JPS58128365A - 5-sulfamoylsalicylamide derivative, its preparation and use - Google Patents

Abstract

NEW MATERIAL:The compound of formulaI(R<1> is halogen; R<2> and R<3> are H or lower alkyl; R<4> and R<5> are H, halogen, lower alkyl, etc.; R<6> is halogen, lower alkyl or lower alkoxy; X is O, S, sulfinyl or a bond; n is 0-3) and its salt. EXAMPLE:4-Chloro-N-(5-methyl-2-phenoxyphenyl)-5-sulfamoylsalicylamide. USE:Diuretic and hypotensive agent. PROCESS:The compound of formulaIcan be prepared by reacting the substituted salicylic acid of formula II or its reactive derivative at the carboxyl group with the substituted aniline of formula III or its reactive derivative at the amino group, preferably in the presence of a condensation agent (e.g. N,N'-dicyclohexyl carbodiimide, phosphorus trichloride, etc.) in a solvent such as methanol.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 5-sulfamoylsalicylamide derivatives and salts thereof having diuretic and antihypertensive effects, and more specifically, in the formula, R1 represents a halogen atom, R2 and R3 are the same or different and represent a hydrogen atom or a lower alkyl group; R and R are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a halo (low i ) alkyl The present invention relates to 5-sulfamoylsalicylamide derivatives and salts thereof, their production methods, and diuretic/hypertensive agents containing them as active ingredients.

The definitions of each substituent in the above general formula (1), which is the object compound of this invention, will be explained below.

Examples of the halogen atoms in Pl, R4, R5 and R6 include chlor, bromo, iodo and fluoro, and among these, chloro and fluoro are preferred.

The lower alkyl group in R2, Sawa 6, R4, R5 and R6 is a straight chain or branched chain hydrocarbon residue having 1 to 7 carbon atoms, specifically methyl, ethyl, propyl, isopropyl, butyl. , isobutyl, secondary butyl,
6th butyl, pentyl, impentyl, neobenz
UJ! ;2P! Examples include t, pentyl, 39th pentyl, hexyl, heptyl, and the like.

Examples of the lower alkoxy group in R4, R5 and R6 include methoxy, polyoxy, propoxy, impropoxy, butoxy, isobutoxy, secondary butoxy, 6th butoxy, pentyloxy, isobutylamide, neopentyloxy, secondary Examples include tertiary pentyloxy, tertiary pentyloxy, hexyloxy, etc., and preferred examples include methoxy, ethoxy, etc.

The halo (lower) alkyl group in R4 and R5 is
The above-mentioned halogen is substituted at any position of the above-mentioned lower alkyl group, specifically chloromethyl, pro-7methyl, iodomethyl, dichloromethyl,
Dibromomethyl, difluoromethyl, trifluoromethyl, chloropropyl, chlorobutyl, chloropentyl,
Examples include chlorohexyl and the like, and the most preferred among these is trifluoromethyl.

The lower alkanoylamino group in R4 and R5 is an amino group substituted with a lower alkanoyl group such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, invaleryl, pivaloyl, hexanoyl, etc. Preferred examples thereof include formamide, Examples include acetamide, propionamide, butyramide, isobutyramide, and the like.

Examples of the 5-nulfamoylsalicylamide derivative (1) include salts with bases such as amorphous earth metal salts and ammonium salts.

The object compound (1) of this invention can be obtained by the following method.

Production method 1 General formula: [In the formula, R1, R2 and R3 have the same meanings as above] Substituted salicylic acid or its reactive derivative at the carboxy group is substituted with the general formula: [In the formula, R4, R5,
R6, X and n each have the same meanings as before] substituted aniline or its amino group represented by [wherein R1, R2, R3, R4, R5, R6, X and n each have the same meanings as before] A method for obtaining a 5-sulfamoylsalicylamide 8-derivative or a salt thereof.

Manufacturing method 2 [wherein, R1, R2, R3, R4, R5, R6 and n
each has the same meaning as before] A compound represented by or a salt thereof is subjected to an oxidation reaction [wherein R1, R2, Sawa3, R4, R5, R6 and n each have the same meaning as before] 5-null represented by A method for obtaining a famoyl salicylamide derivative or a salt thereof.

Next, the above manufacturing method will be explained in detail.

Production method 1 The target compound (1) and its salt are obtained by adding a substituted aniline represented by the general formula (Tsukuda) or a reactive derivative thereof to the amino group to a substituted salicylic acid represented by the general formula (It) or a reactive derivative thereof at the carboxy group. It is produced by making it act.

Examples of reactive derivatives at the carboxyl group of salicylic acid represented by the general formula (1) include acid halides such as acid chloride and acid bromide, methyl esters, bromoethyl esters, methyl esters, and cyan methyl esters. IER conversion aliphatic ester, phenyl ester, 3.5-dibromophenyl ester, benzyl ester and other esters containing aromatic rings;
Formed by esters containing heterocycles such as pyridyl esters and 2-pyridon-1-yl esters, esters with N-hydroxy compounds such as 'N,N-dimethylhydroxylamine, carbonate esters, haloformic acid esters, etc. Examples include mixed acid anhydrides, N-substituted amides or unsubstituted amides such as N-methylamide and N-phenylamide, acid azides, acid hydrazides, organic phosphoric acid esters, and nryl esters. Among these, acid halides are the most preferred example.

Examples of reactive derivatives of the substituted aniline represented by the general formula (Ill') at the amine 7 group include reaction products with phosphorus compounds such as phosphorus trichloride and phosphorus oxychloride, dialkyl, and V is the reaction product with orthophenylenechlorohonupite, alkyl is the reaction product with aryl dichlorophosphite, isothiocyanate of amine, substituted urea, sulfamide, isocyanate 1-, base of ship, hydrochloric acid, hydrogen bromide Examples include salts with acids and the like, and reaction products with silyl compounds such as trimethylsilyl chloride.

When the free acid (If) and the free amine (0]) are reacted, it is preferable to carry out the reaction in the presence of a condensing agent. Examples of such a condensing agent include N, N'- Dicyclohexylcarbodiimide, N-cyclohexyl-N
l-morpholinoethylcarbodiimide, N-cyclohexy)v-Nl-(4-diethylaminocyclohexy/I
/) Carbodiimide, N,N'-diethylcarbodiimide, N,N'-diethylcarbo-11-shiimide, N,N',-diisopropylcarbodiimide, N-ethyl/l/-N'-(3-dimethylaminopropyl)carbodiimide , N, Nl-carbonylbis(
2-methylimidazole), pentamethyleneketene-N
-Cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride,
Triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5-(3-
Sulfophenyl/l/)inoxazolium hydroxide, (chloromethylene)dimethylammonium chloride, 2.2.4.4.6.6-hexachloro-1,3,
Condensing agents such as 5,2,4,6-triazatrifonuphine, triphenylphosphine and carbon tetrahalides such as carbon tetrachloride and carbon tetrabromide or halogens such as chlorine, bromine and iodine are used. Illustrated. Among these, the most preferred condensing agent is phosphorus trichloride.

This reaction is carried out in the presence or absence of a solvent, and methanol, ethanol, butanol, acetone, benzene, toluene, chlorobenzene, siogysan, chloroform, dimethylformamide, etc. are often used as solvents, but there are also other solvents that are used in this reaction. Any general organic solvent that does not have an adverse effect can be used.

1. The target compound (Ia) and its salts can also be obtained by subjecting a compound represented by the general formula (Ia) or its salts to an oxidation reaction.

Examples of oxidizing agents used in this oxidation reaction include chlorine,
Halogens such as bromine, iodine, periodic acid and its salts, N-halocarboxylic acid amides, hypohalous acid esters, iodosyl compounds; perbenzoic acid, mechchloroperbenzoic acid, monoperoxyphthalic acid, performic acid, chloroperacetic acid , organic peracids such as peracetic acid, trifluoroperacetic acid, manganese dioxide,) manganese compounds such as permanganate; chromic acid such as chromium oxide (5), dichromate, chromate, chromyl chloride, and chromate ester and its salts; lead tetraacetate; ruthenium tetroxide; oxygen; ozone; water peroxide*; inorganic nitrogen compounds such as nitric acid and dinitrogen tetroxide; organic compounds such as dimethyl sulfoxide and ethyl azodicarboxylate; In addition, electrolytic oxidation can also be used, but the method is not limited to these methods, and all oxidation methods capable of converting a thio group into a nurfinyl group can be applied. In particular, the reaction often proceeds simply and advantageously using organic peracids such as perbenzoic acid, trichloroperbenzoic acid, peracetic acid, and trifluoroperacetic acid.

The solvent is appropriately selected depending on the type of oxidizing agent, but solvents that do not have an adverse effect on the oxidation reaction are often used, such as 1M', chloroform, dichloromethane, benzene, pyridine, water, tetrahydrofuran, dimethylformamide, and dioxane. be done.

The reaction temperature is not particularly limited, and the reaction can be carried out either under cooling or under heating.

The target compound (1) obtained by the above method is isolated and purified by conventional methods, and if desired, can be converted into various salts by conventional methods. .

Incidentally, among the raw material compounds (1), (1) and (lv) in the above production method, the new compound can be obtained by the method shown in the Examples or by a chemically equivalent method.

As is clear from the following test results, the object compound (1) of the present invention has diuretic and hypoallergenic effects and is useful as a therapeutic agent for hypertension and edema associated with various diseases.

Diuretic effect test method: SD male and female rats aged 6 weeks or older fasted for 18 to 24 hours. After oral loading of 20 d/Ky of physiological saline, the test drug was suspended in 0.5% kiln cellulose and 100 V5
waste//K9 administered orally). Urine was collected up to 6 hours after administration of the test drug, and the urine volume, Na, K, and R- electrolytic W concentrations, and uric acid concentrations were determined.

The table below shows the relative values of the rats administered with each test substance when the control group was set as 1.0.

Antihypertensive effect test method: suspended in peanut oil and tested twice a week (301
1f//Y171 times) Administer subcutaneously. At the same time as DOCA administration begins, 1% saline is given instead of drinking water.

After 5 to 7 weeks, the animals were treated with an average surface pressure of 150 to 200 MgHg, and 111 molluscs were administered intrathecally (10 Da/immediately).

Blood pressure is determined by connecting a cannula inserted into the femoral artery to a blood pressure transducer to determine the average blood pressure. The percentage decrease in mean blood pressure 6 hours after administration of the test drug is shown in the table.

Test compound: “'74-2゜a”-N-to’-9a”a-2119,
8-16 = Test results; As is clear from the above test results, the object compound of the invention has excellent diuretic and hypotensive effects.

The object compound (1) of this invention or a salt thereof is usually administered at a dose of 2 to 500 μg/day, 1 to 4 times a day, such as tablets, granules, powders, capsules, syrups, injections, suppositories, etc. administered in the form of The dosage may be adjusted as appropriate depending on the patient's age, body weight, symptoms, etc., or depending on the administration method. The various formulations mentioned above can be manufactured by conventional methods using conventional additives.

Next, the present invention will be explained with reference to examples.

Example 1 5-methy)v-2-phenoxyaniline (5,0&),
4-chloro-5-sulfamoylsalicylic acid (6,3P
) and phosphorus trioxide (1,7!f) in anhydrous chlorobenzene (150 ml), and the solution was stirred for 1 hour and heated to reflux. After the reaction was completed, the solvent was separated by decantation while hot, and the residue was separated. is washed with hot benzene (50 g/).The previously separated chlorobenzene solution and tobenzene washing solution are combined and left overnight, and the resulting crystals are added.When recrystallized from aqueous methanol, colorless needle-shaped 4-chloro -N-(5
-methy/l/-2-phenoxypheny/L')-5-nulfamoylsalicylamide 4/6 hydrate (8,41
7) is obtained. mP2O3-205℃.

Engineering E (Nujol): 3530.3300.2700.
1640,1595°1335.1165cIn NMR (DMSO-d, s, δ): 2.40 (3H,
S), 3.50 (IH, S.

D20 disappearance), 6.92-7.50 (8H, m),
7.50 (2H, s.

D20 disappearance), 8.40 (IH, S), 8.66 (IH
,s).

10.76 (IH, s, D20 disappearance) Elemental analysis: (C20H+zCdN205S・4/3H
20) Calculated values: C52,58, H4,34, H6,1
3, H2O3,26 actual risk m: C52,09, H4,1
5, H6,04, H2O4,78 Example 2 Rusalicylamide (2,85y) is obtained. mp212-
216°C (recrystallized from aqueous methanol) 6IR (Nujol): 3450.3360.3300.3120.1
650i1HMR(DMSO-dJ:3.60(1H,
S, D20 disappearance), 758-7.58-7.68 (9H
, m), 7.58 (2H, S, D20 disappearance).

8.28 (IH, d, J = 8H2), 8.68 (IH
, S), 10.24 (1H, s, D20 disappearance) 19- Elemental analysis: (C19H15Nzc104S) Calculated value:
C56,65,H3,75,H6,95 Experimental value: C5
6,52,H3,68,H6,93Next WeekSabe In the same manner as in Example 1, 2-(2-chlorophenoxy)
Aniline (3,91 and 4-chloro-5-sulfamoylsalicylic acid (4,51) colorless needle-like crystals of 4-chloro-N-C2-C2-chlorophenoxy) Phenyl/L/
) -5-sulfamoylsalicyl'7mide (3,1
obtain f). mP2O6 - 208°C (recrystallized from aqueous methanol).

Engineering R: 3400, 3170.1645.
16103-1HMR (DMSO-d6): 3.20
(IH,s, D20 disappearance).

6.68-7.79 (8H, m), 7.54 (2H
, 8, D20 disappearance).

8.50-8.63 (IH, m), 8.21 (IH, S
), 10.97 (IH, 8, D20 disappearance) Elemental analysis: (C19H14N2C120sS) Calculated value: C50,34, H3,11, H6,18 Experimental value:
C49,95, H3,02, H6,1520 Example 4-2-(2-)lyloxy)aniline (3,2y), phosphorus trichloride N,1y) and anhydrous chlorobenzene (70g/
) and stir for 5 minutes at room temperature. 4-chloro-5-sulf7moylsalicylic acid (4,0,F) is added to this solution, and the mixture is stirred and heated under reflux for 1.5 hours. After the reaction is completed and heated, the solvent is separated by decanting, and the yellow residue is washed with hot benzene (50℃?). The previously separated chlorobenzene solution and tobenzene washing solution are combined, n-hexane (SO) is added to this mixture, and the mixture is left overnight. Add the precipitated pale yellow crystals and dry. Two-layer recrystallization from aqueous methanol gives colorless needle-like crystals of 4-chloro-5-sulfamoy/L/-N-(2-(2-)!J/reoxy)phenyl]salicylamide (5,09). mP2O
0-202°c0 Engineering R (nujo-/l'): 3400.3330.327
D, 3200, 1650G 'NME? (DMSO-
d): 2.10 (3H, s), 6.63-Otsu 69 (
8H, m), 7.54 (2H, s, D20 disappearance),
8.50-8.63 ('1H, m), 8.69 (IH,
S), 11.08NH,s.

D20 disappearance) Elemental analysis: (C20H17C1N205S) Calculated value:
C55,49, H3,96, N6.47 Experimental value: C
55,68, H3,87, N6.41 Example 5 In the same manner as in Example 4, 2-(4-)IJ-ruoxy)aniline (3,2y) and 4-chloro-5=sulfamoylsalicylic acid (4 , Oy) to colorless needle-like crystals of 4-chloro-N-(2-(4-)lyloxy)phenyl]-5
- Sulfamoyl salicylamide (recrystallized from aqueous methanol).

Engineering R (Nujol): 3400.3390.3210,
1650.

1605m-1 NMR (DMSO G6): 2.35 (3H, 8),
3.40 (IH, S.

D20 disappearance), 6.86-7.67 (8H, m
), 7.5'6 ('2H, s.

D20 disappearance), 8.50-8.67 (IH, m),
8.73 (11H, s).

11, []3 ('IH, s, D20 disappearance) elemental analysis: (
C2oH17ClN205S) Calculated value: C55.49,
H3.96, N6.47 Experimental value: C55.84, l
-13.77, N6.59 Example 6 4-chloro-2-phenoxyaniline hydrochloride ('3.1
y) is suspended in water (20%), 10% aqueous sodium hydroxide solution is added to this suspension to make the liquid alkaline, and then extracted with ether. The ether layer is separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4-di-rho-2-phenoxyaniline (2.4y) as a colorless oil.

4-chloro-2-phenoxyani IJ obtained above
(2.4 y) 4-chloro-5-sulfamoylsalicylic acid (3.0 y) and phosphorus trichloride (0.79 y)
) is mixed with anhydrous chlorobenzene (60 m/), and the solution is stirred and refluxed for 2.5 hours in a nitrogen stream.

After the reaction is completed, the solvent is separated by decanting when hot, and the remaining yellow residue is washed with hot benzene (100 ml). Combine the previously separated chlorobenzene solution and tobenzene washing solution,
Add n-hexane (100 liters?) to this mixture and leave it overnight.

The precipitated pale yellow needles were added and recrystallized from aqueous methanol to give colorless needles of 4-chloro-N-'(4-chloro-2-phenoxyphenylene/l')-5-sulfamoylsalicyl. Amide (2.7y)'! Ru. mp
243-245°C0 Engineering R (Nujol): 3400, 3240.3050,
1655.

1600, 1590, 1360.1165z 'NMR
(DMSO-d): 3.40 (IH, brd.s)
, 6.90 (1H.

d. , J=2Hz), 7.04 to 7.60 (7H, m
), 7.52 (2H.

s), 8.56NH, d, J=10Hz), B. 64(
1'H. S).

if]. 90 (IH, S) Elemental analysis: (C1, H14C12N205S) Calculated value:
C50.34, H3.1 1, N6.1 8 Experimental values: C50.65, H3.1 1, N6.07
Example 7 2-phenoxy-5-°trifluoromethylaniline (
3.0y), 4-chloro-5-sulfamoylsalicylic acid (3.OF) and phosphorus trichloride (082y) were mixed in anhydrous chlorobenzene (60 ml), and the solution was incubated in a nitrogen stream for 2.5 hours. Stir and reflux.

After the reaction is completed and hot, the solvent is separated by decanting and the residue is washed with hot benzene (100g+/-). Combine the previously separated chlorobenzene solution and benzene cleaning solution, and add n
- Add hexane (200*Z) and leave in the refrigerator overnight. The precipitated crystals are collected, washed with a mixed solvent of benzene and n-hexane, and then air-dried. When this crystal is recrystallized from aqueous methanol, 4-chloro~
N-(2-phenoxy-5-trifluoromethylpheni/L/)-5-nurfumoylsalicylamide (3.5
3') is obtained. mp215-217°C.

Engineering E (Nujol): 3400.3300.1650.
1580.

1540, 1330, 1175crI'NMR (DMS
O-46, δ): 3.66 (IH, s, D20 disappearance).

7,00 to 7.83 (8H, m), 7.78 (2H,
s, D20 disappearance).

8, 73 (IH, s), 9.02 (IH, d, J=2f
lHz), 11.40 (j) 1, S, D20 disappearance) Elemental analysis - (C2oH14N2C4F305S) Calculated value: C49.34, H2.90, N5.75 Experimental value:
C49.31, H310, N5.71 Example 8 In the same manner as in Example 1, 5-chloro-2-(phenylthio)aniline (6,7F) and 4-chloro-5-sulfamoylsalicylic acid (6,OF ), colorless needle-like crystals of 4-chloro-N-(5-chloro-2-phenylthiophene/l/)-5-71 famoyl salicylamide (6,
5)). mI] 210-212°C (recrystallized from aqueous methanol-μ).

Engineering R (nuji * zushi): 3320, 3250.165
5.1575.1320°1280, 980 steel NMR (DMSO-d 6.δ) near, 01S ~7.
74 (8E (, m), 7.56 (2H, S, D20 disappearance) t 8.66 (IH, S), 8.71 (IH, S
, D20 disappearance), 1130 (1H, s, D20 disappearance) Elemental analysis = (C49H14C12N204S2) Calculated value:
C48,62, H3,01, N5.97 experiment ff:
C48,l, H3,02, N5.91 Example 9 6-chloro-2-phenoxy, aniline i, 0F) 4-
Chloro-5-sulfamoylsalicylic acid (3,5)) and phosphorus trichloride (0,94y) were dissolved in anhydrous chlorobenzene (
60 ml) and stirred and refluxed for 16 hours in a nitrogen stream. After the reaction is completed and heated, the solvent is separated by decanting and a yellow 8
The residue is washed with hot benzene (100 ml). The previously separated chlorobenzene solution and benzene washing solution are combined and concentrated under reduced pressure to 3011/ml. Add n-hexane (200+l) to this solution and leave to cool. When the precipitated pale yellow needle crystals are added and recrystallized from a mixed solvent of leiobenzene and n-hexane, colorless needle crystals of 4-chloro-N
-(6-chloro-2-phenogysipheni/V)-5-sulfamoylsalicylamide (1,7p) is obtained. mp
166-170°C.

IR (nujo-zlz): 3270, 1645, 158
0.1330.1160t7n”NMR(DMSO-
46, δ): 6.86-7.59 (11H, m).

8.66 (IH, s), 10.36 (IH, s, D20
Disappearance) Elemental analysis: (C1, H14C12N205S) Calculated value: C50,34, H3,11, N6.18 Experimental value: C50, []6. FI3.16. N6.09 Example 1
0 In the same manner as in Example 7, colorless needle-shaped 4-chloro- N-(3-chloro-2-phenoxyphenylene/l/)-5-sulfamoylsalicylamide (4
, 2F) are obtained. mI) 225-230°C (recrystallized from aqueous methanol).

IR (nujo/l'): 3550.3230.31
50,1640.

1590.1325.1175~ NV port R ('DMSO-+-t, δ):4. D(1
H,brd,s,D20nB)6.84~7.50('
10H, m), 8.50-8.73 (2H, m).

10, Near 6 (1H, s, D20 disappearance) elemental analysis: (C
1, H14C12N205S) Calculated value: CsO, 34,
H3,11, N6.18 Experimental value: C50,4B, H5,
16,N6.09 Example 11 In the same manner as in Example 7, 2-(6-chlorophenoxy)
Aniline 1. OF) and 4-chloro-5-sulfamoylsalicylic acid < s, 5y) 4-
Chloro-N-(2-('3-chlorophenoxy)phenylcy 5-sulfamoylsa 28-ritylamide (3,9y) is obtained. mI) 218-22
1°C (recrystallized from aqueous methanol).

IR (Nujoko M): 3430,33 [10,3100
, 1660, 1360゜1170m-1 Ninka (DMSO-(16, δ): 6.80-7.62(
9H, m), 7.46 (2H, s, D20 disappearance),
8.40-8.60 (IH, m).

8.58(IH,,S), 10.70(IH,s,
, D20 disappearance) Elemental analysis: (C1, H14Ce2N20
5S) Calculated values: C50, 34, H3, 11, N6.1
8 experimental values: C5D, D4, H3,22, N6.06
Example 12 In the same manner as in Example 7, 6-methy1v-2-phenoxyaniline (2,7y) and 4-chloro-5-sulfamoylsalicylic acid (3,59) were prepared in the same manner as in Example 7. −
Chloro-N-(6-methy/l/-2-phenoxyphenylene/V)-5-sulfamoylsalicylamide (3,
2y) is obtained. mI) 205-208°C (recrystallized from aqueous methanol).

Engineering R (Meshor): 3400.3340.1635,
1340°1170α-1 NMR (DMSO-(16,δ):226(3H,S)
, 6.66-7.59 (10H, m), 7.46 (2
H,s, D20 disappearance), 8.56 (IH,s), 1
0.13 (IH,s, D20 disappearance) Elemental analysis: (C2
oH17C4N205s, 115H2o) Calculated value: C
55,04, H4,02, H6,42, H20B3 Experimental values: C54,91, H3,99, H6,14.

20076 Example 13 In the same manner as in Example 7, 2-(4-chlorophenoxy)
Aniline (5,Qy) and 4-chloro-5-sulfamoylsalicylic acid (6,5y) to give colorless needle-like crystals of 4-chloro-N-C2-C'4-chlorophenoxy)phenyl-5-sulfamoyl Salicylamide (s, a#) is obtained. mp 230-233°C (recrystallized from aqueous methanol).

IR (nuji a-pre C3400, 3230, 1640,
1360°1170z' NMR (DMSO-d 6.δ) near, DO~7.66
(8H, m).

7.10 (IH,s, D20 disappearance), 7.53 (2
H,s.

D2071'j%: ), 8.55-8.66(
IH,m) -866 (IH,S).

10.79 (IH, s, D2C @ Somo) Elemental analysis: (C
1, H14C42N205S/115H20) Calculated value:
C49,95,E(3,18,H6,16,E(20
0.79 Experimental value: C49.76, H2.95, H6
,02,H200,83 Example 14 In the same manner as in Example 1, colorless needles were prepared from 5-me-1-xy-2-phenoxyaniline (3,OF) oyohi 4-chloro-5-nulfamoylsalicylic acid (3,5y). crystal 4
-chloro-N-(5-methoxy-2-phenoxophene/l/) -5-nulfamoylsalicylamide (4,
3F) is obtained. mp185-189°C (recrystallization using a mixed solvent of acetone-methanol-water).

IP (Nujol): 3400.5300, 1680.
1360.

170tM NMR (DMSO-(16,δ): 3.79(3H,S
), 6.67f-7,59(9H,rn), 7.53
(2, H, s, D20 disappearance).

8.26 (1H, d, J=3.0Hz), 8.66<I
H,s).

10.79 (IH, S, D20 disappearance) Elemental analysis: (C2oH17N2C4O6S) Calculated value:
C53,52, ] (3,82, H6,24 experimental value: C!
53.19. H3,68,H5,84 Example 15 In the same manner as in Example 7, 5-chloro-2-(4-chlorophenoxy)aniline i, Oy) and 4-chloro-5
- From sulfamoylsalicylic acid (3,0y), colorless needle-like crystals of 4-chloro-N-[5nichloro-2-(4-10
(lophenoxy)phenyl) -5-'7. /L/7moyl salicylamide (3,7y) is obtained. mp219-
221°C (recrystallized from aqueous methanol).

IR (medi-1-pre): 3350, 1660, 160
0.1340°1170n' NMR (DMSO-d 6.δ): 6.84-7.5
0 (9H, m).

8.58 (2H, s), 10.83 (IH, s) Elemental analysis' (C19H13N2Cj?305S) Calculated value:
C46,79, H2,69, H5,74 Experimental value: C4
6,49, H2,64, H5,57 Example 16 In the same manner as in Example 1, 5-chloro-2-phenoxyaniline (2,4y) and 4-chloro-5-(dimethylnulfamoy/v) Colorless needle-like crystals of 4-chloro-N-(5-chloro-2-phenoxyphenylene/V)-5-dimethylsulfamoylsalicylamide (4,Oj') are obtained from salicylic acid (3,0y).

mp213-214°C (acetone-mep)-)v-recrystallized from a mixed solvent of water).

Wang, R (nujiqzshi): 5300, 1630, 159
0.1335°1160m” NMR (DMSO-d 6.δ): 2.76 (6H, s
), 6B6-759 (8H, m), 8.66 (IH, d
, J=2.0Hz), 11.03 (IH.

S, D20 disappearance) Elemental analysis: (C211 (18C42N205S) calculated value: C52,40, H3,77, H5,82 experimental value:
C52,38, H3,74, H5,68 Example 17 In the same manner as in Example 1, 2,3-dichloro-6-phenoxyaniline (2,5F) and 4-chloro-5-sulfamoylsalicylic acid (2 , 5y) to obtain 2-Ichiban phenoxypheni/V)-5-sulf7 moyl salicylamide (1,6,9'). mp122
-160°C (decomposition) (recrystallized from a mixed solvent of toluene-n-hexane).

Engineering R (Nujo Sole): 3670, 1645, 1365
．． 1160αNMB (DMSO-d 6.δ): 6
B5-7.6+ (8H, m).

7.46 (2H,s, D20 disappearance), 8.50 (IH
, S), /10.26 (IH, s, D20 disappearance) Elemental analysis: (C1, H16C16N205S) Calculated value: C
46,79, H2,69, N5.74 Experimental value: 046.
7+, H2,84, N5.35 This starting material 2,6-dichloro-6-phenoxyaniline is obtained as follows.

(1) tert-butynitrite (t-buty)v (4,7y) and anhydrous cupric chloride (4,9y) were dried in acetonitrile (150m/
) and mix under water cooling. A solution of 2-chloro-6-ditro-4-phenoxyaniline (7, OF) in anhydrous acetonitrile ('3.0 diluted) was added dropwise to this solution at 3-5°C for 11 hours while stirring.

After the addition was completed, the mixture was further stirred at room temperature for 1.5 hours, and then the solvent was distilled off from the reaction solution under reduced pressure. The resulting dark brown residue was treated with diethyl ether) v (200+++t) and 65% hydrochloric acid (6
After adding CI+/) and shaking, the organic layer is separated.

The organic layer is washed successively with saturated brine, saturated hydrogen carbonate solution, and then saturated brine, and then dried over anhydrous magnesium sulfate. The brown solid obtained by distilling off the solvent under reduced pressure was recrystallized from aqueous methanol to give yellow needle-like crystals of 2,6-dichloro-6-(phenoxy)nitrobenzene (47y).
get. mp82~84°C0 Engineering R (Nushor Cl530, 1360ff ”NM
R (carbon tetrachloride, δ): 6.76 (1H, d, J = 9
．． 0Hz).

6.97-7.40 (5H, m), 7.40 (IH, d
, J=9.0Hz) Elemental analysis: (C12H7Ce2NO
3) Calculation: C50,74, H2,48, N4.9
3 Experimental values: C50,85, H2,/)1, N4.9
6(2) Iron powder (5,0y) and ammonium chloride (0
, 5sn in ethanol (60 l) and water (10 l)
) and stir and reflux for 15 minutes.
The ethanol solution of 2,6-dichloro-6-(phenoxy)nitrobenzene (s, Oy) obtained in step 1) was added dropwise over 40 minutes while stirring and refluxing. After the addition is complete, the mixture is refluxed for an additional 3 hours with stirring. The reaction solution is filtered while hot to remove insoluble inorganic substances. The solvent was distilled off from the furnace solution under reduced pressure, and the resulting residue was dissolved in diethyl ether (200 ml). This solution is sequentially washed with a saturated aqueous sodium hydrogen oxide solution and saturated brine, and dried over anhydrous magnesium sulfate.

The oily residue obtained by distilling off the solvent under reduced pressure was crystallized from petroleum ether to give 2,3-dichloro-6- as grayish brown needles.
Funinoxiani! Get J (4,3y). m956
~58°C0 Engineering R (nujol: 3460, 3380.1610α
NMR (carbon tetrachloride, δ): 4.23 (2H,S),
6.50-7.40 (7H, m) Elemental analysis: ('Cl2H,0ff2NO) Calculated value:
C56,72, H3,57, N5.51 Experimental value: C5
6,97, I (3,56, N5.58 Example 18 In the same manner as in Example 1, 2-phenoxyaniline (2,
06y-) and 4-chloro-5-sulfamoylresalicylic acid (2,8y) to produce colorless fine needle-like crystals of 4-chloro-N~(2-phenoxyphenyl)-5-sulfamoylsalicylicylamide (2,1y). ). m9199-2
00°C (recrystallized from aqueous ethanol).

IP (Nujol): 3450.3300.1660,
1360°1170α NMR (DMSO-46, δ) near, 00-7.42 (
11H, m) Elemental analysis: (C1, H15N2C4O5S
) Calculated values: C54.48, H3.61, N6.69.
S7.66C18,46 Experimental value: C54,22, H5,54, N6.65,
S7.84.

CIB, 56 1? Example H♀ 2-1.4.5-1-rimethoxyphenoxy)aniline ('3.29y) and -(3
,4,5-)rimethoxyphenoxy)phenyldi-5-
Nulphamoyl salicylamide (3,3F) is obtained. m
p220-222°C (recrystallized from aqueous methanol).

Engineering R (nujo/shi): 338Q, 3250, 1630
．． 1160 anNME (DMSO (16, δ): 3.6
0 (3I-T, s), 3.66 (6H, s).

6.41 (2H, s), 6.92~7.23 (4H
, m), 7.50 (2H.

s, D202B), 8.40--i3.63(2
H, m), 10B6 (I H, S, D2071J
) Elemental analysis: (C22H21C4N208S-H20) Calculated values: C5[], 15, H4,40, H5,31,
Setsumotoi 86.0B, Ce6.72, H2O3,41
Experimental value: C48,95,H4,43,H5,18,S
6.12. C16,79°H203,27 Example 20 Recrystallized 2-(phenylthio) from 4-chloro-N-(2-(phenylthio)phenyl 5-sulfamoylsalicylamidotanol) in the same manner as in Example 1. .

Engineering R (Nujol): 3400.3300.1620,
1340゜1175cr” NMEt (DMSO-46, δ) Near, 10~7.6
7 (9H, m), 7.57 (2H, S, D20 disappearance)
, 8.47-8.67 (2H, m) Elemental analysis: (C1
, H15C4N2S204) Calculated value: C52,47,
H3,48, H6,44, Sl 4.75.

(J8.15 experimental values: C52,27, H5,46, N63B, S
l 436. CIB, 65 Example 21 5-chloro-2-phenoxyaniline CB, 73y),
4-chloro-5-sulfamoylsalicylic acid <1o,'
.

y) and phosphorus trichloride (1,73 m?') are mixed in anhydrous chlorobenzene (200 ml) and heated under reflux for 2 hours with stirring. The reaction solution was filtered while hot to remove the yellow residue. Cool the P liquid and add the crystals that precipitate.

After washing the crystals with benzene and recrystallizing them from aqueous methanol, 1/4 of 4-chloro-N-(5-1'rolo-2-phenoxyphenyl')-5,-sulfamoylsalicylamide was obtained as white powdery crystals. Hydrate (11,6y) is obtained. mp199-201°C3lR (Nujo Sole): 3
410.3275.1645, 1530°1350.1
+30.11601'7ff'NMR(DMSO-(
16, δ): 3.20 (IH, S), 6.87-7.
57 (10H, m), 8.70 (2H, S), 11.0
7 (IH, s) elemental analysis: (C1, H14Ce2N20
5S・1/4H20) Calculated value: C49,84, H3,
19, H6, 12 experimental value: C49,41, H3,08
, H5,98 Example 22 4-chloro-5-sulfamoylsalicylic acid (1,6y
) and thionichloride/' (50 ml) are mixed in dry benzene (30 ml) and the solution is heated to reflux with stirring for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was washed with ne-hebutane to give a colorless powder of 4-chloro-5-
Sulfamoylsalicylic acid chloride (1,7y) is obtained.

5-acetamido-2-phenoxyaniline (1,5F
) and powdered potassium carbonate (2,0y) were added to dry acetone (30g?), and to this solution was added a solution of the above-obtained salicylic acid chloride derivative in dry acetone (30*l) at 5-5°C for 30 minutes. Drips in minutes. After the addition was completed, the mixture was kept at the same temperature for 1 hour, and then at 60°C.

Stir for 2 hours. After the reaction is complete, remove insoluble inorganic substances,
Concentrate the filtrate under reduced pressure. The resulting residue is washed with benzene (50 bonito/bonito) to obtain a yellow powder (4.0!?). This powder was recrystallized from aqueous methanol to give a light yellow powder (3,
8y) is obtained. Powder obtained) Ethanol (70 shoulders/)
and a 1N aqueous potassium hydroxide solution (60*l) to remove insoluble materials. The F5 liquid was dissolved in concentrated hydrochloric acid (05 stomach t).
) to set the pI (2.0) and collect the precipitated crystals. When the crystals are washed with water and dried, colorless fine needle-shaped N-
(5-acetamido-2-phenoxyphenyl) −,
4-tffO-5-sulfamoylsalicylamide (
1,7y) is obtained. mp295-298°cD) solution).

Engineering'R (Nujol): 3400.3310.3290
．． 3070,2680°2550.1,640,161
0.1330.1170-1FMR (DMSO-d
6. δ): 2.07 (3H, s), 6.83 to 7.66
(8H, m), 7.50 (2H, 8, D20 disappearance) Elemental analysis: (C21H18N3C406S・1/2H20)
Calculated values: C52.02, H395, N8.67, H
2O1,86 experimental value: C52,16, H3,84, N
8.56, H2O1,97 Example 23 4-chloro-N-(5-chloro-2-phenyl-F-ophenyl)-5-sulfamoylsalicylamide (4,
8,F) in acetic acid (150 liters) and acetone (75*
m-chloroperbenzoic acid (2,1y) in acetic acid (30*t) solution at 6-5°C.
It takes 40 minutes to drip. After dropping, add another 1 at the same temperature.
Stir for an hour. After concentrating the reaction solution to 100*Z under reduced pressure, water (101)+l) was added and left overnight. The precipitated crystals are fixed, washed successively with 50% aqueous methanol and water, and then dried under reduced pressure.

When the obtained crude crystals (4,5y) were recrystallized from a mixed solvent of acetone, methanol and water, 4-
Chloro-N-[5-chloro-2-(phenylsulficono-phenyl-5-sulfamoylsalicylamide (
4,3,Sl') obtained. mp234-237°C0 IR (Nujol): 32.50.3100.1650
．． 1600°1570.1330,1160,1050
Bei-1HMR (DMSO-(16, δ): 4.0 (IH
,brd,s),7.20-7.69(9H,m),7
．． 83 (IH, d, J=8.0Hz).

8.08 (IH, d, J = 2.0Hz), 8.46 (I
H, s) Elemental analysis: (C1, H14N2C4205S2
) Calculated value: C47,02, H2,91, N5.77 Experimental value: C47,03, E(2,81, N5.67 Patent applicant Fujisawa Pharmaceutical Co., Ltd. agent Patent attorney Aomizu High procedural amendment (voluntary) ) April 72, 1981 1. Case description 1987 Patent Application No. 12011 2. Title of the invention 5 - Flufamoyl salicylamide derivative, sono production method and use 3. Person making the amendment Patent applicant 4-3 Doshomachi, Higashi-ku, Osaka (524) Fujisawa Pharmaceutical Co., Ltd. Representative Tomoyoshibe Fujisawa 4, Agent 2-1-6-5 Kashima, Yodoyo-ku, Osaka 532 Column 6 of ``Detailed Description of the Invention'' Contents of Amendment (1) Correct the term ``0,5 polycellulose'' in the bottom two lines of page 16 of the specification to ``05% methyl cellulose.''

(2) 4 lines from the bottom of page 20 17.58～" will be deleted.

that's all

Claims (1)

[Claims] 1. General formula: [In the formula, Fl represents a halogen atom, R2 and H3 are the same or different and represent a hydrogen atom or a lower argyl group, R
4 and R5 are the same or different and are hydrogen atom, halogen atom, lower alkyl group, lower alkoxy group, halo (low M
) alkyl group or lower alkanoylamino group, R
6 is a halogen atom, a lower alkyl group or a lower alkoxy group, X is an oxygen atom, a sulfur atom, a nurfinyl group or a bond, and n is an integer from 0 to 3.] 5-sulfamoylsalicyl represented by Amide derivatives and their salts. 2. General formula: [In the formula, R1 is a halogen atom, R2 and R6 are the same -
[H4 and R
5 is the same or different hydrogen atom, halogen atom, lower alkyl group, lower alkoxy group, halo(lower) alkyl group or lower alkanoylamino group, R6 is a halogen atom, lower alkyl group or lower alkoxy group,
X is an oxygen atom, a sulfur atom, a sulfinyl group, or a bond;
R2, R3, R4, R5, R6, A method for producing derivatives or their salts. [In the formula, R represents a halogen, R and R6 are the same or different and represent a hydrogen atom or a lower alkyl group, R4
and R5 are the same or different and are hydrogen atom, halogen atom, lower alkyl group, lower alkoxy group, halo (lower)
alkyl) V group or lower alkanoylamino group, R
6 represents a norogen atom, a lower alkyl group, or a lower alkoxy group, and n represents an integer of O to 6, respectively] or a salt thereof is subjected to an oxidation reaction [in the formula,
R1, R2, R6, R4, R5, R6 and n each have the same meaning as above.] 5-sulfamoylsalicylamide, characterized in that it obtains a 5-nulfamoylsalicylamide derivative or a salt thereof represented by Method for producing derivatives or salts thereof. [In the formula, R1 is a halogen atom, R2 and R3 are the same or different and are a hydrogen atom or a lower alkyl group, R
4 and R5 are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a halo(lower) alkyl group, a lower ffi, l) an alkanoylamino group, R6 a single halogen, a lower alkyl group, or a lower 5-nulfamoylsalicylamide derivatives or their salts are used as active ingredients. A diuretic/antihypertensive agent characterized by containing: