EP1943220A2 - Nouveaux beta antagonistes contenant de l'indole, procede de production associe et utilisation en tant que medicaments - Google Patents

Nouveaux beta antagonistes contenant de l'indole, procede de production associe et utilisation en tant que medicaments

Info

Publication number
EP1943220A2
EP1943220A2 EP06807619A EP06807619A EP1943220A2 EP 1943220 A2 EP1943220 A2 EP 1943220A2 EP 06807619 A EP06807619 A EP 06807619A EP 06807619 A EP06807619 A EP 06807619A EP 1943220 A2 EP1943220 A2 EP 1943220A2
Authority
EP
European Patent Office
Prior art keywords
group
alkyl
phenyl
substituted
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06807619A
Other languages
German (de)
English (en)
Inventor
Thomas Trieselmann
Rainer Walter
Matthew R. Netherton
Ingo Konetzki
Marco Santagostino
Bradford S. Hamilton
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
Publication of EP1943220A2 publication Critical patent/EP1943220A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • 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
    • 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
    • A61P1/12—Antidiarrhoeals
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel beta-agonists of the general formula (I)
  • radicals R 1 and R 2 have the meanings mentioned in the claims and the description, their tautomers, their racemates, their enantiomers, their diastereomers, their solvates, their hydrates, their mixtures, their prodrugs and their salts, in particular their physiologically acceptable Salts with inorganic or organic acids or bases, process for the preparation of these compounds and their use as medicaments.
  • Beta-3 receptor agonists are known to have a marked effect on lipolysis, thermogenesis and serum glucose levels in animal type II diabetes models (Arch JR beta (3) adrenoceptor agonists: potential, pitfalls and progress, Eur J Pharmacol., 2002 Apr 12; 440 (2-3): 99-107).
  • compounds of the general formula (I) in which the radicals R 1 and R 2 have the meanings mentioned below act as selective beta-3 agonists.
  • the compounds of the invention can be used to treat diseases associated with the stimulation of beta-3 receptors.
  • the present invention therefore relates to compounds of the general formula (I)
  • R 1 is a phenyl group which may be mono- or disubstituted by fluorine, chlorine or bromine atoms or methyl, methoxy, trifluoromethoxy or difluoromethoxy groups, wherein the substituents are the same or different, or
  • heteroaryl group selected from the group consisting of pyridinyl and thienyl
  • R is a hydrogen, fluorine, chlorine, bromine or iodine atom
  • Ci -3 alkylsulphanyl Ci -3 alkylsulfinyl, Ci -3 alkylsulfonyl, tetrazolyl, 5 Oxo-4,5-dihydro- [1, 3,4] oxadiazol-2-yl, or 5-oxo-2,5-dihydro- [1,2,4] oxadiazol-3-yl group,
  • an amino group which by a Carboxycarbonyl-, aminocarbonyl, Ci-6-alkyl- aminocarbonyl, phenylaminocarbonyl, Ci- 6 alkyl-carbonyl, benzyloxy-Ci -3 alkyl carbonyl, cyano-Ci -3 - alkyl-carbonyl, C 3-7 cycloalkyl-carbonyl or Ci -3 - may be substituted alkylsulfonyl group,
  • C 1-6 -alkyl-carbonyl group may be straight-chain or branched and may be substituted in the alkyl part by an amino group
  • Ci -3 alkyl group which fluoromethyl independently by one or two tri-, hydroxy, carboxy or C 6 alkyloxy-carbonyl groups may be substituted
  • Ci -3 alkyloxy group which group by a carboxy or Ci -3 alkyloxy-carbonyl may be substituted
  • Ci -3 alkyl-carbonyl group which is substituted by a Ci -3 alkylsulfonyl
  • Ci-6-alkyloxy-carbonyl group which in the alkyl moiety by a di- (Ci -3 -alkyl) -aminocarbonyl, Ci-6-alkyl-carbonyloxy, Ci-6-alkyloxy-carbonyloxy or pyridinyl or by a optionally substituted by a Ci -3 alkyl substituted 2-oxo- [1, 3] dioxolyl distr may be substituted,
  • C2-6-alkyloxy-carbonyl group which in the alkyl moiety from position 2 by a di- (Ci -4 - alkyl) -amino, N- (Ci -3 alkyl) -N-benzyl-amino or Ci -3 - alkyloxy-Ci -3 alkyloxy group or 7-membered cycloalkyleneimino group by a 3- to is substituted, wherein one or two methyl groups, a carbonyl, sulfonyl or a group of -N (Ci- 3 - alkyl) - in the above-mentioned 5- to 7-membered cycloalkyleneimino group, independently from each other by an oxygen or sulfur atom and / or group can be replaced,
  • an aminocarbonyl group which is selected on the nitrogen atom independently of one another by one or two groups selected from the group consisting of cyano, hydroxy, Ci-6-alkyl, C3 -7 cycloalkyl, Ci-3-alkoxy, amino, di (Ci-3- alkyl) -amino, (4-methylphenyl) sulfonyl, may be substituted,
  • alkyl group may be straight-chain or branched and may be substituted by one to three fluorine atoms or by a carboxy, C 1-3 -alkoxycarbonyl, C 3-7 -cycloalkyl or C 1-3 -alkylsulphonyl group,
  • a methylene group may be replaced by an oxygen or sulfur atom or a carbonyl or sulfonyl group
  • R denotes a hydrogen atom or a hydroxyl group
  • alkyl groups contained in the abovementioned groups can each be straight-chain or branched, as well as their prodrugs, tautomers, racemates, enantiomers, diastereomers, solvates, hydrates, their mixtures and their salts.
  • R 2 is defined as mentioned above and
  • R 1 represents a phenyl group which may be substituted by a fluorine, chlorine or bromine atom or a methyl, methoxy, trifluoromethoxy or difluoromethoxy group,
  • R 2 is defined as mentioned above and
  • R 1 represents a phenyl group
  • R 2 is a hydrogen atom or a cyano, carboxy, Ci-4-alkyloxy-carbonyl, tetrazolyl, 5-oxo-2, 5-dihydro- [1, 2,4] oxadiazol-3-yl or 5-oxo-4,5 -dihydro- [1,4, 4] oxadiazol-2-yl group,
  • amino group which may be substituted by a carboxycarbonyl, aminocarbonyl, C 1.3 alkylcarbonyl or cyanoacetyl group,
  • aminocarbonyl group which may be independently substituted on the nitrogen atom by one or two groups selected from the group consisting of hydroxy, methyl, amino, and cyclopropylmethyl,
  • alkyl group contained in the abovementioned groups can each be straight-chain or branched
  • R 1 is a phenyl group which may be mono- or disubstituted by fluorine, chlorine or bromine atoms or methyl, methoxy, trifluoromethoxy or difluoromethoxy groups, wherein the substituents are the same or different, or
  • heteroaryl group selected from the group consisting of pyridinyl and thienyl
  • R 2 is a hydrogen, fluorine, chlorine, bromine or iodine atom or an amino, cyano, methoxy, trifluoromethoxy, dilformethoxy, carboxy, C 1-6 -alkyloxycarbonyl, aminocarbonyl, C 1-3 -alkylsulphinyl, C 1-3 -alkylsulphonyl, tetrazolyl or 1, 2,4-oxadiazol-5-on-3-yl group,
  • aminocarbonyl group on the nitrogen atom can be substituted independently of one another by one or two groups selected from the group consisting of C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy and cyano,
  • alkyl groups contained in the abovementioned groups can each be straight-chain or branched
  • R 2 is defined as mentioned above and
  • R 1 represents a phenyl group which may be substituted by a fluorine, chlorine or bromine atom or a methyl, methoxy, trifluoromethoxy or difluoromethoxy group,
  • R 2 is defined as mentioned above and
  • R 1 represents a phenyl group
  • R 2 is a hydrogen, fluorine, chlorine or bromine atom or
  • aminocarbonyl group on the nitrogen independently of one another by one or two groups selected from the group consisting of C 1-3 -alkyl,
  • Ci-3-alkoxy, hydroxy and cyano may be substituted
  • alkyl group contained in the abovementioned groups can each be straight-chain or branched
  • a preferred subgroup relates to those compounds of the general formula (I) in which R 1 and R 2 are defined as mentioned above and in which the radical R 2 is in position 5 or 6, in particular in position 5 of the indole, their tautomers, their enantiomers, their diastereomers, their mixtures and their salts.
  • a second preferred subgroup relates to the (R) -enantiomer of formula (Ia)
  • a third preferred subgroup relates to the (S) -enantiomer of formula (Ib)
  • Another object of the invention are compounds of general formula (I) for use as medicaments.
  • Another object of the invention are compounds of general formula (I) for use as drugs with selective beta-3-agonistic action.
  • Another object of the invention are compounds of general formula (I) for the manufacture of a medicament for the treatment and / or prevention of diseases associated with the stimulation of beta-3 receptors.
  • Another object of the invention is a method for the treatment and / or prevention of diseases associated with the stimulation of beta-3 receptors, wherein a patient administered an effective amount of a compound of the general formula I.
  • Another object of the invention is a pharmaceutical composition containing as active ingredient one or more compounds of general formula (I), optionally in combination with conventional excipients and / or carriers.
  • Another object of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient one or more compounds of general formula (I) or their physiologically acceptable salts and one or more active substances selected from the group consisting of antidiabetics, inhibitors of protein tyrosine phosphatase 1, substances that one deregulated Glucose production in the liver, lipid-lowering drugs, cholesterol absorption inhibitors, HDL-increasing compounds, drugs for the treatment of obesity and modulators or stimulators of the adrenergic system via alpha 1 and alpha 2 as well as beta 1, beta 2 and beta 3 receptors.
  • active substances selected from the group consisting of antidiabetics, inhibitors of protein tyrosine phosphatase 1, substances that one deregulated Glucose production in the liver, lipid-lowering drugs, cholesterol absorption inhibitors, HDL-increasing compounds, drugs for the treatment of obesity and modulators or stimulators of the adrenergic system via alpha 1 and alpha 2 as well as beta 1,
  • a further subject of the invention is a process for the preparation of a compound of general formula (I), wherein
  • R 1 and R 2 may have the meanings given above, where a compound of the formula (II)
  • R 1 has the meaning indicated above
  • Another aspect of the invention relates to an improved process for the preparation of the compound (IIIb), which is described by way of example in the experimental part.
  • Alkyl groups and alkyl groups which are part of other groups are, unless stated otherwise, branched and unbranched alkyl groups having 1 to 10 carbon atoms, with groups having 1 to 6 carbon atoms being preferred. Particularly preferred are alkyl groups having 1 to 4 carbon atoms, especially those having 1 or 2 carbon atoms. Examples include: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.
  • propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl include all of the possible isomeric forms.
  • propyl comprises the two isomeric radicals n-propyl and isopropyl
  • one or more hydrogen atoms it is optionally possible for one or more hydrogen atoms to be replaced by other radicals.
  • Alkyl groups be substituted by the halogen atoms fluorine, chlorine, bromine or iodine.
  • the substituents are preferably fluorine or chlorine. Particularly preferred is the substituent fluorine. If appropriate, all hydrogen atoms of the alkyl group may also be replaced.
  • one or more hydrogen atoms are selected, for example, by OH, NO 2 , CN or an optionally substituted radical selected from the group consisting of -O- (C 1 -C 5 -alkyl), preferably Methoxy or ethoxy, -O- (C 6 -C 4 -aryl), preferably phenyloxy, -O-heteroaryl, preferably -O-thienyl, -O-thiazolyl, -O-imidazolyl, -O-pyridyl, -O-pyrimidyl or -O-pyrazinyl, saturated or unsaturated -O-heterocycloalkyl, preferably -O-pyrazolyl, -O-pyrrolidinyl, -O-piperidinyl, -O-piperazinyl or -O-tetrahydro-oxazin
  • Amine radical preferably methylamine, benzylamine, phenylamine or heteroarylamine, saturated or unsaturated bicyclic ring systems, preferably benzimidazolyl and C3-C ⁇ -cycloalkyl, preferably cyclohexyl or cyclopropyl, to be replaced.
  • alkenyl groups and alkenyl groups which are part of other groups branched and unbranched alkyl groups having 1 to 10 carbon atoms are preferably 1 to 6, more preferably 1 to 4 carbon atoms containing at least one carbon-carbon double bond.
  • alkenyl groups and alkenyl groups which are part of other groups branched and unbranched alkyl groups having 1 to 10 carbon atoms are preferably 1 to 6, more preferably 1 to 4 carbon atoms containing at least one carbon-carbon double bond.
  • alkenyl groups optionally one or more hydrogen atoms may be replaced by other groups.
  • these alkenyl groups can be substituted by the halogen atoms fluorine, chlorine, bromine or iodine. be.
  • the substituents are preferably fluorine or chlorine. Particularly preferred is the substituent fluorine. If appropriate, all hydrogen atoms of the alkenyl group may also be replaced.
  • alkynyl groups and alkynyl groups which are part of other groups branched and unbranched alkyl groups having 1 to 10 carbon atoms are preferably 1 to 6, more preferably 1 to 4 carbon atoms which contain at least one carbon-carbon triple bond. Examples which may be mentioned are: ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl.
  • alkynyl optionally one or more hydrogen atoms may be replaced by other radicals.
  • these alkynyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine.
  • the substituents are preferably fluorine or chlorine. Particularly preferred is the substituent fluorine.
  • all hydrogen atoms of the alkynyl group may also be replaced.
  • aryl stands for an aromatic ring system having 6 to 18 carbon atoms, preferably 6 to 14 carbon atoms, preferably 6 or 10 carbon atoms, more preferably phenyl, which may be optionally substituted and may preferably carry one or more of the substituents mentioned below OH, NO 2 , CN, -OCHF 2 , -OCF 3 , -NH 2 , -NH-alkyl, -N (alkyl) -alkyl, -NH-aryl, -N (alkyl) -aryl, -NHCO-alkyl , -NHCO-aryl, -N (alkyl) -CO-alkyl, -N (alkyl) -CO-aryl, -NHSO 2 -alkyl, -NHSO 2 -N (alkyl) 2 , -NHSO 2 -aryl, -N (Alkyl) -SO 2 -alkyl, -N (alkyl)
  • Heteroaryl radicals are to be understood as meaning 5- to 10-membered mono- or bicyclic heteroaryl rings in which one to three carbon atoms in each case can be replaced by a heteroatom selected from the group oxygen, nitrogen or sulfur.
  • Examples which may be mentioned are furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, each of the abovementioned heterocycles optionally further fused to a benzene ring may be, such as benzimidazole, and wherein these heterocycles may optionally be substituted and may preferably carry one or more of the following substituents: OH, NO 2 , CN, -NH 2 , -NH-alkyl, -N (al
  • Cycloalkyl radicals are saturated or unsaturated cycloalkyl radicals having 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl, where each of the abovementioned cycloalkyl radicals is optionally also a or may bear a plurality of substituents or may be fused to a benzene ring.
  • heterocycloalkyl or heterocyclyl radicals unless otherwise specified in the definitions, 5, 6 or 7-membered, saturated or unsaturated heterocycles which may contain nitrogen, oxygen or sulfur as heteroatoms, denotes, for example, tetrahydrofuran, tetrahydrofuranone, ⁇ -butyrolactone, ⁇ -pyran, ⁇ -pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, Piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepane, oxazine, tetrahydro-oxaziny
  • the compounds of the above general formula (I) which contain an in vivo cleavable radical represent so-called prodrugs, and compounds of general formula I which contain two in vivo cleavable radicals, so-called double prodrugs.
  • a convertible in vivo into a carboxy group is, for example, an ester of the formula -CO 2 R 11 to understand, wherein R 11 is hydroxymethyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkenyl, heterocyclo alkyl, dC 3 alkoxycarbonyl, 1, 3- Dihydro-3-oxo-1-isobenzofuranol, -C (alkyl) (-alkyl) -OC (O) -alkyl, -CHC (O) NH (-alkyl), -CHC (O) N (-alkyl) ( -Alkyl), -alkyl, preferably C 1 -C 6 -alkyl, particularly preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl or n-hexyl, cycloalkyl, preferably C 1 -C 6
  • a group which can be converted into a sulfonamide or amino group in vivo is one of the following groups: -OH, -formyl, -C (O) -alkyl, -C (O) -aryl, -C (O) -Heteroaryl, -CH 2 OC (O) -alkyl,
  • -CO 2 -alkyl preferably C 1 -C 6 -alkoxycarbonyl, more preferably methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyl-oxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl-, Cyclohexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl or n-nonyloxycarbonyl,
  • -C (O) -aryl preferably benzoyl, -C (O) -Heteroaryl, preferably pyridinoyl or nicotinoyl or
  • -C (O) -alkyl preferably -C (O) (- C 1 -C 6 -alkyl), more preferably 2-methylsulfonylethoxycarbonyl, 2- (2-ethoxy) -ethoxycarbonyl-.
  • the halogen is generally fluorine, chlorine, bromine or iodine, preferably chlorine or fluorine, especially preferably fluorine.
  • the compounds according to the invention can be used in the form of the individual optical isomers, mixtures of the individual enantiomers, diastereomers or racemates, prodrugs, double prodrugs and in the form of the tautomers, salts, solvates and hydrates and in the form of the free bases or the corresponding acid addition salts with pharmacological non-hazardous acids - such as acid addition salts with hydrohalic acids, for example hydrochloric or hydrobromic acid, or organic acids, such as oxalic, fumaric, diglycol, formic, malic, benzoic, benzenesulfonic, camphorsulfonic, acetic, ethanesulfonic , Glutamic, maleic, almond, lactic, phosphoric, nitric, sulfuric, succinic, para-toluenesulfonic, trifluoroacetic, tartaric, citric or methanesulfonic acid.
  • hydrohalic acids for example hydro
  • novel compounds of the formula I thus obtained if they contain a carboxy group or another acidic group, can then, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for the pharmaceutical application into their physiologically tolerated salts.
  • the bases used here are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and ethanolamine Tn into consideration.
  • the compounds of general formula I which are obtained in racemates can be prepared by methods known per se (see Allinger NL and ENeI EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and Compounds of general formula I having at least two asymmetric carbon atoms due to their physicochemical differences according to known methods, eg by chromatography and / or fractional crystallization, into their diastereomers, which, if they are obtained in racemic form, can then be separated into the enantiomers as mentioned above.
  • the separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with a, with the racemic compound salts or derivatives such as esters or amides forming optically active substance, in particular acids and their activated derivatives or alcohols, and Separation of the thus obtained diastereomeric salt mixture or derivative, for example due to different solubilities, wherein from the pure diastereomeric salts or derivatives, the free antipodes can be released by the action of suitable agents.
  • optically active acids are, for example, the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid.
  • optically active alcohol for example, (+) - or (-) - menthol and as an optically active acyl radical in amides, for example, the (+) - or (-) - Menthyloxycarbonylrest into consideration.
  • the compounds of the general formula (I) are distinguished by a variety of possible uses in the therapeutic field. Particularly noteworthy are those applications for which the effect of beta-3 agonists, in particular of selective beta-3 agonists play a role.
  • Such diseases include, for example:
  • Atherosclerosis, cholangitis, gallbladder disease, chronic cystitis, chronic cystitis; chronic prostatitis, cystospasm, depression, duodenal ulcer, duodenitis, dysmenorrhea, increased intraocular pressure and glaucoma, enteritis, esophagitis, gastric ulcer, gastritis, gastrointestinal disorders caused by contraction (s) of smooth muscle, gastrointestinal disorders including gastric ulcer, gastrointestinal ulcerations, gastrointestinal ulcers, glaucoma, glucosuria, hyperanakinesia, hypercholesterolemia, hyperglycemia, hyperlipemia, arterial hypertension, hypertriglyceridemia, insulin resistance, intestinal ulceration or small bowel ulcers (including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis fistula inflammation), irritable colon and other diseases with decreased intestinal motility, depression, melancholia, melanobia, pollakiuria, frequent urinary urgency, neurogenic inflammatory neurogenesis
  • OAB is preferred with increased frequency of micturition, with or without urge incontinence, with or without nocturnal urination.
  • the compounds can also be used in conditions of the prostate or lower genitourinary tract.
  • the relevant diseases include benign prostatic hyperplasia (BPH), prostatitis, in particular chronic abacterial prostatitis, neurogenic, muscular or bacterial origin, chronic pelvic pain syndrome, pelvic myoneuropathy, prostate dynia, lower urinary tract symptoms (LUTS), obstructive bladder dysfunction (BOO) and / or prostateopathy.
  • BPH benign prostatic hyperplasia
  • prostatitis in particular chronic abacterial prostatitis, neurogenic, muscular or bacterial origin, chronic pelvic pain syndrome, pelvic myoneuropathy, prostate dynia, lower urinary tract symptoms (LUTS), obstructive bladder dysfunction (BOO) and / or prostateopathy.
  • the use according to the invention is aimed not only at the causative treatment of said indications, but also at the treatment of concomitant symptoms, in particular pain or urinary diversion problems, pain and discomfort in the vicinity of the prostate or lower urinary tract, including the penis, in pain in erection or ejaculation, pain in defecation, erectile dysfunction.
  • the compounds according to the invention are also useful for the treatment of neurodegenerative diseases such as e.g. Alzheimer's disease (Alzheimer's disease), vascular dementia, Parkinson's disease (Parkinson's disease), Huntington's chorea, dystonia or degenerative ataxia.
  • neurodegenerative diseases such as e.g. Alzheimer's disease (Alzheimer's disease), vascular dementia, Parkinson's disease (Parkinson's disease), Huntington's chorea, dystonia or degenerative ataxia.
  • beta-3 agonists of the invention for the treatment of obesity, insulin resistance, type 2 diabetes mellitus, urinary incontinence, irritable colon and other diseases with decreased intestinal motility or depression, especially for the treatment of diabetes and obesity.
  • the activity of the beta-3 agonists can be determined, for example, in a lipolysis test.
  • the test method can be performed as described below:
  • Adipocytes were isolated from ex vivo adipose tissue by modification of a Rodbell method (Rodbell, M. Metabolism of Isolated Fat Cells, J. Biol. Chem. 239: 375-380, 1964). Cut out fatty tissue was cut into small pieces and mixed with 1 mg / ml CoIIa in Krebs Ringer buffer (KBR) containing 6 mM glucose and 2% albumin by gentle shaking for 30-40 min at 37 ° C. The cells were filtered through a gauze, washed twice with KRB and centrifuged 50-15Og for 5 min.
  • KBR Krebs Ringer buffer
  • Glycerol is phosphorylated by ATP via glycerol kinase.
  • the resulting glycerol-1-phosphate is oxidized by glycerol phosphate oxidase to dihydroxyacetone phosphate and hydrogen peroxide.
  • a quinoneimine dye is formed.
  • the dye shows an absorption maximum at 540 nm. The absorption is directly proportional to the glycerol concentration in the samples.
  • novel compounds can be used for the prevention, short-term or long-term treatment of the abovementioned diseases, also in combination with other active substances which are used for the same indications.
  • active substances include, for example, antidiabetic agents such as metformin, sulfonylureas (eg glibenclamide, tolbutamide, glimepiride), nateglinides, repaglinides, thiazolidinediones (eg rosiglitazones, pioglitazones), PPAR-gamma agonists (eg Gl 262570), alpha-glucosidase inhibitors (eg acarbose, voglibose ), alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (eg exendin-4) or amylin.
  • antidiabetic agents such as metformin, sulfonylureas (eg
  • inhibitors of protein tyrosine phosphatase 1 substances that influence a deregulated glucose production in the liver, such as inhibitors of glucose-6-phosphatase, or fructose-1, 6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase, the Glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents such as HMG-CoA reductase inhibitors (eg simvastatin, atorvastatin), fibrates (eg Bezafibrate, fenofibrate), nicotinic acid and its derivatives, cholesterol absorption inhibitors such as ezetimibe, bile acid-binding substances such as colestyramine, HDL-increasing compounds such as inhibitors of CETP or regulators of ABC1 or drugs for the treatment of over-sitas, such as Sibutr
  • a combination with drugs for influencing hypertension such as e.g. All antagonists or ACE inhibitors, diuretics, ß-blockers, as well as other modulators of the adrenergic system or combinations thereof.
  • drugs for influencing hypertension such as e.g. All antagonists or ACE inhibitors, diuretics, ß-blockers, as well as other modulators of the adrenergic system or combinations thereof.
  • combinations with stimulators of the adrenergic system via alpha 1 and alpha 2 as well as beta 1, beta 2 and beta 3 receptors are particularly suitable.
  • the compounds of the general formula (I) can be used alone or in combination with other active compounds according to the invention, if appropriate also in combination with other pharmacologically active substances.
  • Suitable application forms are, for example, tablets, capsules, suppositories, solutions, in particular solutions for injection (s.al., i.v., i.m.) and infusion, juices, emulsions or dispersible powders.
  • the proportion of the pharmaceutically active compound (s) in each case in the range of 0.1 to 90 wt .-%, preferably 0.5 to 50 wt .-% of the total composition, i. in amounts sufficient to reach the dosage range given below.
  • the said doses may, if necessary, be given several times a day.
  • Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or means for achieving the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • excipients for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or means for achieving the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • Coated tablets can be prepared accordingly by coating cores produced analogously to the tablets with agents normally used in tablet coatings, Kollidon or shellac, gum arabic, talc, titanium dioxide or sugar, for example.
  • the core can also consist of several layers.
  • the dragee sheath to achieve a depot effect of several layers may consist of the above mentioned in the tablets excipients can be used.
  • Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, as well as a taste-improving agent, e.g. Flavorings such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • a sweetener such as saccharin, cyclamate, glycerol or sugar
  • a taste-improving agent e.g. Flavorings such as vanillin or orange extract.
  • suspending aids or thickening agents such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • Injection and infusion solutions are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, optionally with the use of emulsifiers and / or dispersants, wherein, for example, when using water as a diluent organic solvent, e.g., preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, optionally with the use of emulsifiers and / or dispersants, wherein, for example, when using water as a diluent organic solvent, emulsifiers and / or dispersants, wherein, for example, when using water as a diluent organic solvent, emulsifiers and / or dispersants, wherein, for example, when using water as
  • Solvent can be used as a solubilizer or Hilf insectssmittel, prepared and filled into injection bottles or ampoules or infusion bottles.
  • the capsules containing one or more active substances or combinations of active substances can be prepared, for example, by dissolving the
  • Active ingredients with inert carriers such as lactose or sorbitol, mixed and encapsulated in gelatin capsules.
  • Suitable suppositories can be prepared, for example, by mixing with excipients intended for this purpose, such as neutral fats or polyethylene glycol or its derivatives.
  • excipients for example, water, pharmaceutically acceptable organic solvents, such as paraffins (eg petroleum fractions), oils of vegetable origin (eg peanut or sesame oil), mono- or polyfunctional alcohols (eg ethanol or glycerol), excipients such as natural minerals (eg kaolin, Clays, talc, chalk) synthetic minerals (eg finely divided silicic acid and silicates), sugars (eg, cane, milk and glucose), emulsifiers (eg lignin, liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate).
  • paraffins eg petroleum fractions
  • oils of vegetable origin eg peanut or sesame oil
  • the application is carried out in a customary manner, preferably orally or transdermally, in particular orally.
  • the tablets may also contain additives other than those mentioned.
  • Sodium citrate, calcium carbonate and dicalcium phosphate together with various supplements such as starch, preferably potato starch, gelatin and the like.
  • lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting.
  • the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.
  • solutions of the active ingredients may be employed using suitable liquid carrier materials.
  • the dosage for intravenous use is 1 - 1000 mg per hour, preferably between 5 - 500 mg per hour.
  • the finely ground active substance, lactose and part of the corn starch are mixed together.
  • the mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried.
  • the granules, the remainder of the corn starch and the magnesium stearate are sieved and mixed together.
  • the mixture is compressed into tablets of suitable shape and size.
  • the finely ground active ingredient, a portion of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the remainder of the corn starch and water to a granulate which is dried and sieved. To this is added the sodium carboxymethyl starch and the magnesium stearate, mixed and pressed the mixture into tablets of suitable size.
  • the active ingredient is dissolved in water at its own pH or optionally at pH 5.5-6.5 and treated with sodium chloride as isotonan.
  • the resulting solution is filtered pyrogen-free and the filtrate filled under aseptic conditions in ampoules, which are then sterilized and sealed.
  • the vials contain 5 mg, 25 mg and 50 mg active ingredient.
  • Acetonitrile / methanol / glacial acetic acid / triethylamine (15: 85: 0.05: 0.05) at a flow of 2 ml / min, a temperature of 35 ° C, and detection at 300 nM.
  • reaction solution is poured onto water and extracted with ethyl acetate.
  • organic phases are combined, dried over sodium sulfate and freed from the solvent in vacuo.
  • product fractions are combined and freed from the solvent in vacuo.
  • the residue is dissolved in 5 ml of methanol and poured into 50 ml of hot water. The precipitate thus obtained is filtered off with suction and dried in vacuo and reacted further without further purification.
  • 3-Amino-3-methylbutan-1-ol (200.0 g, 1.94 mol) is dissolved in ethyl acetate (0.75 l) and treated with a solution of di-tert-butyl-dicarbonate (435.0 g, 1.99 mol) within 1 h Ethyl acetate (0.75 l).
  • the Reaction mixture stirred for a further 30 min. After removal of the solvent gives the title compound, which is used without further purification in the next stage.
  • (3-hydroxy-1, 1-dimethylpropyl) -carbamic acid tert-butyl ester may also be prepared according to, for example, J. of Labeil. Compounds & Radioph. 2001, 44 (4), 265-275 or WO 03/037327, p. 82/83.
  • acetonitrile for example, dichloromethane, dimethoxyethane, acetone, methyl ethyl ketone, ethyl acetate, DMF, N-methylpyrrolidone or DMPU can be used.
  • acetonitrile is preferred.
  • a base other aromatic bases such as imidazole or N-methylimidazole or a combination of these bases with aliphatic bases, for example pyridine / triethylamine (TEA) can be used as an alternative to pyridine.
  • TAA triethylamine
  • DMAP dimethylaminopyridine
  • Step b can also be carried out without DMAP addition.
  • a solution of ruthenium (III) chloride hydrate (440 mg, 2.12 mmol, 0.003 equiv) and sodium metaperiodate (132.2 g, 0.62 mol) in water (1.5 L) is stirred for 45 min and at a temperature of 20-25 0 C over a Period of 35 min to a suspension of the crude product from stage b (140 g) in a mixture of acetonitrile (0.6 l) and saturated aqueous solution of disodium hydrogen phosphate (0.3 l).
  • the pH of the suspension is maintained between 6.9 and 7.3 by continuous addition of additional saturated aqueous solution of disodium hydrogen phosphate (1.0 L).
  • a buffered (disodium hydrogen phosphate) environment is optional, but is preferred.
  • disodium hydrogen phosphate would be, for example, sodium phosphate, sodium and / or potassium bicarbonate, sodium and / or potassium carbonate or sodium and / or potassium hydroxide.
  • Possible alternative ruthenium sources include, for example, ruthenium (VIII) tetroxide, ruthenium (IV) oxide, ruthenium (III) bromide, ruthenium (III) iodide (anhydrous or hydrates) and perruthenates (Ru (VII)).
  • potassium permanganate or oxone may alternatively be used instead of sodium metaperiodate.
  • N- (3 - ⁇ (R) -2- [3- (5-cyanophenyl) -1,1-dimethylpropylaminol-1-hydroxy-ethyl) -phenvD-benzenesulfonamide 700 mg (1.09 mmol) of N- (3 - ⁇ (R) -2- [3- (5-cyanoindol-1-yl) -1, 1-dimethyl-propylamino] -1-hydroxy-ethyl ⁇ -phenyl ) -Dibenzolsulfonamid are dissolved in 10 ml of ethanol and treated with 10 ml of 4N sodium hydroxide solution.
  • Example 6 1- ⁇ 3 - [(R) -2- [3- (Phenylsulfonylamino) -phenyl] -2-hydroxy-ethylamino] -3-methylbutyl ⁇ -1H-indole-5-carboxylic acid hydrotrifluoroacetate
  • the free base (zwitterion; 1- ⁇ 3 - [(R) -2- [3- (phenylsulfonylamino) -phenyl] -2-hydroxyethylamino] -3-methyl-butyl ⁇ -1H-indole-5-carboxylic acid ) is prepared from an aqueous solution of 1 - ⁇ 3 - [(R) -2- [3- (phenylsulfonylamino) -phenyl] -2-hydroxy-ethylamino] -3-methyl-butyl ⁇ -1H-indole-5- carboxylic acid hydrotrifluoroacetate prepared by adjusting the pH to 7.6 with sodium hydroxide solution. The precipitate is then filtered off, washed with water and dried in a vacuum oven.
  • Example 2 Prepared analogously to Example 1 by epoxide ring opening with the corresponding aminoindole (building blocks VI-IX) from N - [(R) -3-oxiranyl-phenyl] -dibenzenesulfonamide (building block II) and subsequent basic benzenesulfonyl cleavage.
  • the compounds are prepared as free bases or hydrotrifluoroacetate salts.
  • the free base (N- (3 - ⁇ (R) -2- [3- (5-aminoindol-1-yl) -1, 1-dimethyl-propylamino] -1-hydroxy-ethyl ⁇ -phenyl) - benzenesulfonamide) is prepared as follows: A mixture of N- (3 - ⁇ (R) -2- [3- (5-amino-indol-1-yl) -1, 1-dimethyl-propylamino] -1-hydroxy- ethyl ⁇ - phenyl) -benzenesulfonamide hydrotrifluoroacetate) in chloroform and saturated sodium carbonate solution is stirred for 10 minutes. The organic phase is separated, dried over sodium sulfate and the solvent removed in vacuo.
  • Example 34 1- ⁇ 3 - [(R) -2- [3- (Phenylsulfonylamino) -phenyl] -2-hydroxyethylamino] -3-methylbutyl ⁇ -1H-indole-5-carboxylic acid dimethylamide
  • Examples 36-54 (Table 3) Prepared analogously to Example 35 by amide linkage with the corresponding substituted amine (see Rb group in Table 3).
  • Example 57 1- ⁇ 3 - [(R) -2- [3- (Phenylsulfonylamino) -phenyl] -2-hydroxy-ethylamino] -3-methylbutyl-1H-indole- ⁇ -carboxylic acid dimethylcarbamoyl methoxyester hydrotrifluor - acetate
  • reaction mixture is diluted with 30 ml of ethyl acetate and extracted four times with 15 ml of ice water.
  • the organic phase is dried over magnesium sulfate, acidified with about 0.5 ml of TFA and the solvent removed in vacuo.
  • reaction mixture is stirred for 24 hours at RT and 3 bar hydrogen. After filtering off the Katylsators the solvent of the filtrate is removed in vacuo.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Psychiatry (AREA)
  • Reproductive Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Ophthalmology & Optometry (AREA)
  • Emergency Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Vascular Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pulmonology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

L'invention concerne de nouveaux antagonistes de formule (I), dans laquelle les résidus R<SUP>1</SUP> et R<SUP>2</SUP> sont spécifiés dans les revendications et la description. L'invention concerne également leurs tautomères, leurs racémates, leurs énantiomères, leurs diastéréomères, leurs solvates, leurs hydrates, leurs mélanges, leurs promédicaments et leurs sels, en particulier des sels physiologiquement acceptables présentant des acides organiques ou non organiques ou des bases. L'invention concerne, en outre, des procédés de production desdits composés et leur utilisation en tant que médicaments.
EP06807619A 2005-10-28 2006-10-27 Nouveaux beta antagonistes contenant de l'indole, procede de production associe et utilisation en tant que medicaments Withdrawn EP1943220A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005052127A DE102005052127A1 (de) 2005-10-28 2005-10-28 Neue indol-haltige Beta-Agonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
PCT/EP2006/067872 WO2007048841A2 (fr) 2005-10-28 2006-10-27 Nouveaux beta antagonistes contenant de l'indole, procede de production associe et utilisation en tant que medicaments

Publications (1)

Publication Number Publication Date
EP1943220A2 true EP1943220A2 (fr) 2008-07-16

Family

ID=37820611

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06807619A Withdrawn EP1943220A2 (fr) 2005-10-28 2006-10-27 Nouveaux beta antagonistes contenant de l'indole, procede de production associe et utilisation en tant que medicaments

Country Status (15)

Country Link
US (1) US7754756B2 (fr)
EP (1) EP1943220A2 (fr)
JP (1) JP2009514817A (fr)
KR (1) KR20080065674A (fr)
CN (1) CN101296903A (fr)
AR (1) AR058162A1 (fr)
AU (1) AU2006307907A1 (fr)
BR (1) BRPI0617851A2 (fr)
CA (1) CA2627486A1 (fr)
DE (1) DE102005052127A1 (fr)
PE (1) PE20070694A1 (fr)
TW (1) TW200800187A (fr)
UY (1) UY29883A1 (fr)
WO (1) WO2007048841A2 (fr)
ZA (1) ZA200803116B (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004021779A1 (de) * 2004-04-30 2005-11-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Beta-Agonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
DE102005052102A1 (de) * 2005-10-28 2007-05-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Beta-Agonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
DE102005052101A1 (de) * 2005-10-28 2007-05-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Beta-Agonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
US8338416B2 (en) * 2006-03-16 2012-12-25 Pharmacylics, Inc. Indole derivatives as inhibitors of histone deacetylase
WO2008132162A1 (fr) * 2007-04-26 2008-11-06 Boehringer Ingelheim International Gmbh Dérivés de 3-(sulfonylamino)-phényl-2-hydroxy-éthylamino utiles en tant que bêta-agonistes, leurs procédés de préparation et leur utilisation en tant que médicaments
CN102764438A (zh) * 2012-01-30 2012-11-07 林曙光 β3肾上腺素受体激动剂的新用途
CN107434819B (zh) * 2017-02-15 2020-03-17 河北医科大学第二医院 吲哚-tempo缀合物及其在保护远隔器官对抗缺血再灌注损伤中的用途

Family Cites Families (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2943090A (en) 1957-09-23 1960-06-28 American Cyanamid Co Substituted piperazines and method of preparing the same
US3092636A (en) 1959-10-21 1963-06-04 Upjohn Co Alpha-[2-(1-alkyleneimino) ethylamino]-alkanophenones and the corresponding alcohols
GB1200886A (en) 1966-09-23 1970-08-05 Allen & Hanburys Ltd Phenylaminoethanol derivatives
DE2115926C3 (de) 1971-04-01 1978-05-03 C.H. Boehringer Sohn, 6507 Ingelheim 1 -(4-Hydroxy-3-dimethylaminosuIfamidophenyI)-2-aminoäthanderivate, Verfahren zu ihrer Herstellung und diese enthaltende Mittel
DE2609645A1 (de) 1976-03-09 1977-09-15 Boehringer Sohn Ingelheim Aminoalkylheterocyclen
DE2833140A1 (de) 1978-07-28 1980-02-07 Boehringer Sohn Ingelheim Neue n-substituierte heterocyclen
JPS6183147A (ja) 1984-09-28 1986-04-26 Nippon Chemiphar Co Ltd 新規なアミノアルコール誘導体およびその製造法並びにそれを有効成分とするグルタミン酸遮断剤
US5776983A (en) 1993-12-21 1998-07-07 Bristol-Myers Squibb Company Catecholamine surrogates useful as β3 agonists
IL113410A (en) 1994-04-26 1999-11-30 Merck & Co Inc Substituted sulfonamides having an asymmetric center and pharmaceutical compositions containing them
GB9525177D0 (en) 1995-12-08 1996-02-07 Glaxo Group Ltd Chemical compounds
GB9805520D0 (en) 1998-03-17 1998-05-13 Zeneca Ltd Chemical compounds
GB2356197A (en) 1999-10-12 2001-05-16 Merck & Co Inc Amide derivatives as beta 3 agonists
AUPQ585000A0 (en) 2000-02-28 2000-03-16 Fujisawa Pharmaceutical Co., Ltd. Aminoalcohol derivatives
AU2001252575A1 (en) 2000-04-28 2001-11-12 Asahi Kasei Kabushiki Kaisha Novel tricyclic compounds
CN1430603A (zh) 2000-04-28 2003-07-16 旭化成株式会社 新型双环化合物
WO2003016307A1 (fr) * 2001-08-14 2003-02-27 Eli Lilly And Company Agonistes de beta-3 adrenergiques
PT1447400E (pt) 2001-10-25 2008-12-19 Asahi Kasei Pharma Corp Composto bicíclico
CA2488699A1 (fr) * 2002-06-12 2003-12-24 Sumitomo Pharmaceuticals Co., Ltd. Indole, indazole, et derive benzazole
US20040127733A1 (en) 2002-10-31 2004-07-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg New beta-agonists, processes for preparing them and their use as pharmaceutical compositions
DE10251170A1 (de) 2002-10-31 2004-05-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Beta-Agonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
JP2004323519A (ja) * 2003-04-10 2004-11-18 Dainippon Pharmaceut Co Ltd スルホン酸アニリド誘導体及びそれを含有する医薬組成物
DE102004021779A1 (de) 2004-04-30 2005-11-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Beta-Agonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
DE102005052103A1 (de) 2005-10-28 2007-05-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Beta-Agonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
DE102005052102A1 (de) 2005-10-28 2007-05-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Beta-Agonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
DE102005052101A1 (de) 2005-10-28 2007-05-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Beta-Agonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007048841A2 *

Also Published As

Publication number Publication date
AU2006307907A1 (en) 2007-05-03
US7754756B2 (en) 2010-07-13
AR058162A1 (es) 2008-01-23
US20070105906A1 (en) 2007-05-10
DE102005052127A1 (de) 2007-05-03
WO2007048841A2 (fr) 2007-05-03
WO2007048841A3 (fr) 2007-06-21
UY29883A1 (es) 2007-05-31
BRPI0617851A2 (pt) 2011-08-09
TW200800187A (en) 2008-01-01
CA2627486A1 (fr) 2007-05-03
JP2009514817A (ja) 2009-04-09
ZA200803116B (en) 2009-09-30
PE20070694A1 (es) 2007-08-21
KR20080065674A (ko) 2008-07-14
CN101296903A (zh) 2008-10-29

Similar Documents

Publication Publication Date Title
DE60211199T2 (de) 3-substituierte oxindol-beta-3-agonisten
EP1943227A1 (fr) Nouveaux agonistes beta, leur procede de fabrication et leur utilisation en tant que medicaments
EP1530568A1 (fr) DERIVES D&#39;INDOLE OU DE BENZIMIDAZOLE POUR MODULER L&#39;I(k)B KINASE
EP1943220A2 (fr) Nouveaux beta antagonistes contenant de l&#39;indole, procede de production associe et utilisation en tant que medicaments
JP4662979B2 (ja) 新規なβ−アゴニスト、その製造方法及びその薬物としての使用
EP0682021A1 (fr) Benzimidazoles, médicaments contenant ces composés et procédé pour leur préparation
CA2741500A1 (fr) Compose de carbamate ou son sel
EP3066095A1 (fr) 1,2,4-triazine-3,5-diones substitués et leur utilisation comme inhibiteurs de la chimase
CA2504213A1 (fr) Nouveaux agonistes beta, leurs procedes de preparation et leur utilisation comme compositions pharmaceutiques
EP1943229A1 (fr) Derives de benzimidazole utilises en tant qu&#39;agonistes du recepteur beta-3
US20040127733A1 (en) New beta-agonists, processes for preparing them and their use as pharmaceutical compositions
WO2007048843A2 (fr) Nouveaux beta-agonistes, procede de production associe et utilisation en tant que medicaments
DE60013607T2 (de) Bemzimidazolverbindungen und medikamente die diese enthalten
WO2008132162A1 (fr) Dérivés de 3-(sulfonylamino)-phényl-2-hydroxy-éthylamino utiles en tant que bêta-agonistes, leurs procédés de préparation et leur utilisation en tant que médicaments
EP1237877B1 (fr) Derive de benzimidazole substitues par carboxamide, leur procede de production et leur utilisation comme medicaments
DE69534574T2 (de) Verfahren zur Herstellung von substituierten N-(Indol-2-carbonyl)-glycinamiden
DE19751939A1 (de) Disubstituierte bicyclische Heterocyclen, ihre Herstellung und ihre Verwendung als Arzneimittel

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20080528

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

17Q First examination report despatched

Effective date: 20100115

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: C07D 209/18 20060101ALI20111201BHEP

Ipc: C07D 401/12 20060101ALI20111201BHEP

Ipc: C07D 405/12 20060101ALI20111201BHEP

Ipc: C07D 413/12 20060101ALI20111201BHEP

Ipc: C07D 403/04 20060101AFI20111201BHEP

Ipc: C07D 209/42 20060101ALI20111201BHEP

Ipc: C07D 209/08 20060101ALI20111201BHEP

Ipc: C07D 403/12 20060101ALI20111201BHEP

RTI1 Title (correction)

Free format text: INDOLE-CONTAINING BETA AGONISTS, METHOD FOR PRODUCING THEM AND THEIR USE AS DRUGS

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20120503