CA1220208A

CA1220208A - 4-(benzisothiazol-3-yl) phenoxyacetic acid 1',1'- dioxides, a process for preparing the same, intermediates thereof and their use as medicaments

Info

Publication number: CA1220208A
Application number: CA000503713A
Authority: CA
Inventors: Gregory M. Shutske
Original assignee: Hoechst Roussel Pharmaceuticals Inc
Current assignee: Aventis Pharmaceuticals Inc
Priority date: 1982-11-03
Filing date: 1986-03-10
Publication date: 1987-04-07

Abstract

Abstract of the Disclosure Novel compounds of the formula II

II

wherein X is hydrogen, halogen or lower alkyl;
R1 is hydrogen or loweralkyl and R2 and R3 are each independently C1, Br or CH3, and process for their preparation, as described. Compounds of the formula II are useful intermediates in the production of 4-(benzisothiazol-3-yl) phenoxyacetic acid 1', 1'-dioxides, which in turn are useful diuretics.

Description

~ ~ - 2 ~ 1220~8 This applicatio~ is a di~isional of Canadian Patent Application Serial number 440,279, filed November 2, 1983.

This invention relates to novel 4-(benzisotnia~ol-3-yl)-phenoxyacetic acid l',l'-dioxides, esters thereof and related compounds which are useful in diuretics, to methods of their preparation and to pharmaceutical com-positions containing such a compound as an active ingre-dient.
This invention relates to intermediate compounds useful in the preparatin fthe above-mentioned com-pounds and to methods of synthesizing same.
To the best of our knowledge, the compounds of the present invention have not been heretofore made, des-cribed or suggested.
The compounds of this invention which are useful as diuretics can be depicted by the general formula OCH2C02R1 .
R2 (Ij ~\ ' C _N~O

X ~ ~ O

~rhere X is hydrogen, halogen or loweralkyl; Rl is hydro-gen or loweralkyl; R2 and R3 are each independently Cl, Br or CH3. Also included within the scope of the present invention are physiologically acceptable salts of the above-depicted compounds.
Another group of the compounds of this invention which are useful as intermediates for the compounds of formula I can be depicted by the general formula .

` " 3L~21~2~3 .
OCH2co2R1 .

~ 3 ~ ~
~S

where X, Rl, R2 and R3 are as defined above.
Unless otherwise stated or indicated, the lollo~ing terms have tne following meanings throughout the speci-fication and the appended claims:
"lower" means 1 to 6 carbon atoms;
'lloweralkyl" means an alkyl group of l to 6 carbon atoms;
'lalkyl'l means a straight or branched chain hydrocar-bon containing no unsaturation;
llhalogen" means chlorine, bromine or fluorine.
The physiologically acceptable salts of this invention - include those formed with an alkali or alkaline earth metal base or wi~h a non~toxi.c org~nic base such as ethanolamine, N-methyl-D-glucamine, etc.
The compounds of the present invention can be pre-pared according to one or more of the following steps in which X, Rl, R2 and R3, unless otherwise indicated, are as defined above.
.
METHOD A
.
A phenol or an alkoxybenzene of the formula OR
. 1 4 ~R~ III

., .

- 4 - HOE 82/S.037 where R4 is hydrogen or lo~eralkyl, is reacted under Friedel-C~a~ts condition3 ~ith an acid shalide of the formula O
cl_Y
,~' X ~ IV

where Y is chlorine or bromine, to provide a compound of the following formula.

C--O

~ ~ F
X -W ' ' Preferably, 1,2-dichloroethane is used as a solvent and aluminum chloride as the Friedel-Crafts catalyst.
The compound V ls treated ~ith ammonia and elemen-tal sulfur in a suitable solvent such as methoxyet'nanol at an elevated temperature, e.g. about 150C, for a suf-ficient period of time, e.g. 7 hours at 150~C, to providea benzisothiazole compound of the following formula.

~ R3 ~ = ~ VI
,~S
X~

.

2~

The compound VI, when it is an alkoxyphenol cor,lpound, namely, ~hen R4 is lowera]kyl, is first converted to the correspondin~ phenol by any conventional dea~ylation me-thod, e.~. by heating it in a suitable solvent such as 1,2-dichlorethane in the presence of an acid such as bo-ron tribromide.
The phenol com?ound is reacted with a halogenatedacetic acid or an ester thereof of the formula YCH2CG2R1, ~here Y and Rl are as earlier defined, to form a compound of the formllla II.
The compound II is oxidized in a conventional manner SUC}l as by reaction witn a suitable oxidizing agent, e.g., hydro~en peroxide, in a suitable solvent such as acetic acid, to form a compound of the formula I.
All startin~ materials sho-;rn above are either known compounds or are easily prepared by routine methods - known to the art from readily available materials.
Effective quantities of the compounds of the inven~
tion may be adminstered to a patient by any of the va-rious met'nods, for example, orally as in capsules or ta-blets, parenterally in the form of sterile solutions orsuspensions, and in some cases intravenously in the form of sterile solutio~s. The free acid final products, while effective themse~les, may be formulated and administered in the form of their pharamaceutically acceptable addi~
tion salts for purposes of stability, convenience of crystallization, increased solubility and the like.
The active compounds of the present invention may be orally administered, for exampl e, with an irert di-luent or with an edible carrier, or they may be enclosed in gelatin capsules, or they may be compressed into tablets. For the purpose of oral therapeutic administra-tion, the active compounds of the invention may be in-corporated with excipients and used in the form of ta-blets, troches, capsules, elixirs, suspensions, syrups, ~rafers, che~Jing gum and the like. These preparations should contain at leas~ 0.5 % of active compound, but .... .

02~8 may be varied depending upon the particular ~orm and may eonveniently ~e between 4 % to about 70 ~ o~ the weight o~ the unit. The amoun~ of active eompound in such com-positions ls such that a suitable dosage wil be obtained.
Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 1.0 - 300 milligramms or ae-tive eompound.
The tablets, pills, eapsules, trocnes and the like may also eontain the following ingredients: a binder sueh as micro-erystalline eel].ulose, gum tragaeanth or gelatin; an exeipient sueh as starch or lactose, a dis-integrating agent such as alginic acid, Primogel, corn-starch and the like; a lubricant such as magnesium stea-rate, a glidant such as colloidal silieon dioxide; and as~eetening agent such as sucrose or saccnarin may ~e ad-ded or a flavoring agen~ such as peppermint, methyl sa licylate, or orange flavoring. l~hen the dosa~e unit from is a capsule, it may contain, in addition to materials of tne above type, a liquid carrier such as a fatty oil.
Other dosage unit forms may contain other various mate-rials which modify the physieal form of the dosage unit, for example, as coatings. Thus tablets or pills ~ay be coated witn sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the aetive eompounds, suerose as a sweetening agent and certain preservatives, dyes, colorings and flavors. Materials used in preparing t'nese various compositions should be pnarmaeeutieally pure and non-toxie in the amounts used.
For the purposes of parenteral therapeutic admi-nistration, the active compounds of the invention may be ineorporated into a solution or suspension. These prepa-rations should eontain at least 0.1 % act~ve compound, but may be varied to be between 0.5 and about 30 % of the weight thereof. The amount of active compound in such eompositions is such that a suitable dosage will be .
.

-` 3L2;~Z~
- 7 - HO~ 82/S 037-obtained. Preferred compositions and preparations accor~
ding to the present invention are prepared so that a pa-renteral dosage unit contains between 0.~ to 100 milli-gramms of active compound.
The solutions or suspension may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glykols, glycerine~ propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents suc'n as ethylendiami-netetraacetic acid; buffers usch as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. ~he parenteral pre-paration can be enclosed in disposable syringes or rnul-tiple doze vials made of glass or plastic.
The compounds of the invention are useful as di-uretics due to their ability ot produce diuresis in mammals. Such utility is effected ~Yhen a compound of the invention is administered to a patient requiring appro-priate treatment at an oral, parenteral or intravenousdose of from l to 200 mg/kg of body weight per day.
The diuretic activity of the compounds of the sub-ject invention are determined by the diurectic screen test designated ass the "Acute Sodium Loaded ~ouse"
screen. This screen is carried out in the follo~ling manner. The acute sodium loaded mouse experimen~s are performed with groups of male mice weighing 18 - 24 gms.
Drugs are prepared in 1 % saline and orally administered in a dosage ~olume of lO ml/kg. The animals are housed in metabolic cages, each treatment group consisting of lO animals, 5 per cage. The tests consist of a vehicle control, a positive control group of lO00 ml/kg urea-treated mice and the potential diurectic agent given at 64 mg/kg.
The resultant pooled urine samples are analyzed for sodium, using a flame photometer. Sodium vlues are ex-pressed as the mean milliequivalents (mEq)/kg/5 hrs~
.
.

2~21)~3 -- 8 - HOE 82,iS 037 Listed below is the diuretic acitivity of a repre-sentative compound OL this invention.

Control mEqNa /kg/5 hrs.

5 4-(Benzisothiazol-3-yl)-2,3-dichloro-.phenox~acetic acid l',l'-dioxide 2.03 Control o.8 Compounds of this invention include 4-(benzisothiazol-

3-yl)-2,3-dic'nlorphenoxyacetic acid l'~l~-dioxide and 4-(benzisothiazol-3-yl)-2,3-dichlorophenoxyacetic acid.
The present invention is further illustrated by the following examples of representative compounds and pro-cedures:

EXAMPLE i 2l-Fluoro-4-methoxy-2,3-dic'._lorobenzophenone To a solution o~ 31.55 g of o-flucrobenzoyl chloride in 100 ml l,~-dichloroethane, 26.54 g of AlC13 was added over a 30 minute period. A solution of 22 g of 2,3-di-chloroanisole in 50 ml of 1,2-dichloret'nane was added dropwise. There was an evolution of gas and the tempera-ture rose to 35. The mixture was stirred 2 hours and then poured over a mixture of 100 ml concen-trated HCl and 100 ml ice. The organic solvent wa~ evapora~ed in vacuo and the mixture extracted with ether. The ether extract was washed with 10 % K2C03, washed with water, and dried over Na2S04, and the et'ner ~^ras evaporated to give a solid. Recrystallization of the solid from the ether-hexane mixture gave 38.69 g (70 %) of 2'-fluoro-

4-methoxy-2,3-dichlorobenzophenone, m.p. 74 - 77.

" ~2~208 ` .
- 9 - H=E 82/S 037 ANALYSIS
_ Calculated for C14HgC12F02: 56.21 %C 3~03 %H 6.35 %F
Found: 56.20 gC 3.02 %H 6.58 %F

EXA~LE 2 3-(2,3-Dichloro-4-methoxy~henyl)benzisothiazole _ _ _ _ _ 10 One hunded grams (100 g) of 2'-fluoro-4-methoxy-2,3-dic'nlorobenzophenone was suspended in 40C ml of metho~y ethanol that was previsously saturated with about 50 grams of NX3. Twelve grams (12 g) of elemental sulfur was added to the mixture and the mixture was heated for 7 hours at 150. The reaction mixture was cooled and some insoluble material was filtered off. The resulting solution ~as concentrated under reduced pressure and then purified by'high pressure liquid chromato~raphy on silica gel (40 % CH2C12/hexane, 250 ml/min) to giv-e 15.80 g (15 %)of 3-(2,3-dichloro-4-methoxyphenyl)benz-isothiazole An analytical sample was recrystallized 3CN, which had a m~p. 176 - 177.

ANALYSI_ Calculated for C14HgCL2NOS: 54-20 ~C 2-92 %~ 4-52 %N
Found: 54.25 ~C 2.95 %H 4.68 %N

' "
4-(Benzisothiazol-3-yl)-2,3-dichloroph_ oxyacetic acid A mixture containing 8.2 g of 3-(2,3-dichloro-4-methoxyphenyl)benzisothiazole, 100 ml of 1,2-dichloro-ethane and 100 ml of BR3 was refluxed for 30 minutes.It W2S then poured into ice/water and the organiF solvent ~ .

.
was remo~ed under reduced pressure. The product was t'nen filtered off, washed with hexane and dried to give 7.50 g (96 %) of 4-(benzisothiazol-3-yl)-2,3-dichlorophenol.
The phenol product was warmed at 50 for 30 minut~s in 100 ml of dimethylformamide containing 2.00 ml of ethyl bromoacetate and 5-5 g of K2cO . Twe~t~ mi~ iters (20 ml) of 20 ~ aqueous NaOH was t'nen added to the mix-ture and warming Wa5 continued an additional 30 minutes with vigo.ous stirring. The product acid ~ ich was in the sodium salt form was filtered off and washed with water, and then with ether. It ~as then distributed bet~teen 2-but~none and 5 % HCl. The organic phase was withdral,~n, dried and concentrated under reduced pressure. A~ter re-crystallization from acetone/H2O, 8.4 g of a pure product (84 % from the methoxy compound), m.p. 224 - 226 was obtained.
ANALYSIS
Calculated for C15~9C12NO3S: 50.86 %C 2.56 %H 3.96 ,~vt~
20 Found: 50.57 %C 2.64 %H 4.03 ~H

.
4-(Benzisothiazol-3-yl)-2,3-dichlorophenoxyacetic acid l',l'-dioxide A mixture containing 5.0 g of 4-(benzisothiazol-3-yl)-2,3-dichlorophenoxyacetic acid, 200 ml of Ac0H and 50 ml of 30 % H202 was warme~ at 90 for 90 minutes. The reaction mixture was then poured into H20 and the pro-duct filtered off. Af'ter recrystallization ~rom EtOAc/
hexane, 3.20 g (60 %) of an analytically pure product m.p. 230 - 232 was obtained.
ANALYSIS
or C15H9 2~2 : 46.64 %C 2.35 %H 3.63 ,~F
Found: ' 46.67 %C 2.43 %H 3.51 %F

~ HOE ~2/S 037 In a simllar manner as E~amples 1 - 3, 2,3-dimevhJrl-anisole is converted into 4-(benzisothiazol-3-yl)2,3-di-me'hylphenoxyaceti~ acid.

EXA'~IPLE 6 . .

The compou1ld obtained in Example 5 is con~rer~ed into 4-(benziso'hiazol-3-yl)-2,3-dime~hylphenoxyacetic acid 1',1'-dioxide in a similar m~.nner as Example 4.
.

, . . .

Claims

CLAIMS: -

1. A process for the preparation of a compound of the formula II

II

wherein X is hydrogen, halogen or loweralkyl; R1 is hydrogen or loweralkyl; R2 and R3 are each independently Cl, Br or CH3; and the physiologically acceptable salts thereof, in which a compound of the formula VII

VII

wherein X, R2 and R3 are as defined above, is reacted with a compound of the formula YCH2CO2R1 wherein Y is bromine or chlorine and R1 is as defined above, to form a reaction product of the formula II.

2. A compound of the formula II

II

wherein X is hydrogen, halogen or loweralky; R1 is hydrogen or loweralky; R2 and R3 are each independently Cl, Br or CH3, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A process as claimed in claim 1 wherein R2 and R3 are chlorine.

4. A compound of the formula II as set forth in claim 1, wherein X and R1 are as defined in claim 1 and R2 and R3 are chlorine, and the physiologically acceptable salts thereof, whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

5. A process as claimed in claim 1 wherein R2 and R3 are CH3.

6. A compound of the formula II as set forth in claim 1, wherein X and R1 are as defined in claim 1 and R2 and R3 are CH3, and the physiologically acceptable salts thereof, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

7. A process for the preparation of 4-(benzisothiazol-3-yl)-2,3-dichlorophenoxyacetic acid, comprising reacting 4-(benzisothiazol-3-yl)-2,3-dichlorophenol with ethyl bromo-acetate.

8. A process as defined in claim 7, wherein the react-ion with ethylbromoacetate is conducted in dimethylformamide with K2CO3 at 50°C for about 30 minutes to form the acid product, which is converted to the sodium salt with aqueous NaOH and is extracted from the organic phase of a mixture of 2-butanone and aqueous HCl.

9. The compound 4-(benzisothiazol-3-yl)-2,3-dichloro-phenoxyacetic acid, whenever prepared by the process of claim 7 or 8 or by an obvious chemical equivalent thereof.

10. A process for the preparation of 4-(benzisothiazol-3-yl)-2,3-dimethylphenoxyacetic acid, comprising reacting 4-(benzisothiazol-3-yl)-2,3-dimethylphenol with ethylbromo-acetate.

11. A process as defined in claim 10, wherein the react-ion with ethylbromoacetate is conducted in dimethylformamide with K2CO3 at 50°C for about 30 minutes to form the acid product, which is converted to the sodium salt with aqueous NaOH and is extracted from the organic phase of a mixture of 2-butanone and aqueous HC1.

12. The compound 4-(benzisothiazol-3-yl)-2,3-dimethyl-phenoxyacetic acid, whenever prepared by -the process of claim 10 or 11 or by an obvious chemical equivalent thereof.