EP1673344A1 - Pentan-2-oles substitues en 1-(quinoleine-amino) et 1-(isoquinoleine-amino), un procede de production de ces composes, et leur utilisation en tant qu'anti-inflammatoires - Google Patents

Pentan-2-oles substitues en 1-(quinoleine-amino) et 1-(isoquinoleine-amino), un procede de production de ces composes, et leur utilisation en tant qu'anti-inflammatoires

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Publication number
EP1673344A1
EP1673344A1 EP04787047A EP04787047A EP1673344A1 EP 1673344 A1 EP1673344 A1 EP 1673344A1 EP 04787047 A EP04787047 A EP 04787047A EP 04787047 A EP04787047 A EP 04787047A EP 1673344 A1 EP1673344 A1 EP 1673344A1
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Prior art keywords
alkyl
group
aryl
cycloalkyl
compounds
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.)
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EP04787047A
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German (de)
English (en)
Inventor
Stefan Jaroch
Stefan BÄURLE
Markus Berger
Konrad Krolikiewicz
Duy Nguyen
Hartmut Rehwinkel
Norbert Schmees
Werner Skuballa
Heike Schäcke
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Bayer Pharma AG
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Schering AG
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Publication of EP1673344A1 publication Critical patent/EP1673344A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • the invention relates to quinoline and isoquinoline derivatives, a process for their preparation and their use as anti-inflammatories.
  • Anti-inflammatory agents of the general formula are from the prior art DE 100 38 639 and WO02 / 10143
  • the Ar radical comprising phthalides, thiophthalides, benzoxazinones or phthalazinones.
  • these compounds show dissociations of effects between anti-inflammatory and undesirable metabolic effects and are superior to the non-steroidal glucocorticoids described hitherto or at least have an equally good effect.
  • the present invention therefore relates to compounds of the general formula I.
  • R 1 and R 2 independently of one another are a hydrogen atom, a methyl or ethyl group or, together with the carbon atom of the chain, a C 3 -C 6 cycloalkyl ring,
  • R 3 is an optionally substituted group selected from C 4 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 7 heterocyclyl, aryl, Heteroaryl, (C C ⁇ -alkyl Cs-C ⁇ -cycloalkyl, (CC 8 -alkyl) aryl, or (d-Cs-alkyl heteroaryl B) a methylene group or a carbonyl group which is optionally substituted by a methyl or ethyl group, and Q is any position means associated quinolinyl or isoquinolinyl which may be optionally substituted by one or more radicals from the group C ⁇ -C 5 alkyl, C 1 -C 5 alkoxy, -C 5 alkylthio, CRCS perfluoroalkyl, halogen, hydroxy, cyano, Nitro, or NR 4 R 5
  • An aryl group includes phenyl and naphthyl. Phenyl is preferred.
  • the substituted aryl, benzyl or phenethyl groups have 1-3 substituents, preferably 2 substituents, on the ring.
  • substitution patterns on ring A are a particular subject of the invention: 2,5-disubstituted phenyl derivatives and 2,4-disubstituted phenyl derivatives.
  • the CC 5 alkyl groups in A, R 4 , and R 5 can be straight-chain or branched and for a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl - or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group.
  • a methyl or ethyl group is preferred.
  • the C 4 -Cs alkyl group R 3 can be straight-chain or branched and, for example, butyl, isobutyl, tert. Butyl, pentyl, isopentyl mean.
  • the C 2 -C 6 alkenyl group is straight-chain or branched, for example vinyl, propenyl, isopropenyl, butenyl, isobutenyl are suitable.
  • the C 2 -C 6 alkynyl group is straight-chain or branched, for example ethynyl, propynyl, butynyl can be used.
  • cycloalkyl group for example cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl are suitable.
  • the heterocyclyl group is not aromatic and can be, for example, pyrrolidine, imidazolidine, pyrazolidine, piperidine.
  • the C 8 -C 8 alkyl (C 3 -C 8 ) cycloalkyl group can be, for example, cyclobutyl methyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl.
  • the chain is linked via the alkyl group.
  • Phenyl and naphthyl are suitable for an aryl group, and benzyl and homobenzyl are suitable for (C 1 -C 8 ) alkylaryl.
  • Heteroaryl includes furanyl, thienyl, thiazolyl, oxazolyl, imidazoyl, triazolyl, pyridyl and pyrimidyl;
  • (-CC 8 alkyl) heteroaryl includes all combinations of the above definition of alkyl with monocyclic aromatic heterocycles.
  • the chain is linked via the alkyl group, which in turn is linked at any chemically possible position of the heterocycle.
  • the substituents of the groups in R 3 can be C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - Ce alkynyl, CC 6 alkoxy, halogen, hydroxy, NR 4 R 5 .
  • the alkyl radicals R 1 and R 2 can form a 3 to 6-membered ring together with the carbon atom of the chain.
  • the C 5 -C 5 alkoxy groups in A and Q can be straight-chain or branched and for a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy or n -Pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy group.
  • a methoxy or ethoxy group is preferred.
  • the -CC alkylthio groups in A and Q can be straight-chain or branched and for a methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, tert-butylthio or n- Pentylthio, 2,2-dimethylpropylthio, 2-methylbutylthio or 3-methylbutylthio group.
  • a methylthio or ethylthio group is preferred.
  • halogen atom or halogen means a fluorine, chlorine, bromine or iodine atom.
  • a fluorine, chlorine or bromine atom is preferred.
  • the NR 4 R 5 group can, for example, NH 2 , N (H) CH 3 , N (CH 3 ) 2 , N (H) (CO) CH 3 , N (CH 3 ) (CO) CH 3 , N [( CO) CH 3 ] 2 , N (H) CO 2 CH 3 , N (CH 3 ) CO 2 CH 3 , N (CO 2 CH 3 ) 2) .
  • alkyl radicals R 4 and R 5 C 1 -C 3 -alkyl are preferred.
  • Preferred acyl radicals R 4 and R 5 are (CO) -CC 3 -alkyl.
  • radical B the unsubstituted methylene group and the carbonyl group are preferred.
  • the radical Q can be linked to the (NH) group of the chain via any ring carbon atom.
  • the 4-, 5-, and 8-positions are preferred for the quinoline ring and the 1-position for the isoquinoline ring.
  • the compounds of general formula I according to the invention can exist as different stereoisomers due to the presence of asymmetry centers. Both the racemates and the separately present stereoisomers belong to the subject of the present invention.
  • a particular subject of the present invention are the separately present stereoisomers, i.e. (+) - enantiomers and (-) - enantiomers.
  • the invention further relates to compounds in which A represents an aryl, a benzyl or a phenethyl group, where the aryl, benzyl or phenethyl group may optionally be substituted by one or more radicals from the group CrC 5 -alkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkylthio, CC 5 perfluoroalkyl, halogen, hydroxy, cyano, nitro, or NR 4 R 5 , where R 4 and R 5 independently of one another are hydrogen, C 5 -C 5 alkyl or can be (CO) -CC 5 -alkyl,
  • R 3 is an optionally substituted group selected from C 4 -C 8 alkyl, O
  • C 3 -C 8 cycloalkyl C 3 -C 7 heterocyclyl, aryl, heteroaryl, (C Cs-alkyl Cs-Cs cycloalkyl, (CC 8- alkyl)) aryl, or (d-Cs-alkyl heteroaryl).
  • the invention further relates to compounds according to Claim 1, in which R 3 is an optionally substituted group selected from C 3 -C 6 cycloalkyl, C 3 -C 7 heterocyclyl, phenyl, heteroaryl, (CC 3 alkyl) C 3 -C 6 - Cycloalkyl, (CC 3 alkyl) phenyl, or (CC 3 alkyl) heteroaryl.
  • R 3 is an optionally substituted group selected from C 3 -C 6 cycloalkyl, C 3 -C 7 heterocyclyl, phenyl, heteroaryl, (CC 3 alkyl) C 3 -C 6 - Cycloalkyl, (CC 3 alkyl) phenyl, or (CC 3 alkyl) heteroaryl.
  • the invention further relates to compounds of the general formula I in which A is an unsubstituted phenyl group, R 1 and R 2 is methyl, R 3 is a cyclopentyl group, a methylcyclohexyl group or a phenyl group, B is a methylene group and Q is a quinoline or isoquinoline group.
  • the invention further relates to compounds of the general formula I in which A is an unsubstituted phenyl group, R 1 and R 2 are a methyl group, R 3 is a cyclopentyl group, a methylcyclohexyl group or a phenyl group, B is a methylene group and Q is a quinoline group.
  • the invention furthermore relates to the use of the compounds according to claim 1 for the production of medicaments, the use of the compounds according to claim 1 to the production of a medicament for the treatment of inflammatory diseases, and pharmaceutical preparations containing at least one compound according to claim 1 or mixtures thereof and pharmaceutically acceptable Carrier.
  • a preferred subject of the invention are compounds of the general formula I in which R 3 is C 3 -C 8 -cycloalkyl, (CrC 8 alkyl) C 3 -C 8 -cycloalkyl, benzyl or phenyl.
  • a particularly preferred object of the invention are compounds of the general formula I in which R 3 is C 3 -C 8 -cycloalkyl, (-C-C 8 alkyl) C 3 -C 8 -cycloalkyl or phenyl, very particularly preferred are compounds of the general formula I. wherein wherein R 3 is cyclopentyl, methylcyclohexyl or phenyl, as described in the examples.
  • the processes for the preparation of the compounds from WO98 / 54159 (51488), WO00 / 32584 (51642) and WO02 / 10143 (51877) can also be used for the preparation of the compounds according to the invention can be used.
  • the following process steps can be carried out to link the quin ⁇ lin or isoquinoline group which is characteristic of the compounds according to the invention:
  • the ⁇ -ketoamide (III) is used using dehydrating coupling reagents, such as are known from peptide chemistry, for example dicyclohexylcarbodiimide, or by converting the acid into an acid chloride, for example with thionyl chloride or POCI 3 and subsequent reaction with Q-NH 2. receive.
  • dehydrating coupling reagents such as are known from peptide chemistry, for example dicyclohexylcarbodiimide, or by converting the acid into an acid chloride, for example with thionyl chloride or POCI 3 and subsequent reaction with Q-NH 2.
  • R 3 has the meaning given above and R 6 denotes a -C 5 alkyl group, in the presence of a catalyst, for example fluoride salts or bases, such as alkali carbonates (J. Am. Chem. Soc. 1989, 111, 393), to give the title compound (I).
  • a catalyst for example fluoride salts or bases, such as alkali carbonates (J. Am. Chem. Soc. 1989, 111, 393), to give the title compound (I).
  • R 1 and R 2 are defined as described above and R 7 is C 1 -C 4 -alkyl, are esterified by the customary methods, for example with thionyl chloride in methanol or ethanol or with methyl iodide and alkali metal carbonate and in analogy to reaction sequence A1) from (III) to (I) in compound (VI).
  • This is used for coupling with an aminoquinoline or aminoisoquinoline or a (partially) hydrogenated quinoline or isoquinoline derivative (Q-NH 2 ) using a common activation reagent, e.g. thionyl chloride, optionally in the presence of a catalyst such as dimethylaminopyridine, to give the title compound ( I) implemented.
  • a common activation reagent e.g. thionyl chloride
  • a catalyst such as dimethylaminopyridine
  • the title compound (I) can also be synthesized by reductive amination of a compound of the formula (XII) with Q-NH 2 , where, for example, sodium cyanoborohydride or sodium triacetoxyborohydride are suitable as reducing agents.
  • R represents methyl or ethyl according to the substituents defined for the methylene group in B.
  • the compounds of the general formula I are present as salts, this can be, for example, in the form of the hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate.
  • the compounds according to the invention are present as racemic mixtures, they can be separated into the pure, optically active forms by methods of racemate separation familiar to the person skilled in the art.
  • the racemic mixtures can be separated into the pure isomers by chromatography on a self-optically active carrier material (CHIRALPAK AD®).
  • CHIRALPAK AD® self-optically active carrier material
  • esterify the free hydroxyl group in a racemic compound of the general formula I with an optically active acid and to separate the diastereoisomeric esters obtained by fractional crystallization or chromatographically and the to saponify separate esters to give the optically pure isomers.
  • mandelic acid, camphorsulfonic acid or tartaric acid can be used as the optically active acid.
  • glucocorticoid receptor glucocorticoid receptor
  • MR mineral corticoid receptor
  • PR progesterone receptor
  • AR androgen receptor
  • quinolines and isoquinolines of the formula (I) described here show a high selectivity for the glucocorticoid receptor.
  • GR-mediated inhibition of the transcription of cytokines, adhesion molecules, enzymes and other pro-inflammatory factors is regarded as an essential molecular mechanism for the anti-inflammatory effect of glucocorticoids. This inhibition is caused by an interaction of the GR with other transcription factors, e.g. AP-1 and NF-kappa- B, effects (for an overview see Cato, AGB and Wade E, BioEssays 18, 371-378 1996).
  • the compounds of the general formula I according to the invention inhibit the secretion of the cytokine IL-8 triggered by lipopolysacchard (LPS) in the human monocyte cell line THP-1.
  • the concentration of the cytokines in the supernatant was determined using commercially available ELISA kits.
  • the anti-inflammatory activity of the compounds of the general formula I were tested in animal experiments by testing in croton oil-induced inflammation in the rat and the mouse (J. Exp. Med. (1995), 182, 99-108). For this purpose, croton oil was applied topically to the ears in ethanolic solution. The test substances were also applied topically or systemically at the same time or two hours before the croton oil.
  • the ear weight was measured as a measure of the inflammatory edema, the peroxidase activity as a measure of the immigration of granulocytes and the elastase activity as a measure of the immigration of neutrophilic granulocytes.
  • the compounds of the general formula I inhibit the three above-mentioned inflammation parameters in this test both after topical and after systemic application.
  • glucocorticoid therapy One of the most common undesirable effects of glucocorticoid therapy is the so-called "steroid diabetes" [cf. Hatz, HJ, Glucocorticoide: Basic Immunology, Pharmacology and Therapy Guidelines, Horschafliche Verlagsgesellschaft mbH, Stuttgart, 1998].
  • the reason for this is the stimulation of gluconeogenesis in the liver by induction of the enzymes responsible for this and by free amino acids that result from the breakdown of proteins (catabolic effect of the glucocorticoids).
  • a key enzyme of the catabolic metabolism in the liver is tyrosine aminotranferase (TAT).
  • TAT tyrosine aminotranferase
  • the animals are sacrificed 8 hours after the administration of the test substances, the liver is removed and the TAT activity in the Homogenate measured.
  • the compounds of the general formula I do not induce the tyrosine aminotransferase, or do so only to a small extent, in which they are anti-inflammatory.
  • the compounds of general formula I according to the invention can be used as medicaments for the treatment or prophylaxis of the following disease states in mammals and humans:
  • the term "DISEASE” stands for the following indications:
  • Lung diseases that are associated with inflammatory, allergic and / or proliferative processes - Chronic obstructive lung diseases of any genesis, especially bronchial asthma - Bronchitis of different origins - All forms of restrictive lung diseases, especially allergic alveolitis, - All forms of pulmonary edema, especially toxic pulmonary edema - sarcoidosis and granulomatosis, especially Boeck's disease
  • rheumatic diseases / autoimmune diseases / joint diseases that are associated with inflammatory, allergic and / or proliferative processes - all forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, polymyalgia - Reactive arthritis - Inflammatory soft tissue diseases of other genesis - Arthritic symptoms in degenerative joint diseases (arthrosis) - Traumatic arthritis - Collagenosis of any genesis, e.g. systemic lupus erythematosus
  • Dermatological diseases that are associated with inflammatory, allergic and / or proliferative processes - Atopic dermatitis (especially in children) - Psoriasis - Pityriasis rubra pilaris - Erythematous diseases caused by different noxious substances, e.g. radiation, chemicals, burns etc. - Bullous dermatoses - Diseases of the lichenoid form, - Pruritus (e.g.
  • Kidney diseases that are associated with inflammatory, allergic and / or proliferative processes - Neph rot syndrome - All nephritis
  • Liver diseases that are associated with inflammatory, allergic and / or proliferative processes - acute liver cell disintegration, acute hepatitis of different origins, e.g. viral, toxic, drug-induced - chronically aggressive and / or chronic intermittent hepatitis
  • gastrointestinal diseases which are associated with inflammatory, allergic and / or proliferative processes are associated: - regional enteritis (Crohn's disease) - ulcerative colitis - gastritis - Refluxoesophagitis - Gastroenteritis of another genesis, e.g.
  • proctological diseases that are associated with inflammatory, allergic and / or proliferative processes - anal eczema - fissures - hemorrhoids - idiopathic proctitis (x) eye diseases that are associated with inflammatory, allergic and / or proliferative processes are associated: - allergic keratitis, uveitis, ulceris, - conjunctivitis - blepharitis - neuritis nervi optici - chorioditis - ophtalmia sympathica (xi) diseases of the ear, nose and throat area, which are associated with inflammatory, allergic and / or proliferative processes:
  • Otitis externa e.g. due to contact x, infection etc.
  • Neurological diseases associated with inflammatory, allergic and / or proliferative processes - cerebral edema, especially tumor-related cerebral edema - multiple sclerosis - acute encephalomyelitis - meningitis - various forms of seizures, e.g.
  • BNS convulsions Blood disorders that are associated with inflammatory, allergic and / or proliferative processes: - Acquired hemolytic anemia - Idopathic thrombocytopenia (xiv) Tumor diseases that are associated with inflammatory, allergic and / or proliferative processes: - Acute lymphoblastic leukemia - Malignant lymphomas - Lymphogranulomatoses - Lymphosarcomas - Extensive metastases, especially in breast, bronchial and prostate cancer
  • xvi organ and tissue transplantation, graft-versus-host disease
  • severe shock conditions e.g. anaphylactic shock, systemic inflammatory response syndrome (SIRS)
  • xviii substitution therapy for: congenital primary adrenal insufficiency, e.g. congenital adrenogenital syndrome - acquired primary adrenal insufficiency, e.g. Addison's disease, autoimmune adrenalitis, post-infectious, tumors, metastases etc.
  • congenital secondary adrenal insufficiency e.g. congenital hypopitutitarianism - acquired secondary adrenal insufficiency, e.g. post-infectious, tumors etc.
  • the suitable dose for the therapeutic effects in the abovementioned disease states is different and depends, for example, on the potency of the compound of the general formula I, the host, the mode of administration and the type and severity of the conditions to be treated, and the use as a prophylactic or therapeutic agent.
  • the invention further provides
  • a pharmaceutical composition for the treatment of a DISEASE which treatment comprises one of the compounds according to the invention or their mixture and at least one pharmaceutical auxiliary and / or carrier.
  • the daily doses comprise a range from 1 ⁇ g to 100,000 ⁇ g of the compound according to the invention per kg of body weight.
  • a recommended daily dose is in the range of 1 ⁇ g to 100,000 ⁇ g per kg body weight.
  • a dose of 10 to 30,000 ⁇ g per kg body weight is preferred, more preferably a dose of 10 to 10,000 ⁇ g per kg body weight.
  • this dose is conveniently administered several times a day.
  • acute shock e.g. anaphylactic shock
  • single doses can be given that are clearly above the doses mentioned above.
  • the formulation of the pharmaceutical preparations based on the new compounds is carried out in a manner known per se by processing the active ingredient with the carrier substances, fillers, disintegrants, binders, humectants, lubricants, absorbents, diluents, taste-correcting agents, colorants, etc. customary in galenics and converted into the desired application form.
  • the carrier substances fillers, disintegrants, binders, humectants, lubricants, absorbents, diluents, taste-correcting agents, colorants, etc. customary in galenics and converted into the desired application form.
  • Remington 's Pharmaceutical Science 15th ed. Mack Publishing Company, East Pennsylvania (1980).
  • Tablets, coated tablets, capsules, pills, powders, granules, pastilles, suspensions, emulsions or solutions are particularly suitable for oral administration.
  • Appropriately prepared crystal suspensions can be used for intra-articular injection.
  • Aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used for intramuscular injection.
  • the new compounds in the form of suppositories, capsules, solutions (for example in the form of clysms) and ointments can be used both for systemic and for local therapy.
  • the pulmonary application of the new compounds can be used in the form of aerosols and inhalants.
  • the new compounds can be used as drops, ointments and tinctures in corresponding pharmaceutical preparations for local use on the eyes, external auditory canal, middle ear, nasal cavity and paranasal sinuses.
  • formulations in gels, ointments, fatty ointments, creams, pastes, powder, milk and tinctures are possible.
  • the dosage of the compounds of the general formula I should be 0.01% to 20% in these preparations in order to achieve a sufficient pharmacological effect.
  • the invention also encompasses the compounds of the general formula I according to the invention as a therapeutic active ingredient.
  • the invention furthermore relates to the compounds of the general formula I according to the invention as a therapeutic active ingredient together with pharmaceutically acceptable and acceptable excipients and carriers.
  • the invention also comprises a pharmaceutical composition which contains one of the pharmaceutically active compounds according to the invention or their mixture or their pharmaceutically acceptable salt and a pharmaceutically acceptable salt or pharmaceutically acceptable adjuvants and carriers.
  • 2-Cvclopentyl-4-methyl-4-phenyl-1, 2-pentanediol 320 mg of ethyl 2-cyclopentyl-2-hydroxy-4-methyl-4-phenylpentanoate are converted into 185 mg of product with 92 mg of lithium aluminum hydride.
  • ⁇ NMR (CDCI 3 ); ⁇ 1.10 - 1.70 (m, 8H), 1.40 (s, 3H), 1.49 (s, 3H), 2.00 (AB system, 2H), 2.08 (m, 1H), 3.18 (AB system, 2H), 7.20 (t, 1H), 7.32 (t, 2H), 7.45 (d, 2H).
  • Triethylamine converted to 390 mg aldehyde.

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Abstract

L'invention concerne des pentanols substitués, un procédé de production de ces pentanols substitués, ainsi que leur utilisation en tant qu'anti-inflammatoires.
EP04787047A 2003-10-06 2004-09-24 Pentan-2-oles substitues en 1-(quinoleine-amino) et 1-(isoquinoleine-amino), un procede de production de ces composes, et leur utilisation en tant qu'anti-inflammatoires Withdrawn EP1673344A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10346940A DE10346940B3 (de) 2003-10-06 2003-10-06 Substituierte Pentanole, ihre Verwendung zur Herstellung von Arzneimitteln speziell Entzündungshemmer sowie diese enthaltende pharmazeutische Präparate
PCT/EP2004/010880 WO2005035502A1 (fr) 2003-10-06 2004-09-24 Pentan-2-oles substitues en 1-(quinoleine-amino) et 1-(isoquinoleine-amino), un procede de production de ces composes, et leur utilisation en tant qu'anti-inflammatoires

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EP1673344A1 true EP1673344A1 (fr) 2006-06-28

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EP (1) EP1673344A1 (fr)
JP (1) JP2007507450A (fr)
KR (1) KR20060121894A (fr)
CN (1) CN1863775A (fr)
AU (1) AU2004279544A1 (fr)
BR (1) BRPI0415084A (fr)
CA (1) CA2539572A1 (fr)
DE (1) DE10346940B3 (fr)
IL (1) IL174433A0 (fr)
MX (1) MXPA06003895A (fr)
NO (1) NO20062022L (fr)
WO (1) WO2005035502A1 (fr)
ZA (1) ZA200603601B (fr)

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KR101534422B1 (ko) 2008-05-14 2015-07-09 오토노미, 인코포레이티드 귀 질환 치료를 위한 제어 방출형 코르티코스테로이드 조성물 및 방법
US8236786B2 (en) 2008-08-07 2012-08-07 Pulmagen Therapeutics (Inflammation) Limited Respiratory disease treatment
NZ594157A (en) 2008-12-30 2013-07-26 Pulmagen Therapeutics Inflammation Ltd Sulfonamide compounds for the treatment of respiratory disorders
WO2010150014A1 (fr) 2009-06-24 2010-12-29 Pulmagen Therapeutics (Inflammation) Limited Glitazones 5r-5–deutérés pour le traitement de maladies respiratoires
WO2011098746A1 (fr) 2010-02-09 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Sels d'addition acide cristallins de l'énantiomère (5r) de la pioglitazone
GB201002224D0 (en) 2010-02-10 2010-03-31 Argenta Therapeutics Ltd Respiratory disease treatment
GB201002243D0 (en) 2010-02-10 2010-03-31 Argenta Therapeutics Ltd Respiratory disease treatment

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DE19723722A1 (de) * 1997-05-30 1998-12-10 Schering Ag Nichtsteroidale Gestagene
DE19856475A1 (de) * 1998-11-27 2000-05-31 Schering Ag Nichtsteroidale Entzündungshemmer
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

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DE10346940B3 (de) 2005-06-16
CN1863775A (zh) 2006-11-15
ZA200603601B (en) 2007-07-25
JP2007507450A (ja) 2007-03-29
CA2539572A1 (fr) 2005-04-21
IL174433A0 (en) 2006-08-01
WO2005035502A1 (fr) 2005-04-21
AU2004279544A1 (en) 2005-04-21
BRPI0415084A (pt) 2006-12-12
MXPA06003895A (es) 2006-07-03
NO20062022L (no) 2006-05-05
KR20060121894A (ko) 2006-11-29

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