CN103694240B

CN103694240B - Solvate of lixivaptan and its production and use

Info

Publication number: CN103694240B
Application number: CN201310428811.7A
Authority: CN
Inventors: 刘登科; 白玫; 刘颖; 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: 2013-09-18
Filing date: 2013-09-18
Publication date: 2015-11-18
Anticipated expiration: 2033-09-18
Also published as: CN103694240A

Abstract

The present invention relates to solvate of lixivaptan and preparation method thereof, also relate to the pharmaceutical composition and purposes prepared by gained solvate of lixivaptan of the present invention.This solvate of lixivaptan characterizes with its powder x-ray diffraction figure.

Description

Solvate of lixivaptan and its production and use

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 solvate 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.The synthetic route of 1 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 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 solvate of lixivaptan.

Another object of the present invention is to provide the preparation method of solvate of lixivaptan.

A further object of the invention is to provide solvate of lixivaptan 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:

Wherein X is 0.5-1.5.

Solvate of lixivaptan 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.See accompanying drawing 2.

Spectral line number	2 θ (degree)	Spacing (d)	I/I ₀
				1	5.220	16.9154	100
2	8.560	10.3212	4
				3	10.420	8.4827	85
4	11.780	7.5062	5
				5	12.340	7.1668	11
6	12.820	6.8995	8
				7	13.080	6.7630	13
8	13.700	6.4583	6
				9	14.120	6.2671	13
10	14.500	6.1037	23
				11	15.640	5.6613	44
12	16.060	5.5142	7
				13	16.700	5.3042	19
14	18.420	4.8126	39
				15	19.620	4.5209	14
16	19.960	4.4447	14
				17	20.900	4.2468	35
18	21.280	4.1719	14
				19	22.360	3.9727	6
20	23.480	3.7857	15
				21	23.700	3.7511	18
22	23.940	3.7140	26
				23	24.600	3.6158	17
24	24.900	3.5729	8
				25	25.880	3.4398	5
26	26.200	3.3985	9
				27	26.460	3.3657	7
28	27.520	3.2384	5
				29	28.360	3.1444	33
30	28.880	3.0890	8
				31	29.260	3.0497	10
32	29.860	2.9898	7
				33	30.360	2.9417	4
34	31.620	2.8273	5
				35	31.980	2.7962	5
36	33.660	2.6604	4
				37	35.240	2.5447	4
38	36.380	2.4675	4
				39	37.180	2.4162	5
40	38.260	2.3505	3
				41	39.600	2.2740	5
42	40.080	2.2478	6

43	41.920	2.1533	3
				44	42.700	2.1158	5
45	43.680	2.0706	4
				46	44.520	2.0334	4
47	45.160	2.0061	4

Solvate of lixivaptan, purity is 99.6%, mp89.1-90.9 DEG C.

For the preparation of the lixivaptan of solvate of lixivaptan, can be obtained by two kinds of synthetic methods.As document Journalofmedicinalchemistry, 1998,41 (14): 2442-2444. and US, 5516774 [P],

The method of 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 solvate of lixivaptan is refining in ethyl acetate-water obtaining.

Specific operation process is: in obtained lixivaptan, and add 2-5 ethyl acetate-water (volume ratio is 9:1) doubly, described multiple is volume-mass ratio, unit is mL/g, is heated to 65 DEG C of stirring and dissolving, naturally cools to room temperature, separate out solid, filter, obtain solvate of lixivaptan.

Then feature is determined through X-powder diffraction method.

Crystallization ethyl acetate (see accompanying drawing 4,5) is contained in hydrogen nuclear magnetic resonance spectrogram and thermogravimetric analysis display solvate of lixivaptan.

In the hydrogen nuclear magnetic resonance spectrogram of solvate of lixivaptan, δ: 1.147-1.182 is the methyl hydrogen of " 3 " position; δ: 1.971-1.977 is the methyl hydrogen of " 1 " position; δ: 3.994-4.047 is the methylene radical hydrogen of " 2 " position.

Per molecule lixivaptan contains 0.5-1.5 ethyl acetate molecule, or every mole of lixivaptan contains the ethyl acetate of 0.5-1.5 mole.

The solvate purity that the method obtains is high, and purity is 99.6%, mp89.1-90.9 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 solvate of lixivaptan 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%.

Diuresis is tested

By the SD rat raised, be divided into 2 groups at random, dosage: lixivaptan reference substance is 10mgkg ^-1, solvate of lixivaptan is 11.86mgkg ^-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 is in table 1.

Table 1 diuretic properties is tested

Conclusion: both obvious indifferences.

Accompanying drawing explanation

Fig. 1 is contrast lixivaptan product X-powder diagram;

Fig. 2 is the X-powder diagram of solvate of lixivaptan;

Fig. 3 is the mass spectrum of lixivaptan;

Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram of solvate of lixivaptan;

Fig. 5 is the thermal multigraph of solvate 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 65mL ethyl acetate-water (9:1, volume-mass ratio, mL/g), be heated to 65 DEG C of stirring and dissolving, naturally cool to room temperature, separate out solid, filter, obtain solvate of lixivaptan.

embodiment 2:

Take lixivaptan 20.0g, add 40mL ethyl acetate-water (9:1, volume-mass ratio, mL/g), be heated to 65 DEG C of stirring and dissolving, naturally cool to room temperature, separate out solid, filter, obtain solvate of lixivaptan.

embodiment 3:

Take lixivaptan 20.0g, add 100mL ethyl acetate-water (9:1, volume-mass ratio, mL/g), be heated to 65 DEG C of stirring and dissolving, naturally cool to room temperature, separate out solid, filter, obtain solvate of lixivaptan.

embodiment 4:

Every sheet is prepared containing the tablet of mg 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.

Claims

1. a solvate for lixivaptan, is characterized in that: described solvate X-ray powder diffraction charateristic avsorption band (2 θ angle) value is: 5.220,10.420,12.340,13.080,14.120,14.500,15.640,16.700,18.420,19.620,19.960,20.900,21.280,23.480,23.700,23.940,24.600,28.360,29.260; Described 2 θ angular units are degree, and error is ± 0.2.

2. the preparation method of solvate of lixivaptan as claimed in claim 1, it is characterized in that: lixivaptan adds ethyl acetate-water mixed liquid, in described mixed solution, the volume ratio of ethyl acetate and water is 9:1; Be heated to 65 DEG C of stirring and dissolving, naturally cool to room temperature, separate out solid, filter, obtain solvate of lixivaptan.

3. the preparation method of solvate of lixivaptan as claimed in claim 2, is characterized in that: lixivaptan adds 2-5 ethyl acetate-water mixed liquid doubly, and described multiple is volume-mass ratio, and unit is mL/g.

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

5. the purposes of solvate of lixivaptan as claimed in claim 1 in preparation treatment hyponatremia medicine.