CN106831735A - It is a kind of to treat heterocyclic compound of osteoporosis and its production and use - Google Patents
It is a kind of to treat heterocyclic compound of osteoporosis and its production and use Download PDFInfo
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- CN106831735A CN106831735A CN201710062522.8A CN201710062522A CN106831735A CN 106831735 A CN106831735 A CN 106831735A CN 201710062522 A CN201710062522 A CN 201710062522A CN 106831735 A CN106831735 A CN 106831735A
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- 0 CC(C(c1ccccc1)=C1OC(C(*2)=CC3=C2C#CCC=C3)=O)=NC1C1=CCCC=N1 Chemical compound CC(C(c1ccccc1)=C1OC(C(*2)=CC3=C2C#CCC=C3)=O)=NC1C1=CCCC=N1 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
Drug field the present invention relates to prevent and treat osteoporosis.The invention provides a kind of pyrazoles heterocyclic compounds or its pharmaceutically acceptable salt.The present invention has found that the pyrazoles heterocyclic compounds can suppress the enhancing of bone conversion ratio and destruction of bone that removal ovary causes by vivo studies, while blood calcium concentration can be improved, is conducive to the deposition of bone, therefore with the effect of significant prevention and treatment osteoporosis.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of pyrazoles heterocyclic compounds.The invention further relates to the change
The preparation method of compound, its pharmaceutical composition and its purposes for preparing the medicine of prevention or treatment osteoporosis.
Background technology
Osteoporosis (osteoporosis) is that a kind of general bone amount being characterized with bone tissue Microstructure Fracture shows
The illness for reducing is write, it causes skeletal fragility increase and pathologic fracture.Bone amount is affected by various factors, for example heredity, nutrition,
Difference of the change of hormonal readiness, motion and life style etc., and known osteoporosis main cause be aging, motion not
Foot, underweight, smoking, low calcium diet intake, menopause, oophorectomy etc..For most people, bone amount reaches at 14-18 Sui
To peak value, and the annual reduction about 1% in old age.At present, osteoporosis total prevalence rate is in more than 50 years old crowd of China
15.7%, with the extension of population life, this ratio is being stepped up.Especially, in the case of women, bone loss are 30
Persistently occur after year, and it is fast-developing due to the change of hormonal balance during menopause.I.e. when women reaches climacteric,
Estrogen level is reduced rapidly.At this moment, a large amount of B- lymphocytes are formed, it appears that occur by interleukin=7 (IL-7), and
Pre B cell is accumulated in marrow, as a result causes IL-6 levels to raise, therefore causes the activity increase of osteoclast and final bone amount
Level reduction.Therefore, osteoporosis is inevitable disease condition for the women after the elderly particularly climacteric.
Though the research of development of drugs in treating primary osteoporosis has made great progress, the medicine for clinically using at present lacks
Weary specificity, the more serious side effect of generally existing.For example, being most commonly used as the therapeutic agent of osteoporosis but not yet confirming its reality
The estrogen of effect adversely needs administration throughout one's life, and its long term administration may cause adverse side effect, for example breast cancer or
The risk of the cancer of the uterus increases.Alendronate is then slow gastrointestinal absorption, and is the hair of intestines and stomach and esophageal mucosa membrane inflammation
Anttdisease Mechanism.Known calcium product has less side effect and fabulous effect, but it is prophylactic rather than therapeutic agent.This
Outward, it is known that vitamin D product such as calcitonin, but not yet fully study their effect and side effect.Accordingly, it would be desirable to develop new
Osteoporosis therapy agent, it has less side effect and fabulous effect.
As solve the above problems and develop anti-osteoporosis disease effective medicine further investigation and experiment
As a result, the present inventor has successfully synthesized novel pyrazole heterocyclic compounds, and it was found that these compounds are to sclerotin
The treatment and prevention of osteoporosis have excellent effect.
The content of the invention
It is an object of the invention to provide a kind of pyrazoles heterocycle for osteoporosis with excellent preventive and therapeutic action
Compound.
Further, it is an object of the invention to provide the method for preparing the pyrazoles heterocyclic compounds.
Further, it is an object of the invention to provide for prevent or treat osteoporosis, include pyrazoles heterocycle
The pharmaceutical composition of compound.
Further, it is an object of the invention to provide the method for preventing or treating osteoporosis, it include to have need
The individuality wanted gives the pyrazoles heterocyclic compounds of effective dose, and provides pyrazoles heterocyclic compounds of the invention in preparation use
In prevention or the purposes of the medicine for the treatment of osteoporosis.
The present invention provides the pyrazoles heterocyclic compounds represented by such as Formulas I, and its pharmaceutically acceptable salt：
Wherein：
X1Selected from O, S or NH；
Each X2N or CR can be each independently selected from identical or different1；
Each X3N or CR can be each independently selected from identical or different2, and the X3In at least one be N；
R1、R2It is each independently selected from hydrogen, halogen, alkyl, alkoxy, alkylthio group, cyano group, hydroxyl, nitro, NR3R4、
CONR3R4, substituted or non-substituted aryl, substituted or non-substituted aralkyl, substituted or non-substituted heteroaryl, substitution or non-
Substituted heteroarylalkyl；
Each RaCan be with identical or different, each RbCan be with identical or different, and Ra、RbIt is each independently selected from hydrogen, halogen
Element, alkyl, alkoxy, alkylthio group, cyano group, hydroxyl, nitro, NRaR4、CONRaR4, substituted or non-substituted aryl, substitution or non-
Substituted aralkyl, substituted or non-substituted heteroaryl, substituted or non-substituted heteroarylalkyl；
Wherein, R3、R4It is each independently selected from hydrogen or alkyl, or R3And R4It is collectively forming substituted or non-substituted heterocycle
Base.
In preferred scheme of the invention, the substituted aryl, substitution aralkyl, substitution heteroaryl, substitution it is miscellaneous
Substitution base in aralkyl, the heterocyclic radical of substitution is selected from halogen, alkyl, hydroxyl, cyano group, nitro or NR5R6, wherein the R5、R6
It is each independently selected from hydrogen or alkyl.
In preferred scheme of the invention, the halogen includes fluorine, chlorine, bromine, iodine, preferably chlorine or bromine.
In preferred scheme of the invention, the alkyl includes the straight or branched alkyl of C1-C6, the preferably straight chain of C1-C4
Or branched alkyl, more preferably methyl, ethyl, isopropyl, n-propyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, positive penta
Any one of base, isopentyl, n-hexyl, isohesyl.
In preferred scheme of the invention, the aryl includes C6-C10 aryl, preferably phenyl, naphthyl, tetralyl
Any one.
In preferred scheme of the invention, the heteroaryl includes heteroatomic 5-, 6- selected from N, O, S containing one to three
Or 7- units aromatic group, preferably thienyl, furyl, pyrrole radicals, pyridine radicals, pyrimidine radicals, imidazole radicals, pyrazinyl, thiazolyl
Any one.
In preferred scheme of the invention, the heterocyclic radical includes saturation or unsaturated 5-, 6- or 7 unitary cyclic groups
Group, the heterocyclic radical includes 1 or 2 hetero atom selected from N, O and S in addition to the N atoms for being connected, also；The heterocyclic radical
Preferably nafoxidine base, piperidyl, homopiperidinyl, piperazinyl, morpholinyl, thio-morpholinyl, dithiane base, pyridazinyl, pyrrole
Any one of piperazine base or triazine radical.
In preferred scheme of the invention, the compound is selected from：
1- (pyridine -2- bases) -1H- pyrazoles -5- bases benzofuran -2- carboxylates (compound 1)；
3- methyl 4-phenyls -1- (pyridine -2- bases) -1H- pyrazoles -5- bases benzofuran -2- carboxylates (compound 2)；
3- (piperidin-1-yl) -1- (pyridine -2- bases) -1H- pyrazoles -5- bases benzothiophene -2- carboxylates (compound 3)；
4- ethyls-(pyrimidine -2-base) -1H- pyrazoles -5- bases thiophene [2,3-b] pyridine-2-carboxylic acids ester (compound 4)；
4- morpholinyls -1- (pyrimidine -2-base) -1H- pyrazoles -5- bases benzothiophene -2- carboxylates (compound 5)；
1- (pyridine -2- bases) -1H- pyrazoles -5- bases 5- phenyl-benzothiophene -2- carboxylates (compound 6)；
1- (pyrazine -2- bases) -1H- pyrazoles -5- bases 5- dimethylaminos-benzothiophene -2- carboxylates (compound 7)；
1- (pyridine -2- bases) -1H- pyrazoles -5- bases chloro- 1H indole-2-carboxylic acids esters (compound 8) of 6-；
3- methyl isophthalic acids-(1H- pyrroles -1- bases)-benzofuran -2- carboxylic acids of (pyridine -2- bases) -1H- pyrazoles -5- bases 7- fluoro- 3
Ester (compound 9).
For compound of formula I of the invention, the pharmaceutically acceptable salt refers to pharmaceutically acceptable trip
From the salt of acid.The free acid can be inorganic acid or organic acid.The example of inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid and phosphorus
Acid.The example of organic acid includes citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, first
Sulfonic acid, benzene sulfonic acid, maleic acid, benzoic acid, gluconic acid, glycolic, butanedioic acid, 4- morpholino b acids, camphorsulfonic acid, 4- nitros
Benzene sulfonic acid, hydroxyl-O- sulfonic acid, p-methyl benzenesulfonic acid, galacturonic acid, pamoic acid, glutamic acid and aspartic acid.Preferably, institute
Inorganic acid is stated for hydrochloric acid, and organic acid is methanesulfonic acid.
The present invention provides a kind of pyrazoles heterocyclic compounds prepared shown in the Formulas I or the side of its pharmaceutically acceptable salt
Method, methods described includes：
Step 1) compound shown in the compound and formula III shown in Formula II is added dropwise in polar organic solvent；And
The polar organic solvent of the compound shown in the compound and formula III shown in contained II is heated, to obtain the change shown in formula IV
Compound：
Step 2) compound shown in Formula V, the compound shown in Formula IV are placed in aprotic solvent, inorganic base is added,
After stirring reaction, the compound shown in Formula VII is obtained：
Step 3) compound shown in Formula VII is hydrolyzed in the alkaline aqueous solution after, under thionyl chloride effect, heat back
Stream forms acyl chlorides, then at low temperature, adds acid binding agent to obtain mixed liquor；By the compound shown in the mixed liquor and formula IV under normal temperature
Reaction obtains target compound I；
Step 4) it is necessary when, the compound shown in Formulas I is converted into its pharmaceutically acceptable salt.
Wherein, X1、X2、X3、Ra、RbAs defined above, R is C1-C4 alkyl, and M is OH or NO2, RxIt is C1-C4 alcoxyls
Base, X is halogen or sulfydryl, preferably chlorine or bromine.
In preferred scheme of the invention, the polar organic solvent is selected from C1-C4 alcohol such as methyl alcohol, ethanol, normal propyl alcohol, isopropyl
Alcohol, n-butanol or the tert-butyl alcohol, acetic acid or their mixture, and preferred alcohol or acetic acid.
In preferred scheme of the invention, the aprotic solvent is DMF or DMSO.
In preferred scheme of the invention, the inorganic base includes hydroxide, carbonate, bicarbonate, preferably hydrogen-oxygen
Change sodium, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus.
In preferred scheme of the invention, the alkaline aqueous solution is sodium hydrate aqueous solution or potassium hydroxide aqueous solution.
In preferred scheme of the invention, the acid binding agent is tertiary amine such as triethylamine.
Another object of the present invention is to provide a kind of pharmaceutical composition for preventing or treating osteoporosis, it contains
The pyrazoles heterocyclic compounds of the present invention or its pharmaceutical salts and pharmaceutically acceptable carrier of therapeutically effective amount.
In the preferred technical solution of the present invention, the pyrazoles heterocyclic compounds or its pharmaceutical salts are in pharmaceutical composition
Content is 0.1wt.%-99.5wt.%, preferably 0.5wt.%-95wt.%.
The various formulations that the present composition can be well known in the art, be suitable for formulation of the invention be selected from oral formulations,
External preparation or injection, preferably oral formulations.Oral formulations are selected from tablet, granule, capsule, powder, pill, drop
Ball, syrup, distillate medicinal water, effervescent agent, oral liquid, suspending agent etc.；External preparation is selected from gel, paste, liniment, lotion, smearing
Agent, creme, ointment etc.；Injection is selected from injection, transfusion or freeze-dried powder etc..Preparation technique hand well known in the art can be used
Section prepares composition of the invention.
The conventional figuration for preparing above-mentioned preparation that pharmaceutically acceptable carrier of the present invention is well known in the art
Agent or auxiliary material.Oral formulations or the conventional excipient of external preparation or auxiliary material include but are not limited to filler, diluent, lubrication
Agent, dispersant, wetting agent, adhesive, conditioning agent, solubilizer, antioxidant, bacteriostatic agent, emulsifying agent, disintegrant etc., such as syrup,
Arabic gum, gelatin, lactose, Icing Sugar, dextrin, superfine silica gel powder, magnesium stearate, talcum powder, aluminium hydroxide, starch and its derivative
Thing, polyvinylpyrrolidone, lauryl sodium sulfate, water or alcohol etc..
The conventional excipient of injection of the present invention or auxiliary material are included but are not limited to：Antioxidant, bacteriostatic agent, regulation
Agent, emulsifying agent, solubilizer etc., such as sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, 0.5% phenol, 0.3% cresols, salt
Acid, citric acid, Tween-80, lecithin, Fabaceous Lecithin, Tween-80, bile, glycerine etc..
Beneficial effect
The present invention has found that the pyrazoles heterocyclic compounds can suppress the bone conversion that removal ovary causes by vivo studies
Rate strengthens and destruction of bone, while blood calcium concentration can be improved, is conducive to the deposition of bone, therefore with significant prevention and treatment
The effect of osteoporosis.
Specific embodiment
The present invention is described below in more detail to contribute to the understanding of the present invention.
It should be appreciated that the term for using in the specification and in the claims or word be not construed as have
In dictionary limit implication, and be interpreted as on the basis of following principle have and its implication one in the context of the present invention
The implication of cause：The concept of term can be suitably by inventor in order to limit best illustration of the invention.
Embodiment 1：1- (pyridine -2- bases) -1H- pyrazoles -5- bases benzofuran -2- carboxylates (compound 1)
Step 1) 3- oxo-propionates (2.32g, 20.0mmol) and ethanol (20mL) are placed in round-bottomed flask, and
And the 2- hydrazino pyridines (2.58g, 23.6mmol) diluted with ethanol (20mL) are lentamente added dropwise at 0 DEG C.By the molten of gained
Liquid is under reflux in heating 3 days at 100 DEG C.Solvent is removed by distilling under reduced pressure, by the solid hexane and second of gained
Acetoacetic ester is washed and is vacuum dried, and obtains white solid 1- (pyridine -2- bases) -1H- pyrazoles -5- alcohol 2.91g, yield 90%.
ESI-MS：162.06[M+H]+
Step 2) under condition of ice bath, by 2- hydroxy-benzaldehydes (2.68g, 22.0mmol) and anhydrous K2CO3(4.4g,
31.2mmol) it is dissolved in DMF (40ml), is slowly added dropwise bromoethyl acetate (4.1g, 26.0mmol).Completion of dropping, -5 DEG C
Stirring 30 minutes, then reacts 12 hours in 50 DEG C of oil baths.Reaction solution is poured into frozen water, is filtered, chloroform dissolved solid, nothing
Water Na2SO4Dry, filtering, after being spin-dried for solvent, separated through silica gel column chromatography, obtain yellow solid benzofuran -2- carboxylic acid, ethyl esters
3.52g, yield is 84%.
ESI-MS：191.06[M+H]+
Step 3) benzofuran -2- carboxylic acid, ethyl esters (1.90g, 10.0mmol) is dissolved in dioxane (20ml), add
The sodium hydroxide solution (12ml) of 1N, stirring at normal temperature is dissolved for 2 hours, and dioxane is evaporated, and remaining liq is poured into frozen water, is used
Dichloromethane is washed, and adjusts pH value to 2, and filtering is collected solid, is dissolved in thionyl chloride (30ml), adds triethylamine
0.5ml, after stirring, adds 1- (pyridine -2- bases) -1H- pyrazoles -5- alcohol (1.93g, 12.0mmol), is heated to reflux 1 hour, subtracts
Pressure is evaporated off unnecessary thionyl chloride, is cooled to 0 DEG C, and addition contains N, N- dimethyl-ethylenediamines (0.77g) and triethylamine
In the dichloromethane solution (20ml) of (0.5ml), stirring at normal temperature 4h obtains compound 1：1- (pyridine -2- bases) -1H- pyrazoles -5-
Base benzofuran -2- carboxylate 2.61g, yield 86%.
ESI-MS：305.10[M+H]+
Elementary analysis：Theoretical value/measured value, C (67.10/67.02), H (3.97/4.03), N (18.41/18.34), 0
(10.52/10.61)
1H NMR (400MHz, CDCl3) δ 8.40 (d, 1H), 8.05 (m, 1H), 7.32-7.86 (m, 8H), 6.35 (m, 1H).
Embodiment 2：3- methyl 4-phenyls -1- (pyridine -2- bases) -1H- pyrazoles -5- base benzofuran -2- carboxylates (are changed
Compound 2)
Step 1) 3- oxo -2- phenyl-propanoates (4.12g, 20.0mmol) and ethanol (20mL) are placed in round bottom burning
In bottle, and the 2- hydrazino pyridines (2.58g, 23.6mmol) diluted with ethanol (20mL) are lentamente added dropwise at 0 DEG C.By institute
The solution for obtaining is under reflux in heating 3 days at 100 DEG C.Solvent is removed by distilling under reduced pressure, the solid of gained is used oneself
Alkane and ethyl acetate are washed and are vacuum dried, and obtain white solid 3- methyl 4-phenyls -1- (pyridine -2- bases) -1H- pyrazoles -5-
Alcohol 4.42g, yield 88%.
ESI-MS：252.11[M+H]+
Step 2) under condition of ice bath, by 2- hydroxy-benzaldehydes (2.68g, 22.0mmol) and anhydrous K2CO3(4.4g,
31.2mmol) it is dissolved in DMF (40ml), is slowly added dropwise bromoethyl acetate (4.1g, 26.0mmol).Completion of dropping, -5 DEG C
Stirring 30 minutes, then reacts 12 hours in 50 DEG C of oil baths.Reaction solution is poured into frozen water, is filtered, chloroform dissolved solid, nothing
Water Na2SO4Dry, filtering, after being spin-dried for solvent, separated through silica gel column chromatography, obtain yellow solid benzofuran -2- carboxylic acid, ethyl esters
3.52g, yield is 84%.
ESI-MS：191.06[M+H]+
Step 3) benzofuran -2- carboxylic acid, ethyl esters (1.90g, 10.0mmol) is dissolved in dioxane (20ml), add
The sodium hydroxide solution (12ml) of 1N, stirring at normal temperature is dissolved for 2 hours, and dioxane is evaporated, and remaining liq is poured into frozen water, is used
Dichloromethane is washed, and adjusts pH value to 2, and filtering is collected solid, is dissolved in thionyl chloride (30ml), adds triethylamine
0.5ml, after stirring, adds 3- methyl 4-phenyls -1- (pyridine -2- bases) -1H- pyrazoles -5- alcohol (3.01g, 12.0mmol), plus
Heat backflow 1 hour, removes unnecessary thionyl chloride under reduced pressure, is cooled to 0 DEG C, and addition contains N, N- dimethyl-ethylenediamines
In the dichloromethane solution (20ml) of (0.77g) and triethylamine (0.5ml), stirring at normal temperature 4h obtains compound 1：3- methyl -4-
Phenyl -1- (pyridine -2- bases) -1H- pyrazoles -5- base benzofuran -2- carboxylate 3.16g, yield 80%.
ESI-MS：396.13[M+H]+
Elementary analysis：Theoretical value/measured value, C (72.90/72.79), H (4.33/4.41), N (10.63/10.58), 0
(12.14/12.22)
1H NMR (400MHz, CDCl3) δ 8.40 (d, 1H), 8.05 (m, 1H), 7.32-7.86 (m, 12H), 2.05 (s,
3H)。
Embodiment 3：3- (piperidin-1-yl) -1- (pyridine -2- bases) -1H- pyrazoles -5- base benzothiophene -2- carboxylates (are changed
Compound 3)
Step 1) 3- oxos -3- (piperidin-1-yl)-ethyl propionate (4.02g, 20.0mmol) and ethanol (20mL) are placed in
In round-bottomed flask, and at 0 DEG C lentamente be added dropwise to ethanol (20mL) dilute 2- hydrazino pyridines (2.58g,
23.6mmol).By the solution of gained under reflux in heating 3 days at 100 DEG C.Solvent is removed by distilling under reduced pressure, will
The solid of gained is washed and is vacuum dried with hexane and ethyl acetate, obtains white solid 3- (piperidin-1-yl) -1- (pyridine -2-
Base) -1H- pyrazoles -5- alcohol 3.91g, yield 81%.
ESI-MS：245.13[M+H]+
Step 2) under condition of ice bath, by 2- nitro-benzaIdehydes (3.02g, 20mmol) and anhydrous K2CO3(4.4g,
31.2mmol) it is dissolved in DMF (40ml), is slowly added dropwise ethyl thioglycolate (2.40g, 20mmol).Completion of dropping, 0 DEG C is stirred
Mix 30 minutes, then reacted 8 hours in 50 DEG C of oil baths.Reaction solution is poured into frozen water, is filtered, chloroform dissolved solid is anhydrous
Na2SO4Dry, filtering, after being spin-dried for solvent, separated through silica gel column chromatography, obtain yellow solid benzothiophene -2- carboxylic acid, ethyl esters
2.67g, yield is 75%.
ESI-MS：179.01[M+H]+
Step 3) benzothiophene -2- carboxylic acid, ethyl esters (1.78g, 10.0mmol) is dissolved in dioxane (20ml), add
The sodium hydroxide solution (12ml) of 1N, stirring at normal temperature is dissolved for 2 hours, and dioxane is evaporated, and remaining liq is poured into frozen water, is used
Dichloromethane is washed, and adjusts pH value to 2, and filtering is collected solid, is dissolved in thionyl chloride (30ml), adds triethylamine
0.5ml, after stirring, adds 3- (piperidin-1-yl) -1- (pyridine -2- bases) -1H- pyrazoles -5- alcohol (2.93g, 12.0mmol), plus
Heat backflow 1 hour, removes unnecessary thionyl chloride under reduced pressure, is cooled to 0 DEG C, and addition contains N, N- dimethyl-ethylenediamines
In the dichloromethane solution (20ml) of (0.77g) and triethylamine (0.5ml), stirring at normal temperature 4h obtains compound 1：3- (piperidines-
1- yls) -1- (pyridine -2- bases) -1H- pyrazoles -5- base benzothiophene -2- carboxylate 3.16g, yield 80%.
ESI-MS：305.13[M+H]+
Elementary analysis：Theoretical value/measured value, C (65.33/65.18), H (4.98/4.91), N (13.85/13.96), 0
(7.91/7.90), S (7.93/8.05)
1H NMR (400MHz, CDCl3) δ 8.42 (d, 1H), 8.32 (s, 1H), 8.02 (m, 1H), 7.32-7.86 (m, 6H),
6.35 (m, 1H), 3.70 (t, 4H), 1.50 (m, 6H).
Embodiment 4：4- ethyls-(pyrimidine -2-base) -1H- pyrazoles -5- bases thiophene [2,3-b] pyridine-2-carboxylic acids ester (chemical combination
Thing 4)
Step 1) 3- oxos -2- ethyls-ethyl propionate (2.90g, 20.0mmol) and ethanol (20mL) are placed in round bottom burning
In bottle, and the 2- hydrazinopyrimidines (2.50g, 24mmol) diluted with ethanol (20mL) are lentamente added dropwise at 0 DEG C.By gained
Solution under reflux at 100 DEG C heat 2 days.Solvent is removed by distilling under reduced pressure, by the solid hexane of gained
Washed with ethyl acetate and be vacuum dried, obtain white solid 2- ethyls -1- (pyridine -2- bases) -1H- pyrazoles -5- alcohol 2.85g,
Yield 75%.
ESI-MS：190.09[M+H]+
Step 2) under condition of ice bath, by 2- nitros-nicotine (3.02g, 20mmol) and anhydrous K2CO3(4.4g, 31.2mmol)
It is dissolved in DMF (40ml), is slowly added dropwise ethyl thioglycolate (2.40g, 20mmol).Completion of dropping, 0 DEG C is stirred 30 minutes,
Then reacted 8 hours in 50 DEG C of oil baths.Reaction solution is poured into frozen water, is filtered, chloroform dissolved solid, anhydrous Na2SO4Dry,
Filtering, after being spin-dried for solvent, separates through silica gel column chromatography, obtains yellow solid thiophene [2,3-b] pyridine-2-carboxylic acids ethyl ester 2.51g,
Yield is 70%.
ESI-MS：180.01[M+H]+
Step 3) thiophene [2,3-b] pyridine-2-carboxylic acids ethyl ester (1.79g, 10.0mmol) is dissolved in dioxane (20ml)
In, the sodium hydroxide solution (12ml) of 1N is added, stirring at normal temperature dissolves, dioxane is evaporated for 2 hours, and remaining liq is poured into ice
In water, washed with dichloromethane, adjust pH value to 2, filtering is collected solid, is dissolved in thionyl chloride (30ml), adds three second
Amine 0.5ml, after stirring, adds 2- ethyls -1- (pyridine -2- bases) -1H- pyrazoles -5- alcohol (2.30g, 12.0mmol), is heated to reflux
1 hour, remove unnecessary thionyl chloride under reduced pressure, be cooled to 0 DEG C, addition contains N, N- dimethyl-ethylenediamines (0.77g) and three
In the dichloromethane solution (20ml) of ethamine (0.5ml), stirring at normal temperature 4h obtains compound 1：4- ethyls-(pyrimidine -2-base)-
1H- pyrazoles -5- bases thiophene [2,3-b] pyridine-2-carboxylic acids ester 2.91g, yield 83%.
ESI-MS：352.18[M+H]+
Elementary analysis：Theoretical value/measured value, C (58.11/58.21), H (3.73/3.68), N (19.93/19.85), 0
(9.11/9.04), S (9.13/9.32)
1H NMR (400MHz, CDCl3) δ 8.85-8.31 (m, 5H), 7.71 (S, 1H), 7.36 (S, 1H), 7.40 (S, 1H),
2.52 (m, 2H), 1.25 (t, 3H).
Embodiment 5-9：Synthesize following compound 5-9 in a similar way, difference is to use corresponding starting compound
It is replaced.
Table 1
Biological activity determination embodiment：The detection of the function of resisting osteoporosis of the compounds of this invention
1st, materials and methods
Ten week old healthy SD raettins are randomly divided into 11 groups, every group 10：Embodiment compound 1-9 groups, sham-operation group
(Sham), ovary cuts off model group (OVX).Rearing conditions：Temperature is (23 ± 2) DEG C, illumination: dark is 12: 12.Make each group big
Mouse adapts to environment and starts osteoporosis modeling operation after 2 weeks：Each group rat anaesthetizes (6ml/kg through the urethane of intraperitoneal injection 20%
Body weight), Sham groups close abdomen after opening abdomen, remaining each group row bilateral oophorectomy.From postoperative 4th week, Sham groups and OVX groups are daily
Fed standard feed and deionized water, the daily fed standard feed of compound 1-9 groups and deionized water, while gavage gives respectively
Each 10mg/kg of compound 1-9, continuous 3 months, claim weekly a body weight.After experiment terminates, anaesthetized with urethane, win eyeball
Blood sampling, 2000r/min centrifugations, draws supernatant (i.e. serum).Rat uterus are extractd, is weighed rapidly.Take out rats with bilateral femur and
Bilateral tibial, rejects soft tissue.Two shin bones claim ash weight through being ashed 8h in 800 DEG C of high temperature furnaces, after cooling.Ash is pulverized into mortar
Shape, takes 0.1g bone ashes and is dissolved in 1ml, in 6mol/l hydrochloric acid, takes 0.2ml ultra-pure waters and is diluted to 1ml when surveying bone calcium and bone phosphorus, with complete
Automatic biochemistry analyzer detects bone calcium and bone phosphorus content.Fl measures bone density (BMD) with borne densitometers.Biochemical Indices In Serum
Determine：Serum 0.5ml is taken, serum alkaline phosphatase (ALP), calcium (Ca) and phosphorus (P) are detected with automatic clinical chemistry analyzer.
2nd, result
1) serum levels of ALP, serum Ca and blood-serum P
Influence of the compounds of this invention of table 2 to Bilateral oophorectomy rat blood serum ALP, serum Ca and blood-serum P
* P ＜ 0.05, * * P ＜ 0.01, VS OVX groups
From the results shown in Table 2, after the ovary of rat is removed, OVX group rat blood serum alkaline phosphatase activitieses
Increase.This is because when the removal ovary after, estrogen deficiency in rat body causes bone conversion ratio to increase, and it is with postmenopausal women's
Transformant osteoporosis high is consistent.In contrast, the result of the test of compound 1-9 groups shows, when giving the compounds of this invention 3
After individual month, alkaline phosphatase activities is remarkably decreased, it is meant that the compounds of this invention can suppress the bone conversion ratio that removal ovary causes
Increase, reduce sclerotin destruction.Data are also shown compared with Sham groups in table, and OVX group rat blood serum calcium is decreased obviously, and changes
Compound 1-9 groups then show the serum calcium cancentration being obviously improved, and show that the compounds of this invention has the work of lifting serum calcium cancentration
With.And serum calcium is the important marker of bon e formation, this explanation present invention can be reversed effectively due to blood caused by ovary excision
The reduction of clear calcium, is conducive to the formation of bone.
2) bone density (BMD)
Influence of the compounds of this invention of table 3 to Bilateral oophorectomy rat fl BMD
* P ＜ 0.05, * * P ＜ 0.01, VS OVX groups
The result of table 3 shows that OVX groups rat fl bone density is remarkably decreased compared with Sham groups after removal ovary, gives this hair
After 3 months, rat bone density is dramatically increased bright compound.
3) bilateral tibial parameter
Influence of the compounds of this invention of table 4 to Bilateral oophorectomy rats with bilateral tibia parameters
* P ＜ 0.05, * * P ＜ 0.01, VS OVX groups
The result of table 4 is shown, compared with Sham groups, the double shin bone ashes of OVX groups rat are significantly reduced again, and compound 1-9 groups
Significantly raised compared with OVX groups.Additionally, compound 1-9 also can significantly rise processus styloideus radii calcium and bone phosphorus content.
To sum up, pyrazoles heterocyclic compounds of the invention can suppress bone conversion ratio enhancing that removal ovary causes and sclerotin breaks
It is bad, while blood calcium concentration can be improved, be conducive to the deposition of bone.For due to caused by estrogen deficiency osteoporosis have it is anti-
Control effect, and no estrogen sample side effect.Therefore can be used for the prevention and treatment of osteoporosis.
The preferred embodiment for the present invention is the foregoing described, so it is not limited to the present invention.Those skilled in the art couple
Embodiment disclosed herein can carry out improvement and the change without departing from scope and spirit.
Claims (9)
1. a kind of pyrazoles heterocyclic compounds represented such as Formulas I, and its pharmaceutically acceptable salt：
Wherein：
X1Selected from O, S or NH；
Each X2N or CR can be each independently selected from identical or different1；
Each X3N or CR can be each independently selected from identical or different2, and the X3In at least one be N；
R1、R2It is each independently selected from hydrogen, halogen, alkyl, alkoxy, alkylthio group, cyano group, hydroxyl, nitro, NR3R4、CONR3R4、
It is substituted or non-substituted aryl, substituted or non-substituted aralkyl, substituted or non-substituted heteroaryl, substituted or non-substituted miscellaneous
Aralkyl；
Each RaCan be with identical or different, each RbCan be with identical or different, and Ra、RbIt is each independently selected from hydrogen, halogen, alkane
Base, alkoxy, alkylthio group, cyano group, hydroxyl, nitro, NR3R4、CONR3R4, it is substituted or non-substituted aryl, substituted or non-substituted
Aralkyl, substituted or non-substituted heteroaryl, substituted or non-substituted heteroarylalkyl；
Wherein, R3、R4It is each independently selected from hydrogen or alkyl, or R3And R4It is collectively forming substituted or non-substituted heterocyclic radical.
2. pyrazoles heterocyclic compounds according to claim 1, it is characterised in that the substituted aryl, the virtue of substitution
Substitution base in alkyl, the heteroaryl of substitution, the heteroarylalkyl of substitution, the heterocyclic radical of substitution is selected from halogen, alkyl, hydroxyl, cyanogen
Base, nitro or NR5R6, wherein the R5、R6It is each independently selected from hydrogen or alkyl.
3. pyrazoles heterocyclic compounds according to claim 1, it is characterised in that described X1It is 0.
4. pyrazoles heterocyclic compounds according to claim 1, it is characterised in that the alkyl is selected from the straight chain of C1-C6
Or branched alkyl, preferably methyl, ethyl, isopropyl, n-propyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl,
Any one of isopentyl, n-hexyl, isohesyl.
5. pyrazoles heterocyclic compounds according to claim 1, it is characterised in that the aryl be preferably phenyl, naphthyl,
Any one of tetralyl, the heteroaryl is preferably thienyl, furyl, pyrrole radicals, pyridine radicals, pyrimidine radicals, imidazole radicals, pyrrole
Any one of piperazine base, thiazolyl, the heterocyclic radical be preferably nafoxidine base, piperidyl, homopiperidinyl, piperazinyl, morpholinyl,
Any one of thio-morpholinyl, dithiane base, pyridazinyl, pyrazinyl or triazine radical.
6. pyrazoles heterocyclic compounds according to claim 1, the compound is selected from：
1- (pyridine -2- bases) -1H- pyrazoles -5- base benzofuran -2- carboxylates；
3- methyl 4-phenyls -1- (pyridine -2- bases) -1H- pyrazoles -5- base benzofuran -2- carboxylates；
3- (piperidin-1-yl) -1- (pyridine -2- bases) -1H- pyrazoles -5- base benzothiophene -2- carboxylates；
4- ethyls-(pyrimidine -2-base) -1H- pyrazoles -5- bases thiophene [2,3-b] pyridine-2-carboxylic acids ester；
4- morpholinyls -1- (pyrimidine -2-base) -1H- pyrazoles -5- base benzothiophene -2- carboxylates；
1- (pyridine -2- bases) -1H- pyrazoles -5- bases 5- phenyl-benzothiophene -2- carboxylates；
1- (pyrazine -2- bases) -1H- pyrazoles -5- bases 5- dimethylaminos-benzothiophene -2- carboxylates；
1- (pyridine -2- bases) -1H- pyrazoles -5- bases chloro- 1H indole-2-carboxylic acids esters of 6-；
3- methyl isophthalic acids-(1H- pyrroles -1- bases)-benzofuran -2- carboxylates of (pyridine -2- bases) -1H- pyrazoles -5- bases 7- fluoro- 3.
7. the preparation method of pyrazoles heterocyclic compounds according to claim 1 or its pharmaceutically acceptable salt, the side
Method includes：
Step 1) compound shown in the compound and formula III shown in Formula II is added dropwise in polar organic solvent；And heating
The polar organic solvent of the compound shown in compound and formula III shown in contained II, to obtain the compound shown in formula IV：
Step 2) compound shown in Formula V, the compound shown in Formula IV are placed in aprotic solvent, add inorganic base, stirring
After reaction, the compound shown in Formula VII is obtained：
Step 3) compound shown in Formula VII is hydrolyzed in the alkaline aqueous solution after, under thionyl chloride effect, be heated to reflux shape
Into acyl chlorides, then at low temperature, acid binding agent is added to obtain mixed liquor；By the compound reaction shown in the mixed liquor and formula IV under normal temperature
Obtain target compound I；
Step 4) it is necessary when, the compound shown in Formulas I is converted into its pharmaceutically acceptable salt；
Wherein, X1、X2、X3、Ra、RbDefinition as described in the appended claim 1, R be C1-C4 alkyl, M be OH or NO2, RxIt is C1-C4
Alkoxy, X is halogen or sulfydryl, preferably chlorine or bromine.
8. a kind of pharmaceutical composition, it includes the pyrazoles heterocyclic compounds or its medicine according to claim any one of 1-6
Acceptable salt on, and pharmaceutically acceptable carrier.
9. the pyrazoles heterocyclic compounds or its pharmaceutically acceptable salt according to claim any one of 1-6 are preparing use
In prevention or the purposes of the medicine for the treatment of osteoporosis.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107892687A (en) * | 2018-01-21 | 2018-04-10 | 吕迎春 | A kind of 2 acetic acid esters glyoxaline compound and its application in medicine for treating osteoporosis is prevented and treated |
| US11034669B2 (en) | 2018-11-30 | 2021-06-15 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
| US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
| CN115515948A (en) * | 2020-03-20 | 2022-12-23 | 阿克比治疗有限公司 | PHD inhibitor compounds, compositions and uses |
| CN115991698A (en) * | 2022-11-03 | 2023-04-21 | 广东中科药物研究有限公司 | Heterocyclic compound and preparation method and application thereof |
| US11926616B2 (en) | 2018-03-08 | 2024-03-12 | Incyte Corporation | Aminopyrazine diol compounds as PI3K-γ inhibitors |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1331688A (en) * | 1998-12-25 | 2002-01-16 | 帝国脏器制药株式会社 | Aminopyrazole derivatives |
| CN1353704A (en) * | 1999-06-03 | 2002-06-12 | 帝国脏器制药株式会社 | Substituted pyrazole compounds |
| WO2006069155A2 (en) * | 2004-12-21 | 2006-06-29 | Bristol-Myers Squibb Company | Inhibitors of protein arginine methyl transferases |
-
2017
- 2017-01-23 CN CN201710062522.8A patent/CN106831735B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1331688A (en) * | 1998-12-25 | 2002-01-16 | 帝国脏器制药株式会社 | Aminopyrazole derivatives |
| CN1353704A (en) * | 1999-06-03 | 2002-06-12 | 帝国脏器制药株式会社 | Substituted pyrazole compounds |
| WO2006069155A2 (en) * | 2004-12-21 | 2006-06-29 | Bristol-Myers Squibb Company | Inhibitors of protein arginine methyl transferases |
Non-Patent Citations (1)
| Title |
|---|
| MATTHEW W. CARSON，等: "HDX reveals unique fragment ligands for the vitamin D receptor", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107892687A (en) * | 2018-01-21 | 2018-04-10 | 吕迎春 | A kind of 2 acetic acid esters glyoxaline compound and its application in medicine for treating osteoporosis is prevented and treated |
| CN108912103A (en) * | 2018-01-21 | 2018-11-30 | 吕迎春 | A kind of 2- acetic acid esters glyoxaline compound and its application in prevention and treatment medicine for treating osteoporosis |
| US11926616B2 (en) | 2018-03-08 | 2024-03-12 | Incyte Corporation | Aminopyrazine diol compounds as PI3K-γ inhibitors |
| US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
| US11034669B2 (en) | 2018-11-30 | 2021-06-15 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
| CN115515948A (en) * | 2020-03-20 | 2022-12-23 | 阿克比治疗有限公司 | PHD inhibitor compounds, compositions and uses |
| CN115991698A (en) * | 2022-11-03 | 2023-04-21 | 广东中科药物研究有限公司 | Heterocyclic compound and preparation method and application thereof |
| CN115991698B (en) * | 2022-11-03 | 2024-03-29 | 广东中科药物研究有限公司 | Heterocyclic compound and preparation method and application thereof |
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