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WO2011030873A1 - Composés benzyliques - Google Patents

Composés benzyliques Download PDF

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Publication number
WO2011030873A1
WO2011030873A1 PCT/JP2010/065659 JP2010065659W WO2011030873A1 WO 2011030873 A1 WO2011030873 A1 WO 2011030873A1 JP 2010065659 W JP2010065659 W JP 2010065659W WO 2011030873 A1 WO2011030873 A1 WO 2011030873A1
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Prior art keywords
group
alkyl
pyridin
phenyl
methyl
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English (en)
Japanese (ja)
Inventor
亮 岩村
信彦 柴川
昌彦 萩原
栄治 岡成
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Ube Corp
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Ube Industries Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

  • the present invention relates to a novel benzyl compound useful as a medicine or a pharmacologically acceptable salt thereof. More specifically, since the benzyl compound according to the present invention has an EP2 agonistic action, for example, a therapeutic and / or prophylactic agent for respiratory diseases such as asthma and chronic obstructive pulmonary disease (hereinafter abbreviated as COPD). Useful as.
  • an EP2 agonistic action for example, a therapeutic and / or prophylactic agent for respiratory diseases such as asthma and chronic obstructive pulmonary disease (hereinafter abbreviated as COPD).
  • COPD chronic obstructive pulmonary disease
  • PGE 2 prostaglandin E 2
  • PGE 2 is known to act as an agonist for receptors such as EP1, EP2, EP3, and EP4, and among them, the agonistic action for EP2 receptor is deeply involved in the bronchodilating action.
  • EP1, EP2, EP3, and EP4 the agonistic action for EP2 receptor is deeply involved in the bronchodilating action.
  • Patent Documents 1 to 4 it is known that sulfonamide compounds having a structure similar to the compound of the present invention have EP2 agonistic activity (see Patent Documents 1 to 4).
  • the compound described as Example 14e in Patent Document 2 has an effect of accelerating the healing of fractures by increasing the concentration of cyclic adenosine monophosphate (hereinafter abbreviated as cAMP) by the EP2 agonist action.
  • cAMP cyclic adenosine monophosphate
  • Non-Patent Document 3 it is not specifically described that the compounds described in Patent Documents 1 to 4 have a bronchodilator action due to EP2 agonistic action.
  • none of the above-mentioned documents relates to the compound of the present invention. There is no specific disclosure of a phenyl group having a specific substituent and a sulfonamide compound having pyridylaminoacetic acid and its ester as a partial structure.
  • a novel benzyl compound having a specific structure is a powerful EP2 Has excellent bronchodilator action based on agonistic action, and further, tissue transferability, bioavailability (BA), rapid onset of drug effect, sustained drug effect, solubility, physical stability, drug interaction
  • a therapeutic agent and / or preventive agent preferably a therapeutic agent for respiratory diseases such as asthma and COPD. completed.
  • the present invention has a novel bronchodilator action based on a strong EP2 agonist action, and is particularly useful as a therapeutic agent and / or preventive agent (preferably a therapeutic agent) for respiratory diseases such as asthma and COPD.
  • a benzyl compound or a pharmacologically acceptable salt thereof is particularly useful as a therapeutic agent and / or preventive agent (preferably a therapeutic agent) for respiratory diseases such as asthma and COPD.
  • a benzyl compound or a pharmacologically acceptable salt thereof is provided.
  • the “benzyl compound” in the present invention means a compound represented by the following general formula (I).
  • R 1 represents a hydrogen atom or a C 1 -C 6 alkyl group which may be substituted with a halogeno group
  • R 2 and R 3 each independently represents a hydrogen atom or a C 1 -C 6 alkyl group
  • A represents an aryl group, heteroaryl group or heterocyclic group which may be substituted with the same or different 1 to 3 groups selected from the substituent group ⁇
  • Y is a C 1 -C 6 alkyl group, C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group ⁇ C 3 -C 8 cycloalkyl group, C 5 -C 8 cycloalkenyl group, aryl group, heteroaryl group or heterocyclic group
  • Z is a C 1 -C 6 alkyl group, C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group which may be
  • the benzyl compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof exhibits an excellent bronchodilator action based on a strong EP2 agonist action, and further, tissue transferability, bioavailability; (BA), rapid onset of drug efficacy, sustained efficacy, solubility, physical stability, drug interaction, toxicity, etc., together with the present invention, respiratory disease (for example, asthma) , COPD, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary hypertension, etc.)
  • respiratory disease for example, asthma
  • COPD COPD
  • bronchitis emphysema
  • pulmonary fibrosis pulmonary fibrosis
  • ARDS acute respiratory distress syndrome
  • cystic fibrosis pulmonary hypertension, etc.
  • the compound represented by the general formula (1) of the present invention is also useful as a therapeutic and / or prophylactic agent for diseases (for example, bone diseases, gastric ulcers, hypertension, glaucoma, etc.) for which EP2 agonist action is considered useful. It is.
  • diseases for example, bone diseases, gastric ulcers, hypertension, glaucoma, etc.
  • C 1 -C 6 alkyl group represented by each substituent and the “C 1 -C 6 alkyl group” portion in each substituent each mean a “C 1 -C 6 alkyl group” having the same meaning.
  • Examples of such “C 1 -C 6 alkyl group” include, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, Isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1-ethylpropyl group, 1,2-dimethylpropyl group, hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1-ethylbutyl group, 2-ethylbutyl group,
  • the “C 2 -C 6 alkenyl group” represented by each substituent means a “C 2 -C 6 alkenyl group” having the same meaning, and as such a “C 2 -C 6 alkenyl group”,
  • vinyl group 1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group, 2-methyl-1- Propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-ethylvinyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl- 1-butenyl group, 2-methyl-1-butenyl group, 3-methyl-1-butenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 3-methyl-2-butenyl group, 1-methyl -3-butenyl,
  • the “C 2 -C 6 alkynyl group” represented by each substituent means a “C 2 -C 6 alkynyl group” having the same meaning, and as such a “C 2 -C 6 alkynyl group”,
  • ethynyl group 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 3-methyl-1-butynyl group, 1-methyl-2-butynyl group, 1-methyl-3-butynyl group, 2-methyl-3-butynyl group, 1-ethyl- 2-propynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-
  • Base More preferred is a 2-propynyl group, 2-butynyl group, 3-butynyl group, 2-pentynyl group, 3-pentynyl group or 4-pentynyl group, and particularly preferred is a 2-propynyl group or 2-butynyl group. is there.
  • C 3 -C 8 cycloalkyl group indicated by each substituent, "C 3 -C 8 cycloalkyl group” moiety in each substituent both have the same meaning "C 3 -C 8 cycloalkyl group means ", such as” C 3 -C 8 cycloalkyl group ", for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, C 3 -C 8, such as a cyclohexyl group, cycloheptyl group or cyclooctyl group Examples thereof include a cycloalkyl group, preferably a C 3 -C 6 cycloalkyl group, more preferably a cyclopropyl group, a cyclobutyl group or a cyclopentyl group, and particularly preferably a cyclopropyl group or a cyclobutyl group.
  • the “C 5 -C 8 cycloalkenyl group” represented by each substituent means a “C 5 -C 8 cycloalkenyl group” having the same meaning, and such a “C 5 -C 8 cycloalkenyl group”.
  • cyclopentenyl cyclopenten-3-yl, cyclohexenyl, cyclohexen-3-yl, cyclohexen-4-yl, cycloheptenyl, cyclohepten-3-yl, cyclohepten-4-yl Group, cyclohepten-5-yl group, cyclooctenyl group, cycloocten-3-yl group, cycloocten-4-yl group, cycloocten-5-yl group and the like, and preferred are C 5 -C 8 cycloalkenyl groups.
  • cyclopentenyl group is a C 5 -C 6 cycloalkenyl group, more preferably, cyclopentenyl group, cyclopentene -3 A yl group or a cyclohexenyl group, particularly preferably a cyclopentenyl group or cyclohexenyl group.
  • C 1 -C 6 alkoxy group or “C 1 -C 6 alkoxy group” moiety in the substituent group ⁇ are both mean "C 1 -C 6 alkoxy group” having the same significance, such Examples of the “C 1 -C 6 alkoxy group” include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy Group, neopentyloxy group, tert-pentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1-ethylpropoxy group, 1,2-dimethylpropoxy group, hexyloxy group, 1-methylpentyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 4-methylpentyloxy group, 1-ethylbutoxy 2-ethylbutoxy group, 1,1-dimethylbutoxy group, 1,2-d
  • C 2 -C 6 alkanoyl group and “C 2 -C 6 alkanoyl group” moiety in the substituent group ⁇ are all means “C 2 -C 6 alkanoyl group” having the same significance, such Examples of the “C 2 -C 6 alkanoyl group” include acetyl group, propanoyl group, butanoyl group, 2-methylpropanoyl group, pentanoyl group, 2-methylbutanoyl group, 3-methylbutanoyl group, 2,2 -Dimethylpropanoyl group, hexanoyl group, 2-methylpentanoyl group, 3-methylpentanoyl group, 4-methylpentanoyl group, 2-ethylbutanoyl group, 2,2-dimethylbutanoyl group, 2,3- Examples thereof include a linear or branched C 2 -C 6 alkanoyl group such as a dimethylbutanoyl group or a 3,3-
  • Examples of the “C 7 -C 12 aralkyl group” in the substituent group ⁇ include, for example, benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-phenylpropyl group, 2-phenylpropyl group, 3-phenylpropyl group.
  • benzyl group 1-phenylethyl group, 2-phenylethyl group or 1- A methyl-2-phenylethyl group, more preferably a benzyl group, a 1-phenylethyl group or a 2-phenylethyl group. Particularly preferred is benzyl or 2-phenylethyl.
  • Examples of the “C 7 -C 12 aralkyloxy group” in the substituent group ⁇ include, for example, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group, 1-phenylpropyloxy group, 2-phenylpropyloxy group Group, 3-phenylpropyloxy group, phenylbutyloxy group, phenylpentyloxy group, phenylhexyloxy group, naphthalen-1-ylmethyloxy group, naphthalen-2-ylmethyloxy group, 1- (naphthalen-1-yl) ) Ethyloxy group, 2- (naphthalen-1-yl) ethyloxy group, 1- (naphthalen-2-yl) ethyloxy group, 2- (naphthalen-2-yl) ethyloxy group, etc., preferably benzyloxy Group, 1-phenylethyloxy group, 2-phenylethyloxy group
  • aryl group represented by each substituent and the “aryl group” portion in each substituent all mean an “aryl group” having the same significance. Examples of such an “aryl group” include phenyl Group or naphthyl group.
  • heteroaryl group represented by each substituent and the “heteroaryl group” part in each substituent all mean a “heteroaryl group” having the same significance, and as such a “heteroaryl group”,
  • heterocyclic group represented by each substituent means a “heterocyclic group” having the same significance, and such a “heterocyclic group” is a group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
  • As the partially unsaturated heterocyclic group for example, 4,5-dihydro-1H-imidazolyl group, 4,5-dihydrooxazolyl group, 4,5-dihydrothiazolyl group, 1,4,5, Examples include a 6-tetrahydropyrimidinyl group, a 5,6-dihydro-4H-1,3-oxazinyl group, or a 5,6-dihydro-4H-1,3-thiazinyl group.
  • Examples of the fully saturated heterocyclic group include Pyrrolidinyl group, tetrahydrofuryl group, 1,3- Oxolanyl group, a piperidinyl group, tetrahydropyranyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, and 1,3-dioxanyl group or a 1,4-dioxanyl group.
  • the “heterocyclic group” represented by each substituent is preferably a 4,5-dihydro-1H-imidazolyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, or a thiomorpholinyl group, and more preferably , Azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group or morpholinyl group, particularly preferably pyrrolidinyl group or piperidinyl group.
  • halogeno group represented by each substituent means a “halogeno group” having the same significance.
  • examples of such a “halogeno group” include a fluoro group, a chloro group, a bromo group, and an iodo group.
  • it is a fluoro group, a chloro group or a bromo group.
  • the preferred substituent is a combination of the respective preferred substituents.
  • a substituent include a halogeno C 1 -C 4 alkyl group, a halogeno C 1 -C 4 alkoxy group, or a C 1 -C 4 alkylamino-C 1 -C 4 alkyl group.
  • R 1 is preferably a hydrogen atom or a C 1 -C 4 alkyl group, more preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a tert-butyl group, and particularly preferably , Hydrogen atom, methyl group, ethyl group or isopropyl group.
  • R 2 is preferably a hydrogen atom or a C 1 -C 4 alkyl group, more preferably a hydrogen atom or a methyl group, and particularly preferably a hydrogen atom.
  • R 3 is preferably a hydrogen atom or a C 1 -C 4 alkyl group, more preferably a hydrogen atom or a methyl group, and particularly preferably a hydrogen atom.
  • A is preferably a hydroxy group, a halogeno group, a cyano group, a C 1 -C 4 alkyl group, a halogeno C 1 -C 4 alkyl group, a C 7 -C 12 aralkyl group, a C 3 -C 5 alkenyl group, C 3- C 5 alkynyl group, C 1 -C 4 alkoxy group, C 7 -C 12 aralkyloxy group, C 3 -C 6 cycloalkyl group, C 5 -C 6 cycloalkenyl group, arylcarbonyl group, C 1 -C 4 alkoxycarbonyl group, C 1 -C 4 alkylthio group, C 1 -C 4 alkylsulfinyl group, C 1 -C 4 alkylsulfonyl group, C 1 -C 4 alkylamino group, di- (C 1 -C 4 alkyl) amino group, an arylamino group
  • Y is preferably a halogeno group, a C 1 -C 4 alkoxy group, a C 3 -C 6 cycloalkyl group, a C 1 -C 4 alkoxycarbonyl group, a C 1 -C 4 alkylthio group, or a C 1 -C 4 alkyl group.
  • Alkyl group trifluoromethyl group, methoxymethyl group, cyclopropylmethyl group, 2-methylaminoethyl group, 2-dimethylaminoethyl Group, 2- (pyrrolidin-1-yl) ethyl group, 1-propenyl group, 1-butenyl group, 2-propynyl group, 2-butynyl group, cyclopropyl group, cyclopentenyl group, [fluoro group, chloro group, cyano group Group, methyl group, ethyl group, benzyl group, benzyloxy group, cyclopropyl group, methoxycarbonyl group, methylthio group, methylamino group, dimethylamino group, anilino group, acetylamino group, methoxycarbonylamino group, phenyl group, pyrrolidinyl A phenyl group, a thienyl group, a pyrazolyl group,
  • Z is preferably a halogeno group, a C 7 -C 12 aralkyl group, a C 1 -C 4 alkoxy group, a C 7 -C 12 aralkyloxy group, a C 3 -C 6 cycloalkyl group, or a C 5 -C 6 cyclo group.
  • the compound represented by the general formula (I) of the present invention is easily converted into a pharmacologically acceptable acid addition salt by treating with an acid.
  • salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or phosphate; or acetate, trifluoroacetate, benzoate Oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p -Organic acid salts such as toluene sulfonate, glutamate or aspartate.
  • R 1 is a hydrogen atom
  • the compound represented by the general formula (I) of the present invention is easily converted into a pharmacologically acceptable basic salt by treatment with a base.
  • salts include metal salts such as sodium salts, potassium salts, calcium salts, and magnesium salts; inorganic salts such as ammonium salts; and organic amine salts such as triethylamine salts and guanidine salts.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof can exist as a hydrate or a solvate, and these are also included in the present invention.
  • a compound in which R 1 is a hydrogen atom or a C 1 -C 4 alkyl group (2) Compound wherein R 1 is a hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group or tert-butyl group (3) Compound wherein R 1 is a hydrogen atom, methyl group, ethyl group or isopropyl group, (4) the compound wherein R 2 and R 3 are each independently a hydrogen atom or a C 1 -C 4 alkyl group, (5) A compound in which R 2 and R 3 are each independently a hydrogen atom or a methyl group, (6) A compound in which R 2 and R 3 are both hydrogen atoms, (7) A is a hydroxy group, halogeno group, cyano group, C 1 -C 4 alkyl group, halogeno C 1 -C 4 alkyl group, C 7 -C 12
  • a compound, (17) Z is a methyl group, an ethyl group, a trifluoromethyl group, a 2-phenylethyl group, a cyclopropyl group, a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, 2- Chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 4-cyanophenyl group, 4-cyclopropylphenyl group, 4-methoxyphenyl group, thiophen-2-yl group, thiophen-3-yl group, pyridine-2- A compound which is an yl group, a pyridin-3-yl group or a pyridin-4-yl group, (18) A compound wherein Z is a phenyl group, a 4-fluorophenyl group, a pyridin-2-yl group or a pyridin-3-y
  • R 1 is from groups (1) to (3)
  • R 2 and R 3 are from groups (4) to (6)
  • A is from groups (7) to (10).
  • Y is arbitrarily selected from groups (11)-(14)
  • Z is arbitrarily selected from groups (15)-(18), and compounds obtained by arbitrarily combining these are also preferred compounds.
  • R 1 is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group or a tert-butyl group
  • R 2 and R 3 are each independently a hydrogen atom or a methyl group
  • A is a hydroxy group, halogeno group, cyano group, C 1 -C 4 alkyl group, halogeno C 1 -C 4 alkyl group, C 7 -C 12 aralkyl group, C 3 -C 5 alkenyl group, C 3 -C 5 Alkynyl group, C 1 -C 4 alkoxy group, C 7 -C 12 aralkyloxy group, C 3 -C 6 cycloalkyl group, C 5 -C 6 cycloalkenyl group, arylcarbonyl group, C 1 -C 4 alkoxycarbonyl group C 1 -C 4 alkylthio group, C 1 -C 4 alkyls
  • R 1 is a hydrogen atom, a methyl group, an ethyl group or an isopropyl group
  • R 2 and R 3 are both hydrogen atoms
  • A is a phenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-methylphenyl group, 4-trifluoromethylphenyl group, 4- (1-propenyl) phenyl group, 4-methoxy Phenyl group, 4-cyclopropylphenyl group, 4-methoxycarbonylphenyl group, 4-methylthiophenyl group, 4-dimethylaminophenyl group, 4- (pyrrolidin-1-yl) phenyl group, naphthalen-1-yl group, naphthalene A -2-yl group, a thiophen-2-yl group, a thiazol-2-yl group, a thiazol-4-yl group, a pyridin
  • benzyl compound preferably [6-( ⁇ 4- [bis (4-fluorophenyl) methyl] benzyl ⁇ (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid, [6-( ⁇ 4- [1- (Naphthalen-2-yl) ethyl] benzyl ⁇ (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid, or [6-( ⁇ 4- [phenyl And compounds such as (pyridin-4-yl) methyl] benzyl ⁇ (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid.
  • a pharmaceutical composition comprising as an active ingredient the compound represented by the above general formula (I), the sulfonamide compound according to any one of (1) to (23) or a pharmacologically acceptable salt thereof And (25) the pharmaceutical composition according to (24) for the prevention or treatment of respiratory diseases.
  • R 2 , R 3 , A, Y and Z are as defined above, and X is a hydroxy group, a chloro group, a bromo group, an iodo group, a methanesulfonyloxy group, a benzenesulfonyloxy group, p - indicates toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, Boc represents a tert- butoxycarbonyl group, Bu t represents a tert- butyl group. ]
  • Synthetic pathways 1 to 3 Compound A and Compound B, or Compound C and Compound D, or Compound E and Compound F are reacted in an organic solvent in the presence of a condensing agent or a base.
  • Compound (I ′) which is a precursor can be obtained.
  • Compounds of the invention wherein R 1 is a hydrogen atom (Ia) may be a precursor compound of the Boc group and Bu t group (I ') obtained by deprotection by acid treatment.
  • a desired substituent may be introduced from the beginning, and after the basic skeleton is produced by the above method, oxidation, reduction , Alkylation, esterification, amidation, dehydration reaction, deprotection reaction, acetylation, hydrolysis, coupling reaction, cyclization reaction and / or using synthetic methods that combine these reactions, A desired substituent may be introduced into the skeleton.
  • the method for producing the synthetic intermediate of the compound of the present invention will be described in detail in the Examples below.
  • the target compound produced in each reaction can be obtained from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, and then an organic solvent such as ethyl acetate that is immiscible with water is added.
  • It isolate separates and it obtains by distilling a solvent off after drying with desiccants, such as anhydrous magnesium sulfate or anhydrous sodium sulfate.
  • the obtained target compound can be obtained by a conventional method such as recrystallization; reprecipitation; or a method commonly used for separation and purification of organic compounds (for example, adsorption column chromatography using a carrier such as silica gel or alumina).
  • the compound represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt according to a conventional method, if necessary, but can also be separated directly from the reaction mixture as a salt.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof can be administered as it is (as it is in the bulk) or an appropriate pharmacology.
  • Oral or parenteral intravenous, intramuscular, intraperitoneal, transdermal, transrespiratory, intradermal, or subcutaneous
  • suppositories ointments, lotions, inhalants or injections Etc.
  • additives such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents or diluting seats.
  • Excipients include, for example, organic excipients or inorganic excipients.
  • organic excipient include sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, ⁇ -starch or dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; Dextran; or pullulan and the like.
  • inorganic excipients include light anhydrous silicic acid; or sulfates such as calcium sulfate.
  • Lubricants include, for example, stearic acid; stearic acid metal salts such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or gallow; boric acid; adipic acid; sulfate such as sodium sulfate; glycol Fumaric acid; sodium benzoate; D, L-leucine; sodium lauryl sulfate; silicic acids such as anhydrous silicic acid or silicic acid hydrate; or starch derivatives in the above-mentioned excipients.
  • binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and compounds represented by the above excipients.
  • Disintegrants include, for example, cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or internally crosslinked carboxymethylcellulose calcium; crosslinked polyvinylpyrrolidone; or chemically modified starch such as carboxymethyl starch or sodium carboxymethyl starch Or a cellulose derivative is mentioned.
  • the emulsifier is, for example, colloidal clay such as bentonite or bee gum; an anionic surfactant such as sodium lauryl sulfate; a cationic surfactant such as benzalkonium chloride; or polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester Or nonionic surfactants, such as sucrose fatty acid ester, etc. are mentioned.
  • Stabilizers include, for example, parahydroxybenzoates such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; acetic anhydride Or sorbic acid.
  • parahydroxybenzoates such as methylparaben or propylparaben
  • alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol
  • benzalkonium chloride phenols such as phenol or cresol
  • thimerosal acetic anhydride Or sorbic acid.
  • sweeteners such as saccharin sodium or aspartame
  • acidulants such as citric acid, malic acid or tartaric acid
  • flavors such as menthol, lemon extract or orange extract.
  • Diluents are compounds that are commonly used as diluents, such as lactose, mannitol, glucose, sucrose, calcium sulfate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch , Polyvinylpyrrolidone or a mixture thereof.
  • the dose of the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof can vary depending on conditions such as the patient's symptoms, age, body weight, etc.
  • the lower limit is 0.001 mg / Kg (preferably 0.01 mg / Kg) and the upper limit is 20 mg / Kg (preferably 10 mg / Kg) per dose.
  • the lower limit is 0.0001 mg per dose.
  • / Kg preferably 0.0005 mg / Kg
  • an upper limit of 10 mg / Kg preferably 5 mg / Kg
  • Rf values in the examples, thin layer chromatography is a value measured using a (Merck, TLC plate silica gel 60F 254 (trade name)), is described in parentheses represent the developing solvent (volume ratio) .
  • test compound dissolved in dimethyl sulfoxide and [ 3 H] prostaglandin E 2 (NET-428, manufactured by PerkinElmer) (final concentration: 10 nM) were added, and incubated at 30 ° C. for 60 minutes.
  • NET-428 [ 3 H] prostaglandin E 2
  • the membrane fraction was collected on glass fiber filter paper (GF / B, Whatman) and buffered (10 mM MES-KOH (pH 6.0), 10 mM MgCl 2 ). ), And the radioactivity was measured with a liquid scintillation analyzer (2000 CA, manufactured by Packard).
  • EXSAS version 7.1.6, manufactured by Arm Systex
  • IC 50 value concentration of the test compound required to replace 50% of [ 3 H] prostaglandin E 2 bound to the receptor.
  • the dissociation constant (Kd value) was calculated by Scatchard analysis.
  • the compound of the present invention showed an excellent EP2 receptor binding action.
  • EP2 agonist activity was measured according to the method of Wilson et al. (European Journal of Pharmacology, 501, 49 (2004)).
  • HEK293 cells ES-562-C, manufactured by Euroscreen
  • HEK293 cells expressing human EP2 receptor were cultured in MEM medium containing 10% FBS, and 2 ⁇ 10 4 cells were seeded in 96-well plates. The next day, the medium was replaced with a serum-free MEM medium containing 3-isobutyl-1-methylxanthine (final concentration 500 ⁇ M) and incubated for 30 minutes, and then the test compound dissolved in dimethyl sulfoxide was added and left in a carbon dioxide incubator.
  • the amount of intracellular cAMP was measured with a cAMP Biotrak EIA System kit (GE Healthcare Bioscience).
  • concentration (EC 50 value) of the test compound required to raise cAMP to 50% of the maximum increase amount was calculated using EXSAS by nonlinear regression between the test compound concentration and the cAMP amount.
  • the compound of the present invention showed excellent EP2 agonist activity.
  • the tracheal specimen was stimulated and contracted with an electric stimulator (SEN-3401, manufactured by Nihon Kohden Co., Ltd.), and after the contraction reaction was stabilized, the test compound (concentration 10 ⁇ M) dissolved in dimethyl sulfoxide was added to relax the tracheal specimen. .
  • the inhibition rate for the contraction reaction before the compound addition was calculated. The test results are shown in Table 1.
  • the compound of the present invention exhibited an excellent tracheal contraction inhibitory action.
  • Formulation Example 1 (Hard Capsule) 50 mg of the powdered compound of Example 7, 128.7 mg of lactose, 70 mg of cellulose and 1.3 mg of magnesium stearate were mixed, passed through a 60 mesh sieve, and 250 mg of this powder was put into a No. 3 gelatin capsule. Into capsules.
  • Formulation Example 2 (Tablet) 50 mg of the compound of Example 7, 124 mg of lactose, 25 mg of cellulose and 1 mg of magnesium stearate are mixed, and tableted by a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.
  • the benzyl compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof exhibits an excellent bronchodilator action based on a strong EP2 agonist action, and further, tissue transferability, bioavailability; BA), the rapid onset of drug efficacy, sustained drug efficacy, solubility, physical stability, drug interaction, toxicity, etc.
  • a medicament for the treatment and / or prevention of respiratory diseases eg, asthma, COPD, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary hypertension, etc.
  • respiratory diseases eg, asthma, COPD, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary hypertension, etc.
  • diseases for example, bone diseases, gastric ulcers, hypertension, glaucoma, etc.
  • EP2 agonist action seems to be useful.
  • Also useful as a pharmaceutical for the treatment and / or prevention of diseases.

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  • Heart & Thoracic Surgery (AREA)
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Abstract

La présente invention a pour objet de nouveaux composés benzyliques représentés par la formule générale (I), qui présentent un excellent effet bronchodilatateur qui dépend d'une activité puissante d'agoniste d'EP2; ou leurs sels.
PCT/JP2010/065659 2009-09-11 2010-09-10 Composés benzyliques Ceased WO2011030873A1 (fr)

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WO2014157672A1 (fr) 2013-03-28 2014-10-02 宇部興産株式会社 Composé biaryle substitué
WO2015030250A1 (fr) 2013-09-02 2015-03-05 宇部興産株式会社 Composition pharmaceutique pour le traitement et/ou la prévention d'une maladie pulmonaire
WO2016047743A1 (fr) * 2014-09-26 2016-03-31 宇部興産株式会社 Composition pharmaceutique pour le traitement et/ou la prévention d'une maladie respiratoire
WO2016047741A1 (fr) * 2014-09-26 2016-03-31 宇部興産株式会社 Association d'un composé biaryle substitué et d'un autre composé pharmaceutique

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WO1998027053A1 (fr) * 1996-12-18 1998-06-25 Ono Pharmaceutical Co., Ltd. Derives de sulfamide et de carboxamide, et medicaments contenant ces derives en tant que principe actif
JP2006519250A (ja) * 2003-03-04 2006-08-24 ファイザー・プロダクツ・インク 医療処置におけるｅｐ２選択的受容体アゴニストの使用
JP2007515467A (ja) * 2003-12-22 2007-06-14 アステランド ユーケイ リミテッド Ｅｐ２受容体アゴニスト
JP2007186424A (ja) * 2004-11-26 2007-07-26 Ono Pharmaceut Co Ltd 気管支拡張剤
WO2008015517A2 (fr) * 2006-07-28 2008-02-07 Pfizer Products Inc. Agonistes de ep2
JP2009502982A (ja) * 2005-08-03 2009-01-29 メルク フロスト カナダ リミテツド Ｅｐ４受容体アゴニスト、この組成物および方法
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WO1998027053A1 (fr) * 1996-12-18 1998-06-25 Ono Pharmaceutical Co., Ltd. Derives de sulfamide et de carboxamide, et medicaments contenant ces derives en tant que principe actif
JP2006519250A (ja) * 2003-03-04 2006-08-24 ファイザー・プロダクツ・インク 医療処置におけるｅｐ２選択的受容体アゴニストの使用
JP2007515467A (ja) * 2003-12-22 2007-06-14 アステランド ユーケイ リミテッド Ｅｐ２受容体アゴニスト
JP2007186424A (ja) * 2004-11-26 2007-07-26 Ono Pharmaceut Co Ltd 気管支拡張剤
JP2009502982A (ja) * 2005-08-03 2009-01-29 メルク フロスト カナダ リミテツド Ｅｐ４受容体アゴニスト、この組成物および方法
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014157672A1 (fr) 2013-03-28 2014-10-02 宇部興産株式会社 Composé biaryle substitué
US9676720B2 (en) 2013-03-28 2017-06-13 Ube Industries, Ltd. Substituted biaryl compound
WO2015030250A1 (fr) 2013-09-02 2015-03-05 宇部興産株式会社 Composition pharmaceutique pour le traitement et/ou la prévention d'une maladie pulmonaire
WO2016047743A1 (fr) * 2014-09-26 2016-03-31 宇部興産株式会社 Composition pharmaceutique pour le traitement et/ou la prévention d'une maladie respiratoire
WO2016047741A1 (fr) * 2014-09-26 2016-03-31 宇部興産株式会社 Association d'un composé biaryle substitué et d'un autre composé pharmaceutique

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