DE10143840A1 - New acylated hydroxamates useful for the treatment of e.g. wound healing - Google Patents

New acylated hydroxamates useful for the treatment of e.g. wound healing

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Publication number
DE10143840A1
DE10143840A1 DE10143840A DE10143840A DE10143840A1 DE 10143840 A1 DE10143840 A1 DE 10143840A1 DE 10143840 A DE10143840 A DE 10143840A DE 10143840 A DE10143840 A DE 10143840A DE 10143840 A1 DE10143840 A1 DE 10143840A1
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branched
unbranched
chain
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cycloalkyl
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Hans-Ulrich Demuth
Ulrich Heiser
Andre J Nistroj
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Vivoryon Therapeutics AG
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Probiodrug AG
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Priority to DE10143840A priority Critical patent/DE10143840A1/en
Priority to EP02779316A priority patent/EP1423410A2/en
Priority to US10/236,136 priority patent/US6844316B2/en
Priority to AU2002342657A priority patent/AU2002342657A1/en
Priority to JP2003526944A priority patent/JP2005511505A/en
Priority to PCT/EP2002/010020 priority patent/WO2003022871A2/en
Publication of DE10143840A1 publication Critical patent/DE10143840A1/en
Priority to US10/997,821 priority patent/US7144856B2/en
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    • 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

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  • Hematology (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Obesity (AREA)
  • Dermatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

Acylated hydroxamates (I) or their salts are new. Acylated hydroxamates of formula (I): R-AS-AS-NH-O-C(=E)-R' (I) or their salts are new. R = 1-9C alkyl, 2-9C alkenyl, 2-9C alkynyl (all optionally branched), an acyl-residue containing a urethane or peptide, 3-9C cycloalkyl, 4-9C carbocyclic, 5-14C aryl, 3-9C heteroaryl, 3-9C heterocyclic (all optionally substituted) or H; AS-AS = dipeptide or its mimetic; E = O or S; and R' = 1-9C alkyl, 2-9C alkenyl, 2-9C alkynyl (all optionally branched), 2-9C heterocycloalkyl, 3-9C heterocycloalkenyl, 3-9C heteroaryl, 3-9C heterocyclic (containing 6 heteroatoms in the ring), 3-9C cycloalkyl, 4-9C cycloalkenyl, 5-14C aryl, amino acid, peptide, peptide mimetic (all optionally substituted), H, alkoxy, alkenyloxy, alkynyloxy, carbocyclicoxy, heteroaryloxy, heterocyclicoxy, thioether or a substituted residue. AN Independent claim is included for the use of (I) in the preparation of a medicament for the treatment of diseases of mammals by modulation of the activity of cysteine protease dipeptidyl peptidase 1 (DP 1) and/or DP 1-like enzymes.

Description

Die vorliegende Erfindung betrifft Verbindungen, die als spezifische Inhibitoren der Cysteinprotease Dipeptidyl Peptidase I (DP I) wirken. Diese Verbindungen werden durch die allgemeine Formel R-A-B-NH-O-C(O)R' repräsentiert, in der R eine verzweigte oder unverzweigte C1-9 Alkylkette, eine verzweigte oder unverzweigte C2-9 Alkenylkette, eine verzweigte oder unverzweigte C2-9 Alkinylkette, ein C3-9 Cycloalkyl, C4-9 Cycloalkenyl, C5-14 Aryl, alle vorstehenden Reste optional substituiert, oder H ist, A eine Aminosäure oder ein Mimetikum dieser Aminosäure ist, die in Peptidbindung mit B vorliegt, B eine Aminosäure oder ein Mimetikum dieser Aminosäure, außer Prolin und Hydroxyprolin, ist und R' eine verzweigte oder unverzweigte C1-C9 Alkylkette, eine verzweigte oder unverzweigte C2-C9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9 Alkinylkette, ein C3-9 Cycloalkyl, C4-C9 Cycloalkenyl, C2-C9 Heterocycloalkyl, C3-C9 Heterocycloalkenyl, C5-14 Aryl, das im Ring bis zu 6 Heteroatome aufweisen kann, eine Aminosäure oder ein Mimetikum dieser Aminosäure, alle vorstehenden Reste optional substituiert, oder H ist. The present invention relates to compounds which act as specific inhibitors of the cysteine protease dipeptidyl peptidase I (DP I). These compounds are represented by the general formula RAB-NH-OC (O) R ', in which R is a branched or unbranched C 1-9 alkyl chain, a branched or unbranched C 2-9 alkenyl chain, a branched or unbranched C 2-9 Alkynyl chain, a C 3-9 cycloalkyl, C 4-9 cycloalkenyl, C 5-14 aryl, all of the above radicals are optionally substituted, or H is, A is an amino acid or a mimetic of this amino acid which is in peptide bond with B, B is a Amino acid or a mimetic of this amino acid, other than proline and hydroxyproline, and R '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 C 3-9 cycloalkyl, C 4 -C 9 cycloalkenyl, C 2 -C 9 heterocycloalkyl, C 3 -C 9 heterocycloalkenyl, C 5-14 aryl, which can have up to 6 heteroatoms in the ring, an amino acid or a mimetic of this amino acid , all of the above radicals optionally substituted rt, or H.

Derartige Verbindungen zeichnen sich dadurch aus, daß sie in wäßrigen Lösungen, einschließlich biologischer Flüssigkeiten, chemisch stabil sind. Unmittelbar nach enzymatischer Einwirkung durch DP I auf diese Verbindungen entfalten diese ihre inhibitorische Aktivität gegenüber dem Targetenzym, was schließlich zur effizienten und vollständigen Inhibierung der DP I führt. Such connections are characterized in that they are in aqueous solutions, including biological liquids, are chemically stable. Immediately after enzymatic The influence of DP I on these connections unfold theirs inhibitory activity against the target enzyme what finally, for efficient and complete inhibition of the DP I leads.

Von Dipeptidyl Peptidase I ist bekannt, daß sie aktive, granulozytäre Serinproteasen lymphatischer Zellen aus ihren Pro- Formen freisetzt, also bei Mechanismen mitwirkt, die physiologisch durch cytotoxische Lymphozyten bei der Immunabwehr genutzt werden. Bei pathophysiologischen Entartungen zellulärer Prozesse wie malignen Transformationen myeloider und lymphatischer Zellen kann die Suppression derartiger Mechanismen zur Behandlung von Krebs- oder Immunerkrankungen oder Stoffwechselerkrankungen genutzt werden. Die erfindungsgemäßen Inhibitoren der DP I können zur Behandlung von derartigen pathophysiologischen Zuständen bzw. Erkrankungen eingesetzt werden. Dipeptidyl peptidase I is known to be active, granulocytic serine proteases of lymphatic cells from their pro Releases forms, i.e. participates in mechanisms that physiologically by cytotoxic lymphocytes in the immune system be used. With pathophysiological degeneration cellular processes like malignant transformations myeloid and Lymphatic cells can suppress such mechanisms for the treatment of cancer or immune diseases or Metabolic diseases can be used. The Inhibitors of DP I according to the invention can be used for treatment of such pathophysiological conditions or Diseases are used.

Neben Proteasen, die in unspezifische Proteolyse einbezogen sind, was letztlich den Abbau von Proteinen zu Aminosäuren bewirkt, kennt man regulatorische Proteasen, die an der Funktionalisierung (Aktivierung, Deaktivierung, Modulierung) von endogenen Peptidwirkstoffen beteiligt sind (Kirschke et al., 1995) Kräusslich & Wimmer, 1987). Insbesondere im Zusammenhang mit der Immunforschung und der Neuropeptidforschung sind eine Reihe solcher sogenannten Konvertasen, Signalpeptidasen oder Enkephalinasen entdeckt worden (Gomez et al., 1988) (Ansorge et al., 1991). In addition to proteases involved in non-specific proteolysis are what ultimately breaks down proteins into amino acids causes, one knows regulatory proteases, which on the Functionalization (activation, deactivation, modulation) of endogenous peptide agents are involved (Kirschke et al., 1995) Krausslich & Wimmer, 1987). Especially in Are related to immune research and neuropeptide research a number of such so-called convertases, signal peptidases or enkephalinases have been discovered (Gomez et al., 1988) (Ansorge et al., 1991).

Dipeptidyl Peptidase I (DP I, Peptidase Klassifizierung Clan CA, Familie C1, IUBMB Enzym Klassifizierung EC 3.4.14.1, CAS Registration Nr. 9032-68-2) wurde von Gutman & Fruton 1948 entdeckt. DP I spaltet mit relativ breiter Substratspezifität sequentiell Dipeptide von unsubstituierten N-Termini von Polypeptidsubstraten ab (McDonald et al., 1971; McDonald & Schwabe, 1977). DP I ist eine lysosomale Cysteinprotease, die durch die Abspaltung N-terminaler Dipeptide aktive Enzyme aus Proenzymen, wie Granzym A, Granzym B, Leukozyten Elastase, Cathepsin B, Neuraminidase in den lysosomalen Granula cytotoxischer T-Lymphozyten freisetzen kann (Kummer et al., 1996; Thiele & Lipsky, 1997. Dipeptidyl peptidase I (DP I, peptidase classification clan CA, family C1, IUBMB enzyme classification EC 3.4.14.1, CAS Registration No. 9032-68-2) was made by Gutman & Fruton in 1948 discovered. DP I cleaves with a relatively broad substrate specificity sequentially dipeptides of unsubstituted N-termini from Polypeptide substrates (McDonald et al., 1971; McDonald & Schwabe, 1977). DP I is a lysosomal cysteine protease that active enzymes by cleaving N-terminal dipeptides Proenzymes, such as granzyme A, granzyme B, leukocyte elastase, Cathepsin B, neuraminidase in the lysosomal granules can release cytotoxic T lymphocytes (Kummer et al., 1996; Thiele & Lipsky, 1997.

Es wird daher vermutet, daß DP I in pathologische Mechanismen wie apoptotische Prozesse, Muskeldystrophie und Krebsentstehung involviert ist (Aoyagi et al., 1983; Gelman et al., 1980; Schlangenauff et al., 1992; Shi et al., 1992). It is therefore suspected that DP I in pathological mechanisms like apoptotic processes, muscular dystrophy and Cancer formation is involved (Aoyagi et al., 1983; Gelman et al., 1980; Schlangenauff et al., 1992; Shi et al., 1992).

DP I ist als Konvertase des Blutzucker-steigernden Hormons Glukagon bekannt, das bei enzymatisch verminderter Konzentration zu lebensbedrohlicher Hypoglykämie führen kann (McDonald, J. K et al., 1971). DP I is a convertase of the blood sugar-increasing hormone Known glucagon, which is enzymatically reduced Concentration can lead to life-threatening hypoglycemia (McDonald, J.K et al., 1971).

DP I wird durch reversible und irreversible Cysteinproteaseinhibitoren wie Leupeptin bzw. E-64 nur schwach inhibiert (Nikawa et al., 1992). Stärkere reversible Inhibitoren sind Stefin A und Chicken Cystatin, Proteininhibitoren aus der Cystatin Superfamilie (Nicklin & Barrett, 1984). Eine spezifische Inhibierung wurde mit den a priori reaktiven affinity label vom Typ der Diazomethylketone und Sulphonylmethylketone erreicht (Angliker et al., 1989; Green & Shaw, 1981; Hanzlik, R. P. & Xing, R., 1998). In den letzten Jahren wurden weitere neuartige reversible DP I-Inhibitoren sowie irreversibel wirkende affinity label der DP I bekannt (Palmer et. al., 1998; Thiele et al., 1997). DP I becomes reversible and irreversible Cysteine protease inhibitors such as leupeptin or E-64 only weakly inhibited (Nikawa et al., 1992). Stronger reversible inhibitors are Stefin A and Chicken Cystatin, protein inhibitors from the Cystatin superfamily (Nicklin & Barrett, 1984). A specific inhibition was reactive with the a priori affinity label of the diazomethyl ketone and Sulphonyl methyl ketones achieved (Angliker et al., 1989; Green & Shaw, 1981; Hanzlik, R.P. & Xing, R., 1998). In recent years were other novel reversible DP I inhibitors as well known irreversible affinity label of the DP I (Palmer et. al., 1998; Thiele et al., 1997).

Im Gegensatz zu derartigen reversiblen Inhibitoren, die aufgrund von Diffusionsprozessen nur kurzzeitige Wirkungen entfalten können, und den in vitro auf das Zielenzym zwar irreversibel wirkenden affinity label, die aber durch ihren a priori vorhandenen chemisch reaktiven Rest vor ihrer Interaktion mit dem Zielprotein mit anderen Nukleophilen oder Elektrophilen in biologischen Flüssigkeiten reagieren können, zeichnen sich mechanismus-orientierte Inhibitoren dadurch aus, daß sie nur durch das Zielenzym katalytisch angegriffen und erst dadurch aktiviert werden. Derartige Inhibitoren sind auch als Selbstmord-Inaktivatoren bekannt. Solche hocheffizienten Selbstmordinaktivatoren für Cysteinproteasen wurden mit der Klasse der N-Peptidyl, O-Acyl Hydroxlamine entwickelt (Brömme et al., 1996). Inhibitoren der DP I wurden aus dieser Verbindungsklasse nicht abgeleitet, da sich DP I gegenüber typischen irreversiblen Cysteinproteaseinhibitoren wie z. B. E-64 inert verhält. In contrast to such reversible inhibitors that only short-term effects due to diffusion processes can unfold, and in vitro on the target enzyme irreversible affinity label, but by its a priori existing chemically reactive residue before their Interaction with the target protein with other nucleophiles or Electrophiles can react in biological fluids, Mechanism-oriented inhibitors are characterized by this from the fact that they are only catalytically attacked by the target enzyme and only then be activated. Such inhibitors are also known as suicide inactivators. Such highly efficient suicide inactivators for cysteine proteases have been identified developed the class of N-peptidyl, O-acyl hydroxlamine (Brömme et al., 1996). Inhibitors of DP I were derived from this Connection class not derived because DP I are opposite each other typical irreversible cysteine protease inhibitors such. B. E-64 behaves inertly.

Weiterhin neigen N-terminal ungeschützte Dipeptid-Derivate zu rapider, intramolekularer Zersetzung. Furthermore, N-terminally unprotected dipeptide derivatives tend to rapid, intramolecular decomposition.

Der Erfindung liegt daher der überraschende Befund zugrunde, daß sich erfindungsgemäße Verbindungen der allgemeinen Formel R-A-B-NH-O-C(O)R' mit einer für die Dipeptidyl Peptidase I charakteristischen Substratstruktur als hochpotente und hydrolytisch stabile irreversible Selbstmordinaktivatoren der DP I erweisen. Im Vergleich zu bisher bekannten DP I- Inhibitoren sind die erfindungsgemäßen Verbindungen außerordentlich potent. The invention is therefore based on the surprising finding that compounds of the general formula according to the invention R-A-B-NH-O-C (O) R 'with one for the dipeptidyl peptidase I characteristic substrate structure as highly potent and hydrolytically stable irreversible suicide inactivators of DP I prove. Compared to previously known DP I- The compounds according to the invention are inhibitors extremely potent.

Damit ist es möglich, selektive Inhibitoren der Dipeptidyl Peptidase I darzustellen, die sich durch hohe Stabilität und Selektivität gegenüber dem Zielenzym ausweisen. Derartige Verbindungen können zur Beeinflussung DP I-vermittelter pathologischer Prozesse dienen. Die erfindungsgemäßen Inhibitoren der DP I können in pharmazeutischen Formulierungen zur Behandlung von derartigen pathophysiologischen Zuständen bzw. Erkrankungen eingesetzt werden. This makes it possible to use selective inhibitors of dipeptidyl To represent peptidase I, which is characterized by high stability and Show selectivity towards the target enzyme. such Connections can be used to influence DP-mediated serve pathological processes. The invention Inhibitors of DP I can be used in pharmaceutical formulations Treatment of such pathophysiological conditions or Diseases are used.

Verbindungen der Formel R1-CO-NH-O-CO-R2 sind an sich bekannt, vgl. DD 294 711, wobei die Reste R1-CO- N-geschützte oder ungeschützte Aminosäurereste sowie N-geschützte oder ungeschützte Peptidylreste sein können; und die Reste R2-CO- aliphatische, verzweigte, aromatische sowie aromatische substituierte Acylreste, wie substituierte Benzoylreste, unsubstituierte heterocyclische Acylreste, primäre oder sekundäre, aliphatische, verzweigt aliphatische, heterocyclische oder aromatische, substituierte oder unsubstituierte Amine oder C-terminal geschützte oder ungeschützte Aminosäuren oder Peptide sein können. Compounds of the formula R 1 -CO-NH-O-CO-R 2 are known per se, cf. DD 294 711, where the residues R 1 can be -CO- N-protected or unprotected amino acid residues and N-protected or unprotected peptidyl residues; and the radicals R 2 -CO- aliphatic, branched, aromatic and aromatic substituted acyl radicals, such as substituted benzoyl radicals, unsubstituted heterocyclic acyl radicals, primary or secondary, aliphatic, branched aliphatic, heterocyclic or aromatic, substituted or unsubstituted amines or C-terminally protected or unprotected Amino acids or peptides can be.

Erfindungsgemäß ist nun gefunden worden, daß Verbindungen der allgemeinen Formel R-A-B-NH-O-C(O)R' überraschend gut zur Inibierung von Dipeptidyl Peptidase 1 geeignet sind, in der R eine verzweigte oder unverzweigte C1-9 Alkylkette, eine verzweigte oder unverzweigte C2-9 Alkenylkette, eine verzweigte oder unverzweigte C2-9 Alkinylkette, ein C3-9 Cycloalkyl, C4-9 Cycloalkenyl, C5-14 Aryl, alle vorstehenden Reste optional substituiert, oder H ist, A eine Aminosäure oder ein Mimetikum dieser Aminosäure ist, die in Peptidbindung mit B vorliegt, B eine Aminosäure oder ein Mimetikum dieser Aminosäure, außer Prolin und Hydroxyprolin, ist und R' eine verzweigte oder unverzweigte C1-C9 Alkylkette, eine verzweigte oder unverzweigte C2-C9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9 Alkinylkette, ein C3-9 Cycloalkyl, C4-C9 Cycloalkenyl, C2-C9 Heterocycloalkyl, C3-C9 Heterocycloalkenyl, C5-14 Aryl, das im Ring bis zu 6 Heteroatome aufweisen kann, eine Aminosäure oder ein Mimetikum dieser Aminosäure, alle vorstehenden Reste optional substituiert, oder H ist. According to the invention, it has now been found that compounds of the general formula RAB-NH-OC (O) R 'are surprisingly well suited for inhibiting dipeptidyl peptidase 1 in which R is a branched or unbranched C 1-9 alkyl chain, a branched or unbranched C 2-9 alkenyl chain, a branched or unbranched C 2-9 alkynyl chain, a C 3-9 cycloalkyl, C 4-9 cycloalkenyl, C 5-14 aryl, all the above radicals are optionally substituted, or H, A is an amino acid or a mimetic this amino acid which is in peptide bond with B, B is an amino acid or a mimetic of this amino acid, apart from proline and hydroxyproline, and R '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 C 3-9 cycloalkyl, C 4 -C 9 cycloalkenyl, C 2 -C 9 heterocycloalkyl, C 3 -C 9 heterocycloalkenyl, C 5-14 aryl which is in the ring up may have up to 6 heteroatoms, an amino acid or a mimetic of this amino acid, all of the above radicals are optionally substituted, or H is.

Es hat sich als besonders vorteilhaft herausgestellt, wenn der Rest R ein Phenyl- oder Naphthylrest ist, der optional einfach oder mehrfach mit C1-C6 Alkoxy, C1-C6 Alkyl, NO2-, NH2-, F-, Cl-, Br-, I- Atomen bzw. Gruppen substituiert ist. It has turned out to be particularly advantageous if the radical R is a phenyl or naphthyl radical which may optionally be mono- or polysilicon with C 1 -C 6 alkoxy, C 1 -C 6 alkyl, NO 2 -, NH 2 -, F-, Cl, Br, I atoms or groups is substituted.

Besonders bevorzugt wird, wenn R' ein Phenyl- oder Naphthylrest ist, der optional einfach oder mehrfach mit C1- C6 Alkoxy, C1-C6 Alkyl, NO2-, NH2-, F-, Cl-, Br-, I-Atomen bzw. Gruppen substituiert ist, oder
wenn R' optional substituiertes


ist, wobei V gleich N oder CH und n = 1-6 ist. It is particularly preferred if R 'is a phenyl or naphthyl radical optionally mono- or polysubstituted with C 1 - C 6 alkoxy, C 1 -C 6 alkyl, NO 2 -, NH 2 -, F-, Cl-, Br- , I atoms or groups is substituted, or
if R 'is optionally substituted


where V is N or CH and n = 1-6.

Gemäß einer weiteren Ausführungsform werden erfindungsgemäß Verbindungen der Formel 1 bereitgestellt, wobei R' optional substituiertes

ist, wobei T1 gleich CH oder N ist,
W1, X1, Y1, Z1 unabhängig voneinander CH2, NR1, N+(R2)2, O, S, SO, S (R3)2, SO2 sind,
R1 eine verzweigte oder unverzweigte C1-C9 Alkylkette, eine verzweigte oder unverzweigte C2-C9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9 Alkinylkette, C3-9 Cycloalkyl, C4-C9 Cycloalkenyl oder H ist,
R2 unabhängig voneinander eine verzweigte oder unverzweigte C1-9 Alkylkette, eine verzweigte oder unverzweigte C2-9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9 Alkinylkette, C3-9 Cycloalkyl, C4-C9 Cycloalkenyl oder H ist und
R3 unabhängig voneinander eine verzweigte oder unverzweigte C1-C9 Alkylkette, eine verzweigte oder unverzweigte C2-C9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9 Alkinylkette, C3-9 Cycloalkyl, C4-C9 Cycloalkenyl oder H ist, wobei die Verbindungen pharmazeutisch akzeptable Anionen aufweisen können,
oder
erfindungsgemäße Verbindungen, wobei R' optional substituiertes


ist, wobei T2 gleich C oder N+ ist,
W2, X2, Y2, Z2 unabhängig voneinander CH, N, N+R4 oder S+R5 sind,
R4 eine verzweigte oder unverzweigte C1-C9 Alkylkette, eine verzweigte oder unverzweigte C2-C9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9 Alkinylkette, eine Cycloalkyl, C4-C9 Cycloalkenyl oder H ist,
R5 eine verzweigte oder unverzweigte C1-C9 Alkylkette, eine verzweigte oder unverzweigte C2-C9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9 Alkinylkette, C3-9 Cycloalkyl, C4-C9 Cycloalkenyl oder H ist, wobei die Verbindungen pharmazeutisch akzeptable Anionen aufweisen können, oder
oder
erfindungsgemäße Verbindungen, wobei R' optional substituiertes


ist, wobei S, W3, X3, Y3, Z3 unabhängig voneinander CH, N+R7 oder S+R8 sind,
R7 eine verzweigte oder unverzweigte C1-C9 Alkylkette, eine verzweigte oder unverzweigte C2-C9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9 Alkinylkette, C3-9 Cycloalkyl, C4-C9 Cycloalkenyl oder H ist,
R8 eine verzweigte oder unverzweigte C1-C9 Alkylkette, eine verzweigte oder unverzweigte C2-C9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9 Alkinylkette, C3-9 Cycloalkyl, C4-C9 Cycloalkenyl oder H ist, wobei die Verbindungen pharmazeutisch akzeptable Anionen aufweisen können,
oder
erfindungsgemäße Verbindungen, wobei R' optional substituiertes


ist, wobei T3 gleich C oder N+ ist, wobei die Verbindungen pharmazeutisch akzeptable Anionen aufweisen können. According to a further embodiment, compounds of formula 1 are provided according to the invention, where R 'is optionally substituted

where T 1 is CH or N,
W 1 , X 1 , Y 1 , Z 1 are independently CH 2 , NR 1 , N + (R 2 ) 2 , O, S, SO, S (R 3 ) 2 , SO 2 ,
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, C 3-9 cycloalkyl, C 4 -C 9 cycloalkenyl or H. .
R 2 is independently a branched or unbranched C 1-9 alkyl chain, a branched or unbranched C 2-9 alkenyl chain, a branched or unbranched C 2 -C 9 alkynyl chain, C 3-9 cycloalkyl, C 4 -C 9 cycloalkenyl or H. and
R 3 independently of one another 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, C 3-9 cycloalkyl, C 4 -C 9 cycloalkenyl or Is H, where the compounds may have pharmaceutically acceptable anions,
or
Compounds according to the invention, where R 'is optionally substituted


where T 2 is C or N + ,
W 2 , X 2 , Y 2 , Z 2 are independently CH, N, N + R 4 or S + R 5 ,
R 4 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 cycloalkyl, C 4 -C 9 cycloalkenyl or H,
R 5 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, C 3-9 cycloalkyl, C 4 -C 9 cycloalkenyl or H. , wherein the compounds can have pharmaceutically acceptable anions, or
or
Compounds according to the invention, where R 'is optionally substituted


where S, W 3 , X 3 , Y 3 , Z 3 are independently CH, N + R 7 or S + R 8 ,
R 7 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, C 3-9 cycloalkyl, C 4 -C 9 cycloalkenyl or H. .
R 8 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, C 3-9 cycloalkyl, C 4 -C 9 cycloalkenyl or H. , where the compounds can have pharmaceutically acceptable anions,
or
Compounds according to the invention, where R 'is optionally substituted


where T 3 is C or N + , where the compounds may have pharmaceutically acceptable anions.

Die in der Beschreibung und den Ansprüchen definierten Reste R' können einfach oder mehrfach mit C1-C6 Alkoxy, C1-C6 Alkyl, NO2-, NH2-, F-, Cl-, Br-, I- Atomen bzw. Gruppen substituiert sein, wobei eine einfache oder zweifache Substitution bevorzugt ist. The radicals R 'defined in the description and the claims can be mono- or polysubstituted by C 1 -C 6 alkoxy, C 1 -C 6 alkyl, NO 2 , NH 2 , F, Cl, Br, I atoms or groups may be substituted, with a single or double substitution being preferred.

Weiter werden erfindungsgemäß Verbindungen offenbart, bei denen R' eine Aminosäure oder Mimetikum dieser Aminosäure ist. According to the invention, compounds are also disclosed in which R 'is an amino acid or mimetic of this amino acid is.

Die erfindungsgemäßen Verbindungen können auch als Prodrugs vorliegen. The compounds according to the invention can also be used as prodrugs available.

Erfindungsgemäß werden weiter pharmazeutische Zusammensetzungen bereitgestellt, die mindestens eine erfindungsgemäße Verbindung, optional in Kombination mit an sich üblichen Trägern und/oder Adjuvantien etc., umfassen. According to the invention further pharmaceutical Compositions provided that at least one of the invention Connection, optionally in combination with conventional ones Carriers and / or adjuvants etc. include.

Die erfindungsgemäßen Verbindungen bzw. Zusammensetzungen können zur in vivo Inhibierung des Enzyms Dipeptidyl Peptidase I oder zur DP I ähnlichen Enzymen verwendet werden. The compounds or compositions according to the invention can inhibit the enzyme dipeptidyl in vivo Peptidase I or enzymes similar to DP I can be used.

Insbesondere können sie zur Behandlung von Erkrankungen von Säugern verwendet werden, die durch Modulation der DP I-Aktivität in verschiedenen Zellen, Geweben und Organen beeinflußt werden können. In particular, they can be used to treat diseases of Mammals used by modulating the DP I activity in different cells, tissues and organs affected can be.

Sie sind insbesondere zur Behandlung von DP I-vermittelten malignen Zell-Entartungen, Immun- und Stoffwechselerkrankungen des Menschen geeignet. They are especially I-mediated for the treatment of DP malignant cell degeneracy, immune and Metabolic diseases of humans suitable.

Ferner betrifft die vorliegende Erfindung die Verwendung der erfindungsgemäßen Verbindungen und Zusammensetzungen zur Verbesserung des Wundheilungsprozesses und zur Therapie von beeinträchtigter Wundheilung des Menschen. Furthermore, the present invention relates to the use of the Compounds and compositions according to the invention for Improvement of the wound healing process and for the therapy of impaired wound healing in humans.

Insbesondere können die Verbindungen in Prodrugform vorliegen und zum Einsatz kommen. Literaturverzeichnis Ansorge, S., Schön, E., and Kunz, D. (1991). Membrane-bound peptidases of lymphocytes: functional implications. Biomed. Biochim. Acta 50, 799-807.
Angliker, H., Wikstrom, P., Kirschke, H., and Shaw, E. (1989). The inactivation of the cysteinyl exopeptidases cathepsin H and C by affinity - labelling reagents. Biochem. J. 262, 63-68.
Aoyagi T., Wada, T., Kojima, F., Nagai, M., Miyoshino, S., and Umezawa, H. (1983). Two different modes of enzymatic changes in serum with progression of Duchenne muscular dystrophy. Clin. Chim. Acta 129, 165-173.
Brömme, D., Neumann, U., Kirschke, H., and Demuth, H.-U. (1996). Novel N-peptidyl-O-acyl hydroxamates: selective inhibitors of cysteine proteinases. Biochim. Biophys. Acta. 1202, 271-276.
Gelman B. B., Papa, L., Davis, M. H., and Gruenstein, E. (1980). Decreased lysosomal dipeptidyl aminopeptidase I activity in cultured human skin fibroblasts in Duchenne's muscular dystrophy. J. Clin. Invest. 65, 1398-1406.
Gomez, S., Gluschankof, P., Lepage, A., and Cohen, P. (1988). Relationship between endo- and exopeptidases in a processing enzyme system: activation of an endoprotease by the aminopeptidase B-like activity in somatostatin-28 convertase. Proc Natl Acad Sci USA 85, 5468-5472.
Green G. D. J. & Shaw, E. (1981). Peptidyl diazomethyl ketones are specific inactivators of thiol proteinases. J. Biol. Chem. 256, 1923-1928.
Gutman H. R. & Fruton, J. S. (1948). On the proteolytic enzymes of animal tissues VIII. An intracellular enzyme related to chymotrypsin. J. Biol. Chem. 174, 851-858.
Hanzlik, R. P. & Xing, R. (1998). Azapeptides as inhibitors and active site titrants for cysteine Proteinases. J. Med. Chem. 41, 1344-1351.
Kirschke, H., Barrett, A. J., and Rawlings, N. D. (1995). Proteinases 1: lysosomal cysteine proteinases. Protein Profile 2, 1581-1643.
Kräusslich, H.-G. and Wimmer, E. (1987). Viral Proteinases. Ann. Rev. Biochem. 57, 701
Kummer, J. A., Kamp, A. M., Citarella, F., Horrevoets, A. J. G., and Hack, C. E. (1996). Expression of human recombinant granzyme A zymogen and its activation by the cysteine proteinase cathepsin C. J. Biol. Chem. 271, 9281-9286.
McDonald, J. K, Callahan, P. X., Ellis, S., and Smith, R. E. (1971). Polypeptide degradation by dipeptidyl aminopeptidase I (cathepsin C) and related peptidases. In: Tissue Proteinases (Barrett, A. J. & Dingle, J. T., eds). Amsterdam: North-Holland Publishing, pp. 69-107.
McDonald, J. K. & Schwabe, C. (1977). Intracellular exopeptidases. In: Proteinases in Mammalian Cells and Tissues (Barrett, A. J., ed.). Amsterdam: North Holland Publishing, pp. 311-391.
Nicklin, M. J. H. & Barrett, A. J. (1984). Inhibition of cysteine proteinases and dipeptidyl peptidase I by eggwhite cystatin. Biochem. J. 223, 245-253.
Nikawa, T., Towatari, T., and Katunuma, N. (1992). Purification and characterization of cathepsin J from rat liver. Eur. J. Biochem. 204, 381-393.
Palmer, J. T., Rasnick, D., and Klaus, J. L. (1998). Reversible protease inhibitors. US-Pat. 5,776,718.
Schlagenauff, B., Klessen, C., Teichmann-Dörr, S., Breuninger, H., and Rassner, G. (1992). Demonstration of proteases in basal cell carcinomas. A histochemical study using amino acid-4-methoxy-2-naphthylamides as chromogenic substrates. Cancer 70, 1133-1140.
Shi, L., Kam, C.-M., Powers, J. C., Aebersold, R., and Greenberg, A. H. (1992). Purification of three cytotoxic lymphocyte granule serine proteases that induce apoptosis through distinct substrate and target cell interactions. J. Exp. Med. 176, 1521-1529.
Thiele, D. L., Lipsky, P. E., and McGuire, M. J. (1997). Dipeptidyl Peptidase-I inhibitors and uses thereof. US-Pat. 5,602,102. In particular, the compounds can be in prodrug form and can be used. Bibliography Ansorge, S., Schön, E., and Kunz, D. (1991). Membrane-bound peptidases of lymphocytes: functional implications. Biomed. Biochim. Acta 50, 799-807.
Angliker, H., Wikstrom, P., Kirschke, H., and Shaw, E. (1989). The inactivation of the cysteinyl exopeptidases cathepsin H and C by affinity - labeling reagents. Biochem. J. 262, 63-68.
Aoyagi T., Wada, T., Kojima, F., Nagai, M., Miyoshino, S., and Umezawa, H. (1983). Two different modes of enzymatic changes in serum with progression of Duchenne muscular dystrophy. Clin. Chim. Acta 129, 165-173.
Brömme, D., Neumann, U., Kirschke, H., and Demuth, H.-U. (1996). Novel N-peptidyl-O-acyl hydroxamates: selective inhibitors of cysteine proteinases. Biochim. Biophys. Acta. 1202, 271-276.
Gelman BB, Papa, L., Davis, MH, and Gruenstein, E. (1980). Decreased lysosomal dipeptidyl aminopeptidase I activity in cultured human skin fibroblasts in Duchenne's muscular dystrophy. J. Clin. Invest. 65, 1398-1406.
Gomez, S., Gluschankof, P., Lepage, A., and Cohen, P. (1988). Relationship between endo- and exopeptidases in a processing enzyme system: activation of an endoprotease by the aminopeptidase B-like activity in somatostatin-28 convertase. Proc Natl Acad Sci USA 85, 5468-5472.
Green GDJ & Shaw, E. (1981). Peptidyl diazomethyl ketones are specific inactivators of thiol proteinases. J. Biol. Chem. 256, 1923-1928.
Gutman HR & Fruton, JS (1948). On the proteolytic enzymes of animal tissues VIII. An intracellular enzyme related to chymotrypsin. J. Biol. Chem. 174, 851-858.
Hanzlik, RP & Xing, R. (1998). Azapeptides as inhibitors and active site titrants for cysteine proteinases. J. Med. Chem. 41, 1344-1351.
Kirschke, H., Barrett, AJ, and Rawlings, ND (1995). Proteinases 1: lysosomal cysteine proteinases. Protein Profile 2, 1581-1643.
Krausslich, H.-G. and Wimmer, E. (1987). Viral proteinases. Ann. Rev. Biochem. 57, 701
Kummer, JA, Kamp, AM, Citarella, F., Horrevoets, AJG, and Hack, CE (1996). Expression of human recombinant granzyme A zymogen and its activation by the cysteine proteinase cathepsin CJ Biol. Chem. 271, 9281-9286.
McDonald, J.K. Callahan, PX, Ellis, S., and Smith, RE (1971). Polypeptide degradation by dipeptidyl aminopeptidase I (cathepsin C) and related peptidases. In: Tissue Proteinases (Barrett, AJ & Dingle, JT, eds). Amsterdam: North-Holland Publishing, pp. 69-107.
McDonald, JK & Schwabe, C. (1977). Intracellular exopeptidases. In: Proteinases in Mammalian Cells and Tissues (Barrett, AJ, ed.). Amsterdam: North Holland Publishing, pp. 311-391.
Nicklin, MJH & Barrett, AJ (1984). Inhibition of cysteine proteinases and dipeptidyl peptidase I by eggwhite cystatin. Biochem. J. 223, 245-253.
Nikawa, T., Towatari, T., and Katunuma, N. (1992). Purification and characterization of cathepsin J from rat liver. Eur. J. Biochem. 204, 381-393.
Palmer, JT, Rasnick, D., and Klaus, JL (1998). Reversible protease inhibitors. US Pat. 5,776,718.
Schlagenauff, B., Klessen, C., Teichmann-Dörr, S., Breuninger, H., and Rassner, G. (1992). Demonstration of proteases in basal cell carcinomas. A histochemical study using amino acid-4-methoxy-2-naphthylamides as chromogenic substrates. Cancer 70, 1133-1140.
Shi, L., Kam, C.-M., Powers, JC, Aebersold, R., and Greenberg, AH (1992). Purification of three cytotoxic lymphocyte granule serine proteases that induce apoptosis through distinct substrate and target cell interactions. J. Exp. Med. 176, 1521-1529.
Thiele, DL, Lipsky, PE, and McGuire, MJ (1997). Dipeptidyl peptidase-I inhibitors and uses thereof. US Pat. 5,602,102.

Claims (17)

1. Verbindungen der allgemeinen Formel 1 und die pharmazeutischen Salze davon,


in der R eine verzweigte oder unverzweigte C1-9 Alkylkette, eine verzweigte oder unverzweigte C2-9 Alkenylkette, eine verzweigte oder unverzweigte C2-9 Alkinylkette, ein C3-9 Cycloalkyl, C4-9 Cycloalkenyl, C5-14 Aryl, alle vorstehenden Reste optional substituiert, oder H ist, A eine Aminosäure oder ein Mimetikum dieser Aminosäure ist, die in Peptidbindung mit B vorliegt, B eine Aminosäure oder ein Mimetikum dieser Aminosäure, außer Prolin und Hydroxyprolin, ist und R' eine verzweigte oder unverzweigte C1-C9 Alkylkette, eine verzweigte oder unverzweigte C2-C9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9 Alkinylkette, ein C3-9 Cycloalkyl, C4-C9 Cycloalkenyl, C2-C9 Heterocycloalkyl, C3-C9 Heterocycloalkenyl, C5-14 Aryl, das im Ring bis zu 6 Heteroatome aufweisen kann, eine Aminosäure oder ein Mimetikum dieser Aminosäure, alle vorstehenden Reste optional substituiert, oder H ist. 1. Compounds of the general formula 1 and the pharmaceutical salts thereof,


in which R is a branched or unbranched C 1-9 alkyl chain, a branched or unbranched C 2-9 alkenyl chain, a branched or unbranched C 2-9 alkynyl chain, a C 3-9 cycloalkyl, C 4-9 cycloalkenyl, C 5-14 Aryl, all of the above radicals are optionally substituted, or H is, A is an amino acid or a mimetic of this amino acid which is in peptide bond with B, B is an amino acid or a mimetic of this amino acid, except proline and hydroxyproline, and R '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 C 3-9 cycloalkyl, C 4 -C 9 cycloalkenyl, C 2 -C 9 heterocycloalkyl , C 3 -C 9 heterocycloalkenyl, C 5-14 aryl which can have up to 6 heteroatoms in the ring, an amino acid or a mimetic of this amino acid, all of the above radicals are optionally substituted, or H 2. Verbindungen nach Anspruch 1, wobei R ein Phenyl oder Naphthyl, optional einfach oder mehrfach mit C1-C6 Alkoxy, C1- C6 Alkyl, NO2-, NH2-, F-, Cl-, Br-, I- Atomen bzw. Gruppen substituiert, ist. 2. Compounds according to claim 1, wherein R is a phenyl or naphthyl, optionally one or more times with C 1 -C 6 alkoxy, C 1 - C 6 alkyl, NO 2 -, NH 2 -, F-, Cl-, Br-, I atoms or groups is substituted. 3. Verbindungen nach Anspruch 1 oder 2, wobei R' ein Phenyl oder Naphthyl ist. 3. Compounds according to claim 1 or 2, wherein R 'is a phenyl or is naphthyl. 4. Verbindungen nach Anspruch 1 oder 2, wobei R' optional substituiertes


ist, wobei V gleich N oder CH und n = 1-6 ist. 4. Compounds according to claim 1 or 2, wherein R 'optionally substituted


where V is N or CH and n = 1-6. 5. Verbindungen nach Anspruch 1 oder 2, wobei R' optional substituiertes


ist, wobei T1 gleich CH oder N ist,
W1, X1, Y1, Z1 unabhängig voneinander CH2, NR1, N+(R2)2, O, S, SO, S(R3)2, SO2 sind,
R1 eine verzweigte oder unverzweigte C1-C9 Alkylkette, eine verzweigte oder unverzweigte C2-C9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9 Alkinylkette, C3-9 Cycloalkyl, C4-C9 Cycloalkenyl oder H ist,
R2 unabhängig voneinander eine verzweigte oder unverzweigte C1-9 Alkylkette, eine verzweigte oder unverzweigte C2-9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9Alkinylkette, C3-9 Cycloalkyl, C4-C9 Cycloalkenyl oder H ist und
R3 unabhängig voneinander eine verzweigte oder unverzweigte C1-C9 Alkylkette, eine verzweigte oder unverzweigte C2-C9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9 Alkinylkette, C3-9 Cycloalkyl, C4-C9 Cycloalkenyl oder H ist,
wobei die Verbindungen pharmazeutisch akzeptable Anionen aufweisen können. 5. Compounds according to claim 1 or 2, wherein R 'optionally substituted


where T 1 is CH or N,
W 1 , X 1 , Y 1 , Z 1 are independently CH 2 , NR 1 , N + (R 2 ) 2 , O, S, SO, S (R 3 ) 2 , SO 2 ,
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, C 3-9 cycloalkyl, C 4 -C 9 cycloalkenyl or H. .
R 2 is independently a branched or unbranched C 1-9 alkyl chain, a branched or unbranched C 2-9 alkenyl chain, a branched or unbranched C 2 -C 9 alkynyl chain, C 3-9 cycloalkyl, C 4 -C 9 cycloalkenyl or H. and
R 3 independently of one another 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, C 3-9 cycloalkyl, C 4 -C 9 cycloalkenyl or H is
the compounds may have pharmaceutically acceptable anions. 6. Verbindungen nach Anspruch 1 oder 2, wobei R' optional substituiertes


ist, wobei T2 gleich C oder N+ ist,
W2, X2, Y2, Z2 unabhängig voneinander CH, N, N+R4 oder S+R5 sind,
R4 eine verzweigte oder unverzweigte C1-C9 Alkylkette, eine verzweigte oder unverzweigte C2-C9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9 Alkinylkette, C3-9 Cycloalkyl, C4-C9 Cycloalkenyl oder H ist,
R5 eine verzweigte oder unverzweigte C1-C9 Alkylkette, eine verzweigte oder unverzweigte C2-C9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9 Alkinylkette, C3-9 Cycloalkyl, C4-C9 Cycloalkenyl oder H ist, wobei die Verbindungen pharmazeutisch akzeptable Anionen aufweisen können. 6. Compounds according to claim 1 or 2, wherein R 'optionally substituted


where T 2 is C or N + ,
W 2 , X 2 , Y 2 , Z 2 are independently CH, N, N + R 4 or S + R 5 ,
R 4 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, C 3-9 cycloalkyl, C 4 -C 9 cycloalkenyl or H. .
R 5 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, C 3-9 cycloalkyl, C 4 -C 9 cycloalkenyl or H. , wherein the compounds may have pharmaceutically acceptable anions. 7. Verbindungen nach Anspruch 1 oder 2, wobei R' optional substituiertes


ist, wobei S, W3, X3, Y3, Z3 unabhängig voneinander CH, N+R7 oder S+R8 sind,
R7 eine verzweigte oder unverzweigte C1-C9 Alkylkette, eine verzweigte oder unverzweigte C2-C9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9 Alkinylkette, C3-9 Cycloalkyl, C4-C9 Cycloalkenyl oder H ist,
R8 eine verzweigte oder unverzweigte C1-C9 Alkylkette, eine verzweigte oder unverzweigte C2-C9 Alkenylkette, eine verzweigte oder unverzweigte C2-C9 Alkinylkette, C3-9 Cycloalkyl, C4-C9 Cycloalkenyl oder H ist, wobei die Verbindungen pharmazeutisch akzeptable Anionen aufweisen können. 7. Compounds according to claim 1 or 2, wherein R 'optionally substituted


where S, W 3 , X 3 , Y 3 , Z 3 are independently CH, N + R 7 or S + R 8 ,
R 7 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, C 3-9 cycloalkyl, C 4 -C 9 cycloalkenyl or H. .
R 8 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, C 3-9 cycloalkyl, C 4 -C 9 cycloalkenyl or H. , wherein the compounds may have pharmaceutically acceptable anions. 8. Verbindungen nach Anspruch 1 oder 2, wobei R' optional substituiertes


ist, wobei T3 gleich C oder N+ ist, wobei die Verbindungen pharmazeutisch akzeptable Anionen aufweisen können. 8. Compounds according to claim 1 or 2, wherein R 'optionally substituted


where T 3 is C or N + , where the compounds may have pharmaceutically acceptable anions. 9. Verbindungen nach einem der vorstehenden Ansprüche, wobei alle als R' definierten Reste einfach oder mehrfach mit C1-C6 Alkoxy, C1-C6 Alkyl, NO2-, NH2-, F-, Cl-, Br-, I-Atomen bzw. Gruppen substituiert sein können. 9. Compounds according to any one of the preceding claims, wherein all radicals defined as R 'are singly or multiply with C 1 -C 6 alkoxy, C 1 -C 6 alkyl, NO 2 -, NH 2 -, F-, Cl-, Br- , I atoms or groups can be substituted. 10. Verbindungen nach Anspruch 1 oder 2, wobei R' eine Aminosäure oder ein Mimetikum dieser Aminosäure ist. 10. Compounds according to claim 1 or 2, wherein R 'is a Amino acid or a mimetic of this amino acid. 11. Verbindungen nach einem der vorstehenden Ansprüche, dadurch gekennzeichnet, daß sie als Prodrugs vorliegen. 11. Compounds according to one of the preceding claims, characterized in that they are present as prodrugs. 12. Pharmazeutische Zusammensetzung, dadurch gekennzeichnet, daß sie eine Verbindung nach einem der vorstehenden Ansprüche optional in Kombination mit pharmazeutisch akzeptablen Trägern und/oder Adjuvantien enthält. 12. Pharmaceutical composition, characterized in that they have a connection according to one of the preceding claims optionally in combination with pharmaceutically acceptable Contains carriers and / or adjuvants. 13. Verwendung von Verbindungen oder pharmazeutischen Zusammensetzungen nach einem der vorstehenden Ansprüche zur Herstellung eines Medikaments zur in vivo-Inhibierung von DP I oder/und DP I ähnlichen Enzymen. 13. Use of compounds or pharmaceutical Compositions according to one of the preceding claims for Manufacture of a medicament for in vivo inhibition of DP I or / and DP I-like enzymes. 14. Verwendung von Verbindungen oder pharmazeutischen Zusammensetzungen nach einem der Ansprüche 1 bis 12 zur Behandlung von Erkrankungen von Säugern, die durch Modulation der DP I-Aktivität eines Säugers behandelt werden können. 14. Use of compounds or pharmaceutical Compositions according to one of claims 1 to 12 for Treatment of diseases of mammals by modulation the DP I activity of a mammal can be treated. 15. Verwendung nach Anspruch 14 zur Behandlung von malignen Zellentartungen, Immun- und Stoffwechselerkrankungen des Menschen. 15. Use according to claim 14 for the treatment of malignancies Cell degeneration, immune and metabolic diseases of the People. 16. Verwendung nach Anspruch 14 zur Verbesserung des Wundheilungsprozesses und zur Therapie von beeinträchtigter Wundheilung des Menschen. 16. Use according to claim 14 to improve the Wound healing process and for the therapy of impaired Human wound healing. 17. Verwendung nach Anspruch 13-16, wobei die Verbindungen in Prodrugform vorliegen. 17. Use according to claim 13-16, wherein the compounds in Prodrug form available.
DE10143840A 2001-09-06 2001-09-06 New acylated hydroxamates useful for the treatment of e.g. wound healing Withdrawn DE10143840A1 (en)

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EP02779316A EP1423410A2 (en) 2001-09-06 2002-09-06 Peptides having a c-terminal hydroxylamino group as inhibitors of dipeptidyl peptidase i
US10/236,136 US6844316B2 (en) 2001-09-06 2002-09-06 Inhibitors of dipeptidyl peptidase I
AU2002342657A AU2002342657A1 (en) 2001-09-06 2002-09-06 Peptides having a c- terminal hydroxylamino group as inhibitors of dipeptidyl peptidase i
JP2003526944A JP2005511505A (en) 2001-09-06 2002-09-06 Novel inhibitors of dipeptidyl peptidase I
PCT/EP2002/010020 WO2003022871A2 (en) 2001-09-06 2002-09-06 Peptides having a c- terminal hydroxylamino group as inhibitors of dipeptidyl peptidase i
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