DE1812971A1 - Benzoylfluoroalkylsulfonanilides - Google Patents

Description

Description of the patent application

MINNESOTA MINING AND MANIh ¹ ACTURING COMPANY 25o1 Hudson Road, Saint Paul, Minnesota 551o1, USA

concerning

Benzoylfluoralkylaulfonanilide (addendum to patent ... ^ "patent application P 16 68 42o.iJ7) '

In the main patent, perfluoroalkylsulfonamides substituted on nitrogen are described as novel compounds, the have anti-inflammatory, analgesic and antipyretic effects.

In the pharmacological testing of the new class of compounds it has now been found that a narrower group of im Main patent described compounds characterized by particularly valuable physiological effects and especially for Combating inflammatory processes in the mammalian organism is suitable.

For the treatment of inflammatory (e.g. arthritic) conditions So far, steroids with a cortisone-like effect have been used. While these remedies are effective, they do have certain points undesirable side effects, especially those affecting the endocrine system. There has therefore been a need for effective ones anti-inflammatory agents free from such drawbacks.

The novel novel as inflammation inhibitors Acting compounds meet these conditions. They are not steroids and therefore their use does not lead to any

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the inevitable side effects of steroid therapy » A particularly valuable property of the drugs prepared with these compounds is that they are relatively low Toxicity of the active ingredients; they are in the gastrointestinal tract well tolerated.

The compounds according to the invention belong to the class of the N-substituted fluoroalkylsulfonamides of the general formula

HjSO ₂ N,

where R _f denotes a fluorocarbon group with up to 8 carbon atoms, Rp denotes hydrogen, a lower alkyl group or a cation and R ^ denotes an organic group containing a heteroatom which is bonded to the nitrogen atom of the formula via an aromatic ring -

Stria.
registration P 16 68 42o.1) and is characterized in that

they of the general formula

R _f SO ₂ N

correspond, in which R _{f is} a partially fluorinated alkyl group with up to 4 carbon atoms, in which at least one fluorine atom is bonded to the «^ carbon atom or which, if no fluorine is bonded to the ^ carbon atom _? at least 2 fluorine atoms at the beta-Kohlenstoffatom.trägt, and wherein the same 'or different substituents Chen Y and Y ⁵ each represent hydrogen, a hydroxy group, a halogen atom or an alkyl or alkoxy group having up to 4 carbon atoms are and pharmaceutically acceptable salts of these connections.

The compounds of the invention are therefore (ggf.substituierte) Benzoylfluoralkylsulfonanilide or ₀ pharmaceutically acceptable salts thereof. - 3 -

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In the compounds according to the invention, the fluoroalkylsulfonamide group is preferably in the meta position to the garbonyl group ·

In addition to the anti-inflammatory effect already mentioned, some of the products according to the invention have analgesic and antipyretic effects. The anti-inflammatory activity can be demonstrated as usual by experiments in which the suitability AEII Ve * indungen to jtatagonisierung of local edema, which is one of the Oharakteristikum antiinflammato- gs smell Ansprecbena actual tested (rat foot edema test) for further consideration concerns the . Ability of the compounds to prevent the occurrence of erythematic inflammation (guinea pig erythematous test)

The edema test is carried out on adult rats of both sexes. A first group of ten rats serve as untreated control animals, while another group of ten rats are treated d-re with the test compound at various times prior to induction of the edema, usually 15 minutes, 1 hour and / or 18 hours beforehand. The test compound is suspended in 4 $ aqueous gum arabic solution (with a content of o, 9 $> NaCl) administered (| ranges The edema is induced by plantar injection of O |. 5 f> Carrageeain (o, 1 ml . per FuS) into the right hind foot the left hind receive the same volume of o, 9 $> - saline solution one hour later, the volume of both hind feet is determined plethysmographically edema is expressed as the percentage increase in volume of ödemogen injizierttD foot (.. Volume of "edema foot" minus volume of "saline foot" divided by the latter, multiplied by 100. The percent inhibition is calculated by dividing the mean percentage increase in edema on the edema of the edema in the treated group by the mean increase

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ί
in the untreated group, multiplied by 1oo. The active dose is that which produced a statistically significant inhibition, usually 3o - 35 #, of the induced edema

The main publications about this method are:

1. Adamkiewicz et al., Canada J. Biochem. Physio. 2Σ * 332, 1955j

2. Selye, Brit. Med. J ₀ Zt 1129 ,. 1949, - and

3o winter, Proc. Soc * Exper. Biol. Med. 111 »544 # 1962.

The erythematous test is carried out on adult guinea pigs of both sexes with a weight of 400 to 600 g. With the help of a depilatory mixture, the hair is removed from the abdomen of the animals in the afternoon before the day on which they are to be treated. One group of 5 animals serves as untreated control animals, while another group of 5 animals is administered the test compound 30 minutes prior to immediate exposure to ultraviolet light. To induce erythema, the animal is strapped to a small experimental board. Three circular sections (6 ~ 8 mm in diameter) on the ventrolateral ventral side of the animal are then subjected to a controlled amount of ultraviolet radiation. 2 hours after the irradiation, the erythema is marked with ο to 5. «depending on the intensity and completeness (full or partial circles). evaluates. The maximum rating per animal is 15. The percentage inhibition by the agents according to the invention is calculated on the basis of the mean rating for the treated group versus the non-treated group. The active dose is that which shows a statistically significant inhibition of the induced erythema of usually 35 ^ * ⁸ 40 <fo . Modifications of this method of analysis, and "a _o with respect to the treatment time and / or the method of administration, are possible

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The main publications about this method are:

1 Wilhelm, Switzerland. Med · Guard. 23x511% 1949 and 2, Winder et al., Arch Int Pharmacodyn 116 * 261, 1958

In the rat foot edema test and (or · or) the guinea pig erythema test the following compounds have proven to be effective anti-inflammatory agents (i.e. those with especially clear effect) proven; the dosage was 200 mg / kg or less when administered once

3-benzoyl difluoromethanesulfonanilide,
3 ~ Benzoyl difluoromethanesulfonanilide, sodium salt, 3-Benzoylfluoromethanesulfonanilide,
4-benzoylfluoromethanesulfonanilide, potassium salt, 2-benzoyldifluoromethanesulfonanilide,
3- (4-methylbenzoyl) difluoromethanesulfonanilide, 3- (4-methylbenzoyl) -fluoromethanesulfonanilide, 3- (4.-chlorobenzoyl) ~ difluoromethanesulfonanilide, 3-benzoyl-2,2,2-trifluoroethanesulfonanilide, 3- (4th) -Methoxybenzoyl) ~ difluoromethanesulphonanilide, 3- (4-methoxybenzoyl) -fluoromethanesulphonanilide, 4-benzoyldifluoromethanesulphonanilide

The above listed compounds and their salts according to known methods, see, 8ind as described below and explained in detail in Examples 1 to 7 _s prepared

Aspirin, which is widely used as an anti-inflammatory agent is, at 150 mg / kg in the rat foot edema test, it is only effective to a limited extent.

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To prepare the compounds of formula I condensed an aminobenzophenone with a fluoroalkylsulfonyihalide or anhydride according to the following scheme

R _f SO ₂ X

R _f S0 ₂ NH

where R _f , Y and Ύ ^{1 have} the above meanings and X stands for a halogen atom, preferably chlorine or fluorine, or the corresponding anhydride group -OSO ₂ R. * (R _f with the above meaning) «You bring approximately equivalent amounts of the reactants Temperatures together, which are mostly between about -15 and + 15o ° C. If necessary or desirable, the reaction can be carried out in a pressure vessel. Preferably, but not necessarily, the reaction is carried out in the presence of an acid acceptor, e.g. an alkali or alkaline earth carbonate or bicarbonate or a tertiary amine, such as pyridine, triethylamine or iijH-dimethylaniline. The amount of acid acceptor can vary widely, but usually an excess of 10 mol $ is used over the amount of base that is sufficient to bind the strong acid (HX) released »

The condensation is usually carried out in the presence of a suitable inert organic solvent. Typical solvents for this purpose are methylene chloride, chloroform _g, carbon tetrachloride, benzene, toluene, ^, 1 .2 _S-Dimeth oxyäthan, bis- (2 ~ methoxyethyl) ether _i) acetonitrile, _f I! Dimethylformamide uad like ₀

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After the reaction has ended, the mixture obtained can

extracted with a dilute aqueous base. A salt is obtained which is usually soluble in the aqueous layer and from it by adding a mineral acid! how hydrochloric or sulfuric acid is precipitated and filtered off the compounds prepared in the manner described are crystalline Pest substances that can be easily cleaned, generally by recrystallization from aqueous alcohol, tricolor ethyl en, hexane, benzene / hexane and the like.

Other, · methods known per se for the preparation of ER ^ compounds of this invention, in .denen Y ¹ is a hydroxy group, the cleavage of the alkoxy group of the corresponding sulfonanilides in which Y ¹ is alkoxy. This can easily be achieved with the help of mixtures of hydrogen iodide and acetic acid.

As already mentioned, the compounds of the invention are due to the presence of an acidic hydrogen atom on the nitrogen atom of the sulfonaniline group of their nature after sour. As a result, they easily form salts with basic ones Substances such as alkali or alkaline earth metals or amines. Pharmaceutically acceptable salts of these acidic compounds {| are also encompassed by the invention

The salts can be easily prepared by adding the stoichiometric to the acidic compound in an inert solvent Add amount of the base in question. The resulting solution becomes the solvent, e.g. by evaporation under reduced pressure. The salts are processed in the usual way into pharmaceutical preparations that are used for The compounds are suitable for administration, e.g., in capsules for oral administration.

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Suitable fluorocarbonsulfonyl anhydrides and halides

Chlorides and florides), which can serve as the starting material for these operations, are known to the person skilled in the art j Z ₀ Bt may be mentioned:

Fluoromethanesulfonyl chloride, Difluoromethanesulfonyl chloride, 2,2,2-trifluoroethanesulfonyl chloride, 1,1,2,2-tetrafluoroethanesulfonyl chloride, 2,2,3,3-tetrafluoropropanesulfonyl chloride and 2-hydroperfluoropropanesulfonyl chloride "

The aminobenzophenones required for the preparation of the compounds according to the invention are described in the literature or can be prepared from the corresponding known substituted nitrobenzophenones by reduction. Examples of such starting materials are i

^ -Amino-i-chlorobenzophenone, 3-amino-4'-fluorobenzophenone, 3-amino-5-bromobenzophenone, 3-amino-4'-ethylbenzophenone, 3-amino-2'-ethoxybenzophenone, 3-amino-4'- ethoxybenzophenone etc ₀

The examples explain the invention in more detail without it to restrict »Unless otherwise stated, the parts are always parts by weight o

Example 1 follows

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• Example 1

Preparation of 3-benzoylfluoromethanesulfonanilide

A 5oo ml flask equipped with a reflux condenser was charged with 8.7 g of N, N-dimethylaniline (0.72 mol), a solution of 12.8 g of 3-aminobenzophenone (0.065 mol) in 50 ml of methylene chloride, 8, 6 g Pluormethansulfonylchlorid (o, o65 mole, bp. 138-141 ⁰ C) and 2oo ml of methylene chloride The mixture was kept under reflux overnight, then cooled, washed twice with 1 ml of the above hydrochloric acid 5oo and dried over anhydrous magnesium sulfate. The solvent was evaporated, leaving an oil which crystallized after 3 hours in a vacuum oven to a relatively pure product, mp. 116-119 ° C _{β The solid was dissolved in 3oo ml 1 above aqueous sodium hydroxide solution absorbed the solution was heated, treated with activated charcoal and "acidified with concentrated hydrochloric acid to a pH of 1 was formed initially an oil, which, however, rapidly crystallized to a solid, mp. 115-117 ⁰ C, which was recrystallized from 95 $ strength ethanol and an analytically pure product, mp _e 117-12o ° C would result

Analysis: 2 C ₁₄ H ₁₂ PNO ₃ S 57 σ 4th H calculatedi 57 , 3 4th ,1 found t , 7 ,1 example

Preparation of 3-benzoyl difluoromethanesulfonanilide

Am 11 flask equipped with a reflux condenser was charged with 0.1 mol of 3-aminobenzophenone, 10 ml of pyridine, 0.1 mol of difluoromethanesulfonyl chloride and 400 ml of benzene · Das Mixture was kept at 5o-55 ° C for 72 hours and then with 1 of the above sodium hydroxide solution extracted »When acidifying the alkaline

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Layer you got a pest, which after recrystallization from mixtures of trichlorethylene and hexane an ana Lytically pure product with a melting point of 99-1oo.5 ° C would result

Analysis; C ₁₄ H ₁₁ J ₂ NO ₅ SCHN

calculated! , 54.1 3.6 4.4 found! 53 »9 3.6 4.4

Examples 3 to__18_

When using the general working methods according to the * "Game 1 and 2 and use of other fluoroalkyl sulfonyl chlorides and other substituted aminobenzophenones, all of which are known, are obtained as starting materials, for example the following connections

Example Pp »° C

(uncorrected)

3 2-Benzoyl difluoromethanesulfonanilide 79? 5-81

4 3- (4-methylbenzoyl) difluoromethanesulfonanilide 119-121

5 3 »(4-chlorobenzoyl) ~ difluoromethanesulfonanilide 127-129

6 3- (4-methoxybenzoyl) fluoromethanesulfonanilide 116.5-118.5

7 3-Benzoyl-4-chlorodifluoromethanesulfonanilide 99-1o2

8 3-Benzoyl-4-chloromonofluoromethanesulfonanilide 113-116

9 4-Benzoyl difluoromethanesulfonanilide 124.5-126.5

10 2-Benzoylfluoromethanesulfonanilide 74.5-75 _? 5

11 3- (4-chlorobenzoyl) fluoromethanesulfonanilide 118-12o

12, 3- (4-n-butoxybenzoyl) fluoromethanesulfonanilide 113-117

13 3- (4-t-Butylbenzoyl) -fluoromethanesulfonanilide 1o2-1o5

14 3- (4-fluorobenzoyl) 4ifluoromethanesulfonanilide 80-84

15 4- (4-fluorobenzoyl) fluoromethanesulfonanilide 127-129.5

16 3- (4-Hydroxybenzoyl) difluoromethanesulfonanilide 15o -152

17 2-benzoyl-4-chlorodifluoromethanesulfonanilide 98 · -I00

18 2-Benzoyl-4-chloromonofluoromethanesulfonanilide 88-89 ',' 5

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■ ^ί ί | ΐ "ΐπ! Π, Η !! ^111. ■ '.'""I;-" ¹ !!: ¹¹ Ia !! ¹¹¹ Uj!

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Example 19

Preparation of the sodium salt of 3-benzoyldifluoromethanesulfonanilide

To a solution of 12.21 g of sodium hydroxide (0.3o5 mol) in 300 ml of water was added 95 g of 3-benzoyldifluoromethanesulfonanilide (0.3o5 mol). The mixture was stirred until complete dissolution occurred and the solution had a pH of 7.2 had (fet "provided with reagent paper) · After evaporation of the water received / a yellow solid, which was about included in M 2oo ml Glykoldimethyläther and treated with activated charcoal. the clear solution was then added dropwise with vigorous stirring to 5 1 of ethyl ether . The crystalline salt was filtered off, washed with 4 1 of ethyl ether and dried to give an analytically pure product Pp. (dec.) 232 ⁰ C.

Analysis" ^C 14 ^H 1o ^F 2 ^M0 3 ^S 0 3 H calculated" 5o, 45 3 »O5 found : 50.6 , 2

Other salts were prepared in the same manner, the sodium hydroxide was ow ers-by other alkali or alkaline earth _β alcoholic solutions of STO / chiometrischen amounts of amines were used in the same way to prepare the amine salts; this is how, for example, the diethanolaminoethanol salt was produced «

Example 2o

Production of 3- (4-methoxybenzoyl) -difluoromethanesulfonanllide

A 1 liter flask equipped with a reflux condenser

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was charged with 56.8 g of 3-amino-4 · methoxybenzophenone (0.25 mol), 26.5 g of N, N-dimethylaniline (0.3o mol), 37.8 g of difluoromethanesulfonyl chloride (0.25 mol) and 35o ml of methylene chloride. The mixture was refluxed for 36 hours and then extracted with dilute sodium hydroxide solution. After treatment using charcoal and acidifying the alkaline extract gave a solid which was washed with hot heptane and was recrystallized from mixtures of carbon tetrachloride and hexane · An analytically pure product was obtained from m.p. 118-12o ° C

Analysis: C ₁ CH ₁ , F ₂ NO ₄ SCHH "

calculated: 52.8 3.9 4.1 found t 52.6 3.9 4.2.

Example 21

Preparation of 3-benzoyl-2,2,2-trifluoroethanesulfonanilide

A 1 liter flask was charged with 29 _Λ , 6 g of 3-aminobenzophenone (0.15 mol), 9.2 g of 2,2,2-trifluoroethanesulfonyl chloride (0.05 mol) and 250 ml of methylene chloride. The mixture was allowed to stand for about 1 hour with occasional shaking. The reaction mixture was then washed with dilute hydrochloric acid in order to remove the excess 3-aminobenzophenone, and after the solvent had been stripped off, a solid product was obtained which, after repeated recrystallization from trichlorethylene and drying, was an analytically pure substance with a melting point of 105.5-1o7 ° C.

Analysis: ^C 15 ^H 12 ^P 3 ^N0 3 ^S. C. H N calculated: 52.5 3.5 4.1 found t 52.7 3.7 4.1

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Example 22

Preparation of 3- (4-methylbenzoyl) fluoromethanesulfonanilide

A 500 ml flask fitted with a reflux condenser was added charged with 10.5 g of 3-amino-4'-methylbenzophenone (0.05 mol), 6.7 g Ν, Ν-dimethylaniline (0.055 mol), 6.6 g fluoromethanesulfonyl chloride (0.05 mol) and 150 ml of methylene chloride. The reaction mixture was refluxed for 20 hours. Then the methylene chloride was evaporated and the residue ^ extracted with dilute sodium hydroxide solution. The alkaline extract was washed with ethyl ether, treated with charcoal and acidified * The precipitated solid was repeatedly from Recrystallized ethanol-water and gave an analytically pure product of]? P. 118-12o C.

Analysis: 23 C ₁₅ H ₁₄ MO ₃ S. 58 C. 4th H 4th IT calculated: 58 , 7 4th ■ i6 4th , 6 found : | 8 ,8th , 5 Examples Ms 26

Using the general procedure of Example 2o to 22, and the other P _o lyfluoralkansulfonylanhydride and halides as starting materials, the following compounds could be obtained, for example:

example

24 3-Benzoyl-1,1,2,2-tetrafluoroethanesulfonanilide

25 3-Benzoyl-1,1,3-trihydroperfluoropropanesulfonanilide

26 3-Benzoyl-2-hydroperfluoropropanesulfonanilide

Claims

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Claims (5)

Claims where R _f denotes a fluorocarbon group with up to 8 carbon atoms, Rp denotes hydrogen, a lower alkyl group or a cation and R denotes an organic group containing a hetero atom which is bonded to the nitrogen atom of the formula via an aromatic ring according to the patent "."". (Patent application P 16 68 42o.1), characterized in that it has the general formula R _f S0 ₂ N where R _{f is} a partially fluorinated alkyl group with up to 4 carbon atoms in which at least one fluorine atom is bonded to the ^ carbon atom or which, if no fluorine is bonded to the ^ carbon atom, has at least 2 fluorine atoms on the β carbon atom , and in which the same or different substituents Y and Y ¹ each represent water 009838/2273 ? 1-35 361 etoff, a hydroxy group, a halogen atom or an alkyl
or alkoxy groups with up to 4 carbon atoms, as well as pharmaceutically acceptable salts of these compounds. 2. Compounds according to claim 1 or their salts, characterized characterized in that the fluoroalkylsulfonamido group is in meta position to the carbonyl group. 3 · Compounds according to claim 2 or their salts, characterized in that R- stands for the group HCF ₂ -. ™ 4 «Compounds according to claim 2 or their salts, characterized in that R _{f stands} for the group HgCP-. 5. Compounds of the formula R _f SO ₂ N- wherein R _{f is} a hydrofluorocarbon group having 1 or 2 carbon atoms, in which at least one fluorine atom is attached to the
ot-carbon atom is bonded or which, if to this
Carbon atom, no fluorine is bonded, has 2 fluorine atoms on the ß-carbon atom, as well as pharmaceutically acceptable
Salts of these compounds. 6 · 3-Benzoyl difluoromethanesulfonanilide.
7 3-Benzoylfluoromethanesulfonanilide 043838/2273