GB2376943A - Heterocyclic bicyclic fused diketo compounds and their therapeutic use - Google Patents

Abstract

Pyrrolo thiazine diones, for therapeutic use, are of formula 1 <EMI ID=1.1 HE=40 WI=72 LX=251 LY=789 TI=CF> <PC>R<SB>1</SB> is C<SB>1-6</SB> alkyl, phenyl or heterocyclyl and is optionally additionally substituted by one or more groups selected from C<SB>1-6</SB> alkyl, halogen, OR, OH, NO<SB>2</SB>, CF ý , NR4R5 and CO<SB>2</SB>R4; R2 is phenyl, heterocyclyl or C<SB>1-6</SB> alkyl, and is optionally additionally substituted by one or more groups selected from alkyl, halogen, hydroxy, alkoxy, nitro, acid, ester and trifluoromethyl; X is a bond or a C<SB>1-6</SB> alkyl spacer which may optionally be branched or substituted by one or more R3 groups; R3 is hydrogen, a halogen atom, -CO<SB>2</SB>R4, CONR4R5, CF<SB>3</SB>, -OH, -OR4, -NR<SB>4</SB>R<SB>5</SB>, -OCOR4, NR5COR4, SR4, SOR<SB>4</SB> or SO<SB>2</SB>R4; and R4 is hydrogen, CF<SB>3</SB> or a C<SB>1-6</SB> alkyl group which may optionally be branched; or a salt thereof.

Description

COMPOUNDS AND THEIR THERAPEUTIC IJSE

Field of the Invention

This invention relates to compounds, and more specifically to pyrrolothiazines, and to their therapeutic use Backeround to the invention Several chemical classes of compound are known that possess considerable antibacterial activity, and these have proven of immense value in the treatment of bacterial diseases and infection. They include among others, the penicillins, the cephalosporins, the aminoglycoside antibiotics, vancomycin analogues and the sulfonamide drugs.

The mechanism of action of a number of known antibiotics is by the direct inhibition of enzymes of essential bacterial biosynthetic pathways. These include, amongst others, trimethoprim and the sulfonamide drugs.

Chorismate synthase, an enzyme in the shikimate pathway has been shown to be essential for bacterial viability (EP0913480). Compounds that inhibit this enzyme could therefore be useful antibacterial agents. Compounds of similar Structure to those of the invention have been described previously, although there are no reports of biological activity, or specifically, antibacterial activity.

Sulfur letters 16 (5-6), 191-194 (1993) describes the synthesis of compounds of formula l where R3 is H. R2 is phenyl and R1 is phenyl, 4chlorophenyl, 4-methylphenyl or 4-methoxphenyl.

Chem. Pharm. Bull., 41(1) 50-54 (1993) describes mechanistic aspects of the synthesis of compounds of formula 1 where R1 is phenyl, R3 is H and R2 is methyl or phenyl.

The compounds described in the invention are structurally distinct from previously described antibiotics. Summarv of the Invention This invention relates to compounds, and more specifically to pyrrolo[3,4-e]-1,3thiazine-

1(2H),3(3aH)-diones, defined by Formula 1, and to their therapeutic use. The compounds and their pharmaceutically acceptable salts are claimed as the active ingredients in medicines for the treatment of bacterial infection in man and animals.

Formula 1 R1 o wherein R1 is C.6 alkyl, phenyl or heterocyclyl and is optionally additionally substituted by one or more groups selected from Ci 6 alkyl, halogen, OR, OH, NO2, CF3, NR4R5, CO2R4. R2 is phenyl, heterocyclyl or

C.6 alkyl, and is optionally additionally substituted by one or more groups selected from alkyl, halogen, hydroxy, aLkoxy, nitro, acid, ester and trifluoromethyl. X is a bond or a C.6 alkyl spacer which may optionally be branched or substituted by one or more R3 groups R3 is deemed as a hydrogen, a halogen atom, -CO2R4, CONR4R5, CF3, -OH, -OR4, NR4115, -OCOR4, NR5COR4, SR4, SOR4, SO2R4. R4 is defined as a hydrogen atom, a CF3 group, or a C -6 alkyl group which may optionally be branched.

Compounds of the invention include salts thereof Compounds of the invention, most of which are new, have therapeutic utility. In particular, they exhibit inhibition of the enzyme chorismate synthase. The compounds are useful as active ingredients in medicines, for the treatment of bacterial infection in man and animals.

Description of the invention

Certain compounds of this invention are preferred The term "Cn6 alkyl" as used herein refers to straight and branched chain aL'cyl groups having up to 6 C atoms. Examples are methyl, ethyl, propyl, isopropyl, n-butyl, secbutyl and tert-butyl. "ALkyl" may have the same meaning. "Halogen" means F. Cl, Br or I. "ALkoxy" means C -6 aLkyl-O-. "Heterocyclyl" means a saturated, unsaturated or aromatic ring of 5 to atoms containing one or more heteroatoms such as O. S or N. and which may be bonded via any C or ring atom.

Compounds of formula 1 may contain one or more chiral centres and exist in optically active forms. When a compound of formula 1 or a salt thereof contains a single chiral centre (for example sec-

butyl) it may exist in two enantiomeric forms. The present invention includes individual enantiomers and mixtures of these enantiomers. The enantiomers may be obtained by methods known to those skilled in the art. Such methods typically include resolution via formation of diastereomeric salts or complexes which may be separated, for example, by crystallisation; resolution via formation of diastereomeric derivatives or complexes which may be separated, for example, by crystallisation, gasliquid or liquid chromatography; selective reaction with one enantiomer by reaction with an enantiomer-specific reagent, for example, enzymatic esterification, oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation processes described above, at least one further step will subsequently be required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into another by asymmetric transformation.

When a compound of formula 1 or a salt thereof contains more than one chiral centre it may exist in diastereomeric forms. The diastereomeric pairs may be separated by methods known to those skilled in the art, for example, chromatography or crystallisation and the individual enantiomers within each pair may be separated as described above. The present invention includes each diastereomer of compounds of formula 1 and mixtures thereof.

Some compounds of formula 1 may exist in the form of solvates, for example, hydrates, which also fall within the scope of the present invention.

The compounds of formula 1 may form organic or inorganic salts, for example, the compounds of formula 1 may form addition salts with inorganic or organic acids, e.g. hydrochloric acid, hydrobromie acid, fi maric acid, tartaric acid, citric acid, sulfuric acid, hydiodie acid, maleic acid acetic acid, succinie acid, benzoic acid' pamoie acid, palmitic acid, dodecanoic acid and acidic amino-acids such as glutamic acid. Such compounds of formula 1 may form base addition salts, for example, with alkali metal hydroxides e.g. sodium hydroxide, with amino- acids e.g. lysine or arginine or with organic bases e.g. meglumaine. It will be appreciated that such salts, provided that they are pharmaceutically acceptable may be used in therapy in place of compounds of formula 1. Such salts are prepared by reacting the compound of formula 1 with a suitable acid or base in a conventional manner. Such salts may also exist in the form of solvates, for example, hydrates. The present invention includes each salt and any solvate thereof.

Certain compounds of formula 1 or salts thereof may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof "Pharmaceutically acceptable salts" are acid addition salts which can be prepared by any of the art recogmsed means. Typical acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, acetate, propionate, lactate, malate, succinate, tartrate, cyclohexanesulphamates, methanesulphonates, ethanesulphonates, benzenesulphonates, toluenesulphonates, fumarates and other pharmaceutically acceptable counter ions for amines.

R1 J:N + IN-R2 'N:

R3 0 Formula 2 Formula 3 Formula 1 Scheme 1 The preferred procedure for preparing compounds of the invention is shown in Scheme 1. In this method, compounds of formula 1 are prepared in a single step from compounds of formulae 2 and 3. The reaction can be carried out by combining compounds of formulae 2 and 3 at a temperature in the range -

80 C to 250 C, optionally in the presence of acid, and preferably in the presence of an inert organic solvent, to give the compounds of the invention

Compounds of formula 3 are known. For example, they may be synthesised by a number of methods including but not limited to that described in Tetrahedron Len., 42, 573-576 (2001). The preferred method is a two step procedure which involves treatment of maleic anhydride with an amine of formula R2-NH2 preferably in the presence of an inert organic solvent at a temperature in the range -80 C to 250 C to give a carboxylic acid-amide. In a second step, this is converted to compounds of formula 3 by heating alone, or treatment with a suitable dehydrating agent such as acetic anhydride The second step is performed preferably in the presence of an inert organic solvent at a temperature in the range -80 C to 250 C.

Compounds of formula 2 have been described in J. Org. Chem., 45, 37503753 (1980) wherein X is a bond, R3 is H and Y is -N(CH3)2. More generally they may be synthesised as shown in Scheme 2.

R1 J NH2 R3 R]::

R3 Formula 4 Formula 5 Formula 2 Scheme 2 Compounds of formula 4 are known. Compounds of formula 5 wherein X and R3 are as defined in formula 1, and Y and Z are leaving groups. Y and Z are individually chosen from alcohol, aLkoxy, halogen, or amine. The reaction can be carried out at a temperature in the range -20 C to 100 C, with or without the presence of an organic solvent. The preferred method involves treatment of a thioamide of formula 4 with an amidoacetal Me2N-C(XR3)(0alkyl)2 of formula 5 to generate compound of formula 2 wherein Y is-NMe2.

More generally, compounds of formula 1 can be prepared by any one of the methods shown in Scheme 3 and 4. In Scheme 3, a compound of formula 7, in which T is O or NH, is reacted with a compound of formula 2 to give a compound of formula 6. The reaction is carried out in the presence of an organic solvent at a temperature of 0-100 C. Compounds of formula 6 where T is an oxygen may be converted to compounds of formula 1 by reaction with an amine R2-NH2 followed by closure of the intermediate acid-amide using a dehydrating agent. Compounds of formula 6 where T is NH can be converted to compounds of formula 1 by reaction with R2-OH in a Mitsunobu reaction, or with R2-halogen in an aLkylation procedure. The following references illustrate reactions of these types but are in no way meant to limit the scope of claimed methods for converting compounds of formula 6 into compounds of formula 1.

s Mitsunobu reactions: JOC 1988, 53, 4339-4348

JCS, Perkin Trans. I 1989, 655-661.

TL 1990, 31, 3957-3960.

Synth. Comm. 1992, 22, 6, 913 AL sylation reactions: JOC 1981, 46, 27572764.

Tetrahedron 1984, 40,3329-3330.

JCS, Perkin Trans. 1984, 11, 2477-2489.

Scheme 3 R1 X'R3

Formula2 Formula 7 Formulas Formula 1 Scheme 4 R3 R1 IS V

Formula 2 Formula 9 Formula 8 Compounds of the invention may be prepared from compounds of formula 8 according to Scheme 4. In fonnula 8, W and V are together, -CO2H and -CO2H, -CO2H and -CO2alkyl, -CO2aLkyl andCO2alkyl -C0NHR2 and-CO2allyl -CONS and-CO2H Compounds of formula 8 may be converted by standard functional group interconversion to the last mentioned example wherein W and V are -C0NHR2 and -CO2H, which is converted to formula 1 by a dehydration reaction.

Compounds of formula 8 may be prepared from compounds of formulae 2 and 9 under similar reaction conditions to those described for the cyclisation reaction between compounds of formulae 2 and 3.

The carbon-carbon double bond in formula 9 can be of E or Z geometry. Compounds of formulae 2 and 9 are commercially available or known in the art.

The reactions described herein will be generally understood by one of ordinary skill in the art.

The starting materials are available or can readily be prepared by one of ordinary skill in the art.

Compounds of this invention have therapeutic utility, as antibacterial agents. They are especially useful for the treatment of infections caused by gram positive organisms such as S. aureus or S pneumonias. Without wishing to be bound by theory, their activity may be due to their ability to inhibit an enzyme of the shikimate biosynthetic pathway, chorismate synthase.

The present invention also provides pharmaceutical compositions containing a therapeutically effective amount of a compound of formula 1 including pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable diluent or carrier As used hereinafter, the term "active compound" denotes a compound of formula 1 including pharmaceutically acceptable salts thereof. In therapeutic use, the active compound may be administered orally, rectally, parenterally, topically, ocularly, aurally, nasally, intravaginally or to the buccal cavity, to give a local and/or systemic effect. Thus the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration. The compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention.

Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The compositions of the invention may contain 0.1-99% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. Preferably the unit dosage of active ingredient is 1-500 ma. The excipients used in the preparation of these compositions are the excipients known in the pharmacist's art.

Compositions for oral administration are preferred compositions of the invention and there are known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oily suspensions.

Tablets may be prepared from a mixture of the active compound with fillers such as lactose or calcium phosphate, disintegrating agents, for example maize starch, lubricating agents, for example magnesium stearate, binders for example microcrystalline cellulose or polyvinyl pyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods. The tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethylcellulose phthalate. The tablets may be formulated in a manner known to those skilled in the art so as to give a sust uned release of the compounds of the present invention Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate.

Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and if desired, provided with enteric coatings in a known manner. The tablets and capsules may conveniently each contain 0.1 to 1000 mg (for example 10 ma, 50 ma, 100 ma, 200 ma, 400 ma, 600 ma, or 800 ma) of the active compound. Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions contairung a compound of the present invention in a suitable vegetable oil, for example sunflower oil.

The active compound may be formulated into granules with or without additional excipients. The granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example water) before ingestion. The granules may contain disintegrants (for example a pharmaceutically acceptable effervescent couple formed from an acid and a carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium.

Compositions for topical administration are also preferred compositions of the invention. The pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel. A suitable cream may be prepared by incorporating the active compound in a topical vehicle such as petrolatum and/or light liquid paragon, dispersed in an aqueous medium using surfactants. An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil, petrolatum and/or a wax e.g. paraffin wax or beeswax. A gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent e.g. basified Carbomer BP, in the presence of water. Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transderrnally. A suitable transderrnal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as described above, together with a potential transdermal accelerate such as dimethyl sulphoxide or propylene glycol.

Compositions of the invention suitable for rectal administration are known pharmaceutical forms for such administration, for example suppositories with hard fat, synthetic glycerides or polyethylene glycol bases. Compositions of the invention suitable for parenteral administration are known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.

Compositions of the invention suitable for inhalation via the mouth and/or the nose are the known pharmaceutical forms for such administration, for example aerosols, nebulised solutions or powders.

Metered dose systems, known to those skilled in the art, may be used.

Compositions suitable for application to the buccal cavity include slow dissolving tablets, troches, chewing gum, gels, pastes, powders, mouthwashes or rinses.

The compounds of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion, or from a source of the compound placed

within the body, internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be a) liquid such as an oily solution or suspension of the compound to be infused for example in the form of a very sparingly water-

soluble derivative such as a dodecanoate salt or b) solid in the form of an implanted support for example of a synthetic resin of waxy material for the compound to be infused. The support may be a single body containing the entire compound or a series of several bodies each containing part of the compound to be delivered. In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.

The following examples illustrate the invention. The intermediates illustrate the preparation of precursors. Intermediate 1. 4-Chloro-N(dimethylaminomethylene)thiobenzamide _. CiJ I A mixture of 4chlorothiobenzamide ( 6.86 g, 40 mmol) and dimethylformamide dimethyl acetal (6.4 ml, 48 mmol) was stirred for I hour. Volatile organics were removed at room temperature at high vacuum. The resulting solid was triturated with ether and dried under vacuum to give 4<hloro-N-

(dimethylaminomethylene)thiobenzamide as a red solid (8.2 g, 36.4 mmol, 91%).

OH Now (400 MHz) CDC1a o; 8.77 (1H, s), 8.39 (2H, d), 7.34 (2H, d), 3.29 (6H, d).

Intermediate 2. N-('chlorophenyl)maleimide t^,0 N To maleic anhydride (0. 98g, 10 mmol) in DMF (10 ml) was added 4-chloroaniline (1.28g, 10 mmol) and stored for 1 hour under nitrogen. The solvent was evaporated and the resulting solid taken up in acetic anhydride (5 ml). Sodium acetate (0.5g) was added and the solution stirred for 0.5 hour at 100 C.

The solution was cooled, poured into ice/water and the resulting solid collected and dried to give N-(4-

chlorophenyl)maleirnide (1.34g,6.4 mmol, 64%) iH NMR (400 MHz) CDCI3 b; 7. 47-7.32 (4H, m), 6.88 (2H, s) Compound 1; 2,5-Bis(4-chlorophenyl)pyrrolo[3,4-el-1,3-thiazine-1(2El),3(3alI)-dione C1 3( Ott A mixture of N(4-chlorophenyl)maleimide (916 ma, 4 mmol) and 4-chloro-N (dimethylaminomethylene)thiobenzamide (l.Og, 4 mmol) in dichloromethane (15 ml)/acetic acid (5ml) were stirred for 1 hour. The resulting solid was collected, washed with water, methanol and dried to yield 2,5bis(4<hlorophenyl)-pyrrolo[3,4-e]-1,3-thiazine-1(2H),3(3aH)-dione as a yellow solid: (667 ma, 1.72 mmol, 43 /0).

OH NMR (400 MHz) CDCI3 6; 8.11 (1H, d), 8.09 (2H, d), 7.53 (2H, d), 7.51 (2H, d), 7.42 (2H, d), 4.80 (1H, d).

Compound 2: 5-(4-Chlorophenyl)-2-(3-trifluoromethylphenyl)-pyrrolo[3,4-e]1,3-thiazine 1 (21I),3(3aH)-dione C1 0

INN O CF3 5-(4-Chlorophenyl)-2-(3-trifluoromethylphenyl)-pyrrolo[3,4-e] 1,3-thiazine-1 (2H),3(3aH)-dione was purchased from Bionet.

Compound 3: 5-(4-Chlorophenyl)-2-(3-methoxyphenyl)pyrrolol3,4-e]-1,3thiazine-1(21I),3(3an)-

dione C13 O

N [ OMe 5-(4-Chlorophenyl)-2-(3 -methoxyphenyl)pyrrolo[3,4-e]-1,3thiazine- 1 (2H),3 (3aH)-dione was synthesized from 4-chloro-N(dimethylaminomethylene)thiobenzamide and N-(3 methoxyphenyl)maleimide according to the method for compound 1.

H NMR (400 MHz) CDCI3 6; 8.01 (1H, d), 7.92 (2H, d), 7.42 (2H, d), 7.34 (2H, dd), 7 19 (1H, s), 6.86 (1H, dd), 4.71 (1H, s), 3.76 (3H, s) Compound 4: 5-(4-Chlorophenyl)-2-(2-methuxyphenyl)pyrrolo[3,4-e]-1,3- thiazine-1 (2),3(3aH) dione Cl O MeO 5-(4-Chlorophenyl)-2-(2methoxyphenyl)pyrrolo[3,4-e]- 1,3-thiazine- 1 (2H),3(3aH) dione was synthesized from 4-chloro-N-(dimethylaminomethylene)thiobenzamide and N(2 methoxyphenyl)maleimide according to the method for compound 1.

IH NM:R (400 MHz) CDCI3 8; 8.00 (3H, m), 7.43 (2H, d), 7.40 (1H, m), 7.16 (1H, m), 7.00 (2H, m), 4.74 (1H, s), 3.77 (3H, s).

Compound 5: Ethyl 2-[5-(4<hloropbenyl)-1,3-dioxo-1,2,3,3atetrahydropycrolo[3,4-e]-1,3-thiazin 2-yl]benzoate IS CO2Et Ethyl 2-[5-(4chlorophenyl)-1,3-dioxo-1,2,3,3a-tetrahydropyrrolo[3,4-e]- 1,3-thiazin-2yl]benzoate was synthesized from 4-chloro-N-(dimethylaminomethylene) thiobenzamide and ethyl 2-(2,5-dioxo-3 pyrrolin-1-yl)benzoate according to the method for compound 1 OH NMR (400 MHz) CDCI3 o; 8.21 (1H, d), 8.09 (2H, d), 7.72 (1H, dd), 7 59 (1H, dd), 7.52 (3H, m), 7.37 (1H, dd), 4.81 (1H, d), 4.31 (2H, m), 1.34 (3H, m).

Compound 6: 5-(4-Chlorophenyl)-2-(3-hydroxyphenyl)pycrolo[3,4-e]-1,3thiazine-1 (2),3(3aH) dione Cl (/N o So iN OH To compound 3 (100 ma, 0.26 mmol) in DCM (2 ml)was added boron tribromide (0.26 ml, 0.26 mmol, 1M in DCM) at -78 C under nitrogen. After warming to room temperature the reaction was quenched by addition of water (5 ml) and the resulting solid filtered and dried to give 5-(4-chlorophenyl)-2-

(3-hydroxyphenyl)pyrrolo[3,4-e]-1,3-thiazine-1(2H),3(3aH)-dione (85 ma, 0. 23 mmol, 88%) tH NMR (400 MHz) CDC13 o; 8.10 (2H, d), 8.04 (1H, d), 7.69 (2H, d), 7.31 (1H, dd), 6.81 (3H, m), 5.29 (1H, d)

Compound 7: 5-(4-Chlorophenyl)-2-(4-trifluoromethylphenyl)pyrrolo[3,4-e]1,3-thiazine 1(2:),3(3alI)-dione CI S 5-(4-Chlorophenyl)-2-(4trifluoromethylphenyl)pyrrolo[3,4-e]-1,3-thiazine-1 (2H),3(3aH)-dione was prepared 4-chloro-N-(dimethylaminomethylene)thiobenzamide and N-(4ifluoromethylphenyl) maleimide according to the method for compound 1.

AH NMR (400 MHz) CDCI3 6; 8.05 (1H, d), 8.01 (2H, d), 7.70 (2H, d), 7.52 (2H, d), 7.42 (2H, d), 4.74 (1H, d).

Compound 8: 5-(4-Chlorophenyl)-2-(3-fluorophenyl)pyrrolo[3,4-e]-1,3thiazine-1(2),3(3aH)-dione IS F 5-(4-Chloropheny)-2-(3-fluorophenyl) pyrrolo[3,4-e]-1,3-thiazine-1(2H),3(3aH)-dione was prepared 4<hloro-N(dimethylaminomethylene)thiobenzamide and N-(4-trifluoromethylphenyl) maleimide according to the method for compound 1.

AH NMR (400 MHz) CDCI3 6; 8.12 (1H, d), 8.10 (2H, d), 7.54 (2H, d), 7.48 (1H, m), 7.27-7.14 (3H, m), 4.81 (1H, s)

Compound 9; 2,5-Bis(4<hlorophenyl)-7-methylpyrrolo[3,4-e]-1,3-thiazine1(2II),3(3aH)-dione C1 0

N. it, 2,5-Bis(4-chlorophenyl)-7-methylpyrrolo[3,4-e]-1,3-thiazine-1(2H), 3(3aH)-dione was prepared from prepared 4-chloro-N-(ldimethylaminoethylidene)thiobenzemide and N-(4-chlorophenyl)maleirnide according to the method for compound 1.

AH NMR (400 MHz) CDCI3 8; 8.10 (2H, d), 7.50 (4H, m), 7.39 (2H, d), 4.79 (1H, s), 2.68 (3H, s).

Compound 10: Methyl 3-15-(4<hlorophenyl)-1,3-dioxo-1,2,3,3atetrabydropycrolol3,4-e]-1,3 thiazin-2-yl] benzoate Cl TO S: iN CO2Me Methyl 3-[5-(4-chlorophenyl)- 1,3-dioxo-1,2,3,3a-tetrabydropyrrolo[3,4-e]1,3-thiazin-2-

yl]benzoate was synthesized from 4-chloro-N-(dimethylaminomethylene) thiobenzamide and methyl 3-(2,5-

dioxo-3-pyrrolin-1-yl)benzoate according to the method for compound 1.

AH NMR (400 MHz) CDC13 b; 8.16-8.09 (5H, m), 7.64 (2H, m), 7.53 (2H, d), 4.83 (1H, s), 3.96 (3H, s) Compound 11: Ethyl 4-[5-(4<hlorophenyl)-1,3dio o-1,2,3,3a-tetrahydropyrrolo[3,4-e]-1,3-thiazin 2 yl]butyrate Cl -to o

Ethyl 4- 5-(4-chlorophenyl)-1,3-dioKo-1,2,3,3a-tetrahydropyrrolo[3,4-e]-1, 3-thiazin-2-yl]butyrate was synthesized from 4-chloro-N(dimethylaminomethylene)thiobenzamide and ethyl 4-(2,5-dioxo-3-

pyrrolin-l-yl)butyrate according to the method for compound 1.

iH NMR (400 MHz) CDC13 6; 8.07 (2H, d), 7.95 (1H, d), 7.65 (2H, d), 5.11 (1H, d), 4.04 (2H, q), 3.56 (2H, m), 2.35 (2H, t), 1.82 (2H, quintet), 1. 19 (3H, I).

C Measurement of IC50 The inhibitory effect of a compound can be described by an IC50 value, that is the concentration of inhibitor at which half (50 /O) inhibition of the maximal (100%) inhibition occurs. ICso values were determined by measuring the extent of inhibition over a range of concentrations of the compound, preferably a range where the degree of inhibition varied from no inhibition (0 /u) to complete inhibition (100%). The IC50 value can be estimated from a plot of % inhibition against concentration of inhibitor, or can be calculated using data fitting programs, such Grant (Elsevier) or EnzFitter (Biosoft).

Representative compounds are shown in table 1.

_ Compound IC50 vs SpCl/llM MIC Sp/ M 1.8 250

2 1.4 250

3 8.9 500

4.8 500

5 5.5 1000

8.2 62

7 6.1 62

8 6.0 250

7.5 250

10 1.6 500

11 7.9 500

Table 1. IC50s and antibacterial activity of representative compounds of the invention

Claims (10)

Claims

1. A compound, for therapeutic use, of formula 1 R3 N; 4 ll I N-R2 R1 S o wherein R1 is Cl 6 alkyl, phenyl or heterocyclyl and is optionally additionally substituted by one or more groups selected from Cl 6 alkyl, halogen, OR, OH, NOz, CF3, NR4R5 and CO2R4; R2 is phenyl, heterocyclyl or Cl 6 alkyl, and is optionally additionally substituted by one or more groups selected from aLkyl, halogen, hydroxy, alkoxy, nitro, acid, ester and trifluoromethyl; X is a bond or a Cal 6 alkyl spacer which may optionally be branched or substituted by one or more R3 groups; R3 is hydrogen, a halogen atom, -CO2R4, CONR4R5, CF3, -OH, -OR4, -NR4R5, -OCOR4, NR5COR4, SR4, SOR4 or SO2R4; and R4 is hydrogen, CF3 or a Cl 6alkyl group which may optionally be branched; or a salt thereof.

2. A compound of claim 1, independent of use, excluding 2,5-bis(4chlorophenyl)pyrrolo[3,4-e]-1,

3 thiazine- 1 (2H), 3 (3 aH) -dione and 5 (

4 -chlorophenyl) -2 -(3 -trifluoromethylphenyl)pyrrolo [3, 4 -e] -1, 3 thiazine-1(2H),3(3aH)-dione 3. A compound of claim 2, selected from 5-(4chlorophenyl)-2-(3-methoxyphenyl)pyrrolo[3,4-e]-1,3-thiazine- 1 (2H), 3(3aH)-dione 5-(4-chlorophenyl)-2-(2-methoxyphenyl)pyrrolo[3,4-e]-1,3thiazine- 1 (2H),3(3aH)-dione ethyl 2-[5-(4-chlorophenyl)-1,3-dioxo- 1,2, 3,3a-tetrahydropyrrolo[3,4-e] -1,3-tluazin-2-yl]benzoate 5-(4chlorophenyl)-2-(3-hydroxyphenyl)pyrrolo[3,4-e]-1,3-thiazine- 1 (2H),3 (3aH)-dione 5 -(4-chlorophenyl)-2-(4-trifluoromethylphenyl)pyrrolo[3,4-e]1,3 -thiazine- 1 (2H),3 (3aH)-dione 5-(4-chloropheny)-2-(3-fluorophenyl) pyrrolo[3,4-e]-1,3-thin ne- 1 (2H),3(3aH)-dione 2,5-bis(4-chlorophenyl)-7methylpyrrolo[3,4-e]-1,3-thiazine- 1 (2H),3 (3aH)-dione methyl 3-[5-(4chlorophenyl)- 1,3-dioxo-1,2,3,3a-tetrahydropyrrolo[3,4-e] -1,3-tbiazin-2 yl]benzoate and ethyl 4-[5-(4-chlorophenyl)-1,3 ioxo-1,2,3,3atetrahydropyrrolo[3,4-e]-1,3-thiazin-2-yl]butyrate 4. A pharmaceutical composition comprising as an active ingredient a compound of any preceding claim, together with a carrier or diluent.

5. Use of a compound of any of claims 1 to 4, for the manufacture of a medicament for the treatment of a bacterial infection.

6. The use of claim 5, wherein the infection is caused by a gram positive organism.

7. The use of claim 6, wherein the organism is S. aureus.

8. The use of claim 6, wherein the organism is S. pneumonias

9. A method of making a compound of claim 2 from compounds of formulae 2 and 3 R1J:N + CHIN-R2 NO

XlY O R1 S N-R2 R3 0 Formula2 Formula 3 Formula 1 wherein R1, R2, R3 and X are as defined for formula 1 in claim 1, Y is -NR4R5, -OR4, -OCOR4, - SR4 or halogen, and R4 and R5 are independently Cat 6 aL cyl or CF3.

10. The use of compounds of formula 6 or 8 as intermediates in the synthesis of compounds of claim 2 x'R3 x'R3 Jet 1 R1 S R1 S V

o Formula 6 Formula 8 wherein R1, R2, R3 and X are as defined for fonnula 1 in claim 1, T is NH or O. and W and V are together -CO2H and -CONFER, or both -CO2H, or both -CO-halogen.