CN111138422B

CN111138422B - Medicine for preventing and treating lupus erythematosus and preparation method thereof

Info

Publication number: CN111138422B
Application number: CN202010003677.6A
Authority: CN
Inventors: 程艳; 由丽梅; 宋大华; 徐红纳; 邓代千; 邹桂华; 孟祥玉
Original assignee: Mudanjiang Medical University
Current assignee: Mudanjiang Medical University
Priority date: 2020-01-02
Filing date: 2020-01-02
Publication date: 2020-11-17
Anticipated expiration: 2040-01-02
Also published as: CN111138422A

Abstract

The invention provides a medicament with excellent effects of preventing and treating lupus erythematosus, in particular systemic lupus erythematosus. The compound can obviously reduce the anti-ds-DNA antibody and urine protein level of a mouse with systemic lupus erythematosus, improve the kidney pathology of the mouse, and show good treatment effect on the systemic lupus erythematosus, particularly the systemic lupus erythematosus.

Description

Medicine for preventing and treating lupus erythematosus and preparation method thereof

Technical Field

The invention relates to the field of medicines, in particular to a medicine for preventing and treating lupus erythematosus. The invention also relates to the application of the medicine in preventing and treating lupus erythematosus, in particular to systemic lupus erythematosus, and a preparation method thereof.

Background

Lupus Erythematous (LE) is a typical autoimmune connective tissue disease, which is common in women aged 15-40. Lupus Erythematosus is a disease spectrum disease, and can be divided into subtypes such as Discoid Lupus Erythematosus (DLE), Subacute Cutaneous Lupus Erythematosus (SCLE), deep Lupus Erythematosus (LEP), Neonatal Lupus Erythematosus (NLE), Drug-Induced Lupus Erythematosus (DILE), Systemic Lupus Erythematosus (SLE), and the like.

SLE is an autoimmune disease characterized by a systemic inflammatory pathology caused by tissue deposition of DNA-anti-DNA immune complexes. Symptoms of SLE are alleviated by treatment, but most of them undergo a repetitive and lengthy process of remission and worsening. The incidence of SLE is presumed to be 0.1% to 1%, whereas in the case of patients with SLE in the first parent the incidence rises to 2-4%, in the case of an ovoid twin, to 25%. Thus, SEL can be considered a disease with a large genetic element. In addition, although the ratio of the incidence rate is 1: 9, young women of 20-40 years old are susceptible to the disease if the age group capable of delivery is not included (Nippon Rinsho 200563 (Suppl 5), 247-.

On the other hand, factors such as uv light, bacterial infection, trauma, surgery, pregnancy, childbirth, and drug treatment can also cause tissue damage, leaving large amounts of nuclei and cellular components in the blood, which is believed to be the cause of SLE, and cause immune responses to self-antigens.

SLE is systemically developed and has a variety of conditions, including roughly: fatigue feeling, easy fatigue feeling, fever and the like of the whole body; butterfly erythema and discoid rash on skin and mucosa, and aggravation of disease by sunlight irradiation; muscle pain, joint pain; glomerulonephritis (lupus nephritis); mental symptoms such as depression, disorientation, delusions, etc., spasm, cerebrovascular disorder, etc.; epicardial inflammation; pleurisy; the onset of mesenteric vasculitis or lupus peritonitis with abdominal pain; hemolytic anemia; lymph nodes swell.

The symptoms due to SLE are various. Thus, its treatment was mainly (Nippon Rinsho 200563 (Suppl 5), 253-259): a powerful immunosuppressive therapy for SLE autoimmunity; treatment of systemic multi-organ lesions; a long-term treatment plan for SLE as a chronic disease, in which life prognosis and organ prognosis are considered; of particular interest for young women (particularly pregnancy, osteoporosis); concern over environmental factors.

Currently available markers for systemic lupus erythematosus include antinuclear antibodies (ANAs), anti-ds-DNA antibodies, anti-Sm antibodies, and the like. Antinuclear antibodies are commonly found in patients as markers of the disease, and in the diagnosis standard, the standard of antinuclear antibodies refers to that under the condition of not using drugs to induce drug lupus, the immunofluorescence or other experiment antinuclear antibody titer equivalent to the method is abnormal; serum levels of anti-ds-DNA antibodies were significantly associated with disease activity and impaired renal function, with high concentrations of anti-ds-DNA antibodies being found almost exclusively in SLE, which can be specifically detected by detecting anti-ds-DNA antibody levels.

Currently, the drugs clinically used for treating SLE are mainly:

1. glucocorticoids: is the first choice of the existing medicines for treating systemic lupus erythematosus and is used for treating acute fulminant lupus erythematosus, organ damage, acute hemolytic anemia, thrombocytopenic purpura and the like. Prednisone is typically employed. The long-term taking of the medicine can induce diseases such as infection, water and salt metabolism disorder, neuropsychiatric disorder, osteoporosis and the like.

2. Non-steroidal anti-inflammatory drugs: mainly used for mild patients with fever, joint and muscle ache but no obvious blood pathological changes, and aspirin, ibuprofen and the like are commonly used.

3. Immunosuppressant: is mainly used for patients who are easy to relapse but cannot use hormone due to serious adverse reactions. Azathioprine, cyclophosphamide, methotrexate, vincristine and the like are commonly used, but have great toxicity and side effects.

4. Antimalarial drugs: primarily for the treatment of discoid lupus, chloroquine phosphate is commonly used, which accumulates in the body, causing retinal degeneration.

Because of the large side effects of SLE therapeutic drugs, there is a great need to develop more effective drugs that can be used to treat SLE.

Disclosure of Invention

The purpose of the present invention is to provide a drug having an excellent effect of preventing and treating lupus erythematosus, particularly systemic lupus erythematosus.

The invention provides a medicament which is a compound shown in a formula I, and a stereoisomer, a tautomer, a pharmaceutically acceptable salt, an oxide, a prodrug or a solvate thereof:

wherein:

R₁selected from C1-C6 alkyl optionally substituted with one or more of halogen, cyano, nitro, amino, C1-C4 alkoxy, C1-C4 alkylamino, C6-C14 aryl, or 3-14 membered heteroaryl, and said C6-C14 aryl, 3-14 membered heteroaryl is further optionally substituted with 1 or more R;

R₂、R₃each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy;

R₄、R₅、R₆each independently selected from hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl;

R₇selected from C1-C6 alkyl or halogenated C1-C6 alkyl;

R₈selected from a C6-C14 aryl group or a 3-14 membered heteroaryl group, said C6-C14 aryl, 3-14 membered heteroaryl group being optionally substituted with 1 or more R;

r is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or nitro.

In addition, the invention also provides a pharmaceutical composition, which comprises the compound of the formula I, the stereoisomer, the tautomer, the pharmaceutically acceptable salt, the nitrogen oxide, the prodrug and the solvate thereof, and a pharmaceutically acceptable carrier and excipient.

The invention provides a compound shown in formula I, and application of a stereoisomer, a tautomer, a pharmaceutically acceptable salt, an oxide, a prodrug or a solvate thereof in preparing a medicament for preventing and treating lupus erythematosus, in particular systemic lupus erythematosus.

Advantageous effects

The compound can obviously reduce the anti-ds-DNA antibody and urine protein level of a mouse with systemic lupus erythematosus, improve the kidney pathology of the mouse, and show good treatment effect on the systemic lupus erythematosus, particularly the systemic lupus erythematosus.

Detailed Description

The invention is described using the following definitions unless otherwise indicated.

The term "halogen or halo" is used to denote fluorine, chlorine, bromine or iodine.

Alkyl refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. "Cx-Cy alkyl" refers to an alkyl group having from x to y carbons. The term includes, for example, straight and branched chain alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl and the like.

"aryl" means a monovalent aromatic carbocyclic group of 6 to 14, preferably 6 to 10, carbon atoms having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracenyl) which may or may not be aromatic, provided that the point of attachment is at an aromatic carbon atom. "Cx-Cy aryl" refers to aryl groups having from x to y carbons. Aryl groups include phenyl and naphthyl and the like.

"heteroaryl" refers to a 3 to 14-membered, preferably 3 to 6-membered, aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring. Such heteroaryl groups may have a single ring or multiple fused rings, wherein the fused rings may or may not be aromatic and/or contain heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment of the invention, the nitrogen and/or sulfur ring atoms of the heteroaryl group are optionally oxidized to the N-oxide (N → O), sulfinyl, or sulfonyl group. Preferred heteroaryl groups include pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and the like.

The term "compound" as used herein refers to the general formulae disclosed herein, to compounds encompassed by any subgenera of these general formulae, and to any particular compound having the general formulae and subgenera, including pharmaceutically acceptable salts, nitrogen oxides, prodrugs, or solvates thereof. The term further includes stereoisomers and tautomers of the compounds.

"stereoisomers" refers to compounds that differ in chirality at one or more stereocenters. Stereoisomers include enantiomers and diastereomers.

"tautomers" refer to tautomeric forms of compounds that differ in the position of the proton, such as enol-ketone and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms attached to both a ring-NH-moiety and a ring ═ N-moiety.

"pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counterions known in the art, representative salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, and undecanoate. In addition, the basic nitrogen-containing groups may be quaternized with the following agents: such as alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, aralkyl halides such as benzyl bromide and phenethyl bromide, and the like.

"nitroxides" the nitroxides of the compounds of the present invention can be prepared by oxidation of the corresponding nitrogen-containing basic species at elevated temperatures using common oxidants (e.g., hydrogen peroxide) in the presence of bases, optionally such as sodium bicarbonate, or by reaction with peracids in suitable solvents, such as with peroxyacetic acid in dichloromethane, ethyl acetate or methyl acetate, or with m-chloroperoxybenzoic acid in chloroform or dichloromethane.

"prodrug" refers to any derivative of a compound of the present embodiments that, when administered to a subject, is capable of providing, directly or indirectly, a compound of the present invention or an active metabolite or residue thereof. Particularly preferred derivatives and prodrugs are those that increase the bioavailability of the compounds of this embodiment when such compounds are administered to a subject or that increase the delivery of the parent compound into the biological compartment relative to the parent species. Prodrugs include ester forms of the compounds of the present invention. Examples of ester prodrugs include formate, acetate, propionate, butyrate, acrylate, and ethyl succinate derivatives.

"solvates" refers to those compounds that are combined with a stoichiometric or non-stoichiometric amount of solvent. Preferred solvents are volatile, non-toxic and/or acceptable for administration to humans in trace amounts. Suitable solvates include water.

The present invention provides a compound of formula I, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, an oxide, a prodrug, or a solvate thereof:

wherein:

R₇selected from C1-C6 alkylOr halogenated C1-C6 alkyl;

In one embodiment of the invention, said R₁、R₂、R₃、R₄Each independently selected from hydrogen, C1-C6 alkyl, halo C1-C6 alkyl, C1-6 alkoxy C1-C6 alkyl, or di (C1-C6 alkyl) amino C1-C6 alkyl.

In one embodiment of the invention, said R₁Selected from C1-C4 alkyl.

In one embodiment of the invention, said R₁Selected from C1-C4 alkyl substituted with one or more of halogen, C6-C14 aryl, or 3-14 membered heteroaryl, wherein C6-C14 aryl, 3-14 membered heteroaryl are optionally substituted with 1 or more R.

In one embodiment of the invention, said R₁Selected from C1-C2 alkyl substituted with one or more of F, Cl, Br, C6-C10 aryl, or 3-6 membered monocyclic heteroaryl, wherein C6-C10 aryl, 3-6 membered heteroaryl are optionally substituted with 1 or more R.

In one embodiment of the invention, said R₂、R₃Each independently selected from hydrogen, halogen, C1-C4 alkyl, or C1-C4 haloalkyl.

In one embodiment of the invention, said R₂、R₃Each independently selected from hydrogen or C1-C4 alkyl.

In one embodiment of the invention, said R₄、R₅、R₆Each independently selected from hydrogen or halogen.

In one embodiment of the invention, said R₇Selected from C1-C4 alkyl.

In one embodiment of the invention, said R₇Selected from methyl or ethyl.

In one embodiment of the invention, said R₈Selected from C6-C10 aryl or 3-6 membered heteroaryl, wherein C6-C10 aryl, 3-6 membered heteroaryl are optionally substituted with 1 or more R.

In one embodiment of the invention, said R₈Selected from phenyl, naphthyl, pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or pyranyl, optionally substituted with 1 or more R.

In one embodiment of the invention, said R₈Selected from phenyl, thiazolyl or pyrazolyl, optionally substituted with 1 or more R.

The following compounds are preferred in the present invention:

5- (1- (3-bromopropyl) -1H-indol-5-yl) -2-methyl-2- (pyridin-3-yl) furan-3 (2H) -one (compound 1);

5- (1-benzyl-4-fluoro-1H-indol-5-yl) -2-methyl-2- (pyridin-3-yl) furan-3 (2H) -one (compound 2);

2- (2-chlorophenyl) -5- (1-isopropyl-2, 3-dimethyl-1H-indol-5-yl) -2-methylfuran-3 (2H) -one (compound 3);

5- (1- (2-fluoroethyl) -1H-indol-5-yl) -2-methyl-2- (4-methylthiazol-2-yl) furan-3 (2H) -one (compound 4);

2-Ethyl-5- (1-phenethyl-1H-indol-5-yl) -2- (4- (trifluoromethyl) phenyl) furan-3 (2H) -one (Compound 5).

Pharmaceutical compositions, formulations and administrations

The pharmaceutical composition of the present invention comprises any one of the compounds of formula I of the present invention, stereoisomers, tautomers, pharmaceutically acceptable salts, oxides, prodrugs, solvates thereof, and pharmaceutically acceptable carriers and excipients.

The compounds of the present invention may be administered orally, sublingually, parenterally, by aerosol or inhalation spray, rectally, or topically in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles as appropriate. Topical application also includes the use of transdermal application, such as transdermal patches or iontophoretic devices. "parenteral" includes subcutaneous injections, intravenous, intrathecal, intramuscular, intrasternal injection or infusion techniques.

Pharmaceutical preparations suitable for these administration modes can be prepared by appropriately combining pharmaceutically acceptable carriers such as excipients or extenders such as starches, lactose, sucrose, mannitol, silicic acid, etc.; binders such as hydroxypropylmethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, and the like; disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, and specific complex silicate; diluents such as lactose, corn starch, and the like; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof; buffers such as organic acids including citric acid, tartaric acid, and lactic acid, inorganic acids including phosphoric acid and hydrochloric acid, alkali hydroxides such as sodium hydroxide and calcium hydroxide, and amines such as triethanolamine, diethanolamine, and diisopropanolamine; preservatives such as parabens and benzalkonium chloride; emulsifiers such as nonionic surfactants including glyceryl monostearate, sucrose fatty acid ester, polyoxyethylene hardened castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, and polyoxyethylene alkyl ether; anionic surfactants such as calcium stearate, magnesium stearate, and sodium lauryl sulfate; stabilizers such as sodium sulfite, sodium bisulfite, dibutylhydroxytoluene, butylhydroxyanisole, ethylenediaminetetraacetic acid, etc.; other deodorant, dispersant, preservative, perfume, etc. may be used as required.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent. Carriers and solvents that can be used are water and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be combined with at least one inert diluent, such as starch, glucose, sucrose, lactose, or combinations thereof. Typically, such dosage forms may also contain other materials in addition to the inert diluent, such as lubricants, dispersants, and the like. In the case of capsules, tablets and pills, such dosage forms may also comprise buffering agents. Additionally, tablets and pills may additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. These compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Although the compounds of the present invention may be administered as single active agents, they may also be used in combination with one or more other active agents for the treatment of lupus erythematosus, including: glucocorticosteroids, such as prednisone; non-steroidal anti-inflammatory drugs such as aspirin, ibuprofen, and the like; immunosuppressive agents, such as azathioprine, cyclophosphamide, methotrexate, vincristine, and the like; antimalarial drugs, such as chloroquine phosphate.

The compounds of the present invention will be administered in therapeutically effective amounts by any of the recognized modes of administration of agents that serve similar utilities. The actual amount of the compound, i.e., the active ingredient, will depend on various factors such as the severity of the disease to be treated, the age and relative health of the individual, the potency of the compound used, the route and form of administration, and other factors. The medicament may be administered more than 1 time per day, preferably 1 or 2 times per day.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary with the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. A therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.

A therapeutically effective dose is generally a total daily dose administered to the host in single or divided doses and may be, for example, in amounts of about 0.01 to about 1000mg/kg body weight/day and about 1.0 to about 30mg/kg body weight/day. Dosage unit compositions may contain such submultiples thereof to achieve a daily dosage.

The invention also relates to processes for preparing pharmaceutical compositions comprising a compound of the invention and pharmaceutically acceptable salts, oxides, prodrugs, solvates, stereoisomers and tautomers thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the compounds of the invention may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

Use of

The present invention relates to a compound of formula I, and the use of stereoisomers, tautomers, pharmaceutically acceptable salts, oxides, prodrugs or solvates thereof.

The compound of the formula I, and the stereoisomer, the tautomer, the pharmaceutically acceptable salt, the oxide, the prodrug or the solvate thereof can obviously reduce the anti-ds-DNA antibody and the urine protein level of a mouse with systemic lupus erythematosus, improve the kidney pathology of the mouse with the systemic lupus erythematosus and show good treatment effect on the systemic lupus erythematosus, particularly the systemic lupus erythematosus. Therefore, the compound of the present invention can be used for preventing and treating lupus erythematosus, especially systemic lupus erythematosus.

In some embodiments, the present invention provides the use of a compound of formula I, as well as stereoisomers, tautomers, pharmaceutically acceptable salts, oxides, prodrugs or solvates thereof, for the preparation of a medicament for the prevention and treatment of lupus erythematosus, particularly systemic lupus erythematosus.

General Synthesis of Compounds of the invention

In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula I.

In general, the compounds of the invention may be prepared by a process as described herein, wherein the substituents are as defined for compounds of formula I, unless otherwise specified, said process comprising:

step 1

Step 2

Step 3

Step 1: reacting a compound of formula II and a compound of formula III in the presence of butyllithium to obtain a compound of formula IV;

step 2: oxidizing the compound of formula IV to obtain a compound of formula V;

and step 3: the cyclization reaction is carried out in the presence of a base to obtain the compound of formula I.

Wherein R is₁-R₈As defined herein.

Step 2 is performed using an oxidizing agent comprising manganese dioxide.

The base in step 3 includes inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate; and organic bases such as diethylamine, triethylamine or pyridine.

Detailed Description

The compounds of the present invention may be prepared by a number of methods well known to those skilled in the art of synthesis. The compounds of the invention may be prepared, for example, using the reactions and techniques listed below, together with methods known in the art of synthetic organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent suitable for the reagents and materials used and for the conversion to be effected. Furthermore, in the synthetic methods described below, it is to be understood that all proposed reaction conditions (including choice of solvent, reaction atmosphere, reaction temperature, experimental duration and work-up procedures) are selected as standard conditions for the reaction, which should be readily ascertained by one skilled in the art of organic synthesis. Not all compounds falling within a given class may be compatible with certain reaction conditions required in certain of the described methods. These limitations on substituents compatible with reaction conditions will be apparent to those skilled in the art and alternative methods may be used.

Example 1: 5- (1- (3-bromopropyl) -1H-indol-5-yl) -2-methyl-2- (pyridin-3-yl) furan-3 (2H) -one (Compound 1)

Step 12- (pyridin-3-yl) but-3-yn-2-ol (50mmol) was dissolved in 80mL of dried tetrahydrofuran under nitrogen, cooled to-70 ℃ and butyllithium (12mL, 30mmol, 2.5M) was added slowly over 30 minutes. A solution of 1- (3-bromopropyl) -1H-indole-5-carbaldehyde (20mmol) in 40mL of dried tetrahydrofuran was added dropwise slowly over 1 hour. The reaction was then allowed to spontaneously warm to room temperature and stirred at room temperature for 4 hours. Saturated aqueous ammonium chloride was added for quenching, followed by extraction with dichloromethane 2 times. Combining the extracts, washing with saturated saline water, evaporating under reduced pressure to remove the solvent to obtain a crude product, and recrystallizing with ethanol to obtain an intermediate: 6.77g of 1- (1- (3-bromopropyl) -1H-indol-5-yl) -4- (pyridin-3-yl) pent-2-yne-1, 4-diol was obtained in 82% yield. MS (ES) M + H/M + H +2 theoretical 413.09/415.09, found 413.15/415.13.

Step 2 1- (1- (3-bromopropyl) -1H-indol-5-yl) -4- (pyridin-3-yl) pent-2-yn-1, 4-diol (10mmol) was dissolved in 100mL of dichloromethane, manganese dioxide (4.3g, 50mmol) was added, the reaction mixture was stirred at room temperature overnight, insoluble materials were removed by filtration, the solvent was evaporated under reduced pressure from the filtrate, and recrystallization from methanol gave 3.82g of intermediate 1- (1- (3-bromopropyl) -1H-indol-5-yl) -4-hydroxy-4- (pyridin-3-yl) pent-2-yn-1-one in 93% yield. MS (ES) M + H/MS (ES) M + H +2 theoretical 411.07/413.07, found 411.22/413.18.

Step 3 1- (1- (3-bromopropyl) -1H-indol-5-yl) -4-hydroxy-4- (pyridin-3-yl) pent-2-yn-1-one (5mmol) was added to 70mL of ethanol, stirred to dissolve, triethylamine (1mL) was slowly added dropwise, and the reaction was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, the residue was partitioned between dichloromethane and deionized water, the organic phase was washed with saturated brine and deionized water, dried over anhydrous sodium sulfate, distilled under reduced pressure and purified by silica gel column chromatography to give the title compound as a white solid in 1.79g, yield 87%.

MS (ES) M + H/MS (ES) M + H +2 theoretical 411.07/413.07, found 411.12/413.25.

Elemental analysis: theoretical value C, 61.33; h, 4.66; br, 19.43; n, 6.81; o,7.78

Found C, 61.58; h, 4.90; br, 19.24; n, 6.61; o,7.67

Hydrogen spectrum (400MHz, DMSO-d6)8.62(s,1H),8.60(d,1H, J ═ 7.5Hz),7.82(s,1H),7.66-7.70(m,2H),7.54(d,1H, J ═ 7.5Hz),7.28-7.36(m,2H),6.62(s,1H),6.56(d,1H, J ═ 7.5Hz),4.06(t,2H, J ═ 7.1Hz),3.42(t,2H, J ═ 7.1Hz),2.12(m,2H),1.84(s, 3H).

Example 2: 5- (1-benzyl-4-fluoro-1H-indol-5-yl) -2-methyl-2- (pyridin-3-yl) furan-3 (2H) -one (Compound 2)

Step 12- (pyridin-3-yl) but-3-yn-2-ol (50mmol) was dissolved in 80mL of dried tetrahydrofuran under nitrogen, cooled to-70 ℃ and butyllithium (12mL, 30mmol, 2.5M) was added slowly over 30 minutes. A solution of 1-benzyl-1H-indole-5-carbaldehyde (20mmol) in 40mL of dried tetrahydrofuran was added dropwise slowly over 1 hour. The reaction was then allowed to spontaneously warm to room temperature and stirred at room temperature for 6 hours. Saturated aqueous ammonium chloride was added for quenching, followed by extraction with dichloromethane 2 times. Combining the extracts, washing with saturated saline, evaporating under reduced pressure to remove the solvent to obtain a crude product, and recrystallizing with toluol to obtain an intermediate: 1- (1-benzyl-1H-indol-5-yl) -4- (pyridin-3-yl) pent-2-yne-1, 4-diol (5.81g, yield 76%. MS (ES) M + H theoretical 401.17, found 401.11.

Step 2 1- (1-benzyl-1H-indol-5-yl) -4- (pyridin-3-yl) pent-2-yn-1, 4-diol (10mmol) was dissolved in 100mL of chloroform, manganese dioxide (4.3g, 50mmol) was added, the reaction mixture was stirred at room temperature overnight, insoluble materials were removed by filtration, the solvent was evaporated under reduced pressure from the filtrate, and recrystallization was carried out with ethanol to give 3.27g of intermediate 1- (1-benzyl-1H-indol-5-yl) -4-hydroxy-4- (pyridin-3-yl) pent-2-yn-1-one in 86% yield. MS (ES) M + H theoretical 399.15, found 399.18.

Step 3 1- (1-benzyl-1H-indol-5-yl) -4-hydroxy-4- (pyridin-3-yl) pent-2-yn-1-one (5mmol) was added to 70mL of ethanol, stirred until dissolved, then triethylamine (1mL) was slowly added dropwise and the reaction was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, the residue was partitioned between dichloromethane and deionized water, the organic phase was washed with saturated brine and deionized water, dried over anhydrous sodium sulfate, distilled under reduced pressure and purified by silica gel column chromatography to give the title compound as a white solid in 1.79g, yield 87%.

MS (ES) M + H theoretical 399.15, found 399.25.

Elemental analysis: theoretical value C, 75.36; h, 4.81; f, 4.77; n, 7.03; o,8.03

Found C, 75.01; h, 4.58; f, 4.47; n, 7.54; o,8.40

Hydrogen spectrum (400MHz, DMSO-d6)8.62(s,1H),8.60(d,1H, J ═ 7.5Hz),7.67-7.71(m,2H),7.51(d,1H, J ═ 7.5Hz),7.12-7.36(m,8H),6.60(s,1H),5.43(s,2H),1.84(s, 3H).

Example 3: 2- (2-chlorophenyl) -5- (1-isopropyl-2, 3-dimethyl-1H-indol-5-yl) -2-methylfuran-3 (2H) -one (Compound 3)

The title compound was obtained in a similar manner to example 1, except that 1-isopropyl-2, 3-dimethyl-1H-indole-5-carbaldehyde was used instead of 1- (3-bromopropyl) -1H-indole-5-carbaldehyde and 2- (2-chlorophenyl) but-3-yn-2-ol was used instead of 2- (pyridin-3-yl) but-3-yn-2-ol, and the total yield in three steps was 46%.

MS (ES) M + H: theoretical 394.16, found 394.19.

Elemental analysis: theoretical value C, 73.18; h, 6.14; cl, 9.00; n, 3.56; o,8.12

Found C, 73.67; h, 6.29; cl, 9.18; n, 3.36; o,7.50

Hydrogen spectrum (400MHz, DMSO-d6)7.72(s,1H),7.64(d,1H, J ═ 7.5Hz),7.20-7.46(m,4H),6.61(s,1H),6.56(d,1H, J ═ 7.5Hz),4.66(m,2H),2.27(s,3H),2.25(s,3H),1.84(s,3H),1.48(q,6H, J ═ 6.8 Hz).

Example 4: 5- (1- (2-fluoroethyl) -1H-indol-5-yl) -2-methyl-2- (4-methylthiazol-2-yl) furan-3 (2H) -one (Compound 4)

Using a similar procedure as in example 1, except substituting 1- (2-fluoroethyl) -1H-indole-5-carbaldehyde for 1- (3-bromopropyl) -1H-indole-5-carbaldehyde and 2- (4-methylthiazol-2-yl) but-3-yn-2-ol for 2- (pyridin-3-yl) but-3-yn-2-ol, the title compound was obtained in 51% three-step overall yield.

MS (ES) M + H: theoretical 357.11, found 357.17.

Elemental analysis: theoretical value C, 64.03; h, 4.81; f, 5.33; n, 7.86; o, 8.98; s,9.00

Found C, 64.23; h, 4.71; f, 5.57; n, 7.65; o, 8.58; s,9.26

Hydrogen spectrum (400MHz, DMSO-d6)7.82(s,1H),7.66(d,1H, J ═ 7.5Hz),7.64(d,1H, J ═ 7.5Hz),7.29(d,1H, J ═ 7.5Hz),6.90(s,1H),6.66(d,1H, J ═ 7.5Hz),6.61(s,1H),4.57(tt,2H, J ═ 46.4Hz,7.1Hz),4.02(tt,2H, J ═ 46.4Hz,7.1Hz),2.41(s,3H),1.90(s, 3H).

Example 5: 2-Ethyl-5- (1-phenethyl-1H-indol-5-yl) -2- (4- (trifluoromethyl) phenyl) furan-3 (2H) -one (Compound 5)

The title compound was obtained in a similar manner to example 1, except that 1-phenethyl-1H-indole-5-carbaldehyde was used instead of 1- (3-bromopropyl) -1H-indole-5-carbaldehyde and 3- (4- (trifluoromethyl) phenyl) pent-1-yn-3-ol instead of 2- (pyridin-3-yl) but-3-yn-2-ol, and the total yield in three steps was 42%.

MS (ES) M + H: theoretical 476.18, found 476.11.

Elemental analysis: theoretical value C, 73.25; h, 5.09; f, 11.99; n, 2.95; o,6.73

Found C, 73.44; h, 5.30; f, 11.42; n, 2.88; o,6.96

Hydrogen spectrum (400MHz, DMSO-d6)7.82(s,1H),7.64-7.70(m,3H),7.64(d,1H, J ═ 7.5Hz),7.39(d,2H, J ═ 7.5Hz),7.17-7.27(m,6H),6.67(s,1H),6.64(d,1H, J ═ 7.5Hz),4.17(t,2H, J ═ 7.1Hz),2.91(t,2H, J ═ 7.1Hz),1.02(t,3H, J ═ 8.0Hz),2.26(q,2H, J ═ 8.0 Hz).

Examples of drug activity test:

test example 1: effect of Compounds of the invention on MRL/lpr systemic lupus erythematosus in mice

60 MRL/lpr lupus-like mice (SFP grade, female, 20 weeks old, body weight 34.8 + -5.9 g) were randomly assigned to 5 groups of 10 mice each, each of which was a model group and a compound 1-5 group. In addition, 10 normal C57BL/6 mice (female, 8 weeks old, 21.8. + -. 1.9g in body weight) were used as normal control groups. The compound 1-5 groups were administered with 20mg/kg/d of a physiological saline suspension of the compound, and the normal control group and the model group were administered with an equal volume of physiological saline and administered by gastric lavage. Continuously feeding for 50 days. Retroorbital venous blood was taken from each mouse before the start of the experiment (0d), during the experiment (25d) and at the end of the experiment (50d), and serum was frozen for anti-ds-DNA antibody; meanwhile, 24h urine is collected by a metabolism cage every time and is used for quantitative determination of 24h urine protein. After the experiment was completed, the animals were sacrificed under anesthesia, and the right kidneys of the mice were taken and fixed with 4% formaldehyde for histopathological examination.

Wherein, the detection of the peripheral blood anti-ds-DNA antibody adopts an enzyme-linked immunosorbent assay (ELISA) method and is operated according to the instruction. The 24h urine protein quantification was determined by Coomassie blue staining.

Kidney pathology was determined by: conventional dehydration and paraffin embedding are carried out on kidney tissues fixed by 4% formaldehyde, the section thickness is 2-4 mu m, HE staining and mounting are carried out, and the pathological form of the kidney is observed through an optical microscope. Pathological observation and semi-quantitative scoring standard reference reports are carried out (research on NF-k B signal transduction pathway mechanism of tripterygium glycosides for inducing rat renal cell apoptosis, Ningqiang and the like, Chengdu university of traditional Chinese medicine, 2011, 34(2): 39-44): 1 minute: basal membrane of small ball and interstitial mild hyperplasia; small tubular epithelial cell mild edema, small amount of cast; focal necrosis, small inflammatory cell infiltration; and 2, dividing: the basement membrane and interstitial hyperplasia of the globule are obvious; diffuse tubular epithelial cells with moderate edema and more cast; obvious inflammatory cell infiltration; and 3, dividing: the basement membrane and the stroma of the small ball obviously proliferate; diffuse small duct epithelial cells with severe edema and a large number of cast types; diffuse inflammatory cell infiltration.

As a result:

TABLE 1 Effect of Compounds on anti-ds-DNA antibodies

Group of	0d(ng/ml)	25d(ng/ml)	50d(ng/ml)
				Normal control group	0.052±0.015	0.079±0.022	0.066±0.028
Model set	32.56±8.62*	34.78±7.39*	33.21±9.11*
				Compound group 1	34.10±7.88*	17.20±3.85*^#	12.54±2.75*^#
Compound 2 group	33.44±8.15*	14.08±3.96*^#	11.02±3.01*^#
				Compound 3 group	32.75±9.22*	10.34±2.12*^#	7.09±1.88*^#
Compound 4 group	31.09±7.92*	18.25±4.04*^#	11.83±2.75*^#
				Compound 5 group	33.79±8.57*	15.39±3.18*^#	9.75±2.52*^#

Note: p compared to normal control<0.05; in comparison to the set of models,^#P<0.05

TABLE 2 Effect of Compounds on 24h urine protein

Group of	0d (g/24 hours)	25d (g/24 hours)	50d (g/24 hours)
				Normal control group	0.0052±0.0015	0.0049±0.0022	0.0036±0.0018
Model set	1.46±0.42*	1.49±0.39*	1.61±0.59*
				Compound group 1	1.45±0.35*	0.95±0.31*^#	0.59±0.15*^#
Compound 2 group	1.74±0.57*	0.86±0.34*^#	0.51±0.17*^#
				Compound 3 group	1.49±0.41*	0.69±0.27*^#	0.37±0.12*^#
Compound 4 group	1.64±0.50*	1.01±0.42*^#	0.64±0.23*^#
				Compound 5 group	1.54±0.37*	0.75±0.19*^#	0.43±0.11*^#

TABLE 3 Effect of Compounds on Kidney pathologies

Group of	Score of
		Model set	2.92±0.49
Compound group 1	1.63±0.18^#
		Compound 2 group	1.51±0.12^#
Compound 3 group	1.32±0.14^#
		Compound 4 group	1.79±0.23^#
Compound 5 group	1.57±0.16^#

Note: in comparison to the set of models,^#P<0.05

the kidney of the model group mouse shows the pathological change of the typical lupus nephritis, the proliferation of capillary endothelial cells, a large amount of inflammatory cell infiltration, the formation of granuloma and serious pathological change degree. The mice of the administration group have the phenomena of inflammatory cell infiltration and erythrocyte exudation in the vascular cavity, and the pathological condition of the kidney is greatly improved.

The results show that the anti-ds-DNA antibody and urine protein of each group of mice are at higher levels before the drug treatment, and no significant difference exists among the groups, but significant difference exists between the anti-ds-DNA antibody and urine protein of each group of mice and the C57BL/6 mice of a normal control group, which indicates that MRL/lpr systemic lupus erythematosus mice are successfully modeled, and the MRL/lpr systemic lupus erythematosus mice are also confirmed by high kidney pathology scores of the mice of the model group. Compared with a model group, mice of each administration group have obvious reduction of anti-ds-DNA antibody and urinary protein level and obvious improvement of kidney pathology, which shows that the compound has good treatment effect on lupus erythematosus mice.

The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations of the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.

Claims

1. A compound of formula I, and pharmaceutically acceptable salts thereof:

wherein:

R₁selected from C1-C6 alkyl optionally substituted with one or more of halogen or C6-C14 aryl, and said C6-C14 aryl is further optionally substituted with 1 or more R;

R₂、R₃each independently selected from hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl;

R₄、R₅、R₆each independently selected from hydrogen or halogen;

R₇selected from C1-C6 alkyl or halogenated C1-C6 alkyl;

R₈selected from a C6-C14 aryl group or a 3-14 membered heteroaryl group, said C6-C14 aryl, 3-14 membered heteroaryl group being optionally substituted with 1 or more R; wherein the C6-C14 aryl is selected from phenyl, the 3-14 membered heteroaryl is selected from pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl or pyrimidinyl;

r is selected from halogen, C1-C4 alkyl or C1-C4 haloalkyl.

2. A compound of claim 1, wherein R is₁Selected from C1-C2 alkyl substituted by one or more of F, Cl, Br, C6-C10 aryl.

3. A compound of claim 1, wherein R is₂、R₃Each independently selected from hydrogen or C1-C4 alkyl.

4. A compound of claim 1, wherein R is₄、R₅、R₆Each independently selected from hydrogen.

5. A compound of claim 1, wherein R is₇Selected from C1-C4 alkyl.

6. A compound of claim 1, wherein R is₇Selected from methyl or ethyl.

7. The compound of claim 1, wherein the compound of formula I is selected from the group consisting of:

8. A process for the preparation of a compound of formula I according to claim 1, characterized in that it comprises:

step 1

Step 2

Step 3

step 2: oxidizing the compound of formula IV to obtain a compound of formula V;

and step 3: performing a cyclization reaction in the presence of a base to obtain a compound of formula I;

wherein R is₁-R₈As defined in claim 1.

9. A pharmaceutical composition comprising a compound of formula I as described in any one of claims 1-7, and pharmaceutically acceptable salts thereof, together with pharmaceutically acceptable carriers and excipients.

10. The use of compounds of formula I as claimed in any of claims 1 to 7, and of pharmaceutically acceptable salts thereof, for the preparation of medicaments for the prophylaxis and treatment of lupus erythematosus.

11. The use of a compound of formula I as claimed in any one of claims 1 to 7, and pharmaceutically acceptable salts thereof, for the preparation of a medicament for the prevention and treatment of systemic lupus erythematosus.