CN106946851B - It is a kind of for preventing and treating the drug of kidney stone - Google Patents
It is a kind of for preventing and treating the drug of kidney stone Download PDFInfo
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- CN106946851B CN106946851B CN201710151838.4A CN201710151838A CN106946851B CN 106946851 B CN106946851 B CN 106946851B CN 201710151838 A CN201710151838 A CN 201710151838A CN 106946851 B CN106946851 B CN 106946851B
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- compound
- hybar
- pharmaceutically acceptable
- acceptable salt
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- 208000000913 Kidney Calculi Diseases 0.000 title claims abstract description 23
- 206010029148 Nephrolithiasis Diseases 0.000 title claims abstract description 21
- 239000003814 drug Substances 0.000 title claims description 11
- 229940079593 drug Drugs 0.000 title claims description 7
- -1 hybar X class compound Chemical class 0.000 claims abstract description 65
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 20
- 125000004429 atom Chemical group 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000005864 Sulphur Substances 0.000 claims description 3
- 125000001118 alkylidene group Chemical group 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims 1
- 210000003734 kidney Anatomy 0.000 abstract description 20
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 abstract description 14
- 210000002966 serum Anatomy 0.000 abstract description 12
- 239000012453 solvate Substances 0.000 abstract description 8
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- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 abstract description 7
- 239000011575 calcium Substances 0.000 abstract description 7
- 229910052791 calcium Inorganic materials 0.000 abstract description 7
- 229940109239 creatinine Drugs 0.000 abstract description 7
- 229940002612 prodrug Drugs 0.000 abstract description 7
- 239000000651 prodrug Substances 0.000 abstract description 7
- 230000002265 prevention Effects 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
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- 239000002585 base Substances 0.000 description 35
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 8
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 5
- 239000004202 carbamide Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 239000004575 stone Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
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- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
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- 239000011591 potassium Substances 0.000 description 3
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Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
The invention discloses the hybar X class compound and its pharmaceutically acceptable salt of a kind of Formula I, prodrug and solvates.Pharmacological testing shows that the hybar X class compound of Formula I of the present invention can significantly reduce kidney stone rate and kidney calcium content, serum urea nitrogen and serum creatinine, can significantly improve Kidney coefficients, has good prevention and treatment effect for kidney stone.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and the invention discloses the drugs for preventing and treating kidney stone.
Background technique
Kidney stone, which refers to, betides kidney calices, the calculus of renal plevis and renal plevis and urine output pipe jointing part.Majority is located in renal plevis kidney calices,
Kidney essence calculus is rare, and plain film shows that there are single or multiple round, ovals or obtuse triangle densification shadow, density Gao Erjun in kidney area
Even, how smooth edge is, but also has rough in mulberry fruit shape.The calculus at any position of urinary system can be primary in kidney.According to
The difference of stone composition, kidney stone can divide calcinm oxalate calculus, calcium phosphate calculus, uric acid (lithate) calculus, struvite calculus,
Six class of cystine stone and purine calculus.Kidney stone be due to caused by colloid in body and crystal metabolic dysequilibrium, with infection,
Nutrition and Metabolism disorder, urinary system foreign matter, urine smoulders and the factors such as geography and climate are related, may occur in which ipsilateral pain in the loins, renal colic,
Symptoms, the Yi Yinfa gout and diabetes, hypertension, acute pyelonephritis, chronic renal failure, uremia etc. such as band blood are a variety of in urine
The disease of Health and Living is seriously affected, clinical incidence increases trend in recent years.
It is clinical at present to take Extracorporeal shock wave lithotripsy (ESWL) or other row's Stone techniques more.Though this method can be such that calculus arranges
Out, but side effect is very more, and the residual rate of calculus and recurrence rate are very high.According to statistics, the risk of relapse of kidney stone 5 years
It is interior up in 50%, 9 year up in 67%, 25 year up to 75%.Therefore it is very necessary to find a kind of efficiently and effectively therapeutic modality.
Summary of the invention
The purpose of the present invention is to provide the drugs that a kind of pair of kidney stone has preventive and therapeutic action.
According to an aspect of the present invention, the present invention provides a kind of hybar X class compounds, and its can pharmaceutically connect
Salt, prodrug and the solvate received.
According to another aspect of the present invention, it is also another object of the present invention to provide the hybar X class compound,
And its preparation method of pharmaceutically acceptable salt, prodrug and solvate.
According to another aspect of the present invention, it is also another object of the present invention to provide the hybar X class compound,
And its application of pharmaceutically acceptable salt, prodrug and solvate in medicine preparation, the drug is for preventing and treating
Kidney stone.
According to another aspect of the present invention, it is also another object of the present invention to provide one kind comprising being selected from the pyrimidine two
One of ketone compounds and its pharmaceutically acceptable salt, prodrug and solvate or a variety of pharmaceutical compositions.
Hybar X class compound according to the present invention is indicated by following below formula I:
[Formula I]
In Formulas I,
W1、W2Can be identical or different, it is each independently selected from: N or CR1；
A is selected from: substituted or unsubstituted C1-6 alkylidene, replaces or does not take substituted or unsubstituted C3-6 cycloalkylidene
The arlydene of the C6-12 in generation, wherein substituent group is C1-6 alkyl, C3-6 naphthenic base or halogen, and one or more in A
A-CH2The group that-NH- ,-O- or-S- can be optionally selected from replaces, and condition is cannot there are two selected from-NH- ,-O-
Or the group of-S- links together；
R1It is each independently selected from: H, halogen, C1-6 alkyl, CN, OH, amino, the C1-6 optionally replaced by halogen or OH
Alkoxy, C2-6 alkynyl, C2-6 alkenyl, C3-6 naphthenic base, C1-6 alkyl amino, formoxyl, COOH, COOR2、COR2、
CONR2R2a、-NHCOR2、-NHSO2R2, Heterocyclylalkyl, aryl, heteroaryl, C1-6 alkyl sulphonyl, aryl sulfonyl or heteroaryl
Base sulfonyl；R2And R2aIt is each independently selected from C1-6 alkyl, C3-6 naphthenic base or Heterocyclylalkyl, alternatively, R2And R2aWith them
The N atom connected is formed together the Heterocyclylalkyl of 3-7 member；
Hy indicates that heteroaryl, the heteroaryl are optionally substituted by one or more substituents, these substituent groups independently select
From H, halogen, optionally the C1-6 alkyl, CN, OH, amino, C1-6 alkoxy, C2-6 alkynyl, the C2-6 alkene that are replaced by halogen or OH
Base, C3-6 naphthenic base, C1-6 alkyl amino, formoxyl, COOH, COOR3、COR3、CONR3R3a、-NHCOR3、-NHSO3R3；R3With
R3aIt is each independently selected from C1-6 alkyl, C3-6 naphthenic base or Heterocyclylalkyl, alternatively, R3And R3aN atom connected to them
It is formed together the Heterocyclylalkyl of 3-7 member；
N indicates 0,1,2 or 3.
In a preferred embodiment, W1、W2It is each independently selected from: N.
In a preferred embodiment, W1Selected from N, W2Selected from CR1。
In a preferred embodiment, A is selected from: substituted or unsubstituted C1-6 alkylidene.
In a preferred embodiment, A is selected from :-CH2CH2-、-CH2CH2CH2-、-CH2CH2OCH2-、-CH2CH(CH3)
CH2-。
In a preferred embodiment, A is selected from: 1 or 4 cyclohexylidene.
In a preferred embodiment, heteroaryl represented by Hy is the miscellaneous original comprising 1 to 4 selected from oxygen, sulphur and nitrogen
Son is used as annular atom, remaining annular atom is 5 to 10 yuan of preferably 5- or 6-membered aryl of carbon.
Currently preferred compound is:
In a preferred embodiment of the invention, the present invention provides the medicine of the hybar X class compound of Formula I
Acceptable salt is selected from base addition salts and acid-addition salts on.Preferably, the base addition salts are selected from sodium salt, sylvite, calcium salt, lithium
Salt, magnesium salts, zinc salt, ammonium salt, tetramethyl ammonium, tetraethyl ammonium salt, triethylamine salt, leptodactyline, ethylamine salt, diethanol amine
Salt, arginine salt or lysine salt；Or acid-addition salts be selected from hydrochloride, hydrobromate, phosphate, sulfate, mesylate or
Tosilate.
The present invention also includes the compound of the present invention through isotope labelling, if not one or more atoms are by having and nature
Except in the case of the atom of the common atomic mass in boundary or the different atomic mass or mass number of mass number substitution, otherwise this is through same position
The compound of element label is identical as those compounds as described herein.The example that may be incorporated into the isotope of the compounds of this invention includes
Hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine isotope, such as2H、3H、13C、14C、15N、18O、17O、18F and36Cl。
In the present invention, the prodrug of the compounds of this invention is not specifically limited, as long as it can be metabolized in vivo
At the compounds of this invention, without limitation including ester etc., such as methyl esters, ethyl ester etc..
In the present invention, solvate of the invention refers to one or more solvent molecules and the compound of the present invention institute shape
At associated matter.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, second
Acetoacetic ester, acetic acid, ethylaminoethanol.
Group definition
Unless stated to the contrary, otherwise following that there are following meanings with term in the specification and in the claims.
Term " alkyl " refers to the aliphatic hydrocarbon group of saturation, straight chain and branched group including 1 to 20 carbon atom.It is preferred that containing
There are the alkyl of 1 to 10 carbon atom, the alkyl of further preferably 1 to 6 carbon atom.Non-limiting embodiment includes methyl, second
Base, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl
Propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl third
Base, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethyl butyrate
Base, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2,3- dimethylbutyl, n-heptyl, 2- methyl oneself
Base, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2,3- dimethyl amyl group, 2,4- dimethyl amyl group, 2,2- dimethyl
Amyl, 3,3- dimethyl amyl group, 2- ethylpentyl, 3- ethylpentyl, n-octyl, 2,3- dimethylhexanyl, 2,4- dimethyl oneself
Base, 2,5- dimethylhexanyl, 2,2- dimethylhexanyl, 3,3- dimethylhexanyl, 4,4- dimethylhexanyl, 2- ethylhexyl, 3-
Ethylhexyl, 4- ethylhexyl, 2- methyl -2- ethylpentyl, 2- methyl -3- ethylpentyl, n-nonyl, 2- methyl -2- ethyl
Hexyl, 2- methyl -3- ethylhexyl, 2,2- diethyl amyl group, positive decyl, 3,3- diethylhexyl, 2,2- diethylhexyl, and
Its various branched isomer etc..
Term " alkenyl " refers to the alkane as defined above by being at least made of two carbon atoms and at least one carbon-to-carbon double bond
Base, such as vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- cyclobutenyl etc..It is preferred that C2-10 alkenyl, more preferable C2-6 alkene
Base, most preferably C2-4 alkenyl.
Term " alkynyl " refers to the alkane as defined above being at least made of two carbon atoms and at least one carbon-carbon triple bond
Base, such as acetenyl, 1- propinyl, 2-propynyl, 1-, 2- or 3- butynyl etc..It is preferred that C2-10 alkynyl, more preferable C2-6 alkynes
Base, most preferably C2-4 alkynyl.
Term " naphthenic base " refers to saturation monocycle cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms preferably include 3 to 12
A carbon atom, more preferable cycloalkyl ring include 3 to 10 carbon atoms, and most preferably cycloalkyl ring includes 3 to 6 carbon atoms.Monocycle
The non-limiting embodiment of naphthenic base includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, suberyl, cyclooctyl
Deng preferred cyclopropyl.
Term " aryl " refers to that 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle are (namely shared
The ring of adjacent carbon atoms pair) group, preferably 6 to 10 yuan, more preferable phenyl and naphthalene, most preferably phenyl.
Term " heteroaryl " refers to 1 to 4 hetero atom selected from oxygen, sulphur and nitrogen as annular atom, remaining annular atom
For 5 to 14 yuan of aryl of carbon.Heteroaryl is preferably 5 to 10 yuan, more preferably 5- or 6-membered, such as furyl, thienyl, pyridine
Base, pyrrole radicals, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical, tetrazole etc..
Term " Heterocyclylalkyl " refers to saturation monocycle or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 annular atoms, wherein one
A or multiple annular atoms are selected from nitrogen, oxygen or S (O)m(wherein m be 0 to 2 integer) hetero atom, but do not include-O-O- ,-O-S-
Or the loop section of-S-S-, remaining annular atom are carbon.3 to 12 annular atoms are preferably included, wherein 1~4 is hetero atom, it is more excellent
Selecting heterocyclic ring includes 3 to 10 annular atoms, and more preferable heterocyclic ring includes 5 to 6 annular atoms.Monocyclic heterocycles base it is unrestricted
Property embodiment include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, high piperazine base, pyranose, dihydrofuran
Base, tetrahydrofuran base etc..Multiring heterocyclic includes the heterocycle of loop coil, condensed ring and bridged ring.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Pharmaceutical composition
Term " pharmaceutical composition " used refers to: containing at least one sheet with pharmaceutically acceptable excipient
The combination of the hybar X class compound and its pharmaceutically acceptable salt, prodrug and solvate of the invention Formula I
Object.Typical pharmaceutical composition are as follows: powder, granule, capsule, solution, emulsion, suspension, injection, is sprayed tablet
Agent, aerosol, powder spray, lotion, liniment, ointment, emplastrum, paste, patch etc..
Term used herein " excipient " refers to: anti stickness agent, antioxidant, binder, coating agent, tabletting help
Agent, disintegrating agent, lubricant, emulsifier etc..Typical excipient are as follows: Butylated Hydroxytoluene, calcium carbonate, calcium phosphate, calcium stearate, crosslinking
Carboxymethyl cellulose, crosslinked polyvinylpyrrolidone, citric acid, Crospovidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl
It is base cellulose, hydroxypropyl methyl cellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, right
Methyl hydroxybenzoate, polyethylene glycol, sodium citrate, sorbierite, starch, stearic acid, sucrose, talcum powder, titanium dioxide, dimension life
Plain A, vitamin C, vitamin E, xylitol etc..
Synthetic method of the invention
The hybar X class compound of Formula I of the present invention can be prepared by the following method:
Step 1:
The step includes making the compound of Formulae II and the compound of formula iii and palladium catalyst, alkali in inertia
It is reacted in solvent to prepare the compound of Formula I V.
Solvent for the step can be alcohol, such as methanol, ethyl alcohol, isopropanol etc.；Aromatic hydrocarbons, such as benzene, toluene or diformazan
Benzene；Halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride；Nitrile solvents, such as acetonitrile；Ether solvent, such as tetrahydrofuran, 1,
4- dioxane；Or their mixed solvent.Solvent is preferably Isosorbide-5-Nitrae-dioxane.
Alkali for the step can be hydroxide, such as sodium hydroxide, potassium hydroxide；Carbonate, such as sodium carbonate, carbon
Sour potassium, cesium carbonate；Bicarbonate, such as sodium bicarbonate, saleratus.Alkali is preferably carbonate, more preferable potassium carbonate.
Step 2:
The step includes making the compound of chemical formula V and the compound of chemical formula VI and alkali, catalyst in atent solvent
It is middle to react to prepare the compound of chemical formula VII.
Solvent for the step can be alcohol, such as methanol, ethyl alcohol, isopropanol etc.；Aromatic hydrocarbons, such as benzene, toluene or diformazan
Benzene；Halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride；Nitrile solvents, such as acetonitrile；Or their mixed solvent.Solvent is excellent
It is selected as acetonitrile.
Alkali for the step can be hydroxide, such as sodium hydroxide, potassium hydroxide；Carbonate, such as sodium carbonate, carbon
Sour potassium；Bicarbonate, such as sodium bicarbonate, saleratus；Acetate, such as sodium acetate or potassium acetate.Alkali is preferably bicarbonate
Salt, more preferable saleratus.
Catalyst for the step can be cuprous salt, such as cuprous iodide.
Step 3:
The step includes reacting Formula I V compound in atent solvent to make with chemical formula VII compound and alkali
The compound of standby Formula I.
Solvent for the step can be alcohol, such as methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, tertiary fourth
Alcohol, isoamyl alcohol, octanol, cyclohexanol, 2-methyl cellosolve, diethylene glycol (DEG) or glycerol；Aromatic hydrocarbons, such as benzene, toluene or dimethylbenzene；It is halogenated
Hydrocarbon, such as chloroform, methylene chloride；Or their mixed solvent.Solvent is preferably aromatic hydrocarbons, more preferable toluene.
Alkali for the step can be hydroxide, such as sodium hydroxide, potassium hydroxide；Carbonate, such as sodium carbonate, carbon
Sour potassium, cesium carbonate；Bicarbonate, such as sodium bicarbonate, saleratus.Alkali is preferably carbonate, more preferable cesium carbonate.
In above-mentioned steps, W1、W2、A、R1, Hy, n it is as defined above, X1、X2Can be identical or different, each independently
Selected from halogen, preferably chlorine or bromine.
Beneficial effect
Hybar X class compound of the present invention can significantly reduce kidney stone rate and kidney calcium content, serum urea
Nitrogen and serum creatinine can significantly improve Kidney coefficients, have good prevention and treatment effect for kidney stone.
Specific embodiment
The present invention is described below in more detail to facilitate the understanding of the present invention.
Embodiment 1:1- (3- (2,4- dioxo -6- (pyridine -2- base) -3,4- dihydro-pyrimidin -1 (2H)-yl) propyl) -3-
(pyrimidine -2-base) urea (compound 1)
Step 1: into dry Schlenk reaction tube be added 6- chlorine pyrimidine -2,4 (1H, 3H)-diketone (0.29g,
2.0mmol), pyridine -2- ylboronic acid (0.30g, 2.2mmol), tetrakis triphenylphosphine palladium (29mg, 0.025mmol), K2CO3
Isosorbide-5-Nitrae-dioxane (10mL), water (2mL), 45 DEG C of reaction 4h are added under nitrogen protection in (0.33g, 2.4mmol).Reaction knot
Solvent is removed under reduced pressure in Shu Hou, and residue is separated after being dissolved with ethyl acetate with silica gel column chromatography, with petrol ether/ethyl acetate 20:
1 elution, obtains light yellow solid 6- (pyridine -2- base) pyrimidine -2,4 (1H, 3H)-diketone, is light yellow solid 0.28g, pure
Degree 98%, yield 74%.ESI-MS:190.05 [M+H]+。
Step 2: by 1,3- dibromopropane (1.00g, 5.0mmol), KHCO3(1.03g, 7.5.0mmol), CuI
(0.095g, 0.5mmol) and toluene (50ml) mix, and 80 DEG C are heated under stirring, then by 1- (pyrimidine -2-base) urea
The solution of (0.69g, 5.0mmol) in toluene (30ml) is slowly added dropwise into, is added dropwise within 1 hour, stirs in the case where being heated to reflux
It mixes 6 hours.Evaporating solvent under reduced pressure after reaction, residue ethyl alcohol recrystallization obtain white crystal 1- (3- bromopropyl) -3-
(pyrimidine -2-base) urea 1.07g, purity 97%, yield 85%.ESI-MS:259.01 [M+H]+。
Step 3: by 6- (pyridine -2- base) pyrimidine -2,4 (1H, 3H)-diketone (0.19g, 1.0mmol), 1- (3- bromine third
Base) -3- (pyrimidine -2-base) urea (0.28g, 1.1mmol), mixture of the potassium carbonate (0.28g, 2mmol) in acetonitrile (30mL)
In 60 DEG C of stirring 12h, solvent is removed under reduced pressure, by residue by silica gel chromatography, is washed with petrol ether/ethyl acetate 4: 1
It is de-, obtain white solid 1- (3- (2,4- dioxo -6- (pyridine -2- base) -3,4- dihydro-pyrimidin -1 (2H)-yl) propyl) -3-
(pyrimidine -2-base) urea 0.30g, purity 99%, yield 81%.
ESI-MS:368.14 [M+H]+
Elemental analysis: theoretical value/measured value, C (55.58/55.42), H (4.66/4.74), N (26.69/26.61), O
(13.07/13.23)
1H NMR (400MHz, DMSO-D6) δ 11.99 (s, 1H), 9.92 (s, 1H), 8.42 (m, 3H), 7.41-7.48 (m,
3H), 6.98 (q, 1H), 6.57 (s, 1H), 6.04 (s, 1H), 4.01 (t, 2H), 3.31 (t, 2H), 1.74 (m, 2H).
In a similar way, following compound is synthesized:
Pharmacological examples Example: preventive and therapeutic action of the target compound to kidney stone
1. influence of the compound 1-4 to rat kidney stone and kidney parameter
Male Wistar rat 60 of 180-220g are taken, seven groups, i.e. control group, model group, compound 1-5 are randomly divided into
Group (is referred to as experimental group).Each group rat uses normal diet and distilled water to raise.Five groups of model group, experimental group rats use
+ 2% ammonium chloride (AC) of 1% ethylene glycol (EG) stomach-filling daily 2mL/ is only.Modeling starts to be administered, once a day, continuous eight weeks.Sun
Property control group selection Chinese medicine granules for treating nephrolith as positive control drug, daily stomach-filling 3g/kg.The daily stomach-filling 20mg/kg of experimental group.
After last dose 1h, using yellow Jackets anesthetized animal, abdominal aortic blood detects blood urea nitrogen, creatinine content, takes kidney
Kidney coefficients are detected, left kidney is taken to survey kidney calcium content, right kidney does pathological examination, surveys gallstone formation rate.Experimental result application SPSS statistics
Software.
Influence of 1 target compound of table to rat kidney stone
Influence of 2 target compound of table to rat kidney coefficient, kidney calcium content, serum creatinine and serum urea nitrogen
Note: compared with blank control group, * P < 0.05, * * P < 0.01；
Above-mentioned test result shows that compared with the control group the calculus rate of model group rats is significantly higher than control group, kidney system
Number is substantially less than control group, and kidney calcium content, serum urea nitrogen and serum creatinine are significantly higher than control group, prompts stone model modeling
Success.Compared with model group, the calculus rate and kidney calcium content, serum urea nitrogen and serum creatinine of experimental group rat decline to a great extent,
Kidney coefficients are then to significantly improve (P < 0.01).Compared with positive control, the compounds of this invention for kidney stone prevention and control
Therapeutic effect is suitable with existing granules for treating nephrolith.Therefore, the compounds of this invention has good prevention and treatment for kidney stone
Effect.
In conclusion hybar X class compound of the present invention can significantly reduce kidney stone rate and kidney calcium contains
Amount, serum urea nitrogen and serum creatinine, can significantly improve Kidney coefficients, and kidney stone is imitated with good prevention and treatment
Fruit.
The foregoing describe the preferred embodiment for the present invention, and however, it is not to limit the invention.Those skilled in the art couple
Embodiment disclosed herein can carry out the improvements and changes without departing from scope and spirit.
Claims (9)
1. the hybar X class compound and its pharmaceutically acceptable salt of a kind of Formula I:
[Formula I]
In Formulas I,
W1、W2Can be identical or different, it is each independently selected from: N or CR1；
A is selected from: substituted or unsubstituted C1-6 alkylidene, substituted or unsubstituted C3-6 cycloalkylidene, and wherein substituent group is C1-
6 alkyl；
R1It is each independently selected from H, halogen, amino, C1-6 alkoxy, COR2、CONR2R2a；
R2And R2aIt is each independently selected from C1-6 alkyl, alternatively, R2And R2aN atom connected to them is formed together 3-7 member
Heterocyclylalkyl；
Hy indicates heteroaryl, and the heteroaryl is hetero atom comprising 1 to 4 selected from oxygen, sulphur and nitrogen as annular atom, remaining
Annular atom is the 5- or 6-membered aryl of carbon, which is optionally substituted by one or more substituents, these substituent groups are only
On the spot it is selected from H, halogen, C1-6 alkyl；
N indicates 0,1,2 or 3.
2. hybar X class compound according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that described
W1、W2It is each independently selected from: N.
3. hybar X class compound according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that institute
It states A to be selected from :-CH2CH2-、-CH2CH2CH2-、-CH2CH(CH3)CH2-。
4. hybar X class compound according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that described
A is selected from: 1 or 4 cyclohexylidene.
5. a kind of hybar X class compound and its pharmaceutically acceptable salt, which is characterized in that the hybar X class chemical combination
Object is selected from:
6. a kind of method for preparing hybar X class compound described in claim 1, the described method comprises the following steps:
Step 1:
The step includes making the compound of Formulae II and the compound of formula iii and palladium catalyst, alkali in atent solvent
It is middle to react to prepare the compound of Formula I V；
Step 2:
The step includes keeping the compound of chemical formula V and the compound of chemical formula VI and alkali, catalyst anti-in atent solvent
It should be to prepare the compound of chemical formula VII；
Step 3:
The step includes reacting Formula I V compound with preparation in atent solvent with chemical formula VII compound and alkali
Learn the compound of Formulas I；
In above-mentioned steps, W1、W2、A、R1, Hy, n definition as described in the appended claim 1, X1、X2Can be identical or different, respectively
Independently selected from halogen.
7. according to the method described in claim 6, it is characterized in that, X1、X2Can be identical or different, it is each independently selected from chlorine
Or bromine.
8. a kind of pharmaceutical composition, contain with pharmaceutically acceptable excipient it is at least one according to claim 1-
5 described in any item hybar X class compounds and its pharmaceutically acceptable salt.
9. hybar X class compound according to claim 1-5 and its pharmaceutically acceptable salt are preparing medicine
Application in object, the drug is for preventing and treating kidney stone.
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