WO2004089933A1 - フルオロベンズアミド誘導体の新規結晶 - Google Patents
フルオロベンズアミド誘導体の新規結晶 Download PDFInfo
- Publication number
- WO2004089933A1 WO2004089933A1 PCT/JP2004/004794 JP2004004794W WO2004089933A1 WO 2004089933 A1 WO2004089933 A1 WO 2004089933A1 JP 2004004794 W JP2004004794 W JP 2004004794W WO 2004089933 A1 WO2004089933 A1 WO 2004089933A1
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- WO
- WIPO (PCT)
- Prior art keywords
- compound
- added
- crystal
- crystals
- ethyl
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- the present invention relates to (-)-N- ⁇ 2-[(i?)-3- (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbo-nore) piperidino] ethyl ⁇
- the present invention relates to a novel crystal of -4-flurobenzamide monophosphate (hereinafter, referred to as "compound A”) and a method for producing the same.
- compound A novel crystal of -4-flurobenzamide monophosphate
- Compound A has a potent and specific activity in inhibiting If current, selectively lowering heart rate and reducing cardiovascular oxygen consumption, and thus has a strong and specific activity. It is known to be useful as a prophylactic and Z or therapeutic agent for ischemic heart disease such as infarction, circulatory disease such as depressive heart failure and arrhythmia (Patent Document 1).
- Example 49 of the document specifically discloses Compound A, and describes that the crystals exhibit a melting point of 197-199 ° C. However, there is no disclosure or suggestion that Compound A exhibits polymorphism.
- a compound in which a crystalline polymorph exists has various properties different depending on the crystalline form, so that even the same compound may exhibit completely different effects.
- a compound with a different effect is expected and used with the same potency, it will produce a different effect than expected and may lead to an unexpected situation, so a constant effect can always be expected. It is required to provide compounds of the same quality. Therefore, when a compound having a crystalline polymorph is used as a pharmaceutical, a single crystal with the compound must be kept at a constant level in order to ensure uniform quality and certain effects required for the pharmaceutical. It is necessary to provide. Under the circumstances described above, from the viewpoint of drug substance supply, it is desired to establish a crystal of compound A that can ensure uniform quality and a certain level of effect and that can be stably supplied in industrial production, and a method for producing the same. ing.
- Patent Document 1 WO 00/75133 Pamphlet Disclosure of the Invention
- the present inventors have conducted intensive studies on the provision of Compound A crystals, and as a result, surprisingly, it has been found that the generated crystals fluctuate due to differences in the detailed production conditions, that is, the existence of a polymorph in Compound A. I found it.
- crystals having the powder X-ray diffraction spectrum shown in Fig. 1 are particularly excellent in hygroscopic properties, so that they can be used in the handling of drug substances and in formulation. It was found to be advantageous, and moreover, to be stable in industrial production.
- the inventors found that there was a crystal having a powder X-ray diffraction spectrum shown in FIG. That is, the present invention has been completed on the basis of these findings, and according to the present invention, the powder X-ray diffraction spectrum obtained using Cu- ⁇ radiation, the lattice spacing of 19.36, 6.23 , 4.73 and 3.81 A crystals having a main peak around A; preferably, a lattice spacing and a relative intensity in a powder X-ray diffraction spectrum obtained using Cu-Ka ray.
- a crystal of Compound A characterized by the fact that is shown in Table 1; and a crystal of Compound A, characterized by having an endothermic peak top temperature near 206-207 ° C in the DSC curve. You. (table 1 )
- the powder X-ray diffraction spectrum obtained using Cu- ⁇ rays has a main peak at a lattice spacing of around 18.40, 6.52, 5.22, 4.38 and 4.09 A.
- a crystal of compound A preferably having a lattice spacing and a relative intensity shown in Table 2 in a powder X-ray diffraction spectrum obtained using Cu-Ka radiation.
- a crystal of Compound A, wherein the DSC curve has an endothermic peak top temperature near 176-177 ° C.
- the crystal lattice spacing and overall pattern are important in determining the identity of a crystal, and the relative intensity is determined by the direction of crystal growth, the size of the particles, and the measurement. It should not be interpreted rigorously, as it can vary somewhat with conditions.
- the present invention relates to a pure crystal and a crystal of Compound A, but a mixture which can be essentially identified as a pure a-type crystal, and a type 8 crystal is also included in the present invention. You. Hereinafter, the present invention will be described in detail.
- the term “near” used for the value of the lattice spacing in the powder X-ray diffraction spectrum means that the value is approximately the value of the lattice spacing, and preferably around the value. It means that it should be in the range of 1.0 A, and more preferably, it should be in the range of 0.3 A before and after the value.
- the term “near” used for the value of the endothermic peak top temperature in the DSC curve means approximately the value of the temperature of the endothermic peak, preferably within 2 ° C around the value. It means that the temperature should be within 1 ° C before and after the value.
- the corresponding A-shaped crystals of the compound A of the present invention are salted with phosphoric acid using phosphoric acid, the crystals are heated to about 30 ° C in an ethanol (EtOH) solvent or an EtOH solvent containing a small amount of water. It can be manufactured by performing at a temperature.
- EtOH ethanol
- the crystal is cooled in an EtOH solvent or an EtOH solvent containing a small amount of water under cooling at about 5 ° C. It can be manufactured by performing.
- o-type crystals of the compound A of the present invention can be produced by recrystallizing the obtained crystals in an EtOH solvent or an EtOH solvent to which water has been added.
- seeding can be performed by inoculation, but in order to prevent rapid crystallization, the inoculation temperature is preferably room temperature or higher, more preferably 30 ° C or higher, and particularly preferably. Is above 50 ° C.
- the ⁇ -form crystal of the compound A of the present invention is obtained by suspending a mixture of the a-form crystal and the form crystal, or the form crystal in an EtOH solvent or an EtOH solvent to which water is added, and stirring at about 40 ° C. Can also be obtained.
- FIGS. 5 and 6 show the moisture absorption characteristics of two types of novel crystals of compound A according to the present invention. Show.
- ⁇ - form crystals of the compound A of the present invention are superior in the hygroscopic property as compared with the type crystals, which is advantageous in handling of the drug substance and formulation. Further, if the ⁇ - form crystal of compound (2) is produced as a single crystal form by the above production method, a certain quality required as a pharmaceutical can be secured.
- the ⁇ - type crystal and the type crystal of the compound of the present invention are morphologically pure.
- TGA-DSC thermal analysis was performed as follows.
- the heating furnace After filling 5 mg of the sample into the sample container, the heating furnace is heated at a constant heating rate (10 ° CZ minute), and the calorie change (DSC) and thermogravimetric change generated in the sample during this temperature change Changes (TGA) were continuously measured and recorded.
- DSC calorie change
- TGA thermogravimetric change generated in the sample during this temperature change Changes
- NMR shows a peak value (ppm) in 1H-NMR using (CH 3 ) 4 Si as an internal standard and using DMSO (dimethyl sulfoxide) -d 6 as a measurement solvent unless otherwise specified.
- Example 1 (Production of a Form Crystal of Compound A) EtOH was added to and dissolved in 11.94 g of the compound obtained in the same manner as in Reference Example 1 to make a total amount of 97.8 g. 5 ml of EtOH and 0.47 g of water were added to 32.6 g of this solution, and 0.86 g of 85% phosphoric acid was further added, followed by washing with 5 ml of EtOH. The crystallized solution was stirred at 30 ° C. under reduced pressure. The crystals were collected by filtration, washed with EtOH, and dried under reduced pressure to give 95.8% pure (-)-N- ⁇ 2-[(-3- (6,7-dimethoxy-1,1). 3.38 g of 2,3,4-tetrahydroisoquinoline-2-carbonyl) piperidino] ethyl ⁇ -4-fluorobenzamide monophosphate ( ⁇ -type crystal) was obtained.
- FIG. 2 is a chart showing powder X-ray diffraction data of the compound of Example 2
- FIG. 4 is a chart showing TGA-DSC thermal analysis data
- FIG. 6 is a chart showing moisture absorption characteristics.
- Toluene 440 1, 25.1 kg of (R) -piridin-3-carboxylic acid ethyl ester and 26.6 kg of? -Toluenesulfonic acid monohydrate were added to the toluene-EtO Ac solution obtained in Reference Example 2-b, The mixture was heated and the solvent was distilled off at atmospheric pressure to remove 2601. Thereafter, the mixture was stirred under reflux for 32 hours. The reaction mixture was cooled, EtOAc 260 1 and 4% (w / v) to NaPIC0 3 aq was added 180 1. The reaction solution was allowed to stand and liquid was separated at an internal temperature of around 30 ° C.
- EtOH 2601 was added to the compound obtained in Reference Example 2-c, and then water 641 was added. After cooling, NaOH aq (NaOH 8.0 kg / water 90 1) was added, and the mixture was stirred at 25 ° C. or lower for 2 hours. Under cooling, concentrated hydrochloric acid was added to the reaction solution to adjust the pH to 3.06. This solution was concentrated under reduced pressure, and toluene 1901 was added to the residue, and concentrated under reduced pressure. Toluene 1901 was added to the residue and concentrated under reduced pressure.
- Toluene 1901 was added to the residue, and the mixture was concentrated under reduced pressure to obtain ( ⁇ 1- ⁇ 2-[(4-fluorobenzobenzoyl) amino] ethyl] piperidine-3-potassic acid having a purity of 90.4%.
- Example 3 (Preparation of ⁇ type crystal of compound A) EtOH 3301 was added to the EtOH solution obtained in Reference Example 2_e. Next, 11.5 kg of 85% phosphoric acid and 521 were added, heated, and the solution was filtered. The filtrate was heated with stirring and then cooled, and a compound having the same crystal form as in Example 1 was added as a seed crystal at around 55 ° C, further cooled, and stirred at 0 to 5 ° C. The precipitated crystals were collected by filtration, washed with EtOH, and dried under reduced pressure to give (-)-N- ⁇ 2-[(i?)-3- (6,7-) with a purity of 98.9%. Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) piperidino] ethyl ⁇ -4-fluorobenzamide monophosphate ( ⁇ -type crystal) (36.51 kg) was obtained.
- FIG. 1 is a chart showing powder X-ray diffraction data of the compound of Example 3
- FIG. 3 is a chart showing TGA-DSC thermal analysis data
- FIG. 5 is a chart showing moisture absorption characteristics
- Example 4 (Production of ⁇ Form Crystal of Compound A) To 80.0 g of the compound of Example 3 were added 800 ml of EtOH and 91 nil of water, and the mixture was dissolved by heating, and the solution was filtered. The filtrate was heated with stirring and then cooled, and a compound having the same crystal form as in Example 1 was added as a seed crystal at around 60 ° C., further cooled to around 20 ° C., and stirred for crystallization.
- the present invention has the action of inhibiting If current, selectively lowers heart rate, and reduces myocardial oxygen consumption.
- ⁇ ; -type crystals and 0-type crystals of compound A which are useful as agents for preventing and / or treating cardiovascular diseases such as ischemic heart disease such as infarction, depressive heart failure and arrhythmia. Since these crystals are a pure form crystal and a form crystal of the pure compound A or a mixture that can be essentially identified with the pure ⁇ form crystal and the form crystal thereof, they are required as pharmaceuticals by the present invention. It is possible to constantly provide a single crystal that can ensure uniform quality and a certain effect. BRIEF DESCRIPTION OF THE FIGURES
- Figure 1 Powder X-ray diffraction data of ⁇ -type crystal of compound ((Example 3) The vertical axis indicates the X-ray intensity, and the horizontal axis indicates the diffraction angle (20).
- FIG. 2 is a chart showing powder X-ray diffraction data of ⁇ -type crystal of compound A (Example 2), in which the vertical axis indicates X-ray intensity and the horizontal axis indicates diffraction angle (2 °).
- FIG. 3 is a chart showing TGA-DSC thermal analysis data of the ⁇ -type crystal of Compound II (Example 3).
- FIG. 4 is a chart showing TGA-DSC thermal analysis data of] type 3 crystal (Example 2) of compound II.
- FIG. 5 A chart showing the moisture absorption characteristics of the ⁇ -type crystal of compound A (Example 3).
- FIG. 6 is a chart showing the moisture absorption characteristics of] type 3 crystal of compound (Example 2).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2005505254A JPWO2004089933A1 (ja) | 2003-04-02 | 2004-04-01 | フルオロベンズアミド誘導体の新規結晶 |
CA002519882A CA2519882A1 (en) | 2003-04-02 | 2004-04-01 | Novel crystals of fluorobenzamide derivative |
US10/552,019 US20070129357A1 (en) | 2003-04-02 | 2004-04-01 | Novel crystals of fluorobenzamide derivative |
EP04725182A EP1609788A4 (en) | 2003-04-02 | 2004-04-01 | NEW CRYSTAL OF FLUOROBENZAMIDE DERIVATIVE |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003-099411 | 2003-04-02 | ||
JP2003099411 | 2003-04-02 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2004089933A1 true WO2004089933A1 (ja) | 2004-10-21 |
Family
ID=33156697
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2004/004794 WO2004089933A1 (ja) | 2003-04-02 | 2004-04-01 | フルオロベンズアミド誘導体の新規結晶 |
Country Status (7)
Country | Link |
---|---|
US (1) | US20070129357A1 (ja) |
EP (1) | EP1609788A4 (ja) |
JP (1) | JPWO2004089933A1 (ja) |
KR (1) | KR20060029209A (ja) |
CN (1) | CN1771245A (ja) |
CA (1) | CA2519882A1 (ja) |
WO (1) | WO2004089933A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017517532A (ja) * | 2014-06-11 | 2017-06-29 | ギリアド ファーマセット エルエルシー | 抗ウイルス化合物の固体形態 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000075133A1 (fr) * | 1999-06-03 | 2000-12-14 | Yamanouchi Pharmaceutical Co., Ltd. | Derives d'isoquinoline ou leurs sels |
-
2004
- 2004-04-01 CN CNA2004800094516A patent/CN1771245A/zh active Pending
- 2004-04-01 US US10/552,019 patent/US20070129357A1/en not_active Abandoned
- 2004-04-01 EP EP04725182A patent/EP1609788A4/en not_active Withdrawn
- 2004-04-01 KR KR1020057018707A patent/KR20060029209A/ko not_active Application Discontinuation
- 2004-04-01 JP JP2005505254A patent/JPWO2004089933A1/ja not_active Abandoned
- 2004-04-01 CA CA002519882A patent/CA2519882A1/en not_active Abandoned
- 2004-04-01 WO PCT/JP2004/004794 patent/WO2004089933A1/ja active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000075133A1 (fr) * | 1999-06-03 | 2000-12-14 | Yamanouchi Pharmaceutical Co., Ltd. | Derives d'isoquinoline ou leurs sels |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017517532A (ja) * | 2014-06-11 | 2017-06-29 | ギリアド ファーマセット エルエルシー | 抗ウイルス化合物の固体形態 |
JP2019070057A (ja) * | 2014-06-11 | 2019-05-09 | ギリアド ファーマセット エルエルシー | 抗ウイルス化合物の固体形態 |
Also Published As
Publication number | Publication date |
---|---|
EP1609788A4 (en) | 2007-10-03 |
CN1771245A (zh) | 2006-05-10 |
CA2519882A1 (en) | 2004-10-21 |
EP1609788A1 (en) | 2005-12-28 |
JPWO2004089933A1 (ja) | 2006-07-06 |
KR20060029209A (ko) | 2006-04-05 |
US20070129357A1 (en) | 2007-06-07 |
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