CN104140429B - Lixivaptan crystalline form V and its production and use - Google Patents
Lixivaptan crystalline form V and its production and use Download PDFInfo
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- CN104140429B CN104140429B CN201410359832.2A CN201410359832A CN104140429B CN 104140429 B CN104140429 B CN 104140429B CN 201410359832 A CN201410359832 A CN 201410359832A CN 104140429 B CN104140429 B CN 104140429B
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- 0 C[N+](C(C=CC(C(O)=O)=C)=CC*)[O-] Chemical compound C[N+](C(C=CC(C(O)=O)=C)=CC*)[O-] 0.000 description 5
- POAQFKSUTQWHMZ-UHFFFAOYSA-N C(c1ccc[n]1C1)Nc2c1cccc2 Chemical compound C(c1ccc[n]1C1)Nc2c1cccc2 POAQFKSUTQWHMZ-UHFFFAOYSA-N 0.000 description 1
- UQOQKWQBSKFITF-UHFFFAOYSA-N CC(c1c(C)ccc(F)c1)Nc1ccc(C(Cl)=O)c(Cl)c1 Chemical compound CC(c1c(C)ccc(F)c1)Nc1ccc(C(Cl)=O)c(Cl)c1 UQOQKWQBSKFITF-UHFFFAOYSA-N 0.000 description 1
- DSHBGNPOIBSIOQ-UHFFFAOYSA-N COC(c(c(Cl)c1)ccc1N)=O Chemical compound COC(c(c(Cl)c1)ccc1N)=O DSHBGNPOIBSIOQ-UHFFFAOYSA-N 0.000 description 1
- HBAQRSDZSVESSF-UHFFFAOYSA-N Cc(ccc(F)c1)c1C(Cl)=O Chemical compound Cc(ccc(F)c1)c1C(Cl)=O HBAQRSDZSVESSF-UHFFFAOYSA-N 0.000 description 1
- PPHTXRNHTVLQED-UHFFFAOYSA-N Cc(ccc(F)c1)c1C(Nc1ccc(C(N(C2)c3ccccc3C[n]3c2ccc3)=O)c(Cl)c1)=O Chemical compound Cc(ccc(F)c1)c1C(Nc1ccc(C(N(C2)c3ccccc3C[n]3c2ccc3)=O)c(Cl)c1)=O PPHTXRNHTVLQED-UHFFFAOYSA-N 0.000 description 1
- XKQPFXGJKICVEM-UHFFFAOYSA-N Cc1cc(C(Nc2ccc(C(N(C3)c4ccccc4C[n]4c3ccc4)=O)c(Cl)c2)=O)c(C)cc1 Chemical compound Cc1cc(C(Nc2ccc(C(N(C3)c4ccccc4C[n]4c3ccc4)=O)c(Cl)c2)=O)c(C)cc1 XKQPFXGJKICVEM-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
Abstract
The present invention relates to lixivaptan crystalline form V and preparation method thereof, also relate to the pharmaceutical composition and purposes prepared with gained lixivaptan crystalline form V of the present invention.This lixivaptan crystalline form V characterizes with its powder x-ray diffraction figure.
Description
Technical field
The invention belongs to heart failure resistance pharmaceutical field, more particularly, relate to N-[the chloro-4-(10 of 3-of lixivaptan (lixivaptan) or formula I, 11-dihydro-5H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] benzodiazepine-10-base carbonyl) phenyl] and-5-fluoro-2-methylbenzene methane amide crystalline form V and preparation method thereof, containing it pharmaceutical composition and manufacturing the purposes in treatment hyponatremia medicine.
Background technology
Arginine vasopressin (AVP) is also known as β-hypophamine, antidiuretic hormone, being produced by hypothalamus and the one 9 peptide ring-type hormone of hypophysis release, producing antidiuresis by combining from different AVP receptor subtypes, vasoconstriction, reinforcement remember, participate in the body temperature physiological action different with immunomodulatory, participation social behavior adjustment etc.AVP acceptor belongs to G-protein linked receptor, is divided into 3 kinds of hypotypes: Vla, Vlb and V2 acceptor according to the difference of transmission mechanism.V1a acceptor is mainly distributed in the positions such as vascular smooth muscle cell, thrombocyte, adrenal cortex and myometrium, main mediate vascular contraction, platelet aggregation and uterine contraction.V1b acceptor is mainly distributed in prepituitary gland, mediation ACTH release; V2 acceptor is positioned at collecting duct, and main participation regulates collecting tubule to the permeability of water.AVP take part in the process of the diseases such as Raynaud's syndrome, dysmenorrhoea, premature labor, corticotropin releasing hormone parasecretion, dysthymia disorders, chronic heart failure, liver cirrhosis, the disorderly syndromes of antidiuretic hormone secretion, therefore, AVP receptor antagonist is the focus of research in world wide always.
The interest that people develop AVP receptor antagonist starts from the exploitation of early 1960s peptide class AVP receptor antagonist.But these peptides are short for biological half-life, and oral administration biaavailability is low, although have antagonistic action in experimentation on animals, more weak to the AVP receptor antagonist activity of human body, be difficult to develop further as ideal medicament.From first non-peptide class AVP receptor antagonist OPC-21268 in 1991 since Japan finds, a series of non-peptide class AVP receptor antagonist is come out one after another, wherein conivaptan, mozavaptan, tolvaptan granted listing abroad successively.These non-peptide compounds have better bioavailability and longer biological half-life than previous peptides.Therefore, the focus that efficient non-peptide class AVP receptor antagonist is pharmacy worker is always found.
Lixivaptan (Lixivaptan, 1) be a kind of non-peptide class oral selectivity arginine vasopressin V2 receptor antagonist researched and developed by U.S. Hui Shi (wyeth) company, chemistry N-[the chloro-4-(10 of 3-by name, 11-dihydro-5H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] benzodiazepine-10-base carbonyl) phenyl]-5-fluoro-2-methylbenzene methane amide.Clinical study shows, compared with traditional diuretics, lixivaptan be used for the treatment of congestive heart failure (CHF), Patients with Liver Cirrhosis Accompanied hyponatremia and syndrome of inappropriate ADH secretion (SIADH) patient time, it does not affect the discharge of kidney sodium while improving free water clearance, also can not activate neuroendocrine system, and there is higher security and tolerance.Lixivaptan, to the tolvaptan of the selectivity of V2 acceptor higher than in May, 2009 U.S. FDA approval, in the III phase clinical study of U.S.'s completed treatment hyponatremia, has been in pre-registration stage.
Document (Journalofmedicinalchemistry, 1998,41 (14): 2442-2444.) report that lixivaptan has two synthetic routes, route one is with 10,11-dihydro-5H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] benzodiazepine (2) is raw material, 4-nitro benzoyl chloro-with 2-and 5-fluoro-2-methylbenzene formyl radical dock successively, and obtained 1; Route two is first by chloro-for 2-PABA methyl esters (5) and 5-fluoro-2-methylbenzene formyl chloride (7) docking, through hydrolysis, the obtained chloro-4-of 2-of the reaction such as chloride [(5-fluoro-2-methylbenzene formyl) is amino] Benzoyl chloride (10), then react obtained 1 with 2.Because raw material divalent lattice are expensive, route one is with 2 for starting raw material, and through polystep reaction, its utilization ratio is lower, and production cost is higher.Therefore this research is with reference to route two, with the chloro-4-nitrobenzoic acid (3) of 2-for starting raw material, through esterification, and hydro-reduction, acylations, hydrolysis, the reaction such as chloride obtained 10; 10 obtain 1 with 2 through N-acylation reaction again.1 synthetic route is as follows.
Chemical structure:
(Ⅰ)
Molecular formula: C
27h
21clFN
3o
2
Molecular weight: 473.93
The preparation method of this product abroad has been reported, as document Journalofmedicinalchemistry, and 1998,41 (14): 2442-2444. and US, 5516774 [P], 1996-5-14.At present, lixivaptan (lixivaptan) is in III phase clinical investigation phase abroad, has good development prospect, in view of the pharmacy value of this compound, obtain purity high, have and determine crystal formation very much and the compound of favorable reproducibility is important.
The present inventor is repeated document US, the method for 5516774, and the lixivaptan purity obtained is 97.5%, mp191-195 DEG C, and through the research of multiple batches, fusing point is consistent, and its powder x-ray diffraction figure is shown in accompanying drawing 1.
Summary of the invention
An object of the present invention is to provide lixivaptan crystalline form V.
Another object of the present invention is to provide the preparation method of lixivaptan crystalline form V.
A further object of the invention is to provide lixivaptan crystalline form V as effective constituent, and containing the medicinal compositions of one or more pharmaceutically acceptable carrier, vehicle or thinners, and as the application of argnine vasopressin receptor antagonist.
Now in conjunction with the object of the invention, content of the present invention is specifically described.
Lixivaptan of the present invention has following structural formula:
Lixivaptan crystalline form V has following characteristics:
Measure with D/Max-2500 type x-ray diffractometer, condition determination: CuKa, 40KV, 100mA, its collection of illustrative plates has following diffraction angle (2 θ), spacing (d value) and intensity (%), and the error of 2 θ is 0.2.In table 1, refer to Figure of description 2.
Table 1 lixivaptan crystalline form V measurement result
| Spectral line number | 2 θ (degree) | Spacing (d) | I/I 0 |
| 1 | 6.940 | 12.7265 | 100 |
| 2 | 8.080 | 10.9333 | 7 |
| 3 | 12.020 | 7.3569 | 2 |
| 4 | 13.080 | 6.7630 | 2 |
| 5 | 13.960 | 6.3386 | 13 |
| 6 | 14.260 | 6.2059 | 23 |
| 7 | 14.560 | 6.0787 | 51 |
| 8 | 16.060 | 5.5142 | 7 |
| 9 | 16.320 | 5.4269 | 16 |
| 10 | 18.020 | 4.9186 | 4 |
| 11 | 19.040 | 4.6573 | 3 |
| 12 | 19.480 | 4.5531 | 5 |
| 13 | 20.240 | 4.3838 | 11 |
| 14 | 21.040 | 4.2189 | 7 |
| 15 | 21.440 | 4.1411 | 10 |
| 16 | 22.220 | 3.9974 | 11 |
| 17 | 22.680 | 3.9174 | 12 |
| 18 | 23.100 | 3.8471 | 4 |
| 19 | 23.820 | 3.7324 | 4 |
| 20 | 24.540 | 3.6245 | 26 |
| 21 | 25.120 | 3.5421 | 6 |
| 22 | 26.060 | 3.4165 | 5 |
| 23 | 26.960 | 3.3044 | 6 |
| 24 | 27.600 | 3.2292 | 2 |
| 25 | 28.200 | 3.1619 | 6 |
| 26 | 28.520 | 3.1271 | 4 |
| 27 | 29.380 | 3.0375 | 3 |
| 28 | 31.940 | 2.7997 | 3 |
| 29 | 33.000 | 2.7121 | 3 |
| 30 | 34.160 | 2.6226 | 2 |
| 31 | 35.540 | 2.5239 | 7 |
| 32 | 36.460 | 2.4623 | 3 |
| 33 | 38.080 | 2.3612 | 3 |
| 34 | 39.480 | 2.2806 | 4 |
| 35 | 40.940 | 2.2026 | 2 |
| 36 | 43.980 | 2.0571 | 2 |
| 37 | 46.780 | 1.9403 | 3 |
Lixivaptan crystalline form V, purity is 99.9%, mp170.8-172.0 DEG C.
For the preparation of the lixivaptan of lixivaptan crystalline form V, can be obtained by two kinds of synthetic methods.As document Journalofmedicinalchemistry, 1998,41 (14): 2442-2444. and US, the method for 5516774 [P], 1996-5-14. report.The route reaction formula that the present invention adopts is expressed as follows:
Synthesis lixivaptan, through proton nmr spectra (
1h-NMR), its chemical structure of the confirmation such as mass spectrum (MS), infrared spectra (IR) (mass spectrum is shown in accompanying drawing 3).Testing tool is BrukerAV400 type nuclear magnetic resonance analyser, and deuterated reagent is the DMSO-d of CambridgeIsotopeLaboratories company
6.
ESI-HRMS(m/z):474.17[M+H]
+；
1HNMR(400MHz,DMSO-d
6)δ:10.49(s,1H),7.84(s,1H),7.40(d,J＝6.8Hz,2H),7.33(d,J＝8.4Hz,3H),7.23(t,J＝8.4Hz,1H),7.13(t,J＝5.6Hz,2H),7.05(d,J＝6.8Hz,1H),6.82(s,1H),5.94(d,J＝32Hz,2H),5.23(br,4H),2.30(s,3H)。
The above-mentioned product obtained, purity is 97.5%, mp191-195 DEG C.
The crystalline form V of lixivaptan disperses to obtain in ethanol-toluene mixed solution.Usage quantity is 8 ~ 12 times (volume-mass ratio, mL/g) of lixivaptan quality.Wherein the volume ratio of ethanol and toluene is 2 ~ 5:1.
Specific operation process is: in obtained lixivaptan, adds 8-12 ethanol-toluene mixed solution doubly, is heated to 80 DEG C and stirs 1.5 hours, slowly cool to room temperature, controlling cooling rate is cooling per hour 5 DEG C, separates out solid, filter, obtain lixivaptan crystalline form V.
Then feature is determined through X-powder diffraction method.
Not containing crystal water and recrystallisation solvent in thermogravimetric analysis display lixivaptan crystalline form V.
The crystalline form V purity that the method obtains is high, and purity is 99.9%, mp170.8-172.0 DEG C, very important to the medicine of obtained high-quality.In the process parameters range described in the method, repeat multiple batches, circulation ratio is fabulous.
The preparation method of lixivaptan crystalline form V pharmaceutical composition of the present invention is as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet etc.Solid carrier can be at least one material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances such as methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension such as injection, pulvis etc.
The amount of the active ingredient contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, usually, the weight range of active compound is 0.5% ~ 90% (weight) of composition.Another preferred scope is 0.5% ~ 70%.
Accompanying drawing explanation
Fig. 1 is the X-powder diagram of contrast lixivaptan;
Fig. 2 is the X-powder diagram of lixivaptan crystalline form V;
Fig. 3 is the mass spectrum of lixivaptan.
Embodiment
Be described further the present invention below in conjunction with embodiment, embodiment is only indicative, never means that it limits the scope of the invention by any way.
embodiment 1:
Take lixivaptan 20.0g, add 160mL ethanol-toluene mixed solution (volume ratio is 5:1), be heated to 80 DEG C and stir 1.5 hours, slowly cool to room temperature, separate out solid, filter, vacuum-drying about 24 hours, Xi Putan white crystal (crystalline form V) of namely getting profit.
embodiment 2:
Take lixivaptan 20.0g, add 200mL ethanol-toluene mixed solution (volume ratio is 4:1), be heated to 80 DEG C and stir 1.5 hours, slowly cool to room temperature, separate out solid, filter, vacuum-drying about 24 hours, Xi Putan white crystal (crystalline form V) of namely getting profit.
embodiment 3:
Take lixivaptan 20.0g, add 240mL ethanol-toluene mixed solution (volume ratio is 5:1), be heated to 80 DEG C and stir 1.5 hours, delay and be cooled to room temperature, separate out solid, filter, vacuum-drying about 24 hours, Xi Putan white crystal (crystalline form V) of namely getting profit.
embodiment 4:
Every sheet is prepared containing the tablet of 50mg activeconstituents:
Technique: activeconstituents, lactose, starch are crossed 100 mesh sieves respectively, take by recipe quantity and fully mix, the 2% hypromellose aqueous solution is joined in said mixture and granulates, cross 20 mesh sieve softwoods, Magnesium Stearate, in 45 ~ 55 DEG C of drying about 2-3 hour, is joined compressing tablet in above-mentioned dried particles by obtained wet granular.
embodiment 5:
Diuresis is tested
By the SD rat raised, be divided into 2 groups at random, dosage: the general smooth reference substance of interest and crystalline form V, be 10mgkg
-1.Rat is placed in metabolic cage, collects spontaneous urine.Every rat collects urine in 0-4h, 4-8h, 8-20h several time period respectively, and graduated cylinder is quantitative.The physiological saline of gavage 5% body weight before administration, to increase Water l oad.Each measurement data represents with mean ± standard deviation (M ± S.D.).
Experimental result: in table 2.
Table 2 diuretic properties experimental result
Conclusion: both obvious indifferences.
Claims (7)
1. a crystalline form V for lixivaptan, is characterized in that: described crystal form X-ray powder diffraction charateristic avsorption band (2 θ angle) value is: 6.940,13.960,14.260,14.560,16.320,20.240,21.440,22.220,22.680,24.540; Described 2 θ angular units are degree, and error is ± 0.2.
2. the preparation method of lixivaptan crystalline form V as claimed in claim 1, is characterized in that: will add ethanol-toluene mixed solution in lixivaptan, is heated to 80 DEG C of stirrings, is cooled to room temperature, separates out solid, filters, obtains lixivaptan crystalline form V.
3. the preparation method of lixivaptan crystalline form V as claimed in claim 2, is characterized in that: will add 8-12 ethanol-toluene mixed solution doubly in lixivaptan, described multiple is volume-mass ratio, and unit is mL/g.
4. the preparation method of lixivaptan crystalline form V as claimed in claim 2 or claim 3, is characterized in that: the volume ratio of described ethanol and toluene is 2 ~ 5:1.
5. the preparation method of lixivaptan crystalline form V as claimed in claim 2, is characterized in that: wherein speed of cooling is cooling per hour 5 DEG C.
6. a pharmaceutical composition, is characterized in that: comprise the lixivaptan crystalline form V as claimed in claim 1 as activeconstituents and one or more pharmaceutically useful carriers.
7. the purposes of lixivaptan crystalline form V as claimed in claim 1 in preparation treatment hyponatremia medicine.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5516774A (en) * | 1993-07-29 | 1996-05-14 | American Cyanamid Company | Tricyclic diazepine vasopressin antagonists and oxytocin antagonists |
| CN102020609A (en) * | 2009-09-17 | 2011-04-20 | 北京本草天源药物研究院 | Tolvapta crystal or amorphous substance and preparation method thereof |
| CN102918038A (en) * | 2010-04-01 | 2013-02-06 | 万梯雅有限公司 | New polymorph |
-
2014
- 2014-07-25 CN CN201410359832.2A patent/CN104140429B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5516774A (en) * | 1993-07-29 | 1996-05-14 | American Cyanamid Company | Tricyclic diazepine vasopressin antagonists and oxytocin antagonists |
| CN102020609A (en) * | 2009-09-17 | 2011-04-20 | 北京本草天源药物研究院 | Tolvapta crystal or amorphous substance and preparation method thereof |
| CN102918038A (en) * | 2010-04-01 | 2013-02-06 | 万梯雅有限公司 | New polymorph |
Non-Patent Citations (1)
| Title |
|---|
| 吕扬 等."第七章 晶型药物的研究方法".《晶型药物》.2009,第136-139页. * |
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