JPS6317870A - Naphthalenesulfonamide derivative - Google Patents

Abstract

NEW MATERIAL:A naphthalenesulfonamide derivative shown by formula I (R1 and R2 are H, halogen, lower alkyl, lower alkoxy, hydroxy, amino, lower alkylamino, lower acylamino, nitro or cyano) and an acid addition salt. EXAMPLE:1-( 5-Methoxynaphthalene-1-sulfonyl )-1H-hexahydro-1, 4-diazepine.hy drochloride. USE:Has inhibitory action on calmodulin, inhibitory action on activity of myosin light chain kinase following the action, relaxing action on smooth muscle and vasodilating action is useful as vasodilator, hypotensor, improver for cerebral circulation, remedy for angina pectoris, preventive and remedy for thrombosis of cerebral and cardiovascular system. PREPARATION:For example, a sulfonic acid hylogenide derivative shown by formula II (X is halogen) is reacted with homopiperazine in a solvent to give a compound shown by formula I.

Description

[Detailed description of the invention]

- Part 1 of Hiraki The invention relates to 11-naphthalene sulfonamide derivatives and pharmacologically acceptable acid adducts thereof, which are used as therapeutic agents for cardiovascular diseases. Follow] Takupu Danj

[Naphthalene sulfonamide derivatives are disclosed in Japanese Unexamined Patent Application Publication No. 50-13
No. 1942, JP-A-52-257421-. JP-A-52-100439, JP-A-56-40660
No., JP-A-57-98253 and JP-A-56-686
It is described in Publication No. 10, etc. ■ Or! However, there is room for improvement in the group of compounds disclosed in the above-mentioned publication in terms of action on the circulatory system, organ selectivity of the action, and safety. Therefore, the present inventors developed a vasodilator and an antihypertensive agent. Cerebral circulation rate and drugs, angina treatment drugs, cerebral cardiovascular system thrombus Mr
- As a result of intensive research on compounds useful as preventive and therapeutic agents, we succeeded in synthesizing a naphthalene sulfonamide derivative that exhibits excellent effects and completed the present invention. The present invention relates to the general formula (I) f--\ (wherein R and R2 are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group) , a hydroxy group, an amino group, a lower alkylamino group, a lower acylamino group, a nitro group, or an ano group), and their pharmacologically acceptable acid addition salts. . In the general formula (I) of the present invention, examples of the halogen atoms represented by R1 and R2 include chlorine. Examples of lower alkyl groups include fluorine, bromine, and iodine atoms, such as methyl, ethyl, and propyl. Isopropyl, butyl, isobutyl groups, etc.; examples of lower alkoxy groups include methoxy, ethoyne, propoxy, impropoxy, butoxy groups, etc.; examples of lower alkylamino groups include methylamino, ethylamino, dimethylamino, diethylamino, etc. Examples of lower acyl groups include formamide, acetamide, propionamide, butyramide, and valeramide groups. The compound represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable acid addition salt as desired, or the generated acid addition salt or base can be liberated. Examples of the pharmacologically acceptable acid addition salts of the compound represented by the general formula (I) of the present invention include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid. salt,
Alternatively, acetic acid, maleic acid, fumaric acid, citric acid,
Examples include q-acid salts such as oxalic acid and tartaric acid. The novel naphthalene sulfonamide derivative represented by the general formula (I) of the present invention can be produced by various methods. According to the first mode of the method for producing a compound according to the present invention, the compound represented by the general formula (I) is produced by the following general formula (
II) (In the formula, R and R2 have the same meanings as above, and X represents a halogen atom.) It can be produced by reacting a sulfonic acid halide derivative represented by the formula with homopiperazine in a solvent. can. A particularly preferred embodiment of the method of the present invention is the general formula (
1 equivalent of the sulfonic acid halide derivative represented by n) is reacted with 3 to 5 equivalents of homopiperazine in a solvent. The solvent used in the method of the present invention may be any solvent as long as it does not inhibit the reaction, and examples thereof include tofu, chloroform, benzene, toluene, dioxane, hexane, and the like. Further, the reaction is carried out in a range from 0° to the heating reflux temperature of the solvent used. According to the second mode of the method for producing a compound according to the present invention, the compound in which R or R2 in the general formula (I) is an amino group, It can be produced by hydrolyzing a compound in which R2 is a lower acylamide 7 group with an acid or base in a solvent. The acid used in this reaction is hydrochloric acid. Sulfuric acid etc., bases include sodium hydroxide, potassium hydroxide etc., and solvents used include water,
Examples include methanol and ethanol. Further, the reaction is carried out at a temperature ranging from room temperature to the temperature at which the solvent is heated to reflux. Further, according to the third mode of the method for producing a compound according to the present invention, the compound in which R1 or R2 is a hydroxy group in the general formula (I) has the following general formula (III) (in the formula, R3 and R4 are the same or different and represent an acetyloquine group; It can be produced by hydrolysis in the presence of. A particularly preferred embodiment of the reaction between the sulfone III\logenide derivative represented by the general formula (III) and homopiperazine is a reaction in a solvent using 3 to 5 equivalents of homopiperazine per equivalent of the sulfonic acid halide derivative. It is a matter of coercion. Any solvent may be used in this reaction as long as it does not inhibit the reaction, and examples include chloroform, benzene, toluene, dioxane, and hexane. Further, the reaction is carried out in a range from Oo to the heating reflux temperature of the solvent used. In addition, the acids used in the hydrolysis reaction include hydrochloric acid, sulfuric acid, etc., and the bases include thorium hydroxide,
Examples of the solvent include potassium hydroxide, and examples of the solvent used include water, methanol, and ethanol. Further, the reaction is carried out at a temperature ranging from room temperature to the heating reflux temperature of the solvent. The compounds represented by the general formula (II) or general formula (III) used as raw materials here are manufactured by The Journal Kyooboo Organi and Riken Chemistry (The J
our own organic chemist
ry) Vol. 39, p. 92465 (1974) 9 Roki Kagaku Zasshi Vol. 90, p. 318 (1969), etc. These are known compounds, but some new compounds are also included, including the following general formula (IV) (In the formula, RI and R2 represent the same α meanings as above.) A chlorinating agent is applied to the naphthalene sulfonic acid derivative represented by the following formula (V ) (In the formula, R1 and R2 represent the same meanings as above.) It can be produced by reacting chlorosulfonic acid without a solvent or in an organic solvent. In addition, in the general formula (IV), a compound in which R or R2 is a halogen atom can be prepared by reacting sodium nitrite with a compound in which R1 or R2 is an amine 7 group in the general formula (IV) to form a diazonium salt. After that, it can be produced by reacting with ferrous chloride, cuprous bromide, potassium iodide, etc. 1 Dish The naphthalene sulfonamide derivative represented by the general formula (I) of the present invention has a calmodulin inhibitory effect, and has a strong inhibitory effect on the subsequent myosin light chain kinase activity, and Due to its relaxing and vasodilatory effects, it can be used as a vasodilator, antihypertensive agent, cerebral circulation improver, angina treatment agent, and f.
It is useful as a preventive and therapeutic agent. The compound represented by the general formula (1) according to 1Tif of the present invention and its acid addition salt can be used as is, but it is preferably applied by injection, oral application, mucosal application, etc., and usually excipients, diluents, etc. It is mixed with adjuvants, etc., and formulated into injections, capsules, suppositories, etc. using conventional methods. Administration of the compound of the present invention (4 is usually 1 to 10 times per day)
It is 0 mg. Rabbits weighing 1.9 to 2.8 kg were sacrificed by exsanguination, followed by laparotomy, and the superior mesenteric artery (outer diameter 2.0 to 3.hm) was removed. The extracted blood vessel was incised in a spiral shape according to the usual method, and the width was 1.5 mm.
~2.5+u+, with a length of 20-30 mm. The spiral strip specimen was kept at a temperature of 37±0.5°*
It was suspended in 20 ml Krebs-Henseleit solution with a tension of 2 g to 0.5 g applied in advance. These nutrient solutions are always kept warm at 37±0.5° and exposed to 95% oxygen and 5% oxygen.
It was aerated with carbon dioxide mixed gas. One end of the specimen was fixed, and one end was attached to a Nihon Kohden F-1 transducer (
SR-IT) to record isometric tension changes. The specimens were suspended in the nutrient solution for at least 60 minutes before starting the experiment, during which time the nutrient solution was changed every 15 minutes. Vascular smooth muscle relaxing effect was determined by preparing a spiral strip specimen for 20 m beforehand.
After contracting with MKCl and maintaining constant tension, the drug of interest was administered cumulatively. The relaxation effect was expressed as 100% of the contraction tension due to MCI, and the %ED50 was expressed at 70 degrees for a drug that was 50% relaxed. The results are shown in Table 1. Table 1 Example 18 9.4 Example 20 9.0 [Action on myosin light chain kinase] Using chicken gizzard smooth muscle myosin light chain as a substrate, [γ-32P]ATP
Enzyme activity was measured by measuring the incorporation of radioactive phosphate into the substrate protein. The total number of reaction solutions is 20.
The composition was 25mM Trjs-HCI (
pH 7.0), 10mM MgCl2. 40 u
The g-myosin light chain was prepared by preparing myosin from pizzeria smooth muscle and then denaturing it with guanidine. ), 200 uM CaCl2, 80 ng calmodulin (prepared from bovine brain), myosin light chain kinase prepared from gizzard smooth muscle. ), and various 1
It was a drug of 8 degrees. The reaction was carried out at 30″, 100 μM
[γ-32p ATP20μ! Start by adding 2
It was stopped by adding 10.5 ml of 0% TC. After stopping the reaction, add 5% TCA3i1 and 1 g/ml albumin solution at 0.00%.
11 and centrifuged to fix the acid-insoluble protein on the bottom of the test tube. Remove the supernatant, add 3 ml of 5% TCA, and centrifuge. I repeated the operation two or three times. The precipitated protein was diluted with 1N-NaOH.
Dissolve in 2 ml and put into a vial containing about 101 Ch
It is measured using a liquid anti-tillation counter using the erenkov effect. Activity in presence of calcium is 100
, Calcium non-(j lower right activity was set as 0. The γ degree of the drug that inhibited 50% from the activity when the drug was added to the reaction solution was set as IC5°. The results are shown in Table 2. 2 Hereinafter, the present invention will be explained with reference to Reference Examples and Examples. Reference Example 1 6-Bromo-1-naphthalenesulfonic acid/potassium salt 6-amino-1-naphthalenesulfonic acid 5.00z suspended in water 30-1 Add 1.3 ml of sodium carbonate to the cloudy solution, stirring at room temperature.
Add 0 g to dissolve all the sulfonic acid. Subsequently, 7 ml of 47% hydrogen bromide was added to the reaction solution, and the mixture was cooled with water.
At HO~5°, a solution of 1.70 g of sodium sulfite in water 121 is gradually added dropwise. After the addition, the reaction solution is stirred at room temperature for 30 minutes. The precipitated crystals are collected by filtration and gradually added under stirring to a solution of 3.54 g of cuprous bromide in 47% hydrobromic acid 43-1, which has been previously cooled to below 0°. After the addition, the reaction solution was stirred at room temperature for 30 minutes, then at 80° for 30 minutes, and then cooled with water. The precipitated crystals were collected by filtration and dissolved in 50 l of water. Add 50% potassium hydroxide aqueous solution and filter the precipitated crystals to obtain light brown crystals with 2.39%
get g. Recrystallization from water gives light brown crystals with a melting point of 300° or higher. Reference Example 2 6-iodo-1-naphthalenesulfonic acid/potassium salt 1.30 g of sodium carbonate was added to a suspension of 5.00 g of 6-amino-1-naphthalenesulfonic acid in 301 g of water under stirring at room temperature.
g to dissolve all the sulfonic acid. Subsequently, 71 parts of hydrochloric acid are added to the reaction mixture, and a solution of 1.70 g of sodium nitrite in 12 parts of water is gradually added dropwise at an internal temperature of 0 to 5°. After the addition, the reaction solution is stirred at room temperature for 30 minutes. Next, in a water-cooled container, a solution of 4.12 g of potassium iodide in water was added, and the mixture was stirred at room temperature for 30 minutes and then at an internal temperature of 80° for 30 minutes. To the reaction mixture was added 4.27 g of IJumite under water cooling, and the mixture was stirred at room temperature for 10 minutes, and the precipitated crystals were collected by filtration. Dissolve the precipitated crystals in water, add 50% potassium hydroxide aqueous solution, collect the precipitated crystals by filtration, and obtain pale red crystals 1.3
Obtain 0g. Crystallize from water at +1F to obtain pale red crystals with a melting point of over 300°. Example 1 1-(Naphthalene-1-sulfonyl)-18-hexahydro-1,4-diazepine hydrochloride homopiperazine 5.
To 50 g of chloroform 101 solution, α-
Add a solution of 2.50 g of naphthalenesulfonyl chloride in 20 ml of chloroform to i! After i'F, stir at room temperature for 30 minutes. The reaction solution was condensed, and the resulting residue was dissolved in an aqueous hydrochloric acid solution and washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and then extracted with ethyl acetate. After the ethyl acetate layer is dehydrated, the solvent is distilled off. The obtained residue was dissolved in chloroform, ethanolic hydrochloric acid was added, and the precipitated crystals were collected by filtration to obtain colorless crystals. Get Log. Recrystallization from ethanol gives colorless needle crystals with a melting point of 203-205@. Elemental analysis value C15H engineering. N202S11HC1 theoretical value C, 55, +2; H, 5,86; N, 8.5
7 experiments [C,55,21; H,5,8G; N,
8.37 Compounds of Examples 2-4 are obtained analogously to Example 1 using substituted naphthalenesulfonyl chloride. Example 2 l-(5-methquinaphthalene-1-sulfonyl hydrochloride pale yellow needle crystals Melting point 219.5-221.5° (EtOH1 elemental analysis value C engineering. H2oN203S1LHCI theory efi
C, 53.85; H, 5.93
; N, 7.85 experimental value C, 53.74;
H, G. 14; N, 7.73 Example 3 1-(5-tumethylaminonaphthalene-1-sulfonyl)-18-hexahydro-1,4-noazepine scribe maleate pale yellow needles Melting point 175-176° ( EtOH) Elemental analysis value C1□H 23 N302S ” C4H
404 theory (mI C, 5G.I]; H.G.
．． 05; N, 9.35 experimental value C, 55.72;
H, G. 31; N, 9.30 Example 4 1-(naphthalene-2-sulfonyl)-18-hexahydro-1,4-noazepine hydrochloride Colorless separate product 1. '． j 195-198° (EtOH) elemental analysis value C engineering. H. N2C'2S ” H C 1・l
/2 9H,OH Theoretical value C, 54, 93: H, G, 34; N,
8.01 Experimental value C,,54,94; H,6,24
: N, 7.84 Example 5 l-(2-chloronaphthalene-1-sulfonyl)-IH
-Hexahydro-1,4-diazepine hydrochloride 2-chloro-1-naphthalenesulfonic acid potassium salt 2
．． Add 4.50 g of phosphorus pentachloride to OOg and heat at 60° for 1
Heat and stir for an hour. After the reaction, the reaction solution is poured into water ice and extracted with benzene. After the benzene layer is dehydrated, the solvent is distilled off to obtain 1.70 g of 2-chlorna-7talenesulfonyl chloride as a yellow liquid. Then homopiperazine 2. OOg
After adding dropwise the previously obtained liquid chloroform 101 solution to the chloroform 301 solution under water cooling and stirring, at room temperature,
Stir for 1 hour. The reaction solution is concentrated, and the resulting residue is dissolved in an aqueous hydrochloric acid solution and washed with ethyl acetate. The aqueous layer is made alkaline with potassium carbonate and then extracted with chloroform. After dehydrating the chloroform core, 1.70 g of a yellow liquid was obtained by distilling off the solvent. This was converted into a hydrochloride salt by a conventional method to obtain 1.51 g of pale yellow crystals. Re-crystallization from ethanol gives pale yellow needle crystals with a melting point of 201-203°. Elemental analysis value Cl, HF ClN202S/HCI theoretical value C, 49,87; H, 5,02; N, 7.
75 Experimental value CI 49.63; H, 5,29;
Nt 7.55 Compounds of Examples 6 to 17 are obtained analogously to Example 5 using substituted naphthalene sulfonic acid potassium salts. Example 6 l-(4-chloronaphthalene-1-sulfonyl)-IH
-Hexahydro-1,4-diazepine hydrochloride pale yellow prism melting point 217-219' (MeOH) elemental analysis value C
HClNO3-HCl theoretical value C, 49,87; H, 5,02; N,
7.75 Experimental value C, 49, G2; H, 5, 18;
N, 7J3 Example 7 l-(5-chloronaphthalene-1-sulfonyl)-IH
-Hexahydro-1,4-diazepine hydrochloride Colorless prismatic product Melting point 198-200° (MeOH) Elemental analysis value C15H1□ClN202SIHC1・l
/2H20 ■Ron Inao C, 48, 1liS; H, 5, 1
F; N, 7.57 Experimental value C, 48, 49;
H, 5,42; N, 7.55 Example 8 l-(5-bromnaphthalene-1-sulfonyl)-1H
-Hexahydro-1,4-diazepine 11 hydrochloride pale yellow crystal Melting point 196-200° (MeOH) Elemental analysis C15H17B r N202S *H
'CI theory ViC, 44, 40; H, 4, 47;
N, 8.90 experimental value C, 44,10; H, 4,
71; N, Ili, 5G Example 9 l-(5-iodonaphthalene-1-sulfonyl)-IH
-Hexahydro-1,4-diazepine hydrochloride brown needle crystals Melting point 246-248' (decomposition) (G20-MeOH-Et20) Elemental analysis values Cl, H, 1N2Q2S-HCI theoretical values C, 39,79; H, 4, 01; N, G, I
9 experimental values C, 39,74; H, 4,28; N,
5.9G Example 10 1-(6-chloronaphthalene-1-sulfonyl)-IH
-Hexahydro-1,4-diazepine Φ hydrochloride Colorless needles Melting point 234-235° (MeOH) Elemental analysis values, C engineering, H engineering, ClN2O. S@HCI theoretical value C, 49,87; H, 5,02; N, 7.
75 experimental value C, 49, 81; H, 5, 25; N
, 7.45 Example 11 1-(8-bromnaphthalene-1-sulfonyl)-IH
-Hexahydro-1,4-diazepine hydrochloride colorless needle crystals Melting point 239-241° (decomposition) (MeOH) Elemental analysis value C15H17B r N202S @HC1 theory ViC, 44,40; H, 4,47; N, G
, 90 experimental value C, 44, 1G; H, 4, C9;
N, 6.81 Example 12 1-(8-iodonaphthalene-1-sulfonyl)-IH
-Hexahydro-1,4-diazepine Pale yellow crystal Melting point 129-130' (EtOH) Elemental analysis value C
15H171N202S theoretical value C, 43, 28;
H, 4, 12; N, 6.73 experimental value C, 43, 4
3: H, 4, 29; N, G,! 2 Example 13 1-(7-chlornaphthalene-1-sulfonyl)-IH
-Hexahydro-1,4-diazepine hydrochloride colorless needle crystals Melting point 185-187° (EtOH) Elemental analysis value C,, H1□CI N202S @ HC
1 Theoretical value C, 49,87; H, 5,02; N,
7.75 Experimental value C, 49, 75: H, 5, 20
; N, 7.65 Example 14 1-(5-chlornaphthalene-2-sulfonyl)-IH
-Hexahydro-1,4-diazepine hydrochloride Colorless crystal Melting point 226-229' (DMSO-EtOH) Elemental analysis C15N17 CI N202S 1LHC
I theoretical value C, 49,87; H, 5,02; N,
7.75 Experimental value c, 4a, ci4; H, 5,
09; N, 7.52 Example 15 1-(8-chlornaphthalene-2-sulfonyl)-IH
-Hexahydro-1,4-diazepine hydrochloride pale yellow needle crystals Melting point 233-235° (MeOH) Elemental analysis C engineering, H F ClN202SIHC1 Theory fjI C,49,87; H,5,02; N,
7.75 Experimental value C, 49,9G; H, 5,22
; N, 7.84 Example 16 1-(7-chlornaphthalene-2-sulfonyl)-IH
-Hexahydro-1,4-diazepine hydrochloride Colorless crystal Melting point 198-201° (EtOH) Elemental analysis C1s N17 CI N202S・HC
I theoretical value C, 49,87; H, 5,02; N,
7.75 Experimental value C, 49,27; H, 5,07
; N, 7.52 Example 17 1-(8-chloronaphthalene-2-sulfonyl)-IH
-Hexahydro-1,4-diazepine hydrochloride pale yellow needle crystals Melting point 195.5-197.5° (MeOH) Elemental analysis value C15H17ClN2Q2s @ HC1
I17 C, 49,87; H, 5,02;
N, 7.75 experimental value C, 49,82; H,
5,2G;N, 7.70 Example 18 1-(2-methquinnaphthalene/-1-sulfonyl)-1
H-hexahydro-1,4-ene azepine hydrochloride 2-methoxynaphthalene2. OOg chloroform 61
A solution containing 2.5 ml of chlorosulfonic acid in chloroform 61111i was added to the solution under stirring under water cooling, and the mixture was stirred for 30 minutes. After the reaction, pour the reaction solution into ice water and separate the chloroform layer. After the chloroform layer is dehydrated, it is added dropwise to a solution of 3.70 g of homopiperane in chloroform 51 under water cooling and stirring, and the mixture is stirred at room temperature for 30 minutes. The solvent was distilled off, the resulting residue was dissolved in an aqueous hydrochloric acid solution, and then washed with ethyl acetate. The aqueous layer is made alkaline with potassium carbonate and extracted with chloroform. After the chloroform layer is dehydrated, the solvent is distilled off. This was converted into a hydrochloride salt using a conventional method to obtain 0.85 g of colorless crystals. Recrystallization from methanol gives colorless needles with a melting point of 210-212°. Elemental analysis value C engineering. H2oN203S11HC1 theoretical value C, 53,85; H, 5,93; N, 7.8
5 Experimental direct C, 53, 71; H, G, lO;
N, 7.51 Analogously to Example 18, using substituted naphthalenes, the compounds of Examples 19 to 24 are obtained. Example 19 1-(4-fluoronaphthalene-1-sul7yl)-1
8-hexahydro-1,4-diazepine + 1 hydrochloride colorless needle crystal Melting point 213-213.5° (EtOH) Elemental analysis value
C15N17 F N202S ” HC1 theory (ri
C, 52,25; H, 5,2S; N, 8.12
Experimental value C, 52, +4; H, 5, 33; N,
8.02 Example 20 1-(4-methoxynaphthalene-1-sulfonyl) -
18-hexahydro-1,4-diazepine hydrochloride colorless needle crystal Melting point 208-209.5° (EtOH) Elemental analysis value
(46H2ON203S ” HC1 theoretical value C, 53
, 85; H, 5, 93; N, 7.85 experimental value
C, 53,78; H, 6,06; N, 7.73 Example 21 1-(4-methylnaphthalene-1-sulfonyl)-IH
-Hexahydro-1,4-diazepine hydrochloride pale yellow needle crystals Melting point 198-200.5° (Etol () elemental analysis value C,, H2oN20°S @ HC1 theoretical value C,5
G, 38; H, Ei, 21; N, 8.22 Experimental value C, 5G, 12: H, lli, 25; N,
7.85 Example 22 1-(4-ethylnaphthalene-1-sulfonyl)-IH
-Hexahydro-1,4-diazepine hydrochloride Colorless scales Melting point 109.5-110.5° (Etou-Et20
) Elemental analysis value C engineering. H22N20□5-HCI theoretical value c, 57.53; H,8,53: N97.8
9 Experimental values C, 57, 13; H, 6, 77; N,
7.74 Example 23 1-(5-nitronaphthalene-1-sulfonyl-IH-
Hexahydro-1,4-diazepine hydrochloride Light reddish brown scales Melting point 228-231' ()12o-EtoH
) Elemental analysis value C engineering 5 H 17 N304S' H
C 1 theoretical value C, 48.45; H, 4.8
8;N. 11.30 Experimental value C, 48.17;
H, 5. H; N, 11.18 Example 24 1-(5-cyanonaphthalene-1-sulfonyl-IH-
Hexahydro-1,4-diazepine hydrochloride colorless needle crystals Melting point 254-256” (N20-EtO)1)
Elemental analysis value C engineering. H F N302S @HCI111/
2H20 theoretical value C, 53.2G; H, 5.3
1; N, IIJ4 experimental value C, 53.14; H
, 5.32; N. Il. 53 Example 25 1-(4-hydroxynaphthalene-1-sulfonyl)-
To a solution of 2.94 g of 18-hexahydro-1,4-diazepine hydrochloride homopiperazine in 10 ml of chloroform was added 1.58 g of 4-acetyl ox-7-1-naphthalenesulfonyl chloride in 10 ml of chloroform under stirring while cooling with water.
After dropping the solution, it is stirred at room temperature for 1.5 hours. The reaction solution was condensed, and the resulting residue was made acidic by adding an aqueous solution of hydrochloric acid, and then heated under reflux for 1 hour. The reaction solution is condensed, ethanol is added to the resulting residue, the precipitated crystals are collected by filtration, and then recrystallized from ethanol to obtain 1.00 g of pale brown crystals with a melting point of 222-224°. Elemental analysis value C15HI3 N203S @HC1 theoretical value C, 52,55; H, 5,59; N, 8.
17 Experimental value C, 52, 57; H, 5, 75; N
, 7.85 Example 26 1-(5-hydroxynaphthalene-1-sulfonyl)-
Into a solution of 4.74 g of 1H-hexahydro-1,4-diazepine hydrochloride homopiperazine in chloroform 51,
While cooling with water and stirring, a solution of 2.10 g of 5-acetyloxy-1-naphthalenesulfonyl chloride in chloroform 20i1 was added dropwise, and the mixture was stirred at room temperature for 1 hour. Furthermore, a solution of 0.82 g of sodium hydroxide in 5 n+l of water and 51 liters of ethanol is added to the reaction solution, and the mixture is heated under reflux for 2 hours. Mix the reaction solution l:i
After shrinkage, an aqueous hydrochloric acid solution is added to the resulting residue and the precipitated crystals are collected by filtration to obtain 2.01 g of a yellowish brown solid. Recrystallized from a mixture of methanol and ether, melting point 242 ~
A 245° (decomposed) Ei2 brown prism product is obtained. Elemental analysis values C engineering, H engineering. N203S ” HC1 theoretical value C, 52, 55; H, 5, 5: It; N,
8.17 Experimental value C, 52, 21; H, 5, 94;
N, 8.08 Example 27 1-(5-acetylamino/naphthalene-1-sulfonyl)-18-hexahydro-1,4-diazepine 5-acetylamino-1-naphthalenesulfonic acid, sodium salt 8.40 g Sulfonic acid 17.00ml
and heat and stir at 35" for 4.5 hours. After the reaction,
The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration to obtain 6.80 g of 5-acetylamino-1-naphthalenesulfonyl chloride as light brown crystals. Next, 30 ml of ethyl acetate containing the crystals obtained earlier was added to a 1/8 solution of homopiperazine 12 and 00 g of chloroform in 30 ml of chloroform under stirring while cooling with water.
The suspension is stirred overnight at room temperature after 4 hours. The reaction solution was concentrated, water and ethyl acetate were added to the resulting residue, and the precipitated crystals were collected by filtration to obtain 1.22 g of colorless crystals. lf-crystallization from ethanol yields a colorless needle-like product with a melting point of 179-180°. Elemental analysis value C F H2, N303S ■Ron I Nao C,58,77; H,6,0!3
; N, 12.03 experimental value C, 58,82; H
, G, 01; N, 12.10 Example 28 1-(5-aminonaphthalene-1-sulfonyl)-IH
-Hexahydro-1,4-diazepine hydrochloride 1-(5-aryaminonaphthalene-1-sulfonyl) -18-hexahydro-1,4-diazepine 0.
Add 10% aqueous hydrochloric acid solution 101 to 70g, and add 211::
1 Heat to reflux. After the reaction, water is added to the reaction solution and extracted with chloroform. After the chloroform layer is dehydrated, it is made acidic with ethanolic hydrochloric acid, and the precipitated crystals are collected by filtration to obtain 0.50 g of yellow crystals. 11 crystals from water, melting point 2
06-208° yellow scales are obtained. Elemental analysis value C engineering, H engineering, N302S112HC1・l
/ 2 H20 theoretical value C, 4G, 52; H, 5
,72; N,IO,85 Experimental value C,411i,17
; H, 5,80; N, 10.52 Example 29 1-(6-acetylaminonaphthalene-1-sulfonyl)-LH-hexahydro-1,4-noazepine hydrochloride 6-acetylamino-1- Naphthalenesulfonic acid, sodium salt 6.25g and chlorosulfonic acid 13.00ml
was added, and heated and stirred at 35° for 4.5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. After dehydrating the ethyl acetate layer, it was added dropwise to a solution of 8.30 g of homopiperazine in 20+1 ethyl acetate under water cooling and stirring, and the mixture was stirred in room M for 1 hour. After the reaction, an aqueous hydrochloric acid solution is added to the reaction solution, and the precipitated crystals are collected by filtration to obtain 3.18 g of colorless crystals. Recrystallized from a mixture of dimethylformamide and ether, melting point 263.
Colorless scales of ~265° are obtained. Elemental analysis value C, N2. N303S11HC1 theoretical value C, 53,19; H, 5,78; N, 10.8
5 Experimental values C, 52,87; H, 8,09; N,
11.04 Example 30 1-(8-aminonaphthalene-1-sulfonyl-IH-
Add 251 g of a 10% aqueous hydrochloric acid solution to 2.50 g of hexahydro-1,4-diazepine hydrochloride 1-(6-acetylaminonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine hydrochloride, Heat to reflux for 1 hour. After the reaction, the reaction solution is made alkaline by adding an aqueous sodium hydroxide solution, and then extracted with chloroform. After the chloroform layer was dehydrated, it was made acidic with ethanolic hydrochloric acid, and the precipitated crystals were collected by filtration to obtain colorless crystals. Get OOg. F from dimethyl sulfoxide and ethanol mixture
IT crystallization gives light brown needles with a melting point of 198-201°. Elemental analysis value C, H, N302S ・2HC 1 Theoretical value C, 47J2; H, 5.59; N,
11.11 Experimental value C, 47.31; H, 5.
8Ei; N, 10.75 Example 31 1-(6-methylnaphthalene-1-sulfonyl)-IH
-hexahydro-1,4-diazepine hydrochloride 6-methyl-2-naphthalenesulfonic acid sodium 1
．． 0.80 ml of f-onyl chloride is added to a suspension of 70 g of dimethylformamide 101, and the mixture is heated and stirred at 70 to 80° for 1 hour. Pour the reaction solution into ice water and filter the precipitated crystals. The obtained crystals are dissolved in chloroform and dehydrated using a water washer. The solvent was distilled off and 6-methyl-2-
1.12 g of naphthalenesulfonyl chloride are obtained. Next, to a solution of 1.39 g of homopiperazine in 201 chloroform was added a solution 1 of the crystals obtained previously in chloroform under stirring while cooling with water.
After dropping 01, the mixture was stirred at room temperature for 1 hour. Thereafter, 0.58 g of colorless crystals were obtained by performing the same operation as in Example 1. Recrystallized from ethanol, melting point 195.5-1
Colorless scales of 96.5° are obtained. Elemental analysis value C engineering. N2oN20□SIIHC1・I/
4H20 theoretical value C, 55J4; H, G. 27
; N, 8.11 experimental value C, 55.59; H
, G. 39; N, 7.78 Patent applicant: Hokuriku Pharmaceutical Co., Ltd. (voluntary) 1. Display of case 1986 patent application No. 161500 2
, Title of the invention Naphthalene sulfonamide derivative 3, Person performing extraction IL 5, Subject of amendment Column 6 of "Detailed explanation of the invention" in the first specification, Contents of the amendment (1) Specification 3, page 37, line 17 After that, add the following sentences. “Example 32 1-(4-iodonaphthalene-1-sulfonyl)-18
-Hexahydro-1,4-noazepine chloride hydrochloride Homopiperazine 2.80 g of chloroform 101 solution was cooled with water and a solution of 3.29 g of 4-iodonaphthalene-1-sulfonyl chloride in chloroform 201 solution was added dropwise, and the temperature was increased to 1M in the room. Stir for 1 hour. Add water to the reaction solution and extract with chloroform. The chloroform layer is extracted with an aqueous hydrochloric acid solution, the aqueous layer is made alkaline with potassium carbonate, and then extracted with chloroform. After the chloroform layer is dehydrated, the solvent is distilled off. The resulting residue was subjected to column chromatography (
Silica gel, chloroform-methanol (20:1)
) to obtain 3.23 g of a brown liquid. It is converted into a hydrochloride salt by a conventional method and recrystallized from water-methanol to obtain a reddish-brown prism product with a melting point of 231-234° (decomposition). Elemental analysis value C15N17 I N202S ・HC
I theoretical value C, 39,79; H, 4,01; N, 8
．． 19 Experimental value C, 39J4; H, 4, 12: N
, 8.24 In the same manner as in Example 32, the compound of Example 33 is obtained using 4-promonafucrene-1-sulfonyl chloride. Example 33 1-(4-bromonaphthalene-1-sulfonyl)-18
-Hexahydro-1,4-diazepine hydrochloride pale yellow prism product

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. , lower alkylamino group, lower acylamino group, nitro group or cyano group), and pharmacologically acceptable acid addition salts thereof.