CN101362751A - Tandospirone citrate, preparation method thereof, formulations and quality control method - Google Patents
Tandospirone citrate, preparation method thereof, formulations and quality control method Download PDFInfo
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- CN101362751A CN101362751A CNA2008101350897A CN200810135089A CN101362751A CN 101362751 A CN101362751 A CN 101362751A CN A2008101350897 A CNA2008101350897 A CN A2008101350897A CN 200810135089 A CN200810135089 A CN 200810135089A CN 101362751 A CN101362751 A CN 101362751A
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- heptane
- cis
- dicarboximides
- tandospirone
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- CEIJFEGBUDEYSX-FZDBZEDMSA-N tandospirone Chemical compound O=C([C@@H]1[C@H]2CC[C@H](C2)[C@@H]1C1=O)N1CCCCN(CC1)CCN1C1=NC=CC=N1 CEIJFEGBUDEYSX-FZDBZEDMSA-N 0.000 title claims abstract description 104
- 229950000505 tandospirone Drugs 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 238000003908 quality control method Methods 0.000 title claims abstract description 7
- 239000000203 mixture Substances 0.000 title claims description 5
- 238000009472 formulation Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- NLYIQTFGJPERCS-UHFFFAOYSA-N 3-butyl-4-methylpyrrolidine-2,5-dione Chemical class CCCCC1C(C)C(=O)NC1=O NLYIQTFGJPERCS-UHFFFAOYSA-N 0.000 claims description 55
- 238000000034 method Methods 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 14
- 230000007704 transition Effects 0.000 claims description 13
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 12
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 10
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 10
- 238000000967 suction filtration Methods 0.000 claims description 9
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 238000001514 detection method Methods 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 7
- 239000000377 silicon dioxide Substances 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 150000001412 amines Chemical group 0.000 claims description 6
- 150000004678 hydrides Chemical class 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims description 5
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- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
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- XUKLTPZEKXTPBT-UHFFFAOYSA-N 3-oxatricyclo[5.2.1.01,5]dec-5-ene-2,4-dione Chemical compound C1CC2C=C3C(=O)OC(=O)C13C2 XUKLTPZEKXTPBT-UHFFFAOYSA-N 0.000 claims description 3
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
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- 239000003054 catalyst Substances 0.000 claims 1
- 238000012360 testing method Methods 0.000 abstract description 22
- 230000000694 effects Effects 0.000 abstract description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 abstract description 4
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- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract 2
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- 208000019901 Anxiety disease Diseases 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
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- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 3
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides citrate tandospirone which is characterized by comprising a compound I with the weight percent content not more than 0.5 percent and a compound II with the weight percent content not more than 0.5 percent. The structure formulas of the compound I and the compound II are as the right formulas. The invention also provides a preparation method and a quality control method of the citrate tandospirone. The results of a pharmacodynamic test and clinical observation show that after the quality standard of the citrate tandospirone is improved, the effect of clinical antianxiety is obviously improved and untoward effect is obviously reduced.
Description
Technical field
The present invention relates to SM-3997, particularly, relate to highly purified SM-3997, belong to pharmaceutical field.
Background technology
Tandospirone belongs to spiral shell ketone medicine, is the 5-HT receptor stimulant, and it is highly selected and 5-HT
1AReceptors bind.5-HT
1AAcceptor mainly concentrate on hippocampus, in cerebral limbic system such as, interpeduncular nucleus, amygdala and seam gland nuclear.The 5-HT of the exciting postsynaptic membrane of Tandospirone selectivity.Suppress hyperfunction serotonin energy nervous activity, make the 5-HT of 5-HT and postsynaptic membrane
1AAnd 5-HT
2AThe combination of the acceptor state that restores balance, thereby performance angst resistance effect, the side reaction such as of flaccid muscles, anticonvulsion that does not produce the benzodiazepines anxiolytic medicament.The preclinical test data show that the angst resistance effect and the diazepam of Tandospirone are close, and toxic side effect such as infringement of nervimotion sexual function and drug abuse are littler than diazepam.Tandospirone also has certain antidepressant effect, therefore can bring into play better effect for the patient who is mixed with anxiety and depression.Preclinical study shows that Tandospirone is higher than the angst resistance effect selectivity of its original shape medicine azaspiro ketone and buspirone, and potential applicability in clinical practice is better.In a research, there are 202 routine patients (having anxiety or depressed mental symptom respectively) to accept the treatment of various dose Tandospirone (7.5mg/d, 15mg/d, 30mg/d and 60mg/d), continued for 4 weeks.Moderate or significant improvement comprehensively appear in 4 dosage group patients, and ratio is followed successively by 29%, 19%, 33% and 46%, in addition behind two groups of patient undergoing treatments of 30mg/d and 60mg/d.There are 45.8% various mental symptoms of patient moderate to occur or significantly improve.The anxiety effect that patient accepts Tandospirone 30mg/d or 60mg/d is gratifying.
The security of Tandospirone (comprising SM-3997) is relatively good, and adverse reaction rate is low, and degree is light.In 1451 routine patients, there are 150 examples (10.3%) untoward reaction to occur.Main adverse reactions has drowsiness 43 examples (3.0%), 16 examples of lurching (1.1%), 13 examples (0.9%) of feeling sick, taediumvitae 11 examples (0.8%), unhappy 11 examples (0.8%), appetite descend 10 examples (0.7%).Cause the reason of above-mentioned untoward reaction still not have the pertinent literature report at present, therefore, in order to protect the security of Tandospirone, the quality of strict control SM-3997 is very necessary.
The synthetic method of Tandospirone is seen US4507303, and US4818756, JP60087262 etc. all have report.But its synthetic method is compared with this patent, its production cost height, and yield is low, is unfavorable for scale operation.
Still useless at present cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides and quaternary amine carry out the synthetic method of condensation prepared Tandospirone, do not use succinimide and cyclopentadiene to react the synthetic method that cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides are made in hydrogenation more yet, do not have the high purity of use cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides yet and prepare the report of high purity Tandospirone, more do not have and adopt the HPLC method not transition of cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides in cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides and cis-outer-two ring [2.2.1] heptane-analysis of 2.3-dicarboximide and the reports of quality control that do not reduce, there is not in the synthesis technique of Tandospirone composition about impurity yet, the relevant report of structure and character does not have the drug effect of concrete which kind of impurity to Tandospirone yet, the relevant report of Safety Effect.
Summary of the invention
Technical scheme of the present invention has provided a kind of SM-3997, and the present invention also provides the preparation method and the quality controlling means of SM-3997.
The invention provides a kind of SM-3997, the weight percentage that it contains Compound I must not be higher than 0.5%, and the weight percentage that contains Compound I I must not be higher than 0.5%, and the structural formula of Compound I, II is:
Compound I Compound I I.
Compound I I is the enantiomer of Tandospirone, chemistry (3e α, 4 β, 7 β, 7e α)-six hydrogen-2-[4-(2-pyrimidyl) by name-1-(piperidyl)-butyl]-4,7-methylene radical-1H-isoindole-1,3 (2H)-diketone citrate.
Further preferably, the weight percentage that it contains Compound I is: 0%-0.3%, the weight percentage that contains Compound I I is: 0%-0.3%.
Further preferably, the weight percentage that it contains Compound I is: 0-0.1%, the weight percentage that contains Compound I I is: 0-0.1%.
Can be further preferably, the weight percentage that it contains Compound I is: 0.04-0.31%, the weight percentage that contains Compound I I is: 0.05-0.29%.
SM-3997 of the present invention, its HPLC chromatogram as shown in Figure 1, by at least one characteristic peak, the appearance time of this characteristic peak is: 9.513-9.857min, and the chromatographic condition of high performance liquid chromatography is: with octadecylsilane chemically bonded silica is weighting agent; 0.01mol/L potassium dihydrogen phosphate-acetonitrile (60 ± 5:40 ± 5) is a moving phase; The detection wavelength is 243nm, and number of theoretical plate calculates by the Tandospirone peak should be not less than 5000.
Further, the HPLC color atlas also contains two characteristic peaks, go out the peak respectively condition be: 6.342-6.608min, 7.835-8.082min.But in concrete testing process, because of the difference of used equipment, operator, environment, its appearance time may occur in advance or postpone situation about 1min.
The present invention also provides a kind of pharmaceutical composition antianxity, and it is that SM-3997 by described significant quantity is an activeconstituents, adds the medicament that acceptable accessories or complementary composition are prepared from.
Wherein, described medicament is an oral preparations.Described oral preparations is tablet, capsule or granule etc.
The present invention also provides the method for preparing described SM-3997, and it comprises the steps:
Following compound is called for short quaternary ammonium salt
Wherein
Represent Cl
-, Br
-, I
-, CH
3SO
3 -
With cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides, quaternary amine mol ratio is 1: 1, N, and dinethylformamide, Anhydrous potassium carbonate join in the reactor, are incubated 113-157 ℃ of stirring reactions 5-10 hours.Reaction finishes, and reaction solution is cooled to and slowly adds under the stirring at room in the entry, fully stirs again, leaves standstill suction filtration, filter cake water thorough washing; With the filter cake acetic acid ethyl dissolution, add the hydrochloric acid soln acidifying, to pH2-3, tell acid solution, it is an amount of to add gac in acid solution, fully stirs, and cold decolouring is filtered; Filtrate uses the sodium hydroxide solution adjust pH to 10-11, produces the off-white color precipitation, stirs, leave standstill, and suction filtration, filtrate is reclaimed, and filter cake washs with tap water, drains, and gets Tandospirone alkali, through the Citric Acid salify, obtains SM-3997; Wherein, described cis-[2.2.1] heptane-2.3-dicarboximide purity must not be less than 99.0% for outer-two rings.
Cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides and specific quaternary ammonium salts condensation get Tandospirone alkali, get the SM-3997 crude product with the Citric Acid salify in ethanol solution, carry out recrystallization with dehydrated alcohol and get finished product.
Cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides also can be obtained by following two kinds of methods:
A、
By norbornene dicarboxylic anhydride 190-210 ℃ make the transition transition thing, transition, thing was that hydrogenation gets hydride under the condition of catalyzer at palladium carbon, hydride makes cis-outer-two through the ammoniacal liquor ammonification and encircles [2.2.1] heptane-2.3-dicarboximides.
B、
With the reaction of maleimide and cyclopentadiene, get required article by crystallization process with single-minded configuration, promptly get the cis-outer-two for preparing Tandospirone alkali through hydrogenation again and encircle [2.2.1] heptane-2.3-dicarboximides.
Encircle under the purity of [2.2.1] heptane-2.3-dicarboximides in strictness control cis-outer-two, can be prepared into the SM-3997 that meets requirement of the present invention.
The control of purity method of cis provided by the invention-outer-two ring [2.2.1] heptane-2.3-dicarboximides is:
Purity is measured according to " high performance liquid chromatography working specification ".
Chromatographic condition and system suitability test are weighting agent with octadecylsilane chemically bonded silica; 0.01mol/L (regulating pH to 7.5 with 10% sodium hydroxide solution)-acetonitrile (80:20) is a moving phase to potassium dihydrogen phosphate; The detection wavelength is 243nm.Number of theoretical plate calculates and should be not less than 1500 by cis-outer-two ring [2.2.1] heptane-2.3-dicarboximide peaks.
Assay method is got the about 0.1g of this product, puts in the 10ml measuring bottle, adds the moving phase dissolving, and is diluted to scale, shakes up, as need testing solution; Precision is measured each 20 μ l of need testing solution, injects liquid chromatograph respectively, and the record color atlas is to 2 times of principal constituent peak retention time.
Calculate by area normalization method, the impurity of RRT=0.43 must not be greater than 0.5%; The impurity of RRT=0.65 (the unreduced cis that do not make the transition-outer-two ring [2.2.1] heptane-2.3-dicarboximides) must not be greater than 0.1%; The impurity of RRT=0.78 (the as-reduced cis that do not make the transition-outer-two ring [2.2.1] heptane-2.3-dicarboximides) must not be greater than 0.30%; The impurity of RRT=0.87 (the unreduced cis that makes the transition-outer-two ring [2.2.1] heptane-2.3-dicarboximides) must not be greater than 0.4%; Cis-[2.2.1] heptane-2.3-dicarboximide purity must not be less than 99.0% for outer-two rings.
The present invention also provides a kind of method of controlling described SM-3997, and it is to be index components with Compound I, Compound I I, carries out quality control.
Quality controlling means of the present invention, it is that chromatographic condition is: with octadecylsilane chemically bonded silica is weighting agent according to high effective liquid chromatography for measuring; 0.01mol/L potassium dihydrogen phosphate-acetonitrile (volume ratio is 60 ± 5:40 ± 5) is a moving phase; The detection wavelength is 243nm, and number of theoretical plate calculates by the Tandospirone peak should be not less than 5000.
The contriver studies the related substance of SM-3997 in process of production, find in the related substance that an impurity is intermediate as-reduced cis-outer-two ring impurity that [2.2.1] heptane-the 2.3-dicarboximide produces that do not make the transition in the synthesis technique, be an isomer of SM-3997, called after isomer B (Compound I I).In synthesis technique, exist all the time, only cis-outside in-two ring [2.2.1] heptane-2.3-dicarboximide quality the strict control as-reduced cis-outer-two that do not make the transition encircle [2.2.1] heptane-2.3-dicarboximide limits, impurity isomer B be can control to minimum.And another impurity (this impurity be in the synthesis technique intermediate both failed the transition, the impurity of failing the cis that is reduced-outer-two ring [2.2.1] heptane-2.3-dicarboximides again and producing, called after impurity A (Compound I) is similarly the impurity that produces in the synthesis technique, its content is very low, only cis-outside in-two ring [2.2.1] heptane-2.3-dicarboximide quality standards the strict control unreduced cis-outer-two that do not make the transition encircle [2.2.1] heptane-2.3-dicarboximide limits, could control impurity A (Compound I).By test, find that isomer B and impurity A are the impurity that must produce in synthetic this product process, and can influence the drug effect and the side effect of SM-3997, and only total impurities be limited the amount of any impurity of not concrete quantitatively restriction in the proper mass standard.Be the better quality of control SM-3997, the contriver has also carried out confirming and the research of limiting the quantity of to impurity isomer B and impurity A, has determined limiting the quantity of of impurity isomer B and impurity A according to many batches of big production samples.The result shows that SM-3997 is after the standard that improves the quality, and clinical effect antianxity is significantly increased, and untoward reaction has tangible reduction.
Description of drawings
Fig. 1 SM-3997 (lot number 060101) color atlas;
Fig. 2 SM-3997 (lot number 060101) own control color atlas (contrast solution in the measuring method reaches and is own control);
Fig. 3 SM-3997 (lot number 060102) color atlas;
Fig. 4 SM-3997 (lot number 060102) own control color atlas;
Fig. 5 SM-3997 (lot number 060103) color atlas;
Fig. 6 SM-3997 (lot number 060103) own control color atlas;
Fig. 7 SM-3997 (lot number 060401) color atlas;
Fig. 8 SM-3997 (lot number 060401) own control color atlas;
Fig. 9 SM-3997 (lot number 060402) color atlas;
Figure 10 SM-3997 (lot number 060402) own control color atlas.
Figure 11 cis-outer-two ring [2.2.1] heptane-2.3-dicarboximide (lot number 060101) purity color atlass
Figure 12 cis-outer-two ring [2.2.1] heptane-2.3-dicarboximide (lot number 060102) purity color atlass
Figure 13 cis-outer-two ring [2.2.1] heptane-2.3-dicarboximide (lot number 060103) purity color atlass
Figure 14 cis-outer-two ring [2.2.1] heptane-2.3-dicarboximide (lot number 060104) purity color atlass
Embodiment
The preparation of embodiment 1 cis of the present invention-outer-two ring [2.2.1] heptane-2.3-dicarboximides
By norbornene dicarboxylic anhydride 190-210 ℃ make the transition transition thing, transition, thing was that hydrogenation gets hydride under the condition of catalyzer at palladium carbon, hydride makes cis-outer-two through the ammoniacal liquor ammonification and encircles [2.2.1] heptane-2.3-dicarboximides.
The another kind of embodiment 2 cis of the present invention-outer-two ring [2.2.1] heptane-2.3-dicarboximides prepares scheme:
In 97g maleimide adding reaction flask, add the 1000ml ethyl acetate, stir and make its dissolving, add the 93g cyclopentadiene, stirred 24 hours, pressure reducing and steaming 75% solvent filters, and with an amount of ether washing leaching cake, gets particular configuration thing 163g, yield about 86%.Particular configuration thing 163g is dissolved among the 2500ml THF, adds the 5% palladium charcoal of 163g cyclohexene and 5g, feed hydrogen under greater than the 0.01MPa situation at pressure, reactant backflow 9h, after the cooling, the pressure reducing and steaming solvent, residue gets product 161g with the toluene recrystallization, yield about 98%.The purity of the cis that makes of method-outer-two ring [2.2.1] heptane-2.3-dicarboximides meet the specification of quality of the described high purity cis of this patent-outer-two ring [2.2.1] heptane-2.3-dicarboximides thus.
The quality controlling means of embodiment 3 cis of the present invention-outer-two ring [2.2.1] heptane-2.3-dicarboximides
Cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides of embodiment 1,2 preparations are carried out quality determination.
Cis-outer-two ring [2.2.1] heptane-2.3-dicarboximide purity testings are measured according to " high performance liquid chromatography working specification ".
Chromatographic condition and system suitability test are weighting agent with octadecylsilane chemically bonded silica; 0.01mol/L (regulating pH to 7.5 with 10% sodium hydroxide solution)-acetonitrile (80:20) is a moving phase to potassium dihydrogen phosphate; The detection wavelength is 243nm.Number of theoretical plate calculates and should be not less than 1500 by cis-outer-two ring [2.2.1] heptane-2.3-dicarboximide peaks.
Assay method is got cis-outer-two ring [2.2.1] heptane-about 0.1g of 2.3-dicarboximide, puts in the 10ml measuring bottle, adds the moving phase dissolving, and is diluted to scale, shakes up, as need testing solution; Precision is measured each 20 μ l of need testing solution, injects liquid chromatograph respectively, and the record color atlas is to 2 times of principal constituent peak retention time.
Calculate by area normalization method, the impurity of RRT=0.43 must not be greater than 0.5%; The impurity of RRT=0.65 must not be greater than 0.1%; The impurity of RRT=0.78 must not be greater than 0.30%; The impurity of RRT=0.87 must not be greater than 0.4%; Cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides must not be less than 99.0%.
Get cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides by embodiment 1, the preparation of embodiment 2 methods, lot number is: 060101,060102,060103,060104, detect as stated above, and the results are shown in Table 2, Figure 11-14.
Table 2 cis-outer-two ring [2.2.1] heptane-2.3-dicarboximide purity tests
Said determination is the result prove, the purity of the cis of embodiment 1,2 preparations-outer-two ring [2.2.1] heptane-2.3-dicarboximides all is higher than 99%.
The preparation of embodiment 4 SM-3997 of the present invention
Wherein
Represent Cl
-, Br
-, I
-, CH
3SO
3 -
Cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides get Tandospirone alkali with specific quaternary ammonium salts condensation, get the SM-3997 crude product with the Citric Acid salify in ethanol solution, measure dehydrated alcohols with 15 times and carry out recrystallization and get finished product.Concrete preparation method is:
With cis-(purity is all greater than 99% for outer-two ring [2.2.1] heptane-2.3-dicarboximides, by embodiment 1 or embodiment 2 preparations) 16.5kg (100mol), quaternary amine 100mol (bromide, muriate, iodide, methylsulfonic acid thing all can), N, dinethylformamide 230L, Anhydrous potassium carbonate 42kg join in the reactor, are incubated 113-157 ℃ of stirring reactions 5-10 hours.Reaction finishes, and reaction solution is cooled under the stirring at room and slowly adds in 500-900 kg of water, fully stirs again, leaves standstill suction filtration, filter cake water thorough washing secondary.With the filter cake acetic acid ethyl dissolution, add the hydrochloric acid soln acidifying, to pH2-3, tell acid solution, it is an amount of to add gac in acid solution, fully stirs, and cold decolouring is filtered.Filtrate to 10-11, produces the off-white color precipitation with the sodium hydroxide solution adjust pH, stirs, leave standstill, and suction filtration, filtrate is reclaimed, and filter cake is fully drained with tap water thorough washing secondary; Dry white or off-white color Tandospirone alkali 34.5 ± 3.9kg.The yield scope: 90 ± 5%, yield=Tandospirone alkali weight/(cis-outer-two ring [2.2.1] heptane-2.3-dicarboximide weight * 2.32) * 100%.
The selection result by holding temperature sees the following form, and shows that holding temperature is the most suitable at 125 ± 2 ℃.
| Temperature | Yield | Remarks |
| 115±2℃ | 45±5％ | Yield is lower |
| 125±2℃ | 90±5％ | The yield height, the product proterties is good |
| 135±2℃ | 90±5％ | Color is slightly dark |
| 145±2℃ | 87±5％ | Color requires high more deeply to production unit, energy consumption is big |
| 155±2℃ | 80.±5％ | Color is darker, and production unit is required height, and energy consumption is big |
The quality controlling means of embodiment 5 SM-3997 of the present invention
Related substance is measured according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2005).
Chromatographic condition and system suitability test are weighting agent with octadecylsilane chemically bonded silica; 0.01mol/L (regulating pH to 7.5 with 10% sodium hydroxide solution)-acetonitrile (60:40) is a moving phase to potassium dihydrogen phosphate; The detection wavelength is 243nm.Number of theoretical plate calculates by the Tandospirone peak should be not less than 5000.
Assay method is got the about 50mg of this product, puts in the 100ml measuring bottle, adds the moving phase dissolving, and is diluted to scale, shakes up, as need testing solution; Precision is measured 1ml, puts in the 100ml measuring bottle, adds moving phase and is diluted to scale, shakes up, in contrast solution (I); It is an amount of that other gets the Compound I reference substance, adds moving phase and make the solution that contains 2.5 μ g among every 1ml approximately, in contrast product solution (II); It is an amount of to get Compound I I reference substance again, adds moving phase and makes the solution that contains 2.5 μ g among every 1ml approximately, in contrast product solution (III).Precision is measured contrast solution (I) 20 μ l, injects liquid chromatograph, regulates detection sensitivity, makes the peak height of principal constituent chromatographic peak be about 20～25% of full range; Precision is measured need testing solution, contrast solution (I), reference substance solution (II), each 20 μ l of reference substance solution (III) again, injects liquid chromatograph respectively, and the record color atlas is to 2 times of principal constituent peak retention time.In the color atlas of need testing solution as show impurity peaks, each impurity peak area and, must not cross the main peak area (1.0%) of contrast solution (I), in its need testing solution as Compound I occurs, its peak area must not be crossed the main peak area (0.5%) of contrast solution (II), as Compound I I occurring, its peak area must not be crossed the main peak area (0.5%) of contrast solution (III) in its need testing solution.See Fig. 1-Figure 10
Get the sample of embodiment 4 preparations, lot number is: 060101,060102,060103,060401,060402,060501,060502, detect as stated above, and the results are shown in Table 1.
The inspection of table 1 related substance
The result shows: the related substance of above many batch samples all meets the requirement of quality standard draft.
The result shows: the purity of above many batch samples all meets cis-outer-two ring [2.2.1] heptane-2.3-dicarboximide requirements for quality control.
Adopt purity to be lower than cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides of 99%, the method preparation of pressing embodiment 4:
With cis-outer-two ring [2.2.1] heptane-2.3-dicarboximide 165g (purity 98%), quaternary amine 386g (bromide), N, dinethylformamide 230ml, Anhydrous potassium carbonate 420g join in the reactor, are incubated 113-157 ℃ of stirring reactions 5-10 hours.Reaction finishes, and reaction solution is cooled under the stirring at room and slowly adds in 6 kg of water, fully stirs again, leaves standstill suction filtration, filter cake water thorough washing secondary.With the filter cake acetic acid ethyl dissolution, add the hydrochloric acid soln acidifying, to pH2-3, tell acid solution, it is an amount of to add gac in acid solution, fully stirs, and cold decolouring is filtered.Filtrate to 10-11, produces the off-white color precipitation with the sodium hydroxide solution adjust pH, stirs, leave standstill, and suction filtration, filtrate is reclaimed, and filter cake is fully drained with tap water thorough washing secondary.Dry white or off-white color Tandospirone alkali 300g.With Tandospirone alkali 300g, a hydration Citric Acid 164g, dehydrated alcohol 3600ml adds in the reactor, is warmed up to 80 ℃, refluxes 30 minutes, puts and is chilled to room temperature, leaves standstill, and suction filtration is used absolute ethanol washing, and drying gets SM-3997 430g.Method check through providing by embodiment 5, related substance is:
Above-mentioned evidence, the purity of cis of the present invention-outer-two ring [2.2.1] heptane-2.3-dicarboximides are that can decision be prepared into the factor that meets the SM-3997 that the present invention requires, by limiting the purity of cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides, can realize purpose of the present invention.
Tandospirone 0.157mol (being equivalent to the 60g Tandospirone approximately)
Vltra tears (HPMC K4M) 64.8g
75% ethanol is an amount of
Lactose 110g
Magnesium stearate 3g
Talcum powder 6g
Preparation technology: with Tandospirone bulk drug and Vltra tears, the lactose of embodiment 4 preparation, mix, sieve, add 75% ethanolic soln system softwood, cross 20 mesh sieve system wet granulars, oven dry in about 50 ℃, the whole grain of 20 mesh sieves adds Magnesium Stearate and talcum powder, mixes the back compressing tablet.Make 1000 altogether.
Tandospirone 0.313mol (being equivalent to the 120g Tandospirone approximately)
Starch 200g
Microcrystalline Cellulose 5g
Preparation technology: with the Tandospirone of embodiment 4 preparation and starch by behind the equivalent incremental method mixing, again with the Microcrystalline Cellulose mixing, granulation, compressing tablet promptly gets tablet; Or encapsulated, promptly get capsule.
SM-3997 0.052mol (being equivalent to the 20g Tandospirone approximately)
Starch 230g
Microcrystalline Cellulose 25g
With the SM-3997 of embodiment 4 preparation and starch by behind the equivalent incremental method mixing, again with the Microcrystalline Cellulose mixing, granulation, encapsulated, promptly get capsule.
Tandospirone 0.157mol (being equivalent to the 60g Tandospirone approximately)
Physiological saline 2000ml
Method for making: with an amount of physiological saline solution, the solution filter adds the injection water to 2000ml to clear and bright on filter, potting, and sterilization promptly gets 1000 of injections.
SM-3997 0.052mol (being equivalent to the 20g Tandospirone approximately)
Water for injection 2000ml
Method for making: with the proper amount of water for injection dissolving, the solution filter adds the injection water to 2000ml to clear and bright on filter, potting, and sterilization promptly gets 1000 of injections.
SM-3997 0.078mol (about 30g Tandospirone)
Icing Sugar 400g
Dextrin 200g
Zulkovsky starch 400g
Correctives 1g
The SM-3997 and the dextrin of embodiment 4 preparations are passed through equivalent incremental method mixing, and again with other auxiliary materials and mixing, granulating promptly gets 1000 bags of particles.
SM-3997 0.131mol (about 50g SM-3997)
Correctives 1.5g
Distilled water is an amount of
Starch 80g
Dextrin 20g
The SM-3997 of embodiment 4 preparation and starch by behind the equivalent incremental method mixing, again with dextrin, correctives mixing, are lacked ball, be drying to obtain 1000 pills.
Below further specify beneficial effect of the present invention by pharmacodynamics test and clinical trial.
Define SM-3997 and the difference of existing SM-3997 of Compound I and Compound I I for exploration.Carried out the comparative study before and after quality standard improves, obtained the mass efficient reliable test data, conclusion is as follows:
The polycentric clinically opening experiment of test example 1
Group improves the quality: wherein Compound I (0.05%), Compound I I (0.06%); Proper mass group: Compound I (0.6%) wherein, Compound I I (0.7%).
Medicine of the present invention has carried out the clinical observation experiment of multicenter open in the whole nation, adopt Hamilton anxiety scale (HAMA) and clinical global impression scale (CGI) as the efficacy determination instrument, estimate the security of medicine with adverse drug reaction scale (TESS)., and subtract the branch rate with HAMA and judge curative effect as main evaluation index with HAMA.Follow up a case by regular visits in the case in high quality group 1107 examples, total effective rate is 76.54%, and adverse reaction rate is 6.8%, is slight.Be mainly gastrointestinal reaction, rare dizzy, drowsiness, nervous and fash.1205 examples in the standard group that do not improve the quality are followed up a case by regular visits in the case, and total effective rate is 65.4%, and adverse reaction rate is 11.4%, mostly are slight, are individually moderate.The untoward reaction of seeing at most is dizzy, drowsiness and gastrointestinal reaction.
Clinical observation result shows, by with Compound I and the Compound I I reference index as drug effect and untoward reaction, SM-3997 is after the standard that improves the quality, and clinical effect antianxity is significantly increased, and untoward reaction has tangible reduction.
Test example 2 anxiety animal model experiments
1, elevated plus-maze test
50 healthy mices are divided into 5 groups at random, and 10 every group, each administration group is pressed the continuous gastric infusion 5d of medicine shown in the table 1,1 time/d, behind the last administration 60min, mouse is placed overhead cross labyrinth open portion of central authorities, (overhead cross labyrinth comprises that two are opened arm (long 30cm to head towards closing arm, wide 6cm) closes arm (long 30cm with two, wide 6cm, high 10cm), close the arm opened upper end, there is the open portion of one 5 * 5cm in central authorities, and the labyrinth is high 50cm far from ground).By DigBehv animal behavior analytical system 2.0 automatically in the record 5min animal enter out arm and the number of times that closes arm and opening arm with close in the arm and the labyrinth central area in run duration and move distance.With enter out arm number of times and the percentage of always going into the arm number of times when in opening arm run duration with open the per-cent that arm closes the total time in the arm and represent the angst resistance effect index.(seeing Table 2)
The result shows, diazepam group and quality standard raising group can be obviously or significantly increased number of times that mouse enters out arm, open arm residence time and per-cent (P＜0.05 or P＜0.01) thereof, and the raising of angst resistance effect is significant.
2, to the influence of mouse cat ladder (the staircase test) behavior
When mouse is introduced into a new environment, anxiety reaction can occur, increase as the alertness behavior.The index of exploratory behavior of cat ladder behavior evaluation or reactivity, upright then as the parameter of anxiety state, antianxiety agent makes the number of standing reduce under the dosage that does not reduce the cat ladder number.
50 of mouse, male and female half and half are divided into 5 groups at random by physique amount, sex equilibrium, press the gastric infusion of medicine shown in the table 2, and 30min places the bottom of case with mouse after the administration, and the back of the body is taken the mouse behavior towards stair with Digital Video, and the experimenter leaves to reduce and disturbs.The mouse cat ladder number (all climbing up stair with four limbs is as the criterion) and the number of standing in the record 3min.Experimentize under the 18:00～21:00 point red light every day, and every experimentation on animals finishes back cleaning experimental box rapidly, to get rid of the interference of sense of smell hint to next animal.
The result shows not have significant difference though each administration group cat ladder number reduces, and can obviously, significantly reduce the number (P＜0.01 and P＜0.05) of standing, and with high quality group most pronounced effects, points out its angst resistance effect stronger.
The influence of table 3 pair mouse cat ladder behavior
3, rat social stress animal model and behavioral implications
Male Sprague-Dawley rat, body weight 200-300g, according to the method for Miscek, male rat is long-term raises separately.During the experiment beginning, the experimental group rat is put into independent raising rat cage, raise mouse separately and can attack experimental mouse, spread the neck and the back of stinging the effractor.Attacking generation back Therapy lasted 8 minutes for the first time, allowing 10 minutes as attacking latent period.Experimental rat is subjected to once attacking at least, and shows taming posture, and is upright as defense, lies on the back, and transfixion etc. are society's failure (social defeat).Society's failure (social defeat) has the tangible generation effect of anxiety behavior afterwards.
Adopt overhead cross labyrinth (plus maze) method and barnyard experiment the carrying out behavior test of reflection anxiety.Overhead cross labyrinth comprise two open arms (50 * 10cm) and two closure arm (50 * 10 * 40cm), (10 * 10cm) connect, and indoor is half-light (80lux) by central area.Experimentation companion white Gaussian noise.Single blind, the viewer observes every group 50% animal respectively.Rat is put into the labyrinth from center lattice towards closure arm, writes down active situation in 5 minutes, observation index: (1) closure arm enters number of times (must have two fore paws to enter in the arm); (2) open arms enters number of times; (3) the closure arm residence time; (4) the open arms residence time.B. reflect the barnyard experiment (open field method) of inquiry activity and emotional reactions: wooden (-packing) case 100 * 100 * 50cm, the floor becomes 25 grids, 20 * 20cm with stroke, claims the periphery lattice along the wall lattice, and all the other are center lattice.Animal is placed on the centre lattice, observes active situation in 12 minutes.Walk number of times between observation index (1) grid: the number of times that strides into adjacent lattice more than the three-jaw; (2) hold up or modify number of times: the number of times that the liftoff 1cm of two forelimbs is above; (3) the center lattice residence time.Experimental result is analyzed with the SPSS statistical software, all uses the (± SD) expression of mean ± standard deviation.A plurality of sample averages are relatively used one-way analysis of variance, the relatively employing independent sample t of mean check between two groups, significance level p＜0.05.
The result shows, each group have anti-society's failure (social defeat) produce stress after the effect of anxiety behavior.Wherein the effect of the anti-stress anxiety of high quality group is better than other group.
Table 4 rat social stress's animal model and behavioral implications (overhead cross labyrinth)
Table 5 rat social stress's animal model and behavioral implications (barnyard experiment)
According to the improve the quality test of pesticide effectiveness of group [Compound I (0.05%) Compound I I (0.06%)] of 10mg, the rule that the contriver limits production quality control according to those skilled in the art is defined as Compound I and Compound I I further and is not higher than 0.1%.
By above-mentioned pharmacology comparative study as can be known, improving the quality group SM-3997 in the scope that defines " weight percentage of Compound I must not be higher than 0.5%; weight percentage that contains Compound I I must not be higher than 0.5% " in effect antianxity apparently higher than the proper mass group, and minimizing along with the content of Compound I, Compound I I, drug effect obviously improves, wherein, " weight percentage of Compound I is: 0%-0.3%, the weight percentage that contains Compound I I is: 0%-0.3%." be further preferred range, " weight percentage that contains Compound I is: 0-0.1%, the weight percentage that contains Compound I I is: 0-0.1% " is preferred range further; Polycentric clinically opening experiment result also shows: the effect clinical antianxity of SM-3997 is significantly increased, untoward reaction reduces.Explanation in the framework of the present definition, can effectively improve the drug effect of SM-3997 by Compound I, Compound I I are controlled as index components, reduces untoward reaction.
Claims (10)
1, SM-3997 is characterized in that: the weight percentage that contains Compound I must not be higher than 0.5%, and the weight percentage that contains Compound I I must not be higher than 0.5%, and the structural formula of Compound I, II is:
Compound I Compound I I.
2, SM-3997 according to claim 1 is characterized in that: the weight percentage that contains Compound I is: 0%-0.31%, the weight percentage that contains Compound I I is: 0%-0.3%.
3, SM-3997 according to claim 1 is characterized in that: the weight percentage that contains Compound I is: 0.04-0.31%, the weight percentage that contains Compound I I is: 0.05-0.29%.
4, according to each described SM-3997 of claim 1-3, it is characterized in that: its HPLC chromatogram contains at least one characteristic peak as shown in Figure 1;
The chromatographic condition of high performance liquid chromatography is: with octadecylsilane chemically bonded silica is weighting agent; 0.01mol/L potassium dihydrogen phosphate-acetonitrile, volume ratio are (60 ± 5): (40 ± 5) are moving phase; The detection wavelength is 243nm, and number of theoretical plate calculates by the Tandospirone peak should be not less than 5000.
5, SM-3997 according to claim 4 is characterized in that: the HPLC color atlas also contains two characteristic peaks.
6, a kind of pharmaceutical composition antianxity, it is that SM-3997 by each described significant quantity of claim 1-5 is an activeconstituents, adds the medicament that acceptable accessories or complementary composition are prepared from.
7, pharmaceutical composition antianxity according to claim 6 is characterized in that: described medicament is an oral preparations.
8, a kind of method for preparing the described SM-3997 of claim 1, it comprises the steps:
With cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides, quaternary amine, N, dinethylformamide, Anhydrous potassium carbonate join in the reactor, are incubated 113-157 ℃ of stirring reactions 5-10 hours; Reaction finishes, and reaction solution is cooled to and slowly adds under the stirring at room in the entry, fully stirs again, leaves standstill suction filtration, filter cake water thorough washing; With the filter cake acetic acid ethyl dissolution, add the hydrochloric acid soln acidifying, to pH2-3, tell acid solution, it is an amount of to add gac in acid solution, fully stirs, and cold decolouring is filtered; Filtrate uses the sodium hydroxide solution adjust pH to 10-11, produces the off-white color precipitation, stirs, leave standstill, and suction filtration, filtrate is reclaimed, and filter cake washs with tap water, drains, and gets Tandospirone alkali, through the Citric Acid salify, obtains SM-3997; Wherein, the purity of described cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides must not be less than 99.0%.
9, the method for SM-3997 according to claim 8 is characterized in that: wherein cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides are realized by following two kinds of methods:
A, by norbornene dicarboxylic anhydride 190-210 ℃ of following transition, transition thing hydrogenation is hydride under the situation of palladium-carbon catalyst having, hydride ammonification under ammonia environment is that cis-outer-two is encircled [2.2.1] heptane-2.3-dicarboximides;
B, by maleimide and cyclopentadiene reaction gains, again through hydrogenation promptly get cis-outside-two encircle [2.2.1] heptane-2.3-dicarboximides, concrete steps are:
Maleimide is added in the reaction flask, add ethyl acetate, stir and make its dissolving, add cyclopentadiene, wherein the weight proportion of cyclopentadiene and maleimide is: 1: 1-2, stir pressure reducing and steaming 75% solvent, filter, use the ether washing leaching cake, get the particular configuration thing; The particular configuration thing is dissolved among the THF, adds cyclohexene and 5% palladium charcoal, feed hydrogen under greater than the 0.01MPa situation at pressure, reactant backflow 9h, after the cooling, the pressure reducing and steaming solvent, residue gets cis-outer-two ring [2.2.1] heptane-2.3-dicarboximides with the toluene recrystallization.
10, the described SM-3997 method for quality of a kind of control claim 1, it is to be index components with Compound I, Compound I I, carry out quality control, it is that chromatographic condition is: with octadecylsilane chemically bonded silica is weighting agent according to high effective liquid chromatography for measuring; 0.01mol/L potassium dihydrogen phosphate-acetonitrile, volume ratio: 60 ± 5:40 ± 5 are moving phase; The detection wavelength is 243nm, and number of theoretical plate calculates by the Tandospirone peak should be not less than 5000.
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| US4351939A (en) * | 1980-10-16 | 1982-09-28 | Mead Johnson & Company | Spiro-quaternary ammonium halides and N-(2-pyrimidinyl)piperazinylalkylazaspiroalkanedione process |
| JPH0413663A (en) | 1990-04-27 | 1992-01-17 | Sumitomo Pharmaceut Co Ltd | Production of dicarboxylic acid imide derivative |
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