CN1312149C - Bucillamine synthesizing novel intermediate 5,5-dimethyl-2-thione-4-one-1-sulfur-3-oxy-hetero pentocyclic - Google Patents
Bucillamine synthesizing novel intermediate 5,5-dimethyl-2-thione-4-one-1-sulfur-3-oxy-hetero pentocyclic Download PDFInfo
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- CN1312149C CN1312149C CNB021576653A CN02157665A CN1312149C CN 1312149 C CN1312149 C CN 1312149C CN B021576653 A CNB021576653 A CN B021576653A CN 02157665 A CN02157665 A CN 02157665A CN 1312149 C CN1312149 C CN 1312149C
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- VUAFHZCUKUDDBC-SCSAIBSYSA-N (2s)-2-[(2-methyl-2-sulfanylpropanoyl)amino]-3-sulfanylpropanoic acid Chemical compound CC(C)(S)C(=O)N[C@H](CS)C(O)=O VUAFHZCUKUDDBC-SCSAIBSYSA-N 0.000 title claims abstract description 17
- 229960004272 bucillamine Drugs 0.000 title claims abstract description 17
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- ZOOODBUHSVUZEM-UHFFFAOYSA-N ethoxymethanedithioic acid Chemical compound CCOC(S)=S ZOOODBUHSVUZEM-UHFFFAOYSA-N 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 4
- 101150065749 Churc1 gene Proteins 0.000 description 4
- 102100038239 Protein Churchill Human genes 0.000 description 4
- VLSOAXRVHARBEQ-UHFFFAOYSA-N [4-fluoro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=C(F)C=C1CO VLSOAXRVHARBEQ-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- FAYOCELKCDKZCA-UHFFFAOYSA-N 5-hydroxy-2,4-dimethylthiophen-3-one Chemical group CC1SC(O)=C(C)C1=O FAYOCELKCDKZCA-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 206010011778 Cystinuria Diseases 0.000 description 1
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 208000000857 Hepatic Insufficiency Diseases 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000032825 Ring chromosome 2 syndrome Diseases 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
The present invention relates to 5, 5-dimethyl-2-thione-4-1-sulfur-3-oxy-hetero hetero pentocyclic as a new intermediate body for synthesizing Bucillamoine and the preparation thereof. The Bucillamine is synthesized by the intermediate body of the present invention, and the obtained intermediate body has advantages of stability, convenient and simple synthesis, high yield and low cost.
Description
Technical field:
It is synthetic to the present invention relates to medicine, is specifically related to the intermediate 5 of synthetic Bucillamine, 5-dimethyl-2-thioketones-4-ketone-1-sulphur-3-oxygen-assorted penta ring and preparation thereof.
Background technology:
Bucillamine (III) be a kind ofly be used for the treatment of chronic rheumatoid arthritis, reduce phlegm, the medicine of hepatic insufficiency inhibitor, report is also arranged, and it can be used for the treatment of various diseases that cystinuria is caused.Find that in the recent period Bucillamine can induce the generation of peroxy radical (ROS), the apoptosis cancer cells may have antitumous effect.This medicine is similar to the Trolovol effect, but than latter's curative effect height, toxic side effect is little.
Bucillamine delivers the structure patent by Germany at first, then by Japanese trituration, goes on the market in Japan.Its main synthesis technique has two pieces of patent reports, JP 54-63017 and US 4,305,958.
The synthetic route of I, US 4,305,958 reports is:
a)
Above-mentioned starting raw material SHCH
2C
6H
5The cost height; intermediate (IV) is an oily matter; difficult purifying, the palpus column chromatography for separation, as be made into sodium salt; filtration difficulty; dry to moisture less than 0.5% unusual difficulty, and next step makes Bucillamine with sloughing protecting group under the liquefied ammonia/Na ,-40 ℃, needs cyrogenic equipment; energy consumption is big, unsuitable industrialized production.Above-mentioned route yield is low, crude product purity is low about 70%, make salable product after, the cost height.
II, JP 54-63017 patent report synthetic route be:
Because the NaSH instability is difficult to preserve, and H
2S gas toxicity is big, and above-mentioned route is unfavorable for suitability for industrialized production.And the very easily oxidation of above-mentioned intermediate V that makes should not be preserved, and needs to make condensing agent with DCC in synthesis technique, and price is expensive.Be condensed into [SC (CH
3)
2CO-]
nIntermediate is extremely unstable, and difficult quality control is final with [SC (CH
3)
2CO-]
nBe condensed into Bucillamine (III) with L-cysteine hydrochloride (VI), it is very low to obtain product yield, and content in crude product is low about 70%, thereby the cost height.
All there is the cost height in above-mentioned two synthesis routes, and preparation intermediate difficulty height is not suitable for reasons such as suitability for industrialized production.
Summary of the invention:
Technical problem to be solved by this invention is the intermediate of employing I compound as synthetic Bucillamine, provides an intermediate to stablize, synthesize the synthetic Bucillamine route conveniently easy, that yield is high, cost is low.
Intermediate disclosed by the invention has the structure of following formula I:
R wherein
1, R
2Be respectively hydrogen or C
1-C
4Alkane; Ia is R
1=CH
3, R
2=CH
3
Formula I compound of the present invention can obtain by the following formula reaction, and reaction formula is as follows:
Formula I compound gets a-bromo alkanoic acid (2) by rudimentary alkanoic acid of a-hydrogen (1) and bromine reaction, gets a-oxyethyl group xanthogen alkanoic acid (3) with the xanthogenic acid nak response again, and cyclization makes Compound I under the sulfur oxychloride condition at last.
Formula I compound is at R
1=CH
3, R
2=CH
3The time be 5,5-dimethyl-2-thioketones-4-ketone-1-sulphur-3-oxygen-assorted penta ring (Ia), Ia and the condensation of L-halfcystine, acquisition Bucillamine (III), reaction formula is as follows:
It is raw material and bromine reaction that this up-to-date style Ia compound adopts isopropylformic acid, get a-bromo acid (2), get a-oxyethyl group xanthogen isopropylformic acid (3) with the xanthogenic acid nak response, cyclization becomes 5 under the sulfur oxychloride condition at last, 5-dimethyl-1-sulphur-3-oxygen-assorted penta ring-2-sulfo-ketone-4-ketone (Ia).Intermediate a-oxyethyl group xanthogen isopropylformic acid (3) is preparation easily, and stable in properties, the purity height, and HPLC content is greater than 99%.Use SOCl
2Make form and the L-halfcystine condensation of compound (I) with oxyethyl group xanthogen formation thiolactone ring protection sulfydryl, thiolactone ring protection base can come off voluntarily during reaction, reduces the deprotection reaction step.The all control easily of each step reaction conditions of synthetic method of the present invention, the product yield height (about 70%) that obtains, the about 80-90% of content in crude product, easily purifying.
On the other hand, because L-halfcystine raw material need not be gone up protecting group, also reduced the first protecting group that goes up, the step of back deprotection reaction is simplified technology, and simplified apparatus reduces cost simultaneously.After suitability for industrialized production, cost is low, and end product quality HPLC is about 99%, and optically-active+33-+36.5 °, fusing point 13
7-140 ℃ etc., meet documentation standards.
Formula I compound of the present invention also can make a series of amino acid derived compounds with each seed amino acid reaction, and reaction formula is as follows:
R wherein
1=CH
3, C
2H
5, C
3H
7
R
2=H,CH
3,C
2H
5
R
3=-CH
2CH
2SH,>C (CH
3)
2,>CHCH
2CH
3>CHCH
2C
6H
4Cl ,-CH
2CH
2-,>CHCH
2C
6H
11,>CHCH (CH
3)
2, etc.
Description of drawings:
Fig. 1, Compound I a mass spectrum MS:162
Fig. 2, Compound I a infrared spectrogram
Fig. 3, Compound I a700-4000cm
-1The zone infrared spectrogram
Embodiment:
Example 1.5, the preparation of 5-dimethyl-2-thioketones-4-ketone-1-sulphur-3-oxygen-assorted penta ring (I)
1, the preparation of a-bromo acid (2)
Add the 25.0g isopropylformic acid to the exsiccant reaction flask, suck the 2.5g phosphorus tribromide under the room temperature, be warming up between 110-120 ℃, from dropping funnel, drip bromine 46.5g, add the back and continue reaction 3 hours, detect isopropylformic acid less than 2% o'clock, react completely with GC.Underpressure distillation gets the a-bromo acid, and weighing gets 45kg, yield about 94.85%.M.P.42-43℃?GC>95%
2, the preparation of a-oxyethyl group xanthogen (3)
In reaction flask, add 250g water, stir adding 200g potassium ethyl xanthonate down, dissolving.Add 100g a-bromo acid and 50gK2CO3, reacted 6 hours, reaction finishes.With 60g petroleum ether extraction three times, water layer is regulated pH3.5 with the about 80mL of dense HCl, and crystallization is separated out, and gets rid of filter.Wet product steep with the 60g sherwood oil to be washed, dry 75g a-oxyethyl group xanthogen isopropylformic acid.
M.P.108-110℃?HPLC>99%
3,5, the preparation of 5-dimethyl-2-thioketones-4-ketone-1-sulphur-3-oxygen-assorted penta ring (Ia)
The toluene that adds 30g in reactor stirs the a-oxyethyl group xanthogen isopropylformic acid that adds 5.5g down, dissolving.Under the room temperature condition, the sulfur oxychloride of suction 3.8g stirred after 4 hours, and with GC side transformation efficiency, GC content 97% is reacted to terminal point, and calculated amount gets 4.28g.
G.C.>97%, MS:162, infrared spectra is seen Fig. 2, Fig. 3, mass spectrum is seen Fig. 1.
The preparation of example 2.Bucillamine (III)
Add the water of 20.0g and the L-cysteine hydrochloride of 6.0g in reactor, dissolving adds 30% sodium hydroxide 9.1g, and solution is alkalescence, pH9-9.5.Slowly add the Compound I that example 1 makes, reaction is to complete.It is extremely acid that the layer of fetching water is regulated pH with hydrochloric acid, uses ethyl acetate extraction 3 times, merges organic layer, is evaporated to solid and separates out, and filter is got rid of in cooling, gets the 4g dry product, crude product yield 69.62%, and content (HPLC) is 90%.Content behind the recrystallization (HPLC) is 99.08%.
M.P.137-140 ℃ optically-active+34-+36 °
Example 3.5, the preparation of 5-dimethyl-2-thioketones-4-ketone-1-sulphur-3-oxygen-assorted penta ring (Ia)
1, the preparation of a-bromo acid (2)
Take out the 250Kg isopropylformic acid to the exsiccant reactor, suction 25Kg phosphorus tribromide under the room temperature is warming up between 110-120 ℃, drips bromine 465Kg from header tank, adds the back and continues reaction 3 hours, detects isopropylformic acid less than 2% o'clock with GC, reacts completely.Underpressure distillation gets the a-bromo acid, and weighing gets 440kg yield about 92.7%.
2, the preparation of a-oxyethyl group xanthogen (3)
In reactor, add 250Kg water, stir adding 200Kg potassium ethyl xanthonate down, dissolving.Add 100Kg a-bromo acid and 50Kg K
2CO
3, to react 6 hours, reaction finishes.With 60Kg petroleum ether extraction three times, water layer is regulated pH3.5 with the about 80L of dense HCl, and crystallization is separated out, and gets rid of filter.Wet product steep with the 60Kg sherwood oil to be washed, dry 70Kg a-oxyethyl group xanthogen isopropylformic acid.
3,5, the preparation of 5-dimethyl-2-thioketones-4-ketone-1-sulphur-3-oxygen-assorted penta ring (Ia)
The toluene that adds 300Kg in reactor stirs the a-oxyethyl group xanthogen isopropylformic acid that adds 55kg down, dissolving.Under the room temperature condition, the sulfur oxychloride of suction 38Kg stirred after 4 hours, and with GC side transformation efficiency, GC content 95% is reacted to terminal point, calculates 40.69Kg.
The preparation of example 4, Bucillamine (III)
Add the water of 200Kg and the L-cysteine hydrochloride of 60Kg in reactor, dissolving adds 30% sodium hydroxide 91Kg, and solution is alkalescence, pH9-9.5.Slowly add the Compound I that above-mentioned example 2 makes, reaction is to complete.It is extremely acid that the layer of fetching water is regulated pH with hydrochloric acid, uses ethyl acetate extraction 3 times, merges organic layer, is evaporated to solid and separates out, and filter is got rid of in cooling, gets the 40Kg dry product, crude product yield 69.32%, and content (HPLC) is 85%.Content behind the recrystallization (HPLC) is 99.13%.
Example 5.
1, the preparation of a-bromo acid (2)
Take out the 250Kg isopropylformic acid to the exsiccant reactor, suction 25Kg phosphorus tribromide under the room temperature is warming up between 110-120 ℃, drips bromine 465Kg from header tank, adds the back and continues reaction 3 hours, detects isopropylformic acid less than 2% o'clock with GC, reacts completely.Underpressure distillation gets the a-bromo acid, and weighing gets 442kg yield about 93.16%.
2, the preparation of a-oxyethyl group xanthogen (3)
In reactor, add 250Kg water, stir adding 200Kg potassium ethyl xanthonate down, dissolving.Add 100Kg a-bromo acid and 50Kg K
2CO
3, to react 6 hours, reaction finishes.With 60Kg petroleum ether extraction three times, water layer is regulated pH3.5 with the about 80L of dense HCl, and crystallization is separated out, and gets rid of filter.Wet product steep with the 60Kg sherwood oil to be washed, dry 72.5Kg a-xanthogenic acid base isopropylformic acid.
3,5, the preparation of 5-dimethyl-2-thioketones-4-ketone-1-sulphur-3-oxygen-assorted penta ring (Ia)
The toluene that adds 300Kg in reactor stirs the a-xanthogenic acid base isopropylformic acid that adds 55kg down, dissolving.Under the room temperature condition, the sulfur oxychloride of suction 38Kg stirred after 4 hours, and with GC side transformation efficiency, GC content 96% is reacted to terminal point, calculates 41Kg.
4, the preparation of Bucillamine (III)
Add the water of 200Kg and the L-cysteine hydrochloride of 60Kg in reactor, dissolving adds 30% sodium hydroxide 91Kg, and solution is alkalescence, pH9-9.5.Slowly add above-mentioned cyclocomplex, reaction is to complete.The layer of fetching water is regulated pH to acid with hydrochloric acid, uses ethyl acetate extraction 3 times, merges organic layer, is evaporated to solid and separates out, and filter is got rid of in cooling, the 38Kg dry product, and crude product yield 67%, content (HPLC) is 88%.Content behind the recrystallization (HPLC) is 99.16%.
Claims (5)
2, a kind of compound as claimed in claim 1 is characterized in that wherein R
1=CH
3, R
2=CH
3
3, a kind of preparation method of compound as claimed in claim 1 or 2, it is characterized in that this compound is by rudimentary alkanoic acid of a-hydrogen and bromine reaction, get a-bromo alkanoic acid, get a-oxyethyl group xanthogen alkanoic acid with the xanthogenic acid nak response again, cyclization makes under the sulfur oxychloride condition at last.
4, a kind of application of compound as claimed in claim 1 or 2 is characterized in that this compound can be used for the synthetic of Bucillamine.
5, a kind of application as claimed in claim 4 is characterized in that described compound and the condensation of L-halfcystine, and reaction obtains Bucillamine.
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CNB021576653A CN1312149C (en) | 2002-12-23 | 2002-12-23 | Bucillamine synthesizing novel intermediate 5,5-dimethyl-2-thione-4-one-1-sulfur-3-oxy-hetero pentocyclic |
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CNB021576653A CN1312149C (en) | 2002-12-23 | 2002-12-23 | Bucillamine synthesizing novel intermediate 5,5-dimethyl-2-thione-4-one-1-sulfur-3-oxy-hetero pentocyclic |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4305958A (en) * | 1976-03-08 | 1981-12-15 | Santen Pharmaceutical Co., Ltd. | Cysteine derivatives |
WO2000078305A1 (en) * | 1999-06-21 | 2000-12-28 | Santen Pharmaceutical Co., Ltd. | Remedies for arthrosis deformans |
-
2002
- 2002-12-23 CN CNB021576653A patent/CN1312149C/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4305958A (en) * | 1976-03-08 | 1981-12-15 | Santen Pharmaceutical Co., Ltd. | Cysteine derivatives |
WO2000078305A1 (en) * | 1999-06-21 | 2000-12-28 | Santen Pharmaceutical Co., Ltd. | Remedies for arthrosis deformans |
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Granted publication date: 20070425 Termination date: 20101223 |