CN104140429A

CN104140429A - Lixivaptan crystal form V and preparation method and application

Info

Publication number: CN104140429A
Application number: CN201410359832.2A
Authority: CN
Inventors: 刘登科; 刘颖; 刘冰妮; 张旭阳; 王澳轩; 王平保
Original assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Current assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Priority date: 2014-07-25
Filing date: 2014-07-25
Publication date: 2014-11-12
Anticipated expiration: 2034-07-25
Also published as: CN104140429B

Abstract

The invention relates to a lixivaptan crystal form V and a preparation method thereof, and further relates to a pharmaceutical composition prepared through the lixivaptan crystal form V and an application of the lixivaptan crystal form V. The lixivaptan crystal form V is represented through an X-ray diffraction pattern of powder of the lixivaptan crystal form V.

Description

Lixivaptan crystalline form V and its production and use

Technical field

The invention belongs to heart failure resistance pharmaceutical field, more particularly, relate to the chloro-4-(10 of N-[3-of lixivaptan (lixivaptan) or formula I, 11-dihydro-5H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] benzodiazepine-10-base carbonyl) phenyl] crystalline form V and preparation method thereof of-5-fluoro-2-methylbenzene methane amide, the pharmaceutical composition that contains it and in the purposes of manufacturing in treatment hyponatremia medicine.

Background technology

Arginine vasopressin (AVP) claim again β-hypophamine, antidiuretic hormone, by the one 9 peptide ring-type hormones that hypothalamus produces and hypophysis discharges, by remembering, participate in the body temperature physiological action different with immunomodulatory, participation social behavior adjusting etc. from different AVP receptor subtypes in conjunction with generation antidiuresis, vasoconstriction, reinforcement.AVP acceptor belongs to G-protein linked receptor, is divided into 3 kinds of hypotype: 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, mainly mediates vasoconstriction, platelet aggregation and uterine contraction.V1b acceptor is mainly distributed in prepituitary gland, and mediation ACTH discharges; V2 acceptor is positioned at collecting duct, the main permeability of adjusting collecting tubule to water that participate in.AVP has participated 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 biological half-life, oral administration biaavailability is low, although in experimentation on animals, have antagonistic action, to the AVP receptor antagonist activity of human body a little less than, be difficult to further develop 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 antagonists were 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, find efficient non-peptide class AVP receptor antagonist is pharmacy worker's focus always.

Lixivaptan (Lixivaptan, 1) be the oral selectivity arginine vasopressin of the non-peptide class of the one V2 receptor antagonist by the research and development of U.S. Hui Shi (wyeth) company, the chemistry chloro-4-(10 of N-[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 diuretic(s), lixivaptan is in the time being used for the treatment of congestive heart failure (CHF), Patients with Liver Cirrhosis Accompanied hyponatremia and syndrome of inappropriate ADH secretion (SIADH) patient, it does not affect the discharge of kidney sodium in improving free water clearance, can not activate neuroendocrine system, and there is higher security and tolerance yet.Lixivaptan is the tolvaptan higher than in May, 2009 U.S. FDA approval to the selectivity of V2 acceptor, in the III phase clinical study of U.S.'s completed treatment hyponatremia, in pre-registration stage.

Document (Journal of medicinal chemistry, 1998,41 (14): 2442-2444.) report 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, dock with the chloro-4-nitro benzoyl of 2-and 5-fluoro-2-methylbenzene formyl radical successively, make 1; Route two is first by chloro-2-PABA methyl esters (5) and 5-fluoro-2-methylbenzene formyl chloride (7) docking, through hydrolysis, the reactions such as chloride make the chloro-4-[(5-fluoro-2-methylbenzene of 2-formyl) amino] Benzoyl chloride (10), then react and make 1 with 2.Due to raw material divalent lattice costliness, route one is taking 2 as 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, taking the chloro-4-nitrobenzoic acid of 2-(3) as starting raw material, and through esterification, hydro-reduction, acylations, hydrolysis, the reactions such as chloride make 10; 10 make 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 Journal of medicinal chemistry, 1998,41 (14): 2442-2444. and US, 5516774[P], 1996-5-14.At present, lixivaptan (lixivaptan) in clinical study stage III phase, has good development prospect abroad, and in view of the pharmacy value of this compound, it is important obtaining purity compound high, that have very definite crystal formation and favorable reproducibility.

The inventor has repeated document US, 5516774 method, and the lixivaptan purity obtaining 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 the medicinal compositions that contains one or more pharmaceutically acceptable carriers, vehicle or thinner, 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:

By D/Max-2500 type x-ray diffractometer mensuration, condition determination: CuKa, 40KV, 100 mA, its collection of illustrative plates has following diffraction angle (2 θ), spacing (d value) and intensity (%), 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

Spectrum wire size	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 made by two kinds of synthetic methods.As document Journal of medicinal chemistry, 1998,41 (14): 2442-2444. and US, 5516774[P], the method for 1996-5-14. report.The route that the present invention adopts is expressed as follows with reaction formula:

Synthetic lixivaptan, through proton nmr spectra ( ¹h-NMR), its chemical structure of confirmation (mass spectrum is shown in accompanying drawing 3) such as mass spectrum (MS), infrared spectra (IR).Testing tool is Bruker AV 400 type nuclear magnetic resonance analyser, and deuterated reagent is the DMSO-d of Cambridge Isotope Laboratories company ₆.

ESI-HRMS(m/z):474.17[M+H] ⁺； ¹H?NMR(400?MHz,DMSO-d ₆)δ:10.49(s,1H),7.84(s,1H),7.40(d,J＝6.8?Hz,2H),7.33(d,J＝8.4?Hz,3H),7.23(t,J＝8.4?Hz,1H),7.13(t,J＝5.6?Hz,2H),7.05(d,J＝6.8?Hz,1H),6.82(s,1H),5.94(d,J＝32?Hz,2H),5.23(br,4H),2.30(s,3H)。

The above-mentioned product obtaining, purity is 97.5%, mp191-195 DEG C.

The crystalline form V of lixivaptan is in ethanol-toluene mixture liquid, to disperse to obtain.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 the lixivaptan making, add 8-12 ethanol-toluene mixture liquid doubly, be heated to 80 DEG C and stir 1.5 hours, slowly cool to room temperature, controlling cooling rate is 5 DEG C of coolings per hour, separates out solid, filter, obtain lixivaptan crystalline form V.

Then measured feature through X-powder diffraction method.

Thermogravimetric analysis shows in lixivaptan crystalline form V not containing crystal water and recrystallisation solvent.

The crystalline form V purity that the method makes is high, and purity is 99.9%, mp170.8-172.0 DEG C, very important to making the medicine of 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 and 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 for example injection, pulvis etc.

The amount of the active ingredient containing in pharmaceutical composition and unit dosage form can specifically be applied according to the situation of patient's the state of an illness, diagnosis, the amount of compound used or concentration regulate in a wider scope, conventionally 0.5%～90% (weight) that, the weight range of active compound is composition.Another preferred scope is 0.5%～70%.

Brief description of the drawings

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

Below in conjunction with embodiment, the present invention is described further, embodiment is only indicative, never means that it limits the scope of the invention by any way.

embodiment 1:

Take lixivaptan 20.0 g, add 160 mL ethanol-toluene mixture liquid (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 approximately 24 hours, the Xi Putan white crystal (crystalline form V) of getting profit.

embodiment 2:

Take lixivaptan 20.0 g, add 200 mL ethanol-toluene mixture liquid (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 approximately 24 hours, the Xi Putan white crystal (crystalline form V) of getting profit.

embodiment 3:

Take lixivaptan 20.0 g, add 240 mL ethanol-toluene mixture liquid (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 approximately 24 hours, the Xi Putan white crystal (crystalline form V) of getting profit.

embodiment 4:

The every preparation of the tablet containing 50 mg activeconstituentss:

Technique: activeconstituents, lactose, starch are crossed respectively to 100 mesh sieves, take and fully mix by recipe quantity, the 2% hypromellose aqueous solution is joined in said mixture and granulated, cross 20 mesh sieve softwood processed, make wet granular in 45～55 DEG C of dry about 2-3 hour, Magnesium Stearate is joined to compressing tablet in above-mentioned dried particles.

embodiment 5:

Diuresis experiment

By the SD rat of raising, be divided at random 2 groups, dosage: the general smooth reference substance of interest and crystalline form V, be 10 mgkg ^-1.Rat is placed in metabolic cage, collects spontaneous urine.Every rat is respectively at 0-4 h, 4-8 h, and several time periods of 8-20 h are collected urine, and graduated cylinder is quantitative.The physiological saline of gavage 5% body weight before administration, to increase water load.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

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 in lixivaptan, add ethanol-toluene mixture liquid, be heated to 80 DEG C of stirrings, be cooled to room temperature, separate out solid, filter, obtain lixivaptan crystalline form V.

3. the preparation method of lixivaptan crystalline form V as claimed in claim 2, is characterized in that: will in lixivaptan, add 8-12 ethanol-toluene mixture liquid doubly, 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 5 DEG C of coolings per hour.

6. a pharmaceutical composition, is characterized in that: comprise lixivaptan crystalline form V as claimed in claim 1 and one or more pharmaceutically useful carriers as activeconstituents.

7. the purposes of lixivaptan crystalline form V as claimed in claim 1 in preparation treatment hyponatremia medicine.