CN103755707A

CN103755707A - Lixivaptan crystal form II, preparation method and use thereof

Info

Publication number: CN103755707A
Application number: CN201310428660.5A
Authority: CN
Inventors: 刘登科; 刘颖; 白玫; 穆帅; 张大帅
Original assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Current assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Priority date: 2013-09-17
Filing date: 2013-09-17
Publication date: 2014-04-30
Anticipated expiration: 2033-09-17
Also published as: CN103755707B

Abstract

The invention belongs to the field of anti-heart failure drugs, and more particularly relates to a lixivaptan crystal form II and a preparation method thereof, a drug composition containing the lixivaptan crystal form II, and a use of the lixivaptan crystal form II in preparation of hyponatremia treatment drugs. According to the present invention, 2-chloro-4-nitrobenzoic acid is adopted as a starting raw material, and esterification, hydrogenation reduction, acylation, hydrolysis, chlorination and other reaction steps are performed to prepare the lixivaptan crystal form II, wherein the purity of the obtained lixivaptan is 97.5%, and the lixivaptan crystal form II is characterized by the powder X-ray diffraction pattern; and due to the good development prospects and the pharmaceutical values of the compound, it is important to obtain the compound with characteristics of high purity, determined crystal form and good reproducibility.

Description

Lixivaptan crystal form II 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] crystal form II 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, according to the difference of transmission mechanism, is divided into 3 kinds of hypotype: Vla, Vlb and V2 acceptor.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 as ideal medicament, further develop.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 when 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 when 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 take 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, take 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:

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 ℃, 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 crystal form II.

Another object of the present invention is to provide the preparation method of lixivaptan crystal form II.

A further object of the invention is to provide lixivaptan crystal form II 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 crystal form II has following characteristics:

By D/Max-2500 type x-ray diffractometer mensuration, condition determination: CuKa, 40KV, 100mA, its collection of illustrative plates has following diffraction angle (2 θ), spacing (d value) and intensity (%), the error of 2 θ is ± 0.2.See accompanying drawing 2.

Spectrum wire size	2 θ (degree)	Spacing (d)	I/I ₀
				1	5.160	17.1119	27

[0022]?

2	10.260	8.6146	13
				3	10.980	8.0513	10
4	12.580	7.0306	10
				5	14.300	6.1886	9
6	15.380	5.7564	32
				7	16.520	5.3616	6
8	17.480	5.0693	12
				9	18.460	4.8023	81
10	19.300	4.5952	100
				11	19.620	4.5209	17
12	20.280	4.3753	48
				13	20.540	4.3205	30
14	20.840	4.2589	24
				15	21.400	4.1487	22
16	22.660	3.9208	13
				17	23.780	3.7386	16
18	24.440	3.6391	7
				19	24.860	3.5786	10
20	25.240	3.5256	21
				21	26.540	3.3558	12
22	27.480	3.2431	28
				23	28.420	3.1379	12
24	28.860	3.0911	8
				25	29.440	3.0315	10
26	30.400	2.9379	6
				27	31.000	2.8824	8
28	31.380	2.8483	8
				29	31.600	2.8290	9
30	32.100	2.7861	7
				31	33.620	2.6635	6
32	34.400	2.6049	5
				33	34.920	2.5673	6
34	36.340	2.4701	9
				35	38.980	2.3087	7
36	39.840	2.2608	6
				37	41.160	2.1913	8
38	41.720	2.1632	6
				39	43.520	2.0778	8
40	44.800	2.0214	8
				41	45.220	2.0036	14
42	45.720	1.9828	10

Lixivaptan crystal form II, purity is 99.2%, mp180.2-181.17 ℃.

For the preparation of the lixivaptan of lixivaptan crystal form II, 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 of 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 AV400 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(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 obtaining, purity is 97.5%, mp191-195 ℃.

The crystal form II of lixivaptan is refining obtaining in methylene dichloride-acetone equal-volume mixed solution (1:1).

Specific operation process is: in the lixivaptan making, add doubly (volume-mass ratio, mL/g) methylene dichloride-acetone mixed solution (mixing of 1:1 equal-volume) of 6-8, be heated to 40 ℃ of stirring and dissolving, naturally cool to room temperature, separate out solid, filter, dry, obtain lixivaptan crystal form II.

Then through X-powder diffraction method, measured feature.

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

The crystal form II purity that the method makes is high, and purity is 99.7%, mp180.2-181.17 ℃, 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 crystal form II 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%.

Diuresis experiment

By the SD rat of raising, be divided at random 2 groups, dosage: lixivaptan reference substance and crystal form II, be 10mgkg ^-1.Rat is placed in metabolic cage, collects spontaneous urine.Every rat is respectively at 0-4h, 4-8h, and several time periods of 8-20h 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 is in Table 1.

The experiment of table 1 diuretic properties

Conclusion: both obvious indifferences.

Accompanying drawing explanation

Fig. 1 is the X-powder diagram of contrast lixivaptan;

Fig. 2 is the X-powder diagram of lixivaptan crystal form II;

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 20.0g, add 140mL methylene dichloride-acetone (1:1), be heated to 40 ℃ of stirring and dissolving, naturally cool to room temperature, separate out solid, filter, dry, the Xi Putan white crystal (crystal form II) of getting profit.

embodiment 2:

Take lixivaptan 20.0g, add 120mL methylene dichloride-acetone (1:1), be heated to 40 ℃ of stirring and dissolving, naturally cool to room temperature, separate out solid, filter, dry, the Xi Putan white crystal (crystal form II) of getting profit.

embodiment 3:

embodiment 4:

The every preparation of the tablet containing 25mg activeconstituents:

Consumption/sheet

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

Claims

1. a crystal form II for lixivaptan, is characterized in that: described crystal form X-ray powder diffraction charateristic avsorption band (2 θ angle) value is: 5.160,10.260,10.980,12.580,15.380,17.480,18.460,19.300,19.620,20.280,20.540,20.840,21.400,22.660,23.780,24.860,25.240,26.540,27.480,28.420,29.440,45.220,45.720; Described 2 θ angular units are degree, and error is ± 0.2.

2. the preparation method of lixivaptan crystal form II as claimed in claim 1, is characterized in that: lixivaptan is added to methylene dichloride-acetone equal-volume mixed solution, be heated to 40 ℃ of stirring and dissolving, naturally cool to room temperature, separate out solid, filter, dry, obtain lixivaptan crystal form II.

3. the preparation method of lixivaptan crystal form II as claimed in claim 2, is characterized in that: lixivaptan is added to 6-8 times of methylene dichloride-acetone equivalent mixed liquor, and described multiple is volume-mass ratio, and unit is mL/g.

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

5. the purposes of lixivaptan crystal form II as claimed in claim 1 in preparation treatment hyponatremia medicine.