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WO2001023349A1 - Derives d'acylsulfonamide - Google Patents

Derives d'acylsulfonamide Download PDF

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Publication number
WO2001023349A1
WO2001023349A1 PCT/JP2000/006695 JP0006695W WO0123349A1 WO 2001023349 A1 WO2001023349 A1 WO 2001023349A1 JP 0006695 W JP0006695 W JP 0006695W WO 0123349 A1 WO0123349 A1 WO 0123349A1
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group
substituent
ring
pharmaceutically acceptable
acceptable salt
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PCT/JP2000/006695
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English (en)
Japanese (ja)
Inventor
Yukio Aoyama
Maki Seki
Hirokazu Masuda
Yoshihiro Usui
Yuji Abe
Mayumi Shimada
Mutsuya Yamamoto
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Mitsubishi Chemical Corporation
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Priority to AU74475/00A priority Critical patent/AU7447500A/en
Priority to JP2001526504A priority patent/JP4556371B2/ja
Publication of WO2001023349A1 publication Critical patent/WO2001023349A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/52—Y being a hetero atom
    • C07C311/54—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea
    • C07C311/57—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/58—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings having nitrogen atoms of the sulfonylurea groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to a novel acylsulfonamide derivative having a chymase inhibitory action.
  • Chymase is a serine proteinase that is present in mast cell granules and has specificity for chymotrybcin-like substrates, but is secreted by degranulation of fertilizing cells and is secreted. By binding to extracellular matrices such as phosphosulfate proteodarican, it exerts enzymatic activity over a long period of time in the heart, blood vessels, skin, etc., and is deeply involved in various biological reactions It is known to be involved.
  • compounds having a chymase inhibitory activity are new therapeutic agents for cardiovascular diseases involving rygiotensin II (eg, hypertension, heart failure, coronary artery disease, diabetic and non-diabetic nephropathy). Is expected.
  • rygiotensin II eg, hypertension, heart failure, coronary artery disease, diabetic and non-diabetic nephropathy.
  • chymase promotes degranulation of mast cells, activates interloukin 1—, and increases the rate of matrix metabolism. It has a variety of effects, including the activation of thease, the release of transformants, and a new type of anti-inflammatory drug.
  • Drugs Attention has been paid that they can be anti-allergic drugs.
  • An object of the present invention is to provide a novel acylsulfonamide derivative which can prevent and treat various diseases by selectively inhibiting human chymase, and a medicament containing the same as an active ingredient. That is.
  • the present inventors have conducted intensive studies in order to achieve the above object, and as a result, have found a novel acylsulfonamide derivative having excellent chymase inhibitory activity. That is, the gist of the present invention is represented by the following general formula (I)
  • R 1 represents a aryl group which may have a substituent or a heterocyclic group which may have a substituent
  • n is an integer of 1 to 4
  • m is 0 or Or 1
  • R 2 represents an aryl group which may have a substituent or a heterocyclic group which may have a substituent.
  • R 3 represents a naphthyl group which may have a substituent or a heterocyclic group which may have a substituent.
  • R 3 is a phenyl group which may have a substituent, a naphthyl group which may have a substituent, or a substituent A heterocyclic group which may have ),
  • the gist of the present invention is represented by the following general formula (II)
  • R represents an aryl group which may have a substituent or a heterocyclic group which may have a substituent
  • X represents a CH group or an N atom
  • Y is one O —
  • n 0 or 1
  • n ' is an integer from 0 to 2
  • P ' represents an integer of 0 to 6.
  • R 5 / has a substituent and is not a trimethylpyridyl group
  • f f represents an amino acid residue which may have one substituent.
  • R 3 / represents a aryl group which may have a substituent or a heterocyclic group which may have a substituent.
  • R 4 ′ and R 5 ′ may have a cyclic structure, and the cyclic structure may be
  • the compounds of the general formulas (I) and (II) have optical isomers, and any of the R configuration, the S configuration, and a mixed configuration thereof are included in the scope of the present invention.
  • the gist of the present invention is to provide a pharmaceutical composition, a chymase inhibitor, and a therapeutic and / or prophylactic agent for the following diseases, each of which contains the compound represented by the general formula (I) or (II) as an active ingredient.
  • a pharmaceutical composition a chymase inhibitor, and a therapeutic and / or prophylactic agent for the following diseases, each of which contains the compound represented by the general formula (I) or (II) as an active ingredient.
  • Hypertension congestive heart failure, cardiomyopathy, atherosclerosis, coronary artery disease, myocardial infarction, vascular restenosis after angioplasty or thrombolytic treatment, peripheral circulatory disorders, vasculitis, diabetic or non-diabetic Renal disease, pulmonary hypertension, bronchial asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, allergic rhinitis, atopic dermatitis, rheumatism, arthritis, cancer.
  • FIG. 1 is a diagram showing the flow from the ability of human heart chimase to obtain cDNA to the construction of pET-hchy.
  • novel acylsulfonamide derivative of the present invention is represented by the above general formula (I).
  • R 1 may have a substituent A represents a monocyclic group or a heterocyclic group.
  • the aryl group which may have a substituent represented by R 1 is a monocyclic or condensed polycyclic aromatic hydrocarbon ring group having 54 carbon atoms.
  • the heterocyclic ring of the heterocyclic group which may have a substituent represented by R 1 is a 5- to 14-membered saturated or unsaturated group containing one or more heteroatoms. It represents a single ring or a condensed polycyclic ring.
  • Preferable heterocycles include a Chiophane ring, a thiazlen ring, a fran ring, a pyran ring, an isobenzofuran ring, a chromene ring, and a xanthane ring.
  • C i C i which may have a substituent.
  • C 1 to C 1 which may have an alkyl group or a substituent.
  • C i C i which may have an alkoxy group or a substituent.
  • Rere may also be Rere to have a substituent Rere c, of ⁇ c 4 alkyl Cano main one capital group,
  • Alkyl amide cyano group of c, to c fi which may have a substituent
  • a sulfonamide group which may have a substituent
  • Examples of the hydrogen atom include a fluorine atom, a chlorine atom, a bromine atom, etc., and an alkyl group, an alkoxy group, an alkylthio group, an alkylsulfinyl group, an alkylsulfol group, an alkynoleamino group,
  • Examples of the alkyl chain portion in the alkylamino group, alkylcarbamate group, alkylcarnomoyl group, alkylamide group, and alkoxyalkyl group include a methyl group, an ethyl group, a propyl group, Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, Examples
  • Examples of the noroalkyl group include a trifluoromethyl group, a pentaphenylenoethyl group, a heptaphenylolpropinole group, a nonafluorobutyl group, and the like.
  • the noroalkoxy groups include trifluoromethyoxy group, difluoromethoxy group, 2,2,2—trifluoroethoxy group, 1,1,2,2—tetra La fluoroethoxy group and the like.
  • alkoxycarbonyl group examples include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbinole group, and a pentyloxycarbonyl group.
  • alkylamino group examples include an alkylamino group corresponding to the above alkyl group, such as a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, and the like.
  • examples of the killamino group include a dimethylamino group, a getylamino group, a dipropylamino group, and the like.
  • R 1 represents a phenyl group, a naphthyl group, a 1,2,3,4-tetrahydroquinoline ring, an indole ring, an imidazo [1,2-A] Pyrimidine ring, 3,4-methylenedioxyphenyl group, 1,3—benzodiazonole ring, 4,5,6,7—tetrahydro-12H—indazole ring, Phthalimide group, 3,4—dihydro 2 H—1,3—oxazine-1 4—one ring, and 3,4-dihydro 2 H—1,3—benzoxazine 1 4
  • One ring (the above groups or rings may each have a substituent) is preferably selected from the forces, and even if R 1 has a substituent
  • n represents an integer of 1 to 4, preferably 1 or 4, and more preferably 1.
  • n 0 or 1, and is preferably 0.
  • R 2 represents an aryl group which may have a substituent or a heterocyclic group which may have a substituent
  • R 2 and R 3 represent the following ( 1) or (2).
  • R 3 may be a naphthyl group which may have a substituent or a heterocyclic ring which may have a substituent.
  • R 2 is a heterocyclic group which may have a substituent
  • R 3 is a phenyl group, a naphthyl group or a heterocyclic group which may have a substituent.
  • R 2 represents an aryl group which may have a substituent
  • the aryl group may be the same monocyclic or condensed polycyclic as exemplified for R 1 .
  • examples thereof include an aryl group having 5 to 14 carbon atoms, and preferably a phenyl group or a naphthyl group.
  • the aryl group substituent include the aryl group substituents exemplified for R 1 , an amidino group, a carbamoyl group, a C 2 to C M alkyl labamoyl group, C, ⁇ C t .
  • a carboxyl group having an alkyl group or an alkenyl group, a phenolic hydroxyl group, a cyano group, and a heterocyclic group examples include an alkyl group and an alkenyl group in which a primary to tertiary carbon is substituted with a carboxyl group.
  • alkyl carbamoyl group examples include a methylcarbamoyl group, a ethynolecanol group, an n-propynolecarnoyl group, an i-propynolecarnoyl group, and an n-ptimeleca group.
  • C 1 to C 1 such as a phenol group, a cyclopropynolecarnoyl group, and a cyclopentylcarnoyl group.
  • heterocyclic group in the substituent of the aryl group described above includes:
  • R 3 is a naphthyl group which may have a substituent or a heterocyclic group which may have a substituent.
  • heterocyclic group examples include a benzochenyl group, a 1-thienylphenyl group, a 2-thiocyanylenyl group, a 2-benzophenyl group, a 2H-pyran-3-yl group, 2H—pyran-1-4—yl group, 2H—pyran-15—yl group, 2H—pyran-16—yl group, isobenzofuranyl group, 2H—chrome 1- 3 -yl group, 2H-chromin-4 -yl group, 2H-chromin-1-5-yl group, 2H-chromin-6-yl group, 2 H—Chrome 7—yl group, 2 H—Chrome 8—yl group, 2 H—Pyrrole 3 —yl group, 2 H—Pyro 1—4 Phenolic group, 2H—pyroquinone 1-5—yl / yl group, 3-pyridazinyl group, 4—pyridazinyl group, 1—indrid
  • 1,1 monooxide group syn—triadinyl group, as—triadinyl group, optionally substituted 2,3—dihydrobenzofuran ring, substituted May have a bearin ring, may have a substituent, and may have a substituent.
  • one two Three
  • Examples of the substituent of the naphthyl group or the heterocyclic group include the same groups as the substituent of R 1 .
  • R 2 is a heterocyclic group which may have a substituent
  • R 3 is a phenyl group, a naphthyl group or a heterocyclic group which may have a substituent. The case where it is a group will be described.
  • the heterocyclic group represented by R 2 includes 2 phenyl, 3 phenyl, benzothenyl, 1-thianthrenyl, 2 —thianthrenyl, 2 _furyl, 3 — Furyl group, 2—benzofuranyl group, 2H—pyran-13-yl group, 2H—pyran-14-yl group, 2
  • 3 Carboline 1 8 —yl group, 1-acrylidinyl group, 2 —acrylicinyl group, 3 —acrylicinyl group, 4 —acrylicinyl group, 9-acrylidinyl Group, 1 _ phenazinyl group, 2 — phenazinyl group, 1-phenothiazinyl group, 2 — phenothiazinyl group, 3 — phenothiazinyl group, 4 — phenothiazinyl group, 3 — flazanil group, 1 phenoxazinyl group, 2 — phenoxazinyl group, 3 — phenoxazinyl group, 4-phenyl Enoxazinyl group, 1—isochromanyl group, 3—isochromanyl group, 4-isochromanyl group, 6—isochromanyl group, 7—isochromyl group Romaninole, 8—Isochromanyl, 2—Ch
  • heterocyclic group for R 3 As the heterocyclic group for R 3 , the same groups as exemplified in the above (1) can be mentioned.
  • Examples of the substituent for the heterocyclic group of R 2 and R 3 include the same functional groups as those exemplified in the above (1).
  • R 3 is a phenyl group or a naphthyl group
  • the substituent may also be the same functional group as in the case of (1).
  • R 2 is a phenyl group, a pyridine group, a benzyl group, a piperazinyl group, an imidazolyl group, a benzimidazolyl group, a chenyl group, Li group, rather then preferred that the this selected pyrazolium Li Le group and thiazolium Li Le group (or groups or rings may have a substituent, respectively) force al, is La, R 2 Is a phenyl group which may have a substituent or has a substituent Particularly preferred is a pyridyl group which may be substituted or a phenyl group which may have a substituent.
  • R 3 represents a naphthyl group, a phenyl group, a thiadiazolyl group, a 3,4-ethylenedioxyphenyl group, a pyridyl group, a 1,2,3 , 4 — tetrahydroisoquinoline ring, 2H-1, 4 — benzoxazine-13 (4H) 1one 1-6 —yl group, 2,3 — dihydrobenzo [b ]
  • the acylsulfonamide derivative of the general formula (I) can be produced by a combination of known reactions suitable for the target compound.
  • the compound (Ia) of m 0 can be produced, for example, by the following method.
  • R 1 and R 2 have the same meanings as above, H a 1 is a nitrogen, and R is a lower alkyl.
  • the compounds (1) and (2) are condensed under appropriate conditions to obtain a compound (3), which is hydrolyzed by a usual method to obtain a compound (4).
  • the condensation reaction is carried out in a solvent such as dimethylformamide or tetrahydrofuran at 0 ° C in the presence of a base such as sodium hydride or hydrogen hydride.
  • the reaction is carried out under heating, preferably at around room temperature (20 ° C), for several hours to 24 hours, preferably for 1 hour to 6 hours.
  • a base such as a medium, between 180 ° C and 0 ° C, preferably around 180 ° C, for several hours to 24 hours, preferably for one hour.
  • the reaction may be performed for about an hour.
  • compound (3) is dissolved in a lower alcohol such as methanol or ethanol, and a suitable concentration, for example, 1N sodium hydroxide is added.
  • the compound (4) can be obtained by adding a base such as aqueous potassium hydroxide and reacting it under cooling and then heating, preferably at about room temperature for about 1 to 24 hours. .
  • a lower alcohol compound (5) such as methanol or ethanol is dissolved, and palladium black is added thereto.
  • the compound (3-a) can be obtained by reacting the mixture preferably at around room temperature for 0.5 to 24 hours, preferably for about 0.5 hours.
  • the solvent examples include tetrahydrofuran, getyl ether, dimethoxetane, methylene chloride, 1,2-dichloroethane, N, N-dimethylformamide, N-methylpyrrolidone or the like may be used, and for example, for activation of the carboxyl group,]., 1'-carbonyldiimidazole, thionyl chloride, and oxalyl chloride are used.
  • the base for example, N, N-dimethylamino pyridine, triethylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] pendez-17 —Yen good] j (You can use it.
  • the reaction that produces isocyanate from the carboxylic acid of the dangid product (4) is based on the H ofmann rearrangement (ES. Wa11 is, et. Al, Organic Reactions 3, 267 (1 9 4 6)) and the Lossen rearrangement (H.L.Ya1e, Chem.
  • hydroxamic acid derived from carboxylic acid (4) or an acyl derivative thereof can be treated with an appropriate base to give an isocyanate. Can be done.
  • the carboxyl group of (4) is converted to an acid chloride or mixed acid anhydride, and sodium nitride is reacted with the acid chloride to synthesize acylazide.
  • a carboxyl group is converted to an ester, hydrazide is formed by hydrazine treatment, and nitrous acid is reacted with the hydrazide to form an acylazide.
  • the carboxylic acid (4) is converted to diphenylphosphine azide (DP) in the presence of triethylamine. PA) and heated reflux in toluene.
  • DP diphenylphosphine azide
  • R represents an aryl group or a heterocyclic group which may have a substituent.
  • a heterocyclic group which may have a substituent represented by R " is a 5- to 14-membered saturated ring containing one or more heteroatoms. It represents a sum or unsaturated monocyclic or fused polycyclic ring.
  • Preferred heterocycles include a thiophene ring, a thienslen ring, a franne ring, a pyran ring, an isobenzofuran ring, a chromene ring, a xanthen ring, and a pheno ring.
  • C i C i which may have a substituent. May have an alkyl group or a substituent.
  • CiCi which may have an alkoxy group or a substituent.
  • Nono b ⁇ / Rekiru group substituent may Rere be to have a ci ⁇ C 4, Les to have a substituent, which may be c, have the Nono b Anore co key sheet group substituent of ⁇ c 4 Anore breath shea force / repurchase Le group which may also be C 2 ⁇ C 8
  • Anoreki Luke Le Bo second also good Rere CC ⁇ ⁇ to Le based on
  • a sulfonamide group which may have a substituent
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and an alkyl group, an alkoxy group, Alkyl chain part in alkylthio group, alkynyl sulfide group, phenol phenol group, phenol phenol group, dialkyl phenol group, alkoxy alkyl group, etc.
  • a straight-chain or branched-chain alkyl group such as a pentyl group, a hexyl group, an isohexyl group, a heptyl group, an octyl group, a nonyl group and a decyl group.
  • Examples of the noroalkyl group include a trifluoromethyl group, a pentaphenylolethizole group, a hepta-funorolopropynole group, and a nonaf / reolobutyl group.
  • the noroalkoxy groups include trifluoromethyoxy group, difluoromethyoxy group, 2,2,2—trifluoroethoxy group, 1,1,2,2—tetra Fluoroethoxy group and the like.
  • alkoxycarbyl group examples include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycanolecarbonyl group, a pentyloxycarbonyl group, and the like.
  • alkylamino group examples include an alkylamino group corresponding to the above alkyl group, such as a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, and the like.
  • dialkylamino group examples include a dimethylamino group, a getylamino group, and a dipropylamino group.
  • aryl groups such as aryl groups, aryl olenoles honinole groups and aryl olecanoleboninole groups include, for example, phenyl and naphthyl groups. Is mentioned.
  • R represents an indole ring, a naphthyl group or a phenyl group.
  • R represents an indole ring, a naphthyl group or a phenyl group.
  • a 3,4-methylenedioxyphenyl group (the above groups or rings may each have a substituent), and more preferably has a substituent.
  • Especially preferred is a good naphthyl group
  • X represents a CH atom group or an N atom, and particularly preferably a CH atom group.
  • Y is one O —
  • Y is a single bond, one NH, or — (CH 2 ) p ′ (p ′ represents 1, 3, 4, or 5), and furthermore, the Y force S— ( It is particularly preferred that CH 2 ) p '— ( ⁇ ' represents 3, 4 or 5).
  • m 1 represents 0 or 1, and is preferably 0.
  • n ' is an integer from 0 to 2
  • ⁇ ' indicates an integer from 0 to 6.
  • R 5 ′ may have a substituent, and may be a phenyl group or a 3-pyridyl group.
  • heterocyclic ring which may have a substituent (excluding 3-substituted monopyridine ring), or (ff) —shows an amino acid residue which may have a substituent.
  • heterocyclic group examples include 2-phenyl, 3-phenyl, benzophenyl, 1-thienyl, 2-dithienyl, 2-furyl, 3 — furyl group, 2 benzofuranyl group, 2 H — pyran-1 3 —yl group, 2 H — pyran-1
  • Examples include a 1,1-dioxide group, syn—triazinyl group, and as—triazinyl group.
  • R ′′ represents a hydrogen atom, an alkyl group, an amino group, a carboxyl group, a cyano group, a C (NH) —NH 2 group, —S (O) n′—pyridyl Group (excluding 3-position monosubstituted pyridyl group), one CO—piperazinyl group, one NHCOO—alkyl group one COO—benzyl group, one N— (hydrogen atom or cycloalkyl group) one CO— ( An alkylphenyl group, an alkynole group, a phenyl group, a cycloalkyl group, a heterocyclic ring, or an amino acid residue), or an —NH-cycloalkyl group (the above groups or rings are substituents, respectively)
  • R 2 ' represents a cyano group or one NR "COR 5 /
  • R 4 / represents a hydrogen atom.
  • R 3 / is a aryl group which may have a substituent or a heterocyclic group which may have a substituent.
  • heterocyclic group in addition to those described for R 2 / , a 3-pyridyl group and the like can be mentioned.
  • Examples of the substituent for the aryl group and the heterocyclic group include those described for R 2 / .
  • R 3 / is rather to preferred is that it is a good Ia Li Lumpur group optionally have a substituent, R 3 / good even though have a substituent Hue It is particularly preferable that the compound is a naphthyl group which may have a substituent or a substituent.
  • the substituent has the same meaning as (1) in (d) and () in (d).
  • amino acid residue which may have a substituent is shown.
  • the amino acid of the amino acid residue in this case includes alanine and aramin.
  • Luginin, Asuno Lagin, asparaginic acid, cystine, glutamin, glutamic acid, glycine, histidine, isoloicin, lysin, resin, Examples include Jhionin, Phenyl / Rarelanin, Proline, Serine, Threonine, Triptophan, Tyrosine, Nocline, and so on.
  • (c) may have a substituent—indicates an alkyl group of (C i—C 4 );
  • Biphenyl-1 Carboxylic acid [6— (Naphthalene-2—yl) -17—Oxo-17— (T / Ren-4—Sulfoninolea mino) Heptyl] ami
  • the acylsulfonamide derivative of the general formula (II) can be produced by a combination of known reactions suitable for the target compound.
  • the following are examples of typical methods for synthesizing compounds, but are not limited to the methods described below.
  • R 1 ′ and R 2 / have the same meanings as described above, Ha 1 is halogen, and R ′ is lower alkyl.
  • the compounds (1) 'and (2)' are condensed under appropriate conditions to obtain a compound (3) ', which is hydrolyzed by an ordinary method.
  • the condensation reaction is carried out in a solvent such as dimethyl honolemamide, tetrahydrofuran, etc. in the presence of a base such as sodium hydride and hydrogenation power at 0 ° C.
  • the reaction is carried out at a temperature, preferably around room temperature (20 ° C), for several hours to 24 hours, preferably for 1 hour to 6 hours.
  • __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ either media such as furan, dioxane, etc. in the presence of bases such as pyramid and lithium bis-trimethylsilylamide.
  • the reaction may be carried out at C to 0 ° C, preferably around 178 "C, for several hours to 24 hours, preferably for one hour to about six hours.
  • Compound (3) ' is dissolved in a lower alcohol such as ethanol or ethanol, and a suitable concentration, for example, 1N sodium hydroxide or aqueous sodium hydroxide is used.
  • the compound (4) ′ is obtained by adding the base and reacting the mixture under cooling to heating, preferably at about room temperature for about 1 hour to 24 hours.
  • the solvent examples include tetrahydrofuran, diethyl ether, dimethoxetane, methylene chloride, and 1,2-dichlorobenzene.
  • the same solvent as described for the above-mentioned compound (I-a) may be used.
  • the carboxyl group for example, 1,1′-carboerdiimidazole or the above-mentioned compound (Ia)
  • the same activator as described in Ia) can be used.
  • the base for example, 1,8-diazabicyclo [5.4.0] endez-17-ene can be suitably used.
  • bromide or chlorine is reacted with primary amide derived from (4) 'in an alkaline hydroxide. If you do so, you will be able to give an isocyanate via N-Chamid Amido.
  • It can be formed by heating and refluxing P A) in toluene.
  • the compound (5) ′ is dissolved in a lower alcohol such as methanol or ethanol, and an acid such as hydrogen chloride is allowed to act on the solution, and the mixture is heated to 0 ° C.
  • a lower alcohol such as methanol or ethanol
  • an acid such as hydrogen chloride
  • the compound (6) ' is reacted at about room temperature, preferably for about 1 to 24 hours, to obtain a compound (7) by reacting with ammonia, ammonium carbonate, or the like.
  • 'Is obtained.
  • acylsulfonamide derivatives of the general formulas (I) and (II) have a selective inhibitory action on chymase and are therefore useful for treatment and prevention of various diseases involving chymase.
  • hypertension congestive heart failure, cardiomyopathy, arteriosclerosis, coronary artery disease, myocardial infarction, vascular restenosis after angioplasty or thrombolytic treatment, peripheral circulatory disturbance, vasculitis, diabetic or Non-glycuric kidney disease, pulmonary hypertension, bronchial asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, allergic rhinitis, atopic dermatitis, rheumatism, arthritis, cancer and the like.
  • the compound having the structure defined by the present invention or a pharmaceutically acceptable salt thereof, and hydrates and solvates thereof are used as the active ingredient.
  • Parenteral administration includes, for example, intravenous, subcutaneous, intramuscular, transdermal, rectal, nasal, and intraocular administration.
  • the ratio of the active ingredient to the carrier component can be varied between 1 and 90% by weight.
  • Examples of the dosage form for oral administration include tablets, pills, granules, powders, solutions, syrups, capsules and the like.
  • Pharmaceutical preparations such as excipients, binders, disintegrants, etc. It can be molded by an ordinary method using a carrier that is acceptable to the manufacturer. Pills, granules, and powders can be molded by ordinary methods using excipients and the like as in the case of tablets.
  • Liquids and syrups can be molded by ordinary methods using glycerin esters, alcohols, water, vegetable oils, and the like.
  • the capsule can be molded by filling granules, powders, or liquids into capsules such as gelatin.
  • Intravenous, subcutaneous, or intramuscular administration of parenteral drugs can be administered as an injection.
  • a compound having a structure defined by the present invention or a pharmaceutically acceptable salt thereof is dissolved in a water-soluble solution such as physiological saline or propylene glycol, Dissolving in water-insoluble liquids composed of organic esters such as polyester, polyethylene glycol, vegetable oil, and the like.
  • transdermal administration for example, it can be used as an ointment, a cream and the like. That is, the compound defining the structure in the present invention or a pharmaceutically acceptable salt thereof is mixed as an ointment with fats and oils or petrolatum to form a cream. Alternatively, it can be mixed with an emulsifier and molded.
  • suppositories can be prepared using gelatin soft capsules or the like.
  • intranasal administration it can be used as a preparation comprising a liquid or powdery composition.
  • a base of the liquid agent water, saline, phosphate buffer, acetate buffer, and the like are used, and further, a surfactant, an antioxidant, a stabilizer, a preservative, and a viscosity-imparting agent are included. You may go out.
  • the powder base include, for example, water-soluble polyacrylates, cellulose lower alkynoleate, polyethylene glycol, vinylolenate, and phenol.
  • Water-absorbing materials such as dong, amirose, or examples thereof include poorly water-soluble substances such as celluloses, proteins, gums, and crosslinked vinyl polymers, and these may be used as a mixture. Further, an antioxidant, a coloring agent, a preservative, a preservative, a preservative, and the like may be added to the powder.
  • aqueous or non-aqueous eye drop In the case of intraocular administration, it can be used as an aqueous or non-aqueous eye drop.
  • aqueous eye drops sterilized purified water, physiological saline, or the like can be used as a solvent.
  • a suspending agent such as a surfactant and a polymer thickener.
  • a solubilizing agent such as an activator may be added for use as a solubilizing ophthalmic solution.
  • a non-aqueous ophthalmic solution a non-aqueous solvent for injection can be used as a solvent, and it can be used as a non-aqueous suspension ophthalmic solution.
  • the compound having the structure defined by the present invention or a pharmaceutically acceptable salt thereof is used as a solution or suspension with commonly used pharmaceutical excipients.
  • administration is carried out using an inhalation aerosol spray.
  • the compound having the structure defined by the present invention or a pharmaceutically acceptable salt thereof can be made into a dry powder form and administered using an inhaler or the like which is brought into direct contact with the lung.
  • These various drugs may include pharmaceutically acceptable carriers, such as isotonic agents, preservatives, preservatives, preservatives, wetting agents, buffers, emulsifiers, dispersants, and stabilizers, as necessary. Can be added. In addition, these preparations can be sterilized by treating them with a bactericide, filtration using a retention filter, heating, irradiation, etc., as necessary. And can be. Alternatively, a sterile solid preparation can be manufactured and dissolved or suspended in an appropriate sterile solution immediately before use.
  • pharmaceutically acceptable carriers such as isotonic agents, preservatives, preservatives, preservatives, wetting agents, buffers, emulsifiers, dispersants, and stabilizers, as necessary. Can be added. In addition, these preparations can be sterilized by treating them with a bactericide, filtration using a retention filter, heating, irradiation, etc., as necessary. And can be. Alternatively, a sterile solid
  • the clinical dose depends on the type of disease, route of administration, patient condition, age, It is desirable to consider the gender, body weight, etc., but when administering orally to adults, administer 1 to 100 mg / day in 1 to several divided doses I do. In the case of parenteral administration, 0.1 mg to 100 mg / day is usually administered in a single dose or several doses, although it varies greatly depending on the administration route.
  • the method of obtaining the chimase used in the pharmacological test is shown as a reference example.
  • compound N 0. Is the corresponding compounds of Table one 1 wherein N o..
  • cDNA of human heart chimase was obtained by the PCR (polymeleshasechanhaiin) method.
  • the sequence of the synthetic oligonucleotide DNA used in the reaction is as follows.
  • This primer sequence was determined with reference to the accession number M691336 of GenBank.
  • lul of cDNA derived from human heart, 2.5 ⁇ M dATP, 2.5 ⁇ M d TTP, 2.5 ⁇ M d GTP, 2.5 ⁇ M dCTP were 2 ⁇ l and 2 ⁇ l.
  • 0 uMMY81 1 is 5 ul
  • 20 uMMY82 is 5 ul
  • Taqpolymerase (Perkin-Elmer) is lul, reaction buffer attached to Taqpolymerase.
  • the amplified DNA is registered as GenBank accession number M691336, and the amplified DNA sequence is numbered 16 to 759. It was confirmed that it was a DNA encoding the protein of human heart chimase, including the region between the two.
  • a vector for expressing the human chymase gene in Escherichia coli was constructed.
  • PCR was performed using the pCRII-hChy vector obtained in Reference Example 1 as a type I, and Sp6 and MY119 as primers, respectively.
  • the sequences of the synthetic oligonucleotides DNA primers Sp6 and MY119 are as follows.
  • the MY119 contains the nucleotide sequence necessary for amplifying the human chimney gene.
  • SspI restriction enzyme cleavage site an amino acid sequence that is cleaved by the factor Xa protease (IEGR: isolysin, glutamate, and glycin) And arginine) have been added.
  • the approximately 800 bp DNA fragment amplified by PCR is treated with the restriction enzymes SspI and EcoRI, and then directly treated with the restriction enzymes EheI and EcoRI.
  • Chained p PROE A ligation reaction was performed with X-1 vector (manufactured by Life Techno ogies). When the obtained construct was subjected to sequence analysis of the protein translation region using a fluorescent DNA sequencer, it was derived from pPROEX-1 vector at the N-terminal side. Peptides (including the translation initiation methionine, six consecutive histidine residues, and the rTEV protease cleavage sequence) were placed at the C-terminal end by the factor Xa protease.
  • the pPRO-hChy vector is cleaved into two DNA fragments when treated with the restriction enzymes NcoI and EcoRI.
  • the smaller, approximately 770 bp fragment was purified by agarose gel electrophoresis and linearized by treatment with the restriction enzymes NcoI and EcoRI to form pET24D vector.
  • a ligation reaction was performed with a tar (manufactured by Novagen). Sequence analysis of the protein translation region of the resulting construc- tion using a fluorescent DNA sequencer revealed that the fusion protein was exactly the same as pPRO-hChy. Was confirmed to be a DNA sequence to be translated. We called this vector pET — hChy.
  • Fig. 1 shows the flow from the ability of human heart chimase to obtain cDNA to the construction of pET-hChy.
  • a peptide having the sequence of N-CVGNPRKTKSAFKGDSGG-C (SEQ ID NO: 7 in the sequence listing) is synthesized and bound to KLH (keyhole 1 impethemocyanin) via MBS (m-ma1 eimidobenzoyl——hydroxysuccinimideester).
  • KLH keyhole 1 impethemocyanin
  • MBS m-ma1 eimidobenzoyl——hydroxysuccinimideester.
  • This complex is injected into female Japanese White Herons with complete Freund's adjuvant or incomplete Freund's adjuvant.
  • the resulting antiserum was called V80.
  • Panafirm Laboratories Ltd. was requested to synthesize the peptide and obtain antiserum.
  • the pPRO-hChy vector shown in Reference Example 2 was introduced into the E. coli BL21 strain Selective culture was performed on LB (Luria-Bertani medium) agarose plate containing ampicillin.
  • the pET-hChy vector shown in Reference Example 3 was introduced into the E. coli BL21 (DE3) strain concomitant cells, and the LB agarose spray containing 30 ug / ml kanamycin was introduced. The cells were selectively cultured.
  • coli cloned on the plate contains lOOug Zml of ampicillin or SOug Zml of kanamycin; Shaking culture was performed at 37 ° C in LB medium. After 12 hours, the culture was added to a new 900 ml LB medium containing 100 ug / ml ampicillin or 50 ug / ml kanamycin. And the shaking culture was continued at 37 ° C. 6 0
  • Escherichia coli grown in large amounts in liquid medium was 40000 Xg, 20 min, 4. C. Precipitate by centrifugation in C, and mix 100 ml of the binding buffer, 5 mM imidazole, 0.5 M sodium chloride, and 20 mM buffer. The suspension was resuspended at 4 ° C. in an aqueous solution (PH 7.9)) and precipitated again by centrifugation at 4 ° C. for 4 minutes at 40000 ⁇ g. The recovered E. coli was resuspended in a 100 ml binding buffer, and a sonicator (TAITEC, u1trason 1 cator) was output. 0, the cycle was set to 40% BX and crushed at 4 ° C.
  • TITEC a sonicator
  • the sonicated sample was centrifuged at 2000 xg for 20 minutes at 4 ° C to form a supernatant (called supernatant) and a precipitate (called precipitate 1).
  • the supernatant was further centrifuged at 1200 xg for 20 minutes at 4 ° C to separate into a supernatant (called supernatant supernatant 2) and a precipitate (called precipitate 2).
  • Precipitate and Precipitate 2 were combined together, 100 ml of binding buffer containing 6 M urea was added, and the mixture was completely resuspended in a solution under the same conditions for 1 hour. Incubated on ice.
  • the solution was subjected to JS 'at 1200 xg for 20 min at 4 ° C and separated into a supernatant (called supernatant 3) and a precipitate (called precipitate 3).
  • the minutes are as follows.
  • a nickel-on-chelate column manufactured by Novagen
  • histidine guaninoic acid system IJ was used.
  • the usual binding buffer, washing buffer, and elution buffer were used, but when purifying from supernatant 3 containing urea.
  • 6 M urea was added to each of the knockers.
  • pre-treat ram resin using 20 ml of supernatant and 1 ml of resin volume
  • 5 times the volume of 50 mM nickel sulfate aqueous solution and bind 3 times the binding buffer. Equilibrated with buffer.
  • the supernatants 2 and 3 were filtered through a 0.45 ⁇ m pore-size Vinoreta (manufactured by Mi11ipore), and then loaded onto a column. After loading the sample, the column contains 10 volumes of binding buffer, 6 volumes of washing buffer (20 mM imidazole, 0.5 M chloride). Wash with sodium, 20 mM Tris-HCl buffer (pH 7.9)), and elute with a 5-fold volume of elution buffer (1 M imidazole, 0.5 M). Elution was performed with sodium chloride (M) and 20 mM Tris-HCl buffer (pH 7.9). The eluate was collected as 1.25 ml fractions and stored at 120 ° C. In which fraction the fusion protein had been eluted was analyzed by Western blotting using an anti-human lipase antibody (V80).
  • V80 anti-human lipase antibody
  • the eluate When purified from supernatant 3, the eluate contains 6 M urea. Prevent protein precipitation as much as possible and purify protein This urea was removed under conditions where the quality retained enzyme activity.
  • the eluate was diluted 10-fold with a binding buffer containing 6 M urea and 0.1% triton X—100, and a solution of 4) was prepared as shown below. (2 L of dialysate was used for 50 ml of the diluted sample) and dialyzed in this order at 4 ° C for 12 hours for a total of 48 hours.
  • Tris-HCl buffer pH 8
  • Triton X—100 0.1% Triton X—100
  • ImM ImM after dialysis
  • the sample was centrifuged at 12 and OOOX g at 4 ° C for 20 minutes to remove precipitates, and further filtered through a 0.22 um filter. It was concentrated about 10-fold using Centricone 10 (manufactured by Amicon). The protein concentration of the concentrated solution was quantified by using a protein assay (manufactured by Biorad).
  • the chima- zeta protein translated in the cell has a signal peptide sequence of 19 amino acid residues at the N-terminal side.
  • the signal peptide region is cleaved, and glycine and glutamate diamino acids are added to the N-terminus of the mature form. It becomes a pro-form with residues.
  • the pro-form does not have protease activity, and any protease may cause this 2-amino acid pro-sequence to occur. Has been found to be processed and converted to an active mature form. .
  • the mature human chymidase expressed in Escherichia coli herein has six consecutive histidine residues on the N-terminal side of the mature human chymidase.
  • the factor Xa D anex Biotek.
  • Angiotensin I has been known to be degraded by activated chimase into angiotensin II and a histidine-monolysin dipeptide.
  • the Factor Xa-treated chymase sample was added to a 0.77 mM ammonium salt solution in 15 OmM sodium borate-sodium tetraborate buffer (pH 8.5). Incubation with Incin I was performed at 37 ° C for 2 hours. This protease reaction was carried out by reversed-phase chromatography (column: Wide — Porte Octadecyl (C18) 5 umstandardanalytical 4.6 X 250 mm (J.T.
  • the reaction (1) was evaluated with multiple samples, and the reaction and measurement were performed using a microplate to quantify the efficiency of the reaction. After applying 9% trichloroacetic acid, centrifuge for 5 minutes at 10, OO O rpm. Collect the supernatant, add 0.74 N sodium hydroxide and 0.77% orthophthalaldehyde, and react at room temperature (25 ° C) for 5 minutes. 2.6 N hydrochloric acid was added, the mixture was excited at 340 nm, and the fluorescence intensity at 490 nm was measured. as a result,
  • Reference Example 1 unit is the enzyme activity of chimase, which produces 1 pmo 1 of angiotensin II from angiotensin I per second
  • the substrate was ImM methoxine succinyl / lea noregininole 1-pro linoleic tyro-sinole 1 / lanitroa 2 40 ⁇ l of lid (CHROMOGENIX) was added and reacted at room temperature. The change with time of the absorbance at 405 nm was measured, and the inhibitory activity was examined. The results are compared to the C hymotrypsin IC 5Q value (5
  • the concentration of the test compound required for 0% inhibition was expressed as ⁇ )).
  • THF Tetrahydrofuran 0.74 g (2.5 mmo 1) in 10 ml of 2- (3,4-dichlorophenyl) 13_ Dissolve phenylpropionic acid and add 0.41 g (2.
  • Diazabicyclo [5.4.0] _ 7 Indecene was added and the mixture was heated under reflux for 1 hour. A 10% aqueous solution of citric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. As a sodium salt, 0.68 g (yield 56%) of the title compound was obtained as a white solid.
  • the reaction was stopped with 100 ml of a 10% aqueous solution of citric acid and extracted three times with ethyl acetate.
  • the organic layer was combined, washed with saturated saline, dried over anhydrous sodium sulfate, the solid residue was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the concentrated residue was suspended and washed with a mixed solvent of ethyl acetate (30 ml) and hexane (60 ml), filtered, and the filtrate was further dissolved by heating with ethyl acetate (100 ml). Thereafter, about 50 ml of ethyl acetate as a solvent was distilled off.
  • the title compound was obtained as a white solid 0.60 g (yield 51%) in the same manner as in Example 3 using 5 mM 0 1) of 2 -naphthalenesulfonamide.
  • the mixture was stirred at 78 ° C for 5 hours. Then, 4.6 m 1 (38.5 mmo 1) of benzyl bromide was added dropwise, and the mixture was stirred at 178 ° C for 1.5 hours and then at 25 ° C for 2 hours. .
  • the reaction solution was poured into ice water and acidified with hydrochloric acid, and then extracted with ethyl ether. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 150 ml of ethanol, and 90 ml (90 mmol) of an aqueous solution of IN sodium hydroxide was added thereto, followed by stirring at 80 ° C for 2 hours.
  • Example 1 was obtained from 0.28 g (1.0 mmol) of this compound and 0.21 g (10 mmo 1) of 2-naphthalenesulfonamide. In the same manner as in the above, 0.15 g (yield 32%) of the title compound was obtained as a white solid.
  • the title compound was white from 800 mg (2.885 mmo 1) and 597.9 mg (2.885 mmol) of 2_ naphthalenesulfonamide of this compound. 775.4 mg (yield 57.6%) was obtained as a solid.
  • the title compound was obtained as a white solid from a _4-sulfonamide as a white solid (277 g, yield 83.2%).
  • Example 2 As in Example 1, 0.30 g (1.1 mmol) of 2— (2-naphthyl) -13-phenylpropionic acid and 0.25 g (1.1 mmol) of 5 , 7-Dimethyl-1- [1,2,4] triazole [1,5—a] pyridin-12-sulfonamide gives 0.3% of the title compound as a white solid. 3 g (62% yield) was obtained.
  • the reaction was stopped with 40 ml of a 10% aqueous solution of citric acid. After extraction with ethyl acetate three times, the extract was washed with distilled water and saturated saline. After drying over anhydrous sodium sulfate, the solid residue is filtered off, the filtrate is concentrated under reduced pressure, and the concentrated residue is purified by silica gel chromatography (hexane-ethyl acetate). ,
  • Example 41 In the same manner as in Example 1, 2.07 g (10.35 mmo 1) of 2—methyl naphthyl acetate and 2.0 g (10.86 mmo 1) of 4—chloro were used. 1.7162 g (yield 53.2%) of an intermediate a having the following structure was obtained from methyl 1-2-methylthiazole hydrochloride.
  • reaction mixture was poured into 30% by weight of a 10% by weight aqueous solution of citric acid to precipitate a yellow solid.
  • the yellow solid was collected by filtration, suspended in getyl ether-methanol, filtered, and dried by heating at 80 ° C.
  • the title compound was obtained as a white solid in an amount of 1.35588 g (312 mmol, yield 62.0%).
  • Chymase 1 C 50 0.27

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Abstract

L'invention concerne des dérivés d'acylsulfonamide des formules (I) et (II). Elle concerne également des inhibiteurs de la chymase et des médicaments thérapeutiques et/ou préventifs contre l'hypertension ou analogue contenant ces dérivés en tant que principe actif.
PCT/JP2000/006695 1999-09-30 2000-09-28 Derives d'acylsulfonamide WO2001023349A1 (fr)

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WO2004113316A1 (fr) * 2003-05-20 2004-12-29 Genentech, Inc. Benzofuranes inhibiteurs du facteur viia
EP1426360A4 (fr) * 2001-09-12 2006-04-12 Kaken Pharma Co Ltd Derive d'acide 2-phenyle-3-heteroarylpropionique ou son sel et medicaments le contenant
US7482462B2 (en) 2001-10-05 2009-01-27 Amarylla Horvath Acylsulfonamides as inhibitors of steroid sulfatase
WO2016132483A1 (fr) * 2015-02-18 2016-08-25 学校法人福岡大学 Inhibiteur de chymase humaine et médicament pour prévenir et traiter une maladie associée à une activité de chymase humaine
JP2020537657A (ja) * 2017-10-17 2020-12-24 ノバルティス インフラマソーム リサーチ，インコーポレイテッド Ｎｌｒｐ活性に関連する病態を治療するためのスルホンアミド及びその組成物
US11518757B2 (en) 2017-12-18 2022-12-06 NodThera Limited Sulphonyl urea derivatives as NLRP3 inflammasome modulators
US12054461B2 (en) 2019-06-12 2024-08-06 NodThera Limited Sulfonylurea derivatives and uses thereof

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EP0513533A2 (fr) * 1991-04-26 1992-11-19 Bayer Ag Dérivés substitués hétérocycliques de l'acide phenyl acétique, procédé pour leur fabrication et leur application comme médicaments
WO1995003295A1 (fr) * 1993-07-20 1995-02-02 Merck & Co., Inc. Antagonistes de l'endotheline
WO2000041531A2 (fr) * 1999-01-13 2000-07-20 Genentech, Inc. Inhibiteurs de la serine protease

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US5389682A (en) * 1992-09-18 1995-02-14 Warner-Lambert Company Agents acting at cholecystokinin receptors
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WO2016132483A1 (fr) * 2015-02-18 2016-08-25 学校法人福岡大学 Inhibiteur de chymase humaine et médicament pour prévenir et traiter une maladie associée à une activité de chymase humaine
JP2020537657A (ja) * 2017-10-17 2020-12-24 ノバルティス インフラマソーム リサーチ，インコーポレイテッド Ｎｌｒｐ活性に関連する病態を治療するためのスルホンアミド及びその組成物
JP7157804B2 (ja) 2017-10-17 2022-10-20 ノバルティス アーゲー Ｎｌｒｐ活性に関連する病態を治療するためのスルホンアミド及びその組成物
US11718631B2 (en) 2017-10-17 2023-08-08 Novartis Ag Sulphonamides and compositions thereof for treating conditions associated with NLRP activity
US11518757B2 (en) 2017-12-18 2022-12-06 NodThera Limited Sulphonyl urea derivatives as NLRP3 inflammasome modulators
US12012397B2 (en) 2017-12-18 2024-06-18 NodThera Limited Sulphonyl urea derivatives as NLRP3 inflammasome modulators
US12054461B2 (en) 2019-06-12 2024-08-06 NodThera Limited Sulfonylurea derivatives and uses thereof

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