WO2003022871A2 - Nouveaux inhibiteurs de dipeptidylpeptidase i - Google Patents

Nouveaux inhibiteurs de dipeptidylpeptidase i Download PDF

Info

Publication number
WO2003022871A2
WO2003022871A2 PCT/EP2002/010020 EP0210020W WO03022871A2 WO 2003022871 A2 WO2003022871 A2 WO 2003022871A2 EP 0210020 W EP0210020 W EP 0210020W WO 03022871 A2 WO03022871 A2 WO 03022871A2
Authority
WO
WIPO (PCT)
Prior art keywords
unbranched
branched
chain
compounds
residue
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.)
Ceased
Application number
PCT/EP2002/010020
Other languages
English (en)
Other versions
WO2003022871A3 (fr
Inventor
Hans-Ulrich Demuth
Ulrich Heiser
André NIESTROJ
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.)
Vivoryon Therapeutics AG
Original Assignee
Probiodrug AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Probiodrug AG filed Critical Probiodrug AG
Priority to JP2003526944A priority Critical patent/JP2005511505A/ja
Priority to EP02779316A priority patent/EP1423410A2/fr
Priority to AU2002342657A priority patent/AU2002342657A1/en
Publication of WO2003022871A2 publication Critical patent/WO2003022871A2/fr
Publication of WO2003022871A3 publication Critical patent/WO2003022871A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to compounds that act as specific inhibitors of the cysteine protease dipeptidyl peptidase I (DP I).
  • DP I cysteine protease dipeptidyl peptidase I
  • Compounds based on acylated hydroxamates are distinguished by being chemically stable in aqueous solutions, including biological fluids (Br ⁇ mme & Demuth, 1994).
  • Acylated hydroxamates are suicide inhibitors which deactivate the DP I by the reaction with the nucleophilic active site thiol residue.
  • Dipeptidyl peptidase I is known to release active granulocyte serine proteases of lymphatic cells from their pro-forms. It participates in mechanisms that are used physiologically by cytotoxic lymphocytes in immune defence. In the case of pathophysiological processes such as malignant transformations of myeloid and lymphatic cells, the suppression of such mechanisms can be used for the treatment of carcinomas, immune diseases or metabolic diseases.
  • the inhibitors of DP I according to the invention can be used for the treatment of such pathophysiological conditions and diseases.
  • DP I Peptidase Classification Clan CA, Family C1 , IUB B Enzyme Classification EC 3.4.14.1 , CAS Registration No. 9032-68-2
  • DP I removes dipeptides sequentially from unsubstituted N-termini of polypeptide substrates with a relatively broad substrate specificity (McDonald et al., 1971 ; McDonald & Schwabe, 1977).
  • DP I is a lysosomal cysteine protease which, by removing N-terminal dipeptides, is able to release active enzymes from proenzymes, such as granzyme A, granzyme B, leucocyte elastase, cathepsin B, neuraminidase, in the lysosomal granula of cytotoxic T-lymphocytes (Kummer et al., 1996; Thiele & Lipsky, 1997).
  • proenzymes such as granzyme A, granzyme B, leucocyte elastase, cathepsin B, neuraminidase
  • DP I is involved in pathological mechanisms such as apoptotic processes, muscular dystrophy and carcinogenesis (Aoyagi et al., 1983; Gelman et al., 1980; Sch Wegauff et al., 1992; Shi et al., 1992).
  • DP I is known as the convertase of the blood-sugar-raising hormone glucagon which, in enzymatically reduced concentration, can lead to life-threatening hypoglycaemia (McDonald, J.K. et al., 1971 ).
  • Such reversible inhibitors which are able to display only short-term effects caused by diffusion processes, and the affinity labels that act irreversibly on the target enzyme in vitro but which, because of their chemically reactive radical which is present a priori, are able to react, prior to their interaction with the target enzyme, with other nucleophiles and electrophiles in biological fluids.
  • Another type, mechanism-oriented inhibitors are distinguished by becoming catalytically attacked and activated only by the target enzyme.
  • Such inhibitors are also known as suicide inactivators. Highly efficient suicide inactivators for cysteine proteases have been developed with the class of N-peptidyl, O-acyl hydroxylamines (Br ⁇ mme et al., 1996). Inhibitors of DP I have not been derived from that class of compounds since DP I is inert towards typical irreversible cysteine protease-inhibitors known in the art, such as, for example, E-64.
  • N-terminally unprotected dipeptide derivatives tend towards rapid, intramolecular decomposition.
  • Inhibitors of DP I are described in WO9324634; US5776718; EP0995756; DE19834610; WO0220804; EP1188765, which are incorporated herein in their entirety concerning their structure, production and use.
  • the invention relates to inhibitors of DPI having the general formula (I)
  • R is an acyl-residue including a urethane or peptide, or a branched or unbranched C 1 -C 9 alkyl chain, a branched or unbranched C 2 -C 9 alkenyl chain, a branched or unbranched C 2 -C 9 alkynyl chain, a C 3 -C 9 cycloalkyl, C 4 -C 9 carbocyclic, C 5 -C ⁇ 4 aryl, C 3 -C 9 heteroaryl, C 3 -C 9 heterocyclic, all of the above residues optionally being substituted, or R is H, the residue AS- AS is a dipeptide or a mimetic thereof, E is O or S, and
  • R' is a branched or unbranched C 1 -C 9 alkyl chain, a branched or unbranched C 2 -C alkenyl chain, a branched or unbranched C 2 -C 9 alkynyl chain, a C 3 -C 9 cycloalkyl, C 4 -C 9 cycloalkenyl, C 2 -C 9 heterocycloalkyl, C 3 -C 9 heterocycloalkenyl, C 5 -Cu aryl, C 3 -C 9 heteroaryl, C 3 -C 9 heterocyclic, wherein the heterocycloalkyl, heterocycloalkenyl, heteroaryl, heterocyclic residue can have up to 6 hetero atoms in the ring, or R x is an amino acid or a peptide or a mimetic thereof, all of the above residues optionally being substituted, or K is H or alkoxy, alkenyloxy, alkynyloxy, carbocyclicoxy, heteror
  • R' especially stands for H and for any alkyl, alkenyl, alkynyl, acyl, carbocyclic, aryl, heteroaryl, heterocyclic, alkoxy, alkenyloxy, alkynyloxy, carbocyclicoxy, heteroaryloxy, heterocyclicoxy, thioether or a substituted residue thereof.
  • the compounds according to the invention may also be in the form of prodrugs.
  • compositions that comprise at least one compound according to the invention, optionally in combination with carriers and/or adjuncts etc. that are customary per se.
  • the compounds and compositions according to the invention can be used for the in vivo inhibition of the enzyme dipeptidyl peptidase I or of enzymes similar to DP I.
  • They can be used especially for the treatment of diseases of mammals that can be influenced by modulation of the DP I activity in various cells, tissues and organs.
  • the present invention further relates to the use of the compounds and compositions according to the invention for improving the wound-healing process and for the treatment of impaired wound-healing in humans.
  • the invention relates to inhibitors of DP I having the general formula (I):
  • R is an acyl-residue including a urethane or peptide, or a branched or unbranched C Cg alkyl chain, a branched or unbranched C 2 -C 9 alkenyl chain, a branched or unbranched C 2 -C 9 alkynyl chain, a C 3 -C 9 cycloalkyl, C 4 -C 9 carbocyclic, C 5 -C ⁇ aryl, C 3 -C 9 heteroaryl, C 3 -C 9 heterocyclic, all of the above residues optionally being substituted, or R is H, the residue AS-AS is a dipeptide or a mimetic thereof,
  • R 1 is a branched or unbranched C 1 -C 9 alkyl chain, a branched or unbranched C 2 -C 9 alkenyl chain, a branched or unbranched C 2 -C 9 alkynyl chain, a C3-C 9 cycloalkyl, C 4 -C 9 cycloalkenyl, C 2 -C 9 heterocycloalkyl, C 3 -C 9 heterocycloalkenyl, C 5 -d 4 aryl, C 3 -C 9 heteroaryl, C 3 -C9 heterocyclic, wherein the heterocycloalkyl, heterocycloalkenyl, heteroaryl, heterocyclic residue can have up to 6 hetero atoms in the ring, or K is an amino acid or a peptide or a mimetic thereof, all of the above residues optionally being substituted, or K is H or alkoxy, alkenyloxy, alkynyloxy, carbocycl
  • the group AS-AS is bound with a peptide bond to R.
  • residue R is a phenyl or naphthyl residue that optionally is mono-, di-, or poly-substituted by C C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl, C C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 3 -C 9 heteroaryloxy, C3-C9 heterocyclicoxy, C ⁇ -C 6 thioether or a substituted residue thereof, NO 2 , NH 2) F, Cl, Br, I atoms or groups.
  • the above residues can be branched or unbranched.
  • R' is NO 2 , NH 2 , F, Cl, Br, I atoms or groups or is a phenyl or naphthyl residue, which is optionally mono-, di-, or poly-substituted by C C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C ⁇ -C 6 acyl, C C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 3 -C 9 heteroaryloxy, C 3 -C 9 heterocyclicoxy, C ⁇ C 6 thioether or a substituted residue thereof, NO 2 , NH 2 , F, Cl, Br, I atoms or groups,
  • T 1 is CH or N
  • W 1 , X 1 , Y and Z 1 are independently from each other selected from CH 2 , NR 2 , N + (R 3 ) 2 , O, S,
  • R 2 , R 3 and R 4 are independently from each other a branched or unbranched C 1 -C 9 alkyl chain, a branched or unbranched C 2 -Cg alkenyl chain, a branched or unbranched C 2 -C 9 alkynyl chain, C 3 -C 9 cycloalkyl, C 4 -C 9 cycloalkenyl or H or pharmaceutically acceptable salts thereof.
  • T 2 is C or N + .
  • W 2 , X 2 , Y 2 and Z 2 are independently from each other CH, N, N + R 5 or S + R 6 with the proviso that at least two or three of W 2 , X 2 , Y 2 and Z 2 are CH 2 -groups,
  • R 5 and R 6 are independently from each other a branched or unbranched C 1 -C 9 alkyl chain, a branched or unbranched C 2 -C 8 alkenyl chain, a branched or unbranched C 2 -C 9 alkynyl chain,
  • T 3 , W 3 , X 3 , Y 3 and Z 3 independently from each other are CH, N + R 7 or S + R 8 with the proviso that at least two or three of T 3 , W 3 , X 3 , Y 3 and Z 3 are CH 2 -groups,
  • R 7 and R 8 are independently a branched or unbranched C Cg alkyl chain, a branched or unbranched C 2 -Cg alkenyl chain, a branched or unbranched C 2 -C 9 alkynyl chain, C 3 -Cg cycloalkyl, C 4 -Cg cycloalkenyl or H, or pharmaceutically acceptable salts thereof.
  • the present invention further provides compounds of formula (I), wherein R' is
  • T 4 is C or N + , or pharmaceutically acceptable salts thereof.
  • residues R' defined in the description and the claims may be mono- or poly-substituted by, e.g., alkyl, alkoxy, alkenyl, alkynyl, acyl, carbocyclic, aryl, heteroaryl, heterocyclic, thioether, NO 2 , NH 2 , F, Cl, Br, I atoms or groups, mono- or di-substitution being preferred. It is especially preferred that the substituents are not substituted any further.
  • R' is an amino acid, a peptide or a dipeptide or a mimetic thereof.
  • the salts of the compounds of the invention may, assuming that they have basic properties, be in the form of inorganic or organic salts.
  • the compounds of the present invention can be converted into and used as acid addition salts, especially pharmaceutically acceptable acid addition salts.
  • the pharmaceutically acceptable salt generally takes a form in which a basic side chain is protonated with an inorganic or organic acid.
  • Representative organic or inorganic acids include hydrochloric, hydrobromic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p- toulenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid. All pharmaceutically acceptable acid addition salt forms of the compounds of the present invention are intended to be embraced by the scope of this invention
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • the compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • acyl can denote a C 1-2 o acyl residue, preferably a C ⁇ -8 acyl residue and especially preferred a C 1- acyl residue
  • carbocyclic or cycloalkyl can denote a C 3 - 12 carbocyclic residue, preferably a C , C 5 or C 6 carbocyclic residue
  • cycloalkenyl can denote a C 3 . 12 carbocyclic residue, preferably a C 5 or C 6 carbocyclic residue having at least one double band at any desired location.
  • Heteroaryl is defined as an aryl residue, wherein 1 to 4, preferably 1 , 2 or 3 ring atoms are replaced by heteroatoms like N, S or O.
  • Heterocycloalkyl or “heterocyclic” is defined as a cycloalkyl residue, wherein 1 , 2 or 3 ring atoms are replaced by heteroatoms like N, S or O.
  • Heterocycloalkenyl is defined as a heterocycloalkyl residue having at least one double bond at any desired location.
  • alkyl can denote a C ⁇ .
  • alkyl group preferably a C 6- 3o alkyl group, especially a C 8 .- ⁇ 2 alkyl group; an alkyl group may also be a methyl, ethyl, propyl, isopropyl or butyl group.
  • aryl is defined as an aromatic residue, preferably substituted or optionally unsubstituted phenyl, benzyl, naphthyl, biphenyl or anthracene groups, which preferably have 6-24, more preferred 8-14 C ring atoms;
  • alkenyl can denote a C 2 . ⁇ o alkenyl group, preferably a C 2-6 alkenyl group, which has the double bond or the double bonds at any desired location and may be substituted or unsubstituted;
  • alkynyl can denote a C 2-10 alkynyl group, preferably a C 2-6 alkynyl group, which has the triple bond or the triple bonds at any desired location and may be substituted or unsubstituted;
  • alkoxy can denote a C 1-50 alkyl-oxygen group, preferably a C 1-6 alkyl-oxygen group;
  • alkenyloxy can denote a C 2-10
  • Organic amines, amides, alcohols or acids each having from 8 to 50 C atoms, preferably from 10 to 20 C atoms, can have the formulae (alkyl) 2 N- or alkyl-NH-, -CO-N(alkyl) 2 or -CO-NH(alkyl), - alkyl-OH or -alkyl-COOH.
  • urethanes can denote a compound of the formula R-NH-CO-OR"", wherein R"" is a substituted alkyl, acyl, alkenyl, alkynyl, carbocyclic, heteroaryl, heterocyclic or aryl residues.
  • R is identical to the residue R of formula I and is as defined for formula I.
  • Preferred for R"" are unsubstituted or substituted alkyl residues, e. g. methyl, ethyl, ferf-butyl, 2,2,2- trichloroethyl, 2-(trimethylsilyI)ethyl; unsubstituted or substituted alkenyl residues, e. g. allyl; unsubstituted or substituted aryl residues, e. g. phenyl, benzyl, 9-fluorenylmethyl.
  • residues or groups can - if possible - be branched or unbranched, unsubstituted or substituted with, e. g., 1 , 2, 3, 4 or 5 substitutents, whereof 1 or 2 substituents are preferred.
  • the expression "peptide" for the definition of the residue R can denote any di-, tri-, tetra-, penta-, hexa-, or polypeptide.
  • the peptide can be constituted of any amino acids or mimetics of amino acids or peptides.
  • group AS-AS can be constituted of any two amino acids or mimetics thereof.
  • amino acids are: aspartic acid (Asp), glutamic acid (Glu), arginine (Arg), lysine (Lys), histidine (His), glycine (Gly), serine (Ser) and cysteine (Cys), threonine (Thr), asparagine (Asn), glutamine (Gin), tyrosine (Tyr), alanine (Ala), proline (Pro), valine (Val), isoleucine (lie), leucine (Leu), methionine (Met), phenylalanine (Phe), tryptophan (Trp), hydroxyproline (Hyp), beta-alanine (beta-Ala), 2-amino octanoic acid (Aoa), azetidine-(2)-carboxylic acid (Ace), pipecolic acid (Pip), 3-amino propionic, 4-amino butyric and so forth, alpha-aminoisobutyric acid
  • ⁇ -amino acids are e.g.: 5-Ara (aminoraleric acid), 6-Ahx (aminohexanoic acid), 8-Aoc (aminooctanoic aicd), 9-Anc (aminovanoic aicd), 10-Adc (aminodecanoic acid), 11-Aun (aminoundecanoic acid), 12-Ado (aminododecanoic acid).
  • amino acids are: indanylglycine (Igl), indoline-2-carboxylic acid (Idc), octahydroindole- 2-carboxylic acid (Oic), diaminopropionic acid (Dpr), diaminobutyric acid (Dbu), naphtylalanine (1-Nal), (2-Nai), 4-aminophenylalanin (Phe(4-NH 2 )), 4-benzoylphenylalanine (Bpa), diphenylalanine (Dip), 4-bromophenylalanine (Phe(4-Br)), 2-chlorophenylalanine (Phe(2-CI)), 3-chlorophenylalanine (Phe(3-CI)), 4-chlorophenylalanine (Phe(4-CI)), 3,4- chlorophenylalanine (Phe(3,4-CI 2 )), 3- fluorophenylalanine (Phe(3-F)
  • Proteinogenic amino acids are defined as natural protein-derived ⁇ -amino acids. Non- proteinogenic amino acids are defined as all other amino acids, which are not building blocks of common natural proteins.
  • Peptide mimetics per se are known to a person skilled in the art. They are preferably defined as compounds which have a secondary structure like a peptide and optionally further structural characteristics; their mode of action is largely similar or identical to the mode of action of the native peptide; however, their activity (e.g. as an antagonist or inhibitor) can be modified as compared with the native peptide, especially vis a vis receptors or enzymes. Moreover, they can imitate the effect of the native peptide (agonist).
  • Examples of peptide mimetics are scaffold mimetics, non-peptidic mimetics, peptoides, peptide nucleic acids, oligopyrrolinones, vinylogpeptides and oligocarbamates. For the definitions of these peptide mimetics see Lexikon der Chemie, Spektrum Akademischer Verlag Heidelberg, Berlin, 1999.
  • the present invention further includes within its scope prodrugs of the compounds, provided herein.
  • prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound.
  • the use of the present invention shall encompass the treatment of the various disorders described with prodrug versions of one or more of the claimed compounds, but which converts to the above specified compound in vivo after administration to the subject.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • Such prodrugs can be cleaved and the active inhibitors can be released. This activation of the active inhibitors can be achieved both by chemical and enzymatic reactions.
  • Esterases, proteases and peptidases serve to release the active inhibitors from the compounds according to the invention. Esterases, proteases and peptidases, which are suitable in such manner, are disclosed in WO 97/45117, US 5433955, US 5614379 and US 5624894.
  • Preferred proteases are aminopeptidases, dipeptidyl aminopeptidases, endoproteases, and endopeptidases.
  • proteases for the release of the active inhibitors from the precursor of the present invention are aminopeptidase N, aminopeptidase P, pyroglutaminyl aminopeptidase, dipeptidyl peptidase IV and dipeptidyl peptidase IV-like enzymes.
  • aminopeptidase N aminopeptidase N
  • aminopeptidase P aminopeptidase P
  • pyroglutaminyl aminopeptidase aminopeptidase P
  • dipeptidyl peptidase IV dipeptidyl peptidase IV-like enzymes.
  • the present invention accordingly also uses the concept to stabilize e.g. unstable inhibitors by masking them in prodrug form.
  • the properties of the active inhibitors can be modulated.
  • the prodrugs according to the invention have the advantage that the active inhibitors of DP I are released according to individual patients' needs.
  • this invention has the further advantage that each organism will release exactly that amount of active inhibitor that is necessary to inhibit that amount of DP l molecules, which is present in the body of the respective organism.
  • a prodrug according to the invention interacts with an enzyme as mentioned above, it is cleaved by this enzyme and the active inhibitor is released.
  • the active inhibitor will inhibit DP I so that DP I cannot cleave any further compounds for a defined time.
  • the remaining prodrugs are not degraded during a defined time and thus, constitute an inhibitor reservoir until the concentration of DP I molecules rises again or active inhibitor molecules are eliminated or inactivated.
  • compositions that comprise at least one compound according to the invention, optionally in combination with carriers and/or adjuncts etc. that are customary per se.
  • the compounds and compositions according to the invention can be used for the in vivo inhibition of the enzyme dipeptidyl peptidase I or of enzymes similar to DP I.
  • They can be used especially for the treatment of diseases of mammals that can be influenced by modulation of the DP I activity in various cells, tissues and organs.
  • the present invention further relates to the use of the compounds and compositions according to the invention for improving the wound-healing process and for the treatment of impaired wound-healing in humans.
  • the compounds may especially be in prodrug form and be used in prodrug form.
  • the compounds provided herein are highly specific inhibitors of the cysteine protease DP I.
  • Selected compounds, based on the general formula (II) below, were tested concerning their inhibitory potential against DP I and for their cross-reactivity against three more cysteine proteases, namely cathepsin B, H, L and another dipeptidyl peptidase, dipeptidyl peptidase IV (DP IV).
  • the IC 50 values of the tested compounds are given in table 1.
  • the inhibitory potential of the compounds is shown in table 2 (kj nac t/ i).
  • the toxicological potential of the compounds provided therein against murine cell lines is different from their toxicological potential against human cell lines.
  • the LD 50 values of the tested compounds are given in table 2.
  • the inhibitors 10-14 were prepared as described in Scheme 1.
  • the dipeptides 1 and 2 were prepared starting from HCI * H-Phe-OMe and Boc-Gly-OH or Boc-Sar-OH respectively (obtained from Bachem) according to a procedure described in Bodansky, M. and Bodansky,A. (Method A).
  • the dipeptides were converted into the peptidylhydroxylamines 3 and 4 by treatment with hydroxylamine (Method B). Acylation with various carbonic acid chlorides in the presence of triethylamine gave the corresponding acetyl derivatives 5-9 (Method C). Treatment of the compounds 5-9 with trifluoroacetic acid provided the inhibitors 10-14 (Method D).
  • NMR spectra were performed on Varian Unity 500 and Bruker AM 400 spectrometers. The following abbrevations are used: s, singlet; d, doublet; t, triplet; q, quartet; br., broad. Melting points were measured on a Leica Galen 111 melting point apparatus and are uncorrected.
  • ESI- MS Mass spectra were taken with an MDS Sciex API 365 mass spectrometer equipped with an lonsprayTM interface (MDS Sciex; Thorn Hill, ON, Canada). The instrument settings, data acquisition and processing were controlled by the Applied Biosystems (Foster City, CA, USA) AnalystTM software for Windows NTTM.
  • Sample solutions were diluted with 50 % methanol in 0.5 % formic acid to reach concentrations about 10 g/ml.
  • Each sample solution was introduced directly by a microsyringe (1 ml) through an infusion pump (Havard Apperatus 22; Havard Instruments; Holliston, MA, USA) and fused silica capillary tubing at a rate of 20 ⁇ l/min.
  • Thin layer chromatography (TLC) was done with Macherey Nagel Polygram ® SIL G/UV 245 .
  • Methylmorpholine, PE Petroleum ether.
  • Method B Conversation into the peptidylhydroxylamines:
  • the peptidylhydroxylamines were prepared according to the method of Br ⁇ mme, D., Demuth, H.U., N,O-Diacyl hydroxamates as selective and irreversible inhibitors of cysteine proteinases. Methods in Enzym. 244, 671 - 685. Hydroxylamine hydrochloride (827 mg, 11.9 mmol, 4.0 equiv) was dissolved in 18 ml of dry methanol. 17 ml of fresh prepared NaOMe solution (3.5 M in absolute methanol) was added dropwise.
  • the mixture was filtered after 20 min of stirring and the filtrate was dropped into a chilled and stirred solution of the dipeptide (2.97 mmol, 1.0 equiv) in 4 ml of dry methanol. After 8 h of stirring at 0°C the solvent was removed and the remaining oil was taken up in 3 ml of water and extracted with 3 ml of ethyl acetate. The aqueous phase was brought to a pH-value of 3 by means of adding KHSO and again extracted three times by means of 15 ml ethyl acetate. The organic layer was dried over Na 2 SO , filtered and evaporated. The residue was recrystallized by means of MeOH/pentane.
  • Boc-Gly-L-Phe-OMe (1) was prepared according to Method A in a yield of 98%.
  • Boc-Gly-L-Phe-NHOH (3) was prepared according to Method B in a yield of 72%.
  • Boc-Sar-L-Phe-NHOH (4) was prepared according to Method B in a yield of 88%.
  • Boc-Gly-L-Phe-NHO-Ac (5) was prepared according to Method C in a yield of 62%.
  • Boc-Gly-L-Phe-NHO-Bz (6) was prepared according to Method C in a yield of 48%.
  • Synthesis of Boc-Gly-L-Phe-NHO-Bz-p-CH 3 (7) was prepared according to Method C in a yield of 52%.
  • Boc-Gly-L-Phe-NHO-Bz-p-NO 2 was prepared according to Method C in a yield of 62%.
  • Boc-Sar-L-Phe-NHO-Bz (9) was prepared according to Method C in a yield of 78%.
  • the present invention includes the use of the compounds provided herein for the preparation of a medicament for the treatment of a condition mediated by modulation of the DP I activity in a subject.
  • the compound may be administered to a patient by any conventional route of administration, including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal, parenteral and topical. Especially preferred is topical administration.
  • the present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically active carrier.
  • compositions of this invention one or more active compounds or salts thereof of the invention as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
  • the carrier will usually comprise glycerolmonostearate, cetyl alcohol, triglycerides, vaseline, propylenglycole, water and paraffins.
  • Injectable suspensions may also prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
  • the pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.03 mg to 100 mg/kg/bw (preferred 0.1 - 30 mg/kg/bw) and may be given at a dosage of from about 0.1 - 300 mg/kg/day/bw (preferred 1 - 50 mg/kg/day/bw).
  • the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
  • compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the composition may be presented in a form suitable for once-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • a pharmaceutical carrier e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.01 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
  • Suitable carriers for topical administration include glycerolmonostearate, cetyl alcohol, triglycerides, vaseline, propylenglycole, water or paraffins.
  • the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the method of treating conditions modulated by DP I described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may contain between about 0.01 mg and 500 mg, preferably about 5 to 50 mg, of the compound, and may be formulated into any form suitable for the mode of administration selected.
  • Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions.
  • forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
  • Formulations or topical administration include creams, gels, sprays etc.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the compounds of the present invention are administered topically.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • liquid forms in suitable flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • suitable suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • tragacanth for example, tragacanth, acacia, methyl-cellulose and the like.
  • methyl-cellulose methyl-cellulose and the like.
  • suitable suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • the compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, olyhydroxyethylaspartamidephenol, or polyethyl eneoxidepolyllysine substituted with palmitoyl residue.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of the addressed disorders is required.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1.000 mg per adult human per day.
  • the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg to about 500 mg per adult human per day.
  • the range is from about 1 to about 250 mg per adult human per day.
  • compositions are preferably provided in the form of creams, gels or sprays, containing from about 0.01 to 10 %, preferably 0,1 to 10%, most preferably 1 to 10% of the active ingredient.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • the compounds or compositions of the present invention may be taken before a meal, while taking a meal or after a meal.
  • the compounds or compositions of the present invention can be taken 1 hour, preferably 30 or even 15 or 5 minutes before eating.
  • the compounds or compositions of the present invention can be mixed into the meal or taken in a separate dosage form as described above.
  • the compounds and compositions of the present invention can be taken 5, 15, or 30 minutes or even 1 hour after finishing a meal.
  • TFA ⁇ -Gly-L-Phe-NHO-Ac 10 was prepared according to Method D.
  • the compound was purified by flash chromatography to give the product as a white solid (93%) of m.p. 71-73°C. -
  • TFA*H-Gly-L-Phe-NHO-Bz-p-NO 2 (13) was prepared according to Method D.
  • the compound was purified by flash chromatography to give the product as a white solid (32%) of m.p. 80-
  • TFA ⁇ -Sar-L-Phe-NHO-Bz (14) was prepared according to Method D.
  • the compound was purified by flash chromatography to give the product as a white solid (82%) of m.p. 69-71 °C. -
  • DP I was obtained from Qiagen.
  • the assay was performed at 30°C, using a MES-buffered system (pH 5.6, 0.104 M (2-[4-Morpholino]ethanesulphonic acid) hydrat /0.0104 M KCI) containing 0.0104 M dithiothreitol and 0.0052 M EDTA.
  • the obtained data were analyzed with the enzyme kinetic calculation program Grafit 4.016 (Erithacus Ltd, UK).
  • DP I (1 U/mg, assay condition: Tagzyme handbook, Qiagen, Hilden, Germany) was diluted in MES-buffer (1 :1000) and preincubated and activated for 30 min on crashed ice.
  • the reaction mixture consists: 500 ⁇ stock solution MES-buffer, 500 /I HCI * Gly-L-Arg-pNA, 250 / I inhibitor, 50 ⁇ l DP I.
  • HEP-G2 a human hepatocyte cell line (ACC180) and L-929, a mouse fibroplast cell line (ACC2) were grown in RPM1 1604 with 10% fetal bovine serum and 60 vg/ml gentamycin. All cultures were fed every 2-3 days and incubated in an humified chamber at 37°C and 5% CO 2 .
  • Proteinases 1 lysosomal cysteine proteinases. Protein Profile 2, 1581 -1643.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Obesity (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dermatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne de nouveaux composés qui agissent en tant qu'inhibiteurs spécifiques de la cystéine protéase dipeptidylpeptidase I (DP I), lesquels sont représentés par la formule générale (I), ainsi que des sels pharmaceutiquement acceptables de ceux-ci. Dans cette formule générale (I), R représente un résidu d'acyle comprenant un uréthanne et un peptide, ou une chaîne alkyle C1-C9 ramifiée ou non ramifiée, une chaîne alcényle C2-C9 ramifiée ou non ramifiée, une chaîne alcynyle C2-C9 ramifiée ou non ramifiée, un cycloalkyle C3-C9, un carbocycle C4-C9, un aryle C5-C14, un hétéroaryle C3-C9, un hétérocycle C3-C9, tous les résidus susmentionnnés pouvant être éventuellement substitués, ou représente H, AS représentant un acide aminé ou un peptide mimétique de celui-ci. Cet acide aminé possède une liaison peptidique avec R, et R' représente une chaîne alkyle C1-C9 ramifiée ou non ramifiée, une chaîne alcényle C2-C9 ramifiée ou non ramifiée, une chaîne alcynyle C2-C9 ramifiée ou non ramifiée, un cycloalkyle C3-C9, un cycloalcényle C4-C9, un hétérocycloalkyle C2-C9, un hétérocycloalcényle C3-C9, un aryle C5-C14, un hétéroaryle C3-C9, un hétérocycle C3-C9, le résidu hétérocylcoalkyle, hétérocycloalcényle, hétéroaryle, hétérocylcique pouvant posséder jusqu'à 6 hétéroatomes sur le cycle, un acide aminé ou un peptide mimétique de celui-ci, touts les résidus susmentionnés pouvant être éventuellement substitués, ou représente H.
PCT/EP2002/010020 2001-09-06 2002-09-06 Nouveaux inhibiteurs de dipeptidylpeptidase i Ceased WO2003022871A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2003526944A JP2005511505A (ja) 2001-09-06 2002-09-06 ジペプチジルペプチダーゼｉの新規な阻害剤
EP02779316A EP1423410A2 (fr) 2001-09-06 2002-09-06 Inhibiteurs de dipeptidylpeptidase i renfermant un group hydroxylamino c-terminal
AU2002342657A AU2002342657A1 (en) 2001-09-06 2002-09-06 Peptides having a c- terminal hydroxylamino group as inhibitors of dipeptidyl peptidase i

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10143840A DE10143840A1 (de) 2001-09-06 2001-09-06 Neue Inhibitoren der Dipeptidylpeptidase I
DE10143840.0 2001-09-06

Publications (2)

Publication Number Publication Date
WO2003022871A2 true WO2003022871A2 (fr) 2003-03-20
WO2003022871A3 WO2003022871A3 (fr) 2003-11-13

Family

ID=7698010

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/010020 Ceased WO2003022871A2 (fr) 2001-09-06 2002-09-06 Nouveaux inhibiteurs de dipeptidylpeptidase i

Country Status (5)

Country Link
EP (1) EP1423410A2 (fr)
JP (1) JP2005511505A (fr)
AU (1) AU2002342657A1 (fr)
DE (1) DE10143840A1 (fr)
WO (1) WO2003022871A2 (fr)

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004106289A1 (fr) * 2003-05-30 2004-12-09 Prozymex A/S Inhibiteurs de protease
US7169926B1 (en) 2003-08-13 2007-01-30 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2007120702A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Agonistes du récepteur de gpr119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose et autres états se caractérisant par une masse osseuse faible, et thérapie de combinaison associée
US7470700B2 (en) 2003-08-13 2008-12-30 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7550590B2 (en) 2003-03-25 2009-06-23 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
EP2116235A1 (fr) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Thérapie combinée pour le traitement des diabètes et des conditions associées, et pour le traitement des conditions améliorées par l'augmentation du niveau de sang GLP-1
US7678909B1 (en) 2003-08-13 2010-03-16 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7687638B2 (en) 2004-06-04 2010-03-30 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US7732446B1 (en) 2004-03-11 2010-06-08 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7781584B2 (en) 2004-03-15 2010-08-24 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7790734B2 (en) 2003-09-08 2010-09-07 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7825242B2 (en) 2004-07-16 2010-11-02 Takeda Pharmaceutical Company Limted Dipeptidyl peptidase inhibitors
WO2011005929A1 (fr) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité
US7872124B2 (en) 2004-12-21 2011-01-18 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2011127051A1 (fr) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur de gpr119 et traitement de troubles associés
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
WO2012040279A1 (fr) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement des troubles qui lui sont liés
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2012135570A1 (fr) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles qui lui sont associés
WO2012145361A1 (fr) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145603A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145604A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2014074668A1 (fr) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulateurs de gpr119 et traitement de troubles associés à ceux-ci
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
CN113292465A (zh) * 2021-06-17 2021-08-24 贵州医科大学 一种半胱氨酸衍生物及其合成方法、应用
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
EP4000630A1 (fr) 2014-09-03 2022-05-25 Invex Therapeutics Ltd Traitement de la pression intracrânienne élevée

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004103993A1 (fr) 2003-05-14 2004-12-02 Syrrx, Inc. Inhibiteurs de dipeptidyl peptidase
EP2017620A3 (fr) * 2004-04-28 2009-04-22 Bayer HealthCare AG Diagnostics et thérapeutiques de maladies associées à la dipeptidyl-peptidase 1 (DPP1)
SG10201404220TA (en) 2006-04-11 2014-10-30 Arena Pharm Inc Methods of using gpr119 receptor to identify compounds useful for increasing bone mass in an individual
EP2108960A1 (fr) 2008-04-07 2009-10-14 Arena Pharmaceuticals, Inc. Procédés d'utilisation d'un récepteur couplé à protéine G pour identifier les secrétagogues de peptide YY (PYY) et composés utiles dans le traitement des conditions modulées de secrétagogues BY (PYY) et composés utiles dans le traitement des conditions par PYY

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR016751A1 (es) * 1996-11-22 2001-08-01 Athena Neurosciences Inc Metodo para inhibir la liberacion del peptido beta-amiloide en una celula, composicion farmaceutica y compuestos utiles en dicho metodo
DE19834610A1 (de) * 1998-07-31 2000-02-24 Probiodrug Ges Fuer Arzneim Mechanismus-orientierte Inhibitoren der Dipeptidyl Peptidase I

Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7687625B2 (en) 2003-03-25 2010-03-30 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7550590B2 (en) 2003-03-25 2009-06-23 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2004106289A1 (fr) * 2003-05-30 2004-12-09 Prozymex A/S Inhibiteurs de protease
EP1975153A2 (fr) 2003-05-30 2008-10-01 Prozymex A/S Inhibiteurs de protéase
EP1975153A3 (fr) * 2003-05-30 2010-03-31 Prozymex A/S Inhibiteurs de protéase
US7579357B2 (en) 2003-08-13 2009-08-25 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7790736B2 (en) 2003-08-13 2010-09-07 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7678909B1 (en) 2003-08-13 2010-03-16 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7169926B1 (en) 2003-08-13 2007-01-30 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7470700B2 (en) 2003-08-13 2008-12-30 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7723344B2 (en) 2003-08-13 2010-05-25 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US7790734B2 (en) 2003-09-08 2010-09-07 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7732446B1 (en) 2004-03-11 2010-06-08 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8288539B2 (en) 2004-03-15 2012-10-16 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7781584B2 (en) 2004-03-15 2010-08-24 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8329900B2 (en) 2004-03-15 2012-12-11 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7807689B2 (en) 2004-03-15 2010-10-05 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8188275B2 (en) 2004-03-15 2012-05-29 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8173663B2 (en) 2004-03-15 2012-05-08 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7687638B2 (en) 2004-06-04 2010-03-30 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US7825242B2 (en) 2004-07-16 2010-11-02 Takeda Pharmaceutical Company Limted Dipeptidyl peptidase inhibitors
US7872124B2 (en) 2004-12-21 2011-01-18 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
EP2116235A1 (fr) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Thérapie combinée pour le traitement des diabètes et des conditions associées, et pour le traitement des conditions améliorées par l'augmentation du niveau de sang GLP-1
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
EP2253311A2 (fr) 2006-04-11 2010-11-24 Arena Pharmaceuticals, Inc. Utilisation d'agonistes du récepteur de GPR119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose, et thérapie de combinaison associée
WO2007120702A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Agonistes du récepteur de gpr119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose et autres états se caractérisant par une masse osseuse faible, et thérapie de combinaison associée
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
WO2011005929A1 (fr) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité
WO2011127051A1 (fr) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur de gpr119 et traitement de troubles associés
EP3323818A1 (fr) 2010-09-22 2018-05-23 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2012040279A1 (fr) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement des troubles qui lui sont liés
WO2012135570A1 (fr) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles qui lui sont associés
WO2012145361A1 (fr) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145604A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145603A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2014074668A1 (fr) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulateurs de gpr119 et traitement de troubles associés à ceux-ci
EP4000630A1 (fr) 2014-09-03 2022-05-25 Invex Therapeutics Ltd Traitement de la pression intracrânienne élevée
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10772865B2 (en) 2015-03-09 2020-09-15 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11400072B2 (en) 2015-03-09 2022-08-02 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
CN113292465A (zh) * 2021-06-17 2021-08-24 贵州医科大学 一种半胱氨酸衍生物及其合成方法、应用

Also Published As

Publication number Publication date
DE10143840A1 (de) 2003-03-27
JP2005511505A (ja) 2005-04-28
WO2003022871A3 (fr) 2003-11-13
AU2002342657A1 (en) 2003-03-24
EP1423410A2 (fr) 2004-06-02

Similar Documents

Publication Publication Date Title
US6844316B2 (en) Inhibitors of dipeptidyl peptidase I
WO2003022871A2 (fr) Nouveaux inhibiteurs de dipeptidylpeptidase i
JP2005511505A6 (ja) ジペプチジルペプチダーゼｉの新規な阻害剤
US7279550B2 (en) Irreversible cysteine protease inhibitors of legumain
RU2299066C2 (ru) Новые ингибиторы дипептидилпептидазы iv и их применение в качестве противораковых агентов
CA2246758C (fr) Inhibiteurs peptidomimetiques de la cathepsine d et des plasmepsines i et ii
AU2002331224B2 (en) Peptidyl ketones as inhibitors of DPIV
AU2002331224A1 (en) Peptidyl ketones as inhibitors of DPIV
RU2191193C2 (ru) Ингибиторы серинпротеазы
NZ230916A (en) Peptidase inhibitors and pharmaceutical compositions thereof
JP2004521149A (ja) 新規なジペプチジルぺプチダ−ゼｉｖ阻害剤およびそれらの抗癌剤としての使用
JP2005514336A5 (fr)
EP2697246B1 (fr) Inhibiteurs sélectifs de cystéine protéase et leurs utilisations
US12590123B2 (en) Compounds and methods for treating cancer, viral infections, and allergic conditions
US20180066015A1 (en) Inhibitors of growth factor activation enzymes
ES2199505T3 (es) Agentes inhibidores de la dipeptidil peptidasa i, orientados a un mecanismo.
EP0295316A2 (fr) Dérivés d'amino-acides et peptides de 1,4-bis[(aminoalkyl et hydroxyaminoalkyl)-amino]-5,8-dihydroxyanthraquinones
CA2412954A1 (fr) Inhibiteurs peptidomimetiques de la cathepsine d et des plasmepsines i et ii

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BY BZ CA CH CN CO CR CU CZ DE DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR LC LK LR LS LT LU LV MA MD MG MN MW MX MZ NO NZ OM PH PL PT RU SD SE SG SI SK SL TJ TM TN TR TZ UA UG US UZ VN YU ZA ZM

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ UG ZM ZW AM AZ BY KG KZ RU TJ TM AT BE BG CH CY CZ DK EE ES FI FR GB GR IE IT LU MC PT SE SK TR BF BJ CF CG CI GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2002779316

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2003526944

Country of ref document: JP

WWP Wipo information: published in national office

Ref document number: 2002779316

Country of ref document: EP