US3287215A - 6-nitro-2-substituted-benzothiadiazines - Google Patents

6-nitro-2-substituted-benzothiadiazines Download PDF

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US3287215A
US3287215A US117288A US11728861A US3287215A US 3287215 A US3287215 A US 3287215A US 117288 A US117288 A US 117288A US 11728861 A US11728861 A US 11728861A US 3287215 A US3287215 A US 3287215A
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nitro
sulfamyl
dihydro
dioxide
benzothiadiazine
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Jerry E Robertson
Pierro Frank Di
John H Biel
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Colgate Palmolive Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
    • C07D285/26—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals
    • C07D285/28—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
    • C07D285/26—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals
    • C07D285/30—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals with hydrocarbon radicals, substituted by hetero atoms, attached in position 3

Definitions

  • This invention relates to chemical compounds and processes of producing the same. More particularly, this invention is concerned with novel derivatives of benzothiadiazine, their preparation and uses.
  • novel 2-substit-uted benzothiadiazines of the formulas ii 0m n,
  • R is a lower alkyl such as methyl, ethyl, propyl and butyl, halo-lower alkyls such as -B,p, 3-triiluoroethyl, a lower ralkenyl such as ally], a lower alkynyl such as propargyl, a di lower alkyl amino-lower 'alkyl group such as dimethylaminoethyl, phenyl, a phenyl-lower alkyl in which the lower alkyl is straight or branched and the phenyl is unsubstituted or substituted such as with one or more halo, nitro, lower 'alkoxy, lower alkyl or hydroxy groups such as the benzyl, phenethyl, phenylisopropyl, phenylprop
  • the compounds of this invention can be produced by reacting an appropriate 2,4-disulfam-ylaniline with an aldehyde.
  • an appropriate 2,4-disulfam-ylaniline with an aldehyde.
  • the same process is used although with different reactants. These processes will be illustrated separately to maintain simplicity.
  • R R and R have the assigned significance.
  • the compounds of Formula II can be produced by reacting an appropriate 2,4-disulfamylanil-ine with a ketoaldehyde or ketoacetal.
  • the reaction can be represented as follows:
  • R Y and Z have the significance previously assigned and R is a lower alkyl such as methyl or ethyl.
  • aldehydes or equivalent acetals, which can be used in the process are formaldehyde, acetaldehyde, propionaldehyde, n-valeraldehyde, caproaldehyde, benzaldehyde, phenylacetaldehyde, beta-phenylpropionaldehyde, beta-methoxypropionaldehyde, diphenylacetaldehyde, p-chlorophenylacetaldehyde diethyl acetal, bromoacetaldehyde diethyl acetal, dichloroacetaldehyde, trifiuoroacetaldehyde, phenylacetaldehyde dimethylacetal, dichloroacetaldehyde and chloroacetal.
  • ketoaldehydes and their equivalent ketcacetals can also be employed in the process.
  • the compounds of this invention can be produced by reacting the appropriate 2,4-disulfamylaniline with the appropriate aldehyde in the presence of a suitable inert organic reaction medium such as dimethyl formamide and at a moderately elevated temperature such as from about 70 to 150 C. Water can be present in the reaction mixture.
  • a catalytic amount of an acid such as aqueous hydrochloric acid or p-toluenesulfonic acid is included inthe reaction mixture to promote the reaction.
  • the reaction is generally completed in about one-half to three hours.
  • the solvent is removed as by evaporation under reduced pressure, the residue taken up in alcohol and crystallized from aqueous alcohol.
  • the compounds of this invention can be administered in pharmaceutical unit-dosage forms formed by combining one or more of the active compounds with a pharmaceutical carrier and then manufacturing capsules, tabletsand powders therefrom.
  • Such unit-dosage forms can contain about 5 to 500 -mgm., and advisably 5 to -mgm., of one or more of the active compounds of this invention.
  • HzNSO SOaNHRx used in the described process in which R has the assigned meaning could be produced by reacting a 3-keto-7-sulfamyl-ZH-1,2,4-benz0thiadiazine-l,l-dioxide with an alkylating agent to produce a 2-substituted-3-keto-7-sulfamyl-l,2,4-benzothiadiazine-1,1-dioxide and treating said compound with a base to open the ring and form a 2-substituted sulfamyl 4 sulfamyl aniline according to the scheme as reported in J. Am. Chem. Soc. 82, 2042 (1960).
  • NHz S S OzNH-Rz where R has the assigned meaning, can be prepared by reacting S-nitroaniline-2,4-disu1fonylchloride first with ammonia and then with the monosubstituted amine. This process can be represented as follows:
  • the first step of the process is readily effected by bringing 5-nitroaniline-2,4-disulfonylchloride into contact wit-h ammonia, advisably in a suitable solvent and particularly ethanol.
  • the ammonia can be suitably employed dissolved in the ethanol.
  • the reaction proceeds readily at room temperature and can be considered complete in 0.5 to 1 hour.
  • the monosubstituted amine can then be added as in ethanol solution, to the reaction mixture. This reaction also proceeds at room temperature but slightly elevated temperatures serve to promote the reaction.
  • the desired product can be recovered by diluting the reaction mixture with water and partially evaporating the solution to precipitate out the product.
  • Some of the monosubstituted amines which can be used in the process are methylamine, ethylamine, propylamine, isopropylamine, allylamine, benzylamine, phenethylamine, aniline, B,,B,fi-trifluoroethylamine, propargylamine, dimethylaminoethylamine and cinnamylamine.
  • Example 1 -2-methylsulfamyl-S-nitro- 4-sulfamylaniline
  • 6.0 g. (0.180 mole) of monomethylamine in 50 ml. of ethanol was added to the mixture containing 5-nitroaniline-4-sulfamyl-2-sulfonylchloride and the reaction mixture was held at 3035 C. for one hour. Dilution with 500 ml.
  • Example 2 -2-ethylsulfamyl-5-nitro-4-sulfamy[aniline A procedure identical to that given in Example 1 was used except that 0.18 mole of ethylamine was used in place of methylamine. The product was obtained in 75% yield, M.P. 168171 C.
  • Example 3 -2-pr0pylsulfamyl-5-nitr0-4-sulfamylaniline
  • a stirred suspension of 8.5 g. (0.025 mole) of 5- nitroaniline-2,4-disulfonyl chloride in 50 ml. of ethanol at 20 C. was added 10 ml. of cold 5.07 N ethanolic ammonia (0.050 mole) over about one hour. After stirring at about 20 C. for an additional hour, 5.9 g. (0.10 mole) of n-propylamine was added in one portion. The resultant exothermic reaction was controlled with an ice water bath.
  • reaction mixture After one hour of standing at room temperature, the reaction mixture was reduced in vacuo in about one-half of the original volume and then poured into 300 ml. of Water. After standing at room temperature for two days, the solid which separated was collected by filtration, washed with water, dried and pulverized to afford 6.0 g. (71%) of product, M.P. 148153 C. (dec.)
  • Example 5.3 benzyl 3,4 dihydro 2 methyl 6- nitro 7 sulfamyl 1,2,4 benzothiadiazine 1,] dioxide 2 methylsulfarnyl 5 nitro-4-snlfamylaniline (4.1 g., 0.013 mole), 2.3 g. (0.014 mole) of phenylacetaldehyde dimethylacetal, and 1.0 ml. of concentrated hydrochloric acid were dissolved in 25 ml. of dimethylformamide and held at 90-100 C. for 1.5 hours. The solvent was removed in vacuo and the residue dissolved in about 60 ml. of hot ethanol, the solution was filtered, and hot water was added to the cloud point (about 10 ml.). Cooling gave a solid which afforded 4.0 g. (76%) of product, M.P. 240-245 C.
  • Example 8-3 chloromethyl 3,4 dihydro 2 ethyl- 6 nitro 7 sulfamyl 1,2,4 benzothiadiazine 1,1- dioxide Z-ethylsulfarnyl 5 nitro 4 sulfamylaniline (3.0 g.,
  • Example 10 -2-benzylsulfamyl-5-nitr0-4-sulfamylaniline
  • ml. of 5.07 N ethanolic ammonia 0.050 mole
  • 10 g. (0.10 mole) of benzylamine was added in one portion.
  • the exothermic reaction was controlled with an ice water bath.
  • the mixture was poured into 300 ml. of water and allowed to stand at room temperature over- 1 night. The solid was collected, rinsed with water, dried, and ground under ether and then redried to afiord 7.3 g. (75%) of product, M.P. 159-161 C.

Description

United States Patent 3,287,215 6-NlTRO-2-SUBSTITUTED-BENZOTHIADIAZ1NES Jerry E. Robertson, Frank Di Pietro, and John H. Biel,
Milwaukee, Wis., assignors to Colgate-Palmolive Company, a corporation of Delaware No Drawing. Filed June 15, 1961, Ser. No. 117,288 20 Claims. (Cl. 167-65) This invention relates to chemical compounds and processes of producing the same. More particularly, this invention is concerned with novel derivatives of benzothiadiazine, their preparation and uses.
This application is a continuation-impart of copending application Serial No. 35,916, *filed June 14, 1960, now abandoned, and of copending application Serial No. 74,- 229, filed December 7, 1960.
According to the present invention there are provided novel 2-substit-uted benzothiadiazines of the formulas ii 0m n,
NR1 mNso s/ 0, I and N i OzN Y-C-Z N-Rg mNso S/ wherein R is a lower alkyl such as methyl, ethyl, propyl and butyl, halo-lower alkyls such as -B,p, 3-triiluoroethyl, a lower ralkenyl such as ally], a lower alkynyl such as propargyl, a di lower alkyl amino-lower 'alkyl group such as dimethylaminoethyl, phenyl, a phenyl-lower alkyl in which the lower alkyl is straight or branched and the phenyl is unsubstituted or substituted such as with one or more halo, nitro, lower 'alkoxy, lower alkyl or hydroxy groups such as the benzyl, phenethyl, phenylisopropyl, phenylpropyl, p methylbenzyl and p chlorophenethyl groups, a phenyl-lower alkenyl group such as cinnamyl, R is hydrogen, a lower alkyl such as methyl, ethyl, propyl, isopropyl and butyl, a halo-lower alkyl such as chlorornethyl, dichloromethyl, trifluoromethyl and betabromoethyl, an aralkyl group and particularly a phenyllower alkyl in which the lower alkyl is straight or branched and the phenyl is unsubstituted or substituted such as with one or more halo, nitro, lower alkoxy, lower alkyl or hydroxy groups such as benzyl, phenethyl, paramethoxyphenylethyl and diphenylmethyl, a cycloalkyllower alkyl such as cyclopentylmet-hyl and cyclohexylethyl and other such groups in which the cycloalkyl has 5 to 7 carbons in the ring, a cycloalkenyl-lower alkyl in which the cycloalkenyl has 5 to 7 carbons in the ring such as 3-(cyclohexene) -methyl and cycloalkadienyl-lower :alkyl groups in which the cycloalkadienyl has 5 to 7 carbans in the ring such as 5-(1,3-cyclopentadienyD-methyl, Y is a chemical bond or a straight or branched lower alkylene as of 1 to :8 carbon atoms such as methylene, ethylene and propylene and Z is a lower alkyl such as methyl, ethyl, isopropyl, propyl, butyl, isobutyl, tertiary butyl and arnyl, an aryl group such as phenyl and substituted phenyl groups like halophenyl, lower alkoxyphenyl and lower alkyl-phenyl, aralkyl :groups such as phenyl-lower alkyl groups like benzyl and phenylethyl, or a halo-lower alkyl such as chloromethyl, dichloromethyl and bromophenyl.
The compounds of this invention can be produced by reacting an appropriate 2,4-disulfam-ylaniline with an aldehyde. In forming the compounds of Formulas I and 3,287,215 Patented Nov. 22, 1966 11 above, the same process is used although with different reactants. These processes will be illustrated separately to maintain simplicity.
The process of forming the compounds of Formula I can be represented as follows:
wherein R R and R have the assigned significance.
The compounds of Formula II can be produced by reacting an appropriate 2,4-disulfamylanil-ine with a ketoaldehyde or ketoacetal. The reaction can be represented as follows:
wherein R Y and Z have the significance previously assigned and R is a lower alkyl such as methyl or ethyl.
Some of the 2-substituted-2,4-disulfamylaniline derivatives which can be used in this reaction are:
2-methylsulfamyl-4-sulfamyl-5-nitro-aniline, 2-ethylsulfamyl-4-sulfamyl-5-nitro-aniline, 249,5,B-trifluoroethylsulfamyl-4-sulfamyl-5 -nitro-aniline, 2-allylsulfamyl-4-sulfamyl-S-nitro-aniline, 2-propargylsulfamyl-4-sulfamyl-5-nitro-aniline, 2-benzylsulfamyl-4-sulfamyl-S-nitro-aniline, 2- beta-dimethylaminoethyl) -sulfamyl-4-sulfamyl-5- nitro-aniline, 2- bet-a-phenethyl) -sulfamyl-4-sulfamyl-S-nitro-aniline, 2-phenylsulfamyl-4-sulfan1yl-5-nitro-aniline, 2-cyclohexylmethylsulfamyl-4-sulfamyl-5 -nitro-aniline, 2-cyclopenthy1methylsulfamyl-4-sulfamyl-S -nitro-aniline, 2- (para-methoxybenzyl) -sulfamyl-4-sulfamyl-S-nitroaniline, 2- (beta-p-chloro-phenethyl) -sulfamyl-4-sulfamyl-5- nitro-aniline, 2-butenylsulfamyl-4-sulfamyl-5-nitro-aniline and 2-pente-nylsulfamyl-4-sulfamyl-5-nitro-aniline.
Some of the aldehydes, or equivalent acetals, which can be used in the process are formaldehyde, acetaldehyde, propionaldehyde, n-valeraldehyde, caproaldehyde, benzaldehyde, phenylacetaldehyde, beta-phenylpropionaldehyde, beta-methoxypropionaldehyde, diphenylacetaldehyde, p-chlorophenylacetaldehyde diethyl acetal, bromoacetaldehyde diethyl acetal, dichloroacetaldehyde, trifiuoroacetaldehyde, phenylacetaldehyde dimethylacetal, dichloroacetaldehyde and chloroacetal.
In addition, ketoaldehydes and their equivalent ketcacetals can also be employed in the process. Some of the ketoaldehydes which can be used, either as the free aldehyde or as an acetal, are 3-ketobutyraldehyde-ldimethylacetal, pyruvaldehyde, dichloropyruvaldehyde, levulinaldehyde, trifluoromethylpyruvaldehyde, 4-phenyl- 3-ketobutyraldehyde dimethylacetal, 3-ketohexanal-l,4- keto-S-chloro-octanal-l and Z-keto-S-phenyl-pentanal-l,
4-(para nitrophenyl) 3-ketobutyr-aldehyde, 4-(para-trifluoromethylphenyl) 3 ketobutyraldehyde and 4-(metachlorophenyl)-3-ketobutyraldehyde, 3-ketopentanal, 4- ketohexanal, and 3-keto-3-phenylpropanal. The compounds of this invention can be produced by reacting the appropriate 2,4-disulfamylaniline with the appropriate aldehyde in the presence of a suitable inert organic reaction medium such as dimethyl formamide and at a moderately elevated temperature such as from about 70 to 150 C. Water can be present in the reaction mixture. A catalytic amount of an acid such as aqueous hydrochloric acid or p-toluenesulfonic acid is included inthe reaction mixture to promote the reaction. The reaction is generally completed in about one-half to three hours. After the reaction is terminated, the solvent is removed as by evaporation under reduced pressure, the residue taken up in alcohol and crystallized from aqueous alcohol.
Some of the 2-substituted benzothiadiazines which are produced as described are:
2-allyl-3,4-dihydro-6-nitro-7-sulfamyl-1,2,4-benzothiadizine-1,1-dioxide,
' 2-propargyl-3,4-dihydro-6-nitro-7-sulfamyl-1,2,4-benzothiadiazinel l-dioxide, 2-benzyl-3,4-dihydro-6-nitro-7-sulfamyl-l ,2,4-benbothiadiazine-l,1-dioxide, 2-phenethyl-3,4-dihydro-6-nitro-7-sulfamyl-1,2,4-benzothiadiazinel l-dioxide, 2-allyl-3-methyl-3 ,4-dihydro-6-nitro-7-sulfamyl-1,2,4-
benzothiadiazinel l-dioxide, 2-propargyl-3-ethyl-3 ,4-dihydro-6-nitro-7-sulfamyl-1,2,4-
benzothiadiazine- 1 l-dioxide, 2-benzyl-3 -phenethyl-3,4-dihydro-6-nitro-7-sulfamyl- 1,2,4-benzothiadiazine-1,l-dioxide, 2-phenethyl-3-chlor0methyl-3,4-dihydro-6-nitro-7- sulfamyl-1,2,4-benzthiadiazine-1,l-dioxide, 2-benzyl-3 -dichlorornethyl-3 ,4-dihydro-6-nitro-7 -sulfamyl- 1,2,4-benzothiadiazine-1,l-dioxide, 2-allyl-3,4-dihydro-3- (beta-keto-n-propyl) -6-nitro-7- sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide, 2-allyl-3-acetyl-3,4-dihydro-7-sulfamyl-6-nitro-1,2,4-
benzothiadiazine-1,1-dioxide, 2-benzyl-6-nitro-3,4-dihydro-3- beta-keto-n-propyl -7- sulfamyl-l ,2,4-benzothiadiazine-l ,l-dioxide, 2-phenethyl-3,4-dihydro-6-nitro-3- beta-keto-n-propyl) 7 -sulfamyl-1,2,4-benzothiadiazine- 1 l-dioxide, 2-ally-3-acetyl-6-nitro-3,4-dihydro-7-sulfamyl-l ,2,4
benzothiadiazine-l 1 -dioxide, 2-benzyl-3,4-dihydro-6-nitro-3-dichloroacetyl-7-sulfamy1- 1,2,4-benzothiadiazine-1,l-dioxide, 2 allyl-3,4-dihydro-6-nitro-3- gamma-phenyl-beta-ketopropyl)-7-sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide, 2-phenylisopropyl-3 ,4-dihydro-6-nitro-3- gamma-tritiuoromethyl-phenyl-bet a-ke to-propyl) -7-sulfamy-l-1,2,4- benzothiadiazinel l-dioxide, 2-propargyl-3,4-dihydro-6-nitro- 3- (gamma-keto-butyl) -7- sulfamyl-l,2,4-benzothiadiazine-1,1-dioxide, 2-propargyl-3 ,4-dihydro-6-nitro-3- (beta-keto-propyl) -7- sulfamyl-l ,2,4-benzothiadiazine-l l-dioxide, 2-benzyl-3-acetyl-3,4-dihydro-6-nitro-7-sulfamyl-1,2,4-
benzothiadiazine-l l-dioxide, 2- beta-phenethyl) -3,4-dihydro-6-nitro-3- beta-keto-betaphenethyl)-7-sulfamyl-l,2,4-benzothiadiazine-1,1- dioxide, 2-allyl-3,4-dihydro-6-nitro-3 -propionyl-7-su1famyl-1,2,4-
benzothiacliazine-l l-dioxide, 2-cinnamyl-3,4-dihydro-3- ('beta-keto-n-propyl) -6-nit ro- 7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide, 2-allyl-6-nitro-3,4-dihydro-3- (beta-keto-n-propyl) -7- sulfamyl-1,2,4-benzothiadiazine-1,1-di0xide, 2-benzyl-3 -acety1-6-nitro-3 ,4-dihydro-7-sulfamyl-1,2,4:
benzothiadiazine-1,1-dioxide, 2-allyl-3 ,4-dihydro-6-nitro-3 -dichloroacetyl-7-sulfamyl- 1,2,4-benzothiadiazine-1,1-di0xide,
2-(beta-dimethylaminoethyl)-3,4-dihydro-6nitro-3- (gamma-keto-butyl) -7-sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide,
2-benzyl-3,4-dihydro-6-nitro-3- (beta-keto-beta-phenethyl) 7-sulfamyl-1,2,4-benzothiadiazine-l ,l-dioxide,
2-benzyl-3,4-dihydro-6-nitro-3-propi0nyl-7-sulfamy1- 1,2,4-benzothiadiazine-1,l-dioxide, and
2- (beta-phenethyl) -3,4-dihydro-6-nitro-3- gamma-ke-tobutyl) -7-sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide.
2 methyl 3,4 dihydro-6-nitro-7-sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide,
2 methyl 3 methyl 3,4 -dihydro-6-nitro-7-sulfamyl+ 1,2,4-benzothiadiazine-1,l-dioxide,
2 propyl 3 ethyl-3,4-dihydro-6-nitro-7-sulfamyl-1,2,4-
benzothiadiazine-l,l-dioxide, V
2 methyl 3 phenethyl-3,4-dihydro-6-nitro-7-sulfamyl- 1,2,4-benzothiadiazine-l,l-dioxide,
2 ethyl 3-chloron1ethyl-3,4-dihydro-6-nitro-7-sulfamyl-.
keto propyl)-7-sulfarnyl-1,2,4-benzothiadiazine-l,ldi-
oxide.
These and other compounds of this invention are highly effective diuretic agents which promote the excretion of excess fluid and sodium chloride from animals and are,
therefore, useful in the treatment of congestive heart 1 failure. They are also hypotensive agents.
The compounds of this invention can be administered in pharmaceutical unit-dosage forms formed by combining one or more of the active compounds with a pharmaceutical carrier and then manufacturing capsules, tabletsand powders therefrom. Such unit-dosage forms can contain about 5 to 500 -mgm., and advisably 5 to -mgm., of one or more of the active compounds of this invention.
It had been thought that the reactants of the formula.
OaN NH:
HzNSO SOaNHRx used in the described process in which R has the assigned meaning could be produced by reacting a 3-keto-7-sulfamyl-ZH-1,2,4-benz0thiadiazine-l,l-dioxide with an alkylating agent to produce a 2-substituted-3-keto-7-sulfamyl-l,2,4-benzothiadiazine-1,1-dioxide and treating said compound with a base to open the ring and form a 2-substituted sulfamyl 4 sulfamyl aniline according to the scheme as reported in J. Am. Chem. Soc. 82, 2042 (1960).
Surprisingly, the compounds of the formula NO NH:
This process, however, did not function satisfactorily when methylamine was replaced by ethylamine or benzylamine. Also, it could not be applied successfully to 5-nitroaniline-2,4-disulfonylchloride.
It has been found, however, that the compounds of the formula NO NH:
NHz S S OzNH-Rz where R has the assigned meaning, can be prepared by reacting S-nitroaniline-2,4-disu1fonylchloride first with ammonia and then with the monosubstituted amine. This process can be represented as follows:
NOr- NH:
l NH; C1028 S 0201 NO2 NH: NHFRZ NO NH:
NHzOzS S O2Cl NHzOzS SO2NH-Rz wherein R has the assigned meaning.
The first step of the process is readily effected by bringing 5-nitroaniline-2,4-disulfonylchloride into contact wit-h ammonia, advisably in a suitable solvent and particularly ethanol. The ammonia can be suitably employed dissolved in the ethanol. The reaction proceeds readily at room temperature and can be considered complete in 0.5 to 1 hour. The monosubstituted amine can then be added as in ethanol solution, to the reaction mixture. This reaction also proceeds at room temperature but slightly elevated temperatures serve to promote the reaction. The desired product can be recovered by diluting the reaction mixture with water and partially evaporating the solution to precipitate out the product.
Some of the monosubstituted amines which can be used in the process are methylamine, ethylamine, propylamine, isopropylamine, allylamine, benzylamine, phenethylamine, aniline, B,,B,fi-trifluoroethylamine, propargylamine, dimethylaminoethylamine and cinnamylamine.
Some of the products obtained as described are:
Z-methylsulfamyl-S-nitro-4-sulfamy1aniline,
2-ethylsulfamyl-5-nitro-4-sulfamylaniline,
2-propylsulfamyl-5-nitro-4-sulfamylaniline,
2-allylsulfamyl-5-nitro-4-sulfamylaniline,
6 Z-phenylsulfamyl-S-nitro-4-sulfamylaniline, 2-benzylsulfamyl-5-nitro-4-sulfamylauiline and 2- (beta-phenet-hyl) -sulfamyl-5-nitro-4-sulfamylaniline.
The following examples are presented to illustrate the invention.
Example 1.-2-methylsulfamyl-S-nitro- 4-sulfamylaniline To a stirred suspension of 8.5 g. (0.025 mole) of 5- nitronani1ine-2,4-disulfonylchloride in 50 ml. of ethanol at room temperature was added 39 ml. of cold 1.27 N ethanolic ammonia (0.050 mole) over one hour. After stirring for an additional hour, 6.0 g. (0.180 mole) of monomethylamine in 50 ml. of ethanol was added to the mixture containing 5-nitroaniline-4-sulfamyl-2-sulfonylchloride and the reaction mixture was held at 3035 C. for one hour. Dilution with 500 ml. of water, concentration in vacuo to about 400 ml., and cooling gave a solid which was collected and recrystallized from water to afiord 4.0 g. (55%) of product, M.P. 176180 C. (dec.)
Analysis.Calcd. for C7H1QN4S20Z S, 20.65. Found: S, 20.53.
Example 2.-2-ethylsulfamyl-5-nitro-4-sulfamy[aniline A procedure identical to that given in Example 1 was used except that 0.18 mole of ethylamine was used in place of methylamine. The product was obtained in 75% yield, M.P. 168171 C.
Analysis.-Calcd. for C H N O N, 17.28; S, 19.75. Found: N, 17.42; S, 20.09.
Example 3.-2-pr0pylsulfamyl-5-nitr0-4-sulfamylaniline To a stirred suspension of 8.5 g. (0.025 mole) of 5- nitroaniline-2,4-disulfonyl chloride in 50 ml. of ethanol at 20 C. was added 10 ml. of cold 5.07 N ethanolic ammonia (0.050 mole) over about one hour. After stirring at about 20 C. for an additional hour, 5.9 g. (0.10 mole) of n-propylamine was added in one portion. The resultant exothermic reaction was controlled with an ice water bath. After one hour of standing at room temperature, the reaction mixture was reduced in vacuo in about one-half of the original volume and then poured into 300 ml. of Water. After standing at room temperature for two days, the solid which separated was collected by filtration, washed with water, dried and pulverized to afford 6.0 g. (71%) of product, M.P. 148153 C. (dec.)
Analysis.Calcd. for C H N O S N, 16.57; S, 18.93. Found: N, 16.10; S, 18.61.
Example 4.3,4 dihydro 2 methyl 6 nitro 3- (beta ketopropyl) 7 sulfamyl 1,2,4 benzothiadiazine 1,] dioxide 2 methylsulfamyl 5 nitro-4-sulfamylaniline (4.1 g., 0.013 mole), 1.9 g. (0.014 mole) of 3-ketobutyraldehyde dimethylacetal, and 1.0 ml. concentrated HCl were dissolved in 25 ml. of dimethyl formamide and then held at -100 C. for 30 minutes. The solvent was removed in vacuo and the residue dissolved in about 60 m1. of hot ethanol. After filtration, hot water was added to the cloud point (about ml.) and the solution cooled. A solid separated which aiforded 3.5 g. (71%) of product, M.P. 215-217 C.
Analysis.-Calcd. for C H N O S S, 16.94; N, 14.82. Found: S, 16.85; N, 14.66.
Example 5.3 benzyl 3,4 dihydro 2 methyl 6- nitro 7 sulfamyl 1,2,4 benzothiadiazine 1,] dioxide 2 methylsulfarnyl 5 nitro-4-snlfamylaniline (4.1 g., 0.013 mole), 2.3 g. (0.014 mole) of phenylacetaldehyde dimethylacetal, and 1.0 ml. of concentrated hydrochloric acid were dissolved in 25 ml. of dimethylformamide and held at 90-100 C. for 1.5 hours. The solvent was removed in vacuo and the residue dissolved in about 60 ml. of hot ethanol, the solution was filtered, and hot water was added to the cloud point (about 10 ml.). Cooling gave a solid which afforded 4.0 g. (76%) of product, M.P. 240-245 C.
Analysis.-Calcd. for C H N O S S, 15.56; N, 13.59. Found: S, 15.33; N, 13.57.
Example 6.3 benzyl 3,4 dihydro 2 ethyl 6 nitro- 7 sulfamyl 1,2,4 benzothiadiazine 1,1 dioxide Z-ethylsulfamyl-5-nitro-4-sulfamylaniline (4.2 g., 0.013 mole) was condensed with phenylacetaldehyde dimethylacetal as in Example 5 to afford 4.1 g. (74%) (chloroform washed) of product, M.P. 207-212 C.
Analysis.C-alcd. for C H N O S S, 15.06; N, 13.16. Found: S, 14.87; N, 13.19.
Example 7.3 dichloromethyl 3,4 dihydro 2 methyl 6 nitro 7 sulfamyl 1,2,4 benzothiadiazine- 1,1 dioxide Z-methylsulfamyl-5-nitro-4-sulfamylaniline (10.0 g., 0.032 mole), 5 ml. of concentrated hydrochloric acid and 3.7 g. (0.04 mole) of dichloroacetaldehyde (freshly distilled) were dissolved in 30 ml. of dimethylformamide and the solution Was heated at 90-100 C. for 2.5 hours. The solvent was removed in vacuo and the residue dissolved in a solution of 5.0 ml. of concentrated hydrochloric acid in 100 ml. of ethanol (room temperature). Dilution of this solution with cool water to the cloud point (about 100 ml.) and further cooling gave after another similar recrystallization, 4.1 g. (32%) of product, M.P. 266-267 C. (dec., prior char-ring).
Analysis.-Calcd. for C H Cl N O S Cl, 17.49; N, 13.83. Found: Cl, 16.96; N, 14.02.
Example 8.-3 chloromethyl 3,4 dihydro 2 ethyl- 6 nitro 7 sulfamyl 1,2,4 benzothiadiazine 1,1- dioxide Z-ethylsulfarnyl 5 nitro 4 sulfamylaniline (3.0 g.,
0.0091 mole), 1.45 g. (0.0095 mole) of chloroacetal, and
0.5 ml. of concentrated hydrochloric acid were dissolved in 20 rnl. of dimethylformamide and the solution held at 90-100 C. for 4 hours. The solvent was removed in vacuo and the residue crystallized and recrystallized from dilute ethanolto afford 2.1 g. (60%) of product, M.P.
Analysis-Calcd. for C H ClN S Cl, 9.21; S, 16.66. Found: Cl, 9.29; S, 16.49.
Example 9.3,4 dihydro 2 ethyl 6 nitro 3 (betaoxo beta phenylethyl) ,7 sulfamyl 1,2,4 benzethiadiazine 1,1 dioxide 2 ethylsulfamyl nitro 4 sulfamylaniline (4.5 g., 0.0137 mole), 2.0 ml. concentrated hydrochloric acid and 2.4 g. (0.014 mole) of the sodium salt of 3-keto-3-phenylpropanol were mixed in 25 ml. of dimethylforrnamide. After one hour at 90-100 C., the precipitated NaCl was collected and washed with dimethylformamide. The solvent was removed from the combined filtrate and washings to afford-a gum which was crystallized and recrystallized from dilute ethanol and then from water-acetone to give 0.9 g. (14%) of product, M.P. 221-222 C.
Analysis.Calcd. for c H mo s z C, 44.85; H, 3.90; N, 12.35. Found: C, 45.00; H, 4.00; N, 12.06.
Example 10.--2-benzylsulfamyl-5-nitr0-4-sulfamylaniline To a stirred suspension of 8.5 g. (0.025 mole) of S-nitro-aniline-2,4-disulfonyl chloride and 50 ml. of ethanol at 20 C. was added ml. of 5.07 N ethanolic ammonia (0.050 mole) diluted with 15 ml. of ethanol over about one hour. After stirringat 20 C. for an additional hour, 10 g. (0.10 mole) of benzylamine was added in one portion. The exothermic reaction was controlled with an ice water bath. After stirring at 20-25 C. for another hour, the mixture was poured into 300 ml. of water and allowed to stand at room temperature over- 1 night. The solid was collected, rinsed with water, dried, and ground under ether and then redried to afiord 7.3 g. (75%) of product, M.P. 159-161 C.
Analysis.Ca.lcd. for C H N O S S, 16.58. Found: S, 16.42.
another hour at 20 C. Reduction of the volume by onehalf in vacuo and dilution to about 300 ml. with water gave, after standing 2 days at room temperature, a solid. This material was collected, washed with water, dried,
triturated with ether, and redried to afford 3.0 g. (32%) of product, M.P. 199-201 C.
Analysis.Calcd. for C H N4O F N, 16.93; S, 14.81. Found: N, 17.10; S, 14.87. Example 12.3-benzyl-3,4-dihydr0-6-niir0-7-sulfamyl-Z- ,B,fi,B-triflu0r0ethyl) -1 ,2,4-benz0thiadiazine-1,1-di0xide 1 5-nitro-4-sulfamyl-2-( 3,3,5 trifiuoroethyl)sulfamylaniline (3.8 g., 0.010 mole), 1.7 g. (0.010 mole) of phenylacetaldehyde dimethylacetal, and 0.5 ml. of concentrated hydrochloric acid were dissolved in 25 m1. of dimethylformamide and the solution was held at -l00 C. for The solvent was removed in vacuo and the, 1
4.5 hours.
residue dissolved in about 60 ml. of hot ethanol. This solution was treated with activated charcoal, filtered, and 1 diluted with hot water to the cloud point (about 30 1111.). Cooling gave a solid which was collected, washed with di- 1 lute ethanol and dried to afford 3.5 g. (70%) of product, M.P. 224226 C.
12.92. Found: N, 11.32; S, 12.88.
5-nitro-4-sulfamyl-2-(5,5,;3-trifluoroethyl) sulfarnylaniline (3.8 g., 0.010 mole), 1 drop of concentrated sulfuric acid and 1.4 g. (0.012 mole) of freshly distilled dichloroacetaldehyde were dissolved in 25 ml. of dimethylformamide and the solution held at 90-100 C. for 7 hours. The solvent was removed in vacuo and the residue dissolved in 70 ml. of ethanol. This solution was treated with activated charcoal, filtered, and diluted with 50 ml. of concentrated hydrochloric acid and then water to the cloud point (about 50 ml.). Cooling gave a solid which was collected, washed with dilute ethanol, and dried to afford 2.9 g. (61%) of product, M.P. 236-238 C.
Analysis.Calcd. for C I-I Cl F N O S3: C], 14.98; S,
13.55. Found: Cl, 14.80; S, 13.87.
Example 14. 3-chIoromethyl-3,4-dihydr0-6-nitro-7-sulfamyl-Z-(B,fl,fl-triflu0r0ethyl)'-1,2,4 benzothiadiazine- 1,1-dioxide 5-nitro-4-sulfamyl-2-(fl,;3,/8-trifluoroethyl) sulfarnylaniline (3.0 g., 0.0080 mole), 1.4 g. (0.0090 mole) of chloroacetal, and 0.5 ml. of concentrated hydrochloric acid were dissolved in 25 ml. of dimethylformamide and the solution held at 90-100 C. for 6 hours. The solvent was removed in vacuo and the residue dissolved in 40 m1. of
9 hot ethanol. This solution was treated with activated charcoal, filtered, and diluted with 100 ml. of hot water. Cooling gave a solid which was collected, washed with water and dried to yield 2.5 g. (71%) of product, M.P.
Analysis.Calcd. for C H ClF N O S Cl, 8.08; S, 14.62. Found: Cl, 8.05; S, 14.59.
Example 15.-3,4-dihydro-3-(B-ketopropyl)-6-nitr0-7-sulfamyl-Z-(3,5,,8-trifluroethyl)-1,2,4 benzothiadiazine- Ll-dioxide 5-nitro-4-sulfamyl-2 (fiflfi-trifluoroethyl)sulfamylaniline (3.0 g., 0.010 mole), 1.5 g. (0.011 mole) of 3-ketobutyraldehyde-1-dimethylacetal, and 0.5 ml. of concentrated hydrochloric acid were dissolved in 25 m1. of 'di- Example 16.3,4-dihydro-2-ethyl-3-(fi-ketopropyl) -6-m'- tro-7 -sulfamyl-1 ,2,4-benzothiadiazine-1 ,1 -dioxide 2 ethylsulfamyl 5 nitro 4 sulfamylaniline (2.0 g., 0.00615 mole), 0.5 ml. of concentrated hydrochloric acid, and 1.1 g. (0.0080 mole) of 3-ketobutyraldehyde-l-dimethylacetal were dissolved in ml. of dimethylformamide and the solution was held at 90-100 C. for 30 minutes. The solvent was removed in vacuo and the residue dissolved in 60 ml. of ethanol. This solution was treated with activated charcoal, filtered, and diluted to the cloud point with hot water (about 100 ml.). Cooling gave a solid which was collected, washed with water and dried to afiord 1.4 g. (50%) of product, M.P. 196-199 C.
Analysis.-Calcd. for C H N O' S N, 14.32; S, 16.38. Found: N, 14.38; 8, 16.51.
Example 17.3-dich'l0r0methyl-3,4-dihydr0-2-ethyl-6-nitr0-7-suIfamyl-1 ,2,4-benz0thiadiazine-1 ,1 -dioxide 2 ethylsulfamyl 5 nitro 4-sulfamylaniline (1.3 g., 0.0040 mole), 1 drop of concentrated sulfuric acid and 0.6 g. (0.0050 mole) of freshly distilled dichloroacetaldehyde were dissolved in 20 ml. of dimethylformamide and the solution was held at 90-100 C. for 6 hours. The solvent was removed in vacuo and the residue dissolved in 40 ml. of hot ethanol. The solution was treated with activated charcoal, filtered, diluted with about 100 ml. of concentrated hydrochloric acid and then 30 ml. of water. Cooling gave a small first crop of solid which was collected and discarded. The mother liquor was diluted with about 150 ml. of water and the solid which separated was collected, washed with cold water and dried to afford 0.8 g. of crude product. This material was dissolved in ethanol, reprecipitated with n-hexane, collected and redried to provide 0.4 g. (24%) of product, M.P. 222- 224 C.
Analysis.Calcd. for C H C1 N O S C, 28.64; H, 2.89. Found: C, 28.62; H, 3.20.
Example 18.2 benzyl-3-dichloromethyl-3,4-dihydro-6- nitr0-7sul;famyl-I,2,4-benzothiodiazine-1,1dioxide 2-benzylsulfamyl-5-nitro 4 sulfamylaniline (2.6 g., 0.0067 mole), 1 drop of concentrated sulfuric acid and 0.90 g. (0.0080 mole) of freshly distilled dichloroacetaldehyde were dissolved in 25 ml. of dimethylformamide and the solution held at 90-100" C. for 6 hours. The solvent was removed in vacuo and the residue dissolved in 40 ml. of ethanol. The solution was treated with activated charcoal, filtered, diluted with 100 ml. of concentra'ted hydrochloric acid, and then about 30 m1. of water. Cooling gave a small first crop which was collected and discarded. Dilution of the mother liquor with about ml. of water gave a second crop of solid which was collected, washed with water and dried. This crude product was dissolved in ethanol and reprecipitated with n-hexane to aflord 0.9 g. (28%) of product, M.P. 222-223 C.
Analysis.Calcd. for C H Cl N O S C, 37.43; H, 2.93; N, 11.64. Found: C, 38.16; H, 3.25; N, 11.65.
Various changes and modifications of the invention can be made and, to the extent that such variations incorporate the spirit of this invention, they are intended to be included within the scope of the appended claims.
What is claimed is:
1. A member of the group consisting of compounds of the formulas s a t 0,N- n-R, OIN- n-y-o-z and mN s o NRg HIN s o /NR| wherein R is a member of the group consisting of lower alkyl, halo-lower alkyl, lower alkenyl, lower alkynyl, dilower alkyl amino-lower alkyl, phenyl, phenyl-lower alkyl and phenyl-lower alkenyl groups, R is a member of the group consisting of hydrogen, lower alkyl, halo-lower alkyl, phenyl-lower alkyl, cycloalkyl-lower alkyl, in which the cycloalkyl has 5 to 7 carbon atoms, cycloalkenyl-lower alkyl, in which the cycloalkenyl has 5 to 7 carbon atoms, and cycloalkadienyl-lower alkyl groups, in which the cycloalkadienyl has 5 to 7 carbon atoms, Y is a member of the group consisting of a single chemical bond and lower alkylene groups and Z is a member of the group consisting of lower alkyl, phenyl, phenyl-lower and halo-lower alkyl groups.
2. 2 lower alkyl 3,4 dihydro-6-nitro-3-(beta-keto-npropyl)-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide.
3. 2 lower alkyl 3 acetyl 6-nitro-3,4-dihydro-7-sulfamyl- 1,2,4-b enzothiadiazine- 1, l-dioxide.
4. 2-lower alkyl-6-nitro-3,4-dihydro-3-lower alkanone- 7-sulfamyl-1,2,4-benzothiadiazine-l,l-doxide.
5. 2 methyl 3,4-dihydro-3-(beta-ketopropyl)-6-nitro- 7-sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide.
6. 2 methyl 3,4-dihydro-3-benzyl-6-nitro-7-sulfamyl- 1,2,4-benzothiadiazine-1,1-dioxide.
7. 2 ethyl-3,4-dihydro-3-benzyl-6-nitro-7-sulfamyl-1,2, 4-benzothiadiazine-1,1-dioxide.
8. 2 methyl 3,4-dihydro-3-dichloromethyl-6-nitro-7- sulfamyl-1,2,4-benzothiadiazine-1,1 dioxide.
9. 2 ethyl 3-chloromethyl-3,4-dihydro-7-sulfamyl-6- nitro-1,2,4-benzothiadiazine-1,l-dioxide.
10. 3,4 dihydro 2 ethyl 6-nitro-3-(beta-oxo-betaphenyl ethyl) 7 sulfamyl 1,2,4-benzothiadiazine-1,1- dioxide.
11. 3 benzyl 3,4-dihydro-6-nitro-7-sulfamyl-2-(5,13,13- trifluoroethyl -1,2,4-benzothiadiazine-1, l-dioxide.
12. 3 dichloromethyl 3,4 dihydro 7 sulfamyl-2- (5,3,5 trifluoroethyl)-6-nitro-1,2,4-benzothiadiazine-1,1- dioxide.
13. 3 chloromethyl 3,4-dihydro-6-nitro-7-sulfamyl-2- 3, 8, ,8-trifluoroethyl) 1,2,4-benzothiadiazinel l-dioxide.
14. 3,4 dihydro 3-(fi-ketopropyl)-6-nitro-7-sulfamyl- 2- (8,5,;8-trifluoroethyl 1,2,4-benzothiadiazine- 1, l-dioxide.
15. 3,4 dihydro 2 ethyl-3-(fl-ketopropyl)-6-nitro-7' sulfamyl-1,2,4-benzothiadiazine-1, l-dioxide.
16. 3 dichloromethyl 3,4 dihydro-2-ethyl-6-nitro-7- sulfamyl-1,2,4-benzothiadiazine-1, l-dioxide.
17. 2 benzyl 3-dichloromethyl-3,4-dihydro-6-nitro-7- sulfamyl-1,2,4-benzothiadiazine-1, l-dioxide.
18. 2 lower alkyl 3,4-dihydro-6-nitro-3-haloalkyl-7- sulfamyl-1,2,4-benzothiadiazine-1, l-dioxide.
19. 2 phenyl-lower alkyl 3,4-dihydro-6-nitro-3-haloalkyl-7-sulfamyl-1,2,4-benzothiadiazine-1, l-dioxide.
Refrences Cited by the Examiner UNITED STATES PATENTS 2,910,473 10/1959 Novello 260243 12 Novello 260-243 Novello 260-397.7 Konig et a1 260-3977 McLamore et a1 260-243 De Stevens et a1 260243 NICHOLAS S. RIZZO; Primary Examiner.

Claims (2)

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULAS
20. A PHARMACEUTICAL COMPOSITION IN UNIT DOSAGE FORM CONTAINING 5 TO 500 MGM. OF A COMPOUND OF CLAIM 1.
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EP0264639A1 (en) * 1986-09-25 1988-04-27 Boehringer Ingelheim Kg Aryloxyaminoalkanes, their preparation and use

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US2910476A (en) * 1957-09-13 1959-10-27 Merck & Co Inc Process for preparing benzothiadiazine-1, 1-dioxides
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US2910476A (en) * 1957-09-13 1959-10-27 Merck & Co Inc Process for preparing benzothiadiazine-1, 1-dioxides
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EP0264639A1 (en) * 1986-09-25 1988-04-27 Boehringer Ingelheim Kg Aryloxyaminoalkanes, their preparation and use

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