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WO2006026927A1 - Nouveau polymorphe de monohydrate de mesylate de dolasetron et sa preparation - Google Patents

Nouveau polymorphe de monohydrate de mesylate de dolasetron et sa preparation Download PDF

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Publication number
WO2006026927A1
WO2006026927A1 PCT/CN2005/001440 CN2005001440W WO2006026927A1 WO 2006026927 A1 WO2006026927 A1 WO 2006026927A1 CN 2005001440 W CN2005001440 W CN 2005001440W WO 2006026927 A1 WO2006026927 A1 WO 2006026927A1
Authority
WO
WIPO (PCT)
Prior art keywords
dolasetron
acid
mesylate
melting point
crystalline form
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2005/001440
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English (en)
Chinese (zh)
Inventor
Yong Qin
Peiliang Guo
Junguo Xin
Yin Wang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CHENGDU GIANTECH HI-TECHNOLOGY DEVELOPMENT Co Ltd
Original Assignee
CHENGDU GIANTECH HI-TECHNOLOGY DEVELOPMENT Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Application filed by CHENGDU GIANTECH HI-TECHNOLOGY DEVELOPMENT Co Ltd filed Critical CHENGDU GIANTECH HI-TECHNOLOGY DEVELOPMENT Co Ltd
Publication of WO2006026927A1 publication Critical patent/WO2006026927A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems

Definitions

  • the invention relates to a new crystal form of dolasetron mesylate and a preparation method thereof.
  • Dolasetron mesylate is a synthetic serotonin subtype 5HT 3 receptor antagonist with high specific activity and high selectivity containing pseudo-phenoline skeleton. It is widely used in clinical treatment. Headaches and similar conditions, as well as treatment of vomiting due to surgery or by cytotoxic drugs (MW Gittos and M. Fatmi, Actual Chim. Ther. 1989, 16, 187; US4906755).
  • Dolasetron mesylate monohydrate The chemical structure of dolasetron mesylate is shown in the above figure, and its chemical name is ( p ⁇ -3-carboxylic acid-2 ⁇ , 6 ⁇ , 8 ⁇ , 9 ⁇ ⁇ ) - octahydro - 3-Oxo-2,6-methylene-dihydro-quinoline-8-ester monohydrate methanesulfonate.
  • the only one monohydrate known to it is a crystalline form having a melting point of 278 ° C, which has a higher melting point.
  • the ketone group of dolasetron is first reduced in vivo to a hydroxy group by a carbonyl reductase.
  • a carbonyl reductase To be reduced form of dolasetron (J. Dow et al. Chirality 1995, 7, 342; H. Boxenbaum et al. Biopharm. Drug Dispos. 1992, 13, 693; H. Boxenbaum et al. Biopharm. Drug Dispos. 1993, 14, 131).
  • the body is directly effective in the reduced form of dolasetron, and in vitro tests have shown that the reduced form of dolasetron is at least 35 times more potent than dolasetron (PH Boeijinga et al. Euro. J. Pharm. 1992:
  • the technical problem to be solved by the present invention is to overcome the defects of the existing crystal form of dolastatin mesylate, and provide a new crystal form of dolasetron mesylate, which has high stability and can satisfy all the raw materials as preparation materials. It is required to be clinically useful for the treatment of migraine and the like, as well as for the treatment of vomiting caused by cytotoxic drugs.
  • the present invention uses the following technical solutions:
  • the novel crystalline form of dolasetron mesylate of the present invention is a white powdery crystal having a melting point of 160 - 170 ° C, a differential thermal analysis peak of 434 - 437 K, and a peak range of 420 K to .445 K, molecular
  • the composition is C 19 H 2 . N 2 0 3 .CH 4 0 3 SH 2 0, the molecular structure is as follows
  • the novel crystalline form of dolasetron mesylate of the present invention has a melting point of from 160 to 165 Torr, more preferably, a melting point of from 162 to 164 °C.
  • the invention also provides a preparation method of the novel crystal form of dolasetron methanesulfonic acid, which is prepared by the condensation of alcohol with an alcohol and catalyzed by doracin free amine. Compounds, as well as starting from dolastatin ketal compounds, hydrolyzed and reconstituted from water
  • the present invention dolasetron free amine is p-indol-3-carboxylic acid -2 ⁇ , 6 ⁇ , 8 ⁇ , 9 ⁇ ⁇ - octahydro --3 _ Yue alkylene oxide group _2,6- - dihydro - a quinoline-8-ester, the acid being at least one selected from the group consisting of methanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid and p-toluenesulfonic acid pyridinium, the alcohol being selected from one to eight carbon atoms At least one of a linear or branched alcohol, a 3- to 8-membered cyclic alcohol, and a vicinal diol having two to eight carbon atoms, the condensation reaction condition being the above-mentioned free amine, the alcohol and the acid heated to 60-150 °C for 1 to 24 hours, the hydrolysis reaction conditions are that
  • the crystal form of the drug molecule is closely related to the stability of the drug and its bioavailability in vivo when administered orally.
  • the crystalline form of the lower melting point of the same drug has a better bioavailability when administered orally than the high melting crystalline form, exhibiting different pharmacokinetics.
  • the ketone group of dolasetron is first reduced in vivo to a hydroxyl group by a carbonyl reductase to a reduced form of dolasetron (J. Dow et al. Chirality 1995, 7, 342; H. Boxenbaum et al. Biopharm. Drug Dispos. 1992, 13, 693; H. Boxenbaum et al. Biopharm. Drug Dispos. 1993, 14, 131 ).
  • the reduced form of dolasetron is at least 35 times more potent than dolasetron (R H. Boeijinga et al. Euro. J. Pharm. 1992, 219,
  • dorsalazine derivatives with different functional groups may be one of the feasible methods to improve the bioavailability of dolasetron.
  • the present invention prepares a dolase ketal precursor by a novel synthesis process, and prepares a methanesulfonic acid having a specific crystal form having a melting point of 160 - 170 ° C by using such an ketal precursor. Rastron, this crystal form has the same chemical structure and chemical composition as the melting point of 278 ° C of dolase.
  • the dolastatin ketal precursor compound has the molecular structure and composition described above. a substituted, unsubstituted cyclic alkyl group wherein R is a linear or branched alkyl group of 3 to 8 carbon atoms or a 3-membered ring; RR is a substituted 5 or 6-membered ring, unsubstituted 2 A ketal fragment.
  • dolasetron monomethanesulfonate Hydrolysis of the ketal precursor compound of the above-described dolastatin, the hydrolyzate is recrystallized from water to obtain dolasetron monomethanesulfonate, which is an off-white powdery crystal having a melting point of 160 - 170 Specific crystal form of °C.
  • the preparation of dolasetron mesylate by hydrolysis of the dolastatin ketal precursor compound can not only prepare a novel crystal form having a melting point of 160 - 170'C, but also makes the target product easy to be colored with impurities and traces. Separation of matter.
  • the precursor compound of the dorasagirol ketal can be prepared by refluxing the corresponding anhydrous alcohol with the dolastatin free amine under acid catalysis for high yield.
  • dorsalazine free amine and anhydrous ethanol are refluxed in the presence of one equivalent of methanesulfonic acid, a diethoxy condensed dolastatin mesylate white crystal having a melting point of 247 ° C is obtained.
  • dolasetron free amine and ethanol are directly recrystallized after heating to 60 ° C in the presence of about one equivalent of methanesulfonic acid, but the melting point is 278 ° C.
  • White powdery crystals (US 4,906,755).
  • the melting point obtained by the synthetic preparation method of the ketal precursor compound is 160 -
  • the 170 ⁇ specific crystal form of dolaserone monohydrate has the same activity as the crystalline form of dolasetron monohydrate of 278 ° C claimed by the drug manufacturer of dolasetron. Moreover, the crystal form has high stability and a low melting point, and may have good bioavailability, and can better meet all the requirements as a raw material for the preparation.
  • the new crystalline form of the precursor compounds of dolasetron and dolase ketal is a serotonin subtype 5HT3 receptor antagonist, which is clinically useful for the treatment of migraine and similar conditions, as well as treatment. Vomiting due to surgery or by drugs with cytotoxicity.
  • Figure 1 is an X-ray powder diffraction pattern of the novel crystal form of the present invention.
  • FIG. 2 is a differential thermal analysis map (DSC) of the new crystal form of the present invention.
  • Example 3 Melting point: 162-164 ° C - Doraspirin mesylate ( ⁇ -3-carboxylic acid-2 ⁇ , 6 ⁇ , 8 ⁇ , 9 ⁇ ⁇ - octahydro-3-oxo-2,6 -methylene-dihydro-quinoline-8-ester monomethanesulfonate) preparation
  • Mass spectrometry (MS 324, EI ): 323 ( M-1+ ); X-ray scattering spectra: 12.429, 9.181, 8.629, 7.667, 6.938, 5.874, 5.238, 4.917, 4.708, 4.541, 4.246, 3.991, 3.812, 3.616, 3.431, 3.373, 3.301 , 3.204, 3.115, 3.008, 2.842, 2.741, 2.543, 2.457, 2.394, 2.342, 2.227, 2.117, 2.087, 1.985, 1.960, 1.856.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau polymorphe de monohydrate de mésylate de dolasétron et sa préparation. Le polymorphe est une poudre cristalline blanche, le point de fusion du polymorphe est de 160-170 °C, la valeur de crête de l'analyse thermale différentielle est de 434-437 K, et les crêtes sont comprises entre 420K et 445K. La stabilité élevée du polymorphe permet de l'utiliser en tant que matière pour formulations. Il peut être utilisé dans le traitement de l'hémicrânie et des maladies analogues et dans le traitement des vomissements causés par l'action d'agents cytotoxiques.
PCT/CN2005/001440 2004-09-10 2005-09-09 Nouveau polymorphe de monohydrate de mesylate de dolasetron et sa preparation Ceased WO2006026927A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNB2004100746545A CN100390172C (zh) 2004-09-10 2004-09-10 一种甲磺酸多拉司琼晶型及其制备方法
CN200410074654.5 2004-09-10

Publications (1)

Publication Number Publication Date
WO2006026927A1 true WO2006026927A1 (fr) 2006-03-16

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CN (1) CN100390172C (fr)
WO (1) WO2006026927A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007081909A3 (fr) * 2006-01-05 2007-11-22 Teva Gyogyszergyar Zartkoruen Formes du mésylate de dolasetron et leurs procédés de préparation
WO2007072506A3 (fr) * 2005-12-23 2008-05-08 Usv Ltd Formes polymorphes de mesylate de dolasetron et procedes correspondants

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109503580A (zh) * 2019-01-15 2019-03-22 南京恩泰医药科技有限公司 一种甲磺酸多拉司琼晶型及制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0266730A1 (fr) * 1986-11-03 1988-05-11 Merrell Dow Pharmaceuticals Inc. Esters de l'hexahydro-8-hydroxy-2,6-méthano-2H-quinolizin-3-(4H)-one et composés apparentés
US4906755A (en) * 1986-11-03 1990-03-06 Merrell Dow Pharmaceuticals Inc. Esters of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one and related compounds

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2531083B1 (fr) * 1982-06-29 1986-11-28 Sandoz Sa Nouveaux derives de la piperidine, leur preparation et leur utilisation comme medicaments
DE3689974T2 (de) * 1985-03-14 1994-11-03 Beecham Group Plc Arzneimittel zur Behandlung von Emesis.
GB8520616D0 (en) * 1985-08-16 1985-09-25 Beecham Group Plc Compounds
US4910193A (en) * 1985-12-16 1990-03-20 Sandoz Ltd. Treatment of gastrointestinal disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0266730A1 (fr) * 1986-11-03 1988-05-11 Merrell Dow Pharmaceuticals Inc. Esters de l'hexahydro-8-hydroxy-2,6-méthano-2H-quinolizin-3-(4H)-one et composés apparentés
US4906755A (en) * 1986-11-03 1990-03-06 Merrell Dow Pharmaceuticals Inc. Esters of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one and related compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MORAN P M AND MOSER P C.: "MDL 73,147EF,a 5-HT3 antagonist, facilities latent inhibition in the rat.", PHARMACOL BIOCHEM BEHAV., vol. 42, no. 3, 1992, pages 519 - 522 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007072506A3 (fr) * 2005-12-23 2008-05-08 Usv Ltd Formes polymorphes de mesylate de dolasetron et procedes correspondants
WO2007081909A3 (fr) * 2006-01-05 2007-11-22 Teva Gyogyszergyar Zartkoruen Formes du mésylate de dolasetron et leurs procédés de préparation
US7608714B2 (en) 2006-01-05 2009-10-27 TEVA Gyógyszergyár Zártkörúen Müködö Részvénytársaság Production of dolasetron

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CN100390172C (zh) 2008-05-28
CN1629161A (zh) 2005-06-22

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