R 1 represents H, substituted or unsubstituted C 1-3 alkyl
  • R 2 represents optionally substituted heteroaryl or fused heteroaryl with one to four heteroatoms, R 5 CO or R 5 NHCO wherein R 5 may be substituted or unsubstituted and represents H, C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, aryl, arylC 1-3 alkyl or heteroaryl containing one or more heteroatoms;
  • R 3 represents R 3a CO; wherein R 3a represents
  • R 4 represents the group R 6 -X- ; wherein R 6 represents
  • Y represents a hetero atom such as O, S or N, wherein N is optionally further substituted
  • W represents hydrogen or C 1-3 alkyl and Z represents hydrogen, halogen, C 1-6 alkyl, aryl, C 1-6 alkoxy, C n H 2n+1 OC m H 2rn wherein n and m are independently selected integers 1-3, CF 3 , O-haloC 1-3 alkyl, S-C 1 . 3 alkyl, S-haloC 1-3 alkyl, O-aryl, C 2-4 alkenyl or N(A)B wherein A and B are independently selected from H and C 1-4 alkyl;
  • R 1 represents C 2- alkyl, C 2-4 alkenyl, C 1-3 alkoxy or C 1-3 alkylthio.
  • R 1 represents H, substituted or unsubstituted C ⁇ alkyl.
  • R 1 represents C 2- alkyl, C 2- alkenyl, C 1-3 alkoxy or C 1-3 alkylthio;
  • R 2a represents C 1-6 alkyl; -CH 2 (CF 2 )o -4 CF 3 ; aryl or heteroaryl, which aryl or heteroaryl are mono-ring, or have two fused rings one of which may be saturated, and which aryl and heteroaryl groups may be substituted by one or more C 1-4 alkyl, halo, -NR 7 R 8 , -SO 2 NR 7 R 8 , -CONR 7 R 8 , -C 1-6 alkyl ester, -CN,
  • aryl-C 1-4 alkyl aryl-C 1-4 alkyl-NH- or aryl-C 2 . 4 alkenyl, or such groups wherein aryl is substituted by one or more C 1- alkyl or halo groups;
  • R 7 , R 8 independently represent hydrogen or C 1- alkyl.
  • R 1 represents H, substituted or unsubstituted C 1-3 alkyl
  • R 2 represents optionally substituted heteroaryl or fused heteroaryl with one to four heteroatoms, R 5 CO or R 5 NHCO wherein R 5 may be substituted or unsubstituted and represents H, C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, aryl, arylC 1 . 3 alkyl or heteroaryl containing one or more heteroatoms.

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Abstract

L'invention concerne un inhibiteur d'une enzyme sérine protéase, ledit inhibiteur consistant en un dérivé substitué de trans-hexahydropyrrolo[3,2-b]pyrrol-2-one, à l'exception d'un composé représenté par la formule IA et IB (définie dans l'annexe 1).
EP98948907A 1997-09-09 1998-09-07 Procede d'inhibition d'enzymes serine proteases Withdrawn EP1015454A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9719189 1997-09-09
GBGB9719189.4A GB9719189D0 (en) 1997-09-09 1997-09-09 New therapeutic method
PCT/EP1998/005607 WO1999012932A1 (fr) 1997-09-09 1998-09-07 Procede d'inhibition d'enzymes serine proteases

Publications (1)

Publication Number Publication Date
EP1015454A1 true EP1015454A1 (fr) 2000-07-05

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EP98948907A Withdrawn EP1015454A1 (fr) 1997-09-09 1998-09-07 Procede d'inhibition d'enzymes serine proteases

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EP (1) EP1015454A1 (fr)
JP (1) JP2001515903A (fr)
AU (1) AU9536298A (fr)
GB (1) GB9719189D0 (fr)
WO (1) WO1999012932A1 (fr)
ZA (1) ZA988160B (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0110832D0 (en) * 2001-05-03 2001-06-27 Virogen Ltd Antiviral compounds

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9211783D0 (en) * 1992-06-04 1992-07-15 Ici Plc Amide derivatives
WO1995003278A1 (fr) * 1993-07-26 1995-02-02 Zaidan Hojin Biseibutsu Kagaku Kenkyukai Derive de pyrrolidine ou sel de celui-ci pharmaceutiquement acceptable
PL329153A1 (en) * 1996-03-28 1999-03-15 Glaxo Group Ltd Derivatives of pyrrolopyrolone as inhibitors of neutropil elastase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9912932A1 *

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JP2001515903A (ja) 2001-09-25
WO1999012932A1 (fr) 1999-03-18
AU9536298A (en) 1999-03-29
GB9719189D0 (en) 1997-11-12
ZA988160B (en) 2000-03-22

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