CN106946851A - A kind of medicine for being used to prevent and treat kidney stone - Google Patents
A kind of medicine for being used to prevent and treat kidney stone Download PDFInfo
- Publication number
- CN106946851A CN106946851A CN201710151838.4A CN201710151838A CN106946851A CN 106946851 A CN106946851 A CN 106946851A CN 201710151838 A CN201710151838 A CN 201710151838A CN 106946851 A CN106946851 A CN 106946851A
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- Prior art keywords
- hybar
- pharmaceutically acceptable
- prodrug
- formula
- compound
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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
- -1 hybar X class compound Chemical class 0.000 claims abstract description 51
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 229940002612 prodrug Drugs 0.000 claims abstract description 15
- 239000000651 prodrug Substances 0.000 claims abstract description 15
- 239000012453 solvate Substances 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 32
- 239000002585 base Substances 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 20
- 125000004429 atom Chemical group 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 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
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 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
- 238000000034 method Methods 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 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
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 238000007614 solvation Methods 0.000 claims 5
- 125000005143 heteroarylsulfonyl group Chemical group 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
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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
- 230000002265 prevention Effects 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
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- 241000700159 Rattus Species 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
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- 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
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- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
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- 239000003795 chemical substances by application Substances 0.000 description 4
- 125000000753 cycloalkyl 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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- 0 CC(N1)N(CCCNC(*c2ccccn2)S)C(c2ccccn2)=CC1=* Chemical compound CC(N1)N(CCCNC(*c2ccccn2)S)C(c2ccccn2)=CC1=* 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 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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- 125000002950 monocyclic group Chemical group 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
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- 235000011056 potassium acetate Nutrition 0.000 description 1
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- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
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- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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- UMLDUMMLRZFROX-UHFFFAOYSA-N pyridin-2-ylboronic acid Chemical class OB(O)C1=CC=CC=N1 UMLDUMMLRZFROX-UHFFFAOYSA-N 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
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- 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
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- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical class CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
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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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the hybar X class compound and its pharmaceutically acceptable salt of a kind of Formula I, prodrug and solvate.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, have good prevention and treatment effect for kidney stone.
Description
Technical field
The present invention relates to pharmaceutical technology field, the invention discloses the medicine for preventing and treating kidney stone.
Background technology
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 circular, ovals or the fine and close shadow of obtuse triangle, density Gao Erjun in kidney area
Even, how smooth edge is, but it is in mulberry fruit shape also to have rough.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,
Cystine stone and the class of purine calculus six.Kidney stone is due in body caused by colloid and crystal metabolic dysequilibrium, with infection,
Nutrition and Metabolism disorder, urinary system foreign matter, urine smoulders and the factor such as geography and climate is relevant, may occur in which homonymy pain in the back, renal colic,
The symptom such as band blood in urine, easily triggers gout and diabetes, hypertension, acute pyelonephritis, chronic renal failure, uremia etc. a variety of
The disease of Health and Living is had a strong impact on, clinical onset rate 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 arrange calculus
Go out, but side effect is very more, and also the residual rate and recurrence rate of calculus 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 a kind of efficiently and effectively therapeutic modality is found very necessary.
The content of the invention
It is an object of the invention to provide a kind of medicine to kidney stone with preventive and therapeutic action.
According to an aspect of the present invention, the invention provides a kind of hybar X class compound, and its it 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 is prepared, the medicine is for preventing and treating
Kidney stone.
According to another aspect of the present invention, included it is also another object of the present invention to provide one kind and be selected from the pyrimidine two
One or more pharmaceutical compositions in ketone compounds, and its pharmaceutically acceptable salt, prodrug and solvate.
Represented according to the hybar X class compound of the present invention by below formula I：
[Formula I]
In Formulas I,
W1、W2It can be each independently selected from identical or different：N or CR1；
A is selected from：Substituted or unsubstituted C1-6 alkylidenes, substituted or unsubstituted C3-6 cycloalkylidenes, substitution do not take
The C6-12 in generation arlydene, wherein substituent are one or more in C1-6 alkyl, C3-6 cycloalkyl or halogen, and A
Individual-CH2- the group that can be optionally selected from-NH- ,-O- or-S- is replaced, and condition is that can not have two to be selected from-NH- ,-O-
Or-S- group links together；
R1 is each independently selected from：H, halogen, the C1-6 alkyl optionally replaced by halogen or OH, CN, OH, amino, C1-6
Alkoxy, C2-6 alkynyls, C2-6 alkenyls, C3-6 cycloalkyl, C1-6 alkyl aminos, formoxyl, COOH, COOR2、COR2、
CONR2R2a、-NHCOR2、-NHSO2R2, Heterocyclylalkyl, aryl, heteroaryl, C1-6 alkyl sulphonyls, aryl sulfonyl or heteroaryl
Base sulfonyl；R2And R2aC1-6 alkyl, C3-6 cycloalkyl or Heterocyclylalkyl are each independently selected from, or, R2And R2aWith them
The N atoms connected form the Heterocyclylalkyl of 3-7 members together；
Hy represents heteroaryl, and the heteroaryl is optionally substituted by one or more substituents, and these substituents are independently selected
From H, halogen, the C1-6 alkyl optionally replaced by halogen or OH, CN, OH, amino, C1-6 alkoxies, C2-6 alkynyls, C2-6 alkene
Base, C3-6 cycloalkyl, C1-6 alkyl aminos, formoxyl, COOH, COOR3、COR3、CONR3R3a、-NHCOR3、-NHSO3R3；R3With
R3aC1-6 alkyl, C3-6 cycloalkyl or Heterocyclylalkyl are each independently selected from, or, R3And R3aThe N atoms being connected with them
The Heterocyclylalkyl of 3-7 members is formed together；
N represents 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 alkylidenes.
In a preferred embodiment, A is selected from：-CH2CH2-、-CH2CH2CH2-、-CH2CH2OCH2-、-CH2CH(CH3)
CH2-。
In a preferred embodiment, A is selected from：Isosorbide-5-Nitrae-cyclohexylidene.
In a preferred embodiment, the heteroaryl represented by Hy is comprising 1 to 4 miscellaneous original for being selected from oxygen, sulphur and nitrogen
Son is as annular atom, and remaining annular atom is 5 to 10 yuan preferably 5 yuan or 6 yuan of 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 include the compound of the invention through isotope marks, if not one or more atoms by with nature
Except in the case of the atom of the common atomic mass in boundary or the different atomic mass of mass number or mass number is substituted, otherwise this is through same position
The compound of element mark is identical with those compounds as described herein.May be incorporated into the example of the isotope of the compounds of this invention includes
Hydrogen, carbon, nitrogen, oxygen, the isotope of fluorine and chlorine, 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
Into the compounds of this invention, without limitation including ester etc., such as methyl esters, ethyl ester.
In the present invention, solvate of the invention refers to one or more solvent molecules and the compound institute shape of the present invention
Into associated matter.The solvent for forming solvate is included, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, second
Acetoacetic ester, acetic acid, ethylaminoethanol.
Group definition
Unless stated to the contrary, it is otherwise following that there are following implications with term in the specification and in the claims.
Term " alkyl " refers to the aliphatic hydrocarbon group of saturation, includes the straight chain and branched group of 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 example includes methyl, second
Base, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl
Propyl group, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls third
Base, 1,1,2- thmethylpropyl, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethyl butyrates
Base, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls, n-heptyl, 2- methyl oneself
Base, 3- methylhexyls, 4- methylhexyls, 5- methylhexyls, 2,3- dimethyl amyl groups, 2,4- dimethyl amyl groups, 2,2- dimethyl
Amyl group, 3,3- dimethyl amyl groups, 2- ethyl pentyl groups, 3- ethyl pentyl groups, n-octyl, 2,3- dimethylhexanyls, 2,4- dimethyl oneself
Base, 2,5- dimethylhexanyls, 2,2- dimethylhexanyls, 3,3- dimethylhexanyls, 4,4- dimethylhexanyls, 2- ethylhexyls, 3-
Ethylhexyl, 4- ethylhexyls, 2- methyl -2- ethyl pentyl groups, 2- methyl -3- ethyl pentyl groups, n-nonyl, 2- methyl -2- ethyls
Hexyl, 2- methyl -3- ethylhexyls, 2,2- diethyl amyl groups, positive decyl, 3,3- diethylhexyls, 2,2- diethylhexyls, and
Its various branched chain isomer etc..
Term " alkenyl " refers to the alkane as defined above by being at least made up 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.It is preferred that C2-10 alkenyls, more preferably C2-6 alkene
Base, most preferably C2-4 alkenyls.
Term " alkynyl " refers to the alkane as defined above being at least made up of two carbon atoms and at least one carbon-to-carbon triple bond
Base, such as acetenyl, 1- propinyls, 2-propynyl, 1-, 2- or 3- butynyl.It is preferred that C2-10 alkynyls, more preferably C2-6 alkynes
Base, most preferably C2-4 alkynyls.
Term " cycloalkyl " refers to the monocyclic cyclic hydrocarbon substituent of saturation, and it includes 3 to 20 carbon atoms, preferably includes 3 to 12
Individual carbon atom, more preferably cycloalkyl ring include 3 to 10 carbon atoms, and most preferably cycloalkyl ring includes 3 to 6 carbon atoms.It is monocyclic
The non-limiting example of cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, suberyl, cyclooctyl
Deng preferred cyclopropyl.
Term " aryl ", which refers to, has 6 to 14 yuan of full carbon of the pi-electron system being conjugated monocyclic or fused polycycle (is namely shared
The ring of adjacent carbon atoms pair) group, more preferably preferably 6 to 10 yuan, most preferably phenyl and naphthyl, 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 yuan or 6 yuan, 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 that saturation is monocyclic or polycyclic cyclic hydrocarbon substituent, and it includes 3 to 20 annular atoms, wherein one
Individual or multiple annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is 0 to 2 integer), but do not include-O-O- ,-O-S-
Or-S-S- loop section, remaining annular atom is carbon.3 to 12 annular atoms are preferably included, wherein 1~4 is hetero atom, it is more excellent
Heterocyclic ring is selected to include 3 to 10 annular atoms, more preferably heterocyclic ring includes 5 to 6 annular atoms.Monocyclic heterocycles base it is unrestricted
Property embodiment include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base, pyranose, dihydrofuran
Base, tetrahydrofuran base etc..Multiring heterocyclic includes the heterocyclic radical 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：Contain at least one sheet with pharmaceutically acceptable excipient
The hybar X class compound of the described Formula I of invention and its combination of pharmaceutically acceptable salt, prodrug and solvate
Thing.Typically pharmaceutical composition is：Powder, tablet, granule, capsule, solution, emulsion, supensoid agent, injection, spraying
Agent, aerosol, powder spray, lotion, liniment, ointment, emplastrum, paste, patch etc..
Term used herein " excipient " is referred to：Anti stickness agent, antioxidant, binder, coating agent, compressing tablet are helped
Agent, disintegrant, lubricant, emulsifying agent etc..Typically excipient is：Butylated Hydroxytoluene, calcium carbonate, calcium phosphate, calcium stearate, crosslinking
Carboxymethyl cellulose, PVPP, 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..
The synthetic method of the present invention
The hybar X class compound of Formula I of the present invention can be prepared by the following method：
Step one：
The step includes making the compound of Formulae II and the compound of formula iii and palladium catalyst, alkali in inertia
React to prepare Formula I V compound in solvent.
Solvent for the step can be alcohol, such as methanol, ethanol, isopropanol；Aromatic hydrocarbons, such as benzene, toluene or diformazan
Benzene；Halogenated hydrocarbons, such as dichloromethane, 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 NaOH, potassium hydroxide；Carbonate, such as sodium carbonate, carbon
Sour potassium, cesium carbonate；Bicarbonate, such as sodium acid carbonate, saleratus.Alkali is preferably carbonate, more preferably potassium carbonate.
Step 2：
The step includes making chemical formula V compound with chemical formula VI compound and alkali, catalyst in atent solvent
It is middle to react to prepare chemical formula VII compound.
Solvent for the step can be alcohol, such as methanol, ethanol, isopropanol；Aromatic hydrocarbons, such as benzene, toluene or diformazan
Benzene；Halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride；Nitrile solvents, such as acetonitrile；Or their mixed solvent.Solvent is excellent
Elect acetonitrile as.
Alkali for the step can be hydroxide, such as NaOH, potassium hydroxide；Carbonate, such as sodium carbonate, carbon
Sour potassium；Bicarbonate, such as sodium acid carbonate, saleratus；Acetate, such as sodium acetate or potassium acetate.Alkali is preferably bicarbonate
Salt, more preferably saleratus.
Catalyst for the step can be cuprous salt, such as cuprous iodide.
Step 3：
The step includes making Formula I V compounds react to make in atent solvent with chemical formula VII compounds and alkali
The compound of standby Formula I.
Solvent for the step can be alcohol, such as methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, tertiary fourth
Alcohol, isoamyl alcohol, octanol, cyclohexanol, 2-methyl cellosolve, diethylene glycol (DEG) or glycerine；Aromatic hydrocarbons, such as benzene, toluene or dimethylbenzene；Halo
Hydrocarbon, such as chloroform, dichloromethane；Or their mixed solvent.Solvent is preferably aromatic hydrocarbons, more preferably toluene.
Alkali for the step can be hydroxide, such as NaOH, potassium hydroxide；Carbonate, such as sodium carbonate, carbon
Sour potassium, cesium carbonate；Bicarbonate, such as sodium acid carbonate, saleratus.Alkali is preferably carbonate, more preferably cesium carbonate.
In above-mentioned steps, W1、W2、A、R1, Hy, n it is as defined above, X1、X2Can be with identical or different, independently of one another
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.
Embodiment
The present invention is described below in more detail to contribute to the understanding of the present invention.
Embodiment 1：1- (3- (2,4- dioxo -6- (pyridine -2- bases) -3,4- dihydro-pyrimidins -1 (2H)-yl) propyl group) -3-
(pyrimidine -2-base) urea (compound 1)
Step 1: added into dry Schlenk reaction tubes 6- chlorine pyrimidine -2,4 (1H, 3H)-diketone (0.29g,
2.0mmol), pyridine -2- ylboronic acids (0.30g, 2.2mmol), tetrakis triphenylphosphine palladium (29mg, 0.025mmol), K2CO3
(0.33g, 2.4mmol), under nitrogen protection, adds Isosorbide-5-Nitrae-dioxane (10mL), water (2mL), 45 DEG C of reaction 4h.Reaction knot
Shu Hou, removal of solvent under reduced pressure, 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- bases) pyrimidine -2,4 (1H, 3H)-diketone, and it is light yellow solid 0.28g, pure
Degree 98%, yield 74%.ESI-MS：190.05[M+H]+。
Step 2：By 1,3- dibromopropanes (1.00g, 5.0mmol), KHCO3(1.03g, 7.5.0mmol), CuI
(0.095g, 0.5mmol) and toluene (50ml) are mixed, 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, and 1 hour completion of dropping is stirred in the case where being heated to reflux
Mix 6 hours.Reaction removes solvent under reduced pressure after terminating, and residue ethyl alcohol recrystallization obtains white crystal 1- (3- bromopropyls) -3-
(pyrimidine -2-base) urea 1.07g, purity 97%, yield 85%.ESI-MS：259.01[M+H]+。
Step 3：By 6- (pyridine -2- bases) pyrimidine -2,4 (1H, 3H)-diketone (0.19g, 1.0mmol), 1- (3- bromines third
Base) -3- (pyrimidine -2-base) urea (0.28g, 1.1mmol), mixture of the potassium carbonate (0.28g, 2mmol) in acetonitrile (30mL)
12h is stirred at 60 DEG C, removal of solvent 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- bases) -3,4- dihydro-pyrimidins -1 (2H) -- base) propyl group) -3-
(pyrimidine -2-base) urea 0.30g, purity 99%, yield 81%.
ESI-MS：368.14[M+H]+
Elementary 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. influences of the compound 1-4 to rat kidney stone and kidney parameter
180-220g male Wistar rat 60 is taken, seven groups, i.e. control group, model group, compound 1-5 is randomly divided into
Group (general designation experimental group).Each group rat is raised using normal diet and distilled water.Model group, five groups of rats of experimental group use
The ammonium chloride (AC) of 1% ethylene glycol (EG)+2% gavage 2mL/ daily.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 gavage 3g/kg.The daily gavage 20mg/kg of experimental group.
After last dose 1h, using yellow Jackets anesthetized animal, abdominal aortic blood, detection blood urea nitrogen, creatinine content take kidney
Kidney coefficients are detected, take left kidney to survey kidney calcium content, right kidney does pathological examination, surveys gallstone formation rate.Experimental result application SPSS is counted
Software.
Influence of the target compound of table 1 to rat kidney stone
The target compound of table 2 to rat kidney coefficient, kidney calcium content, serum creatinine and, the influence of serum urea nitrogen
Note：Compared with blank control group, * P ＜ 0.05, * * P ＜ 0.01；
Above-mentioned result of the test shows, compared with control group, and 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, point out 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 summary, 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, for kidney stone there are good prevention and treatment to imitate
Really.
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 hybar X class compound of Formula I, and its pharmaceutically acceptable salt, prodrug and solvate：
[Formula I]
In Formulas I,
W1、W2It can be each independently selected from identical or different：N or CR1；
A is selected from：It is substituted or unsubstituted C1-6 alkylidenes, substituted or unsubstituted C3-6 cycloalkylidenes, substituted or unsubstituted
C6-12 arlydene, wherein substituent be in C1-6 alkyl, C3-6 cycloalkyl or halogen, and A it is one or more-
CH2- the group that can be optionally selected from-NH- ,-O- or-S- is replaced, condition be can not have two selected from-NH- ,-O- or-
S- group links together；
R1It is each independently selected from：H, halogen, the C1-6 alkyl optionally replaced by halogen or OH, CN, OH, amino, C1-6 alcoxyls
Base, C2-6 alkynyls, C2-6 alkenyls, C3-6 cycloalkyl, C1-6 alkyl aminos, formoxyl, COOH, COOR2、COR2、CONR2R2a、-
NHCOR2、-NHSO2R2, Heterocyclylalkyl, aryl, heteroaryl, C1-6 alkyl sulphonyls, aryl sulfonyl or heteroarylsulfonyl；
R2And R2aC1-6 alkyl, C3-6 cycloalkyl or Heterocyclylalkyl are each independently selected from, or, R2And R2aThe N being connected with them
Atom forms the Heterocyclylalkyl of 3-7 members together；
Hy represents heteroaryl, and the heteroaryl is optionally substituted by one or more substituents, these substituents independently selected from H,
Halogen, the C1-6 alkyl optionally replaced by halogen or OH, CN, OH, amino, C1-6 alkoxies, C2-6 alkynyls, C2-6 alkenyls, C3-
6 cycloalkyl, C1-6 alkyl aminos, formoxyl, COOH, COOR3、COR3、CONR3R3a、-NHCOR3、-NHSO3R3；R3And R3aEach
Independently selected from C1-6 alkyl, C3-6 cycloalkyl or Heterocyclylalkyl, or, R3And R3aThe shape together with the N atoms that they are connected
Into the Heterocyclylalkyl of 3-7 members；
N represents 0,1,2 or 3.
2. hybar X class compound according to claim 1, and its pharmaceutically acceptable salt, prodrug and solvation
Thing, it is characterised in that the W1、W2It is each independently selected from：N.
3. hybar X class compound according to claim 1, and its pharmaceutically acceptable salt, prodrug and solvation
Thing, it is characterised in that the A is selected from：-CH2CH2-、-CH2CH2CH2-、-CH2CH2OCH2-、-CH2CH(CH3)CH2-。
4. hybar X class compound according to claim 1, and its pharmaceutically acceptable salt, prodrug and solvation
Thing, it is characterised in that the A is selected from：Isosorbide-5-Nitrae-cyclohexylidene.
5. hybar X class compound according to claim 1, and its pharmaceutically acceptable salt, prodrug and solvation
Thing, it is characterised in that heteroaryl represented by Hy be comprising 1 to 4 hetero atom selected from oxygen, sulphur and nitrogen as annular atom, its
Remaining annular atom is 5 to 10 yuan preferably 5 yuan or 6 yuan of aryl of carbon.
6. hybar X class compound according to claim 1, and its pharmaceutically acceptable salt, prodrug and solvation
Thing, it is characterised in that the hybar X class compound is selected from：
7. a kind of method for preparing hybar X class compound according to claim 1, the described method comprises the following steps：
Step one：
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 Formula I V compound；
Step 2：
The step includes making chemical formula V compound and chemical formula VI compound and alkali, catalyst anti-in atent solvent
Should be to prepare chemical formula VII compound；
Step 3：
The step includes making Formula I V compounds react with preparation in atent solvent with chemical formula VII compounds 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 with identical or different, each
Independently selected from halogen, preferably chlorine or bromine.
8. a kind of pharmaceutical composition, it contains at least one with pharmaceutically acceptable excipient according to claim 1-
The hybar X class compound and its pharmaceutically acceptable salt, prodrug and solvate of Formula I described in 6 any one.
9. the hybar X class compound of the Formula I according to claim any one of 1-6 and its pharmaceutically acceptable
The application of salt, prodrug and solvate in medicine is prepared, the medicine is used to prevent and treat kidney stone.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007035629A2 (en) * | 2005-09-16 | 2007-03-29 | Takeda Pharmaceutical Company Limited | Process for the preparation of pyrimidinedione derivatives |
| WO2008084223A2 (en) * | 2007-01-11 | 2008-07-17 | Astrazeneca Ab | Chemical compounds 637: pyridopyrimidinediones as pde4 inhibitors |
| CN101238120A (en) * | 2005-04-29 | 2008-08-06 | 加拉佩格斯有限公司 | Urea derivatives methods for their manufacture and uses thereof |
| WO2014205223A1 (en) * | 2013-06-21 | 2014-12-24 | MyoKardia, Inc. | Pyrimidinedione compounds against cardiac conditions |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101238120A (en) * | 2005-04-29 | 2008-08-06 | 加拉佩格斯有限公司 | Urea derivatives methods for their manufacture and uses thereof |
| WO2007035629A2 (en) * | 2005-09-16 | 2007-03-29 | Takeda Pharmaceutical Company Limited | Process for the preparation of pyrimidinedione derivatives |
| WO2008084223A2 (en) * | 2007-01-11 | 2008-07-17 | Astrazeneca Ab | Chemical compounds 637: pyridopyrimidinediones as pde4 inhibitors |
| WO2014205223A1 (en) * | 2013-06-21 | 2014-12-24 | MyoKardia, Inc. | Pyrimidinedione compounds against cardiac conditions |
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| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20191112 |