WO2018038297A1 - (r)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트의 신규염 및 이의 결정형 - Google Patents
(r)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트의 신규염 및 이의 결정형 Download PDFInfo
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- WO2018038297A1 WO2018038297A1 PCT/KR2016/009558 KR2016009558W WO2018038297A1 WO 2018038297 A1 WO2018038297 A1 WO 2018038297A1 KR 2016009558 W KR2016009558 W KR 2016009558W WO 2018038297 A1 WO2018038297 A1 WO 2018038297A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention is novel for (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate Salts and their crystalline forms.
- Muscarinic receptors vary widely throughout the body, from the human brain to the salivary glands, which are members of G-protein coupled receptors and are subdivided into five subtypes, from M1 to M5. Of these, the M1, M2, and M3 receptors have been widely characterized for their pharmacological characteristics in animal and human tissues. Muscarinic M1 receptors are mainly expressed in the cerebral cortex and are involved in regulating high cognitive functions. M2 receptors are mainly present in the heart and bladder smooth muscle and are involved in heart rate regulation. M3 receptors are widely expressed in many peripheral tissues and are known to be involved in gastrointestinal and urinary tract irritation and saliva secretion. M4 and M5 receptors are present in the brain and mainly M4 receptors are involved in exercise, but little is known about the role of M5 receptors.
- muscarinic receptor antagonists include various diseases, such as chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, Spasmodic colitis, chronic cystitis Alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophageal refluxcardiac cardiac arrhythmias arrhythmia and hyper salvation syndromes.
- diseases such as chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, Spasmodic colitis, chronic cystitis Alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophageal refluxcardiac cardiac arrhythmias arrhythmia and hyper salvation syndromes.
- M2 and M3 are predominantly present in muscarinic receptor subtypes in human bladder, and they are known to play a role in regulating bladder contraction mechanism.
- the M2 receptor is more than three times higher than the M3 receptor in the bladder, but it plays a role in inhibiting bladder relaxation through the beta receptor rather than directly involved in bladder contraction. Is considered. Therefore, the selective antagonist of the M3 receptor shows an excellent inhibitory effect on muscarinic bladder contraction, but at the same time it causes dry mouth by inhibiting salivary gland secretion.
- Korean Unexamined Patent Application Publication No. 2015-0014673 discloses (R)-(1-methylpyrrolidin-3-yl) methyl (3'-) represented by the following formula A which selectively binds to the muscarinic M3 receptor and shows functional activity. Chloro-4'-fluoro- [l, l'-biphenyl] -2-yl) carbamate is disclosed.
- the compound in order to be considered as a candidate for development as a medicament, the compound must have not only desirable biological properties but also physical properties that enable its use in the manufacture of pharmaceutical compositions.
- such compounds should form stable, preferably crystalline solids which can be easily prepared and formulated.
- the compound of formula A is not suitable for development as a medicament as a foam or oil compound, and there is a disadvantage that it is not easy to handle industrially.
- the present inventors have therefore found that (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- is suitable for development as a medicament and improved for easier handling in industry.
- a new salt of [1,1'-biphenyl] -2-yl) carbamate and its crystalline polymorph were explored.
- the present invention provides (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2- To provide carbamate oxalate.
- (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalic acid of the present invention Salt is crystalline.
- the oxalate of the present invention may exist in Form I to Form VIII, and the present invention provides the Form I to Form VIII.
- crystalline form means a crystalline solid, ie a crystalline solid that is not a solvate, that does not contain a substantially fixed molar ratio of solvent molecules in the crystal lattice.
- the present invention relates to (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate Provides Form I.
- the (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [l, l'-biphenyl] -2- Form I of carbamate oxalate has three X-ray powder diffraction patterns selected from the group consisting of 13.402 ⁇ 0.2 °, 14.300 ⁇ 0.2 °, 18.519 ⁇ 0.2 °, 19.577 ⁇ 0.2 °, and diffraction angle 2 ⁇ of 21.499 ⁇ 0.2 ° These diffraction peaks are included.
- Form I of carbamate oxalate comprises diffraction peaks at diffraction angles 2 ⁇ of 13.402 ⁇ 0.2 °, 14.300 ⁇ 0.2 °, 18.519 ⁇ 0.2 °, 19.577 ⁇ 0.2 ° and 21.499 ⁇ 0.2 ° of X-ray powder diffraction pattern.
- (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl]- Form I of 2-yl) carbamate oxalate has an X-ray powder diffraction pattern of 7.182 ⁇ 0.2 °, 8.379 ⁇ 0.2 °, 8.679 ⁇ 0.2 °, 11.180 ⁇ 0.2 °, 16.320 ⁇ 0.2 °, 16.659 ⁇ 0.2 °, 17.321 ⁇ 0.2 °, 17.861 ⁇ 0.2 °, 20.632 ⁇ 0.2 °, 22.180 ⁇ 0.2 °, 22.922 ⁇ 0.2 °, 23.339 ⁇ 0.2 °, 24.019 ⁇ 0.2 °, 24.297 ⁇ 0.2 °, 24.699 ⁇ 0.2 °, 25.441 ⁇ 0.2 °, 27.239 ⁇ 0.2 And at least one diffraction
- the peak position of the X-ray powder diffraction pattern may substantially coincide with the peak position of FIG. 1.
- the above (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl]- Form I of 2-yl) carbamate oxalate has an onset of 121.85 ° C. ( ⁇ 0.5 ° C.) and 126.96 ° C. ( ⁇ 0.5 ° C.) in differential scanning calorimetry (DSC) analysis at elevated temperatures of 20 ° C./min. It has an endothermic peak. More preferably, the differential scanning calorific value (DSC) endothermic peak may substantially coincide with that shown in FIG. 2.
- the present invention relates to (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate Provides Form II.
- (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2- Form II of carbamate oxalate has three X-ray powder diffraction patterns selected from the group consisting of diffraction angles 2 ⁇ of 13.439 ⁇ 0.2 °, 14.481 ⁇ 0.2 °, 18.501 ⁇ 0.2 °, 21.779 ⁇ 0.2 ° and 23.358 ⁇ 0.2 ° These diffraction peaks are included.
- the (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2- Form II of the carbamate oxalate comprises diffraction peaks at diffraction angles 2 ⁇ of 13.439 ⁇ 0.2 °, 14.481 ⁇ 0.2 °, 18.501 ⁇ 0.2 °, 21.779 ⁇ 0.2 ° and 23.358 ⁇ 0.2 °.
- Form II of carbamate oxalate has an X-ray powder diffraction pattern of 8.360 ⁇ 0.2 °, 11.340 ⁇ 0.2 °, 16.401 ⁇ 0.2 °, 16.739 ⁇ 0.2 °, 17.360 ⁇ 0.2 °, 17.938 ⁇ 0.2 °, 22.179 ⁇ 0.2 °
- the peak position of the X-ray powder diffraction pattern may substantially coincide with the peak position of FIG. 10.
- the crystalline Form II is (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1 ' Crystalline Form II of -biphenyl] -2-yl) carbamate oxalate has an onset of 130.20 ° C. ( ⁇ 0.5 ° C.) and 127.39 ° C. (DSC) analysis at a temperature rise rate of 20 ° C./min. Endothermic peak). More preferably, the differential scanning calorific value (DSC) endothermic peak may substantially coincide with that shown in FIG. 11.
- the present invention relates to (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate Provides Form III.
- the (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2 Form III of carbamate oxalate has 3 X-ray powder diffraction patterns selected from the group consisting of 10.720 ⁇ 0.2 °, 11.018 ⁇ 0.2 °, 14.239 ⁇ 0.2 °, diffraction angle 2 ⁇ of 17.880 ⁇ 0.2 ° and 21.440 ⁇ 0.2 ° More than one diffraction peak.
- the (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2- Form III of the carbamate oxalate comprises diffraction peaks at diffraction angles 2 ⁇ of 10.720 ⁇ 0.2 °, 11.018 ⁇ 0.2 °, 14.239 ⁇ 0.2 °, 17.880 ⁇ 0.2 ° and 21.440 ⁇ 0.2 °.
- the (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2 Form III of carbamate oxalate has an X-ray powder diffraction pattern of 8.700 ⁇ 0.2 °, 13.098 ⁇ 0.2 °, 14.959, ⁇ 0.2 °, 15.382 ⁇ 0.2 °, 16.701 ⁇ 0.2 °, 17.309 ⁇ 0.2 °, 18.680 ⁇ 0.2 °, 19.561 ⁇ 0.2 °, 20.560 ⁇ 0.2 °, 22.042 ⁇ 0.2 °, 22.762 ⁇ 0.2 °, 23.940 ⁇ 0.2 °, 24.141 ⁇ 0.2 °, 26.855 ⁇ 0.2 °, 27.379 ⁇ 0.2 ° and 29.006 ⁇ 0.2 ° diffraction angle 2 ⁇ It further comprises at least one diffraction
- the above (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2 Form III of the -yl) carbamate oxalate may have the peak position of the X-ray powder diffraction pattern substantially coincident with the peak position of FIG. 12.
- the above (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl]- Form III of 2-yl) carbamate oxalate has an onset of 123.68 ° C ( ⁇ 0.5 ° C) and 128.37 ° C ( ⁇ 0.5 ° C) in differential scanning calorimetry (DSC) analysis when the temperature rise rate is 20 ° C / min. It has an endothermic peak. More preferably, the differential scanning calorific value (DSC) endothermic peak may substantially coincide with that shown in FIG. 13.
- the present invention relates to (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate Provides Form IV.
- Form IV of carbamate oxalate has a X-ray powder diffraction pattern of 3 selected from the group consisting of 16.642 ⁇ 0.2 °, 17.839 ⁇ 0.2 °, 20.981 ⁇ 0.2 °, 21.580 ⁇ 0.2 ° and a diffraction angle 2 ⁇ of 22.701 ⁇ 0.2 ° More than one diffraction peak.
- the (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2- Form IV of the carbamate oxalate comprises diffraction peaks at diffraction angles 2 ⁇ of 16.642 ⁇ 0.2 °, 17.839 ⁇ 0.2 °, 20.981 ⁇ 0.2 °, 21.580 ⁇ 0.2 ° and 22.701 ⁇ 0.2 °.
- Form IV of carbamate oxalate has X-ray powder diffraction pattern of 8.355 ⁇ 0.2 °, 11.415 ⁇ 0.2 °, 13.419 ⁇ 0.2 °, 13.956 ⁇ 0.2 °, 15.619 ⁇ 0.2 °, 18.579 ⁇ 0.2 °, 23.219 ⁇ 0.2 °
- at least one diffraction peak selected from the group consisting of 24.720 ⁇ 0.2 °, 26.478 ⁇ 0.2 °, 27.195 ⁇ 0.2 °, 28.143 ⁇ 0.2 ° and a diffraction angle 2 ⁇ of 29.172 ⁇ 0.2 °.
- the (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2 Form IV of the -yl) carbamate oxalate may have a peak position of the X-ray powder diffraction pattern substantially coincident with the peak position of FIG. 14.
- the crystalline Form IV is (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-ratio).
- Form IV of phenyl] -2-yl) carbamate oxalate has an onset of 120.60 ° C. ( ⁇ 0.5 ° C.) and 126.88 ° C. ( ⁇ 0.5) when differential heating calorimetry (DSC) analysis is performed at an elevated rate of 20 ° C./min. Endothermic peak). More preferably, the differential scanning calorific value (DSC) endothermic peak may substantially coincide with that shown in FIG. 15.
- the present invention relates to (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate Provides Form V.
- Form V of carbamate oxalate comprises at least three diffraction peaks selected from the group consisting of 10.925 ⁇ 0.2 °, 14.200 ⁇ 0.2 °, 20.559 ⁇ 0.2 ° and 21.396 ⁇ 0.2 ° diffraction angles 2 ⁇ . Include.
- Form V of carbamate oxalate comprises diffraction peaks at diffraction angles 2 ⁇ of 10.925 ⁇ 0.2 °, 14.200 ⁇ 0.2 °, 20.559 ⁇ 0.2 ° and 21.396 ⁇ 0.2 ° of X-ray powder diffraction pattern.
- Form V of carbamate oxalate has an X-ray powder diffraction pattern of 7.049 ⁇ 0.2 °, 8.592 ⁇ 0.2 °, 16.081 ⁇ 0.2 °, 17.226 ⁇ 0.2 °, 17.840 ⁇ 0.2 ° and 19.565 ⁇ 0.2 ° It further comprises one or more diffraction peaks selected from the group consisting of.
- the (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2- Form V of the carbamate oxalate may have the peak position of the X-ray powder diffraction pattern substantially coincident with the peak position of FIG. 16.
- the present invention relates to (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate Provides Form VI.
- Form VI of carbamate oxalate has at least three diffraction peaks selected from the group consisting of 10.127 ⁇ 0.2 °, 10.893 ⁇ 0.2 °, 11.751 ⁇ 0.2 °, and diffraction angles 2 ⁇ of 17.978 ⁇ 0.2 °.
- Form VI of the carbamate oxalate contains diffraction peaks at diffraction angles 2 ⁇ of 10.127 ⁇ 0.2 °, 10.893 ⁇ 0.2 °, 11.751 ⁇ 0.2 ° and 17.978 ⁇ 0.2 ° of X-ray powder diffraction pattern.
- the (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl Form VI of the carbamate oxalate has at least one X-ray powder diffraction pattern selected from the group consisting of 7.150 ⁇ 0.2 °, 14.362 ⁇ 0.2 °, 14.654 ⁇ 0.2 °, 15.251 ⁇ 0.2 ° and a diffraction angle 2 ⁇ of 16.360 ⁇ 0.2 ° It further comprises a diffraction peak.
- the (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2 Form VI of the -yl) carbamate oxalate may have the peak position of the X-ray powder diffraction pattern substantially coincident with the peak position of FIG. 17.
- the present invention relates to (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate To give crystalline form VII.
- the crystalline form of the carbamate oxalate has three or more diffraction peaks selected from the group consisting of a diffraction angle 2 ⁇ of 8.169 ⁇ 0.2 °, 8.847 ⁇ 0.2 °, 11.071 ⁇ 0.2 ° and 13.156 ⁇ 0.2 ° Include.
- the crystal form VII of the carbamate oxalate has a diffraction peak at diffraction angles 2 ⁇ of 8.169 ⁇ 0.2 °, 8.847 ⁇ 0.2 °, 11.071 ⁇ 0.2 ° and 13.156 ⁇ 0.2 °.
- Crystalline thin X-ray powder diffraction pattern of carbamate oxalate was selected from the group consisting of diffraction angles 2 ⁇ of 13.3454 ⁇ 0.2 °, 14.220 ⁇ 0.2 °, 15.828 ⁇ 0.2 °, 16.486 ⁇ 0.2 ° and 17.186 ⁇ 0.2 ° More than one diffraction peak.
- the present invention relates to (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate Provides Form VIII.
- Form VIII of carbamate oxalate comprises at least three diffraction peaks selected from the group consisting of a diffraction angle 2 ⁇ of 8.903 ⁇ 0.2 °, 13.090 ⁇ 0.2 °, 14.347 ⁇ 0.2 ° and 15.871 ⁇ 0.2 ° do.
- the (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2- Form VIII of the carbamate oxalate has an X-ray powder diffraction pattern comprising diffraction peaks at diffraction angles 2 ⁇ of 8.903 ⁇ 0.2 °, 13.090 ⁇ 0.2 °, 14.347 ⁇ 0.2 ° and 15.871 ⁇ 0.2 °.
- the (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2- Form VIII of carbamate oxalate has one X-ray powder diffraction pattern selected from the group consisting of 6.720 ⁇ 0.2 °, 10.646 ⁇ 0.2 °, 11.683 ⁇ 0.2 °, diffraction angle 2 ⁇ of 13.490 ⁇ 0.2 ° and 17.941 ⁇ 0.2 ° The diffraction peaks above are further included.
- Form VIII may have a peak position of the X-ray powder diffraction pattern substantially coincident with the peak position of FIG. 19.
- the present invention relates to (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate free base Dissolving in acetone; Adding oxalic acid to the solution and stirring; And (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-ratio) comprising crystallizing with methyl-t-butyl ether Phenyl] -2-yl) carbamate oxalate Crystalline Form I is provided.
- the present invention relates to (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate Recrystallizing oxalate crystalline Form I with one or two or more solvents selected from the group consisting of alcohol solvents, ether solvents, ester solvents, ketone solvents, halogenated hydrocarbon solvents, nitrile solvents and hydrocarbon solvents (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalic acid
- solvents selected from the group consisting of alcohol solvents, ether solvents, ester solvents, ketone solvents, halogenated hydrocarbon solvents, nitrile solvents and hydrocarbon solvents
- the present invention provides the above-mentioned (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) Carbamate oxalate crystalline Form I is dichloromethane; Acetone; Heptane; Methyl ethyl ketone; Acetonitrile; And (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1, comprising recrystallization with a recrystallization solvent selected from the group consisting of a mixture thereof.
- recrystallization with the recrystallization solvent may further include adding a recrystallization solvent and centrifuging.
- the present invention also provides the above-mentioned (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carba Mate oxalate crystal Form I is ethanol; Methyl t-butyl ether; Heptane; 1,4-dioxane; Isopropyl acetate; Dichloromethane; Isopropanol; And (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1, comprising recrystallization with a recrystallization solvent selected from the group consisting of a mixture thereof. 1'-biphenyl] -2-yl) carbamate oxalate Crystalline Form III is provided.
- Recrystallization with the recrystallization solvent in the method for preparing carbamate oxalate crystalline Form III may further include the step of adding a recrystallization solvent, stirring, and centrifugation.
- the present invention also provides the above-mentioned (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carba (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1 comprising recrystallizing mate oxalate crystalline Form I with 1,4-dioxane
- recrystallization with the recrystallization solvent may further include adding a recrystallization solvent and centrifuging.
- the (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2- (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1) comprising the step of recrystallizing the carbamate oxalate crystalline Form II with butanol; '-Biphenyl] -2-yl) carbamate oxalate Crystalline Form V is provided.
- (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1 ') comprising recrystallizing carbamate oxalate crystalline Form II with methanol -Biphenyl] -2-yl) carbamate oxalate crystal Form VI is provided.
- Recrystallization with the recrystallization solvent in the method for preparing carbamate oxalate crystalline form VII may include sequentially adding the recrystallization solvent.
- Recrystallization with the recrystallization solvent in the method for preparing carbamate oxalate crystalline Form VIII may include sequentially adding the recrystallization solvent.
- the drying temperature can be adjusted according to the type of the crystalline form to be acquired.
- the aforementioned (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] Provides a muscarinic M3 antagonist comprising 2-yl) carbamate oxalate as an active ingredient.
- the muscarinic M3 receptor antagonist is chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis.
- colitis, chronic cystitis, Alzheimer disease, senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux disease, cardiac arrhythmia, Hyper salivation syndroms may be a composition for the prevention or treatment of diseases selected from the group consisting of nocturnal enuresis, neuronal urinary, neurogenic bladder, unstable bladder, bladder spasm and urinary frequency.
- the muscarinic M3 antagonist is (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1 '
- it may further comprise one or more active ingredients exhibiting the same or similar function.
- the present invention is prepared by including one or more pharmaceutically acceptable carriers in addition to the above-described active ingredient for administration
- the pharmaceutically acceptable carrier is saline, sterile Water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components can be mixed and used as needed.
- Other conventional additives such as antioxidants, buffers and bacteriostatic agents can be added as necessary. Can be.
- diluents, dispersants, surfactants, binders and lubricants may be additionally added to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.
- it may be preferably formulated according to each disease or component by an appropriate method in the art or using a method disclosed in Remington's Pharmaceutical Science, Merck Publishing Company, Easton PA.
- the pharmaceutical composition may be administered orally or parenterally in the form of injection, suppository, transdermal, inhalant, or intra-bladder injection.
- muscarinic M3 receptor antagonist of the present invention when the muscarinic M3 receptor antagonist of the present invention is for oral administration, (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1] of the present invention , 1'-biphenyl] -2-yl) carbamate oxalate may be contained from 0.1% to 95% by weight in the formulation.
- the present invention also relates to (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) of the present invention.
- a method for treating or alleviating a disease caused by a decrease in muscarinic M3 receptor effect by administering a muscarinic M3 receptor antagonist containing carbamate oxalate as an active ingredient to a mammal including a human in need of the muscarinic M3 receptor antagonist effect. do.
- the muscarinic M3 receptor antagonist of the present invention may be used alone or in combination with methods using surgery, hormonal therapy, drug treatment and biological response modifiers for the prevention and treatment of diseases caused by reduced muscarinic M3 receptor effects. .
- Oxalate is another of (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate
- the salt form it has a relatively high melting point, low hygroscopicity, and is a crystalline form that allows for rapid dissolution, making it well suited for formulation.
- it is excellent in storage stability, excellent in mechanical stability and fluidity, and uniform in particle, making it very suitable as a raw medicine.
- (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate There are various forms of crystalline forms, which are the properties of the occurrence of different crystalline forms of a single compound and the combination of several compounds. These crystalline polymorphs are recognized as different solids that share the same molecular formula, and have unique physicochemical properties such as solubility, melting point, and X-ray powder diffraction pattern. In addition, it can improve the stability and efficacy of medicines by improving solubility.
- Figure 2 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate The results of the differential scanning calorimetry of Form I are shown.
- Figure 3 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate Nuclear magnetic resonance results of Form I are shown.
- Figure 4 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate citrate X-ray powder diffraction (XPRD) results are shown.
- FIG. 6 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate citrate Nuclear magnetic resonance results are shown.
- Figure 7 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate phosphate X-ray powder diffraction (XPRD) results are shown.
- Figure 8 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate phosphate The results of the differential scanning calorimetry are shown.
- Figure 9 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate phosphate Nuclear magnetic resonance results are shown.
- Figure 10 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate X-ray powder diffraction (XPRD) results of Form II are shown.
- Figure 11 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate The results of the differential scanning calorimetry of Form II are shown.
- Figure 12 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate X-ray powder diffraction (XPRD) results of Form III are shown.
- FIG. 13 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate The results of the differential scanning calorimetry of Form III are shown.
- Figure 14 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate X-ray powder diffraction (XPRD) results of Form IV are shown.
- Figure 15 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate The results of the differential scanning calorimetry of Form IV are shown.
- Figure 16 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate X-ray powder diffraction (XPRD) results of Form V are shown.
- Figure 17 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate X-ray powder diffraction (XPRD) results of Form VI are shown.
- Figure 18 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate X-ray powder diffraction (XPRD) results of Form VII are shown.
- Figure 19 shows (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate X-ray powder diffraction (XPRD) results of Form VIII are shown.
- An X-ray powder diffraction pattern was obtained using a BRUKER D8 ADVANCE model using CuK ⁇ irradiation at 1.54178 Hz (40 kV, 40 mA) with a solid-state detector. The analysis was measured with a 0.02 ° step size over a range of 3 ° to 50 ° at a 2 ⁇ angle.
- DSC Differential Scanning Calorimetry
- Nuclear magnetic resonance (NMR) analysis was performed using Varian oxford 400 MHz and Agilent 600 MHz.
- Mobile phase buffer Prepare 0.01M (NH 4 ) HCO 3 solution and adjust pH to 10.5 with ammonia water.
- the title compound was obtained.
- the X-ray powder diffraction (XPRD) pattern thereof is shown in FIG. 4, the differential scanning calorimetry (DSC) result is shown in FIG. 5, and the nuclear magnetic resonance (NMR) analysis result is shown in FIG. 6.
- Form I of (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate 40 mg) was dissolved in acetone (2 mL) and heptane (2 mL) was added thereto. After stirring for 24 hours at room temperature centrifuged and dried at 40 °C to prepare Form II.
- Form I of (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate 50 mg) was added to acetone (0.6 mL) and completely dissolved at 60 ° C. After dissolution, the resulting crystals were cooled to room temperature, and the resulting crystals were centrifuged and dried at 40 ° C. to prepare Form II.
- Form II was prepared using methyl ethyl ketone instead of acetone in the same manner as in Example 5.
- Form II was prepared using acetonitrile instead of acetone in the same manner as in Example 5.
- Form II was prepared using acetone instead of dichloromethane in the same manner as in Example 3.
- Form I of (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate 40 mg) was dissolved in ethanol (1 mL), and heptane (1 mL) was added thereto. After stirring for 1 hour at room temperature, the resultant was centrifuged and dried at 40 ° C. to prepare Form III.
- Form I of (R)-(1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate 40 mg) was dissolved in dichloromethane (2 mL), and isopropyl acetate (2 mL) was added thereto. After stirring for 1 hour at room temperature, centrifugation and drying at 40 °C to prepare Form III.
- Form III was prepared using isopropanol instead of acetone.
- Form IV was prepared using 1,4-dioxane instead of acetone in the same manner as in Example 5.
- the X-ray powder diffraction (XPRD) pattern thereof is shown in FIG. 14, and the differential scanning calorimetry (DSC) result is shown in FIG. 15.
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Abstract
Description
Claims (31)
- 제1항에 있어서, 상기 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염은 결정성인 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염.
- X선 분말 회절 패턴이 13.402±0.2°, 14.300±0.2°, 18.519±0.2°, 19.577±0.2° 및 21.499±0.2°의 회절각 2θ으로 이루어진 군으로부터 선택된 3 개 이상의 회절 피크를 포함하는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅰ.
- 제3항에 있어서, X선 분말 회절 패턴이 7.182±0.2°, 8.379±0.2°, 8.679±0.2°, 11.180±0.2°, 16.320±0.2°, 16.659±0.2°, 17.321±0.2°, 17.861±0.2°, 20.632±0.2°, 22.180±0.2°, 22.922±0.2°, 23.339±0.2°, 24.019±0.2°, 24.297±0.2°, 24.699±0.2°, 25.441±0.2°, 27.239±0.2° 및 29.880±0.2°의 회절각 2θ으로 이루어진 군으로부터 선택된 1 개 이상의 회절 피크를 더 포함하는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 I.
- 제3항에 있어서, 승온속도가 20 ℃/분인 경우, 시차주사열량(DSC) 분석시 121.85℃ (±0.5℃)의 개시온도(onset)와 126.96℃ (±0.5℃)의 흡열피크를 갖는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅰ.
- (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 유리 염기를 아세톤에 용해하는 단계; 상기 용액에 옥살산을 투입하고, 교반하는 단계; 및 메틸-t-부틸 에테르로 결정화시키는 단계를 포함하는 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염 결정형 Ⅰ의 제조 방법.
- X선 분말 회절 패턴이 13.439±0.2°, 14.481±0.2°, 18.501±0.2°, 21.779±0.2° 및 23.358±0.2°의 회절각 2θ으로 이루어진 군으로부터 선택된 3 개 이상의 회절 피크를 포함하는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅱ.
- 제7항에 있어서, X선 분말 회절 패턴이 8.360±0.2°, 11.340±0.2°, 16.401±0.2°, 16.739±0.2°, 17.360±0.2°, 17.938±0.2°, 22.179±0.2°, 24.299±0.2°, 24.641±0.2°, 25.500±0.2°, 26.422±0.2°, 27.260±0.2°, 28.201±0.2° 및 29.878±0.2°의 회절각 2θ으로 이루어진 군으로부터 선택된 1 개 이상의 회절 피크를 더 포함하는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅱ.
- 제7항에 있어서, 승온속도가 20 ℃/분인 경우, 시차주사열량(DSC) 분석시 127.39℃ (±0.5℃)의 개시온도(onset)와 130.20℃ (±0.5℃)의 흡열피크를 갖는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅱ.
- (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅰ을 디클로로메탄; 아세톤; 헵탄; 메틸에틸케톤; 아세토니트릴; 및 이들의 혼합물로 이루어진 군에서 선택된 재결정 용매로 재결정하는 단계를 포함하는 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염 결정형 Ⅱ의 제조 방법.
- X선 분말 회절 패턴이 10.720±0.2°, 11.018±0.2°, 14.239±0.2°, 17.880 ±0.2° 및 21.440±0.2°의 회절각 2θ으로 이루어진 군으로부터 선택된 3 개 이상의 회절 피크를 포함하는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅲ.
- 제11항에 있어서, X선 분말 회절 패턴이 8.700±0.2°, 13.098±0.2°, 14.959, ±0.2°, 15.382±0.2°, 16.701±0.2°, 17.309±0.2°, 18.680±0.2°, 19.561±0.2°, 20.560±0.2°, 22.042±0.2°, 22.762±0.2°, 23.940±0.2°, 24.141±0.2°, 26.855±0.2°, 27.379±0.2° 및 29.006±0.2°의 회절각 2θ으로 이루어진 군으로부터 선택된 1 개 이상의 회절 피크를 더 포함하는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅲ.
- 제11항에 있어서, 승온속도가 20 ℃/분인 경우, 시차주사열량(DSC) 분석시 123.68℃ (±0.5℃)의 개시온도(onset)와 128.37℃ (±0.5℃)의 흡열피크를 갖는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅲ.
- (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅰ을 에탄올; 메틸-t-부틸에테르; 헵탄; 1,4-디옥산; 이소프로필아세테이트; 디클로로메탄; 이소프로판올; 및 이들의 혼합물로 이루어진 군에서 선택된 재결정 용매로 재결정하는 단계를 포함하는 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염 결정형 Ⅲ의 제조 방법.
- X선 분말 회절 패턴이 16.642±0.2°, 17.839±0.2°, 20.981±0.2°, 21.580 ±0.2° 및 22.701±0.2°의 회절각 2θ으로 이루어진 군으로부터 선택된 3 개 이상의 회절 피크를 포함하는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅳ.
- 제15항에 있어서, X선 분말 회절 패턴이 8.355±0.2°, 11.415±0.2°, 13.419±0.2°, 13.956±0.2°, 15.619±0.2°, 18.579±0.2°, 23.219±0.2°, 24.720±0.2°, 26.478±0.2°, 27.195±0.2°, 28.143±0.2°및 29.172±0.2°의 회절각 2θ으로 이루어진 군으로부터 선택된 1 개 이상의 회절 피크를 더 포함하는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅳ.
- 제15항에 있어서, 승온속도가 20 ℃/분인 경우, 시차주사열량(DSC) 분석시 120.60℃ (±0.5℃)의 개시온도(onset)와 126.88℃ (±0.5℃)의 흡열피크를 갖는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅳ.
- (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅰ을 1,4-디옥산으로 재결정하는 단계를 포함하는 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염 결정형 Ⅳ의 제조 방법.
- X선 분말 회절 패턴이 10.925±0.2°, 14.200±0.2°, 20.559±0.2° 및 21.396±0.2°의 회절각 2θ으로 이루어진 군으로부터 선택된 3 개 이상의 회절 피크를 포함하는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅴ.
- 제19항에 있어서, 상기 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅴ는 X선 분말 회절 패턴이 7.049±0.2°, 8.592±0.2°, 16.081±0.2°, 17.226±0.2°, 17.840±0.2°및 19.565±0.2°의 회절각 2θ으로 이루어진 군으로부터 선택된 1 개 이상의 회절 피크를 더 포함하는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅴ.
- (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅱ를 부탄올로 재결정하는 단계를 포함하는 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염 결정형 Ⅴ의 제조 방법.
- X선 분말 회절 패턴이 10.127±0.2°, 10.893±0.2°, 11.751±0.2° 및 17.978±0.2°의 회절각 2θ으로 이루어진 군으로부터 선택된 3 개 이상의 회절 피크를 포함하는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅵ.
- 제22항에 있어서, X선 분말 회절 패턴이 7.150±0.2°, 14.362±0.2°, 14.654±0.2°, 15.251±0.2°및 16.360±0.2°의 회절각 2θ으로 이루어진 군으로부터 선택된 1 개 이상의 회절 피크를 더 포함하는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅵ.
- (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅱ를 메탄올로 재결정하는 단계를 포함하는 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염 결정형 Ⅵ의 제조 방법.
- X선 분말 회절 패턴이 8.169±0.2°, 8.847±0.2°, 11.071±0.2° 및 13.156±0.2°의 회절각 2θ으로 이루어진 군으로부터 선택된 3 개 이상의 회절 피크를 포함하는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅶ.
- 제25항에 있어서, X선 분말 회절 패턴이 13.3454±0.2°, 14.220±0.2°, 15.828±0.2°, 16.486±0.2° 및 17.186±0.2°의 회절각 2θ으로 이루어진 군으로부터 선택된 1 개 이상의 회절 피크를 더 포함하는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅶ.
- (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅱ를 에탄올; 벤젠; 및 이들의 혼합물로 이루어진 군에서 선택된 재결정 용매로 재결정하는 단계를 포함하는 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염 결정형 Ⅶ의 제조 방법.
- X선 분말 회절 패턴이 8.903±0.2°, 13.090±0.2°, 14.347±0.2° 및 15.871±0.2°의 회절각 2θ으로 이루어진 군으로부터 선택된 3 개 이상의 회절 피크를 포함하는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 VIII.
- 제28항에 있어서, X선 분말 회절 패턴이 6.720±0.2°, 10.646±0.2°, 11.683±0.2°, 13.490±0.2°및 17.941±0.2°의 회절각 2θ으로 이루어진 군으로부터 선택된 1 개 이상의 회절 피크를 더 포함하는 것인 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 VIII.
- (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염의 결정형 Ⅱ를 에탄올; 벤젠; 및 이들의 혼합물로 이루어진 군에서 선택된 재결정 용매로 재결정하는 단계를 포함하는 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염 결정형 VIII의 제조 방법.
- 제1항 내지 제5항, 제7항 내지 제9항, 제11항 내지 제13항, 제15항 내지 제17항, 제19항, 제20항, 제22항, 제23항, 제25항, 제26항, 제28항 및 제29항 중 어느 한 항에 따른 (R)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트 옥살산염을 유효 성분으로 포함하는, 만성 폐쇄성 폐질환(chronic obstructive pulmonary disease), 천식(asthma), 과민성 대장 증후군(irritable bowel syndrome), 요실금(urinary incontinence), 비염(rhinitis), 경련성 대장염(spasmodic colitis), 만성 방광염(chronic cystitis), 알츠하이머병(Alzheimer disease), 노인성 치매(senile dementia), 녹내장(glaucoma), 조현병(schizophrenia), 역류성 식도염(gastroesophogeal reflux disease), 심장 부정맥(cardiac arrhythmia), 타액분비항진증(hyper salivation syndroms), 야뇨증, 신경성 빈뇨, 신경 원인성 방광, 불안정 방광, 방광 연축 및 빈뇨로 이루어진 군으로부터 선택되는 질환의 예방 또는 치료용 무스카린 M3 수용체 길항제.
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CA3034535A CA3034535C (en) | 2016-08-26 | 2016-08-26 | Novel salt of (r)-(1-methylpyrrolidine-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate and a crystal form thereof |
UAA201902823A UA124156C2 (uk) | 2016-08-26 | 2016-08-26 | Сіль (r)-(1-метилпіролідин-3-іл)метил(3'-хлор-4'-фтор-[1,1'-біфеніл]-2-іл)карбамату та її кристалічна форма |
SG11201901431PA SG11201901431PA (en) | 2016-08-26 | 2016-08-26 | Novel salt of (r)-(1-methylpyrrolidine-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate and a crystal form thereof |
AU2016420300A AU2016420300B2 (en) | 2016-08-26 | 2016-08-26 | Novel salt of (R)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate and crystal form thereof |
MX2019002301A MX2019002301A (es) | 2016-08-26 | 2016-08-26 | Nueva sal de (r)-(1-metilpirrolidin-3-il) metil (3'-chloro-4'-fluoro- [1,1'-bifenil]-2-il) carbamato y una forma cristalina del misma. |
US16/328,492 US10894768B2 (en) | 2016-08-26 | 2016-08-26 | Salt of (R)-(1-methylpyrrolidine-3-yl)methyl(3′-chloro-4′-fluoro-[1,1′-biphenyl]-2-yl)carbamate and crystal form thereof |
PCT/KR2016/009558 WO2018038297A1 (ko) | 2016-08-26 | 2016-08-26 | (r)-(1-메틸피롤리딘-3-일)메틸(3'-클로로-4'-플루오로-[1,1'-비페닐]-2-일)카바메이트의 신규염 및 이의 결정형 |
BR112019003949-0A BR112019003949B1 (pt) | 2016-08-26 | 2016-08-26 | Sal de (r)-(1-metilpirrolidina-3-il)metil(3-cloro-4- fluoro-[1,1-bifenil] -2-il)carbamato inovador e uma forma cristalina dos mesmos |
PH12019500380A PH12019500380A1 (en) | 2016-08-26 | 2019-02-22 | Novel salt of (r)-(1-methylpyrrolidine-3-yl)methyl(3`-chloro-4`fluoro-[1,1`-biphenyl]-2-yl)carbamate and a crystal form thereof |
CONC2019/0001740A CO2019001740A2 (es) | 2016-08-26 | 2019-02-26 | Nueva sal de (r)-(1-metilpirrolidin-3-il)metil(3'-cloro-4'-fluoro-[1,1'-bifenil]-2-il)carbamato y una forma cristalina del misma |
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CO (1) | CO2019001740A2 (ko) |
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Citations (5)
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EP0747355A1 (en) * | 1994-02-10 | 1996-12-11 | Yamanouchi Pharmaceutical Co. Ltd. | Novel carbamate derivative and medicinal composition containing the same |
KR20060129017A (ko) * | 2004-01-13 | 2006-12-14 | 글락소 그룹 리미티드 | 무스카린성 아세틸콜린 수용체 길항제 |
US20100105658A1 (en) * | 2007-02-09 | 2010-04-29 | Astellas Pharma Inc. | Aza-bridged-ring compound |
US20140080800A1 (en) * | 2011-04-28 | 2014-03-20 | The Broad Institute, Inc. | Inhibitors of Histone Deacetylase |
KR20150014673A (ko) * | 2013-07-30 | 2015-02-09 | 동아에스티 주식회사 | 신규한 바이페닐 유도체 및 그의 제조방법 |
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- 2016-08-26 US US16/328,492 patent/US10894768B2/en active Active
- 2016-08-26 WO PCT/KR2016/009558 patent/WO2018038297A1/ko active Application Filing
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2019
- 2019-02-22 PH PH12019500380A patent/PH12019500380A1/en unknown
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0747355A1 (en) * | 1994-02-10 | 1996-12-11 | Yamanouchi Pharmaceutical Co. Ltd. | Novel carbamate derivative and medicinal composition containing the same |
KR20060129017A (ko) * | 2004-01-13 | 2006-12-14 | 글락소 그룹 리미티드 | 무스카린성 아세틸콜린 수용체 길항제 |
US20100105658A1 (en) * | 2007-02-09 | 2010-04-29 | Astellas Pharma Inc. | Aza-bridged-ring compound |
US20140080800A1 (en) * | 2011-04-28 | 2014-03-20 | The Broad Institute, Inc. | Inhibitors of Histone Deacetylase |
KR20150014673A (ko) * | 2013-07-30 | 2015-02-09 | 동아에스티 주식회사 | 신규한 바이페닐 유도체 및 그의 제조방법 |
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MX2019002301A (es) | 2019-12-11 |
CA3034535C (en) | 2021-07-06 |
CA3034535A1 (en) | 2018-03-01 |
US20190194129A1 (en) | 2019-06-27 |
BR112019003949B1 (pt) | 2023-12-12 |
PH12019500380A1 (en) | 2019-11-25 |
BR112019003949A2 (pt) | 2019-05-21 |
US10894768B2 (en) | 2021-01-19 |
AU2016420300A1 (en) | 2019-03-14 |
AU2016420300B2 (en) | 2019-11-21 |
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