FR2526426A1 - NOVEL AMINOSULFONYLBENZOATES AND PROCESS FOR THEIR PREPARATION - Google Patents

Abstract

NEW AMINOSULFONYLBENZOATES USEFUL IN PARTICULAR AS ANTIVIRAL MEDICINAL PRODUCTS AND A METHOD FOR THEIR PREPARATION; THESE COMPOUNDS MEET FORMULA (I) (CF DRAWING IN BOPI) IN WHICH X AND Y REPRESENT INDEPENDENTLY FROM ONE OF THE OTHER AN ATOM OF FLUOR, CHLORINE, BROMINE OR HYDROGEN, AND R REPRESENTS AN ALKYL GROUP , ALCENYL, CYCLOALKYL OR BENZYL; A PROCESS FOR THEIR PREPARATION IS ALSO DESCRIBED.

Description

The present invention relates to novel amino

  sulphonyl benzoates and a process for their preparation.

  More particularly, the invention relates to novel aminosulfonyl denzoates of formula (I):

I 41502 NH 2 (I)

y / X

Y 'X

  where X and Y independently represent one of the

  be a fluorine atom, a chlorine atom, a bromine atom or a hydrogen atom and R is an alkyl group, a group

  alkenyl groups, a cycloalkyl group or a benzyl group, these

  poses being useful because of their antiviral action.

  In the course of considerable studies on

  substances with physiological activity, the plaintiffs

  covered that particular aminosulfonylbenzoates present

  antiviral activities and the invention is based on this

covered.

  The compounds of the invention can generally

  neral be prepared in the following way.

  A haloaminosulic acid chloride is obtained

  fonyibeuizoic acid by heating a halogenoaminosulfonyl acid

  Benzoic acid in thionyl chloride (British patent

  915 259) The haloamino acid chloride is reacted with

  sulfonylbenzoic acid thus obtained with an alcohol of formula (II)

ROH (II)

  in which R has the same meaning as in the formula

  (I), in the presence of a solvent such as dioxane, tetra-

  hydrofuran, chloroform, dichloromethane, benzene and the like or the like (II)

  at room temperature or hot, if it is

  necessary to obtain the desired compound of the invention.

  The alkyl group represented by R is a linear or branched chain group having 1 to 12 carbon atoms which can in particular be a methyl, ethayl or isopropyl group,

  n-propyl, n-butyl, sec-butyl or n-octyl The alce-

  nyl represented by R may be preferably the allyl group.

  The cycloalkyl group preferably is the cyclohexyl group. The aminosulfonyl group may preferably be attached to the 3 or 5 position of the phenyl ring while X and Y may preferably be attached to the 2 and / or 4 position.

of this cycle.

  Preferably, X and Y do not represent all

two a hydrogen atom.

  The processes for preparing particular compounds

  The invention, which are described in more detail by way of example, is purely illustrative and does not limit

in no way the invention.

  Synthesis Example 1 1.08 g of benzyl alcohol is added to 2.89 g of 5-aminosulfonyl-2,4-dichlorobenzoyl chloride dissolved in

  ml of dioxane After 2 hours of hot reflux,

  father the dioxane under reduced pressure and recrystallize the

  residue in methanol to give 3.19 g of 5-aminosulfonyl-

  Benzyl 2,4-dichlorobenzoate in the form of white crystals.

  When determining the melting point according to the indi-

  in the Japanese Pharmacopoeia, this compound melts at 161.5-

  163 C The basic analysis of this product is as follows:

C H C 1 N S

  Theoretical: 46.68 3.08 19.68 3.89 8.90 Found: 46.40 3.01 19.39 3.92 8.75 Synthesis Example 2:

  2.38 g of this 3-aminosulfonyl-4-chloride are added

  Fluorobenzoyl in 15 ml of methanol After 4 hours of reaction

  at room temperature, concentrate the reaction mixture

  under reduced pressure and the precipitated crystals are filtered off. The crystals are then recrystallized.

  in methanol to obtain 1.84 g of this 3-aminosuifonyl-4-fluoro

  Methyl benzoate in the form of olancial crystals When determining the melting point according to the inaiquee method

  the Japanese Pharmacopecr, this compound melts at 122-1-24 ° C.

  Elemental analysis of this product is shown below

C H P N S

  Theoretical 41.20 3.46 8.15 6.01 13.75 Calculated 41.40 3.41 8.10 5.92 13.65 The compounds indicated in the table are prepared

  1 in the same way as in Synthesis Examples 1 and 2.

  Example of Name of Coimposite Appearance F (Methylaminosulfonyl-2, 4-uiciilobrobenzoate-ethylaminosulfonyl-2,4-dichlorobenzoate-n-propylaminosulfonyl-2,4-dichlorobenzoate-2,4-aminosulononylbenzyl) isobutyl dichlorobenzoate-aminosulonyl-2,4-n-butyl dichlorobenzoate-sec-butyl-2-butylbenzyl-2,4-dicarboxylic acid

f-aminosulfonyl-2,4-dichloaro-

  cyclohexyl-aminosulfonyl-2,4-dichlorobenzoate-n-octyl-cyclohexyl-2,4-dichloro-benzoate c-allyl-aminosulphonyl-4-chloro-2-fluorobenzoate methyl-aminosulfonyl-2-chloro-4- benzoate ethyl fluorobenzoate

3-anminosulfonyl-4-bromine

6 'isopropyl benzoate

3-aminosulfonyl-4-bromio

  n-butyl benzoate White crystals

201.5 -

204 u C 124 -

126, 50 C

124 -

OC 126.55

149,5-

151 oc do -92 e C

137.5 -

142 O C

do

81-86 OC

-

133 OC

109 -

112 O C

157 -

161 OC

123 -

129 O C

  Each of the compounds of the invention exhibits effective antiviral activity when used at a dose of 200 mg / ml.

  or 100 mg / kg in the protection test in the mouse

  influenza A / WJSN and in particular

  poses 7, 9 and 15 are ten times more powerful than Amantadine

  which is an antiviral agent conventionally employed.

  The compounds according to the invention have a high degree of safety with these LD 50 values greater than 3000 mg / kg for oral administration and greater than 1000 mg / kg for oral administration.

  intraperitoneal administration -

  In particular, in the case where

  the compounds of the invention to humans, the dosage for adults is 30 to 5000 mg / day for compounds 2-5, 12 and 13; 10 to 5000 mg / day for compounds 7, 9 and 15; and

  at 5000 mg / day for compounds 1, 6, 8, 10, 11 and 14.

  However, the dosage may be increased or decreased beyond the indicated ranges depending on symptoms, age and

other factors.

  The compounds of the invention may be presented in the form of pharmaceutical preparations in a conventional manner, alone or in combination with other active ingredients, and

  if it is necessary, with vehicles, bases or ex-

  commonly used pharmaceutically acceptable containers.

  These preparations may for example be

  capsules, tablets, powders or preparations

  oral fluids (including dehydrated syrups) for oral use; suppositories for rectal use; and, for use by injection, they may for example be freeze-dried preparations which can be dissolved in

  injectable distilled water immediately before administration

  tration; other preparations may also be used

  such as nasal drops or a product to inhale.

  Non-limiting examples of pheromone preparations

are listed below.

  Example 1: Tablets I) Compound 7 50 g II) Lactose q.s. III) Crystalline Cellulose IV) Amiaon this apple this earth V) Stearate this magnesium to 54 g 2 (J ') 9 - 5 One homogeneously alange the ingre Cdients (1) to (IV) and one adds to the mixture ci- cessation of the punch at 10%

  prepared with some of the ingredient (IV) that has been prepared

  lablement reservee, to obtain pellets and then dry

  the granules are then mixed with the granules

  (V) to obtain tablets each weighing 200 mg. If desired, the tablets may be coated with

usual way.

  Example 2: Compound Powder Compound 9 100 g Lactose 890 g Magnesium Stearate 10 to 1000 g After weighing each of the above ingredients, they are homogeneously mixed to prepare a powder.

10%.

  Example 3: Capsules I) Compound 15 50 g II) Calcium hygrogenophosphate 50 g

III) Aluminum silicate q s.

IV) Crystalline cellulose 60 g

V) magnesium stearate 2 g.

  The ingredients (I) to (V) above are combined and thoroughly mixed by sieving through a sieve.

  and the usual preparation is made from the mixture of

sules each weighing 200 nma.

s 1 dss'e 2 oriula ():

é W <2 (1)

<E

  where X and Y independently represent one of

  a fluorine atom, a chlorine atom, a bromine atom a hydrogen atom and R is an alkyl group, an uroupe

  -lcénle, a cycloaljle group or a benzyl group.

  Compounds according to claim 1, in which

  X and Y are not simultaneously a hydrogen atom -t is a straight or branched chain alkyl group having

  L to 12 carbon atoms, an allyl group, a cycloalkyl group,

  Kyle or a cyclohexyl group 3 Compounds according to claim 1, wherein the aminosulfonyl group is attached to the 3 or 5 position of the benzene ring, while X and Y are attached to

  2 and / or 4 positions of the benzene ring.

  Compounds according to claim 2, wherein the aminosulphonyl group is attached to the 3 or 5 position of the benzene ring, while X and Y are attached to

  2 and / or 4 positions of the benzene ring.

  A compound according to claim 1, which is n-butylaminosulfonyl-2,4-dichlorobenzoate. Compound according to claim 1, which is the

  5-aminosulfonyl-2,4-dichlorobenzoate n-octyl.

  Compound according to claim 1, which is the

  3 n-butyl aminosulfonyl-4-bromobenzodide.

  A compound according to claim 1 which is benzylaminosulfonyl-2,4-dichlorobenzoate. Compound according to claim 1, which is the

  Methyl 3-aminosulfonyl-4-fluorobenzoate.

  A compound according to claim 1 which is methylaminosulfonyl-2,4dichlorobenzoate. A compound according to claim 1 which is ethylaminosulfonyl-2,4-dichlorobenzoate. Compound according to claim 1, which is the

  5-aminosulfonyl-2,4-dichlorobenzoate n-propyl.

  A compound according to claim 1 which is isopropyl 2,4-aminosulfonyl-2,4-dichlorobenzoate. A compound according to claim 1, which is sec-butylaminosulfonyl-2,4-dichlorobenzoate. A compound according to claim 1 which is cyclohexylaminosulfonyl-2,4-dichlorobenzoate. A compound according to claim 1, which is allyl aminosulfonyl-2,4-dichlorobenzoate. Compound according to claim 1, which is the

  Methyl 5-aminosulfonyl-4-chloro-2-fluorobenzoate.

  A compound according to claim 1 which is ethylaminosulfonyl-2-chloro-4-fluorobenzoate. A compound according to claim 1 which is isopropyl aminosulfonyl-4-bromobenzoate. Process for preparing a compound of formula (I) COOR

-502 NH 2 (I)

Y 2

  where X and Y independently of one another represent

  smell of a fluorine, chlorine or bromine atom or a hydrogen atom, and R is an alkyl group, a group

  alkenyl, a cycloalkyl group or a benzyl group,

  characterized in that it consists in reacting an acid with

  logenoaminosulfonylbenzo, that of formula: CO Oa X.

  in which X and Y have the same meanings as

  above, with thionyl chloride to obtain a chlorine

  haloaminosulfonylbenzoic acid and reacting the haloaminosulfonylbenzoic acid chloride thus obtained with an alcohol of the formula: ROH

  wherein R has the same meaning as above.

  The process according to claim 20, wherein X and Y are not simultaneously hydrogen and R is a linear or branched alkyl group having 1 to 12 carbon atoms, an allyl group, a cycloalkyl group

or a cyclohexyl group.

  The method of claim 20, wherein the aminosulfonyl group is attached at the 3 or 5 position of the benzene ring while X and Y are attached at the

  position 2 and / or 4 of the benzene ring.

  The process of claim 21 wherein the aminosulfonyl group is attached at the 3 or 5 position of the benzene ring while X and Y are attached at the

  position 2 and / or 4 of the benzene ring.