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WO2013050426A1 - Carbonic anhydrase inhibitor comprising a dithiocarbamate - Google Patents

Carbonic anhydrase inhibitor comprising a dithiocarbamate Download PDF

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Publication number
WO2013050426A1
WO2013050426A1 PCT/EP2012/069548 EP2012069548W WO2013050426A1 WO 2013050426 A1 WO2013050426 A1 WO 2013050426A1 EP 2012069548 W EP2012069548 W EP 2012069548W WO 2013050426 A1 WO2013050426 A1 WO 2013050426A1
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WIPO (PCT)
Prior art keywords
carbonic anhydrase
anhydrase inhibitor
inhibitor according
carbon atoms
preferably less
Prior art date
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PCT/EP2012/069548
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French (fr)
Inventor
Claudiu T. Supuran
Andrea Scozzafava
Emanuela Masini
Fabrizio Carta
Erik Olai Pettersen
Peter Ebbesen
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.)
Universita degli Studi di Firenze
Universitetet i Oslo
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Universita degli Studi di Firenze
Universitetet i Oslo
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Publication of WO2013050426A1 publication Critical patent/WO2013050426A1/en
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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    • A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
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    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
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    • A61K31/425—Thiazoles
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07C333/14—Dithiocarbamic acids; Derivatives thereof
    • C07C333/16—Salts of dithiocarbamic acids
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • C07D207/04—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
    • 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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    • C07D211/06—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
    • 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
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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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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    • C07D233/54—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
    • 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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    • C07D277/20—Heterocyclic 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
    • C07D277/32—Heterocyclic 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
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    • C07D277/44—Acylated amino or imino radicals
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur 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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Abstract

A carbonic anhydrase inhibitor which comprises a compound of general formula: R1R2N-CS2 -M+ for use in the treatment of microbial infection, eye disease or cancer; wherein R1 and R2 are each independently selected from H or an organic substituent, or together form a ring, and optionally contain one or more heteroatoms; wherein R and R2 together comprise at least 5 carbon atoms or at least 2 carbon atoms and a heteroatom, or R2 comprises at least 4 carbon atoms; and wherein M+ comprises a monovalent cation.

Description

CARBONIC ANHYDRASE INHIBITOR COMPRISING A DITHIOCARBAMATE
Field of the Invention
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.
Background of the Invention
Carbonic anhydrases (CAs) 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: C02+H20=H++HC03 ~. In humans, 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.
Many of the CA isozymes are important therapeutic targets with the potential to be inhibited to treat a range of disorders. 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.
As some solid cancer tumours grow in cancer patients, 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"). Under hypoxic conditions, the distribution of isoforms of carbonic anhydrase (CA) is altered as compared with normoxic cells. As a result, CA isozymes IX and XII are found to be overexpressed in hypoxic tumour cells. Unlike many CAs, 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. In contrast, 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.
Efforts have been made to find inhibitors for the various carbonic anhydrase isozymes. Sulfonamide inhibitors have been described widely and sulfamate and sulfamide inhibitors have also been proposed (WO201 1/098610).
Among the many carbonic anhydrase inhibitors (CAIs) investigated to date [1], trithiocarbonate (CS3 2~) a compound similar to carbonate, has recently been investigated and shown to constitute a "lead" for novel CAIs [2,3].
The X-ray crystal structure for the adduct of trithiocarbonate (CS3 2~), bound to hCA II has recently been reported [4] (Fig. 1). The inhibitor binds to the Zn2+ 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 same sulfur makes a hydrogen bond to the OH of Thrl99 whereas a second sulfur atom participates to another hydrogen bond with the NH group of the same amino acid residues, Thrl99 [4]. This probably explains the low micromolar affinity of this inhibitor to many of the CA isoforms discussed above
It has been shown to be an active CAI, with submicromolar inhibitory activity [2,3],
There is a need in this art to find new inhibitors for therapeutically important CA isozymes. These inhibitors may be useful in pharmaceutical applications including therapy for eye disease, cancer and microbial infections.
Summary of the invention
Accordingly, in a first aspect, the present invention provides a carbonic anhydrase inhibitor which comprises a compound of general formula:
R' R2N-CS2 "M+
1 2
wherein 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 R1 and R2 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
wherein M+ comprises a monovalent cation.
It has surprisingly been found that 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.
The exact nature of the 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 R1 and R2 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.
There is no particular limitation on the size of the R groups provided that they are not so large or bulky that they interfere with the binding of the inhibitor to the zinc ion in the active site of the CA. Accordingly, the aggregate number of carbon atoms in R1 and R2 together is typically no more than 20, preferably no more than 16 and more preferably no more than 12.
Some compounds according to the invention have R1 as H. In these compounds R2 comprises at least four carbon atoms or at least two carbon atoms and a heteroatom. R2 is preferably selected from Ph, 0[(CH2CH2)]2N, MeN[(CH2CH2)]2N , 2-butyl, 0[(CH2CH2)]2N(CH2)2, N[(CH2CH2)N]3, PhCH2, 4-PyridylCH2, Et NH, [(CH2)5N]CH2CH2, 2-thiazolyl, Et3NH, KOOCCH2 or imidazol-1 - yi-(C¾)3.
In an alternative arrangement, R1 and R2 together comprise at least five carbon atoms or at least two carbon atoms and a heteroatom. Subject to this constraint, R1 and/or R2 may be chosen from Me, Et, Pr, Bu, Ph, PhCH2, hexyl or HO-CH2-CH2. Preferably, R1 and R2 are chosen wherein R1 is Et and R2 is n-Bu, R1 is Me and R2 is Ph or R1 is Me and R2 is PhCH2 or R1 and R2 together form a ring, such as (CH2)5, 0[(CH2CH2)]2, NaS(S=C)N[(CH2CH2)]2, ( C)(Ph)C(CH2CH2)2, (5)- [CH2CH2CH2CH(COONa)] .
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 Et3NH+ or imidazol-l-yl- (CH2)3NH3 +.
The effectiveness of the compounds of the invention as CA inhibitors was assessed by determination of their Ki values. Typically, 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.
According to the present invention the Ki for human CAII is typically less than ΙμΜ, preferably less than lOOnM, still more preferably less than 60nM, even more preferably less than ΙΟηΜ, 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.
Diseases and conditions mediated by or associated with cationic anhydrase activity or expression are treatable according to the present invention.
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. In a further aspect, 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. Such CAs may be responsible for secretion of bicarbonate. By inhibiting CAII the rate of biocarbonate secretion may be reduced, resulting in a decrease in intraoccular pressure (IOP) that would otherwise cause irreversible damage to the optic nerve.
In a further aspect, 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. Here, the therapeutic target is typically CAIX.
In a further aspect, 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. Here, the therapeutic target is carbonic anhydrase mtCAl and/or mtCA3.
In a further aspect, pharmaceutical 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. For example, where the carbonic anhydrase inhibitor bears a carboxylic acid group, 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. Alternatively, 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.
Pharmaceutical compositions may contain a prodrug form of the carbonic anhydrase inhibitor which is intended to become active only when metabolised by the subject. Such 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).
The precise form of pharmaceutical composition and dosage thereof will also be dependent upon the subject to be treated including body weight, route of administration and precise disease conditions.
Pharmaceutically-acceptable derivatives include esters, amides, salts and nanoparticles based on the dithiocarbamates described herein.
As will be appreciated, 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.
In a further aspect, a product is provided 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. In this way, a kit may be provided containing the present inhibitors and further chemotherapeutic agents typically in separate containers. Alternatively, where appropriate, the chemotherapeutic agent and inhibitor may be administered to the subject together.
In a further aspect, the 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. For these applications, the inhibitor typically includes a label appropriate to the particular diagnosis or imaging method. Such labels include fluorescent labels, spin labels, radiolabels or heavy atoms.
In a further aspect of the present invention, there is provided 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.
Brief Description of the Drawings
The present invention will now be described in further detail, by way of example only, with reference to the following examples and accompanying drawings in which:
FIGURE 1 shows trithiocarbonate (CS3 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 μυ> 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).
Detailed description of the invention
General experimental details.
Ή, 13C, DEPT, COSY, HMQC and HMBC spectra were recorded using a Bruker Advance III 400 MHz spectrometer. The chemical shifts are reported in parts per million (ppm) and the coupling constants (J) are expressed in Hertz (Hz). For all new compounds DEPT, COSY, HMQC and HMBC were routinely used to definitely assign the signals ofΉ and 13C.
Infrared spectra were recorded on a Perkin Elmer Spectrum R XI spectrometer as solids on KBr plates.
Melting points (m.p.) were measured in open capillary tubes, unless otherwise stated, using a Buchi Melting Point B-540 melting point apparatus and are uncorrected.
Thin layer chromatography (TLC) was carried out on Merck silica gel 60 F254 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.
All other solvents and chemicals were used as supplied from Aldrich Chemical Co., Acros, Fisher, Alfa Aesar or Lancaster Synthesis.
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 dimethyldithiocarbamate 13a (CAS 128-04-1 ), sodium diethyldithiocarbamate 14a, Pyrrolidine 15 (CAS 123-75-1), Diisobutylamine 16 (CAS 1 10-96-3), Dipropylamine 17 (CAS 142-84-7), Dibutylamine 18 (CAS 1 1 1 -92-2), Dihexylamine 19 (CAS 143-16-8), Ethylbutyamine 20 (CAS 13360-63-9), Diethanolamine 21 (CAS 1 1 1-42-2), N- methylbenzenamine 22 (CAS 100-61 -8), N,N-Benzylmethylamine 23 (CAS 103-67-3), Morpholine 24 (CAS 1 10-91-8), Piperazine 25 (CAS 1 10-85-0), 4-Cyano-4-phenylpiperidine hydrochloride 26 (CAS 51304-58-6), L-Proline 27 (CAS 147-85-3) were purchased from Aldrich.
General procedure for the synthesis of compounds la-27a.5
Scheme 1 :
Figure imgf000010_0001
1-27 la-27a
(Na is replaced by other cations as shown in Table 1, for some of the prepared compounds)
Secondary/primary amines 1-27 (1.0 g, 1.0 eq) were treated with a NaOH, OH or Et3N (1.0 - 2.2 eq), 4.0 ml of MeOH as co-solvent was used, and the solutions were stirred at 0°C for 20 min (Scheme 1 ). Then carbon disulfide (1.2 - 2.4 eq) was added dropwise and the mixture was stirred at r.t. until starting material was consumed (TLC monitoring). The solvents were removed under vacuo at r.t. and the residues obtained were dissolved in MeOH, filtered off trough Celite and the filtrate was concentrated in vacuo not exceeding 20 °C.
Synthesis of triethylammonium phenylcarbamodithioate la
Figure imgf000010_0002
4
1 la
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.
Triethylammonium phenylcarbamodithioate la: vmax (KBr) cm"1, 2960, 2886, 1648, 1599, 1520, 1451 ; δΗ (400 MHz, DMSO-<¾ 1.13 (9H, t, J 6.8, 3x CH2CH3), 2.98 (6H, brs, 3x CH2CH3), 6.97 (1H, t, J 8.0, 4-H), 7.22 (2H, dd, J 8.3, 8.0, 2x 3-H), 7.93 (2H, d, J 8.3, 2x 2-H), 9.00 (1H, brs, exchange with D20, (CH3CH2)3N+-H), 10.10 (1H, brs, exchange with D20, N-H); 5C (100 MHz, DMSO-ί ή) 10.0, 46.6, 1 14.8, 122.9, 128.4, 143.2, 215.5 (C=S); m/z (ESI), 168 [M-Na]". Synthesis of potassium morpholinocarbamodithioate 2a
Figure imgf000011_0001
2 2a
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: vmax (KBr) cm"1, 2960, 2890, 1648, 1598, 1520, 1430, 1 190; δΗ (400 MHz, DMSO-Js) 2.78 (4H, m, 2 x 3-H2), 3.60 (4H, m, 2 x 2-H2), 8.62 (1H, brs, exchange with D20, N-H); 5C (100 MHz, DMSO- ) 55.0 (C-3), 66.9 (C-2), 213.4 (OS); m/z (ESI), 177 [M-Na]\
Synthesis of potassium 4-methylpiperazin-l -ylcarbamodithioate 3a
Figure imgf000011_0002
3 3a
4-Methylpiperazin-l -amine 3 (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 white solid in 66 % yield.
4-Methylpiperazin-l-ylcarbamodithioate 3a: vmax (KBr) cm"1, 2954, 1630, 1597, 1520, 1424; δΗ (400 MHz, DMSO-<¾) 2.26 (3H, s, CH3), 2.49 (4H, m, 2 x 3-H2), 2.81 (4H, m, 2 x 2-H2), 8.65 (1H, brs, exchange with D20, N-H); 5C (100 MHz, DMSO-i¾) 46.4 ( H3), 54.1 , 55.2, 213.4 (OS); m/z (ESI), 190 [M-Na]\
Synthesis of (±) potassium sec-butylcarbamodithioate 4a
Figure imgf000012_0001
(±) sec-Butylamine 4 (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 yellow residue that was dispersed in MeOH (15ml) filtered through Celite, the filtrated was concentrated in vacuo to afford the titled compound as a yellow semisolid in 65 % yield.
(±) Potassium sec-butylcarbamodithioate 4a: vmax (KBr) cm"1, 2947, 2892, 1650, 1600, 1520, 1421 , 1 190; δΗ (400 MHz, DMSO-<¾) 0.86 (3H, t, J 6.7, 4-CH3), 1.16 (3Η, d, J 6.6, 1-CH3), 1.20-1.60 (2Η, m, 3-H2), 4.30 (1H, m, 2-H), 7.68 (1H, brs, exchange with D20, N-H); 5C (100 MHz, DMSO- d6) 1 1.5, 20.3, 29.4, 53.4, 214.7 (OS); m/z (ESI), 148 [M-Na]". Synthesis of potassium 2'-morpholinoethylcarbamodithioate 5a
Figure imgf000013_0001
5 5a
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.
Potassium 2'-morpholinoethylcarbamodithioate 5a: vmax (KBr) cm"1, 2970, 2888, 1650, 1600, 1520; δΗ (400 MHz, DMSO-<¾ 2.41 (6H, m, 2x 2-H2, 2'-H2), 3.52 (2H, m, l '-H2), 3.60 (4H, m, 3-H2), 7.78 (IH, brs, exchange with D20, N-H); 5C (100 MHz, DMSO-i¾ 44.1, 54.2, 57.7, 67.1 , 215.7 (OS); m/z (ESI), 205 [M-Na]'.
Synthesis of potassium 2,2',2"-nitrilotris(ethane-2,l-diyl)tricarbamodithioate 6a
Figure imgf000014_0001
6 6a
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 wanned 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.
Potassium 2,2',2"-nitrilotris(ethane-2,l-diyl)tricarbamodithioate 6a vmax (KBr) cm"1, 2962, 2880, 1653, 1594, 1517, 1452; δΗ (400 MHz, DMSO- 6) 2.60-2.90 (12H, m), 7.67 (lH,brs, exchange with D20, N-H), 7.92 (lH,brs, exchange with D20, N-H), 8.37 (lH.brs, exchange with D20, N-H); 5C (100 MHz, DMSO-i¾ 45.24, 53.7, 215.5 (OS); m/z (ESI), 371 [M-Na]".
Synthesis of sodium benzylcarbamodithioate 7a
Figure imgf000014_0002
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.
Sodium benzylcarbamodithioate 7a: vmax (KBr) cm"1, 2961 , 2892, 1648, 1580, 1521 , 1450; δΗ (400 MHz, DMSO-J6) 4.75 (2H, d, J 6.6, V-H2), 7.18-7.25 (5H, m, Ar-H), 8.42 (1 H, brs, exchange with D20, N-H); 5C (100 MHz, DMSO-i¾ 50.5, 127.0, 128.3, 128.6, 141.5, 216.3 (C=S); m/z (ESI), 182 [M-Na]".
Synthesis of triethylammonium pyridin-4-ylmethylcarbamodithioate 8a
Figure imgf000015_0001
8
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: vmax (KBr) cm"1, 2960, 2884, 1650, 1578, 1518, 1449; δΗ (400 MHz, DMSO-i¾ 1.22 (9H, t, J 7.4, 3x CH2G¾), 3.14 (6H, q, J 7.4, 3x CH2CH3), 4.74 (2H, d, J 6.4, V-H2), 7.25 (2H, d, J 6.0, Ar-H), 8.46 (2H, d, J 6.0, Ar-H), 8.70 (1H, brs, exchange with D20, N-H), 9.18 (1Η, brs, exchange with D20, (CH3CH2)3N+-H); 5C (100 MHz, DMSO-rfi) 9.6, 46.6, 49.7, 123.3, 149.9, 150.5, 216.7 (OS); m/z (ESI), 183 [M-Na]".
Synthesis of potassium 2'-(piperidin-l -yl)ethylcarbamodithioate 9a
Figure imgf000016_0001
9 9a
2'-(Piperidin-l-yl)ethanamine 9 (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, wanned 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 pale yellow solid in 65 % yield.
Potassium 2'-(piperidin-l-yl)ethylcarbamodithioate 9a: vmax (KBr) cm"1, 2976, 2894, 1656, 1520; δΗ (400 MHz, DMSO-<¾ 1.42 (2H, m, 4-H2), 1.53 (4H, m, 2x 3-H2), 2.40 (6H, m, 2x 2-H2, 2'-H2), 3.48 (4H, m, l '-H2), 7.72 (1H, brs, exchange with D20, N-H); 5C (100 MHz, DMSO-Jtf) 25.0, 26.4. 44.4, 54.9, 57.9, 215.7 (C=S); m/z (ESI), 203 [M-Na]'. Synthesis of tri ethyl ammonium thiazol-2-ylcarbamodithioate 10a
Figure imgf000017_0001
10 10a
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.
Triethylammonium thiazol-2-ylcarbamodithioate 10a: vmax (KBr) cm"1 , 2960, 2892, 1650, 1578, 1519, 1450; δΗ (400 MHz, DMSO- ) 1.21 (9H, t, J 7.2, 3x CH2CH3), 3.1 1 (6H, q, J 7.4, 3x CH2CH3), 6.87 (1 H, d, J 3.2, Ar-H), 7.34 (1 H, d, J 3.2, Ar-H), 9.25 (1 H, brs, exchange with D20, (CH3CH2)3N+-H), 10.83 (1H, brs, exchange with D20, N-H); 5C (100 MHz, DMSO-<¾ 9.6, 46.5, 1 1 1.7, 137.3, 162.6, 213.0 (C=S); m/z (ESI), 175 [M-Na]".
Data are in agreement with reported data. 6
Synthesis of potassium 2-(dithiocarboxylatoamino)acetate 11a
Figure imgf000017_0002
11 11a Glycine 11 (0.5 g, 1.0 eq) was treated with powdered KOH (2.0 eq) at 0 °C in diethyl ether (20 ml) followed by addition of carbon disulfide (2.0 eq). The mixture was stirred at the same temperature for 6h, warmed to r.t.. The solid formed was collected by filtration and triturated from diethyl ether to afford the titled compound as a light-brown solid in 50% yield.
Potassium 2-(dithiocarboxylatoamino)acetate 11a: vmax (KBr) cm"1, 2962, 2876, 1652, 1600, 1520, 1450; δΗ (400 MHz, DMSO^) 3.52 (2H, d, J 5.2, G¾), 7.80 (1H, brs, exchange with D20, NH); 5C (100 MHz, DMSO-i¾ 53.4, 172.1 , 213.0 (C=S); m/z (ESI), 149 [M-Na]".
Synthesis of 3 -(lH-imidazol-l "-yl)propan- "-aminium 3'-(lH-imidazol- yl)propylcarbamodithioate 12a
Figure imgf000018_0001
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.
3 -(lH-Imidazol-l "-yl)propan- "-aminium 3'-(lH-imidazol- -yl)propylcarbamodithioate 12a: vmax (KBr) cm"1, 2965, 2893, 1650, 1590, 1520, 1448; δΗ (400 MHz, DMSO-i¾ 1.99 (4H, m, 2'-H2, 2"'-H2), 2.76 (2H, t, J 7.6, l '-H2), 3.39 (2H, m, 1 "'-H2), 3.98 (2H, t, J 7.2, 373"'-H2), 4.10 (2H, t, J 7.2, 373"'-H2), 6.90 (1H, s, 5-H/5'-H), 6.95 (1H, s, 5-H/5'-H), 7.21 (2H, s, 4-H, 4'-H), 7.68 (2H, s, 2-H, 2'-H), 7.71 (3H, brs, exchange with D20, -NH3), 8.29 (1 H, brs, exchange with D20, -NH); 5C (100 MHz, DMSO-i¾ 30.3, 31.7, 38.0, 45.1 , 45.6, 45.9, 121.4, 124.5, 129.5, 130.0, 138.9, 139.0, 215.1 (C=S); m/z (ESI), 200 [M-Na]".
Synthesis of 1 -pyrrolidinecarbodithioic acid sodium salt 15a.
Figure imgf000019_0001
15 15a
Pyrrolidine 15 (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 56 % yield.
1 -Pyrrolidinecarbodithioic acid sodium salt 15a: m.p. > 300 °C (Lit2 > 300 °C); vmax (KBr) cm"1 , 2970, 2863, 1520, 1 161 ; δΗ (400 MHz, D20) 2.01 (4H, m), 3.78 (4H, m); 5C (100 MHz, D20) 26.1 , 55.5, 203.1 (OS); m/z (ESI), 146 [M-Na]".
Data are in agreement with reported data.7
Synthesis of diisobutylcarbodithioic acid sodium salt 16a.
Figure imgf000019_0002
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; ; vmax (KBr) cm" 1 , 2961 , 2933,
2867, 1640, 1601 , 1520, 1480, 1090; δΗ (400 MHz, DMSO-<¾ 0.84 (12H, d, J 6.8, 4 x CH3), 2.43 (4H, m, 2 x CH), 3.86 (4H, d, J 7.2, 2 x G¾); 5C (100 MHz, DMSO-^) 21.2, 27.4, 61.5, 215.4 (OS); m/z (ESI), 204 [M-Na]".
Data are in agreement with reported data.8
Synthesis of dipropylcarbamodithioate sodium salt 17a
Figure imgf000020_0001
17 17a
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.
Dipropylcarbamodithioate sodium salt 17a: m.p.1 12- 1 14 °C ; vmax (KBr) cm"1, 2961 , 2930, 2871 , 1635, 1520, 1470, 1 198; δΗ (400 MHz, DMSO-i¾ 0.82 (6H, t, J 7.6, 2 x CH3), 1.65 (4H, m, 2 x CH2), 3.90 (4H, m, 2 x CH2); δα (100 MHz, DMSO-i¾ 12.3 ( H3), 21.0, 55.2, 213.5 (C=S); m/z (ESI), 176 [M-Na]".
Data are in agreement with reported data.9 Synthesis of dibutylcarbamodithioate sodium salt 18a.
Figure imgf000021_0001
18 18a
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.
Dibutylcarbamodithioate sodium salt 18a: semisolid at r.t. ; vmax (KBr) cm"1 , 2959, 2935, 2870, 1637, 1520, 1475, 1 190; δΗ (400 MHz, DMSO-t¼) 0.91 (6H, t, J 8.0, 2 x CH3), 1 -26 (4H, m, 2 x CH2), 1 .62 (4H, m, 2 x CH2), 3.95 (4H, m, 2 x CH2); 5C (100 MHz, DMSO-i¾) 14.9 (CH3), 20.7, 30.0, 53.0, 213.5 (C=S); m/z (ESI), 204 [M-Na]".
Data are in agreement with reported data.8a
Synthesis of dihexylcarbamodithioate sodium salt 19a.
Figure imgf000021_0002
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. Dihexylcarbamodithioate sodium salt 19a: semisolid at r.t.; vmax ( Br) cm"' , 2960, 2930, 2890, 1638, 1520, 1414, 1 188; δΗ (400 MHz, DMSO-c 6) 0.91 (6H, t, J 6.8, 2 x CH3), 1.29 (12H, m, 2 x CH2), 1 .63 (4H, m, 2 x CH2), 3.93 (4H, m, 2 x CH2); δα (100 MHz, DMSO-i¾ 14.9 (CH3), 23.1 , 27.2, 27.8, 32.1 , 53.2, 213.6 (C=S); m/z (ESI), 260 [M-Na]'.
Synthesis of ethylbutylcarbamodithioate sodium salt 20a.
NH + CS2 NaOH 1.0M aq. - NTX S© N ©a
20 20a
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.
Ethylbutylcarbamodithioate sodium salt 20a: m.p. 71 -73 °C; vmax (KBr) cm"1, 2958, 2929, 2860, 1641 , 1626, 1520, 1409, 1 195; δΗ (400 MHz, DMSO-<¾ 0.92 (3H, t, J 8.0, CH3), 1 - 12 (3H, t, J 8.0, CH3), 1.27 (2H, m, CH2), 1.61 (2H, m, CH2), 3.95 (2H, m, CH2), 4.03 (2H, q, J 8.0, CH2); 5C (100 MHz, DMSO-ί ή) 13.4 ( H3), 14.9 (CH3), 20.8, 30.1 , 47.6, 52.5, 213.3 (C=S); m/z (ESI), 176 [M- Na]\
Synthesis of sodium bis(2-hydroxyethyl)carbamodithioate 21a
Figure imgf000022_0001
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.
Sodium bis(2-hydroxyethyl)carbamodithioate 21a: vmax (KBr) cm"1, 2960, 2890, 1651 , 1600, 1520, 1453; δΗ (400 MHz, DMSO-c ) 3.67 (4H, q, J 6.8, 2x 2-H2), 4.13 (4H, t, J 6.9, 2x 1 -H2), 4.90 (2H, t, J 6.8, exchange with D20, 2x O-H); 5C (100 MHz, DMSO-ck) 56.6, 60.3, 215.7 (OS); m/z (ESI), 180 [M-Na]".
Synthesis of sodium methyl(phenyl)carbamodithioate 22a
Figure imgf000023_0001
22 22a
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.
Sodium methyl(phenyl)carbamodithioate 22a: vmax (KBr) cm"1, 2958, 2890, 1630, 1582, 1520, 1450; 5H (400 MHz, DMSO-c¾ 3.66 (3H, s, CH3), 7.17 (3H, m, 2x 2-H 4-H), 7.29 (2H, dd, J 8.3, 7.2, 2x 3-H); 5C (100 MHz, DMSO-e¾ 46.7, 125.7, 128.3, 129.0, 151.6, 216.9 (C=S); m/z (ESI), 182 [M-Na]". Synthesis of NN-benzylmethylcarbamodithioate sodium salt 23a.
Figure imgf000024_0001
23 23a
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.
N,N-Benzylmethylcarbamodithioate sodium salt 23a: m.p. 258-260 °C; vmax (KBr) cm"1, 2960, 2930, 1643, 1626, 1520, 1346, 1080; δΗ (400 MHz, DMSO-i¾ 3.32 (3H, s, G¾), 5.50 (2H, s, CH2), 7.26 (5H, m, Ar-H); 5C (100 MHz, DMSO-<¾) 41.5 (CH3), 58.4 (CH2), 127.3, 128.2, 128.9, 140.0 (ipso), 216.1 (C=S); m/z (ESI), 196 [M-Na]\
Synthesis of morpholinecarbamodithioate sodium salt 24a.
Figure imgf000024_0002
24 24a
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. 320 °C with dec; vmax ( Br) cm" , 2966, 2901 , 2854, 1625, 1520, 1416, 1215; δΗ (400 MHz, DMSO-i¾ 3.52 (4H, t, J 8.0 G¾), 4.33 (2H, t, J 8.0, CH2); 5C (100 MHz, DMSO-<¾) 50.6, 67.1 , 215.4 (OS); m/z (ESI), 162 [M-Na]".
Data are in agreement with reported data.
Synthesis of piperazinecarbamodithioate disodium salt 25a.
S
NH + cs? NaOH l .OM aq. N ΛΘ S N ©a
HN
Na® O S
25 25a
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 (Lit7 1 10 °C); vmax (KBr) cm"1, 2939, 2917, 2890, 1520, 1618, 1419, 1154; δΗ (400 MHz, DMSO-c^) 4.27 (8H, s, 4 x CH2); 6c (100 MHz, DMSO-i¾ 50.0, 214.7 (OS); m/z (ESI), 258 [M-Na]", 160 [M-CS2Na]\
Data are in agreement with reported data.9
Synthesis of 4-cyano-4-phenylpiperidinecarbamodithiate sodium salt 26a.
Figure imgf000025_0001
26 26a 4-Cyano-4-phenylpiperidine hydrochloride 26 (1.0 g, 1.0 eq) was treated according to the general procedure with 1.0 M aqueous solution of NaOH (2.2 eq) followed by addition of carbon disulfide (1.2 eq). The title compound was obtained as a white solid in 93 % yield.
4-Cyano-4-phenylpiperidinecarbamodithiate sodium salt 26a: m.p. > 320 °C with dec; vmax (KBr) cm"1 , 2961, 2891 , 1648, 1598, 1520, 1414, 1 186; 6H (400 MHz, DMSO-i¾) 1.89 (2H, td, J 12.8, 3.6, 2 x 3Hax), 2.14 (2H, d, J 12.8, 2 x 3Heq), 3.15 (2H, t, J 12.8, 2 x 2Hax), 6.15 (2H, d, J 12.8, 2 x 2Heq); 6C (100 MHz, DMSO- 6) 36.6, 43.3, 51.1, 123.2, 126.5, 129.0, 130.0 (ipso), 141.0, 216.1 (OS); m/z (ESI), 261 [M-Na]\
Synthesis of sodium (S)-l-dithiocarboxylatopyrrolidine-2-carboxylate 27a
Figure imgf000026_0001
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.
Sodium (5 -l -dithiocarboxylatopyrrolidine-2-carboxylate 27a: vmax (KBr) cm"', 2962, 2892, 1650, 1598, 1519, 1445; δΗ (400 MHz, D20) 2.00 (3H, m), 2.30 (1H, m, 2-H), 3.81-4.00 (2H, m), 4.80 (1H, m); 5C (100 MHz, D20) 24.9, 31.8, 49.5, 55.9, 69.7, 180.4 (CO), 206.0 (OS); m/z (ESI), 244 [M-Na]". Abbreviation List aq. aqueous br broad brd broad doublet brs broad singlet
°C temperature in degrees Centigrade eq equivalents h hour(s)
Hz Hertz
J coupling constant in Hz lit. literature
Umax wavenumber min minutes mol moles
M molarity
MeOH methanol
MHz megaHertz m.p. melting point
NMR nuclear magnetic resonance ppm parts per million q quartet r.t. room temperature
5C 13C chemical shift reported in ppm δΗ H chemical shift reported in
TLC thin layer chromatography
References
1. a) C.T. Supuran, Nature Rev. Drug Discov. 7 (2008) 168-181 ;
b) D. Neri, C.T. Supuran, Nature Rev. Drug Discov. 10 (201 1) 767-777.
2. A. Innocenti, A. Scozzafava, C.T. Supuran, Bioorg. Med. Chem. Lett. 19 (2009) 1855-1857.
3. A. Innocenti, A. Scozzafava, C.T. Supuran, Bioorg. Med. Chem. Lett. 20 (2010) 1548-1550.
4. C. Temperini, A. Scozzafava, C.T. Supuran, Bioorg. Med. Chem. Lett. 20 (2010) 474-478.
5a) Shell International Research Maatschappij B. V., Organic Molibdenum compounds, use thereof as friction modifiers and lubricating compositions, W.O. 2008/1 13814 Al .
5b) S.T.V.S. Kiran Kumar , L., Kumar, V. L. Sharma, A. Jain, R. K. Jain, J. P. Maikhuri, M. Kumar, P. K. Shukla, G. Gupta, Carbodithioic acid esters of fluoxetine, a novel class of dual- function spermicides, Eur. J. Med. Chem., 2008, 43, 2247-256.
6) Treasurywala, Adi M.; Bagli, Jehan; Baker, Harold, Substituted pyrimidones with antifungal properties, CA 1232904 (Al )
7) Soliman, Raafat; Egyptian Journal of Chemistry, 1990, 31, 175-86.
8a) Ivanov, A. V.; Korneeva, E. V.; Gerasimenko, A. V.; Forsling, W, Structural Organization of Nickel(II), Zinc(II), and Copper(II) Complexes with Diisobutyldithiocarbamate: EPR, 13C and 15N CP/MAS NMR, and X-Ray Diffraction Studies, Russian Journal of Coordination Chemistry, 2005, 31, 695-707.
8b) Rodina, Tatyana A.; Ivanov, Alexander V.; Gerasimenko, Andrey V.; Ivanov, Maxim A.; Zaeva, Anna S.; Philippova, Tatyana S.; Antzutkin, Oleg N. , A pyridine adduct of bis(di-iso- butyldithiocarbamato-S,S')cadmium(II): Multinuclear (13C, 15N, 1 13Cd) CP/MAS NMR spectroscopy, crystal and molecular structure, and thermal behavior, Inorganica Chimica Acta, 2011, 368, 263-270.
9) Ivanov, A. V.; Pakusina, A. P.; Ivanov, M. A.; Sharutin, V. V.; Gerasimenko, A. V.; Antzutkin, O. N.; Groebner, G.; Forsling, W, Synthesis and single-crystal X-ray diffraction and CP/MAS 13C and 15N NMR study of tetraphenylantimony N,N-dialkyldithiocarbamate complexes: A manifestation of conformational isomerism, Physical Chemistry, 2005, 401, 44-48.
10) K.S. Siddiqi, S. A. A. Nami, Y. Chebude and A. Marzotto, Piperazine-bridged homodinuclear transition metal complexes, J. Chem. Res. 2006, 67-71.
Table 1 : CA I, II, IX and XII inhibition data with dithiocarbamates la-27a by a stopped-flow, C02 hydrase assay.
R'R2N-CSS"M+
la-27a
Cmpnd R1 R2 i (nM) M
hCA I hCA II hCA IX hCA XII
la H Ph 4.8 4.5 4.2 4.3 Et3NH
2a H 0[(CH2CH2)]2N 4.8 3.6 29.1 9.2 K
3a H MeN[(CH2CH2)]2N 33.5 33.0 22.1 17.5 K
4a H 2-butyl 21.1 29.4 4.6 31.7 K
5a H 0[(CH2CH2)]2N(CH2)2 31.8 36.3 4.5 4.2 K
6a* H N[(CH2CH2)N]3 31.9 13.5 27.4 9.3 K
7a H PhCH2 4.1 0.7 19.2 1 1.5 Na
8a H 4-PyridylCH2 3.5 16.6 26.0 24.1 Et3NH
9a H [(CH2)5N]CH2CH2 4.5 20.3 3.6 20.5 K
10a H 2-thiazolyl 3.9 4.6 12.6 22.0 Et3NH
11a H OOCCH2 13.1 325 57.1 6.7 K
12a H imidazol- 1 -yl-(CH2)3 8.6 24.7 4.3 6.5 imidazol- 1 -yl-(CH2)3NH3
13a Me Me 699 6910 714 798 Na
14a Et Et 790 3100 1413 1 105 Na
15a (CH2)5 0.96 27.5 70.4 46.1 Na
16a iso-Bu iso-Bu 0.97 0.95 4.5 0.99 Na
17a n-Pr n-Pr 1838 55.5 53.8 7.0 Na
(Table 1 , continued)
18a n-Bu n-Bu 43.1 50.9 50.3 5.8 Na
19a n-Hex n-Hex 48.0 51.3 27.4 16.1 Na
20a Et n-Bu 157 27.8 25.9 7.5 Na
21a HOCH2CH2 HOCH2CH2 9.2 4.0 4.3 4.2 Na
22a Me Ph 39.6 21.5 28.2 7.7 Na 23a Me PhCH2 69.9 25.4 53.0 3.0 Na 24a 0[(CH2CH2)]2 0.88 0.95 6.2 3.4 Na 25a NaS(S=C)N[(CH2CH2)]2 12.6 0.92 37.5 0.78 Na
26a (NC)(Ph)C(CH2CH2)2 40.8 757 169 Na
27a** 0S)-[CH2CH2CH2CH(COONa)] 17.3 4.1 4.0 Na
*Tris-dithiocarbamate; **(5)-proline dithiocarbamate
From Innocenti et al, Bioorganic & Medicinal Chemistry Letters 19 (2009) 1855-1857
Table 2: CA I, II, and Mycobacterial CA isoforms mtCA 1 and 3 inhibition data with dithiocarbamates by a stopped-flow, C02 hydrase assay.
R'R2N-CSSNa
13a-26a
CmpndR1 R2 K[ (nM)
hCA I hCA II mtCA 1 mtCA 3
13a Me Me 699 6910 893 659
14a Et Et 790 3100 615 431
15a (CH2)5 0.96 27.5 90.5 4.1
16a iso-Bu iso-Bu 0.97 0.95 86.2 43.0
17a n-Pr n-Pr 1838 55.5 74.8 80.0
18a n-Bu n-Bu 43.1 50.9 81.7 72.8
19a n-Hex n-Hex 48.0 51.3 95.4 51.7
20a Et n-Bu 157 27.8 91.6 63.5
22a Me PhCH2 69.9 25.4 72.0 62.5
24a 0[(CH2CH2)]2 0.88 0.95 0.94 0.91
25a NaS2CN[(CH2CH2)]2 12.6 0.92 7.7 8.0
26a (NC)(Ph)C(CH2CH2)2 48.4 40.8 93.0 61.2

Claims

Claims
1. A carbonic anhydrase inhibitor which comprises a compound of general formula:
R'R2N-CS2 "M+
for use in the treatment of microbial infection;
wherein R1 and R2 are each independently selected from H or an organic substituent, or together form a ring, and optionally contain one or more heteroatoms;
wherein R and R 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
wherein M+ comprises a monovalent cation.
2. A carbonic anhydrase inhibitor according to claim 1 , wherein the microbial infection comprises tuberculosis.
3. A carbonic anhydrase inhibitor according to claim 1 or claim 2, wherein Ki for Mycobacterium tuberculosis carbonic anhydrase CAl or CA3 is less than lOOnM, preferably less than Ι ΟηΜ, more preferably less than InM.
4. A carbonic anhydrase inhibitor which comprises a compound of general formula:
R'R2N-CS2 ~M+
for use in the treatment of eye disease;
wherein R1 and R2 are each independently selected from H or an organic substituent, or together form a ring, and optionally contain one or more heteroatoms;
wherein R1 and R2 together comprise at least 5 carbon atoms or at least 2 carbon atoms and a heteroatom, or R2 comprises at least 4 carbon atoms; and
wherein M+ comprises a monovalent cation.
5. A carbonic anhydrase inhibitor according to claim 4, wherein the eye disease is glaucoma.
6. A carbonic anhydrase inhibitor according to claim 4 or claim 5, wherein i for human carbonic anhydrase II is less than Ι ΟΟηΜ, preferably less than 60nM, more preferably less than Ι ΟηΜ.
7. A carbonic anhydrase inhibitor which comprises a compound of general formula:
R'R2N-CS2 "M+
for use in the treatment of cancer;
wherein 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 R1 and R2 together comprise at least 5 carbon atoms or at least 2 carbon atoms and a heteroatom, or R2 comprises at least 4 carbon atoms; and
wherein M+ comprises a monovalent cation.
8. A carbonic anhydrase inhibitor according to claim 7, wherein the treatment of cancer comprises treating a hypoxic tumour.
9. A carbonic anhydrase inhibitor according to claim 7 or claim 8, wherein Ki for human carbonic anhydrase IX is less than Ι ΟΟηΜ, preferably less than 60nM, more preferably less than ΙΟηΜ.
10. A carbonic anhydrase inhibitor according to any one of claims 7 to 9, for use in cancer treatment of a subject who is treated additionally with chemotherapy, radiation therapy or surgery.
1 1. A carbonic anhydrase inhibitor according to any one of claims 7 to 9, which inhibitor includes a label suitable for use in diagnosis or imaging.
12. A carbonic anhydrase inhibitor according to claim 11, for use in cancer diagnosis.
13. A carbonic anhydrase inhibitor according to any one of the preceding claims, wherein
1 2
R and R together comprise no more than 12 carbon atoms.
14. A carbonic anhydrase inhibitor according to any one of the preceding claims, wherein M+ is an alkali metal cation or a base.
15. A carbonic anhydrase inhibitor according to claim 14, wherein M+ is an alkali metal cation which is Na+ or K+.
16. A carbonic anhydrase inhibitor according to claim 14, wherein M+ is a base which is Et3NH+ or imidazol-l-yl-(C¾)3NH3 +.
17. A carbonic anhydrase inhibitor according to any one of the preceding claims wherein R1 is H.
18. A carbonic anhydrase inhibitor according to claim 17, wherein R2 is selected from Ph, 0[(CH2CH2)]2N, MeN[(CH2CH2)]2N , 2-butyl, 0[(CH2CH2)]2N(CH2)2, N[(CH2CH2)N]3, PhCH2, 4-PyridylCH2, [(CH2)5N]CH2CH2, 2-thiazolyl, KOOCCH2 or imidazol-l-yl-(CH2)3.
19. A carbonic anhydrase inhibitor according to any one of claims 1 to 16, wherein R1 and R are each iso-Bu, n-Pr, n-Bu, n-Hex or HO-CH2-CH2; wherein R is Et and R" is n-Bu, R1 is Me and R2 is Ph or R1 is Me and R2 is PhCH2 or R1 and R2 together form a ring as (CH2)5, 0[(CH2CH2)]2, NaS(S=C)N[(CH2CH2)]2, (NC)(Ph)C(CH2CH2)2 or (5)- [CH2CH2CH2CH(COONa)] .
20. A carbonic anhydrase inhibitor which comprises a compound of general formula:
R' R2N-CS2 "M+
wherein R1 is H, and R2 is selected from Ph, 0[(CH2CH2)]2N, MeN[(CH2CH2)]2N , 2-butyl, 0[(CH2CH2)]2N(CH2)2, N[(CH2CH2)N]3, PhCH2, 4-PyridylCH2, [(CH2)5N]CH2CH2, 2- thiazolyl, KOOCCH2 or imidazol-l-yl-(CH2)3 ; or wherein R1 and R2 are each iso-Bu, n-Pr, n-Bu, n-Hex or HO-CH2-CH2; wherein R1 is Et and R2 is n-Bu, R1 is Me and R2 is Ph or R1 is Me and R2 is PhCH2; or wherein R1 and R2 together form a ring; and
wherein M+ comprises a monovalent cation.
21. A carbonic anhydrase inhibitor according to claim 20, wherein R and R together form a ring and comprise no more than 12 carbon atoms.
22. A carbonic anhydrase accordingto claim 21 , wherein R and R together form a ring as (CH2)5, 0[(CH2CH2)]2, NaS(S=C)N[(CH2CH2)]2, (NC)(Ph)C(CH2CH2)2 or (S)- [CH2CH2CH2CH(COONa)] .
23. A carbonic anhydrase inhibitor according to any one of claims 20 to 22, wherein M+ is an alkali metal cation or a base.
24. A carbonic anhydrase inhibitor according to claim 23, wherein M+ is an alkali metal cation which is Na+ or K+.
25. A carbonic anhydrase inhibitor according to claim 23, wherein M+ is a base which is Et3NH+ or imidazol-l-yl-(CH2)3NH3 +.
26. A carbonic anhydrase inhibitor according to any one of claims 20 to 25, for use in medicine.
27. An imaging composition comprising a carbonic anhydrase inhibitor according to any one of claims 12 to 25 and a suitable diluent, excipient or carrier, wherein the inhibitor includes a label suitable for use in imaging.
28. A pharmaceutical composition comprising a carbonic anhydrase inhibitor according to any one of claims 20 to 25 and a pharmaceutically-acceptable diluent, excipient or carrier.
29. A product comprising a carbonic anhydrase inhibitor according to any one of claims 7 to 9 or 20 to 25 and a chemotherapeutic agent as a combined preparation for simultaneous, separate or sequential use in cancer treatment.
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