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EP1673075A2 - Nouveaux inhibiteurs d'alanyl-aminopeptidases destines a exercer une influence fonctionnelle sur diverses cellules et a constituer un traitement immunologique de maladies inflammatoires, neuronales et autres - Google Patents

Nouveaux inhibiteurs d'alanyl-aminopeptidases destines a exercer une influence fonctionnelle sur diverses cellules et a constituer un traitement immunologique de maladies inflammatoires, neuronales et autres

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Publication number
EP1673075A2
EP1673075A2 EP04790485A EP04790485A EP1673075A2 EP 1673075 A2 EP1673075 A2 EP 1673075A2 EP 04790485 A EP04790485 A EP 04790485A EP 04790485 A EP04790485 A EP 04790485A EP 1673075 A2 EP1673075 A2 EP 1673075A2
Authority
EP
European Patent Office
Prior art keywords
unsubstituted
compounds
substituted
tautomers
stereoisomers
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04790485A
Other languages
German (de)
English (en)
Inventor
Siegfried Ansorge
Ute Bank
Karsten Nordhoff
Michael TÄGER
Frank Striggow
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.)
IMTM GmbH
KeyNeurotek AG
Original Assignee
IMTM GmbH
KeyNeurotek 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 IMTM GmbH, KeyNeurotek AG filed Critical IMTM GmbH
Publication of EP1673075A2 publication Critical patent/EP1673075A2/fr
Withdrawn legal-status Critical Current

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    • C07C327/48—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
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Definitions

  • New alanyl aminopeptidase inhibitors for the functional influencing of different cells and for the treatment of immunological, inflammatory, neuronal and other diseases
  • the ubiquitous alanyl aminopeptidases include the aminopeptidase N (APN, CD 13, EC 3.4.11.2), which predominantly occurs as type II membrane protein, and the cytosolic, soluble alanyl aminopeptidase (EC 3.4.11.14, puromycin-sensitive aminopeptidase, aminopeptidase PS, Enkephaiin-degrading aminopeptidase). Both peptidases are metal-dependent and catalyze the hydrolysis of peptide bonds behind N-terminal amino acids of oligopeptides, in the case of APN with a preference for alanine at the N-terminus (AJ Barrett et al .: Handbook of Proteolytic Enzymes, Academic Press 1998 ).
  • the receptor for coronaviruses which among other things cause the disease SARS, is the aminopeptidase N.
  • the isolated inhibition of the alanyl aminopeptidases and analog peptidases leads to a strong inhibition of D ⁇ A synthesis on immune cells and thus to cell proliferation and to a change in cytokine production, in particular to induction of the immunoregulatory effect TGF-ßl (international patent application WO 01/89569 AI, international patent application WO 02/053170 A3).
  • Alanyl aminopeptidase inhibitors cause a strong induction of TGF- ⁇ 1 (international patent application PCT EP 03 07199) on regulatory T cells.
  • a reduction or delay in acute and chronic cerebral damage processes has been demonstrated in the neuronal system by inhibiting the alanyl aminopeptidases, but especially by combined inhibition of the alanyl aminopeptidases and the dipeptidyl peptidase IV and analogous enzymes (international patent application WO 02/053169 A3 and German patent application DE -A 103 37 074.9). It has also been shown on fibroblasts (German patent application DE-A D 103 30 842.3), keratinocytes (international patent application WO 02/0531 70) and sebocytes (international patent application PCT EP 03/02356) that the inhibition of alanyl aminopeptidases, but especially that Inhibition of both peptidase systems, an inhibition of growth and a change in cytokine production.
  • the object of the present invention was to find further effective inhibitors of alanyl aminopeptidases.
  • low molecular weight, easily accessible compounds should be found which are effective, i.e. H. allow effective inhibition of alanyl aminopeptidases and analog enzymes.
  • the invention therefore relates to substances which specifically inhibit Ala-p-nitroanilide-cleaving peptidases.
  • the present invention relates to compounds of the general formulas AI to A14 according to claims 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and 27 as well as tautomers and stereoisomers of the compounds mentioned general formulas AI to A14 and pharmaceutically acceptable salts, salt derivatives, tautomers and stereoisomers thereof, for use in medicine.
  • the invention relates to specific, preferred compounds of the special formulas AI.001 to A14.003, which fall under the above general formulas AI to A14 and which are exemplary, but not restrictive, in claims 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 and 28 are listed in the form of tables, and tautomers and stereoisomers of the compounds mentioned of the general formulas AI .001 to AI 4.003 and pharmaceutically acceptable salts, salt derivatives, tautomers and stereoisomers thereof, for use in medicine.
  • the invention further relates to pharmaceutical compositions which comprise at least one compound of one of the general formulas AI to A14, optionally in combination with carriers or adjuvants which are customary per se.
  • the invention further relates to cosmetic compositions which comprise at least one compound of one of the general formulas AI to AI 4, optionally in combination with conventional carriers or adjuvants.
  • the invention further relates to the use of at least one compound of the general formulas AI to A14 or at least one of the abovementioned pharmaceutical or cosmetic compositions for inhibiting the activity of alanyl aminopeptidases or analogous enzymes, either alone or in combination with inhibitors of DPIV or analogous enzymes ,
  • the invention further relates to the use of at least one compound of the general formulas AI to A14 or at least one of the abovementioned pharmaceutical or cosmetic compositions for topically influencing the activity of alanyl aminopeptidases or analogous enzymes, either alone or in combination with inhibitors of DPIN or analogues enzymes.
  • the invention further relates to the use of at least one compound of the general formulas AI to A14 or at least one of the aforementioned pharmaceutical or, if appropriate, also cosmetic compositions for the prophylaxis and therapy of a whole number of diseases, which are claimed in claims 33 to 45 by way of example.
  • the compounds of the general formulas AI to AI 4 in particular those in Table 1 to 14 listed, particularly preferred individual compounds AI.001 to A14.003, as such or as starting materials for other substances and in combination with inhibitors of DPIN and analogous enzymes for the therapy of diseases with an excessive immune response (autoimmune diseases, allergies and transplant rejections), of other chronic inflammatory ones Diseases, neuronal diseases and cerebral damage, skin diseases (including acne and psoriasis), tumor diseases and special viral infections (including SARS) can be used.
  • the invention further relates to the use of at least one compound of the general formulas AI to A14 or at least one of the aforementioned pharmaceutical or cosmetic compositions for the manufacture of a medicament for inhibiting the activity of alanyl aminopeptidases or analogous enzymes, either alone or in combination with inhibitors of DPIN or analog enzymes.
  • the invention further relates to the use of at least one compound of the general formulas AI to A14 or at least one of the aforementioned pharmaceutical or cosmetic compositions for the manufacture of a medicament for topically influencing the activity of alanyl aminopeptidases or analogous enzymes, either alone or in combination with inhibitors the DP1Y or analog enzymes.
  • the invention further relates to the use of at least one compound of the general formulas AI to AI 4 or at least one of the aforementioned pharmaceutical or optionally also cosmetic compositions for the production of a medicament for the prophylaxis and therapy of a whole number of diseases, which are exemplary in claims 48 to 60 are claimed.
  • the compounds of the general formulas AI to AI 4 in particular the particularly preferred individual compounds AI.001 to A14.003 listed in Tables 1 to 14, as such or as starting materials for further substances and in Combination with DPIV inhibitors and analogous enzymes for the manufacture of a medicament for the therapy of diseases with excessive immune response (autoimmune diseases, allergies and graft rejections), other chronic inflammatory ones Diseases, neuronal diseases and cerebral damage, skin diseases (including acne and psoriasis), tumor diseases and special viral infections (including SARS) can be used.
  • the invention further relates to a method for inhibiting the activity of the alanyl peptidases or analogous enzymes alone or in combination with inhibitors of the DPIV and analogous enzymes by administration of at least one compound of the general formulas AI to A14 or at least one of the above pharmaceutical or cosmetic compositions in one for the Inhibition of the amount of enzyme activity required.
  • the invention further relates to a method for topically influencing the activity of alanyl peptidases or analogous enzymes alone or in combination with inhibitors of DPIV and analogous enzymes by administration of at least one compound of the general formulas AI to AI 4 or at least one of the above pharmaceutical or cosmetic compositions in one amount required to inhibit enzyme activity.
  • the invention further relates to a method for the prophylaxis and / or therapy of one of the diseases or conditions claimed in claims 63 to 76 while inhibiting the activity of alanyl peptidases or analogous enzymes alone or in combination with inhibitors of DPIN and analogous enzymes by administration of at least one compound of the general formulas AI to AI 4 or at least one of the above pharmaceutical or cosmetic compositions in an amount required for prophylaxis or therapy.
  • analogous enzymes refers to enzymes which have an enzyme activity analogous to the membrane-bound alanyl aminopeptidase, as is the case, for example, for the cytosolic alanyl aminopeptidase.
  • the term is in this sense also explained in the above-cited publication "AJ Barrett et al .: Handbook of Proteolytic Enzymes, Academic Press 1998".
  • radicals Rn are in the general formulas AI to A14, as can be seen from claims 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and 27 in general form , ie the radicals Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, Rl l, R12 and R13 each independently for a radical which is selected from the group consisting of hydrogen , un- substituted or substituted, straight or branched C ⁇ - to C 12 - alkyl, C 2 - to C 12 alkenyl and C 2 - to C 12 alkynyl, hydroxy, thiol, C ⁇ - C 12 alkoxy, - to C 12 - alkylthio, unsubstituted or substituted, uncondensed or condensed, optionally containing one or more heteroatoms from the group consisting of N, O, P and S aryl and cycloalkyl, unsubstituted or substituted amino, unsubstituted or
  • radicals Rn in embodiments according to the invention if they represent unsubstituted straight-chain or branched alkyl groups having 1 to 12 carbon atoms, in preferred embodiments methyl, ethyl, n-propyl, i-propyl, n-butyl, i - Butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, sec-pentyl, tert-pentyl, n-hexyl, i-hexyl, 3-methylpentyl, 2-ethylbutyl, 2,2-dimethylbutyl and for the residues heptyl, octyl, nonyl.
  • Decyl, undecyl and dodecyl all straight-chain and branched isomers.
  • particularly preferred from the aforementioned group are alkyl groups with 1 to 6 carbon atoms; of these, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and tert-butyl are more preferred.
  • the radicals Rn can also stand for straight-chain and branched alkenyl groups with several double bonds.
  • Preferred radicals from this group are the butadienyl group and the isoprenyl group.
  • Particular preferred from the aforementioned group are alkenyl Groups with 2 to 6 carbon atoms; of these, vinyl, allyl, 1-butenyl and 2-butenyl are more preferred.
  • the radicals Rn when they represent unsubstituted straight-chain or branched alkynyl groups having 2 to 12 carbon atoms, in preferred embodiments are ethynyl, propynyl, 1-butynyl, 2-butynyl, and for the radicals pentynyl, hexynyl, Heptinyl, octynyl, nonynyl, decynyl, undecynyl and dodecynyl all straight-chain and branched residues conceivable with regard to the position of the C ⁇ C triple bond.
  • particularly preferred from the aforementioned group are alkynyl groups with 2 to 6 C atoms; of these, ethynyl, propynyl, 1-butynyl and 2-butynyl are more preferred.
  • both straight-chain and branched alkyl, alkenyl or alkynyl radicals can be substituted in a further embodiment.
  • the substituents can be located at any position on the basic structure formed from carbon atoms and can be selected from the group consisting of halogen atoms such as fluorine, Cng, bromine and iodine, alkyl groups with 1 to 6 C atoms, alkoxy groups with 1 to 6 C atoms in the alkyl radical and unsubstituted or with one or two alkyl radicals each independently substituted by 1 to 6 carbon atoms.
  • the radicals Rn in the general formulas AI to A14 Ci- to C 12 alkoxy mean radicals or C to C 12 - alkylthio radicals.
  • the abovementioned definitions of straight-chain and branched alkyl radicals also apply to the C 1 -C 12 -alkyl groups of these alkoxy or alkylthio radicals.
  • Straight-chain Ci- are particularly preferred to C 6 alkoxy radicals and straight-chain Ci to C6 alkylthio radicals, and are particularly preferably the radicals methoxy, Etlioxy, n-propoxy, methylthio, ethylthio and n-propylthio.
  • the radicals Rn of the general formulas AI to AI 4 can also represent unsubstituted or substituted cycloalkyl radicals. According to the invention, these can preferably contain three to eight atoms in the ring and can either consist of finally consist of carbon atoms or contain one or more heteroatoms.
  • cyclopentyl particularly preferred among the purely carbocyclic rings are cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl and cycloheptatrienyl;
  • cycloalkyl radicals containing heteroatoms in further embodiments of the invention are the radicals tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, hnidazolidinyl, piperidinyl, piperazinyl and morpholinyl.
  • Possible substituents on these carbocyclic or heterocyclic cycloalkyl radicals can be selected from the above group of substituents for linear alkyl groups.
  • the radicals Rn on the compounds of the general formulas AI to A14 can be uncondensed or condensed aryl radicals optionally containing one or more heteroatoms from the group consisting of N, O, P and S.
  • the aryl radicals can consist of one or more rings, preferably two rings in the case of several rings; a ring can further preferably have five, six or seven ring members.
  • benzo-condensed rings are particularly preferred, i. H. Ring systems in which at least one of the rings is an aromatic six-membered ring.
  • the aryl radicals consisting purely of carbon atoms are particularly preferably selected from phenyl, cyclopentadienyl, cycloheptatrienyl and naphthyl;
  • Aryl radicals containing particularly preferred heteroatoms are selected, for example, from indolyl, coumaronyl, thionaphthenyl, quinolinyl (benzopyridyl), quinazolinyl (benzopyrimidinyl) and quinoxylinyl (benzopyrazinyi).
  • aryl radicals consisting of one ring as well as several rings, both containing only carbon atoms and also containing heteroatoms, can be substituted according to the invention.
  • the substituents can be located at any position in the ring system, both on the carbon atoms and on the heteroatoms, and can be selected, for example, from the group consisting of halogen atoms such as fluorine, chlorine, bromine and iodine, alkyl groups with 1 to 6 carbon atoms, Alkoxy groups with 1 to 6 carbon atoms in the alkyl radical and unsubstituted or with one or two alkyl radicals each with independently substituted 1 to 6 C atoms amino groups.
  • the substituents Rl and Rm therein have the meanings defined in detail above for the radicals Rn and can be identical or different.
  • substituents Rm of substituted carbonyl radicals or substituted thiocarbonyl radicals have the meanings defined above in detail for the possible substituents of the radicals Rn.
  • the radicals Rn are connected to the respective basic structures of the general formulas AI to A14 via the hetero atom or one of their heteroatoms.
  • the radicals Y each independently represent one of the radicals O, S or NRn, for example NR3 or NR4 or NR5, which are bonded to a carbon atom via a double bond
  • the radicals Rn (for example R3 or R4 or R5) may have the meanings given above, including the meaning water material.
  • Y particularly preferably represents O bonded to a C atom via a double bond.
  • X, XI, X2 and Z represent radicals which each have a CX single bond (or C-Xl single bond or C-X2 single bond) or a CZ single bond are bonded to two different carbon atoms.
  • radicals X and Z in the general formulas in which they occur each independently represent one of the radicals>NH,> NRn (e.g.> NR5 or> NR10), each bonded to a single bond to two different carbon atoms, - O-, -S-, -CH 2 -, -CHRn- or -CRn 2 -, in which the radicals Rn have the meaning given above, or stand for one of the radicals bonded via three single bonds to three different carbon atoms, > CH- or> CRn- (e.g.> CR8- or> CR9-), wherein Rn (e.g. R8, R9) have the meanings given above.
  • NRn e.g.> NR5 or> NR10
  • Z represents P or S.
  • X and Z independently of one another represent radicals from the group consisting of hydroxy, thiol, - to C 12 -alkoxy, C ⁇ - to C 12 -alkylthio, unsubstituted or substituted, uncondensed or condensed, optionally one or more heteroatoms from the group consisting of N, O, P and S containing aryl and cycloalkyl and amino (NH 2 , NHRl, NR1R2), in which all of the aforementioned meanings of X and Z correspond to those for alkoxy, alkylthio, aryl, cycloalkyl and amino , which were defined above for the radicals Rn of the general formulas AI to AI 4 in detail.
  • XI and X2 can be identical or different and are selected independently of one another from the group consisting of hydroxyl, thiol, Ci to -C 2 alkoxy, - to C 12 alkylthio, unsubstituted or substituted, uncondensed or condensed, optionally containing one or more heteroatom (s) from the group N, O, P and S aryl or cycloalkyl, hydroxy, thiol, and amino (NH 2 , HNR1, NR1R2).
  • Rl and R2 have the meanings given above.
  • the radicals R8, R9 and RIO have the meanings given above.
  • the compounds corresponding to the general formulas AI to A14 in general and the special compounds AI .001 to AI 4.003 mentioned in Tables 1 to 14 are claimed in preferred embodiments of the invention for use in medicine.
  • the term “for use in medicine” is understood here in its broadest meaning as in the patent claims and relates to all conceivable fields of application in which the compounds of the general formulas AI to 14 defined by the present invention and, in preferred embodiments, the compounds AI .001 to A14.003, as specifically listed in Tables 1 to 14, can be effective in connection with medically relevant conditions of the mammalian body, in particular the human body.
  • the compounds of the general formulas AI to AI 4 are used in general and the preferred compounds AI.001 to A14.003 according to Tables 1 to 14 are used either in the form of the use of a single compound or in the form of the Use of several compounds of the general formulas AI to A14 (in particular the preferred compounds AI.001 to A14.003 according to Tables 1 to 14) instead.
  • the use of one or more of the compounds of the general formulas AI to AI 4, preferably one or more compounds from the group selected from the compounds AI.001 to A14.003 according to Tables 1 to 14 Combination with other active ingredients, for example with one or more compounds, the effectiveness in the indi- bition of alanyl aminopeptidases or of analogous enzymes (i.e. enzymes with the same substrate specificity) and / or effectiveness in the inhibition of other enzymes, for example the dipeptidyl peptidase IN (DPIV) or of analogous enzymes (i.e. enzymes with the same substrate specificity).
  • DPIV dipeptidyl peptidase IN
  • analogous enzymes i.e. enzymes with the same substrate specificity
  • inhibitors which act as inhibitors of alanylamino peptidase may include, for example: actinonine, leuhistine, phebestine, amastatin, admire, probestin, ⁇ -aminothiols, ⁇ -aminophosphinic acids, aminophosphinic acid derivatives, preferably D-Phe- ⁇ / '- PO (OH) -CH 2 ] -Phe Phe.
  • Particularly preferred known inhibitors for the alanyl amino peptidase to be used together with the compounds according to the invention are Bestaun (Ubenimex), Actinonin, Probestin, Phebestin, RB3014 or Leuhistin.
  • a further embodiment of the invention relates to pharmaceutical preparations which contain at least one, optionally also two or even more, compound (s) of the general formulas AI to A14, particularly preferably selected from the compounds AI .001 to A14.003 according to Tables 1 to 14 , include.
  • Such pharmaceutical preparations comprise one or more of the compounds mentioned in each case in such an amount as is necessary for the development of a pharmaceutical effect.
  • the person skilled in the art can determine such quantities easily and without inventive step using a few routine tests; they are generally in the range from 0.01 to 1000 mg of each of the compounds of the general formulas AI to A14, particularly preferably the compounds AI.001 to A14.003 according to Tables 1 to 14, per administration unit, even more preferably in the range from 0 , 1 to 100 mg of each of the compounds mentioned per dosage unit.
  • Quantities tailored to the individual mammalian organism or human organism can easily determine and, if necessary, also provide that a sufficient concentration of the compounds (s) to be used is achieved by administering divided or several dosage forms.
  • a further embodiment of the invention relates to cosmetic preparations which contain at least one, optionally also two or even more, compound (s) of the general formulas AI to A14, particularly preferably selected from the compounds AI .001 to A14.003 according to Tables 1 to 14 , include.
  • Such cosmetic preparations comprise one or more of the compounds mentioned in each case in such an amount as is necessary for the development of a desired, for example cosmetic, effect.
  • the person skilled in the art can determine such quantities easily and without inventive step using a few routine tests; they are generally in the range from 0.01 to 1000 mg of each of the compounds of the general formulas AI to A14, particularly preferably the compounds AI.001 to A14.003 according to Tables 1 to 14, per administration unit, even more preferably in the range from 0 , 1 to 100 mg of each of the compounds mentioned per dosage unit.
  • the person skilled in the art can easily determine quantities which are matched to the respective individual mammal organism or human organism and, if appropriate, also provide that a sufficient concentration of the compounds to be used is achieved by administering divided or several dosage forms.
  • the one or more compounds according to the present invention or pharmaceutical or cosmetic preparations containing them are administered simultaneously with known carriers and / or auxiliaries (adjuvants).
  • carriers and auxiliary substances are known to the person skilled in the art as such and also with regard to their function and mode of use and therefore do not require any detailed explanation at this point.
  • the invention also includes pharmaceutical preparations which comprise: one or more of the inhibitors of DP IN or the inhibitors of enzymes with DP IV-analogous enzyme activity or / and the inhibitors of APN or the inhibitors of enzymes with APN-analogous enzyme activity according to the prior art, together with one or more compound (s) of the general formulas AI to AI 4, particularly preferred together with one or more of the Neritatien, which are selected from Neritatien AI .001 to A14.003 from Table 1 to 14, in spatially restricted formulation in combination with known carrier, auxiliary and / or additives for simultaneous or immediately consecutive ner administration with the aim of a common effect.
  • the Ner administration of the Neritatien of the general formulas AI to A14 in general and preferably of the compounds AI.001 to A14.003 according to Tables 1 to 14 or pharmaceutical or cosmetic preparations which contain one or more of the abovementioned compounds together with conventional carriers, Auxiliaries and / or additives comprise, on the one hand, as a topical application in the form of, for example Creams, ointments, pastes, gels, solutions, sprays, liposomes and ⁇ anosomes, shake mixes, "pegylated” formulations, degradable (ie degradable under physiological conditions) depot matrices, hydrocolloid dressings, plasters, microsponges, prepolyomers and similar new carrier substrates, jet -Injection or other dermatological bases / vehicles including instillative application, and on the other hand as a systemic application for oral, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular, intrathecal use in suitable formulations or in suitable galenics.
  • the compounds of the general formulas AI to AI 4 in general and preferably the compounds AI.001 to AI 4.003 according to Tables 1 to 14 individually or in combination, or else pharmaceutical or cosmetic compositions which comprise one or more of the compounds mentioned Inhibition of the activity of alanyl aminopeptidases or analog enzymes used alone or in combination with inhibitors of dipeptidyl peptidase IV and inhibitors of analog enzymes.
  • the compounds of the general formulas AI to A14 in general and preferably the compounds AI.001 to A14.003 according to Tables 1 to 14 individually or in combination, or else pharmaceutical or cosmetic compositions which comprise one or more of the mentioned compounds include, for topical influencing the activity of alanyl aminopeptidases or analogous enzymes used alone or in combination with inhibitors of Dipeptidylpeptidase TV and inhibitors of analogous enzymes.
  • the compounds of the general formulas AI to AI 4 in general and preferably the compounds AI.001 to A14.003 according to Tables 1 to 14 are used individually or in combination, or else pharmaceutical or cosmetic compositions are used, which comprise one or more of the compounds mentioned, for the prophylaxis and therapy of diseases such as, for example, multiple sclerosis, Crohn's disease, ulcerative colitis, and other autoimmune diseases and inflammatory diseases, bronchial asthma and other allergic diseases, skin and mucous membrane diseases, for example psoriasis, Acne and dermatological diseases with hyperproliferation and altered differentiation states of fibroblasts, benign fibrosing and sclerosing skin diseases and malignant fibroblastic hyperproliferation states, acute neuronal diseases, such as ischemia-bed Severe cerebral damage after an ischemic or hemorrhagic stroke, skull / brain trauma, cardiac arrest, heart attack or as a result of cardiac surgery, chronic neuronal diseases, for example Alzheimer's disease, Pick's
  • diseases such as, for
  • the compounds of the general formulas AI to AI 4 are used in general and preferably the compounds AI.001 to A14.003 according to Tables 1 to 14 individually or in combination, or else the pharmaceutical or cosmetic compositions, which comprise one or more of the compounds mentioned, for the prophylaxis and therapy of the rejection of trans planted tissues and cells.
  • the use of one or more of the above-mentioned compounds or a pharmaceutical composition containing one or more of the above-mentioned compounds in allogeneic kidney or stem cell transplants can be mentioned.
  • the compounds of the general formulas AI to A14 are used in general and preferably the compounds AI.001 to A14.003 according to Tables 1 to 14 individually or in combination, or else the pharmaceutical or cosmetic compositions which comprise one or more of the compounds mentioned, for the prophylaxis and therapy of the rejection or inflammatory reactions on or by medical objects implanted in an organism (“medical devices”).
  • the compounds of the general formulas AI to A14 are used in general and preferably the compounds AI.001 to A14.003 according to Tables 1 to 14 individually or in Combination, or the pharmaceutical Chen or cosmetic compositions, which comprise one or more of the compounds mentioned, in such a way that the compounds) or composition (s) in the form of a coating or wetting are applied to the article or articles or at least one of the compounds or compositions as a substance is mixed with the material of the object (s). In this case too, it is of course possible to administer at least one of the compounds or compositions locally or systemically, if appropriate in chronological order or in parallel.
  • the compounds of the general formulas AI to A14 in general and the compounds A1.001 to A14 can be used in the same way as described above - and for the comparable purposes or for the prophylaxis and therapy of the diseases and conditions mentioned by way of example but not exhaustively.
  • 003 according to Tables 1 to 14 in preferred embodiments, and the pharmaceutical and cosmetic compositions described above and containing the compounds mentioned, alone or in Combination of several of them can be used to manufacture medicines to treat the above diseases or conditions.
  • These may include the compounds mentioned in the amounts mentioned above, if appropriate together with carriers, auxiliaries and / or additives known per se.
  • the invention also relates to a method for inhibiting the activity of the alanyl aminopeptidases or analogous enzymes alone or in combination with inhibitors of the DPIV and analogous enzymes by the administration of at least one compound or pharmaceutical or cosmetic composition according to the detailed description above in one for the inhibition of the Enzyme activity required amount.
  • the amounts of one of the compounds of the general formulas AI to AI 4 in general or of the compounds AI.001 to A14.003 according to Tables 1 to 14 are - as indicated above - in the range from 0.01 to 1000 mg of a compound per administration unit, preferably in the range of 0.1 to 100 mg per administration unit.
  • the invention also relates to a method for topically influencing the activity of the alanyl ammopeptidases or analogous enzymes alone or in combination with inhibitors of the DPIV or analogous enzymes by administration of at least one compound or pharmaceutical or cosmetic composition according to the detailed description above in one for the influencing the amount of enzyme activity required.
  • the amounts of the compound (s) are in the range given above.
  • the invention also relates to a method for the prophylaxis and therapy of a large number of diseases, for example diseases with an excessive immune response (autoimmune diseases, allergies and transplant rejections), other chronic inflammatory diseases, neuronal diseases and cerebral damage, skin diseases (including acne and psoriasis), Tumor diseases and special viral infections (including SARS) and in particular the diseases mentioned in detail above, by administration of at least one compound or pharmaceutical or cosmetic composition according to the detailed description above in an amount required for the prophylaxis or therapy of the respective disease.
  • diseases with an excessive immune response autoimmune diseases, allergies and transplant rejections
  • other chronic inflammatory diseases include neuronal diseases and cerebral damage
  • skin diseases including acne and psoriasis
  • Tumor diseases and special viral infections including SARS
  • the amounts of the compound (s) range from 0.01 to 1000 mg of a compound per administration unit, preferably in the range from 0.1 to 100 mg per administration unit.
  • Tables 1 to 14 below summarize new inhibitors for which the applicants have shown that they are capable of inhibiting the enzymatic activity of alanyl aminopeptidases.
  • the measured inhibition characteristics are given as IC-50 or ID-50 values (the latter marked with “*”) for both enzymes.
  • the enzymatic activity was determined with the aid of the fluorogenic substrate product (Ala) 2 - rhodamine 110.
  • the disease scores [vDl] are defined by different degrees of paralysis. Healthy animals have a disease score of 0. Actinonin was used as the alanyl aminopeptidase inhibitor and Lys [Z ( ⁇ O2)] pyrrolidide as the dipeptidylpeptidase IN inhibitor. Treatment was continued for 46 days after immunization. The results can be seen in FIG. 1. The curves clearly show a strongest and most lasting [vD2] therapeutic effect after combined inhibition of both peptidases.
  • Inflammation predominantly affecting the colon was induced by ner administration of 3% sodium dextran sulfate in drinking water in 8-week-old female Balb / c mice. After 3 days, all animals show clear symptoms typical of the disease.
  • the peptidase inhibitors and the phosphate-buffered saline as placebo were administered intraperitoneally from day 5 on for three consecutive days. The severity is determined using a recognized rating system.
  • Sensitization to the bronchial-inducing antigen ovalbumin was carried out on female Balb / c mice by intraperitoneal administration of 10 ⁇ g ovalbumin each on days 0, 14 and 21. On days 27/28, the animals were boosted by inhalation with ovalbumin [vD3]. After intraperitoneal application of the peptidase inhibitors on days 28-35, an intranasal ovalbumin challenge was carried out on day 35 and the early allergic reaction via the lung function was checked. The mean expiratory flow EF50, the tidal volume, the respiratory rate and the minute volume as well as the number of eosinophilic granulocytes in the bronchoalveolar lavage were measured.

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Abstract

La présente invention concerne des substances inhibant spécifiquement des peptidases divisant ala-p-nitroanilide, destinées à une utilisation en médecine. L'invention concerne également l'utilisation d'au moins une telle substance ou d'au moins une composition pharmaceutique ou cosmétique contenant au moins une telle substance, dans la prophylaxie et la thérapie de maladies, notamment de maladies caractérisées par une réponse immunitaire excessive (maladies auto-immunes, allergies et rejets de greffes), d'autres maladies inflammatoires chroniques, de maladies neuronales, de traumatismes cérébraux, de maladies dermatologiques (par ex. l'acné et le psoriasis), de maladies tumorales et d'infections virales spécifiques (par ex. le SRAS).
EP04790485A 2003-10-15 2004-10-15 Nouveaux inhibiteurs d'alanyl-aminopeptidases destines a exercer une influence fonctionnelle sur diverses cellules et a constituer un traitement immunologique de maladies inflammatoires, neuronales et autres Withdrawn EP1673075A2 (fr)

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DE10348023A DE10348023A1 (de) 2003-10-15 2003-10-15 Neue Alanyl-Aminopeptidasen-Inhibitoren zur funktionellen Beeinflussung unterschiedlicher Zellen und zur Behandlung immunologischer, entzündlicher, neuronaler und anderer Erkrankungen
PCT/EP2004/011643 WO2005037257A2 (fr) 2003-10-15 2004-10-15 Nouveaux inhibiteurs d'alanyl-aminopeptidases destines a exercer une influence fonctionnelle sur diverses cellules et a constituer un traitement immunologique de maladies inflammatoires, neuronales et autres

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AU2004281536B9 (en) 2009-10-08
WO2005037257A3 (fr) 2006-09-14
CN1897928A (zh) 2007-01-17
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CA2542723A1 (fr) 2005-04-28
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