DE1153024B - Process for the preparation of 3 - {[1 ', 1', 1'-Trifluoraethyl- (2 ')] - mercaptomethyl} -7-sulfamyl-3, 4-dihydro-1, 2, 4-benzothiadiazine-1, 1- dioxides - Google Patents

Description

The invention relates to a process for the preparation of 3 - {[l ', l ^/ , l ^/ -trifluoroethyl- (2 ^/ )] - mercaptomethyl} - 7-sulfamyl-3,4-dihydro -1,2,4-benzothiadiazine- l, l-dioxyden of the general formula

CH-CH ₂ -S-CH ₂ -CF ₃ NR ₃

RiHNO ₂ S- ¹

in which Ri is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, R _{2 is} a hydrogen, chlorine or bromine atom, a trifluoromethyl group or an alkyl or alkoxy group containing 1 to 3 carbon atoms and R _{3 is} a hydrogen atom or a methyl, ethyl or n-propyl group, and their salts, preferably with pharmacologically acceptable bases.

The new compounds are prepared by either in a known manner

a) a 2,4-disulfamylaniline of the general formula

NH ₂
SO ₂ NHR ₃

with the aldehyde of the formula

CF ₃ - CH ₂ - S - CH ₂ - CHO

or an acetal or hemiacetal of this aldehyde or condensed
b) a 7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-l, l-dioxide of the general formula

R ₂ -1

RiHNO ₂ S- ¹

v \ _s /

CH-CH ₂ -Y
NR ₃

wherein Y is a halogen atom or an alkyl or arylsulfonic acid radical means in a basic process for preparation

of 3- {[1 ', 1', r-TrifluOrathyl- (20] -

mercaptomethyl} -7-sulfamyl-3,4-dihydro-

1,2,4-benzothiadiazine-1,1-dioxides

Applicant:

Chas. Pfizer & Co., Inc., Brooklyn, NY
(V. St. A.)

Representative: Dr. W. Beil, A. Hoeppener

and Dr. H. J. WoUf, Lawyers,

Frankfurt / M.-Höchst, Antoniterstr. 36

Claimed priority:

V. St. v. America June 3 to September 14, 1960

and February 1, 1961 (No. 33 644, No. 55 869 and No. 86 322)

and Great Britain of July 18, 1960 (No. 24953)

James Michael McManus, Uncasville, Conn.,

and Carl John Buck, Gales Ferry, Conn. (V. St: Α.), Have been named as inventors

Reacts medium with 2,2,2-trifluoroethyl mercaptan;
and optionally subsequently obtained compounds in which R _{3 represents} a hydrogen atom, in the presence of a basic condensing agent or in the form of an alkali metal salt with a compound of the general formula

R ₃ ¹ X

where R ₃ 'represents a methyl, ethyl or n-propyl group and X represents a bromine or iodine atom, converts it and / or converts the compounds obtained with bases into their salts.

In procedure a), an approximately equimolar mixture of the reactants in an inert organic solvent, e.g. Heated B. Butylenglykoldimethyläther or Äthylenglykoldipropyläther on etwa.60 to 120 ⁰ C. It has been found to be between about ¹ Iz and 5 hours. Reaction time, excellent yields of the desired product

309 668/322

products are preserved. Longer reaction times can also be used, but provide no significant benefit. A slight excess of aldehyde or its acetals or hemiacetals, z. Up to 10% can be used; larger surpluses should be avoided as the 3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide yield could thereby be reduced.

If acetals are used instead of the aldehyde, it is advantageous if a small amount aqueous mineral acid is added. In general, a few drops of aqueous acid are sufficient, e.g. B. Hydrochloric acid, sulfuric acid or phosphoric acid. The addition of acid only increases the rate of the reaction.

In the reaction mentioned under b), the reactants are generally in the presence a strong base, preferably an alkali or alkaline earth metal hydroxide. It Organic bases such as tertiary amines can also be used. The mono-, di- and tri-substituted pyridines of the general formula

R ₅

in the R4 a chlorine or. Bromine atom or one Alkyl radical containing 1 to 3 carbon atoms and R5 and Re hydrogen, chlorine or bromine atoms or alkyl groups containing 1 to 3 carbon atoms are preferred. The alkali or Alkaline earth metal hydroxide is best used in the form of an aqueous solution which is im generally contains about 5 to 20, preferably 5 to 15 percent by weight of the hydroxide.

The reaction proceeds satisfactorily in aqueous solution; by adding an organic However, the formation of the desired compounds is made much easier using a solvent, as this results in the reactants, who are only partially soluble in water, in better ones Get in touch. Suitable organic solvents are ketones, such as acetone and ethyl ketone, lower alkanols such as methanol, ethanol and the propanols, and preferably dimethylformamide and similar lower alkylated formamides.

If the reactants are used in equimolar amounts, the yield is good; in order to achieve the best yields, however, excess 2,2,2-trifluoroethyl mercaptan is generally used used An excess of up to about 40 mol percent proved to be particularly suitable, while larger surpluses do not produce any significant benefit.

The reaction is advantageously carried out at temperatures between 20 and 120 ^{° C. for about 1 to 12 hours.} Even longer and stronger heating can result in decreasing yields of the desired product.

When carrying out the alkylation of a compound obtained in which R3 is a hydrogen atom, an alkali metal hydride, alkoxide or amide or an alkali metal alkyl or aryl compound is preferably used as the basic condensing agent, e.g. B. sodium hydride, lithium hydride and potassium hydride, lower sodium and potassium alkanolates, such as sodium methylate and potassium tert-butoxide, sodium amide, lithium amide and potassium amide. This reaction is carried out in an inert, polar organic solvent, preferably in an amide of a saturated lower aliphatic carboxylic acid, the nitrogen atom of which is disubstituted by lower alkyl radicals. Particularly favorable solvents for this alkylation process are, for. B. N, N-dimethylformamide, N, N - diethylformamide, N, N - di - (n - propyl) - formamide, Ν, Ν-dimethylacetamide, N, N-diethylacetamide and Ν, Ν-dimethylpropionamide.
The 3 - {[I ', l', l'-trinuoroethyl- (20] -

mercaptomethyty-T-sulfamyl-i ^ dihydro-1,2,4-benzothiadiazine-1,1-dioxide is approximately equimolar Amount of a compound of the general formula

Rs'X

d. H. with about 0.8 to about 1.25 mol in the presence of the basic condensing agent and the solvent reacted for about 15 minutes to 2 hours at about 5 to 35 ° C. The reaction is generally carried out carried out at room temperature and in a time of less than half an hour. The temperature should in no case be above the upper limit of the specified range, otherwise an undesirable contamination of the end product with a by-product that is in the 2-position and on the sulfamyl group is substituted in the 7-position, would occur. In the case of volatile halides preferably worked in a closed vessel, with the halide by slightly increased pressure is kept in solution. The alkylation can optionally be carried out in the case of less reactive compounds the general formula

Rs'X

by adding an accelerator such as potassium iodide or sodium bromide. The corresponding chlorides can also be used as alkyl halides, if these are suitable Substances, e.g. B. calcium iodide, in a closed tube (cf. Romburgh, Recueil des travaux chimiques des Pays-Bas, 1, p. 151 [1883]) or potassium iodide in methanol (Finkelstein, Chemical reports, 43, p. 1528 [1910]), which contain the desired alkyl bromides or - Form iodides in situ.

This alkylation process gives high yields (80 to 95%) of the desired one 2-methyl, ethyl or n-propyl compound. The resulting product is of high purity what has been detected by qualitative and quantitative paper chromatogram analysis, d. H. the 2-methyl, ethyl or n-propyl compound becomes practical get pure; contamination by unreacted 3,4-dihydro-1,2,4-benzothiadiazine-1,2-dioxide which is unsubstituted in the 2-position is of little importance, and a by-product that is in the 2-position and on the sulfamyl group in the 7-position is substituted, can only occasionally be found in traces in the compound substituted in the 2-position prove.

The salts of the compounds obtainable according to the invention with bases can be used by conventional methods.

Pharmacologically acceptable bases are understood as meaning non-toxic bases, as they are usually used used in pharmacology to neutralize acidic substances. Examples of such Bases are e.g. B. sodium, potassium, calcium and magnesium hydroxide. The salts with pharmacological Unsuitable bases can be used for the purification of process products and as intermediates can be used for the production of pharmacologically suitable salts.

The 2,4-disulfamylanilines and substituted in the 5-position mentioned as starting compounds the aldehyde and the 7-sulfamyl-3,4-dihydrol, 2,4-benzothiadiazine-l, l-dioxyde required as starting materials in procedure b) are known or can be prepared by processes described in the literature.

The compounds obtainable according to the invention proved to be very diuretic. They particularly cause increased sodium and chloruresis, without the potassium uresis increasing to the same extent. Such an effect is very desirable to avoid hypocalemia.

The greater effectiveness of the compounds obtainable according to the invention than that of known, Compounds that are equally effective can be illustrated by the following comparative experiments.

a) The well-known S-dichloromethyl-o-chloro ^ -sulfamyl-3,4-dihydro-l, 2,4-benzothiadiazine-l, l-dioxide and the 3 - {[l ', l', l'-trifluoroethyl- (2 ')] - mercaptomethylj-o-chloro-y-sulfamyl-S ^ -dihydro-l ^^ - benzothiadiazine-l, l-dioxide as well as its 2-methyl derivative

ίο were used to determine the saluretic effectiveness in dogs (body weight 8 to 12 kg) according to the method described in "Journal of Pharmacology and Experimental Therapeutics", 133, p. 351 [1961], initially using 40 cm ^{3 of} water per kg orally ^{and then added 20 cm 3} / kg every hour for the entire duration of the experiment. The compounds mentioned were administered orally in three different doses during diuresis, each dose being tested in a total of four animals. The results are summarized in the following table, the maximum values of saluresis being used for the statistical evaluation.

Compound dosage

r / kg

Maximum change in excretion *) Na ⁺ ((lEq./min/kg) | Cl- (| xEq./min/kg)

y
thiadiazine-l, l-dioxide

3 - {[l ', l', l'-trifluoroethyl- (2 ')] - mercaptomethyl} -6-chloro-7-sulfamyl-3,4-dihydro-l, 2,4-benzothiadiazine-l, l- dioxide

2-methyl-3 - {[l ', 1', 1 '-trifluoroethyl- (2')] - mercaptomethyl} -o-chloro-T-sulfamyl-S ^ dihydro-1,2,4-benzothiadiazine-1, 1-dioxide

*) Average values for four dogs ± standard error.

2.0

8.0

2.0

8.0

2.0

8.0

no effect

1.3 ± 1.1

4.4 ± 1.2

0.4 ± 1.4
2.9 ± 0.3
6.6 ± 1.1

no effect 2.8 ± 0.7
7.0 ± 0.7

no effect 3.5 ± 1.1 6.3 ± 0.8

1.3 ± 1.2 4.7 ± 0.2 7.7 ± 1.2

no effect 4.5 ± 0.8 8.7 ± 0.6

From the above it can be seen that both 3 - {[1 ', 1', 1 '- trifluoroethyl - (2')] - mercaptomethyl} -6-chloro-7-sulfamyl-3,4-dihydro- 1,2,4-benzothiadiazine-l, l-dioxide and 2-methyl-3 - {[l ', 1', I'-trifluoroethyl - (2 ')] - mercaptomethyl} - 6 - chloro - 7 - sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide cause a greater increase in saluresis than 3-dichloromethyl - 6 - chloro - 7 - sulfamyl - 3, 4 - dihydrol, 2,4-benzothiadiazine-l, l-dioxide with the same dosage.

The following examples serve to illustrate the invention:

example 1

9.8 g (0.048 mol) of [1,1,1-trifluoroethyl] are added to a suspension of 11.4 g (0.04 mol) of 5-chloro-2,4-disulfamyl-aniline in 60 ecm of 1,2-dimethoxyethane, with stirring - (2)] - mercaptoacetaldehyde - dimethylacetal and then 20 drops of 12 η-hydrochloric acid were added. The mixture obtained is refluxed for IV2 hours, cooled and poured into 50 ecm of ice water with stirring. The crude product is filtered and dried and gives 15.2 g of 3 - {[Γ, Ι ', 1' - trifluoroethyl - (2 ')] - mercaptomethyl} -6 - chloro - 7 - sulfamyl - 3,4 - dihydro - 1,2,4 - benzothiadiazine-l, l-dioxide, melting at 203 to 205 ⁰ C.

The product is recrystallized from acetone-benzene and then melts at 206 to 207 ° C.

The sodium salt of the compound obtained is prepared by dissolving it in water, which is a Contains molar equivalent of sodium hydroxide, and the mixture is freeze-dried thereon.

The potassium, calcium and magnesium salts are also made in the same way.

A well stirred solution of 4.3 g (0.01 mol) 3 - {[1 ', 1', 1 '- trifluoroethylthio - (2')] - mercaptomethyl} -6 - chlorine - 7 - sulfamyl - 3,4 - dihydro -1,2,4 - benzotbiadiazine-l, l-dioxide in 35 ecm of dry Ν, Ν-dimethylformamide were 0.46 g of sodium hydride in Added in the form of a 53% suspension in oil (0.01 mol). There was immediate foaming instead, which is due to the formation of hydrogen, and the temperature rose to about 40 ° C. After the solution had been stirred for a further quarter of an hour at room temperature, the hydride had completely dissolved. Within 20 minutes the reaction mixture dropwise a solution of 1.42 g (0.01 mol) of methyl iodide in 10 ecm of dry N, N-dimethylformamide added; with constant stirring.

The resulting mixture was then stirred for an additional hour at room temperature; then

7 8

400 ecm were rapidly added with vigorous stirring. Water was then added dropwise to the resulting reaction mixture. After one hour, the was stirred for a further 5 liters of ¹ Iz hours at room temperature; The resulting white solid was collected, then 400 ecm of ice water were quickly added dropwise, washed with water and for about 16 hours in vacuo, while vigorous stirring was continued. The white, dried at 80 ° C. In this way, 3.5 g of 5 solid precipitate that formed was filtered off with suction, (80% yield) 2-methyl-3 - {[r, r, r-trifiuor- washed thoroughly with cold water and anäthyl- ( 2 ')] - mercaptothiomethyl} -6-chloro-7-sulfamylschließend at 25 ⁰ C in vacuo over Phosphorpent-3,4-dihydro-l, 2,4-benzothiadiazine-l, l-dioxide oxide overall dried. In this way 3.5 g was obtained; F. 199-204 ° C. After one (75 ° / _o yield) of 2- (n-propyl) -3 - {[l ', l', l'-trifluoro-recrystallization from acetone-toluene of 10 was ethyl - (2 ')] - mercapto} -6-chloro-7-sulfamyl-3,4-dihydro-melting point increased to 207-208 ⁰ C. Ver 1,2,4-benzothiadiazine-l, l-dioxide obtained after mixing the substance with a sample prepared in another way of recrystallization from methylene chloride at 184, so no melting point up to 185 ° C was melted.

depression noted. A paper chromatography The reaction described above was carried out

chromatographic analysis of the product gave an about i ₅ strength using 1.71 g (0.011 mol) of ethyl 90% purity, the starting material was repeated only in iodide in place of n-propyl bromide, tracks present. 0.61g (0.011 mol) of sodium methoxide were used

The above procedure was used with each. In this way, 3.6 g (80% 0.1 mol of the starting materials were repeated. The yield of 2-ethyl-3 - {[l ', l', l'-trifluoroethyl- (2 ^/ )] - was with direct Precipitation from the aqueous 20 mercaptomethyl} -6-chloro-7-sulfamyl-3,4-dihydro solution gives a 91% yield of 2-methyl-3 - {[l ', r, l, 2,4-benzothiadiazine- L, l-dioxide achieved after Γ - trifluoroethyl - (2 ')] - mercaptomethyl} - 6 - chlorine to recrystallize from methylene chloride at 7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-l , l-di- 186 to 188 ° C melted.

oxide achieved. This fabric was 95% pure. The procedure described above is used

on, as repeated from the paper chromatographic analysis 25, with the modification that the N ₅ N-Di preceded, the starting material was only present in a good trace of methyl formamide solution of methyl iodide. stirred solution of 4.52 g (0.01 mol) of the previously

The above procedure was carried out with the sodium salt of the 3 - {[l ', r, r-trifluorje 0.02 mol of the starting materials with 70 ecm of dry ethyl - (2 ')] - mercaptomethyl} - 6 - chloro - 7 - sulfamyl-Ν, Ν-dimethylacetamide instead of N, N-dimethyl-30 3,4-dihydro -1,2,4-benzothiadiazine -1,1-dioxyds in formamid repeated. In this case, a 35 ecm Ν, Ν-dimethylformamide was added. In 88% yield of 2-methyl-3 - {[r, r, r-trifluoro- in this case the 2-methyl compound is 80% ethyl - (2 ')] - mercaptomethyl} - 6 - chloro - 7 - sulfamyl yield. 3,4-dihydro-l, 2,4-benzothiazine-l, l-dioxide (F. 199 Rpisniel?

to 203 ⁰ C) achieved. Through quantitative paper chroma- 35 ceispiei ζ

A mixture of 0.03 mol of 5-chloro-2,4-bis-

binding was 97% pure. (N-methylsulfamyl) aniline and 0.033 mol [1,1,1-tri-

The working fluoroethyl (2)] mercaptoacetaldehyde dimethylacetal mentioned in the preceding paragraph was repeated, with the modification that in 15 ecm 1,2-dimethoxyethane, the twelve drops contain a 10 mol% excess of methyl iodide 40 12 η-hydrochloric acid, is used under rehydration and sodium hydride for 3 hours. Heated in this river. The reaction mixture is then in case a 99% yield of 2-methyl- half of its volume was concentrated and with 3 - {[Γ, Γ, Γ-trifluoro- (2)] - mercaptomethyl} -6-chloro-200 ecm cold water, which is added dropwise to 7-sulfamyl-3,4-dihydro-l, 2,4-benzothiadiazine-l, l-di- is diluted. The rubbery 2-methyl-3 - {[l ', r, oxide achieved (F. 195 to 201 ⁰ C). On a qualitative 45 1 '- trifluoroethyl - (2)] - mercaptomethyl} - 6 - chloro paper chromatogram, the product showed a 7- (N-methylsulfamyl) -3,4-dihydro-1,2,4-benzothia-single spot. diazine-l, l-dioxide, which separates and

The working strength specified in the previous paragraph is repeated from methanol by adding weise, but powdered water was recrystallized, whereby a pure crystalline sodium methoxide was used instead of sodium hydride 50 lines product with a melting point of 200 to. In this case an 88% 204 ^° C. was obtained.

Yield of 2-methyl-3 - {[r, r, r-trifluoroethyl- (2 ')] - The [1,1,1-tri-

mercaptomethyl} - 6 - chloro - 7 - sulfamyl - 3,4 - dihydro- fluoroethyl - (2)] - mercaptoacetaldehyde - dimethylacetal ■ l, 2,4-benzothiadiazine-l, l-dioxide obtained. was made in the following way:

The working 55 to a solution of 4.6 g (0.2 mol) sodium wisely, 0.1 mol of each of the starting materials in 75 ecm of absolute methanol was added quickly repeatedly and there was a 90% yield of 24.4 g (0.2 mole) of mercaptoacetaldehyde dimethylacetal of 2-methyl-3 - {[Γ, Γ, Γ-trifluoroethyl- (2 ')] - mer- and then dropwise 42.0g (0.2 mol) captomethyl} - 6 - chloro - 7 - sulfamyl - 3,4 - dihydro trifluoroethyl iodide. The resulting reddish l, 2,4-benzothiadiazine-l, l-dioxide. 60 mixture is taking 1 hour on a steam bath

A well-stirred solution of 4.25 g (0.01 mol) was heated to reflux. Half of the alcohol is 3 - {[Γ, Γ, Γ - trifluoroethyl - (2 ')] - mercaptomethyl} - evaporated off, the remainder is mixed with several volumes of 6-chloro-7-sulfamyl-3,4-dihydro-1 Diluted 2,4-benzothia water and extracted with ether. The verdiazin-l _r i-dioxide and 0.65 g (0.012 mol) of sodium ether extracts are dried over sodium sulfate methoxide in 10 ecm Ν, Ν-dimethylformamide, the ether is then dried within 20 minutes at reduced 1 , 48 g (0.012 mol) pressure evaporated and the residue distilled. n-propyl bromide (1-bromopropane), dissolved in 5 ecm of water. aldehyde dimethyl acetal weighs 30g and boils at

82 ° C / 25 mm. The analysis of the product gives the following results:

C6H11O2SF3:

Calculated ... C 35.29%; H 5.43%;
found ... C 35.57%; H 5.44%.

Example 3

A mixture of 3- (chloromethyl) -6-chloro-7-sulfamyl-3,4-dihydro-benzothiadiazine-1,1-dioxide (0.02 mol), 1,1,1-trifluoroethyl mercaptan (0.024 mol), 20 ecm 10% sodium hydroxide and 20 ecm dimethylformamide is stirred for 6 hours at room temperature. After the mixture has been heated on a steam bath for 10 minutes, it is cooled and acidified with 6η hydrochloric acid. After recrystallization from acetone, the product melts at 206 to 207 ^° C.

The compound obtainable according to Example 2 can also by this procedure from the corresponding Starting materials are produced.

Example 4

To 4.6 g (0.015 mol) of 5-chloro-2- (N-methylsulfamyl> 4-sulfamylaniline in 30 ecm of ethylene glycol dimethyl ether, 4.08 g (0.02 mol) of [1,1,1-trifluoroethyl- (2)] Mercaptoacetaldehyde dimethylacetal and then 1 ecm ethyl acetate saturated with hydrogen chloride are added. The resulting solution is refluxed for IV2 hours, cooled and then slowly and dropwise added to cold water with stirring. The crude 2-methyl-3 - {[Ι ', Ι ', ν - trifluoroethyl - (2')] - mercaptomethyl} -6 - chloro - 7 - sulfamyl - 3,4 - dihydro - 1,2,4 - benzothiadiazine-l, l-dioxide is filtered off, dried and from isopropanol recrystallized: yield: 3.2 g; F. 202 to 205.5 ⁰ C. After a second recrystallization from isopropanol, the melting point was Elemental analysis gave the following values at 202-203 ⁰ C.:

C11H13O4N3S3CIF3:

Calculated ... C 30.0%; H 3.0%; N 9.6%;
found ... C 30.1%; H 3.4%; N 9.5%.

Claims (1)

PATENT CLAIM: RiHNO ₂ S-> ⁴⁵ Process for the preparation of 3 - {[l ', l', l'-trifluoroethyl - (2 ')] - mercaptomethyl} - 7 - sulfamyl-3,4-dihydro -1,2,4-benzothiadiazine -1,1-dioxydes the general formula CH-CH ₂ -S-CH2-CF3 NR ₃ 55 in which Ri is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R2 is a hydrogen, chlorine or bromine atom, a trifluoromethyl group or an alkyl or alkoxy group containing 1 to 3 carbon atoms and R3 is a hydrogen atom or a methyl, ethyl or n -Propylgruppe, and their salts, characterized in that either in a known manner
a) a 2,4-disulfamylaniline of the general formula R ₂ R1HNO2S - \ -NH ₂
SO ₂ NHR ₃ with the aldehyde of the formula CF ₃ - CH ₂ - S - CH ₂ - CHO or an acetal or hemiacetal of this aldehyde or condensed
b) a 7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide of the general formula wherein Y is a halogen atom or an alkyl or arylsulfonic acid radical means in a basic medium with 2,2,2-trifluoroethylmercaptan implements and optionally subsequently obtained compounds in which R3 is a hydrogen atom represents, in the presence of a basic condensing agent or in the form of an alkali metal salt with a compound of the general formula Rs'X where R3 'is a methyl, ethyl or n-propyl group and X is a bromine or iodine atom, converts and / or obtained compounds with bases in their salts. Considered publications:
Publication of documents of Belgian patent No. 576 304, 584 839;
Journ. amer. formerly soc, 82 [1960], p. 1132 ff. © 309 668/322 8.63