CA1281333C - Sulfonylurea derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

This invention provides sulfonamide derivatives of formula (I):

(I) in which A is -O-, ?CH3, -CH2-, -CH2CH2-, or -CH2O-;
D is -CH2- or -O-;
provided that neither A nor D can be -O- unless both A and D are -O-;
R1 is hydrogen or halo, and R2 is halo or trifluoromethyl. These derivatives are useful in the treatment of susceptible neoplasms in warm-blooded animals.

Description

~:~2~33~1 SULFONYLUREA DERIVATIVES

Despite the development of numerous chemical agents and sophisticated regimens of drug therapy, 5 cancer continues to extract an ever-incr~asing human toll of suffering and death. Although many advances have been made, especially in the area of combination drllg therapy, the need for new and better methods of treating neoplasms and leukemias has not diminished.
This is especially evident in the area of inopexable or metastatic solid tumors, such as various forms of lung cancer.
To be especially useful, new chemotherapeutic agents should have a wide spectrum of activity, a large therapeutic index, and be chemically stable and compati-ble with other agents. In addition, new agents having oral activity would be especially useful so that initial treatment and subseguent maintenance therapy can be made easily and without incon~enience or pain to the patient.
The present invention provides a series of sulfonylureas which are useful in the treatment of tumors. The compounds are orally active and relatively non-toxic providing an excellent therapeutic index.
Sulfonylureas are known in the art, particu-larly for their oral hypoglycemic utilities. See, for example, Chemical Abstracts 71:11457w (1969), Holland, et al., J. Med. Pharm. Chem., 3 (1), 99 (1961), Gandhi, et al., Arzneim.-Forsch., 21, 968 (1971), Rajagopalan, et al., J. ~ Chem., 30, 3369 ~1965), and Petersen, -~ Z~33~

Chem. Ber., 83, 551 (1950). In addition, some antimy-cotic activity is noted and the compounds have also been prepared as derivatives of carbodiimides. A general review of compounds of this structural type may be found in Kurzer, Chem. Rev., 50, 1 (1952). Bicyclic sulfonyl-ureas also are known in the art as hypoglycemic agents See, e.q., Chemical Abstracts 67:54036t (abstracting German OLS 1,249,866~, U.S. Patent 3,097,242, Chemical Abstracts 60:9220h (abstracting German OLS 1,159,937), and Lerner, et al., Metab., Clin. Exptl., 14(5), 578 (1965). These references, however, do not disclose any anti-tumor activity of these compounds.
Thus, in accordance with the invention, sulfo-nylurea derivatives of formula (I):

~ ~H~NH~

in which A is -O-, -NCH3, -CH2-, -CH2CH2-, or -CH2O-;
D is -CH2- or -O-;
provided that neither A nor D can be -O- unless both A and D are -O-;
Rl is hydrogen or halo; and R2 is halo or trifluoromethyl, are useful as antineoplastic agents.
This invention also provides a method for treating susceptible neoplasms in a warm-blooded animal . .. 0 which comprises administering to said animal a compound of formula (I~.
In addition, this invention provides pharma-ceutical formulations comprising as an active ingredient a compound of formula (I~ in combination with a pharma ceutical-acceptable carrier, diluent, or excipient therefor. These formulations are particularly useful in treating mammals suffering from susceptible neoplasms.
The term "halo" refers to fluoro, chloro, bromo, and iodo. The term "C1-C3 alkyl" refers to methyl, ethyl, propyl, and isopropyl.
The preferred compounds of this invention are those of formula (I) in which a) R1 is hydrogen, b) R2 is halo, especially bromo, chloro, or fluoro, or trifluoromethyl, and c) A is -CH2-.
The most preferred compound of this invention is N-([(4-chlorophenyl)amino]carbonyl)-2,3-dihydro-lH-indene-5-sulfonamide.
The compounds of formula (I) generally are referred to as derivatives of N-([(substituted phenyl)-amino]carbonyl)arylsulfonamides, for example, as used in the previous paragraph. Alternatively, the compounds are referred to as 1-(substituted phenyl)-3-(arylsul-fonyl)ureas.
The compounds of formula (I) may be prepared by any number of methods known in the literature. These methods are summarized by Kurzer, Chem. Rev., 50, l (1952), especially pages 4-19. Specific references L3~3 describing processes that can be employed in the prepa-ration of compounds of formula (I) are those previously described in the references cited above.

A preferred method of preparing the compounds of formula (I) is that of the reaction of a sulfonyliso-cyanate of formula (II): _ I < D~-~NCO (Il) with an aniline derivative of the formula ~III):

/~ -o~Rl H2N-d~ ~a-R2 (III) where A, D, Rl, and R2 are as previously defined.
The reaction between compounds II and III is usually performed using equimolar amounts of the two reactants, although other ratios are operative. The reaction usually is carried out in an aprotic non-reactive solvent such as benzene, toluene, acetonitrile, diethyl ether, tetrahydrofuran, dioxane, or preferably methylene chloride. The reaction may be carried out at ~;~8~L333 temperatures from about 0C up to the boiling point of the reaction mixture. At the preferred temperature range of about 20-30C, the r~eaction produces a strong exotherm and the reaction usu,ally is complete within 1 hour. The product obtained m,ay be recovered by filtra-tion and may be purified, if Idesired, by any number of methods known to those skilled in the art, such as chromatography or crystallization.
Alternatively, an appropriately substituted sulfonamide of formula (IVj:
t~
~ S02NH2 (IV) may be reacted with an isocyanate of formula ~V):
~o o~l 0~0 ( V ) to provide the compounds of formula (I). The reaction generally is carried out in a water miscibl~, non-reactive solvent such as tetrahydrofuran or acetone.Generally, an equimolar amount or slight molar excess of the formula (V) compound is employed, although other ratios are operative. In addition, an aqueous solution of a base, such as sodium or potassium hydroxide, is employed. Usually the amount of base used is approximatelv ,i, , q ~

~28~333 equimolar to the amount of compound (IV). The reaction generally is carried out from about 0C up to the boiling point of the reaction mixture. At the preferred temperature range o:E 20-30C, the reaction 5 usually is complete within about three days.
Another preferred method of preparing com-pounds of formula (I) involves the reaction of sulfonamide (IV) with an alkyl haloformate to provide carbamate (VI~
which is then reacted with an:iline (III) to provide the correspondlng product (I) (IV) + XCOOR3 ~ SO2NH~COOR3 __~ (I) ~ /- (IV) where X is bromo or chloro and R3 is Cl-C3 alkyl. The transformation of compound (IV) into colllpound (VI) usually is accomplished in a non-reactive solvent, such as acetone or methyl ethyl ketone, in the presence of an acid scavenger, such as an alkali metal carbonate, for example potassium carbonate. A molar excess of the haloformate usually is added, although other ratios are operative, and the reaction mixture heated at a tempera ture from about 30C up to the reflux temperature for a period of 1-5 hours to provide the desired intermediate (VI). Intermediate carbamate (VI) and aniline (III) then are heated together in an inert high-boiling solvent, such as dioxane, toluene, or diglyme, at temperatures from about 50~C up to the reflux tempera-ture of the mixture to provide the desired product.

Thus, i.n a further aspect of the invention, there is provided a process for preparing a compound of formula (I), as defined above, which comprises reacting with a compound of the formula y~ R2 in which Y is -NH2 or -MCO, and R1 and R2 are as defined above, a sulfonyl compound of the formula:

~ ~ 9 _ _o~ --S02X
' in which X is -NCO, -NH2 or -NH-COOR3 in which R3 is C1-C3 alkyl, and A and D are as defined above, provided that if X is -NCO or -NHCOOR3 then Y is -NH2 and if X is -NH2 then Y is -NCO.
Intermediates tII), (III), ~IV~, and (V~ and any other reagents required for other methods of prepa-ration, are either commercially available, are known inthe literature, or can be prepared by methods known in the art.
Certain intermediates of formula (IV), espe-cially those in which A and D are, independently, -O-or -CH2-, may be prepared by chlorosulfonating an appropriately substituted benzene compound at 50-130C
with a Villsmeier reagent prepared from sulfuryl chlo-ride and dimethylformamide followed by ammonolysis with ammonia or ammonium hydroxide. Examples 7A and 8 below - 5 illustrate this process.
The following non-limiting exam~les are provided to further illustrate the invention.

Example 1 N-~[(4-chlorophenyl)amino]carbonyl)-2,3-dihydro-lH-indene-5-sulfonamide To a solution of 93.2 g of 2,3-dihydro-5-indenylsulfonamide in 300 ml of acetone were added 490 ml of a lN sodium hydroxide solution. A solution of 79.36 g of 4-chlorophenylisocyanate in 250 ml of acetone was added to the reaction mixture with stirring. After stirring at room temperature for 18 hours, the reaction mixture was filtered and 490 ml of lN hydrochloric acid were added to the filtrate there~y providing a fine white precipitate. One liter of water was added, and the solid was recovered by filtration to provide 144.86 g of the desired title product, m,p. 169-172C.
Analysis for C16Hl5ClN2 03 S
Calculated: C, 54.78; H, 4.31; N, 7.79;
Found: C, 54.95; H, 4.43; N, 7.94.

, ' 33~

Example 2 N-([(4-chlorophenyl~amino]carbonyl)-5,6,7,8-tetrahydro-~-naphthalenesulfonamide The title compound was prepared by the method of Example 1 in 56% yield from 5,6,7,8-tetrahydro-2-naphthalenesulfonamide and 4-chlorophenylisocyanate, m.p. 163-165 a C .
Analysis for C17H17ClN203S:
Calculated: C, 55.96; H, 4.70; M, 7.68;
S, 8.79;
Found: C, 55.91; H, 4.62; N, 7.56;
S, 9.00.

Example 3 Alternate preparation of N-(C(4-chlorophenyl)-amino]carbonyl)~2,3-dihydro-lH-indene-5-sulfonamide A. Preparation of t(2,3-dihydro-lH-inden-5-yl)sulfonyl]carbamic acid ethyl ester.

Two hundred eighty grams of potassium carbon-ate were added to a solution of 181.4 g of 2,3-dihydro-5-indenylsulfonamide in three liters of methyl ethyl ketone. The suspension was stirred for 45 minutes at which time 98 ml of ethyl chloroformate were added in dropwise manner. After stirring for one hour at room '333 temperature, the mixture was heated to reflux and stirred an additional three hours. After cooling, the mixture was added to ice water, filtered, brought to a pH of 1, and extracted three ti.mes with ethyl acetate.
The combined organic extracts were washed with water and a saturated sodium chloride so]ution, dried over sodium sulfate, and evaporated to dr~less in vacuo. Crystal-lization of the residue from toluene provided 176.2 g of the desired subtitle intermediate, m.p. 92-95C.
Analysis for C12H15NO~S:
Calculated: C, 53.52; H, 5.61; N, 5.~0;
Found: C, 53.76; H, 5.71; N, 5.08.

B. Preparation of N-(~(4-chlorophenyl)amino]-carbonyl)-2,3-dihydro-lH-indene-5-sulfonamide.

A solution of 2.69 g of [(2,3-dihydro-lH-inden-5-yl)sulfonyl]carbamic acid ethyl ester and 1.27 g. of 4-chloroaniline in 50 ml of dioxane was ~0 heated at reflux for 16 hours under a nitrogen atmo-sphere. The solution was added to water and extracted with ethyl acetate. The organic extract was dried over $odium sulfate and concentrated ln vacuo giving a crystalline solid. The solid was triturated with toluene and filtered to provide 1.6 g of the desired title product, m.p. 175-177C.
Analysis for C1 6 H1sClN2 03 S
Calculated: C, 54.78; H, 4.31; N, 7.79;
Found: C, 54.63; H, 4.47; N, 7.84.

3~3 Example 4 N-{[(4-chlorophenyl)amino]carbonyl~-2,3-dihydro-5-benzofuransulfonamide The title product was prepared in 26.1~ yield from 2,3-dihydro-5-benzofuransulfonamide and 4-chloro-phenylisocyanate following the procedure of Example 1, m.p. 190-194C.
AnalysiS for C15H13ClN2O4S:
Calculated: C, 51.07; H, 3.71; N, 7.94;
S, 9.07;
Found: C, 51.32; H, 4.00; N, 7.73;
S, 9.02.
Example 5 N-~[(4-chlorophenyl)amino]carbonyl}-2,3-dihydro-1-methyl-lH-indole-5-sulfonamide Following the procedure of Example 3B, the title product was prepared in 60% yield from [(2,3-dihydro-1-methyl-lH-indol-5-yl)sulfonyl]carbamic acid ethyl ester and 4-chloroaniline, m.p. 145--147C.
Analysis for C16H16ClN3O3S:
Calculated: C, 52.53; H, 4.41; N, 11.49;
S, 8.76;
Found: C, 52.78; H, 4.47; N, 11.19;
S, 8.56.

~8~3~33 Example 6 N-{[(3,4-dichlorophenyl)amino]carbonyl}-2,3 dihydro-lH-indene-5-sulfonamide A solution of 2.67 g of 3,4-dichloroaniline in 10 ml of toluene was added to 3.87 g of 2,3-dihydro-5-indenylsulfonylisocyanate in 20 ml of toluene. After stirring 7 hours, the resulting precipitate was recov-ered by filtration, washed with toluene and driedproviding 5.38 g of the title product, m.p. 155.5-158C.
Analysis for Cl6H1 4 Cl2 N2 3 S
Calculated: C, 49.88; H, 3.66; N, 7.27;
S, 8.32;
Found: C, 50.13; H, 3.84; N, 7.31;
S, 8.05.

Exam~le 7 N-{[(4-chlorophenyl)amino]carbonyl}-1,3-benzo dioxole-5-sulfonamide A. Preparation of 1,3-benzodioxole-5-: sulfonamide.
A 500 ml 3-neck round bottom flask was charged with 38.7 g (0.52 mole) of dimethylformamide. The contents of the flask were cooled to 0C. After cool-ing, 70.18 g ~0.52 mole) of sulfuryl chloride were added and the contents of the flask stirred for 10 minutes while maintaining the temperature at approximately 10C.

After the Villsmeier reagent was formed, 61.06 g (0.5 mole) of 1,3-benzodioxole were added over a period of S minutes. The mixture was heated to 80C for approximately 10 minutes. The temperature was increased to 110C, and maintained for 5 minutes. The reaction mixture was allowed to cool to 40C and poured into a mixture of 450 g crushed ice, 200 ml water, and 200 ml of chloroform.
The resulting organic layer was decanted and then dripped into 200 ml of concentrated ammonium hydroxide. The solution was stirred for approximately 11~ hours. After stirring, the organic and aqueous phases were allowed to separate and a yellow granular precipitate formed at the interface of the two layers.
This solid was collected by filtration, washed with 100 ml of water, and dried o~ernight at 40C to provide 26.9 g of the desired subtitle intermediate, m.p.
158-160C. Both mass spectroscopy and NMR spectra were consistent with the structure of the desired intermediate.

B. Pxeparation of N-{[(4-chlorophenyl~amino]-carbonyl}-1,3-benzodioxole-5-sulfonamide.

The title product was prepared in 75% yield from the intermediate of Example 7A and 4-chlorophenyl-isocyanate following the procedure of Example 1.
Analysis for C14H11ClN205S:
Calculated: C, 47.40; H, 3.13; N, 7.90;
Found: C, 47.54; H, 3.23; N, 8.10.

X-6457~ -14-Example 8 N-{[(4-Chlorophenyl)amino~carbonyl~-2,3-dihydro-1,4-benzodioxin-6-sulfonamide Following the procedure of Example 7A, 1,4-benzodioxan was transformed into 1,4-benzodioxan-6-sulfonamide in 34% yield. This sulfonamide was then converted into the title sulfonylurea in 66% yield 0 according to the procedure of Example 1, m.p. 191C.
Analysis for C15H13ClN2OsS:
Calculated: C, 48.85; H, 3.55; N, 7.60, Found: C, 48.57; H, 3.75; N, 7.gO.

The compounds of formula I have ~een shown to be active against transplanted mouse tumors ln vivo.
The compounds are active in the test systems when administered according to a variety of dosage schedules.
In general, the compounds were administered orally daily or twice daily for 8-10 days.
To demonstrate the anti-tumor activity of the compounds of Formula I, ~he compounds were tested in animals bearing a 6C3HED lymphosarcoma, also known as the Gardner lymphosarcoma (GLS). Table 1 gives the results of several experiments in mice bearing this tumor when compounds were administered orally. In the Table, column 1 gives the example number of the com-pound; column 2, the dose level; and column 3, the percent inhibition of tumor growth. The results are the 3~33 X-6457A -lS-average of 10 animals per group as compared with suitable control group.

Table 1 Activity of the Compounds of Formula I
Against the 6C3~ED Lymphosarcoma*
Compound of Percent 10 ExamPle No._ Dose** Inhibition 50 twice daily 65 75 twice daily 89 100 twice daily 93 150 twice daily 100 2Q0 twice daily 99 300 ~wice daily 100 400 twice daily 100 Tested in C3H mice~
mg/kg administered orally in"Emulphor."l Dosing began the day following inoculation. Compounds were dosed once every day ~or eight days, except where noted.
1 Trademark for a series of polyoxyethylene ~atty acid esters L33.J3.

In addition, one of the compounds of for-mula (I), the compound of Example 1, was tested orally in additional test systems. These include the sub-cutaneous B-16 melanoma (B16-sc), the X5563 plasma cell myeloma (X5563), the M-5 ovarian carcinoma (M-5), the C3H mammary carcinoma (C3H), colon carcinoma-26 (C6), the CA-755 adenocarcinoma (CA755), the Madison Lung Carcinoma (Madison), the P388 lymphocytic leukemia (P388), and the Lewis Lung carcinoma (LL). A summary of .these test results is provided in Table 2.

..

Table 2 Activity of Compound 1 against a variety of t.umor models Compound of Percent Example No. Tumor Dose* Inhibition 1 CA755 37.5 30 75.0 67 LL 37.5 4 300 ~8 C6 37.5 24 75.0 36 300 ~5 600 lO0 M-5 37.5 53 7~.0 76 Madison 37.5 44 75.0 ~5 ~2~333 Table 2 cont'd.
Compound of Percent Example No. Tumor Dose* Inhibition X5563** 37.5 0-38 300 4~-66 C3H 37.5 49 300 ~00 P388 12.510***
25 8***
5013***
10019***
20051***
B16-sc 37.5 13 mg~kg per dose administered orally in "Emulphor~
Dosing began the day followin~ inoculation.
Compounds were dosed twice daily for 10 days.
Summary of two e~periments.
percent`prolongation of life.

1 Trademark 7,~

The compounds of formula ~I) are antineoplastic agents, thus the present invention also provides a method of treating susceptible neoplasms. The method comprises administering a compound of formula (I) by various routes including the oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes, being usually employed in the form of a pharma-ceutical composition. A special feature of these compounds is that they are effective when administered orally. Such compositions are prepared in a mann~r well-known in the pharmaceutical art and comprise at least one active compound of formula (I). Accordinglyt in addition to providing compounds of formula I, the invention also provides pharmaceutical compositions comprising as active ingredient a compound of formula I
associated with a pharmaceutically acceptable carrier.
In makin~ the compositions of the present invention, the active ingredient usually will be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or o-ther container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the composi-tions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
Some examples of suitabla carriers, excipi-ents, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrroli-done, cellulose, water, syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate and mineral oil. The formulations can include additionally lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, s~eetening agents or flavoring agents. The compositions of the invention may be formulated so as to provide ~uick, sustained or delayed release of the active ingredient, after adminis-tration to the patient, by employing procedures well known in the art.
The compositions preferably are formulated in a unit dosage form, each dosage containing from about 5 to about 500 mg, more usually about 25 to about 300 mg, of the active ingredient. The term "unit dosage form"
refers to physically discrete units suitable as unitary dosages for human subjects or other warm-blooded ani-mals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
The active compounds are effective over a wide dosage range. For example, dosages per day will normal-ly fall within the range of about 0.5 to about 600 mg/kg of body weight. In the treatment of adult humans, the range of about 1 to about 50 mg/kg, in single or divided doses, is preferred. However, the amount of the com-pound actua~ly administered will be determined ~y a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, the chosen route of admin-istration, the age, weight, and response of the individ-ual patient, and the severity of the patient's symptoms.
Therefore, the above dosage ranges are no-t intended to limit the scope of the invention in any way.
The following non-limiting formulation exam-ples may employ as active compounds any of the compounds of formula (I) and are provided for illustrative purposes only.

Example 9 Hard gelatin capsules are prepared using the following ingredients:
Quantity (mg/capsule) N-~[(4-trifluoromethylphenyl)-amino]carbonyl~-2,3-dihydro-1,4-benzodioxin-6-sulfonamide250 Starch dried 200 Magnesium stearate 10 The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.

~Z~33 X-6457A -22~

Example 10 A tablet formula is prepared using the ingre-dients below:
Quantity (m~/tabl~t) N-(~(3-fluoro-4-trifluoro-methylphenyl)amino]carbonyl)-2,3-dihydro-lH-indene-5-sulfo:namide 250 Cellulose, microcrystalli:ne 400 Silicon dioxide, fumed 10 Stearic acid 5 The components are blended and compressed to form tablets each weighing 665 mg.
Example 11 An aerosol solution is prepared containing the following components:
Weight %
N-([(3-chloro-4-fluorophenyl)-amino]carbonyl)-5,6,7,8-tetra-hydro-2-naphthalenesulfonamide 0.25 Ethanol 29.75 Propellant 22 70.00 (Chlorodifluoromethane) The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30C and transferred to a filling device.
The required amount is then fed to a stainless steel 33~3 container and diluted with the remainder of the propel-lant. The valve units are then fitted to the container.

Example 12 Tablets each containing 60 mg of active ingredient are made up as follows:
N-([(4-chlorophenyl)amino]-carbonyl~-2,3-dihydro-lH--indene-5-sulfonamide 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as 10% solution in water) 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total 150 mg The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which then are passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50-60C and passed through a No.
18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, then are added -to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

Example 13 Capsules each containing 80 mg of medicament are made as follows:
N-t[(4-fluorophenyl)aminol-carbonyl)-2,3-dihydro-lH
indene-5-sulfonamide 80 mg Starch 59 mg Microcrystalline cellulose59 mg Magnesium stearate 2 m~
Total 200 mg The active ingredient, cellulose, staEch and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.

Example 14 Suppositories each containing 225 mg of active ingredient are made as follows:
N-([(3,4-dichlorophenyl)amino]-carbonyl)-5,6,7,8-tetrahydro-2-naphthalenesulfonamide 225 mg Saturated fatty acid glycerides to 2,000 mg The active ingredient is passed through a No.
60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat , - ' . ' ~2~33:3 necessary. The mixture then is poured into a supposi-tory mold of nominal 2 g capacity and allowed to cool.

Example 15 Suspensions each containing 50 mg of medica-ment per 5 ml dose are made as follows:
N-([(3,4-difluorophenyl)amino]-carbonyl)-2,3-dihydro-lH-indene-5-sulfonamide 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v.
Color g.v.
Purified water to 5 ml The medicamen~ is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with some of the water and added, wi-th stirring. Sufficient water is then added to produce the required volume.

Example 16 Capsules each containing 150 mg of medicament are made as follows:

L3~3 N-([(4-chlorophenyl)amino]carbonyl)-2,3-dihydro-lH-indene-5-sulfonamide 150 mg Starch 164 mg Microcrystalline cellulose 164 mg Magnesium stearate 22 m~
Total . 500 mg The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 500 mg quantities. .

Claims (19)

1. A process for preparing a compound of formula (I):

(I) in which A is -O-, ?CH3, -CH2-, -CH2CH2-, or -CH2O-;
D is -CH2- or -O-;
provided that neither A nor D can be -O- unless both A and D are -O-;
R1 is hydrogen or halo, and R2 is halo or trifluoromethyl, which comprises reacting with a compound of the formula in which Y is -NH2 or -NCO, and R1 and R2 are as defined above, a sulfonyl compound of the formula:

X-6457A-(Canada) -28-in which X is -NCO, -NH2 or -NH-COOR3 in which R3 is C1-C3 alkyl, and A and D are as defined above, provided that if X is -NCO or -NHCOOR3 then Y is -NH2 and if X is -NH2 then Y is -NCO.

2. A process for preparing a compound of formula (I), as claimed in claim 1 which is in which A is -CH2- or -CH2CH2-, R1 is hydrogen or halo, and R2 is halo or trifluoromethyl.

3. A process for preparing a compound as claimed in claim 1 or 2 in which R1 is hydrogen.

4. A process for preparing a compound as claimed in claim 3 in which R2 is halo.

5. A process for preparing a compound as claimed in claim 4 in which R2 is chloro.

6. A process as claimed in claim 1 for preparing N-{[(4-chlorophenyl)amino]carbonyl}-2,3-dihydro-1H-indene-5-sulfonamide, N-{[(4-chlorophenyl)amino]carbonyl}-5,6,7,8-tetrahydro-2-naphthalenesulfonamide, or N-{[(4-chlorophenyl)amino]carbonyl}-1,3-benzodioxole-5-sulfonamide.

7. A compound of formula (I), as defined in claim 1, whenever prepared by a process as claimed in claim 1, or by an obvious chemical equivalent thereof.

X-6457A-(CAN) -29-

8. A compound of formula (I):

(I) in which A is -O-, ?CH3, -CH2-, -CH2CH2-, or -CH2O-;
D is -CH2- or -O-;
provided that neither A nor D can be -O- unless both A and D are -O-;
R1 is hydrogen or halo, and R2 is halo or trifluoromethyl.

9. A compound of formula (I), as claimed in claim 8 which is in which A is -CH2- or -CH2CH2-, R1 is hydrogen or halo, and R2 is halo or trifluoromethyl.

10. A compound as claimed in claim 8 in which R1 is hydrogen.

11. A compound as claimed in claim 10 in which R2 is halo.

X-6457A-(EPO) -30-

12.A compound as claimed in claim 11 in which R2 is chloro.

13.N-{[(4-chlorophenyl)amino]carbonyl}-2,3-dihydro-1H-indene-5-sulfonamide, N-{[(4-chlorophenyl)amino]carbonyl}-5,6,7,8-tetrahydro-2-naphthalenesulfonamide, or N-{[(4-chlorophenyl)amino]carbonyl}-1,3-benzodioxole-5-sulfonamide.

14. A pharmaceutical formulation which comprises, as an active ingredient, a compound of formula (I) as defined in claim 8, in association with a pharmaceutically acceptable carrier, diluent or excipient therefor.

15. A pharmaceutical formulation according to claim 14 wherein the active ingredient is a compound as defined in claim 9.

16. A pharmaceutical formulation according to claim 14 wherein the active ingredient is a compound as defined in claim 10.

17. A pharmaceutical formulation according to claim 14 wherein the active ingredient is a compound as defined in claim 11.

18. A pharmaceutical formulation according to claim 14 wherein the active ingredient is a compound as defined in claim 12.

19. A pharmaceutical formulation according to claim 14 wherein the active ingredient is a compound as defined in claim 13.