CN1031529A - pharmaceutical composition - Google Patents

Abstract

The present invention relates to a certain drug for the treatment of diabetes and galactosemia new pharmaceutical composition for these complications, which contains a nitromethane derivative substance (or its non-toxic salt) as the active ingredient. Nitromethane derivatives Inhibitor of aldose reductase. Many of these inhibitors are new of, together with their methods of production and use, provide the present invention with further many features.

Description

Pharmaceutical composition

The present invention relates to contain the new pharmaceutical compositions of nitromethane derivative, this derivative is the inhibitor of aldose reductase, and new pharmaceutical compositions has practical value, for example treats some peripheral effect (Peripheral effects) of diabetes or galactosemia.The present invention also provides and has used nitromethane derivative to treat the method for one or more above-mentioned peripheral effects.Also have in addition, the invention still further relates to new nitromethane derivative and make the method for described new derivative and contain the method for the medication preparation of any described nitromethane derivative.

Aldose reductase is to cause the intravital aldose of warm-blooded animal (as the people) (as glucose and semi-lactosi) to be catalytically converted into the reason of corresponding alcohol sugar (promptly being separately converted to Sorbitol Powder and melampyrum).Alcohol sugar is difficult for permeates cell membranes, in case generate, has only by further metabolism and just can remove.So alcohol sugar is easily assembled, and cause the rising of osmotic pressure in the cell in the cytolemma of its generation.In the rising of pressing be enough to make the function of cell itself to be damaged and weaken.The affinity of aldose reductase is lower, only under the dense situation of aldose activity is arranged just usually.The aldose of this high density is present in the clinical setting of diabetes (glucose surplus) and galactosemia (semi-lactosi surplus).Therefore, be because Sorbitol Powder or melampyrum accumulate respectively alleviating or suppressing part, and cause the development of diabetes or the peripheral effect of galactosemia that at this moment aldose reductase inhibitor is useful in tissues such as eyes, nerve or kidney.These peripheral effects such as mottled oedema, cataract, retinopathy, neuropathy or nerve conduction damage.Although had been found that many aldose reductase inhibitors, and carried out clinical evaluation,, people's inhibitor that still constantly need alternate.The present invention's part reason is according to this needs, and another kind of reason is that we have found that aldose reductase is subjected to the unimaginable restraining effect of giving of some Nitromethane 99Min..

According to a kind of new pharmaceutical composition provided by the invention, wherein be Q.SO with the structure ₂.CH ₂.NO ₂The formula I Nitromethane 99Min. as active ingredient.Q is 6 in the formula; the aromatics part of 10 or 14 atoms; can select to have 1 therebetween; 2 or 3 substituting groups; these substituting groups are selected from: hydrogen; halogen; cyano group; nitro; hydroxyl; carboxyl; amino; be at most the alkylamino or the dialkyl amido of 6 carbon atoms; (1-6C) alkanoyl amino; (1-6C) alkanoyl; (1-6C) alkyl; (2-6C) alkenyl; (3-6C) alkenyloxy; fluoro (1-4C) alkyl; (1-6C) alkoxyl group; fluoro (1-4C) alkoxyl group; hydroxyl (1-6C) alkyl; (1-4C) alkoxyl group (1-4C) alkyl; formamyl is at most the alkyl or the dialkyl amido formyl radical of seven carbon atoms; sulfamyl; be at most the alkyl or the dialkyl sulfamine of six carbon atom; (1-6C) alkoxy carbonyl; (1-4C) alkylenedioxy group; (1-6C) alkane sulfonamido; (1-6C) alkyl.S(O) n-(wherein n is zero, 1 or 2), phenyl, phenoxy group, benzyloxy, benzyloxycarbonyl, benzamido and phenylsulfonamido, the benzene part of 6 groups in back can select to have halogen, (1-4C) alkyl or (1-4C) alkoxy substituent; Perhaps Q has 4 or 5 and is selected from halogen, cyano group, (1-6) alkyl or (1-6C) substituting group of alkoxyl group arbitrarily; But do not comprise that Q is the compound of 2-carboxyl-phenyl; Or the nontoxicity salt of above-mentioned formula I Nitromethane 99Min.; Attenuant that allows on the medicine or carrier in addition.

Term " alkyl " comprises straight chain and two kinds of alkyl of side chain in this manual, yet only refers in particular to straight chain (" positive structure ") type for single alkyl group as " propyl group ", and any branched chain isomer need be pointed out especially as " sec.-propyl ".Similarly custom also is applicable to other general terms.

Be understandable that the substituting group that contains asymmetric replacement atom by means of one or more, with regard to above some generalformula that limits can optically-active or the racemization form exist, selectively contain optically-active or racemization type compound according to the qualification the present invention to activeconstituents, these compounds all have the character that suppresses aldose reductase.Organic chemistry general technology of the prior art is used for synthesizing the compound of opticity, for example, can synthesize or take apart racemoid from the starting material of choosing wantonly with opticity.Equally, adopt the method for inspection of common laboratory hereinafter described, can estimate its rejection characteristic aldose reductase.

For aromatics part Q, useful especially part is the carbocyclic aromatic part, and for example phenyl, naphthyl, phenanthryl or anthryl are wherein best with the effect of phenyl and naphthyl especially.

Special useful part can comprise following groups as an example in the optional substituting group of the last existence of Q:

Halogen: fluorine, chlorine, bromine and iodine;

Be at most the alkylamino or the dialkyl amido of six carbon atom: methylamino-, ethylamino, third amino, fourth amino, dimethylamino, diethylin and (first) (third) amino;

(1-6C) alkanoyl amino: (1-4C) alkanoyl amido, as formamido group, kharophen and propionamido;

Can have a substituent benzamido arbitrarily: have fluorine, chlorine, bromine, methyl, ethyl, the substituent benzamido of methoxy or ethoxy arbitrarily;

(1-6C) alkanoyl: formyl and (2-4C) alkanoyl, for example ethanoyl, propionyl and butyryl radicals;

(1-6C) alkyl: (1-4C) alkyl, as methyl, ethyl, propyl group, sec.-propyl, butyl, secondary monobutyl and uncle's monobutyl;

(2-6C) alkenyl: (2-4C) alkenyl, as vinyl, allyl group, 1-propenyl and 2-methyl-2-propenyl;

(3-6C) alkenyloxy: allyloxy, 2-methyl-2-propenyloxy group and 3-methyl-3-butenyloxy;

Fluoro-(1-4C) alkyl: trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl and 3,3,3-trifluoro propyl;

(1-6C) alkoxyl group: (1-4C) alkoxyl group, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy and uncle's one butoxy;

Fluoro-(1-4C) alkoxyl group: trifluoromethoxy, 2,2,2-trifluoro ethoxy and five fluorine oxyethyl groups;

Have substituent phenyl, phenoxy group, benzyloxy or benzyloxycarbonyl arbitrarily: phenyl, phenoxy group, benzyloxy or have fluorine, chlorine, bromine, methyl, ethyl, the substituent benzyloxycarbonyl of methoxy or ethoxy arbitrarily;

The alkyl of hydroxyl-(1-6C): hydroxyl-(1-4C) alkyl, for example methylol, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl;

(1-4C) alkoxyl group (1-4C) alkyl: methoxymethyl, ethoxyl methyl, 1-methoxy ethyl, 2-methoxy ethyl and 3-methoxy-propyl;

(1-6C) alkoxy carbonyl: (1-4C) alkoxy carbonyl, for example methoxycarbonyl, ethoxy carbonyl, isopropoxy carbonyl and uncle's one butoxy carbonyl;

(1-4C) alkylenedioxy group: methylene-dioxy, ethylenedioxy and the inferior different third dioxy base are incorporated into the adjacent atom on the aromatics part Q;

(1-6C) alkane sulfonamide base: (1-4C) alkane sulfonamide base, for example sulfonyl methane amido, ethane sulphonamide base and butane sulfoamido;

Have a substituent benzene sulfonamido arbitrarily: have fluorine, chlorine, bromine, methyl, ethyl, the substituent benzene sulfonamido of methoxy or ethoxy arbitrarily;

Alkyl or dialkyl amido formyl radical that six carbon atom is arranged at the most: N-methylamino formyl radical, N, N-formyl-dimethylamino, N-ethylamino formyl radical, N, N-diethylamino formyl radical and N, N-dipropyl formamyl;

Alkyl or dialkyl sulfamine that six carbon atom is arranged at the most: N-methyl sulfamyl, N-ethyl sulfamyl, N-propyl group sulfamyl, N-butyl sulfamyl, N, N-dimethylamino alkylsulfonyl and N, N-dipropyl sulfamyl; With

(1-6C) alkyl.S(O) n ^-: (1-4C) alkyl.S(O) n ^-For example methylthio group, ethylmercapto group, methylsulfinyl, ethyl sulfinyl, methyl sulphonyl and ethylsulfonyl.

In general, Q has 3 substituent phenyl or naphthyls typically at the most arbitrarily.

Some nitromethane derivative is known.For example, in the corresponding dibromonitromethane derivative process of preparation as antibiotic, it will Q wherein be that the formula I derivative of phenyl or 4-aminomethyl phenyl is as chemical intermediates that U.S. Patent number 4053633 has been described.Similarly, people such as Kelly are at J.Heterocyclic Chemistry, and 1977,14, Q described be phenyl or 4-fluorine, 4-chlorine among the 1415-1416.The formula I derivative of 4-methyl or 4-acetylaminohydroxyphenylarsonic acid phenyl is not mentioned application.Similarly, at J.Polymer Science, Polymer, Chem.Ed., 1985,23(7), among the 1963-72, Chemical Abstracts, Vol.59, Abstract No.6341g, and J.Pract.Chem., 1920,101, among the 136-157, the formula I derivative of having put down in writing Q respectively and be 4-ethenylphenyl, 2-carboxyl phenyl and 4-bromophenyl is as chemical intermediates.Yet before the present invention, nobody knows that these nitromethane derivatives have the character that suppresses aldose reductase.

The known predetermined substance that is used as the nitromethane derivative of aldose reductase inhibitor comprises that structure is X.Q.SO ₂.CH ₂.NO ₂General formula II compound, wherein Q is a benzene, and X is hydrogen or methyl, fluorine, chlorine, bromine or is attached to kharophen substituting group and nontoxic salt thereof on 4 of Q.The present invention also comprises the pharmaceutical composition of the diluent or carrier that allows as activeconstituents and medicine with general formula II compound or its nontoxic salt.Comprise formula I or II compound or its non-toxic salt by using significant quantity in addition in the present invention, the method for one or more peripheral effects of treatment or prevent diabetes or galactosemia.Another feature of the present invention be the formula I that above limits and II compound or its non-toxic salt manufacturing be used for the treatment of or one or more peripheral side effect novel drugs of prevent diabetes or galactosemia in purposes.

In the present invention; there is the general formula II known compound of Special Significance to contain as aldose reductase inhibitor just like phenyl sulfonyl Nitromethane 99Min., (4-bromophenyl alkylsulfonyl) Nitromethane 99Min. and (4-aminomethyl phenyl alkylsulfonyl) Nitromethane 99Min., and nontoxic salt.

Composition of the present invention can various common formulations exist.For example, be applicable to oral (as tablet, lozenge, hard or soft capsule, water or oiliness suspension agent, emulsion, dispersible powder or saccharoid, syrup or elixir), local (as creme, ointment, gel, water or oil solution or suspension) or the parenteral admin that uses (as with sterilized water or oil solution, at intravenously, subcutaneous, muscle or intravascular administration or as the suppository of rectal administration).

By ordinary method of the prior art, adopt general drug excipient can obtain composition of the present invention.For example, as oral composition can contain that one or more are painted, edulcorant, fragrance and/or sanitas.

The medicine that is used for tablet formulation allows appropriate excipients to comprise as inert diluent, as lactose, yellow soda ash, calcium phosphate or lime carbonate; Granulation or disintegrating agent are as W-Gum or alginic acid; Tackiness agent is as gelatin or starch; Lubricant is as Magnesium Stearate, stearic acid or talcum; Sanitas is as para-hydroxybenzoic acid ethyl ester or propyl ester; Antioxidant is as xitix.But the tablet formulation obducens is obducens not also.In order that improve their slaking and thereafter in intestines and stomach to the absorption of activeconstituents, or improve their stability and/or outward appearance.No matter be used for which kind of purpose, all can adopt the dressing reagent and the method for prior art.

Oral compositions can be made hard gelatine capsule, and active ingredient wherein and inert solid diluent are mixed as lime carbonate, calcium phosphate or the white pottery soil phase.Perhaps make soft gelatine capsule, active ingredient wherein and water or oil as peanut oil, white oil or sweet oil, mix mutually.

Usually aqeous suspension contains fine powder active ingredient and one or more suspension agents, as sodium carboxy methyl cellulose, methylcellulose gum, Vltra tears, sodiun alginate, polyvinyl-pyrrolidone, and Tragacanth and gum arabic; Disperse or wetting agent, condensation product as Yelkin TTS or alkylene oxide and lipid acid (as polyoxyethylene stearic acid ester), oxyethane and long chain aliphatic alcohol, condenses as heptadecaethylene oxycetanol (heptadecaet h ylenecetanol), or oxyethane and by the condensation product of the part ester of lipid acid and hexitol, as polyoxyethylene sorbitol-oleic acid ester, or the condenses of oxyethane and the incomplete ester made by lipid acid and hexitan, as polyethylene dehydration sorbose-olein.Aq suspension also can contain one or more sanitass (as ethyl p-hydroxybenzoate or propyl ester), oxidation inhibitor (as xitix), tinting material, perfume compound and/or edulcorant (as sucrose, asccharin or aspartame).

The preparation of oily suspensions is that activeconstituents is suspended in vegetables oil (as peanut oil, sweet oil, sesame oil or Oleum Cocois), or in the mineral oil (as white oil).Also can contain thickening material in the oily suspensions,, hard paraffin cured or hexadecanol as honeybee.Edulcorant, as the edulcorant of having mentioned above adding, perfume compound make oral preparations become good to eat.Adding oxidation inhibitor such as xitix can make these compositions be protected.

Be suitable for adding dispersed powders and the particle that water prepares aqeous suspension, contain activeconstituents and dispersion agent or wetting agent usually, suspension agent and one or more sanitass.Suitable dispersion agent or wetting agent and suspension agent have been lifted the explanation of row example hereinbefore.Other vehicle such as edulcorant, perfume compound and tinting material also can add.

Pharmaceutical composition of the present invention is oil hydrosol formulation also.Oil phase can be a vegetables oil, as sweet oil or peanut oil.Or mineral oil, as white oil or its mixture.Suitable emulsifying agent can be as natural natural gum, as Sudan Gum-arabic or Tragacanth.Natural phosphatide such as soybean, Yelkin TTS or the ester or the part ester that make by lipid acid and hexitan (polyoxyethylene-sorbitan mono-oleate), and the condensation product of described part ester and oxyethane, as the pure monoleate in polyoxyethylene dehydration mountain (pears).Emulsifying agent also can contain edulcorant, perfume compound and sanitas.

Syrup and elixir can also can contain demulcen, sanitas, perfume compound and/or tinting material with edulcorant such as glycerine, propylene glycol, sorbyl alcohol, aspartame or sucrose preparation.

Pharmaceutical composition also can be made into sterilized water or oil suspension injection, and process for preparation adopts known program, one or more the suitable dispersion agents or wetting agent and the suspension agent that use the front to mention.Nontoxic thinner or solvent that the also available permission parenteral of aseptic injection uses as 1,3 butylene glycol solution, are made sterile solution or suspension injection.

With activeconstituents and suitable non-irritating mixed with excipients and make the suppository medicament.Vehicle herein is solid at normal temperatures, yet is liquid under the temperature of rectum, and this suppository is melted at internal rectum and discharges medicine like this.Suitable vehicle comprises as oleum theobromatis or polyoxyethylene glycol.

The medicament of local use, solution or suspension as creme, ointment, gel and water or oil can adopt ordinary method of the prior art usually, and is formulated by activeconstituents and carrier or thinner commonly used, that allow the part to use.The part that is applicable to eyes makes normally ointment of with medicament.Gel or through the buffering sterile solution (this pH value can by eyes be accepted) of pH value in the 7.0-7.6 scope.

Obtain the amount of a dose unit activeconstituents with one or more mixed with excipients, must change according to the ad hoc fashion of curer and administration.For example, be used for the oral medicament of human body and contain promoting agent usually just like 0.5mg-2g, it and 5 to 98% the mixed with excipients that accounts for composition total weight, this amount is suitable.1 dose unit contains the activeconstituents of about 1mg to about 500mg usually.

Suitable non-toxic salts comprises as the salt that allows on the medicament, as basic metal (as potassium or sodium), alkaline-earth metal (as calcium or magnesium), ammonium and aluminium salt and the salt that can form for the cationic organic bases that permission is provided on the physiology (salt that forms as methylamine, dimethylamine, Trimethylamine 99, piperidines and morpholine etc.).In addition, for the suitable nontoxic salt of the activeconstituents that enough alkalescence is arranged (as containing alkylamino or dialkyl amido), comprise as acid-additive salt (acid-addition) as with the salt of hydrogen halide, sulfuric acid, phosphoric acid, citric acid and toxilic acid, these salt are allowed by medicine and physiology.

The nitromethane derivative of most of formula I is new.According to another characteristic of the present invention, according to above to the qualification of activeconstituents in the present composition, the present invention also provides the formula I new compound, or its non-toxic salt, but do not comprise that Q in the compound is unsubstituted phenyl and the phenyl and the alkaline metal salt thereof that have 4-fluorine, 4-chlorine, 4-bromine, 4-methyl, 4-vinyl, 4-kharophen or 2-carboxyl substituent.

According to above eliminating situation, go up optional substituent concrete choosing value for Q that limits and Q, should comprise those contents that above limit.

The interested especially one group of new compound of the present invention comprises the compound of general formula III (above stating), X in the formula ¹Be selected from the alkyl of the alkyl of halogen, (1-6C) alkyl, (1-6C) alkoxyl group, (3-6C) alkenyloxy, hydroxyl, cyano group, hydroxyl-(1-6C), fluoro-(1-4C); X ²Be hydrogen or X ¹A group of middle regulation; X ³If a kind of substituting group on the Q that is limited for hydrogen or when the above-mentioned qualification activeconstituents of the present invention, and nontoxicity salt are X ¹When being 4-fluorine, 4-chlorine, 4-bromine, 4-methyl or 2-carboxyl, then can not X ²And X ³The both is a hydrogen.

Other one group of new compound that the present invention also has comprises those compounds of formula I, and wherein Q is:

(a) naphthyl;

(b) phenanthryl; Or

(c) anthryl;

And in each group, Q is unsubstituted or has 3 at the most and be selected from above to X ¹, X ²And X ³The substituting group that is limited; And nontoxicity salt.

X ¹Best value comprises as halogen and (1-6C) alkyl (particularly fluorine, chlorine and methyl).X ²Best value comprises as hydrogen and (1-6C) alkyl (particularly hydrogen methyl).X ³Best value comprise as hydrogen, halogen and (1-6C) alkyl (particularly hydrogen, fluorine, chlorine and methyl).

Introduced new compound of the present invention among the incidental embodiment, wherein special compound of interest and nontoxicity salt thereof are included in hereinafter among the embodiment 1,2,6,7,9,19,20,30,46 and 50, and these are another feature of the present invention.

Utilize the usual way of the known production similar structures of organic chemistry compound to synthesize new compound of the present invention.For example, Zeilstra et alia has summarized one or more methods at Rec.Trav.Chim.Pays Bas 1974,93 in one piece of paper among the 11-14.These methods provide another feature of present method, and describe by following method, and wherein any substituting group on Q and the Q has the whole implications that above limit.

A) in the presence of basic metal (1-6C) alkoxide such as uncle's one butanols potassium or sodium methylate, be Q.SO with general formula ^- ₂M ⁺Basic metal-sulfinate (IV), (M in the formula ⁺Be alkali metal cation, as sodium or potassium) and Nitromethane 99Min. and Iod R.

The optimum condition that reaction is carried out is that suitable polar solvent is arranged, and as dimethyl formamide (best) or N-N-methyl-2-2-pyrrolidone N-, temperature range is as-30 to 20 ℃, is generally 0 ℃.Nitromethane 99Min. is generally excessive.

The acquisition of basic metal-sulfinate is by general formula Q.SO ₂Corresponding-sulfinic acid of H and suitable alkali metal hydroxide or (1-6C) methylate or the ethylate reaction of alkoxide such as sodium or potassium.-sulfinic acid itself is to adopt S-WAT or zinc soil and water, through the conventional reduction method, by general formula Q.SO ₂The corresponding SULPHURYL CHLORIDE of Cl obtains.SULPHURYL CHLORIDE normally obtains general formula Q.SO by the suitable combination thing of sulfonation general formula Q.H ₃.H sulfonic acid is afterwards again by changing into SULPHURYL CHLORIDE with reaction as phosphorus pentachloride.

(b) having in the presence of the highly basic, general formula Q.SO ₂.CH ₃Sulfone (V) and the reaction of (1-5C) alkyl nitrate ester selected (as ethyl nitrate, propyl ester, isopropyl ester or pentyl ester).

Specially suitable highly basic is (1-6C) alkali alkyl, as butyllithium.

Reaction preferably has suitable solvent or thinner, carries out under-80 to 10 ℃ as ether (as tetrahydrofuran (THF) or uncle's one fourth methyl ether) and temperature range.

Utilizing the general method of prior art can make the necessary sulfone class of general formula V, as with the conditions of similarity described in the following method (c), is Q.S.CH with general formula ₃Corresponding methylthiolation compound (VI) oxidation.

(c) the oxidation general formula is Q.S.CH ₂.NO ₂Thioether (VII)

Suitable oxygenant comprises that being used for transforming thio group is the well known in the prior art of alkylsulfonyl and when go up the oxygenant that stands good when substituent other responsive functional group exists as Q.For example, can adopt hydrogen peroxide, organic peracid (as peroxybenzoic acid) or lead tetraacetate.Perhaps, can use basic metal periodate (as sodium metaperiodate), persulphate (as mistake-vitriolate of tartar) or permanganate (as potassium permanganate), or the gas oxygen in the presence of appropriate catalyst (as platinum).Oxidizing reaction is preferably being used for the suitable conventional solvent or the thinner of this oxidizing reaction, as acetate or propionic acid, and carries out under as 0 to 80 ℃ in the scope of temperature.

In some cases, general formula is that the corresponding sulfoxide derivant of thioether of VII can be used as and can form by isolating intermediate product.Method of the present invention also is included in suitable solvent such as acetate and in certain temperature range under the condition of (as 20 to 80 ℃), by with alkali-metal permanganate (potassium permanganate) reaction, this sulfoxide intermediate product is oxidized to the sulfone that general formula is an I.

General formula is that the initial thioether of VII can make with vitochemical general method, as having in the presence of the suitable alkali, by corresponding thiophenol (VIII) potassium or sodium salt and chloro or monobromo-acetic acid (or its (1-4C) alkyl ester) reaction of general formula Q.SH, changing into general formula thus is Q.S.CH ₂CO ₂The corresponding thioacetic acid (IX) of H (or its (1-4C) alkyl ester (as methyl or ethyl ester).Make sour IX (or its (1-4C) alkyl ester) and (1-5C) alkyl nitrate ester selected and (1-6C) alkali alkyl then, as nitro propyl ester and butyllithium, react being similar under the employed condition of aforesaid method (b), just can obtain general formula is Q.S.CH(NO ₂) .CO ₂Corresponding 2-nitroacetic acid (XI) an alkali metal salt of H (or its (1-4C) alkyl ester).The acid of general formula XI is unsettled, and easy decarboxylize, and an alkali metal salt of acidifying general formula XI acid is with regard to the separable thioether that goes out the general formula VII.Can make general formula as the aqueous solution with alkali is the acid that the ester of XI acid is hydrolyzed into the general formula XI, and acidifying obtains the thioether of general formula VII then.Having under the such alkali existence condition of Potassium monofluoride,, be easy to obtain the ester of general formula XI acid suitable (1-4C) nitroacetic acid alkyl ester and needed thiophenyl chlorine (general formula VIII, hydrogen is replaced by chlorine) reaction.

Be to be appreciated that at general formula of the present invention be in the compound of I, Q can have the substituted radical of various responding property.Therefore, before the arbitrary method in finishing aforesaid method (a)-(c), be necessary to protect one or more such substituted in reaction groups with method commonly used with suitable protecting group on a certain stage, in the end a step is removed protecting group then.For example use acyl group (as the acetyl or benzoyl base), uncle's monobutyl, allyl group or phenmethyl protecting group protection hydroxyl substituent; With protecting amino substituting group as the blocking group of acyl group (as the acetyl or benzoyl base); Ketone group can its ketal form be protected (as make its ketal with 1); Carboxyl substituent can its (1-4C) alkyl (especially methyl, ethyl or uncle's monobutyl) or the form protection of benzyl esters.On the common textbook of organic chemistry, describe the protection of substituted in reaction base and gone necessary suitable protecting group of provide protection and method.The present invention includes the method (a) and (b) of the formula I new compound that production above limits or result of study (c); it is characterized in that using respectively the starting material of general formula IV, V or VII; wherein the one or more substituted in reaction bases that exist as the last substituting group (as hydroxyl, amino, ketone or carboxyl) of Q are protected with suitable protecting group, and in the end a step is removed this protecting group with suitable method.

In addition, being to be appreciated that has many substituting groups to be obtained by other substituting group in the generalformula on the Q, and they itself then utilize the mutual conversion of common functional group of the prior art, by above-mentioned (a) and (b) or (c) method obtain at first.This mutual conversion comprises, as:

(1) be about room temperature, under the alkali existence just like triethylamine, amino group and acylating agent (as paraffinic acid muriate, combination chain alkanoic acid anhydride or chloroformic acid alkyl or benzyl ester) reaction;

(2) temperature in as the solvent that (1-4C) alkyl alcohol is suitable, makes the hydrolysis of alkanoyl amino group by the reaction with highly basic or strong acid between 35 to 80 ℃;

(3) under the temperature about room temperature, suitable condensing agent is arranged (when promptly using free carboxy usually, there is carbodiimide to exist, and when using carbonyl chloride or carbonyl bromide, have alkali such as triethylamine to exist), make carboxyl (or corresponding carbonyl chloride or carbonyl bromide) and suitable alkyl alcohol, benzylalcohol or amine condensation;

(4) be between-70 to 0 ℃ in temperature, bromo or iodo group and lithium reagent such as butyllithium reacted, subsequently with carbon dioxide reaction;

(5) temperature makes formamido-be reduced into methylamino-with appropriate reductant (as borane, more convenient with the mixture of methyl-sulfide) in 0 to 25 ℃ of scope;

(6) temperature uses appropriate reductant (as borane, with comparatively suitable with the mixture of methyl-sulfide) that carboxyl reduction is become methylol between 10 to 40 ℃;

(7) temperature is used suitable dewatering agent (as phosphoryl chloride) between 60-110 ℃, makes formamyl be dehydrated into cyano group;

(8) use and the similar condition of qualification aforesaid method (c), (as permonosulphuric acid potassium is to serve as that the conversion alkylthio is the alkyl sulfinyl with suitable oxygenant, or potassium permanganate is alkyl sulphonyl for transforming alkylthio or alkyl sulfinyl) the oxidation alkylthio is that alkyl sulfinyl and/or alkyl sulphonyl and alkyl sulfinyl are alkyl sulphonyl;

(9) temperature is about under the room temperature, and using suitable oxygenant (as pyridinium chlorochromate) oxidation hydroxyalkyl is corresponding ketone group; With

(10) temperature is between 20 to 80 ℃, by with suitable paraffinic acid and sodium borohydride reaction, amino reductive alkylation is become corresponding alkylamino or dialkyl amido.

This class tautomerism of great majority describes in detail in incidental embodiment, and also is included among the embodiment as another feature of the present invention.

In addition, when the needs non-toxic salts, generalformula can with the suitable alkali reaction that has non-toxic cation, and when Q contains a suitable basic group (as alkylamino or dialkyl amido), with suitable acid-respons, can prepare a kind of nontoxic acid-additive salt with innoxious negative ion.

As mentioned above, generalformula suppresses aldose reductase.Therefore, the Practical significance of this compound is to treat because the catalyzed reaction of aldose reductase has taken place in vivo, and forms excessive as this class product of Sorbitol Powder thereby disease that causes or symptom.

With the characteristic that suppresses aldose reductase in the method for inspection display body of following common lab.For example, take streptozotocin to mouse and make it get diabetes (evidence is that serious glycosuria is arranged), take test compound for every day then these animals, continue one, two or five day.After the medication 2-6 hour the last time, kill these animals, take out eyes crystal and/or sciatic nerve.After a common processing treatment program, residual concentration of sorbitol in each tissue of available vapour-liquid chromatography, Sorbitol Powder has been converted into poly-trimethyl silane radical derivative before mensuration.Then, residual concentration of sorbitol in the tissue of residual concentration of sorbitol in the tissue of the diabetes mouse of taking medicine group and the normal mouse group that does not have medication diabetes mouse group and do not take medicine is done one relatively, with the retarding effect of aldose reductase in this estimated body.

Also can show the characteristic that suppresses aldose reductase external.Therefore, the aldose reductase that from Niu Jingti, separates incomplete purifying with currently known methods.This kind of enzyme that is caused by test compound is a polyhydroxy-alcohol at external catalytic reduction aldose, and the glucose that particularly reduces is the inhibition per-cent of Sorbitol Powder ability, and available common spectrophotometric methods is measured.

In order to describe the rejection characteristic of generalformula to aldose reductase in detail, this compound IC50 in above-mentioned in vitro tests is 3.2 * 10 among the embodiment ^-7M.Change along with chemical structure to a certain extent though the activity of each compound of formula I is inevitable, in general, in the in vitro tests of mentioning in the above, when dosage (usually P.O) is 100mg/kg or few when not having the overt toxicity sign, generalformula demonstrates the obvious suppression effect, and IC50 is 10 in above-mentioned in vitro tests ^-5M or still less.

Absorption was administered to warm-blooded animal (generally by mouth) in the compound of formula I was main, reached prevention effect by the restraining effect of aldose reductase, and for example the per daily dose scope is 1 to 40mg/kg.For the people, imagine for each person every day taking dose and be 15 to 800mg, if in case of necessity, divide and take several times.

Yet the compound of taking is accurately measured nature with the condition of patient's age, sex and the state of an illness and treatment and slightly different.

Generalformula also can locally use, and for example directly is applied to tissue or the organ that needs inhibitory enzyme by topical, uses as the part on eyes.The accurate amount of this compound administration must decide according to employed prescription.For example, when using solution, compound concentrations reaches as high as 0.01%(weight meter usually).Similarly, when using ointment, this compound concentrations reaches as high as 2%(weight meter).The part of generalformula makes with medicament, can be applied on the eyes of animal, receives treatment and/or to prevent the people or the dog of glycosuria cataract or retinopathy, usual method be with drops or wash a topical agent as needs.

Said composition also can comprise one or more other known to treatment diabetes or the medicable reagent of galactosemia, as hypoglycemic drugs (hypoglycaemic agent) such as tolbutamide, P-607 or glyburide.

To describe the present invention in detail by following unrestricted embodiment, unless otherwise stated:

(ⅰ) all evaporations all are to adopt rotary evaporation in vacuo;

(ⅱ) all operation is all carried out under scope is 18-26 ℃ room temperature;

(ⅲ) use nuclear magnetic resonance spectrum and thin-layer chromatographic analysis and/or trace analysis to evaluate the purity of chemical products;

(ⅳ) " mmol " expression mmole equivalent;

(ⅴ) sherwood oil (b.p.60-80 ℃) is considered to " gasoline " 60-80 °.

(ⅵ) productive rate only is explanation, rather than through updating the maximum that method can reach; With

(ⅶ) medium pressure liquid chromatography (MPLC) is at silica gel (Merck Art.9385, by West Germany E Merck and Co., Darmstadt obtains).

Example 1

(6.72ml 124mmol) is added drop-wise to uncle's one butanols potassium (6.27g, N 55.8mmol), dinethylformamide (DMF with Nitromethane 99Min. under stirring; 250ml) in the solution, in ice bath, be cooled to 0 ℃.Add finish after, continue 0 ℃ of following restir 30 minutes.Add then naphthalene-1--sulfinic acid sodium salt (12g, 56mmol), add immediately iodine (7.2g, 28.3mmol).Rise to room temperature after stirring this mixture overnight.The aqueous solution that S-WAT is dense is added to and makes its part decolouring in the reaction mixture.Pour into then in the water (1 liter), use the hcl acidifying of 2M again.Use the ethyl acetate extraction aqueous mixture.Close the And extraction liquid, water, salt water washing, dry again (MgSO ₄).Evaporation removes and desolvates.Residual yellow liquid medium pressure liquid chromatography (MPLC) purifying of silica gel, (1: 10V/V rises to 1 gradually: 5V/V) wash-out with ethyl acetate isohexane.(1-naphthyl-alkylsulfonyl) Nitromethane 99Min. that obtains like this is colourless oily matter, with ether (ether) crystallization, can obtain a solid (1.85g), m.p.99-101 ℃.

Make starting material as follows:

The sodium bicarbonate of crossing toward vigorous stirring (8.4g, 100mmol) and sodium sulphite anhydrous 99.3 (12g in water 95mmol) (50ml) solution, divides some parts to add naphthalene-1-SULPHURYL CHLORIDE (11.5g, 50mmol), the while is stirring tempestuously.Being interrupted heating makes temperature remain on 70-80 ℃.Add finish after, under 70-80 ℃, heat and stirred this mixture 1 hour.With the time more than 4 hours mixture is cooled to room temperature then, uses the 2M hcl acidifying again.By filtering the solid of collecting precipitation, wash dry air with water.Use the aqueous ethanolic solution recrystallization again, obtain naphthalene-1--sulfinic acid solid, m.p.86-87 ℃.

By adding the methanol solution of sodium methylate (1 equivalent), and the evaporation gained solution, make this acid be converted into its sodium salt.Use this sodium salt need not purifying or description.

Example 2

Make the similarity method of use-case 1 description, obtain the solid of (2,4,6-trimethylphenyl alkylsulfonyl) Nitromethane 99Min., m.p.92-93 ℃ (using the ethyl acetate/hexane recrystallization).With 2,4, the 6-trimethylbenzene chloride makes initial-sulfinic acid sodium salt as initial reagent with the similar approach for preparing starting material in the example 1.

Example 3

(12.0g 100mmol) splashes in uncle's one butanols potassium (20g, dry DMF(200ml 178mmol)) solution of stirring, makes temperature be controlled at 0-5 ℃ by exterior cooling with Nitromethane 99Min..Add finish after, with mixture 0-5 ℃ of following restir 30 minutes.Add then 4-iodobenzene-sulfinic acid sodium (29.0g, 100mmol), then add iodine (22.8g, 90mmol).This mixture was at room temperature stirred 2 hours, pour into then in the water (3 liters).With making its part decolouring in the dense sodium sulfite aqueous solution adding reaction mixture, use the 2M hcl acidifying again.Filter the solid of collecting precipitation, wash the back with water with ethyl alcohol recrystallization 4 times, obtain m.p.177-179 ℃ in the crystal (0.8g) of (4-iodophenyl alkylsulfonyl) Nitromethane 99Min., trace analysis is found: C, 25.56; H, 1.83; N, 4.18%; C ₇H ₆INO ₄Contain among the S: C, 25.70; H, 1.85; N, 4.30%.

The method that makes initial-sulfinate is as follows:

Under 70-80 ℃ with 4-phenyl-iodide SULPHURYL CHLORIDE (30.2g, 100mmol) divide the some parts of sodium bicarbonates that add vigorous stirring (16.8g, 200mmol) and sodium sulphite anhydrous 99.3 (24g is in water 190mmol) (100ml) solution.Being interrupted heating makes temperature remain on 70-80 ℃.After interpolation finishes, mixture was stirred 1 hour at 70-80 ℃ of reheat.Then mixture is filtered, make the filtrate cooling near 40 ℃.Filtering solution is isolated the crystalline solid, and with behind the ice-cold water washing, vacuum-drying is 48 hours on sodium hydroxide and calcium chloride, obtains 4-iodo benzene sulfinic acid sodium salt, m.p.＞350 ℃, and this salt need not be further purified or describe and can use.

Example 4-12

Adopt the similarity method of (the 4-iodophenyl alkylsulfonyl) Nitromethane 99Min. described in the example 3, to obtain productive rate be 1-30% and have satisfied ultimate analysis and the following generalformula of NMR spectrum :-

M.p.(℃ of embodiment Q) recrystallization liquor (S)

43,5-two (trifluoromethyl) phenyl 76-78 hexane

5 4-Trifluoromethoxyphen-l 110-112 toluene/hexane

6 3-chloro-phenyl-67-69 toluene/hexane

73,4-dichlorophenyl 92-94 methyl alcohol

8 3-aminomethyl phenyl 67-69 ethanol

9 ^* _*2-aminomethyl phenyl 47-49 toluene/hexane

10 4-hexyl phenyl 95-97 ethanol

11 4-butoxy phenyl 84-86 methyl alcohol

12 ^* _*4-benzyloxy phenyl 115-117 ethyl acetate

( ^* _*This compound is to obtain from the acidified reaction mixture of dichloromethane extraction.Dry (Na ₂SO ₄) extraction liquid and evaporating solvent.Then with 7: the hexane/ethyl acetate of 3V/V is as elutriant, with flash chromatography purifying residue).

Usually the similarity method of the 4-iodobenzene-sulfinic acid sodium described in the use-case 3 prepares the necessary-sulfinic acid sodium of general formula IV, and obtain be to use the time the high melting point solid that need not fully describe.Yet under the situation as the sulphite starting material of example 8 and 9, dilute with water-sulfinate reaction mixture is acidified to PH1 with concentrated hydrochloric acid, uses dichloromethane extraction then.Extraction liquid drying (Na ₂SO ₄) the back evaporating solvent.Handle by methanol solution, make the-sulfinic acid that obtains be converted into its sodium salt, the evaporation methyl alcohol that continues with the equivalent sodium methylate.

Needed initial SULPHURYL CHLORIDE is not to have bought easily exactly to make by usual way of the prior art.For example; adopt Organic Syntheses; Collected Volume; go up described method for 1,85 page, the suitable compound of mutual-through type Q-H carries out chlorosulfonylation; or employing Organie Syntieses; Volume 60, and the method for describing on 121 pages makes the reaction of suitable diazonium salt and sulfurous gas.SULPHURYL CHLORIDE in the example 11 and 12 is to adopt Helvetica Chimica Acta, 1956,39, and the method described in the 1579-1586 makes.

Example 13

With mistake-vitriolate of tartar (trade mark " Oxone "; 38.7g, 63mmol) water (100ml) solution once all add (uncle's 4-monobutyl phenyl sulfo-) Nitromethane 99Min. (A) of vigorous stirring (4.76g be in methyl alcohol 21.9mmol) (90ml) solution.Form a kind of cream-colored precipitation.Stir this mixture overnight.Add water (200ml) then, use the ethyl acetate extraction mixture again.Close the And extraction liquid, dry (MgSO ₄) and the evaporative removal solvent.Remaining yellow solid hexanaphthene recrystallization obtains (4-tert-butyl phenyl sulfonyl) Nitromethane 99Min. colorless solid (3.34g), and m.p.90-91 ℃, trace analysis is found: C, 51.4; H, 5.9; N, 5.4%; C ₁₁H ₁₅NO ₄Contain among the S: C, 51.4; H, 5.9; N, 5.4%.

Make starting material (A) by following method :-

(ⅰ) under 80 ℃ of agitation conditions, (6.29g, (10.8ml is in aqueous solution 81mmol) 54mmol) to add 4-tert-butyl benzenethiol (9.0g, 30%(W/V 54mmol)) sodium hydroxide with sodium chloroacetate to divide some parts.After adding end, continue down to stir 2 hours, form a kind of heavy-gravity white depositions therebetween in 80 ℃.Reaction mixture is added in the entry (200ml), and adds the 2M hcl acidifying,, close the extraction liquid of And and use 10%(W/V again with this mixture of ethyl acetate extraction to PH2) wet chemical extract.Aqueous extract is used ethyl acetate extraction again by adding the 2M hcl acidifying to PH2.These are closed the extract drying (MgSO of And ₄), the evaporative removal solvent obtains 2-(4-tert-butyl phenyl sulfo-) acetate (B) deadgress oily matter (9.07g); This product has satisfied NMR spectrum.

(ⅱ) in argon gas, (51.25ml, 82mmol) solution splashes into the B(9.07g of stirring, 40.5mmol) remains in-40 ℃ anhydrous tetrahydro furan (150ml) solution with the hexane of 1.6M butyllithium.After interpolation finishes, mixture was stirred 1 hour down in-5 ℃.(12.92g 123mmol) splashes under-5 ℃ in the said mixture of stirring, and then stirs 2 hours, and whole process temperature remains on below 0 ℃ always with propyl nitrate.The dilithium salt that adds 2M hcl acidifying mixture (containing 2-(4-tert-butyl phenyl sulfo-)-2-nitroacetic acid) to PH2.Due to the decarboxylation of carbonic acid gas (because of 2-(4-tert-butyl phenyl sulfo-)-2-nitroacetic acid) discharge stop after, made mixture at room temperature static 30 minutes.Add water (300ml) then and with this mixture of ethyl acetate extraction.Close the extraction liquid of And and wash continuously, dry again (MgSO with the aqueous solution, water and the salt solution of sodium bicarbonate ₄), the evaporative removal solvent.Residual oily matter silica gel chromatography purifying, use (3: 20V/V) ethyl acetate/hexane wash-out, obtain the tangerine look oily matter (4.76g) of (4-tert-butyl phenyl sulfo-) Nitromethane 99Min. (A), NMR composes (200MHZ, d ₆DMSO): 1.27(S, 9H), 6.02(S, 2H), 7.42(S, 4H).

Example 14-16

Adopt the similarity method of describing in the example 13, but, make following compounds from the suitable thioether of general formula VII :-

(example 14):

By (3-p-methoxy-phenyl sulfo-) Nitromethane 99Min. is that ((1: behind MPLC purifying 5V/V), be separated as the oily body, this oily body has satisfied NMR spectrum (90MHz, CDCI to itself to raw material using ethyl acetate/hexane ₃): 3.79(S, 3H), 5.41(S, 2H), 6.74-7.34(m, 4 fragrant H)) make (3-p-methoxy-phenyl alkylsulfonyl) Nitromethane 99Min. solid, m.p.57-58 ℃; (with ethyl acetate/hexane (1: MPLC purifying 10V/V)); Trace analysis is found: C, 42.1; H, 4.0; N5.95%; C ₈H ₉NO ₅Contain among the S: C, 41.6; H, 3.9; N, 6.1%, productive rate is 77%.

(example 15):

With (3-trifluoromethyl sulfo-) Nitromethane 99Min. is raw material (itself ethyl acetate/hexane (7: behind MPLC purifying 3V/V), to have satisfied NMR spectrum (200MHz, CDCI ₃): 5.49(S, 2H), 7.46-7.83(m, 4 fragrant H) oily matter isolate) make (3-trifluoromethyl alkylsulfonyl) Nitromethane 99Min. solid, m.p.96-97 ℃; Trace analysis is found: C, 36.1; H, 2.3; N, 4.9%; C ₈H ₆F ₃NO ₄Contain among the S: C, 35.7; H, 2.2; N, 5.2%; (sublimation purification); Productive rate is 42%.

(example 16):

(itself is the solid that begins to make (2-naphthyl alkylsulfonyl) Nitromethane 99Min. with ethyl acetate/hexane (1: behind MPLC purifying 5V/V), isolate with oily matter), m.p.106-107 ℃ from (2-naphthyl sulfo-) Nitromethane 99Min.; Trace analysis is found: C, 52.9; H, 3.5; N, 5.5%; C ₁₁H ₉NSO ₄In contain: C, 52.6; H, 3.6; N, 5.6%; (with ethyl acetate/hexane (1: MPLC purifying 10V/V)); Productive rate is 14%.

Adopt the similar approach of describing in the example 13, make initial thioether in the general formula VII, promptly by the thiacetic nitration reaction of general formula IX and the acid of the nitroacetic acid of the general formula XI that continues-catalytic decarboxylation reaction.Make the similar approach of describing in the use-case 13 can obtain the thioacetic acid of general formula IX itself, promptly pass through suitable mercaptan and the sodium chloroacetate and the sodium hydroxide reaction of general formula VIII.Usually, this starting material need not be described.

Example 17

(1.68g, 10.6mmol) water (56ml) solution once all adds (2,4,5-trichlorophenyl sulfo-) Nitromethane 99Min. (2.45g in acetate 9mmol) (50ml) solution, cools off this mixture immediately in ice bath with potassium permanganate under 20 ℃.Stirred the mixture 10 minutes, water (100ml) dilution with the sodium sulfite solution decolouring, is used ethyl acetate (2 * 75ml) extractions again.Close the And extraction liquid, dry (MgSO ₄) and evaporation.Develop residue with hexane, and filter out the solid that is produced, (1: 5V/V) the MPLC purifying of wash-out obtains the colorless solid (0.8g) of (2,4,5-trichlorophenyl alkylsulfonyl) Nitromethane 99Min., m.p.122-123 ℃ with ethyl acetate/hexane; Trace analysis is found: C, 28.0, H, 1.4; N, 4.9%; C ₇H ₄Cl ₃NO ₄Contain among the S: C, 27.6; H, 1.3; N, 4.6%.

Adopt the similar approach of describing in the example 13, from 2,4,5-trichlorophenyl thioacetic acid begins to obtain the initial thioether of buttery, and the NMR spectrum (200MHz, CDCL3): 7.63(S, 1H), 7.53(S, 1H), 5.43(S, 2H) (ethyl acetate/hexane (1: behind MPLC purifying 5V/V)), 2,4,5-trichlorophenyl thioacetic acid itself is from 2,4,5-trichlorobenzene mercaptan begins, and what obtain is solids, m.p.111-112 ℃ (using the ethyl acetate/hexane recrystallization).

Example 18-19

Except under 50 ℃, carrying out 3 hours oxidizing reaction, all adopt the similarity method of describing in the example 17, make following compounds:

(example 18):

(4-(4-chloro-phenyl-) phenyl sulfonyl) Nitromethane 99Min.; by (4-4(-chloro-phenyl-) phenyl sulfo-) Nitromethane 99Min. begins (with dichloromethane/hexane (7: 3V/V) behind the MPLC purifying of wash-out; obtain its solid; satisfied trace analysis result and NMR spectrum (200MHz/CDCI3): 5.49(d is arranged; 2H), 7.38-7.63(m, 8H)) obtain solid; m.p.175-176 ℃ (with hexane development back), productive rate is 84%.With

(example 19):

(2,6-3,5-dimethylphenyl alkylsulfonyl) Nitromethane 99Min. is that raw material is (with ethyl acetate/hexane (1: 5V/V) behind the MPLC purifying of wash-out, obtain its oily body, satisfied NMR spectrum (200MHz, CDCl are arranged with (2,6-3,5-dimethylphenyl sulfo-) Nitromethane 99Min. ₃): 2.52(S, 6H), 5.25(S, 2H), 7.10-7.26(m, 3H)), obtaining solids, m.p.70-71 ℃ (using ethyl acetate/hexane (1: behind MPLC purifying 10V/V)), productive rate is 44%.

Adopting the similar approach of describing in the example 13, is that the corresponding thioacetic acid of IX and the mercaptan acquisition general formula of general formula VIII are the necessary thioether of VII from general formula.Separate the thioacetic acid solid that obtains the general formula IX, it has satisfied NMR spectrum, does not need other evaluation.

Example 20

(the 3%W/V solution of 58.67ml, (2.0g is in acetate 9.28mmol) (75ml) solution 11.14mmol) once all to add (the 4-chloro-2.5-3,5-dimethylphenyl sulfinyl) Nitromethane 99Min. that stirs with the potassium permanganate solution of preparation newly.Under 50 ℃, stirred the mixture 3 hours, and be cooled to room temperature then.The saturated solution of S-WAT splashed into its part is faded, pour into again in the water (350ml).With extracted with diethyl ether three times.Close the extraction liquid of And with the salt water washing, dry (MgSO ₄), evaporation removes and desolvates, and obtains oily matter (2.0g).Behind the MPLC of methylene dichloride wash-out purifying, obtain the solid (1.47g, productive rate are 60%) of (4-chloro-2,5-3,5-dimethylphenyl alkylsulfonyl) Nitromethane 99Min., m.p.113-114 ℃ (behind hexane development solid); Trace analysis is found: C, 41.1; H, 3.8; N, 5.2%; C ₉H ₁₀ClNO ₄Contain among the S: C, 41.0; H, 3.8; N, 5.3%.

The method that makes starting material is as follows:

(trade mark is " Oxone " with permonosulphuric acid potassium, 29.7g, 48.3mmol) water (70ml) solution once all add (4-chloro-2.5-3,5-dimethylphenyl sulfo-) Nitromethane 99Min. (A) of vigorous stirring (3.7g be in methyl alcohol 18.5mmol) (60ml) solution.Put in reaction vessel water-soluble under room temperature, thermopositive reaction speed is slowed down.Stirred this mixture 16 hours, water (500ml) dilution then.Use the aqueous mixture of ethyl acetate extraction again.Wash the extraction liquid (being neutrality) that closes And with water, use the salt water washing again, dry (MgSO until washings ₄), evaporating solvent obtains the faint yellow solid (2.95g, productive rate are 64%) of (4-chloro-2,5-3,5-dimethylphenyl sulfinyl) Nitromethane 99Min., m.p.124-125 ℃ (behind the hexane/ethyl acetate recrystallization); Trace analysis is found: C, 43.6; H, 4.1; N, 5.5%; C ₉H ₁₀ClNO ₃Contain among the S: C, 43.6; H, 4.1; N, 5.7%.

With (4-chloro-2,5-3,5-dimethylphenyl sulfo-) acetate is the oily body that raw material (itself makes from 4-chloro-2.5-dimethyl benzene mercaptan) makes thioether (A), and it has good NMR spectrum (200MHz/CDCl ₃): 2.33(S, 3H); 2.42(S, 3H), 5.37(S, 2H), 7.26(S, 1H), 7.35(S, 1H).Above-mentioned two kinds of situations adopt the similar approach described in the example 13.

Example 21

Under 70 ℃ of intense stirring condition, with 4-fluoro-3,5-dimethyl benzene SULPHURYL CHLORIDE (5.56g, 25mmol) divide some parts add sodium sulphite anhydrous 99.3s (6.0g, 47.6mmol) and sodium bicarbonate (4.2g is in water 50mmol) (25ml) solution.After interpolation finished, this mixture stirred 2 hours at 70 ℃ of reheat.Cooling mixture filters and collects the solid that crystallizes out from solution, and with minimum water dissolution, (3 * 75ml) extract resulting throw out, close And extraction liquid after drying (MgSO with ethyl acetate to PH1. with the 2M hcl acidifying again ₄).Evaporating solvent is developed solid residue with ether, and solid collected by filtration with the ether washing, obtains 4-fluoro-3 through vacuum-drying, 5-dimethyl benzene-sulfinic acid (4.7g).Methanol solution by adding sodium methylate (1 equivalent) also evaporates this solution, makes above-mentioned acid directly transform into its sodium salt.

Under the agitation condition, (2.7ml 50mmol) splashes in uncle-sodium butylate (2.5g, DMF(100ml 22.3mmol)) solution with Nitromethane 99Min..After interpolation finishes, continue down to stir 30 minutes in 0 ℃.Once all add giving the 4-fluoro-3.5-dimethyl benzene sulfinic acid sodium salt for preparing earlier, then add iodine (2.88g immediately; 11.3mmol).Remove cooling bath, restir mixture 3 hours with in the dense sodium sulfite aqueous solution adding reaction mixture its part being faded, is poured mixture in the water (500ml) then, uses the 2M hcl acidifying to PH1.Filter the solid of collecting precipitation, wash with water, use ethyl acetate (100ml) dissolving again, this solution washes with water earlier, washes with salt again.Final drying (MgSO ₄), evaporating solvent.Resulting faint yellow solid is through ethyl acetate/hexane (1: 10V/V, increase to 1 gradually: 5V/V) the MPLC purifying of wash-out, obtain the colorless solid (0.6g) of (4-fluoro-3.5-3,5-dimethylphenyl alkylsulfonyl) Nitromethane 99Min., m.p.131-132 ℃ (using the ethyl acetate/hexane recrystallization); Trace analysis is found: C, 43.7; H, 4.1; N, 5.6%; C ₉H ₁₀FNO ₄Contain among the S: C, 43.7; H, 4.1; N, 5.7%.

Example 22-25

Adopt the similar approach of describing in the example 21, but from the suitable-sulfinic acid sodium (M=sodium) of general formula IV, make productive rate and be 4 to 12% formula I following compounds:

M.p.(℃ of example Q) recrystallization solvent (S)

22 4-p-methoxy-phenyl 84-85 ethyl acetate/hexane

23 3-acetylaminohydroxyphenylarsonic acid 4-p-methoxy-phenyl 181-182 ethyl acetate/hexanols

24 4-acetylaminohydroxyphenylarsonic acids 2,5-3,5-dimethylphenyl 185-186 ethyl acetate/hexane

25 2,5-3,5-dimethylphenyl 55-56 ^* _*

( ^* _*With dichloromethane/hexane (1: MPLC purifying 1V/V)).

Adopt the similar approach of describing in the example 21, can make the-sulfinate of general formula IV from suitable SULPHURYL CHLORIDE, for example, the suitable combination thing sulfochlorination by general formula Q.H makes.

Example 26

(4-acetylamino phenyl alkylsulfonyl) Nitromethane 99Min. (is pressed J Het.Chem.; 1977; 14; 1415 described methods obtain) (10.0g; 38.8mmol) once all add in the boiling mixture of concentrated hydrochloric acid (20ml), water (100ml) and ethanol (40ml); backflow stirs the mixture until the limpid solution (about 20 minutes) of formation, and then continues to stir 5 minutes.The reaction mixture of heat is poured in a large amount of ice-refrigerative saturated solution of sodium bicarbonate, used ethyl acetate extraction again.Close the extraction liquid of And with the salt water washing, dry (MgSO ₄) and evaporate except that desolvating.Therefore obtain the faint yellow solid (5.2g, productive rate are 62%) of (4-aminophenyl alkylsulfonyl) Nitromethane 99Min., n.p.132-133 ℃, trace analysis is found: C, 39.2; H, 3.8; N, 12.9%; C ₇H ₈N ₂O ₄Contain among the S: C, 38.9; H, 3.7; N, 12.95%.

Example 27

(0.96g 4.44mmol) is suspended in the ether (50ml) with (4-aminophenyl alkylsulfonyl) Nitromethane 99Min..Splash into the second formic anhydride (1.0g, 11.36mmol), and stirred reaction mixture 16 hours.Filter and collect white depositions,, make (4-formamido-phenyl sulfonyl) Nitromethane 99Min. (0.98g, productive rate are 90%) like this with ether (50ml) development, m.p.192-193 ℃ (using the aqueous methanol recrystallization), trace analysis is found: C, 39.3; H, 3.1; N, 11.4%; C ₈H ₈N ₂O ₅Contain among the S: C, 39.3; H, 3.3; N, 11.5%.

Example 28

In argon gas with (4-aminophenyl alkylsulfonyl) Nitromethane 99Min. (0.86g; 4mmol) be dissolved in the exsiccant tetrahydrofuran (THF) (20ml); add triethylamine (0.61g again; 6mmol); (0.62g 4.4mmol), stirred the mixture 2 hours then then to add Benzoyl chloride; remove by filter sedimentary triethylamine hydrochloride, filtrate concentrates in a vacuum.Resulting orange dichloromethane/ethyl acetate (9: 1V/V) behind the MPLC purifying of wash-out, obtain the solid of (4-benzamido phenyl sulfonyl) Nitromethane 99Min. (0.25g, productive rate are 20%), m.p.211-212 ℃; Trace analysis is found: C, 52.3; H, 3.7; N, 8.4%; C ₁₄H ₁₂N ₂O ₅Contain among the S: C, 52.5; H, 3.75; N, 8.75%.

Example 29-31

Adopt the similarity method of describing in the example 13, but originate in the suitable thioether of general formula VII, make following compounds:

(example 29):

(itself separates with oily matter, is using ethyl acetate/hexane (1: after MPLC purifying 10V/V), have satisfied NMR spectrum (200MHz, CDCl with (3-fluoro-phenyl sulfo-) Nitromethane 99Min. ₃): 5.48(S, 2H), 7.0-7.43(m, 4 fragrant H)) make (3-fluorophenyl alkylsulfonyl) Nitromethane 99Min. solid, m.p.68-69 ℃ for raw material; (using ethyl acetate/hexane (1: behind MPLC purifying 10V/V)); Trace analysis is found: C, 38.5; H, 2.76; N, 6.39%; C ₇H ₆FNO ₄Contain among the S: C, 38.36; H, 2.8; N, 6.2%, productive rate is 12%;

(example 30):

(itself is to separate with oily matter to Nitromethane 99Min. from (2-chloro-3-aminomethyl phenyl sulfo-), using ethyl acetate/hexane (1: behind MPLC purifying 10V/V), have gratifying NMR spectrum) beginning, make the solid of (2-chloro-3-aminomethyl phenyl alkylsulfonyl) Nitromethane 99Min., m.p.95-97 ℃; (with ethyl acetate/hexane (1: behind MPLC purifying 10V/V)); Trace analysis is found: C, 38.0; H, 3.2; N, 5.1%; C ₈H ₈ClNO ₄.1/4H ₂Contain among the O: C, 37.8, H, 3.4; N, 5.5%; Productive rate is 25%;

(example 31):

By (4-(N, N-dipropyl sulfamyl) phenyl sulfo-) Nitromethane 99Min. (itself with solids constituent from, with ethyl acetate/hexane (1: behind MPLC purifying 10V/V), have gratifying NMR spectrum (200MHz, d ₆DMSO): 0.7-0.9(t, 6H), 1.35-1.6(m, 6H), 2.95-3.1(t, 4H), 6.25(S, 2H), 7.6-7.8(m, 4 fragrant H)) as raw material, make (4-(N, N-dipropyl sulfamyl) solid of Nitromethane 99Min. phenyl sulfonyl), m.p.103-104 ℃; (using the ethyl acetate/hexane recrystallization purifying); Trace analysis is found: C, 43.2; H, 5.6; N, 7.5%; C ₁₃H ₂₀N ₂O ₆S ₂In contain: C, 42.9; H, 5.5; N, 7.7%; Productive rate is 51%;

Example 32

(40ml, (5.6g is in anhydrous tetrahydro furan 20mmol) (250ml) solution 62mmol) to splash into stirring (the 4-bromophenyl alkylsulfonyl) Nitromethane 99Min. (A) that remains under-65 to-70 ℃ with the butyllithium of 1.55M in argon gas.After interpolation finishes, mixture was stirred 20 minutes down in-70 ℃.Again mixture is poured in the hexane that contains solidified carbon dioxide, made temperature recovery to room temperature.To PH2, static 1 hour, use ethyl acetate extraction then with 2M hcl acidifying mixture.Extraction liquid is closed And, dry (MgSO ₄), the evaporative removal solvent.Develop residue with ether, filter and collect the colorless solid that produces, thereby obtain (4-carboxyl-phenyl sulfonyl) Nitromethane 99Min. (0.28g), m.p.213-215 ℃.(using the ethyl acetate/hexane recrystallization); Trace analysis is found: C, 39.5; H, 2.9; N, 5.5%; C ₈H ₇NO ₆Contain among the S: C, 39.2; H, 2.9; N, 5.7%.

Adopt the similar approach of describing in the example 3, by the solid of 4-bromobenzene-sulfinic acid sodium acquisition starting material (A), m.p.163-165 ℃ (using the ethyl acetate/hexane recrystallization).

Example 33

(0.33ml, (1.0g is 4mmol) in ice-salt bath in refrigerative methyl alcohol (12ml) solution 4.5mmol) to splash into (4-carboxyl phenyl alkylsulfonyl) Nitromethane 99Min. of stirring with thionyl chloride.Mixture at room temperature stirs 16 hours revaporization solvents.The residue methylene dichloride, after increase gradually ethanol/methylene (1: 50V/V) the MPLC purifying of wash-out, thereby obtain (4-methoxycarbonyl phenyl sulfonyl) Nitromethane 99Min. (0.45g), m.p.106-108 ℃; Trace analysis is found: C, 41.8; H, 3.5; N, 5.2%; C ₉H ₉NO ₆Contain among the S: C, 41.7; H, 3.5; N, 5.4%.

Example 34

With thionyl chloride (10ml, 13.7mmol) add (4-carboxyl phenyl alkylsulfonyl) Nitromethane 99Min. (1g, 4mmol) in, under agitation mixture refluxed 15 minutes.Add toluene (10ml) behind the evaporating solns.Gained solution is again through evaporation, and residual oily matter is dissolved in (10ml) in the chloroform.This solution is cooled to 0 ℃, the chloroformic solution of dimethylamine is splashed in the stirred mixture, to excessive dimethylamine existence is arranged.Evaporation after stirring the mixture 15 minutes.Residue is used ethyl acetate extraction after with the 2M hcl acidifying again.Close the extraction liquid drying (MgSO of And ₄) after, evaporation removes and desolvates.Remaining pale yellow colored solid body and function re-crystallizing in ethyl acetate, thereby obtain (4-(N, N formyl-dimethylamino phenyl sulfonyl)) m.p.144-146 ℃ of Nitromethane 99Min. (0.4g); Trace analysis is found: C, 44.0; H, 4.4; N, 10.1%; C ₁₀H ₁₂N ₂O ₅Contain among the S: C, 44.1; H, 4.4; N, 10.3%.

Example 35

(0.1ml, (0.25g, in the solution of anhydrous tetrahydro furan 1mmol) (5ml), this mixture is stirred 2 hours 1mmol) to add (4-carboxyl phenyl alkylsulfonyl) Nitromethane 99Min. with borane-methyl-sulfide title complex.To PH1, use ethyl acetate extraction with 2M hcl acidifying mixture again.Close the extraction liquid drying (MgSO of And ₄) after, revaporization removes and desolvates.Residue is through ethanol/methylene (1: 50V/V) behind the MPLC purifying of wash-out, obtain (4-hydroxymethyl phenyl sulfonyl) Nitromethane 99Min. (0.06g), m.p.73-75 ℃; Trace analysis is found: C, 41.6; H, 3.9; N, 5.8%; C ₈H ₉NO ₅Contain among the S: C, 41.6; H, 3.9; N, 6.1%.

Example 36

0 ℃ (1.70g 7.0mmol) is suspended in the exsiccant tetrahydrofuran (THF) (5.0ml) with (4-formamido-phenyl sulfonyl) Nitromethane 99Min. down at argon gas.(1.75ml 17.5mmol) splashes into borane-methyl-sulfide title complex in more than 30 minutes time.Make reaction mixture drop to room temperature.With the careful acidifying mixture of 2M hydrochloric acid, use extracted with diethyl ether again three times.Close the extraction liquid of And with the salt water washing, dry (MgSO ₄) and evaporate except that desolvating.The yellow solid that the is obtained solid of ethyl acetate/hexane (1: 1V/V) behind the MPLC purifying of wash-out, can obtain (4-(N-methylamino-phenyl sulfonyl)) Nitromethane 99Min..(0.43g, productive rate 27%) m.p.123-124 ℃ (used ethyl acetate/hexane (1: 4V/V) recrystallization); Trace analysis is found: C, 41.8; H, 4.2; N, 11.8%; C ₈H ₁₀N ₂O ₄Contain among the S: C, 41.7; H, 4.35; N, 12.1%.

Example 37

(0.76g, (1.08g is in acetate 5mmol) (20ml) solution 20mmol) to divide some parts of addings (4-aminophenyl alkylsulfonyl) Nitromethane 99Min. with sodium borohydride.After the intensive boiling is calmed down, mixture is incubated 16 hours down in 60 ℃.Evaporation removes and desolvates.Crystallization residuum ethyl acetate/hexane (3: 10V/V) behind the MPLC purifying of wash-out, get an oily matter.This oily matter is developed with hexane, collects the solid that produces with filtration method.So just obtained (4-(N, N-diethylin phenyl alkylsulfonyl) Nitromethane 99Min. (0.37 gram), m.p.102-103 ℃; Trace analysis is found: C, 48.7; H, 5.9; N, 10.2%; C ₁₁H ₁₆N ₂O ₄Contain among the S: C, 48.5, H, 5.9; N, 10.3%.

Example 38

In argon gas with (4-aminophenyl alkylsulfonyl) Nitromethane 99Min. (1.62g 7.5mmol) is dissolved in the exsiccant tetrahydrofuran (THF) (35ml), add triethylamine (1.14g, 11.25mmol), add subsequently butyryl chloride (0.88g, 8.25mmol).Stirred the mixture 2 hours.Sedimentary triethylamine hydrochloride is removed with filtration method, concentrates under the filtrate vacuum.The brown oil that obtains with methylene chloride (99: 1V/V) the MPLC purifying of wash-out, thereby obtain the solid of (4-amide-based small phenyl sulfonyl) Nitromethane 99Min. (0.16g, productive rate 7.5%), m.p.155-156 ℃; Trace analysis is found: C, 45.8; H, 4.8; N, 9.6%; C ₁₁H ₁₄N ₂O ₅Contain among the S: C, 46.1; H, 4.9; N, 9.8%.

Example 39

(1.7g 6.9mmol) adds in the thionyl chloride (17ml), and the gained mixture heating up refluxed 15 minutes, and the yellow solution evaporation of generation also adds exsiccant toluene (20ml) with (4-carboxyl phenyl alkylsulfonyl) Nitromethane 99Min..Mixture is after evaporation, and residual oily matter is dissolved in the diox (4ml) again.Stir down solution slowly is added to ice-cold ammonia solution (density, 0.91g/ml; 20ml).When interpolation finishes, under 0 ℃, stirred the mixture 30 minutes.Make mixture be acidified to PH2 by adding 2M hydrochloric acid, use ethyl acetate extraction again.Close the extraction liquid drying (MgSO of And ₄) the back evaporating solvent.Solid residue ethanol/methylene (1: 20V/V, bring up to 1 gradually: 5V/V) behind the MPLC purifying of wash-out, can obtain (4-carboxyl amido phenyl alkylsulfonyl) (4-carboxamidophenylsulphonyl) Nitromethane 99Min. (0.5g), m.p.174-176 ℃; Trace analysis is found: C, 39.5; H, 3.2; N, 11.0%; C ₈H ₈N ₂O ₅Contain among the S: C, 39.3; H, 3.3; N, 11.5%.

Example 40

With phosphoryl chloride (5ml) add (4-carboxyl amido phenyl alkylsulfonyl) Nitromethane 99Min. (0.75g, 3mmol) in, made the stirred mixture reflux 40 minutes.Make the mixture cooling again, excessive phosphoryl chloride is removed by evaporation.On the rocks in the residue, make mixture temperature reduce to room temperature.Use the ethyl acetate extraction mixture, dry again (MgSO ₄) close the extraction liquid of And.Can obtain (4-cyano-phenyl-alkylsulfonyl) Nitromethane 99Min. (0.5g) after the solvent evaporation, m.p.158-160 ℃ (behind the ethyl acetate/hexane recrystallization); Trace analysis is found C, 42.5; H, 2.7; N, 11.9%; C ₈H ₆N ₂O ₄Contain among the S: C, 42.5; H, 2.7; N, 12.4%.

Example 41

Make the similar approach of describing in the use-case 21, (itself is by J.C.S. with 4-methyl thio phenyl-sulfinic acid, 1948, the described acquisition of 604-605) make the solid of (4-methyl thio-phenyl alkylsulfonyl) Nitromethane 99Min. for raw material, m.p.98-100 ℃ (behind the ethyl acetate/hexane recrystallization), trace analysis is found: C, 39.3; H, 3.6; N, 5.5%; C ₈H ₉NO ₄S ₂In contain: C, 38.9; H, 3.6; N, 5.7%, productive rate is 7%.

Example 42

With mistake-vitriolate of tartar (" Oxone " (trade mark); 4.17g, 6.75mmol) water (12.5ml) solution once all add vigorous stirring (4-hydroxy phenyl sulfo-) Nitromethane 99Min. (A) (850mg, 4.58mmol) 1, in 2-glycol dimethyl ether (25ml) solution.Stir this mixture overnight.Mixture is added in the entry (400ml), use ethyl acetate extraction.Close the extraction liquid of And with the salt water washing, dry (MgSO ₄), the revaporization solvent.After residual solid is used the chloroform recrystallization, can obtain the white solid (373mg) of (6-hydroxy phenyl alkylsulfonyl) Nitromethane 99Min., m.p.93-95 ℃, trace analysis is found: C, 38.7; H, 3.2; N, 6.2%; C ₇H ₇NO ₅Contain among the S: C, 38.7; H, 3.2; N, 6.45%.

The method that makes starting material is as follows:

With (4-hydroxy phenyl sulfo-) acetate (by No. 818783 described making of English Patent) (0.5g, 2.72mmol) the solution of anhydrous tetrahydro furan (20ml) splash under the nitrogen atmosphere, (5.35ml is 8.56mmol) and in the stirring the mixture of anhydrous tetrahydro furan (20ml) to keep the hexane of-40 to-45 ℃ 1.6M butyllithium.When interpolation finished, this mixture stirred one hour down at-40 ℃.Make mixture 0 ℃ of insulation down then, be cooled to-40 ℃ again.(1.08g 8.12mmol) once all adds with isoamyl nitrate.Stirred reaction mixture also makes temperature bring up to ambient temperature overnight.After with the hydrochloric acid of 1.6M mixture being acidified to PH2, restir 1 hour, add entry (250ml) after, use ethyl acetate extraction.Close the extract of And, revaporization solvent with the phase separation filter paper filtering.

Residue silica gel chromatography purifying, with ethanol/methylene (1: 100V/V) wash-out, just can make the oily matter of (4-hydroxy phenyl sulfo-) Nitromethane 99Min. (A), crystallizable (61mg), NMR composes (200MHz, CDCl ₃): 5.35(S, 2H), and 6.8(m, 2 fragrant H), 7.42(m, 2 fragrant H).

Example 43

(solution of 30ml3%W/V, (1g is in acetate 4mmol) (30ml) stirred solution 5.7mmol) once all to add (4-methyl thio-phenyl alkylsulfonyl) Nitromethane 99Min. with potassium permanganate solution.Restir mixture 30 minutes, water (100ml) dilute and decolour with sodium sulfite solution.The solid collected by filtration throw out washes the back dry air with water, can make (4-methyl sulphonyl phenyl sulfonyl) Nitromethane 99Min. (0.76g), m.p.220-221 ℃ (behind the ethyl acetate/hexane recrystallization); Trace analysis is found: C, 34.4; H, 3.2; N, 4.8%; C ₈H ₉NO ₆S ₂In contain: C, 34.4; H, 3.2; N, 5.0%.

Example 44

Under 0 ℃ with mistake-vitriolate of tartar (trade mark " Oxone "); 0.86g, 1.4mmol) water (10ml) solution once all add vigorous stirring (4-methyl thio-phenyl alkylsulfonyl) Nitromethane 99Min. (0.54g, 1.18mmol) 1, in 2-glycol dimethyl ether (10ml) solution.Under 0 ℃, stirred the mixture 30 minutes, then dilute with water.The solid collected by filtration throw out washes dry air again with water.Can make the solid (0.24g) of (4-methyl sulfinyl phenyl sulfonyl) Nitromethane 99Min., m.p.145-146 ℃ (using the ethyl acetate/hexane recrystallization); Trace analysis is found: C, 36.7; H, 3.4; N, 5.0%; C ₈H ₉NO ₅S ₂In contain: C, 36.5; H, 3.4; N, 5.3%.

Example 45

Adopt the similarity method of describing in the example 13, (itself is being used ethyl acetate/hexane (1: 20V/V) behind the MPLC purifying of wash-out, separate obtaining oily matter by (3,4-methylenedioxyphenyl sulfo-) Nitromethane 99Min. (A), have good NMR spectrum (200MHz, CDCl ₃): 6.2-7.1(m, 3H), 6.0(S, 2H), 5.35(S, 2H)) making the solid of (3,4-methylenedioxyphenyl alkylsulfonyl) Nitromethane 99Min., m.p.131-132 ℃ (with ethyl acetate/hexane (1: MPLC purifying 10V/V); Trace analysis is found: C, 39.2; H, 2.9; N, 5.7%; C ₈H ₇NO ₆Contain among the S: C, 39.2; H, 2.9; N, 5.7%; Productive rate is 3.6%.

Initial sulfonyl (A) itself is the similar approach that adopts example 13 to describe, and from 3,4-methylenedioxyphenyl thioacetic acid makes, and its method is as follows:

(ⅰ) (45g, (20.3g is in anhydrous acetic acid 290mmol) (600ml) solution 139mmol) to divide the chlorine that some parts are added to stirring with plumbous rhodanate in argon gas.Stirred this mixture 15 minutes.Once add 1, and the 2-methylenedioxybenzenes (35g, 286mmol).1 hour after-filtration stirs the mixture.Filtrate is added in the ice-water (3.5 liters).Filter the solid of collecting precipitation, with the dry again (MgSO of acetic acid ethyl dissolution ₄).Evaporation can make 3, the light green oily matter of 4-methylenedioxyphenyl thiocyanic ester (40.3g, productive rate are 79%) after removing and desolvating.Solidified oil can use and need not be further purified or identify,

(ⅱ) in argon atmospher, in 10 minutes, with sodium borohydride (8.4g, 220mmol) divide some parts to be added to 3 of stirring, (35.9g is in ethanol 200mmol) (1.06 liters) solution for 4-methylenedioxyphenyl thiocyanic ester, this mixture restir 10 minutes, reflux is 10 minutes afterwards.Make mixture be cooled to room temperature.With the time that surpasses 1 minute; Ethanol (250ml) solution of sodium hydroxide (13g) is added in the stirred mixture, add subsequently sodium chloroacetate (23.3g, 200mmol).Stirred the mixture 16 hours.Behind 2M hcl acidifying mixture, use ethyl acetate extraction.Saturated aqueous solution with sodium bicarbonate extracts the extraction liquid that closes And again.Aqueous extract is used ethyl acetate extraction after using the 2M hcl acidifying again.Extraction liquid drying (the MgSO of And will be closed ₄), evaporation makes 3 except that desolvating, 4-methylenedioxyphenyl thioacetic acid colorless solid (18g, productive rate 42%), and NMR composes (200MHz, CDCl ₃): 3.57(S, 2H), 5.98(S, 2H), and 6.7-7.1(m, 3 fragrant H), 9.81(S, 1H).

Example 46

Adopt the similarity method of describing in the example 20, different is to carry out 5 minutes oxidizing reactions under the greenhouse, (itself is made by (3-chloro-2-aminomethyl phenyl sulfo-) Nitromethane 99Min. (A) from (3-chloro-2-aminomethyl phenyl sulfinyl) Nitromethane 99Min., adopt the similar approach described in the example 20) make the solid of (3-chloro-2-aminomethyl phenyl alkylsulfonyl) Nitromethane 99Min., m.p.78-79 ℃, productive rate is 19%; Trace analysis is found: C, 38.5; H, 3.2; N, 5.3%; C ₈H ₈ClNO ₄Contain among the S: C, 38.5; H, 3.2; N, 5.6%.

Thioacetic acid makes initial thioether (A) by (3-chloro-2-aminomethyl phenyl), and itself is made by 3-chloro-2-methylbenzene mercaptan, and both all adopt the similar approach of describing in the example 13.

Example 47

Adopt the similarity method of describing in the example 13, different is 60 ℃ of following oxidations 6 hours and uses 1, and the 2-glycol dimethyl ether replaces methyl alcohol.With (4-Phenoxyphenyl sulfo-) Nitromethane 99Min. (A) is that (itself is being used silica gel (Merck kieselgel Art.9385) flash chromatography to raw material, with ether/hexane (1: 4V/V) be the elutriant purifying after, isolate oily matter, have satisfied NMR spectrum (200MHz, CDCl ₃): 5.38(S, 2H), 6.93-7.33(m, 9 fragrant H)) make (4-Phenoxyphenyl alkylsulfonyl) Nitromethane 99Min. solid, m.p.118-120 ℃; Trace analysis is found: C, 53.4; H, 3.8; N, 4.7%; C ₁₃H ₁₁NO ₅Contain among the S: C, 53.2; H, 3.8; N, 4.8%; (behind the toluene recrystallization purifying); Productive rate is 38%.

Initial thioether (A) is made by corresponding thioacetic acid, uses the method similar with example 13, and it is as follows to make method:

(30g 162mmol) divides in water (480ml) solution of the 98%W/V sulfuric acid (93) that some parts are added to stirring with 4-benzene aniline.Mixture was heated 30 minutes down in 80 ℃, be cooled to 0-5 ℃ afterwards.(13.5g, water 196mmol) (60ml) solution stir mixture 45 minutes in 0 ℃ to splash into Sodium Nitrite again.Excessive nitrous acid destroys with thionamic acid.Under 0 ℃, solution is added to the Z-Thiovanic acid, and (14.7ml, 211mmol), (10.8g is 49mmol) and in the stirring the mixture of acetone (180ml) for ventilation breather.Mixture is incubated under room temperature.Adding ethyl acetate (200ml) after 1 hour refilters and removes insoluble material.Filtrate is used ethyl acetate extraction.Extract the extraction liquid that closes And with saturated sodium hydrogen carbonate solution.The aqueous extract that adding 2M hcl acidifying closes And is used ethyl acetate extraction again to PH2.Close the extraction liquid after drying (MgSO of And with the salt water washing ₄).After solvent is evaporated, with ethyl acetate/dichloromethane (1: the 1V/V) silica gel of wash-out (Merck kieselgel Art 9385) flash chromatography purifying).Can make the thiacetic oily matter of 4-Phenoxyphenyl (12.3g), it has satisfied NMR spectrum (200MHz, CDCl ₃); 3.61(S, 2H), 6.93-7.46(m, 9 fragrant H).

Example 48

Make the similarity method of describing in the use-case 13, make (4-methoxyl group-1-naphthyl alkylsulfonyl) Nitromethane 99Min. white solid, m.p.109-110 ℃ (after recrystallizing methanol); Trace analysis is found: C, 51.1; H, 3.9; N, 4.9%; C ₁₂H ₁₁NO ₅Contain among the S: C, 51.3; H, 3.9; N, 5.0%, productive rate is 21%, the raw material that uses is (4-methoxyl group-1-naphthyl sulfo-) Nitromethane 99Min. (itself separates with oily matter), adopt the similar approach described in the example 13, and be raw material with 4-methoxyl group-1-naphthyl thioacetic acid, the method that obtains itself is as follows:

(ⅰ) under 0 ℃, the methyl acetate (150ml) of thiocyanogen (69.6mmol) (is pressed people such as YTamura at Tetrahedron Letters, making described in 1977,4417) solution is added to the 1-methoxynaphthalene (10.92g is in methyl acetate 69.3mmol) (80ml) solution.Under room temperature, resulting yellow solution was stirred 16 hours again.Add saturated solution of sodium bicarbonate (100ml), the mixture diatomite filtration separates organic phase, dry (Na ₂SO ₄).Can make the white solid (7.5g) of 4-methoxyl group-1-naphthyl thiocyanic ester (A) behind the evaporating solvent, m.p.100-102 ℃ (with sherwood oil (b.p.80-100 ℃) recrystallization).

(ⅱ) (1.7 grams 45mmol) are added to A(7.5g, in the aaerosol solution of the ethanol of 34.9mmol (150ml) with sodium borohydride.Argon gas is by this mixture.Mixture stirred after 30 minutes, again 80 ℃ of heating 30 minutes, with potassium hydroxide (5.04g, ethanol 90mmol) (60ml) solution is added in the stirred mixture, add subsequently Mono Chloro Acetic Acid (4.25g, 450mmol).After stirring the mixture 30 minutes, heated 30 minutes down in 80 ℃ again.Make the reaction mixture cooling, be added to then (1 liter) in the water, use extracted with diethyl ether again.Water to PH2, is used ethyl acetate extraction with the 2M hcl acidifying.Close the extraction liquid drying (Na of And ₂SO ₄) and evaporate except that after desolvating, can make 4-methoxyl group-1-naphthyl thioacetic acid (5.38g), m.p.114-115 ℃, (with ethanol/water (1: 1V/V) recrystallization).

Example 49-51

Adopt the similarity method of describing in the example 3, obtain productive rate and be 1-27%'s and the following generalformula of good results of elemental analyses and NMR spectrum arranged :-

Example m.p. ℃ of recrystallization solvent of Q (S)

49 4-propyl group phenyl 92-94 ethanol

50 ^* _*3-chloro-4-fluorophenyl 57-60 toluene/hexane

51 4-allyloxy phenyl 88-90 ethanol

( ^* _*This compound is that use-case 9 described similar approach are made by acidified reaction mixture).

Employing is similar to example 3 described methods and prepares the necessary-sulfinic acid sodium of general formula IV.Yet the-sulfinate starting material of example 51 is by example 8 described making.

The initial SULPHURYL CHLORIDE that needs is promptly available, also can produce by the general method of prior art, as reference example 4-12.The SULPHURYL CHLORIDE of example 51 is by Helvetica Chimica Acta, 1956,39, and the illustrated method of 1579-1586 makes.

Example 52

With acetic acid solution (32Wt%, 4ml 19mmol) splash into the 9-phenanthryl sulfo-that the stirs effectively) Nitromethane 99Min. (A) of peracetic acid, (1g is in the chloroform of 3.7mmol (50ml) solution.Mixture stirs water (20ml) dilution after 20 hours.Separate the solution washing that organic phase is also used sodium metabisulfite.Use the salt water washing again, dry (Na ₂SO ₄).Evaporation obtains yellow solid after removing and desolvating.With silica gel (Merck kieselgel Art.7736) flash chromatography purifying, just can make the white crystalline solid (180mg, productive rate 16%) of (9-phenanthryl alkylsulfonyl) Nitromethane 99Min., m.p.165-166 ℃ (using the toluene recrystallization) with the toluene wash-out; Trace analysis is found: C, 59.7; H, 3.7; N, 4.6%; C ₁₅H ₁₁NO ₄Contain among the S: C, 59.8; H, 3.7; N, 4.7%.

Initial thioether (A) makes with solid form itself, m.p.85-86 ℃ (with hexamethylene ring recrystallization); Trace analysis is found: C, 67.3; H, 4.2; N, 5.0%; C ₁₅H ₁₁NO ₂Contain C among the S, 66.9; H, 4.1; N, 5.2%; Employing is similar in the example 13 method of describing, and raw materials used is 9-phenanthryl thioacetic acid, itself be by people such as Wynberg at JACS 1967,89, method makes described in 3487.

Example 53

Adopt the similarity method of describing in the example 42; with (3-(1-hydroxyethyl) phenyl sulfo-) Nitromethane 99Min. (A) is that raw material makes (3-(1-hydroxyethyl) phenyl sulfonyl) oily matter of Nitromethane 99Min.; productive rate 87% is (with ethyl acetate/toluene (1: 10V/V) behind the silica gel chromatography purifying of wash-out); have good NMR spectrum (200MHz, CDCl ₃): 1.51(d, 3H), 2.43(S, 1H), 5.00(q, 1H), 5.64(S, 2H), and 7.55-8.00(m, 4 fragrant H), mass spectrum (chemi-ionization effect) m/e263(M+NH ₄) ⁺

Adopt method similar and described in the example 42, the thioether that makes (A) oily matter is to use the 3-(1-hydroxyethyl) the phenyl thioacetic acid makes raw material, itself is by the 1-(3-aminophenyl) ethanol, adopt to be similar to the white solid that the method described in the example 47 makes, m.p.83-84 ℃.

Example 54

With (3-(1-hydroxyethyl) phenyl sulfonyl) (1.10g, (1.45g is in methylene dichloride 6.7mmol) (10ml) suspension for the pyridinium chlorochromate of the solution adding vigorous stirring of methylene dichloride 4.5mmol) (10ml) for Nitromethane 99Min..Mixture stirred 2 hours.Add ethyl acetate (100ml) back decantation solvent.Wash black residue twice with ethyl acetate.The solution of extract and decantation closes And, and recycle silicon acid magnesium (" Florisil " (trade mark)) filters.Evaporating solvent.Residual yellow solid can make (3-acetyl phenyl sulfonyl) Nitromethane 99Min. solid (0.67g) after using the toluene recrystallization, and m.p.99-100 ℃, trace analysis is found: C, 44.7; H, 3.8; N, 5.7; C ₉H ₉NO ₅Contain among the S: C, 44.4; H, 3.2; N, 5.8%.

Example 55

Adopt the similar approach of describing in the example 20, obtained the solid of (pentamethyl-phenyl alkylsulfonyl) Nitromethane 99Min., m.p.140-147 ℃; ((2: MPLC purifying 1V/V)), trace analysis is found: C, 53.4 with dichloromethane/hexane; H, 6.5; N, 5.2%; C ₁₂H ₁₇O ₄N ₅Contain among the S: C, 53.1; H, 6.3; N, 5.2%; Productive rate is 10.5%, raw material be (pentamethyl-phenyl sulfinyl) Nitromethane 99Min. (itself with behind the ethyl acetate/hexane recrystallization with solids constituent from, have good NMR spectrum (200MHz, CDCl ₃); 2.15-2.25(m, 9H), 2.5-2.63(m, 6H), 5.35-5.83(q, 2H)).Productive rate is 79%, starts from (pentamethyl-phenyl sulfo-) Nitromethane 99Min. (A)).Thioether (A) starts from pentamethyl-phenyl thioacetic acid, and is separated with the oily body, has good NMR spectrum (200MHz, CDCl ₃); 2.1-2.2(S, 9H), 2.4-2.5(m, 6H), and 5.55(S, 2H), (with behind the silica gel chromatography purifying of hexane) adopts the example 13 described methods that are similar to.

It is as follows that the necessary thioacetic acid of general formula VII makes method:

Under argon atmospher, the solution of the ether (235ml) of 1M lithium aluminium hydride is splashed into the pentamethylbenzene SULPHURYL CHLORIDE of stirring, and (25g is in the solution of anhydrous diethyl ether 101.4mmol) (300ml).When interpolation finished, with reaction mixture reflux 4 hours, postcooling was to room temperature.Drip water and stop to discharge until gas, sulfuric acid (150ml) aqueous solution of adding 10% is with the dissolving lithium salts.Add toluene (200ml), separate organic phase, water, salt water washing, dry again (MgSO ₄).Stir add down 1N sodium hydroxide (101.4ml, 101.4mmol) solution, add subsequently sodium chloroacetate (11.8g, 101.4mmol).Stirred the mixture 24 hours.Again reaction mixture is poured in the water into (1 liter) and used the 2M hcl acidifying.Aqueous solution ethyl acetate extraction.Extraction liquid closes And, water, salt water washing, dry again (MgSO ₄).After removing and desolvate, evaporation obtains the cream-colored solid (16g) of pentamethyl-phenyl thioacetic acid; Trace analysis is found: C, 65.5; H, 7.6%; C ₁₃H ₁₈O ₂Contain among the S: C, 65.55; H, 7.56%.

Example 56

Under 0 ℃ with m-chloro peroxybenzoic acid (80-85%; 1.27g) some parts of addings of branch 2-methyl-2-(4-(nitro methyl sulfo-) phenyl) 1, in 3-dioxolane (A) chloroform (10ml) solution (2.7g).3 hours after-filtration of mixture, limpid filtrate is with 20% sodium metabisulfite (2 * 15ml) solution washings.Dry organic phase and evaporation remove to desolvate and obtain white solid.This solid is dissolved in ethanol (5ml), adds 2M hydrochloric acid (2ml) again.Solution stirring concentrated under vacuum after 3 hours.(2 * 10ml) extractions are closed And solvent and evaporation except that desolvating with chloroform behind the residue dilute with water.Resulting white solid is behind the silica gel chromatography purifying of ethyl acetate/hexane (1: 4 V/V) wash-out, can make (4-acetyl phenyl sulfonyl) Nitromethane 99Min. solid (180mg), m.p.94-95 ℃ (with methanol (2: 1V/V) recrystallization); Trace analysis is found: C, 44.8; H, 3.7; N, 5.3%; C ₉H ₉NO ₅Contain among the S: C, 44.4; H, 3.7; N, 5.8%.

The method that makes starting material (A) is as follows:

(ⅰ) with 4-acetylphenyl thioacetic acid (8.4g; 40mmol) (press Walker and Leib at J.Org.Chem.1963; 28; the method of describing among the 3077-3082 makes), 1; 2-ethylidene glycol (4.96g; 80mmol) and benzene (80ml) solution of the p-toluenesulphonic acids of catalytic amount reflux 16 hours on Dean and Stark device, collect water (1.5ml, 80mmol).Evaporation obtains oily matter except that desolvating.Add ethanol (30ml) and 2N sodium hydroxide (1 equivalent), mixture stirred 1 hour, concentrated under vacuum.It is 80ml that residue is diluted with water to volume.Add ether (50ml), mixture cools off vigorous stirring in ice.Adding 10% aqueous citric acid solution makes PH reach 6.5.(20 * 50ml) extract this mixture with ether.Drying is closed behind the extract of And evaporation and is removed and desolvate, and can obtain a kind of white solid, adds water in solid, the restir mixture.Solid collected by filtration and vacuum-drying on Vanadium Pentoxide in FLAKES.Obtain the 4-(2-methyl isophthalic acid, 3-dioxolane-2-yl) solid (5.2g, productive rate are 51%) of phenyl thioacetic acid (B); NMR composes (200MHz, d ₆DMSO): 1.49(S, 3H), 3.62(m, 2H), 3.72(S, 2H), 3.9(m, 2H), 7.25(m, 4H).

(ⅱ) in-70 ℃ argon gas, by hexane (9.23ml with the 1.6M butyllithium, 15mmol) solution is added to Diisopropylamine (2.07ml, in the stirred solution of dry tetrahydrofuran 15mmol) (10ml) and prepare the solution of LDA, this solution is put-70 ℃ and was kept 30 minutes.Keeping splashing into B(1.5g, tetrahydrofuran solution 5.9mmol) under-70 ℃ of temperature.This mixture place-70 ℃ 1 hour, heat afterwards to-40 ℃.(2.37ml, 17.7mmol), mixture kept 1 hour on this temperature again, was warming up to room temperature with the time chien shih mixture more than 90 minutes then to add down slowly isoamyl nitrates at-40 ℃.Reaction mixture is poured in the stirring the mixture of ether (150ml) and water (150ml).Carefully add 10% aqueous citric acid solution so that PH reaches 6.5 to 7.0.1 after hour, separate the ether phase, dry (Na ₂SO ₄), revaporization removes and desolvates, and obtains 2-methyl-2-(4-(nitro methyl sulfo-) phenyl)-1,3-dioxolane (A) oily matter (2.7g), it has good NMR spectrum.

Example 57

Adopt the similar approach of describing in the example 13, make (2-isopropyl phenyl alkylsulfonyl) Nitromethane 99Min. solid, m.p.113-114 ℃, productive rate is 28%; (with the MPLC purifying of methylene dichloride); Trace analysis is found: C, 49.3; H, 5.3; N, 5.8%; C ₁₀H ₁₃NO ₄Contain among the S: C, 49.4; H, 5.4; N, 5.8%; Initiator is that (itself separates as oily matter with behind the MPLC purifying of methylene dichloride (2-isopropyl phenyl sulfo-) Nitromethane 99Min., has good NMR spectrum (200MHz, CDCl ₃): 1.25(d, 6H), and 3.57(Septet, 1H), 5.41(S, 1H), 7.11-7.50(m, 4 fragrant H)).Initial thioether itself makes with 2-isopropyl phenyl thioacetic acid, and this organic acid is obtained by 2-isopropyl benzene mercaptan, and both all adopt the similar approach described in the example 13.

Example 58

Adopt the similarity method of describing in the example 20, make the solid of (2,3,5,6-tetrafluoro phenyl sulfonyl) Nitromethane 99Min., m.p.86-87 ℃; (with ethyl acetate/hexane (1: silica gel chromatography purifying 7V/V)); Trace analysis is found: C, 31.1; H, 1.2; N, 5.0%; C ₇H ₃F ₄NO ₄Contain among the S: C, 30.8; H, 1.1; N, 5.1%; Productive rate 19%, starting material are (2,3,5,6-tetrafluoro phenyl sulfinyl) Nitromethane 99Min..Itself be with the crystalline solids constituent from, m.p.116-117 ℃; (developing purifying) with hexane; Trace analysis is found: C, 33.0; H, 1.3; N, 5.2%; C ₇H ₃F ₄NO ₃Contain among the S: C, 32.7; H, 1.2; N, 5.4%; Productive rate is 63%; Starting material is (2,3,5,6-tetrafluoro phenyl sulfo-) Nitromethane 99Min. (A).

Initial thioether oily body is with 2,3,5, and 6-tetrafluoro phenyl thioacetic acid makes as raw material, and it has good NMR spectrum (200MHz, CDCl ₃): 5.46(S, 2H), and 7.11-7.30(m, 1H), and above-mentioned acetogenin is with 2,3,5, and 6-tetra fluoro benzene mercaptan is raw material, and both all adopt the method that is similar to described in the example 13.

Example 59

Use is similar to the method described in the example 20,, makes (7-chloro-1-naphthyl alkylsulfonyl) Nitromethane 99Min. solid behind the re-crystallizing in ethyl acetate purifying, m.p.136-138 ℃, good NMR spectrum (200MHz, CDCl is arranged ₃), 5.76(S, 2H), 7.65(d; 1H), 7.67(d, 1H); 7.99(d, 1H), 8.24(d; 1H), 8.39(d, 1H); 8.64(S 1H), productive rate is 27%; starting material is that (itself is behind the ethyl acetate/hexane recrystallization purifying, and isolating solid has good NMR spectrum (200MHZ, d for (7-chloro-1-naphthyl sulfinyl) Nitromethane 99Min. ₆-DMSO) 5.97(d, 1H), 6.26(d, 1H), 7.65-8.33(m, 6 fragrant H); Productive rate is 35%, and starting material is (7-chloro-1-naphthyl sulfo-) Nitromethane 99Min. (A).Initial thioether (A) is to adopt the oily matter that is similar to example 13 described methods and makes (with ethyl acetate/hexane (1: behind MPLC purifying 10V/V)), to originate in 7-chloro-1-naphthyl thioacetic acid.

Example 60

Hereinafter will explain the treatment that is used for the people or prevent the representational drug dose type that contains a kind of compound of general formula 1; or its non-toxic salt (hereinafter claiming " compounds X "); (for example; above illustrational a kind of new compound or known compound (4-bromo-phenyl sulfonyl) Nitromethane 99Min., or its non-toxic salt) :-

(a) tablet I mg/ sheet

Compounds X 100

Lactose Ph.Eur 182.75

Croscarmellose sodium 12.0

Corn starch paste (5%W/V paste) 2.25

Magnesium Stearate 3.0

(b) tablet II mg/ sheet

Compounds X 50

Lactose Ph.Eur 223.75

Croscarmellose sodium 6.0

W-Gum 15.0

Polyvinylpyrrolidone (5%W/V paste) 2.25

Magnesium Stearate 3.0

(c) tablet III mg/ sheet

Compounds X 1.0

Lactose Ph.Eur 93.25

Croscarmellose sodium 4.0

Corn starch paste (5%W/V paste) 0.75

Magnesium Stearate 1.0

(d) capsule mg/ capsule

Compounds X 10

Lactose Pr.Bur 488.5

Magnesium Stearate 1.5

(e) agent I (50mg/ml) is penetrated on a left side

Compounds X 5.0%W/V

1M sodium hydroxide solution 15.0%V/V

0.1M hydrochloric acid (regulating PH to 7.6)

Poly(oxyethylene glycol) 400 4.5%W/V

Water for injection to 100%

(f) injection II (10mg/ml)

Compounds X 1.0%W/V

Sodium phosphate EP 3.6%W/V

0.1M sodium hydroxide solution 15.0%V/V

Water for injection to 100%

(g) injection III (1mg/ml is buffered to PH6)

Compounds X 0.1%W/V

Sodium phosphate BP 2.26%W/V

Citric acid 0.38%W/V

Poly(oxyethylene glycol) 400 3.5%W/V

Water for injection to 100%

Annotate

Can obtain above-mentioned prescription by known ordinary method in the pharmaceutical technology.For a kind of dressing of Cellacefate is provided, the available ordinary method of tablet (a)-(e) is enteric coated.

Chemical general formula

Ⅰ Q.SO ₂.CH ₂.NO ₂

Ⅱ X.Q.SO ₂.CH ₂.NO ₂

Ⅲ

SO ₂.CH ₂.NO ₂

Ⅳ Q.SO ^- ₂M ⁺

Ⅴ Q.SO ₂.CH ₃

Ⅵ Q.S.CH ₃

Ⅶ Q.S.CH ₂.NO ₂

Ⅷ Q.SH

Ⅸ Q.S.CH ₂CO ₂H

Ⅺ Q.S.CH（NO ₂）.CO ₂H

Claims (17)

1. A pharmaceutical composition, characterized in that it contains nitromethane of the general formula I with the structure Q·SO ₂ ·CH ₂ ·NO ₂ as an active ingredient, wherein Q is an aromatic compound with 6, 10 or 14 carbon atoms. Moiety, optionally with 1, 2, or 3 substituents, which can be arbitrarily selected from: hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, amino, alkylamino or dialkylamino with up to 6 carbon atoms, (1-6C)alkanoylamino, (1-6C)alkanoyl, (1-6C) alkyl, (2-6C) alkenyl, (3-6C) alkenyloxy, fluoro (1-4C) alkyl, (1-6C) alkoxy, fluoro (1 -4C)alkoxy, hydroxy(1-6C)alkyl, (1-4C)alkoxy(1-4C)alkyl, carbamoyl, alkyl or dialkylcarbamoyl of up to 7 carbon atoms Acyl, sulfamoyl, alkyl or dialkylsulfamoyl up to six carbon atoms, (1-6C) alkoxycarbonyl, (1-4C) alkylenedioxy, (1-6C) alkane Sulfonamide group, (1-6C) alkyl·S(O)n-[where n is zero, 1 or 2], phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and benzenesulfonamido, the last six benzene moieties optionally have halogen, (1-4C) alkyl or (1-4C) alkoxy substituents; or Q has 4 or 5 substituents, Substituents that can be arbitrarily selected from halogen, cyano, (1-6C) alkyl or (1-6C) alkoxy; but do not include compounds where Q is 2-carboxy-phenyl; or the general formula I Non-toxic salts of nitromethane, and pharmaceutically acceptable diluents or carriers. 2. The composition according to claim 1, characterized in that the group Q in the active ingredient of the general formula I is selected from phenyl, naphthyl, phenanthrenyl and anthracenyl, which are unsubstituted or have 1, 2 Or 3 substituents, these substituents can be randomly selected from: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, methylamino, ethylamino, propylamino, butylamino, dimethylamino, Diethylamino, (a) (propyl) amino, formamido, acetamido, propionyl, formyl, acetyl, propionyl, butyryl, methyl, ethyl, propyl, isopropyl, butyl Base, sec-butyl, tert-butyl, vinyl, allyl, 1-propenyl, 2-methyl-2-propenyl, allyloxy, 2-methyl-2-propenyloxy, 3-methyl-3-butenyloxy, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, methoxy, ethoxy radical, propoxy, isopropoxy, butoxy, tert-butoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, hydroxymethyl, 1 -Hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 1-methoxyethyl, 2-methoxyethyl, 3-methoxypropyl, methoxycarbonyl, ethoxycarbonyl , isopropoxycarbonyl, tert-butoxycarbonyl, methylenedioxy, ethylenedioxy, isopropylenedioxy, any of the last three groups are associated with the aromatic moiety Q Ortho-atom bonding, methanesulfonylamino, ethylsulfinylamino, butanesulfinylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl , N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-butyl Amylsulfamoyl, N, N-dimethylsulfamoyl, N, N-dipropylsulfamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl Acyl, ethylsulfonyl, phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and benzenesulfonylamido, any of the last six groups may be unsubstituted or by themselves With fluorine, chlorine, bromine, methyl, ethyl, methoxy, or ethoxy substituents; or the group Q as defined above has 4 or 5 substituents, these substituents are arbitrarily selected from fluorine, chlorine , cyano, methoxy and methyl. 3. The composition according to claim 1 or 2, characterized in that Q in the active ingredient of general formula I is phenyl or naphthyl which is unsubstituted or has 1, 2 or 3 substituents. 4. A pharmaceutical composition characterized by comprising a compound of general formula II with the structure XQSO ₂ .CH ₂ .NO ₂ , Q is benzene and X is hydrogen or methyl, fluorine, chlorine, bromine or the same The acetylamino substituent combined at the 4-position, or its non-toxic salt, and a pharmaceutically acceptable diluent or carrier. 5. A composition according to any one of the preceding claims, characterized in that the active ingredient of formula I or II is selected from (phenylsulfonyl)nitromethane, (4-bromophenylsulfonyl ) nitromethane, (4-methylphenylsulfonyl) nitromethane and their non-toxic salts. 6. A composition according to any one of the preceding claims, characterized in that the composition is in a dosage form suitable for oral, topical or parenteral administration, 7. Nitromethane of general formula I having the structure Q.SO ₂ .CH ₂ .NO ₂ , or a non-toxic salt thereof, as defined in any one of claims 1-5 above, but not including Q is unsubstituted phenyl and Q is phenyl with a 4-fluoro, 4-chloro, 4-bromo, 4-methyl, 4-vinyl, 4-acetamido or 2-carboxy substituent, and Its alkali metal salts. 8. A compound according to claim 7, characterized in that Q is: a) phenyl with a single 4-substituent selected from iodo, hydroxy, amino, methylamino, diethylamino, cyano, carbamoyl, carboxyl, methoxycarbonyl, hydroxymethyl, 1-hydroxyethyl, acetyl, ethyl, propyl, isopropyl, tert-butyl, hexyl, methoxy, ethoxy, butoxy, allyloxy, phenoxy, benzyloxy , formamido, N,N-dimethylformamido, butyrylamino, benzamido, methylthio, methylsulfinyl, methylsulfonyl and N,N-diethylsulfamoyl ; b) phenyl with a single substituent at position 3 selected from fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, trifluoromethoxy, acetyl, hydroxymethyl and 1-hydroxyethyl; c) phenyl with a single 2-substituent selected from methyl, ethyl, isopropyl, fluorine and chlorine; d) phenyl with two substituents, optionally selected from fluorine, chlorine, methyl, trifluoromethyl, methoxy and acetamido, or with a single methylenedioxy substituent; e) phenyl has three substituents, which can be arbitrarily selected from fluorine, chlorine, methyl and acetamido; f) phenyl with 4 or 5 fluoro or methyl substituents; or g) Naphthyl or phenanthrenyl optionally bears one or two substituents, optionally selected from fluoro, chloro, methyl and methoxy substituents. 9. Nitromethane of general formula III

In the formula, ^X1 is halogen, (1-6C) alkyl, (1-6C) alkoxy, (3-6C) alkenyloxy, hydroxyl, cyano, hydroxy-(1-6C) alkyl or fluorine -(1-4C)alkyl; ^X2 is hydrogen or part of a group in ^X1 , and ^X3 is hydrogen or one of the substituents on Q as defined in claims 1-5, 7 or 8 , if X ¹ is 4-fluoro, 4-chloro, 4-bromo, 4-methyl or 2-carboxy, X ² and X ³ cannot all be hydrogen; and non-toxic salts thereof. 10. A compound of general formula I, characterized in that Q is naphthyl, phenanthrenyl or anthracenyl, these groups are unsubstituted or carry up to 3 groups selected from the pair ^X1 , X in claim 9 above ² and a substituent defined by X ³ ; and nontoxic salts thereof. 11. A compound according to claim 9 or 10, characterized in that ^X1 is halogen or (1-4C)alkyl, ^X2 is hydrogen or (1-4C)alkyl and ^X3 is hydrogen, halogen or (1-4C)alkyl. 12. A compound of general formula I selected from the group consisting of: (1-naphthylsulfonyl)nitromethane; (2,4,6-Trimethylphenylsulfonyl)nitromethane, (3-Chlorophenylsulfonyl)nitromethane, (3,4-Dichlorophenylsulfonyl)nitromethane, (2-Methylphenylsulfonyl)nitromethane, (2,6-Dimethylphenylsulfonyl)nitromethane, (4-Chloro-2,5-dimethylphenylsulfonyl)nitromethane, (2-Chloro-3-methylphenylsulfonyl)nitromethane, (3-Chloro-2-methylphenylsulfonyl)nitromethane, (3-Chloro-4-fluorophenylsulfonyl)nitromethane, and their non-toxic salts. 13. A non-toxic salt according to any one of claims 7-12, characterized in that it is a pharmaceutically acceptable salt selected from alkali metal, alkaline earth metal, ammonium and aluminum salts, and having Salts of organic bases which provide physiologically acceptable cations, and for those compounds of formula I containing alkylamino or dialkylamino substituents on Q, additionally, physiologically acceptable Acid addition salts with hydrogen halides, sulfuric acid, phosphoric acid, citric acid and maleic acid. 14. A method for producing the compound of general formula I according to claim 7, characterized in that: a) In the presence of an alkali metal (1-6C) alkoxide, the general formula is Q.SO ^- ₂ M ⁺ where M ⁺ is an alkali metal cation of an alkali metal sulfinate (IV) with nitromethane and iodine reaction; b) in the presence of a strong base, the sulfone (V) of the general formula Q.SO ₂ .CH ₃ reacts with (1-5C) alkyl nitrate; c) oxidation of sulfides (VII) of general _{formula QSCH2.NO2} ; or d) Removal of the protecting group from a compound of general formula I which has a hydroxy, amino, ketone or carboxyl group which has been protected by a suitable protecting group in Q. In addition, depending on the desired nature of the substituents on Q, one of the following functional group interconversions can optionally be performed: (1) When alkanoylamino or benzylamino is required, in the presence of a base, the amino group on Q is mixed with an acylating agent, such as alkanoyl chloride or benzoic acid chloride, or mixed alkanoic acid or benzoic acid Anhydride reaction; (2) When an amino group is needed, the alkanoylamino group on Q is hydrolyzed with a strong acid or base; (3) When a carboxylate or amide is required, condense the carboxyl group (or the corresponding carbonyl chloride or carbonyl bromide) on Q with a suitable alkanol, benzyl alcohol or amine in the presence of a suitable condensing agent; (4) When a carboxyl group is desired, react the bromine or iodine group on Q with a lithium reagent followed by carbon dioxide; (5) When a methylamino group is required, the formamide group on Q is reacted with a suitable reducing agent; (6) When a hydroxymethyl group is required, the carboxyl group (or the corresponding alkyl or benzyl ester) on Q is reacted with a suitable reducing agent; (7) When a cyano group is required, react the carbamoyl group on Q with a suitable dehydrating agent (8) reacting a methylthio group (or alternatively a methylsulfinyl group when an alkylsulfonyl group is desired) with a suitable oxidizing agent when an alkylsulfinyl or alkylsulfonyl group is desired; (9) When a keto group is desired, react the corresponding hydroxyalkyl group on Q with a suitable oxidizing agent; or (10) When an alkylamino or dialkylamino group is desired, the amino group on Q is reductively alkylated; and In addition, when a non-toxic salt is required, it is necessary to react the compound of general formula I with a suitable base having a non-toxic cation, and, when Q contains a basic alkylamino or dialkylamino group and is non-toxic, an acid - In addition salts, the compounds of general formula I are reacted with a suitable acid having a non-toxic anion. 15. A novel thioether (VII) of _the general formula _QSCH2.NO2 , wherein Q has the full meaning defined in claim 1. 16. A nitromethane of the general formula I as defined in claim 1 for use in medicine. 17. Use of compounds of general formula I as defined in claim 1 for the production of novel medicaments.