CN108689948A - 6- (3,4- substituted-phenyls) -2- mercaptopyrimidine -4- formic acid compounds and its preparation method and application - Google Patents
6- (3,4- substituted-phenyls) -2- mercaptopyrimidine -4- formic acid compounds and its preparation method and application Download PDFInfo
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Abstract
The invention belongs to pharmaceutical technology fields, it is related to the 6- (3 with the general formula I of xanthine oxidase inhibitory activity, 4- substituted-phenyls) -2- mercaptopyrimidine -4- formic acid compounds, pharmaceutical salt, pharmaceutical solvate and preparation method thereof, the invention further relates to purposes of these compounds in treatment hyperuricemia and gout medicine.The general structure of described 6- (3,4- the substituted-phenyls) -2- mercaptopyrimidine -4- formic acid compounds is as follows:Wherein, R and X is as described in claim and specification.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to 6- (3,4- substituted-phenyl) -2- mercaptopyrimidine -4- formic acid compounds
And its preparation method and application;More particularly to 6- (3,4- substituted-phenyls) -2- mercaptopyrimidine -4- formic acid compounds, pharmaceutically acceptable
Purposes in the drug for preparing treatment gout of salt, pharmaceutical solvate and preparation method thereof and these compounds.
Background technology
Gout is internal purine metabolic disturbance or underexcretion and leads to internal joint etc. deposition uric acid and causes
A series of inflammatory reactions.With the variation of people's dietary structure, intake animal protein and fat increase, hyperuricemia and
Patient with gout has notable increasing trend, has become global metabolic disease.The clinical characters of gout be hyperuricemia with
And thus caused by tophaceous deposition, urarthritis recurrent exerbation, tophaceous chornic arthritis and joint deformity.Uric acid
Also kidney is often accumulated on, arteriosclerotic kidney and uric acid kidney stone are caused.Lasting high lithemia value is to cause pain in blood
An important factor for wind.Xanthine oxidase inhibitor can inhibit uric acid to generate, and be accounted in the treatment of hyperuricemia and gout
Use consequence.Allopurinol (allopurinol) is clinically first xanthine oxidation for inhibiting uric acid to generate
Enzyme inhibitor, and the gold medicine as gout is widely used in clinic, but need to repeat large dosage administration to remain higher
Levels of drugs, while causing the serious or even fatal adverse reaction caused by drug accumulation.
Febuxostat (febuxostat) is disclosed in WO9209279A1, for xanthine oxidase inhibitor of new generation, is faced
For treating gout and hyperuricemia on bed.The success of Febuxostat makes non-purines xanthine oxidase inhibitor become drop
The hot spot of uric acid drug development.Currently, the research of Febuxostat analog is focused primarily upon replaces non-cloth with other five-ring heterocycles
The thiazole ring of sotan, five-ring heterocycles used include pyrazoles, thiophene, selenazoles, oxazole, isoxazoles, imidazoles, triazole etc..However,
The example that Febuxostat thiazole ring is replaced using hexa-member heterocycle is seldom, is only limitted to pyridine (WO2010044411A1) etc..
6- (3,4- substituted-phenyls) -2- mercaptopyrimidine -4- formic acid compounds grinding as xanthine oxidase inhibitor
Study carefully not yet reported.The synthetic method report of 6- (substituted-phenyl) -2- mercaptopyrimidine -4- formic acid compounds is only limited
In a non-patent literature (American Journal of Chemistry, 2012,2 (1):1-6.), which depict with (E)
4- (4- bromophenyls) -4- oxo but-2-ene acid is that raw material and thiocarbamide flow back in the presence of sodium ethoxide in ethyl alcohol to obtain bromobenzene 6- (4-
Bromophenyl) -2- mercaptopyrimidine -4- formic acid.
Invention content
6- (the 3,4- substitutions with good xanthine oxidase inhibitory activity that it is an object of the present invention to provide a kind of
Phenyl) -2- mercaptopyrimidine -4- formic acid compounds, it can be used for preparing treatment hyperuricemia and gout medicine.
It is a further object to provide one kind by (Z) -4- (3,4- substituted-phenyls) -2- hydroxyl -4- oxo butyl- 2-
It is phonetic that with thiocarbamide or its ackd salt 6- (3,4- substituted-phenyls) -2- sulfydryls are obtained by the reaction in olefin(e) acid in one or more dicyandiamide solutions
The preparation method of pyridine -4- formic acid compounds, this method without special reaction reagent, without special reaction unit, be not necessarily to
Expensive catalyst, operability are good.
Technical scheme is as follows:
General formula (1) or (1 ') 6- (3,4- substituted-phenyls) -2- mercaptopyrimidine -4- formic acid compounds, pharmaceutical salt, can
Medicinal solvate:
Wherein,
R be the C1-C10 alkyl of linear chain or branched chain, C3-C10 allylic alkylations, C3-C10 alkynes alkyl, C4-C7 cycloalkyl-alkyls,
C7-C10 aryl alkyls;
X is halogen, cyano or nitro.
Preferably,
R be the C1-C8 alkyl of linear chain or branched chain, C3-C8 allylic alkylations, C3-C8 alkynes alkyl, C4-C6 cycloalkyl-alkyls,
C7-C9 aryl alkyls;X is bromine, iodine, cyano or nitro.
It is highly preferred that
R is C1-C6 alkyl, C3-C6 allylic alkylations, C3-C6 alkynes alkyl, C4-C6 cycloalkyl-alkyls, the C7- of linear chain or branched chain
C9 aryl alkyls;X is bromine, iodine, cyano or nitro.
Most preferably,
R is n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, n-pentyl, isopentyl, neopentyl, tertiary amyl;X is
Bromine, iodine, cyano or nitro.
Compound of the present invention further include compound shown in structure above be formed by it is pharmaceutically acceptable
Nontoxic salts and its hydrate or other prodrug forms, these pharmaceutically acceptable nontoxic salts include the derivative and alkali institute shape
At salt.Such as:Alkali metal salt such as Li, Na and K salt;Alkali salt such as Ca and Mg salt;Organic alkali salt, such as lysine, smart ammonia
Acid, guanidine, diethanol amine, choline, tromethamine etc.;Ammonium or substituted ammonium salt and aluminium salt.The hydration number of the hydrate
Arbitrary real number in being 0~16.These salt and prodrug forms respectively can dissociate structure above compound.
The most preferred part of compounds structure and name that the present invention obtains are as follows:
Compound 1
Compound 2
Compound 3
Compound 4
Compound 5
Compound 6
Compound 7
Compound 8
Compound 9
Compound 10
Compound 11
Compound 12
Compound 13
Compound 14
Compound 15
Compound 16
Compound 17
Compound 18
The invention further relates to 6- (3,4- substituted-phenyls) -2- mercaptopyrimidine -4- formic acid class chemical combination that a kind of general formula (1) indicates
The preparation method of object (such compound can also be indicated with its mutual variant (1 ')), it is characterized in that:(Z)-indicated by general formula (2)
(such compound can also use its mutual variant to 4- (3,4- substituted-phenyls) -2- hydroxyl -4- oxo but-2-enes acid compounds
(2 ') indicate) with thiocarbamide or its acid reactant salt, obtain general formula (1) (such compound can also use its mutual variant (1 ') to indicate)
Compound preparation method.
R and the meaning of X and R in formula (1) are identical as the meaning of X in general formula (2).
The preparation method of (1) or (1 ') of the present invention is as follows:(Z) -4- (3,4- indicated by general formula (2) or (2 ')
Substituted-phenyl) -2- hydroxyl -4- oxo but-2-ene acid compounds and thiocarbamide or its acid reactant salt, obtain general formula (1) or
(1')。
Wherein, the dosage of thiocarbamide or its ackd salt, if the amount for the progress that can react fully, such as relative to general formula
(1) when expression is 1 mole, the range of thiocarbamide or its ackd salt at 0.2-20 moles, more preferably in 0.5-10 moles of model
It encloses.
The carboxylic acids such as formic acid, acetic acid, propionic acid, and the above solvent and other poles can be used as the solvent in the method for the present invention
Property solvent (such as N,N-dimethylformamide, 1,4- dioxane, isopropanol) or nonpolar solvent (benzene, toluene, chlorobenzene etc.)
Mixed solvent.Further preferably acetic acid and other polarity or the mixed solvent of nonpolar solvent.
The reaction temperature of the reaction is preferably 20 DEG C of reflux temperatures to used solvent, further preferably 60 DEG C to institute
Use the reflux temperature of solvent.
The reaction time of the reaction is preferably 0.5 hour to 24 hours.Further preferably 1 hour to 10 hours.
It is of the present invention by (Z) -4- (3,4- substituted-phenyls) -2- hydroxyl -4- oxo but-2-ene acid and thiocarbamide or its acid
The reaction equation that property reactant salt prepares 6- (3,4- substituted-phenyls) -2- mercaptopyrimidine -4- formic acid compounds is as follows:
It is (Z)-that the present invention, which prepares the raw material used in 6- (3,4- substituted-phenyls) -2- mercaptopyrimidine -4- formic acid compounds,
4- (3,4- substituted-phenyl) -2- hydroxyl -4- oxos but-2-enes acid, the synthetic method of the raw material is referring to US8822467, and 2014.;
European Journal of Medicinal Chemistry,2010,45(6):2663。
The preparation method letter of 6- (3,4- substituted-phenyls) -2- mercaptopyrimidine -4- formic acid compounds provided by the present invention
Single feasible, yield is preferable.
6- (3,4- substituted-phenyls) -2- mercaptopyrimidine -4- formic acid compounds inhibit with preferable xanthine oxidase
Effect, can be used for preparing antigout, antihyperuricemic disease drug.
Specific implementation mode
It will be helpful to understand the present invention by following examples, but present disclosure is not limited to example.
Agents useful for same of the present invention is commercially available, and nuclear magnetic resoance spectrum is by AVANCE-400/600, Bruker ARX-300 Fouriers
Leaf transformation nuclear magnetic resonance chemical analyser measures, and mass spectrum is by Brukee Esqure 2000, Shimadzu GCMS-QP5050A type mass spectrums
Instrument measures.
Embodiment 1:The preparation of 6- (the bromo- 4- isopropyl phenyls of 3-) -2- mercaptopyrimidine -4- formic acid (compound 1)
Sour (0.66g, 2mmol), the sulphur by (Z) -4- (the bromo- 4- isopropyl phenyls of 3-) -2- hydroxyl -4- oxos but-2-ene
Urea (0.76g, 10mmol) is added into glacial acetic acid (30mL), is warming up to 100 DEG C and reacts 8 hours.The system of waiting for is cooled to room temperature,
Organic solvent is removed under reduced pressure, solid purifies to obtain 6- (the bromo- 4- isopropyl phenyls of 3-) -2- mercaptopyrimidine -4- formic acid through column chromatography.
The yield of 6- (the bromo- 4- isopropyl phenyls of 3-) -2- mercaptopyrimidine -4- formic acid (compound 1) is 66%, structure
Formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 2:The preparation of 6- (the bromo- 4- isobutoxy phenyls of 3-) -2- mercaptopyrimidine -4- formic acid (compound 2)
Other than using corresponding alkylating reagent in being alkylated a step, 6- (3- are prepared in 1 identical method of embodiment
Bromo- 4- isobutoxy phenyls) -2- mercaptopyrimidine -4- formic acid (compound 2), yield 71%, structural formula,1H-NMR and MS
Data are listed in the table below in -1.
Embodiment 3:The preparation of 6- (the bromo- 4- isoamoxy phenyl of 3-) -2- mercaptopyrimidine -4- formic acid (compound 3)
6- (the bromo- 4- isoamoxy phenyl of 3-) -2- mercaptopyrimidine -4- formic acid (chemical combination is prepared in 1 identical method of embodiment
Object 3), yield 67%, structural formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 4:The preparation of 6- (the iodo- 4- isoamoxy phenyl of 3-) -2- mercaptopyrimidine -4- formic acid (compound 4)
6- (the iodo- 4- isopropyl phenyls of 3-) -2- mercaptopyrimidine -4- formic acid (chemical combination is prepared in 1 identical method of embodiment
Object 4), yield 81%, structural formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 5:The preparation of 6- (the iodo- 4- n-butoxyphenyls of 3-) -2- mercaptopyrimidine -4- formic acid (compound 5)
6- (the iodo- 4- n-butoxyphenyls of 3-) -2- mercaptopyrimidine -4- formic acid (chemical combination is prepared in 1 identical method of embodiment
Object 5), yield 76%, structural formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 6:The preparation of 6- (the iodo- 4- sec-butoxies phenyl of 3-) -2- mercaptopyrimidine -4- formic acid (compound 6)
6- (the iodo- 4- sec-butoxies phenyl of 3-) -2- mercaptopyrimidine -4- formic acid (chemical combination is prepared in 1 identical method of embodiment
Object 6), yield 65%, structural formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 7:The preparation of 6- (the iodo- 4- isobutoxy phenyls of 3-) -2- mercaptopyrimidine -4- formic acid (compound 7)
6- (the iodo- 4- isobutoxy phenyls of 3-) -2- mercaptopyrimidine -4- formic acid (chemical combination is prepared in 1 identical method of embodiment
Object 7), yield 83%, structural formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 8:The preparation of 6- (the iodo- 4- isoamoxy phenyl of 3-) -2- mercaptopyrimidine -4- formic acid (compound 8)
6- (the iodo- 4- isoamoxy phenyl of 3-) -2- mercaptopyrimidine -4- formic acid (chemical combination is prepared in 1 identical method of embodiment
Object 8), yield 79%, structural formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 9:The preparation of 6- (3- cyano -4- isopropyl phenyls) -2- mercaptopyrimidine -4- formic acid (compound 9)
6- (3- cyano -4- isopropyl phenyls) -2- mercaptopyrimidine -4- formic acid is prepared in 1 identical method of embodiment (to change
Close object 10), yield 63%, structural formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 10:The preparation of 6- (3- cyano -4- n-butoxyphenyls) -2- mercaptopyrimidine -4- formic acid (compound 10)
6- (3- cyano -4- n-butoxyphenyls) -2- mercaptopyrimidine -4- formic acid is prepared in 1 identical method of embodiment (to change
Close object 10), yield 67%, structural formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 11:The preparation of 6- (3- cyano -4- sec-butoxies phenyl) -2- mercaptopyrimidine -4- formic acid (compound 11)
6- (3- cyano -4- sec-butoxies phenyl) -2- mercaptopyrimidine -4- formic acid is prepared in 1 identical method of embodiment (to change
Close object 11), yield 55%, structural formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 12:The preparation of 6- (3- cyano-4-isobutoxy phenyls) -2- mercaptopyrimidine -4- formic acid (compound 12)
6- (3- cyano-4-isobutoxy phenyls) -2- mercaptopyrimidine -4- formic acid is prepared in 1 identical method of embodiment (to change
Close object 12), yield 60%, structural formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 13:The preparation of 6- (3- cyano -4- isoamoxy phenyl) -2- mercaptopyrimidine -4- formic acid (compound 13)
6- (3- cyano -4- isoamoxy phenyl) -2- mercaptopyrimidine -4- formic acid is prepared in 1 identical method of embodiment (to change
Close object 13), yield 58%, structural formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 14:The preparation of 6- (3- nitro 4- isopropyl phenyls) -2- mercaptopyrimidine -4- formic acid (compound 14)
6- (3- nitro -4- isopropyl phenyls) -2- mercaptopyrimidine -4- formic acid is prepared in 1 identical method of embodiment (to change
Close object 14), yield 57%, structural formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 15:The preparation of 6- (3- nitro 4- n-butoxyphenyls) -2- mercaptopyrimidine -4- formic acid (compound 15)
6- (3- nitro 4- n-butoxyphenyls) -2- mercaptopyrimidine -4- formic acid is prepared in 1 identical method of embodiment (to change
Close object 15), yield 50%, structural formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 16:The preparation of 6- (3- nitro 4- sec-butoxies phenyl) -2- mercaptopyrimidine -4- formic acid (compound 16)
6- (3- nitro 4- sec-butoxies phenyl) -2- mercaptopyrimidine -4- formic acid is prepared in 1 identical method of embodiment (to change
Close object 16), yield 51%, structural formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 17:The preparation of 6- (3- nitro 4- isobutoxy phenyls) -2- mercaptopyrimidine -4- formic acid (compound 17)
6- (3- nitro 4- isobutoxy phenyls) -2- mercaptopyrimidine -4- formic acid is prepared in 1 identical method of embodiment (to change
Close object 16), yield 61%, structural formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 18:The preparation of 6- (3- nitro 4- isoamoxy phenyl) -2- mercaptopyrimidine -4- formic acid (compound 18)
6- (3- nitro 4- isoamoxy phenyl) -2- mercaptopyrimidine -4- formic acid is prepared in 1 identical method of embodiment (to change
Close object 16), yield 62%, structural formula,1H-NMR and MS data are listed in the table below in -1.
Embodiment 21:The external pharmacology of the compound of the present invention is tested
(1) experimental principle:It is that substrate detects XOD (being purchased from SIGMA) activity with xanthine (being purchased from SIGMA).Observe sample
To the activity suppression of enzyme, to evaluate the inhibition of sample.The positive reference compound used is allopurinol
(allopurinol)。
(2) external activity test method and result:In 200 μ L reaction systems containing 7.4 phosphate buffer of appropriate XOD, pH,
Xanthine (being purchased from SIGMA) kindly product, while setting up blank control (without enzyme and sample) and negative control (being free of sample), sample
A concentration of 10 μm of olL of product-1, 25 DEG C of reactions 90min, 293nM measure OD values, calculate inhibiting rate, each chemical combination according to following formula
The inhibiting rate value of object is shown in Table -2.
Table -1
Table -2
Claims (10)
1. a kind of as general formula (1) or the compound of (1 '), pharmaceutically acceptable salt, hydrate or dissolved matter, feature exist
In:
R is C1-C10 alkyl, C3-C10 allylic alkylations, C3-C10 alkynes alkyl, C4-C7 cycloalkyl-alkyls, the C7- of linear chain or branched chain
C10 aryl alkyls;X is halogen, cyano or nitro.
2. compound according to claim 1, pharmaceutically acceptable salt, hydrate or solvate, feature exist
In:
R is C1-C8 alkyl, C3-C8 allylic alkylations, C3-C8 alkynes alkyl, C4-C6 cycloalkyl-alkyls, the C7-C9 virtues of linear chain or branched chain
Base alkyl;X is bromine, iodine, cyano or nitro.
3. compound according to claim 1, pharmaceutically acceptable salt, hydrate or solvate, feature exist
In:
R is C1-C6 alkyl, C3-C6 allylic alkylations, C3-C6 alkynes alkyl, C4-C6 cycloalkyl-alkyls, the C7-C9 of linear chain or branched chain
Aryl alkyl;X is bromine, iodine, cyano or nitro.
4. compound according to claim 1, pharmaceutically acceptable salt, hydrate or solvate, feature exist
In:R is n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, n-pentyl, isopentyl, neopentyl, tertiary amyl;X be bromine,
Iodine, cyano or nitro.
5. compound according to claim 1, pharmaceutically acceptable salt, hydrate or solvate, feature exist
In:The salt is that the compound is formed by salt with alkali;The hydration number of the hydrate is the arbitrary reality in 0~16
Number.
6. compound according to claim 5, pharmaceutically acceptable salt, hydrate or solvate, feature exist
In:Wherein the salt is alkali metal salt, alkali salt or organic alkali salt, and the alkali metal salt is Li, Na or K salt, institute
The alkali salt stated is Ca or Mg salt, and organic alkali salt is lysine, arginine, guanidine, diethanol amine, choline or ammonia fourth
The salt of triol, ammonium or substituted ammonium salt and aluminium salt.
7. compound described in claim 1, pharmaceutically acceptable salt, hydrate or solvate, are selected from:
6- (the bromo- 4- isopropyl phenyls of 3-) -2- mercaptopyrimidine -4- formic acid
6- (the bromo- 4- isobutoxy phenyls of 3-) -2- mercaptopyrimidine -4- formic acid
6- (the bromo- 4- isoamoxy phenyl of 3-) -2- mercaptopyrimidine -4- formic acid
6- (the iodo- 4- isopropyl phenyls of 3-) -2- mercaptopyrimidine -4- formic acid
6- (the iodo- 4- isobutoxy phenyls of 3-) -2- mercaptopyrimidine -4- formic acid
6- (the iodo- 4- isoamoxy phenyl of 3-) -2- mercaptopyrimidine -4- formic acid
6- (the iodo- 4- n-butoxyphenyls of 3-) -2- mercaptopyrimidine -4- formic acid
6- (the iodo- 4- sec-butoxies phenyl of 3-) -2- mercaptopyrimidine -4- formic acid
6- (3- cyano -4- isopropyl phenyls) -2- mercaptopyrimidine -4- formic acid
6- (3- cyano-4-isobutoxy phenyls) -2- mercaptopyrimidine -4- formic acid
6- (3- cyano -4- isoamoxy phenyl) -2- mercaptopyrimidine -4- formic acid
6- (3- cyano -4- n-butoxyphenyls) -2- mercaptopyrimidine -4- formic acid
6- (3- cyano -4- sec-butoxies phenyl) -2- mercaptopyrimidine -4- formic acid
6- (3- nitro -4- isopropyl phenyls) -2- mercaptopyrimidine -4- formic acid
6- (3- nitro 4- isobutoxy phenyls) -2- mercaptopyrimidine -4- formic acid
6- (3- nitro -4- isoamoxy phenyl) -2- mercaptopyrimidine -4- formic acid
6- (3- nitro -4- n-butoxyphenyls) -2- mercaptopyrimidine -4- formic acid
6- (3- nitro -4- sec-butoxies phenyl) -2- mercaptopyrimidine -4- formic acid.
8. a kind of pharmaceutical composition, including the compound described in claim 1-7 any one, pharmaceutically acceptable salt,
Hydrate or solvate and pharmaceutically acceptable carrier.
9. a kind of preparation side of 6- as described in claim 1 (3,4- substituted-phenyls) -2- mercaptopyrimidine -4- formic acid compounds
Method, it is characterised in that:
(Z) -4- (3,4- the substituted-phenyls) -2- hydroxyl -4- oxo but-2-ene acid compounds indicated by general formula (2) or (2 ')
With thiocarbamide or its acid reactant salt, obtains general formula (1) or (1 ') indicates compound;
The molar ratio of the thiocarbamide or its ackd salt is 1:0.2-20, preferably:1:0.5-10;
The solvent of the reaction be formic acid, acetic acid, propionic acid or more solvent and other polarity (such as N,N-dimethylformamide, 1,
4- dioxane, isopropanol etc.) or nonpolar solvent (benzene, toluene, chlorobenzene etc.) mixed solvent
Reaction temperature is by 20 DEG C to the reflux temperature using solvent, preferably 60 DEG C to used solvent of reflux temperature;
Reaction time is 0.5 hour to 24 hours, preferably 1 hour to 10 hours.
10. 6- (3,4- substituted-phenyls) -2- mercaptopyrimidine -4- formic acid compounds described in claim 1-7 any one, its
Pharmaceutically acceptable salt, hydrate or solvate or composition according to any one of claims 8 are preparing antigout, anti-high lithemia
Application in mass formed by blood stasis drug.
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