EP1926486A1 - Nouveaux polymorphes de monotartrate de(s)-2,6-diamino-4,5,6,7-tétrahydrobenzothiazole et procédés de production et d'utilisation de ceux-ci - Google Patents

Nouveaux polymorphes de monotartrate de(s)-2,6-diamino-4,5,6,7-tétrahydrobenzothiazole et procédés de production et d'utilisation de ceux-ci

Info

Publication number
EP1926486A1
EP1926486A1 EP05798176A EP05798176A EP1926486A1 EP 1926486 A1 EP1926486 A1 EP 1926486A1 EP 05798176 A EP05798176 A EP 05798176A EP 05798176 A EP05798176 A EP 05798176A EP 1926486 A1 EP1926486 A1 EP 1926486A1
Authority
EP
European Patent Office
Prior art keywords
monotartrate
diamino
tetrahydrobenzothiazole
crystalline solid
diat
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.)
Pending
Application number
EP05798176A
Other languages
German (de)
English (en)
Other versions
EP1926486A4 (fr
Inventor
Itai Adin
Michael Brand
Carmen Iustain
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.)
Wavelength Enterprises Ltd
Original Assignee
Chemagis 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
Application filed by Chemagis Ltd filed Critical Chemagis Ltd
Publication of EP1926486A1 publication Critical patent/EP1926486A1/fr
Publication of EP1926486A4 publication Critical patent/EP1926486A4/fr
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms

Definitions

  • Parkinson's disease is a common neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra (an area in the basal ganglia) and resulting in slowing of emotional and voluntary movement, muscular rigidity, postural abnormality and tremor.
  • Therapy has focused on replacing depleted dopamine via supplementation with L-dopa or dopamine agonists such as pramipexole, ropinirole, lisuride, cabergoline, apomorphine, pergolide or bromocriptine.
  • (propylamino)benzothiazole is a synthetic aminobenzothiazole derivative, marketed under the trade name Mirapex , represented by molecular formula 1 :
  • pramipexole is prepared from (iS)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate (formula 2), as illustrated in scheme 1 : Scheme 1
  • the (5)-2,6-diamino-4,5,6,7- tetrahydrobenzothiazole monotartrate is then alkylated (in this case via conversion to the propionamide followed by reduction of the amide) to produce (S)-2-amino- 4,5,6,7-tetrahydro-6-(propylamino)benzothiazole (pramipexole).
  • (>S)-2,6-diamino-4,5,6,7- tetrahydrobenzothiazole monotartrate which can facilitate the production of pramipexole.
  • the present invention provides stable, crystalline forms of (5)-2,6- diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate, which can facilitate the production of pramipexole.
  • the present invention provides stable crystalline forms of (S)-2,6- diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate ("DIAT").
  • the crystalline forms of the present invention preferably include DIAT form I, DIAT form II and DIAT form III, as described herein.
  • the present invention provides a method for producing DIAT form I, which method includes crystallizing DIAT from a solution, which is preferably an aqueous solution, e.g., water or a mixture of water and one or more organic solvents.
  • DIAT form I is prepared by crystallizing DIAT from a mixture of water and at least one polar organic solvent, which is preferably selected from the group consisting of methanol, ethanol, acetonitrile and combinations thereof, to produce DIAT form I.
  • the crystallization can be carried out in the presence of one or more amino acids (e.g., about 1% (1 wt%) of one or more amino acids) in the solution, to produce DIAT form I.
  • one or more amino acids e.g., about 1% (1 wt%) of one or more amino acids
  • the present invention also provides a method for producing DIAT form
  • the present invention additionally provides a method for producing DIAT form II, which method includes drying DIAT form I at elevated temperature, optionally under reduced pressure, to produce DIAT form II.
  • the present invention further provides a method for producing DIAT form III, which method includes drying DIAT form II at elevated temperature to produce DIAT form III.
  • the present invention still further provides a method of producing pramipexole by converting DIAT form I, DIAT form II, DIAT form III, or a combination thereof, into pramipexole (which includes pramipexole free base and salts thereof, e.g., pharmaceutically acceptable salts such as, e.g., the monohydrochloride or dihydrochloride).
  • DIAT form I, DIAT form II, DIAT form III, or a combination thereof can be converted into pramipexole using methods that are well known in the art, e.g., by alkylating the 6-amino to produce (5)-2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole (pramipexole).
  • DIAT form I, DIAT form II, DIAT form III, or any suitable combination thereof can be converted into pramipexole by alkylating the 6-amino to produce pramipexole.
  • the alkylation can include, e.g., amidating/acylating the 6- amino to produce (S)-2-amino-4,5,6,7-tetrahydro-6-(propionamido)benzothiazole, and reducing the amide to produce (5)-2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole (pramipexole).
  • the alkylation can include, e.g., amidating/acylating the 6- amino to produce (S)-2-amino-4,5,6,7-tetrahydro-6-(propionamido)benzothiazole, and reducing the amide to produce (5)-2-amino-4,5,6,7-tetrahydro-6- (propylamino)benz
  • Figure 1 depicts an optical microscopy (x40) image of DIAT form I.
  • Figure 2 depicts an optical microscopy (x40) image of DIAT form II.
  • Figure 3 depicts an X-ray powder diffraction pattern of DIAT form I.
  • Figure 4 depicts an infrared spectrum of DIAT form I.
  • Figure 5 depicts a differential scanning calorimetry (DSC) curve of DIAT form I.
  • FIG. 6 depicts a thermogravimetric analysis (TGA) curve of DIAT form I.
  • Figure 7 depicts an X-ray powder diffraction pattern of DIAT form II.
  • Figure 8 depicts an alternative X-ray powder diffraction pattern of DIAT form II.
  • Figure 9 depicts a DSC curve of DIAT form II.
  • Figure 10 depicts a TGA curve of DIAT form II.
  • Figure 11 depicts an alternative TGA curve of DIAT form II.
  • Figure 12 depicts an X-ray powder diffraction pattern of DIAT form III.
  • Figure 13 depicts an infrared spectrum of DIAT form III.
  • Figure 14 depicts a DSC curve of DIAT form III.
  • Figure 15 depicts a TGA curve of DIAT form III.
  • DIAT form I produces an X-ray powder diffraction pattern, e.g., as depicted in Figure 3.
  • a peak listing is provided in Table 1.
  • Table 1 DIAT form I - X-ray powder diffraction peak position and intensities
  • DIAT form I can contain crystals in the shape of long prisms, with narrow to medium width, e.g., as shown in Figure 1.
  • DIAT form I can exist as a hydrate, e.g., containing about 15 ⁇ 2 percent water or about three molar equivalents of water.
  • a phase transformation from DIAT form I to DIAT form II occurs. This transformation is not clearly observed by thermal analysis. While not wishing to be bound by any particular theory, the reason for this phenomenon may be that the transformation takes place simultaneously with water discharge, and the two events overlap in DSC.
  • no melting is observed throughout the entire temperature range based on the weight loss curve observed in TGA.
  • a characteristic DSC curve of DIAT form I (e.g., as illustrated in Figure
  • the DSC curve of DIAT form I typically contains three peaks.
  • the DSC curve of DIAT form I exhibits peaks with onsets at about 120 0 C, about 135-140 0 C and about 195-200 0 C.
  • the intensity of the second peak can vary (e.g., can be much larger) depending on the sample preparation.
  • the third peak (onset about 200 0 C) is believed to correspond to the melting and decomposition of the in- situ created anhydrous form III.
  • a characteristic TGA curve is depicted in Figure 6. [0032]
  • a characteristic infrared spectrum of DIAT Form I is shown in Figure 4.
  • DIAT form I can be prepared by a method, which comprises crystallizing DIAT from an aqueous solution containing about 1% of an amino acid, to obtain large single crystals of DIAT form I.
  • An exemplary crystallization process for preparing DIAT form I in the presense of one or more amino acids includes:
  • Suitable amino acids can include natural as well as synthetic amino acids, e.g., L-amino acids, D-amino acids or DL-amino acids.
  • Exemplary amino acids can include one or more amino acids selected from the group consisting of L-alanine, L- tyrosine, D-alanine, L-tryptophan, D-tryptophan, DL-phenylalanine, L-phenylalanine, D-phenylalanine, D-tyrosine, and the like, and combinations thereof.
  • DIAT form I also can be prepared, e.g., by crystallizing DIAT from an aqueous solution, e.g., water or a mixture of water and one or more polar organic solvents, and optionally isolating the resulting crystals.
  • Suitable polar organic solvent can include, e.g., methanol, ethanol, acetonitrile, and combinations thereof.
  • An exemplary process for preparing DIAT form I by crystallization includes: (i) refluxing a mixture of DIAT, water and, optionally, one or more polar organic solvents, preferably selected from the group consisting of methanol, ethanol, acetonitrile and combinations thereof;
  • DIAT form II produces an X-ray powder diffraction pattern, e.g., as shown in Figure 7.
  • a peak listing is provided in Table 2.
  • DIAT form II can produce a slightly different X-ray powder diffraction pattern, e.g., as depicted in Figure 8.
  • a peak listing for the alternative X-ray powder diffraction pattern is provided in Table 3.
  • DIAT form II can exist as a hydrate containing about 5-15 % of water or about 1-3 equivalents of water.
  • the water content in DIAT form II is typically less than the water content in DIAT form I.
  • DIAT form II can be produced by the drying/heating of DIAT form I. It has been found that the amount of water in DIAT form II can vary without any observable change in the crystalline structure. However, DIAT form II, which contains about 5% of water, may absorb water, e.g., from the environment, and transform into DIAT form I. Preferably, when DIAT form II is heated, no melting is observed, based on the weight loss curve observed in TGA, throughout the entire temperature range in which the hydrated form II exists. [0042] DIAT form II also can be produced by a process that includes crystallizing DIAT from a mixture of water and a suitable organic solvent, and optionally isolating the crystals. Suitable organic solvents can include, e.g., one or more organic solvents selected from the group consisting of isopropanol, ethyl acetate, and combinations thereof.
  • An exemplary process for preparing DIAT form II via crystallization includes:
  • DIAT form III can be produced by heating DIAT form II at temperatures above about 16O 0 C, at which DIAT form II can be substantially dried, to produce a phase transition from DIAT form II to substantially water-free (e.g., anhydrous) DIAT form III. Care should be taken when heating to convert DIAT form II into DIAT form III to avoid decomposition, which can occur at high temperatures.
  • a characteristic DSC curve exhibited by DIAT form II is depicted in Figure 9.
  • water discharge in DIAT form II can begin at higher temperatures, e.g., as shown in the alternative TGA curve depicted in Figure 11. Both DSC and TGA curves may change due to changes in water content.
  • the intensity of the second peak (onset 135-14O 0 C) can depend on the sample preparation, and can become much larger.
  • DIAT form III produces an X-ray powder diffraction pattern, e.g., as shown in Figure 12.
  • a peak listing is provided in Table 4.
  • Table 4 DIAT form III - X-ray powder diffraction peak position and intensities
  • the DIAT form III is preferably anhydrous, e.g., containing less than about 0.3% water.
  • the DIAT form III can be produced by substantially dehydrating
  • DIAT form II at temperatures of at least about 160 0 C (e.g., above about 160 0 C), although, as noted above, degradation has been observed above 16O 0 C in some cases.
  • a characteristic infrared spectrum exhibited by DIAT form III is depicted in Figure 13.
  • the strong absorption peaks at 1614, 1121, 1061 and 847 ⁇ 4 cm "1 are characteristic bands associated with DIAT form III.
  • a characteristic DSC curve of DIAT form III is depicted in Figure 14, and shows the melting peak at 191 0 C.
  • a characteristic TGA curve of DIAT form III is depicted in Figure 15, and indicates that there is no weight loss from about room temperature to about 18O 0 C.
  • DIAT crystalline forms I, II and III were characterized by powder X-ray diffraction, thereby generating fingerprint powder X-ray diffraction patterns for each particular crystalline form. Measurements of 2 ⁇ values typically are accurate to within ⁇ 0.2 degrees 2 ⁇ .
  • DIAT crystalline forms I 3 II and III of the present invention were further characterized by Fourier-transform infrared (FTIR) spectroscopy to an accuracy of ⁇
  • FTIR is a well-known spectroscopic analytical tool, which measures the absorption of IR energy by a sample from transitions in molecular vibrational energy levels. While FTIR is primarily used for identification of functional groups in a molecule, different polymorphic forms also can exhibit differences in FTIR.
  • DIAT crystalline forms I 3 II and III of the present invention also were characterized by differential scanning calorimetry (DSC), run on TA instruments model QlOOO, with Universal software version 3.88. Samples were analyzed inside crimped 40 ⁇ l Aluminum pans. Heating rate for all samples was 5 °C/min.
  • DSC Differential scanning calorimetry
  • DIAT crystalline forms I 3 II and III of the present invention also were characterized by thermogravimetric analysis (TGA), a measure of the thermally induced weight loss of a material as a function of the applied temperature.
  • TGA thermogravimetric analysis
  • Thermogravimetric analysis (TGA) was performed using a TA Instruments Q500
  • DIAT starting material was prepared by resolving the racemic diamine as described in Schneider et al., J. Med. Chem., 30, 494-498 (1987).
  • This example demonstrates a method for preparing DIAT form I.
  • DIAT form I This example demonstrates the preparation of DIAT form I.
  • DIAT Ig
  • methanol 10 ml
  • the mixture was heated to reflux and methanol was added in 4 ml portions until a solution was obtained (the total added volume was 80 ml). Refluxing was maintained while water was added (45 ml). The solution was allowed to cool to 25 0 C, and then stirred for 1 hour at that temperature. The solution was cooled to 5 0 C and stirring was continued at that temperature for additional 1 hour.
  • the resulting suspension was filtered and washed with a cold mixture of water : methanol (1 :2 (vol./vol.)). The resulting crystals were dried at 6O 0 C under vacuum to afford DIAT Form I (0.83g).
  • DIAT form I This example demonstrates the preparation of DIAT form I.
  • DIAT 9.5 g
  • Ethanol was added in several portions while refluxing (total volume of the added ethanol was 25 ml).
  • the solution was allowed to cool to room temperature and stirred at room temperature for 1 hour.
  • the solution was cooled to 5 0 C, and stirring was maintained for additional 1 hour at 5 0 C, followed by filtration.
  • the resulting cake was washed with cold mixture of water and ethanol (1:1 (vol./vol.)).
  • the resulting crystals were dried under vacuum at 6O 0 C to afford DIAT form I (0.52 g)-
  • This example demonstrates the preparation of DIAT form II.
  • DIAT (1 g) was mixed with water (30 ml).
  • the solution was heated to reflux and ethyl acetate was added in several portions while refluxing (total volume of the added ethyl acetate was 30 ml).
  • the two-phase mixture was cooled to 25 0 C, stirred at that temperature for 1 hour, then cooled to 5 0 C and stirred at that temperature for 1 hour.
  • the resulting slurry was filtered and the solid thereby obtained was washed with cold ethyl acetate.
  • the resulting solid was dried at 6O 0 C under vacuum to obtain DIAT form II (0.83 g).
  • DIAT form II (Ig) was dried at 80 0 C under vacuum for 2 hours, to produce DIAT form II.
  • the resulting material contained 5% water (by TGA).
  • DIAT form III This example demonstrates the preparation of DIAT form III.
  • DIAT form II (1 g) was heated for 10 minutes at 160 0 C, to produce DIAT form III.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des formes cristallines de monotartrate de (S)-2,6-diamino-4,5,6,7-tétrahydrobenzothiazole (DIAT), y compris la forme I du DIAT, la forme II du DIAT, et la forme III du DIAT. L'invention concerne aussi des procédés de préparation des formes I, II et III du DIAT et des procédés de préparation de pramipexole grâce à eux.
EP05798176A 2005-09-21 2005-09-21 Nouveaux polymorphes de monotartrate de(s)-2,6-diamino-4,5,6,7-tétrahydrobenzothiazole et procédés de production et d'utilisation de ceux-ci Pending EP1926486A4 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2005/033635 WO2007040474A1 (fr) 2005-09-21 2005-09-21 Nouveaux polymorphes de monotartrate de(s)-2,6-diamino-4,5,6,7-tétrahydrobenzothiazole et procédés de production et d'utilisation de ceux-ci

Publications (2)

Publication Number Publication Date
EP1926486A1 true EP1926486A1 (fr) 2008-06-04
EP1926486A4 EP1926486A4 (fr) 2009-06-10

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EP05798176A Pending EP1926486A4 (fr) 2005-09-21 2005-09-21 Nouveaux polymorphes de monotartrate de(s)-2,6-diamino-4,5,6,7-tétrahydrobenzothiazole et procédés de production et d'utilisation de ceux-ci

Country Status (2)

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EP (1) EP1926486A4 (fr)
WO (1) WO2007040474A1 (fr)

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CN115215818B (zh) * 2022-07-26 2023-03-17 山东京卫制药有限公司 一种普拉克索三苯乙酸盐及其药物缓释制剂

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006003677A1 (fr) * 2004-07-01 2006-01-12 Alembic Limited Procede ameliore de preparation d'un derive de tetrahydrobenzothiazole biologiquement actif

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Publication number Priority date Publication date Assignee Title
ES2187249B1 (es) * 2000-09-18 2004-09-16 Synthon Bv Procedimiento para la preparacion de 2-amino-6-(alquil)amino-4,5,6,7-tetrahidrobenzotiazoles.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006003677A1 (fr) * 2004-07-01 2006-01-12 Alembic Limited Procede ameliore de preparation d'un derive de tetrahydrobenzothiazole biologiquement actif

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SCHNEIDER C S ET AL: "Dopamine autoreceptor agonists: resolution and pharmacological activity of 2,6-diaminotetrahydrobenzothiazole and aminothiazole analogue of apomorphine" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US, vol. 30, no. 3, 1 March 1987 (1987-03-01), pages 494-498, XP002186199 ISSN: 0022-2623 *
See also references of WO2007040474A1 *

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EP1926486A4 (fr) 2009-06-10

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