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EP0775131A2 - Derives d'indol, d'indazol, de pyridopyrrol et de pyridopyrazol a effet antiasthmatique, antiallergique, anti-inflammatoire et immunomodulateur - Google Patents

Derives d'indol, d'indazol, de pyridopyrrol et de pyridopyrazol a effet antiasthmatique, antiallergique, anti-inflammatoire et immunomodulateur

Info

Publication number
EP0775131A2
EP0775131A2 EP95927679A EP95927679A EP0775131A2 EP 0775131 A2 EP0775131 A2 EP 0775131A2 EP 95927679 A EP95927679 A EP 95927679A EP 95927679 A EP95927679 A EP 95927679A EP 0775131 A2 EP0775131 A2 EP 0775131A2
Authority
EP
European Patent Office
Prior art keywords
pyridin
indol
alkyl
compounds
fluorobenzyl
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Withdrawn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
EP95927679A
Other languages
German (de)
English (en)
Inventor
Guillaume Lebaut
Fabienne Fouchard
Bernhard Kutscher
Peter Emig
Ilona Fleischhauer
Jürgen Schmidt
Stefan Szelenyi
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.)
Asta Medica GmbH
Original Assignee
Asta Medica GmbH
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
Priority claimed from DE19511916A external-priority patent/DE19511916A1/de
Application filed by Asta Medica GmbH filed Critical Asta Medica GmbH
Publication of EP0775131A2 publication Critical patent/EP0775131A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • 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
    • 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
    • A61P37/04—Immunostimulants
    • 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
    • A61P37/08—Antiallergic agents
    • 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
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the drugs indomethacin and acemetacin have an N-substituted indole skeleton.
  • Indomethacin is the prototype of compounds with
  • the indazole derivative is the anti-inflammatory substance bendazac, the synthesis of the substance with the IUPAC name [(1-benzyl-1H-indazol-3-yl) oxy] acetic acid is described in US Pat. No. 3,470,194.
  • DE-OS 42 25 756 and EP 392 317 describe benzimidazoles which are angiotensin antagonists, in particular angiotensin II antagonists.
  • Colantti (Chim. Ther 6 (5), 367-79) describe indole derivatives which have coccidiostatic properties.
  • EP 485 962 describes N-methyl indole derivatives as S 3 receptor antagonists.
  • WO 88/5432 describes N-alkyl-substituted 3-indole
  • Carboxylic acid derivatives as diuretics and cardiovascular substances are Carboxylic acid derivatives as diuretics and cardiovascular substances.
  • WO 93/2062 also describes N-alkyl-substituted 3-indole carboxamides, the amide nitrogen of which
  • Heterocycles such as the tetrazole ring and the substituted tetrazole ring, is substituted.
  • EP 580 502 describes 3- (hydroxybenzylidenyl) indolin-2-one derivatives with anti-inflammatory, analgesic,
  • the compounds which may exist as a mixture of E / Z isomers, inhibit LTB4 synthesis.
  • the compounds have different substituents on the indole nitrogen, and on the 2-carbon atom of the indole ring there is a keto or a thioketo group.
  • the object of the invention is to create new compounds
  • the object of the invention therefore includes compounds of general formula 1
  • R 1 hydrogen, (C 1 -C 6 ) alkyl, where the alkyl group can be straight-chain or branched and one or more times by halogen, phenyl, which in turn one or more times by halogen, (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl,
  • R 2 and R 3 may be the same or different and
  • Halogen, benzyloxy, hydroxyl, furthermore R 2 and R 3 may be the nitro group, the amino group which may be substituted as described above, which
  • W can be CH or N
  • Y can be O or S
  • X can be CH or N
  • X furthermore, if Y stands for a single bond, such that the heterocycle is directly connected to the group - (CH) n -,
  • Methylene group is bonded to the nitrogen atom of the group NR 5 R 7 of R 5 , and further applies that for the If R 6 and R 7 are hydrogen, this hydrogen is replaced,
  • R 4 hydrogen, (C 1 -C 6 alkyl), where the alkyl group can be straight-chain or branched, (C 3 -C 7 )
  • R 3 can be N- (C 1 -C 6 ) alkyl-2-pyrrolidinyl or the rest
  • R 8 and R 9 can be different and as radicals R 8 and R 9 the meaning (C 1 -C 6 ) alkyl, where the alkyl group can be straight-chain or branched, (C 3 -C 7 ) cycloalkyl, (C 1 -C 6 ) alkoxy, NO 2 , NH 2 , ethoxycarbonylamino or may have phenoxycarbonylamino, furthermore R 6 and R 7 together with the N atom to which they are attached can form a piperazine skeleton of the formula 2 formula 2
  • R 10 is the groups (C 1 -C 6 ) alkyl, where the alkyl group can be straight-chain or branched, (C 3 - C 7 ) cycloalkyl and phenyl, which with alkyl, alkoxy, halogen, the benzylhydryl and the bis-pF-benzhydryl group may be substituted, may furthermore
  • R 5 is a 2- or 4-pyrimidinylamino ring
  • 2-pyrimidinylamino ring can be substituted one or more times with methyl, or represent a 4-piperidylamino ring, where the N atom of the piperidine radical in each case with H, (C 1 -C 6 ) alkyl, the alkyl group being straight-chain or can be branched, (C 3 -C 7 ) cycloalkyl, aralkyl, phenyl or that substituted by the groups NH 2 , NO 2 , OCH 3 and NHCOOEt
  • R 5 also means the 3- or 4-
  • Tetrahydropyridinylamino ring the N atom of which can be substituted by H, (C 1 -C 6 ) -alkyl, where the alkyl group can be straight-chain or branched, (C 3 -C 7 ) -cycloalkyl and aralkyl,
  • Z can be O or S
  • R 11 can have the same meaning as R 1 ,
  • R 12 and R 13 may be the same or different and
  • R 14 is benzyl, which is substituted one or more times by halogen, (C 1 -C 6 ) -alkyl, where the alkyl group can be straight-chain or branched, (C 1 -C 6 ) -alkoxy or benzyloxy, or the group
  • 4-pyridylamino which may be substituted with an amino, nitro or (C 1 -C 4 ) alkoxycarbonyl and (C 1 -C 4 ) alkoxycarbonylamino, 4-quinolylamino which may be substituted with (C 1 -C 4 ) alkyl or
  • the compounds according to the invention can also be present as acid addition salts, for example as salts of
  • Mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, salts of organic acids, such as
  • straight-chain alkyl group means, for example, radicals such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and "branched alkyl group” means radicals such as isopropyl or tert-but.l. Under the designation “alkyl groups” are both
  • Cycloalkyl includes residues such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
  • halogen stands for fluorine, chlorine, bromine or iodine.
  • alkoxy group represents radicals such as methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy or pentoxy.
  • the compounds according to the invention show a good activity in the pharmacological models for histamine release according to the following specification:
  • Sprague-Dawley rats were killed against chicken egg white (HEW) by subcutaneous injection of 30 mg HEW along with
  • the mast cells of the peritoneal and pleural cavity were isolated from these animals four weeks later.
  • the cells were washed in Tris-Gel CM (the Tris-Gel CM buffer has the following composition: Tris 25 mmol / 1
  • Murine T helper cells (D10.G4) were used as IL-4 / IL-5 producing cells. These cells were preincubated with the test substances for 30 minutes at 37 ° C.
  • the cells were then stimulated at 37 ° C. by adding a monoclonal antibody against the T cell receptor domain CD3 (anti-CD3) to produce interleukins. After 16 hours, the cells were centrifuged off and the interleukins released were quantified in the cell supernatant using ELISAs for murine IL-4 or IL-5.
  • anti-CD3 monoclonal antibody against the T cell receptor domain CD3
  • guinea pigs Male guinea pigs (Pirbright White, 200-250 g, Charles River Wiga, Sulfeld) were actively sensitized using a s.c. Injection of ovalbumin (10 ⁇ g + 100 mg aluminum hydroxide) and boosted 2 weeks later. One week after the booster injection, the animals were exposed to an aerosol made from 0.5% ovalbumin solution for 30 seconds. 24 hours later, bronchoalveolar lavage (BAL) with 2 x 5 ml physiol.
  • ovalbumin 10 ⁇ g + 100 mg aluminum hydroxide
  • the lava fluid was pooled, centrifuged at 400 xg for 10 minutes and the cell pellet in 1 ml physiol.
  • Eosinophil test kit from Becton-Dickinson were stained. Percent inhibition of eosinophilia in the lavage was calculated by using the number of eosinophils
  • Substance-treated groups were compared with the eosinophil number of normal (non-challenged) and challenged, untreated control groups.
  • the group sizes were 10 animals each.
  • Test substances were given either prophylactically 2 hours before allergen challenge (-2h) or therapeutically 4 hours after challenge (+4 h). If the therapeutic
  • DMSO dimethyl sulfoxide
  • the indole carboxylic acid derivative is in a protic, dipolar aprotic or non-polar organic
  • Solvents such as isopropanol, THF, DMSO, DMA, dioxane, toluene, DMF, N-methylpyrrolidone or
  • Heteroaralkyl or aryl halide optionally with the addition of a catalyst such as Cu, is allowed to react for some time, for example 30 minutes to 3 hours, and maintains the temperature within a range from 0 ° C. to 120 ° C., preferably 30 ° C. to 80 ° ° C, especially at 50 ° C - 60 ° C. After the reaction has ended, the
  • Reaction mixture added to the water, for example with diethyl ether dichloromethane, methyl tert. -butyl ether or tetrahydrofuran extracted and the organic phase obtained in each case with dried anhydrous sodium sulfate.
  • the organic phase is concentrated in vac. one, crystallizes the
  • the N-substituted indolecarboxylic acid ester obtained according to the above regulation (1st stage) is dissolved in ethanol and IN sodium hydroxide solution is added.
  • the saponification reaction is carried out between 20 ° and 100 ° C., preferably between 40 ° C. and 80 ° C., in particular between 50 ° C. and 60 ° C. After 1-2 hours, the mixture is cooled to room temperature, acidified with hydrochloric acid or concentrated and concentrated
  • the acid obtained according to the above procedure (2nd stage) is dissolved in anhydrous tetrahydrofuran.
  • Dicyclohexylcarbodiimide is added as the condensing agent and then the substituted primary or secondary amine is added.
  • the urea formed is filtered.
  • the residue is recrystallized or purified chromatographically on silica gel.
  • a solvent e.g. a mixture of dichloromethane and ethanol (95: 5, vol / vol) use.
  • Condensation reaction in stage 3 can be as Condensing agents can also be used diisopropylcarbodiimide (DIC).
  • DIC diisopropylcarbodiimide
  • the condensation reaction of stage 3 can also be carried out using triphenylphoshin and bromotrichloromethane in THF at a temperature of 30-70 ° C. instead of using DCC / THF or DIC / TMF.
  • the combinations carbonyldiimidazole in anhydrous THF at a temperature of 0 ° C to 60 ° C, preferably at a temperature of 10 ° C - 30 ° C, especially at 25 ° C were used for the condensation reaction (stage 3). Also used for the condensation reaction in stage 3
  • dicyclohexylcarbodiimide or diisopropylcarbodiimide solvent anhydrous tetrahydrofuran
  • the final stage D 23714 is made from D 23720 by
  • the indol-3-ylcarboxamide is placed in a reflux condenser under a nitrogen atmosphere in an anhydrous organic solvent, such as, for example, diethyl ether, THF, dioxane or toluene. After adding 2-5 times,
  • reducing agent such as lithium aluminum hydride
  • the base obtained above is in an organic solvent, preferably an alcohol such as methanol, ethanol or isopropanol or not in one
  • protic solvents such as ethyl acetate or
  • Table 2 below are from the general formula 1 and the substituents YG, W, X, R 1 , R 2 and R 3 , the
  • N- (3-nitro-6-methoxy-pyridin-2-yl) -1,2,3,4-tetrahydro- ⁇ -carboline 200 ml of acetonitrile and 3.01 g of K 2 CO 3 are added to a flask. It is cooled with an ice-salt mixture and 2.5 g (14.5 mmol) of 1,2,3,4-tetr1hydro-ß-carboline and 2.71 g (14.5 mmol) of 2-chloro-3-nitro are added -6-methoxypyridine too. Under Stirring is allowed to come to room temperature and heated to reflux temperature for 2 hours. Then i.Vak.
  • N- (3-ethoxycarbonylamino-6-methoxypyridin-2-yl) -1,2,3,4-tetrahydro- ⁇ -carboline In a three-necked flask with 200 ml of anhydrous ethanol, 4 g (12.3 mmol) of N- (3-nitro-6-methoxy-pyridin-2-yl) -1,2,3,4-tetrahydro- ⁇ -carboline. 2 g of sodium borohydride and 0.5 g of palladium-carbon are added under a nitrogen atmosphere. With further nitrogen gassing, the mixture is heated to boiling for 2 hours. The mixture is then cooled to 10 ° C. and 4.07 g (37 mmol) are left
  • Tryptamine hydrochloride is dissolved in water in a flask while heating. Glyoxylic acid monohydrate and a solution of an inorganic base such as NaOH, KOH, LiOH or Ba (OH) 2 are added. After the reaction, the precipitate formed is filtered off and washed. Then the precipitate is heated in an inorganic acid such as
  • Hydrochloric acid or sulfuric acid are additionally conc.
  • Alkali hydrogen carbonates in an organic solvent such as acetonitrile, propionitrile, THF, diethyl ether or
  • the dichloromethane extracts are dried with anhydrous sodium sulfate, filtered and concentrated. The residue is purified by column chromatography on silica gel. Eluent: dichloromethane / ethanol 95: 5 (v / v). Recrystallization of the compound is absolute. Ethanol performed.
  • the 2- (1-methylindol-3-yl) isopropylamii used, for example, for the end compound D 23202 can be synthesized according to the following reaction route:
  • Lithium aluminum hydride slowly destroyed by adding 150 ml of ice water and the resulting mixture with
  • Benzyl-1H-indazol-3-yl) oxyacetic acid ethyl ester are mixed with sodium hydroxide solution at 50 ° C in a solvent mixture
  • Triphenylphosphine added and then a solution of 5.1 g (29 mmol) of diethyl azodicarboxylate in 10 ml
  • a solution of the amine is added dropwise at room temperature to a solution of the indazole derivative in an organic solvent, such as THF, dioxane, DMF or DMA.
  • an organic solvent such as THF, dioxane, DMF or DMA.
  • the mixture is stirred briefly before triphenylphosphine and azodicarboxylic acid ester in THF are added.
  • the mixture is stirred and the solvent is stripped off after the end of the reaction. The cleaning is done via

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Les dérivés N-benzylindol et benzopyrazol de formule générale (1) présentent un effet antiasthmatique, antiallergique, anti-inflammatoire et immunomodulateur et sont utilisés pour la fabrication de médicaments.
EP95927679A 1994-08-03 1995-07-20 Derives d'indol, d'indazol, de pyridopyrrol et de pyridopyrazol a effet antiasthmatique, antiallergique, anti-inflammatoire et immunomodulateur Withdrawn EP0775131A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE4427393 1994-08-03
DE4427393 1994-08-03
DE19511916 1995-03-31
DE19511916A DE19511916A1 (de) 1994-08-03 1995-03-31 Neue N-Benzylindol- und Benzopyrazol-Derivate mit antiasthmatischer, antiallergischer, entzündungshemmender und immunmodulierender Wirkung
PCT/EP1995/002867 WO1996004266A2 (fr) 1994-08-03 1995-07-20 Derives d'indol, d'indazol, de pyridopyrrol et de pyridopyrazol a effet antiasthmatique, antiallergique, anti-inflammatoire et immunomodulateur

Publications (1)

Publication Number Publication Date
EP0775131A2 true EP0775131A2 (fr) 1997-05-28

Family

ID=25938901

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95927679A Withdrawn EP0775131A2 (fr) 1994-08-03 1995-07-20 Derives d'indol, d'indazol, de pyridopyrrol et de pyridopyrazol a effet antiasthmatique, antiallergique, anti-inflammatoire et immunomodulateur

Country Status (13)

Country Link
US (1) US5965582A (fr)
EP (1) EP0775131A2 (fr)
JP (1) JPH10503501A (fr)
AU (1) AU3162695A (fr)
CA (1) CA2195850A1 (fr)
EG (1) EG21559A (fr)
FI (1) FI971334A (fr)
HR (1) HRP950435A2 (fr)
IL (1) IL114795A (fr)
NO (1) NO970412L (fr)
TR (1) TR199500952A2 (fr)
TW (1) TW434227B (fr)
WO (1) WO1996004266A2 (fr)

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WO2013019690A1 (fr) * 2011-07-29 2013-02-07 The Ohio State University Petites molécules inhibant l'il-6 et leurs utilisations
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EG21559A (en) 2001-12-31
CA2195850A1 (fr) 1996-02-15
WO1996004266A3 (fr) 1996-05-17
IL114795A (en) 1999-11-30
NO970412L (no) 1997-02-27
WO1996004266A2 (fr) 1996-02-15
JPH10503501A (ja) 1998-03-31
US5965582A (en) 1999-10-12
NO970412D0 (no) 1997-01-30
FI971334A0 (fi) 1997-04-01
AU3162695A (en) 1996-03-04
TR199500952A2 (tr) 1996-07-21
TW434227B (en) 2001-05-16
IL114795A0 (en) 1995-12-08
HRP950435A2 (en) 1997-12-31
FI971334A (fi) 1997-04-01

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