CN108929329B - 2-azacyclo-5-trifluoromethyl-8-nitrobenz (thio) pyran-4-ones - Google Patents
2-azacyclo-5-trifluoromethyl-8-nitrobenz (thio) pyran-4-ones Download PDFInfo
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Abstract
The invention discloses a 2-nitrogen heterocyclic-5-trifluoromethyl-8-nitrobenz (thio) pyran-4-ketone compound, a preparation method thereof and application thereof in medicaments for treating and/or preventing infectious diseases caused by mycobacterium tuberculosis. In particular, the invention relates to a compound shown as a formula (I) and isomers thereof, pharmaceutically acceptable salts thereof and a pharmaceutical composition containing the compound, wherein X, Y, R1、R2And n is as described in the specification. The present invention aims to prepare novel compounds having activity against mycobacterium tuberculosis, which are useful as potential novel drugs for the therapeutic or prophylactic treatment of infectious diseases caused by bacteria, in particular Tuberculosis (TB) diseases caused by mycobacteria, while overcoming the problems associated with drug resistance against mycobacterium tuberculosis.
Description
Technical Field
The invention belongs to the technical field of medicines. In particular to 2-nitrogen heterocyclic-5-trifluoromethyl-8-nitrobenz (thio) pyran-4-ketone compounds shown in a general formula (I), a preparation method thereof, a pharmaceutical composition taking the compounds as active ingredients, and application of the compounds in treating and/or preventing infectious diseases caused by mycobacterium tuberculosis.
Background
Tuberculosis (TB) is a chronic fatal disease caused by Mycobacterium tuberculosis, is a major infectious disease which endangers human health and causes human death, and is one of the main causes of death worldwide like AIDS. According to the World Health Organization (WHO) estimate (Global tuberculosis report2016), the number of new tuberculosis worldwide in 2015 is about 1040 ten thousand, of which 590 thousand are male (56%), 350 thousand are female (34%) and 100 thousand are children (10%). 120 ten thousand new cases of tuberculosis are HIV-infected persons (11%), and it is estimated that 140 ten thousand persons die of tuberculosis and 40 ten thousand HIV-infected persons die of tuberculosis.
Chemotherapy is the primary means of tuberculosis treatment. The streptomycin is used in 1944, a new era of antituberculosis drug treatment is created, with the successive appearance of isoniazid, rifampicin and pyrazinamide, the treatment course for treating tuberculosis is shortened to 6 months, and the 'short-range chemotherapy era' is entered. Nevertheless, long-term drug combination therapy causes adverse reactions of patients and is difficult to adhere to regular medication, and in addition, most of the drugs are born in the fifth and sixty years of the last century, and the development of drug-resistant bacteria is gradually serious due to long-term, wide-range and irregular use, so that multi-drug-resistant tuberculosis (MDR-TB), wide-range drug-resistant tuberculosis (XDR-TB) and total drug-resistant tuberculosis (TDR-TB) appear. In the face of drug-resistant tuberculosis, a second-line or even third-line antitubercular drug which is expensive and has high toxicity needs to be used. Therefore, the research and development of antituberculous drugs with novel frameworks and novel action mechanisms for treating and controlling tuberculosis, especially drug-resistant tuberculosis, is urgent. New antituberculotic drugs are required to have high efficacy, low toxicity and the ability to shorten the treatment time.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a 2-nitrogen heterocyclic-5-trifluoromethyl-8-nitrobenz (thio) pyran-4-ketone compound which has a novel structure and strong activity against mycobacterium tuberculosis. The invention discovers that 2-azacyclo-5-trifluoromethyl-8-nitrobenz (thio) pyran-4-ketone compounds have strong anti-mycobacterium tuberculosis effect, can be used for treating or preventing infectious diseases caused by bacteria, particularly Tuberculosis (TB) diseases caused by mycobacteria, and can be used for overcoming the problems related to drug resistance. The present invention has been completed based on the above findings.
Summary of The Invention
Therefore, the invention provides a compound shown in a general formula (I) and an isomer thereof, or a pharmaceutically acceptable salt thereof in a first aspect,
wherein the content of the first and second substances,
x is O or S;
y is C or N;
R1is H, C1-C3Alkyl radical, C1-C3Alkoxy, F, Cl, Br, CN, OH, (═ O), and (═ S);
n is 0,1 or 2;
R2is F, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted C3-C6Heterocyclic radical, substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted C2-C9Heteroaryl, or together with the carbon atoms to which they are both attached, represents a substituted or unsubstituted cycloalkyl group containing 3 to 8 carbon atoms or a substituted or unsubstituted 4-to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur;
said C is3-C6A heterocyclic radical, C2-C9Heteroaryl contains at least one heteroatom selected from N, O, S;
the R is2Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy and C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy or C1-C3An alkylamino group.
In a preferred embodiment, the compound is represented by the structural formula (II):
wherein, Y, R1、R2And n is as defined in the first aspect of the invention.
In another preferred embodiment, the compound is represented by the structural formula (III):
wherein, Y, R1、R2And n is as defined in the first aspect of the invention.
In some aspects, the compound of formula (I) is selected from compounds of formula (II-a):
wherein the content of the first and second substances,
R1is H, C1-C3Alkyl, F, Cl or (═ O);
n is 0 or 1;
R2is F, a substituted or unsubstituted cyclohexyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted thiazolyl group, or together with the carbon atom to which they are commonly attached represents a substituted or unsubstituted cyclopentyl group or a substituted or unsubstituted 5-membered heterocyclic group containing 1 to 2 heteroatoms selected from oxygen, sulfur;
the R is2Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy and C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy or C1-C3An alkylamino group.
In some aspects, the compound of formula (I) is selected from compounds of formula (II-b):
wherein the content of the first and second substances,
R1is H, C1-C3Alkyl, F, Cl or (═ O);
n is 0 or 1;
R2is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl;
the R is2Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy and C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy or C1-C3An alkylamino group;
in some aspects, the compound of formula (I) is selected from compounds of formula (III-a):
wherein the content of the first and second substances,
R1is H, C1-C3Alkyl, F, Cl or (═ O);
n is 0 or 1;
R2is F, a substituted or unsubstituted cyclohexyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted thiazolyl group, or together with the carbon atom to which they are commonly attached represents a substituted or unsubstituted cyclopentyl group or a substituted or unsubstituted 5-membered heterocyclic group containing 1 to 2 heteroatoms selected from oxygen, sulfur;
the R is2Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy、C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy or C1-C3An alkylamino group;
in some aspects, the compound of formula (I) is selected from compounds of formula (III-b):
wherein the content of the first and second substances,
R1is H, C1-C3Alkyl, F, Cl or (═ O);
n is 0 or 1;
R2is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl;
the R is2Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy and C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy or C1-C3An alkylamino group;
in the schemes of formulae (II) and (III),
n is preferably 0,1 or 2;
R1preferably H, C1-C3Alkyl radical, C1-C3Alkoxy, F, Cl, Br, CN, OH, (═ O), or (═ S);
when the Y is C, the compound has the structure of,
R2preferably F,
When the Y is an amino group represented by the formula (I),
R2preferably, it is
Rx is F, Cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy or C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy or C1-C3An alkylamino group;
the pharmaceutically acceptable salts described in the present invention are salts of the compounds of the present invention with an acid selected from the group consisting of: hydrochloric acid, p-toluenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid. Preferably hydrochloric acid, p-toluenesulfonic acid or trifluoroacetic acid.
A compound according to any one of the first aspect of the invention, which is the subject compound of the invention prepared in the examples (represented by the structural formula or described by systematic name) and isomers thereof, pharmaceutically acceptable salts thereof.
A compound according to any one of the first aspect of the invention, which is a compound selected from:
in a second aspect, the present invention provides a process for the preparation of a compound according to any one of the first aspect of the invention, comprising the steps of:
compound A is reacted with an amine compound B in a suitable solvent (e.g. dichloromethane, tetrahydrofuran, acetonitrile, preferably dichloromethane) under the action of a condensing agent (e.g. CDI, DCC, EDCI \ HOBT, HATU, preferably DCC) in air or an inert gas (Ar or N)2) Under protection, the mixture is placed at the temperature of-10 ℃ to 50 ℃ for reaction for 1 to 24 hours, wherein the room temperature is preferred for reaction for 8 to 15 hours, and the compound shown in the formula C is obtained;
a compound of formula C is prepared in a suitable solvent (e.g., DMF, DMSO, preferably DMF) under basic conditions (e.g., sodium carbonate, potassium carbonate or cesium carbonate, preferably potassium carbonate) in an inert gas (Ar or N)2) Under protection, reacting at 20-140 ℃ for 0.5-12 hours, preferably at 110 ℃ for 1-5 hours to obtain the compound of formula (II).
The compound A of the present invention can be easily prepared by referring to a method known in the prior publications, for example (J.Med.chem.2007,50, 3369-3379).
Compound D is reacted with carbon disulfide in a suitable solvent (e.g. toluene, acetone, tetrahydrofuran, DMF, DMSO, preferably DMSO) under basic conditions (e.g. NaH, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, preferably sodium hydroxide) in air or an inert gas (Ar or N)2) Reacting at-10-30 ℃ for 10-60 minutes under protection, preferably at 15-25 ℃ for 15-30 minutes, and then adding MeI at 15-25 ℃ for 30-60 minutes to obtain a compound E;
compound E with amine compound B in a suitable solvent (e.g. tert-butanol, isopropanol, ethylene glycol dimethyl ether, DMF, DMSO, preferably isopropanol) in air or an inert gas (Ar or N)2) Health-care productUnder the protection of the catalyst, reacting at 80-160 ℃ for 1-48 hours, preferably at 120-140 ℃ for 20-25 hours to obtain the compound of formula (III).
Dissolving or suspending the compound of formula (III) in a suitable solvent (e.g. dichloromethane, tetrahydrofuran, methanol, ethanol, isopropanol, preferably ethanol, isopropanol) at room temperature or under heating, in air or an inert gas (Ar or N)2) Adding corresponding acid solution (such as hydrochloric acid, sulfuric acid, hydrochloric acid ethanol, preferably hydrochloric acid ethanol) under protection, stirring at room temperature or heating for 1-48 hr, preferably stirring at room temperature for 2 hr, filtering, washing with corresponding solvent, and drying to obtain corresponding salt of compound of formula (III).
In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the first aspect of the present invention and pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable excipients.
The fourth aspect of the present invention provides a compound of any one of the first aspect of the present invention and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of the third aspect of the present invention, for use in the preparation of a medicament for the treatment and/or prevention of an infectious disease caused by mycobacterium tuberculosis.
The foregoing merely outlines certain aspects of the invention, but is not limited in this respect. These and other aspects will be more fully described in greater detail below.
Detailed Description
Various aspects and features of the disclosure are described further below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure. The following are definitions of various terms used herein, which apply to the terms used throughout the specification of the present application unless otherwise specified in specific instances.
In general, the term "substituted or unsubstituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When not only one position of a given structure can be substituted with one or more substituents selected from a particular group at all times, the substituents may be substituted at various positions, identically or differently.
Ci-CjDenotes a moiety having an integer "i" (inclusive of i) to an integer "j" (inclusive of j) carbon atoms. Thus, for example, C1-C3Alkyl refers to alkyl groups having 1 to 3 (including 1 and 3) carbon atoms. E.g. C2-C9Heteroaryl refers to heteroaryl having 2 to 9 (including 2 and 9) carbon atoms, including tetrazolyl, triazolyl, thienyl, pyridyl, pyrimidinyl, quinolinyl.
As used herein, the term "alkyl" refers to an alkyl group having the specified number of carbon atoms, which is a straight or branched chain alkyl group, and which may include a sub-group thereof, such as the reference to "C1-C3When "alkyl", it may also include C1-C2Alkyl represents a sub-range of groups, and specific groups such as methyl, ethyl, n-propyl, isopropyl.
As used herein, the terms "alkoxy" and "alkylamino" are intended to be generic and refer to an alkyl group attached to the remainder of the molecule through an oxygen atom or an amine group, respectively, wherein the alkyl group is as described herein.
As used herein, the term "haloalkyl" means an alkyl group wherein the hydrogen is replaced by one or more halogen atoms, examples of which include, but are not limited to, monofluoromethyl, monofluoromethoxy, and the like.
As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having the number of ring carbon atoms specified, and which may include a sub-group thereof, for example, reference to "C3-C6When cycloalkyl "is present, it may also include C3-C5Cycloalkyl radical, C4-C6Cycloalkyl, and the like, as well as specific groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
As used herein, the term "C3-C6Heterocycloalkyl ", unless otherwise stated or limited, refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 6 ring carbon atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH2The group may optionally be replaced by a carbonyl group. The sulfur atom of the ring may optionally be oxidized to the S-oxide. Heterocyclyl groups include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine, homopiperazinyl, and the like.
As used herein, the term "C6-C10Aryl "means monocyclic and bicyclic carbocyclic ring systems containing 6 ring atoms or 6 to 10 ring atoms, wherein at least one ring is aromatic, wherein each ring comprises a ring of 3 to 6 atoms, and wherein one or more attachment points in the ring system are attached to the rest of the molecule. The aromatic group may include phenyl and naphthyl.
As used herein, the term "C2-C9Heteroaryl "herein refers to an aromatic group having 1 to 3 heteroatoms as ring atoms, the remaining ring atoms being carbon, the heteroatoms including oxygen, sulfur and nitrogen. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, imidazolyl, furyl, thienyl, pyrazinyl, and the like.
As used herein, the term "ring" means a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. The so-called ring includes fused rings. The number of atoms in the ring is generally defined as the number of ring members, e.g. "C3-C6By ring is meant 3-6 atoms arranged around the ring.
As used herein, the term "heteroatom" refers to O, S, N, including any oxidation state form of N, S; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted.
As used herein, the terms "halogen", "halo", and the like, refer to fluorine (F), chlorine (Cl), or bromine (Br).
"room temperature" in the present invention means a temperature of from 10 ℃ to 40 ℃. In some embodiments, "room temperature" refers to a temperature from 20 ℃ to 30 ℃; in other embodiments, room temperature refers to 25 ℃.
As used herein, the term "effective amount" refers to an amount of a drug that achieves the desired treatment of a disease or disorder described herein in a subject.
As used herein, the term "pharmaceutically acceptable" when describing a "pharmaceutically acceptable salt," for example, means that the salt is not only physiologically acceptable to the subject, but may also refer to a synthetic substance of pharmaceutical value.
As used herein, the term "pharmaceutical composition" may also refer to a "composition" that may be used to effect treatment of a disease or disorder described herein in a subject, particularly a mammal.
"treatment" of a disease includes:
(1) preventing the disease, i.e., causing the clinical symptoms of the disease not to occur in a mammal exposed to or susceptible to the disease but who has not experienced or exhibited symptoms of the disease,
(2) inhibiting the disease, i.e., preventing or reducing the progression of the disease or its clinical symptoms,
(3) alleviating the disease, i.e., causing the recovery of the disease or its clinical symptoms.
"therapeutically effective amount" refers to the amount of a compound that is sufficient to effect treatment of a disease when administered to a mammal for the treatment of the disease. The therapeutically effective amount will vary depending on the compound, the disease to be treated and its severity, as well as the age, weight, sex, etc., of the mammal. A therapeutically effective amount may also refer to any amount of the compound sufficient to achieve a desired beneficial effect, including preventing, inhibiting, or ameliorating a disease as described in (1) - (3) above. For example, the amount of the compound may be between 0.1 and 250mg/kg, or preferably, 0.5 and 100mg/kg, or more preferably, 1 and 50mg/kg, or even more preferably, 2 and 20 mg/kg. Preferably, the amount of the compound is administered to the mammal twice daily. More preferably, the amount of the compound is administered to the mammal once daily.
As used herein, the term "disease and/or disorder" refers to a physical condition of the subject that is associated with the disease and/or disorder of the present invention. For example, the disease and/or disorder of the present invention refers to a tubercle bacillus infectious disease.
As used herein, the term "subject" can refer to a patient or other animal, particularly a mammal, e.g., a human, dog, monkey, cow, horse, etc., that receives a compound of formula I of the invention or a pharmaceutical composition thereof for treating a disease or disorder described herein.
In still another aspect, the present invention relates to pharmaceutical compositions containing the compounds of the present invention as active ingredients. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.
For tableting the compound of the present invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, and solubilizers. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and cosolvent may be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
To encapsulate the administration unit, the active ingredient of the compound of the present invention may be mixed with a diluent and a cosolvent, and the mixture may be directly placed in a hard capsule or soft capsule. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The diluents, binders, wetting agents, disintegrants, and cosolvents used to prepare the compound tablets of the present invention can also be used to prepare capsules of the compounds of the present invention.
For preparing the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixture can be used as solvent, and appropriate amount of solubilizer, cosolvent, pH regulator, and osmotic pressure regulator commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.
Advantageous technical effects
The inventors of the present application have made extensive studies to synthesize a series of compounds and have synthesized them by the MABA (microplate alamar blue assay) method in M.tuberculosis H37The Rv strain is subjected to Minimum Inhibitory Concentration (MIC) determination, and shows good activity against mycobacterium tuberculosis, wherein MIC is obtained<0.5. mu.g/mL of 14 compounds, 13 compounds had MICs of 10-8g/mL, equivalent to isoniazid as the first line antituberculotic, and low toxicity to Vero cell (IC)50Greater than 64 μ g/mL) and shows higher safety in the HepG2 cytotoxicity test than the benzothiazinone compound PBTZ169(EMBO mol. med.2014,6,372-383). Part of compounds in the invention are used in the metabolic stability test of liver microsomes and liver cellsAll show better metabolic properties than PBTZ 169. The in vivo pharmacokinetic results of mice show that compound 11 has in vivo pharmacokinetic properties superior to PBTZ 169. The invention provides a novel compound with novel structure, strong in vivo antitubercular activity and good pharmacokinetic property, wherein the parent nucleus structure is a benzopyrone or benzothiopyrone structure, and the compound can be used for treating infectious diseases caused by bacteria, particularly for treating or preventing tuberculosis caused by mycobacterium tuberculosis, and can also be used for overcoming the problems related to drug resistance.
Detailed Description
The present invention will be described in detail by the following examples, but is not intended to limit the present invention in any way. Having described the invention in detail and having disclosed specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
For all of the following examples, standard procedures and purification methods known to those skilled in the art may be used. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. The structure of the compound is determined by nuclear magnetic resonance spectroscopy (NMR).
Preparation examples section
The structure of the compound is shown by nuclear magnetic resonance hydrogen spectrum (1H NMR). The nmr hydrogen spectra and the carbon spectral shifts () are given in parts per million (ppm). The coupling constant (J) is in Hertz (Hz). NMR spectra were measured using a Mercury-400 NMR spectrometer, deuterated chloroform (CDCl)3) As solvent Tetramethylsilane (TMS) was used as internal standard.
The electronic balance used was an electronic balance model Yanaco LY-300, Japan.
The column chromatography generally uses 200-300 mesh silica gel as a carrier.
The anhydrous solvents were all processed by standard methods. Other reagents were all commercially available analytical grade.
The invention employs the following abbreviations:
CDI is carbonyldiimidazole.
DCC is dicyclohexylcarbodiimide.
DMF is N, N-dimethylformamide.
DMSO is dimethyl sulfoxide.
EDCI is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
HOBT is 1-hydroxybenzotriazole.
HATU is 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.
Examples
Example 1
(S) -2- (2-methyl-1, 4-dioxa-8-azaspiro [4.5] decan-8-yl) -6-trifluoromethyl-8-nitro-chromen-4-one
The route is as follows:
the experimental steps are as follows:
first step preparation of (S) -1- (2-chloro-3-nitro-5- (trifluoromethyl) phenyl) -3- (2-methyl-1, 4-dioxa-8-azaspiro [4.5] decan-8-yl) propane-1, 3-dione B-1
In a 25mL reaction flask, compound 3- (2-chloro-3-nitro-5- (trifluoromethyl) phenyl) -3-oxopropanoic acid A (311mg, 1.0mmol), DCC (201mg, 1.0mmol) were dissolved in dry dichloromethane (5mL), Ar gas protected, (S) -2-methyl-1, 4-dioxa-8-azaspiro [4.5] decane (157mg, 1.0mmol) was added and stirred at room temperature for 12 hours. Filtering out insoluble solids, concentrating, and separating by silica gel (200-300 meshes) column chromatography, wherein an ethyl acetate-petroleum ether (V: 5-15: 100) mixed solution is used as an eluent. Intermediate B-1 was obtained as a pale yellow solid, 250mg, yield 55.5%.
1H NMR(400MHz,CDCl3):15.64(brs,1H),8.01(s,1H),8.00(s,1H),5.72(s,1H),4.30-4.13(m,1H),4.12-4.08(m,1H),3.75-3.47(m,5H),1.79-1.75(m,4H),1.30(m,3H).
Second step preparation of (S) -2- (2-methyl-1, 4-dioxa-8-azaspiro [4.5] decan-8-yl) -6-trifluoromethyl-8-nitro-chromen-4-one II-1 (Compound 1)
In a 10mL reaction flask, compound (S) -1- (2-chloro-3-nitro-5- (trifluoromethyl) phenyl) -3- (2-methyl-1, 4-dioxa-8-azaspiro [4.5] decan-8-yl) propane-1, 3-dione B-1(90mg, 0.2mmol), potassium carbonate (28mg, 0.2mmol) were dissolved in DMF (2mL) under Ar gas protection and warmed to 110 ℃ for 1 hour. The solvent was evaporated to dryness, 25mL of dichloromethane was added, washed with water and brine in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography on silica gel (200-. Compound II-1 (Compound 1) was obtained in a yield of 69.9% as a pale yellow solid 58 mg.
1H NMR(400MHz,CDCl3):8.74(s,1H),8.51(s,1H),5.66(s,1H),4.32-4.27(m,1H),4.14-4.10(m,1H),3.77-3.71(m,4H),3.53-3.49(m,1H),1.88-1.85(m,4H),1.31(d,J＝6.0Hz,3H).
Example 2
2- (4- (cyclohexylmethyl) piperazin-1-yl) -6-trifluoromethyl-8-nitro-chromen-4-one
The route is as follows:
the experimental steps are as follows:
first step preparation of 1- (2-chloro-3-nitro-5-trifluoromethylphenyl) -3- (4- (cyclohexylmethyl) piperazin-1-yl) propane-1, 3-dione B-2
Starting from 1- (cyclohexylmethyl) piperazine (182mg, 1.0mmol), the procedure was analogous to the first step in example 1 to give intermediate B-2 as a pale yellow solid, 272mg, yield 57.1%.
1H NMR(400MHz,CDCl3):15.62(brs,1H),8.01(s,1H),8.00(s,1H),5.67(s,1H),3.73-3.49(m,4H),2.45(m,4H),2.17(m,2H),1.79-1.71(m,5H),1.26-1.20(m,4H),0.90-0.87(m,2H).
Second step preparation of 2- (4- (cyclohexylmethyl) piperazin-1-yl) -6-trifluoromethyl-8-nitro-chromen-4-one II-2 (Compound 2)
Starting from 1- (2-chloro-3-nitro-5-trifluoromethylphenyl) -3- (4- (cyclohexylmethyl) piperazin-1-yl) propane-1, 3-dione (95mg, 0.2mmol), using the second similar procedure as in example 1, compound II-2 (compound 2) was obtained as a pale yellow solid, 46mg, yield 52.3%.
1H NMR(400MHz,CDCl3):8.74(d,J＝2.0Hz,1H),8.50(d,J＝2.0Hz,1H),5.59(s,1H),3.65(m,4H),2.55(m,4H),2.20(m,2H),1.80-1.62(m,5H),1.28-1.19(m,4H),0.91-0.86(m,2H).
Example 3
2- (4- (cyclohexylmethyl) piperazin-2-one-1-yl) -6-trifluoromethyl-8-nitro-chromen-4-one
Using 1- (cyclohexylmethyl) piperazin-2-one (39mg, 0.2mmol) as a starting material, the similar procedure as in example 2 was used to give compound II-3 (compound 3) as a pale yellow solid, 42mg, yield 46.4%.
1H NMR(400MHz,CDCl3):8.76(d,J＝2.0Hz,1H),8.55(d,J＝2.0Hz,1H),5.54(s,1H),4.14(s,2H),3.98-3.96(m,2H),3.58-3.56(m,2H),3.34(d,J＝7.2Hz,2H),1.77-1.66(m,5H),1.29-1.19(m,4H),1.02-0.99(m,2H).
Fruit of Chinese wolfberryExample 4
2- (2-methyl-1, 4-dioxa-8-azaspiro [4.5] decan-8-yl) -6- (trifluoromethyl) -8-nitro-benzothiopyran-4-one
Route of road
The experimental steps are as follows:
first step preparation of 2-methylsulfanyl-8-nitro-6- (trifluoromethyl) -4H-thiochromen-4-one D
In a 50mL reaction flask, NaOH (800mg, 20mmol) was dissolved in DMSO (5mL), carbon disulfide (2.34g, 30mmol) was added at 20 ℃ and 2-chloro-3-nitro-5-trifluoromethylacetophenone (2.67g, 10mmol) was added in portions, and after 15 minutes, methyl iodide (10mmol) was added at 20 ℃ for 30 minutes. Adding 100mL of ethyl acetate, washing with 100mL of water and brine in sequence, drying with anhydrous sodium sulfate, filtering, concentrating, and separating by silica gel (200-300 meshes) column chromatography, wherein a mixed solution of ethyl acetate and petroleum ether (V: 7:100) is used as an eluent. Intermediate D was obtained as a pale yellow solid 1.83g, yield 60.0%.
1H NMR(400MHz,CDCl3):9.12(d,J＝2.0Hz,1H),8.84(d,J＝2.0Hz,1H),6.91(s,1H),2.70(s,3H).
Second step preparation of (2-methyl-1, 4-dioxa-8-azaspiro [4.5] decan-8-yl) -6- (trifluoromethyl) -8-nitro-benzothiopyran-4-one III-1 (Compound 4)
In a 25mL reaction flask, 2-methylsulfanyl-8-nitro-6- (trifluoromethyl) -4H-thiochromen-4-one (64mg, 0.2mmol), (S) -2-methyl-1, 4-dioxa-8-azaspiro [4.5] decane (157mg, 1.0mmol) was dissolved in isopropanol (5mL) and reacted under Ar protection at 140 ℃ for 24 hours to give compound III-1 (compound 4) as a pale yellow solid 57mg in 66.3% yield.
1H NMR(300MHz,CDCl3):9.13(s,1H),8.77(s,1H),6.45(s,1H),4.28(m,1H),4.12(m,1H),3.82(m,4H),3.51(m,1H),1.88(m,4H),1.32(d,J＝6Hz,3H).
Example 5
2- (1, 4-dioxa-8-azaspiro [4.5] decan-8-yl) -6- (trifluoromethyl) -8-nitro-benzothiopyran-4-one
Using 1, 4-dioxa-8-azaspiro [4.5] decane (143mg, 1.0mmol) as a starting material, by the second similar procedure in example 4, compound III-2 (compound 5) was obtained as a pale yellow solid, 60mg, yield 72.2%.
1H NMR(400MHz,CDCl3):9.13(s,1H),8.76(s,1H),6.41(s,1H),4.03(s,4H),3.81(m,4H),1.88(m,4H).
Example 6
2- (1, 4-dithio-8-azaspiro [4.5] decan-8-yl) -6- (trifluoromethyl) -8-nitro-benzothiopyran-4-one
Using 1, 4-dithia-8-azaspiro [4.5] decane (175mg, 1.0mmol) as a starting material, by performing the similar operation in the second step in example 4, compound III-3 (compound 6) was obtained as a pale yellow solid in an yield of 70mg (77.8%).
1H NMR(400MHz,CDCl3):9.12(d,J＝1.6Hz,1H),8.78(d,J＝1.6Hz,1H),6.54(s,1H),3.83(m,4H),3.39(s,4H),2.28(m,4H).
Example 7
2- (1-oxa-4-thia-8-azaspiro [4.5] decan-8-yl) -6- (trifluoromethyl) -8-nitro-benzothiopyran-4-one
Using 1-oxa-4-thia-8-azaspiro [4.5] decane (159mg, 1.0mmol) as a starting material, the procedure was analogous to the second step in example 4 to give compound III-4 (compound 7) as a pale yellow solid, 52mg, yield 60.5%.
1H NMR(400MHz,CDCl3):9.13(s,1H),8.80(s,1H),6.78(s,1H),4.23(m,2H),3.86(m,4H),3.16(m,2H),2.17(m,4H).
Example 8
2- (4- (cyclohexylmethyl) -3-oxo-piperazin-1-yl) -6- (trifluoromethyl) -8-nitro-benzothiopyran-4-one
Using 1- (cyclohexylmethyl) -piperazin-2-one (196mg, 1.0mmol) as a starting material, the procedure was analogous to the second step in example 4 to give compound III-5 (compound 8) as a pale yellow solid, 61mg, yield 64.8%.
1H NMR(400MHz,CDCl3):9.16(s,1H),8.80(s,1H),6.19(s,1H),4.24(m,2H),3.90(m,2H),3.59(m,2H),3.36(m,2H),1.73-1.66(m,6H),1.26-1.21(m,3H),1.02-1.00(m,2H).
Example 9
2- (4, 4-Difluoropiperidin-1-yl) -6- (trifluoromethyl) -8-nitro-benzothiopyran-4-one
Using 4, 4-difluoropiperidine (121mg, 1.0mmol) as a starting material, the procedure was carried out in a similar manner to the second step in example 4 to give compound III-6 (compound 9) as a pale yellow solid, 63mg, in 79.7% yield.
1H NMR(400MHz,CDCl3):9.13(s,1H),8.80(s,1H),6.41(s,1H),3.83(m,4H),2.20(m,4H).
Example 10
2- (4- (thiazol-2-yl) piperazin-1-yl) -6- (trifluoromethyl) -8-nitro-benzothiopyran-4-one
Using (piperazin-1-yl) thiazole (169mg, 1.0mmol) as a starting material, the same procedures as in the second step of example 4 were carried out to give compound III-7 (compound 10) as a pale yellow solid, 43mg in 48.9% yield.
1H NMR(400MHz,CDCl3):9.14(s,1H),8.80(s,1H),7.28(d,J＝3.6Hz,1H),6.70(d,J＝3.6Hz,1H),6.31(s,1H),3.84(m,8H).
Example 11
2- (4- (cyclohexylmethyl) piperazin-1-yl) -6- (trifluoromethyl) -8-nitro-benzothiopyran-4-one
Using 1- (cyclohexylmethyl) piperazine (182mg, 1.0mmol) as a starting material, the second similar procedure as in example 4 was carried out to give compound III-8 (compound 11) as an orange solid in 66mg, yield 72.5%.
1H NMR(400MHz,CDCl3):9.12(s,1H),8.75(s,1H),6.25(s,1H),3.66(m,4H),2.56(m,4H),2.20(m,2H),1.80-1.67(m,5H),1.51(m,1H),1.26-1.16(m,3H),0.94-0.88(m,2H).
Example 12
2- (4- (cyclohexylmethyl) -3-methyl-piperazin-1-yl) -6- (trifluoromethyl) -8-nitro-benzothiopyran-4-one
Using 1- (cyclohexylmethyl) -2-methylpiperazine (196mg, 1.0mmol) as a starting material, by carrying out the second similar procedure in example 4, compound III-9 (compound 12) was obtained as a pale yellow solid (67 mg, yield 71.3%).
1H NMR(400MHz,CDCl3):9.12(s,1H),8.74(s,1H),6.24(s,1H),3.80-3.77(m,2H),3.47(m,1H),3.19(m,1H),2.95(m,1H),2.58(m,1H),2.50(m,1H),2.36(m,1H),2.01(m,1H),1.87(m,1H),1.71(m,4H),1.46(m,1H),1.25-1.11(m,6H),0.91-0.88(m,2H).
Example 13
2- (4- (benzyl) piperazin-1-yl) -6- (trifluoromethyl) -8-nitro-benzothiopyran-4-one
Using N-benzylpiperazine (176mg, 1.0mmol) as a starting material, the procedure was analogous to the second step in example 4 to give compound III-10 (compound 13) as a pale yellow solid, 55mg, yield 61.1%.
1H NMR(400MHz,CDCl3):9.12(s,1H),8.75(s,1H),7.35(m,5H),6.24(s,1H),3.68(m,4H),3.60(s,2H),2.63(m,4H).
Example 14
2- (4-benzyl-3-methyl-piperazin-1-yl) -6- (trifluoromethyl) -8-nitro-benzothiopyran-4-one
Using 1-benzyl-2-methylpiperazine (190mg, 1.0mmol) as a starting material, by carrying out the similar procedure in the second step in example 4, compound III-11 (compound 21) was obtained as a pale yellow solid (47 mg, yield 50.7%).
1H NMR(400MHz,CDCl3):9.12(s,1H),8.75(s,1H),7.35-7.26(m,5H),6.23(s,1H),4.06(d,J＝13.2Hz,1H),3.84(t,J＝15.2Hz,2H),3.40(t,J＝9.6Hz,1H),3.27-3.20(m,2H),2.85(d,J＝12.4Hz,1H),2.71(brs,1H),2.32(t,J＝9.2Hz,1H),1.26(d,J＝6.0Hz,3H).
Example 15
2- (4- (cyclohexylmethyl) piperazin-1-yl) -6- (trifluoromethyl) -8-nitro-benzothiopyran-4-one hydrochloride
2- (4- (cyclohexylmethyl) piperazin-1-yl) -6- (trifluoromethyl) -8-nitro-benzothiopyran-4-one (46mg, 0.1mmol) was placed in 5mL of ethanol, heated to dissolve, 0.1mL of 1N ethanol hydrochloride solution was added dropwise with stirring, after the addition was completed, stirring was carried out for 2 hours, cooling was carried out, filtration was carried out, a small amount of cold ethanol was washed, and drying was carried out to give compound III-12 (compound 22) as a yellow solid in 47mg yield of 95.6%.
1H NMR(400MHz,DMSO-d6):10.48(brs,1H),8.87(s,1H),8.86(s,1H),6.44(s,1H),4.31-4.28(m,2H),3.77-3.70(m,2H),3.61-3.58(m,2H),3.19-3.17(m,2H),2.99(brs,2H),1.83-1.80(m,3H),1.70-1.67(m,2H),1.64-1.60(m,1H),1.26-1.12(m,3H),0.98-0.95(m,2H).
Example 16
2- (4- (benzyl) piperazin-1-yl) -6- (trifluoromethyl) -8-nitro-benzothiopyran-4-one hydrochloride
2- (4- (benzyl) piperazin-1-yl) -6- (trifluoromethyl) -8-nitro-benzothiopyran-4-one (45mg, 0.1mmol) was placed in 5mL of ethanol, heated to dissolve, 0.1mL of 1N ethanol hydrochloride solution was added dropwise with stirring, after the addition was completed, stirring was carried out for 2 hours, cooling was carried out, filtration was carried out, a small amount of cold ethanol was washed, and drying was carried out to obtain compound III-13 (compound 26) as a yellow solid (46mg, yield 94.7%).
1H NMR(400MHz,DMSO-d6):11.3(brs,1H),8.88(s,1H),8.85(s,1H),7.58(brs,2H),7.47(brs,3H),6.42(s,1H),4.37-4.33(m,4H),3.66-3.60(m,2H),3.41-3.39(m,2H),3.23-3.21(m,2H).
Biological activity assay
1. In vitro antitubercular Activity test
The determination method comprises the following steps: the Microplate Alamar Blue Assay (MABA) method measures in vitro anti-tubercular activity.
The experimental principle is as follows: alamar Blue added to the medium can act as a redox indicator, changing the color from Blue to red, reflecting the consumption of oxygen molecules by the microorganism under study. The color change of Alamar Blue can be determined photometrically and has an emission wavelength of 590 nm.
The experimental method comprises the following steps: sterile 96-well plates (Falcon 3072; Becton Dickinson, Lincoln Park, n.j.), test compounds were dissolved in DMSO to make a primary solution with a concentration of 5mg/mL, 199 μ L of 7H9 medium and 1 μ L of the primary solution of the compound were added to the highest concentration well, mixed well, and diluted 2-fold sequentially to the remaining wells, the final concentration of the compound was: 25. 12.5, 6.25, 3.125, 1.56, 0.78, 0.39, 0.2, 0.1, 0.05, 0.025 μ g/mL. Selecting Mycobacterium tuberculosis H37Rv(or clinical separation of drug-resistant strains) culturing for 2-3 weeks to obtain a bacterial suspension, inoculating to 7H9 medium containing 0.05% Tween80 and 10% ADC, standing at 37 deg.C for 1-2 weeks, and growing to turbidity of McFarland 1 (equivalent to 10)7CFU/mL), 1: after 20 dilutions, 100. mu.L of each well was added to the suspension to a final concentration of 106CFU/mL. Each plate was plated with 2 growth control wells containing no antimicrobial, and the 96-well plates were incubated at 37 ℃. Adding 20 μ L of 10 × Alamar Blue and 5% Tween 8050 μ L of mixed solution into growth control wells after 7 days, incubating at 37 deg.C for 24 hours, adding the above amount of Alamar Blue and Tween80 mixed solution into each experimental drug well if the color changes from Blue to pink, incubating at 37 deg.C for 24 hours, recording the color of each well, measuring 590nm fluorescence value by using microplate reader, calculating MIC90。
TABLE 1 in vitro anti-Mycobacterium tuberculosis H of some of the compounds of the present invention37RvActivity of
TABLE 2 in vitro anti-drug resistant Mycobacterium tuberculosis Activity of some of the Compounds of the invention
aIsoniazid, rifampicin, streptomycin, ethambutol, rifapentine, rifabutin and benzoylaminosalicylic acid.
bIsoniazid, ethambutol, rifampin, rifapentine, rifabutin, amikacin, and capreomycin resistance.
As can be seen from the data in tables 1 and 2, the compounds of the present invention have strong in vitro activity against tuberculosis-sensitive bacteria and drug-resistant bacteria.
2. Cytotoxicity test
The determination method comprises the following steps: MTT method
The experimental principle is as follows: the activity of the cells is determined by that the 3- (4, 5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide (trade name: thiazole blue)/MTT [3- (4, 5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide ] in an oxidation state is reduced into a difficultly soluble blue formazan compound through an intramitochondrial dehydrogenase (such as succinate dehydrogenase), and the converted amount is positively related to the number of living cells by color development after being dissolved in DMSO.
The experimental method comprises the following steps: 1. preparation of cell suspension. And (3) digesting the Vero/HepG2 cells cultured to the logarithmic phase for 2-3 min by using 0.25% pancreatin, removing the digestive juice by suction, adding a proper amount of culture solution, uniformly mixing, taking 20 mu L, counting under a microscope by using a blood cell counter, and preparing cell suspension with a proper concentration for later use. Meanwhile, 5g/L MTT solution is prepared by PBS (phosphate buffered solution), and the MTT solution is filtered and sterilized for later use. 2. Medicine preparation and cytotoxicity detection. The test drug was dissolved in DMSO, diluted 50-fold with medium to the highest concentration tested, and then serially diluted 1: 3 in 96-well plates with 6 concentrations of each compound, with a maximum concentration of 64 μ g/mL, 6 parallel wells per concentration, 50 μ L/well in medium. The prepared cell suspension is inoculated into a 96-well plate, 50 mu L/well, the cell concentration is 4 multiplied by 105one/mL. Meanwhile, a cell control hole without medicine and a culture medium blank control hole are arranged. After 48 hours of incubation, 10. mu.L/well of MTT was added and incubation was continued for 4 hours. Taking out and culturingThe plate, carefully discard the medium in the wells, add 100 μ L DMSO per well, shake until the formazan particles are completely dissolved, and measure their optical density values (OD) at 570nm wavelength with an enzyme linked immunosorbent detector570). 3. And (6) data processing. Percent (%) cell inhibition ═ cell control OD570Value-addition medicine OD570Value)/(cell control OD570Value-blank OD570Value)]X 100%. Dose-response curve fitting was performed using origin7.0 software to calculate the concentration (IC) at which each compound inhibited 50% of cells50)。
TABLE 3 Vero cytotoxicity of partial compounds of the invention
TABLE 4 cytotoxicity of partial compound of the invention HepG2
As is clear from the data in tables 3 and 4, the compound of the present invention has low cytotoxicity and shows higher safety than the positive drug PBTZ 169.
3. Liver microsome metabolic stability test
The experimental method comprises the following steps:
selecting a target compound to carry out metabolic stability research on liver microsomes (mixed human source (Biorecamation)), wherein the specific method comprises the following steps: the synthesized target compounds were prepared into 1 μ M test solutions, respectively. The microsomal protein concentration was 1 mg/mL. The reaction was initiated by addition of NADPH (1mM) and the samples were incubated in a shaking incubator at 37 ℃ for up to 60 minutes. The reaction was terminated at 0,5,15 and 30 minutes by the addition of ice cold acetonitrile/methanol (50:50) containing internal standard. Aliquots of the reaction mixture were removed at 0,5,15,30 and 60 minutes respectively, and ice cold acetonitrile/methanol (50:50, v/v) containing the internal standard was added. The samples were centrifuged at 4 ℃ for 15 minutes (4,000 rpm) and the supernatants were analyzed by LC-MS/MS. Chromatographic conditions are as follows: a chromatographic column: KinetexC 18100A (30 mm. times.3.0 mm, 2.6 μm); column temperature: room temperature, mobile phase: an acetonitrile-water (containing 0.1% formic acid) gradient; flow rate: 0.9 mL/min. The metabolic stability of the compounds was assessed by measuring the residual amount of the compound with or without NADPH cofactor.
TABLE 5 human liver microsome metabolic stability data for partial compounds of the invention
As can be seen from the data in Table 5, the compounds of the present invention have high metabolic stability of liver microsomes.
4. Hepatocyte metabolic stability test
The experimental method comprises the following steps:
the assays were performed using hepatocytes from mixed CD-1 mice (bioreduction IVT), mixed SD rats (bioreduction IVT), mixed male dogs (bioreduction IVT), mixed male cynomolgus monkeys (RILD), and mixed humans (bioreduction IVT). Compounds (compound 11 and PBTZ169) were tested at a concentration of 1 μ M, with a final hepatocyte concentration of 1 million cells/mL. The reaction was initiated by adding a pre-warmed hepatocyte solution (200 ten thousand cells/mL) to the compound solution (2 μ M). CO at 100 rpm of the reaction mixture2Incubate at 37 ℃ for 120 minutes in an incubator. At predetermined time points (0,15,30,60,90 and 120 min), 30. mu.L of the reaction mixture was removed and the reaction was stopped by adding 200. mu.L of ice cold ACN/MeOH (50:50) containing an internal standard. The samples were mixed well, centrifuged at 4 ℃ for 15 minutes (4,000 rpm), and the supernatant analyzed by LC-MS/MS. Chromatographic conditions are as follows: a chromatographic column: kinetex C18100A (30 mm. times.3.0 mm, 2.6 μm); column temperature: room temperature, mobile phase: an acetonitrile-water (containing 0.1% formic acid) gradient; flow rate: 0.9 mL/min. The metabolic stability of the compounds in hepatocytes was evaluated by measuring the remaining amount of the compounds.
TABLE 6 hepatocyte metabolic stability of Compound 11 and PBTZ169
As can be seen from the data in Table 6, the compound 11 of the present invention has longer half-life in the five kinds of hepatocytes than the positive control PBTZ169, and the metabolic stability is significantly better than that of PBTZ 169.
5. In vivo pharmacokinetic assay in mice with Compound 11, Compound 22 and PBTZ169
The experimental method comprises the following steps:
pharmacokinetic studies of compound 11, compound 22 and PBTZ169 were performed in three Balb/c mice (male) weighing 22-23 grams per group. Compound 11 was formulated as a 2.5mg/mL suspension with 0.5% carboxymethylcellulose and 0.5% Tween80, compound 22 was formulated as a 2.5mg/mL suspension with 0.5% carboxymethylcellulose, PBTZ169 was formulated as a 2.5mg/mL suspension with 0.5% carboxymethylcellulose and 4 molar equivalents of 1N hydrochloric acid, all compounds were given a dose of 25 mg/kg. Plasma samples were collected at 5,15,30 minutes, and 1,2,4,7,24 hours after oral administration. The collected plasma samples were stored at-80 ℃ until used for analysis. Plasma samples were extracted with acetonitrile containing an internal terfenadine standard at a ratio of extractant to plasma of 20: 1. Analyte quantification was performed by LC/TSQQuantum Access Mass Spectroscopy (AB Sciex 5500). Chromatographic conditions are as follows: a chromatographic column: kinetex C18100A (30 mm. times.3.0 mm, 2.6 μm); column temperature: room temperature, mobile phase: acetonitrile/water (80:20, v/v) (containing 0.1% formic acid); flow rate: 0.8 mL/min. Compound detection on the mass spectrometer was performed in electrospray positive ionization mode. The MRM mode detects m/z 456.17/359.80 (Compound 11), 456.17/359.80 (Compound 22), and m/z 457.16/344.20(PBTZ 169). Pharmacokinetic parameters were calculated using WinNonlin software (6.3Pharsight Corporation, Mountain View, USA).
TABLE 7 plasma pharmacokinetic parameters following oral administration of Compound 11, Compound 22 and PBTZ169 in mice
From table 7, it can be seen that compound 11 and compound 22 of the present invention have a longer half-life in mice than PBTZ169, and their pharmacokinetic properties are better than PBTZ169, indicating that the number of administrations can be reduced in clinical use, thereby improving patient compliance.
6. Stability Studies of Compound 11, Compound 22 and PBTZ169
The stability of compound 11, compound 22 and PBTZ169 under light, high temperature and high humidity conditions for 10 days was examined by HPLC, and the results are shown in table 8.
TABLE 8 stability test results for Compound 11, Compound 22 and PBTZ169
The purity of the compound was checked using a Waters e2695-PDA HPLC system. Chromatographic conditions are as follows: a chromatographic column: kromasil C18(250 mm. times.4.6 mm, 5 μm); column temperature: 30 ℃, mobile phase: an equal gradient of acetonitrile/water (84:16, v/v); flow rate: 1.0 mL/min. From table 8, it can be seen that compound 11 and compound 22 of the present invention have significantly better stability under light conditions than PBTZ 169. Compared with PBTZ169, the compound 11 and the compound 22 have better physicochemical properties.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (13)
1. A compound of formula (I) and isomers, or pharmaceutically acceptable salts thereof:
wherein the content of the first and second substances,
x is O or S;
y is C or N;
R1is H, C1-C3Alkyl radical, C1-C3Alkoxy, F, Cl, Br, CN, OH, (═ O), or (═ S);
n is 0,1 or 2;
R2is F, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted C3-C6Heterocyclic radical, substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted C2-C9Heteroaryl, or together with the carbon atoms to which they are both attached, represents a substituted or unsubstituted cycloalkyl group containing 3 to 8 carbon atoms or a substituted or unsubstituted 4-to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur;
said C3-C6Heterocyclic group, C2-C9Heteroaryl contains at least one heteroatom selected from N, O, S;
the R is2Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy and C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy or C1-C3An alkylamino group.
2. The compound according to claim 1, which is represented by the general formula (II);
wherein the content of the first and second substances,
y is C or N;
R1is H, C1-C3Alkyl radical, C1-C3Alkoxy, F, Cl, Br, CN, OH, (═ O), or (═ S);
n is 0,1 or 2;
R2is F, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted C3-C6Heterocyclic radical, substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted C2-C9Heteroaryl, or together with the carbon atoms to which they are both attached, represents a substituted or unsubstituted cycloalkyl group containing 3 to 8 carbon atoms or a substituted or unsubstituted 4-to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur;
said C3-C6Heterocyclic group, C2-C9Heteroaryl contains at least one heteroatom selected from N, O, S;
the R is2Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy and C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy or C1-C3An alkylamino group.
3. The compound according to claim 1, which is represented by the general formula (III);
wherein the content of the first and second substances,
y is C or N;
R1is H, C1-C3Alkyl radical, C1-C3Alkoxy, F, Cl, Br, CN, OH, (═ O), or (═ S);
n is 0,1 or 2;
R2is F, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted C3-C6Heterocyclic radical, substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted C2-C9Heteroaryl, or together with the carbon atoms to which they are both attached, represents a substituted or unsubstituted cycloalkyl group containing 3 to 8 carbon atoms or a substituted or unsubstituted 4-to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur;
said C3-C6Heterocyclic group, C2-C9The heteroaryl group containing at least oneA heteroatom selected from N, O, S;
the R is2Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy and C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy or C1-C3An alkylamino group.
4. The compound according to claim 1 or 2, which is represented by the general formula (II-a):
wherein the content of the first and second substances,
R1is H, C1-C3Alkyl, F, Cl or (═ O);
n is 0 or 1;
R2is F, a substituted or unsubstituted cyclohexyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted thiazolyl group, or together with the carbon atom to which they are commonly attached represents a substituted or unsubstituted cyclopentyl group or a substituted or unsubstituted 5-membered heterocyclic group containing 1 to 2 heteroatoms selected from oxygen, sulfur;
the R is2Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy and C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy or C1-C3An alkylamino group.
5. The compound according to claim 1 or 2, which is represented by the general formula (II-b):
wherein the content of the first and second substances,
R1is H, C1-C3Alkyl, F, Cl or (═ O);
n is 0 or 1;
R2is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, or substituted or unsubstituted thiazolyl;
the R is2Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy and C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy or C1-C3An alkylamino group.
6. The compound according to claim 1 or 3, which is represented by the general formula (III-a):
wherein the content of the first and second substances,
R1is H, C1-C3Alkyl, F, Cl or (═ O);
n is 0 or 1;
R2is F, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furylUnsubstituted thienyl, substituted or unsubstituted thiazolyl, or together with the carbon atom to which they are both attached represent a substituted or unsubstituted cyclopentyl or a substituted or unsubstituted 5-membered heterocyclic group containing 1-2 heteroatoms selected from oxygen, sulfur;
the R is2Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy and C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy or C1-C3An alkylamino group.
7. The compound according to claim 1 or 3, which is represented by the general formula (III-b):
wherein the content of the first and second substances,
R1is H, C1-C3Alkyl, F, Cl or (═ O);
n is 0 or 1;
R2is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl;
the R is2Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy and C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy or C1-C3An alkylamino group.
8. The compound according to claim 2 and isomers thereof, or pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
R1is H, C1-C3Alkyl radical, C1-C3Alkoxy, F, Cl, Br, CN, OH, (═ O), or (═ S);
n is 0,1 or 2;
when the Y is C, the compound has the structure of,
R2is F,
When the Y is an amino group represented by the formula (I),
R2is composed of
Rx is F, Cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy or C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy or C1-C3An alkylamino group.
9. A compound according to claim 3 and isomers thereof, or pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
R1is H, C1-C3Alkyl radical, C1-C3Alkoxy, F, Cl, Br, CN, OH, (═ O), or (═ S);
n is 0,1 or 2;
when the Y is C, the compound has the structure of,
R2is F,
When the Y is an amino group represented by the formula (I),
R2is composed of
Rx is F, Cl, Br, hydroxyl, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy or C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy or C1-C3An alkylamino group.
10. A compound according to claim 1 and isomers thereof, or pharmaceutically acceptable salts thereof, selected from the following compounds:
11. a process for the preparation of a compound according to any one of claims 1 to 10, comprising the steps of:
(1)
condensing the compound A and a nitrogen heterocyclic side chain B to obtain a compound shown in a formula C, and then closing a ring under an alkaline condition to obtain a compound shown in a formula (II);
or (2)
The compound D reacts with carbon disulfide under alkaline conditions, then is methylated to obtain a compound E, and then is subjected to substitution reaction with a nitrogen heterocyclic side chain B to obtain a compound shown in a formula (III), the compound shown in the formula (III) can be treated by corresponding acid in a known proper solvent and is converted into pharmaceutically acceptable salt, wherein the acceptable salt is selected from hydrochloride, p-toluenesulfonate, tartrate, maleate, lactate, methanesulfonate, sulfate, phosphate, citrate, acetate or trifluoroacetate,
wherein, Y, R1、R2N is as defined in any one of claims 1 to 9.
12. A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound of any one of claims 1 to 10, and isomers thereof, or pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable carriers, excipients, diluents, adjuvants and vehicles.
13. Use of a compound according to any one of claims 1 to 10, an isomer thereof or a pharmaceutically acceptable salt thereof, or a composition according to claim 12 for the manufacture of a medicament for the treatment and/or prevention of infectious diseases caused by mycobacterium tuberculosis.
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| WO2018214639A1 (en) | 2018-11-29 |
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