CN1964966A - Rosiglitazone phosphate and polymorphic forms - Google Patents

Abstract

The present invention relates to 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate, a novel salt of rosiglitazone and to novel polymorphic forms thereof. The invention is also directed to processes for preparation of rosiglitazone phosphate and its polymorphs. The compounds of the invention are useful for treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

Description

Rosiglitazone phosphate and polymorphic form

Invention field

The present invention relates to novel cpd, relate to the method for preparing this compound, relate to the pharmaceutical composition that comprises this compound, and relate to this compound and the purposes of said composition in medicine.In addition, the present invention comprises the different polymorphic forms of described novel cpd.

Background of invention

Publication number is that 0306228 european patent application relates to as having hypoglycemic and hypolipidemic activity and disclosed some thiazolidine diketone derivative.The compound of EP-A-0306228 embodiment 30 is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione is (according to Merck index/13rd edition, special topic numbers 8346, the CAS number of registration: 122320-73-4), i.e. rosiglitazone.

Publication number is some salt that the international application of WO 94/05659 discloses the compound among the EP-A-0306228.Preferred WO 94/05659 salt is maleate.

Still exist to direct preparation and have on the business level demand of the alternative salt form that is fit to the medicine working properties.

Invention is described

The present inventor has prepared and has described 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the phosphoric acid salt of 4-thiazolidinedione, be 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt, hereinafter be also referred to as " phosphoric acid salt "), and have been found that this " phosphoric acid salt " is stable especially, therefore be fit to a large amount of preparations and processing.

In addition, the present inventor has prepared and has described described " phosphoric acid salt " different polymorphic form, i.e. polymorphic form A, B, B1, C, D and E.Heteromorphism be normally defined material for example pharmaceutically active substances have the ability of two or more different crystal structures.Described different crystal forms is called polymorphic form.Described material also can be enclosed solvent molecule when crystallization, these solvates or hydrate are called pseudopolymorph.Different polymorphic forms, pseudopolymorph or the amorphous form of given material one or more such as fusing point, solubleness and dissociate, on the physical properties of true density, crystal shape, closely knit characteristic, flowing property and/or solid-state stability each other and inequality.Estimate that they can influence medicinal character such as dissolution rate and/or bioavailability.Expect also that from economic angle predetermined substance is not needing the stable longer time under the special storage condition.Therefore, the polymorphic form of pharmaceutically active substances is assessed very important.Term used herein " polymorphic form " is interpreted as that both comprising The compounds of this invention is phosphatic polymorphic form, comprises its pseudopolymorph again.In addition, " polymorphic forms " used herein, " crystal formation ", " polymorphic form ", " crystalline polymorphic form " and " crystalline polymorphic forms " are interpreted as to have identical meanings, and can exchange.

5-[[4-[2-used herein (methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione is interpreted as the rosiglitazone of free alkali form.

Novel phosphoric acid salt and polymorphic form thereof also have useful pharmaceutical properties, and can be used for treating and/or preventing diabetes, the illness relevant with diabetes and its some complication.

Therefore, in one aspect, the invention provides 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the salt of 4-thiazolidinedione and phosphoric acid or its solvate or non-solvent compound form.

Aspect other, the invention provides 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the novel phosphatic new polymorphic forms of 4-thiazolidinedione, described new polymorphic forms is referred to herein as crystal form A, B, B1, C, D or E, and described polymorphic form can be solvate form thereof (crystal form A, C and D), such as hydrate forms (crystal form A and C) or with methanol solvent compound (crystal formation D); Or non-solvent compound form, such as anhydrous form (crystal form B, B1 and E).

Term used herein " non-solvent compound form " is interpreted as and is meant there is not remaining inorganic or organic solvent medium substantially, for example is anhydrous form.

Because phosphoric acid is triprotic acid, so there is more than one stoichiometry in theory in phosphoric acid salt.But up to the present, the present inventor has only separated 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the mol ratio of 4-thiazolidinedione and phosphoric acid is or approximately is the phosphoric acid salt of 1: 1 this form that wherein said mol ratio comprises 1: 0.9 to 1: 1.2 mol ratio.In theory, 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the mol ratio of 4-thiazolidinedione and phosphoric acid also can be 3: 1 or 2: 1.The present invention also comprises these mol ratios.

Therefore, aspect other, the invention provides 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the phosphoric acid salt of 4-thiazolidinedione or its solvate or non-solvent compound form, 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group wherein] phenyl] methyl]-2,4-thiazolidinedione and phosphatic mol ratio are 1: 1.

In addition, the invention provides 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt or its solvate or non-solvent compound form, and its polymorphic form A, B, B1, C, D and E, 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group wherein] phenyl] methyl]-2,4-thiazolidinedione and phosphatic mol ratio are 1: 1.Hereinafter, 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group wherein] phenyl] methyl]-2,4-thiazolidinedione and phosphatic mol ratio are 1: 1 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl groups] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt be also referred to as " 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt (1: 1) ".

Preferably, " phosphoric acid salt " is hydrate or non-hydrate.More preferably, " phosphoric acid salt " is its polymorphic forms A, B, B1 or E.

Described phosphoric acid salt and polymorphic form thereof can exist with a kind of form in several tautomeric forms, and wherein the present invention comprises all tautomeric forms.Be interpreted as that the present invention comprises all isomeric forms of phosphoric acid salt, the preferably water compound comprises its stereoisomeric forms in any ratio arbitrarily, no matter is the independent isomers or the mixture of isomers.

Do not wish to be bound by any concrete mechanism or theory, applicant is thought in 1: 1 salt, phosphate anion is except in conjunction with 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, beyond the 4-thiazolidinedione, can also be in conjunction with proton (hydrogen atom), perhaps in conjunction with other positively charged ion, for example alkali metal cation or ammonium cation.In this case, salt can be described as mixing salt.

As mentioned above, the preferred aspect of the present invention is phosphatic hydrate or non-hydrate, and wherein said phosphatic hydrate or non-hydrate also are called " phosphoric acid salt hydrate " or " phosphoric acid salt non-hydrate " hereinafter.Described phosphoric acid salt hydrate exists with polymorphic forms A or C, wherein preferred crystal form A, and described phosphoric acid salt non-hydrate exists with polymorphic forms B, B1 or E; This depend on hereinafter described preparation method and/or the corresponding starting material of use.

Therefore, on the one hand, the invention provides 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the crystalline polymorphic form of 4-thiazolidinedione phosphoric acid salt hydrate forms, 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group wherein] phenyl] methyl]-2,4-thiazolidinedione and phosphatic mol ratio are 1: 1, this paper is called crystal form A, and it is characterized as at about 15.63,15.75,17.30,19.61 and 21.47 the value place that represents with the 2-θ number of degrees by X-ray powder diffraction (XRPD) collection of illustrative plates has intensity peak.Crystalline polymorphic form A also can be selected from the following value place that represents with the 2-θ number of degrees and intensity peak occurs arbitrarily one or more: about 4.28,5.38,8.61,9.92,12.44,14.04,16.91,21.66,22.54,24.10,24.43,24.77,25.06,25.81 and 26.28.

On the other hand, crystalline polymorphic form A is characterised in that X-ray powder diffraction (XRPD) collection of illustrative plates and table 1 and Fig. 1 basically identical.

Table 1: the X-ray powder diffraction of crystal form A (XRPD) collection of illustrative plates, show spacing (d, unit _, that is: dust), characteristic XRPD angle (2 θ °) and relative intensity (%)

D value (_)	Angle 2 θ °	Relative intensity (%)
			22.66	3.90	13
20.63	4.28	21
			16.42	5.38	18
14.20	6.22	7
			10.51	8.41	16
10.26	8.61	19
			9.879	8.94	7
8.911	9.92	18
			8.170	10.82	6
7.514	11.77	7
			7.111	12.44	24
6.828	12.96	10
			6.748	13.11	9
6.497	13.62	13
			6.301	14.04	31
5.667	15.63	65
			5.622	15.75	100
5.514	16.06	16
			5.239	16.91	19
5.123	17.30	42
			4.924	18.00	17
4.855	18.26	9

4.663	19.02	15
			4.524	19.61	35
4.342	20.44	14
			4.135	21.47	40
4.100	21.66	33
			4.037	22.00	16
3.941	22.54	30
			3.876	22.93	12
3.817	23.29	13
			3.803	23.37	15
3.777	23.54	16
			3.741	23.77	15
3.690	24.10	18
			3.641	24.43	18
3.591	24.77	18
			3.550	25.06	18
3.449	25.81	19
			3.389	26.28	23
3.279	27.17	8
			3.227	27.62	14
3.201	27.85	14
			3.128	28.51	9
3.066	29.11	10
			3.025	29.51	14
2.957	30.20	9
			2.922	30.57	12
2.910	30.70	13
			2.829	31.60	10
2.807	31.86	9
			2.774	32.25	9
2.759	32.42	9
			2.711	33.01	7
2.674	33.49	7
			2.617	34.24	10
2.608	34.36	11
			2.568	34.91	8
2.556	35.08	8
			2.452	36.61	7
2.421	37.11	7
			2.367	37.98	6
2.330	38.60	7
			2.302	39.10	8
2.273	39.62	8

Randomly, crystalline polymorphic form A extraly by infrared spectrum characterization for as shown in Figure 2,2704,1748,1701,1643,1611,1546,1513,1469,1420,1391,1330,1302,1244,1110,1028,928,821,767,716cm ^-1The place observes spectrum band.Therefore, crystal form A provides the infrared spectra with Fig. 2 basically identical.

The infrared absorption spectrum of phosphatic polymorphic form as herein described uses BRUKERFTIR-Tensor 27 to measure.

As mentioned below, the X-ray powder diffraction that this paper provides (XRPD) collection of illustrative plates uses the 2-θ accuracy of x-ray powder diffraction instrument D-8 (AXS-BRUKER) and sample data to measure for the copper radiation (copper radiation) of ± 0.05 degree:

According to Kofler method (Practical Organic Chemistry, the third edition, the 82nd page described for Vogel for example, A.I.), the melting range of crystal form A is 171-177 ℃.

Therefore, crystal form A is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione and phosphoric acid ratio (mol ratio) are 1: 1 phosphoric acid salt, and the phosphoric acid salt hydrate with the water that comprises about 0.1%-4.5% (for example approximately 0.8%-4%, for example preferred 1.6%-3.6%) weight ratio obtains separating.

The specific examples of crystal form A comprises about 0.87% water, is equivalent to 1: 0.23 hydrate.More specific examples comprises about 1.6% water, is equivalent to 1: 0.42 hydrate; Perhaps comprise about 2.3% water, be equivalent to 1: 0.60 hydrate; Perhaps comprise 3.3% water, be equivalent to 1: 0.79 hydrate; Perhaps comprise 3.58% water, be equivalent to 1: 0.94 hydrate.All percentage ratios are weight ratio.

Dry crystal form A produces about 1: 0.4 hydrate under room temperature for example; About 45 ℃ with such as P ₂O ₅Capable and experienced drying prescription drying aid, produce about 1: 0.3 hydrate; And carrying out further drying and can produce weight ratio and be lower than 0.1% water-content such as 70 ℃-100 ℃, preferred 80 ℃ high temperature are optional.Room temperature used herein be interpreted as be meant about 20 ℃ to about 35 ℃ medial temperature, for example about 25 ℃ to about 28 ℃.

Crystal form A is exposed to high humidity can produce about 1: 1 hydrate.

Therefore, this paper is called 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of crystal form A] phenyl] methyl]-2, the crystalline polymorphic form of 4-thiazolidinedione phosphoric acid salt (1: 1) hydrate forms comprises the water that approximately is no more than 4.5% weight ratio, the water that for example comprises about 3.6% weight ratio, be equivalent to 1: 0.94 hydrate, perhaps for example comprise the water of about 1.6% weight ratio, be equivalent to 1: 0.42 hydrate.

On the other hand, the invention provides 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the crystalline polymorphic form of 4-thiazolidinedione phosphoric acid salt hydrate forms, 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group wherein] phenyl] methyl]-2,4-thiazolidinedione and phosphatic mol ratio are 1: 1, be called crystal C herein, being characterized as at about 12.86,15.98,16.26,21.60 and 24.50 the value place that the 2-θ number of degrees are represented of its X-ray powder diffraction (XRPD) collection of illustrative plates has intensity peak.Crystalline polymorphic form C can also be selected from the following value place that represents with the 2-θ number of degrees and intensity peak occurs arbitrarily one or more: about 11.32,14.50,16.47,18.91,19.99,20.30,23.45,24.34 and 29.40.

The scope of crystal C water-content weight ratio is 3.8-3.9%.

On the other hand, the X-ray powder diffraction of crystalline polymorphic form C (XRPD) figure spectrum signature and table 2 and Fig. 3 basically identical.

Table 2: the X-ray powder diffraction of crystal C (XRPD) collection of illustrative plates, show spacing (d, unit _, that is: dust), characteristic XRPD angle (2 θ °) and relative intensity (%)

D value (_)	Angle 2 θ °	Relative intensity (%)
			22.18	3.98	20
10.93	8.08	5
			8.842	10.00	4
7.809	11.32	38
			7.294	12.12	20
6.876	12.86	62
			6.104	14.50	25
5.542	15.98	100
			5.448	16.26	79
5.377	16.47	57
			5.193	17.06	7
4.945	17.92	13
			4.911	18.05	11
4.689	18.91	45
			4.438	19.99	55
4.371	20.30	30
			4.250	20.89	17
4.112	21.60	59
			4.072	21.81	21
3.961	22.43	22

3.887	22.86	16
			3.791	23.45	55
3.654	24.34	57
			3.631	24.50	64
3.552	25.05	20
			3.456	25.76	17
3.400	26.19	12
			3.278	27.18	13
3.179	28.04	24
			3.139	28.41	17
3.122	28.57	15
			3.036	29.40	26
3.005	29.71	16
			2.963	30.14	14
2.893	30.88	8
			2.814	31.78	17
2.775	32.24	5
			2.685	33.35	16
2.610	34.34	7
			2.578	34.77	11
2.470	36.34	3
			2.426	37.02	4
2.329	38.62	9

Randomly, crystalline polymorphic form C extraly by infrared spectrum characterization for as shown in Figure 4,3111,2924,2652,2325,2165,2114,2051,1981,1874,1745,1698,1641,1608,1541,1513,1464,1443,1416,1392,1363,1332,1301,1265,1249,1218,1179,1163,1113,1096,1048,1028,995,951,926,905,823,812,774,739,713cm ^-1The place observes spectrum band.Therefore, crystal C provides the infrared spectra with Fig. 4 basically identical.

The present invention also comprises the phosphoric acid salt that exists with non-solvent compound form, for example polymorph b, B1 or E.Described crystal formation can be anhydrous, promptly can be non-hydrate, wherein can comprise the water that is lower than 2% weight ratio, for example be no more than 1.5%, for example crystal form B and B1 perhaps for example are no more than 0.5%, for example be no more than 0.2%, for example be less than the water of 0.1% weight ratio, as crystal formation E.The existence of humidity is depended in the existence of trace water among above-mentioned polymorph b, B1 or the E, refer to that promptly high relative humidity (for example about 80% or higher) causes water-content higher in the above-mentioned polymorphic form, and low relative humidity (for example being no more than 30%) causes the lower water-content of above-mentioned polymorphic form.Preferably, above-mentioned non-hydrate residual organic solvents medium not substantially.

Therefore, further, the invention provides 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the phosphatic crystalline polymorphic form of 4-thiazolidinedione, 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group wherein] phenyl] methyl]-2,4-thiazolidinedione and phosphatic mol ratio are 1: 1, be called crystal form B herein, its X-ray powder diffraction (XRPD) collection of illustrative plates is characterized as at about 4.19,16.45,17.01,18.89 and 21.35 the value place that represents with the 2-θ number of degrees has intensity peak.Crystalline polymorph b can also be selected from the following value place that represents with the 2-θ number of degrees and intensity peak occurs arbitrarily one or more: about 8.44,19.50,20.86,22.15,25.67,26.22 and 27.70.

On the other hand, the X-ray powder diffraction of crystalline polymorph b (XRPD) figure spectrum signature and table 3 and Fig. 5 basically identical.

Crystal form B exists with anhydrous form, for example can not comprise the water of 1.5% weight ratio.

Table 3: the X-ray powder diffraction of crystal form B (XRPD) collection of illustrative plates, show spacing (d, unit _, that is: dust), characteristic XRPD angle (2 θ °) and relative intensity (%)

D value (_)	Angle 2 θ °	Relative intensity (%)
			21.07	4.19	25
10.47	8.44	18
			9.656	9.15	1
8.563	10.32	12
			7.513	11.77	8
6.616	13.37	8
			5.383	16.45	47
5.209	17.01	84
			5.063	17.50	5
4.803	18.46	8
			4.695	18.89	49
4.548	19.50	19
			4.485	19.78	15
4.457	19.90	15
			4.390	20.21	4
4.255	20.86	24
			4.158	21.35	100
4.009	22.15	20
			3.950	22.49	4
3.866	22.99	11

3.811	23.32	12
			3.762	23.63	14
3.733	23.82	11
			3.618	24.59	12
3.574	24.90	14
			3.497	25.45	9
3.468	25.67	22
			3.396	26.22	20
3.301	26.99	15
			3.218	27.70	21
3.153	28.29	5
			3.103	28.75	12
3.052	29.24	4
			2.972	30.04	16
2.883	31.00	6
			2.863	31.21	16
2.836	31.52	3
			2.778	32.20	2
2.742	32.63	16
			2.707	33.06	3
2.604	34.42	12
			2.578	34.76	6
2.562	35.00	3
			2.475	36.27	16
2.422	37.10	1
			2.402	37.41	2
2.357	38.15	8
			2.343	38.39	10
2.297	39.19	2
			2.259	39.87	10

Randomly, crystalline polymorph b extraly by infrared spectrum characterization for as shown in Figure 6,3050,2875,2455,2325,2165,2141,2114,2051,1982,1874,1750,1697,1640,1611,1546,1513,1464,1441,1416,1393,1366,1333,1318,1301,1284,1244,1219,1181,1161,1114,1097,1081,1044,1030,994,948,924,896,826,812,772,741,712cm ^-1The place observes spectrum band.Therefore, crystal form B provides the infrared spectra with Fig. 6 basically identical.

Aspect extra, the invention provides 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the phosphatic crystalline polymorphic form of 4-thiazolidinedione, 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group wherein] phenyl] methyl]-2,4-thiazolidinedione and phosphatic mol ratio are 1: 1, be called crystal form B 1 herein, its X-ray powder diffraction (XRPD) collection of illustrative plates is characterized as at about 16.46,19.51,19.76,19.88 and 23.31 the value place that the 2-θ number of degrees are represented has intensity peak.Crystalline polymorph b 1 can also be selected from the following value place that represents with the 2-θ number of degrees and intensity peak occurs arbitrarily one or more: about 8.39,21.36,23.00,23.61,23.80,24.54,26.20 and 27.71.

Crystal form B 1 exists with anhydrous form, for example comprises the water that is no more than 1.5% weight ratio.

On the other hand, the X-ray powder diffraction of crystalline polymorph b 1 (XRPD) figure spectrum signature and table 4 and Fig. 7 basically identical.

Table 4: the X-ray powder diffraction of crystal form B 1 (XRPD) collection of illustrative plates, show spacing (d, unit _, that is: dust), characteristic XRPD angle (2 θ °) and relative intensity (%)

D value (_)	Angle 2 θ °	Relative intensity (%)
			21.06	4.19	14
10.54	8.39	24
			9.652	9.16	2
8.585	10.30	20
			7.509	11.78	10
6.613	13.38	8
			5.381	16.46	100
*5.254	16.86	17
			5.197	17.05	19
5.061	17.51	10
			4.809	18.43	10
4.692	18.90	21
			4.546	19.51	31
4.489	19.76	40
			4.452	19.88	41
4.388	20.22	9
			4.266	20.81	13
*4.156	21.36	24
			*4.127	22.52	17
*4.008	22.16	21
			3.953	22.47	6
3.864	23.00	27
			3.814	23.31	29
3.765	23.61	29
			3.736	23.80	29
3.625	24.54	24
			3.581	24.85	15
3.504	25.40	13

3.466	25.68	6
			3.398	26.20	27
3.299	27.00	11
			3.216	27.71	24
3.158	28.24	11
			3.102	28.76	14
3.050	29.25	4
			2.971	30.06	6
*2.944	30.33	5
			*2.890	30.92	5
*2.870	31.13	7
			*2.843	31.44	4
*2.790	32.06	4
			2.743	32.61	12
2.709	33.05	4
			*2.689	33.29	4
*2.658	33.69	1
			2.605	34.40	7
2.578	34.77	6
			2.563	34.99	6
*2.499	35.91	4
			2.476	36.25	10
*2.405	37.36	2
			2.356	38.16	6
2.344	38.38	5
			2.297	39.18	4
2.258	39.89	2

Randomly, crystalline polymorph b 1 extraly by infrared spectrum characterization for as shown in Figure 6,3050,2875,2455,2325,2165,2141,2114,2051,1982,1874,1750,1697,1640,1611,1546,1513,1464,1441,1416,1393,1366,1333,1318,1301,1284,1244,1219,1181,1161,1114,1097,1081,1044,1030,994,948,924,896,826,812,772,741,712cm ^-1The place observes spectrum band.Therefore, crystal form B 1 provides the infrared spectra with Fig. 6 basically identical.

The X-ray powder diffraction of crystal form B 1 and crystal form B (XRPD) collection of illustrative plates is only different on the relative intensity of collection of illustrative plates, and wherein the d-value is within specific accuracy of measurement 0.05 degree/2 θ.Some reflections of crystal form B 1 have better resolving power, thereby produce extra reflection, and described extra reflection is used the asterisk mark in table 4.

Therefore, crystal form B has identical infrared spectra with crystal form B 1, but their X-ray powder diffraction (XRPD) collection of illustrative plates difference, some character such as water absorbability are different and their morphology (for example they see in electron microscope crystallographic dimension) difference.In addition, crystal form B and crystal form B 1 can occur with mixture.

Crystal form B and B1 melting range are 175-176 ℃ (Kofler).

Aspect other, the invention provides 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the phosphatic crystalline polymorphic form of 4-thiazolidinedione, 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group wherein] phenyl] methyl]-2,4-thiazolidinedione and phosphatic mol ratio are 1: 1, be called crystal formation E herein, its X-ray powder diffraction (XRPD) collection of illustrative plates is characterized as at about 4.60,13.39,18.20,18.53 and 22.75 the value place that the 2-θ number of degrees are represented has intensity peak.Crystalline polymorphic form E can also be selected from the following value place that represents with the 2-θ number of degrees and intensity peak occurs arbitrarily one or more: about 22.20,22.99,23.24,24.19 and 30.50.

Crystal formation E exists with anhydrous form, for example comprises the water that is no more than 0.5% weight ratio.

On the other hand, the X-ray powder diffraction of crystalline polymorphic form E (XRPD) figure spectrum signature and table 5 and Fig. 8 basically identical.

Table 5: the X-ray powder diffraction of crystal formation E (XRPD) collection of illustrative plates, show spacing (d, unit _, that is: dust), characteristic XRPD angle (2 θ °) and relative intensity (%)

D value (_)	Angle 2 θ °	Relative intensity (%)
			19.19	4.60	44
10.92	8.09	3
			9.570	9.23	2
6.609	13.39	43
			6.332	13.97	5
6.263	14.13	5
			5.964	14.84	5
5.749	15.40	9
			5.450	16.25	2
5.152	17.20	7
			5.075	17.46	5
4.870	18.20	27
			4.785	18.53	100
4.591	19.32	3
			4.382	20.25	3
4.294	20.67	7
			4.170	21.29	4

4.123	21.54	5
			4.001	22.20	12
3.906	22.75	49
			3.865	22.99	20
3.824	23.24	13
			3.799	23.40	7
3.757	23.66	9
			3.677	24.19	23
3.626	24.53	2
			3.606	24.67	2
3.545	25.10	2
			3.500	25.43	3
3.477	25.60	3
			3.400	26.19	3
3.338	26.68	6
			3.308	26.93	1
3.206	27.80	2
			3.189	27.96	2
3.108	28.70	1
			3.097	28.81	2
3.061	29.15	1
			3.011	29.65	4
3.000	29.75	4
			2.929	30.50	10
2.861	31.24	4
			2.817	31.74	3
2.783	32.14	2
			2.729	32.79	2
2.695	33.21	4
			2.658	33.69	4
2.641	33.91	5
			2.586	34.65	1
2.523	35.55	2
			2.493	36.00	1
2.477	36.24	1
			2.449	36.67	2
2.388	37.63	5
			2.342	38.41	2

Randomly, crystalline polymorphic form E extraly by infrared spectrum characterization for as shown in Figure 9,2918,2702,2417,2324,2165,2051,1982,1752,1700,1642,1610,1546,1512,1468,1443,1419,1395,1364,1331,1303,1238,1181,1165,1140,1096,1052,1029,1008,953,906,882,831,819,768,739,714,663cm ^-1The place observes spectrum band.Therefore, crystal formation E provides the infrared spectra with Fig. 9 basically identical.

The melting range of crystal formation E is 167-172 ℃ (Kofler).

Phosphoric acid salt can be with solvate but not hydrate forms obtain, polymorphic form D for example, this depends on and therefrom reclaims phosphatic solvent.This type of solvate is formed a part of the present invention, and comprises its solvate when hereinafter referring to phosphoric acid salt.

Therefore, aspect other, the invention provides 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the phosphatic crystalline polymorphic form of 4-thiazolidinedione, 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group wherein] phenyl] methyl]-2,4-thiazolidinedione and phosphatic mol ratio are 1: 1, be called crystal formation D herein, its X-ray powder diffraction (XRPD) collection of illustrative plates is characterized as at about 14.33,16.05,16.36,21.97 and 22.89 the value place that the 2 θ number of degrees are represented has intensity peak.Crystalline polymorphic form D can also be selected from the following value place that represents with the 2-θ number of degrees and intensity peak occurs arbitrarily one or more: about 4.75,15.04,16.70,19.26,19.57,20.80,21.97,22.74,23.91 and 24.53.

Crystal formation D is a methanol solvent compound form.

On the other hand, the X-ray powder diffraction of crystalline polymorphic form D (XRPD) figure spectrum signature and table 6 and Figure 10 basically identical.

Table 6: the X-ray powder diffraction of crystal formation D (XRPD) collection of illustrative plates, show spacing (d, unit _, that is: dust), characteristic XRPD angle (2 θ °) and relative intensity (%)

D value (_)	Angle 2 θ °	Relative intensity (%)
			20.76	4.25	24
18.61	4.75	33
			12.36	7.15	9
10.70	8.26	12
			10.31	8.57	15
9.960	8.87	5
			9.193	9.61	8
8.538	10.35	20
			7.176	12.33	9
6.852	12.91	15
			6.177	14.33	100
5.887	15.04	39

5.517	16.05	40
			5.414	16.36	63
5.304	16.70	35
			5.135	17.26	26
4.926	17.99	24
			4.748	18.67	8
4.605	19.26	31
			4.534	19.57	36
4.396	20.18	21
			4.312	20.58	24
4.268	20.80	32
			4.094	21.69	26
4.043	21.97	41
			3.977	22.34	25
3.907	22.74	36
			3.882	22.89	43
3.786	23.48	18
			3.719	23.91	35
3.672	24.22	42
			3.627	24.53	37
3.539	25.14	20
			3.448	25.82	28
3.412	26.10	27
			3.279	27.18	16
3.246	27.45	12
			3.204	27.82	8
3.113	28.66	8
			3.036	29.39	10
3.002	29.73	8
			2.949	30.29	11
2.931	30.47	12
			2.905	30.75	18
2.855	31.31	4
			2.730	32.78	13
2.664	33.62	7
			2.629	34.08	11
2.564	34.97	4
			2.514	35.68	4
2.487	36.08	6
			2.473	36.30	5
2.449	36.67	3
			2.378	37.81	7
2.307	39.01	11
			2.724	32.85	2
2.615	34.27	4

2.570	34.88	3
			2.555	35.10	3
2.453	36.61	2
			2.419	37.13	2
2.334	38.55	2
			2.305	39.04	3
2.276	39.57	3

Randomly, crystalline polymorphic form D extraly by infrared spectrum characterization for as shown in figure 11,3129,2933,2684,2325,2165,2150,2113,2051,1982,1743,1699,1641,1604,1538,1511,1467,1446,1412,1389,1357,1332,1303,1279,1242,1164,1107,1077,1063,1021,994,956,928,903,832,802,769,739,719cm ^-1The place observes spectrum band.Therefore, crystal formation D provides the infrared spectra with Figure 11 basically identical.

The accompanying drawing summary:

Fig. 1 shows X-ray powder diffraction (XRPD) collection of illustrative plates of crystal form A

Fig. 2 shows the infrared spectra of crystal form A

Fig. 3 shows X-ray powder diffraction (XRPD) collection of illustrative plates of crystal C

Fig. 4 shows the infrared spectra of crystal C

Fig. 5 shows X-ray powder diffraction (XRPD) collection of illustrative plates of crystal form B

Fig. 6 shows the infrared spectra of crystal form B and crystal form B 1

Fig. 7 shows X-ray powder diffraction (XRPD) collection of illustrative plates of crystal form B 1

Fig. 8 shows X-ray powder diffraction (XRPD) collection of illustrative plates of crystal formation E

Fig. 9 shows the infrared spectra of crystal formation E

Figure 10 shows X-ray powder diffraction (XRPD) collection of illustrative plates of crystal formation D

Figure 11 shows the infrared spectra of crystal formation D

Show that at all the X-coordinate scale is the wave number (cm of unit among the figure of phosphoric acid salt polymorphic form infrared spectra ^-1), and ordinate zou is transmittance (%).Show that at all the X-coordinate scale is the number of degrees 2 θ (2-θ levels) among the figure of phosphoric acid salt polymorphic form X-ray powder diffraction (XRPD) collection of illustrative plates, and ordinate zou is a linear intensity (unit: per second counting (cps)).

The present invention comprises described phosphate and crystalline polymorph A, B, B1, C, D and E, no matter is pure form or the mixture of described polymorph that has separated or is mixed with for example pharmaceutically suitable carrier of other material.

Therefore, on the one hand, provide 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl with unpack format] phenyl] methyl]-2,4-thiazolidinedione phosphate and polymorph A, B, B1, C, D and E.

Aspect other, provide 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl with substantially pure form again] phenyl] methyl]-2,4-thiazolidinedione phosphate and polymorph A, B, B1, C, D and E.

In another aspect of this invention, the form with its mixture provides described phosphate and polymorph A, B, B1, C, D and E.

Described phosphate, preferably phosphoric acid salt hydrate or phosphate non-hydrate, can be that amorphous form exists with amorphous form also, wherein said amorphous form can prepare according to (for example being similar to) conventional method, for example prepare 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl that is dissolved in the mixture that comprises ketone (for example acetone) or is dissolved in alcohol (for example ethanol) and water] phenyl] methyl]-2,4-thiazolidinedione phosphate solution, the then described solution of spray-drying. Alternatively, also can carry out rapid precipitation according to (for example being similar to) known method.

The present invention also comprises for example described phosphate and polymorph A, B, B1, C, D and the E of bulk form (bulk form), and described form can further be processed according to (for example being similar to) known method, for example mills. The present invention also comprises described phosphate and polymorph A, B, B1, C and the E of pharmaceutically acceptable form (form of for example pulverizing).

In addition, the present invention relates to prepare the method for described phosphate and polymorph A, B, B1, C, D and E.

Therefore, the invention provides preparation 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl] phenyl] methyl]-2, the phosphatic method of 4-thiazolidinedione, described method comprises 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl that will be dispersed in or be suspended in or be dissolved in the suitable solvent medium] phenyl] methyl]-2,4-thiazolidinedione or its salt and the reaction of suitable phosphate ion source.

Randomly, as mentioned below subsequently, just can for example in reactant mixture, form 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl] phenyl] methyl]-2, the phosphatic solvate of 4-thiazolidinedione, wherein said reactant mixture is dispersed in or is suspended in or be dissolved in 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl in the appropriate solvent medium by mixing] phenyl] methyl]-2,4-thiazolidinedione or its salt and suitable phosphate ion source mentioned above obtain.

Randomly, can from reactant mixture, reclaim 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl as mentioned belowly] phenyl] methyl]-2,4-thiazolidinedione phosphate, preferably a kind of polymorph form with it reclaims.

Randomly, described 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl] phenyl] methyl]-2,4-thiazolidinedione phosphate, preferably exist with its a kind of polymorphic forms, can carry out drying, preferably in a vacuum.

Randomly, a kind of polymorph can change another polymorph into according to (for example being similar to) known method. For example, under the described condition and/or according to method hereinafter described, crystal form A can change crystal form B or D into hereinafter, and crystal C can change crystal form B or B1 into, and crystal formation D can change crystal form A or B into, and crystal form A, B, B1, D and E can change crystal C into.

Alternatively, as described herein, described a kind of polymorph changes another polymorph into and can carry out in reactant mixture, 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl of wherein said reactant mixture by being dissolved in the appropriate solvent medium] phenyl] methyl]-2, the 4-thiazolidinedione contacts with suitable phosphate ion source and obtains.

Can be according to known manufacturing methods to 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl] phenyl] methyl]-2,4-thiazolidinedione phosphate, preferably exist with its a kind of polymorphic forms and be further processed, for example mill.

On the other hand, the invention provides 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl that preparation exists with polymorphic forms A, B, B1 or E] phenyl] methyl]-2, the phosphatic method of 4-thiazolidinedione, described method comprises 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl that will be dispersed in or be suspended in or be dissolved in the suitable solvent medium] phenyl] methyl]-2,4-thiazolidinedione or its salt and the reaction of suitable phosphate ion source, then implement the following step:

(i) randomly form 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl] phenyl] methyl]-2, the phosphatic solvate of 4-thiazolidinedione,

(ii) reclaim 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl] phenyl] methyl]-2,4-thiazolidinedione phosphate,

(iii) 5-[[4-[2-of drying steps (ii) gained (methyl-2-pyridinylamino) ethyoxyl] phenyl] methyl]-2,4-thiazolidinedione phosphate, especially under vacuum, carry out, in order to obtain 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl of its polymorphic forms A, B, B1 or E] phenyl] methyl]-2,4-thiazolidinedione phosphate.

Randomly, manufacture method that can be known for example method for grinding is further processed phosphate and polymorph A, B, B1 or the E that obtains by said method.

Preferably, phosphoric acid is phosphate ion source suitable in the said method.

Alternatively, can be with 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl] phenyl] methyl]-2,4-thiazolidinedione or its salt join in the suitable phosphate ion source with powder type.

Generally speaking, phosphate and polymorph A, B, B1 or E can pass through contact stoichiometry for example 1: 1 phosphoric acid and 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl] phenyl] methyl]-2, the 4-thiazolidinedione or alternatively use excess phosphoric acid for example phosphoric acid and 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl of 1.1: 1 or 2: 1 to 2.5: 1] phenyl] methyl]-2, the 4-thiazolidinedione is prepared.

5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl] phenyl] methyl]-2, the concentration range of 4-thiazolidinedione is weight/volume, the more preferably weight/volume of 1-10% with respect to the preferred 1-50% of total amount of solvent for use medium in the reaction.

Aforesaid for dissolving, dispersion or suspension 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl] phenyl] methyl]-2,4-thiazolidinedione or its salt and the suitable solvent medium that is used for reacting with suitable phosphate ion source are such organic solvent mediums, ketone for example is as acetone; Perhaps alcohol, C for example₁-C ₄Alcohol, for example ethanol or methyl alcohol; Perhaps nitrile, for example acetonitrile; Perhaps ether, for example oxolane; Perhaps their mixture, or water, or the mixture of described organic solvent and water.

Preferably make water as cosolvent. The preferred amounts of water is that the ratio of water and organic solvent medium is 1-100% (V/V), preferred 1-20% (V/V).

Suitable phosphate ion source is phosphoric acid, the phosphoric acid of the phosphoric acid of 85% (W/W) or lower concentration for example, for example water or with organic solvent medium such as ketone (for example acetone) or alcohol (C for example₁-C ₄Alcohol, for example ethanol or methyl alcohol) or ketone and alcohol mixture carry out 1: 1 to 1: the dilution of 10W/V. Phosphoric acid preferably former state adds, and perhaps for example is dissolved in the solution form adding of any one above-mentioned organic solvent medium with the solution form.

Metaphosphoric acid (preferably with water combination) or with the sodium dihydrogen phosphate of inorganic acid (preferably phosphoric acid) combination or potassium dihydrogen phosphate, sodium hydrogen phosphate or dipotassium hydrogen phosphate or tertiary sodium phosphate or tripotassium phosphate be the alternative source of phosphate ion.

For example some stages of crystal form A need the existence of water forming the phosphate hydrate. Described water may reside in the phosphate ion source, for example is present in the used phosphoric acid, for example by using the phosphoric acid of 85% (w/w) or lower concentration; Perhaps described water is present in the described method as cosolvent, for example is the water of 1-100% (v/v), preferred 1-20% with the organic solvent medium ratio.

Yet, also may by reaction is exposed to carry out under the atmospheric humidity or by use non-dehydrated solvent medium for example aqueous acetone or non-dehydration phosphate ion source for example the phosphoric acid of 85% (w/w) come as the phosphate hydrate for example the formation of crystal form A enough water is provided.

Although can adopt any convenient temperature that required product can be provided, reaction can be in for example about 35 ℃ to about 60 ℃ of the temperature of room temperature or rising, preferably approximately carry out under the reflux temperature of 30 ℃ of extremely about 50 ℃ or solvent mediums.

Phosphatic solvate, preferred water compound can be for example by preparing from solvent medium crystallization mentioned above, it provides or comprises the solvate component, perhaps by preparing in the steam that phosphate is exposed to the solvate component according to (for example being similar to) known method. As indicated above, the formation of described solvate can be carried out in reactant mixture.

Before drying, reclaim for example phosphate (for example with its polymorphic forms) of required compound, comprise from reactant mixture and/or from the appropriate solvent medium and separating; The above-mentioned solvent medium that uses in the optional above-mentioned reaction of wherein said appearance agent medium, preferred water are as cosolvent; The perhaps alternatively mixture of described solvent medium or different solvent medium or its mixtures, for example acetic acid C₁-C ₄Arrcostab or for example hydrogenated carbon, for example hexane. Can from above-mentioned reactant mixture and/or solvent medium, separate required compound by filtering according to known method, and can further comprise washing step subsequently, this means that required compound can wash in one of above-mentioned solvent medium, for example at ethanol, 96% (w/w) ethanol for example, or in its mixture, for example the mixture of acetone and water, for example in the mixture of 95% (v/v) acetone and water.

Alternatively, required compound can obtain separating by crystallizing out from reactant mixture and/or from the mixture of above-mentioned appropriate solvent medium or solvent medium, and wherein said crystallization is by causing with crystal seed. The use that precipitation temperature is strict controlled in about 20 ℃-80 ℃ to 0 ℃-20 ℃ and/or crystal seed for improve phosphate and polymorph thereof for example the repeatability of crystal form A, B, B1 and E all be useful.

Preferably, the phosphate that drying at room temperature is separated under vacuum is its polymorph A, B, B1 and E for example, for example about 20 ℃ to about 35 ℃, for example under the about 25 ℃ temperature; For example about 35 ℃ to about 80 ℃, for example about 40 ℃ to about 60 ℃, preferably approximately 40 ℃ perhaps at elevated temperatures. Randomly, use drier for example phosphorus pentoxide carry out drying. That the weight ratio that dry run continues to water content always is lower than is about 4.5%, for example 3.58%, for example be lower than 0.1%. The not strict restriction of the duration of dry run, can be for example approximately 10-30 hour, for example 15-25 hour, preferably approximately 18-20 hour.

In preferred embodiments, crystal form A can be by being dispersed in or being suspended in or be dissolved in for example 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl in the mixture of acetone and water of appropriate solvent medium] phenyl] methyl]-2,4-thiazolidinedione or its salt and suitable phosphate ion source for example 85% phosphatase reaction are prepared. Randomly, can add the crystal seed of crystal form A, and can temperature as indicated above for example stir the gained mixture for example about 3-5 hour under the nearly room temperature.

Subsequently, can be as indicated above ground, for example by filtering 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl that from mixture, separates polymorphic forms A] phenyl] methyl]-2,4-thiazolidinedione phosphate, and can for example wash with the mixture of acetone and water with suitable solvent medium, and subsequently can be in temperature as indicated above, preferably under nearly room temperature and vacuum, carrying out drying.

In other preferred embodiment, crystal form B can be by being dispersed in or being suspended in or be dissolved in for example 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl in the mixture of acetone and water of appropriate solvent medium] phenyl] methyl]-2,4-thiazolidinedione or its salt and suitable phosphate ion source for example 85% phosphatase reaction are prepared. Randomly, can add the crystal seed of crystal form B, and can for example stir the gained mixture at least about 30 hours under the nearly room temperature in temperature mentioned above.

Subsequently, can be as indicated above ground, for example by filtering 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl that from mixture, separates its polymorphic forms C] phenyl] methyl]-2,4-thiazolidinedione phosphate, and can for example wash with the mixture of acetone and water with suitable solvent medium, and subsequently can be in temperature mentioned above, preferably under about 40 ℃ temperature and vacuum, carry out drying, thereby the acquisition crystal form B wherein may contain trace B1.

In another preferred embodiment, crystal form B 1 can be prepared according to the method that is similar to the above-mentioned B of preparation, but randomly uses the crystal seed of crystal form B 1, but not the crystal seed of crystal form B, and will stir the mixture about at least 50 hours.

In other preferred embodiment, crystal formation E can be as indicated abovely by being dispersed in or being suspended in or be dissolved in for example 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl in the ethanol (for example ethanol of 96% (w/w)) of appropriate solvent medium] phenyl] methyl]-2,4-thiazolidinedione or its salt and suitable phosphate ion source for example 85% phosphoric acid react at elevated temperatures and are prepared. Under agitation cool off subsequently the gained reactant mixture to nearly room temperature. Then, as indicated abovely, for example by filtering 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl that from reactant mixture, separates polymorphic forms E] phenyl] methyl]-2,4-thiazolidinedione phosphate, and can for example use ethanol (for example ethanol of 96% (w/w)) to wash with suitable solvent medium, and subsequently can be in temperature mentioned above, preferably under about 40 ℃ temperature and vacuum, carry out drying.

Crystal form A can change crystal form B into by being heated to about 140 ℃ to about 160 ℃.

On the other hand, the invention provides the phosphatic method of preparation polymorphic forms C, described method comprises the following steps:

(i) with 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl of polymorphic forms A, B, B1, D or E] phenyl] methyl]-2,4-thiazolidinedione phosphate disperses or suspends or be dissolved in the appropriate solvent medium, in order to obtain mixture,

(ii) alternately in about 50 ℃ of whipping steps (i) gained mixture 1 hour, then 10 ℃ were stirred 1 hour, stirred altogether about 3 to about 5 days,

(iii) reclaiming product from step (ii) gained mixture is polymorph C, and

(iv) air-dry step (iii) products therefrom.

In the preparation method of relevant polymorph C and D, term used herein " mixture " is interpreted as 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl that comprises specific compound and for example exist with one of its polymorphic forms] phenyl] methyl]-2, dispersion liquid, suspension and/or the solution of 4-thiazolidinedione phosphate in the appropriate solvent medium.

The step of said method (ii) can be undertaken by replacing whipping step (i) gained mixture, first about 30 ℃-50 ℃, preferably approximately 50 ℃ temperature stirred about 1 hour, and then about 0 ℃ to about 20 ℃, preferably approximately 10 ℃ temperature stirred about 1 hour, stirred altogether about 3 to about 5 days. Alternatively, can interrupt described alternately whipping process evening, mixture is remained on room temperature, then continue described alternately whipping process at second day.

The preferred solvent medium of above-mentioned crystal C preparation method is the mixture of acetone and water, for example the ratio of acetone and water be approximately 2: 1 mixture of (v/v). The step of described method (iii) can followingly be finished, separated product is crystal C from mixture by filtering first, then with the ratio of mixture, for example acetone and the water of acetone and water be approximately 95: the 5 mixture washed product of acetone and water of (v/v). Preferably, from about 0 ℃ to about 30 ℃, preferably approximately carry out described separation process the mixture of 10 ℃ of temperature. The air-dry of step (iv) can carry out for example about 10 hours about 5 hours to about 20 hours.

Term used herein " air-dry " is interpreted as the air drying compound that refers to open, polymorph C for example, described air have about 20% to about 80%, for example about 30% to about relative humidity of 60%, for example about 40% to about 50% and about 18 ℃ to about 25 ℃, about 22 ℃ temperature for example.

Crystal C by the preparation of described method can by about 40 ℃ or higher temperature, for example about 60 ℃ to about 80 ℃, preferably approximately under 50 ℃ the temperature, randomly carry out in a vacuum drying steps (iv) about 5 hours to about 20 hours, for example changed crystal form B 1 in about 10 hours into.

Alternatively, crystal C can prepare by the method that comprises the following steps:

(i) with 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl of polymorph A, B, B1, D or E] phenyl] methyl]-2,4-thiazolidinedione phosphate dissolving or be dispersed or suspended in the appropriate solvent medium, obtaining mixture,

(ii) add suitable phosphate ion source in step (i) the gained mixture, phosphoric acid for example,

(iii) reclaiming product from step (ii) gained mixture is polymorph C, and

(iv) air-dry step (iii) products therefrom.

The preferred solvent medium of the alternative preparation method of above-mentioned crystal C is the mixture of acetone and water, for example the ratio of acetone and water be approximately 1: 1 mixture of (v/v). Step (iii) can followingly be finished, and is crystal C by filtering from the mixture separated product first, then with the ratio of mixture, for example acetone and the water of acetone and water be approximately 95: the 5 mixture washed product of acetone and water of (v/v). The air-dry of step (iv) can carry out for example about 10 hours about 5 hours to about 20 hours.

According to the crystal C of above-mentioned alternative approach preparation by about 40 ℃ or higher temperature, for example about 60 ℃ to about 80 ℃, preferably approximately under 50 ℃ the temperature, randomly in a vacuum drying steps (iv) gained crystal C about 5 hours to about 20 hours, for example changed crystal form B in about 10 hours into.

Aspect other, the invention provides the phosphatic method of preparation polymorphic forms D, described method comprises the following steps:

(i) with 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl of polymorphic forms A] phenyl] methyl]-2,4-thiazolidinedione phosphate dissolving or be dispersed or suspended in the appropriate solvent medium, obtaining mixture,

(ii) heating steps (i) gained mixture heated 4 hours to about 60 ℃ temperature, under then stirring mixture was cooled to nearly room temperature,

(iii) reclaiming product from step (ii) gained mixture is polymorph D, and

(iv) drying steps (iii) products therefrom preferably carries out in a vacuum.

Step (ii) can followingly be finished, at first heating steps (i) gained mixture to about 40 ℃ to about 60 ℃ temperature, heated about 2 hours to 6 hours, then under agitation mixture is cooled to nearly room temperature. Preferably, step (ii) was carried out about 4 hours in about 60 ℃ temperature.

The preferred suitable solvent medium that uses in said method is methyl alcohol.

Following the finishing of the step of described method (iii) is crystal formation D by the isolated by filtration product first, then use methanol wash it. Drying in the step (iv) can 20 ℃ to about 60 ℃, preferably approximately 25 ℃ carried out for example about 10 hours about 5 hours to about 20 hours to about 30 ℃ temperature.

Crystal formation D may contain residual solvent, for example methyl alcohol; In this case, it is not suitable for using in the described pharmaceutical composition hereinafter. But, with crystal formation D be exposed under the humidity, about 60% to about 70% relative humidity for example, it can change crystal form A into. In addition, crystal formation D can discharge its remaining methanol content after being heated to the temperature that is not less than 60 ℃, perhaps can change crystal form B into by being heated to about 120 ℃ or higher temperature. Then, crystal form A and B are fit to mix in the pharmaceutical composition.

Randomly, required compound for example phosphate (being preferably its polymorph A, B, B1, C, D and E) can from above-mentioned reactant mixture, just not separate and be further processed.

5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl] phenyl] methyl]-2, the 4-thiazolidinedione can according to known method for example among the EP-A-0306228 disclosed method be prepared.

As indicated above, compound of the present invention is that phosphate and polymorph A, B, B1, C and E have useful therapeutic properties. Therefore, the invention provides 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl] phenyl] methyl]-2,4-thiazolidinedione phosphate and polymorph A, B, B1, C and E or their mixture be as the purposes of pharmaceutically active substances, for example as the purposes of medicine.

When relating to pharmacy and/or therapeutical uses or composition, term used herein " phosphate and polymorph A, B, B1, C and E " or " 5-[[4-[2-(methyl-2-pyridinylamino) ethyoxyl] phenyl] methyl]-2,4-thiazolidinedione phosphate and polymorph A, B, B1, C and E " be interpreted as respectively and refer to or for these compounds of (being used as) one-component or for its mixture.

Particularly, the invention provides phosphoric acid salt and polymorphic form A, B, B1, C and the E that tool treats and/or prevents human and non-human mammal hyperglycemia purposes.More specifically, the invention provides 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group that is used for the treatment of and/or prevents the mankind or non-human mammal diabetes, diabetes associated conditions and their some complication] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt and polymorphic form A, B, B1, C and E or their mixture.

In this article, used term " prevent diabetes associated conditions " comprises the illness of treatment such as insulin resistance, glucose tolerance reduction, hyperinsulinemia and gestational diabetes.Preferably, diabetes refer to type ii diabetes.The diabetes associated conditions comprises hyperglycemia, hyperlipidaemia, obesity, hypertension, cardiovascular disorder, some eating disorder, polycystic ovarian syndrome and steroid inductive insulin resistance.In this article, the diabetes related complication comprises kidney disease, the kidney disease of especially following type ii diabetes to make progress, and wherein said kidney disease comprises diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage kidney disease.

Described phosphoric acid salt and polymorphic form A, B, B1, C and E itself just can use, and perhaps uses preferably as the pharmaceutical composition that also comprises pharmaceutically acceptable carrier.

Therefore, the present invention also provides and has comprised 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt or its a kind of polymorphic form A, B, B1, C and E or the pharmaceutical composition of their mixture and pharmaceutically acceptable carrier.

Term used herein " pharmaceutically useful " comprises the not only suitable mankind but also is fit to compound, composition and the composition of veterinary purpose.

Identical with the medicinal application of routine, carrier can comprise thinner, weighting agent, disintegrating agent, wetting agent, lubricant, tinting material, flavouring agent or other conventional adjuvant or vehicle.Term used herein " pharmaceutically acceptable carrier " is intended to comprise provides capsular encapsulating material, himself or surround pharmaceutically active substances with other pharmaceutically acceptable carrier.

Compound of the present invention is that phosphoric acid salt and polymorphic form A, B, B1, C and E can use by any suitable pathways, but uses by oral cavity or parenteral route usually.

Pharmaceutical composition can be prepared by mixing, and can adjust so as to be fit to through the oral cavity, parenteral or topical application, but and the form that can so be adjusted into tablet, capsule, liquid oral medicament, pulvis, granule, lozenge, pastille, can rebuild pulvis, injectable and infusion solution or suspension, suppository and endermic device.

The proper method of the pharmaceutical composition of preparation phosphoric acid salt and polymorphic form A, B, B1, C and E is known.

In addition, the invention provides comprise with one or more such as other antidiabetic of biguanides, sulfonylurea and α alpha-glucosidase inhibitors and randomly with 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of pharmaceutically acceptable carrier combination] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt or its a kind of polymorphic form A, B, B1, C and E or the pharmaceutical composition of their mixture.

Aspect other, the invention provides and comprise 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the pharmaceutical composition as pharmaceutical use of 4-thiazolidinedione phosphoric acid salt or its a kind of polymorphic form A, B, B1, C and E or their mixture.

The present invention also provide treat and/or prevent the mankind or non-human mammal diabetes, diabetes relative disease with and the method for some complication, described method comprises to its mankind or non-human mammal of needs uses 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt or polymorphic form A, B, B1, C and E or its mixture.Described phosphoric acid salt or its polymorphic form A, B, B1, C and E or their mixture are used with the effective but nontoxic dosage of pharmacy.

Pharmacy effective dose within the implication of the present invention comprises the physiology that expectation is provided and/or the dosage of pharmacological effect.

In treating and/or preventing diabetes, diabetes associated conditions and its some complication process, phosphoric acid salt and polymorphic form A, B, B1, C and E can use can provide suitable dosage 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the dosage of 4-thiazolidinedione, for example disclosed such among the EPA-0306228.

Aspect other, the invention provides 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt and polymorphic form A, B, B1, C and E or its mixture itself or be included in 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group in the pharmaceutical composition described herein] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt and polymorphic form A, B, B1, C and E or its mixture preparation treat and/or prevent diabetes, diabetes associated conditions with and the medicine of some complication in purposes.

In addition, the invention provides 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group with one or more antidiabetic combinations] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt and polymorphic form A, B, B1, C and E or its mixture preparation treat and/or prevent diabetes, diabetes associated conditions with and the medicine of some complication in purposes, described antidiabetic is biguanides, sulfonylurea and α alpha-glucosidase inhibitors for example.

The following example illustrates the present invention, but the present invention is not done any restriction.All temperature all provide with centigradetemperature, and proofread and correct.

Water-content is measured with Karl Fischer method.

The infrared absorption spectrum of phosphoric acid salt polymorphic form as herein described is measured with BRUKERFTIR-Tensor 27.

X-ray powder diffraction (XRPD) collection of illustrative plates is measured under following condition:

Equipment: x-ray powder diffraction instrument D-8 (AXS-BRUKER), θ-θ-goniometer, sample changer; Target: copper, K α 1+K α 2 λ=1.5406_, collimated beam (parallel beam optics) (receive light Su Laier focusing Di seam: 0.07mm), scintillometer, standard model frame.

Data gathering: test tube anode: Cu; Generator voltage: 40kV; Dynamo current: 40mA; Start angle: 2.0 ° of 2 θ, terminal point angle: 40.0 ° of 2 θ; Step-length: 0.01 ° of 2 θ; Per time in step: 2 seconds; 2 θ may differ the absolute value (absolutely) of 1-3%; 2 θ accuracy of sample data: ± 0.05 degree

Ion chromatography (for example measuring phosphorus acid content) carries out with the commercial IC anion column of Metrohm (Switzerland) SUPER-SEP.

Embodiment 1:

Preparation 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione Phosphatic polymorphic form A

With 5g 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione is dissolved in the about 30 ℃ mixture of 250ml acetone and 20ml water.Stir this solution, and follow and stir adding 1.89ml 85% phosphoric acid.The crystal seed that adds title compound stops to stir, and gained suspension room temperature was placed about 3 hours, stirs 2-3 minute every 30 minutes therebetween.

Separate title compound by sucking-off, with this compound of 25ml washing with acetone, and be placed in the vacuum drying at room temperature about 15 hours, thereby obtain white crystalline solid.

Output (as 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of polymorphic form A] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt hydrate): 5.54g

Water-content (Karl Fischer): 1.6%w/w

Phosphorus acid content: 21.7% (through ion chromatography)

Embodiment 2:

Preparation 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione Phosphatic polymorphic form A

With 25g 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione is dissolved in the about 30 ℃ mixture of 1250ml acetone and 100ml water.Stir this solution, and follow and stir adding 9.45ml 85% phosphoric acid.Stop to stir, and gained suspension room temperature was placed about 18 hours.Stirred gained suspension then gently about 1 hour.Separate white crystals by sucking-off subsequently, wash this crystallization, and it was put in the vacuum drying at room temperature about 3 hours with the mixture of 95ml acetone and 5ml water.

Output (as 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of polymorphic form A] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt hydrate): 28.56g

Water-content (Karl Fischer): 3.3%w/w

The characteristic of embodiment 2 products:

Embodiment 2 gained solid products Infrared absorption spectrumSee Fig. 2, observed spectrum band is as indicated above.

Embodiment 2 gained solid products X-ray powder diffraction (XRPD) collection of illustrative platesAs shown in Figure 1, and table 1 write down spacing (d, unit _, that is: dust), characteristic XRPD angle (2 θ °) and relative intensity (%).

Embodiment 3:

Preparation 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione Phosphatic polymorphic form A

With 10g 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione is dissolved in the about 60 ℃ mixture of 500ml 96% ethanol and 50ml water.The phosphoric acid that adds 2.1ml 85%.Follow to stir and add 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the phosphatic crystal seed of 4-thiazolidinedione stops to stir.Gained suspension was put room temperature about 3 hours, stirred 2-3 minute every 30 minutes therebetween.Separate title compound by sucking-off, with two parts of these compounds of washing with alcohol of 50ml altogether, and it was put in the vacuum drying at room temperature about 4 days, thereby obtain white crystalline solid.

Output (as 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of polymorphic form A] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt hydrate): 10.32g

Water-content (Karl Fischer): 2.3%w/w

Phosphorus acid content: 20.1% (through ion chromatography)

Embodiment 4:

With dry 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of Vanadium Pentoxide in FLAKES] phenyl] first Base]-2, the phosphatic polymorphic form A of 4-thiazolidinedione

There is P ₅O ₂Vacuum in, under about 45 ℃ temperature dry 10g polymorphic forms A, water-content (Karl Fisher) is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of 2.8%w/w] phenyl] methyl]-2, about 24 hours of 4-thiazolidinedione phosphoric acid salt hydrate.

Water-content (Karl Fischer): 0.87%w/w

Embodiment 5:

With 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphorus The polymorphic form A of hydrochlorate is exposed under the humidity

5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group with polymorphic forms A] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt hydrate is exposed under the different relative humidity about 24 hours.

The result provides in the table 7 hereinafter:

Table 7

	Water-content (Karl Fisher) is w/w (%)
		At first	2.8
45% relative humidity	3.42
		63% relative humidity	3.37
86% relative humidity	3.58

Embodiment 6:

Preparation 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione Phosphatic polymorphic form A

Utilize mechanical stirrer to stir down, with 61.2g 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione is dissolved in 3060ml acetone and 244.8ml water in 30 ℃ mixture.Add 23.1ml 85% phosphoric acid.The seed that adds crystal form A, and under about 25 ℃ temperature, stirred the gained mixture about 5 hours.By the filtering separation title compound, in two part of 95% (v/v) acetone of every part of 122.4ml, wash this compound, and under about 25 ℃, it was carried out drying about 18 hours subsequently then.

Output (as 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of polymorphic form A] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt hydrate): 69.1g

Water-content (Karl Fischer): 1.7%w/w

Phosphorus acid content: 21.2% (through ion chromatography)

Embodiment 7:

Preparation 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione Phosphatic polymorph b

Utilize mechanical stirrer to stir down, with 20g 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione is dissolved in about 25-28 ℃ the mixture of 1000ml acetone and 80ml water.The phosphoric acid (1.1 equivalent) that adds 4.16ml 85%.The seed that adds crystal form B, and stirred the gained mixture at least 30 hours in about 25 ℃ temperature.Then by the filtering separation solid, in two part of 95% (v/v) acetone of every part of 32ml this solid of washing and with its put in the vacuum about 40 ℃ dry about 18 hours down, thereby obtain title compound.

Output (as 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of polymorph b] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt): 25g (containing trace B1)

Embodiment 8:

Preparation 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione Phosphatic polymorph b 1

Utilize mechanical stirrer to stir down, with 20g 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione is dissolved in about 25-28 ℃ the mixture of 1000ml acetone and 80ml water.The phosphoric acid (1.1 equivalent) that adds 4.16ml 85%.The seed that adds crystal form B 1, and stirred the gained mixture at least 50 hours in about 25 ℃ temperature.Then by filter with solids constituent in, two part of 95% (v/v) acetone at every part of 32ml this solid of washing and with its put in the vacuum about 40 ℃ dry about 18 hours down, thereby obtain title compound.

Output (as 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of polymorph b 1] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt): about 25g

Embodiment 9:

Preparation 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione Phosphatic polymorph b 1

With 5g 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt crystal form A is suspended in 50ml acetone (2: in mixture 1v/v).Alternately stir the gained mixture whole daytime, elder generation is about 1 hour of about 50 ℃ of stirrings, then about 1 hour of about 10 ℃ of stirrings, and then remain on room temperature with mixture evening.Total repeated this process about 5 days.Then by filtering from suspension (in 10 ℃) separate solid, wash this solid and it was put the vacuum dry about 20 hours with the mixture of 10ml acetone (95%v/v), thus the acquisition title compound.

Output (as 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of polymorph b 1] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt): about 4.3g

Embodiment 10:

Preparation 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione Phosphatic polymorphic form C also changes polymorph b into

With 10g 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt crystal form B is dissolved in about 60 ℃ mixture of 50ml acetone and 50ml water.Follow stirring, add the phosphoric acid of 1.48ml 85%.Gained suspension is cooled to room temperature, and stirs about 3 hours.By the filtering separation product is crystal C, and with the acetone of 20ml (95: 5 (v/v)) washed product altogether, then with it is air-dry (open air, relative humidity is about 28%, about 22 ℃) about 20 hours; Subsequently, crystal C is put in the vacuum to descend dry about 20 hours at about 40 ℃, thereby produce crystal form B.

Output (as 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of polymorph b] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt): 7.02g

Embodiment 11:

Preparation 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione Phosphatic polymorphic form C also changes polymorph b 1 into

With 5g 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt crystal form A is suspended in 50ml acetone (2: in mixture 1v/v).Alternately stir the gained mixture whole daytime, elder generation is in about 50 ℃ of about 1 hour of stirrings down, then about 1 hour of about 10 ℃ of stirrings, and then remain on room temperature with mixture evening.This process amounts to and repeats about 5 days.Isolating product by filtration from suspension (about 10 ℃) is crystal C, usefulness 10ml acetone (95: mixture washed product 5v/v), and with its air-dry about 20 hours.

Output (as 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of polymorphic form C] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt): about 4.3g

At about 40 ℃ of dry down crystal form Bs 1 that produce.

Embodiment 12:

Preparation 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione Phosphatic polymorphic form D

With 10g 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt (crystal form A) is suspended among the 150ml MeOH (methyl alcohol), and this suspension is heated to about 60 ℃, heats about 4 hours.It is extremely thin that gained suspension becomes earlier, and crystal formation D begins crystallization then.And then about 2 hours, and by filtering to isolate title compound, being that the MeOH of 10ml washs this compound, and subsequently it put in the vacuum dry about 20 hours with total amount at this suspension of stirring at room.

Output (as 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of polymorphic form D] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt): about 9.72g

Embodiment 13:

Preparation 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione Phosphatic polymorphic form E

With 10g 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the 4-thiazolidinedione is dissolved in 96% ethanol of the nearly boiling point of 250ml.Stirring makes solution be cooled to about 65 ℃ gently, and adds the phosphoric acid (H of 3.78ml 85% ₃PO ₄).Under mechanical stirrer stirs gently, this solution is cooled to room temperature then.After adding phosphoric acid, in the following following time of temperature stirred solution: about 43 ℃ about 20 minutes, about 39 ℃ about 30 minutes, about 30 ℃ about 60 minutes, about 29 ℃ about 2 hours and about 23 ℃ about 22 hours.Then by the filtering separation title compound, two parts altogether 96% ethanol (EtOH) of 20ml wash this compound, and with its put in the vacuum about 40 ℃ dry about 20 hours down.

Output (as 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of polymorphic form E] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt): 12.1g

Water-content (Karl Fischer): 0.2%w/w

As described herein, phosphoric acid salt and polymorphic form A, B, B1, C, D and E show satisfactory stability.According to currently known methods, crystal form A, B, B1 and E carry out not observing degraded with the HPLC test that standard method is carried out after about 160 hours of the stress test in airtight bottle under 80 ℃.

In addition, the applicant has been found that the oxyethyl group according to 5-[[4-[2-of the present invention (methyl-2-pyridinylamino)] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt and polymorphic form A, B, B1, C, D and E show can compare with rosiglitazone maleate or even the water solubility of (expressed) more fast, wherein said rosiglitazone maleate is the principal mode that present rosiglitazone is introduced to the market as the active substance in the pharmaceutical preparation.For example, crystal form A presents the enhanced water solubility, for example approximately is the twice of maleate form, and this is useful and interesting to industrial application.

In addition, it is relative simple to produce the method for described phosphoric acid salt and polymorphic form A, B, B1, C, D and E.

Claims (36)

1. (1.5-[[4-[2-methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the salt of 4-thiazolidinedione and phosphoric acid, perhaps its solvate or non-solvent compound form.
2. 2. the described salt of claim 1 or its solvate or non-solvent compound form, wherein said salt is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt, 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group wherein] phenyl] methyl]-2,4-thiazolidinedione and phosphatic mol ratio are 1: 1.
3. 3. according to the crystalline polymorphic form A of claim 1 or 2 described salt, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt hydrate is characterised in that X-ray powder diffraction (XRPD) collection of illustrative plates has intensity peak at about 15.63,15.75,17.30,19.61 and 21.47 the value place that represents with the 2-θ number of degrees.
4. 4. according to the crystalline polymorphic form A of claim 1 or 2 described salt, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt hydrate is characterised in that X-ray powder diffraction (XRPD) collection of illustrative plates and table 1 and Fig. 1 basically identical.
5. 5. according to claim 3 or 4 described crystalline polymorphic form A, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt hydrate is characterised in that infrared spectra is at 2704,1748,1701,1643,1611,1546,1513,1469,1420,1391,1330,1302,1244,1110,1028,928,821,767,716 cm ^-1The place observes bands of a spectrum.
6. 6. according to the crystalline polymorph b of claim 1 or 2 described salt, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt is characterised in that X-ray powder diffraction (XRPD) collection of illustrative plates has intensity peak at about 4.19,16.45,17.01,18.89 and 21.35 the value place that represents with the 2-θ number of degrees.
7. 7. according to the crystalline polymorph b of claim 1 or 2 described salt, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt is characterised in that X-ray powder diffraction (XRPD) collection of illustrative plates and table 3 and Fig. 5 basically identical.
8. 8. according to claim 6 or 7 described crystalline polymorph bs, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt is characterised in that infrared spectra is 3050,2875,2455,2325,2165,2141,2114,2051,1982,1874,1750,1697,1640,1611,1546,1513,1464,1441,1416,1393,1366,1333,1318,1301,1284,1244,1219,1181,1161,1114,1097,1081,1044,1030,994,948,924,896,826,812,772,741,712cm ^-1The place observes bands of a spectrum.
9. 9. according to the crystalline polymorph b 1 of claim 1 or 2 described salt, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt is characterised in that X-ray powder diffraction (XRPD) collection of illustrative plates has intensity peak at about 16.46,19.51,19.76,19.88 and 23.31 the value place that represents with the 2-θ number of degrees.
10. 10. according to the crystalline polymorph b 1 of claim 1 or 2 described salt, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt is characterised in that X-ray powder diffraction (XRPD) collection of illustrative plates and table 4 and Fig. 7 basically identical.
11. 11. according to claim 9 or 10 described crystalline polymorph bs 1, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt is characterised in that infrared spectra is 3050,2875,2455,2325,2165,2141,2114,2051,1982,1874,1750,1697,1640,1611,1546,1513,1464,1441,1416,1393,1366,1333,1318,1301,1284,1244,1219,1181,1161,1114,1097,1081,1044,1030,994,948,924,896,826,812,772,741,712cm ^-1The place observes bands of a spectrum.
12. 12. crystalline polymorphic form C according to claim 1 or 2 described salt, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt hydrate is characterised in that X-ray powder diffraction (XRPD) collection of illustrative plates has intensity peak at about 12.86,15.98,16.26,21.60 and 24.50 the value place that represents with the 2-θ number of degrees.
13. 13. crystalline polymorphic form C according to claim 1 or 2 described salt, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt is characterised in that X-ray powder diffraction (XRPD) collection of illustrative plates and table 2 and Fig. 3 basically identical.
14. 14. according to claim 12 or 13 described crystalline polymorphic form C, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt is characterised in that infrared spectra is 3111,2924,2652,2325,2165,2114,2051,1981,1874,1745,1698,1641,1608,1541,1513,1464,1443,1416,1392,1363,1332,1301,1265,1249,1218,1179,1163,1113,1096,1048,1028,995,951,926,905,823,812,774,739,713cm ^-1The place observes bands of a spectrum.
15. 15. crystalline polymorphic form D according to claim 1 or 2 described salt, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt is characterised in that X-ray powder diffraction (XRPD) collection of illustrative plates has intensity peak at about 14.33,16.05,16.36,21.97 and 22.89 the value place that represents with the 2-θ number of degrees.
16. 16. crystalline polymorphic form D according to claim 1 or 2 described salt, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt is characterised in that X-ray powder diffraction (XRPD) collection of illustrative plates and table 6 and Figure 10 basically identical.
17. 17. according to claim 15 or 16 described crystalline polymorphic form D, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt is characterised in that infrared spectra is 3129,2933,2684,2325,2165,2150,2113,2051,1982,1743,1699,1641,1604,1538,1511,1467,1446,1412,1389,1357,1332,1303,1279,1242,1164,1107,1077,1063,1021,994,956,928,903,832,802,769,739,719cm ^-1The place observes bands of a spectrum.
18. 18. crystalline polymorphic form E according to claim 1 or 2 described salt, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt is characterised in that X-ray powder diffraction (XRPD) collection of illustrative plates has intensity peak at about 4.60,13.39,18.20,18.53 and 22.75 the value place that represents with the 2-θ number of degrees.
19. 19. crystalline polymorphic form E according to claim 1 or 2 described salt, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt is characterised in that X-ray powder diffraction (XRPD) collection of illustrative plates and table 5 and Fig. 8 basically identical.
20. 20. according to claim 18 or 19 described crystalline polymorphic form E, it is 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt, be characterised in that infrared spectra 2918,2702,2417,2324,2165,2051,1982,1752,1700,1642,1610,1546,1512,1468,1443,1419,1395,1364,1331,1303,1238,1181,1165,1140,1096,1052,1029,1008,953,906,882,831,819,768,739,714,663cm ^-1The place observes bands of a spectrum.
21. 21. according to any described compound among the claim 1-20, it is a unpack format.
22. 22. according to any described compound among the claim 1-20, it is pure substantially form.
23. 23. preparation is according to the method for claim 1 or 2 described salt, it comprises and will disperse or suspend or be dissolved in 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group in the appropriate solvent medium] phenyl] methyl]-2,4-thiazolidinedione or its salt react with suitable phosphate ion source.
24. 24. preparation is according to the method for any described crystalline polymorphic form A, B, B1 or an E among claim 3-5,6-8,9-11 or the 18-20, it comprises and will disperse or suspend or be dissolved in 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group in the appropriate solvent medium] phenyl] methyl]-2,4-thiazolidinedione or its salt and suitable phosphate ion source reaction, and carry out the following step subsequently:

    (i) randomly form 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2, the phosphatic solvate of 4-thiazolidinedione,

    (ii) reclaim 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt,

    The (iii) ii) 5-[[4-[2-of gained (methyl-2-pyridinylamino) oxyethyl group of drying step] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt, especially dry under vacuum, so that obtain 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of polymorphic forms A, B, B1 or E] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt.
25. 25. according to claim 23 or 24 described methods, wherein suitably phosphate ion source is a phosphoric acid.
26. 26. preparation is according to the method for any described crystalline polymorphic form C among the claim 12-14, it comprises the following steps:

    (i) with 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of polymorphic forms A, B, B1, D or E] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt disperses or suspends or be dissolved in the appropriate solvent medium, so that obtain mixture,

    (ii) whipping step (i) gained mixture alternately, earlier about 50 ℃ stir down about 1 hour, stirred about 1 hour down at about 10 ℃ then, carried out altogether about 3 days to about 5 days,

    (iii) from step (ii) the gained mixture to reclaim product be polymorphic form C, and

    (iv) air-dry step is products therefrom (iii).
27. 27. preparation is according to the method for any described crystalline polymorphic form C among the claim 12-14, it comprises the following steps:

    (i) with 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of polymorphic forms A, B, B1, D or E] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt dissolving or be dispersed or suspended in the appropriate solvent medium, so that obtain mixture,

    (ii) in step (i) gained mixture, add suitable phosphate ion source, phosphoric acid for example,

    (iii) (ii) reclaiming product the gained mixture from step is polymorphic form C, and

    (iv) air-dry step is products therefrom (iii).
28. 28. according to claim 26 or 27 described methods, wherein said appropriate solvent medium is the mixture of acetone and water.
29. 29. preparation is according to the method for any described crystalline polymorphic form D among the claim 15-17, it comprises the following steps:

    (i) with 5-[[4-[2-(methyl-2-pyridinylamino) oxyethyl group of polymorphic forms A] phenyl] methyl]-2,4-thiazolidinedione phosphoric acid salt dissolving or be dispersed or suspended in the appropriate solvent medium, so that obtain mixture,

    About 4 hours of (ii) that step (i) gained mixture heating up is extremely about 60 ℃ temperature under agitation is cooled to nearly room temperature with described mixture subsequently,

    (iii) from step (ii) the gained mixture to reclaim product be polymorphic form D, and

    (iv) (iii) products therefrom of drying step preferably carries out in a vacuum.
30. 30. method according to claim 29, wherein said appropriate solvent medium is a methyl alcohol.
31. 31. according to any described compound or its mixture among claim 1-14 and the 18-20, as medicine.
32. 32., be used to prepare the medicine that treats and/or prevents the mankind or non-human mammal diabetes, diabetes associated conditions and its some complication according to the purposes of any described compound or its mixture among claim 1-14 and the 18-20.
33. 33. pharmaceutical composition, it comprises according to any described compound or its mixture and pharmaceutically acceptable carrier among claim 1-14 and the 18-20.
34. 34. pharmaceutical composition, its comprise with the claim 1-14 of one or more other antidiabetic combination and 18-20 in any described compound or its mixture and pharmaceutically acceptable carrier.
35. 35. treat and/or prevent the method for diabetes, diabetes associated conditions and their some complication, comprise any described compound or its mixture in the people of needs or non-human mammal are used according to claim 1-14 and 18-20.
36. 36. treat and/or prevent the method for diabetes, diabetes associated conditions and their some complication, comprise to the people or the non-human mammal of needs and using according to claim 33 or 34 described pharmaceutical compositions.

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