ITMI932690A1 - ACILSULFAMMIDI WITH ANTI-TUMOR ACTIVITY - Google Patents

Description

Description of the industrial invention entitled: "ACYLSULFAMIDI AD ACTIVIT? ' ANTI-CANCER "

The present invention relates to N-substituted N-acrisultarmides, a method for their preparation and pharmaceutical combinations containing them.

Pi? precisely the invention relates to compounds of formula (I):

in which:

Ar? an aromatic or heteroaramatic group,

? hydrogen and? a phenyl, optionally substituted with from one to three substituents such as halogen atoms (chlorine, bromine, fluorine, iodine), linear alkyl (C1-C5) groups, (C3-C5 branched alkyl, (C3-C7) cycloalkyl, (C1- C5) alkoxy, (C1-C5) alkylthio, trifluoromethyl, anmino, (C1-C5) monoalkylanmino, (C1-C5) dialkylairrtu.no, methylsulfertyl, phenylsulfonyl, (C1-C5) alchrlsulfcnam ido, phenylsulfonarmi, nitylsulfonarmi , (C1-C5) alkoxycarbonyl, atminosulfonyl, amido, (C1-C5) alkylcarbonyl,

or ? a (C1-C7) alkyl group, linear or branched, or a (C3

where R'1 '? a (C1-C7) alkyl or a (C3-C7) cycloalkyl,

or NR1R2? a piperidine-1-yl, pyrrolidin-1-yl, morpholin-4-yl or tichmorpholino-4-yl group.

When Ar? an aromatic group,? preferably phenyl optionally substituted with one to three substituents such as halogen atoms (chlorine, bromine, fluorine, iodine), (C1-C5) linear alkyl, (C3-C5) branched alkyl, (C1-C5) alkoxy, trifluoranethyl groups, armino, (C1-C5) monoalkylamino, (C1-C5) dialkylanniine, methylsulfonyl, phenylsulfonyl, (C3-C7) cycloalkyl, (C1-C5lalkylsulfonanyricide, phenylsulfcnane, cyano, nitro, (C1-C5) thioalkyl, (C1-C5) thioalkyl alkoxycarbonyl, aititiinosulfonyl, amido, (C1-C5) alkylcarbonyl,

or Ar? a naphthyl, indanyl or indenyl group.

When Ar? a heteroarematic group,? preferably a dihydrobenzofuramie, dihydrobenzothiophenyl, quinolimie or isoquinolinyl group of formula:

Said heterocyclic groups are linked to the carbonyl group in positions 4, 5, 6 or 7 in the case of dihydrobenzofuranyl and dihydrobenzothiophenyl; on the other hand, they are bound in positions 5, 6, 7 or 8 in the case of quinolinyl and isoquinolinyl.

Particularly preferred examples of mono and / or poly substituted phenyl groups sine those bearing the following substitutions:

Particularly preferred compounds of formula (I) are:

The compounds of formula (I) are prepared by reaction of the compounds of formula (II):

with an amine of formula (III):

in which Ar, R1 and and R2 have the meanings defined above.

The reaction is preferably carried out at temperatures ranging from room temperature to -50 ° C, in an inert solvent such as for example an ether (canine tetrahydrofuran, ethyl ether, diglima, etc.), a chlorinated solvent (orane methylene chloride, 1, 2-dichloroethane), dimethylformarmide, N-methylpyrrolidone, benzene, toluene, and in the presence of an organic base (orane for example triethylimdna, pyridine, diazabicycloundecene, diazabicyclooctane, etc.) or inorganic (e.g. a hydroxide of an alkaline metal or alkaline earth, potassium carbonate, sodium bicarbonate, eoe.). Preferred temperature conditions are those between 0 ° C and -50 ° C.

The compounds of formula (II) can be prepared starting from the benzoic acids of formula (IV):

by reaction cerichlorosulfcnylisocyanate. The reaction is preferably carried out in an inert solvent such as an arenatic hydrocarbon (orane, for example benzene, toluene, chlorcphoenzene, nitrobenzene), a chlorinated solvent (such as methylene chloride or 1,2-dichloroethane), an ether (such as ethyl ether, tetrahydrofuran , 1,4-dioxane, diglima) or in mixtures thereof and at a temperature which corresponds to the boiling point of said solvents.

The amines of formula (III) and the benzoic acids of formula (IV) are commercially produced or can be prepared with well known methods reported in the literature.

N-ac the sulf amides known in literature [Mcnatsh. Chem. , 117 (1), 123-6 (1986)]. In particular, phenoxybenzoylacylsulfamnides described breast have activity? herbicide [GB 83-9648 (April 8, 1983); US 81-286937 (July 27, 1981)].

The subjects of the invention have shown a remarkable activity? cytotoxic agents in the Soft Agar Diffusion Disk Assay (SADDA) assay, described in Cytotoxic Anticancer Drugs: Models and Ccncepts for Drug disccvery and Development, F.A. Valerio you, T.H. Corbett, L.H. Baker, cap. 3, p. 35-87, KLUWER ACADEMIC PUBLISHERS (1992).

The procedure of this test can? be so? summary:

a drop of ethanolic solution of the molecule to be tested is deposited on a filter paper disc and the solvent is allowed to evaporate. The paper disc is then placed in a Petri dish on the surface of a nutrient medium that already contains? a specific type of cancer cells. Such a plate? divided into "zones" marked with a number. The plate is incubated for a few days, then it is read to determine the degree of cytotoxicity: if the plate shows a zen a around the paper disc in which no more tumor cells are present , then this "zena" is defined by a number that indicates the point at which the cellular colony reappears. If within a "zone" the cellular colony is present in smaller quantities than normal, then a range is indicated for define such zen a.

For example, if a plate? read 250-640, it means that the plate does not show cellular colonies up to the point 250, while it presents them in reduced number in the "zones" from 250 to 640.

The commonly used tumor lines are: L1210 (leukemia); P388 (B-cell lymphoma); C38 (solid murine fear of Coirai); P03 (murine solid fear of the pancreas); M17 / Adr, M16 / c (manmarine raurine solid tumors); H8, H116, CXl (Coirai human solid tumors); MCF-7 (solid breast cancer); H125 (solid human fear of poimeni).

In the test are also used tumor ncn cells to determine a possible selectivity? in the cytotoxic action. Cells used are: IMF (fibroblasts); 118 (Gl epithelial cells).

In Table A breast shown, by way of example, the activities? in the SADDA of some compounds of the invention and of some drugs active in the clinic as anticancer agents.

The compounds of the invention can therefore be used as active ingredients of pharmaceutical compositions suitable for inducing the regression and / or treatment of tumors in mammals when administered intravenously in quantities. ranging from 0.001 mg to 0.4 mg per kilogram of body weight per day, so? to be administered from about 0.07 g to about 3.5 g of the active compound to a subject of about 70 kg of body weight in a period of 24 hours. An alternative route of administration can? be the oral route, using dosages including? between about 0.5 mg and about 600 mg per kilogram of body weight per day. This dosage regimen can be adjusted to provide the optimal therapeutic response. For example, different divided doses can be administered according to the need of the therapeutic situation. Uh major practical advantage? that the compound can? be administered orally, intravenously, intramuscularly or subcutaneously. The compositions object of the invention containing compounds of formula (I) can be used to treat cancerous blood diseases such as leukemia or other tumors such as lung carcinoma, oolon carcinoma, melanocarcinoma and breast tumors. Regression or cure refers to the arrest or retardation of tumor growth.

Suitable forms of administration for intravenous sinus injection consist of sterile physiological solutions. For intramuscular or intraperitinal administration, oily or aqueous injectable preparations are suitable, while for oral administration examples of suitable formulations are syrups, liquid and solid preparations such as capsules, tablets and the like.

The compositions of the invention can be prepared using conventional methods, described for example in "Remington's Pharmaceutical Sciences Hancbook", XVII ed. Mack Pub, N.Y., USA.

The following examples further illustrate the invention.

EXAMPLE 1 - Synthesis of para-toluoilsulfaimoyl chloride

4.76 ml of chlorosulfonyl isocyanate are added dropping to a suspension of 7 g of p-toluic acid in 30 ml of methylene chloride, heated under reflux in an inert gas atmosphere. The reaction mixture is heated for 2 hours under reflux, then is allowed to cool spontaneously to room temperature. After the addition of 60 ml of petroleum ether, a whitish solid precipitates which is separated by filtration and dried under vacuum. 10.9 g of product are obtained with m.p. 115-H7? C.

EXAMPLE 2

A solution is added by dropping a solution to a solution of 4-arrinabenzotrifluoride (3.25 ml) and triethylamine (7.21 ml) in 30 ml of tetryl drof urane, placed under magnetic stirring, in an inert gas atmosphere and cooled to -4 0 ° C. of para-toluoylsulfammoyl chloride (6.05 g) in 15 ml of tetrahydrofuran, ensuring that the temperature does not exceed -30 ° C. The temperature is then made to rise spontaneously to room temperature and the reaction mixture is left under stirring for a further 18 hours, then it is poured into 200 ml of water and repeatedly extracted with ethyl acetate (2x100 ml). The combined organic extracts are washed with 50 ml of saturated aqueous solution of sodium chloride, dried over sodium sulphate and the solvent is evaporated under reduced pressure, obtaining a yellow oil weighing 10.5 g. The residue is purified by chromatography on silica gel (eluent methylene chloride / methanol 98: 2). 2.49 g of ccn p product are obtained. f. 182-184? C.

Elementary analysis: C 49.62% (theoretical 50.28%) H 3.71% (theoretical 3.66%) N 7.67% (theoretical 7.82%) S 8.77% (theoretical 8.95%) F 15.67% (theoretical 15.91%)

EXAMPLE 3

To a solution of 4-chloroaniline (6.07 g) and triethylaniline (6.49 ml) in tetryal drof urane (60 ml), stirred in an inert gas atmosphere and cooled to -55 ° C, is added by dropping in about 1 hour and 40 minutes a solution of para-toluoilsulfamnoyl cloniro (10.9 g) in 50 ml of tetrahydrofuran. The reaction mixture is left for another 4 hours and 30 minutes at -50 ° C, then the temperature is allowed to spontaneously rise to room temperature. After a further 12 hours the mixture of the reactants is poured into 300 ml of water and repeatedly extracted with ethyl acetate (4x250 ml). The combined organic extracts are dried over sodium sulphate and the solvent is evaporated under reduced pressure. The raw reaction product (33 g) is purified by chromatography on silica gel (eluent methylene chloride / methanol 94: 6), obtaining, after crystallization from methanol (15 ml), 8 g of product with m.p. 177-179? C.

EXAMPLE 4 - Synthesis of benzollsulfairmoyl chloride

To a suspension of benzoic acid (3 g) in 10 ml of methylene chloride, placed under stirring and in an inert gas atmosphere, 2.32 ml of chlorosulfonyl isocyanate are added by dropping at ambient temperature. The reaction mixture is left for 1 hour at ambient temperature and 4 hours at reflux, then it is cooled to ambient temperature and 20 ml of petroleum ether is added. The precipitate is filtered and dried under vacuum. 4.61 g of product are obtained with m.p. 110-112? C.

EXAMPLE 5 -

N -benzoylsulfanmoyl chloride (4.6 g) in 20 ml of tetrahydrofuran, causing the temperature to exceed -50 ° C. The reaction mixture is held 1 hour and 30 minutes at -50 ° C, then 72 hours at -7 ° C, then it is poured into a mixture of water (150 ml) and ethyl acetate (300 ml). The organic phase, separated, is washed with 50 ml of saturated sodium chloride solution and dried over sodium sulphate. The solvent is evaporated under reduced pressure and the residue (8.6 g) is purified by crcmatography on silica gel, obtaining, after crystallization from ethyl acetate (10 ml) and petroleum ether (36 ml), 3.37 g of product with m.p. 183-185? C.

Elementary analysis: C 49.29% (theoretical 48.84%) H 3.40% (theoretical 3.22%) N 7.94% (theoretical 8.14%) S 8.99% (theoretical 9.31%) F 15.98% (theoretical 16.55%).

EXAMPLE 6 -

To a suspension of 3 g of 4-cetoxybenzoic acid in 10 ml of methylene chloride, pound under magnetic stirring and in an inert gas atmosphere, 1.8 ml of chlorosulfcyl isocyanate are dropped at room temperature. At the end of the dripping, the reaction mixture is heated under reflux for 1 hour, then it is allowed to cool spontaneously to room temperature and is diluted with 20 ml of petroleum ether. Briefly crystallizes a yellow solid which, filtered and dried under vacuum, gives 4.6 g of product with m.p. 97-99? C.

EXAMPLE 7

A solution is added dropwise to a solution of 4-aminobenzotrifluoride (2.31 ml) and triethylamine (2.56 ml) in 30 ml of methylene chloride, stirred in an inert gas atmosphere and cooled to a temperature of? 40 ° C. of N- (4-methoxybenzoyl) sulfamnoyl chloride (4.6 g) in a mixture of 80 ml of methylene chloride and 15 ml of tetrahydrofuran, always keeping the temperature below -40 ° C. The reaction mixture is maintained for 5 hours at -40 ° C and 12 hours at ambient temperature, then it is poured into 100 ml of water. The separated aqueous phase is again extracted with 70 ml of methylene chloride. The combined organic phases are dried over sodium sulphate and the solvent is evaporated under reduced pressure. The residue (5.9 g) is purified by chromatography on silica gel (eluent methylene chloride / methanol 97: 3) obtaining, after crystallization from ethyl acetate (9 ml) and petroleum ether (36 ml) and drying under vacuum , 2.1 g of product with m.p. 187-189? C.

Elementary analysis: C 48.15% (theoretical 48.13%) H 3.53% (theoretical 3.50%) N 7.49% (theoretical 7.48%) S 8.56% (theoretical 8.57%) F 15.21% (theoretical 15.23%).

EXAMPLE 8 -

To a suspension of 3 g of 4-chlorobenzoic acid in a mixture of methylene chloride (5 ml) and toluene (5 ml), stirred in an inert gas atmosphere, 1.79 ml of chlorosulfonyl isocyanate are added by dropping at room temperature. The reaction mixture is heated for 8 hours at 80 ° C, then it is left for 18 hours at amfcient temperature, at the end of which the precipitate is filtered and dried under vacuum to obtain 2.68 g of product with m.p.

117-1I9? C.

EXAMPLE 9

To a solution of 4-aminobenzotrifluoride (1.32 ml) and triethylanine (1.46 ml) in 10 ml of methylene chloride, stirred in an inert gas atmosphere and cooled to -50 ° C, is added by dropping into the tarp for 1 hour. a solution of 2.67 g of N- (4-chlorobenzoyl) sulfanmoyl chloride in a mixture of tetrahydrofuran (6 ml) and methylene chloride (60 ml). The reaction mixture is left for another hour at -45 ° C, then it is maintained for 12 hours at room temperature; at the end of this time, the mixture of reagents is diluted with 130 ml of methylene chloride and repeatedly washed with water (2x30 ml). The organic phase is anetherified on sodium sulphate and the solvent is evaporated under reduced pressure. The residue (yellow solid, 3.2 g) is purified by chromatography on silica gel (eluent methylene chloride / methanol 9: 1) obtaining, after crystallization from ethanol / water 1: 1, 300 mg of product ccn m.p. 183-185? C.

Elementary analysis: C 43.79% (theoretical 44.40%) H 2.74% (theoretical 2.76%) N 7.30% (theoretical 7.40%) S 8.35% (theoretical 8.47%) Cl 9.35% (theoretical 9.36%) F 14.61% (theoretical 15.05%) ).

EXAMPLE 10

According to the methods described in the previous examples, starting from the suitable N-aryloylsulfantnoyl chlorides, the following N-acylsulfamides are prepared:

Claims (9)

RIVHOICAZICNI Canposed of general formula (I): in which: Ar? an aromatic or heteroarematic group, R1? hydrogen and? a phenyl, optionally substituted with from one to three substituents such as halogen atoms (chlorine, bramo, fluorine, iodine), (C1-C5) linear alkyl, (C3-C5) branched alkyl, (C3-C7) cycloalkyl groups, ( C1-C5) alkoxy, (C1-C5) alkylthio, trifluoranethyl, armine, (Cl-C5) mcnoalkylarman, (C1-C5) dialkylarmine, methylsulphoryl, phenylsulphoryl, (C1-C5) alkylsulfcnanmido, phenylsulphoryl, cyan -C5) alkoxycarbonyl, anminosulfene, armido, (C1-C5) alkylcarbylene, or ? a (C1-C7) alkyl group, linear or branched, or a (C3-C7) cycloalkyl, or ? a 2-pyrimidyl, 2-, 3- or 4-pyridyl, benzyl, 3,4 dimethoxybenzyl, 3,4,5-trimethoxybenzyl, phenethyl, 3-di (C1-C5) alkylaminopropyl, 2-di (C1-C5 ) alkylitminoethyl, 2- (N-piperidino) ethyl, 2- (N-morpholino) ethyl, 2- (N-tichmorfolino) ethyl, (1-methylpiperazin-4-yl) ethyl, 2- (N-pyrrolidino) ethyl, 2- (1-imidazolyl) ethyl, or NRjI ^? a group where R "'1 is a (C1-C7) alkyl or a (C3-C7) cycloalkyl, or NR1R2? a piperidine-1-yl, pyrrolidin-1-yl, morpholin-4-yl or thiomorpholino-4-yl group. 2. Compounds according to claim 1 in which Ar?: phenyl possibly substituted with from one to three substituents such as halogen atoms (chlorine, bromine, fluorine, iodine), raw (C1-C5) linear alkyl, (C3-C5) branched alkyl, (C1-C5) alkoxy, trifluoromethyl, armino , (C1 -C5) mcnoalkylamino, (C1-C5) dialkylathmino, methylsulfonyl, phenylsulfonyl, (C3-C7) cycloalkyl, (C1-C5) alkylsulfonanmido, phenylsulphonar do, cyano, nitro, (C1-C5) alkylthio -C5) alkoxycarbonyl, anminosul phonyl, weapons do, (C1-C5) alkylcarbonyl, or Ar? a naphthyl, indanyl or indenyl group. 3. Compounds according to claim 1 in which Ar?: dihydrobenzofuranyl, dihydrobenzothiophenyl, quinolinyl or isoquinolinyl of formula: said heterocyclic groups being bonded to the cartayl group in positions 4, 5, 6 or 7 in the case of dihydrodibenzofuranyl and dihydrodibenzothiophenyl, being instead bonded in positions 5, 6, 7 or 8 in the case of quinolinyl and isoquinolinyl. 4. Compound according to claims 1-3, selected from the group consisting of: 5. Process for the preparation of the compounds of claims 1-4, characterized in that it involves the reaction of compounds formula (II): where Ar has the meanings defined above with an amine of formula (III): where and R2 have the meanings defined above. 6. Use of the compounds of claims 1-4 meat therapeutic agents. 7. Use of the compounds of claims 1-4 as anticancer agents. 8. Use of the compounds of claims 1-4 as active ingredients for the preparation of a medicament useful for the treatment and / or regression of fears in marble. 9. Pharmaceutical compositions containing a substitute of claims 1-4 as an active principle in admixture with pharmaceutically acceptable carriers.