WO2014080378A1 - Phenothiazine derivatives and their use against tuberculosis - Google Patents
Phenothiazine derivatives and their use against tuberculosis Download PDFInfo
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- WO2014080378A1 WO2014080378A1 PCT/IB2013/060403 IB2013060403W WO2014080378A1 WO 2014080378 A1 WO2014080378 A1 WO 2014080378A1 IB 2013060403 W IB2013060403 W IB 2013060403W WO 2014080378 A1 WO2014080378 A1 WO 2014080378A1
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- 210000002966 serum Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 231100000064 subacute toxicity study Toxicity 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000009044 synergistic interaction Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 235000019143 vitamin K2 Nutrition 0.000 description 1
- 239000011728 vitamin K2 Substances 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 229940041603 vitamin k 3 Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 125000001834 xanthenyl group Chemical class C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
- C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—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 sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
Definitions
- This invention relates to tricyclic derivatives of phenothiazines, phenoxazines, phenazines, acridines, oxazepines, diazepins, xanthenes, thioxanthenes and uses thereof.
- the phenothiazine antipsychotic and antihistaminic drugs prochlorperazine, chlorpromazine, and promazine have demonstrated a synergistic interaction with a wide spectrum of antimicrobial agents.
- the minimum inhibitory concentrations of these antibiotics were sometimes reduced up to 8,000-fold in the presence of the phenothiazines.
- Phenothiazines are also known to increase the NADH/NAD ratio of Mycobacterium tuberculosis via the inhibition of type II NADH:menaquinone oxidoreductase. In this way they are able to increase the reduced state of a cell and are capable of acting synergistically with drugs that require mycothiol for activation such as isoniazid and ethionamide. These combination therapies assist in limiting the emergence of resistance to antimicrobial agents. It has been proven that phenothiazines, such as thioridazine are active against Multi- and Extremely Drug Resistant forms of Mycobacterium tuberculosis.
- Phenothiazines have demonstrated a wide range of biological activities, though they are primarily used as neuroleptic drugs. These neuroleptic attributes limit antimicrobial utility of these drugs in diseases such as tuberculosis as they may induce undesirable central nervous system (CNS) side effects at a mycobactericidal dose. There is thus a need for modified phenothiazine derivatives which exhibit no or minimal undesirable CNS side effects.
- CNS central nervous system
- Ri is an alkyl sulphonate or sulphonamide group
- R 2 is hydrogen, a halogen, a substituted alkyl group, a thioether or an acetyl group
- Y is N, or C
- X is S, SO, SO 2 , N, O, CH 2 , C(O), CO 2 , NHCO
- ring B is a 6, 7 or an 8 membered cycloalkyl ring.
- R 2 is H, CI, Br, SMe, C(O)CH 3 or CF 3 ;
- Y is N or C and X is S, SO, SO 2 , N, O, CH 2 , C(O), CO 2 , NHCO, and
- ring B is a 6, 7 or an 8 membered cycloalkyl ring.
- tricyclic derivative to be selected from: Phenothiazines
- R 2 is not H
- anti-tubercular drugs to be selected from isoniazid, ethionamide, ethambutol, pyrazinamide,rifampicin, amikacin, kanamycin, capreomycin, viomycin, enviomycin, ciprofloxacin, levofloxacin, moxifloxacin, rifabutin, clarithromycin, linezolid, thioacetazone, prothionamide.
- anti-tubercular drug to selected from isoniazid, ethionamide, ethambutol, pyrazinamide, rifampicin, amikacin, kanamycin, capreomycin, viomycin, enviomycin, ciprofloxacin, levofloxacin, moxifloxacin, rifabutin, clarithromycin, linezolid, thioacetazone, prothionamidea.
- Figure 1 shows anti-mycobacterial activity of isoniazid (INH), thioridazine (TZ) and synthesized phenothiazine derivatives C3, C4, C31 , C32 and C33 directly against M.tb H37Rv.gfp using the GFAP microplate assay and a table summarising the derived MIC 5 o values;
- FIG. 2 shows activity of test compounds against intracellular M.tb
- Figure 3a and 3b show results of a radio-ligand binding assay indicating no activity in terms of binding to dopaminergic- receptor subtypes D1 , D2, D3 and serotonergic-receptor subtypes 5-HT1 A, 5-HT2A, and 5-HT2C;
- Figure 3c is a graphical representation of percentage inhibition of C3
- Figure 3d is a graphical representation of percentage inhibition of C4
- Figure 3e is a graphical representation of percentage inhibition of C31
- Figure 4 is a graph showing changes in body weight on a daily basis of mice receiving daily doses of 100 mg/kg of either C3 or C4 and mice left untreated, over a 14 day period;
- Figure 5 are graphs showing organ weights of mice at the end of a
- Tricyclic derivatives of the general formula (1 ) are provided, as illustrated below,
- Ri is an alkyl sulphonate or sulphonamide group
- R 2 is a hydrogen, a halogen, a substituted alkyl group, a thioether or an acetyl group
- Y is N, or C
- X is S, SO, SO 2 , N, O, CH 2 , C(O), CO 2 , NHCO
- ring B is a 6, 7 or an 8 membered cycloalkyi ring.
- R 2 is H, CI, Br, SMe, C(0)CH 3 or CF 3 ;
- Y is N or C and X is S, SO, SO 2 , N, O, CH 2 , C(O), CO 2 , NHCO, and
- ring B is a 6, 7 or an 8 membered cycloalkyi ring.
- the tricyclic derivatives of the general formula (1 ) may be selected from:
- a process for preparing /V-alkylsulfonates of phenothiazine involves:
- phenothiazine derivatives of the invention have been shown to have limited toxicity against primary macrophage cultures as well as limited psychotropic activity.
- phenothiazine drugs are thought to involve the blockade of synaptic dopamine receptors in the brain. It has been shown by means of molecular space filing models that favourable Van der Waal's interactions between the side chain amino of phenothiazines and the 2- substituent on ring A can promote a conformation mimicking that of dopamine. Thus modifications that deviate from this favoured orientation would diminish dopamine receptor binding and reduce CNS effects.
- alkyl sulphonate derivatives of the phenothiazine derivatives are very effective at killing virulent M. tuberculosis when in direct contact with the bacillus indicating that the compounds bypass mechanisms that M. tuberculosis employs to induce tolerance such as efflux pumps.
- M. tuberculosis persist within phagosomes of macrophages, the primary host cells of bacilli, where specific evasion strategies allows it to prevent fusion with lysomes thus preventing degradation by lysosomal enzymes.
- One of the key challenges for potentially new drug candidates is to transverse several of these membrane systems to reach the target organism and induce killing.
- Phenothiazines are known to improve efficacy of isoniazid in latency models in vivo and in vitro. However, pharmacokinetics and pharmacodynamics that favour its psychotic attributes have precluded its utility as an antimicrobial drug in vivo.
- the phenothiazine derivatives of the present invention may be used independently or in combination with known anti-tubercular drugs such as 1 st line drugs; ethambutol, isoniazid, pyrazinamide, rifampicin; 2nd line drugs; aminoglycosides (e.g., amikacin, kanamycin), polypeptides (e.g., capreomycin, viomycin, enviomycin); fluoroquinolones (e.g., ciprofloxacin, levofloxacin, moxifloxacin), thioamides (e.g.
- 1 st line drugs ethambutol, isoniazid, pyrazinamide, rifampicin
- 2nd line drugs aminoglycosides (e.g., amikacin, kanamycin), polypeptides (e.g., capreomycin, viomycin, enviomycin); fluoroquinolones
- ethionamide ethionamide, prothionamide
- 3rd line rifabutin, macrolides (e.g., clarithromycin), linezolid, thioacetazone, thioridazine, arginine, vitamin D and R207910.
- the invention provides for a method of treatment of tuberculosis, wherein the method comprises administering an effective amount of the tricyclic derivative of the invention to a patient in need thereof.
- the administration of the compound is carried out in combination with a second anti-tubercular drug.
- the administration of this combination treatment is carried out by administering both the tricyclic derivative of the invention and the second anti-tubercular drug as a single dosage treatment or the administration is carried out as two consecutive separate dosages.
- the invention further provides for the use of a tricyclic derivative of the invention for the manufacture of a medicament for treating tuberculosis.
- the medicament is manufactured as a solid oral dosage form, being a tablet, pill or capsule, or as a liquid oral dosage form, or as an aerosolized powder for pulmonary delivery, comprising both the tricyclic derivative and a second anti-tubercular drug, or each active ingredient separately to be administered consecutively.
- the medicament having a combination of active ingredients being the tricyclic derivative and second anti-tubercular drug will preferably be in unit dose form. That is to say that both active ingredients will preferably be contained in a single tablet, pill, capsule or the like. Providing both active ingredients in a unit dose simplifies administration to patients, particularly when patients are required to self-administer the medicament. This also results in improved patient compliance and less likelihood of drug-resistant microbial forms developing as a result of partial or non-compliance with dosage regimens.
- the chemically modified phenothiazines of the present invention retain antimicrobial activity and are non-toxic to macrophage cells. It will be appreciated by those skilled in the art that the new phenothiazine will have altered pharmacokinetics and pharmacodynamics across the blood brain barrier and as such minimise or exclude psychotic effects. It will further be appreciated that there are numerous modifications and variations of the embodiments of the invention that would be obvious to a person skilled in the art which are deemed to be within the scope of the invention, the nature of which is to be determined from the above description and the examples. Examples
- Phenothiazine derivatives display direct anti-bacterial activity against M. tuberculosis in culture
- Phenothiazine derivatives are non-toxic for bone marrow derived macrophages in culture
- Table 1 The cytotoxicity of test compounds on macrophages. Macrophages were treated for 5 days and cell viability assessed.
- M. tuberculosis was infected with BMDM and the infected cell cultures treated for 5 days with phenothiazine derivatives, C3 and C4.
- the inhibition of intracellular bacterial growth by either C3 or C4 was calculated and expressed as a percentage of the values obtained in untreated cell cultures.
- the toxicity of the drugs on infected macrophages was also determined using the CellTiter-Blue Cell Viability Assay. The percentage of cell viability was calculated based on the values of infected cells (treated and untreated) versus the value of uninfected cells.
- both INH and TZ could inhibit more than 90% of intracellular M. tuberculosis growth at the concentrations of 1 ⁇ 9/ ⁇ and 3 ⁇ 9/ ⁇ respectively.
- both C3 and C4, tested at 25 ⁇ 9/ ⁇ showed significant antibacterial activity of between 40-50 %, although being less efficient compared to INH and TZ. It is noteworthy that all the infected macrophages were almost completely viable after drug treatment. Thereafter, macrophages were lysed and supernatants plated for CFU determination.
- the results of the radio-ligand binding assay indicated no activity in terms of binding to the dopaminergic-receptor subtypes D1 , D2, D3 and the serotonergic-receptor subtypes 5-HT1 A, 5-HT2A, and 5-HT2C.
- Figures 3a- g The benchmarked, unmodified phenothiazines, thioridazine and chlorpromazine were chosen as a point of reference. Almost complete abolishment of dopamine and serotonin receptor binding was achieved for the structural homologs, i.e. C3, C4, C31 , C32 and C33 (labelled as DS0031 , DS0032, DS0033, DS0034, DS0035).
- Toxicity of the phenothiazine derivatives C3 and C4 at a dose of 100 mg/kg as a maximum starting dose were evaluated and outcomes measured against known, clinically approved phenothiazine, thioridazine (TZ), or against no treatment.
- the comparative toxicity profiles of C3 and C4 is significantly better than that of the clinically approved phenothiazine, TZ, even when the latter is tested at 10 fold lower dose concentration than either C3 or C4. While daily dose administration of either 100 mg/kg or 40 mg/kg TZ resulted in 100% mortality of animals within 48 h, all animals survived administration of C3 or C4 at 100 mg/kg. Nonetheless, although mice survived infection, C3 or C4 treated animals lost approximately 10% of their body weight. Of the organs assessed, brains, livers, lungs, kidneys and hearts showed normal weight distribution while spleens were significantly reduced. Overall, mice displayed no abnormal behaviour tolerated C3 and tolerated therapy over the 14day period.
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Abstract
Tricyclic derivatives of formula (1), wherein R1 may be an alkyl sulphonate or sulphonamide group, are useful as antimicrobial agents. The derivatives are optionally substituted wherein R2 is a hydrogen, a halogen, a substituted alkyl group, a thioether or an acetyl group; Y may be N, or C; X may be S, SO, SO2, N, O, CH2, C(O), CO2, NHCO, and ring B is a 6, 7 or an 8 membered cycloalkyl ring. The tricyclic derivatives, such as phenothiazine derivatives, may be used in treating tuberculosis, especially drug sensitive and resistant forms of tuberculosis. The derivatives of the invention may be used independently or in combination with known anti-tubercular drugs such as isoniazid, ethionamide and ethambutol, and the combination may be administered as a single dose, or as two independent dosages. The tricyclic derivatives may also be used for the manufacture of a medicament for treating tuberculosis.
Description
PHENOTHIAZINE DERIVATIVES AND THEIR USE AGAINST TUBERCULOSIS
FIELD OF THE INVENTION This invention relates to tricyclic derivatives of phenothiazines, phenoxazines, phenazines, acridines, oxazepines, diazepins, xanthenes, thioxanthenes and uses thereof.
BACKGROUND TO THE INVENTION
The phenothiazine antipsychotic and antihistaminic drugs prochlorperazine, chlorpromazine, and promazine have demonstrated a synergistic interaction with a wide spectrum of antimicrobial agents. The minimum inhibitory concentrations of these antibiotics were sometimes reduced up to 8,000-fold in the presence of the phenothiazines.
Phenothiazines are also known to increase the NADH/NAD ratio of Mycobacterium tuberculosis via the inhibition of type II NADH:menaquinone oxidoreductase. In this way they are able to increase the reduced state of a cell and are capable of acting synergistically with drugs that require mycothiol for activation such as isoniazid and ethionamide. These combination therapies assist in limiting the emergence of resistance to antimicrobial agents. It has been proven that phenothiazines, such as thioridazine are active against Multi- and Extremely Drug Resistant forms of Mycobacterium tuberculosis.
Phenothiazines have demonstrated a wide range of biological activities, though they are primarily used as neuroleptic drugs. These neuroleptic attributes limit antimicrobial utility of these drugs in diseases such as tuberculosis as they may induce undesirable central nervous system (CNS) side effects at a mycobactericidal dose.
There is thus a need for modified phenothiazine derivatives which exhibit no or minimal undesirable CNS side effects.
SUMMARY OF THE INVENTION
In accordance with this invention there is provided a tricyclic derivative of formula (1 ),
(1 ) wherein Ri is an alkyl sulphonate or sulphonamide group; R2 is hydrogen, a halogen, a substituted alkyl group, a thioether or an acetyl group; Y is N, or C; X is S, SO, SO2, N, O, CH2, C(O), CO2, NHCO, and ring B is a 6, 7 or an 8 membered cycloalkyl ring. When (1 ) is a phenothiazine derivative, then R2 is not H.
In a preferred embodiment of the invention R is (CH2)nSO3M, wherein n = 1 , 2, 3 or 4 and M = Na, K or H or R is SO2Ar, with Ar optionally substituted; R2 is H, CI, Br, SMe, C(O)CH3 or CF3; Y is N or C and X is S, SO, SO2, N, O, CH2, C(O), CO2, NHCO, and ring B is a 6, 7 or an 8 membered cycloalkyl ring. The substituents on the Ar when R is SO2Ar include ortho and para substituents selected from NO2, NH2, SO3M, CO2R, where M = Na, K or H and R = alkyl.
Further features of the invention provide for the tricyclic derivative to be selected from:
Phenothiazines
When n=3, R2 is not H
Phenazines Phenoxazines Thiazepines
Thioxanthenes Xanthenes H, CI, CF3, SMe, C(0)CH3 2,3 or 4
Still further features of the invention provide for the tricylic derivative to be selected from:
The invention provides for tricyclic derivatives of formula (1 ) as defined above as including phenothiazine derivatives of formula (1 ) wherein n = 3 and R2 = H, for use in treating tuberculosis, preferably drug sensitive and resistant forms of tuberculosis, for the derivatives for use in treating tuberculosis,
wherein the derivative is used independently or in combination with known anti-tubercular drugs.
The invention also provides for a method of treatment of tuberculosis, wherein the method comprises administering a therapeutically effective amount of the tricyclic derivative of formula (1 ) as defined above and including a phenothiazine derivative of formula (1 ) wherein n = 3 and R2 = H, to a patient in need thereof, for the administration of the derivative to be in combination with a second anti-tubercular drug, both of which may be administered as a single dose, or as two separate dosages.
Further features of the invention provide for the anti-tubercular drugs to be selected from isoniazid, ethionamide, ethambutol, pyrazinamide,rifampicin, amikacin, kanamycin, capreomycin, viomycin, enviomycin, ciprofloxacin, levofloxacin, moxifloxacin, rifabutin, clarithromycin, linezolid, thioacetazone, prothionamide.
The invention further provides for the use of a tricyclic derivative of formula (1 ) as defined above and including a phenothiazine derivative of formula (1 ) wherein n = 3 and R2 = H, in the manufacture of a medicament for treating tuberculosis.
The invention yet further provides a medicament in unit dose form, characterised in that each unit dose includes a tricyclic derivative of formula (1 ) as defined above and including a phenothiazine derivative of formula (1 ) wherein n = 3 and R2 = H, and a second anti-tubercular drug.
Further features of the invention provide for the anti-tubercular drug to selected from isoniazid, ethionamide, ethambutol, pyrazinamide, rifampicin, amikacin, kanamycin, capreomycin, viomycin, enviomycin, ciprofloxacin, levofloxacin, moxifloxacin, rifabutin, clarithromycin, linezolid, thioacetazone, prothionamidea.
BRIEF DESCRIPTION OF THE FIGURES
The invention will now be described, by way of example only with reference to the accompanying figures in which:
Figure 1 shows anti-mycobacterial activity of isoniazid (INH), thioridazine (TZ) and synthesized phenothiazine derivatives C3, C4, C31 , C32 and C33 directly against M.tb H37Rv.gfp using the GFAP microplate assay and a table summarising the derived MIC5o values;
Figure 2 shows activity of test compounds against intracellular M.tb
H37Rv where infected macrophages were treated with INH, TZ and test compounds respectively, for five days at the indicated concentration;
Figure 3a and 3b show results of a radio-ligand binding assay indicating no activity in terms of binding to dopaminergic- receptor subtypes D1 , D2, D3 and serotonergic-receptor subtypes 5-HT1 A, 5-HT2A, and 5-HT2C;
Figure 3c is a graphical representation of percentage inhibition of C3
(D50031 ) against dopamine and serotonin inhibitors;
Figure 3d is a graphical representation of percentage inhibition of C4
(D50032) against dopamine and serotonin inhibitors;
Figure 3e is a graphical representation of percentage inhibition of C31
(D50033) against dopamine and serotonin inhibitors;
is a graphical representation of percentage inhibition of C32(D50034) against dopamine and serotonin inhibitors; and Figure 3g is a graphical representation of the percentage inhibition of
C33(D50035) against dopamine and serotonin inhibitors;
Figure 4 is a graph showing changes in body weight on a daily basis of mice receiving daily doses of 100 mg/kg of either C3 or C4 and mice left untreated, over a 14 day period; and
Figure 5 are graphs showing organ weights of mice at the end of a
14 day experiment, after being treated with a daily dose of 100 mg/kg of either C3 or C4 and mice left untreated.
DETAILED DESCRIPTION WITH REFERENCE TO THE FIGURES
Tricyclic derivatives of the general formula (1 ) are provided, as illustrated below,
(1 ) wherein Ri is an alkyl sulphonate or sulphonamide group; R2 is a hydrogen, a halogen, a substituted alkyl group, a thioether or an acetyl group; Y is N, or C; X is S, SO, SO2, N, O, CH2, C(O), CO2, NHCO, and ring B is a 6, 7 or an 8 membered cycloalkyi ring. When (1 ) is a phenothiazine derivative, then R2 is not H.
In a preferred embodiment of the invention R is (CH2)nS03M, wherein n = 1 , 2, 3 or 4 and M = Na, K or H or R is S02Ar with Ar optionally substituted; R2 is H, CI, Br, SMe, C(0)CH3 or CF3; Y is N or C and X is S, SO, SO2, N, O, CH2, C(O), CO2, NHCO, and ring B is a 6, 7 or an 8 membered cycloalkyi ring.
The substituents on the Ar when R is SO2Ar include ortho and para substituents selected from NO2, NH2, SO3M, CO2R, where M = Na, K or H and R = alkyl.
The following compounds represent preferred embodiments of the tricyclic derivatives of the general formula (1 ):
Phenazines Phenoxazines Thiazepines
Thioxanthenes
In a more preferred embodiment, the tricyclic derivatives of the general formula (1 ) may be selected from:
A process for preparing /V-alkylsulfonates of phenothiazine involves:
(a) the preparation of the phenothiazine anion, and
(b) the reaction of said anion with cyclic alkyl sulfonates, such as 1 ,3-propane sultone or 1 ,4-butane sultone as generally described in United States Patent number 7,855,287.
A less efficient, multistep synthetic method was published earlier in the Journal of Physical Chemistry, 1986, 90, 2469-2415.
The phenothiazine derivatives of the invention have been shown to have limited toxicity against primary macrophage cultures as well as limited psychotropic activity.
The anti-schizophrenic activity of phenothiazine drugs are thought to involve the blockade of synaptic dopamine receptors in the brain. It has been shown by means of molecular space filing models that favourable Van der Waal's interactions between the side chain amino of phenothiazines and the 2- substituent on ring A can promote a conformation mimicking that of dopamine. Thus modifications that deviate from this favoured orientation would diminish dopamine receptor binding and reduce CNS effects.
Standard dopamine and serotonin inhibition studies of the compounds of this invention have revealed complete inactivation of binding, thus suggesting a complete abolishment of CNS activity. The compounds of the invention have shown significant mycobacterial inhibition against virulent Mycobacterium tuberculosis, showing a minimum inhibitory concentration (MIC5o) of ~6-12μg/ml in direct killing assays.
From in vitro studies it has been conclusively shown that alkyl sulphonate derivatives of the phenothiazine derivatives, as shown above, are very effective at killing virulent M. tuberculosis when in direct contact with the bacillus indicating that the compounds bypass mechanisms that M. tuberculosis employs to induce tolerance such as efflux pumps. Moreover, it has been well established that M. tuberculosis persist within phagosomes of macrophages, the primary host cells of bacilli, where specific evasion strategies allows it to prevent fusion with lysomes thus preventing degradation by lysosomal enzymes. One of the key challenges for potentially
new drug candidates is to transverse several of these membrane systems to reach the target organism and induce killing. Data obtained clearly demonstrate that these compounds of the invention have the ability to cross all membrane systems and inhibit M. tuberculosis replication. Compared to thioridazine which is neuroleptic and cytotoxic, these compounds are superior in terms of cytotoxicity and are devoid of neuroleptic properties.
Phenothiazines, are known to improve efficacy of isoniazid in latency models in vivo and in vitro. However, pharmacokinetics and pharmacodynamics that favour its psychotic attributes have precluded its utility as an antimicrobial drug in vivo.
The phenothiazine derivatives of the present invention may be used independently or in combination with known anti-tubercular drugs such as 1 st line drugs; ethambutol, isoniazid, pyrazinamide, rifampicin; 2nd line drugs; aminoglycosides (e.g., amikacin, kanamycin), polypeptides (e.g., capreomycin, viomycin, enviomycin); fluoroquinolones (e.g., ciprofloxacin, levofloxacin, moxifloxacin), thioamides (e.g. ethionamide, prothionamide); 3rd line; rifabutin, macrolides (e.g., clarithromycin), linezolid, thioacetazone, thioridazine, arginine, vitamin D and R207910.
The potential synergistic effects of this type of combination therapy are believed to be especially suitable for drug sensitive and resistant forms of M. tuberculosis.
The invention provides for a method of treatment of tuberculosis, wherein the method comprises administering an effective amount of the tricyclic derivative of the invention to a patient in need thereof. In one embodiment of the invention the administration of the compound is carried out in combination with a second anti-tubercular drug. The administration of this combination treatment is carried out by administering both the tricyclic derivative of the invention and the second anti-tubercular drug as a single
dosage treatment or the administration is carried out as two consecutive separate dosages.
The invention further provides for the use of a tricyclic derivative of the invention for the manufacture of a medicament for treating tuberculosis. The medicament is manufactured as a solid oral dosage form, being a tablet, pill or capsule, or as a liquid oral dosage form, or as an aerosolized powder for pulmonary delivery, comprising both the tricyclic derivative and a second anti-tubercular drug, or each active ingredient separately to be administered consecutively.
The medicament having a combination of active ingredients being the tricyclic derivative and second anti-tubercular drug will preferably be in unit dose form. That is to say that both active ingredients will preferably be contained in a single tablet, pill, capsule or the like. Providing both active ingredients in a unit dose simplifies administration to patients, particularly when patients are required to self-administer the medicament. This also results in improved patient compliance and less likelihood of drug-resistant microbial forms developing as a result of partial or non-compliance with dosage regimens.
The chemically modified phenothiazines of the present invention retain antimicrobial activity and are non-toxic to macrophage cells. It will be appreciated by those skilled in the art that the new phenothiazine will have altered pharmacokinetics and pharmacodynamics across the blood brain barrier and as such minimise or exclude psychotic effects. It will further be appreciated that there are numerous modifications and variations of the embodiments of the invention that would be obvious to a person skilled in the art which are deemed to be within the scope of the invention, the nature of which is to be determined from the above description and the examples.
Examples
Phenothiazine derivatives display direct anti-bacterial activity against M. tuberculosis in culture
Five compounds namely C3, C4, C31 , C32 and C33 (shown below) were evaluated against M. tuberculosis using the GFP microplate assay (GFPMA) to screen for the bactericidal/bacteriostatic activity of the phenothiazine derivative
Outcomes were compared with the known phenothiazine derivative thioridazine (TZ) and the first-line drug isoniazid (INH), which were used as positive controls for anti-mycobacterial efficacy. The results obtained have shown that all the test compounds, except for C33, displayed a dosage dependent inhibitory effect on the growth of M.f£>-H37Rv.gfp and the derived MIC50 values are summarised (Figure 1 ). The MIC50 of INH and TZ was similar to published data. Significant antitubercular activity was demonstrated for C3 and C4, which had the lowest MIC as well as for C31 and C32.
Phenothiazine derivatives are non-toxic for bone marrow derived macrophages in culture
The in vitro toxicity effects of C3, C4, C31 , C32 and C33 on bone-marrow- derived-macrophages (BMDM) at concentrations ranging between 0.1953 to 25 μg/ml was examined. Bone marrow was isolated from femurs of na'ive C57BI/6 mice and macrophages cultured at 37 °C under 5% CO2 until
mature. The data showed that the compounds had no effect on the cell viability at all concentrations after 5 days of incubation (Table 1 , below). In contrast, TZ was toxic and induced cell death after 3 days of incubation (data not shown). After 5 days incubating with TZ, 1 00% cell death was observed at the concentrations ranged from 25 μ9/ιτιΙ to 6.25 μ9/ιτιΙ. INH was also included in the analysis at a range of concentrations between 0,00078 μ9/ιτιΙ to 0.1 μ9/ιτιΙ and was not found to be toxic (data not shown).
Table 1 : The cytotoxicity of test compounds on macrophages. Macrophages were treated for 5 days and cell viability assessed.
Intracellular inhibition of M. tuberculosis replication in macrophages by phenothiazine derivatives
To investigate whether compounds of the invention could transverse cell membrane systems and access intracellular bacilli to inhibit replication, M. tuberculosis was infected with BMDM and the infected cell cultures treated for 5 days with phenothiazine derivatives, C3 and C4. The inhibition of intracellular bacterial growth by either C3 or C4 was calculated and
expressed as a percentage of the values obtained in untreated cell cultures. Simultaneously, the toxicity of the drugs on infected macrophages was also determined using the CellTiter-Blue Cell Viability Assay. The percentage of cell viability was calculated based on the values of infected cells (treated and untreated) versus the value of uninfected cells. As shown in Figure 2, both INH and TZ could inhibit more than 90% of intracellular M. tuberculosis growth at the concentrations of 1 μ9/ιτιΙ and 3 μ9/ιτιΙ respectively. Interestingly, both C3 and C4, tested at 25 μ9/ιτιΙ showed significant antibacterial activity of between 40-50 %, although being less efficient compared to INH and TZ. It is noteworthy that all the infected macrophages were almost completely viable after drug treatment. Thereafter, macrophages were lysed and supernatants plated for CFU determination.
Seratonin and Dopamine Binding Studies
The results of the radio-ligand binding assay indicated no activity in terms of binding to the dopaminergic-receptor subtypes D1 , D2, D3 and the serotonergic-receptor subtypes 5-HT1 A, 5-HT2A, and 5-HT2C. (Figures 3a- g). The benchmarked, unmodified phenothiazines, thioridazine and chlorpromazine were chosen as a point of reference. Almost complete abolishment of dopamine and serotonin receptor binding was achieved for the structural homologs, i.e. C3, C4, C31 , C32 and C33 (labelled as DS0031 , DS0032, DS0033, DS0034, DS0035).
Toxicity potential of the compounds C3 and C4 in a small animal model (C57BI/6 mice)
Toxicity of the phenothiazine derivatives C3 and C4 at a dose of 100 mg/kg as a maximum starting dose were evaluated and outcomes measured against known, clinically approved phenothiazine, thioridazine (TZ), or against no treatment.
Initial studies were conducted to evaluate the maximal tolerated dose of TZ in mice because of the variability of reported published data which ranged from
160 mg/kg to 20 mg/kg. The studies challenged 6-8 week old adult female C57BI/6 mice (n=10/group) with 100 mg/kg, 40 mg/kg, 20 mg/kg and 10 mg/kg by oral gavage and monitored animals for survival and measured change in body weight. In an initial sub-acute study TZ was administered once in a volume of 200 μΙ at onset of the experiment and survival and bodyweight changes monitored. It was found that a challenge dose of 40 mg/kg and 100 mg/kg was transiently toxic as animals presented with paralysis within 6 h. However, animals recovered within 24-48 h. Animals transiently lost weight but recovered after 3-4 days. Single dose administration of TZ did not induce mortality at any of the doses tested over a 2 week period.
To evaluate toxicity of single dose (100 mg/kg) administration of C3 and C4, the phenothiazine derivatives were administered by oral gavage in a volume in 200 μΙ. Similar to untreated animals, none of the animals showed significant weight loss over the 14 day period. Similarly, no animal loss on administration of a single dose of 20 mg/kg TZ was found. Mice displayed transient lethargy but recovered within 24 h. This single dose study was repeated with similar outcomes.
Next toxicity was evaluated in animals which received therapy on a daily basis. Briefly, mice (n=10-15/group) received either TZ (10 mg/kg or 20 mg/kg); C3 (100 mg/kg) or C4 (100 mg/kg) administered in 200 μΙ water by oral gavage on a daily basis. Changes in body weights were measured and recorded on a daily basis (Figure 4). The experiment was terminated after 14 days when all animals were humanely sacrificed and organs (heart, lung, brain, kidney, liver and spleen) removed and weighed (Figure 5). Blood was collected and serum stored for further analysis. Animals that did not receive any therapy initially gained bodyweight which thereafter stabilised. Animals which received a daily dose of 100 mg/kg
showed rapid weight loss of approximately 10% in the first week after which it stabilised with possibility of recovering weight loss towards the end of the week 2. Measurement of organs in C3 and C4 treated animals showed a significant reduction in spleen weight in both therapy groups compared to untreated animals. All other organs remained unaffected.
The comparative toxicity profiles of C3 and C4 is significantly better than that of the clinically approved phenothiazine, TZ, even when the latter is tested at 10 fold lower dose concentration than either C3 or C4. While daily dose administration of either 100 mg/kg or 40 mg/kg TZ resulted in 100% mortality of animals within 48 h, all animals survived administration of C3 or C4 at 100 mg/kg. Nonetheless, although mice survived infection, C3 or C4 treated animals lost approximately 10% of their body weight. Of the organs assessed, brains, livers, lungs, kidneys and hearts showed normal weight distribution while spleens were significantly reduced. Overall, mice displayed no abnormal behaviour tolerated C3 and tolerated therapy over the 14day period.
It will be appreciated that there are numerous modifications and variations of the embodiments of the invention that would be obvious to a person skilled in the art which are deemed to be within the scope of the invention, the nature of which are to be determined from the above description and the examples.
Claims
CLAIMS:
wherein Ri is an alkyl sulphonate or sulphonamide group; R2 is a hydrogen, a halogen, a substituted alkyl group, a thioether or an acetyl group; Y is N, or C; X is S, SO, SO2, N, O, CH2, C(O), CO2, NHCO, and ring B is a 6, 7 or an 8 membered cycloalkyi ring and when (1 ) is a phenothiazine derivative, then R2 is not H.
A tricyclic derivative as claimed in claim 1 wherein R is (CH2)nSO3M, with n = 1 , 2, 3 or 4 and M = Na, K or H or R1 is SO2Ar, with Ar optionally substituted; R2 is H, CI, Br, SMe, C(O)CH3 or CF3; Y is N or C and X is S, SO, SO2, N, O, CH2, C(O), CO2, NHCO, and ring B is a 6, 7 or an 8 membered cycloalkyi ring.
A tricyclic derivative as claimed in claim 2 wherein the Ar of SO2Ar is optionally substituted in the ortho or para position with substituents selected from NO2 , NH2, SO3M, CO2R, where M = Na, K or H and R = alkyl.
A tricyclic derivative as claimed in any other the preceding claims wherein the tricyclic derivative is selected from:
Phenothiazines
When n=3, R2 is not H
Phenazines Phenoxazines Thiazepines
Thioxanthenes Xanthenes
5. A tricyclic derivative as claimed in any one of the preceding claims wherein the tricyclic derivative is selected from:
wherein Ri is an alkyl sulphonate or sulphonamide group; R2 is a hydrogen, a halogen, a substituted alkyl group, a thioether or an acetyl group; Y is N, or C; X is S, SO, SO2, N, O, CH2, C(O), CO2, NHCO, and ring B is a 6, 7 or an 8 membered cycloalkyl ring, for use in treating antimicrobial infections.
A tricyclic derivative as claimed in claim 6 for use in treating tuberculosis.
A tricyclic derivative as claimed in claim 6, wherein the derivative is used independently or in combination with a second anti-tubercular drug.
A tricyclic derivative as claimed in claim 8 wherein the second anti- tubercular drug is selected from isoniazid, ethionamide, ethambutol, pyrazinamide,rifampicin, amikacin, kanamycin, capreomycin, viomycin, enviomycin, ciprofloxacin, levofloxacin, moxifloxacin, rifabutin, clarithromycin, linezolid, thioacetazone and prothionamide. 10. A method of treating tuberculosis which includes administering to a patient in need thereof a therapeutically effective amount of a tricyclic derivative of formula
wherein R is an alkyl sulphonate or sulphonamide group; R2 is a hydrogen, a halogen, a substituted alkyl group, a thioether or an acetyl group; Y is N, or C; X is S, SO, SO2, N, O, CH2, C(O), CO2, NHCO, and ring B is a 6, 7 or an 8 membered cycloalkyl ring.
A method of treating tuberculosis as claimed in claim 10 wherein the tricyclic derivative is administered in combination with a second anti- tubercular drug either as a single unit dose or as separate dosages.
12. A method of treating tuberculosis as claimed in claim 1 1 wherein the second anti-tubercular drug is selected from isoniazid, ethionamide, ethambutol, pyrazinamide, rifampicin, amikacin, kanamycin, capreomycin, viomycin, enviomycin, ciprofloxacin, levofloxacin, moxifloxacin, rifabutin, clarithromycin, linezolid, thioacetazone and prothionamide.
13. Use of a tricyclic deri
wherein Ri is an alkyl sulphonate or sulphonamide group; R2 is a hydrogen, a halogen, a substituted alkyl group, a thioether or an acetyl group; Y is N, or C; X is S, SO, SO2, N, O, CH2, C(O), CO2, NHCO, and ring B is a 6, 7 or an 8 membered cycloalkyl ring, in the manufacture of a medicament for use in treating tuberculosis.
14. A medicament in unit dose form, characterised in that each unit dose includes a tricyclic d
(1 )
wherein Ri is an alkyl sulphonate or sulphonamide group; R2 is a hydrogen, a halogen, a substituted alkyl group, a thioether or an acetyl
group; Y is N, or C; X is S, SO, SO2, N, O, CH2, C(O), CO2, NHCO, and ring B is a 6, 7 or an 8 membered cycloalkyi ring,
and a second anti-tubercular drug.
A medicament as claimed in claim 14 wherein the second anti- tubercular drug is selected from isoniazid, ethionamide, ethambutol, pyrazinamide,rifampicin, amikacin, kanamycin, capreomycin, viomycin, enviomycin, ciprofloxacin, levofloxacin, moxifloxacin, rifabutin, clarithromycin, linezolid, thioacetazone and prothionamidea.
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104557775A (en) * | 2014-08-25 | 2015-04-29 | 天津药物研究院 | Disulfamide phenothiazine compound, and preparation method and application thereof |
US10898449B2 (en) | 2016-12-20 | 2021-01-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
US11358942B2 (en) * | 2017-06-05 | 2022-06-14 | Board Of Trustees Of Michigan State University | Substituted phenothiazines as proteasome activators |
WO2023054393A1 (en) * | 2021-09-29 | 2023-04-06 | 保土谷化学工業株式会社 | Compound having sulfonate group, hole-transporting material, hole-transporting material composition for photoelectric conversion element, photoelectric conversion element and solar cell |
US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
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CA3028347A1 (en) * | 2016-06-23 | 2017-12-28 | Bioimics Ab | Anti-infective heterocyclic compounds and uses thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005105145A1 (en) * | 2004-04-30 | 2005-11-10 | Bkg Pharma Aps | Treatment of infectious diseases |
US7855287B2 (en) | 2007-01-24 | 2010-12-21 | Cyanagen Srl | Preparation of high purity phenothiazine N-alkylsulfonates and their use in chemiluminescent assays for the measurement of peroxidase activity |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SU1340077A1 (en) * | 1986-01-02 | 1992-04-07 | Ленинградский Технологический Институт Им.Ленсовета | Hydrochloride 7-bromine-2-amino-3h-oxophenothiazine possessing antituberculous activity |
EP0912097B1 (en) * | 1996-05-09 | 2002-08-07 | Novozymes A/S | Antimicrobial peroxidase compositions |
-
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005105145A1 (en) * | 2004-04-30 | 2005-11-10 | Bkg Pharma Aps | Treatment of infectious diseases |
US7855287B2 (en) | 2007-01-24 | 2010-12-21 | Cyanagen Srl | Preparation of high purity phenothiazine N-alkylsulfonates and their use in chemiluminescent assays for the measurement of peroxidase activity |
Non-Patent Citations (5)
Title |
---|
AMARAL L ET AL: "ACTIVITY OF PHENOTHIAZINES AGAINST ANTIBIOTIC-RESISTANT MYCOBACTERIUM TUBERCULOSIS: A REVIEW SUPPORTING FURTHER STUDIES THAT MAY ELUCIDATE THE POTENTIAL USE OF THIORIDAZINE AS ANTI-TUBERCULOSIS THERAPY", JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, OXFORD UNIVERSITY PRESS, GB, vol. 47, no. 5, 1 May 2001 (2001-05-01), pages 505 - 511, XP008048568, ISSN: 0305-7453, DOI: 10.1093/JAC/47.5.505 * |
JOHN J. LAFFERTY ET AL: "The Synthesis of Phenothiazines. VII.1 Methyl- and Arylsulfonylation of Phenothiazine and Its 10-Substituted Derivatives", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 27, no. 4, 1 April 1962 (1962-04-01), pages 1346 - 1351, XP055076805, ISSN: 0022-3263, DOI: 10.1021/jo01051a052 * |
JOURNAL OF PHYSICAL CHEMISTRY, vol. 90, 1986, pages 2469 - 2415 |
KAATZ G W ET AL: "PHENOTHIAZINES AND THIOXANTHENES INHIBIT MULTIDRUG EFFLUX PUMP ACTIVITY IN STAPHYLOCOCCUS AUREUS", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, AMERICAN SOCIETY FOR MICROBIOLOGY, US, vol. 47, no. 2, 1 February 2003 (2003-02-01), pages 719 - 726, XP008044805, ISSN: 0066-4804, DOI: 10.1128/AAC.47.2.719-726.2003 * |
SUZANNE S. STOKES ET AL: "Inhibitors of the acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridylyltransferase/glucosamine-1-phosphate-acetyltransferase (GlmU). Part 2: Optimization of physical properties leading to antibacterial aryl sulfonamides", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, no. 23, 11 October 2012 (2012-10-11), pages 7019 - 7023, XP055103641, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2012.10.003 * |
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US11358942B2 (en) * | 2017-06-05 | 2022-06-14 | Board Of Trustees Of Michigan State University | Substituted phenothiazines as proteasome activators |
US12060337B2 (en) | 2017-06-05 | 2024-08-13 | Board Of Trustees Of Michigan State University | Substituted dibenzo[b, f]azepines as proteasome activators |
US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
WO2023054393A1 (en) * | 2021-09-29 | 2023-04-06 | 保土谷化学工業株式会社 | Compound having sulfonate group, hole-transporting material, hole-transporting material composition for photoelectric conversion element, photoelectric conversion element and solar cell |
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