GB2227746A - Nitromethane derivatives - Google Patents

Nitromethane derivatives Download PDF

Info

Publication number
GB2227746A
GB2227746A GB9002390A GB9002390A GB2227746A GB 2227746 A GB2227746 A GB 2227746A GB 9002390 A GB9002390 A GB 9002390A GB 9002390 A GB9002390 A GB 9002390A GB 2227746 A GB2227746 A GB 2227746A
Authority
GB
United Kingdom
Prior art keywords
formula
alkyl
compound
substituents
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
GB9002390A
Other versions
GB9002390D0 (en
GB2227746B (en
Inventor
Keith Blakeney Mallion
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Imperial Chemical Industries Ltd
Original Assignee
Imperial Chemical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Imperial Chemical Industries Ltd filed Critical Imperial Chemical Industries Ltd
Publication of GB9002390D0 publication Critical patent/GB9002390D0/en
Publication of GB2227746A publication Critical patent/GB2227746A/en
Application granted granted Critical
Publication of GB2227746B publication Critical patent/GB2227746B/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62Benzothiazoles
    • C07D277/68Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/70Sulfur atoms
    • C07D277/74Sulfur atoms substituted by carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D231/00Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56Benzopyrazoles; Hydrogenated benzopyrazoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26Oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36Sulfur atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Pharmaceutically useful heterocyclic nitromethane derivatives of the formula: Q.SO2.CH2.NO2 (I) in which Q is a mono- or di-cyclic heteroaromatic moiety of 5 or 9 ring atoms containing a 5-membered heterocyclic ring having 2 heteroatoms, one of which is nitrogen and the other of which is oxygen, sulphur or nitrogen. The heteroaromatic ring Q is typically oxazolyl, thiazolyl, imidazolyl, benzimidazolyl or indazolyl and may bear up to 3 substituents as defined herein. The nitromethane derivatives (I) are inhibitors of the enzyme aldose reductase and are of value, for example, in the treatment of peripheral affects of diabetes and galactosemia. Precursors of the above compounds are of the formula Q-SO2H or salts thereof.

Description

NITROKETHANE DERIVATIVES This invention concerns novel heterocyclic nitromethane derivatives which are inhibitors of the enzyme aldose reductase and which are of value, for example, in the treatment of certain peripheral effects of diabetes or galactosemia. A method of treating one or more of such peripheral effects using a heterocyclic nitromethane derivative and pharmaceutical compositions containing such a derivative are also provided. In addition the invention concerns novel processes for the manufacture of the said novel derivatives and for the preparation of medicaments containing any of the nitromethane derivatives.
The enzyme aldose reductase is responsible for the catalytic conversion of aldoses, such as glucose and galactose, to the corresponding alditols, such as sorbitol and galactitol respectively, in warm blooded animals such as man. Alditols penetrate cell membranes poorly and, once formed, tend to be removed only by further metabolism. Consequently, alditols tend to accumulate within cells where they are formed, causing a rise in internal osmotic pressure which may in turn be sufficient to destroy or impair the function of the cells themselves. In addition, raised alditol levels may result in abnormal levels of their metabolites which may themselves impair or damage cellular function. The enzyme aldose reductase has a relatively low substrate affinity and is generally only effective in the presence of relatively large concentrations of aldose.Such large concentrations are present in the clinical conditions of diabetes (excessive glucose) and galactosemia (excessive galactose).
onsequently, aldose rezloctase iIji.ibi'is are useful in the reduction or prevention of the development of those peripheral effects of diabetes or galactosemia which may be due in part to the accumulation of sorbitol or galactitol, respectively, in tissues such as the eye, nerve and kidney. Such peripheral effects include, for example, macular oedema, cataract, retinopathy, neuropathy and impaired neural conduction.
Although a number of aldose reductase inhibitors have been discovered and clinically evaluated, there is a continuing need for alternative inhibitors. The present invention is based in part on this need and on our discovery of the unexpected inhibition of the enzyme aldose reductase by certain heterocyclic nitromethane derivatives.
According to the invention there is provided a novel nitromethane derivative of the formula Q.S02.CH2.N02 (formula I set out hereinafter) wherein Q is a mono- or di-cyclic heteroaromatic moiety of 5 or 9 ring atoms, containing a 5-membered heterocyclic ring having two heteroatoms, one of which is nitrogen and the other of which is oxygen, sulphur or nitrogen, the latter being unsubstituted or bearing an (1-4C)alkyl or phenyl(1-4C)alkyl substituent, the benzene ring of the latter being optionally substituted by 1 or 2 substituents independently selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy; and said moiety Q optionally bears up to three substituents independently selected from: halogeno, (1-6C)alkanoyl, (1-6C)alkyl, (2-6C)alkenyl, (3-6C)alkenyloxy, (1-6C)alkoxy and groups of the formula -S(O)n.R (in which n is zero or the integer 1 or 2 and R is (l-4C)alkyl), and from phenyl and benzyl substituents, the benzene ring of which last two substituents may itself optionally bear 1 or 2 substituents independently selected from halogeno, (l-4C)alkyl and (l-4C)alkoxy substituents; or a non-toxic salt thereof.
In this specification the term 1,alkyl" includes both straight and branched alkyl groups but references to individual alkyl groups such as "propyl" are specific for the straight chain ("normal") version only, any branched chain isomer such as "isopropyl" being referred to specifically. An analogous convention applies to other generic terms.
It is to be understood that, insofar as certain of the compounds of formula I defined above may exist in optically active or racemic forms by virtue of one or more substituents containing an asymmetrically substituted atom, the invention includes in its definition of active ingredient any such optically active or racemic form which possesses the property of inhibiting the enzyme aldose reductase. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, inhibitory properties against aldose reductase may be evaluated using the standard laboratory tests deferred to hereintet.
Particular values for the heteroaromatic moiety Q include, for example, oxazolyl, thiazolyl, benzoxazolyl, benzothiazolyl, imidazolyl, benzimidazolyl and indazolyl, a ring nitrogen atom in which latter three values being unsubstituted or bearing an (1-4C)alkyl or phenyl(l-4C)alkyl substituent on one of the ring nitrogen atoms therein, the benzene ring of the latter substituent being optionally substituted by 1 or 2 substituents independently selected from halogeno, (1-4C)alkyl and (l-4C)alkoxy substituents.
Specific values for the (1-4C)alkyl and phenyl(1-4C)alkyl substituents on a ring nitrogen atom of the heteroaromatic moiety Q include the following, by way of example:for (l-4C)alkyl: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and t-butyl; for phenyl(l-4C)alkyl: phenylmethyl, 1-phenylethyl, 2-phenylethyl, and 3-phenylpropyl, the benzene ring of which latter four compounds optionally bearing 1 or 2 substituents independently selected from fluoro, chloro, bromo, methyl, ethyl, methoxy and ethoxy.
Specific values for optional substituents on the heteroaromatic moiety Q include the following, by way of example:for halogeno: fluoro, chloro, bromo and iodo; for (l-6C)alkanoyl: formyl and (2-4C)alkanoyl, such as acetyl, propionyl and butyryl; for (1-6C)alkyl: (l-4C)alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and t-butyl; for (2-6C)alkenyl: (2-4C)alkenyl, such as vinyl, allyl, 1-propenyl and 2-methyl-2-propenyl; for 6 3-6C;alkenyol:y: ailyloxy, 2-methvl--2-propenylcxy and 3-methyl- butenyloxy; for (1-6C)alkoxy: (1-4C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy; for a group of the formula -S(O)n.R as defined above: methylthio, ethylthio, propylthio, butylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl and ethylsulphonyl; and for phenyl or benzyl optionally bearing halogeno, (l-4C)alkyl or (14C)alkoxy substituents: phenyl or benzyl optionally bearing 1 or 2 substituents independently selected from fluoro, chloro, bromo, methyl, ethyl, methoxy and ethoxy.
A preferred value for Q is, for example, thiazolyl and benzothiazolyl.
One particular group of novel compounds of the invention of particular interest comprises compounds of the formula II (set out hereinafter) wherein X is selected from hydrogen, halogeno, (16C)alkyl, (1-6C)alkoxy, (3-6C)alkenyloxy; and X1 is hydrogen or one of the values defined hereinabove for an optional substituent on Q; or X and X together form a benzene ring which bears 1 or 2 optional substituents selected from any of the values defined hereinabove; together with the non-toxic salts thereof.
A novel compound of particular interest is described in Example 1 hereafter, which is provided, together with its non-toxic salts, as a further feature of the invention.
The invention further comprises pharmaceutical compositions comprising a compound of the formula I or a non-toxic salt thereof, defined above, together with a pharmaceutically acceptable diluent or carrier. The compositions of the invention may be in various conventional forms. Thus, they may be in a form suitable for oral use (for example as-tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels or aqueous or oily solutions or suspensions) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intravascular dosing) or as a suppository for rectal dosing.
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as gelatin or starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl -hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as arachis oil, liquid paraffin or olive oil.
Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyetnylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agzrltsS fla-e,uring -.g ntst anc1/ur sweetening agents tsucll ss sucrose, saccharin or aspartame).
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, or esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents.
Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedures well known in the art. Topical formulations for administration to the eye will generally be in the form of an ointment, gel or sterile solution buffered at an ophthalmically acceptable pH, for example in the range pH 7.0-7.6.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain for example from 5 mg to 1 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 5 mg to about 600 mg of an active ingredient.
Suitable non-toxic salts include, for example, pharmaceutically acceptable salts such as alkali metal (such as potassium or sodium), alkaline earth metal (such as calcium or magnesium) and ammonium salts, and salts with organic bases affording physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine and morpholine.
The novel compounds of the invention may be obtained by standard procedures of organic chemistry already known for the production of scructurally analogous compounds, for example by one or more of the procedures reviewed in the paper by Zeilstra et alia in Rec. Trav. Chim. Pays Bas 1974, 55 11-14. Sich procedures are provided as a further feature of .-he invention and are illustrated by the following procedures in which Q has any of the meanings defined hereinbefore.
(a) Reacting an alkali metal sulphinate of the formula Q.S 2 M+ (formula III) wherein M+ is an alkali metal cation and especially sodium or potassium, with nitromethane and iodine in the presence of an alkali metal (1-6C)alkoxide such as potassium t-butoxide or sodium methoxide. The reaction is preferably carried out in the presence of a suitable polar solvent, for example, dimethylformamide (which is preferred) or N-methyl-2-pyrrolidone, and at a temperature in the range, for example, -30 to 200C and, conveniently, at about OOC. The nitromethane is generally present in an excess.
The alkali metal sulphinates may be obtained, for example, from the corresponding sulphinic acids of the formula Q.S02E by reaction with the appropriate alkali metal hydroxide or (l-6C)alkoxide such as sodium or potassium methoxide or ethoxide. The sulphinic acids may themselves be obtained from the corresponding sulphonyl chlorides of the formula Q.S02C1 by a conventional reduction, for example, using aqueous sodium sulphite in the presence of a suitable buffer (such as sodium hydrogen carbonate), or zinc dust and water. The sulphonyl chlorides may often be obtained by sulphonation of the appropriate compound of the formula Q.H to give the sulphonic acid of the formula Q.S03H which is then converted to the sulphonyl chloride, for example, by reaction with phosphorus pentachloride.Alternatively, the sulphinates of formula III may frequently be obtained, for example, by lithiation of the appropriate heterocyclic compound of the formula Q.H followed by reaction with sulphur dioxide and conversion to the required alkali metal salt as necessary, for example the sodium salt.
(b) Reacting a sulphone of the formula Q.S02.CH3 (formula IV) with a (l-SC)alkyl nitrate, such as ethyl, propyl, isopropyl or iso amyl nitrate in the presence of a strong base.
A A particularly suitable strong base is, for example, an alkali metal (1-6C)alkane such as butyllithium.
The reaction is preferably carried out in the presence of a suitable solvent or diluent, for example an ether such as tetrahydrofuran or t-butyl methyl ether, and at a temperature in the range, for example, -80 to 100C. The necessary sulphones of the formula IV may be made by standard procedures well known in the art, for example by oxidation of the corresponding methylthio compound of the formula Q.SCH3 (formula V) using analogous conditions to those described for process (c) below.
(c) Oxidising a thioether of the formula Q.S.CH2.N02 (formula VI).
Suitable oxidising agents include those which are well known in the art for the conversion of thio to sulphonyl groups and which are compatible with the presence of other sensitive functional groups which may be present as substituents on Q. Thus, for example, hydrogen peroxide, an organic peracid (such as perbenzoic acid) or lead tetraacetate may be used. Alternatively an alkali metal periodate (such as sodium metaperiodate), persulphate (such as potassium monopersulphate) or permanganate (such as potassium permanganate), or gaseous oxygen in the presence of a suitable catalyst such as platinum, may be employed. The oxidation is preferably carried out in a suitable conventional solvent or diluent for such oxidations, for example in acetic or propionic acid, and at a temperature in the general range, for example 0 to 800C.
In certain cases, the corresponding sulphoxide derivative of the thioether of formula VI may be formed as an isolable intermediate.
The process of the invention also includes the oxidation of such a sulphoxide intermediate to a sulphone of formula I, for example, by reaction with an alkali metal permanganate (such as potassium permanganate) in a suitable solvent such as aqueous acetic acid and at a temperature in the range, for example, 20 to 80 OC.
The starting thioethers of formula VI may be obtained by conventional procedures of organic chemistry, for example, from a potassium or sodium salt of the corresponding thiols of the formula Q.SH (formula VII) by conversion to the corresponding thioacetic acids of the formula 0.S.CH2.CO2H (formula VIII) (or a (l-4C)alkyl ester thereof, such as a methyl or ethyl ester) by reaction with chloro- or bromo-acetic acid (or a (1-4C)alkyl ester thereof) in the presence of a suitable base. The acid VIII (or a (1-4C)alkyl ester thereof) is then reacted with an alkali metal (l-6C)alkane and a (1-5C)alkyl nitrate, for example butyllithium and isopropyl nitrate, under similar conditions to those used for profess (b! above, to give the alkali petal sale of Be cwrrespondlng 2 nitLoaXe.lc acid of the formula Q.S.CH(N02).C02E (formula IX) (or of the (l-4C)alkyl ester thereof).
The acids of formula IX are unstable and readily decarboxylate.
Acidification of the alkali metal salt of an acid of formula IX allows the isolation of a thioether of formula VI. An ester of an acid of formula IX may be hydrolysed, for example, using aqueous base, to the acid of formula IX and then acidified to produce a thioether of formula VI. The esters of the acids of formula VIII may also conveniently be obtained by reacting the appropriate (1- 4C)alkyl nitroacetate with the required sulphenyl chloride of the formula Q.SCl (formula XI) in the presence of a base such as potassium fluoride.
The thiols of formula VII may be obtained by conventional procedures of heterocyclic chemistry.
Thioethers of formula VI may also be conveniently obtained using a procedure such as is described in our co-pending applications.
It will be appreciated that in the formula I compounds of the invention Q may bear a wide variety of reactive substituents.
Accordingly, it may be necessary to protect one or more such reactive substituents in a conventional manner at some stage prior to carrying out one of the above procedures (a)-(c) and then to remove the protecting group as a final step. Thus, for example, a ketone group may be protected as its ketal (for example as its ketal with 1,2-ethanediol). The appropriate protecting groups and the procedures necessary for the protection and deprotection of reactive substituents are well described in standard text-books of organic chemistry.
Accordingly, the invention also includes a development of one of the processes (a), (b) or (c) for the production of a compound of formula I, as defined hereinbefore, which is characterised by using a starting material of the formula III, IV or VI, respectively, in which one or more of any reactive substituents present as substituents on Q (such as a ketone) have been protected with appropriate protecting groups, and carrying out the appropriate removal of the protecting group as a final step.
Whereafter, when a compound in which Q bears a halogeno substituent is required, it may be obtained, for example, by using a direct halogenation procedure well known in the art, for example bromination in acetic acid at a temperature in the general range 0-400C.
Whereafter, when a non-toxic salt is required, for example, a compound of formula I may be reacted with an appropriate base having a physiologically accetable cation.
Many of the starting materials referred to herein are novel, for example, the sulphinic acids of formula 0.SO2H, the thioethers of formula VI and the sulphoxides of such thioethers, and are provided as a further feature of the invention.
As stated previously, the compounds of formula I inhibit the enzyme aldose reductase. The compounds are thus of value, for example, in treating those diseases or conditions which are caused by excessive quantities of the products such as sorbitol formed in the body by processes catalysed by the enzyme aldose reductase.
The property of inhibiting the enzyme aldose reductase in vivo may be demonstrated in the following standard laboratory test: Rats are made diabetic (as evidenced by severe glucosuria being present) by dosing with streptozotocin. The animals are then dosed daily with the test compound for one, two or five days. The animals are then sacrificed 2-6 hours after the final dose and the eye lenses and/or sciatic nerves are removed. After a standard work-up procedure the residual sorbitol levels in each tissue are determined by gas liquid chromatography after conversion to the polytrimethylsilyl derivatives. Inhibition of aldose reductase in vivo can then be assessed by comparing the residual sorbitol levels in tissues from the dosed diabetic group of rats with those of an undosed group of diabetic rats and an undosed, normal group of rats.
The property of inhibiting the enzyme aldose reductase may also be demonstrated in vitro. Thus, in a standard procedure partially purified aldose reductase is isolated in known manner from bovine lenses. The percentage inhibition of this enzyme's ability in vitro to catalyse the reduction of aldoses to polyhydric alcohols, and particularly to reduce glucose to sorbitol, caused by a test compound can then be determined using standard spectrophotometric methods.
By way of illustration of the aldose reductase inhibitory properties of compounds of formula I, the compound of Example 1 had an IC50 of 6.2 x 10 8M in the above in vitro test.
In general, compounds of the formula I show significan: inhibition in the above mentioned in vivo test at a dose (generally p.o.) of 100 mg/kg or much less with no evidence of overt toxicity, and have an IC50 in the above mentioned in vitro test of 10 6M or mush less.
The compounds of formula I will primarily be administered systemically (generally by mouth) to a warm-blooded animal to produce a therapeutic or prophylactic effect mediated by inhibition of the enzyme aldose reductase, for example at a daily dose in the range of 1 to 40 mg/kg. In man it is envisaged that a total daily dose in the range 15 to 800 mg. per man will be administered, given if necessary, in divided doses. However, the precise amount of compound administered will naturally vary somewhat, for example, with the age and sex of the patient and the severity and extent of the condition being treated.
The compounds of formula I may also be administered topically, for example by topical administration direct to the tissue or organ in which inhibition of the enzyme is required, for example by topical administration to the eye. The precise amount of compound administered will necessarily depend on the formulation used. Thus, for example, when a solution is administered a concentration of the compound containing up to 0101 by weight will generally be used.
Similarly, when an ointment is administered a concentration of the compound of up to 2% by weight will generally be used. Topical formulations of compounds of formula I may be administered to the eye of an animal, for example, man or dog, requiring treatment and/or prevention of diabetic cataracts or retinopathy, in a conventional manner, for example, using a drop or eyewash topical formulation.
The compositions may also contain one or more other agents which are known to have a useful effect in the treatment of diabetes or galactosemia, for example a hypoglycaemic agent such as tolbutamide, chlorpropamide or glybenclamide.
The invention will now be illustrated by the following non-limiting Examples in which, unless otherwise stated: (i) all evaporations were carried out by rotary evaporation in vacuo.
(ii) all operations were carried out at room temperature, that is in the range 18-260C; (iii) column and flash chromatography was carried out on silica (Merck Art. 7734) and medium pressure liquid chromatography (MPLC) on silica (Merck Art. 9385), both materials available from E Merck and Co., Darmstadt, West Germany; and preparative layer chromatography (PLC) was carried out on silica coated plates (Schleicher & Scull Art.G1505/LS254), available from Schleicher & Scull, Dassel, West Germany; (iv) the purity of chemical products was assessed by nuclear magnetic resonance (NMR) spectroscopy, thin layer chromatographic analysis, mass spectroscopy and/or microanalysis; (v) NMR spectra were determined in deuterochloroform (CDCl3) at the indicated frequency and are given in delta values (parts per million) relative to tetramethylsilane as standard; conventional abbreviations for signal types are used, such as s, singlet; d, doublet; dd, doublet of doublets; br, broad; et cetera; (vi) petroleum ether (b.p. 60-800C) is referred to as "petrol 60-80 ; (vii) yields are for illustration only and are not necessarily the maximum attainable by diligent process development; and (viii) all end-products had microanalyses and NMR spectra consistent with the indicated structures.
Example 1 m-Chloroperbenzoic acid (80-85%, 2.8 g) was added in portions to a stirred solution of 2-(nitromethylthio)-4-phenylthiazole (A) (1.03 g) in dichloromethane (30 ml). An exothermic reaction occurred and the temperature rose to 400C. The mixture was stirred at ambient temperature for 23 hours and then filtered. The filtrate was purified by chromatography on silica eluting with dichloromethane to give 2-(nitromethylsulphonyl)-4-phenylthiazole as a white solid (0.23 g), m.p. 102-103 C; rafter recrystallisation from ethyl acetate/hexane (1:3 v/v)l; NMR (90 MHz): 5.99(s,2H), 7.45(m,3H), 7.88(m,3H); m/e (electron impact): 284 (M+); microanalysis, found: C,42.3; H,2.9; N,9.6%; C1oH8N204S2 requires: C,42.2; H,2.8; N,9.6%.
The starting material (A) was obtained as follows: (i) A solution of 2-mercapto-4-phenylthiazole (3.38 g) in dimethylformamide (DMF) (15 ml) was added to a stirred suspension of sodium-hydride (60% dispersion in mineral oil, 0.77 g) in DMF (15 ml).
The mixture was stirred for one hour. Methyl bromoacetate (2.92 g) was then added dropwise. The mixture was stirred for a further 30 minutes and then poured into water (50 ml) and extracted with ethyl acetate (2 x 100 ml). The combined extracts were washed with water (2 x 100 ml), dried (MgS04) and the solvent was removed by evaporation to give an orange solid. The solid was dissolved in ethanol (30 ml) and 2M sodium hydroxide solution (10 ml) was added. The mixture was stirred for 1 hour and was then acidified to pH 3 with 2M hydrochloric acid. Water (50 ml) was added and the mixture was extracted with ethyl acetate (2 x 50 ml). The combined extracts were extracted with a saturated solution of sodium bicarbonate (2 x 75 ml). The combined basic extracts were acidified with 2M hydrochloric acid. The solution was then extracted with ethyl acetate (2 x 125 ml).The combined extracts were washed with water, dried (MgS04) and the solvent was removed by evaporation to give [2-(4-phenylthiazolyl)thiolacetic acid (B) as a pale brown solid (3.03 g); NMR (90 MHz, DMSO d6): 4.1(s,2H), 7.35(m,3H), 7.85(m,3H); m/e (electron impact): 251 (M+).
(ii) A 1.5M solution of lithium diisopropylamide mono(tetrahydrofuran) in cyclohexane (20.1 ml) was added to a stirred solution of B (3.03 g) in dry tetrahydrofuran (THF) (30 ml) under argon at -700C to -60 C. The temperature was allowed to rise to -400C over 90 minutes. Iso-amyl nitrate (4.8 ml) was added slowly at -4O0C.
The reaction mixture was maintained at this temperature for 1 hour and then allowed to warm to room temperature over 16 hours. The mixture was then acidified to pH 3 with 2M hydrochloric acid and stirred for 2 1/2 hours. Water (100 ml) was added and the mixture was extracted with ethyl acetate (2 x 200 ml). The combined extracts were washed with water (2 x 200 ml), dried (MgSO4) and the solvent was removed by evaporation. The resultant oil was purified by chromatography on silica eluting with ethyl acetate/hexane (1:10 v/v) to give 2-(nitromethylthio)-4-phenylthiazole as an orange solid (1.3 g); m.p.
74-760C; NMR (90 MHz): 5.95(s,2H), 7.4(m,4H), 7.85(m,2H); m/e (chemical ionisation): 253 (M+H)+.
Example 2 m-Chloroperbenzoic acid (80-85%, 1.95 g) was added in portions to a stirred solution of 5-bromo-2-(nitromethylthio)-4phenylthiazole (A) (1.0 g) in chloroform (15 ml). The mixture was stirred at 550C for 4 hours and then allowed to cool to room temperature. The mixture was filtered and the filtrate was washed with a 20% aqueous solution of sodium metabisulphite (20 ml) and then with water (20 ml).The organic phase was purified by chromatography on silica eluting with dichloromethane to give 5-bromo-2-(nitromethylsulphonyl)-4-phenylthiazole as a white solid (0.42 g), m.p. 89-900C; [after recrystallisation from aqueous ethanol; NMR (90 MHz): 5.92(s,2H), 7.49(m,3H), 7.9(m,2H); m/e (electron impact): 362, 364 (M+); micr!analysis, found C,33.3; H,1.9; N,7.7%; C1OH7BrN204S2 requires: C,33.1; H,1.9; N,7.7%.
The starting material (A) vas obtained as follows: romine (0.71 g) in acetic acid (5 ml) was added slowly to a stirred solution of 2-(nitronethylthio)-4-phenylthiazole (1.12 g). The bromine colour was discharged immediately. The reaction mixture was added tr water (50 ml), and extracted vith dichloromethane (2 x 50 ml). The combined extracts were washed successively with water (50 ml), saturated aqueous sodium carbonate solution (50 ml), water (50 ml) and then dried (MgS04).The solvent was removed by evaporation to give 5-bromo-2-(nitromethylthio)-4-phenylthiazole (1.09 g) as an orange solid; NMR (200 MHz): 5.86 (s,2H), 7.22(m,3H), 7.88(m,2H); m/e (electron impact): 330, 332 (M+).
Example 3 Using a similar procedure to that described in Example 2, except that the oxidation was carried out for 3 hours at 550C, there was obtained 2-(nitromethylsulphonyl)thiazole as a white solid, m.p.
66-680C; lafter recrystallisation from aqueous ethanoll; NMR (90 MHz): 5.92(s,1H), 7.88(d,1H), 8.12(d,lH); m/e (electron impact): 209 (M+H)+; microanalysis, found: C,23.5; H,2.0; N,13.2; C4H4N204S2 requires: C,23.1; H,1.9; N,13.5%; in 33% yield, starting from 2-(nitromethylthio)thiazole, itself obtained as follows:- (i) Chloroacetic acid (8.9 g) was added carefully, in portions, to a stirred solution of 2-mercaptothiazole (10.0 g) in water (100 ml) containing sodium hydroxide (6.8 g). The mixture was heated for 2 hours on a steam bath, cooled, and acidified with 2M hydrochloric acid.The precipitate obtained was collected by filtration, washed with water, and dried in vacuo to give (2-thiazolylthio)acetic acid as a pale brown solid (10.5 g); NMR (90 MHz, DMSO d6): 4.0(s,2H), 7.25(d,lH), 7.62(d,1H), 10.28(brs,1H); m/e (electron impact): 176 (M+H)+, 175 (M+).
(ii) A 1.6M solution of butyllithium in hexane (79.8 ml) was added slowly to a solution of (2-thiazolylthio)acetic acid (10.15 g) in dry THF (150 ml) at -400C under argon. The mixture was maintained at -400C for 1 hour. Iso-amyl nitrate (23.3 ml) was then added slowly maintaining the temperature at -400C. After a further 1 hour at -400C, the mixture was allowed to warm gradually to ambient temperature over 16 hours. The mixture was then acidified to pH 2 with 2M hydrochloric acid, stirred for 2 hours, poured into water (150 ml) and extracted with dichloromethane (2 x 200 ml). The combined extracts were washed with a saturated solution of sodium bicarbonate (2 x 200 ml) and then extracted with aqueous 2M sodium hydroxide solution (2 x 200 ml). The latter aqueous alkali extracts were combined, acidified with 2M hydrochloric acid and extracted with dichloromethane (2 x 200 ml). The combined extracts were dried (MgS04) and the solvent was removed by evaporation. The residue was purified by chromatography on silica eluting with ethyl acetate/hexane (1:6 v/v) to give 2-(nitromethylthio)thiazole (2.3 g) as an oil, NMR (90 MHz): 5.9(s,2H), 7.38 (d,lH), 7.72(d,lH); m/e (chemical ionisation) 177 (M+H)+.
Example 4 Using a similar procedure to that described in Example 2, except that the oxidation was carried out at 580C for 16 hours, there was obtained 2-(nitromethylsulphonyl)benzothiazole as a white solid, m.p. 150-1510C; [after recrystallisation from ethanoll; NMR (90 MHz): 6.08 (s,2H), 7.65(m,2H), 8.06(m,lH), 8.25(m,1H); m/e (electron impact): 259 (M+H)+, 258 (M+); microanalysis, found:C,37.4; H,2.3; N,11.0 C8H6N204S2 requires; C,37.2; H,2.3; N,10.9%, in 135 yield, starting from (2-nitromethylthio)benzothiazole, itself obtained as an oil, NMR (90 MHz): 6.03(s,2H), 7.4(m,2H), 7.9(m,2H); m/e (electron impact): 226 (M+); using a similar procedure to that described in Example 1, starting from (2-benzothiazolylthio)acetic acid, itself obtained as a solid, NMR (90 MHz, DMSO-d6): 4.15(s,2H), 7.35(m,2H), 7.82(m,2H); m/e (chemical ionisation): 226 (M+H)+; using a similar procedure to that described in Example 3, starting from 2mercaptobenzothiazole.
Example 5 Using a similar procedure to that described in Example 2 except that the oxidation was carried out for 6 hours at 550C, there was obtained 6-ethoxy-2-(nitromethylsulphonyl)benzothiazole as a white solid m.p. 124-1250C; [after recrystallisation from ethanol; NMR (90 MHz): 1.5(t,3H), 4.15(q,2H), 6.0(s,2H), 7.25(m,2H), 8.1(d,1H); m/e (electron impact): 302 (M+); microanalysis, found: C,39.4; H,3.3; N,9.1%; C1oHloN205S2 requires:C,39.7; H,3.3; N,9.3%, in 11% yield, starting from 6-ethoxy-2-(nitrom.ethylthio)benzothiazole, itself obtained as an oil, NMR (90 MHz): 1.46(t,3H), 4.06(q,2H), 6.0(s,2H), 7.07(dd,lH); 7.2(m,1H), 7.75(d11H); mi- (electron impact): 270 (M+); starting from (6-ethoxy-2-benzothiazolylithio)acetic acid, itself obtained as a solid, NMR (200 MHz, DMSO-d6): 1.35(t,2H); 4.08(q,2H), 4.2(s,2H), 7.03(dd,lH), 7.58(d,1H), 7.72(d,1H); m/e (electron impact): 269 (M+), starting from 6-ethoxy-2-mercaptobenzothiazole, in both cases using analogous procedures to those described in Example 3.
Example 6 Nitromethane (1 ml, 18.5 mmol) was added dropwise to a solution of potassium t-butoxide (922 mg, 8.2 mmol) in redistilled dimethylformamide (DMF) (37 ml) at O C under an atmosphere of argon.
The mixture was stirred for 15 minutes and then sodium 6-indazole sulphinate (1.5 g) was added followed by iodine (1.1 g). The mixture was warmed to room temperature and allowed to stand for 12 hours. A 20% w/v solution of sodium metabisulphite (10 ml) was then added to decolourise the reaction mixture. The mixture was diluted with water (200 ml), acidified to pH 7 with 2M hydrochloric acid and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with brine (2 x 50 ml), dried (Na2S04), and the solvent was removed by evaporation to give a brown oil.The oil was purified by flash chromatography on silica (Merck kieselgel Art. 7736), eluting with dichloromethane/ethyl acetate (4:1 v/v) to give 6-(nitromethylsulphonyl)indazole as a white crystalline solid (130 mg) m.p. 167-80C (after recrystallisation from ethyl acetate/hexane); NMR (200 MHz, DMSO d6): 6.7(s,2H), 7.6-7.7(dd,1H), 8.05-8.15(d,1H), 8.2(s,lH), 8.35(s,1H); m/e (chemical ionisation): 259 (M+NH4)+; (electron impact): 241 (M+); microanalysis, found C,39.8; H,2.9; N,17.4%; C8H7N3O4S requires; C,39.8; H,2.9; N,17.4%.
The starting sulphinate salt was obtained as follows: (i) 6-Aminoindazole (13.3 g, 100 mmol) was added in one portion to a mixture of concentrated hydrochloric acid (33 ml) and acetic acid (10 ml). The mixture was cooled to -100C and a solution of sodium nitrite (7.5 g, 110 mmol) in water (11 ml) was added at such a rate that the temperature never exceeded -50C. The resultant mixture (A) was then stirred for a further 30 minutes. Acetic acid (100 ml) was saturated with sulphur dioxide. Copper (I) chloride (2.5 g, 25 mmol) was added and sulphur dioxide was passed into the solution until the yellow-green suspension became blue-green. The mixture was then cooled to 50C, and mixture A was added in three portions over 10 minutes. The mixture was warmed slowly to ambient temperature.When nitrogen evolution had ceased, the mixture was poured onto ice and the suspended solid was collected by filtration. The solid was suspended in ethyl acetate and washed with a saturated solution of sodium hydrogen carbonate. The organic layer was separated, washed with brine, dried (Na2S04) and the solvent was removed by evaporation. The residue was purified by flash chromatography on silica (Merck kieselgel Art. 7736) eluting with ethyl acetate to give 6indazolesulphonyl chloride as a white crystalline solid (3 g, 14% yield) m.p. 170 C (after recrystallisation from toluene); m/e (electron impact): 216 (M+); and vas used without further puriflcation or characterisation.
(ii) 6-Indazolesulphonyl chloride (3 g, 14 mmol) was added in portions to a stirred solution of sodium sulphite (3.3 g, 26 mmol) and sodium hydrogen carbonate (2.3 g) in water (14 ml) at 700C. The solution was stirred at this temperature for 1 hour, and then cooled to ambient temperature. The mixture was adjusted to pH 7 with 2M hydrochloric acid and the solid precipitate was collected by filtration. The solid was recrystallised from ethanol to give 6indazolesulphinic acid (1.5 g). The acid was then dissolved in methanol (20 ml) containing sodium methoxide (440 mg). After 10 minutes the methanol was removed by evaporation to give sodium 6indazolesulphinate, which was dried in vacuo and used directly without further purification or characterisation.
Example 7 Using a similar procedure to that described in Example 6, there was obtained 5-(nitromethylsulphonyl)benzimidazol-2-one in 9% yield, as a cream coloured solid, m.p. 2400C; microanalysis, found: C,37.4; H,2.9; N,16.1; C8H7N3S05 requires: C,37.4; H,2.7; N,16.3; starting from (2-oxobenzimidazol-5-yl)sulphonyl chloride, itself obtained by the procedure described in Compt. rend. Acad. bulgare des Sciences, 1974, 27(5), 663.
Example 8 The following illustrate representative pharmaceutical dosage forms containing the compound of formula I, or a non-toxic salt thereof (hereafter compound Z), for therapeutic or prophylactic use in humans: (;) Tablet I @g/tablet.
Compound Z................................... 100 Lactose Ph.Eur............................... Ph.Eur 182.75 Croscarmellose sodium........................ sodium 12.0 Maize starch paste (5D w/v paste) 2.25 Magnesium stearate........................... 3.0 (b) Tablet II mg/tablet Compound Z................................... 50.0 Lactose Ph.Eur............................... 223.75 Croscarmellose sodium........................ 6.0 Maize starch................................. 15.0 Polyvinylpyrrolidone (5% w/v paste).......... 2.25 Magnesiumstearate............................ 3.0 (c) Tablet III mg/tablet Compound Z................................... 1.0 Lactose Ph.Eur.............................. 93.25 Croscarmellose sodium....................... 4.0 Maize starch paste (5% w/v paste)........... 0.75 Magnesium stearate 1.0 (d) Capsule mg/capsule Compound Z................................ 10.0 Lactose Ph.Eur ............................ 488.5 Magnesium stearate ........................ 1.5 (e) Injection I (50 mg/ml) Compound Z................................ 5.0% w/v 1M Sodium hydroxide solution ............. 15.0% v/v 0.1M Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400................... 4.5% w/v Water for -to 100% (f) Injection II (10 mg/ml) Compound Z .............................. 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 (lmg/ml, buffered to pH6) Compound Z............................. 0.1% w/v Sodium phosphate BP ................... 2.26% w/v Citric acid ........................... 0.38% w/v Polyethylene glycol 400 ............... 3.5% w/v Water for injection to 100% Note The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
CHEMICAL FORMULAE I Q.SO2.CH2.NO2
III Q.SO2-M+ IV Q.SO2.CH3 V Q.S.CH3 VI Q.S.CH2.NO2 VII Q.SH VIII Q.S.CH2.CO2H IX Q.S.CH(NO2).CO2H XI Q.S.Cl Note: Formula X is not used

Claims (15)

  1. CLAIMS What is claimed is: 1. A novel nitromethane derivative of the formula Q.SO2.C112.NO2 (I) wherein Q is a mono- or di-cyclic heteroaromatic moiety of 5 or 9 ring atoms, containing a 5-membered heterocyclic ring having two heteroatoms, one of which is nitrogen and the other of which is oxygen, sulphur or nitrogen, the latter being unsubstituted or bearing an (l-4C)alkyl or phenyl(1-4C)alkyl substituent, the benzene ring of the latter being optionally substituted by 1 or 2 substituents independently selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy; and said moiety Q optionally bears up to three substituents independently selected from: halogeno, (1-6C)alkanoyl, (l-6C)alkyl, (2-6C)alkenyl, (3-6C)- alkenyloxy, (1-6C)alkoxy and groups of the formula -S(O)n.R (in which n is zero or the integer 1 or 2 and R is (1-4C)alkyl), and from phenyl and benzyl substituents, the benzene ring of which last two substituents may itself optionally bear 1 or 2 substituents independently selected from halogeno, (1-4C)alkyl and (l-4C)alkoxy substituents; or a non-toxic salt thereof.
  2. 2. A compound as claimed in claim 1 wherein Q optionally bears up to three substituents independently selected from: fluoro, chloro, bromo, iodo, formyl, acetyl, propionyl, butyryl, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, vinyl, allyl, 1-propenyl, 2-methyl-2-propenyl, allyloxy, 2-methyl-2-propenyloxy, 3-methyl-3-butenyloxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, methylthio, ethylthio, propylthio, butylthio, metlylsuphinyl, ethylsulphinyl, methylsulphonyl and ethylsulphonyl; and from phenyl and benzyl, themselves optionally bearing 1 or 2 substituents independently selected from fluoro, chloro, bromo, methyl, ethyl, methoxy and ethoxy.
  3. 3. A compound as claimed in claim 1 or 2 wherein Q is selected from oxazolyl, thiazolyl, benzoxazolyl, benzothiazolyl, imidazolyl, benzimidazolyl and indazolyl, a ring nitrogen atom in which latter three being unsubstituted or bearing an (1-4C)alkyl or phenyl(l-4C)alkyl substituent on one of the ring nitrogen atoms therein, the benzene ring of the latter substituent being optionally substituted by 1 or 2 substituents independently selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy substituents.
  4. 4. A compound as claimed in claim 1, 2 or 3 wherein when the second heteroatom in Q is nitrogen bearing a substituent, that substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, phenylmethyl, 1-phenylethyl, 2-phenylethyl and 3-phenylpropyl, the benzene ring of which latter four compounds may optionally bear 1 or 2 substituents independently selected from fluoro, chloro, bromo, methyl, ethyl, methoxy and ethoxy.
  5. 5. A compound as claimed in claim 1,2 or 3 wherein Q is thiazolyl or benzothiazolyl.
  6. 6. A compound of the formula:
    wherein X is selected from hydrogen, halogeno, (1-6C)alkyl, (l-6C)alkoxy, (3-6C)alkenyloxy; and X1 is hydrogen or one of the values for an optional substituent on the heteroaromatic moiety Q defined in claim 1 or 2; or X1 and X together form a benzene ring which bears 1 or 2 optional substituents selected from any of the values for an optional substituent on the heteroaromatic moiety Q defined in claim 1 or 2; or a non-toxic salt thereof.
  7. 7. The compound 2-(nitromethylsulphonyl)-4-phenylthiazole, or non-toxic salt thereof.
  8. 8. A salt as claimed in any one preceding claim which is a pharmaceutically acceptable salt selected from alkali metal, alkaline earth metal and ammonium salts, and from salts with bases affording a physiologically acceptable cation.
  9. 9. A pharmaceutical composition comprising a compound of the formula I, or a non-toxic salt thereof, as defined in any one preceding claim, together with a pharmaceutically acceptable diluent or carrier.
  10. 10. A process for the manufacture of a compound of the formula I, or a non-toxic salt thereof, wherein Q has any of the meanings defined in any of claims 1-6, which comprises: (a) reacting an alkali metal sulphinate of the formula 0.502 M+ (III), wherein M+ is an alkali metal cation with nitromethane and iodine in the presence of an alkali metal (1-6C)alkoxide; (b) reacting a sulphone of the formula Q.S02.CH3 (IV) with a (1-5C)alkyl nitrate in the presence of a strong base; or (c) oxidising a thioether of the formula Q.S.CH2.N02 (VI) or the sulphoxide thereof; whereafter, when a non-toxic salt is required, the ccmpound of formula I is reacted with the appropriate base having a non-toxic cation.
  11. 11. A sulphinic acid of the formula Q.S02E or a salt thereof wherein Q has any of the values defined in any of claims 1-4.
  12. 12. A thioether of the formula Q.S.CH2.N02 (VI) or the sulphoxide thereof wherein Q has any of the values defined in any of claims 1-4.
  13. 13. A compound of the formula I, or a non-toxic salc thereof, in which Q has any of the values set out in any of claims 1-4, substantially as described herein with reference to any one of Examples 1-7.
  14. 14. A process for the manufacture of a compound of the formula I, or a non-toxic salt thereof, in which Q has any of the values set out in any of claims 1-4, substantially as described herein with reference to any one of Examples 1-7.
  15. 15. A pharmaceutical composition comprising as active ingredient a compound of the formula I, or a non-toxic salt thereof, in which Q has any of the values set out in any of claims 1-4, substantially as described in any part of Example 8 hereof.
GB9002390A 1989-02-06 1990-02-02 Nitromethane derivatives Expired - Fee Related GB2227746B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB898902573A GB8902573D0 (en) 1989-02-06 1989-02-06 Heterocyclic derivatives

Publications (3)

Publication Number Publication Date
GB9002390D0 GB9002390D0 (en) 1990-04-04
GB2227746A true GB2227746A (en) 1990-08-08
GB2227746B GB2227746B (en) 1992-07-22

Family

ID=10651186

Family Applications (2)

Application Number Title Priority Date Filing Date
GB898902573A Pending GB8902573D0 (en) 1989-02-06 1989-02-06 Heterocyclic derivatives
GB9002390A Expired - Fee Related GB2227746B (en) 1989-02-06 1990-02-02 Nitromethane derivatives

Family Applications Before (1)

Application Number Title Priority Date Filing Date
GB898902573A Pending GB8902573D0 (en) 1989-02-06 1989-02-06 Heterocyclic derivatives

Country Status (1)

Country Link
GB (2) GB8902573D0 (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2207916A (en) * 1987-08-06 1989-02-15 Ici Plc Nitromethane compounds and pharmaceutical compositions containing them

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2207916A (en) * 1987-08-06 1989-02-15 Ici Plc Nitromethane compounds and pharmaceutical compositions containing them

Also Published As

Publication number Publication date
GB8902573D0 (en) 1989-03-22
GB9002390D0 (en) 1990-04-04
GB2227746B (en) 1992-07-22

Similar Documents

Publication Publication Date Title
US5430060A (en) Acetamide derivatives
CA1338646C (en) (arylsulphonyl) nitromethanes, processes for their preparation and their use in pharmaceutical compositions
US5102905A (en) Thienyl benzothienyl and dibenzothienyl compounds as inhibitors of aldose reductase
EP0408713B1 (en) Phenylsulphone derivatives
GB2227746A (en) Nitromethane derivatives
EP0409949B1 (en) Arylsulphonyl-nitromethanes, process for their preparation and pharmaceutical compositions
US5250570A (en) Amidobenzene derivatives, compositions and use
EP0469888B1 (en) Amidobenzenes
GB2227744A (en) Nitro-methyl-sulphonyl substituted compounds

Legal Events

Date Code Title Description
732E Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977)
PCNP Patent ceased through non-payment of renewal fee

Effective date: 19990202