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  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
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  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
  • C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
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Definitions

• the present invention relates to carbonic anhydrase inhibitors, their use in medicine including treatment of eye disease, cancer and tuberculosis and pharmaceutical compositions containing such inhibitors.
• CAs Carbonic anhydrases
• are widespread zinc metalloenzymes found in higher vertebrates including humans. 16 isozymes have been characterised to date, many of which are involved in critical physiological processes. They catalyse the following reaction: C0 2 +H 2 0 H + +HC0 3 ⁇ .
• CAs are present in a large variety of tissues including the gastrointestinal tract, the reproductive tract, the nervous system, kidneys, lungs, skin and eyes. The different isozymes are localised in different parts of the cell with CA I and CA II, important isozymes in normal cells, being localised in the cytosol.
• CAII plays a role in bicarbonate production in the eye and is therefore thought to provide a potential target for therapy of eye disease such as glaucoma.
• hypoxic regions may be formed, particularly in the interior of the tumour.
• the gene expression profile of a hypoxic cancer cell is different from that of other cancer cells in a normally-oxygenated environment ("normoxic conditions").
• CA carbonic anhydrase
• the distribution of isoforms of carbonic anhydrase (CA) is altered as compared with normoxic cells.
• CA isozymes IX and XII are found to be overexpressed in hypoxic tumour cells.
• CA IX and CA XII are both extracellularly localised on hypoxic tumour cells.
• These enzymes play a role in carbon fixation which may aid the growth of the tumour cells and also in acidification of the cells' micro environment. They are therefore thought to provide a target for cancer therapy because they are relatively specific to the hypoxic tumour cells and appear to be important in the survival and proliferation of those cells.
• Vertebrates CA generally belong to a class of CAs called the alpha- family.
• CAs found in microorganisms may belong to several different CA families including beta, gamma and delta CAs.
• the carbonic anhydrase from Mycobacterium tuberculosis is a beta-CA, for example.
• Microbial CAs are thought to provide potential therapeutic targets for the treatment of infection and associated diseases.
• CAIs carbonic anhydrase inhibitors
• the X-ray crystal structure for the adduct of trithiocarbonate (CS 3 2 ⁇ ), bound to hCA II has recently been reported [4] (Fig. 1).
• the inhibitor binds to the Zn 2+ in the hCA II active site in a slightly distorted tetrahedral geometry of the metal ion, occupying a position similar to that observed in the case of hCA II-bicarbonate complex [4].
• Trithiocarbonate was mono-coordinated to the Zn(II) ion by means of one of the sulfur atoms.
• the present invention provides a carbonic anhydrase inhibitor which comprises a compound of general formula:
• R and R are each independently selected from H or an organic substituent, or together form a ring, and optionally contain one or more heteroatoms; wherein R 1 and R 2 together comprise at least 5 carbon atoms or at least 2 carbon atoms and a heteroatom, or R ⁇ comprises at least 4 carbon atoms; and
• M + comprises a monovalent cation
• carbonic anhydrase inhibitors according to the invention are potent inhibitors of hCAII, hCAIX and mtCAl/3. These inhibitors are dithiocarbamates but are found to be much more strongly inhibitory to CAs than either dimethyl or diethyl dithiocarbamate compounds.
• R group substituent has been found not to be critical provided that at least one of the R groups comprises at least four carbon atoms or R 1 and R 2 together comprise either at least five carbon atoms or at least two carbon atoms and a heteroatom. If smaller, non-hetero atom- containing groups are used, such as found in diethyl or dimethyl dithiocarbamate, the inhibition constant Ki is one or two orders of magnitude larger. This is evident from Table 1 and Table 2 below.
• R' and R ⁇ may each be separate substituents. Alternatively, they may together form a ring with the nitrogen atom of the carbamate.
• the aggregate number of carbon atoms in R 1 and R 2 together is typically no more than 20, preferably no more than 16 and more preferably no more than 12.
• R 2 comprises at least four carbon atoms or at least two carbon atoms and a heteroatom.
• R 2 is preferably selected from Ph, 0[(CH 2 CH 2 )] 2 N, MeN[(CH 2 CH 2 )] 2 N , 2-butyl, 0[(CH 2 CH 2 )] 2 N(CH 2 ) 2 , N[(CH 2 CH 2 )N] 3 , PhCH 2 , 4-PyridylCH 2 , Et NH, [(CH 2 ) 5 N]CH 2 CH 2 , 2-thiazolyl, Et 3 NH, KOOCCH 2 or imidazol-1 - yi-(C3 ⁇ 4) 3 .
• R 1 and R 2 together comprise at least five carbon atoms or at least two carbon atoms and a heteroatom.
• R 1 and/or R 2 may be chosen from Me, Et, Pr, Bu, Ph, PhCH 2 , hexyl or HO-CH 2 -CH 2 .
• M + comprises a monovalent cation which may be an alkyl metal cation or a base.
• the alkali metal cation is preferably sodium or potassium.
• the base is preferably Et 3 NH + or imidazol-l-yl- (CH 2 ) 3 NH 3 + .
• CA inhibition is measured by assaying for CA- catalysed carbon dioxide hydrase activity using an appropriate indicator dye. Phenol red may be used as the indicator and this has an absorbent maximum of 557nm. Stopped flow spectrophotometry may be used to measure the rate of hydrase activity and further details of this technique are presented in WO2011/098610 in the section on CA inhibition in Example 2 thereof.
• the Ki for human CAII is typically less than ⁇ , preferably less than lOOnM, still more preferably less than 60nM, even more preferably less than ⁇ , particularly preferably less than 5nM and most preferably less than InM.
• Ki values for CAIX inhibition are typically less than 500nM, preferably less than lOOnM, more preferably less than 60nM, particularly preferably less than 30nM and most preferably less than l OnM.
• the Ki values for mtCAl inhibition are typically less than 500nM, preferably less than l OOnM, more preferably less than lOnM and most preferably less than InM.
• the Ki values for mtCA3 are typically less than 200nM, preferably less than l OOnM, more preferably less than lOnM and most preferably less than InM.
• the present invention provides a carbonic anhydrase inhibitor as described herein, for use in treatment of eye disease.
• Eye disease in particular degenerative eye disease such as glaucoma may include the involvement of CAs such as CAII.
• CAs may be responsible for secretion of bicarbonate.
• IOP intraoccular pressure
• the present invention provides a carbonic anhydrase inhibitor for use in treatment of cancer, particularly for treating hypoxic tumours.
• Carbonic anhydrase inhibitors according to the invention may be used to treat tumours directly. This is because tumours, such as hypoxic tumours, express certain carbonic anhydrases extracellularly. The inhibitors can therefore be used to effect a reduction in tumour volume.
• the therapeutic target is typically CAIX.
• the present invention provides a carbonic anhydrase inhibitor for use in treatment of microbial infection, particularly in the treatment of infections arising from Mycobacterium tuberculosis.
• the therapeutic target is carbonic anhydrase mtCAl and/or mtCA3.
• compositions may be formulated comprising a carbonic anhydrase inhibitor as described herein or a pharmaceutically-acceptable salt, ester, or prodrug thereof optionally incorporating a pharmaceutically-acceptable diluents, excipient or carrier (including combinations thereof).
• Pharmaceutically-acceptable salts are known in this technical field and include salts with acids or bases which are accepted for the formation of salts for pharmaceutical use.
• such pharmaceutically-acceptable salts include those of non-toxic cations such as quarternary ammonium ions, alkali metals such as sodium or potassium and alkaline earth metals such as calcium.
• Organic bases may also be used, such as ethanolamine, pyridine, trimethyl amine or triethylamine.
• acid addition salts may be formed by the use of pharmaceutically- acceptable non-toxic acids such as hydrochloric acid, nitric acid, sulphuric acid, phosphoric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or an amino acid.
• Other materials may be added to the pharmaceutical compositions depending on the intended route of administration to the subject. Such additional materials include solubilising agents, coating agents, lubricants, binders and suspending agents.
• Non-toxic carriers, diluents and excipients are described in standard textbooks such as Remington's Pharmaceutical Sciences, Mack Publishing Company.
• compositions may contain a prodrug form of the carbonic anhydrase inhibitor which is intended to become active only when metabolised by the subject.
• prodrug forms include esters which can be hydrolyzed in vivo with the formation of the dithiocarbamate inhibitors presented above.
• the present invention is not limited in relation to the particular route of administration to the subject. This may depend in part upon which part of the body of the subject needs to be targeted as well as the tolerance of the carbonic anhydrase inhibitor molecule to that particular route of administration.
• Standard routes of administration include oral, buccal, sublingual, inhalation, topical (including ophthalmic), rectal, vaginal, nasal and parenteral (including intravenous, intraarterial, intramuscular, subcutaneous and intraarticular).
• compositions and dosage thereof will also be dependent upon the subject to be treated including body weight, route of administration and precise disease conditions.
• compositions include esters, amides, salts and nanoparticles based on the dithiocarbamates described herein.
• inhibitors according to the present invention may be used in medicine, and may have particular use in cancer treatment. Whilst treatment of hypoxic cancer tumours is important in itself, a subject with cancer is likely to need additional treatment such as chemotherapy or radiation therapy. Treatments of the hypoxic tumour alone may account for approximately 40% reduction in tumour volume. The remaining tumour volume is therefore preferably treated additionally with chemotherapy or radiation therapy appropriate to normoxic cells. Accordingly, in one aspect, the inhibitors according to the invention are provided for use in cancer treatment of a subject who is treated additionally with chemotherapy or radiation therapy.
• a product comprising a CA inhibitor according to the invention and a chemotherapeutic agent as a combined preparation for simultaneous, separate or sequential use in cancer treatment.
• a kit may be provided containing the present inhibitors and further chemotherapeutic agents typically in separate containers.
• the chemotherapeutic agent and inhibitor may be administered to the subject together.
• CA inhibitors as described herein may be used in the preparation of a medicament for treatment of cancer.
• the CA inhibitors of the present invention may also be used in methods of diagnosis or imaging.
• the inhibitor typically includes a label appropriate to the particular diagnosis or imaging method.
• labels include fluorescent labels, spin labels, radiolabels or heavy atoms.
• an imaging composition comprising such CA inhibitors and a suitable diluents, excipient or carrier.
• Such compositions are typically manufactured for injection or per os administration into the subject.
• FIGURE 1 shows trithiocarbonate (CS 3 2- ), a recently investigated low micromolar CAI [65], binds to the Zn in the hCA II active site in a slightly distorted tetrahedral geometry of the metal ion, occupying a position similar to that observed in the case of hCA II-bicarbonate complex.
• the protein zinc ligands (His94, 96 and 1 19) and Thrl 99 are also shown.
• FIGURE 2 shows A: IOP lowering versus time, of glaucomatous rabbits treated with one drop (50 ⁇ > of a 2 % water solution of DTC 24a and 25a; B: IOP in the eyes treated with vehicle (IOP are the mean from 3 different animals).
• TLC Thin layer chromatography
• Merck silica gel 60 F 254 aluminium backed plates Elution of the plates was carried out using ethyl acetate/rc-hexane or MeOH/DCM systems.
• Visualization was achieved with UV light at 254 nm, by dipping into a 0.5 % aqueous potassium permanganate solution, by Hanessian's Stain solution and heating with a hot air gun or by exposure to iodine.
• Aniline 1 (CAS 62-53-3), Morpholin-4-amine 2 (CAS 4319-49-7), 4-Methylpiperazin-l -amine 3 (CAS 6928-85-4), ( ⁇ ) sec-Butyl amine 4 (CAS 13952-84-6), 2-Morpholinoethanamine 5 (CAS 2038-03-1 ), Ni,Ni-bis(2-Aminoethyl)ethane-l ,2-diamine 6 (CAS 4097-89-6), Benzylamine 7 (CAS 100-46-9), Pyridin-4-ylmethanamine 8 (CAS 3731 -53-1), 2'-(Piperidin-l-yl)ethanamine 9 (CAS 27578-60-5), 2-Aminothiazole 10 (CAS 96-50-4), Glycine 11 (CAS 21931 -03-3), 3-(lH-Imidazol- l -yl)propan-l -amine 12 (CAS 5036-48-6), sodium dimethyldithio
• Aniline 1 (0.5 g, 1.0 eq) was treated with triethylamine (1.0 eq) in benzene (0.5 ml) followed by addition of carbon disulfide (1.0 eq) at 0°C. The mixture was warmed to r.t. and stirred O.N. at r.t.. The solid formed was washed with diethyl ether and dried under vacuo to afford the titled compound as a light yellow solid in 51 % yield.
• Morpholin-4-amine 2 (0.5 g, 1.0 eq) was treated with powdered KOH (1.0 eq) at 0 °C in diethyl ether (20 ml) followed by addition of carbon disulfide (1.0 eq). The mixture was stirred at the same temperature for 6h, warmed to r.t. and the precipitated formed collected by filtration, washed with diethyl ether and dried under vacuo to give the title compound as a pale yellow solid in 75 % yield.
• Potassium morpholinocarbamodithioate 2a v max (KBr) cm “1 , 2960, 2890, 1648, 1598, 1520, 1430, 1 190; ⁇ ⁇ (400 MHz, DMSO-J s ) 2.78 (4H, m, 2 x 3-H 2 ), 3.60 (4H, m, 2 x 2-H 2 ), 8.62 (1H, brs, exchange with D 2 0, N-H); 5 C (100 MHz, DMSO- ) 55.0 (C-3), 66.9 (C-2), 213.4 (OS); m/z (ESI), 177 [M-Na] ⁇
• 2-Morpholinoethanamine 5 (0.5 g, 1.0 eq) was treated with powdered KOH (1.0 eq) at 0 °C in diethyl ether (20 ml) followed by addition of carbon disulfide (1.0 eq). The mixture was stirred at the same temperature for 6h, warmed to r.t.. The solvent was evaporated in vacuo to give a pale yellow residue that was suspended in MeOH (15ml) filtered through Celite, the filtrated was concentrated in vacuo to afford a sticky solid that was triturated from DCM to afford the titled compound as a light brown solid in 58 % yield.
• Ni,Ni-bis(2-Aminoethyl)ethane-l ,2-diamine 6 (0.5 g, 1.0 eq) was treated with powdered KOH (3.05 eq) in MeOH (50 ml) followed by addition of carbon disulfide (3.05 eq) at 0°C. The mixture was warmed to r.t. and stirred for 1.5h. The solution was filtered through Celite and the filtrate was concentrated in vacuo to give a solid that was triturated from DCM to afford the titled compound as a pale yellow solid in 59% yield.
• Benzylamine 7 (0.5 g, 1.0 eq) was treated with NaOH (1.0 eq) in MeOH (20 ml) followed by addition of carbon disulfide (1.0 eq) at 0°C. The mixture was warmed to r.t. and stirred 7h. at r.t.. The solvent was removed in vacuo and the residue obtained was triturated from DCM, collected by filtration, dissolved in MeOH and filtered through Celite. The filtrate was concentrated under vacuo to give a solid that was triturated from diethyl ether to afford the titled compound as a pale yellow solid in 17 % yield.
• Pyridin-4-ylmethanamine 8 (0.5 g, 1.0 eq) was treated with triethylamine (1 .0 eq) in DCM (20 ml) followed by addition of carbon disulfide (1.0 eq) at 0°C. The mixture was warmed to r.t. and stirred 2h. at r.t.. The solvent was removed in vacuo and the residue dissolved in MeOH filtered through Celite, concentrated in vacuo to afford the titled compound as a light brown solid in 74 % yield.
• Triethylammonium pyridin-4-ylmethylcarbamodithioate 8a v max (KBr) cm “1 , 2960, 2884, 1650, 1578, 1518, 1449; ⁇ ⁇ (400 MHz, DMSO-i3 ⁇ 4 1.22 (9H, t, J 7.4, 3x CH 2 G3 ⁇ 4), 3.14 (6H, q, J 7.4, 3x CH 2 CH 3 ), 4.74 (2H, d, J 6.4, V-H 2 ), 7.25 (2H, d, J 6.0, Ar-H), 8.46 (2H, d, J 6.0, Ar-H), 8.70 (1H, brs, exchange with D 2 0, N-H), 9.18 (1 ⁇ , brs, exchange with D 2 0, (CH 3 CH 2 ) 3 N + -H); 5 C (100 MHz, DMSO-rfi) 9.6, 46.6, 49.7, 123.3, 149.9, 150.5, 216.7 (OS); m/z (ESI),
• 2-Aminothiazole 10 (0.5 g, 1.0 eq) was treated with triethylamine (1.0 eq) followed by addition of carbon disulfide (1.0 eq) at 0°C. The mixture was warmed to r.t. and stirred O.N. at r.t. and 100°C for lh. Then the mixture was cooled down to r.t., triturated with diethyl ether to afford the titled compound as a yellow solid in 1 1 % yield.
• 3-(lH-Imidazol-l-yl)propan-l -amine 12 (0.5 g, 1.0 eq) was treated with powdered KOH (1.0 eq) at 0 °C in diethyl ether (20 ml) followed by addition of carbon disulfide (1.0 eq). The mixture was stirred at the same temperature for 4h, warmed to r.t.. The solid formed was collected by filtration and triturated from diethyl ether to afford the titled compound as a white solid in 17% yield.
• 1 -Pyrrolidinecarbodithioic acid sodium salt 15a m.p. > 300 °C (Lit 2 > 300 °C); v max (KBr) cm “1 , 2970, 2863, 1520, 1 161 ; ⁇ ⁇ (400 MHz, D 2 0) 2.01 (4H, m), 3.78 (4H, m); 5 C (100 MHz, D 2 0) 26.1 , 55.5, 203.1 (OS); m/z (ESI), 146 [M-Na] " .
• Diisobutylamine 16 (1.0 g, 1.0 eq) was treated according to the general procedure described above with 1.0 M aqueous solution of NaOH (1.0 eq) followed by addition of carbon disulfide (1.2 eq). The title compound was obtained as a white solid in 83 % yield.
• Diisobutylcarbodithioic acid sodium salt 16a m.p. 220 °C with dec; ; v max (KBr) cm " 1 , 2961 , 2933,
• Dipropylamine 17 (1.0 g, 1 .0 eq) was treated according to the general procedure with 1.0 M aqueous solution of NaOH (1.0 eq) followed by addition of carbon disulfide (1.2 eq). The title compound was obtained as a white semisolid in 87 % yield.
• Dibutylamine 18 (1.0 g, 1.0 eq) was treated according to the general procedure with 1.0 M aqueous solution of NaOH (1 .0 eq) followed by addition of carbon disulfide (1.2 eq). The title compound was obtained as a white solid in 84 % yield.
• Dihexylamine 19 (1.0 g, 1.0 eq) was treated according to the general procedure with 1.0 M aqueous solution of NaOH (1.0 eq) followed by addition of carbon disulfide (1.2 eq). The title compound was obtained as a pale yellow semisolid in 64 % yield.
• Ethylbutyamine 20 (1.0 g, 1.0 eq) was treated according to the general procedure with 1.0 M aqueous solution of NaOH (1.0 eq) followed by addition of carbon disulfide (1.2 eq). The title compound was obtained as a pale yellow semisolid in 98 % yield.
• Diethanolamine 21 (0.5 g, 1.0 eq) was treated with powdered NaOH (1.0 eq) in MeOH (10 ml) followed by addition of carbon disulfide (1.0 eq) at 0°C. The mixture was warmed to r.t. and stirred for 4h. The solution was filtered through Celite and the filtrate was concentrated in vacuo to afford the titled compound as a light yellow solid in 81 % yield.
• N-methylbenzenamine 22 (0.5 g, 1.0 eq) was treated with powdered NaOH (1.0 eq) in MeOH (50 ml) followed by addition of carbon disulfide (1.0 eq) at 0°C. The mixture was warned to r.t. and stirred for 5h at 40°C then cooled to r.t., filtered through Celite and the solvent removed in vacuo to give a solid that was triturated from diethyl ether to afford the titled compound as a pale yellow solid in 51 % yield.
• N,N-Benzylmethylamine 23 (1.0 g, 1.0 eq) was treated according to the general procedure with 1.0 M aqueous solution of NaOH (1.2 eq) followed by addition of carbon disulfide (2.4 eq). The title compound was obtained as a white solid in 97% yield.
• Morpholine 24 (1.0 g, 1.0 eq) was treated according to the general procedure with 1.0 M aqueous solution of NaOH (1.0 eq) followed by addition of carbon disulfide (1.2 eq). The title compound was obtained as a white solid in quantitative yield. Morpholinecarbamodithioate sodium salt 24a: m.p.
• Piperazine 25 (1.0 g, 1.0 eq) was treated according to the general procedure described above with 1.0 M aqueous solution of NaOH (2.2 eq) followed by addition of carbon disulfide (2.4 eq). The title compound was obtained as a white solid in 97% yield.
• Piperazinecarbamodithioate disodium salt disodium salt 25a m.p. > 300 °C (Lit 7 1 10 °C); v max (KBr) cm “1 , 2939, 2917, 2890, 1520, 1618, 1419, 1154; ⁇ ⁇ (400 MHz, DMSO-c ⁇ ) 4.27 (8H, s, 4 x CH 2 ); 6c (100 MHz, DMSO-i3 ⁇ 4 50.0, 214.7 (OS); m/z (ESI), 258 [M-Na] " , 160 [M-CS 2 Na] ⁇
• L-Proline 27 (0.1 g, 1.0 eq) was treated with powdered NaOH (2.0 eq) at 0 °C in diethyl ether (5 ml) followed by addition of carbon disulfide (2.0 eq). The mixture was stirred at the same temperature for 3h, warmed to r.t. The solid formed was collected by filtration and triturated from diethyl ether to afford the titled compound as a white solid in 52% yield.
• Table 1 CA I, II, IX and XII inhibition data with dithiocarbamates la-27a by a stopped-flow, C0 2 hydrase assay.
• Table 2 CA I, II, and Mycobacterial CA isoforms mtCA 1 and 3 inhibition data with dithiocarbamates by a stopped-flow, C0 2 hydrase assay.

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