DE1595954A1 - Benzoazadithiane compounds and their preparation - Google Patents

Description

Benzoazadithlan compounds and their manufacture

The invention relates to benzoazadithiane compounds as well Process for their production

In particular, the invention relates to SuIfamoy1-2,1,4-benzoazadithiane-1,1-dioxide compounds, which have diuretic and aaluretic properties and are therefore useful for Treatments for conditions are those associated with abnormal retention of fluid and / or electrolyte stand"

The invention also relates to the preparation of the benzoazadithiane compounds by cyclization of a 2,4-disulf

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amoylmercaptobenzenes with an aldehyde, acetal, ketone or Ketal.

The preferred compounds of the invention and their Physiologically acceptable salts can be represented by the structural formula below

R ₅ HNO ₂ S-

are shown, in which mean:

R _{1 is} hydrogen, halogen (ie chlorine, brew, iodine _e fluorine), trihalomethyl, in particular trifluonaethyl or trichloromethyl, lower alkyl, lower alkoxy, nitro or amino;

R ₂ and R-, each for hydrogen, low molecular weight alkyl, substituted low molecular weight alkyl, such as haloalkyl or oyoloaliphatic alkyl, cycloaliphatic radicals with 5 or 6 ring carbon atoms, phenyl or substituted phenyl, in particular with alkyl, alkoxy or halogen groups as Substituents, phenalkyl or substituted phenalkyl, in which each of the phenyl or alkyl components or both can be substituted and additional

ORIGINAL

159595 *

7903

borrowed the carbon atoms of the alkyl component a heteroatom or heteroatoms, in particular by

2 3 sulfur can be interrupted; or R and R can be connected to one another and a spiroaliphatic atom to the carbon atom to which they are bound Form a group which can be formed entirely from carbon atoms or one or may contain several heteroatoms, in particular as sulfur, nitrogen or oxygen, and which either unsubstituted or substituted, in particular alkyl or halogen substituted, and R4 and R5 can also be the same or different Radicals from the group hydrogen, lower, -alkyl, substituted lower - alkyl. lower alkeny. · - and the like to be =

The compounds described above can be formulated for oral use by using a diuretic induction and / or saluretic effect sufficient amount of an active ingredient with the usual dilution, extension, Binding «= and / or lubricants mixed, which are used in the manufacture of capsules, pills, tablets or powders or they can be incorporated into elixirs »furthermore, the compounds can be dissolved in aqueous media, which are suitable for parenteral injection

Dis Benzoazadi / chian-Ver »indungen be produced by _t reacting an aldehyde, an acetal or ketone _r * Ke al to the Bi

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captobenzol lets its effect «The implementation is massive Heating the reaction mixture, which advantageously comprises a solvent and an inorganic acid, facilitates heating (Suitable for hydrochloric acid) or an organic acid. The benzoazadithiane is generally in the reaction mixture insoluble and can be separated easily,

The disulfamoyl mercaptobenzene compounds also provide represent new compounds and form part of the invention « This can be prepared by reacting the desired 2,4-disulfamoylhalogenobenzene with sodium polysulfide. The reaction is facilitated by moderate heating of the reactants dissolved in a solvent Disulfamoylmercaptobenzene produced can be separated and purified using conventional methods?

The di- (alkyl8ulfamoyl) mercaptobenzene compounds, in particular those which have a 5-trihalogenoalkyl group, can also be prepared by diazotizing a 5-R -2,4-di- (alkylsulfamoyl) aniline, then reacting the Diazonium compound formed with an alkali metal oxanthate (sodium or potassium xanthate are suitable) to form the 5-R ^^ - Di-ialkylsulfamoylJ-mercaptobenzene compound according to alkaline hydrolysis. This compound is then cyclized by the process described above and obtained End products of the structure shown, wherein R * and R ^ Are alkyl groups,

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The following examples describe the invention in greater detail without restricting it »

example 1

6-chloro-7-8ulfamoyl-2.1 _t 4-benzoazadithiane-1,1-dioxide

Stage A: Preparation of 5-chloro-2,4-di8ulfamoylmercaptobenzene .

A mixture of 6.0 g of 2,4-disulfamoyl-1,5-dichlorobenzene, 5.0 g sodium polysulphide nonahydrate, 1.0 g sulfur in 150 ml Ethanol is heated under reflux conditions for 1.5 hours, cools, filtered and concentrated to dryness in vacuo »the residue it is dissolved in 50 ml of saturated sodium bicarbonate solution, treated with activated charcoal, filtered and acidified with hydrochloric acid on, collects the product and purifies it by precipitation from aqueous sodium bicarbonate solution to obtain 5-chloro-2,4-disulf ~ amoyl mercaptobenzene, pp 282 - 285 ° C, decomposition

Analysis O ₆ H ₇₂₄₅

Calculated: C, 23.78; H 2.33 »S 31.70;

Found: C, 23.70; H 2.25; S 31.56.

Stage Bt Production of 6-0hlor-7-sulfamoyl-2 _t 1.4-benzoazadithiane ° 1 , 1-dioxide

A solution of 3.0 g of 5-chloro-2,4-disulfamoylmercaptobenzene • ^ ₅ BAD ORiGiNAL

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and 0.3 g of paraformaldehyde in 60 ml of ethanol and 60 ml of 6N hydrochloric acid are heated under reflux for 4 hours, cooled, the precipitate is thickened and recrystallized from ethanol-water, whereby 6-chloro-7-sulfamoy1-2.1 ₉ 4 ~ benzoazadithiane-1,1 dioxide as colorless needles, melting point 259 - 262 ° C, decomposition *

Analysis C ₇ H

Calculated: C, 26.68; H 2.24; N 8 _y 89;

Found: C, 27.14; H 2.59; N 8.79 ^

Example 2

6-methyl- »7-aulfamoyl" 2,1,4-benzoazadithiane- ₁ 1-dioxide

Stage A: Production of 5 ~ methyl ~ 2 _y 4-diBulfamoy! Mercaptobenzene

A solution of 10 g of sodium polysulfide nonahydrate and 2.0 g of sulfur in 100 ml of ethanol is refluxed for 30 minutes. 11.2 g of 5-methyl-2,4-disulfamoylchlorobenzene are added and heating is continued for 18 hours, the solution is concentrated to dryness in vacuo, the residue is diluted with 100 ml of water and 25 ml of lithium bicarbonate solution at room temperature, then treated with charcoal, filtered vn * acidified-The product is collected, au & Waaeer and a Spux "Cx.-r.nui recrystallized to yield 5-methyl-2,4 ~ disulfamoy] mercaptobenzene, Pp 228-231 ° C _e

ORIGINAL

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Analysis: CyH ₁₀ N ₂ O ₄ S ^: Calculated: C 29.75ϊ H 5.57j »9.911 Found: G 29.91 | H $ 3.59 N 9.80 *

Step B: Preparation of 6-methyl-7-aulfamoyl-2.1,4-benzoazadithiane-1.1-dihydrate

A solution of 2.8 g of 5-methyl-2,4-disulfamoylmereaptobenzene and 0.4 g of paraffin aldehyde in 30 ml of ethanol and 30 ml of 6N hydrochloric acid are heated for 16 hours under reflux conditions and concentrated to dryness in vacuo. The product is recrystallized from ethanol-water and gives 6-methyl-7-sulfamoyl-2,1,4-benzoazadithiane-1,1-dioxide, pp 234-236 ° C, decomp.

Analysis: CgH ₁ Q ^ OjEU: Calculated: C, 32.60; H 3.42; N 9.52; Found: C, 33.12; H 3.81; H 9.38. Example 3

Spiro-Z6-methyl-7-aulfamoyl-2,1 «4-benzoazadithiane-i. 1 ~ dio3cyd »3» 1 '° (4' -methyl) oyclohexane 7

A solution of 2.8 g of 5-methyl-2 ₉ 4-di8ulfamoylmeroaptobenzol and 4-methyl cyclohexanone! (1.2 ml) in 30 ml of ethanol and 30 ml of 6N hydrochloric acid is heated for 4 hours under reflux and concentrated to dryness in vacuo * The product is collected and

BATHROOM ORIGINAL 7 -

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gives, ", umkripta?" from ethyl acetate-water, spiro / 6-methyl "7-Gulfamoyl-2,1,4-benzoazaditixiun-T, i-dioxide-3 / ' ^l - (4 ^f -methyl) oyclohexane /, M.p. 209-2Vi ⁰ C ^v

Analysis 014H ₂ QN ₂ OiS ,:

Calculated: C, 44.72; H 5.35; N 7.44;

Found: C, 44.96; H 5.56; N 7.48,

Example 4

6 -Bromo-7 "8ulfamoyl ~ 2.1 _t 4-ben7-uazadithian ~ 1 _t 1- dioxyd

This compound is prepared by replacing the 2,4-pisulfamoyl · 1,5-dichlorobenzene used in Example 1, Step A with an equivalent amount of 2 _f 4 · disulfamoyl-1 _f 5 dibromobenzo ?. _? where the reaction conditions according to Example 1, steps A and B are followed and the other reactants mentioned are used .,

Example 5

2-methyl-6-trifluoromethyl-7 ~ methyl8ulfamoyl ~ 2.1 "4-ben zoaz adithian-1, 1» dioxide

Stage A: Production of S-trifluoromethyl ^^ - di-cinethyl "sulfamoyl) -mercaptobenzene

A solution - en 34 _V 7 g (0.1 mol) of 5-trifluoromethyl-2,4-di-

ORIGiNAL 909886/1636

7905

(methylsulfamoyl) aniline in 200 ml of 1N sodium hydroxide is treated dropwise at 0 ° C. with a cold solution of 7 g jiatrium nitrite in 175 ml conc. Hydrochloric acid and then adds that liazonium salt to a solution of 40 g kept at 80 ° C Add potassium ethylxanthate in 150 ml of water. The precipitate is separated off and refluxed for 3 hours with a Solution of 86 g of potassium hydroxide in 150 ml of ethanol and 75 ml of water. The solution is diluted with 1 liter of water »filtered and acidified in the cold with hydrochloric acid collected and recrystallized from alcohol-water and gives 5-trifluoromethyl-2,4-di- (methylsulfamoyl) mercaptobenzene

Stage Bi Preparation of 2-methyl-6-tΓifluormethyl-7Htneth.vl _{8ulfamoyl-2-t-benzoazadithian} 1,4-i, 1-dioxide

This product is produced by cyclizing as described in Step A-5 obtained Trifluormethy1-2,4-di- (methylsulfamoyl) -mercaptobenzol by reaction with ^{para-formaldehyde-i} by substantially the same method described in Example 1, Step B is described.

Example 6

2-Xthyl-6-methoxy-7-ethyl-sulfamoyl-2 , 1,4-benzoazadithiane-1 _t 1 ° dioxide

Stage A: Division of 5-methoxy-2,4 "di- (ethylaulfamoyl) " anjlin

5 "Metho :: yaniline-2,4 ~ aiBulfonylohlori« l {32 g, 0.1 mol)

SAD ORIGINAL

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ΛΟ

portionwise added to 150 ml 40 # strength aqueous ethylamine and heated for one hour on the steam bath * The mixture is cooled, collects the product, washed with water and crystallized from ethanol-water, thus obtaining 5 ~ methoxy-2 _f 4-di- ( ethylsuifamoyl) aniline.

Stage B: Division of 5-methoxy-2,4-di "(ethylaulfamoyl) ~ mercaptobenzene

Bas obtained in stage A product is diazotized and then with Potassium ethylxanthate is reacted according to the method described in Example 5, Step A and gives 5-Meihoxy »" -, 4 · di- (äthy? - ~ sulfamoyl) mercaptobenzene

Stage 0: Preparation of 2 "ethyl-6-methoxy-7-ethyl-8Ülfamoyl-2,1,4-benzoazadithiane-i, 1-oxide

The compound obtained in step B is cyclized by essentially the same procedure as that described in Example i _? Stage B is described with Parafο ^r : '. 'Ehyd and give 2-ethyl-6-methoxy-7-äthylBulfamoyl ~ 2, i, f-Denzoazadithian- Λ. 1 ■ · ♦ Dioxide ^

Example 7

6-methoxy-7-sulfamoyl-2,1,4-benzoazadi thiane-1,1-dioxide

Step A: Preparation of 5-methoxy-2,4 "diaulfamo.ylchlorobenzene

m-chloroanisole (0.5 mol) is added dropwise during a

QAD ORIGINAL

• --η,

9098 8 6/1636

7903

A1

An excess of chloric acid (about 400 ral), cooled in an ice bath, over a period of one hour, 550 g of sodium chloride is added over a period of 2 hours and the mixture is then heated in an oil bath for about 3 hours thoroughly cooling in an ice bath is treated the Reaktionsgemiseh iiiswasaer with one liter, the deposited product _r taken up in ether washed with water and dried. the solvent was removed by evaporation and nimbly "to θ in a El bath cooled residue If) O ml t 28iigem Aiumoniumhydroxyd, As soon as the initially violent reaction naoh-Jaäaat. erv.'ärnit ninn daö Refiktionsgerriach for about one hour on a steam bath ;, cools and collects the precipitated 5-methoxy-2 , 'i'-disulfaracylchlorobenzene

Level B; Herste Settin g of 5- Hethoxy _i-2, 4- ^ disuJ famoylmerc aptς- Bensol

This product is prepared by reacting 5-Methox3 ^r -2,4-disulfamoylchlorbenaol with ITetriumpoljsulfid By essentially the same procedure and using the other reagents in Example 1, Step A. forth.

Level 0; Manufacture of 6 ~ kethoxy-7 "sulfamoyl-2 _f . 1,4-

benz oagadithian-1 _t 1-dioxide

The 5-Metho.xy ·· 2 _e 4-UiSuIfBmOyInIeX ¹ ?, is OaPtObSnSC with Pareform- rlu ^ hyaE according aera in vo3entliehen same procedure cyolj-

BAD ORJGhNAL

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1 59595A

wobbles, which is described in Example 1. "Step B to yield 6-methoxy-7-sulfamoyi ~ 2 _f 1, 4-benzoazadithian-1,1 dioxydo

Example 8

3-dichloromethyl-6-methoxy-7-bulfamoyl-2 _t 1,4-benzoazadithiane-1,1-dioxide

The 7-Bulfamoyl- in Example 7, Steps A and B prepared 5-methoxy "> 2,4-disulfamoylmercaptobenzol is cyclized with dichloroacetaldehyde diethyl acetal according to the _f in Example 1 Step B The method described and obtained 3-dichloromethyl-6 ~ methoxy" 2.1 _t 4-benzoazadithiane ~ 1,1-dioxide _P

Example 9

6-Nitro-7- »Bulfamoyl-2,1.4-benzoazadithiane-i, 1" 4-oxide

Stage As Preparation of 5-Nltro-2 ₁ 4-diBulfamoylmercaptobenzene

This compound is produced by reacting 5-nitro-2,4-di-bulfamoylchlorobenzene with sodium polysulfide, using the method and the other reagents described in Example 1, Step A, was used

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Step B: Preparation of 6-nitro-7-aulfamoyl-2,1 «4-benzoazadithiane * 1,1-dioxide

The 5-nitro-2,4-disulfamoylmercaptobenzene prepared according to stage A then cyclized by reaction with paraformaldehyde according to the method described in Example 1, stage B and receives 6-nitro-7-sulfamoyl-2,1,4-benzoazadithiane-1,1-dioxide

Example 10

6-Amino- »7 ~ sulfamoyl ~ 2 _t 1.4 ° benzoazadithiane-1 _f 1-dioxide

A solution of 3.25 g (0.01 mol) of 6-nitro-7-sulfamoy1-2.1 _{t of} 4-benzoazadithiane-1,1-dioxide (from Example 9) in 500 ml of 50% ethanol-water is hydrogenated at room temperature in the presence of platinum oxide (400 mg) in a Parr apparatus. The catalyst is removed by filtration and the solution is evaporated to dryness in vacuo; the residue is recrystallized from alcohol-water and 6-amino-7-sulfamoyl-2,1,4-benzoazadithiane-1,1-dioxide * is obtained

Example 11

3-Benzylmercaptomethyl-6-chloro-7-bulfamoyl-2,1 ₁ 4-benzoazadithiane-1 _t 1-dioxide

This product is prepared by replacing the paraformaldehyde used in Example 1 ₉ Step B by Benzylmercaptoacetaldehyd and then follows the same method and the

ORIGINAL BATHROOM ... - 13 -

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other reagents are used, which are named there: ··. ·.

eiapiel 12

^, 1,4-benzoazadithiane-1 ₁ 1-dioxide

3,4 '- (1'-ethyl) piperidine 7

This product is prepared by following the procedure described in Example 3 except that the Meroaptobenzene and ketone reactants by 5-chloro-2,4-disulfamoylmercaptobenzene (from Example 1) or 1-ethyl ~ 4-piperidone replaced

Example 13

3t3-Diethyl-6-chloro-7-sulfamoyl "2.1 _t 4-benzoazadlthiane"> _f 1-dioxide

This connection is established by replacing the one in Example 1, Stage B used paraformaldehyde through the ketal 3 »3-diethoxyρentane, using the other reagents and essentially the same reaction conditions as there are described, follows »

Example H

3-Benzyl-7-sulfamoyl-2,1,4-benzoazadithiane-i »1-dioxide

When replacing the 2,4-disulfide used in Example 1, Stage A

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araoyl-1,5-dichlorobenzenes by an equivalent amount of 2,4-DiBulfamoyIchlorbenzol and being the other reagents is used and the reaction conditions are followed, which are described there, the 2,4-biaulfamoylmercaptobenzene is prepared ■ This compound can then be cycled by they are brought to the reaction with phenyl acetaldehyde by the method described in Example t, step B, 3-benzyl-7-sulfamoyl-2,1,4-benzoazadithiane-i, 1-dioxide receives-,

Other 7-sulfamoyl-2,1,4-benzoazadithiane-1,1-dioxide compounds, which after that described in Example 1, stage B. Processes are prepared using intermediates as described in Examples 1 or 2, Step A, are given in Table I. * These compounds are prepared by adding a 5-R-2,4-disulfampylmercaptobenzene, wherein R is chlorine or methyl as indicated in the table below, with the appropriate

ρ
A3.dehyde R CHO, which is also shown in the table below

Is nsnnt 2, brings to reaction to give the 3-R 6-R-7-SuIfamoyl-2,1,4-benzoazadithian-1,1-dioxide compounds, which are referred to in Table I is, ₀

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L / 988606

Table I.

H ₂ NO ₂ S

R ² CHO

SO ₂ NH ₂

H ₂ NO ₂ S

Example R

No.,

(C,
Decomp.)

ANALYZES
CHN

Empirical

formula

Cl Cl-Cl

Cl
Cl
Cl

CH,

CH ₂

216-218 Calculated: 26.44

Found: 27.07

223-224 Calculated: 40.00

Found: 40.42

224-227 Calculated: 41.56

Found: 42.04

251-254 Calculated: 40.98

Found: 41.76

227-228 Calculated: 39.33

Found: 39.83

210-213 Calculated: 46.83

Found: 46.90

248-251 Calculated: 46.20

Found: 46.34

2.22
2.54 7.72
7.57 3.36
3.67 6.22
6.13 3.24
3.96 6.92
6.79 4.66
4.81 6.82
6.71 4.32
4.30
4.20
4.43 7.06
7.30
7.28
7.23 5.67
5.96 7.17
6.97

C ₈ H ₈ Cl ₂ N ₂ O ₄ S ₅

G ₁₅ H ₁₆ N ₂ O ₄ S ₅

C ₁₅ H ₂₂ N ₂ O ₄ S ₅

ve c

VJi

Claims (1)

595954 P 15 95 95 *. 3 ■ ⁷ ^ VSS? **. Merck A Co., Inc. 790? (M 66 616) Claims 1 · 7- sulfaaoyl-2,1,4-henzoazadithlan-l, l-dioxide compounds of the formula and their physiologically usable salts «mean in R | Hydrogen, halogen, trihalomethyl, lower alkyl, lower molar alkoxy, nitro or amino, R ₂ and R, each individually hydrogen, low molar aliphatic, mononuclear aryl or mononuclear arylniedeniol.allphatisohe öruppen or to an identical bit to the nuclear carbon atom to which they are bonded, an allphatic group, and R ^ and R. each for see hydrogen or nlederaol.-alkyl. 2. 6-Chloro-7-sulfanoyl-2,1,4-benzoazadithiane-1,1-dioxld. Nice Unterlaoen (Art 7 a I Para. 2 No. 1 Sentence 3 of the Amendment Lake ·. V. -I ₇ - 909886/1636 _ßAD original J. 6 ~ Methyi-7 "Sulph & moyl <-2,1,4-benzoazadithione.1, i-dioxide 4. Spiro- ^ 5-methyl ~ 7 "sulfainoyl-2., 1, ^ - benxo ^ zadithiane-l ,, 1 dioxide-3 _# 1 '- (4' -methyl)» cycl 5. 3-chloromethyl-6 = chloro, "7-2pl _Eulfaaoyl-i, 4 bsnzoazadithiaii 1,1'dloxid. 6. 3- (3 ^Y , 4'- benzoazadithlan-1 ₃ 1-dioxide. 7. 3 »Benzyl-6-chloro-7-8ulfanioyl-2, l ^ -benzoazadithlan-l, 1-dioxld. 8. 3-Cyclohexylmethyl-6-chloro-7-sulfamoyL-2,1,4-benzoazadithiane ia dioxide. 9. J-Cyolopentylmethyl-e-chloro ^ -sulfamoyl-S, 1,4-benzoazadi thlan-l, l-dicxid. 10. 3 -Ben »yl-6 ° ynethyl-7-8ulfaaoyl-2,1 " 4-bmzoazadithiane-1,1-dioxide. 11 3-Cyolohexylmethyl-6-iiethyl-7-eulfamöyi-2,1 ₁ 4-fcenzoaza- - 18 - 8AD 909886/1636 12. Process ζην production of compounds gent & fls An-Sprüche i to 11, characterized in that “a 2,4-di8ulfamoyl- * I-meroaptobenzene from FohügI .-SH 'NO ₂ S- ^ U-SO ₂ NCT ^ft 5 ^^ ^R 4 in which R ₁ J. Ru and R _{r have} the meanings given above. with an aldehyde or ketone of the formula - 0 in which R ₂ and R- have the meanings just given «or their acetals or ketals _f converts. Medicinal active ingredient consisting of a compound ONE OF THE REQUIREMENTS 1 to 11. BATH ORIGINAL - 19 - 909886/1636