EP0896580A1 - Nouveaux ligands d'immunophiline specifiques utilises comme agents antiasthmatiques et immunosuppressifs - Google Patents

Nouveaux ligands d'immunophiline specifiques utilises comme agents antiasthmatiques et immunosuppressifs

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Publication number
EP0896580A1
EP0896580A1 EP97916432A EP97916432A EP0896580A1 EP 0896580 A1 EP0896580 A1 EP 0896580A1 EP 97916432 A EP97916432 A EP 97916432A EP 97916432 A EP97916432 A EP 97916432A EP 0896580 A1 EP0896580 A1 EP 0896580A1
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EP
European Patent Office
Prior art keywords
groups
acid
carboxylic acid
boc
substituted
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Withdrawn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
EP97916432A
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German (de)
English (en)
Inventor
Dietmar Reichert
Bernhard Kutscher
Holger Bang
Kay Brune
Gerhard Quinkert
Hans-Günter Schaible
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Asta Medica GmbH
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Asta Medica GmbH
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Publication of EP0896580A1 publication Critical patent/EP0896580A1/fr
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to new specific immunophil ligands of the formula
  • R 1, R 2 , R 3 , R 4 , X, Y, A, B and D have the following meaning
  • R T is hydrogen, (-CC 2 ) -alkyl or (C 2 -C 6 ) -alkyloxy groups, the alkyl group being straight-chain or branched and by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S, O , such as morphohn, piperazine, piperidine, indole, indazole, phthalazines, thiophene, furan, imidazole, can be substituted one or more times by a phenylene This phenylene can itself be substituted one or more times by halogen, (C 1 -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, by carboxyl groups, with straight-chain or branched (-C-C 6 ) -alkanols esterified carboxyl groups, carbamoyl groups, tnfluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups
  • Ri can also be the amine residue of the following amino acid methyl esters: histidine, leucine, valine, serine (Bzl), threonm, pipecolinic acid, 4-pipeline dincarboxylic acid, 3-piperidicarboxylic acid, ⁇ -NH 2 -lysine, ⁇ -Z-NH-lysine, ⁇ - 2CI-Z) -NH-lysin, 2-pyridylalanin, phenylalanine, tryptophan, glutamic acid, arginin (Tos), asparagine, citruliin, Hcmocitrullin, ornithine, Prohn, 2- Indohncarbonsaure, Octahyd ⁇ ndohncarbonsaure,
  • R 2 is hydrogen, (dC ⁇ alkyl or (C 2 -C 6 ) alkyloxy groups, the alkyl group being straight-chain or branched and by a mono- or bicyclic heteroaryl having 1-4 heteroatoms, preferably N, S, O, such as morpho ⁇ Piperazine, pipendin, indole, indazole, phthalazines, thiophene, furan, imidazole, can be substituted one or more times by a phenylene This phenyl can itself be substituted one or more times by halogen, (-C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, by carboxyl groups, with straight-chain or branched (C ⁇ CeJ-alkanols esterified carboxyl groups, carbamoyl groups, t ⁇ fluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, amino groups, which
  • R 3 is hydrogen, butyloxycarbonyl, carboxybenzyl, mono- or tricyclic carbonyl aryl or carbonyl heteroaryl with 1-4 heteroatoms, preferably N, S, O, where aryl or heteroaryl itself one or more times by halogen, (C ⁇ -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, by carboxyl groups, with straight-chain or branched (Ci-C ⁇ J-alkanols) esterified carboxyl groups, carbamoyl groups, tifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, amino groups, themselves are substituted by benzyl, benzoyl acetyl, may also be substituted.
  • R 3 can be carboxy- (C 1 -C 6 ) -alkyl, where the alkyl group can be straight-chain or branched and by a mono- or bicyclic heteroaryl with 1-4 heteroatoms, preferably N, S, O, such as morpholine, piperazine, pipendin, indole, indazole, phthalazines, thiophene, furan, imidazole, or can be substituted one or more times by a phenylng, this phenylng itself one or more ach by halogen, (-CC 6 ) -alkyl, (C 3 -C 7 ) - cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (C 1 -C 6 ) -alkanols, carbamoyl groups,
  • R 3 can also be the acid residue of the following amino acids: histidine, leucine, valine, Se ⁇ n (Bzl), threonine, pipecolic acid, 4-Pipe ⁇ d ⁇ ncarbonsaure, 3-piperidinecarboxylic acid, ⁇ -NH 2 -Lys ⁇ n, ⁇ -Z-NH-Lysm, ⁇ - (2Cl-Z) -NH-Lys ⁇ n, 2-pyridylalanine, phenylalanine, tryptophan, glutamic acid, Arg ⁇ n ⁇ n (Tos), asparagine, citrullm, homocitrulhn, ornithine, proline, 2-indolecarboxylic acid, octahydrindoline carboxylic acid, tetrahydrocarboxylic acid, tetrahydroisoquinoline
  • Aminovale ⁇ anklare, 8-Am ⁇ noctanoic acid the N-term of the amino acids by butyloxycarbonyl, carboxybenzyl or by the acid residue of mono- or t ⁇ cychschen aryl or heteroarylcarboxylic acids with 1-4 heteroatoms, preferably N, S, O, such as methoxyphenylacetic acid, naphthyl acetic acid, Py ⁇ dylacetic acid, quinazole monylacetic acid,
  • Indazolylacetic acid indolylgloyxyl acid, phenylglyoxylic acid,
  • R 5 hydrogen, (C 3 -C 7 ) -cycloalkyl, (-C-C 6 ) -alkyl or carboxy- (C ⁇ -C 6 ) -alkyl, where the alkyl group can be straight-chain or branched and by a mono- or t ⁇ cyclisches carbonyl-aryl or carbonyl heteroaryl with 1-4 heteroatoms, preferably N, S, O, wherein aryl or heteroaryl itself one or more times by halogen, (-C-C 6 ) alkyl, (C 3 -C 7 ) -Cycloalkyl, by carboxyl groups, with straight-chain or branched (CrC 6 ) -alkanols esterified carboxyl groups, carbamoyl groups, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, amino groups, which are themselves substituted by benzyl, benzoyl, acetyl
  • the invention further relates to the physiologically tolerable salts of the compounds of the formula I, the processes for preparing the compounds of the formula I and their pharmaceutical use
  • Cyclosporin A (CsA) or FK 506 are immunosuppressive, fungi-derived natural products that inhibit the Ca +2 -dependent signal transmission path in some cell types.
  • both agents inhibit the transcription of a number of genes, including the gene for IL-2, which is activated by stimulation of the T cell receptors (TCR).
  • TCR T cell receptors
  • FK 506 and CsA both bind with high affinity to soluble receptor proteins (G Fischer et al., Nature 337, 476-478, 1989, M W. Harding et al., Nature 341, 755-760, 1989).
  • the FK 506 receptor was called FKBP, the CsA receptor cyclophilm (Cyp). Both proteins catalyze the isomerization of ice and trans amide formation rotamers of peptides and are also often referred to as immunophiles.
  • the overmolecule from CsA-Cyp or FK 506-FKBP binds Calcineu ⁇ n (CN) and inhibits its phosphatase activity.
  • the cellular target molecule of CN was the cytosolic, phosphorylated component of the transcription factor NF-AT, which, in the absence of CN activity, did not affect the activity in the cell nucleus dephosphorylated and thus the active transcription complex on the IL-2 promoter cannot be switched on (MK Rosen, SL Schreiber, Angew. Chem. 104 (7992), 413-430; G Fischer, Angew. Chem. 106 ⁇ 1994), 1479- 1501;
  • the object of the invention is to find new compounds with valuable pharmacological properties and to provide them by targeted synthesis
  • a completely new class of substances which surprisingly specifically binds immunophiles and surprisingly inhibits the IL-2 proliferation, is represented by the compounds of the formula I according to the invention.
  • This class of compounds and their pharmaceutically acceptable salts has a high affinity for immunophilins such as CypA, CypB, CypC and FKBP12
  • Those compounds of formula I which contain asymmetric carbon atoms and are therefore generally obtained as racemates can be separated into the optically active isomers in a manner known per se, for example using an optically active acid.
  • optically active there is also the option of optically active from the outset Use starting substances, in which case corresponding optically active or diastereoisomeric compounds are obtained as the end product
  • the invention thus includes compounds of the formula I which contain an asymmetric carbon atom, the R form, the S form and R, S mixtures, and, in the case of several asymmetric carbon atoms, the diastereoisomeric forms
  • the compounds of the formula I can be obtained as free compounds or in the form of their salts.
  • the salts obtained can be converted into the free bases or acids in a manner known per se, for example using acids, alkali or ion exchangers
  • the compounds of the formula I can be administered in free form or as a salt with a physiologically acceptable acid or base.
  • the application can be peroral, parenteral, intravenous, transdermal or inhalative
  • the invention further relates to pharmaceutical preparations containing at least one compound of the formula I or salts thereof with physiologically acceptable inorganic or organic acids or bases and, if appropriate, pharmaceutically usable excipients and auxiliaries
  • Suitable forms of administration are, for example, tablets or dragees, capsules,
  • Powder preparations The dosage of the aforementioned pharmaceutical preparations depends on the condition of the patient and the form of administration.
  • the daily dose of active ingredient is between 001-100 mg per kg of body weight and day
  • the compounds shown under formula I can be prepared, for example, after the solid-phase synthesis according to B Mer ⁇ field, preferably on an insoluble polymer such as, for example, polystyrene resin in bead form which is swellable in organic solvents (for example a copolymers of polystyrene and 1% divinylbenzene), according to standard peptide coupling methods of peptide solid-phase synthesis
  • the compounds of the general formula I are prepared in such a way that first two of the functionalities ( ⁇ -amino, possibly ⁇ -amino and ⁇ -carboxylic acid group) are provided with protective groups and then the free third functionality is reacted in a suitable manner Where this leads to better results, introduce intermediate protective groups in the first step, which are exchanged for the desired functionality after the second step. Suitable protective groups and methods for attaching the same are known in the art.
  • the step-by-step construction takes place, for example, by first covalently binding the carboxy-terminal amino acid, the ⁇ -positional amino group of which is protected, to an insoluble carrier which is customary for this purpose, and splitting off the ⁇ -amino protective group of this amino acid, to the free amino group thus obtained binds the next protected amino acid via its carboxy group, and in this way links the remaining amino acids of the peptide to be synthesized step by step in the correct order, and, if necessary, splits off other side function protective groups and after linking all the amino acids the finished ligand was examined as an immobilized compound for cyp or FKBP binding.
  • the stepwise condensation is carried out in a conventional manner by synthesis from the corresponding amino acids which are protected in the customary manner. It is also possible to use automatic peptide synthesizers, for example the Labortec SP 650 type from Bachem, Switzerland, using the protected amino acids commercially available.
  • the compounds of the formula can also be prepared by the following method.
  • compounds of the formula I in which R 1, R 2 , R 3 , R 4 , A, B, D, X and Y have the meaning given are prepared by using an indole derivative of the formula II in which R 4 , A, B, D, X and Y have the meaning given, with an alkanol MI of chain length C 1 -C 12 to give an indolated peptide alkyl ester IV in which R 4 , A, B, D, X and Y have the meaning given, this ester IV in a further reaction with a compound V, in which R 3 , X and Y have the meaning given, to a compound VI in which R 3 , R 4 , A, B, D, X and Y have the meaning given, then this compound VI is subjected to saponification to a compound VII, in which R 3 , R4, A, B, D, X and Y have the meaning given, and then the compound VII with a compound VIII,
  • the compounds of the formula I are used with inorganic or organic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, lactic acid or embonic acid, or with inorganic or inorganic bases implemented in a known manner
  • inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, lactic acid or embonic acid, or with inorganic or inorganic bases implemented in a known manner
  • compositions contain at least one compound of the general formula I or its salts with physiologically acceptable inorganic or organic acids or bases and, if appropriate, pharmaceutically usable excipients and auxiliaries
  • the compound of the formula I can be administered in free form or as a salt with a physiologically acceptable acid or base orally, parenterally, intravenously, transdermally or by inhalation
  • Suitable forms of administration are, for example, tablets or dragees, capsules, solutions or ampoules, supposito ⁇ en, plasters or powder preparations which can be used in inhalers
  • the dosage of these aforementioned pharmaceutical preparations depends on the condition of the patient and the form of administration.
  • the daily dose of active ingredient is between 0 01-100 mg per kg of body weight
  • the compounds of the formula (I) according to the invention are distinguished by immunophine binding and inhibit their isomerase activity.
  • This prolyl isomerase activity is tested according to an enzyme test which is customary worldwide G Fischer, H Bang, A Schellenberger, Biochim. Biophys Acta, 791, 87-97, 1984, D H Rieh et al, J Med Chem 38, 4164-4170, 1995)
  • the compounds according to the invention can be cyclospon A (sand immune *, CsA), FK 506 or Rapamycm (tacrohmus) as immunosuppressants (RY Calne et al, Br Med J 282, 934-936, 1981), for the treatment of autoimmune diseases (RH Wiener et al, Hepatology 7, 1025, Abst 9, 1987, L Fry, J Autoimmun 5, 231-240, 1992, GJ Feutren J Autoimmun 5, 183-195, 1992, EP 610,743), allergic inflammation (P Zabel et al, Lancet 343, 1984), asthma (C Bachert, Atemw - Lachekrkh 20, 59, 1994), insulin-dependent diabetes mellitus (CR Stiller, Science, 223, 1362-1367
  • Step 5 N- [1-Boc-PiperidyM-carbonyl] indoline-2- (R, S) -carboxylic acid- [S- (N- ⁇ -Boc) -lysine methyl ester] amide
  • Step 1 Boc- (R, S) -ndoline-2-carboxylic acid
  • Step 2 N- [1-Boc-Indoline-2- (R, S) -carbonyl] -ndoline-2- (R, S) -carboxylic acid, methyl ester
  • Step 3 N- [1-Boc-Indoline-2- (R, S) -carbonyl] -ndoline-2- (R, S) -carboxylic acid
  • Step 4 N- [1-Boc-Indoline-2- (R, S) -carbonyl] -ndoline-2- (R, S) -carboxylic acid- [S-
  • the solvent became iViRV. removed, the residue taken up in 200 ml of EA and the organic phase washed once with water, twice with aqueous semi-saturated KHSO 4 solution, twice with aqueous 2 N NaOH solution and once with aqueous saturated NaCl solution.
  • the solvent became iViRV. removed and the residue purified by chromatography on 400 g of silica gel with CH, CL / MeOH 95: 5. After removing the solvent iViRV. and drying in public transport. 2.21 g (69%) of a brown powder were obtained.
  • EA calculated for C 19 H 2 ⁇ N 3 O 3 (339.40): C 67.84; H 6.29; N 12.49; found: C 67.75; H 6.33; N 12.53.
  • the residue taken up with 100 ml of ethyl acetate, washed 2 times with 10% aqueous HCl solution, 2 times with saturated aqueous NaHCO 3 solution and 1 time with saturated aqueous NaCl solution.
  • the residue was chromatographed on 50 g flash gel with n-hexane / AcOEt. After removing the solvent i. V. i. RV. the residue was crystallized from AcOEt / ether, giving 2.4 g of the product.
  • EA calculated for C ⁇ H ⁇ Oe x H 2 O (716 84) C 65 35, H 6 75, N 7 82, found C 6547, H 6 89, N 7 81
  • the compounds of the formula (I) according to the invention are surprisingly distinguished by immunophine binding and inhibit their peptidyl-prolyl-cis-trans-isomerase (PPIase) activity.
  • PPIase peptidyl-prolyl-cis-trans-isomerase
  • the compounds of the general formula I according to the invention are pramcubated together with 10 nmol Cyp B for 15 min at 4 ° C.
  • the enzyme reaction is started with the test peptide Suc-Ala-Ala-Pro-Phe-Nan after adding chymotrypsin and HEPES buffer the change in absorbance at 390 nm is monitored and evaluated.
  • the change in absorbance as determined by photometry results from two partial reactions a) the rapid chymotryptic cleavage of the trans-peptide, b) the non-enzymatic cis-trans-isomerization, which is catalyzed by cyclophiles.
  • the corresponding PPIase activity of Compounds of the general formula according to the invention are shown in Table 1
  • the II-2-Prohferat ⁇ onstest is based on the incorporation of H-Thym ⁇ d ⁇ n in OKT-3 (human anti-CD-3 anti-bodies) stimulated T cells and is carried out as follows 100000 T cells are selected in 150 ⁇ l culture medium per well in microtiter plates, stimulated by adding OKT-3 (1 ⁇ g / ml) and incubated for 45 h with one of the compounds of the general formula I according to the invention. After this incubation time, each well 10 ⁇ l of the 3 H-thyme solution (0 5 ⁇ Ci) are pipetted in. Then, the mixture is incubated for 6 hours at 37 ° C. in a 5% CO 2 atmosphere. After harvesting the cells, the radioactivity is quantified in the ß counter. The corresponding CD3 - ⁇ nduz ⁇ erte inhibition of prophylaxis

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Abstract

L'invention concerne de nouveaux ligands d'immunophiline spécifiques de la formule générale (I) qui ont un effet antiasthmatique et immunosuppressif et s'utilisent dans la préparation de médicaments.
EP97916432A 1996-04-25 1997-04-04 Nouveaux ligands d'immunophiline specifiques utilises comme agents antiasthmatiques et immunosuppressifs Withdrawn EP0896580A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19616509A DE19616509A1 (de) 1996-04-25 1996-04-25 Neue spezifische Immunophilin-Liganden als Antiasthmatika, Immunsuppressiva
DE19616509 1996-04-25
PCT/EP1997/001681 WO1997041148A1 (fr) 1996-04-25 1997-04-04 Nouveaux ligands d'immunophiline specifiques utilises comme agents antiasthmatiques et immunosuppressifs

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EP0896580A1 true EP0896580A1 (fr) 1999-02-17

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US (1) US6258815B1 (fr)
EP (1) EP0896580A1 (fr)
JP (1) JP3102895B2 (fr)
KR (1) KR20000065003A (fr)
CN (1) CN1214690A (fr)
AU (1) AU719840B2 (fr)
BR (1) BR9708869A (fr)
CA (1) CA2203466A1 (fr)
CZ (1) CZ297298A3 (fr)
DE (1) DE19616509A1 (fr)
HU (1) HUP9901588A3 (fr)
IL (1) IL125340A0 (fr)
IS (1) IS4808A (fr)
NO (1) NO984647L (fr)
NZ (1) NZ331180A (fr)
PL (1) PL329560A1 (fr)
SK (1) SK143998A3 (fr)
TR (1) TR199801949T2 (fr)
WO (1) WO1997041148A1 (fr)
ZA (1) ZA973121B (fr)

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DE19742263A1 (de) * 1997-09-25 1999-04-01 Asta Medica Ag Neue spezifische Immunophilin-Liganden als Antiasthmatika, Antiallergika, Antirheumatika, Immunsuppressiva, Antipsoriatika, Neuroprotektiva
US6251932B1 (en) 1998-09-25 2001-06-26 Asta Medica Ag Immunophilin ligands
WO2006115509A2 (fr) 2004-06-24 2006-11-02 Novartis Vaccines And Diagnostics Inc. Immuno-potentialisateurs a petites molecules et analyses visant a detecter leur presence
CN112022846B (zh) * 2020-09-23 2021-10-08 吕奔 一种吲哚啉衍生物在制备治疗脓毒症药物中的应用

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2585709B1 (fr) * 1985-08-05 1987-10-02 Adir Nouveaux derives peptidiques a structure lactonique ou cycloamidique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
DE3742431A1 (de) * 1987-12-15 1989-07-13 Hoechst Ag Neue derivate cyclischer aminosaeuren, verfahren zu ihrer herstellung, sie enthaltende mittel und deren verwendung
JPH0712045B2 (ja) 1988-03-02 1995-02-08 株式会社東海理化電機製作所 電流検出素子
US5192773A (en) * 1990-07-02 1993-03-09 Vertex Pharmaceuticals, Inc. Immunosuppressive compounds
FR2681864B1 (fr) * 1991-09-27 1995-03-31 Adir Nouveaux derives bicycliques azotes, leur procede de preparation et les compositions pharmaceutiques qui les contiennent.
JP3810097B2 (ja) * 1993-01-15 2006-08-16 明治製菓株式会社 ピロリジン−２−イルカルボニル複素環式化合物誘導体
FR2703050B1 (fr) * 1993-03-24 1995-04-28 Adir Nouveaux dérivés bicycliques azotés, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9741148A1 *

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CZ297298A3 (cs) 1999-03-17
NO984647D0 (no) 1998-10-05
KR20000065003A (ko) 2000-11-06
WO1997041148A1 (fr) 1997-11-06
US6258815B1 (en) 2001-07-10
JP3102895B2 (ja) 2000-10-23
NZ331180A (en) 2000-04-28
HUP9901588A3 (en) 2000-06-28
NO984647L (no) 1998-10-05
AU719840B2 (en) 2000-05-18
CA2203466A1 (fr) 1997-10-25
CN1214690A (zh) 1999-04-21
DE19616509A1 (de) 1998-01-15
IS4808A (is) 1998-07-24
JP2000500776A (ja) 2000-01-25
SK143998A3 (en) 1999-08-06
IL125340A0 (en) 1999-03-12
AU2508297A (en) 1997-11-19
HUP9901588A2 (hu) 1999-08-30
ZA973121B (en) 1997-11-05
BR9708869A (pt) 1999-08-03
TR199801949T2 (xx) 1999-02-22
PL329560A1 (en) 1999-03-29

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