WO1999067207A1 - Derives de naphtalenesulfonamide et medicaments les contenant - Google Patents

Derives de naphtalenesulfonamide et medicaments les contenant Download PDF

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Publication number
WO1999067207A1
WO1999067207A1 PCT/JP1998/002841 JP9802841W WO9967207A1 WO 1999067207 A1 WO1999067207 A1 WO 1999067207A1 JP 9802841 W JP9802841 W JP 9802841W WO 9967207 A1 WO9967207 A1 WO 9967207A1
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WO
WIPO (PCT)
Prior art keywords
salt
derivative
naphthalenesulfonamide
amino
compound
Prior art date
Application number
PCT/JP1998/002841
Other languages
English (en)
Japanese (ja)
Inventor
Hiroyoshi Hidaka
Mitsuhiko Ikura
Hiroshi Muramatsu
Tsutomu Inoue
Isao Umezawa
Tomomitsu Sasaki
Original Assignee
Hiroyoshi Hidaka
Mitsuhiko Ikura
Hiroshi Muramatsu
Tsutomu Inoue
Isao Umezawa
Tomomitsu Sasaki
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP9129497A priority Critical patent/JPH10316649A/ja
Application filed by Hiroyoshi Hidaka, Mitsuhiko Ikura, Hiroshi Muramatsu, Tsutomu Inoue, Isao Umezawa, Tomomitsu Sasaki filed Critical Hiroyoshi Hidaka
Priority to PCT/JP1998/002841 priority patent/WO1999067207A1/fr
Publication of WO1999067207A1 publication Critical patent/WO1999067207A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • 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
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups

Definitions

  • the present invention relates to a naphthene len'sulfonamide derivative which is useful as a medicament for cardiovascular diseases because it inhibits the activity of calmodulin.
  • Calmodulin is a protein widely distributed in eukaryotic cells. When calcium binds, it undergoes a structural change, which binds to an inactive enzyme and causes activation. As a result, calmodulin is involved in platelet aggregation-release reaction, smooth muscle contraction, synthesis and release of neurotransmitters, and cyclic nucleotide metabolism.
  • substances that inhibit the activity of calmodulin can be agents for cardiovascular diseases, such as platelet aggregation inhibitors, antihypertensives, and vasodilators, which differ from the mechanism of action of conventional drugs.
  • cardiovascular diseases such as platelet aggregation inhibitors, antihypertensives, and vasodilators, which differ from the mechanism of action of conventional drugs.
  • examples of the calmodulin inhibitor include compounds described in JP-A-52-25742.
  • an object of the present invention is to provide a new compound having excellent calmodulin inhibitory activity.
  • the present inventors have conducted intensive studies and as a result, have found that a compound represented by the following general formula (1) has excellent calmodulin inhibitory activity and is useful as a medicament such as an agent for preventing or treating cardiovascular diseases.
  • the present invention was found to be useful, and the present invention was completed. That is, the present invention provides the following general formula (1)
  • R -NN - or -HN- A-NH- (wherein, A is a divalent hydrocarbon group or a 2 carbon atoms 8 - (CH 2) 2 -0- (CH 2) 2 X] and X 2 are the same or different and represent an enzyme atom or two hydrogen atoms, Y represents a hydrogen atom or a halogen atom, and n represents a number of 2 to 7. ]
  • the present invention also provides a drug, a calmodulin activity inhibitor, a prophylactic / therapeutic agent for cardiovascular diseases, and an antiplatelet drug containing the naphthene sulfone amide derivative (1) or a salt thereof as an active ingredient.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the naphthalene sulfonamide derivative (1) or a salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides the use of the naphthene sulfone amide derivative (1) or a salt thereof as a medicine, a calmodulin activity inhibitor, a prophylactic or therapeutic agent for cardiovascular diseases, and an antiplatelet agent.
  • the present invention still further provides a method for treating a cardiovascular disease, which comprises administering an effective amount of a naphthalenesulfonamide derivative (1) or a salt thereof.
  • the divalent hydrocarbon group having 2 to 8 carbon atoms represented by A is aliphatic.
  • aromatic groups include ethylene groups and tri groups.
  • a linear or branched alkylene group such as a methylene group, a propylene group, a tetramethylene group, a butylene group, a pentamethylene group, a hexamethylene group, a heptyne methylene group and an octamethylene group is preferred.
  • the aromatic group a phenylene group and a xylylene group are preferable.
  • X 1 and X 2 Represents an oxygen atom or two hydrogen atoms, which may be the same or different.
  • the halogen atom represented by Y include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among them, a chlorine atom is preferable.
  • n is a number of 2 to 7, but 4 to 6 is preferable. .
  • the salt of the compound (1) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, but inorganic hydrochloric acid such as hydrochloride, sulfate, fumarate, succinate, oxalate, etc. Organic acid salts such as acetates are exemplified.
  • the compound (1) of the present invention also includes solvates such as hydrates.
  • the compound (1) of the present invention can be produced, for example, according to the following production methods 1 to 3.
  • the halogenononaphthalenesulfonyl compound (2) is reacted with an amino acid (3) in a suitable solvent to give a compound (4).
  • the compound (4) is halogenated with thionyl chloride or the like.
  • the compound of the present invention (111) can be obtained by reacting the compound with a diamine (6).
  • the compound (1-2) of the present invention can be obtained by catalytic reduction of the compound (111) or reduction using a reducing agent such as a borane methyl sulfide complex.
  • the formula is preferably catalytic reduction in the (l-2) two hydrogen atoms both X 1 and X 2 in, one of X 1 and X 2 only in the two hydrogen atoms It is preferable to use a reducing agent such as a borane methyl sulfide complex.
  • the compound (8) is obtained by reacting the compound (6).
  • the compound (9) By removing the protecting group of the amino group of the compound (8) to obtain the compound (9), and reacting the compound (9) with the halogenonaphthalene sulfonyl compound (2), the compound of the present invention (111) C)
  • the compound (111) can be converted to the compound (112) in the same manner as described above.
  • the compound (12) is obtained by reacting the compound (11) with a halogenone or a diamine (11), and after removing the amino protecting group of the compound (12), the compound is reacted with the halogenonaphthalenesulfonyl compound (2). Thus, the present compound (113) is obtained.
  • Compound (1) can be used in various dosage forms together with pharmaceutically acceptable carriers according to standard methods. It can be a drug composition.
  • the administration form is not particularly limited and can be appropriately selected according to the purpose of treatment. For example, it may be any of a pharmaceutical preparation, an injection, a suppository, and the like. Can be manufactured.
  • an excipient When preparing an oral solid dosage form, add an excipient, and if necessary, a binder, disintegrant, lubricant, coloring agent, flavoring agent, flavoring agent, etc. to compound (1), and then use a conventional method. Tablets, coated tablets, granules, powders, capsules and the like can be manufactured.
  • excipients may be those commonly used in the art, for example, excipients such as lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, polyol, Microcrystalline cellulose, silicic acid, etc.
  • binders are water, ethanol, prano, wool, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxydipropyl Starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc .; disintegrants are dried starch, sodium alginate, powdered sodium, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid Lubricants such as monoglycerides and lactose Is then purified talc, stearic emissions salt, borax, polyethylene glycol, sucrose as a flavoring agent, orange peel, click E phosphate, it can be exemplified tartaric acid.
  • a flavoring agent When preparing an oral liquid preparation, a flavoring agent, a buffering agent, a stabilizing agent, a deodorant and the like can be added to the compound (1) to produce an oral solution, a syrup, an elixir and the like in a usual manner.
  • those mentioned above may be used as the flavoring agent, and sodium citrate or the like may be used as a buffer, and tragacanth, gum arabic, gelatin or the like may be used as a stabilizer.
  • a PH regulator When preparing an injection, add a PH regulator, buffer, stabilizer, isotonic agent, local anesthetic, etc. to compound (1), and subcutaneously, intramuscularly or intravenously according to a conventional method.
  • the pH adjuster and the buffer include sodium citrate, sodium acetate, sodium phosphate and the like.
  • Pyro as stabilizer Examples thereof include sodium sulfite, EDTA, thioglycolic acid, and thiolactic acid.
  • Local anesthetics include proforce in hydrochloride and lidocaine hydrochloride.
  • the tonicity agent include sodium chloride, glucose and the like.
  • compound (1) may be added to a pharmaceutical carrier known in the art, for example, polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, and, if necessary, Tween (registered trademark). After adding various surfactants and the like, it can be produced by an ordinary method.
  • a pharmaceutical carrier known in the art, for example, polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, and, if necessary, Tween (registered trademark).
  • the amount of compound (1) to be incorporated in each of the above dosage unit forms is not fixed depending on the symptoms of the patient to which it is applied or on its dosage form, etc., but in general, about an oral preparation per dosage unit form It is desirable that the amount be 1 to 100 Omg, about 1 to 50 Omg for injections, and about 1 to 100 Omg for suppositories.
  • the daily dose of the drug having the above dosage form varies depending on the patient's symptoms, weight, age, sex, etc., and cannot be determined unconditionally, but is usually about 5 to 200 mg per adult day.
  • the dose is preferably about 5 to 150 Omg, and it is preferable to administer it once or twice to four times a day.
  • 6-Amino-n-caproic acid (2.3 g) and trimethylsilylimidazole (2.94 g) were added to tetrahydrofuran (4), and the mixture was stirred under reflux for 2 hours.
  • triethylamine (2.13 g) 4 Add 1-naphthyl lensulfonyl chloride (4.58 g) and heat to reflux for 5 hours.
  • Water was added to make it acidic with citrate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give a crystalline residue.
  • a mixed solvent of benzene and hexane (6: 4) was added, and the mixture was stirred and filtered to obtain the desired product as white crystals (4.06 g, 65.0%).
  • N, ⁇ '-bis [6- (4-chloro-1-naphthalenesulfonyl) -amino-1-hexanoyl] - ⁇ -xylenediamine (29 Omg) is dissolved in tetrahydrofuran (5 ⁇ ), and borane is stirred in an ice bath. Methyl sulfide (543 mg) was added, and the mixture was stirred overnight at room temperature. After ice was added with stirring in an ice bath to stop foaming, sodium hydrogen carbonate (20 Omgj was added, and the mixture was heated under reflux for 4 hours. After cooling, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and dried.
  • the succinic acid imidoester of carboxylic acid is quantitatively reacted with various diamines in chloroform to yield the corresponding N, N'-bis (6-N-benzyloxycarbonyl) in a yield of 20 to 60%. Amino-11-hexanoyl) form was obtained. Subsequently, each was subjected to a catalytic reduction reaction using a 20% palladium hydroxide catalyst in methanol at room temperature under an atmosphere of hydrogen gas at 1 atm, whereby each was quantitatively obtained as a colorless powder.
  • the residue was obtained by drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure.
  • the residue obtained was subjected to silica gel column chromatography.
  • the C a M kinase I activity was determined using a 50 ⁇ reaction mixture (35 mM HE PES (pH 7.5), 1 OmM MgC 2 .lraM dithiothreitol, 0.01% v / v) Tween 20, 50 / M Synthide 2, 100 M Cr- 33 P) ATP (200 cpm / pmoi), 62 Ong C aM Kinase I, 0.5 mM a C £ Measurements were performed at 30 ° C. for 10 minutes with 3 and 10 OnM calmodulin or lmM EGTA). The reaction was started by adding ATP, and stopped by dropping the reaction solution into P-81 filter paper (Pittman) at 25 ⁇ ⁇ .
  • P-81 filter paper Pittman
  • the filter paper was washed with a 76 mM phosphoric acid solution, dried, and then counted for radioactivity.
  • Yeast The elementary activity was determined by subtracting the count in the presence of EGTA from the count in the presence of C a C £ 2 -calmodulin, and the IC 5 Q of the example compound was calculated as the concentration that inhibited the enzyme activity by 50%. . Table 1 shows the results.
  • the naphthalene sulfonamide derivative (1) of the present invention or a salt thereof is useful as a drug for cardiovascular diseases such as a platelet aggregation inhibitor, an antihypertensive agent, and a vasodilator since it has an excellent inhibitory effect on calmodulin activity. It is.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des dérivés de naphtalènesulfonamide représentés par la formule générale suivante (1) ou leurs sels, ainsi que des médicaments les contenant comme ingrédient actif; dans la formule (1), R représente (a) ou-HN-A-NH- (A représentant un groupe d'hydrocarbures divalent en C2-8 ou (CH2)2-O-(CH2)2-); X1 et X2 sont les mêmes ou sont différents, chacun représentant un atome d'oxygène ou deux atomes d'hydrogène; Y représente un hydrogène ou un halogéno; et n représente un nombre de 2 à 7. Parce qu'ils possèdent un excellent effet d'inhibition de la calmoduline, ces composés s'utilisent comme médicaments, notamment comme anti-agrégants plaquettaires.
PCT/JP1998/002841 1997-05-20 1998-06-25 Derives de naphtalenesulfonamide et medicaments les contenant WO1999067207A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP9129497A JPH10316649A (ja) 1997-05-20 1997-05-20 ナフタレンスルホンアミド誘導体及びこれを含有する医薬
PCT/JP1998/002841 WO1999067207A1 (fr) 1997-05-20 1998-06-25 Derives de naphtalenesulfonamide et medicaments les contenant

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9129497A JPH10316649A (ja) 1997-05-20 1997-05-20 ナフタレンスルホンアミド誘導体及びこれを含有する医薬
PCT/JP1998/002841 WO1999067207A1 (fr) 1997-05-20 1998-06-25 Derives de naphtalenesulfonamide et medicaments les contenant

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WO1999067207A1 true WO1999067207A1 (fr) 1999-12-29

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PCT/JP1998/002841 WO1999067207A1 (fr) 1997-05-20 1998-06-25 Derives de naphtalenesulfonamide et medicaments les contenant

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WO (1) WO1999067207A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2970965A1 (fr) * 2011-01-31 2012-08-03 Centre Nat Rech Scient Composes anti-angiogeniques, compositions pharmaceutiques les comprenant, et leur utilisation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05225742A (ja) * 1992-02-14 1993-09-03 Hitachi Ltd ディスクカートリッジ

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05225742A (ja) * 1992-02-14 1993-09-03 Hitachi Ltd ディスクカートリッジ

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
K. REHSE et al., "Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines, XVIII: Oligoamines with Fluorescent Properties, Part B: Fluorophores in the Molecular Periphery", ARCH. PHARM., (WEINHEIM), (1994), 327, pages 399-404. *

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