CN108164536A - A kind of synthetic method for the new compound for being used to treat rheumatoid arthritis - Google Patents
A kind of synthetic method for the new compound for being used to treat rheumatoid arthritis Download PDFInfo
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- CN108164536A CN108164536A CN201810266514.XA CN201810266514A CN108164536A CN 108164536 A CN108164536 A CN 108164536A CN 201810266514 A CN201810266514 A CN 201810266514A CN 108164536 A CN108164536 A CN 108164536A
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- synthetic method
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- pyrrolopyrazine
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- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 235000009973 maize Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 235000021017 pears Nutrition 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 230000000979 retarding effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000011182 sodium carbonates Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 210000005222 synovial tissue Anatomy 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 210000003371 toe Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of for treating the synthetic method of the new compound of rheumatoid arthritis, the new chemical constitution is formula（Ⅰ）The equal conspicuousness of drug b groups of the present invention, drug c groups, drug d groups, drug e groups serum TNF α compared with positive drug group reduces, drug a groups of the present invention serum TNF α compared with positive drug group is slightly higher, but is significantly reduced compared with model group, this is the experimental results showed that drug formula of the present invention（Ⅰ）The swelling degree in RA joints can effectively be alleviated, hence it is evident that reduce the content of TNF α, so as to block inflammatory reaction, improve function of joint, delay the process of RA, mitigate the destruction of RA.The synthetic method of claimed above-mentioned new compound, step is simple, is easy to industrialized production.
Description
It is on May 8th, 2017 that the application, which is the applying date, and application No. is 201710318830.2, entitled " one kind is used for
The divisional application of the patent of the drug for the treatment of rheumatoid arthritis ".
Technical field
The present invention relates to a kind of for treating the synthetic method of the new compound of rheumatoid arthritis.
Background technology
Rheumatoid arthritis（RA）It is a kind of unknown systemic disease chronic, based on inflammatory synovitis of cause of disease.Its
It is characterized in hand, the multi-joint of sufficient Minor articulus, symmetry, aggressive arthritis, is often accompanied by organ outside joint and is involved serum
Rheumatoid factor positive can cause joint deformity and function to be lost.
Nearly ten years, with the early stage use in conjunction of slow effect antirheumatic drug, treatment and new treatment to lesion outside joint
The emergence of method makes the prognosis of rheumatoid arthritis have clear improvement.The state of an illness of most of rheumatoid arthritis patients can
It is well controlled or even complete incidence graph.It the study found that can be big according to the clinical characters of rheumatoid arthritis morbidity First Year
Cause judges its prognosis, and certain clinical and lab index are meaningful to Estimation About Patient's Condition and direction of medication usage.In addition, patient's receives instruction
It is also related with prognosis to educate degree.The severity and the poor factor of prognosis for prompting rheumatoid arthritis include：Joint duration
Swelling, high titre antibody, the HLA-DR4/DR1 positives, the anaemia that occurs together, rheumatoid nodules, vasculitis, neuropathy or other joints
Outer shower.
Rheumatoid arthritis late, severe or long-term bedridden patients, because of concurrent infection, hemorrhage of digestive tract, the heart, lung or kidney
Lesion etc. can crisis patient vitals.
Invention content
The purpose of the present invention is to provide a kind of for treating the drug of rheumatoid arthritis, chemical constitution is formula
（Ⅰ）,
Wherein, R is,
Wherein, * C atom adjacents are the C atoms with N atomic bondings.
Further, formula（Ⅰ）The compound of expression, its salt or its solvated compounds.
A kind of for treating the drug of rheumatoid arthritis another object of the present invention is to provide, chemical constitution is
Formula（Ⅰ）Synthetic route be：
Wherein, R is。
Preferably：The step（1）Specially：Compound [1,2-a] Pyrrolopyrazine -1- formaldehyde is added in into dichloromethane
With tetrahydrofuran in the mixed solvent, stirring has a small amount of insoluble matter, system is cooled to 0-5 DEG C, adds in pyridinium tribromide thereto
Drone, temperature stirring is kept, then adds in water thereto, steams organic solvent, tetrahydrofuran is added in, then system is slowly added dropwise
Enter in saturated aqueous sodium carbonate, be stirred overnight, be filtered under diminished pressure under mixed system room temperature, be washed with water, be dried in vacuo, obtain Huang
Color solid.
Preferably：The step（2）Specially：By bromo- [1,2-a] Pyrrolopyrazine -1- formaldehyde (10 of compound 6-
Mmol methanol and tetrahydrofuran in the mixed solvent) are added in, stirring has yellow insoluble matter, adds in 3- pyridine boronic acids, leads to argon to system
Gas drives air out of to come, and then adds in four triphenyl phosphorus palladiums, heating, stirring thereto, and solvent under reduced pressure is steamed, uses water by cooling
Mashing, obtains crude product, and crude product is placed in methanol the mashing that flows back, can obtain yellow solid.
Preferably：The step（3）Specially：6- (3- pyridyl groups)-[1,2-a] Pyrrolopyrazine -1- formaldehyde is dissolved in
Tetrahydrofuran adds in the concentrated sulfuric acid thereto, stirring, then adds in potassium permanganate, stirring at normal temperature, filtering, into filtrate thereto
Add in water, be extracted twice with dichloromethane, merge organic phase, anhydrous sodium sulfate drying, decompression steams solvent, with ethyl acetate and
Petroleum ether recrystallizes, and obtains off-white powder.
Preferably：The step（4）Specially：By compound 6- (3- pyridyl groups)-[1,2-a] Pyrrolopyrazine -1- first
Acid is dissolved in dichloromethane, adds in DMF thereto, thionyl chloride is then added dropwise, and is heated to flowing back, and stirring, decompression steams solvent, to
Toluene is wherein added in, decompression steams toluene and simultaneously takes away remaining thionyl chloride, and products obtained therefrom is directly used in react in next step.
Preferably：The step（5）Specially：By step（4）Crude product be dissolved in dichloromethane solution, add in thereto
Triethylamine, control temperature are added dropwise to 6- (3- pyridyl groups)-[1,2-a] Pyrrolopyrazine -1- formyl chlorides into system less than 10 DEG C
Dichloromethane solution, restore room temperature after being added dropwise, stirring at normal temperature, then with 5% aqueous sodium carbonate washing reaction body
System, organic phase anhydrous Na2SO4Dry, after solvent evaporated, obtained solid flash column chromatography detaches, and obtains light yellow solid.
Preferably：The step（6）Specially：By 1- [6- (3- pyridyl groups)-(1,2-a) Pyrrolopyrazine -1- formyls]
Base -1H- imidazoles -4- sulfonic acid chlorides are dissolved in dichloromethane, add in pyridine and dimethyl sulfoxide (DMSO) thereto, keep temperature less than 10 DEG C,
Thereto be added dropwise methylamine, aniline, benzene methanamine,OrDichloromethane solution, restore after being added dropwise
Room temperature, stirring, then decompression steam solvent, are recrystallized with ethyl acetate and petroleum ether, obtain product.
Another object of the present invention is to provide a kind of pharmaceutical composition for being used to treat rheumatoid arthritis, the medicine
Compositions include a effective amount of formula（Ⅰ）And pharmaceutically acceptable carrier,
Wherein, R is。
Further, the pharmaceutically acceptable carrier is filler or bulking agent, adhesive, moisturizer, disintegrant, delays
One or more of solvent, absorbsion accelerator, wetting agent, adsorbent, lubricant.
Further, described pharmaceutical composition is capsule, tablet, pill, powder or granule.
A kind of for treating the drug of rheumatoid arthritis another object of the present invention is to provide, chemical constitution is
Formula（Ⅰ）The application in treating medicine for treating rheumatoid arthritis is being prepared,
Wherein, R is。
The present invention is not to formula（Ⅰ）Or include formula（Ⅰ）The method of application of composition be particularly limited, it is representative to apply
Included with mode（But it is not limited to）：Oral, parenteral（Intravenously, intramuscular or subcutaneous）And local administration.For take orally to
The solid dosage forms of medicine includes capsule, tablet, pill, powder and granule.In these solid dosage forms, formula（Ⅰ）With at least one
Kind conventional inert excipients（Or carrier）Mixing, mixes such as sodium citrate or Dicalcium Phosphate or with following compositions：（a）Filler or
Bulking agent, such as starch, lactose, sucrose, glucose, mannitol and silicic acid；（b）Adhesive, such as hydroxymethyl cellulose, alginic acid
Salt, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；（c）Moisturizer, such as glycerine；（d）Disintegrant, such as fine jade
Fat, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates, sodium carbonate；（e）Retarding solvent, such as paraffin；
（f）Absorbsion accelerator, such as quaternary ammonium compound；（g）Wetting agent, such as cetanol and glycerin monostearate；（h）Adsorbent,
Such as kaolin；（i）Lubricant, such as talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate.
In capsule, tablet and pill, dosage form also may include buffer.
Wherein, gastrointestinal administration preparation is presently the most common administration form, and convenient experimental operation, therefore, this hair
Gastric infusion is used in bright specific embodiment into line（Ⅰ）The test of pesticide effectiveness, it is not intended that, formula（Ⅰ）Administration form
Gastrointestinal administration is only limitted to, those skilled in the art can be according to formula（Ⅰ）Physicochemical properties, with reference to Modern preparations technology and
The actual needs of sufferer is prepared into the several formulations such as injection, scalp absorbable preparation, implantation preparation, so as to expand its to
Medicine approach, and improve target-oriented drug or effectively avoid unnecessary toxic side effect.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture.
In addition to active ingredient beyond the region of objective existence, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase
Solvent and emulsifier, example know ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethylformamide
And oil, the particularly mixture of cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances
Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste
Agent, corrigent and fragrance.
In addition to active ingredient beyond the region of objective existence, suspension may include suspending agent, such as ethoxylation isooctadecane alcohol, polyoxyethylene mountain
Pears alcohol and the mixture of Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these substances etc..
For parenteral injection composition may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or lotion with for re-dissolving into the aseptic powdery of sterile Injectable solution or dispersion liquid.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
Dosage form for the compounds of this invention of local administration includes ointment, powder, patch, propellant and inhalant.
Active constituent aseptically with that physiologically acceptable carrier and any preservative, buffer or may need when necessary
Propellant be mixed together.
The compounds of this invention can be administered alone or with other pharmaceutically acceptable other drugs administering drug combinations.
Drug of the present invention can effectively alleviate the swelling degree in RA joints, hence it is evident that the content of TNF-α be reduced, so as to block inflammation
Disease is reacted, and improves function of joint, delays the process of RA, mitigate the destruction of RA, illustrate that drug of the present invention has RA and significantly control
Treatment acts on, and can be used for preparing treatment medicine for treating rheumatoid arthritis.
The synthetic method of the present invention is easily operated, can be with industrialized production.
Specific embodiment
Embodiment 1：N- methyl-1s-[6- (3- pyridyl groups)-[1,2-a] Pyrrolopyrazine -1- formyls] base -1H- imidazoles -4-
The synthesis of sulfonamide
Step 1：The synthesis of bromo- [1,2-a] Pyrrolopyrazine -1- formaldehyde of 6-
Compound [1,2-a] Pyrrolopyrazine -1- formaldehyde (10 mmol) is added in into 100 milliliters of dichloromethane and tetrahydrofuran（1:
1）In the mixed solvent stirs 20 minutes, there is a small amount of insoluble matter.System is cooled to 0-5 DEG C, thereto add in pyridinium tribromide drone
(11 mmol) keeps temperature to stir 1 hour, then adds in 70 milliliters of water thereto, steam organic solvent, add in 50 milliliter four
Then system is slowly added dropwise in 100 milliliters of saturated aqueous sodium carbonates, is stirred overnight under mixed system room temperature by hydrogen furans.
It is filtered under diminished pressure, is washed with water, 55 DEG C of dryings of vacuum obtain 2.1 grams of yellow solids, yield 93%.1H-NMR (400 MHz,
CDCl3) δ: 6.65(d,1H), 6.70(d.1H), 8.61(d.1H), 8.76(d.1H), 9.75(s,1H). 13C-NMR
(75 MHz, CDCl3) δ: 100.08, 108.44, 113.07, 113.11, 114.59, 131.88, 143.72,
181.73.
Step 2：The synthesis of 6- (3- pyridyl groups)-[1,2-a] Pyrrolopyrazine -1- formaldehyde
Bromo- [1,2-a] Pyrrolopyrazine -1- formaldehyde (10 mmol) of compound 6- are added in into 80 ml methanols and tetrahydrofuran（1:
1）In the mixed solvent stirs 20 minutes, there is yellow insoluble matter, adds in 3- pyridine boronic acids (12 mmol), leads to argon gas 10 to system and divide
Clock drives air out of to come, and then adds in 0.5 gram of four triphenyl phosphorus palladium thereto, is heated to 90 DEG C, stirs 8 hours, cools down, will
Solvent under reduced pressure steams, and is beaten two hours with 50 milliliters of water, obtains crude product, and crude product is placed in reflux mashing 1 hour in methanol, can be obtained
2 grams of yellow solids, yield 90%.1H-NMR (400 MHz, CDCl3) δ: 6.73(q,2H), 7.47(t,1H), 8.33(m,
1H), 8.61(d,1H), 8.70(m,1H), 8.76(d,1H), 9.75(s,1H).
Step 3：The synthesis of 6- (3- pyridyl groups)-[1,2-a] Pyrrolopyrazine -1- formic acid
6- (3- pyridyl groups)-[1,2-a] Pyrrolopyrazine -1- formaldehyde (10 mmol) is dissolved in 50 milliliters of tetrahydrofurans, thereto
2 milliliters of concentrated sulfuric acids are added in, are stirred 5 minutes, then add in 3 grams of potassium permanganate, stirring at normal temperature 5 hours, filtering, to filtrate thereto
30 milliliters of water of middle addition, are extracted twice with 100 milliliters of dichloromethane, merge organic phase, and anhydrous sodium sulfate is dried 2 hours, decompression
Solvent is steamed, with ethyl acetate and petroleum ether (1:4, totally 100 milliliters) recrystallization, obtain 2.1 grams of off-white powders, yield 88%
。1H-NMR (400 MHz, CDCl3) δ: 6.80(d,1H), 6.98(d, 1H), 7.47(t,1H), 8.33(d,1H),
8.61(d,1H), 8.70(m,1H), 8.76(d,H), 9.24(s,1H), 13.02(s,1H). m/z: 239.07
(100.0%), 240.07 (15.2%).
Step 4：The synthesis of 6- (3- pyridyl groups)-[1,2-a] Pyrrolopyrazine -1- formyl chlorides
Compound 6- (3- pyridyl groups)-[1,2-a] Pyrrolopyrazine -1- formic acid (10 mmol) is dissolved in 30 milliliters of dichloromethane,
5 milliliters of DMF are added in thereto, 3 grams of thionyl chlorides are then added dropwise, are heated to flowing back, are stirred 5 hours, and decompression steams solvent, Xiang Qi
20 milliliters of toluene of middle addition, decompression steam toluene and simultaneously take away remaining thionyl chloride, and products obtained therefrom is directly used in next step
Reaction.1H-NMR (400 MHz, CDCl3) δ: 6.76(d,1H), 6.95(d, 1H), 7.51(t,1H), 8.37(d,
1H), 8.56(d,1H), 8.68(m,1H), 8.85(d,H), 9.24(s,1H). m/z: 257.04 (100.0%),
259.03 (32.0%), 258.04 (14.2%).
Step 5：The synthesis of 1- [6- (3- pyridyl groups)-(1,2-a) Pyrrolopyrazine -1- formyls] base -1H- imidazoles -4- sulfonic acid chlorides
2.5 grams of the crude product of previous step is dissolved in 40 milliliters of dichloromethane solutions, adds in 10 milliliters of triethylamines, control temperature thereto
Degree is added dropwise to the two of 6- (3- pyridyl groups)-[1,2-a] Pyrrolopyrazine -1- formyl chlorides (12 mmol) into system less than 10 DEG C
Chloromethanes solution, restore room temperature after being added dropwise, then stirring at normal temperature 10 hours is washed with 50 milliliter 5% of aqueous sodium carbonate
Reaction system is washed, organic phase is dried with anhydrous Na 2SO4, and after solvent evaporated, obtained solid flash column chromatography detaches, and obtains 3 grams
Light yellow solid, yield 77%.1H-NMR (400 MHz, CDCl3) δ: 6.17(d,1H), 6.71(d,1H), 7.47(t,
1H), 8.05(s,1H), 8.14(s,1H), 8.33(dt,1H), 8.61(d,1H), 8.70(d,1H), 8.76(d,1H),
9.24(s,1H). 13C-NMR (75 MHz, CDCl3) δ: 111.35, 113.05, 116.26, 116.74, 121.28,
123.78, 128.74, 129.38, 130.11, 137.19, 149.16, 149.20, 149.28, 150.82,
152.43, 166.90.
Step 6：N- methyl-1s-[6- (3- pyridyl groups)-[1,2-a] Pyrrolopyrazine -1- formyls] base -1H- imidazoles -4- sulphonyl
The synthesis of amine
1- [6- (3- pyridyl groups)-(1,2-a) Pyrrolopyrazine -1- formyls] base -1H- imidazoles -4- sulfonic acid chlorides (10 mmol) is molten
In 30 milliliters of dichloromethane, pyridine is added in thereto（12 mmol）With 3 milliliters of dimethyl sulfoxide (DMSO)s, temperature is kept less than 10 DEG C, to
Methylamine is wherein added dropwise（12 mmol）Dichloromethane solution, restore room temperature after being added dropwise, stir 2 hours, then decompression steams
Solvent, with ethyl acetate and petroleum ether（1:3, totally 80 milliliters）Recrystallization, obtains 2 grams of off-white powders, yield 52%.1H-NMR
(400 MHz, CDCl3) δ: 2.58(s,3H), 4.61(br,1H), 6.15(d,1H), 6.75(d,1H), 7.43(t,
1H), 8.02(s,1H), 8.12(s,1H), 8.31(dt,1H), 8.64(d,1H), 8.73(d,1H), 8.79(d,1H),
9.26(s,1H). 13C-NMR (75 MHz, CDCl3) δ: 27.34, 110.35, 113.34, 116.56, 117.21,
121.59, 124.25, 128.35, 128.76, 130.55, 137.76, 148.89, 148.96, 149.45
150.54, 152.78, 166.98. m/z: 382.08 (100.0%), 383.09 (18.7%), 384.08 (4.6%).
Embodiment 2：N- phenyl -1- [6- (3- pyridyl groups)-[1,2-a] Pyrrolopyrazine -1- formyls] base -1H- imidazoles -4- sulphonyl
The synthesis of amine
Synthetic method such as embodiment 1:By 1- [6- (3- pyridyl groups)-(1,2-a) Pyrrolopyrazine -1- formyls] base -1H- imidazoles -
4- sulfonic acid chlorides (10 mmol) are dissolved in 30 milliliters of dichloromethane, add in pyridine thereto（12 mmol）With 3 milliliters of dimethyl sulfoxide (DMSO)s,
Keep temperature that aniline is added dropwise thereto less than 10 DEG C（12 mmol）Dichloromethane solution, restore room temperature after being added dropwise, stir
It mixes 2 hours, then decompression steams solvent, with ethyl acetate and petroleum ether（1:3, totally 80 milliliters）Recrystallization, obtains 3 grams of off-white colors
Solid, yield 68%.1H-NMR (400 MHz, CDCl3) δ: 6.19(s,1H), 6.27(d,1H), 6.70(m,2H),
6.78(s,1H), 6.82(m,1H), 7.13(m,2H), 7.45(t,1H), 8.12(s,1H), 8.33(s,1H), 8.61
(d,1H), 8.70(dt,1H), 8.76(d,1H), 9.24(s,1H). 13C-NMR (75 MHz, CDCl3) δ:
113.05, 116.26, 116.74, 121.28, 121.78, 123.78, 125.91, 128.74, 128.81,
129.38, 130.11, 131.04, 136.53, 137.12, 137.19, 140.56, 149.16, 149.20,
150.82, 166.90. m/z: 444.10 (100.0%), 445.10 (26.9%), 446.10 (5.9%).
Embodiment 3：N- benzyls -1- [6- (3- pyridyl groups)-[1,2-a] Pyrrolopyrazine -1- formyls] base -1H- imidazoles -4- sulphonyl
The synthesis of amine
Synthetic method such as embodiment 1, wherein, reactant methylamine is replaced with benzene methanamine in 1 step 6 of embodiment, rate of charge and reaction
Condition is constant.Obtain 3.2 grams of light yellow solids, yield 57%.1H-NMR (400 MHz, CDCl3) δ: 3.48(s,2H),
5.60(s,1H), 6.29(d,1H), 6.67(m,2H), 6.75(s,1H), 6.86(m,1H), 7.21(m,2H), 7.47
(t,1H), 8.25(s,1H), 8.38(s,1H), 8.69(d,1H), 8.76(dt,1H), 8.85(d,1H), 9.46(s,
1H). 13C-NMR (75 MHz, CDCl3) δ: 51.61, 114.09, 116.54, 116.87, 121.21, 121.65,
123.67, 124.86, 128.69, 128.85, 129.42, 130.18, 131.34, 136.65, 137.12,
137.26, 141.15, 149.23, 149.47, 150.89, 167.15. m/z: 458.12 (100.0%), 459.12
(26.0%), 460.11 (4.6%).
Embodiment 4：N- (2- pyridyl groups) -1- [6- (3- pyridyl groups)-[1,2-a] Pyrrolopyrazine -1- formyls] base -1H- imidazoles -
The synthesis of 4- sulfonamide
Synthetic method such as embodiment 1, wherein, reactant methylamine is used in 1 step 6 of embodimentInstead of, rate of charge and
Reaction condition is constant.Obtain 3.7 grams of off-white powders, yield 83%.1H-NMR (400 MHz, CDCl3) δ: 6.25(d,
1H), 6.77(d,2H), 6.83(s,1H), 7.03(dd,1H), 7.47(t,2H), 7.63(t,1H), 7.76(m,1H),
8.02(m,1H), 8.14(s,1H), 8.33(d,1H), 8.61(d,1H), 8.70(d,1H), 8.76(d,1H), 9.35
(s,1H). 13C-NMR (75 MHz, CDCl3) δ: 110.62, 113.05, 116.26, 116.74, 116.81,
121.28, 123.78, 128.74, 129.38, 130.11, 131.04, 136.79, 137.12, 137.19,
140.56, 149.16, 149.20, 150.14, 150.82, 154.42, 166.90. m/z: 445.10 (100.0%),
446.10 (23.8%), 447.09 (4.6%).
Embodiment 5：N- (1H-2- pyrrole radicals) -1- [6- (3- pyridyl groups)-[1,2-a] Pyrrolopyrazine -1- formyls] base -1H- miaows
The synthesis of azoles -4- sulfonamide
Synthetic method such as embodiment 1, wherein, reactant methylamine is used in 1 step 6 of embodimentInstead of, rate of charge and
Reaction condition is constant.Obtain 3.1 grams of off-white powders, yield 72%.1H-NMR (400 MHz, CDCl3) δ: 5.12(d,
1H), 6.21(d,2H), 6.27(d,1H), 6.76(d,1H), 6.90(dd, H), 7.47(t,1H), 7.92(t,1H),
8.14(s,1H), 8.33(m,1H), 8.34(m,1H), 8.61(d,1H), 8.70(dd,1H), 8.77(d,1H), 9.26
(s,1H). 13C-NMR (75 MHz, CDCl3) δ: 97.29, 108.41, 113.05, 116.26, 116.74,
121.19, 121.28, 123.78, 128.74, 129.38, 130.11, 132.68, 136.79, 137.12,
137.19, 140.56, 149.16, 149.20, 150.14, 150.82, 166.90. m/z: 433.10 (100.0%),
434.10 (22.7%), 435.09 (4.6%).
Test example：
RA is a kind of systemic autoimmune disease, and the cell factor of inflammatory cell and its release is in arthritis reaction process
In play an important role.Modern medicine study finds that in the inflammatory cell of synovial membrane infiltration, T lymphocytes are than bone-marrow-derived lymphocyte number
Amount is more, in the hydrops articuli and synovial tissue of inflammation part, detectable cytokine profiles, and with new cell because
Sub constantly to find, several mouthfuls of RA joints based intracellular cvtokine detection are also constantly increasing, such as TNF-α, IL-6, IL-8, wherein
The inflammatory reaction of TNF-α mediation is the most prominent.As it can be seen that in RA pathological processes, inflammatory cytokine Showed Very Brisk has obtained public affairs
Recognize, particularly rat blood serum TNF-α content significantly raising is closely related with this disease.
SPF grades of Healthy female SD rats 80 of age in August, weight (350 ± 10) g.II Collagen Type VI, complete Freund's adjuvant（It is beautiful
Sigma companies of state produce）；Rat TNF-α enzyme-linked immunologic detecting kit（R＆D companies of the U.S. produce）.
It is divided into blank group 10, model group 10, every group of drug a, b, c, d, e group of the present invention each 10 and methotrexate (MTX)
（Positive drug）Group 10.TypeⅡ Collagen is taken to be dissolved in 0.l mol/L acetic acid, is made into the solution of a concentration of 2mg/mL, 4 DEG C
Overnight.Next day is with complete Freund's adjuvant with 1:Emulsion is made in 1 volume mixture.It is aspirated repeatedly with syringe, until mixture is complete
Entirely, it is fully emulsified, it is instilled with emulsion not loose in water, floats on water into drop-wise and be that emulsification is complete.The collagen after emulsification is taken to lure
The property led rheumatoid arthritis model (CIA) modeling agent, in addition to blank group, with 75% alcohol to rat root of the tail portion, back, right metapedes
After toes portion carries out disinfection, by 0.4mL/ only in upper 3 intracutaneous injections, see round skin mound and be swollen with, to inject successfully.After modeling
7th day with the booster shots 1 time of same method 3.After booster shots, rat foot claw serious swelling, articulatio talocruralis diameter increasing degree
>=12mm, rear solid end volume increasing degree >=0.80mL are modeling success.
Start to be administered from the 14th day after modeling.Model group：Give physiological saline gavage 1mL/1000g weight；Medicine of the present invention
Object group：The compound of 0.05g adds 1000mL normal salines to give gavage 1mL/1000g weight into suspension；Positive drug first
Aminopterin group：The methotrexate (MTX) of 0.05g adds 1000mL normal salines to give gavage 1mL/1000g weight into suspension.With
On one time a day, successive administration 21d.
By rat after intraperitoneal anesthesia, femoral artery takes blood 4mL or so, centrifuges 20min with 3000r/min, it is standby to draw serum
With rat blood serum TNF-α is measured according to the method for the requirement of detection kit.
Variance analysis carries out every detection data using SPSS15.0 statistical packages, all analysis data results are adopted
It is represented with mean ± standard deviation, P<0.05, to have differences, has statistical significance.
Variation is influenced on each group rat blood serum TNF-α to compare（Ng/L,）It see the table below：
Compared with blank group, * P<0.05；Compared with model group, #P<0.05；Compared with positive drug group, Δ P<0.05.
Drug b groups of the present invention, drug c groups, drug d groups, drug e groups equal conspicuousness of Serum TNF-α compared with positive drug group
It reduces, drug a groups of the present invention Serum TNF-α compared with positive drug group is slightly higher, but is significantly reduced compared with model group, this experiment knot
Fruit shows drug formula of the present invention（Ⅰ）The swelling degree in RA joints can effectively be alleviated, hence it is evident that the content of TNF-α is reduced, so as to hinder
Disconnected inflammatory reaction, improves function of joint, delays the process of RA, mitigates the destruction of RA.Illustrate drug formula of the present invention（Ⅰ）To RA
There is obvious therapeutic action, can be used for preparing treatment medicine for treating rheumatoid arthritis.
Obviously, the above according to the present invention according to the ordinary technical knowledge and means of this field, is not departing from this hair
Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Claims (7)
1. a kind of new Formula for being used to treat rheumatoid arthritis（Ⅰ）Synthetic method, synthetic route is as follows：
Wherein, R is。
2. synthetic method as described in claim 1, it is characterized in that：The step（1）Specially：
Compound [1,2-a] Pyrrolopyrazine -1- formaldehyde is added in into dichloromethane and tetrahydrofuran in the mixed solvent, stirring has
System is cooled to 0-5 DEG C by a small amount of insoluble matter, thereto add in pyridinium tribromide drone, keep temperature stirring, then add in thereto
Water steams organic solvent, adds in tetrahydrofuran, then system is slowly added dropwise in saturated aqueous sodium carbonate, mixed system
It is stirred overnight, is filtered under diminished pressure under room temperature, be washed with water, be dried in vacuo, obtain yellow solid.
3. synthetic method as described in claim 1, it is characterized in that：The step（2）Specially：By the bromo- [1,2- of compound 6-
A] Pyrrolopyrazine -1- formaldehyde (10 mmol) adds in methanol and tetrahydrofuran in the mixed solvent, and stirring has yellow insoluble matter, adds
Entering 3- pyridine boronic acids, lead to argon gas to system, air is driven out of to come, then add in four triphenyl phosphorus palladiums thereto, heating is stirred,
Cooling, solvent under reduced pressure is steamed, is beaten with water, obtains crude product, and crude product is placed in methanol the mashing that flows back, can obtain yellow solid.
4. synthetic method as described in claim 1, it is characterized in that：The step（3）Specially：By 6- (3- pyridyl groups)-[1,
2-a] Pyrrolopyrazine -1- formaldehyde is dissolved in tetrahydrofuran, adds in the concentrated sulfuric acid thereto, and it stirs, then adds in permanganic acid thereto
Potassium, stirring at normal temperature, filtering add in water into filtrate, are extracted twice with dichloromethane, merge organic phase, and anhydrous sodium sulfate is dried,
Decompression steams solvent, is recrystallized with ethyl acetate and petroleum ether, obtains off-white powder.
5. synthetic method as described in claim 1, it is characterized in that：The step（4）Specially：By compound 6- (3- pyridines
Base)-[1,2-a] Pyrrolopyrazine -1- formic acid is dissolved in dichloromethane, adds in DMF thereto, thionyl chloride is then added dropwise, it heats
To reflux, stirring, decompression steams solvent, adds in toluene thereto, and decompression steams toluene and simultaneously takes away remaining thionyl chloride,
Products obtained therefrom is directly used in react in next step.
6. synthetic method as described in claim 1, it is characterized in that：The step（5）Specially：By step（4）Crude product
Dichloromethane solution is dissolved in, adds in triethylamine thereto, control temperature is added dropwise to 6- (3- pyridines into system less than 10 DEG C
Base)-[1,2-a] Pyrrolopyrazine -1- formyl chlorides dichloromethane solution, restore room temperature after being added dropwise, stirring at normal temperature, then
With 5% aqueous sodium carbonate washing reaction system, organic phase anhydrous Na2SO4Dry, after solvent evaporated, obtained solid is fast
Fast pillar layer separation, obtains light yellow solid.
7. synthetic method as described in claim 1, it is characterized in that：The step（6）Specially：By 1- [6- (3- pyridyl groups)-
(1,2-a) Pyrrolopyrazine -1- formyls] base -1H- imidazoles -4- sulfonic acid chlorides are dissolved in dichloromethane, pyridine and diformazan are added in thereto
Base sulfoxide, keeps temperature less than 10 DEG C, be added dropwise thereto methylamine, aniline, benzene methanamine,OrTwo
Chloromethanes solution restores room temperature after being added dropwise, stirring, and then decompression steams solvent, is recrystallized with ethyl acetate and petroleum ether,
Obtain product.
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