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• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • 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
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • 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
  • C07D401/14—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 three or more hetero rings

Definitions

• the invention relates to new specific immunophilin ligands of the formula
• R ⁇ R 2 , R 3 , X, Y, Z, A, B, and D have the following meaning:
• RP hydrogen, (-C 1 -C 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, 0, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazines, thiophene, furan, imidazole, can be substituted one or more times by a phenyl ring, where this phenyl ring itself one or more times by halogen, (-CC 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, by carboxyl groups, carboxyl groups esterified with straight-chain or branched (CC 6 ) al
• Hydroxyl groups methoxy groups, ethoxy groups, benzyloxy groups, amino groups, which are themselves substituted by benzyl, benzoyl acetyl, can be substituted.
• Ri can also be the amine residue of the following amino acid methyl esters: histidine, leucine, valine, serine (Bzl), threonine, pipecolic acid, 4-piperidinecarboxylic acid, 3-piperidinecarboxylic acid, ⁇ -NH 2 -lysine, ⁇ -Z-NH-lysine, ⁇ - (2CI-Z) -NH-lysine, 2-pyridylalanine, phenylalanine, tryptophan, glutamic acid, arginine (Tos), asparagine, citrulline, homocitrulline, ornithine, thiazole carboxylic acid, proline, indoline-2-carboxylic acid, Octahydrindolincarbonklare, tetrahydroiso-quinolinecarboxylic acid, 5 -Aminovaleric acid, 8-amino octanoic acid.
• R 2 hydrogen, (d-C ⁇ 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 morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazines, thiophene, furan, imidazole, can be substituted one or more times by a phenyl ring.
• a mono- or bicyclic heteroaryl having 1-4 heteroatoms preferably N, S, O, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole
• This phenyl ring can itself one or more times by halogen, (Ci-Ce alkyl, (C 3 -C 7 ) cycloalkyl, by carboxyl groups, with straight-chain or branched (C 1 -C 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, or by mono- or tricyclic aryl or heteroaryl with 1-4 heteroatoms, preferably N, S, O or by Carboxy- (-C-C 12 ) alkyl, carboxycyclopentane, carboxycyclohexane, benzoyl, which are substituted by halogen, methoxy groups, amino groups, carbamoyl groups, trifluoromethyl groups, carboxyl groups, with straight-chain or branched (C ⁇ -C 6 ) alkanols esterified carboxyl groups one or more times can be substituted.
• R 2 amino (C 1 -C 2 ) alkyl or amino (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, 0, such as morpholine, piperazine, piperidine, pyridine, isoquinoline, quinoline, pyrimidine, oxazole, oxadiazole, isoxazole, pyrazole, pyrrole, indole, indazole, phthalazines, thiophene, furan, imidazole, can be substituted one or more times by a phenyl ring can.
• This phenyl ring can itself be mono- or polysubstituted by halogen, (C 1 -C 6) alkyl, (C 3 -C 7) -cycloalkyl, by carboxyl groups, with straight-chain or branched (C ⁇ -C6) alkanols esterified straight-chain or branched (-CC 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, or by mono- or tricyclic amino-aryl or amino-heteroaryl with 1-4 heteroatoms, preferably N, S , O or by carboxy- (-C- 2 ) -alkyl, carboxycyclopentane, carboxycyclohexane, benzoyl, which is substituted by halogen, methoxy groups, amino groups, carbamoyl groups,
• Trifluoromethyl groups, carboxyl groups can be substituted one or more times with straight-chain or branched (d-CeJ-alkanols esterified carboxyl groups).
• R 3 H, F, OR 4 , Br, NHR 4 .
• R 4 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 tricyclic carbonyl aryl or carbonyl heteroaryl with 1-4 heteroatoms, preferably N, S, O, where aryl or heteroaryl itself can be substituted one or more times by halogen, (-C 6 ) alkyl, (C 3 -C 7 ) - cycloalkyl, carboxyl groups esterified by carboxyl groups, with straight-chain or branched (C 1 -C 6 ) -alkanols, carbamoyl groups,
• Trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, amino groups, which are themselves substituted by benzyl, benzoyl, acetyl, can be substituted.
• A without ring, aromatic, non-aromatic, aromatic heterocyclic with 1-2 heteroatoms, preferably N, S, O, non-aromatic heterocyclic with 1-2 heteroatoms, preferably N, S, O.
• R 5 hydrogen, (C 1 -C 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 morpholine, piperazine, piperidine, indole, indazole, phthalazines, thiophene, furan, imidazole, can be substituted one or more times by a phenyl ring.
• This phenyl ring can itself one or more times by halogen, (d-CeJ-alkyl, (C 3 -C 7 ) cycloalkyl, by carboxyl groups, with straight-chain or branched (C 1 -C 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, fungal derived natural products that inhibit the Ca +2 -dependent signaling pathway in some cell types.
• both agents inhibit the transcription of a number of genes, including the IL-2 gene, 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; MW Harding et al., Nature 341, 755-760, 1989).
• the FK 506 receptor was called FKBP, the CsA receptor cyclophilin (Cyp). Both proteins catalyze the isomerization of ice and trans amide bond rotamers of peptides and are often referred to as immunophilins.
• the CsA-Cyp or FK 506-FKBP overmolecule binds calcineurin (CN) and inhibits its phosphatase activity.
• the cellular target molecule of CN was the Detected cytosolic, phosphorylated component of the transcription factor NF-AT, which, in the absence of CN activity, does not dephosphorylate for the effect in the cell nucleus and thus the active transcription complex on the IL-2 promoter cannot be switched on.
• asthmatic diseases are based on an inflammatory reaction that is controlled by T cells and their mediators. Corticosteroids are still the drug of choice in the treatment of many allergic diseases. CsA and FK 506 have also proven to be a favorable therapeutic agent in animal experiments as well as in clinical studies in bronchial asthma and underlying inflammation. In animal experiments, the blockade of various cytokines such as IL-2, IL-4 and IL-5, which cause allergy-induced inflammation, was shown.
• the compounds described in this invention stand out clearly at the C-terminus, in their optical purity of the indoline carboxylic acid, from the structure mentioned in the publication and also show a significantly better anti-asthmatic, anti-allergic, anti-rheumatic, anti-inflammatory, anti-psoriatic and immun-suppressive activity.
• the object of the invention is to find new compounds with valuable pharmacological properties and to provide them by targeted synthesis.
• a class of substances which surprisingly specifically bind immunophilins, which inhibits IL-2-dependent proliferation, and the release of TNF- and GM-CSF and which surprisingly blocks a Ca ++ -dependent signal transmission pathway 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 FKBP 12.
• substances of the formula I inhibit various cytokine syntheses and a Ca ++ -dependent signal transmission path.
• Those compounds of the formula I which contain asymmetric carbon atoms and therefore generally are 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 starting substances from the outset, in which case corresponding optically active or diastereoisomeric compounds are then obtained as the end product.
• the invention thus encompasses 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 released in this way can be converted into the corresponding physiologically tolerated acid addition salts using inorganic or organic acids or bases.
• the compounds of formula I can be administered in free form or as a salt with a physiologically acceptable acid or base. It can be administered orally, parenterally, intravenously, transdermally or by inhalation.
• the invention further relates to pharmaceutical preparations containing at least one compound of the formula I or salts thereof with physiologically tolerable inorganic or organic acids or bases and, if appropriate, pharmaceutically usable excipients and auxiliaries.
• the dosage of the aforementioned pharmaceutical preparations depends on the condition of the patient and the form of administration.
• the daily active ingredient dos is between 0.01-100 mg per kg body weight and day.
• Example 1 (2S) -1 - [((2S) -1 - (4-acetylamino) phenylsuifonyl) indolin-2-yl) carbonyl] - N- (2-methoxyethyl) indoline-2-carbamide
• Example 2 (2R) -1 - [((2S) -1 - (4-acetylamino) phenylsulfonyl) indolin-2-yl) carbonyl] - N- (2-methoxyethyl) indoline-2-carbamide
• Example 11 1 - [(2S) -1- (4-acetylaminophenylsulfonyl) indolin-2-yl) carbonyl] -N-leucine
• Example 23 (2RS) -1 - ( ⁇ (2RS) -1 - [4- (acetylamino) phenylsulfonyl] indolin-2-yl ⁇ carbonyl) indoline-2-carboxylic acid
• the compounds of the formula can be prepared by the following methods.
• the compounds of the formula I according to the invention in which R 1, R 2 , R 3 , A, B, D, X, Y and Z have the meaning given are prepared by using a carboxylic acid derivative of the formula II in which R 3 , A, B, D, X, Y and Z have the meaning given, with an amine, alkanol, halogen compound or tosylate III to form an amide, ester or ether IV, where R 1 t R 3 , A, B, D, X , Y and Z have the meaning given, converts this derivative IV after deprotection with acid to an intermediate product V, in which R ⁇ R 3 , A, B, D, X, Y and Z have the meaning given, and in a further reaction with a compound VI, in which R 2 has the meaning given, or with a compound VIII (see process 2), in which R 2 , R 3 , A, B, D, X, Y and Z have the meaning given has converted to the target compound I
• the compounds of the formula I according to the invention in which RR 2 , R 3 , A, B, D, X, Y and Z have the meaning given are prepared by using a carboxylic acid derivative of the formula VII, in which R 3 , A , B, D, X, Y and Z are as defined above, with a sulfonyl chloride VI in which R 2 have the meaning mentioned, is reacted, and in a further reaction with a compound III, wherein R t is as defined above, or with a compound V, wherein R 1, R 3 , A, B, D, X, Y and Z has the meaning given, to give the target compound I.
• the compounds of formula I with inorganic or organic acids, such as. B. 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 in a known manner.
• inorganic or organic acids such as. B. 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 in a known manner.
• compositions contain at least one compound of the general formula I or its salts with physiologically tolerable inorganic or organic acids or bases and optionally pharmaceutically usable excipients and auxiliaries.
• the compounds of formula I can be administered orally, parenterally, intravenously, transdermally or by inhalation in free form or as a salt with a physiologically acceptable acid or base.
• Suitable application forms are, for example, tablets or dragees, capsules, solutions or ampoules, suppositories, 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 0.01-00 mg per kg body weight.
• the compounds of the formula (I) according to the invention are distinguished by immunophilin binding and inhibit their isomerase activity. This prolyl isomerase activity is checked according to an enzyme test which is customary worldwide: G. Fischer, H. Bang, A. Schellenberger, Biochim. Biophys. Acta, 791, 87-97, 984; D.H. Rieh et al., J. Med. Chem. 38, 4164-4170, 1995).
• the immunophilins Without the peptidyl-cis-trans-isomerase activity of the immunophilins being influenced in any case, such compounds surprisingly specifically inhibit TNF- ⁇ , GM-CSF, IL-2, IL-4 or IL-5 proliferation Mast cells, macrophages and activated T cells.
• the compounds according to the invention like cyclosporin A (Sandimmun ' ⁇ CsA), FK 506 or rapamycin (tacrolimus), can be used 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, Abs. 9, 7987; L. Fry, J.
• Example 11 1 - [(2S) -1- (4-acetylaminophenylsulfonyl) indolin-2-yl) carbonyl] -N-
• the immobilized ligands were subjected to SDS-PAGE with cell homogenate.
• Carrier-fixed ligands which have a special affinity for the immunophilins bind them specifically with a high affinity.
• the compounds of the formula (I) according to the invention are distinguished by immunophilin binding and inhibit their peptidyl-prolyl-cis-trans-isomerase (PPIase) activity.
• PPIase peptidyl-prolyl-cis-trans-isomerase
• the compounds of general formula I according to the invention are used together with 10 nmol Cyp B for 15 min. pre-incubated 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 extinction at 390 nm is then monitored and evaluated.
• the change in absorbance, determined photometrically, 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 cyclophilins.
• the corresponding PPIase activity of the compounds of the general formula according to the invention are shown in Table 1:
• the ll-2 proliferation test is based on the incorporation of 3 H-Thymidi ⁇ in with OKT-3
• the compounds of the general formula I according to the invention show in animal experiments the blockade of cytokines such as TNF- ⁇ , GM-CSF, IL-2, IL-4 and IL-5, which in the case of illness cause the allergy-induced inflammation .

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