CN105440051A

CN105440051A - Antituberculosis thienopyridine derivatives

Info

Publication number: CN105440051A
Application number: CN201410482093.6A
Authority: CN
Inventors: 邓杰; 雷皇书; 刘才平; 周昌兵; 刘详均; 徐立炎
Original assignee: Chongqing Pharmaceutical Research Institute Co Ltd
Current assignee: Chongqing Pharmaceutical Research Institute Co Ltd
Priority date: 2014-09-19
Filing date: 2014-09-19
Publication date: 2016-03-30
Anticipated expiration: 2034-09-19
Also published as: CN105440051B

Abstract

The invention relates to antituberculosis thienopyridine derivatives shown as a formula I and pharmaceutically-acceptable salts, R1-R5 are defined in the specification. The compounds possess mycobacterium trberculosis resistant activity. The invention also comprises a pharmaceutical composition containing the formula I compound and application to treat tuberculosis.

Description

Antitubercular thiophene pyridine derivative

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a quinoline thiophene-containing derivative or an optical isomer, a racemate, a non-corresponding isomer, a pharmaceutically acceptable salt, a solvate or an N-oxide thereof, a medicinal composition containing the compound, and application of the compound in resisting mycobacterium tuberculosis.

Background

Tuberculosis is the second leading infection next to aids in global statistics of infections. Despite the numerous antitubercular therapeutic drugs currently in clinical use, first line antitubercular drugs are still available for decades for isoniazid, rifampicins (rifamycins), pyrazinamide and ethambutol. These drugs have significant drawbacks in the treatment of tuberculosis: (1) the drug resistance is serious, and multi-drug resistance and even wide drug resistance tuberculosis strains are caused to appear; (2) the treatment period is too long, the medicine needs to be regularly taken for more than half a year at least, the patient is difficult to insist on, and the generation of drug resistance is promoted; (3) has liver drug enzyme inhibition or induction effect, and is easy to cause interaction during combined medication, so that the liver drug can not be combined with antiviral drugs (AIDS patients); (4) the side effects are more, which causes the patients to be difficult to insist on taking the medicine.

Due to the long-term application of the existing treatment medicines and irregular administration of patients, the tubercle bacillus in the bodies of the patients generates obvious drug resistance to the existing treatment medicines, and even multi-drug resistant tuberculosis resistant to various first-line antitubercular drugs and wide drug resistant tuberculosis resistant to all antitubercular drugs appear. These drug-resistant tuberculosis patients not only have a high fatality rate due to the lack of effective drug therapy, but also can be infected to other people, causing the prevalence of drug-resistant tuberculosis bacteria. The occurrence and prevalence of drug-resistant tuberculosis make tuberculosis become incurable disease again. According to the terms of people related to WHO, the number of tuberculosis patients is increased to more than 3,000 million in the next 10 years, the death of 1,500 million people can be reduced by using the existing medicines, and the life of the other half of people is completely determined by whether new antitubercular medicines can be developed or not. Therefore, the search for new tuberculosis drugs acting target and the development of new anti-tuberculosis drugs are urgent.

Among the antitubercular drugs currently under investigation, ATP synthase inhibitors are the most spotlighted new class of antitubercular drugs with a novel mechanism of action. Qiangsheng company (WO 2004011436A 1) discloses diaryl quinoline derivatives, which have the following chemical structures,

for example, bexaquinoline (TMC 207) has better anti-tubercle bacillus activity, but the compound can only be combined with other anti-tubercle drugs to treat tuberculosis at present, so that the development of the anti-tubercle compound with stronger activity and higher safety is also necessary.

Disclosure of Invention

The invention aims to provide a compound shown in the formula I and a pharmaceutically acceptable salt or solvate thereof, wherein the compound belongs to thiophene pyridine derivatives and has a strong anti-mycobacterium tuberculosis effect.

In one aspect, the compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, of the present invention,

wherein,

R₁represents hydrogen, halogen, hydroxy, alkoxy, alkyl, cyano, amino or nitro;

R₂is lower straight-chain or branched alkane containing 0 to 4 carbon atoms;

R₃represents phenyl, naphthyl and heterocyclyl, unsubstituted or substituted by one or more substituents, each independently, selected from the group consisting of: halogen, hydroxy, alkyl, haloalkyl, alkoxy, cyano, nitro and amino;

R₄、R₅two substituents independently selected from hydrogen, haloalkyl, hydroxy, alkyl, alkoxy, acyl, sulfonyl, Ar-alkyl, Het and Het-alkyl;

when R is₃And R₄When taken together, are selected from groups capable of forming, with a nitrogen atom, a saturated or unsaturated 4-to 7-membered ring containing 1 to 4 heteroatoms.

In one embodiment, the compounds of formula I of the present invention, or a pharmaceutically acceptable salt or solvate thereof,

wherein,

r1 represents hydrogen, halogen, cyano, alkoxy and alkyl;

R₂is methyl, ethyl or propyl

R₃Represents phenyl, naphthyl and heterocyclyl, unsubstituted or substituted by one or more substituents, each independently, selected from halogen, hydroxy, alkoxy and alkyl;

R₄、R₅is twoIndependently selected substituents from the group consisting of hydrogen, haloalkyl, hydroxy, alkyl, alkoxy, acyl, thioacyl, Ar-alkyl, Het and Het-alkyl;

in a preferred embodiment, the compounds of formula I of the present invention, or a pharmaceutically acceptable salt or solvate thereof,

wherein,

R₁represents halogen;

R₂is methyl;

R₃represents phenyl, naphthyl and heterocyclyl, unsubstituted or substituted by one or more substituents, each independently, the substituent(s) being selected from halogen, alkoxy and alkyl;

R₄、R₅are two independent groups, each being a substituent selected from the group consisting of hydrogen, haloalkyl, alkyl, and acyl.

Preferably, the compound of formula I of the present invention, or a pharmaceutically acceptable salt thereof, is selected from the following compounds:

1- (2-bromo-6-methoxy [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenyl-2-butanol;

1- (2-bromo-6-methoxy [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -2- (3-fluorophenyl) -1-phenyl-2-butanol;

1- (2-bromo-6-methoxy [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -2- (3-methoxyphenyl) -1-phenyl-2-butanol;

1- (2-bromo-6-methoxy [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -2- (3, 5-difluorophenyl) -1-phenyl-2-butanol;

1- (2-chloro-6-methoxythiophene [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -1, 2-diphenyl-2-butanol;

1- (2-chloro-6-methoxythiophene [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -1-phenyl-2- (3-methylphenyl) -2-butanol;

1- (2-chloro-6-methoxythiophene [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -2- (3-fluorophenyl) -1-phenyl-2-butanol;

1- (2-chloro-6-methoxythiophene [2,3-b ] pyridin-5-yl) -2- (3, 5-difluorophenyl) -4- (dimethylamino) -1-phenyl-2-butanol;

1- (2-chloro-6-methoxythiophene [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenyl-2-butanol;

1- (2-chloro-6-methoxythiophene [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -2- (3-methoxyphenyl-1-phenyl-2-butanol;

n- (4- (2-bromo-6-methoxythiophene [2,3-b ] pyridin-5-yl) -3-hydroxy-3- (3-methoxyphenyl) -4-phenylbutyl) -N-methylacetamide.

The compounds of formula I of the present invention or pharmaceutically acceptable salts or solvates thereof, including but not limited to hydrochloride, hydrobromide, sulfate, methanesulfonate, p-toluenesulfonate, maleate, fumarate, mandelate, citrate or tartrate; the solvate formed by the solvate compound and water, alcohol, ketone and the like, such as hydrate, methanol compound, ethanol compound and the like, wherein R is₁、R₂、R₃、R₄、R₅The definition of (A) is as above.

The compounds of formula I of the present invention, or pharmaceutically acceptable salts thereof, further include optical properties thereof

Isomers, racemates, diastereomers or N-oxide compounds. The optical isomer can be obtained by a conventional chiral resolution method or a chiral synthesis method, wherein R₁、R₂、R₃、R₄、R₅The definition of (A) is as above.

In another aspect, the present invention also provides a pharmaceutical composition comprising the above formula I of the present inventionA compound or an optical isomer, a pharmaceutically acceptable salt or a solvate thereof, and one or more pharmaceutically acceptable auxiliary materials or carriers optionally, wherein R₁、R₂、R₃、R₄、R₅The definition of (A) is as above.

In a further aspect, the present invention provides a therapeutic use of a compound of formula i, or an optical isomer, racemate, diastereoisomer, pharmaceutically acceptable salt or solvate thereof, according to the invention in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition caused by mycobacterium tuberculosis; that is, a method for treating and/or preventing a disease or disorder caused by Mycobacterium tuberculosis, comprising administering to a patient or subject having tuberculosis an effective amount of a compound of formula I (wherein, R is₁、R₂、R₃、R₄、R₅As defined above), or an optical isomer, racemate, diastereomer, pharmaceutically acceptable salt or solvate thereof, wherein the tuberculosis is pulmonary tuberculosis caused by mycobacterium tuberculosis.

The various terms and phrases used herein have the ordinary and customary meaning as understood by those skilled in the art, even if such terms and phrases are used

As such, these terms and phrases are again more fully described and explained herein, and reference to such terms and phrases is not to be construed as limiting the meaning of the present invention as expressed herein, unless otherwise expressly stated. The following are definitions of certain terms that apply to the terms used throughout this specification unless otherwise specified in specific instances.

In the context of the present invention, a radical, as depicted for example in a compound of the general formula or a specific compound, may have several hydrogen atoms attached to it, so that the radical may satisfy the chemical valence requirements, although the hydrogen atoms of the corresponding radical are not depicted in the structural formula.

"alkyl" is a straight or branched hydrocarbon group of 1 to 6 carbon atoms; a saturated cyclic group containing 3 to 6 carbon atoms; a linear or branched saturated cyclic group having 1 to 6 carbon atoms and 3 to 6 carbon atoms, and hydrogen on the alkyl group may be substituted with hydroxyl or halogen;

"alkoxy" means an alkyl-O-group in which alkyl is as defined above;

"halo" is a substituent selected from fluoro, chloro, bromo, iodo;

"haloalkyl" is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, wherein one or more carbon atoms are substituted with one or more halogen atoms;

"Ar" is a carbocycle selected from phenyl, naphthyl, tetrahydronaphthyl, each carbocycle optionally substituted with 1,2, or 3 substituents each independently selected from hydroxy, halo, cyano, nitro, amino, mono-or dialkylamino, alkyl, haloalkyl, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, morpholinyl, and mono-or dialkylaminocarbonyl;

"Het" is a monocyclic heterocycle selected from the group consisting of N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazole, isoxazole, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or is selected from quinolinyl, quinazolinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazole, benzisothiazolyl, benzofuran, benzothienyl, each monocyclic or bicyclic heterocycle optionally substituted with 1,2 or 3 substituents selected from halo, hydroxy, alkyl, alkoxy or Ar-carbonyl;

"subject" can refer to a patient or an animal, particularly a mammal, e.g., a human, dog, monkey, cow, mouse, etc., that receives a compound of formula I of the invention or a pharmaceutical composition thereof for treating and/or preventing a disease or disorder described herein.

"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.

As used herein, "%" refers to weight/weight percent, particularly where a solid material is described, as not specifically indicated. Of course, in describing liquid materials, the "%" may refer to weight/volume percent (for the case of solids dissolved in liquids) or may refer to volume/volume percent (for the case of liquids dissolved in liquids).

As used herein, "pharmaceutically acceptable" or "pharmaceutically acceptable" used interchangeably therewith, such as when "pharmaceutically acceptable salt" is depicted, means that the salt is not only physiologically acceptable to the subject, but may also refer to a synthetic substance of value in pharmaceutical use, such as a salt formed as an intermediate in the performance of a chiral separation, which salt, although not directly administered to the subject, may play a role in the final product of the invention as "a salt".

In a further aspect, the present invention provides a process for the preparation of a compound of formula i, and optical isomers thereof, or pharmaceutically acceptable salts thereof, which comprises the steps of:

1) the compound of formula III is prepared from the compound of formula II through Vilsmeier reaction, the Vilsmeier reagent is prepared by dropping DMF into phosphorus oxychloride under low temperature condition, the low temperature condition is preferably-20 deg.C to 0 deg.C, the compound of formula II is a commercial product, R is a commercial product₁As defined above for compounds of formula I;

2) the compound shown in the formula IV is prepared by a Witting-Horner reaction of a compound shown in the formula III and triethyl phosphonoacetate in anhydrous THF under an alkaline condition. The base used in the reaction is preferably HMDSNa, HMDSLi, potassium tert-butoxide, DBU, or the like, R₁As defined above for compounds of formula I;

3) the compound of formula V is prepared by reducing the compound of formula IV in tetrahydrofuran, wherein the reducing agent is preferably diisobutylaluminum hydride, lithium aluminum hydride, red aluminum solution, etc., and R is₁As defined above for compounds of formula I;

4) the compound of formula VI is prepared by reflux reaction of the compound of formula V in the corresponding alcohol solution of sodium alkoxide, R₁、R₂As defined above for compounds of formula I;

5) the compound of formula VII is prepared from a compound of formula VI by a Charleses asymmetric epoxidation reaction in which the oxidant is preferably t-butanol peroxide, R₁、R₂As defined above for compounds of formula I;

6) the compound VIII is obtained by ring-opening the compound of formula VII by a Grignard reagent under the catalysis of a cuprous salt, preferably cuprous iodide, cuprous bromide and cuprous cyanide, R₁、R₂As defined above for the compounds of formula I.

7) The compound of formula IX is prepared by oxidizing a compound of formula VII to the corresponding aldehyde by sodium periodate, and then neutralizing with R₃(ii) a Grignard reagentPrepared by reaction, wherein R₁、R₂、R₃As defined above for compounds of formula I;

8) the compound of formula X is obtained by oxidation of a compound of formula IX, preferably by oxidation with Jones reagent, dess-Martin reagent, Stevens oxidation, etc., R₁、R₂、R₃As defined above for compounds of formula I;

9) the XI compound is prepared through reaction of the compound in the formula X with allyl Grignard reagent in the temperature of-100-0 deg.c, and the allyl Grignard reagent is preferably allyl magnesium bromide, allyl magnesium chloride and allyl magnesium iodide, R₁、R₂、R₃As defined above for compounds of formula I;

10) the compound of formula XII is prepared by oxidative cleavage of double bond of compound XI to generate aldehyde, and the oxidation method in the reaction is preferably oxidation of osmium tetroxide with sodium periodate and ozone, R₁、R₂、R₃As defined above for the compounds of formula I.

11) The compound of formula I is prepared from a compound XII and a compound containing R₄、R₅The amine of the substituent is obtained by reductive amination, and the reducing agent of the reaction is preferablySodium borohydride, sodium cyanoborohydride and sodium acetate borohydride; r₁、R₂、 R₃、R₄、R₅As defined above for the compounds of formula I.

The specific synthetic route of the invention is as follows:

wherein R is₁、 R₂、R₃、R₄And R₅As defined above for the compounds of formula I.

The compounds of formula i of the present invention or pharmaceutically acceptable salts thereof may be used alone or in the form of pharmaceutical compositions with pharmaceutically acceptable adjuvants, carriers or excipients, and when used in the form of pharmaceutical compositions, the compounds of formula i of the present invention or pharmaceutically acceptable salts or solvates thereof will generally be mixed in an effective amount with one or more pharmaceutically acceptable adjuvants, carriers or diluents to make suitable dosage forms, and the components will be mixed, granulated, compressed or dissolved by methods conventional in the art.

The pharmaceutical compositions of the present invention containing a compound of formula I may be administered in any manner selected from the following: oral, aerosol inhalation, rectal, nasal, vaginal, topical, parenteral such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or via an external reservoir, with oral, intramuscular, intraperitoneal, or intravenous administration being preferred.

The compounds of formula I of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form. The administration dosage form can be liquid dosage form or solid dosage form. The liquid dosage form can be true solution, colloid, microparticle, emulsion, or mixed suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, clathrate, implant, patch, and liniment.

The pharmaceutical composition of the present invention may further comprise common pharmaceutical excipients, and the pharmaceutically acceptable carriers include but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin and the like. The content of the auxiliary material in the pharmaceutical composition can be 1-98% by weight.

Excipients for oral tablets and capsules include, for example, binders such as syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidone, fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, glycine, lubricants such as magnesium stearate, talc, polyethylene glycol, silica, disintegrants such as potato starch, low-substituted hypromellose, sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, and the like, or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated by methods known in the art of pharmacy.

Oral liquids may be prepared as suspensions, solutions, emulsions, syrups or elixirs in water and oil, or as dry products, supplemented with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gelatin, hydrogenated edible fats and oils, emulsifying agents, such as lecithin, sorbitan monooleate, gum arabic; or a non-aqueous carrier (which may comprise an edible oil), such as almond oil, an oil such as glycerol, ethylene glycol, or ethanol; preservatives, e.g. methyl or propyl p-hydroxybenzoates, sorbic acid. Flavoring or coloring agents may be added if desired.

Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides.

Parenteral administration, usually injection, is usually made of the compound of the invention and injectable excipients and/or solvents. The solvent is preferably water. The compound of the present invention is dissolved in a solvent to form a solution, or is made into a suspension solution in a solvent, and when the compound of the present invention is made into a solution for injection, the compound of the present invention is dissolved in water, filtered and sterilized, and then is filled into a closed bottle or ampoule.

When applied topically to the skin, the compounds of the present invention may be formulated in the form of a suitable ointment, lotion, or cream in which the active ingredient is suspended or dissolved in one or more carriers. Among the carriers that may be used in the ointment formulation include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions and creams may employ carriers including, but not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

In the above pharmaceutical preparation, the compound of formula (I) is present in a concentration of about 0.1 to 99.5%, preferably about 0.5 to 95% by weight based on the total weight of the mixture.

The above pharmaceutical preparations may further comprise other pharmaceutically active compounds in addition to the compound of formula (I).

In general, it has proven advantageous, both in human medicine and in veterinary medicine, to administer the compounds of the invention in a total amount of from about 0.5 to 500mg, preferably l to 100mg, per 24 hours, if appropriate in multiple single doses, in order to achieve the desired effect. The amount of the compound of the present invention in a single dose is preferably about l to 80mg, more preferably l to 50mg, but may be other than the above-mentioned dose, i.e., depending on the kind and body weight of the subject to be treated, the nature and severity of the disease, the type of preparation and the mode of administration of the drug, and the administration period or time interval.

Detailed Description

The following examples are preferred embodiments of the present invention and should not be construed as limiting the invention in any way.

The melting point of the compound was determined by an SGW X-4 type micro melting point apparatus, the thermometer was not calibrated. Mass spectra were determined by SHIMADZULCMS-2020. NMR was measured by Agilent-NMR-vnrs 400 and Agilent-NMR-vnrs 600

The absolute stereochemistry of the chiral carbon atom was not experimentally determined during the preparation of each compound. In this case, the stereochemical configuration is not taken into account.

Preparation of intermediates

Examples 1

Preparation of intermediate III-1

141ml (1.54 mol) of phosphorus oxychloride is put in a 1000ml single-mouth bottle and cooled to 0^oC, slowly adding 58ml (0.77 mol) of DMF dropwise, and maintaining 0 after the addition^oC, reacting for 30min, heating to room temperature, slowly adding 29.4g (0.193 mol) of 2-acetamido 5-bromothiophene in portions, stirring uniformly, and heating to 80 DEG^oC, reacting for 1.5h, cooling the reaction solution to room temperature, slowly pouring the reaction solution into 1200g of ice water, stirring for 30 minutes, extracting with ethyl acetate, separating liquid, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, and recrystallizing a concentrated crude product with 300ml of ethanol to obtain 40.1g of a gray-brown solid intermediate III-1, wherein the yield is as follows: 75.1 percent.

Examples 2

Preparation of intermediate IV-1

39.3g triethyl phosphonoacetate (0.161 mol), about 50ml THF was added and cooled to 0^oAnd C, slowly dropwise adding 81ml (0.161 mol) of HMDSNa solution, heating to room temperature after dropwise adding, stirring to react for 30min, slowly adding the solution into 40.0g (0.146 mol) of intermediate III-1 THF (250 ml) suspension, stirring to react for about 2.5h at room temperature, and detecting that the reaction is basically complete by TLC. Adding 100ml of water to quench the reaction, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, purifying the obtained crude product by column chromatography, wherein the ratio of a mobile phase solvent to ethyl acetate to petroleum ether is =1:5, and finally obtaining 38.6g of a light gray solid intermediate IV-1, wherein the yield is as follows: 76.8 percent.

Examples 3

Preparation of intermediate V-1

33.2g (0.96 mol) of intermediate IX-1 was dissolved in 1000ml of dichloromethane in a single-neck flask, 240ml (1M/L, 0.24 mol) of diisobutylaluminum hydride in toluene was slowly added dropwise in an ice-water bath, and after the addition, the temperature was raised to room temperature for 1.5 hours, and the reaction was detected by TLC to be complete. Adding about 150ml of ice water for quenching, slowly pouring into a 2N hydrochloric acid solution containing 1L of ice blocks, separating after the ice blocks are completely clarified, extracting a water layer twice by using dichloromethane, washing a combined organic phase by using saturated salt water, drying by using anhydrous sodium sulfate, and using ethyl acetate for a crude product: recrystallization from petroleum ether =1:6 gave 26.3g of intermediate v-1 as a dark yellow solid, yield: 90.3 percent.

Examples 4

Preparation of intermediate VI-1

14g (0.605 mol) of sodium metal is cut into small pieces, slowly added into a 1000ml single-neck bottle filled with 500ml of methanol, stirred and condensed until the sodium pieces are completely dissolved, 26.3g (0.086 mol) of intermediate V-1 is added in portions, and then the temperature is raised to 80 percent^oC, stirring the reaction (about 16 h), and detecting the reaction by TLC. After methanol was distilled off, 300ml of water was added to dilute the solution, and the solution was extracted with dichloromethane, separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was purified with dichloromethane: recrystallization from petroleum ether =1:2 gave 18.6g of pale yellow solid intermediate vi-1, yield: 71.8 percent.

Examples 5

Preparation of intermediate VII-1

2.57g (0.0091 mol) of isopropyl titanate is put into a 500ml three-necked bottle, about 150ml of dry dichloromethane is added for dissolution, 20g of dry 4A molecular sieve is added, and the mixture is cooled to-20 DEG^oC, slowly adding 3.18g (0.0136 mol) of dichloromethane solution (about 30 ml) of L- (+) tartaric acid dropwise, and after the dropwise addition, keeping the temperature and stirring for reacting for 30 min. Then adding 6.8g (0.0226 mol) of the intermediate VI-1 in portions, and continuing stirring to react for 40 min; then 56ml (about 4M/L,0.226 mol) of a toluene solution of anhydrous tert-butyl hydroperoxide prepared in advance is added, and the concentration is still within the range of-19 to-23^oThe reaction was carried out for 3.5h at C, and the starting material was almost completely converted as detected by TLC. Adding 20% of hydrogen and oxygenStirring about 100ml of sodium chloride solution for 1.5h, naturally raising the temperature to room temperature, carrying out suction filtration, separating liquid, extracting a water layer for 2 times by using 150ml of dichloromethane respectively, combining organic layers, washing with saturated salt water, drying with anhydrous sodium sulfate, purifying a crude product by using column chromatography, wherein the ratio of a mobile phase solvent to a petroleum ether is =3:10, and then obtaining 5.5g of a pale yellow solid intermediate VII-1, wherein the yield is as follows: 77.0 percent.

Examples 6

Preparation of intermediate VIII-1

Adding 7.87g (0.328 mol) of magnesium chips into a dry 250ml three-necked bottle, adding 80ml of dry THF under the protection of nitrogen, adding 50mg of iodine, stirring uniformly, slowly dropwise adding 17ml (0.164 mol) of bromobenzene, and heating to 55-60% after the initiation reaction is finished^oAnd C, preserving the heat for 1h, and standing at room temperature for later use. Carefully weigh out cuprous cyanide 8.9g (0.0987 mol) and put in a 500ml single-neck flask, then add dry THF150ml, cool to-40 with acetonitrile-liquid nitrogen system^oC, slowly dripping the standby bromobenzene form reagent cooled to room temperature under the protection of nitrogen, and maintaining the temperature to be 40 below zero after the dripping is finished^oC, stirring and reacting for 1 h. 5.2g (0.0164 mol) of the intermediate VII-1 is dissolved in 30ml of THF and slowly dripped into the reaction system, and the reaction is continued at-30 to-40^oAnd C, reacting for 2 hours, detecting the reaction by TLC (thin layer chromatography), completely converting, adding 80ml of ammonium chloride aqueous solution to quench the reaction, adding ethyl acetate to extract, filtering, separating liquid, extracting a water layer with 100ml of ethyl acetate for 2 times, combining organic layers, washing with saturated salt, drying with anhydrous sodium sulfate, purifying an obtained crude product by column chromatography, wherein the ratio of mobile phase solvents to ethyl acetate to petroleum ether is =1:2, and finally obtaining 4.0g of a light yellow oily intermediate VIII-1, wherein the yield is as follows: 61.4 percent.

Preparation of intermediate VIII-2:

the intermediate VIII-2 can be prepared by taking 2-acetamido-5-chlorothiophene as a raw material and referring to the preparation routes of the intermediates III-1, IV-1, V-1, VI-1, VII-1 and VIII-1 in the example 1,2,3,4,5, 6.

Examples 7

Preparation of intermediate IX-1:

1.5g (0.0038 mol) of the intermediate VIII-1 is put into a 100ml single-neck bottle, 20ml of dichloromethane is added and stirred to be dissolved, then 18g (0.027 mol) of 20% sodium periodate silica gel reagent and 0.1ml of water are added, the reaction is stirred at room temperature for 1.5h, the TLC detection reaction is complete, the mixture is filtered, anhydrous sodium sulfate is dried, and the mixture is decompressed and pumped for standby.

Weighing 0.82g (0.034 mol) magnesium strip, cutting into pieces, adding into a dry 100ml two-neck bottle, adding small amount of iodine, stirring, adding dry THF30ml under nitrogen protection, and heating to 50 deg.C^oSlowly dripping 5.3ml (0.038 mol) of bromonaphthalene after C, and after the initiation and reaction are finished, adding 55-60 mol of bromonaphthalene^oKeeping the temperature for 1h at the temperature of C, cooling to room temperature, and cooling to 0 ℃ in an ice water bath^oC, under the protection of nitrogen, slowly adding a THF solution (about 10ml) of the spare compound dropwise, keeping 0^oC, reacting for 2 hours, and detecting the reaction by TLC to be basically completely converted. Adding 30ml of ammonium chloride aqueous solution to quench reaction, extracting with ethyl acetate, extracting a water layer with 50ml of ethyl acetate for 2 times respectively, combining organic layers, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating, purifying a crude product by column chromatography, and obtaining 1.45g of a light yellow solid intermediate IX-1 with a mobile phase solvent ratio of ethyl acetate to petroleum ether =1:10, wherein the yield is as follows: 78.1 percent.

Preparation of intermediates of formulae IX-2 to IX-11:

referring to the preparation of the intermediate compound of formula IX-1 of example 7, starting with compounds of formulae VIII-1 and VIII-2 respectively, the reaction with the appropriate Grignard reagent gives the intermediates of formula IX of Table 1 below (referred to as intermediates of formula IX for short).

Examples 8

Preparation of intermediates of the compound of formula X-1 (abbreviated as "intermediate IX-1")

Weighing 1.2g (0.0024 mol) of intermediate IX-1 into a 100ml three-necked flask, adding 30ml of dichloromethane for dissolving, adding 2.54g (0.006 mol) of newly prepared Dess-Martin reagent, stirring at room temperature for reaction for 3h, detecting by TLC to completely convert, adding 20ml of saturated sodium thiosulfate aqueous solution for quenching reaction, filtering, stirring the filtrate with saturated sodium bicarbonate aqueous solution, separating, extracting the water layer twice with dichloromethane, washing the combined organic layer with saturated saline solution, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, wherein the ratio of mobile phase solvent is ethyl acetate: petroleum ether =1:25, finally obtaining 900mg of white solid intermediate X-1, and the yield: 76.9 percent.

Examples 9

Preparation of intermediate XI-1

Under the protection of nitrogen, allyl is reacted18ml (1.0M/L, 0.0184 mol) of magnesium bromide in ether was injected into a 100ml single-neck flask and cooled to-78 deg.C with an acetone-liquid nitrogen system^oC, 900mg (0.00184 mol) of intermediate X-1 in 8ml of THF are slowly added dropwise and maintained at-80%^oC to-68^oAnd C, reacting for 1.5h, and detecting the reaction by TLC to be complete. Adding 20ml of ammonium chloride aqueous solution to quench the reaction, extracting with ethyl acetate, extracting the water layers with 30ml of ethyl acetate for three times respectively, combining organic layers, washing with saturated saline water, drying with anhydrous sodium sulfate, and purifying the crude product by column chromatography, wherein the ratio of mobile phase solvents is ethyl acetate to petroleum ether =1:20, 762mg of pale yellow solid intermediate XI-1 is obtained, and the yield is: 78.0 percent.

Examples 10

Intermediate XII -1 Preparation of :

595mg (1.12 mmol) of intermediate I1 were placed in a 50ml single neck flask, dissolved in 6ml of mixed solvent (dioxane: water =3: 1), 261ul (2.24 mmol) of 2, 6-lutidine was added, 214ul (0.16 mmol) of osmium tetroxide solution was added slowly dropwise, 980mg (4.6 mmol) of sodium periodate was added, the reaction was stirred at room temperature for 2.5h and checked by TLC. Adding 2ml of water for quenching reaction, filtering, extracting with ethyl acetate, extracting a water layer with 5ml of ethyl acetate for 2 times respectively, washing an organic layer with saturated saline water, drying with anhydrous sodium sulfate, removing the solvent by rotary evaporation, and drying to obtain 450mg of a light brown oily product intermediate XII-1, wherein the intermediate XII-1 is put into the next reaction without purification. Yield: 75.6 percent

Intermediate XII -2 To XII -10 Preparation of：

Intermediates of formula XII (formulae XII-2 to XII-11) in Table 2 below were prepared from intermediates of formulae IX-2 to IX-10, respectively, by reference to the preparation of intermediates of examples 8, 9 and 10.

Preparation of the target compound:

examples 11 Compound I -1 ，Ⅰ -2 The preparation of (1):

586mg (0.0011 mol) of Compound XII-1 was dissolved in 15ml of methanol, and 911mg (0.011 mol) of dimethylamine hydrochloride, 1.673g (0.0123 mol) of sodium acetate and 347mg (0.0055 mol) of sodium cyanoborohydride were added thereto, and the reaction was stirred at room temperature overnight (about 16 hours), and the completion of the conversion of the starting material was checked by TLC and LC-MS. Distilling under reduced pressure to remove most of methanol, diluting with 20ml of water, extracting with dichloromethane, separating, extracting water layer with 20ml of dichloromethane for 3 times, washing combined organic layers with saturated saline solution, drying with anhydrous sodium sulfate, purifying the obtained crude product with column chromatography, wherein the ratio of mobile phase solvent is acetone: petroleum ether =3:20 to obtain two non-corresponding isomers, and the component obtained first is labeled as compoundⅠ -1Total 195mg, yield: 31 percent. The latter fractions are labeled as compoundsⅠ -2Total 20mg, yield: 3.4 percent.

EXAMPLE 12 preparation of Compound with reference to example 10Ⅰ -1 ，Ⅰ -2The compounds shown in the following table 3 are prepared from the intermediate compound shown in the formula XII respectively, and the structure is shown in the following table:

formula (II)I-1 to Compounds of formula I-21Melting point and nuclear magnetic data of 4 ， Watch (A) 4 Is a formulaI-1 to Compounds of formula I-21Melting point and nuclear magnetic data of (c).

In vitro anti-tubercle bacillus Activity of Compounds of the invention: ( MIC ) Detection of

Detecting content

1) Activity test against mycobacterium tuberculosis (mycobacterium bovis GFP-BCG strain, mycobacterium tuberculosis human H37 Rv);

2) activity test of clinical separated strain of mycobacterium tuberculosis (clinical separated sensitive strain 3 strain, clinical separated drug-resistant strain 5 strain)

Detection method

1) Standard strains, clinical isolates and clinical drug-resistant strains (strains preserved in China CDC tuberculosis laboratory) of human mycobacterium tuberculosis are detected by using microplate Alamar Blue assay, and the experiment is completed in the tuberculosis reference laboratory of China center for disease prevention and control. If not noted, the working concentration of the drug was set at 25.6ug/ml start with a 2-fold gradient dilution. Blank control group was DMSO.

2) All experiments were repeated three times.

Detection step

First, preparation of sample stock solution (1.28 mg/mL)

Each sample was accurately weighed. According to the sample information, a certain volume of DMSO is respectively added into each sample tube, ultrasonic assisted dissolution is carried out, and sample stock solutions of 1.28mg/ml are respectively prepared.

Second, preparation of medicine dilution plate

The stock solutions were diluted in DMSO at 2-fold gradient and dispensed into 96-well plates, 200ul per well. The concentration of the sample was:

1.28mg/ml,0.64mg/ml,0.32mg/ml,0.16mg/ml,0.08mg/ml,0.04mg/ml,0.02mg/ml,0.01mg/ml

preparation of bacterial suspension

BCG is referred to the above method.

The preparation method of bacterial suspension of human type Mycobacterium tuberculosis comprises adding appropriate amount of liquid culture medium into Roche culture tube containing Mycobacterium, blowing and beating with suction tube, sucking bacterial liquid, placing in grinding tube, grinding bacteria on vortex device, standing for 15min, and grinding with turbidimetric tube(1 Maifang, concentration 3 × 10⁸) Performing turbidification to obtain final concentration of 3 × 10⁶

Fourth, sample adding

Corning bacteria culture 96-well plates (flat bottom) 50ul of medium was added per well, and then 2ul of compound was transferred to the plate using a 96-well microplate replicator. Then, 48. mu.L/well of the diluted bacterial solution was added to a 96-well plate. The final concentration of DMSO is 2%, see Table 5. After the bacterial suspension was added, the plate was sealed with a transparent tape and placed in a 37 ℃ incubator for cultivation.

Fifth, testing the result

A solution of Resazurin (0.1 mg/ml) was prepared in advance, and the solution was sterilized by filtration.

After 7 days of incubation, 20ul of Resazurin was added and after three days the wells were observed for color change, blue indicating the compound inhibits bacterial growth and pink indicating the compound is inactive. According to the results of photographing the plates, the size of the plaque was visually observed, and the description of the growth of the bacterial strain in each drug well was made, and the minimum inhibitory concentration MIC value was defined as the minimum antimicrobial concentration (MIC 90%) contained in the sterile growth well. The results are shown in Table 6, and Table 6 shows the results of activity (ug/ml) of human Mycobacterium tuberculosis.

Activity test for Mycobacterium bovis

Experimental methods

The BCG JP15 strain used in the experiment carries the pUV3583c-GFP plasmid, the plasmid can express GFP along with the replication and the composition of BCG, the detected GFP fluorescence intensity reflects the inhibition condition of the drug to bacteria, and compared with a method based on absorbance detection, the method has the advantages of higher sensitivity and wider signal window, and compared with staining methods such as AlamarBlue, MTT and the like, the method has the advantages of no need of secondary sample adding and simplified steps. The strain can be operated in a biosafety secondary laboratory. anti-BCG Activity assay model according to Clinical and Laboratory Standards

The Institute instruction manual M24-A was modified for the procedure and was performed in a biosafety secondary laboratory. First, an attenuated strain of M.bovis BCGJP15 was inoculated into 7H9 medium and cultured in a 37 ℃ constant temperature shaker at 60rpm for 7 days to the middle of logarithmic growth. Diluting the strain to OD600=0.025 (corresponding to 106 CFU/mL concentration) by using a fresh 7H9 culture medium, and obtaining a strain suspension. Dissolving each compound to be detected in dimethyl sulfoxide (DMSO), performing 2-fold gradient dilution, sucking 1 mu L of the compound solution to be detected, adding the compound solution to each hole of a 96-hole microporous plate, and sucking 80 mu L of bacterial suspension by using a multi-channel pipettor, and adding the bacterial suspension to each hole of the 96-hole microporous plate. The negative control was DMSO. Each test plate was sealed with a Parafilm sealing film, incubated in a 37 ℃ incubator for 96 hours, and the fluorescence of each well was detected and recorded using a fluorescence microplate reader (Perkin Elmer envision 2100), with an excitation wavelength of 480nm and an emission wavelength of 535 nm. The final concentration of the compound corresponding to the wells in which the growth of BCG was inhibited by more than 90% (fluorescence value less than 90% of the blank control group) was defined as the Minimum Inhibitory Concentration (MIC) of the compound against BCG.

The experimental results are shown in the table 7 。

。

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, solvate,

wherein,

R₂is lower straight-chain or branched alkane containing 0 to 4 carbon atoms;

R4、R₅two substituents independently selected from hydrogen, haloalkyl, hydroxy, alkyl, alkoxy, acyl, sulfonyl, Ar-alkyl, Het and Het-alkyl;

when R is₃And R4 is a group taken together and selected from the group consisting of groups capable of forming with the nitrogen atom a saturated or unsaturated 4-to 7-membered ring containing 1 to 4 heteroatoms.

2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt or solvate thereof,

R₁represents hydrogen, halogen, cyano, alkoxy and alkyl;

R₂is methyl, ethyl or propyl

R4、R₅are two independent groups, each substituent selected from the group consisting of hydrogen, haloalkyl, hydroxy, alkyl, alkoxy, acyl, sulfonyl, Ar-alkyl, Het and Het-alkyl.

3. A compound of formula i according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein

R₁Represents halogen;

R₂is methyl;

R4、R₅is two independent groups, each of which is selected from hydrogen and halogenAlkyl, alkyl and acyl substituents.

4. A compound of formula I according to claim 1, selected from the following compounds:

1- (2-bromo-6-methoxy [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenyl-2-butanol

1- (2-bromo-6-methoxy [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -2- (3-fluorophenyl) -1-phenyl-2-butanol

1- (2-bromo-6-methoxy [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -2- (3-methoxyphenyl) -1-phenyl-2-butanol

1- (2-bromo-6-methoxy [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -2- (3, 5-difluorophenyl) -1-phenyl-2-butanol

1- (2-chloro-6-methoxythiophene [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -1, 2-diphenyl-2-butanol

1- (2-chloro-6-methoxythiophene [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -1-phenyl-2- (3-methylphenyl) -2-butanol

1- (2-chloro-6-methoxythiophene [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -2- (3-fluorophenyl) -1-phenyl-2-butanol

1- (2-chloro-6-methoxythiophene [2,3-b ] pyridin-5-yl) -2- (3, 5-difluorophenyl) -4- (dimethylamino) -1-phenyl-2-butanol

1- (2-chloro-6-methoxythiophene [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenyl-2-butanol

1- (2-chloro-6-methoxythiophene [2,3-b ] pyridin-5-yl) -4- (dimethylamino) -2- (3-methoxyphenyl ] -1-phenyl-2-butanol

5. The compound according to any one of claims 1 to 4, further comprising an optical isomer, racemate, diastereoisomer or N-oxide thereof.

6. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt or solvate according to claims 1-5 and a pharmaceutically acceptable excipient.

7. Use of a compound or pharmaceutically acceptable salt or solvate according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition caused by infection with mycobacterium tuberculosis.