CN106008421A - Human body urate transporter-1 inhibitor capable of promoting uric acid excretion and preparation method thereof - Google Patents
Human body urate transporter-1 inhibitor capable of promoting uric acid excretion and preparation method thereof Download PDFInfo
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- CN106008421A CN106008421A CN201610411507.5A CN201610411507A CN106008421A CN 106008421 A CN106008421 A CN 106008421A CN 201610411507 A CN201610411507 A CN 201610411507A CN 106008421 A CN106008421 A CN 106008421A
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- benzofuran
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- LSCPSQFXENEGOE-UHFFFAOYSA-N CCC(C1CC(c2ccc(C(C3CC3)O)cc2)=O)[O]=C2C1=CC=CC2 Chemical compound CCC(C1CC(c2ccc(C(C3CC3)O)cc2)=O)[O]=C2C1=CC=CC2 LSCPSQFXENEGOE-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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Abstract
The invention relates to the technical field of medicine, and particularly discloses a human body urate transporter-1 inhibitor capable of promoting uric acid excretion and a preparation method thereof. The inhibitor is a compound or salt or a prodrug represented by 4-(2-ethyl-benzofuran-3-carbonyl)-benzoic acid. The inhibitor has good hURAT1 inhibiting ability and selectivity, is low in toxic and side effect and is expected to serve as a uric acid excretion promoting drug with low untoward effects.
Description
Technical field
The present invention relates to pharmaceutical technology field, be specifically related to a kind of Human Urine hydrochlorate transporter-1 that can promote urate excretion
Inhibitor and preparation method thereof, above-mentioned inhibitor is used for treating hyperuricemia, gout and tophaceous deposition.
Background technology
Gout is more common in the middle-aged and elderly people of more than 40 years old, and developed country adult onset leads as 1-2%, its prevalence along with
The increase at age and rise.And along with growth in the living standard, the increase that high purine substance is taken in, gout sickness rate is passed year by year
Increasing, the epidemiology statistics of 2008 shows, the prevalence of gout of China has reached 1.14%.In recent years, whole world gout is sent out
Sick rate substantially rises the trend with rejuvenation and makes people's treatment pay attention to day by day to gout.Medicine for gout clinical treatment
Few and the most of untoward reaction of kind is serious, and hURAT1 specific inhibitor can effectively alleviate the generation of side reaction.Therefore, closely
Over Nian, hURAT1 inhibitor becomes the focus of pharmaceuticals of world research.
HURAT1 transporter is relevant with Congenital Renal hyperuricemia in report in 2002, and it is near that it is mainly expressed in kidney
The tube chamber side form of convoluted tubule epithelial cell, mediated cell apurinic acid, to intracellular transport, completes the re-absorbed first step of uric acid, should
The sudden change of acceptor gene can accelerate the excretion of uric acid, causes Hypouricemia.Therefore, hURAT1 inhibitor can be urinated as novel fall
Acid medicine, is mainly used in treating hyperuricemia, gout and ventilation related symptoms.Within 2016, FDA has just ratified the specificity of listing
HURAT1 inhibitor is Lesinurad, by itself and medicine (such as allopurinol and the Febuxostat) combination reducing uricopoiesis, and can
Increase the response rate of the patient with gout the best to said medicine response.But its independent medication still suffer from kidney relevant risk and
How unsatisfactory curative effect, play the maximum efficiency of hURAT1 inhibitor and overcome its side effect as much as possible, becoming study hotspot.
It is positioned at renal cells and has many different transporters, such as hOAT1 etc., to hURAT1 specific binding capacity
The highest being probably causes one of reason of having side effects of medicine.The medicine that specificity is high can alleviate its poison brought relatively
Side reaction.
Summary of the invention
The technical problem to be solved is for above-mentioned prior art present situation, it is provided that a species specificity is higher
HURAT1 inhibitor, it is 3.5 times of marketed drug Lesinurad to the inhibition strength of hURAT1, and has preferably selection
Property.
For solving above-mentioned technical problem, the technical scheme is that
A kind of Human Urine hydrochlorate transporter-1 inhibitor (i.e. hURAT1 inhibitor) that can promote urate excretion, described suppression
Agent be 4-(2-Ethyl-benzofuran-3-carbonyl)-benzoic acid be the compound of representative or salt or prodrug；
Wherein, described 4-(2-Ethyl-benzofuran-3-carbonyl)-benzoic chemical formula is:
Present invention also offers the preparation method of above-mentioned Human Urine hydrochlorate transporter-1 inhibitor, comprise the following steps:
Step one, take terephthalic acid monomethyl ester and be placed in thionyl chloride, return stirring 4～8h, remove protochloride under reduced pressure
Sulfone, adds 2-ethyl benzofuran and aluminum chloride, is stirred at room temperature 20～30h；Adding frozen water in reactant liquor, stirring stands, point
From organic layer；Add dilute HCl, stirring；Adding distilled water, stirring stands, and separates organic layer；Add saturated NaCl solution, stirring
Stand, separate organic layer, remove organic solvent under reduced pressure；Silica gel column chromatography separating-purifying obtains 4-(2-Ethyl-benzofuran-3-carbonyl
Base)-essence of Niobe；
Step 2,4-(2-Ethyl-benzofuran-3-the carbonyl)-essence of Niobe taking step one prepared are placed in water, first
Alcohol, oxolane mixed solvent in, add sodium hydroxide, stirring at normal temperature 10～14h, remove solvent under reduced pressure；Add distilled water
Making it be completely dissolved, being slowly added dropwise dilute hydrochloric acid to pH is faintly acid；Add chloroform extraction, separate, chloroform is evaporated off；Silica gel column chromatography
Separating-purifying obtains 4-(2-Ethyl-benzofuran-3-carbonyl)-benzoic acid.
Preferably, the 2-ethyl benzofuran of terephthalic acid monomethyl ester's correspondence 1.3mmol of every 1mmol.
Preferably, in the mixed solvent of described water, methanol, oxolane, the mass ratio of each component is 1:1:1.
Compared with prior art, the method have the advantages that by 4-(2-Ethyl-benzofuran-3-carbonyl)-
The picked-up experiment of [14] C uric acid and MTT experiment are proved by benzoic acid, and 4-(2-Ethyl-benzofuran-3-carbonyl)-benzoic acid has
Preferably hURAT1 rejection ability and selectivity, toxic and side effects is relatively light simultaneously, promises to be the uricosuric that untoward reaction is lighter
Excretion medicine.
It should be noted that the essence of the present invention or be improved by by select said components or use said components enter
Row preparation, the solution of its technical problem is only dependent upon the selection of component, and the content of component be those skilled in the art according to
Prior art or just be can determine by simple experiment, those skilled in the art carries out simply according to technique scheme
Deriving or experiment just can be achieved, related component does not carries out definition restriction the most in the above description.
Accompanying drawing explanation
The following drawings is only intended to, in schematically illustrating the present invention and explaining, not delimit the scope of the invention.Wherein:
Fig. 1 is that hURAT1 is relatively pressed down compared with inhibitor in prior art (Lesinurad) by inhibitor of the present invention (B-1)
System can be tried hard to；
Fig. 2 is inhibitor of the present invention (B-1) relatively choosing to hURAT1 compared with inhibitor in prior art (Lesinurad)
Selecting property figure.
Detailed description of the invention
Below in conjunction with the accompanying drawings and embodiment, the present invention is expanded on further.In the following detailed description, only by explanation
Mode describes some one exemplary embodiment of the present invention.Undoubtedly, those of ordinary skill in the art will be consequently realised that,
In the case of without departing from the spirit and scope of the present invention, by various different modes, described embodiment can be repaiied
Just.Therefore, accompanying drawing and description are inherently the most illustrative rather than are used for limiting scope of the claims.
A kind of Human Urine hydrochlorate transporter-1 inhibitor (i.e. hURAT1 inhibitor) that can promote urate excretion, described suppression
Agent be 4-(2-Ethyl-benzofuran-3-carbonyl)-benzoic acid be the compound of representative；
Wherein, described 4-(2-Ethyl-benzofuran-3-carbonyl)-benzoic chemical formula is:
The preparation method of above-mentioned inhibitor, comprises the following steps:
Step one, take terephthalic acid monomethyl ester 500mg and be placed in 6ml thionyl chloride, return stirring 6h, remove chlorine under reduced pressure
Change sulfoxide, add 2-ethyl benzofuran 535mg and aluminum chloride 630mg, 24h is stirred at room temperature；Reactant liquor adds frozen water
10ml, stirring stands, and separates organic layer；Add dilute HCl10ml, stirring；Adding distilled water, stirring stands, and separates organic layer；Add
Entering saturated NaCl solution 20ml, stirring stands, and separates organic layer, removes organic solvent under reduced pressure；Silica gel column chromatography separating-purifying obtains
4-(2-Ethyl-benzofuran-3-carbonyl)-essence of Niobe；Productivity is 26%；
Spectral data: MS:m/z 309 ([M+H]+)。1H-NMR(400MHz,CDCl3)δ8.18–8.14(m,2H),7.89–
7.83 (m, 2H), 7.49 (d, J=8.4Hz, 1H), 7.34 7.27 (m, 2H), 7.22 7.15 (m, 1H), 3.97 (s, 3H),
2.91 (q, J=7.6Hz, 2H), 1.34 (t, J=7.6Hz, 3H)；
Step 2,4-(2-Ethyl-benzofuran-3-the carbonyl)-essence of Niobe taking step one prepared are placed in water, first
Alcohol, oxolane mixed solvent (mass ratio 1:1:1) in, add sodium hydroxide 80mg, stirring at normal temperature 12h, remove under reduced pressure
Solvent；Adding distilled water 10ml makes it be completely dissolved, and being slowly added dropwise dilute hydrochloric acid to pH is faintly acid；Addition chloroform 20ml extraction,
Separate, chloroform is evaporated off；Silica gel column chromatography separating-purifying obtains 4-(2-Ethyl-benzofuran-3-carbonyl)-benzoic acid；Productivity is
72%；
Spectral data: MS:m/z 293 ([M-H]-)。1H-NMR(400MHz,MeOD)δ8.10(s,2H),7.79(s,2H),
7.54 (d, J=8.0Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 7.33 (t, J=8.0,7.6Hz, 1H), 7.22 (t, J=
7.6Hz, 1H), 2.87 (q, J=7.6Hz, 2H), 1.33 (t, J=7.6Hz, 3H).13C-NMR(101MHz,CDCl3)δ
191.19,167.46,153.65,143.89,143.84,130.32,129.64,128.87,126.42,124.58,123.72,
122.10,121.22,115.75,115.30,111.06,21.97,12.19；
Wherein, 4-(2-Ethyl-benzofuran-3-carbonyl)-benzoic acid, English language Chemical name: 4-(2-Ethyl-
Benzofuran-3-carbonyl)-benzoic acid, abbreviation: B-1, synthetic route such as following formula:
With reference to Fig. 1 and Fig. 2, by the picked-up experiment of [14] C uric acid and MTT experiment, hURAT1 inhibitor (B-1) of the present invention
With the rejection ability compareing medicine (Lesinurad) phase comparison hURAT1, such as table 1:
Table 1. rejection ability compares
| Medicine name | B-1(10μM) | Lesinurad(10μM) |
| Suppression ratio | 53% | 28% |
It will thus be seen that hURAT1 inhibitor B-1 of the present invention is higher than marketed drug to the inhibition strength of hURAT1
Lesinurad, has preferable hURAT1 rejection ability.
HURAT1 inhibitor (B-1) of the present invention and the selectivity compareing medicine (Lesinurad) phase comparison hURAT1, such as table 2:
Table 2. selectivity ratios is relatively
| Medicine name | B-1 | Lesinurad |
| HURAT1 suppression ratio (10 μMs) | 53% | 28% |
| HOAT1 suppression ratio (20 μMs) | 40% | 31% |
It will thus be seen that hURAT1 inhibitor B-1 of the present invention is to hURAT1 suppression ratio and the ratio height to hOAT1 suppression ratio
In marketed drug Lesinurad, show that B-1 has preferable selectivity to hURAT1.
The foregoing is only the schematic detailed description of the invention of the present invention, be not limited to the scope of the present invention.Any
Those skilled in the art, equivalent variations done on the premise of without departing from the design of the present invention and principle and amendment, all
The scope of protection of the invention should be belonged to.
Claims (4)
1. Human Urine hydrochlorate transporter-1 inhibitor that can promote urate excretion, it is characterised in that: described inhibitor is 4-
(2-Ethyl-benzofuran-3-carbonyl)-benzoic compound or salt or prodrug；
Wherein, described 4-(2-Ethyl-benzofuran-3-carbonyl)-benzoic chemical formula is:
2. the method preparing Human Urine hydrochlorate transporter-1 inhibitor as claimed in claim 1, it is characterised in that include following step
Rapid:
Step one, take terephthalic acid monomethyl ester and be placed in thionyl chloride, return stirring 4～8h, remove thionyl chloride under reduced pressure, add
Enter 2-ethyl benzofuran and aluminum chloride, be stirred at room temperature 20～30h；Adding frozen water in reactant liquor, stirring stands, separates organic
Layer；Add dilute HCl, stirring；Adding distilled water, stirring stands, and separates organic layer；Adding saturated NaCl solution, stirring stands, point
From organic layer, remove organic solvent under reduced pressure；Silica gel column chromatography separating-purifying obtains 4-(2-Ethyl-benzofuran-3-carbonyl)-benzene first
Acid methyl ester；
Step 2, take step one prepare 4-(2-Ethyl-benzofuran-3-carbonyl)-essence of Niobe be placed in water, methanol, four
In the mixed solvent of hydrogen furan, add sodium hydroxide, stirring at normal temperature 10～14h, remove solvent under reduced pressure；Adding distilled water makes it complete
CL, being slowly added dropwise dilute hydrochloric acid to pH is faintly acid；Add chloroform extraction, separate, chloroform is evaporated off；Silica gel column chromatography separates and carries
Pure 4-(2-Ethyl-benzofuran-3-carbonyl)-benzoic acid.
3. the preparation method of Human Urine hydrochlorate transporter-1 inhibitor as claimed in claim 2, it is characterised in that: every 1mmol's
The 2-ethyl benzofuran of terephthalic acid monomethyl ester's correspondence 1.3mmol.
4. the preparation method of Human Urine hydrochlorate transporter-1 inhibitor as described in Claims 2 or 3, it is characterised in that: described water,
Methanol, oxolane mixed solvent in the mass ratio of each component be 1:1:1.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610411507.5A CN106008421A (en) | 2016-06-12 | 2016-06-12 | Human body urate transporter-1 inhibitor capable of promoting uric acid excretion and preparation method thereof |
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| CN201610411507.5A CN106008421A (en) | 2016-06-12 | 2016-06-12 | Human body urate transporter-1 inhibitor capable of promoting uric acid excretion and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4156732A (en) * | 1977-06-21 | 1979-05-29 | Hoechst Aktiengesellschaft | Certain pharmaceutical sulfamoylbenzoyl benzofurans, benzothiophenes, and indoles |
| US5004750A (en) * | 1982-10-19 | 1991-04-02 | Kotobuki Seiyaku Company Limited | Benzofuran and benzothoiphene derivatives, of tetrazole and anti-hyperuricemia use thereof |
| JPH03261778A (en) * | 1990-03-09 | 1991-11-21 | Kotobuki Seiyaku Kk | New benzofuran derivative, uricosuric agent and production thereof |
| CN102718735A (en) * | 2012-05-28 | 2012-10-10 | 沈阳药科大学 | 2-ethyl-3-(4-hydroxy) benzoyl benzofuran compounds and compositions and preparation methods of compounds |
-
2016
- 2016-06-12 CN CN201610411507.5A patent/CN106008421A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4156732A (en) * | 1977-06-21 | 1979-05-29 | Hoechst Aktiengesellschaft | Certain pharmaceutical sulfamoylbenzoyl benzofurans, benzothiophenes, and indoles |
| US5004750A (en) * | 1982-10-19 | 1991-04-02 | Kotobuki Seiyaku Company Limited | Benzofuran and benzothoiphene derivatives, of tetrazole and anti-hyperuricemia use thereof |
| JPH03261778A (en) * | 1990-03-09 | 1991-11-21 | Kotobuki Seiyaku Kk | New benzofuran derivative, uricosuric agent and production thereof |
| CN102718735A (en) * | 2012-05-28 | 2012-10-10 | 沈阳药科大学 | 2-ethyl-3-(4-hydroxy) benzoyl benzofuran compounds and compositions and preparation methods of compounds |
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