WO1999067207A1

WO1999067207A1 - Naphthalenesulfonamide derivatives and drugs containing the same

Info

Publication number: WO1999067207A1
Application number: PCT/JP1998/002841
Authority: WO
Inventors: 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: 1997-05-20
Filing date: 1998-06-25
Publication date: 1999-12-29
Also published as: JPH10316649A

Abstract

Naphthalenesulfonamide derivatives represented by following general formula (1) or salts thereof and drugs containing the same as the active ingredient, wherein R represents (a) or -HN-A-NH- (wherein A represents a divalent C2-8 hydrocarbon group or -(CH2)2-O-(CH2)2-); X?1 and X2¿ are the same or different and each represents an oxygen atom or two hydrogen atoms; Y represents hydrogen or halogeno; and n is a number of from 2 to 7. Because of having excellent calmodulin activity inhibitory effect, these compounds are useful as drugs such as antiplatelet drugs.

Description

P Description Naphthalenesulfonamide derivatives and pharmaceuticals containing them

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. Background art

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.

Therefore, 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. Conventionally, examples of the calmodulin inhibitor include compounds described in JP-A-52-25742.

However, this compound had the disadvantages of low affinity for caldugulin and a high inhibitory concentration.

Accordingly, an object of the present invention is to provide a new compound having excellent calmodulin inhibitory activity.

Disclosure of the invention

In view of such circumstances, 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)

[Wherein, 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. ]

And a salt thereof. 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 comprising the naphthalene sulfonamide derivative (1) or a salt thereof, and a pharmaceutically acceptable carrier.

Further, 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. BEST MODE FOR CARRYING OUT THE INVENTION

In the naphthalenesulfonamide derivative represented by the general formula (1) of the present invention (hereinafter referred to as “compound (1)”), the divalent hydrocarbon group having 2 to 8 carbon atoms represented by A is aliphatic. And aromatic groups. Aliphatic 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. Further, as the aromatic group, a phenylene group and a xylylene group are preferable. In the general formula (1), R is preferably -NH (CH ₂ ) Factory NH- (= 2 to 8), p-phenylenediamine, p-xylenediamine or piperazine. X ¹ and X ² Represents an oxygen atom or two hydrogen atoms, which may be the same or different. Examples of 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.In addition, 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.

(Production method 1)

( twenty four )

Logenification

( Five )

(1-1)

3S vint

(1-2)

[In the formula, Y, A, X ¹ , X ² and n represent the same as described above, and Q and Ha ^ represent a halogen atom.]

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.

Incidentally, 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.

(Manufacturing method 1)

B-NH (CH ₂ ) _n C00Z + H ₂ NA-NH ₂

(7) (6) nCONH- A-NHCO (CH 2) n NH-B (8)

Deprotection

nC0NH— A— NHC0 (CH ₂ ) _n NH ₂ (9)

(1 1 1) is vault

(1-2)

[Wherein, X, Y and n represent the same as above, B represents an amino protecting group, and Z represents an active ester residue]

Starting from an active ester of an amino acid protected with an amino group such as a benzyloxycarbonyl group, for example, succinic acid imidoester (7), The compound (8) is obtained by reacting the compound (6). 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.

(Production method 3)

B-NH (CH ₂ ) _n CH ₂ Ha £ + H— R—H

(1 0) (1 1)

B-, CH ₂ -R-, ΝΗ-Β (1 2)

H ₂ N (CH ₂ ) _n CH ₂ — R ') ΝΗ (1 3)

(1-1-3)

[Wherein, B, Ha, R, n, Q and Y represent the same as above]

Compound protected with a protecting group such as t-butoxycarbonyl group (10)

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.

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. Such 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. as 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.

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. In this case, 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.

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. Can be manufactured. In this case, examples of 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. Examples of the tonicity agent include sodium chloride, glucose and the like.

In the case of preparing suppositories, 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.

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. In addition, 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. Example

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Reference example 1

N- (4-chloro-1-naphthalenesulfonyl) -1-6-amino-n-caproic acid

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. After cooling, 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%).

¹ H-NMR (270 MHz, CDC ₃ , 5 ppm):

1.1-1.3C4H, m), 1.3-1.6 (8H, m), 2.2 (4H, t, J = 7.2Hz),

2.9K4H, q, J = 7.2Hz), 4.83 (2H, bt), 7.64 (2H, d, J = 8.0Hz), 7.74 (4H, m), 8.17C2H, d, J = 8.0Hz), 8.43 ( 2H, m), 8.68 (2H, m)

Reference example 2

N- (4-1-1-naphthalenesulfonyl)-1-6-amino-n-capric acid

Thionyl chloride (4) was added to N- (4-chloro-one-naphthyl lensulfonyl) -1-6-amino-n-caproic acid (6.1 g), and the mixture was heated under reflux for 2 hours. The thionyl chloride was distilled off under reduced pressure. Hexane was added, stirred, and filtered to obtain off-white crystals (6.23 g, 97.1%).

Example 1

N, N'-bis [6- (4-chloro-1--1-naphthalenesulfonyl) -amino-l-hexanoyl] -p-xylenediamine

Paraxylenediamine (95.2 mg) was dissolved in pyridine, and N- 4'-chloro-1-naphthalenesulfonyl-6-amino-1-n-caproic acid chloride (53 mg) was dissolved in an ice bath with stirring. A solution of tetrahydrofuran (1ίτηί) was added dropwise, and the mixture was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, and (1: 1) water monoacetate (1 酢酸 τη 1) was added to the residue, followed by stirring to obtain the desired product as off-white crystals (29 Omg, 51.0%) o

¹ H-NMR (270 MHz, CDCi ₃ , δ ppm):

1.1-1.65C12H, m), 2.l (4H, bt), 2.83 (4H, bt), 4.35 (4H, bs), 7.23 (4H, bs), lo 7.64 (2H, d, J = 7.9Hz), 7.65-7.8 (4H, m), 8.12 (2H, d, J = 7.9Hz),

8.35-8.5 (2H, m), 8.65-8.8 (2H,)

Example 2

N, N'-bis [6-((4-chloro-1-naphthalenesulfonyl) -amino-1-1-hexyl] -p-xylenediamine

N, Ν'-bis [6- (4-chloro-1-naphthalenesulfonyl) -amino-1-hexanoyl] -ρ-xylenediamine (29 Omg) is dissolved in tetrahydrofuran (5τηβ), 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. Was distilled off under reduced pressure, and the residue was subjected to preparative TLC (Mercck 1055744) using ethyl acetate-methanol acetate (1: 1) as a developing solvent. The portion shown was fractionated, eluted with methanol, and the methanol solution was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the soluble portion was distilled off under reduced pressure to obtain the desired product as a white powder (6). 0.3 mg, Yield = 20.8%) _c ¹ HNR (270MHz, CDC 5ppm):

1.1-1.2C5H, in), 1.2-1.4 (llH, m), 2.5 (4H, t, J = 7.0Hz),

2.87C4H, t, J = 7.0Hz), 3.73 (4H, s), 7.24 (4H, d, J = 5.3Hz),

7.63C2H, d, J = 8.0Hz), 7.65-7.8 (4H, m), 8.16 (2H, d, J = 8.0Hz),

8.35-8.45 (2H, m), 8.65-8.8 (2H, m)

Reference example 3

N, Ν'-bis (6-amino-1-hexanoyl) Ethylenediamine, N, N'-bis (6-amino-1 hexanoyl) 1-1,4-diaminobu, Ν, Ν 'one-bis (6-amino-1-hexanoyl) -1,6-diaminohexane, N, N'-bis (6-amino-1-hexanoyl) -ρ-xylenediamine, Ν, Ν'-bis (6-amino- (1) Hexanoyl) Synthesis of ρ-phenylenediamine 6-Amino-n-bronic acid is N-benzyloquinocarbonylated (91%) and then in 1,4-dioxane with dicyclohexylcarposimid and N-hydric oxisuccinic imid. 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.

Example 3

N, N'-bis [6- (5-chloro-1-naphthalenesulfonyl) amino-1-1-hexanoyl)] ethylenediamine, N, Ν'-bis [6- (5-chloro-1-naphthalenesulfonyl) amino- 1-, 4-diaminobutane, Ν, N'-bis [6- (5-chloro-1--1-naphthyllensulfonyl) ミノ mino 1 1-hexanoyl)] 11,6-diaminohexane, N, N'-bis [6- (5-chloro-1-naphthyl lensulfonyl) amino-11-hexanoyl] -1-ρ-xylenediamine, N, N'-bis [6 -— (5-chloro-1-11-naphthyl) Lensulfonyl) amino-11-hexanoyl)] Synthesis of 1ρ-phenylenediamine

Pyridine is added to the various Ν, Ν'-bis (6-amino-1-hexanoyl) compounds synthesized in Reference Example 3, and 2 equivalents of 5-chloro-11-naphthyllensulfonyl chloride and triethylamine 2. The reaction solution was added successively and stirred for 30 minutes, and the reaction solution was diluted with a 10-fold amount of chloroform. The extract was washed successively with water and a saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was subjected to silica gel column chromatography, and the chromate form: methanol (100: 3 )), A fraction exhibiting an R f value of about 0.3 to 0.6 (Mercck 1.50715, developing solvent = chloroform: methanol = 10: 1) was collected. This was recrystallized from methanol to give the desired product as almost colorless crystals. The yield of each compound is shown below. And physical properties.

(a) Ν, Ν'-bis [6- (5-chloro-1-naphthalenesulfonyl) amino-11-hexanoyl)] ethylenediamine ((; ₃₄ ^ 1 ₄₀ (^ ₂ 0 ₆ 3 ₂ ; Hidden. 735.75) Yield 1 1%

_{- NMR (270MHz, CDCi 3,} dppm):

1.27-1.38 (4H, m), 1.45-1.60C8H, m), 2.2K4H, t, J = 7.3Hz),

2.92 (4H, q, J = 6Hz), 3.48 (4H, br), 6.17 (2H, brt), 6.52 (2H, br),

7.53 (2H, t, J = 8.5Hz), 7.65 (2H, t, J-8.5Hz), 7.67 (2H, d, J = 8.5Hz),

8.3K2H, dd, J = 8.5, 1Hz), 8.57 (2H, d, J = 8.5Hz), 8.7K2H, d, J = 8.5Hz

(b) N, N '- bis [6- (5-black opening one 1 one naphthalene sulfonyl儿) § Mi Bruno - 1 into single Kisanoiru)] - 1, 4- Jiaminobutan _{_{(C 36 H "CN 4 0}} 6 S ₂ , painting .763.8Γ yield 12%

¹ H-NM C270MHz, CDCi ₃ , (5ppm):

1.20-1.35C4H, m), 1.35-L 50 (4H, m), 1.50-1.65 (8H, m),

2.10 (4H, t, J = 7Hz, 2.90 (4H, q, J = 6Hz), 3.28 (4H, br),

5.85C2H, brt, J = 6Hz), 6.13 (2H, brt, J = 6Hz), 7.52 (2H, t, J = 8.5Hz),

7.64 (2H, t, J = 8.5Hz), 7.67 (2H, d, J = 8.5Hz), 8.29 (2H, dd, J = 8.5, 1Hz),

8.56 (2H, d, J = 8.5Hz), 8.66C2H, d, J = 8.5Hz)

(c) N, N '- bis [6- (5-black opening one 1 one-naphthalenesulfonyl) Kisanoiru to Ami no 1 I)] - 1, hexane (C ₃₈ to 6 Jiamino H ₄₈ CN ₄ 0 _{s S} ₂ 791.86).

Yield: 14%

^] H-go R (270MHz, CDC, 5ppm):

1.16-1.34 (8H, m), 1.34-1.50 (12H, m), 2.06C4H, t, J = 7Hz),

2.88 (4H, dt, J = 6.4Hz), 3.19 (4H, q, J = 6.5Hz), 5.95C2H, t, J = 6Hz),

6.09 (2H, brt, J = 6Hz), 7.59 (2H, dt, J = 8.5, 1Hz), 7.62C2H, dt, J = 7.2, 1Hz), 7.65 (2H, dd, J = 7.2, 1Hz),

8.28 (2H, dd, J = 7.2, 1Hz), 8.54 (2H, d, J = 8.5Hz), 8.65 (2H, d, J = 8.5Hz

(d) N, N '- bis [6- (5-chloro-1-naphthoquinone evening Rensuruhoniru) Amino one 1 into single Kisanoiru)] one p- Kishirenjiami emissions _{_{_{(C 4 .H 44 CN 4 0}}} 6 S 2, MW .811.85) Yield: 15%

¹ H-NMR (270 MHz, CDCi 3, (5 ppm):

1.14-1.26C4H, m), 1.27- 1.40 (4H, m), 1.42-1.54 (4H, m),

2.08 (4H, t, J = 7Hz), 2.84 (4H, q, J-6HzX 4.38C4H, d, J = 6Hz),

5.29 (2H, t, J = 6Hz), 6.17 (2H, brt, J = 6Hz), 7.24 (4H, s),

7.50 (2H, dt, J = 8.5, 1Hz), 7.63 (2H, dt, J = 7.5, 1Hz),

7.67 (2H, d, J = 7.5Hz), 8.28 (2H, dd, J = 7.5, 1Hz), 8.55 (2H, dd, J = 8.5, ΙΗζΧ

8.59 (2H, dd, J = 8.5, 1Hz)

(e) N, N '- bis [6- (5-chloro-1 one naphthalene Nsuruhoniru) Ryo amino one 1 into single Kisasoiru)] one p- phenylene Renjiami emissions _{_{_{(C 38 H 40 C 2 N}}} 4 O e S ₂ , marauder. 783.80)

Yield: 23%

NMR (270 MHz, 丽 SO-d ₆ , 5 ppm):

1.11-1.22C4H, m), 1.27-1.45 (8H, m), 2.13 (4H, t, J = 7Hz),

2.79 (4H, q, J = 6Hz), 7.45 (4H, s), 7.70 (2H, dt, J = 8.5.IHz),

7.82 (2H, dt, J = 7.5, 1Hz), 7.86 (2H, d, J = 7.5Hz),

8.06 (2H, t, J = 6Hz), 8.23 (2H, dd, J = 7.5, 1Hz),

8.50C2H, d, J = 8.5Hz), 8.68C2H, d, J = 8.5Hz), 9.7K2H, s)

Reference example 4

N, Ν'-bis (6-amino-n-hexyl) pidazine 4-HC (10) 1 N-t-butoxycarbonylamino-1 6-bromo-n-hexane (5.i 1 g, 18.25 mM), add toluene (5Οτηβ) and dissolve. (8.60 g, 10 OmM) was added, and the mixture was stirred at room temperature for 30 minutes and heated under reflux for 10 minutes. After cooling, the reaction mixture was diluted with ethyl acetate (200 ^), washed with water and saturated saline in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with hexane: ethyl acetate 2: 1 to give N, Ν'-bis (6- ビス -t-butoxycarbonylamino-η-hexyl) pidazine colorless. Obtained as amorphous (4.84 g, quantitative). Subsequently, the whole amount is dissolved in ethyl acetate (3Οτηβ), 4 4-hydrochloric acid-ethyl acetate (2 bmi) is added with stirring at room temperature, the resulting salt is filtered, washed with ethyl acetate, and dried under reduced pressure. As a result, the desired product was obtained as a colorless powder (4.3 g, quantitative).

Example 4

N, N'-bis [6- (4-chloro-1--1-naphthalenesulfonyl) amino] n

N, Ν'-bis [6-amino-1-η-kinyl) piperazine 4-hydrochloride (0.70 g, 1.63 mM) and pyridine (2) —Chloro-1-naphthene lensulfonyl chloride (0.85 g, 3.25 mM) and triethylamine W) were added sequentially, and the mixture was stirred for 30 minutes. The reaction mixture was diluted with chloroform (15), washed successively with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue obtained was subjected to silica gel column chromatography. , Cloth form: fraction eluted with methanol (100: 3), R R value of about 0.4 (Mercck 1.057,15, developing solvent = chloroform: methanol = 10: 1) This was recrystallized from methanol to give the desired product as almost colorless crystals (0.41 g, yield 34%).

(C ₃ 6H46C ₂ N40 ₄ S ₂ , ll '.733.83):

1 H-NMR (270 MHz, DMS0-d 6, 5 pm):

0.90-1.00 (8H, m), 1.00-1.15 (4H, m), 1.15-1.25C4H, m),

2.02 (4H, t, J = 7Hz), 2.20 (4H, br), 2.78 (4H, q, J = 6Hz), 7.82-7.86 (4H, m), 7.87C2H, t, J = 9Hz), 8.06C2H, t, J = 6Hz), 8.09 (2H, d, J = 9Hz),

8.35 (2H, dd, J2 6.6, 3.3Hz), 8.74 (2H, dd, J = 6.6, 3.3Hz)

Example 5

N, N'-bis [6- (5-chloro-1--1-naphthyllensulfonyl) amino-n-hexyl)] pidazine

N, N'-bis (6-amino-1-n-hexyl) pidazine 4-HC (2.15 g, 5.0 Om), pyridine (25 ^) was added, and the mixture was stirred at room temperature. —Α □ α-1-Naphthalenesulfonyl chloride (2.61 g, 10.0 OmM) and triethylamine (2.) were added sequentially and stirred for 30 minutes. 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 fraction exhibiting an Rf value of about 0.4 (Mercck 1.05715, developing solvent dichloride form: methanol 210: 1) eluted at (100: 3) was collected as crystals. This was recrystallized from methanol to give the desired product as almost colorless crystals (1.28 g, yield 35%) (C ₃ sH _4S Ci ₂ N ₄ 0 ₄ S ₂ , MW .733.83):

MR (270 oz z, thigh SO-d ₆ , dppm):

0.95-1.05 (8H, m), 1.05-1.15C4H, ml 1.15-1.25C4H, m), 2.02C4H, t, J = 7Hz), 2.2K4H, br), 2.79 (4H, q, J = 6Hz), 7.7K2H, t, J = 7.3Hz),

7.86C2H, dd, J = 8.9, 8.5Hz), 7.87C2H, d, J = 7.3Hz), 8.05C2H, t, J = 6Hz),

8.23C2H, d, J = 7.3Hz), 8.50 (2H, d, J = 8.5, 1Hz), 8.68 (2H, d, J = 8.9Hz) Example 6

N— [6— (5-chloro-1-1-naphthalenesulfonyl) amino-11-hexano) -N '-[6- (5-chloro-1-naphthalenesulfonyl) amino-1] -1 1,4-diaminobutane

N, N'-bis [6- (5-chloro-1--1-naphthyllensulfonyl) amino-1 —Hexanoyl)] To 1,4-diaminobutane (0.12 g, 0.157 mM), add tetrahydrofuran and borane methylsulfide complex 0.3 τ ^ (3.0 mmoi) sequentially, and allow to stand at room temperature for 2 hours. Stirred. Methanol was added dropwise to the reaction solution in a small amount, and after bubbling was stopped, the reaction solution was diluted with chloroform 10 and washed with water, washed with saturated saline, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to preparative TLC using chloroform: methanol = 1: 0: 1 as a developing solvent, and the fraction having an Rί value of about 0.3 was collected. This was crystallized from methanol to give the desired product as a nearly colorless crystalline powder (25 mg, 21% yield).

_{_{_{(C 36 H 46 (^ 2}}} N 4 0 5 S 2, MW.749.83):

'H-NMR (270MHz, CDCi s, dppm):

1.22- 1.85 (18H, m), 2.05C2H, brt, J = 6Hz), 2.24 (2H, brt, J = 6Hz),

2.80-3.10 (6H, m), 3.35 (2H, brq, J = 6Hz), 6.33 (1H, brt, J = 6Hz

6.91 (lH, brt, J = 6Hz), 7.14 (1H, brt, J = 6Hz), 7.6K1H, t, J-8Hz),

7.63 (1H, t, J = 8Hz), 7.66-7.70 (4H, m), 8.13 (1H, d, J = 8Hz),

8.14C1H, d, J = 8Hz), 8.37C1H, t, J = 8HzX 8.38 (1H, t, J = 8Hz),

8.80-8.84C2H, m), 8.82 (1H, br ^

Example 7

N— [6- (5-chloro-1-1-naphthalenesulfonyl) amino-11-hexano] -N '-[6- (5-chloro-1-naphthalenesulfonyl) amino-1] 1-1,6-diaminohexane

N, Ν'-bis [6- (5-chloro-1- (1-naphthalenesulfonyl) amino-1-hexanoyl)]-1,6-diaminobutane 0.26 g (0.328 mM), The compound was treated in the same manner as in Example 6 using 0.57n (5. Ommo) to give the desired product as an almost colorless crystalline powder (28 mg, 11%).

_{_{_{(C 38 H 5 .Ci 2 N}}} 4 0 5 S 2,丽.777.88):

NMR (270MHz, CDC, oppm): 1.20- 1.58 (10H, m), 1.73-1.85 (2H, m), 185-1.95 (2H, m),

2.15 (2H, t, J-6.5Hz), 2.80-3.02 (8H, m), 3.23C1H, brq, J = 6.5Hz),

6.4K1H, t, J = 6.5Hz), 6.49 (1H, t, J = 6.5Hz), 6.51 (1H, t, J = 6.5Hz),

7.5K2H, t, J = 9Hz), 7.6K2H, d, J = 7.3Hz), 7.63C2H, t, J = 7.3Hz),

8.27C2H, dd, J = 7.3, 1Hz), 8.53 (2H, d, J = 9Hz), 8.68 (2H, d, J = 9Hz)

Example 8

N, N'-bis [6- (5-chloro-111-naphthalenesulfonyl) amino-11-hexyl)] ethylenediamine

N, N'-bis [6- (5-chloro-1-naphthalenesulfonyl) amino 1-hexanoyl)] ethylenediamine 0.29 g (0.3394 mM), borane methyl sulfide complex 0.5 The reaction was carried out in the same manner as in Example 6 by using ^ (5.0 concealed) at room temperature for 2 days to obtain the desired product as an almost colorless crystalline powder (65 mg, 23%).

_{_{_{(C 34 H 44 C 2 N}}} 4 0 4 S 2, MW.707.79):

'Η- hidden _{R (270MHz, CDC 3, (} 5ppm):

1.30-1.45C4H, m), 1.45-1.65 (12H, m), 2.24 (2H, t, J = 8Hz),

2.92C4H, q, J = 6Hz, 3.49 (4H, br), 6.62 (2H, brt \ 6.76 (2H, br),

7.57 (2H, t, J = 7.5Hz), 7.66 (2H, t, J = 9Hz), 7.67 (2H, dd, J = 7.5, 1Hz),

(8.3K2H, dd, J = 7.5, 1Hz), 8.58C2H, d, J = 9Hz), 8.77 (2H, d, J = 9Hz)

Example 9

N, N'-bis [6- (5-chloro-111-naphthalenesulfonyl) amino-11-hexyl)]-1,4-diaminobutane

Ν, Ν'-bis [6- (5-chloro-1-naphthyllensulfonyl) amino-1-hexanoyl)] 1,1,4-diaminobutane 0.12 g (0.157 mM), boranemethylfur The target product was obtained as a nearly colorless crystalline powder by treating the complex with 0.5 τ ^ (5.0 reference 0) in the same manner as in Example 8 (15 mg, 13%). _{_{_{(C 36 H 48 (^ 2}}} N 4 0 4 S 2, MW.735.84):

1 H-NMR (270 MHz, CDCf 3: CD ₃ 0D = 3: 1, (5 ppm):

1.13-1.35 (8H, m), 1.35-1.50 (4H, m), 1.50-1.70 (4H, m), 1.70-1.90 (4H, m), 2.55-2.75C4H, m), 2.80-2.95 (8H, m) m), 7.58 (2H, t, J = 8.5Hz),

7.60 (2H, t, J = 8Hz), 7.69 (2H, d, J = 8Hz), 7.70 (2H, t. J = 8.5Hz),

8.58 (2H, d, J = 8.5Hz), 8.66 (2H, d, J = 8.5Hz)

Example 10

N, N'-bis [6- (5-chloro-1--1-naphthalenesulfonyl) amino-1 1-hexyl)] 1-1,6-diaminohexane

Ν, Ν'-bis [6- (5-chloro-1--1-naphthalenesulfonyl) amino-1—hexanoyl)]-1,6-diaminohexane 0.28 g (0.354 m), borane methyl sulfide complex The same procedure was followed as in Example 8 using 0.5τ ^ (5. Ommoi) to give the desired product as an almost colorless crystalline powder (3 lmg, 11%).

_{_{_{(C 38 H 52 C 2 N}}} 4 0 4 S 2, MW.763.90):

1 H-NMR (270MHz, CDCi 3: CD 3 0D = 5: L dppm):

1.15-1.85C24H, m), 2.60-2.75 (4H, m), 2.80-2.95 (8H, m),

7.58C2H, t, J = 7.2Hz), 7.68 (2H, t, J = 8.5Hz), 7.70 (2H, d, J = 7.2Hz),

8.29C2H, dd, J = 7.2, 3Hz), 8.56C2H, d, J = 8.5Hz), 8.66 (2H, d, J = 8.5Hz)

N, N'-bis [6- (5-chloro-1-naphthalenesulfonyl) amino-1-hexyl)] p-xylenediamine

N, N'-bis [6- (5-chloro-1-naphthalenesulfonyl) amino-11-hexamyl)]-ρ-xylenediamine 0.10g (0.123mM), borane methylsulfide complex 1. Omg ( 1 OmM) to give the target product as a nearly colorless amorphous (30.lmg, 31%).

_{_{_{(C 4 .H 48 Ci 2 N}}} 4 0 4 S 2, MW.783.89): ^! H-NMR (270 MHz, CD 3, (5 pm):

1.06-1.20C4H, m), 1.20-1.40 (8H, m), 1.40-1.70 (4H, m), 2.5K4H, t, J-7Hz), 2.89C4H, t, J = 7Hz), 3.73 (4H's) , 4.60- 5.00 (2H, br), 7.24 (4H, s),

7.55 (2H, t, J = 8.5Hz), 7.65 (2H, t, J = 7.5Hz), 7.69 (2H, dd, J = 7.5, 1Hz),

8.30C2H, dd, J = 7.3, 1Hz), 8.57 (2H, d, J = 8.5Hz), 8.62 (2H, d, J = 8.5Hz)

N, N'-bis [6- (5-chloro-1- (1-naphthalenesulfonyl) amino-1-hexyl)] p-phenylenediamine

N, N'-bis [6- (5-chloro-1-naphthalenesulfonyl) amino-1-hexanoyl)] 1-P-phenylenediamine 0.35 g (0.447 mM), borane tylus The same procedure as in Example 8 was carried out using 0.5 (5 mM) of the sulfide complex to obtain a target substance as a nearly colorless amorphous substance (14.0 mg, 41%).

_{_{_{(C 38 H 44 C 2 N}}} 4 0 4 S 2, W.755.83):

1 H-NMR (270 MHz, CDC ₃ , (Jppm):

1.10-1.25C8H, m \ 1.30-1.45 (8H, m), 2.87-3.0K8H, m), 6.53 (4H, s),

7.53C2H, t, J-7.5Hz), 7.66 (2H, d, J = 7.5Hz), 7.68 (2H, t, J = 8.5Hz),

8.34C2H.d, J = 7.5Hz), 8.58C2H, d, J = 8.5Hz), 8.62 (2H, d, J = 8.5Hz)

Test Example 1 Measurement of C a M kinase I activity

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〃 ^^. 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.

table 1

Calmodulin-dependent protein kinase 1 inhibitory activity

* Compound c of the following formula disclosed in JP-A-52-25742

Industrial applicability

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.

Claims

1. The following general formula (1)

/ ~ \

[Wherein, R - New New - or - HN- A- ΝΗ- (here, Alpha is a divalent hydrocarbon radical or from 2 to 8 carbon _{_{- (CH 2) 2 0- (}} CH 2) 2 - indicates shown), X ¹ and X ² Te same or different dates the enzymatic atom or two hydrogen atoms, Y denotes a囲水atom or a halogen atom, n is a number of 2 to 7 . ]

Or a salt thereof.

2. 1 pound containing the naphthalenesulfonamide derivative or the salt thereof according to claim 1 as an active ingredient.

3. A calmodulin activity inhibitor comprising the naphthalenesulfonamide derivative according to claim 1 or a salt thereof as an active ingredient.

4. An agent for preventing or treating cardiovascular diseases, comprising the naphthalene sulfonamide derivative or a salt thereof according to claim 1 as an active ingredient.

5. An antiplatelet drug comprising the naphthene lensulfonamide derivative according to claim 1 or a salt thereof as an active ingredient.

6. A pharmaceutical composition comprising the naphthalenesulfonamide derivative according to claim 1 or a salt thereof, and a pharmaceutically acceptable carrier.

7. Use of the naphthalenesulfonamide derivative or the salt thereof according to claim 1 as a medicament.

8. Carmoduli lily of the naphthalenesulfonamide derivative or a salt thereof according to claim 1. Use as an activity inhibitor.

9. Use of the naphthalenesulfonamide derivative or a salt thereof according to claim 1 as a prophylactic or therapeutic agent for cardiovascular diseases.

10. Use of the naphthalenesulfonamide derivative or a salt thereof according to claim 1 as an antiplatelet agent.

1 1. A method for treating cardiovascular disease, comprising administering an effective amount of the naphthalene sulfonamide derivative or a salt thereof according to claim 1.