EP1062222A1 - Modulateurs de la serine peptidase - Google Patents

Modulateurs de la serine peptidase

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Publication number
EP1062222A1
EP1062222A1 EP99911781A EP99911781A EP1062222A1 EP 1062222 A1 EP1062222 A1 EP 1062222A1 EP 99911781 A EP99911781 A EP 99911781A EP 99911781 A EP99911781 A EP 99911781A EP 1062222 A1 EP1062222 A1 EP 1062222A1
Authority
EP
European Patent Office
Prior art keywords
compounds
prolyl
phosphonate
pyrrolidine
cooh
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.)
Withdrawn
Application number
EP99911781A
Other languages
German (de)
English (en)
Inventor
Simon Lodewijk Scharpe
Ingrid Anna Jozef De Meester
Alexandre Arkadicvitch; Beliaev
Anne-Marie Virginie Renée LAMBEIR
Koen Jan Ludovicus Augustyns
Achiel Jean-Marie Haemers
Filip Jozef Anny Goossens
Dirk Frans Hendriks
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
FondaTech Benelux NV
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FondaTech Benelux NV
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Filing date
Publication date
Application filed by FondaTech Benelux NV filed Critical FondaTech Benelux NV
Priority to EP99911781A priority Critical patent/EP1062222A1/fr
Publication of EP1062222A1 publication Critical patent/EP1062222A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
    • C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings

Definitions

  • the present invention relates to novel modulators (inhibitors and stimulators) of serine peptidases and proteases in general and dipeptidyl peptidase IV, prolyl oligopeptidase (PO) , dipeptidyl peptidase II (DPP II) , fibroblast activation protein ⁇ (FAP ⁇ ) , lysosomal Pro-X carboxypeptidase and elastase in particular.
  • the invention further relates to the preparation and use of these compounds for selective modulation (inhibition or stimulation) of serine peptidases and proteases and to pharmaceutical preparations comprising them.
  • peptidase and “protease” are used interchangeably.
  • Serine peptidases/proteases like granzymes, mast cell tryptase, elastases, trypsin-like enzymes, prolyl oligopeptidase, dipeptidyl peptidase II and dipeptidyl peptidase IV are involved in various processes that take place in the body, such as blood coagulation, inflammation, immune response, and control of peptide hormone metabolism in general.
  • serine peptidases are a physiological necessity they may also constitute a potential health hazard in case serine peptidase activity in the body is not controlled.
  • Serine peptidases have been described to be involved in various medical indications. Blood coagulation serine proteases are for example responsible for vascular clotting as well as cerebral and coronary infarction. Chymotrypsin-like enzymes and plasmin are involved in tumour invasion, tissue remodeling and clot dissociation. Pancreatitis, emphysema, rheumatoid arthritis, inflammation and adult respiratory distress syndrome may in some instances be caused by the uncontrolled proteolysis by other serine proteases such as elastase. Serine peptidases form a large group with many members that are divided into clans and families.
  • DPP IV dipeptidyl peptidase IV
  • EC 3.4.14.5 dipeptidyl peptidase IV
  • DPP IV EC 3.4.14.5
  • DPP IV is a highly specific exopeptidase with a serine type mechanism of protease activity, cleaving off dipeptides from the amino-terminus of peptides with proline or alanine at the penultimate position.
  • DPP IV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues, and is also found in body fluids. In the hematopoietic system, DPP IV was identified as the leukocyte antigen CD26.
  • Prolyl oligopeptidase (PO, EC 3.4.21.26) was discovered in the human uterus as an oxytoein-degrading enzyme.
  • the enzyme shows a high specificity for proline residues and hydrolyses the peptide bond at its carboxyl side, provided the proline is not at the peptide amino- terminus.
  • This endopeptidase has like DPPIV, a serine type mechanism and it is characterised by its activity on oligopeptides.
  • PO cleaves specifically the Pro-Xaa bond in biological active peptides (substance P, ocytoxin, vasopressin, gonadoliberin, bradykinin, neurotensin) and it is likely to participate in the in vivo regulation of their actions.
  • FAP ⁇ Fibroblast activation protein ⁇
  • Dipeptidyl peptidase II (DPPII, EC 3.4.14.2) releases N-terminal dipeptides from oligopeptides, provided their N-termini are unsubstituted.
  • the preferred PI residues are Ala and Pro.
  • An increase in serum DPPII has been observed in cancer patients and extremely high levels of DPPII are present in human carcinoma cells.
  • DPPII can be inhibited by the classical (unspecific) inhibitors of serine type peptidases (J.K.McDonald in Barrett, supra. p. 408-411) .
  • Elastases are defined by their ability to release soluble peptides from insoluble elastin fibers by a proteolytic process called elastinolysis.
  • Elastase belongs to the chymotrypsin family of leucocyte serine- type proteases.
  • Human leucocyte elastase (EC 3.4.21.37) preferentially cleaves peptides with a Val in PI but also peptide bonds with Ala, Ser and Cys in PI are hydrolyzed and it is believed to possess an extended substrate- binding site.
  • the possible involvement of leucocyte elastase in inflammatory diseases triggered the search for development of specific inhibitors.
  • a pathological role in lung emphysema, cystic fibrosis and adult respiratory distress syndrome has been suggested (J. Bieth in Barrett, supra. p. 54-60; D.Farley et al. in Pharmaceutical Enzymes, ed. A. Lauwers and S. Scharpe, Marcel Dekker, Inc., 1997, p. 306-326).
  • Lysosomal Pro-X carboxypeptidase (prolylcarboxypeptidase, angiotensinase C, EC 3.4.16.2) cleaves C-terminal amino acids from peptides with the general structure X-Pro-Y, where X is either a blocking group, another protected amino acid, or a peptide, and Y is an aromatic or aliphatic amino acid with a free carboxylie group.
  • the enzyme is recovered from the lysosomal fraction of different tissues. Although the enzyme has an acidic pH optimum for small synthetic substrates (pH 5.0), it retains 50% of its maximal activity at physiological pH towards larger peptide substrates.
  • the phosphonate may be substituted with one or two phenyl groups which in turn may be mono-, di- or trisubstituted with a halogen, C 1 -C 6 alkyl, C 1 -C 6 perfluoralkyl, C.-C 6 alkoxy, N0 2 , CN, OH, C0 2 H, amino, C 1 -C 6 alkyla ino, C 2 -C 12 dialkylamino, C 1 -C 6 acyl, and C 1 -C 6 alkoxy-CO-, C,-C 6 alkyl-S-.
  • the present inventors in the research that led to this invention, developed independently the same compounds. However, they found that regarding toxicity, stability and efficacy these compounds did not perform optimally.
  • the object of the present invention to provide inhibitors of serine peptidases/ proteases that have a more optimal combination of inhibitor capacity, stability in plasma, safety, bioavailability, duration of action and straightforward synthesis.
  • the invention has for its object to provide compounds that have a stimulating activity on serine peptidases/ proteases.
  • modulating compounds More in particular, the invention provides compounds having such a more optimal combination for modulating the activity of DPP IV, PO, 5
  • DPP II DPP II, FAP ⁇ , lysosomal Pro-X carboxypeptidase and elastase.
  • compounds as claimed in claim 1 are very potent modulators, in particular inhibitors, of serine peptidases/proteases in general and DPP IV, DPP II, PO, FAP ⁇ , lysosomal Pro-X carboxypeptidase and elastase in particular.
  • the compounds as listed in claim 12 were found to be potent inhibitors of DPP IV and PO.
  • the compounds of the invention are based on peptides. These peptides are constituted by either naturally occurring amino acids or other amino acids. The C-terminal carboxyl function is replaced by a phosphonate group.
  • - A is (R2) or H or C,-C 6 alkyl or halogenoalkyl, except perfluoroalkyl, 6 the phenyl group is mono-, di- or trisubstituted with Rl or R2;
  • X is a peptide- or amino acid-derived moiety; A and the phenyl group substituted with Rl may optionally form a biphenyl diester; all Rl substituents and R2 substituents are each independently selected from the group consisting of: a) C 1 -C 6 acylamino; b) aroylamino, optionally substituted at the o- and/or p- and/or m- position with alkyl, in particular C ⁇
  • C 6 alkyl, and/or a halogen c) C 1 -C 6 alkylsufonylamino ; d) arylsulfonylamino, optionally substituted at the o- and/or p- and/or m- position with alkyl, in particular C 1 -C 6 alkyl, and/or a halogen; e) ⁇ aminoacylamino wherein the ⁇ aminoacyl represents a side chain blocked or unblocked ⁇ -amino acid residue with the L, D or DL configuration at the ⁇ -carbon atom selected from the group consisting of: alanine, methionine, methionine sulfoxide, arginine, homoarginine, phenylalanine, aspartic acid, proline, hydroxyproline, asparagine, serine, cysteine, threonine, histidine, glycine, tyrosine, glutamic acid, pyroglutamic
  • X is a moiety of the general formula (AA) -aa-, wherein: p indicates that there may be 0, 1, 2, 3, 4 or
  • AA and aa are selected from one of the following: a) ⁇ -amino carboxylic acids with in ⁇ position an optionally substituted C 1 -C 6 alkyl or aryl or aralkylmoiety; b) alanine, methionine, methionine sulfoxide, arginine, homoarginine, phenylalanine, aspartic acid, proline, hydroxyproline, asparagine, serine, cysteine, threonine, histidine, 8 glycine, tyrosine, glutamic acid, pyroglutamic acid, tryptophan, glutamine, valine, norvaline, isoleucine, lysine, leucine, norleucine, thioproline, homoproline, 1,2,3,4-tetrahydro- isoquinoline-3-carboxylic acid (Tic) ,
  • X is M-(AA) p -aa- wherein: p, AA and aa are as defined above;
  • M is selected from: a) the group consisting of optionally substituted -CONH 2 , -CSNH 2 , -S0 2 NH 2 , phenyl-S0 2 -, phenyl-CH 2 S0 2 -, 2-furyl- acryloyl ; and b) the group of protecting groups consisting of: acetyl, adamantyloxycarbonyl, benzyl- oxycarbonyl, benzoyl, benzyl, t-butoxycarbonyl, t-butyl, 2,4-dinitrophenyl, formyl, fluorenylmethoxycarbonyl, 4-methoxybenzyl, tosyl, trifluoro- acetyl, trityl, phthaloyl, phenylalkylcarbonyl, 2-indanylacetyl, 2-(l,2,3,4-tetrahydronaphty1) acetyl,
  • X represents AA-aa-, wherein aa is proline and AA is as defined above.
  • X represents AA-aa-, wherein AA and aa are both proline.
  • Rl and R2 may further be selected from:
  • aa is alanine and preferably at least the AA coupled to aa is proline or phenylalanine.
  • Preferred examples of the compounds are Phe-Ala-diphenyl- phosphonate or Pro-Ala-diphenylphosphonate and pharmaceutically acceptable salts thereof.
  • the invention can be divided in three groups of compounds.
  • the phosphonate group is a diphenyl-phosphonate group
  • the first group thus consists of compounds of the general formula II: 10
  • the compounds are 2,2' biphenyl diesters of ⁇ -aminoalkyl phosphonic acid having the general formula III:
  • the third group (group 3) consists of compounds having the general formula IV: Rl o
  • A wherein X and Rl are as defined above, A is H or C 1 -C 6 alkyl or halogenoalkyl, except perfluoroalkyl.
  • X is preferably selected from Cbz-Gly-Leu-Phe-, Z-Phe- Pro-Phe, and Suc-Val-Pro-Phe-.
  • prolyl oligopeptidase X may be selected from among the following: Cbz-Gly-Gly- Pro-, Cbz-Pro-Pro-, Boc-Val-Pro-Val-, MeO-Suc-Ala-Ala- Ala-Val-, MeO-Suc-Ala-Ala-Pro-Val-.
  • X is as follows: Ala-Pro-, Pro-Pro-, Ala-Pip-, Phe-Pro-, lie- Pro-, Arg-Pro-, pF-Phe-Pro-, cyclohexylala-Pro-, Pro- azetidine-, Phe-azetidine-, Lys-Pro-, Lys-azetidine-.
  • X is selected from among Suc-Lys(Cbz) -Val-Pro-Val-, Z-Ala- 11
  • X may be selected from Cbz-(4-amidinophenylalanine)-, Z- Met-, 3-phenyl propanoyl-Pro-(4-aminophenylalanine)-, Cbz-Thr-(4-amidinophenylglycine)-, and Boc-D-Phe-Pro-(4- amidinophenylalanine)-.
  • X may be Z-Phe-Pro-Phe-, Z-Phe-, Suc-Val-Pro-Phe-, MeO-Suc-Ala-Ala-Pro-Phe-, or MeO-Suc- Ala-Ala-Ala-Phe- when the enzyme to be inhibited is chymotrypsine.
  • X may be selected from among Cbz-Orn-, Cbz-Lys-Ala-, Cbz- Lys, Cbz-Ho oLys-, Cbz-(4-amidinophenylalanine)-, Cbz-(4- amidinophenylglycine) -, Ph-CH 2 -S0 2 -Gly-Pro- (4-amidino- phenylglycine)-, 3-(2-furyl)acryloyl-(4-amidinophenyl- glycine) , Cbz-Lys-(4-amidinophenylglycine)-, Cbz-Lys-Ala- (4-amidinophenylglycine)-, Cbz-Thr-(4-amidinophenyl- glycine)-, 3-(2-furyl)acryloyl-(4-amidinophenylalanine)
  • V8 protease of S . aureus X can be either Acetyl.Glu- or Acetyl.Asp-.
  • Rl and R2 are preferably selected from the group consisting of: 3-AcNH, 4-AcNH, 4-MeS0 2 NH, 3-H 2 NCONH, 3-H 2 NCONH, 4-(N-Bz-Gly-NH) , 4-(H-Gly-NH) , 4 (H- (S) -Ala-NH) , 4-((S)-Pyr-NH) , 4-((2S)-Me0 2 CCH(NHAc)CH 2 ) , 4-Me0 2 C, 4- (Et0 2 CCH 2 NHCO) , 4-(Me0 2 C(CH 2 ) 2 NHCO) , 4-CH 3 (CH 2 ) 2 NHCO.
  • Particularly preferred compounds of group 1 are the following:
  • a compound having an inhibitory activity for DPP IV is for example 2 , 2 ' -Biphenyl l-( (S) -prolyl) - pyrrolidine-2(R,S) -phosphonate hydrochloride (19) or a pharmaceutically acceptable salt.
  • Powers' leaving groups are among others 2- methylphenol (o-cresol) , 3-methylphenol (m-cresol) and 4- methylphenol (p-cresol) .
  • the compounds belong to the group of cresols, which are desinfectants. These compounds are toxic to humans. Chronic poisoning from oral or percutaneous absorption may produce digestive disturbances, nervous disorders, vertigo, skin eruptions, jaundice, oliguria, uremia.
  • Another leaving group in Powers' compounds is 4-hydroxybenzoic acid methylester (methyl paraben, Nipagin M) which is also a preservative in foods beverages and cosmetics and of which allergic reactions are frequently observed.
  • 1,4-Benzenediol (hydroquinone) is a photographic developer and reducer and is used as an antioxidant. At very low concentrations there is no systemic toxicity. However, ingestion of more than 1 g results in nausea, vomiting, shortness of breath, cyanosis, convulsions and collapse. It is lethal in a dose above 5
  • the leaving groups of the compounds of the invention are for example 4-hydroxyacetanilide (paracetamol, compound He) which is used commonly as a very safe analgesic/antipyretic drug.
  • Another leaving group is 4-hydroxyhippuric acid ethyl ester (compound lln) of which no toxicity has been noticed, and hippuric acid is known to be a metabolite occurring in human metabolism and a normal constituent in human urine.
  • the compounds of the invention can be used for the therapy of pathological states associated with excessive, impaired or unbalanced activity of said enzymes.
  • the invention relates to the compounds for use as a therapeutical agent.
  • the invention relates to the compounds for use in the treatment or prophylaxis of inflammation, vascular diseases, organ specific or systemic auto-immune diseases (e.g. Graves' disease or multiple slerosis, inflammatory bowel disease) , joint diseases, muscle diseases, neurological diseases, obesity, diseases associated with benign and malign cell transformation, spreading of malignant cells, conditions of glucose-intolerance, abnormal growth or growth retardation, rejection of foreign cells or tissues after transplantation, abnormalities in blood cell development, abnormal blood clotting, pain, or diseases of the central nervous system.
  • organ specific or systemic auto-immune diseases e.g. Graves' disease or multiple slerosis, inflammatory bowel disease
  • joint diseases e.g. Graves' disease or multiple slerosis, inflammatory bowel disease
  • muscle diseases e.g. Graves' disease or multiple slerosis, inflammatory bowel disease
  • neurological diseases e.g
  • the involvement of plasma prekallikrein or kallikrein in shock is described by W. Colman in Barrett, A., et al., supra. page 147-153.
  • the compounds of the invention can be used for prevention and treatment of thrombosis and conjunction therapy of acute myocardial infarction by specifically inhibiting Factor X (Vlasuk, G.P. in New Therapeutic Agents in Thrombosis and Thrombolysis, Sasahara, A., Loscalzo, J., eds (1997), pages 261-283), thrombin
  • Elastase plays a role in autoim unity diseases such as rheumatoid arthritis (Mo ohara, S. et al., Clin. Rheumatol. 16 (1997), 133-140; and Shinguh, Y. et al., Eur. J. Pharmacol. 337 (1997), 63-71; Barrett, supra. Lauwers & Scharpe, supra) .
  • PO Chappell, M.C. et al., Braz. J. Med. Biol. Res. 31 (1998), 1205-1212; and Umemura, K. et al., Br. J. Clin. Pharmacol. 43 (1997), 613-618). PO is furthermore involved in muscle dystrophy
  • DPP IV is a very versatile enzyme according to its localisation and different substrates and correlated with pain (Shane, R. et al., Brain Res. 815 (1999), 278- 286) and obesity (Pederson, R. et al., Diabetes 47 (1998) 1253; Flint, A. et al., J. Clin. Investigation 101 (1998), 515-520) and tissue repair (Drucker, D. et al., Am. J. Physiol. 276 (1999), G79-91) .
  • the present invention also includes derivatives which have been modified in the N-terminal amino acid side chain without abolishing the reactivity with the active site.
  • modifications are the incorporation of a radioactive label such as Iodine 125 into tyrosine, extension of the side chain to attach biotin or a fluorophore.
  • a radioactive label such as Iodine 125 into tyrosine
  • extension of the side chain to attach biotin or a fluorophore to improve the half-life in the circulation the peptide bond between the two amino acids may be replaced by a non-hydrolyzable bond.
  • the incorporation of a radioactive label is useful in diagnostic methods using the modulating compounds.
  • the compounds are for example labeled for use in diagnostic and research methods such as fluorescence and radio-assays, imaging, in situ histochemical and cytochemical staining etc. as will be further explained hereinbelow.
  • the invention relates to the use of the compounds for the preparation of a therapeutical composition for modulating (inhibiting or stimulating) the activity of serine proteases.
  • a therapeutical composition for modulating (inhibiting or stimulating) the activity of serine proteases.
  • Such therapeutical composition is then specifically intended for treatment and prophylaxis of the conditions listed above. 18
  • the invention provides a pharmaceutical preparation comprising one or more compounds of the invention and a suitable excipient, carrier or diluent.
  • Such pharmaceutical preparations are intended for the treatment and prophylaxis of the above conditions.
  • Acceptable excipients, carriers and diluents are well known and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985) .
  • Preservatives, stabilizers, dyes and flavoring agents may be provided in the pharmaceutical compositions.
  • sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives.
  • antioxidants and suspending agents may be used.
  • the compounds of this invention may be formulated and used as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for injectable administration, aerosols, galenic preparations for topical and bucal administration and aerosols for nasal administration.
  • absorption enhancing preparations e.g. liposomes
  • the amount of the active substance (s) in a dosage unit may vary between 0.001 mg and 1 g.
  • the compounds or pharmaceutical compositions of this invention can be used alone or in combination with one another, or in combination with other therapeutic or diagnostic agents.
  • Such other therapeutic or diagnostic agent(s) can have a different dosage form or can be present in the same dosage form as the compounds of the invention.
  • the dosage for the compounds of the present invention can range broadly depending upon the desired effects and the therapeutic indication.
  • the invention also relates to a method for in vitro inhibition or stimulation (modulation) of protease activity by means of a suitable concentration of a 19 compound of the invention.
  • a suitable concentration of a 19 compound of the invention is in particular useful when a protease inactivates a peptide prior to measurement thereof in a peptide assay.
  • the compounds of the invention can be used to inhibit the degradation of the peptide substrate by the enzyme in such assay.
  • the compounds of the invention are also useful in a method for the 'ex vivo' inhibition of protease activity, such as the treatment outside the body of cells and organs for transplantation in order to avoid rejection thereof by the recipient body.
  • the compounds of the invention can be used in a method for in vivo inhibiting or stimulating (modulating) protease activity by means of administering to a living organism a suitable amount of a compound of the invention.
  • Such modulation can be used for pharmacotherapy of disease states related to one of the following conditions: inflammation, organ specific or systemic auto-immune diseases, non-malignant disorder of leukocytes and/or immunoglobulins, rejection of cells or tissues after transplantation, tissue destructive and bone degenerative diseases, neuroendocrine dysfunction, glucose-intolerance, obesitas, functional gastrointestinal disorder, abnormal growth or growth retardation, thrombosis and hemorrhage, vascular and cardiopulmonary diseases, neurodegenerative and affective disorders, pain, diseases associated with neoplasia.
  • the invention also relates to the diagnostic use of the compounds.
  • Labeled inhibitors or stimulators can be used essentially in the same type of applications as labeled monoclonal antibodies, e.g. fluorescence and radioassays, cytofluorimetry, fluorescence activated cell sorting etc.
  • the principles of such techniques can be found in immunochemistry handbooks, for example: Coligan, J. et al., Current Protocols in Immunology, vol. 1, 2 & 3, Wiley, 1998. 20
  • the compounds of the present invention can also be used as affinity ligands for analytical and preparative purposes.
  • modulators can be used to directly visualize the cellular distribution of the target protease.
  • the label can be fluorescent for fluorescence microscopy, radioactive for autoradiography, or electron dense for electron microscopy.
  • the target structures can be whole cells, cells fixed onto slides or sections through solid tissue.
  • a useful modification of these techniques is to use an indirect (“sandwich") assay employing the specific high affinity interaction between biotin and avidin (Coligan et al . , supra) .
  • modulators labeled with a suitable isotope can be injected.
  • tumour can be visualized by radioscintigraphy.
  • the principles of imaging are summarized by A. Bamias & A.A.Epenetos (1995) , Monoclonal antibodies, production, engineering and clinical application (M.A. Ritter and M.M. Ladyman, eds.) Cambridge University Press, Cambridge, pp. 222-246) .
  • the modulators of the invention are suitable for the diagnostic applications described above, such as imaging and histochemical staining of the respective proteases end peptidases, because they form covalent, long-lived adducts with the proteases and peptidases. Because of their small size they are expected to penetrate tissue more easily than, for example, antibodies. In the case of DPP IV it was found that the modulators only recognize DPP IV which is native and enzymatically active. Formulations of the compounds to be used in diagnostic applications are also part of this invention. 21
  • the invention is not limited to the compounds as claimed but also relates to pharmaceutically acceptable salts thereof.
  • the compounds of the invention may be pure diastereo-isomers or racemic mixtures.
  • Serine protease activity can interfere with enzymatic assays for other substrates by cleaving the substrate used in the test and thereby giving either false positive (when a chromogenic substrate is cleaved) or false negative results (when a peptide substrate is degraded) .
  • the inhibitors of this invention can be used to inactivate contaminating serine proteases or peptidases before carrying on with the analysis.
  • This application relates to compounds that can either inhibit or stimulate the activity of serine proteases and peptidases. Because the activity of individual compounds of the group of compounds may be opposed (i.e. either inhibiting or stimulating) the general terms "modulating” and “modulation” are intended when reference is made to a group of compounds. 22
  • Individual compounds will have either a inhibitory or a stimulatory activity on individual serine peptidases and proteases.
  • a prerequisite of the invention is that the compounds that are claimed are active, i.e. have a modulatory (either inhibitory or stimulatory) activity on serine peptidases or serine proteases.
  • di(4-acetamidophenyl) l-(S)-prolyl- pyrrolidine-2-(R,S)- phosphonate (He) is considered as a major improvement and will be a highly valuable DPP IV inhibitor for further studies on the biological function of the enzyme and the therapeutic value of its inhibition.
  • R Z, Boc or Trr ⁇ ivorv
  • Reagents i) PC1 3 ; ii) HC1 ; iii) HOAc, 90 °C, 2 h ; iv) HCl/EtOAc (1 M) ; v) H 2 , Pd/C
  • Rl a) H ; b) 4-OMe ; c) 4-OAc (4-OH for 11) ; d) 3-NHAc ; e) 4-NHAc ; f) 4-NHS ⁇ 2 Me ; g) 3-NHCONH 2 ; h) 4- (N-Bz-Gly-NH) ; i) 4- (N-Z-Gly-NH) [4-(H-Gly-NH) for 11] ; j) 4- (N-Z-(S) -Ala-NH) [ 4- (H-(S) -Ala-NH) for 11] ; k) 4-( (S) -Pyr-NH) ; 1) 4-[(2S)-Me0 2 CCH(NHAc)CH 2 ] ; m) 4-COOMe ; n) 4-(CONHCH 2 COOEt) ; o) 4-[CONH(CH 2 ) 2COOMe] ; p) 4-(CONH(CH 2 COOEt
  • the 4-methylsulfonyl- aminophenol 8f was prepared from the corresponding sulfonylchloride and 4-aminophenol.
  • the 4-acylaminophenols 8h-k were prepared by condensation of the corresponding carboxylic acid with 4-aminophenol using the mixed anhydride method.
  • N-acetyl-L-tyrosine methyl ester (81) was prepared as described (Jackson, E. L. O-p-Toluenesulfonyl-L-tyrosine, its N-acetyl and N-benzoyl Derivatives. J. Am. Chem. Soc. 1952, 74, 26
  • the glycine derivative 8n was obtained after condensation of glycine ethyl ester with 4-hydroxybenzoic acid using diphenylphosphoryl azide (DPPA) .
  • DPPA diphenylphosphoryl azide
  • the synthesis of the 4-hydroxybenzoic acid amides 8o and 8p was accomplished by coupling of 4-acetoxybenzoic acid with the corresponding amine using the mixed anhydride method followed by mild alkaline hydrolysis of the phenyl esters 12 and 13 (B ⁇ chi, G. ; Weinreb, S. M. Total Syntheses of Aflatoxins Ml and Gl and an Improved Synthesis of Aflatoxin Bl. J. Am. Chem. Soc. 1971, 93, 746-752).
  • the triaryl phosphites 9 were then synthesised from the corresponding substituted phenols 8 and phosphorous trichloride.
  • Cyclic N-protected 2 , 2 ' -biphenyl derivatives 17a and 17b were prepared by reacting 2,2 '-biphenylacetyl phosphite (16) with aldehyde 7a or 7b in acetic acid (Scheme 2) . Attempted removal of benzyloxycarbonyl (Z) protection from phosphonate 17a by hydrogenolysis with a Pd/C catalyst in methanol resulted in the opening of the dioxaphosphepan ring to give the mixed methyl aryl ester 18. Deprotection of the Boc-derivative 17b with HCl/EtOAc yielded free 2,2' -biphenyl phosphonate 19.
  • 3-Acetamidophenol (8d) 4-aminobutyraldehyde diethyl acetal, PC1 3 , diphenyl- phosphoryl azide (DPPA) and 4-acetoxybenzoic acid were obtained from Sigma-Aldrich Chemie BV, Belgium.
  • 4-Acetamidophenol (paracetamol) (8e) was obtained from Sterling Organics Ltd., England. Purity of all new synthesised compounds were checked by TLC, ⁇ - MR, 13 C-NMR or MS. The final products were checked by TLC, 1 H-NMR, 13 C-NMR, FAB-MS and(or) elemental analysis.
  • Optical rotation was measured on a Perkin-Elmer 241 polarimeter. Melting points were determined on a Digital Melting Points Apparatus (Electrothermal) and are uncorrected. Z- and Boc-protected amino acids were prepared according to standard procedures (Bodanszky, M. & Bodanszky, A. In The Practice of Peptide Synthesis, 2nd ed. ; Springer-Verlag: Berlin Heidelberg, 1994; pp 11-18 and 28-29) using Z-Cl and (Boc) 2 0, respectively.
  • ⁇ -Alanine methyl ester was synthesised by treatment of the amino acid in methanolic HC1 similarly to described procedure (Bodanszky & Bodanszky (1994), supra) .
  • the preparation of 4- (Z-(S) -prolyl) aminobutyraldehyde diethyl acetal (6a) was described earlier (Belyaev et al., (1995), supra) . 28
  • Tris (3-acetamidophenyl) phosphite (9d) Tris (3-acetamidophenyl) phosphite (9d) .
  • Tris (4-acetamidophenyl) phosphite (9e) Tris (4-acetamidophenyl) phosphite (9e) .
  • Tris (4-methylsulfonylaminophenyl) phosphite (9 ) Tris (4-methylsulfonylaminophenyl) phosphite (9 ) .
  • Tris(4-methoxycarbonylphenyl) phosphite (9m) Tris(4-methoxycarbonylphenyl) phosphite (9m) .
  • Tris 4- r 2 - (methoxycarbonyl ) ethylaminocarbonyl ] henyl ) phosphite (9o) .
  • diaryl l-(t-butyloxycarbonyl-(S) -prolyl) - pyrrolidine-2-phosphonate (10) or diaryl l-(trityl-(S)- prolyl) pyrrolidine-2-phosphonate (10, 5 mmol) was dissolved in a IM HC1 solution in EtOAc (25 mL) and the solution was stirred for 2 h at room temperature. Dry ether (30 mL) was added and the mixture was left in the fridge overnight. If the product crystallised, the crystals were collected by filtration, otherwise the oil was triturated in dry ether. The material obtained was dried in vacuum over NaOH pellets.
  • Diphenyl alanine phosphonates were synthesized following the principle described by Oleksyszyn et al., Synthesis 1979, 985-986. The method was used with acetaldehyde for the preparation of the alanine analogue, diphenyl 1-benzyloxycarbonylaminoethane phosphonate.
  • the mixed anhydride method was used to couple diphenyl 1-aminoethane phosphonate to various amino acids : glycine, L-alanine, L-valine, L-isoleucine,
  • the mixture was heated at 80-85°C for one hour and the volatile products were removed on a rotary evaporator under reduced pressure with heating on a boiling water bath.
  • the oily residue was dissolved in methanol (180 ml) and left overnight for crystallization at -10°C.
  • the crystalline ester was collected by filtration, redissolved in a small amount of hot chloroform (30-40 ml) and recrystallization occurred by adding a 4-fold volume of methanol.
  • Diphenyl 1 (R.S) -rN-benzyloxycarbonyl-L-phenylalanyl]- aminoethane phosphonate Diphenyl l(R.S)-fN-benzyl- oxycarbonyl-L-prol ⁇ l1 aminoethane phosphonate (T, Q) General procedure for the mixed anhydride coupling with isobutyl chloroformate.
  • the Z-protected amino acid (5 mmol) was dissolved in dry tetrahydrofuran (25 ml) and cooled to -150°C in an ice-sodium chloride bath.
  • N-Methyl- morpholine (5 mmol, 0.51 g) and isobutyl chloroformate (5 mmol, 0.68 g) were added to this solution and stirring was continued for 10 minutes.
  • a solution of Y (5 mmol, 1.79 g) and triethylamine (5 mmol, 0.51 g) in dimethyl- formamide (10 ml) was introduced dropwise to the stirring mixture, keeping the temperature below -100 °C.
  • the Z-protected dipeptide phosphonates T and Q (1.5 mmol) were dissolved in dry methanol (20 ml) and acetic acid (0.7 ml). After the addition of palladium on charcoal (10%, 0.25 g) , the air above the solution was displaced with nitrogen and hydrogen was led over the solution for 3 hours. Before removing the solvent under reduced pressure, the flask was flushed with nitrogen for 10 minutes. The residue was dissolved in dry chloroform (15 ml) and 0.5N hydrogen chloride in ethyl acetate was added slowly to the stirring solution. Removal of the solvent under reduced pressure and co-evaporation with 0.5N hydrogen chloride in ethyl acetate (10 ml) afforded a white foam, which was triturated with dry ether. After 46
  • 4-alanylamino (llj) have a comparable activity, but are considerably less stable in plasma than the 4-acetylamino (He) substituted diphenyl phosphonate.
  • the O-methyl derivative (18) is almost as potent and stable as 5.
  • DPP IV was purified from human seminal plasma as described previously (De Meester et al., J. Immunol. Meth. 189, 99-105 (1996)). Enzymatic activity was measured at 37 ⁇ C in a Spectramax 340 (Molecular Devices) microtiterplate reader using Gly-Pro-p-nitroanilide (Sigma) as a chromogenic substrate. The reaction was monitored at 405 nm and the initial rate was determined between 0 and 0.25 absorbance units. The reaction mixture contained 2 mM substrate, approximately 1 mU of DPP IV, 40 mM TRIS-HC1 buffer, pH 8.3, and a suitable amount of inhibitor (ranging between 0 an 10 mM) in a total volume of 0.2 ml. Activity measurements were routinely performed in duplicate.
  • the IC 50 value is defined as the concentration of inhibitor required to reduce the DPP IV activity to 50% after a 15 min pre-incubation with the enzyme at 37 °C before addition of the substrate.
  • Inhibitor stock solutions 100 mM were prepared in DMSO or phosphate buffer, pH 7.4, depending on the solubility of the compound, and stored at -20°C. Stock solutions were diluted with 50 mM TRIS-HC1 buffer, pH 8.3, as required, immediately before the experiment. Since the compounds described in this paper completely inactivate DPP IV following pseudo-first order kinetics, the IC 50 value is inversely correlated with the second order rate constant 49 of inactivation (Lambeir et al., (1996), supra) .
  • IC 50 values were determined after 15 min pre-incubation with DPP IV at 37 *C. The listed values are the average of n independent measurements ⁇ the standard deviation. Functional stability in plasma was estimated by fitting the inverse of the apparent IC 50 values versus time with a single exponential decay. The half-life is listed ⁇ the standard error of fit. 50
  • the inactivation rate constant was determined from the time course of inhibition as described before (Lambeir et al., (1996), supra) .
  • the functional stability of the inhibitors was estimated by measuring the inhibitory potency (apparent IC 50 ) of a 1 mM dilution of the compounds in citrated human plasma at 3 or 4 time points between 0 and 300 min at 37 °C. Fitting the inverse of the apparent IC 50 values versus time with a single exponential decay gives the half-lives reported in table 1.
  • IC 50 values are expressed in ⁇ M
  • Prolyl oligopeptidase was purified from human platelets and the enzyme activity was measured using Z-Gly-Pro-AMC (4.4 mM) as the substrate in a K-phosphate buffer 100 mM, pH 7.5 containing 1 mM EDTA, 1 mM dithiothreitol and 1 mM NaN 3 . The incubation was carried out during 20 min at 37°C. The reaction was stopped by the addition of 5 volumes 1.5 M acetic acid. Fluorescence was measured at 370 and 440 nm as excitation and emission wavelengths respectively. The inhibitors were added at concentrations varying between 1 ⁇ M and 1 mM.
  • Dipeptidyl peptidase II was semi-purified from rabbit kidney and its activity was determined by the hydrolysis of Lys-Ala-4-Me0-2-NA 1.4 mM (Sigma, L-2270) in 100 mM acetate buffer, pH 5.5 containing 2 mM EDTA. After incubation during 20 minutes at 37 °C, the reaction was stopped by the addition of 10 fold excess sodium-acetate pH 3.6. The fluorescence of the formed 4-MeO-2-NA was measured at 340 and 425 nm as excitation and emission wavelengths respectively. For the determination of the IC 50 values the compounds were tested 52 at a series of concentrations ranging from 1 ⁇ M to 5 mM during incubation.
  • Peripheral blood mononuclear cells were isolated from buffy coats (obtained from the blood transfusion center of Antwerp). After dilution (1/4) in phosphate buffer saline (PBS) , cells were layered onto Ficoll-Hypaque density gradient (Pharmacia, Uppsala, Sweden) and centrifuged at room temperature at 550 x g during 20 min. The interfaces were collected and washed 3 times in RPMI-1640. Finally the cells were resuspended at lxlO 6 cells/mL in RPMI-1640 containing 10 % heat-inactivated foetal calf serum, and antibiotics (penicillin/streptomycin) (Gibco) .
  • PBS phosphate buffer saline
  • the remaining cells were washed 3 times in PBS and the final cell pellet was solubilised in 200 ⁇ L PBS containing 1 % v/v Triton X-100 and 100 KIU/mL aprotinin (Bayer) and centrifuged during 10 min at 20000 x g. Supernatants were used immediately for enzyme assay and protein determination by the Bradford micro-assay. Specific activities (U/g protein) are compared and the % inhibition is given toward control samples without inhibitor.
  • FIG. 5 depicts residual plasma DPP IV activity in rats treated subcutaneously on days 0 to 5 with He.
  • mice Male New Zealand white rabbits (2.5-3.5 kg), istar rats (250-350 g) and Swiss mice (23-36 g) were allowed to adjust to their environment for at least 7 days. They received standard diet and water ad lib. Test compounds were dissolved in 50 mM phosphate buffer pH 7.4 at concentrations ranging from 10-100 mg/mL and stored in aliquots at -80"C and were thawed ex tempore. Rabbits 55 received a single slow intravenous bolus injection of test compound or vehicle alone in the marginal ear vein. Blood was sampled from the central ear artery. Rats and mice were injected subcutaneously or intraperitoneally.
  • Rat blood samples were obtained under anesthesia (Forene) from the vena femoralis by puncture after incision of the skin. The mice were bled by orbita puncture after induction of anesthesia with pentobarbital. After clotting, blood samples were centrifuged (3000 x g, 10 min) and the resulting sera were stored at -80 ⁇ C until assayed for DPP IV activity.

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Abstract

La présente invention concerne de nouveaux composés présentant une activité modulatrice (inhibitrice ou stimulatrice) vis-à-vis des serines peptidases et protéases en général et du dipeptidyl peptidase IV, prolyl oligopeptidase (PO), dipeptidyl peptidase II (DPP II), la protéine α de l'activation du fibroblaste (FAPα), le lyosomal Pro-X carboxypeptidase et élastase en particulier. Ces nouveaux composés sont utilisables pour le traitement de diverses conditions pathologiques dans lesquelles ces peptidases sont impliquées.
EP99911781A 1998-03-09 1999-03-09 Modulateurs de la serine peptidase Withdrawn EP1062222A1 (fr)

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