EP1789394A1 - Heterocycles benzocondenses substitues par hydroxy utilises comme beta-agonistes pour le traitement de maladies respiratoires - Google Patents

Heterocycles benzocondenses substitues par hydroxy utilises comme beta-agonistes pour le traitement de maladies respiratoires

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Publication number
EP1789394A1
EP1789394A1 EP05740683A EP05740683A EP1789394A1 EP 1789394 A1 EP1789394 A1 EP 1789394A1 EP 05740683 A EP05740683 A EP 05740683A EP 05740683 A EP05740683 A EP 05740683A EP 1789394 A1 EP1789394 A1 EP 1789394A1
Authority
EP
European Patent Office
Prior art keywords
methyl
ethyl
optionally
hydrogen
cooh
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.)
Ceased
Application number
EP05740683A
Other languages
German (de)
English (en)
Inventor
Ingo Konetzki
Thierry Bouyssou
Philipp Lustenberger
Marco Santagostino
Andreas Schnapp
Christoph Hoenke
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.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Priority to EP05740683A priority Critical patent/EP1789394A1/fr
Publication of EP1789394A1 publication Critical patent/EP1789394A1/fr
Ceased legal-status Critical Current

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Classifications

    • 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
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • 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
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • 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
    • A61P37/08—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
    • 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring

Definitions

  • the present invention relates to compounds of general formula 1
  • radicals n, A, B, R 1 , R 2 and R 3 can have the meanings given in the claims and in the description, processes for their preparation and their use as medicaments, in particular as medicaments for the treatment of respiratory diseases.
  • Betamimetics ( ⁇ -adrenergic substances) are known from the prior art.
  • drugs For drug therapy of diseases, it is often desirable to provide drugs with a longer duration of action. This can generally ensure that the concentration of the active ingredient in the organism required to achieve the therapeutic effect is given over a longer period of time without having to repeat the drug too often.
  • the application of an active ingredient at longer intervals also contributes greatly to the well-being of the patient. It is particularly desirable to provide a drug that can be used therapeutically by applying it once per day (single dose). Use once a day has the advantage that the patient can get used to taking the medication regularly at certain times of the day relatively quickly.
  • betamimetics which, on the one hand, have a therapeutic benefit in the treatment of respiratory diseases and, moreover, are characterized by a longer duration of action and thus can be used for the production of drugs with longer efficacy. It is a particular object of the present invention to provide betamimetics which, owing to their long effectiveness, can be used to produce a medicament which can be applied once a day for the therapy of respiratory diseases. In addition to the above-mentioned objects, it is also an object of the present invention to provide those betamimetics which are not only extremely potent, but are also characterized by a high degree of selectivity towards the ⁇ 2 -adrenoceptor. Detailed description of the invention
  • R 1 and R 2 are identical or different, hydrogen, -CC 4 alkyl, halogen, OH or -O- -C alkyl;
  • R 3 is hydrogen, -CC 4 -alkyl, OH, halogen, -O-C ⁇ -C 4 -alkyl, -COOH, -COO-C, -C 4 -alkyl, -OC, -C 4 -alkylene-COOH or -OC ! -C 4 alkylene-CO-O -CC-C 4 alkyl;
  • R 4 and R 5 are the same or different, hydrogen, -CC 4 alkyl, OH, halogen, -OdC 4 alkyl, -COOH or -COO-C ⁇ alkyl;
  • R ° is hydrogen or -CC 4 alkyl
  • R 7 and R 8 are the same or different, hydrogen or -CC 4 alkyl
  • R 9 and R 10 are the same or different, -CC 4 alkyl, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form of the solvates and / or hydrates.
  • n 1 or 2, preferably 1;
  • R 1 and R 2 are the same or different, hydrogen, methyl, ethyl, propyl, fluorine, chlorine, bromine, OH, methoxy or ethoxy;
  • R 3 hydrogen, methyl, ethyl, propyl, fluorine, chlorine, bromine, OH, methoxy, ethoxy, -COOH, -COOMethy
  • n is 1 or 2, preferably 1;
  • R 1 and R 2 are the same or different, hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy or ethoxy;
  • R 7 and R 8 are the same or different, hydrogen, methyl or ethyl, preferably hydrogen or methyl
  • R 9 and R 10 are the same or different, methyl or ethyl, preferably methyl, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or Racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form of the solvates and / or hydrates.
  • n is 1 or 2, preferably 1;
  • R 1 and R 2 are the same or different, hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy or ethoxy;
  • R 3 is hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy, ethoxy, -COOH, -COOMethyl, -COOEthyl, -O-CH 2 -COOH, -O-CH 2 -COO-methyl, -
  • n 1 or 2, preferably 1;
  • R 1 and R 2 are the same or different, hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy or ethoxy;
  • R 3 is hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy, ethoxy, -COOH, -COOMethyl, -COOEthyl, -O-CH 2 -COOH, -O-CH 2 -COO-methyl, -O-CH 2 -COO-ethyl, -O-CH 2 -CH 2 -COOH, -O-CH 2 -CH 2 -COO-methyl or -O-CH 2 -CH 2 -COO-ethyl;
  • R 9 and R 10 are identical or different, preferably identical, methyl or ethyl, preferably methyl, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form of the solvates and / or hydrates.
  • R 1 and R 2 are the same or different, hydrogen, methyl, ethyl, fluorine, chlorine, OH, methoxy or ethoxy;
  • R 3 is hydrogen, and in which the radicals n, A and B can have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form of the solvates and / or hydrates.
  • R 1 and R 2 are the same or different, hydrogen, methyl, fluorine, chlorine or methoxy;
  • R 3 is hydrogen, methyl, fluorine, chlorine or methoxy, and in which the radicals n, A and B can have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual
  • Enantiomers or racemates optionally in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form of the solvates and / or hydrates.
  • R 3 methyl, ethyl, fluorine, chlorine, OH, methoxy, ethoxy, -COOH, -COOMethyl, -COOEthyl, -O-CH 2 -COOH, -O-CH 2 -COOMethyl, -O-CH 2 -COOEthyl, - O-CH 2 -CH 2 -COOH, -O-CH 2 -CH 2 -COOMethyl or -O-CH 2 -CH 2 -COOEthyl; means and in which the radicals n, R 1 , R 2 , A, B may have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form the solvates and / or hydrates.
  • R 3 denotes methyl, ethyl, OH, methoxy, ethoxy, -O-CH 2 -COOH, -O-CH 2 -COOMethyl or -O-CH 2 -COOEthyl, preferably OH, methoxy or ethoxy, and in which the radicals n, R 1 , R 2 , A, B can have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form of the solvates and / or hydrates.
  • a preferred aspect of the present invention relates to compounds of the formula Ia in which n, R 1 , R 2 and R 3 can have the meanings mentioned above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically harmless acids and optionally in the form of solvates and / or hydrates.
  • a preferred aspect of the present invention relates to compounds of the formula Ib in which n, R, R and R can have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form of the solvates and / or hydrates.
  • a preferred aspect of the present invention relates to compounds of the formula lc in which n, R 1 , R 2 and R 3 can have the meanings mentioned above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically harmless acids and optionally in the form of solvates and / or hydrates.
  • a preferred aspect of the present invention relates to compounds of the formula Id in which n, R 1 , R 2 and R 3 can have the meanings mentioned above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically harmless acids and optionally in the form of solvates and / or hydrates.
  • a preferred aspect of the present invention relates to compounds of the formula le 19 "in which n, R, R and R can have the meanings mentioned above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically harmless acids and optionally in the form of solvates and / or hydrates.
  • a preferred aspect of the present invention relates to compounds of the formula Ig in which n, R 1 , R 2 and R 3 can have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically harmless acids and optionally in the form of solvates and / or hydrates.
  • a preferred aspect of the present invention relates to compounds of the formula lh in which n, R 1 , R 2 and R 3 can have the meanings mentioned above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically harmless acids and optionally in the form of solvates and / or hydrates.
  • a preferred aspect of the present invention relates to compounds of the formula li wherein n, R 1 , R 2 , R 3 , R 4 and R 5 may have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, if appropriate in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form of the solvates and / or hydrates.
  • Preferred compounds of the formula Ii in which R 4 is hydrogen and R 5 can have one of the meanings mentioned above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and, if appropriate in the form of solvates and / or hydrates.
  • a preferred aspect of the present invention relates to compounds of the formula Ij in which n, R 1 , R 2 and R 3 can have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically harmless acids and optionally in the form of solvates and / or hydrates.
  • the hydroxyl function can be linked at 3 positions on the phenyl ring. According to the invention, preference is given to those regioisomers of general formula 1 in which the hydroxyl function is either according to general formula regio-1
  • regio-2 is linked, where the radicals A, B, R 1 , R 2 and R 3 may have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable Acids and optionally in the form of the solvates and / or hydrates.
  • Particularly preferred compounds of the present inventions are 17 'X
  • Enantiomers mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form of the solvates and / or hydrates.
  • n, R 1 , R 2 and R 3 can have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form of Solvates and / or hydrates.
  • n, R 1 , R 2 and R 3 can have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form of solvates and / or hydrates.
  • n, R 1 , R 2 and R 3 can have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form of solvates and or hydrates. Accordingly, compounds of the formula Id are of particular importance in which the hydroxyl function corresponds to the general formula re ⁇ io-2d
  • n, R 1 , R 2 and R 3 can have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form of solvates and / or hydrates.
  • n, R 1 , R 2 and R 3 can have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and, if appropriate in the form of solvates and / or hydrates.
  • compounds of the formula Ig are particularly important in which the hydroxyl function corresponds to the general formula re ⁇ io-2z re ⁇ io-22nd is linked and in which n, R 1 , R 2 and R 3 can have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form of Solvates and / or hydrates.
  • n, R, R and R can have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form of Solvates and / or hydrates.
  • compounds of the formula Ii in which the hydroxyl function corresponds to the general are of particular importance re ⁇ io-2 ⁇ is linked and in which n, R 1 , R 2 , R 3 , R 4 and R 5 may have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their Acid addition salts with pharmacologically acceptable acids and optionally in the form of the solvates and / or hydrates.
  • n, R 1 , R 2 and R 3 can have the meanings given above, optionally in the form of the individual enantiomers, mixtures of the individual enantiomers or racemates, optionally in the form of their acid addition salts with pharmacologically acceptable acids and optionally in the form of the solvates and / or hydrates.
  • the radicals R 1 and R 2 if they are not hydrogen, can each be arranged ortho or meta with respect to the linkage to the benzylic “-CH 2 ” group. If none of the radicals R 1 and R 2 is hydrogen, the use according to the invention of those compounds is 1 7 1
  • compounds of general formula 1 which are selected from the group consisting of - 8-hydroxy-5- ⁇ 1-hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethylethylamino ] - ethyl ⁇ -IH-quinolin-2-one; - 5- ⁇ 2- [2- (2,4-difluorophenyl) -1, l-dimethyl-ethylamino] -l-hydroxyethyl ⁇ -8-hydroxy-3,4-dihydro-1H-quinoline-2 -one; - 8-hydroxy-5- ⁇ 1-hydroxy-2- [2- (4-hydroxyphenyl) -1,1-dimethylethylamino] ethyl ⁇ - 1 H-quinolin-2-one; - 5- ⁇ 2- [2- (4-fluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl ⁇ -8-hydroxy-3,
  • Another aspect of the present invention relates to the above-mentioned new compounds of formula 1 as medicaments.
  • the present invention further relates to the use of the aforementioned compounds of general formula 1 for the manufacture of a medicament for the treatment of respiratory diseases.
  • the present invention preferably relates to the use of the above-mentioned compounds of general formula 1 for the manufacture of a medicament for the treatment of respiratory diseases, which are selected from the group consisting of obstructive lung diseases of different origins, emphysema of different origins, restrictive pulmonary diseases, interstitials
  • Lung diseases cystic fibrosis, bronchitis of various origins, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema.
  • obstructive pulmonary diseases which are selected from the group consisting of COPD (chronic obstructive pulmonary disease), bronchial asthma, pediatric asthma, severe asthma, acute asthma attack and chronic bronchitis, the use of which for the manufacture of a medicament for the treatment bronchial asthma is particularly preferred according to the invention.
  • restrictive lung diseases such as asbestosis or silicosis triggered by noxious agents and restriction due to lung tumors, such as for example Carcinomatous lymphangiosis, bronchoalveolar carcinoma and lymphoma.
  • interstitial lung diseases which are selected from the group consisting of infectious pneumonia, such as, for example, due to an infection with viruses, bacteria, fungi, protozoa, helminths or others Excitation, pneumonitis due to different genesis, such as aspiration and left heart failure, radiation-induced pneumonitis or fibrosis, collagenosis, such as lupus erythematosus, systemic scleroderma or sarcoidosis, granulomatosis, such as Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (fibrosis).
  • infectious pneumonia such as, for example, due to an infection with viruses, bacteria, fungi, protozoa, helminths or others Excitation
  • pneumonitis due to different genesis, such as aspiration and left heart failure, radiation-induced pneumonitis or fibrosis, collagenosis, such as lupus erythematosus, systemic
  • compounds of general formula 1 for the manufacture of a medicament for the treatment of bronchitis, such as, for example, bronchitis due to bacterial or viral infection, allergic bronchitis and toxic bronchitis.
  • compounds of general formula 1 for the manufacture of a medicament for the treatment of ARDS (adult respiratory distress syndrome). It is also preferred to use compounds of general formula 1 for the manufacture of a medicament for the treatment of pulmonary edema, for example toxic pulmonary edema after aspiration or inhalation of toxic substances and foreign substances.
  • the present invention particularly preferably relates to the use of the compounds of the formula 1 for the preparation of a medicament for the treatment of asthma or COPD.
  • the present invention further relates to a method for the treatment of the abovementioned diseases, characterized in that one or more of the abovementioned compounds of the general formula 1 are applied in therapeutically effective amounts.
  • the present invention preferably relates to methods for the treatment of asthma or COPD, characterized in that one or more of the abovementioned compounds of the general formula 1 are administered once a day in therapeutically effective amounts.
  • Another aspect of the present invention relates to the aforementioned new compounds of formula 1 in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates.
  • Compounds of the formula 1 in the form of the enantiomerically pure compounds are particularly preferred, the R-enantiomers of the compounds of the formula 1 being of outstanding importance according to the invention.
  • the R enantiomers of the compounds of formula 1 can be represented by the general formula
  • Another aspect of the present invention relates to the compounds of formula 1 mentioned above in the form of their acid addition salts with pharmacologically acceptable acids and, if appropriate, in the form of the solvates and / or hydrates.
  • salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydratate, and hydrotoxate, hydrooxarate, hydrooxarate, hydrooxarate, hydrooxarate, hydrooxate, hydrooxarate, hydrooxarate, hydrooxate, p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate.
  • the salts of hydrochloric acid, maleic acid and fumaric acid and acetic acid are particularly preferred according to the invention.
  • the alkyl groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl or butyl. Abbreviations Me, Et, Prop or Bu may also be used to denote the groups methyl, ethyl, propyl or butyl. Unless otherwise described, the definitions propyl and butyl encompass all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec. Butyl and tert-butyl, etc.
  • alkylene groups are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms. Examples include: methylene, ethylene, n-propylene or n-butylene.
  • alkyloxy groups designates carbon atoms that are linked via an oxygen atom. Examples include: methylox, ethyloxy, propyloxy or butyloxy.
  • the abbreviations MeO-, EtO-, PropO- or BuO- are also used to denote the groups methyloxy, ethyloxy, propyloxy or butyloxy. Unless otherwise described, the definitions propyloxy and butyloxy encompass all conceivable isomeric forms of the respective radicals.
  • propyloxy includes n-propyloxy and iso-propyloxy
  • butyloxy includes iso-butyloxy, sec. Butyloxy and tert-butyloxy, etc.
  • alkoxy may also be used instead of the term alkyloxy.
  • methoxy, ethoxy, propoxy or butoxy are also used to designate the groups methyloxy, ethyloxy, propyloxy or butyloxy.
  • Halogen in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless stated otherwise, fluorine, chlorine and bromine are preferred halogens.
  • the compounds according to the invention can be prepared analogously to procedures already known in the prior art. Suitable manufacturing processes are known, for example, from US 4460581, to which reference is made here in full.
  • Reaction mixture is heated to 50 ° C for 2 hours, then poured onto ice and concentrated with. Acidified hydrochloric acid. A red-brown solid is isolated, which is repeatedly recrystallized in ethanol with the addition of activated carbon. Yield: 67.5 g (50.6%); Melting range: 163-166 ° C.
  • Example 7 7-Hydroxy-5 - (1-hydroxy-2-r2- (4-methoxy-phenyl) -1.1-dimethyl-ethylamino] -ethyl) -3.4-dihydro-1H-quinolin-2-one
  • Example 8 5- ⁇ 2-r2- (4-ethoxyphenyl) -1, l-dimethyl-ethylamino] -l-hydroxyethyl) -7-hydroxy-3,4-dihydro-1 H-quinoline-2 -one
  • Example 13 7- (2- r2- (4-ethoxy-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl) -5-hvdroxy-3H-benzooxazol-2-one
  • Example 15 8- (2-r2- (4-fluoro-phenyl) -1,1-dimethylethylamino] -1-hydroxyethyl) -6-hydroxy-2,2-dimethyl-4H-benzo 1,4 ] oxazin-3-one
  • Suitable forms of application for applying the compounds of the formula 1 are, for example, tablets, capsules, suppositories, solutions, powders, etc.
  • the proportion of the pharmaceutically active compound (s) should in each case be in the range from 0.05 to 90% by weight, preferably 0.1 up to 50% by weight of the total composition.
  • Corresponding tablets can be mixed, for example, by mixing the active ingredient (s) with known auxiliaries, for example inert diluents such as calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as
  • Magnesium stearate or talc, and / or agents for achieving the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate can be obtained.
  • the tablets can also consist of several layers.
  • coated tablets can be produced by coating cores produced analogously to the tablets with agents conventionally used in coated tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also consist of several layers to achieve a deposit effect or to avoid incompatibilities.
  • the same can also Drage sleeve to achieve a depot effect consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
  • Juices of the active substances or combinations of active substances according to the invention can additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, and a taste-improving agent, for example flavorings, such as vanillin or orange extract. They can also contain suspending agents or thickening agents, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • Solutions are commonly used, e.g. with the addition of isotonants, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants, where, for example, when using water as a diluent, organic solvents can optionally be used as solubilizers or auxiliary solvents , manufactured and filled into injection bottles or ampoules or infusion bottles.
  • isotonants e.g. with the addition of isotonants, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants, where, for example, when using water as a diluent, organic solvents can optionally be used as solubilizers or auxiliary solvents , manufactured and filled into injection
  • the capsules containing one or more active ingredients or combinations of active ingredients can be produced, for example, by inerting the active ingredients
  • ingredients such as milk sugar or sorbitol mix and encapsulate in gelatin capsules.
  • Suitable suppositories can be mixed, for example, with those provided for them
  • Carriers such as neutral fats or polyethylene glycol or the like
  • auxiliary substances are water, pharmaceutically acceptable organic ones
  • Solvents such as paraffins (e.g. petroleum fractions), oils of vegetable origin (e.g. soybean oils), oils of vegetable origin (e.g.
  • Peanut or sesame oil monofunctional or polyfunctional alcohols (e.g. ethanol or
  • Glycerin carriers such as e.g. natural stone flours (e.g. kaolins, clays,
  • Talc chalk
  • synthetic rock flours e.g. highly disperse silica and silicates
  • sugar e.g. cane, milk and glucose
  • emulsifiers e.g. lignin
  • Sufite liquor methyl cellulose, starch and polyvinyl pyrrolidone
  • lubricants e.g.
  • the tablets can of course also contain additives, such as sodium citrate, calcium carbonate and, in addition to the carriers mentioned Contain dicalcium phosphate along with various additives such as starch, preferably potato starch, gelatin and the like.
  • Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting.
  • the active ingredients can be mixed with various flavor enhancers or colorants.
  • inhalable dosage forms inhalation powders containing propellant gas or propellant-free inhalation solutions come into consideration.
  • propellant-free inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions.
  • Inhalable powders which can be used according to the invention can contain 1 either alone or in a mixture with suitable physiologically acceptable auxiliaries. If the active ingredients 1 are contained in a mixture with physiologically acceptable auxiliaries, the following physiologically acceptable auxiliaries can be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligo- and polysaccharides ( e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these auxiliaries with one another.
  • monosaccharides e.g. glucose or arabinose
  • disaccharides e.g. lactose, sucrose, maltose
  • oligo- and polysaccharides e.g. dextrans
  • Mono- or disaccharides are preferably used, the use of lactose or glucose being preferred, in particular, but not exclusively, in the form of their hydrates.
  • Lactose most preferably lactose monohydrate, is used as an auxiliary as particularly preferred in the sense of the invention.
  • the auxiliaries have a maximum average particle size of up to 250 ⁇ m, preferably between 10 and 150 ⁇ m, particularly preferably between 15 and 80 ⁇ m. If appropriate, it may seem sensible to add finer excipient fractions with an average particle size of 1 to 9 ⁇ m to the excipients mentioned above. The latter finer excipients are also selected from the group mentioned above Excipients.
  • micronized active ingredient 1 preferably with an average particle size of 0.5 to 10 ⁇ m, particularly preferably from 1 to 5 ⁇ m, is admixed with the excipient mixture.
  • Processes for producing the inhalable powders according to the invention by grinding and micronizing and by finally mixing the constituents are known from the prior art.
  • the inhalable powders according to the invention can be applied using inhalers known from the prior art.
  • Inhalation aerosols containing propellant gas according to the invention can be dissolved in the propellant gas or contain in dispersed form.
  • the propellant gases which can be used to produce the inhalation aerosols are known from the prior art.
  • Suitable propellants are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • the above-mentioned propellant gases can be used alone or in mixtures thereof.
  • Particularly preferred propellants are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.
  • the inhalation aerosols containing propellant gas may also contain further constituents such as cosolvents, stabilizers, surfactants, antioxidants, lubricants and agents for adjusting the pH. All of these components are known in the art.
  • the active compounds 1 according to the invention can also be applied in the form of propellant-free inhalation solutions and inhalation suspensions.
  • Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic, solutions.
  • the solvent can only be water or it is a mixture of water and ethanol.
  • the relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70 percent by volume, in particular up to 60 percent by volume and particularly preferably up to 30 percent by volume.
  • the remaining volume percentages are filled up with water.
  • the 1_ containing solutions or suspensions are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. Acids selected from inorganic or organic acids can be used to adjust this pH. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid,
  • Nitric acid, sulfuric acid and or phosphoric acid examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others.
  • Preferred inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use the acids which already form an acid addition salt with one of the active ingredients. Ascorbic acid, fumaric acid and citric acid are preferred among the organic acids. If appropriate, mixtures of the acids mentioned can also be used, especially in cases of acids which, in addition to their acidifying properties, also have other properties, e.g. as flavors, antioxidants or complexing agents, such as citric acid or
  • hydrochloric acid is particularly preferably used to adjust the pH.
  • EDTA editic acid
  • sodium edetate sodium edetate
  • the content based on sodium edetate is below 100 mg / 100 ml, preferably below 50 mg / 100 ml, particularly preferably below 20 mg / 100 ml.
  • Inhalation solutions in which the sodium edetate content is 0 to 10 mg / 100 ml are generally preferred.
  • Co-solvents and / or other auxiliaries can be added to the propellant-free inhalation solutions.
  • Preferred co-solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
  • auxiliaries and additives are understood to mean any pharmacologically acceptable substance which is not an active substance but can be formulated together with the active substance (s) in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation.
  • These substances preferably have no or no significant or at least no undesirable pharmacological effect in the context of the desired therapy.
  • auxiliaries and additives include, for example, surface-active substances, such as, for example, soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives which guarantee or extend the useful life of the finished pharmaceutical formulation, flavors, vitamins and / or others known in the art
  • the additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
  • the preferred auxiliaries include antioxidants, such as ascorbic acid, if not already used for adjusting the pH, vitamin A, vitamin E, tocopherols and similar vitamins or pro vitamins occurring in the human organism.
  • Preservatives can be used to protect the formulation from contamination with germs. Suitable preservatives are those known from the prior art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate from those known from the prior art
  • the preservatives mentioned above are preferably present in concentrations of up to 50 mg / 100 ml, particularly preferably between 5 and 20 mg / 100 ml.
  • preferred formulations only contain benzalkonium chloride and sodium edetate.
  • sodium edetate is dispensed with.
  • the dosage of the compounds according to the invention is of course strongly dependent on the type of application and the disease to be treated.
  • the compounds of formula 1 When administered by inhalation, the compounds of formula 1 are highly effective even at doses in the ⁇ g range. Even above the ⁇ g range, the compounds of formula 1 can be used expediently. The dosage can then be in the milligram range, for example.
  • Another aspect of the present invention relates to the pharmaceutical formulations mentioned above, characterized by a content of a compound of the formula 1_ as such, particularly preferably the pharmaceutical formulations mentioned above which can be administered by inhalation.
  • the active ingredient is dissolved in water at its own pH or, if appropriate, at pH 5.5 to 6.5, and sodium chloride is added as an isotonic agent.
  • the solution obtained is filtered pyrogen-free and the filtrate is filled into ampoules under aseptic conditions, which are then sterilized and sealed.
  • the ampoules contain 5 mg, 25 mg and 50 mg of active ingredient.
  • the suspension is filled into a conventional aerosol container with a metering valve. 50 ⁇ l of suspension are preferably dispensed per actuation. If desired, the active ingredient can also be dosed in higher doses
  • the solution is prepared in a conventional manner by mixing the individual components.
  • the inhalable powder is prepared in the usual way by mixing of the individual components.

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Abstract

L'invention concerne des composés générale (1) dans laquelle n, A, B, R1, R2 et R3 ont la signification indiquée dans les revendications et dans la description. L'invention concerne également des procédés pour la production desdits composés ainsi que l'utilisation de ces derniers comme médicaments, notamment comme médicaments servant au traitement de maladies respiratoires.
EP05740683A 2004-05-13 2005-05-10 Heterocycles benzocondenses substitues par hydroxy utilises comme beta-agonistes pour le traitement de maladies respiratoires Ceased EP1789394A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP05740683A EP1789394A1 (fr) 2004-05-13 2005-05-10 Heterocycles benzocondenses substitues par hydroxy utilises comme beta-agonistes pour le traitement de maladies respiratoires

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Application Number Priority Date Filing Date Title
EP04425342 2004-05-13
EP05740683A EP1789394A1 (fr) 2004-05-13 2005-05-10 Heterocycles benzocondenses substitues par hydroxy utilises comme beta-agonistes pour le traitement de maladies respiratoires
PCT/EP2005/005027 WO2005110990A1 (fr) 2004-05-13 2005-05-10 Heterocycles benzocondenses substitues par hydroxy utilises comme beta-agonistes pour le traitement de maladies respiratoires

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EP1789394A1 true EP1789394A1 (fr) 2007-05-30

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EP2379507B1 (fr) 2008-12-30 2013-10-16 Pulmagen Therapeutics (Inflammation) Limited Composés de sulfonamide pour le traitement de troubles respiratoires
WO2010150014A1 (fr) 2009-06-24 2010-12-29 Pulmagen Therapeutics (Inflammation) Limited Glitazones 5r-5–deutérés pour le traitement de maladies respiratoires
GB0918922D0 (en) 2009-10-28 2009-12-16 Vantia Ltd Aminopyridine derivatives
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