JPS5835989B2 - Substituted diphenyl ethers - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention describes the use of alkyl- or (monohalo)alkylsulfonamide groups substituted with a nitro group (as defined below) (there is a criticality as to the position of attachment of these groups). Regarding diphenyl ethers.

In particular, alkyl-
or (monohalo)alkylsulfonamide group, and alkylumata relates to compounds and salts thereof having a nitro group in the 4 or 5 position with respect to the (monohalo)alkylsulfonamide group.

Ring and sulfonamide nitrogens are optionally substituted.

The compounds according to the invention are anti-inflammatory agents.

The preparation and uses of this compound are described herein.

Alkylsulfonamide and haloalkylsulfonamide-substituted diphenyl ethers have been described in the literature.

See British Patent Nos. 738758.854956 and 856452, French Patent No. 1188591 and US Pat. No. 3,223,582.

However, the above-mentioned documents do not disclose or suggest anything about the compounds according to the invention which necessarily contain a nitro or amino group, and do not suggest anything at all about the critical properties for achieving high activity based on the position of the substituent.

Moreover, the pharmacological activity of the compounds according to the invention is not taught by the prior art.

A number of non-steroidal anti-inflammatory drugs have been discovered in recent years and are now being marketed for the treatment of various conditions through the use of anti-inflammatory, analgesic and antipyretic agents.

The above-mentioned drugs exhibit significant side effects that preclude their use in patients.

Research continues to develop anti-inflammatory agents with reduced side effects and improved cure rates.

The compounds according to the invention are effective anti-inflammatory agents achieving excellent cure rates.

According to the invention, the following formula I [where RX is an alkyl or monohaloalkyl group having 1 or 2 carbon atoms, Z is halogen, nitro or hydrogen, 2' is halokene or alkoxy, and n is 0 to 2 (i.e., Oll or 2), with the proviso that RX, Y, and the individual aliphatic groups in the two moieties include lower alkyl of 1 to 2 carbon atoms.

RX preferably contains one carbon atom.

RX is preferably methyl, chloromethyl or fluoromethyl, most preferably a methyl group.

Preferably n is a numerical value of 0 or 1, optimally n is O.

Z' is preferably para- or ortho-positioned when n is 1, optimally 2' is a para-positioned halogen.

However, the coordination is based on Schiffer ether oxygen.

At present, it is preferred that 2 is hydrogen.

When 2 is a halogen, chlorine is preferred as the halogen.

The optimal case is when X is hydrogen and Y is nitro.

Other preferred combinations include when X is amino and Y is hydrogen; when X is ethoxycarbamoyl and Y is hydrogen; when X is dimethylamine and Y is hydrogen; and when X is acetamide and Y is nitro.

The compounds according to the invention are acidic.

Salt is thus produced.

It forms stable salts under ambient conditions and the salts are useful as intermediates.

These salts may be prepared by treating a compound of formula (I>) with a stoichiometric equivalent of the appropriate base under mild conditions.

Among the metal salts suitable for the present invention are salts of alkali metals (such as lithium, sodium and potassium), alkaline earth metals (such as barium, calcium and magnesium) and heavy metals (such as zinc and iron), as well as salts of other metals such as aluminum. There is salt.

Suitable chlorine useful in the preparation of metal salts include metal oxides, hydroxides, carbon salts, bicarbonates, and alkoxides.

Certain salts are prepared by cation exchange reactions (cation exchange reactions based on reacting the salts according to the invention with organic or inorganic salts).

Organic amine salts include aliphatic (eg, alkyl), aromatic, and heterocyclic amines, as well as amines having mixed types of these structures.

Amines useful in the preparation of salts according to the invention may be primary, secondary or tertiary, but preferably do not have more than 20 carbon atoms.

Such amines include, for example, morpholine, methylcyclohexylamine, glucosamine, and others.

These salts and ammonium salts can be prepared by reacting the acid type compound with an appropriate organic base or ammonium hydroxide.

Pharmaceutically acceptable salts are generally alkali metal, alkaline earth metal, ammonium and ammonium salts.

Salts according to the invention are often obtained by reacting their precursors in aqueous solution.

Evaporation of the reaction solution usually yields the salt of the compound as a dry powder.

If a non-aqueous solvent such as alcohol, acetone, etc. is used in such a case, it is difficult to use.

The solvent is removed from the resulting solution, for example by evaporation under reduced pressure.

Since many salts are water soluble, salt solutions are often used in the form of aqueous solutions.

The salts according to the invention are used for formulation in the form of capsules for oral administration.

For the preparation of the compounds according to the invention (acid form) - there are generally three methods.

That is, three methods: a method of manufacturing from a precursor (i.e., a compound outside the definition of formula (I)), and a method of manufacturing from another compound (shown in the following formula) within the scope of the definition of formula (■) There is.

Furthermore, the compounds according to the invention are preferably prepared by a novel nitration process.

Method C includes various methods in which Z and Z' are changed in various ways in the compound of formula (1).

For example, compounds of formula (1) are nitrated or halogenated on the phenyl ring.

Nitration is carried out using 70% nitric acid in acetic acid.

Generally, compounds of formula (1) are obtained in good yields by this procedure.

Other nitration methods that give satisfactory results include nitric acid and acetic anhydride, concentrated nitric acid without solvent, trinitrogen tetroxide in an inert solvent, nitrosyl chloride in an inert solvent, and an inert solvent. ferric chloride in acidic solvents, or nitrites in acidic solvents e.g. sodium nitrite (requires the presence of an oxygen donor e.g. air or solvent), nitrates in acidic solvents e.g. sodium nitrate, nitric acid in acidic solvents and similar Includes methods.

Generally 1 per mole of 2-phenoxysulfonanilide
An equivalent amount of nitrating agent is sufficient to carry out the reaction.

The minimum amount of nitrating agent necessary to react substantially the total amount of starting material is used.

Thin layer solid-liquid chromatography or gas phase chromatography may be used to determine the amount of nitrating agent required to complete the reaction.

This allows the reaction time to be reduced while maximizing the yield.

. The reaction temperature may vary from about -30°C to about +110°C, but may be raised or lowered somewhat to control the reaction rate, and may also be varied by the nitrating agent.

Novel intermediates can be synthesized from known starting materials by known methods.

This nitration occurs specifically in the para position to the sulfonamide group, which is unexpected.

This is because the principles regarding electrophilic aromatic substitution virtually foresee nitration at the orne position.

Suitable alkane-hoyohy(monohalo)alkanesulfonyl halides (eg chlorides and fluorides) for preparing intermediates of compounds of formula (1) are known in the art.

The intermediate primary arylamine of formula (1) is a compound known in the industry or can be prepared by methods known in the industry, generally by reduction of the corresponding nitro compound.

Conventional reduction methods (chemical and catalytic) e.g. in acetic acid,
Sodium sulfide and the most well known Raney nickel and hydrogen gas methods may be used.

As already mentioned, the compounds according to the invention are active anti-inflammatory agents.

Furthermore, some of them have been found to be analgesics and antipyretics, and others to have antimicrobial activity.

The compounds according to the invention also generally have activity as herbicides.

Anti-inflammatory activity can be conveniently displayed by the following methods:
Antagonism test of compounds against local characteristic edema (rat paw edema test) based on P. ponse ) and inhibition of erythema development based on inflammation (guinea pig erythema test).

The literature regarding the rat leg edema test is as follows: 1. Adamkiewicz et al.
etal 0, ('anad, J, B ioche
m, Ph5io, 33°332.1955): 2. Sly's paper (5elye, Br1t 6Me
d, J., 2.1129.1949): and 3. Winter's paper (Winter, Proc.
, Soc.

Exper, Biol, Med, 111.
554.1962).

The literature regarding the guinea pig erythema test is as follows.

■, the paper by Tawilhelmi et al. (Wilhelmi 1S
chweiz, Med, Wshr,, 79.55
7゜1949); and 2, Winder et al.
16, Arch-Int, Pharmacod
yn, 116.261°1958).

Observation of analgesic activity can be observed, for example, in phenylquinone agony (phe
nylquinone writting) and Randall-5elitto
) by standard methods such as tests.

Testing for anti-inflammatory activity can also be performed using test methods known in the industry, such as cotton pellet granuloma (cotton pellet granuloma).
nuloma) test and adjuvant arthritis (adjuva)
nt arthritis) test.

It is preferred to administer the compounds orally as an anti-inflammatory agent, but also by other known methods of administration, such as subepithelial, submucosal (e.g., subcutaneous, intrarectal, etc.) and parenteral administration, such as subcutaneous, intramuscular, and vascular injections. etc. are also used.

Intraocular administration is also included. The dose is 1 kg body weight of the treated animal.
The amount is generally within the range of about 1 to 500 μg/g, but in the case of oral administration, it is usually not more than 100 yn/4 cg, and in the case of injection, it is usually not more than 50 μg/kg.

Preferred forms for oral administration are liquids (for example gum arabic 4% suspension), tablets (anhydrous lactose, microcrystalline cellulose, modified starches, calcium stearate and talc and other conventional formulations and other anti-inflammatory actives). combination) and capsules.

A suitable carrier for topical use is a cream. Includes gel, tape, etc.

Liquid formulations, such as solutions or suspensions of the active substances in inert carriers, are contemplated for administration by injection.

Compounds suitable for the practice of this invention with respect to anti-inflammatory agents include the following rust compounds.

4-2) Rho-2-phenoxychloromethanesulfonanilide: 4-nitro-2-phenoxymethanesulfonanilide; 2-(4-chlorophenoxy)-4-nitrofluoromethanesulfonanilide; 4-nitro-2-phenoxyflu Ormethanesulfonanilide; N-methyl-4-nitro-2-phenoxymethanesulfonanilide; N-ethyl-4-nitroni-2-phenoxymethanesulfonanilide; 4-nitro-2-phenoxyethanesulfonanilide; 2-(4 -Chlorphenoxy)-4-nitrochloromethanesulfonanilide; N-methyl-2-(4-chlorophenoxy)-4-nitrofluoromethanesulfonanilide; N-methyl-4
-nitro-2-phenoxyethanesulfonanilide; N-acetyl-4-nitro-2-phenoxymethanesulfonanilide; and pharmaceutically acceptable salts thereof.

A number of animal studies have been carried out to determine the anti-inflammatory activity of those mentioned as preferred compounds in this invention.

All of the preferred compounds were tested in a rat paw edema test with carrageenan and found to exhibit activity at 25 kg/kg or less.

Most of these compounds have a cure rate (ED35/LD50
='I', Ro) was 5 or more.

The LD50 was carefully examined for certain compounds, but only approximated for others.

The following examples are intended to illustrate the operation of the invention and are not intended to limit the scope of the invention.

Melting points in the examples are uncorrected.

Melting and boiling points are given in Celsius and pressure is Tnffl/Hg
It is indicated by.

Example 1 below relates to the preparation of compounds of general formula (1) by nitration of optionally substituted 2-phenoxyalkane- or (monohalo)alkane-sulfonanilides.

Example 1 2-phenoxymethane-sulfonanilide (17,39
: 0.675 mol) was dissolved in 175 ml of glacial acetic acid by heating.

The mixture was stirred and 5.921 (0.0675 moles) of 70% nitric acid was added dropwise over 15 minutes.

The mixture was heated on a steam bath for 4 hours, poured into water and the precipitate was separated by filtration.

When the product is recrystallized from ethanol, 4-nitro-2
-Phenoxymethanesulfonanilide was obtained as a pale yellow solid.

Melting point: 143-144.5°C. Elemental analysis “C13H1□N
20. Calculated value as S: C, 50,6; H, 3,9;
N, 9.1% Actual value: C, 50,6; H, 3,8; N
, 9.1% The following rust compounds were prepared using the method of Example 1.

2-(4-Chlorphenoxy)-4-nitrofluoromethanesulfonanilide, melting point 137-138.5°C 4-=)Rho 2-phenoxyfluoromethanesulfonanilide, melting point 104-105°C 2-(4- Chlorphenoxy)-4-nitrochloromethane-sulfonanilide, melting point 148-149.5°C 5-chloro-2-(2,4-dichlorophenoxy)-4
-Nitro-methanesulfonanilide, melting point 163-16
5°C 5-chloro-4-nitro-2-phenoxymethanesulfonanilide, melting point 137-139°C 4,6-sinitro-2-phenoxymethanesulfonanilide, melting point 149-139°C
151°C The following rust compound was prepared using the method of Example 1: 4-=t
tl-2-(phenoxy)ethanesulfonanilide, melting point 113-115°C 5-methoxy-4-nitro-2-phenoxymethanesulfonanilide, melting point 150-152.5°C 2,4-dinitro-6-(phenoxy)ethane Sulfonanilide, melting point 108.5-110.5°C 2-(4-methoxyphenoxy)-4-nitromethanesulfonanilide, melting point 12
5-127℃.

Example 2 5,01 dissolved in trifluoroacetic acid (40rrLl)
(19 mmol) of 1,3fI dissolved in water to a water-cooled solution of 2-phenoxymethanesulfonanilide.
A solution of (19 mmol) sodium nitrite was added dropwise.

After stirring for 1 hour, the mixture was poured into water and extracted with dichloromethane.

The extracts were dried over magnesium sulphate and evaporated in vacuo.

When the resulting solid residue was reconsolidated three times from a dichloroethane/hexane mixture, 3.5S' (60%) of 4-nitro-2-phenoxymethanesulfonanilide was recovered.

Melting point 144-147°C.

Example 3 1, dissolved in pyridine (1,65 J) at a temperature of 85 °C,
1.02 kg (8.9 mol) of methanesulfonyl chloride was gradually added to a solution of 685 kg (8.9 mol) of 2-phenoxyaniline over a period of 3 hours.

The mixture was stirred and heated for an additional hour and then poured into a mixture of 61 parts ice and 31 parts concentrated hydrochloric acid.

The solid product was collected by filtration and washed with 10% hydrochloric acid and then water.

2.33 kg (85%) of crude product i.e. 2-phenoxymethanesulfonanilide (melting point 110-117°C)
A more pure product was obtained when reconsolidated from an ethanol-water mixture.

Melting point 118.5-120'C0 Example 4 1,01 (0,01
1 mole) of dinitrogen tetroxide in an ice-cold solution of 1.0 P (0
,0038 mol) of 2-phenoxymethanesulfonanilide was added.

After 15 minutes of stirring, the mixture was evaporated to dryness in vacuo.

0.77 of 4-nitro-2-phenoxymethanesulfonanilide when reconsolidating the solid residue from aqueous ethanol.
? It was returned.

Melting point: 146-148°C, yield: 66%.

Example 5 20rrtl ice-cold! of concentrated nitric acid at 2.0 f (7
, 6 mmol) of 2-phenoxy-methanesulfonanilide was added and the mixture was stirred for 20 minutes.

The mixture was added to 100 ml of water and the product was separated by filtration and washed with water.

When reconsolidated from ethanol, 1.1' (73%) of 4-nitro-2-phenoxymethanesulfonanilide was converted.

Melting point: 143-146°C.

Example 6 2-phenoxymethanesulfonanilide (13,16P, 0.050%/L/) and 2501
Heating rll of acetic anhydride to 100°C, 4.52 (
0.05 mol) of nitric acid was added dropwise over 0.5 hours.

The mixture was kept at a temperature of about 90° C. overnight, then cooled and poured into water.

When the solid product is separated by E-filtration and dried, 13.5% of 2-phenoxy-4-nitromethanesulfonanilide is used.
f (87%) changed.

This is identical to that obtained in Example 11 below.

Example 7 2,01 (7 ml) dissolved in trifluoroacetic acid (30 ml)
, 6 mmol) of 2-phenoxymethanesulfonanilide dissolved in 3 ml of water.
A solution of P (7.7 mmol) in sodium nitrate was added dropwise.

The mixture was allowed to warm to about 25°C and then poured into water.

2.0 of 4-nitro-2-phenoxymethanesulfonanilide when the product is separated by E-filtration and reconsolidated from ethanol. (86%) Changed.

Melting point 144-147°C.

Example 8 Ferric chloride (2r containing 0,5f) rnl of 2,0y (7,6 mmol) of 2 in dichloroethylene
- Nitrosyl chloride was bubbled through the solution of phenoxymethanesulfonanilide for 20 minutes.

The mixture was poured into water and extracted with dichloroethane.

A dark oily solid remained when the extract was evaporated in vacuo.

When reconsolidating twice, 4-nitro-2-phenoxymethanesulfonanilide was changed.

Yield 25%, Melting point: 141-145°C.

Claims (1)

[Claims] 1 General formula: (where RX is alkyl or monohaloalkyl having 1 or 2 carbon atoms; 2 is halogen, nitro or hydrogen; z' is halogen or alkoxy; provided that in which the 2' moieties each contain one or more carbon atoms; and n is a numerical value of 0, ■, or 2). A method for producing a compound of the above general formula, which comprises treating with a curing agent.