CN110105283A - A kind of celecoxib derivative and its preparation method and application - Google Patents
A kind of celecoxib derivative and its preparation method and application Download PDFInfo
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- CN110105283A CN110105283A CN201910444501.1A CN201910444501A CN110105283A CN 110105283 A CN110105283 A CN 110105283A CN 201910444501 A CN201910444501 A CN 201910444501A CN 110105283 A CN110105283 A CN 110105283A
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- China
- Prior art keywords
- formula
- celecoxib
- pharmaceutically acceptable
- acceptable salt
- derivative
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Abstract
Structure celecoxib derivative or its pharmaceutically acceptable salt the invention discloses one kind with formula (I), and its preparation method and application.Compound disclosed by the invention can be used as the substitute of celecoxib, it can exist in the form of hydrate or solvent object, and solving existing celecoxib drug is poorly water soluble drugs, dissolve out bad, the very low problem of body absorption；It analyzes and researches to the structure-activity relationship of celecoxib, it was demonstrated that relative to nitrogen containing derivative, containing the structure of modification such as sulfur derivatives, oxygen ethers, the esterification of alcoholic extract hydroxyl group functional group, celecoxib sulfamide derivative disclosed by the invention, with better medicinal organism activity.
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmaceutical technology field, specifically a kind of celecoxib derivative and preparation method thereof
And purposes.
Background technique
For a long time, people endure the puzzlement of various pain, such as migraine, arthritis to the fullest extent, it was reported that in the U.S., about
There is 1/6 people with various arthritis, wherein osteoarthritis and rheumatoid arthritis are most common and be difficult to eradicate, disability rate
It is quite high.In order to make patient from the torment of inflammation, the various therapeutic agents of clinical application, wherein most common is just non-steroid
Body anti-inflammatory agent (English abbreviation NSAIDs).NSAIDs is applied to clinic 200 for many years, and antipyretic, analgesia, anti-inflammatory effect are
It is widely recognized as clinic, especially as the choice drug of control osteoarthritis and symptoms of rheumatoid arthritis.
Selective COX-2 inhibitor is a kind of new type NS AIDs, because it selectively inhibits COX-2 active, to COX-1 shadow
Sound is smaller, is now widely used in anti-inflammatory, the analgesia therapy of rheumatoid arthritis and osteoarthritis, and working mechanism is COX-2 suppression
Certain functional groups of preparation can be inserted into the hydrophobic pocket formed by COX-2 partial amino-acid residue, bring it about allosteric and lose catalysis
Function, arachidonic acid cannot can not carry out bioconversion, PGs biosynthesis block, resistance by hydrophobic channel under COX-2 catalysis
Broken inflammatory process.
Predominantly two ring classes and the tricyclic compounds of cox 2 inhibitor have been developed at present.Bicyclics compound mainly wraps
Include former times health series derivates, anil, benzsulfamide and sulfonic acid esters, di-t-butyl substituted benzene phenols etc.；Tricyclic antidepressants
Closing object mainly includes heterocycle compound, cyclenes series derivates, triphen series derivates etc..The COX-2 suppression listed at home
In preparation, tricyclic compounds celecoxib is that first of FDA approval is also only one COX-2 selective depressant,
Benzsulfamide structure has higher selectivity to COX-2 receptor, and acts on COX-1 unrestraint；And the aulin of a chain of class,
Meloxicam etc. all has certain inhibiting effect to COX-1.
Celecoxib is white to off-white color crystalline powder, readily soluble in methanol, ethyl alcohol, acetone and dimethyl sulfoxide,
It is almost insoluble in water, almost insoluble in 0.1mol/L hydrochloric acid solution and 0.1mol/L sodium hydroxide solution, fusing point 160.0-
164.0.Celecoxib has good therapeutic effect to arthritis, but celecoxib is poorly water soluble drugs, is dissolved out bad.Mesh
Only Celebret, the body absorption of preceding listing are very low.Therefore, the feasible of exploitation celecoxib derivative is further found
Approach expands its clinical application, to obtain the direction that its effective substitute is this field research.
Summary of the invention
Overall purpose of the invention is to provide a kind of celecoxib derivative, to develop the object with new drug bioactivity
Matter.
The present invention protects a kind of celecoxib derivative or its pharmaceutically acceptable salt with formula (I) structure,
Wherein, R is C1~C4The C that linear or branched alkyl group, hydroxyl replace1~C4Linear or branched alkyl group or C1~C2's
Diamino.
Pharmaceutically acceptable salt is selected from salt, sodium salt, sylvite or magnesium salts.
Preferable compound structure is following six kinds:
The present invention also protects a kind of celecoxib derivative with formula (I) structure or the system of its pharmaceutically acceptable salt
Preparation Method, synthetic route are as follows:
The present invention also protects a kind of pharmaceutical composition, has formula (I) structure celecoxib containing treatment effective dose
Derivative or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or auxiliary material；The optional injection of its dosage form, jelly
Dry or oral solution, preferably injection.
The present invention also protect with formula (I) structure celecoxib derivative or its pharmaceutically acceptable salt as effectively at
Divide for the application in the short drug of preparation treatment postoperative pain.
Celecoxib derivative provided by the invention with formula (I) structure or its pharmaceutically acceptable salt can be with water
The form for closing object or solvent object exists, and no matter any is included within the scope of the present invention.Solvent object as acquisition
Solvent, have methanol, ethyl alcohol, isopropanol, acetone, ethyl acetate, isopropyl ether etc..
The preparation side of celecoxib derivative provided by the invention with formula (I) structure or its pharmaceutically acceptable salt
Method only indicates an example of preparation method, is not limited in the method.Due in a particular embodiment, it being more specifically illustrated
Preparation method, so those skilled in the art, according to the above description with the explanation in specific embodiment, as needed, to this plus
To be appropriately modified, compound or their salt with formula (I) structure can be produced.
Compound disclosed by the invention can be used as the substitute of celecoxib, it can be in the form of hydrate or solvent object
In the presence of solving existing celecoxib drug is poorly water soluble drugs, dissolves out bad, the very low problem of body absorption；Plug is come
The structure-activity relationship of former times cloth is analyzed and researched, it was demonstrated that relative to nitrogen containing derivative, contains sulfur derivatives, oxygen ethers, alcoholic extract hydroxyl group function
The structure of modification such as group's esterification, celecoxib sulfamide derivative disclosed by the invention have better medicinal organism activity.
Specific embodiment
The present invention will be further described in detail below with reference to specific embodiments.The embodiment of the present invention is for example
It is provided with for the sake of description, and is not exhaustively or to limit the invention to disclosed form.Many modifications and change
Change is obvious for the ordinary skill in the art.Selection and description embodiment are to more preferably illustrate this hair
Bright principle and practical application, and make those skilled in the art it will be appreciated that the present invention is suitable for specific use to design
The various embodiments with various modifications on way.
1 chemical compounds I of embodiment1Preparation
100mL dry three-necked flask installs blender, thermometer, is added to fill in thereto and comes former times (95g, 0.249mol)
With dry anhydrous acetonitrile 570mL and potassium carbonate (36g, 0.26mol), stirring；It is slowly added to the second to the methane sulfonyl chloride of 30g
Nitrile solution (60mL, 0.262mmol), is warming up at 75~80 DEG C and reacts 8h, TLC identification terminal (thin-layer developing condition (stone
Oily ether: ethyl acetate=5:1))；End of reaction, reaction solution crystallisation by cooling 2h at 0 DEG C~5 DEG C, filtering, the appropriate second of solid
Nitrile washing, in 65 DEG C~70 DEG C vacuum drying 6h, obtains light yellow crystalline powder shape solid 95g, yield 83.1%, HPLC content
98.9%.Table 1 is chemical compounds I1Elemental analysis.
HPLC method: using octadecylsilane chemically bonded silica as filler, buffer (2.7g/l potassium dihydrogen phosphate phosphoric acid
It is mobile phase, Detection wavelength 215nm, flow velocity 1.5mL/min, column temperature that pH, which is adjusted, as 3.0)-acetonitrile-methanol (60:10:30)
60℃。
Table 1
1H-NMR (500MHz, CH3OH-d3/ TMS):
δH(ppm): 2.379 (3H, s), 2.954 (3H, s), 4.978 (2H, s), 6.739 (1H, s), 7.109 (2H, d, J
=8.0Hz)；7.718 (2H, d, J=8.0Hz)；7.471 (2H, d, J=8.5Hz)；7.898 (2H, d, J=8.5Hz)
MS:m/z:460.4 (M+H)+。
2 chemical compounds I of embodiment1The preparation of sodium salt
100mL three-necked flask is added I1Compound 53g and ethyl alcohol 400mL adds 50% sodium hydroxide solution at room temperature
22mL, 45 DEG C~50 DEG C stirring 30min, 5 DEG C~10 DEG C stand overnight, filtering, the cold ethyl alcohol of solid, and 70 DEG C~75 DEG C of vacuum
It is dry, white crystalline powder shape solid 49.4g, yield: 89.6%, HPLC content 99.6%.
3 chemical compounds I of embodiment2Preparation
Referring to the method for embodiment 1, methane sulfonyl chloride is substituted with ethanesulfonyl chloride, 87g white crystalline solid is made
Close object I2, HPLC content 97.4% (method is with embodiment 1).Table 2 is chemical compounds I2Elemental analysis.
Table 2
1H-NMR (500MHz, CH3OH-d3/ TMS):
δH(ppm): 1.226 (2H, m) 2.379 (3H, s), 3.458 (3H, t, J=7.5Hz；J=1.5Hz, J=
8.0Hz), 4.978 (2H, s), 6.739 (1H, s), 7.109 (2H, d, J=8.0Hz)；7.718 (2H, d, J=8.0Hz)；
7.471 (2H, d, J=8.5Hz)；7.898 (2H, d, J=8.5Hz)
MS:m/z:474.5 (M+H)+。
4 chemical compounds I of embodiment3Preparation
Referring to the method for embodiment 1, methane sulfonyl chloride is substituted with methylol sulfonic acid chloride, 67g white crystalline solid is made
Chemical compounds I3, HPLC content 98.1% (method is with embodiment 1).Table 3 is chemical compounds I3Elemental analysis.
Table 3
1H-NMR (500MHz, CH3OH-d3/ TMS):
δH(ppm): 2.379 (3H, s), 4.978 (2H, s), 5.453 (2H, s), 6.739 (1H, s), 7.109 (2H, d, J
=8.0Hz)；7.718 (2H, d, J=8.0Hz)；7.471 (2H, d, J=8.5Hz)；7.898 (2H, d, J=8.5Hz)
MS:m/z:476.4 (M+H)+。
5 chemical compounds I of embodiment4Preparation
Referring to the method for embodiment 1, methane sulfonyl chloride is substituted with ethoxy sulfonic acid chloride, 23g white crystalline solid is made
Chemical compounds I4, HPLC content 99.0% (method is with embodiment 1).Table 4 is chemical compounds I4Elemental analysis.
Table 4
1H-NMR (500MHz, CH3OH-d3/ TMS):
δH(ppm): 2.379 (3H, s), 3.608 (2H, d, J=7.5Hz)；4.097 (2H, d, J=7.1Hz)；4.978
(2H, s), 6.739 (1H, s), 7.109 (2H, d, J=8.0Hz)；7.718 (2H, d, J=8.0Hz)；7.471 (2H, d, J=
8.5Hz)；(7.898 2H, d, J=8.5Hz)
MS:m/z:490.5 (M+H)+。
6 chemical compounds I of embodiment5Preparation
Referring to the method for embodiment 1, methane sulfonyl chloride is substituted with dimethylaminosulfonyl chloride, it is solid that 32g white crystalline is made
Body chemical compounds I5, HPLC content 96.8% (method is with embodiment 1).Table 5 is chemical compounds I5Elemental analysis.
Table 5
7 chemical compounds I of embodiment6Preparation
Referring to the method for embodiment 1, methane sulfonyl chloride is substituted with lignocaine sulfonic acid chloride, it is solid that 16g white crystalline is made
Body chemical compounds I6, HPLC content 97.6% (method is with embodiment 1).Table 6 is chemical compounds I6Elemental analysis.
Table 6
1H-NMR (500MHz, CH3OH-d3/ TMS):
δH(ppm): 1.066 (6H, t, J=8.0Hz), 2.379 (3H, s), 2.687 (4H, m), 4.978 (2H, s),
6.739 (1H, s), 7.109 (2H, d, J=8.0Hz)；7.718 (2H, d, J=8.0Hz)；7.471 (2H, d, J=8.5Hz)；
7.898 (2H, d, J=8.5Hz)
MS:m/z:517.5 (M+H)+。
8 chemical compounds I of embodiment2The preparation of lithium salts
Referring to the method for embodiment 2, sodium hydroxide is substituted with lithium hydroxide, chemical compounds I has been made2Lithium salts, white crystals
Property solid, yield: 76.3%, HPLC content 99.1%.
9 chemical compounds I of embodiment6The preparation of lithium salts
Referring to the method for embodiment 2, sodium hydroxide is substituted with lithium hydroxide, chemical compounds I has been made6Lithium salts, white crystals
Property solid, yield: 73.4%, HPLC content 98.0%.
Obviously, described embodiment is only a part of the embodiments of the present invention, instead of all the embodiments.It is based on
Embodiment in the present invention, this field and those of ordinary skill in the related art institute without creative labor
The every other embodiment obtained, all should belong to the scope of protection of the invention.
Claims (7)
1. a kind of celecoxib derivative or its pharmaceutically acceptable salt, which is characterized in that celecoxib derivative has formula
(I) structure shown in:
Wherein, R is C1~C4The C that linear or branched alkyl group, hydroxyl replace1~C4Linear or branched alkyl group or C1~C2Diamino
Base.
2. celecoxib derivative according to claim 1 or its pharmaceutically acceptable salt, which is characterized in that R is formula
(Ⅰ1), formula (I2), formula (I3), formula (I4), formula (I5), formula (I6) shown in one of structure, formula (I1), formula (I2), formula (I3), formula
(Ⅰ4), formula (I5), formula (I6) be respectively as follows:
3. celecoxib derivative according to claim 1 or 2 or its pharmaceutically acceptable salt, which is characterized in that medicine
Acceptable salt is lithium salts, sodium salt, sylvite or magnesium salts on.
4. the preparation method of celecoxib derivative described in a kind of claim 1-3 or its pharmaceutically acceptable salt, special
Sign is, synthetic route are as follows:
5. a kind of pharmaceutical composition, which is characterized in that celecoxib described in the claim 1-3 containing treatment effective dose spreads out
Biology or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or auxiliary material.
6. pharmaceutical composition according to claim 5, which is characterized in that its dosage form is injection, freeze-drying, oral solution.
7. celecoxib derivative or its pharmaceutically acceptable salt described in claim 1-3 are controlled as effective component in preparation
Treat the application in the short drug of postoperative pain.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910444501.1A CN110105283A (en) | 2019-05-27 | 2019-05-27 | A kind of celecoxib derivative and its preparation method and application |
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| CN201910444501.1A CN110105283A (en) | 2019-05-27 | 2019-05-27 | A kind of celecoxib derivative and its preparation method and application |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1336602A1 (en) * | 2002-02-13 | 2003-08-20 | Giovanni Scaramuzzino | Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases |
| US20080275053A1 (en) * | 2003-10-08 | 2008-11-06 | Glaxosmithkline | Heterocyclyl Compounds |
-
2019
- 2019-05-27 CN CN201910444501.1A patent/CN110105283A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1336602A1 (en) * | 2002-02-13 | 2003-08-20 | Giovanni Scaramuzzino | Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases |
| US20080275053A1 (en) * | 2003-10-08 | 2008-11-06 | Glaxosmithkline | Heterocyclyl Compounds |
Non-Patent Citations (1)
| Title |
|---|
| MUHAMMAD ABDUL QADIR ET AL.,: "Synthesis, characterization, and antibacterial activities of novel sulfonamides derived through condensation of amino group containing drugs,amino acids, and their analogs", 《BIOMED RESEARCH INTERNATIONAL》 * |
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Application publication date: 20190809 |
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