EP1869013A1 - Derives de chromane substitues, procede pour les preparer, et leur utilisation en tant qu'inhibiteurs d'inflammation - Google Patents

Derives de chromane substitues, procede pour les preparer, et leur utilisation en tant qu'inhibiteurs d'inflammation

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Publication number
EP1869013A1
EP1869013A1 EP06742670A EP06742670A EP1869013A1 EP 1869013 A1 EP1869013 A1 EP 1869013A1 EP 06742670 A EP06742670 A EP 06742670A EP 06742670 A EP06742670 A EP 06742670A EP 1869013 A1 EP1869013 A1 EP 1869013A1
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EP
European Patent Office
Prior art keywords
group
hydroxy
groups
trifluoromethyl
general formula
Prior art date
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EP06742670A
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German (de)
English (en)
Inventor
Norbert Schmees
Markus Berger
Hartmut Rehwinkel
Heike Schäcke
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Bayer Pharma AG
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Bayer Schering Pharma AG
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Publication of EP1869013A1 publication Critical patent/EP1869013A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P17/04—Antipruritics
    • 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
    • A61P17/10—Anti-acne agents
    • 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
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to substituted chroman derivatives, processes for their preparation and their use as anti-inflammatory agents.
  • Open-chain nonsteroidal anti-inflammatory agents are known from the prior art (DE 100 38 639, WO 03/082827 and WO 02/10143). These compounds show in the experiment Wirkdissoziationen between anti-inflammatory and undesirable metabolic effects and are superior to the previously described nonsteroidal glucocorticoids or at least have an equally good effect.
  • nonsteroidal anti-inflammatory agents are provided.
  • the present invention relates to compounds of the general formula (I),
  • R 1 and R 2 are independently a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (Ci-Ci 0) - alkyl group, a (CrCio) alkoxy group, a (CrCio) -alkylthio group, a (CrC 5) - Perfluoroalkyl group, a cyano group, a nitro group, or a -NR 9 R 9a group, or R 1 and R 2 together form a group selected from the groups
  • R 11 is a hydrogen atom, a hydroxy group, a halogen atom, a
  • Cyano group an optionally substituted (C 1 -C 10) -alkyl group, a (C 1 -C 10) -alkoxy group, a (C 1 -C 10) -alkylthio group, or a
  • R 12 is a hydrogen atom, a hydroxy group, a halogen atom, a
  • Cyano group an optionally substituted (C 1 -C 10) -alkyl group, or a (C 1 -C 10) -alkoxy group, an optionally substituted by 1 to 3 hydroxy groups, 1 to 3
  • Halogen atoms and / or 1 to 3 (CrC 5 ) alkoxy substituted
  • Halogen atoms hydroxy groups, -NR 9 R 9a groups, (CrC 5 ) perfluoroalkyl groups, nitro groups, thiol groups, sulfoxyl groups, sulfonic acid groups, sulfonamide groups,
  • Sulfonimine groups cyano groups or - (CO) - (C 1 -C 5 ) -alkyl groups, and exomethylene-substituted, optionally 1 to 4 nitrogen atoms and / or 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms and / or 1 to 2
  • R 3a is a hydrogen atom, a cyano group or an optionally substituted (C 1 -C 5) ) Alkyl group;
  • R 4 , R 5 , R 6 and R 6a independently represent a hydrogen atom, a
  • Halogen atom a hydroxy group, an -NR 9 R 9a group, an optionally substituted (Ci-Cio) alkyl group, a (CrCi 0 ) - alkoxy group or a (CrCi 0 ) -alkylthio group,
  • R 9 and R 9a are each independently a hydrogen atom, a (CrC 5 ) -
  • R 10 is a (CrCi O ) alkyl group or a - (CO) - (CrCi 0 ) alkyl group
  • R 13 is a hydrogen atom or a (CrC 5 ) Alkyl group means
  • R 14 represents a hydrogen atom, a fluorine atom or a partially or fully fluorinated (CrC 5 ) alkyl group
  • the present invention further relates to processes for the preparation of compounds of general formula (I) as described herein.
  • compositions comprising one or more compounds of the general formula (I) in combination with one or more pharmaceutical carriers or excipients.
  • the present invention also relates to the use of the compounds of general formula (I) for the preparation of pharmaceutical compositions having anti-inflammatory activity.
  • the present invention furthermore relates to compounds of the general formula (II).
  • halogen atom or halogen means a fluorine, chlorine, bromine or iodine atom. Preference is given to a fluorine, chlorine or bromine atom.
  • alkyl groups mentioned in the definitions of the general formula (I) may be straight-chain or branched and may be, for example, a methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, tert-butyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group, and the hexyl, heptyl, nonyl, decyl group and their random branched derivatives.
  • Preferred are alkyl groups containing 1 to 10, 1 to 8, or 1 to 5 carbon atoms.
  • a methyl or ethyl group is particularly preferred.
  • the above-mentioned alkyl groups may be optionally substituted by 1 to 5, preferably 1 to 3, groups independently selected from hydroxy, cyano, nitro, -COOR 13 , (CrC 5 ) alkoxy groups, halogen atoms, -NR 9 R 9a , a partially or fully fluorinated (CrC 3 ) alkyl group.
  • the alkyl groups may preferably be substituted by 1 to 3 halogen atoms and / or 1 to 3 hydroxy and / or 1 to 3 cyano and / or 1 to 3 -COOR 13 groups.
  • a particularly preferred subgroup of substituents are fluorine atom, hydroxy-methoxy and / or cyano groups.
  • substituents for the alkyl groups are 1 to 3 hydroxy and / or 1 to 3 -COOR 13 groups. Particularly preferred are the hydroxy groups.
  • a partially or completely fluorinated alkyl group for example, the following partially or fully fluorinated groups are contemplated: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1, 1-difluoroethyl, 1, 2-difluoroethyl, 1, 1, 1-trifluoroethyl, tetrafluoroethyl , Pentafluoroethyl. Of these, preferred are the trifluoromethyl or the pentafluoroethyl group.
  • the fully fluorinated group is also called perfluoroalkyl group.
  • the reagents used during the Synthesis optionally used are commercially available, or the published syntheses of the corresponding reagents belong to the prior art, or published syntheses can be applied anaiog.
  • alkoxy groups mentioned in the definitions of general formula (I) can be straight-chain or branched and are, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy.
  • CrC 5 - and Ci-C 3 -, CrC 8 -, and CrCi 0 -Alkoxy phenomenon are preferred.
  • a methoxy or ethoxy group is particularly preferred.
  • alkylthio groups mentioned in the definitions of general formula (I) may be straight-chain or branched and may be, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio or n-pentylthio, 2,2-dimethylpropylthio, 2-methylbutylthio or 3-methylbutylthio group.
  • CrC 5 alkylthio groups are preferred.
  • a methylthio or ethylthio group is particularly preferred.
  • alkoxy and alkylthio groups described above may bear on their alkyl groups the same substituents as described above for the alkyl groups in general.
  • Preferred substituents for alkoxy and alkylthio groups are independently selected from halogen (especially fluorine and / or chlorine), hydroxy and cyano.
  • the substituent -NR 9 R 9a is , for example, -NH 2 , -NH (CH 3 ), -N (CH 3 J 2 , -NH (C 2 H 5 ), -N (C 2 Hs) 2 , -NH (C 3 H 7 ), -N (C 3 H 7 J 2 , -NH (C 4 H 9 ), -N (C 4 Hg) 2 , -NH (C 5 H 11 ), -N (C 5 Hn) 2 , -NH (CO) CH 3 , -NH (CO) C 2 H 5 , -NH (CO) C 3 H 7 , -NH (CO) C 4 H 9 , -NH (CO) C 5 H 11 .
  • the (C 3 -C 7) cycloalkyl group optionally substituted by one or more groups selected from hydroxy groups, halogen atoms, (CrC 5) alkyl, (C r C 5) alkoxy, -NR 9 R 9a groups, - COOR 13 groups, -CHO, cyano, substituted saturated cyclic group having 3 to 7 ring carbon atoms such as cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, Cylopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, methylcycloheptyl.
  • alkylidene or Exoalkylidenoli is a group having 1 to 10 Kohenstoffatomen to understand, which is bound via an exodo double bond to the system (ring or chain).
  • Preference is given to (C 1 -C 5 ) - and (CrC 3 ) alkylidene, particular preference is given to exomethylene.
  • the heterocyclyl group is a cyclic, non-aromatic group containing one or more heteroatoms and may be, for example, pyrrolidine, imidazolidine, pyrazolidine, piperidine.
  • Perhydroquinoline and perhydroisoquinoline also belong to the heterocyclyl groups according to the invention.
  • Suitable substituents for heterocyclyl and heteroaryl groups are, for example, substituents from the following group: optionally substituted C 1 -C 5 -alkyl group, hydroxy, (C 1 -C 5 ) -alkoxy, -NR 9 R 9a , halogen, cyano, -COOR 13 , -CHO ,
  • the substituents may optionally also be bonded to the nitrogen atom of the heterocyclyl or heteroaryl group; N-oxides are also included in the definition.
  • Aryl groups within the meaning of the invention are aromatic or partially aromatic carbocyclic groups having from 6 to 14 carbon atoms which contain a ring, such as e.g. Phenyl or phenylene or more condensed rings such as e.g. Naphthyl or anthranyl. Examples include phenyl, naphthyl, tetralinyl, anthranyl, indanyl, and indenyl. The optionally substituted phenyl group and the naphthyl group are preferred.
  • the aryl groups may be substituted at any convenient point resulting in a stable compound by one or more of hydroxy, halogen, optionally C 1 -C 3 hydroxy or COOR 13 substituted C 1 -C 5 alkyl, C 1 -C 5 alkoxy , Cyano, -CF 3 , and nitro.
  • the aryl groups may be partially hydrogenated and then additionally or alternatively to the abovementioned substituents also carry keto and / or Exoalkyliden.
  • partially hydrogenated phenyl is meant, for example, cyclohexadienyl, cyclohexenyl, cyclohexyl.
  • a partially hydrogenated substituted naphthalene system is, for example, 1-tetralone or 2-tetraione.
  • the mono- or bicyclic heteroaryl group may optionally contain 1 to 9 groups selected from nitrogen atoms, oxygen atoms, sulfur atoms or keto groups, of which a maximum of 4 nitrogen atoms, a maximum of 2 oxygen atoms, a maximum of 2 sulfur atoms and / or a maximum of 2 keto groups may be included. Any subcombination of these groups is possible.
  • the heteroaryl group may be hydrogenated at one or more sites.
  • Examples of monocyclic heteroaryl groups include pyridine, pyrazine, pyrimidine, pyridazine, triazine, azaindolizine, 2H- and 4H-pyran, 2H- and 4H-thiopyran, furan, thiophene, 1H- and 4H-pyrazole, 1H- and 2H-pyrrole, Oxazole, thiazole, furazane, 1H- and 4H-imidazole, isoxazole, isothiazole, oxadiazole, triazole, tetrazole, thiadiazole.
  • cyclic heteroaryl groups include phthalidyl, thiophthalidyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, benzothiazolyl, indolonyl, dihydroindolonyl, isoindolonyl, dihydroisoindolonyl, benzofuranyl, benzo [b] thienyl, Benzo [c] thienyl, pyrazolo [1,5-a] pyridyl, benzimidazolyl, dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinonyl, phthalazinonyl, dihydrophthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolone, quinazolinyl, Quinox
  • the mono- or bicyclic heteroaryl group may optionally be substituted by one or more substituents selected from optionally substituted by 1 to 3 hydroxy or 1 to 3 -COOR 13 groups substituted d-Cs-alkyl groups, CrC ⁇ alkoxy groups, halogen atoms, and / or exomethylene groups be.
  • the substituents may, if possible, optionally also be bonded directly to the heteroatom (eg on the nitrogen atom). N-oxides are also part of the present invention.
  • hydroxy protecting groups are all conventional hydroxy protecting groups known in the art, in particular silyl ethers or esters of organic acids Ci-Ci O, C 5 ether, benzyl ether or benzyl ester in question.
  • the usual hydroxy protecting groups are described in detail in TW Greene, PGM Wut's Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, 1991).
  • the protecting groups are preferably alkyl, aryl or mixed alkylaryl-substituted silyl groups, for example the trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) or Triisopropylsilyl groups (TIPS) or other common hydroxy protecting group (e.g., methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydrofuranyl, tetrahydropyranyl groups).
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TDMS tert-butyldimethylsilyl
  • TDPS tert-butyldiphenylsilyl
  • TIPS Triisopropylsilyl groups
  • other common hydroxy protecting group e.g., methoxymethyl, meth
  • the compounds of the general formula (I) according to the invention can be present as stereoisomers due to the presence of asymmetric centers.
  • object In the present invention all possible diastereomers are both racemates and enantiomerically pure.
  • stereoisomers also encompasses all possible diastereomers and regioisomers and tautomers (eg keto-enoic tautomers) in which the stereoisomers according to the invention can be present, which are therefore also the subject of the invention.
  • the compounds according to the invention can also be present in the form of salts with pharmacologically acceptable anions, for example in the form of the hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate.
  • derivatives or prodrugs of the compounds of general formula (I) are encompassed by the invention.
  • derivatives or prodrugs are esters, ethers or amides of the compounds of the general formula (I) or other compounds which metabolize in the organism to compounds of the general formula (I). Suitable compounds are listed, for example, in Hans Bundgaard (Ed.), Design of Prodrugs, Elsevier, Amsterdam 1985.
  • a subgroup of compounds of the general formula (I) according to the invention are those compounds in which R 1 and R 2 independently of one another are a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C 1 -C 4) -alkyl group, a (C 1 -C 4) -alkoxy group a (CRCI 0) - are perfluoroalkyl group, a cyano group, a nitro group, or an -NR 9 R 9a group - alkylthio group, a (C 1 -C 5).
  • a preferred group of compounds of general formula (I) are those compounds in which Y represents an oxygen atom, a sulfur atom or a methylene group.
  • R 3 is an optionally substituted aryl or Heteroarylg ⁇ jppe means.
  • R 3 represents an optionally substituted aryl or heteroaryl group selected from the group consisting of naphthyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl , Dihydroisoquinolinyl, thiophthalidyl, benzofuranyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, chromanyl, isochromanyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl -, 1, 7-
  • R 3a is a hydrogen atom or a (C 1 -C 5 ) -alkyl group.
  • R 4 , R 5 , R 6 , and R 6a independently of one another are a hydrogen atom, a halogen atom or an optionally substituted (C 1 -C 10 ) -alkyl group mean.
  • R 1 and R 2 independently of one another represent a hydrogen atom, a halogen atom or an optionally substituted (C 1 -C 10 ) -alkyl group.
  • Another preferred group of compounds of the general formula (I) are those compounds in which the substituents R 11 and R 12 each represent a hydrogen atom.
  • Another preferred group of compounds of the general formula (I) are those compounds in which the substituent R 14 represents a fluorine atom or a trifluoromethyl group.
  • a particularly preferred group of compounds of the general formula (I) are those compounds in which R 1 , R 2 , R 4 , R 5 , R 6 , and R 6a are independent each other represents a hydrogen atom, a halogen atom or an optionally substituted (C 1 -C 10 ) -alkyl group, Y represents an oxygen atom, a sulfur atom or a methylene group, R 33 represents a hydrogen atom or a (C 1 -C 5 ) -alkyl group, R 11 and R 12 each represents a hydrogen atom, R 14 represents a fluorine atom or a trifluoromethyl group, and R 3 represents an optionally substituted aryl or heteroaryl group selected from the group consisting of naphthyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl , Dihydroisoquinolinyl, thiophthalidyl, benzofuranyl
  • the anti-inflammatory activity of the compounds of general formula (I) is tested in animal experiments by testing in croton oil-induced inflammation in rat and mouse (J. Exp. Med. (1995), 182, 99-108).
  • the animals are topically applied croton oil in ethanolic solution to the ears.
  • the test substances are also applied topically or systemically simultaneously or two hours before the croton oil.
  • ear weights are measured as a measure of inflammatory edema, peroxidase activity as a measure of granulocytic immigration, and elastase activity as a measure of neutrophil granulocyte immigration.
  • the compounds of the general formula (I) inhibit the three abovementioned inflammatory parameters in this test both after topical and after systemic administration.
  • glucocorticoid receptor glucocorticoid receptor
  • MR mineral corticoid receptor
  • PR progesterone receptor
  • AR androgen receptor
  • Cytosol preparations of Sf9 cells infected with recombinant baculoviruses encoding the GR are used for the binding assays.
  • the substances show a high affinity for GR.
  • GR-mediated inhibition of transcription of cytokines, adhesion molecules, enzymes, and other pro-inflammatory factors is considered. This inhibition is mediated by an interaction of the GR with other transcription factors, e.g. AP-1 and NF-kappa-B (for review see Cato ACB and Wade E, BioEssays 18, 371-378 1996).
  • the compounds of the general formula (I) according to the invention inhibit the lipopolysaccharide (LPS) -derived secretion of the cytokine IL-8 in the human monocyte cell THP-1.
  • LPS lipopolysaccharide
  • the concentration of cytokines was determined in the supernatant by means of commercially available ELISA kits.
  • glucocorticoid therapy One of the most common adverse effects of glucocorticoid therapy is the so-called "steroid diabetes" [cf. Hatz, HJ, Glucocorticoide: Immunological Foundations, Pharmacology and Therapy Guidelines,ticianliche Verlagsgesellschaft mbH, Stuttgart, 1998].
  • the reason for this is the stimulation of gluconeogenesis in the liver by induction of the responsible enzymes and by free amino acids, which arise from the degradation of proteins (catabolic effect of glucocorticoids).
  • a key enzyme of catabolic metabolism in the liver is tyrosine aminotransferase (TAT). The activity of this enzyme can be determined photometrically from liver homogenates and represents a good measure of the undesired metabolic effects of the glucocorticoids.
  • the compounds of general formula (I) induce, in doses, in this test which they are anti-inflammatory, not or only to a limited extent tyrosine aminotransferase.
  • the compounds of the general formula (I) according to the invention can be used as medicaments for the treatment or prophylaxis of the following disease states in patients, in particular mammals and preferably humans Term "DISEASE" for the following indications:
  • Pulmonary diseases associated with inflammatory, allergic and / or proliferative processes - Chronic obstructive pulmonary diseases of any genesis, especially bronchial asthma
  • Rheumatic diseases / autoimmune diseases / joint diseases associated with inflammatory, allergic and / or proliferative processes All forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica
  • kidney disease associated with inflammatory, allergic and / or proliferative processes (vi) kidney disease associated with inflammatory, allergic and / or proliferative processes:
  • liver disease associated with inflammatory, allergic and / or proliferative processes (vii) liver disease associated with inflammatory, allergic and / or proliferative processes:
  • acute hepatitis of different origins e.g. viral, toxic, drug-induced - chronic aggressive and / or chronic intermittent hepatitis
  • congenital secondary adrenal insufficiency e.g. congenital hypopituitarism - acquired secondary adrenal insufficiency, e.g. postinfectious, tumors etc ..
  • the compounds of the general formula (I) according to the invention can be used for the therapy and prophylaxis of other disease states not mentioned above, for which synthetic giococorticoids are used today (see Hatz, HJ, Giucocorticoide: Immunological Foundations, Pharmacology and Therapy Guidelines, Horschafliche Verlagsgesellschaft mbH , Stuttgart, 1998).
  • the appropriate dose is different and depends, for example, on the potency of the compound of the general formula (I), the patient (eg size, weight, sex, etc.), the mode of administration and the nature and severity of the conditions to be treated, as well as the use as prophylactic or therapeutic.
  • the invention relates to the use of the claimed compounds for the preparation of a pharmaceutical composition.
  • the invention further provides
  • Processes in particular for the treatment of a DISEASE (as defined above), which process comprises administering a pharmaceutically effective amount of a compound of the general formula (I), the amount facilitating or suppressing the disease or the symptoms, and wherein the compound is administered to a patient, preferably a mammal, in particular, to a human requiring such treatment; a pharmaceutical composition for the inhibition of inflammation, in particular for the treatment of a DISEASE (as defined above), the composition being one of the compounds according to the invention or a mixture thereof and optionally at least one pharmaceutical agent
  • Auxiliary and / or carrier comprises.
  • a recommended daily dose is in the range of 1 ⁇ g to 100,000 ⁇ g per kg of body weight.
  • a dose of 10 to 30,000 ⁇ g per kg body weight more preferably a dose of 10 to 10,000 ⁇ g per kg body weight.
  • this dose is conveniently administered several times a day.
  • an acute shock e.g., anaphylactic shock
  • single doses well above the above doses may be given.
  • the formulation of the pharmaceutical preparations based on the novel compounds is carried out in a manner known per se by reacting the active substance with the carriers customarily used in galenicals, fillers, disintegrants, binders, humectants, lubricants, absorbents,
  • aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.
  • the new compounds may be used in the form of suppositories, capsules, solutions (e.g., in the form of enemas) and ointments for both systemic and local therapy.
  • these can be used in the form of aerosols and inhalants.
  • the new compounds may be used as drops, ointments, tinctures and gels in appropriate pharmaceutical preparations.
  • compositions in gels, ointments, greases, creams, pastes, powders, suspensions, emulsions and solutions are possible.
  • the dosage of the compounds of general formula (I) should be 0.01% - 20% in these preparations in order to achieve a sufficient pharmacological effect.
  • the invention likewise encompasses the compounds of the general formula (I) according to the invention as therapeutic active ingredient. Furthermore, the invention compounds of the general formula (I) according to the invention as a therapeutic agent together with one or more pharmaceutically acceptable and acceptable excipients and / or carriers.
  • the compounds of the general formula (I) according to the invention may also be formulated and / or administered in combination with further active compounds.
  • the invention therefore also relates to combination therapies or combined compositions in which a compound of the general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of the general formula (I) or a pharmaceutically acceptable salt thereof, is administered either simultaneously (optionally in the same composition) or sequentially together with one or more medicaments for the treatment of any of the above-mentioned conditions.
  • a compound of the general formula (I) of the present invention may be combined with one or more medicaments for the treatment of such a condition.
  • the drug to be combined may be selected from the following list:
  • a PDE4 inhibitor including an isoform PDE4D inhibitor
  • Adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol;
  • a muscarinic receptor antagonist for example an M1, M2 or M3 antagonist such as a selective M3 antagonist
  • M1, M2 or M3 antagonist such as a selective M3 antagonist
  • ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine;
  • a modulator of chemokine receptor function such as a CCR1 receptor antagonist
  • such a combination with a compound of the general formula (I) or a pharmaceutically acceptable salt thereof is employed for the treatment of COPD, asthma or allergic rhinitis and may be administered by inhalation or orally in combination with xanthine (e.g. For example, aminophylline or theophylline), which can also be administered by inhalation or orally.
  • xanthine e.g., aminophylline or theophylline
  • Process A Preparation of compounds of the general formula (II) from compounds of the general formula (IX) via the intermediate (HIA).
  • R 3a in the compounds of general formula (VIII) represents a hydrogen atom
  • the reaction is carried out by reduction, for. B., by catalytic hydrogenation of the compound (IX) with elemental hydrogen to suitable metal catalysts.
  • Compounds of the general formula (VIII) in which R 3a represents a cyano or alkyl group are obtainable by reacting compounds of the general formula (IX) with cyanide ions or organometallic alkyl compounds (eg copper organic compounds). These methods are known in the art.
  • the aldehydes of the general formula (VI) can be reacted with suitable organometallic reagents M-CF 2 R 14 , whereby the group -CF 2 R 14 can be introduced into the molecule (Scheme 5), wherein M represents an electrophilic leaving group.
  • organometallic reagents for example, compounds of the general formula C n F 2n + i-Si (CH 3 ) 3 in the presence of a
  • Catalyst suitable. Suitable catalysts in this process step are fluoride salts or basic compounds such as alkali metal carbonates (J. Am. Chem. Soc.
  • ketones of general formula (IV) are available (Scheme 6).
  • ketones of the general formula (IV) are then converted into the corresponding cyanohydrins of the general formula (MIA) (Scheme 7).
  • Suitable reagents for this example potassium, sodium or copper cyanide, or trimethylsilyl cyanide.
  • R in the general formula (INA) represents a hydrogen atom or a trimethylsilyl group.
  • the cyanohydrins of the general formula (MIA) are then converted-optionally after removal of the trimethylsilyl group-with a suitable reducing agent (eg diisobutylaluminum hydride) into the aldehydes of the general formula (II) (Scheme 8).
  • a suitable reducing agent eg diisobutylaluminum hydride
  • MIA Process B: Preparation of compounds of the general formula (II) from compounds of the general formula (IX) via the intermediate (MIB)
  • the aldehyde of general formula (IV) is then converted to an unsaturated alcohol of general formula (MIB) with a suitable organometallic reagent (e.g., a Grignard compound such as vinylmagnesium bromide) (Scheme 9).
  • a suitable organometallic reagent e.g., a Grignard compound such as vinylmagnesium bromide
  • the diol of the general formula (XI) can be obtained from the compound of the general formula (XII) (Scheme 12).
  • This diol (XI) can be converted to a compound of the general formula (X) by reduction of the double bond (for example by catalytic hydrogenation with elemental hydrogen over suitable metal catalysts) (Scheme 13).
  • Scheme 13 Preparation of compounds of the general formula (X)
  • esters of the general formula (XII) can also be reduced to the corresponding aldehydes which can be reacted directly with the primary amines of the general formula R 3 -NH 2 . Subsequently, the isolated in the right ring of the compound double bond is hydrogenated with suitable reducing agents. Also from this alternative sequence compounds of the general formula (I) in which the substituents R 3a and R 4 have the meaning of a hydrogen atom.
  • 0.58 ml of oxalyl chloride in 25.0 ml of dichloromethane are mixed at -78 ° C. with 1.0 ml of DMSO in 25.0 ml of dichloromethane. After 5 min. 1.2 g of 2- (4-methylchroman-4-yl) - ethanol in 25.0 ml of dichloromethane are added dropwise at -78 ° C. After 15 min. is added 4 ml of triethylamine and slowly warmed to room temperature. It is mixed with water, brine, 1% sulfuric acid and sat. Washed sodium bicarbonate solution, dried with sodium sulfate and concentrated in vacuo.
  • a solution of 1.3 ml of titanium tetraethylate in 10 ml of toluene is treated at room temperature with 3.54 g of binaphthol and stirred for one hour.
  • a solution of 10 g of 4-methylenethiochroman in 60 ml of toluene and 15 ml of trifluoropyruvate is added.
  • the reaction solution is stirred at 120 ° C. for 3 hours and at room temperature for a further 10 hours.
  • the reaction solution is diluted with water and ethyl acetate and filtered through diatomaceous earth. The organic phase is washed with brine, dried over sodium sulfate and concentrated in vacuo.
  • 2-Hydroxy-3- (thiochroman-4-yl) -2-trifluoromethyl-propionaldehyde 2.4 ml of oxalyl chloride in 240 ml of dichloromethane are treated at -78 ° C. with 4.6 ml of DMSO in 80 ml of dichloromethane. After 5 min. 1.2 l, 2-dihydroxy-3- (thiochroman-4-yl) -2-trifluoromethyl-propane are added dropwise in 80 ml of dichloromethane at -78 ° C. After 15 min. is added 22.8 ml of triethylamine and slowly warmed to room temperature.

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Abstract

La présente invention concerne de nouveaux composés hétérocycliques à substitutions multiples, de formule générale (I), un procédé pour les préparer, et leur utilisation en tant qu'inhibiteurs d'inflammation.
EP06742670A 2005-04-14 2006-04-13 Derives de chromane substitues, procede pour les preparer, et leur utilisation en tant qu'inhibiteurs d'inflammation Withdrawn EP1869013A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005017301A DE102005017301A1 (de) 2005-04-14 2005-04-14 Substituierte Chromanderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer
PCT/EP2006/003780 WO2006108711A1 (fr) 2005-04-14 2006-04-13 Derives de chromane substitues, procede pour les preparer, et leur utilisation en tant qu'inhibiteurs d'inflammation

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EP1869013A1 true EP1869013A1 (fr) 2007-12-26

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EP (1) EP1869013A1 (fr)
JP (1) JP2008535889A (fr)
CN (1) CN101160305A (fr)
CA (1) CA2598207A1 (fr)
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WO (1) WO2006108711A1 (fr)

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DE10038639A1 (de) * 2000-07-28 2002-02-21 Schering Ag Nichtsteroidale Entzündungshemmer
DE10215316C1 (de) * 2002-04-02 2003-12-18 Schering Ag Chinolin- und Isochinolin-Derivate, ein pharmazeutisches Mittel und ihre Verwendung als Entzündungshemmer
WO2004063163A1 (fr) * 2003-01-03 2004-07-29 Boehringer Ingelheim Pharmaceuticals, Inc. Derives de 1-propanol et 1-propylamine et leur utilisation en tant que ligands de glucocorticoide
GB0418045D0 (en) * 2004-08-12 2004-09-15 Glaxo Group Ltd Compounds

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CN101160305A (zh) 2008-04-09
DE102005017301A1 (de) 2006-10-19
WO2006108711A1 (fr) 2006-10-19
CA2598207A1 (fr) 2006-10-19

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