EP1943229A1 - Derives de benzimidazole utilises en tant qu'agonistes du recepteur beta-3 - Google Patents

Derives de benzimidazole utilises en tant qu'agonistes du recepteur beta-3

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Publication number
EP1943229A1
EP1943229A1 EP06807621A EP06807621A EP1943229A1 EP 1943229 A1 EP1943229 A1 EP 1943229A1 EP 06807621 A EP06807621 A EP 06807621A EP 06807621 A EP06807621 A EP 06807621A EP 1943229 A1 EP1943229 A1 EP 1943229A1
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EP
European Patent Office
Prior art keywords
phenyl
benzimidazole
hydroxy
benzenesulfonylamino
carboxylic acid
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Withdrawn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
EP06807621A
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German (de)
English (en)
Inventor
Thomas Trieselmann
Rainer Walter
Matthew R. Netherton
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
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Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Publication of EP1943229A1 publication Critical patent/EP1943229A1/fr
Withdrawn legal-status Critical Current

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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms

Definitions

  • the present invention relates to novel beta-agonists of the general formula (I)
  • radicals R 1 to R 4 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 general formula (I) in which the radicals R 1 to R 4 have the meanings mentioned below act as selective beta-3 agonists.
  • the compounds of the present invention can be used to treat diseases related to the stimulation of beta-3 receptors.
  • the present invention therefore relates to compounds of the general formula (I)
  • R 1 is a Ci-4-alkyl, di- (Ci-3-alkyl) amino, thienyl, pyridyl or phenyl group,
  • phenyl group can be substituted by one to three fluorine, chlorine or bromine atoms or one to three C 1-3 -alkyl, C 1-3 -alkyloxy, trifluoromethoxy or difluoromethoxy groups, where the substituents are identical or different,
  • R 2 is a benzimidazolyl or 1,3-dihydrobenzimidazol-2-one group
  • R 3 and R 4 which are identical or different, each represent a C 1-3 -alkyl group
  • alkyl groups contained in the above-mentioned groups may be straight-chain or branched
  • R 2 , R 3 and R 4 are defined as mentioned above and R 1 represents a phenyl group which may be substituted by a fluorine, chlorine or bromine atom or a C 1-3 -alkyl, C 1-3 -alkyloxy, trifluoromethoxy or difluoromethoxy groups,
  • R 2 is defined as mentioned above,
  • R 1 is a phenyl group
  • R 3 and R 4 each represent a methyl group
  • R 1 is a phenyl group
  • R 2 is a benzimidazol-1-yl or 1,3-dihydrobenzimidazol-2-one-1-yl group
  • R 3 and R 4 each represent a methyl group
  • alkyl groups contained in the above-mentioned groups may be straight-chain or branched
  • R 2 is a benzimidazol-1-yl group
  • alkyl groups contained in the above-mentioned groups may be straight-chain or branched
  • R 1 is a phenyl group
  • R 2 is a benzimidazol-1-yl group
  • R 3 and R 4 each represent a methyl group
  • alkyl groups contained in the above-mentioned groups may be straight-chain or branched, and wherein the compounds
  • a preferred subgroup relates to (R) -enantiomer of the compounds of the formula (Ia) according to the invention
  • R 1 to R 4 are defined as mentioned above, and their salts.
  • a second preferred subgroup relates to the (S) -enantiomer of the compounds of the formula (Ib) according to the invention.
  • R 1 to R 4 are defined as mentioned above, and their salts. Particularly noteworthy are the following connections:
  • Another subject of the invention relates to the compounds
  • Another subgroup of the invention relates to compounds of the general formula (I) in which
  • R 1 is a C 1-4 -alkyl, di (C 1-3 -alkyl) amino, thienyl, pyridyl or phenyl group,
  • phenyl group can be substituted by one to three fluorine, chlorine or bromine atoms or one to three C 1-3 -alkyl, C 1-3 -alkyloxy, trifluoromethoxy or difluoromethoxy groups, where the substituents are identical or different,
  • R 2 is a benzimidazolyl or 1,3-dihydrobenzimidazol-2-one group, which may each be substituted by one or two fluorine, chlorine or bromine atoms or a Ci-3-alkyl, methoxy, trifluoromethoxy, difluoromethoxy, carboxy, Ci -4 - alkyloxy-carbonyl or amino group, wherein the Substituents are the same or different, or
  • R 3 and R 4 which are identical or different, each represent a C 1-3 -alkyl group
  • alkyl groups contained in the above-mentioned groups may be straight-chain or branched
  • R 2 , R 3 and R 4 are defined as mentioned above and
  • R 1 represents a phenyl group which may be substituted by a fluorine, chlorine or bromine atom or a C 1-3 -alkyl, C 1-3 -alkyloxy, trifluoromethoxy or difluoromethoxy groups,
  • R 2 is defined as mentioned above,
  • R 1 is a phenyl group
  • R 3 and R 4 each represent a methyl group
  • a particularly preferred subgroup are those compounds of general formula (I) in which
  • R 1 is a phenyl group
  • R 2 is a benzimidazol-1-yl or 1,3-dihydrobenzimidazol-2-one-1-yl group
  • R 3 and R 4 each represent a methyl group
  • alkyl groups contained in the above-mentioned groups may be straight-chain or branched, and wherein the compounds
  • R 2 is a benzimidazol-1-yl group
  • alkyl groups contained in the above-mentioned groups may be straight-chain or branched
  • 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 containing 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.
  • a further subject of the invention is a process for the preparation of a compound of general formula (I),
  • R 1 to R 4 may have the meanings given above, where a compound of the general formula (II)
  • u 1 ⁇ nd -j ⁇ R> 4 may have the abovementioned meaning, by means of a chlorinating agent in a compound of the formula
  • R 3 and R 4 have the abovementioned meaning, in each case optionally provided with an amino-protecting group, with a compound of the formula
  • R 1 has the meaning indicated above
  • 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, preference being given to groups having 1 to 6 carbon atoms. 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. Unless otherwise mentioned, are from the above
  • Propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl include all of the possible isomeric forms.
  • the term propyl comprises the two isomeric radicals n-propyl and isopropyl
  • one or more may optionally be
  • Hydrogen atoms must be replaced by other radicals.
  • these alkyl 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. 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
  • 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 tuiert and may preferably carry one or more of the following substituents: OH, NO 2 , CN, -NH 2 , -NH-alkyl,
  • 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, such as tetrahydrofuran, tetrahydrofuranone, ⁇ -butyrolactone, ⁇ -pyran, ⁇ -pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetra- zol, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepane, oxazine, tetrahydro-oxazinyl, iso
  • the compounds of the above general formula (I) which contain a residue cleavable in vivo represent so-called prodrugs, and compounds of the general formula I which contain two in vivo cleavable residues, so-called double prodrugs.
  • a group which can be converted into a carboxy group in vivo is, for example, an ester of the formula -CO 2 R 11 , where
  • R 11 is hydroxymethyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkenyl, heterocycloalkyl, C 1 -C 3 -alkoxycarbonyl, 1, 3-dihydro-3-oxo-1-isobenzofuranol, -C (-alkyl) (- Alky I) - 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 -cycloalkyl, more preferably cyclohexyl, - (C 1 -C 3 -alkyl) aryl, preferably (C 1 -C 3 -alkyl) -phenyl, more preferably benzyl, -CHC (O) N (-alkyl) (-alkyl ), preferably -CHC (O) N (-Ci-C 3 -alkyl) (--C 1 -C 3 -alkyl), more preferably -CHC (O) N (CH 3 ) 2 ,
  • -CH (-alkyl) OC (O) -alkyl preferably -CH (-CH 3 ) OC (O) (--C 1 -C 6 -alkyl), more preferably -CH (-CH 3 ) OC (O) -methyl , -CH (CH 3) OC (O) -ethyl, -CH (CH 3) OC (O) -n-propyl, -CH (CH 3) OC (O) -n-butyl or -CH ( -CH 3 ) OC (O) -t-butyl, or -CH 2 OC (O) -alkyl, preferably -CH 2 OC (O) (- Ci-C 6 -alkyl), particularly preferred
  • a group which can be converted into a sulfonamide or amino group in vivo is one of the following groups:
  • -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, -CO 2 (-CrC 3 alkyl) -aryl, preferably -CO 2 (C 1 -C 3 -alkyl) -phenyl, particularly preferably benzyloxycarbonyl, -C (O) -aryl, preferably benzoyl,
  • -C (O) -heteroaryl preferably pyridinoyl or nicotinoyl or -C (O) -alkyl, preferably -C (O) (--C 1 -C 6 -alkyl), particularly 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 acceptable 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,
  • pharmacological acceptable 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,
  • 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.
  • suitable bases are sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and ethanolamine.
  • the resulting compounds of general formula I can be separated into their enantiomers and / or diastereomers.
  • 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 the general formula I having at least two asymmetric carbon atoms on the basis of their physicochemical differences according to known methods, for example by chromatography and / or fractional crystallization, split into their diastereomers, which, if they are obtained in racemic form, then as mentioned above in the Enantiomers can be separated.
  • the enantiomer separation 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.
  • Particularly common optically active acids are e.g.
  • 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 contractions) 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 rectal inflammation), irritable colon and other disorders with decreased intestinal motility, depression, melancholia, melanoclavitis, pollakiuria, urinary frequency, neurogenic inflammation , Neuro
  • Urgency incontinence, stress incontinence, mixed incontinence, overactive bladder (OAB) in wet OAB or dry OAB OAB with imperative urgency, associated with or without urge incontinence, with or without increased urinary frequency, with or without nocturnal urination, dysuria, Nocturia, pollakisuria, residual urine formation.
  • 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 dysynia, lower urinary tract symptoms (LUTS), obstructive bladder voiding disorders (BOO) and / or prostateopathy.
  • the use according to the invention is aimed not only at the causative treatment of the indications mentioned, but also at the treatment of the accompanying symptoms, in particular the pain or the urinary diversion that may be associated therewith.
  • the compounds according to the invention are also useful for the treatment of neurodegenerative diseases such as e.g. Alzheimer's disease, Parkinson's disease or Huntington's disease.
  • beta-3-agonists of the invention 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 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 collagenase in Krebs Ringer buffer (KBR) containing 6 mM glucose and 2% albumin by gently shaking for 30-40 minutes at 37 ° C. The cells were filtered through a gauze, washed twice with KRB and centrifuged 50-15Og for 5 minutes.
  • 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.
  • the peroxidase catalyzed coupling of sodium N-ethyl-N- (3-sulfopropyl) m-ansidine and 4- Aminoantipyrine a quinoneimine dye.
  • 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, repaglinide, thiazolidinediones (eg rosiglitazone, pioglitazone), 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 glib
  • inhibitors of protein tyrosine phosphatase 1 substances that affect deregulated glucose production in the liver, e.g. Inhibitors of glucose-6-phosphatase, or fructose-1, 6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase, 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 Obe sitas, such as sibutr
  • a combination with drugs for influencing high blood pressure 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. ⁇ , iV, im) 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, ie, in amounts which are sufficient to those given below Reach dosage range.
  • 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 obtaining 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 obtaining the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • 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 in the usual way, for example with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilizers, such as alkali salts of ethylenediaminetetraacetic acid, optionally with the use of emulsifiers and / or dispersants, wherein, for example, when using water as a diluent organic solvents may optionally be used as solubilizers or Hilfleriastoff prepared and filled in injection bottles or ampoules or infusion bottles.
  • the capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.
  • inert carriers such as lactose or sorbitol
  • Suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
  • suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
  • suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
  • suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
  • suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
  • suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
  • suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
  • suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
  • suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
  • suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
  • suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
  • suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
  • suitable carriers such as neutral fats
  • ground natural minerals eg kaolins, clays, talc, chalk
  • ground synthetic minerals eg fumed silica and silicates
  • sugars eg cane, milk and dextrose
  • emulsifying agents eg lignin, sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone
  • lubricants for example, magnesium stearate, talc, stearic acid and sodium lauryl sulfate.
  • the application is carried out in a customary manner, preferably orally or transdermally, in particular orally.
  • the tablets may, of course, besides the abovementioned excipients also additives, such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatin, and the like. Further, 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 under aseptic conditions in ampoules bottled, which are then sterilized and sealed.
  • the vials contain 5 mg, 25 mg and 50 mg active ingredient.
  • Component 1 (3-chloro-1,1-dimethyl-propyl) -carbamic acid tert-butyl ester
  • Step 2 (S-Chloro-1-J-dimethyl-propyl-carbamic acid tert-butyl ester
  • Component 2 N- (3-acetyl-phenyl) -benzenesulfonamide
  • Component 3 N- [3- (2-ethoxy-2-hydroxyacetyl) -phenyl] -benzenesulfonamide
  • Component 4 (R) -N- (3-oxiranyl-phenyl) -benzenesulfonamide
  • Step 2 (R) -N- [3- (2-chloro-1-hydroxy-ethyl) -phenyl] -benzenesulfonamide
  • Step 3 (R) -N- (3-oxiranyl-phenyl) -benzenesulfonamide
  • Step 1 N- (3-acetyl-phenyl) -dibenzenesulfonamide
  • Step 2 N- [3- (2-chloro-acetyl) -phenyl] -dibenzenesulfonamide
  • Washed water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution Washed water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution.
  • the organic phase is separated, dried over magnesium sulfate and concentrated on a rotary evaporator.
  • the residue is recrystallized from toluene to a colorless solid.
  • Step 3 N - [(R) -3-oxiranyl-phenyl] -dibenzenesulfonamide
  • the intermediate product is triturated with diisopropyl ether, filtered off with suction and dried.
  • the solid is dissolved in 30 ml of DMF and treated at -5 ° C with stirring over 15 minutes with 8.33 ml of 4 N lithium hydroxide solution. Meanwhile, for better stirrability, 3 ml of DMF and 2 ml of water are added. After 25 minutes, the reaction mixture is acidified at -5 ° C with glacial acetic acid and diluted with water. The precipitated solid is filtered off, washed several times with ice water and dried.
  • Step 1 1, 1-Dimethyl-3- (6-nitro-benzimidazol-1-yl) -propylamine
  • the reaction mixture was treated with 7.522 g (27.0 mmol) of 3-chloro-1, 1-dimethyl-propyl) - (2,6-dichloro-benzylidene) -amine and 0.887 g (2.40 mmol) of tetrabutylammonium iodide and 72 hours stirred at room temperature and at 100 ° C for 5 hours.
  • the reaction mixture is poured into ice-water and extracted with ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulfate and concentrated on a rotary evaporator.
  • Step 2 N- (3- ⁇ 2- [1,1-Dimethyl-3- (6-nitro-benzimidazol-1-yl) -propylamino] -1-hydroxy-ethyl ⁇ -phenyl) -benzenesulfonamide
  • Step 3 N- (3- ⁇ 2- [3- (6-Amino-benzimidazol-1-yl) -1, 1-dimethyl-propylamino] -1-hydroxyethyl ⁇ -phenyl) -benzenesulfonamide
  • Step 2 Ethyl 1 - (3-tert-butoxycarbonylamino-3-methyl-butyl) -1H-benzimidazole-4-carboxylate
  • Trifluoroacetic acid is added.
  • the reaction mixture is stirred for 4 hours at 40 0 C and then concentrated on a rotary evaporator.
  • Rf 0.51 [silica gel, dichloromethane / methanol / ammonia (90/10 / 0.1)]
  • MS [ESI (M + H) + ] 276
  • Step 4 1 - ⁇ 3- [2- (3-Benzenesulfonylamino-phenyl) -2-hydroxy-ethylamino] -3-methyl-butyl ⁇ -1 H-benzimidazole-4-carboxylic acid, ethyl ester
  • Step 5 1 - ⁇ 3- [2- (3-Benzenesulfonylamino-phenyl) -2-hydroxy-ethylamino] -3-methyl-butyl ⁇ -1H-benzimidazole-4-carboxylic acid trifluoroacetate
  • Step 1 4-Fluoro-3-nitro-benzoic acid ethyl ester
  • Step 2 4- (3-Methyl-3-nitro-butylamino) -3-nitro-benzoic acid ethyl ester
  • Step 3 1- (3-Amino-3-methylbutyl) -1H-benzimidazole-5-carboxylic acid ethyl ester
  • Step 4 (R) -1 - ⁇ 3- [2- (3-Benzenesulfonylamino-phenyl) -2-hydroxy-ethylamino] -3-methyl-butyl ⁇ -1 H-benzimidazole-5-carboxylic acid, ethyl ester
  • Rf 0.41 [silica gel, dichloromethane / methanol (9/1)]
  • MS [ESI (M + H) + ] 551
  • reaction mixture is then treated with 9.312 g (42.0 mmol) of tert -butyl (S-chloromethyl) -propyl-carbamate (dissolved in 30 ml of DMPU) and 1.55 g (4.20 mmol) of tert-butylammonium iodide and 18 For hours at 60 ° C.
  • Step 4 Ethyl 1- ⁇ 3- [2- (3-benzenesulfonylamino-phenyl) -2-hydroxyethylamino] -3-methylbutyl ⁇ -1H-benzimidazole-6-carboxylate
  • the reaction mixture is concentrated on a rotary evaporator, the residue is extracted into water and with ethyl acetate.
  • the combined organic phases are discarded, the aqueous phase is adjusted to a pH of 8-9 with concentrated, aqueous ammonia solution and extracted with dichloromethane.
  • the combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator.
  • Step 1 1, 1-Dimethyl-3- (2-methyl-benzimidazol-1-yl) -propylamine dihydrochloride
  • reaction mixture is poured into 600 ml of ice-water, combined with 30 ml of concentrated hydrochloric acid and extracted with ethyl acetate.
  • the organic phase is discarded, the aqueous phase adjusted to pH> 9 with potassium carbonate and extracted with dichloromethane.
  • the combined organic phases are over
  • Step 2 N- (3- ⁇ 2- [1,1-Dimethyl-3- (2-methyl-benzimidazol-1-yl) -propylamino] -1-hydroxy-ethyl ⁇ -phenyl) -benzenesulfonamide hydrotrifluoroacetate
  • Example 13 1- ⁇ 3- [2- (3-Benzenesulfonylamino-phenyl) -2-hydroxy-ethylamino] -3-methyl-butyl ⁇ -2-oxo-2,3-dihydro-1H-benzimidazole-5 carbonklaremethylester
  • Step 1 (3-Hydroxy-1, 1-dimethyl-propyl) -carbamic acid tert-butyl ester
  • Step 2 (3-Amino-1, 1-dimethyl-propyl) -carbamic acid tert-butyl ester
  • the combined organic phases are washed successively with aqueous, potassium hydrogen sulfate solution (0.5 M), aqueous sodium bicarbonate solution (10%) and water, dried over sodium sulfate and concentrated on a rotary evaporator.
  • the residue is dissolved in 700 ml of saturated, ethanolic ammonia and treated at room temperature with 3.52 g of Raney nickel and shaken at room temperature in an autoclave at 3 bar hydrogen atmosphere for 24 hours.
  • the reaction mixture is filtered and the filtrate is concentrated on a rotary evaporator.
  • Step 3 4- (3-tert-Butoxycarbonylamino-3-methylbutylamino) -3-nitrobenzoic acid
  • Step 4 3-Amino-4- (3-tert-butoxycarbonylamino-3-methylbutylamino) benzoic acid
  • Step 5 Methyl (3-tert-butoxycarbonylamino-3-methylbutyl) -2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate
  • Step 7 1- ⁇ 3- [2- (3-Benzenesulfonylamino-phenyl) -2-hydroxy-ethylamino] -3-methyl-butyl ⁇ -2-oxo-2,3-dihydro-1H-benzimidazole-5 carbonklaremethylester
  • Example 14 1- ⁇ 3- [2- (3-Benzenesulfonylamino-phenyl) -2-hydroxy-ethylamino] -3-methyl-butyl ⁇ -2-oxo-2,3-dihydro-1H-benzimidazole-5 carboxylic acid hydrotrifluoroacetate
  • Example 16 1- ⁇ 3- [2- (3-Benzenesulfonylamino-phenyl) -2-hydroxy-ethylamino] -3-methyl-butyl ⁇ -1H-benzimidazole-4-carboxylic acid ethyl ester hydrochloride
  • Example 19 1- ⁇ 3 - [(R) -2- (3-Benzenesulfonylamino-phenyl) -2-hydroxyethylamino] -3-methylbutyl ⁇ -6-methoxy-1H-benzimidazole-5-carboxylic acid hydrotrifluoroacetate
  • Step 1 4- [Acetyl- (3-tert-butoxycarbonylamino-3-methyl-butyl) -amino] -2-methoxy-5-nitro-benzoic acid methyl ester
  • Step 2 4- (3-tert-Butoxycarbonylamino-3-methyl-butylamino) -2-methoxy-5-nitrobenzoic acid methyl ester
  • Step 3 Methyl 1- (3-amino-3-methylbutyl) -6-methoxy-1H-benzimidazole-5-carboxylate
  • Vacuum obtained residue is on silica gel [dichloromethane / methanol / ammonia
  • Step 4 1 - ⁇ 3 - [(R) -2- (3-Dibenzoylsulfonylamino-phenyl) -2-hydroxyethylamino] -3-methylbutyl ⁇ -6-methoxy-1H-benzimidazole-5-carboxylic acid methlyester
  • Step 5 1- ⁇ 3 - [(R) -2- (3-benzenesulfonylamino-phenyl) -2-hydroxy-ethylamino] -3-methylbutylJ- ⁇ -methoxy-1H-benzimidazole- ⁇ -carboxylic acid hydrotrifluoroacetate
  • Example 20 1- ⁇ 3 - [(R) -2- (3-Benzenesulfonylamino-phenyl) -2-hydroxy-ethylamino] -s-methyl-buty- ⁇ -chloro-1H-benzimidazole- ⁇ -carboxylic acid hydrotrifluoroacetate
  • Step 3 1- (3-tert-Butoxycarbonylamino-3-methylbutyl) -6-chloro-1H-benzimidazole-5-carboxylic acid ethyl ester
  • Step 4 ethyl I-S-amino-S-methylbutyl-O-chloro-1H-benzimidazole-6-carboxylate
  • Step 5 1 - ⁇ 3 - [(R) -2- (3-benzenesulfonylamino-phenyl) -2-hydroxy-ethylamino] -3-methylbutylJ- ⁇ -chloro-1H-benzimidazole- ⁇ -carboxylic acid hydrotrifluoroacetate
  • Example 21 1- ⁇ 3 - [(R) -2- (3-Benzenesulfonylamino-phenyl) -2-hydroxyethylamino] -3-methylbutyl ⁇ -5-chloro-1H-benzimidazole-6-carboxylic acid hydrotrifluoroacetate
  • Example 22 1- ⁇ 3 - [(R) -2- (3-Benzenesulfonylamino-phenyl) -2-hydroxyethylamino] -3-methylbutyl ⁇ -4-chloro-1H-benzimidazole-5-carboxylic acid hydrotrifluoroacetate
  • Step 3 4-Chloro-benzimidazole-5-carboxylic acid ethyl ester hydrochloride
  • Step 4 1- (3-tert-Butoxycarbonylamino-3-methylbutyl) -4-chloro-1H-benzimidazole-5-carboxylic acid ethyl ester
  • Step 5 1 - ⁇ 3 - [(R) -2- (3-benzenesulfonylamino-phenyl) -2-hydroxy-ethylamino] -3-methyl-butyl-1-chloro-1H-benzimidazole-6-carboxylic acid hydrotrifluoroacetate
  • Example 23 1- ⁇ 3 - [(R) -2- (3-Benzenesulfonylamino-phenyl) -2-hydroxyethylamino] -3-methylbutyl ⁇ -7-chloro-1H-benzimidazole-6-carboxylic acid hydrotrifluoroacetate
  • Example 24 1- ⁇ 3 - [(R) -2- (3-Benzenesulfonylamino-phenyl) -2-hydroxyethylamino] -3-methylbutyl ⁇ -6-hydroxy-1H-benzimidazole-5-carboxylic acid hydrotrifluoroacetate

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Abstract

L'invention concerne de nouveaux Béta-agonistes de formule (I), les résidus R<SUP>1</SUP> à R<SUP>4</SUP> étant spécifiés dans les revendications et la description, ainsi que leurs tautomères, leurs racémates, leurs énantiomères, leurs diastéréomères, leurs solvates, leurs hydrates, leurs mélanges, leurs promédicaments et leurs sels, en particulier leurs sels physiologiquement acceptables comprenant des acides organiques et non organiques ou des bases. L'invention concerne également des procédés de productions desdits composés ainsi que leur utilisation en tant que médicaments.
EP06807621A 2005-10-28 2006-10-27 Derives de benzimidazole utilises en tant qu'agonistes du recepteur beta-3 Withdrawn EP1943229A1 (fr)

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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
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
EP2298373A1 (fr) 2009-09-22 2011-03-23 ECP Entwicklungsgesellschaft mbH Pompe à fluide dotée d'au moins une aube directrice et d'un dispositif d'appui

Family Cites Families (12)

* 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
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
GB9805520D0 (en) * 1998-03-17 1998-05-13 Zeneca Ltd Chemical compounds
CN1430603A (zh) * 2000-04-28 2003-07-16 旭化成株式会社 新型双环化合物
DE60239170D1 (de) * 2001-10-25 2011-03-24 Asahi Kasei Pharma Corp Bicyclische Verbindungen
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
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
EP1720546B1 (fr) * 2004-02-14 2010-09-01 Boehringer Ingelheim International GmbH Nouveaux beta-2-agonistes a action longue duree et leur utilisation comme medicaments
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
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007048842A1 *

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WO2007048842A1 (fr) 2007-05-03
US20070112033A1 (en) 2007-05-17
AR058161A1 (es) 2008-01-23
JP2009513606A (ja) 2009-04-02
DE102005052102A1 (de) 2007-05-03
US20080103138A1 (en) 2008-05-01
TW200800175A (en) 2008-01-01

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