EP1558583A1 - Neue phenylethanolaminderivate und deren verwendung als beta-3-agonisten - Google Patents

Neue phenylethanolaminderivate und deren verwendung als beta-3-agonisten

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Publication number
EP1558583A1
EP1558583A1 EP03769472A EP03769472A EP1558583A1 EP 1558583 A1 EP1558583 A1 EP 1558583A1 EP 03769472 A EP03769472 A EP 03769472A EP 03769472 A EP03769472 A EP 03769472A EP 1558583 A1 EP1558583 A1 EP 1558583A1
Authority
EP
European Patent Office
Prior art keywords
hydrogen
alkyl
group
aryl
radical selected
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Withdrawn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
EP03769472A
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German (de)
English (en)
French (fr)
Inventor
Thomas Trieselmann
Bradford S. Hamilton
Dirk Stenkamp
Stephan Georg Mueller
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 Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1558583A1 publication Critical patent/EP1558583A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • C07D403/12—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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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 new beta agonists of the general formula 1:
  • radicals R 1 to R 12 have the meanings given in the claims and the description, their isomers, processes for the preparation of these compounds and their use as medicaments.
  • Treatment of type II diabetes and obesity is primarily based on reducing calorie intake and increasing physical activity. This
  • beta-3 receptor agonists have a marked effect on that
  • the present invention therefore relates to compounds of the general formula (I)
  • R 1 , R 2 , R 10 , R 11 independently of one another are a radical selected from the group consisting of hydrogen, halogen, CN, NO 2l and -NHCXNH 2 or a radical selected from the group consisting of optionally substituted
  • R 3 is hydrogen or a radical selected from the group consisting of optionally substituted CrCio-alkyl, C 6 -C ⁇ o-Ar l, heterocyclyl, C 3 -C 8 -
  • R 4 , R 5 independently of one another hydrogen, halogen or optionally substituted C- t -C- t o-alkyl, or
  • R 4 and R 5 together form a C 3 -C 8 alkyl bridge
  • R 6 is a radical selected from the group consisting of the general formulas l, k independently of one another 1, 2 or 3, p 25 R 26 p-, 27 ⁇ R 28 independently of one another a residue selected from
  • R 8 is hydrogen or a radical selected from the group consisting of optionally substituted CiC-io-alkyl, C 6 -C ⁇ 8 aryl, -SO q - CiC-io-alkyl, -SOq -C ⁇ -Cu-aryl, -CX- CrC 10 alkyl, -CX-C 6 -C 14
  • R 12 is hydrogen or a radical selected from the group consisting of optionally substituted benzyl, C 1 -C 2 -alkyl and C 6 -C-
  • R 14 , R 19 , R 29 independently of one another are hydrogen or a radical selected from the group
  • R 17 is a radical selected from the group consisting of CrCio-alkyl, C 6 -C 4 aryl, heterocyclyl, heteroaryl and C 3 -C 8 cycloalkyl
  • R 21 , R 24 are independently hydrogen or OH, or a radical selected from the group consisting of optionally substituted
  • Diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts are included.
  • R 10 , R 11 independently of one another are hydrogen or halogen, m, p, q 0, 1 or 2 n 0, 1, 2 or 3 R 3 are hydrogen or CC 5 alkyl
  • R 4 , R 5 independently of one another are hydrogen or CrC 5 alkyl
  • R 8 is a radical selected from the group consisting of hydrogen, CrC 5 alkyl,
  • R 9 is hydrogen or d-Cio-alkyl '
  • R 12 is hydrogen or benzyl
  • R 13 , R 15 , R 16 , R 18 independently of one another are selected from the group consisting of hydrogen, .CrC 5 alkyl, C 3 -C 6 cycloalkyl and phenyl
  • R 14 , R 19 independently of one another are hydrogen or d-Cs-alkyl
  • R 17 is optionally substituted CrC 5 alkyl or C ⁇ -Cio-aryl.
  • R 10 , R 11 are hydrogen m, p, q 0, 1 or 2 n 0, 1, 2 or 3
  • R 3 is hydrogen
  • R 4 , R 5 independently of one another are hydrogen or methyl
  • R 8 is hydrogen, -SO q -C 6 -C 14 aryl or -SO 2 -CC 5 alkyl
  • R 9 hydrogen R 12 hydrogen or benzyl
  • R 13 , R 15 , R 16 , R 18 independently of one another are selected from the group consisting of hydrogen, .CrC ⁇ 5 alkyl and phenyl,
  • R 14 , R 19 independently of one another are hydrogen or CrC 5 alkyl, and R 17 is C r C 5 alkyl or C 6 -C 4 aryl.
  • R 1 is a radical selected from the group consisting of hydrogen, NO 2 , NH 2 ,
  • R 3 is hydrogen
  • R 4 , R 5 are hydrogen or methyl
  • R 6 is a radical selected from the group consisting of the general formulas
  • R 26 R 27 hydrogen
  • R 8 is hydrogen or -SO 2 CH 3
  • R 9 is hydrogen
  • R 10 , R 11 are hydrogen
  • R 12 is hydrogen or benzyl
  • R 6 is a radical selected from the group consisting of the general formulas
  • the invention further relates to compounds of the formula (I) for
  • the invention further relates to compounds of the formula (I) for use as medicaments with selective beta-3-agonistic activity.
  • Another object of the invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment and / or prevention of diseases which are 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 in Are related, wherein an effective amount of a compound of formula I is administered to a patient.
  • composition containing as active ingredient one or more compounds of the general formula (I) or their physiologically tolerable salts, optionally in combination with customary auxiliaries and / or carriers.
  • compositions containing as active ingredient one or more compounds of the general formula (I) according to one of Claims 1 to 6 or their physiologically tolerable salts and one or more active ingredients selected from the group consisting of antidiabetic agents, inhibitors of protein tyrosine phosphatase 1 , Substances that influence deregulated glucose production in the liver, lipid-lowering agents, cholesterol absorption inhibitors, HDL-increasing compounds, active substances for the treatment of obesity and modulators or stimulators of the adrenergic via alpha 1 and alpha 2 as well as beta 1, beta 2 and beta 3 receptors.
  • active ingredients selected from the group consisting of antidiabetic agents, inhibitors of protein tyrosine phosphatase 1 , Substances that influence deregulated glucose production in the liver, lipid-lowering agents, cholesterol absorption inhibitors, HDL-increasing compounds, active substances for the treatment of obesity and modulators or stimulators of the adrenergic via alpha 1 and alpha 2 as well as beta 1,
  • the invention further provides a process for the preparation of a compound of the general formula (I)
  • R 1 -R 28 and X can have the meaning given above, where a compound of the general formula (II)
  • alkyl groups and alkyl groups which are part of other radicals are preferably 1-6, particularly preferably 1-4 carbon atoms, for example: methyl, ethyl, propyl, butyl, pentyl, hexyl, Heptyl, octyl, nonyl and decyl. Unless otherwise stated, all of the possible isomeric forms are included in the abovementioned designations propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.
  • propyl includes the two isomeric radicals n-propyl and iso-propyl, the term butyl n-butyl, iso-butyl, sec. Butyl and tert-butyl, the term pentyl, iso-pentyl, neopentyl etc.
  • one or more hydrogen atoms can optionally be replaced by other radicals.
  • these alkyl groups can be substituted by the halogen atoms fluorine, chlorine, bromine or iodine.
  • the substituents fluorine or chlorine are preferred.
  • the substituent chlorine is particularly preferred.
  • all hydrogen atoms of the alkyl group can also be replaced.
  • one or more hydrogen atoms in the abovementioned alkyl groups may also be selected, for example, by an optionally substituted radical selected from the group consisting of OH, NO 2 , CN, -O-CrC 5 -alkyl, preferably -O -Methyl or -O- ethyl, O-C ⁇ -C-aryl, preferably O-phenyl, 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-oxazinyl, C ⁇ -C-aryl, preferably phenyl, heteroaryl, preferably thieny
  • aryl stands for an aromatic ring system with 6 to 18 carbon atoms, preferably 6 to 14 carbon atoms, preferably 6 or 10 carbon atoms, particularly preferably phenyl, which, unless otherwise described, can carry, for example, one or more of the following substituents: OH, NO 2 , CN, -OCHF 2 , -OCF 3 , -NH 2 , halogen, for example fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, particularly preferably fluorine, d-Cio-alkyl, preferably CrC 5 alkyl, preferred Cr C 3 alkyl, particularly preferably methyl or ethyl, -O-CrC 3 alkyl, preferably -O- methyl or -O-ethyl, -COOH or -CONH 2 .
  • Heteroaryl radicals are 5-10-membered mono- or bicyclic heteroaryl rings in which up to three C atoms can be replaced by one or more heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, for example furan, thiophene, pyrrole, pyrazole, Imidazole, triazole, tetrazole, pyridine, Pyridazine, pyrimidine, pyrazine, triazine, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, where each of the heterocycles mentioned above may optionally also be fused to a benzene ring, preferably benzimidazole, and these heterocycles, unless otherwise described, for example one or can carry several of the substituents mentioned below: OH, NO 2 , CN, -NH 2 , halogen, preferably fluorine or chlorine, C -C 0 alkyl, preferably dC
  • Cycloalkyl radicals are saturated or unsaturated cycloalkyl radicals having 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyxclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl, each of the above-mentioned cycloalkyl radicals optionally also bearing one or more cycloalkyl radicals or fused to a benzene ring.
  • the heterocycloalkyl radicals are 5-, 6- or 7-membered, saturated or unsaturated heterocycles which may contain nitrogen, oxygen or sulfur as heteroatoms, for example tetrahydrofuran, tetrahydrofuranone, ⁇ -butylrolactone, pyran, ⁇ - pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazinoline, triazine, triazine, triazine, triazine Oxazine, tetrahydro-oxazinyl, isothiazole, pyrazolidine, preferably
  • Halogen is generally referred to as fluorine, chlorine, bromine or iodine, preferably chlorine or fluorine, particularly preferably fluorine.
  • the compounds according to the invention can be in the form of the individual optical isomers, mixtures of the individual enantiomers, diastereomers or racemates, in the form of the tautomers and in the form of the free bases or corresponding acid addition salts with pharmacologically acceptable acids - such as, for example, acid addition salts with hydrohalic acids, for example hydrochloric or hydrobromic acid, or organic acids, for example oxalic, fumaric, diglycolic, formic, apple, benzoic, benzenesulfonic, camphor sulfonic, vinegar , Ethanesulfonic, glutamic, maleic, almond, milk, phosphoric, nitric, sulfuric, succinic, para-toluenesulfonic, trifluoroacetic, wine, lemon or methanesulfonic acid are present.
  • hydrohalic acids for example hydrochloric or hydrobromic acid
  • organic acids for example oxalic, fumaric, dig
  • the substituent R 1 can be a radical selected from the group consisting of hydrogen, halogen, preferably fluorine or chlorine, CN, NO 2 , and -NHCXNH 2 , preferably NHCONH 2, or a radical selected from the group consisting of optionally substituted
  • the substituent R1 particularly preferably denotes —NR 20 SO m R 21 , preferably
  • the substituent R 2 can be a radical selected from the group consisting of hydrogen, halogen, preferably fluorine or chlorine, CN, NO 2 , and -NHCXNH 2 , preferably NHCONH 2 or a radical selected from the group consisting of optionally substituted -COR 7 , -COOR 7, -CONR 7 R 13, -OR 14, preferably OH, NR 13 R 15, C C ⁇ 0 alkyl, C 3 -C 8 - cycloalkyl, -NR 16 CX-R 17, -NR 18 CX-OR 19 , -NR 20 SO m R 21 , -SO p NR 22 R 23 , preferably -SO 2 NHR 23 and -SO q R 23 .
  • the substituent R2 particularly preferably denotes hydrogen or fluorine.
  • the substituents R 10 and R 11 may be the same or different and a radical selected from the group consisting of hydrogen, halogen, preferably fluorine or chlorine, CN, NO 2 , and -NHCXNH 2 , preferably NHCONH 2 or a radical selected from the group consisting of optionally substituted -COR 7 , -COOR 7 , -CONR 7 R 13 , -OR 14 , preferably OH, NR 13 R 15 , C C ⁇ 0 alkyl, C 3 -C 8 cycloalkyl, -NR 16 CX-R 17 , -NR 18 CX-OR 19 , -NR 20 SO m R 21 , -SO p NR 22 R 23 preferably -SO 2 NHR 23 and -SO q R 2 .
  • the substituents R 10 and R 11 particularly preferably signified hydrogen.
  • the variables m, p and q can mean 0.1 or 2, preferably 2.
  • the variable n can mean 0, 1, 2
  • the substituent R 3 can be hydrogen or a radical selected from the group consisting of optionally substituted C 1 -C 8 alkyl, C 6 -C 8 aryl, heterocyclyl and C 3 -C 8 cycloalkyl, -CX- d-C ⁇ 0 alkyl, CX-C 6 -C aryl mean.
  • the substituent R 3 is preferably hydrogen.
  • R 4 and R 5 can be identical or different and can be hydrogen, halogen or optionally substituted CrCio-alkyl, preferably hydrogen or Crdo-alkyl, particularly preferably hydrogen or methyl, or R 4 and R 5 can together be a C 3 -C 8 alkyl bridge, preferably a cyclohexyl, cyclopentyl or cyclopropyl bridge, form.
  • the substituent R 6 can be a radical selected from the group consisting of the general formulas
  • variables I and k independently of one another are 1, 2 or 3, preferably 1.
  • R particularly preferably denotes 6
  • R 25 , R 26 , R 27 , R 28 can be the same or different and a radical selected from the group consisting of hydrogen, OH, halogen, CN and NO 2 , or a radical selected from the group consisting of optionally substituted CrCio -Alkyl, C 6 -C 8 -aryl, preferably phenyl, heteroaryl, preferably pyridyl, heterocyclyl, -CX-R 17 , -OR 14 , NR 13 R 15 , C 2 -C 8 cycloalkyl, -NR 20 SO m R 21 , -SO p NR 22 R 23 , -SO q R 24 , -NR 18 CX-R 19 , -NR 18 CXOR 17 , where R 25 and R 26 cannot simultaneously denote hydrogen,
  • the substituent R 8 can be hydrogen or a radical selected from the group consisting of optionally substituted CrCio-alkyl, C 6 -C 8 aryl, -SO q - C1-C10 alkyl, -SO q -C 6 -C 4 aryl , -CX- C -C 0 alkyl, -CX-C 6 -C ⁇ 4 aryl, C 6 -C ⁇ 0 aryl, heterocyclyl and C 3 -C 8 cycloalkyl, preferably hydrogen or -SO 2 CH 3 mean.
  • the substituent R 9 is selected hydrogen or a radical from the group consisting of optionally substituted d-C ⁇ 0 alkyl, C 6 D 4 aryl, heteroaryl, C 3 -C 8 cycloalkyl, and heterocycloalkyl, are preferably hydrogen.
  • the substituent R 12 can be hydrogen or a radical selected from the group consisting of optionally substituted benzyl, CrC ⁇ 2 alkyl and C 6 -C ⁇ 4 aryl, CX-d-Ci2-alkyl and CX-C 6 -C ⁇ 4 aryl, preferably hydrogen.
  • the substituents R 7 , R 13 , R 15 R 16 , R 18 , R 20 , R 22 , R 23 and R 24 can be the same or different and hydrogen, or a radical selected from the group consisting of optionally substituted.
  • CrCio-alkyl, C 6 -C aryl, heterocyclyl and C 3 -C 8 cycloalkyl mean.
  • the substituent R 20 particularly preferably denotes methyl, ethyl or isopropyl.
  • the substituents R 14 , R 19 and R 29 can be the same or different and hydrogen or a radical selected from the group consisting of optionally substituted d-Cio-alkyl, preferably methyl or difluoromethyl, C ⁇ -Cu-aryl, C 3 -C 8 -Cycloalkyl, heteroaryl, heterocyclyl, -CXNR ⁇ 3 R ⁇ 5 ,
  • the substituent R 14 particularly preferably denotes methyl or difluoromethyl.
  • the substituent R 17 can be a radical selected from the group consisting of CrCio-alkyl, preferably methyl or ethyl, C 6 -d 4 -aryl, heterocyclyl, heteroaryl and C 3 -C 8 -cycloalkyl.
  • the substituent R 21 can be hydrogen or OH, or a radical selected from the group consisting of optionally substituted N (CrC ⁇ o-alkyl) 2 - N (C 3 -C 8 cycloalkyl), d-Cio-alkyl, C 6 -d 4 -Ary !, heterocyclyl, heteroaryl and C 3 -C 8 cycloalkyl.
  • X can be O, S or NR 29 , preferably O.
  • a compound of formula (II) is converted into a by means of a chlorinating agent
  • Compound (II) can be prepared according to regulations known from the literature, for example DE 2200108 (Pander, Hans J. 3-amino-3-methyl-1-butanol, Ger. Offen. (1973), 6 pp.).
  • compound (II) is dissolved or suspended in about 100 to 300 ml of a solvent, preferably in methylene chloride / dimethylformamide (50: 1), pyridine, carbon tetrachloride, chloroform or dichloromethane.
  • a solvent preferably in methylene chloride / dimethylformamide (50: 1), pyridine, carbon tetrachloride, chloroform or dichloromethane.
  • the mixture is at about -3 to 5 ° C, preferably at 0 ° C with stirring 0.4 to 0.9 mol, preferably 0.6 mol of a chlorinating agent, preferably thionyl chloride, N-chlorosuccinimide, para-toluosulfonic acid chloride, methanesulfonic acid chloride / lithium chloride or, zinc (II) chloride / triphenylphosphine / diethyldiazodicarboxylate, particularly preferably thionyl chloride, added dropwise.
  • a chlorinating agent preferably thionyl chloride, N-chlorosuccinimide, para-toluosulfonic acid chloride, methanesulfonic acid chloride / lithium chloride or, zinc (II) chloride / triphenylphosphine / diethyldiazodicarboxylate, particularly preferably thionyl chloride, added dropwise.
  • the base is released from about 80-90, preferably 84.0 mmol of 3-chloro-1, 1-dimethylpropylamine hydrochloride by known methods.
  • the free base is dissolved in about 50 ml of a solvent, preferably toluene, diethyl ethyl ether, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide or methylene chloride, and about 60 to 100 mmol, preferably 80.0 mmol, of 2,6-dichlorobenzaldehyde are added at room temperature with stirring.
  • the reaction mixture is stirred for 5 to 20 h, preferably 15 h at room temperature, dried again and the solvent is removed.
  • the corresponding dichlorobenzylidene amine of the compound (III) is obtained.
  • the reaction mixture is stirred at room temperature for 1 h and then 35 to 45 mmol, preferably 39.0 mmol, of the dichlorobenzylidenamine of the compound (III), dissolved in a solvent, preferably about 50 ml of 1,3-dimethyl-3,4, 5,6-tetrahydro-2 (1 H) -pyrimidone, and 2 to 4 mmol, preferably about 3.3 mmol, of tetrabutylammonium iodide were added.
  • the reaction mixture is stirred for about 5 to 20 hours, preferably 18 hours at room temperature, stirred for about 4 hours at 80 ° and then poured into about 200 ml of ice water / ethyl acetate (1: 1).
  • the phases are separated and the aqueous phase is extracted with ethyl acetate.
  • the combined organic phases are dried and the solvent is removed. Hydrochloric acid was added to the residue and the mixture was stirred at about 100 ° C. for about 1 h.
  • the reaction mixture is cooled to about 0 ° C, mixed with ethyl acetate and the pH value, for example with sodium hydroxide solution set to 10.
  • the phases are separated and the aqueous phase is extracted with ethyl acetate.
  • the combined organic phases are dried and the solvent is removed on a rotary evaporator.
  • the residue is purified, for example, by chromatography. This gives about 430 mmol of compound (V).
  • the base is released from about 3 mmol of the compound (V) by known methods.
  • the free base is dissolved in methylene chloride and about 2.6 mmol of a compound of the formula (VI a-c) and about 2.6 mmol of ytterbium (III) trifluoromethanesulfonate are added at room temperature with stirring.
  • the reaction mixture is stirred for about 3 days at room temperature and then water is added.
  • the phases are separated and the aqueous phase is extracted, for example with methylene chloride.
  • the combined organic phases are dried and the solvent is removed.
  • the residue is purified, for example, by chromatography.
  • platinum (IV) oxide About 0.1 mmol of platinum (IV) oxide are added to a solution of about 0.3 mmol of the purified residue in, for example, about 10 mL of tetrahydrofuran / toluene (1: 1).
  • the reaction mixture is shaken in an autoclave under a hydrogen pressure of a little O psi at room temperature for about 5 to 20 h, preferably 16 h.
  • the platinum (IV) oxide is filtered off and the filtrate is freed from the solvent.
  • the compound I is obtained.
  • reaction mixture was stirred at room temperature for 1 h and then 10.9 g (39.0 mmol) (3-chloro-1, 1-dimethylpropyl) - (2,6-dichlorobenzylidene) amine dissolved in 50 mL 1, 3-Dimethyl-3,4,5,6-tetrahydro-2 (1 H) -pyrimidone, and 1, 20 g (3.33 mmol) of tetrabutylammonium iodide were added.
  • the reaction mixture was stirred at room temperature for 18 h, stirred at 80 ° for 4 h and then poured into 200 ml of ice water / ethyl acetate (1: 1).
  • the phases were separated and the aqueous phase extracted three times with 50 mL ethyl acetate each.
  • the combined organic phases were dried over magnesium sulfate and the solvent was removed.
  • the residue was mixed with 11 ml of hydrochloric acid (3.5 M) and stirred at 100 ° C. for 1 h.
  • the reaction mixture was cooled to 0 ° C., 50 ml of ethyl acetate were added and the pH was adjusted to 10 using sodium hydroxide solution (1 M).
  • the phases were separated and the aqueous phase extracted three times with 50 mL ethyl acetate each.
  • the combined organic phases were dried over magnesium sulfate and the solvent was removed.
  • the solvent was removed on a rotary evaporator and the residue was dissolved in 300 ml of ethyl acetate / water (1: 2).
  • the aqueous phase was concentrated. Ammonia made alkaline and separated from the organic phase.
  • the organic phase was washed twice with 200 ml of water and once with 200 ml of saturated, aqueous sodium chloride solution, dried over sodium sulfate and freed from the solvent on a rotary evaporator.
  • the residue was dissolved in 70 ml of warm ethanol, 5.4 g of oxalic acid were added and the resulting oxalate was recrystallized from ethanol.
  • the solvent was removed on a rotary evaporator and the residue was dissolved in 300 ml of ethyl acetate / water (1: 2).
  • the aqueous phase was concentrated. Ammonia made alkaline and separated from the organic phase.
  • the organic phase was washed twice with 100 ml of water and once with 100 ml of saturated, aqueous sodium chloride solution, dried over sodium sulfate and freed from the solvent on a rotary evaporator.
  • the residue was purified by flash column chromatography
  • reaction mixture was mixed with 100 ml of toluene water (1: 1) at room temperature, the phases were separated and the organic phase was washed three times with 50 ml of water. The organic phase was dried over sodium sulfate and freed from the solvent on a rotary evaporator. The residue was purified by flash column chromatography [methylene chloride / methanol (90:10)]. 0.420 g (0.668 mmol, 88%) of N- (2-benzyloxy-5- ⁇ 2- [1, 1-dimethyl-3- (4-phenylimidazol-1-yl) propylamino] -1-hydroxyethyl ⁇ -phenyl) -phenylsulfonamide obtained as a colorless oil.
  • Example 25 Racemic synthesis of 1- (4-benzyloxy-2-fluoro-phenyl) -2- [3- (4,5-diphenylimidazol-1-yl) -1, 1-dimethyl-propylamino] ethanol :
  • the solvent was removed on a rotary evaporator and the residue was dissolved in 300 ml of ethyl acetate / water (1: 2).
  • the aqueous phase was concentrated. Ammonia made alkaline and separated from the organic phase.
  • the organic phase was washed twice with 200 ml of water and once with 200 ml of saturated, aqueous sodium chloride solution, dried over sodium sulfate and freed from the solvent on a rotary evaporator.
  • the residue was dissolved in 70 ml of warm ethanol, 3.5 g of fumaric acid were added and the fumarate formed was recrystallized from ethanol.
  • the compounds of the general formula (1) are distinguished by a wide range of possible uses in the therapeutic field. Emphasis should be given to those applications for which the action of beta-3 agonists, in particular 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 tract
  • gastrointestinal disorders including gastric ulcer; gastrointestinal ulcers, gastrointestinal ulcers, glaucoma, glucosuria, hyperanakinesia, hypercholesterolaemia, hypercholesterolaemia, hyperglycaemia, hyperlipemia, arterial hypertension, hypertriglyceridaemia, insulin resistance, intestinal ulceration or small bowel ulcers, inflammatory ulcers, mastitis, inflammatory ulcers, inflammatory bowel ulcers, inflammatory bowel ulcers, and inflammatory bowel ulcers (pro Colon and other diseases with decreased intestinal motility Depression, melancholy, pollakiuria, frequent urge to urinate, neurogenic inflammation due to nerves, neurogenic bladder dysfunction, neurogenic inflammation of the respiratory tract, neuropathic bladder dysfunction, nocturia, unspecified diarrhea, abdominal inflammation, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity, obesity,
  • the beta-3 agonists according to the invention are particularly suitable for the treatment of obesity, insulin resistance; Diabetes mellitus' type 2; 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 carried out as described below:
  • Adipocytes were isolated from ex vivo adipose tissue by modifying a Rodbell method (Rodbell, M. Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis. J Biol Chem 239: 375-380, 1964). Cut out adipose tissue was cut into small pieces and mixed with 1 mg / ml collagenase in Krebs Ringer buffer (KBR) containing 6 mM glucose and 2% albumin by gentle shaking at 37 ° C. for 30-40 min. The cells were filtered through a gauze, washed twice with KRB and centrifuged 50-150 g each for 5 min.
  • KBR Krebs Ringer buffer
  • Glycerol is phosphorylated by ATP via glycerol kinase.
  • the resulting glycerol-1-phosphate is oxidized to dihydroxyacetone phosphate and hydrogen peroxide by glycerol phosphate oxidase.
  • a quinonimine dye is then formed by the peroxidase-catalyzed coupling of sodium N-ethyl-N- (3-sulfopropyl) m-ansidine and 4-aminoantipyrine.
  • the dye shows an absorption maximum at 540 nm. The absorption is directly proportional to the glycerol concentration in the samples.
  • the new compounds can be used for the prevention, short-term or long-term treatment of the above-mentioned diseases, also in combination with other active ingredients which are used for the same indications.
  • active ingredients which are used for the same indications.
  • anti-diabetic agents such as metformin, sulfonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), PPAR-gamma agonists (e.g. Gl 262570), alpha-glucosidose inhibitors (e.g.
  • acglibosarbose inhibitors ), alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. Exendin-4) or amylin.
  • inhibitors of protein tyrosine phosphatase 1 substances which influence deregulated glucose production in the liver, such as, for example, inhibitors of glucose-6-phosphatase, or of fructose-1, 6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol-pyruvate carboxy 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, for example
  • a combination with medications for influencing high blood pressure e.g. All antagonists or ACE inhibitors, diuretics, ⁇ -blockers, and other modulators of the adrenergic system or combinations thereof are suitable.
  • combinations with stimulators of the adrenergic system via alpha 1 and alpha 2 and beta 1, beta 2 and beta 3 receptors are particularly suitable.
  • the compounds of general formula (I) can be used alone or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances.
  • Suitable forms of use are, for example, tablets, capsules, suppositories, solutions, in particular solutions for injection (SC, IV, IM) and infusion, juices, emulsions or dispersible powders.
  • the proportion of the pharmaceutically active compound (s) should in each case be in the range from 0.1 to 90% by weight, preferably 0.5 to 50% by weight, of the total composition, i.e. in amounts sufficient to reach the dosage range given below. If necessary, the doses mentioned can be given several times a day.
  • 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, and disintegrants, such as
  • 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 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 coated tablet shell can also consist of several layers in order to achieve a depot effect, 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 as well as a taste-improving agent, e.g. Flavorings, such as vanillin or orange extract, contain. 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.
  • a sweetener such as saccharin, cyclamate, glycerol or sugar
  • a taste-improving agent e.g.
  • Flavorings such as vanillin or orange extract
  • 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.
  • Injection and infusion solutions are used in the usual way, e.g. with the addition of isotonants, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, optionally under
  • organic solvents can optionally be used as solubilizers or auxiliary solvents, produced and filled into injection bottles or ampoules or infusion bottles.
  • the capsules containing one or more active ingredients or combinations of active ingredients can be produced, for example, by mixing the active ingredients with inert carriers, such as milk sugar or sorbitol, and encapsulating them in gelatin capsules.
  • Suitable suppositories can be produced, for example, by mixing them with carrier agents such as neutral fats or polyethylene glycol or its derivatives.
  • auxiliaries are water, pharmaceutically acceptable organic solvents, such as paraffins (for example petroleum fractions), oils of vegetable origin (for example peanut or sesame oil), mono- or polyfunctional alcohols (for example ethanol or glycerol), carriers such as natural rock meal (for example kaolins, Clays, talc, chalk) synthetic powdered stone (e.g. highly disperse silica and silicates), sugar (e.g. cane, milk and glucose) emulsifiers (e.g. lignin, sulfite liquor, methyl cellulose, starch and Polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate) mentioned.
  • paraffins for example petroleum fractions
  • oils of vegetable origin for example peanut or sesame oil
  • mono- or polyfunctional alcohols for example ethanol or glycerol
  • carriers such as natural rock meal (for example kaolins,
  • the application is carried out in the usual way, preferably orally or transdermally, particularly preferably orally.
  • the tablets can of course also contain additives, such as e.g. Contain sodium citrate, calcium carbonate and dicalcium phosphate together 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.
  • solutions of the active ingredients can be used 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 ingredient, milk sugar and part of the corn starch are mixed together.
  • the mixture is sieved, whereupon it is moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
  • the granules, the rest of the corn starch and the magnesium stearate are sieved and mixed together.
  • the mixture is compressed into tablets of a suitable shape and size.
  • the active ingredient is dissolved in water at its own pH or, if appropriate, at pH 5.5-6.5, 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.

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EP03769472A 2002-10-31 2003-10-30 Neue phenylethanolaminderivate und deren verwendung als beta-3-agonisten Withdrawn EP1558583A1 (de)

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US7405232B2 (en) 2004-02-14 2008-07-29 Boehringer Ingelheim International Gmbh Long acting beta-2 agonists and their use as medicaments
WO2005077361A1 (de) * 2004-02-14 2005-08-25 Boehringer Ingelheim International Gmbh Neue langwirksame beta-2-agonisten, und deren verwendung als arzneimittel
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
WO2006042679A1 (de) * 2004-10-18 2006-04-27 Boehringer Ingelheim International Gmbh Verwendung eines beta-3-agonisten zur behandlung von beschwerden der prostata und des unteren urogenitaltrakts
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
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
DE102005052127A1 (de) 2005-10-28 2007-05-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue indol-haltige 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
JP2009519998A (ja) * 2005-12-19 2009-05-21 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング アミノアルコール誘導体の過活動膀胱の治療の為の使用
GB0705400D0 (en) * 2007-03-21 2007-05-02 Univ Aberdeen Therapeutic compounds andm their use
WO2008132162A1 (en) * 2007-04-26 2008-11-06 Boehringer Ingelheim International Gmbh 3- (sulphonylamino) -phenyl-2 -hydroxy-ethylamino derivatives useful as beta-agonists, processes for preparing them and their use as medicaments
GB0817207D0 (en) 2008-09-19 2008-10-29 Pimco 2664 Ltd therapeutic apsac compounds and their use
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