CN107641125A - Ba Ruike is for Buddhist nun's phosphate I crystal and preparation method thereof - Google Patents
Ba Ruike is for Buddhist nun's phosphate I crystal and preparation method thereof Download PDFInfo
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- CN107641125A CN107641125A CN201710779690.9A CN201710779690A CN107641125A CN 107641125 A CN107641125 A CN 107641125A CN 201710779690 A CN201710779690 A CN 201710779690A CN 107641125 A CN107641125 A CN 107641125A
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- buddhist nun
- ruike
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- FOGPJLCTYDHHEJ-UHFFFAOYSA-N CCS(N(C1)CC1(CC=N)[n]1ncc(-c2ncnc3c2cc[nH]3)c1)(=O)=O Chemical compound CCS(N(C1)CC1(CC=N)[n]1ncc(-c2ncnc3c2cc[nH]3)c1)(=O)=O FOGPJLCTYDHHEJ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention provides a kind of Ba Ruike of formula (I) to replace the phosphatic I crystal of Buddhist nun,The XRPD collection of illustrative plates of wherein I crystal has diffraction maximum at 2 θ=8.818,10.442,12.901,14.901,16.076,16.88,17.54,18.677,19.12,19.44,20.596,21.699,22.422,23.181,24.539,25.779,27,28.461, wherein 2 θ values error ranges are ± 0.2.Of the present invention bar of Rake is suitable for Buddhist nun's phosphate with existing X bars of Rake of crystal formation for Buddhist nun's phosphate I crystal stability, and with the solubility higher than crystal formation X, can lift its bioavilability, be advantageous to the processing of its medicine and the use in pharmaceutical composition.
Description
The application is the Chinese invention patent application of 2 months Application No. 201610070654.0 submitted for 1st in 2016《Bar
Rake is for Buddhist nun phosphatic A crystal formations, H crystal form and I crystal and preparation method thereof》Divisional application.
Technical field
The present invention relates to the polymorphic that the Ba Ruike as JAK inhibitor replaces Buddhist nun's derivative, in particular it relates to which Ba Ruike is replaced
Buddhist nun phosphatic A crystal formations, H crystal form and I crystal and preparation method thereof.
Background technology
JAK is Janus kinases (Janus Kinase), is a kind of non-receptor type tyrosine protein kinase, and a kind of non-
The EGFR-TK of transmembrane.Because JAK can phosphorylation cytokine receptor combined with it, and can phosphorylation is more
The individual signaling molecule containing specific SH2 domains.JAK protein families include 4 members altogether：JAK1, JAK2, JAK3 and TYK2,
They have 7 JAK homeodomains (JAK homology domain, JH) in structure, wherein JH1 domains be kinases area,
JH2 domains are that "false" kinases area, JH6 and JH7 are receptorbinding regions.
TYK2 is the potential target spot of Immunoinflammatory Disorders, rejects research confirmation (Levy by people's science of heredity and mouse
D. with Loomis C., 1655-1658 pages of New England Journal of Medicine 357 (2007)).
JAK1 is the novel targets in Immunoinflammatory Disorders field., can the transducer cell factor by JAK1 and other JAK heterodimericization
The pro-inflammatory signals conduction of driving.Therefore, it is contemplated that suppress JAK1 and/or other JAK for a series of inflammatory conditions and other by JAK
The disease of the signal transduction driving of mediation has treatment benefit.
It is entitled { 1- (the ethylsulfonyl) -3- of chemistry that Ba Ruike in the present invention, which replaces Buddhist nun (Baricitinib) phosphate,
[4- (7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yls] azetidine -3- bases } acetonitrile phosphate, such as formula
(I) compound shown in,
It is a kind of JAK classes inhibitor compound, available for treatment JAK participate in autoimmune disease, inflammatory disease or
Cancerous disease.In Chinese invention patent CN 102026999 (WO 2009/114512), the compound and its derivative are disclosed
Thing.Repeat to obtain solid according to this patent, fusing point is 188 DEG C, discloses with patent similar, and " X bars of crystal formation is referred to as in the present invention
Rake replaces Buddhist nun's phosphate ".
It is well known that same medicine, crystal formation is different, and its bioavilability may also can have difference, and it is stable in addition
Property, mobility, compressibility may also can be different, application of these physicochemical properties to medicine produces certain influence, so as to shadow
The effect of ringing medicine.Therefore it is necessary to have the crystal formation that the Ba Ruike of superior physiochemical properties replaces Buddhist nun's derivative, it can be favourable
Ground uses in medicine processing and pharmaceutical composition.The Ba Ruike that the present invention develops has no report for the phosphatic novel crystal forms of Buddhist nun.
The content of the invention
Problem to be solved by this invention is existing bar of Rake for Buddhist nun's Phosphate solubility has much room for improvement and influences biological profit
The problem of expenditure, at the same time it is wished that can seek Ba Ruike replaces the phosphatic novel crystal forms of Buddhist nun, study and provide for the effect of solid drugs
More qualitative, quantitative information.
In order to solve the above-mentioned technical problem, it is phosphatic new for Buddhist nun to provide a kind of Ba Ruike for the first aspect of the invention
Crystal formation, more specifically, being { 1- (ethylsulfonyl) -3- [4- (7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrazoles -1-
Base] azetidine -3- bases } the phosphatic new crystal formation (hereinafter referred to as " Ba Ruike replaces Buddhist nun phosphate A crystal formations ") of acetonitrile, its XRPD
Collection of illustrative plates 2 θ=8.38,8.88,10.48,13.00,15.06,16.22,16.82,17.76,19.18,19.70,21.04,
22.22nd, there is diffraction maximum at 22.68,24.40,24.94,26.48,27.40, wherein 2 θ values error ranges are ± 0.2.
Of the present invention bar of Rake replaces Buddhist nun's phosphate A crystal formations, has the XRPD substantially the same with Figure of description Fig. 1
Collection of illustrative plates.
Present invention also offers a kind of methods of the Ba Ruike for Buddhist nun's phosphate A crystal formations is prepared, comprise the following steps：
(1) added in Ba Ruike replaces Buddhist nun's phosphate for the organic solvent of dissolving and obtain the Ba Ruike and replace Buddhist nun's phosphoric acid
The dissolved matter of salt；
(2) Ba Ruike will be added for the organic solvent of precipitation to replace in the phosphatic dissolved matter of Buddhist nun, makes the Ba Rui
Gram salted out for Buddhist nun's phosphoric acid, obtain the Ba Ruike and replace the phosphatic precipitate of Buddhist nun；
(3) Ba Ruike is dried for the phosphatic precipitate of Buddhist nun, obtains Ba Ruike and replace Buddhist nun's phosphate A crystal formations.
In certain embodiments, preparing the method for the azetidine phosphate A crystal formations also includes replacing the Ba Ruike
The step of phosphatic precipitate of Buddhist nun is filtered.
In certain embodiments, the organic solvent that is used to dissolve be in amide-type any one solvent or two kinds with
Upper solvent is with the mixed solvent of arbitrary proportion.
In some preferred embodiments, the organic solvent for being used to dissolve is DMF.
In certain embodiments, the organic solvent for being used to separate out is any one solvent or two in ethers or esters
Kind above solvent is with the mixed solvent of arbitrary proportion.
In some preferred embodiments, the ether organic solvent is ether, isopropyl ether or methyl tertiary butyl ether(MTBE)；It is described
Based organic solvent is ethyl acetate or isopropyl acetate.
In certain embodiments, after the Ba Ruike salts out for Buddhist nun's phosphoric acid, continuously add and described be used for what is separated out
Organic solvent.
In certain embodiments, the volume ratio of the organic solvent for being used to dissolve and the organic solvent for being used to separate out
Example is 1:2 to 1:15.
In certain embodiments, the precipitate is dried in vacuo and obtains the Ba Ruike and replace Buddhist nun's phosphate A crystal formations.
In some embodiments, the Ba Ruike dissolves or separated out at room temperature for Buddhist nun's phosphate.
In addition, the second aspect of the invention, which provides a kind of Ba Ruike, replaces the phosphatic new crystal formation of Buddhist nun, more specifically,
For { 1- (ethylsulfonyl) -3- [4- (7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yls] azetidine -3-
Base } the phosphatic new crystal formation (hereinafter referred to as " Ba Ruike replaces Buddhist nun's phosphate H crystal form ") of acetonitrile, its XRPD collection of illustrative plates 2 θ=7.94,
12.401、13.539、14.278、15.957、16.779、17.52、19.403、20.282、22.259、24.617、26.04、
There is diffraction maximum at 27.144, wherein 2 θ values error ranges are ± 0.2.
Of the present invention bar of Rake replaces Buddhist nun's phosphate H crystal form, has the XRPD substantially the same with Figure of description Fig. 6
Collection of illustrative plates.
Present invention also offers a kind of methods of the Ba Ruike for Buddhist nun's phosphate H crystal form is prepared, comprise the following steps：
(1) added in Ba Ruike replaces Buddhist nun's phosphate for the organic solvent of dissolving and obtain the Ba Ruike and replace Buddhist nun's phosphoric acid
The dissolved matter of salt；
(2) Ba Ruike will be added for the organic solvent of precipitation to replace in the phosphatic dissolved matter of Buddhist nun, makes the Ba Rui
Gram salted out for Buddhist nun's phosphoric acid, obtain the Ba Ruike and replace the phosphatic precipitate of Buddhist nun；Wherein, the organic solvent for being used to separate out
Temperature is less than room temperature；
(3) Ba Ruike is dried for the phosphatic precipitate of Buddhist nun, obtains Ba Ruike and replace Buddhist nun's phosphate H crystal form.
In certain embodiments, preparing the method for the azetidine phosphate H crystal form also includes replacing the Ba Ruike
The step of phosphatic precipitate of Buddhist nun is filtered.
In certain embodiments, the organic solvent that is used to dissolve be in amide-type any one solvent or two kinds with
Upper solvent is with the mixed solvent of arbitrary proportion.
In some preferred embodiments, the organic solvent for being used to dissolve is DMF.
In certain embodiments, the organic solvent for being used to separate out is any one solvent or two or more in esters
Solvent is with the mixed solvent of arbitrary proportion.
In some preferred embodiments, the based organic solvent is ethyl acetate.
In certain embodiments, the temperature of the organic solvent for being used to separate out is -1 to 3 DEG C, and is used for by described in
After the organic solvent of precipitation is added into the dissolved matter, the precipitate is kept at -1 to 3 DEG C.
In certain embodiments, the precipitate is dried in vacuo and obtains the Ba Ruike and replace Buddhist nun's phosphate H crystal form.
Present invention also offers another methods of the Ba Ruike for Buddhist nun's phosphate H crystal form is prepared, comprise the following steps：
(1) added in Ba Ruike replaces Buddhist nun for the organic solvent of dissolving and obtain the dissolved matter that the Ba Ruike replaces Buddhist nun；
Wherein, the temperature of the organic solvent for being used to dissolve is higher than room temperature；
(2) organic solvent of phosphoric acid is added into the Ba Ruike in the dissolved matter of Buddhist nun, acquisition Ba Ruike replaces Buddhist nun's phosphoric acid
The dissolved matter of salt；
(3) Ba Ruike is rapidly decreased to room temperature for the temperature of the phosphatic dissolved matter of Buddhist nun, the Ba Ruike is replaced Buddhist nun
Phosphoric acid salts out, and obtains the Ba Ruike and replaces the phosphatic precipitate of Buddhist nun；
(4) Ba Ruike is dried for the phosphatic precipitate of Buddhist nun, obtains Ba Ruike and replace Buddhist nun's phosphate H crystal form.
In certain embodiments, preparing the method for the azetidine phosphate H crystal form also includes replacing the Ba Ruike
The step of phosphatic precipitate of Buddhist nun is filtered.
In certain embodiments, the organic solvent for being used to dissolve is any one solvent or two in nitrile or alcohols
Kind above solvent is with the mixed solvent of arbitrary proportion.
In some preferred embodiments, the nitrile organic solvent is acetonitrile；The alcohol organic solvent is ethanol.
In some preferred embodiments, the organic solvent for being used to dissolve is acetonitrile and the mixed solvent of ethanol.
In some preferred embodiments, the volume ratio of the acetonitrile and the ethanol is 3:1 to 5:1.
In some preferred embodiments, the volume ratio of the acetonitrile and the ethanol is 25:8.
In certain embodiments, the temperature of the organic solvent for being used to dissolve is 65 DEG C to 85 DEG C.
In some preferred embodiments, the temperature of the organic solvent for being used to dissolve is 80 DEG C.
In certain embodiments, the organic solvent of the phosphoric acid is the ethanol solution of phosphoric acid.
In certain embodiments, the cool-down method in the step (3) is that the Ba Ruike is replaced into the phosphatic dissolving of Buddhist nun
Thing is passed through 20-30 DEG C of temperature-reducing medium condition to cool.
In certain embodiments, the precipitate is dried in vacuo and obtains the Ba Ruike and replace Buddhist nun's phosphate H crystal form.
In addition, the third aspect of the invention, which provides a kind of Ba Ruike, replaces the phosphatic new crystal formation of Buddhist nun, more specifically,
For { 1- (ethylsulfonyl) -3- [4- (7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yls] azetidine -3-
Base } the phosphatic new crystal formation (hereinafter referred to as " Ba Ruike replaces Buddhist nun's phosphate I crystal ") of acetonitrile, its XRPD collection of illustrative plates 2 θ=8.818,
10.442、12.901、14.901、16.076、16.88、17.54、18.677、19.12、19.44、20.596、21.699、
22.422nd, there is diffraction maximum at 23.181,24.539,25.779,27,28.461, wherein 2 θ values error ranges are ± 0.2.
Of the present invention bar of Rake replaces Buddhist nun's phosphate I crystal, has substantially the same with Figure of description Figure 11
XRPD collection of illustrative plates.
Present invention also offers a kind of methods of the Ba Ruike for Buddhist nun's phosphate I crystal is prepared, comprise the following steps：
(1) added in Ba Ruike replaces Buddhist nun for the organic solvent of dissolving and obtain the dissolved matter that the Ba Ruike replaces Buddhist nun；
Wherein, the temperature of the organic solvent for being used to dissolve is higher than room temperature；
(2) organic solvent of phosphoric acid is added into the Ba Ruike in the dissolved matter of Buddhist nun, acquisition Ba Ruike replaces Buddhist nun's phosphoric acid
The dissolved matter of salt；
(3) Ba Ruike is slowly dropped to room temperature for the temperature of the phosphatic dissolved matter of Buddhist nun, the Ba Ruike is replaced Buddhist nun
Phosphoric acid salts out, and obtains the Ba Ruike and replaces the phosphatic precipitate of Buddhist nun；
(4) Ba Ruike is dried for the phosphatic precipitate of Buddhist nun, obtains Ba Ruike and replace Buddhist nun's phosphate I crystal.
In certain embodiments, preparing the method for the azetidine phosphate I crystal also includes replacing the Ba Ruike
The step of phosphatic precipitate of Buddhist nun is filtered.
In certain embodiments, the organic solvent for being used to dissolve is any one solvent or two in nitrile or alcohols
Kind above solvent is with the mixed solvent of arbitrary proportion.
In some preferred embodiments, the nitrile organic solvent is acetonitrile；The alcohol organic solvent is ethanol.
In some preferred embodiments, the organic solvent for being used to dissolve is acetonitrile and the mixed solvent of ethanol.
In some preferred embodiments, the volume ratio of the acetonitrile and the ethanol is 3:1 to 5:1.
In some preferred embodiments, the volume ratio of the acetonitrile and the ethanol is 25:8.
In certain embodiments, the temperature of the organic solvent for being used to dissolve is 65 DEG C to 85 DEG C.
In some preferred embodiments, the temperature of the organic solvent for being used to dissolve is 80 DEG C.
In certain embodiments, the organic solvent of the phosphoric acid is the ethanol solution of phosphoric acid.
In certain embodiments, the cool-down method in the step (3) is to replace the Ba Ruike within 80-100 minutes
The temperature of the phosphatic dissolved matter of Buddhist nun is reduced to room temperature from the temperature higher than room temperature.
In certain embodiments, the precipitate is dried in vacuo and obtains the Ba Ruike and replace Buddhist nun's phosphate I crystal.
Those of ordinary skill in the art can be carried out according to its knowledge and experience to the dosage of the inventive method agents useful for same
Adjustment, including scale up or reduce raw material dosage and adjust solvent load, and the temperature of the inventive method can be changed.
The scheme of these adjustment is also contained in the method for the present invention.
Of the present invention bar of Rake replaces Buddhist nun phosphate A crystal formations, H crystal form and I crystal, its stability and existing crystal formation X
Ba Ruike is suitable for Buddhist nun's phosphate, and with the phosphatic solubility of Buddhist nun is replaced higher than X bars of Rake of crystal formation, can lift its biological utilisation
Degree, be advantageous to the processing of its medicine and the use in pharmaceutical composition.Ba Ruike replaces Buddhist nun phosphate A crystal formations, H crystal form and I crystal
It can be applied in the medicine for the treatment of autoimmune disease, inflammatory disease or cancer, and there is preferable bioavilability, together
When the qualitative, quantitative information that provides, have great importance the effect of to further studying such solid drugs.
Brief description of the drawings
Fig. 1 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces Buddhist nun's phosphate A crystal formations.
Fig. 2 is XRPD collection of illustrative plates (A of the provided by the invention bar of Rake for the high-temperature stability of Buddhist nun's phosphate A crystal formations：5 days, B：
10 days).
Fig. 3 is XRPD collection of illustrative plates (A of the provided by the invention bar of Rake for the high wet stability of Buddhist nun's phosphate A crystal formations：5 days, B：
10 days).
Fig. 4 is XRPD collection of illustrative plates (A of the provided by the invention bar of Rake for the light durability of Buddhist nun's phosphate A crystal formations：5 days, B：
10 days).
Fig. 5 is that provided by the invention bar of Rake exists for Buddhist nun's phosphate A crystal formations with existing X bars of Rake of crystal formation for Buddhist nun's phosphate
Solubility curve in water.
Fig. 6 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces Buddhist nun's phosphate H crystal form.
Fig. 7 is XRPD collection of illustrative plates (A of the provided by the invention bar of Rake for the high-temperature stability of Buddhist nun's phosphate H crystal form：5 days, B：
10 days).
Fig. 8 is XRPD collection of illustrative plates (A of the provided by the invention bar of Rake for the high wet stability of Buddhist nun's phosphate H crystal form：5 days, B：
10 days).
Fig. 9 is XRPD collection of illustrative plates (A of the provided by the invention bar of Rake for the light durability of Buddhist nun's phosphate H crystal form：5 days, B：
10 days).
Figure 10 is that provided by the invention bar of Rake replaces Buddhist nun's phosphate for Buddhist nun's phosphate H crystal form with existing X bars of Rake of crystal formation
Solubility curve in water
Figure 11 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces Buddhist nun's phosphate I crystal.
Figure 12 is XRPD collection of illustrative plates (A of the provided by the invention bar of Rake for the high-temperature stability of Buddhist nun's phosphate I crystal：5 days,
B：10 days).
Figure 13 is XRPD collection of illustrative plates (A of the provided by the invention bar of Rake for the high wet stability of Buddhist nun's phosphate I crystal：5 days,
B：10 days).
Figure 14 is XRPD collection of illustrative plates (A of the provided by the invention bar of Rake for the light durability of Buddhist nun's phosphate I crystal：5 days,
B：10 days).
Figure 15 is that provided by the invention bar of Rake replaces Buddhist nun's phosphate for Buddhist nun's phosphate I crystal with existing X bars of Rake of crystal formation
Solubility curve in water
Figure 16 is that existing X bars of Rake of crystal formation replaces the phosphatic XRPD collection of illustrative plates of Buddhist nun.
Figure 17 is the XRPD collection of illustrative plates (A that existing X bars of Rake of crystal formation replaces the phosphatic high-temperature stability of Buddhist nun：5 days, B：10
My god).
Figure 18 is the XRPD collection of illustrative plates (A that existing X bars of Rake of crystal formation replaces the phosphatic high wet stability of Buddhist nun：5 days, B：10
My god).
Figure 19 is the XRPD collection of illustrative plates (A that existing X bars of Rake of crystal formation replaces the phosphatic light durability of Buddhist nun：5 days, B：10
My god).
Embodiment
In from detailed description below, aforementioned aspect of the present invention and other aspects of the present invention will be apparent.
1 to 5 bar of Rake of embodiment replaces the preparation of Buddhist nun's phosphate A crystal formations
1.0g bars of Rake is weighed for Buddhist nun's phosphate in sample bottle, adding 5mL DMFs makes it completely molten
Solution, the solvent being then respectively added slowly in the dissolved matter in table 1.Mixing of the solid to be had from the dissolved matter and organic solvent
After separating out in thing, it is further continued for that organic solvent 5mL is additionally added dropwise.Resulting mixture is stood overnight at room temperature, then
Precipitate obtained by standing overnight is filtered, and is dried in vacuo, finally obtains off-white powder, weighs and calculates its yield, knot
Fruit shows in table 1.During used reagent be analysis it is pure.
1 bar of Rake of table replaces the preparation of Buddhist nun's A crystal formations
| Embodiment | Solvent species | Quantity of solvent | Yield |
| 1 | Ether | 20mL | 65% |
| 2 | Isopropyl ether | 75mL | 61% |
| 3 | Methyl tertiary butyl ether(MTBE) | 10mL | 61% |
| 4 | Ethyl acetate | 40mL | 60% |
| 5 | Isopropyl acetate | 50mL | 66% |
Embodiment 6 replaces Buddhist nun's phosphate A crystal formations by XRPD figures to characterize Ba Ruike
The measurement of X-ray powder diffraction (XRPD) collection of illustrative plates, penetrated using the multifunctional assembled X of Rigaku Ultima IV models
Line diffractometer is carried out, and specific collection information is as follows：Cu anodes (40kV, 40mA), °/minute of sweep speed 20, scanning range (2 θ
Scope) 3~45 °, scanning step 0.02, slit width 0.01.Directly suppressed using slide in test board to sample
Reason.Thereafter XRPD collection of illustrative plates uses similar measuring method.
Measure according to the methods described of embodiment 1 prepare Ba Ruike replace Buddhist nun's phosphate A crystal formations XRPD collection of illustrative plates, 2 θ=
8.38,8.88,10.48,13.00,15.06,16.22,16.82,17.76,19.18,19.70,21.04,22.22,22.68,
There is diffraction maximum at 24.40,24.94,26.48,27.40, as shown in Figure 1.Wherein 2 θ values error ranges are ± 0.2.After testing, 2 θ
It can also be ± 0.15 to be worth error range.Buddhist nun's phosphate A crystal formations are replaced according to Ba Ruike prepared by embodiment 2-5 methods describeds, its
XRPD collection of illustrative plates and collection of illustrative plates shown in accompanying drawing 1 are essentially identical.
It will be understood by those skilled in the art that these diffraction maximums, which do not represent Ba Ruike, replaces diffraction shown by Buddhist nun's phosphate A crystal formations
The detailed situation at peak.2 θ values of X-ray powder diffraction figure be can with machine and with the change in sample preparation and batch
Change and slight change between secondary, cited value is not intended as absolute value.It will also be appreciated that the relative intensity at peak may be with orientation
Effect and become, therefore the intensity shown in the XRPD traces contained by the present invention is exemplary, is not used to definitely relatively.
7 bars of Rakes of embodiment are investigated for the high-temperature stability of Buddhist nun's phosphate A crystal formations
Take appropriate Ba Ruike to be placed in for Buddhist nun's phosphate A crystal formations in 60 DEG C of baking ovens, the sample is taken out after 5 days and 10 days and carried out
XRPD tests (as shown in Figure 2), to investigate stability of crystal form of the Ba Ruike for Buddhist nun's phosphate A crystal formations to temperature.As a result show, bar
Rake is stablized under the high temperature conditions for Buddhist nun's phosphate A crystal formations.
8 bars of Rakes of embodiment replace the high humidity study on the stability of Buddhist nun's phosphate A crystal formations
Take appropriate Ba Ruike to be placed in for Buddhist nun's phosphate A crystal formations under 92.5% damp condition, take the sample after 5 days and 10 days
Go out to carry out XRPD tests (as shown in Figure 3), to investigate stability of crystal form of the Ba Ruike for Buddhist nun's phosphate A crystal formations to humidity.As a result
Show, Ba Ruike stablizes under conditions of high humidity for Buddhist nun's phosphate A crystal formations.
9 bars of Rakes of embodiment are investigated for the light durability of Buddhist nun's phosphate A crystal formations
Appropriate Ba Ruike is taken to be placed in for Buddhist nun's phosphate A crystal formations under 4500lux intensity of illumination, by the sample after 5 days and 10 days
Product, which take out, carries out XRPD tests (as shown in Figure 4), to investigate stability of crystal form of the Ba Ruike for Buddhist nun's phosphate A crystal formations to illumination.
As a result show, Ba Ruike stabilizations under illumination condition for Buddhist nun's phosphate A crystal formations.
10 bars of Rakes of embodiment contrast for Buddhist nun's phosphate A crystal formations and X bars of Rake of crystal formation for the phosphatic solubility of Buddhist nun
At 35 DEG C, the Ba Ruike of the gained of embodiment 1 is determined respectively for Buddhist nun's phosphate A crystal formations and the crystalline substance of the gained of comparative example 1
X bars of Rake of type replaces Buddhist nun's phosphate as shown in Figure 5 in the water solubility of different time points, solubility curve, the results showed that, Ba Ruike
It is 4.2mg/mL or so for solubility of Buddhist nun's phosphate A crystal formations in water, and stable level is maintained in minute.
X bars of Rake of crystal formation is 2.5mg/mL or so for solubility of Buddhist nun's phosphate in water.Ba Ruike is for Buddhist nun's phosphate A crystal formations in water
Solubility replace solubility of Buddhist nun's phosphate in water more than X bars of Rake of crystal formation.
11 bars of Rakes of embodiment replace the preparation of Buddhist nun's phosphate H crystal form
1.0g bars of Rake is weighed for Buddhist nun's phosphate in sample bottle, adding 5mL DMFs makes it completely molten
Solution, about 3 DEG C of ethyl acetate 20mL is then added in the dissolved matter, have solid at once from the mixed of the dissolved matter and organic solvent
Separated out in compound, keep stirring 1 hour at 3 DEG C.Resulting precipitate is filtered, and is dried in vacuo, finally obtains off-white color
Solid.During used reagent be analysis it is pure.
12 bars of Rakes of embodiment replace the preparation of Buddhist nun's phosphate H crystal form
1.0g bars of Rake is weighed for Buddhist nun's phosphate in sample bottle, adding 5mL DMFs makes it completely molten
Solution, about -1 DEG C of ethyl acetate 20mL is then added in the dissolved matter, have solid at once from the dissolved matter and organic solvent
Separated out in mixture, keep stirring 1 hour at -1 DEG C.Resulting precipitate is filtered, and is dried in vacuo, it is white to finally obtain class
Color solid.During used reagent be analysis it is pure.
13 bars of Rakes of embodiment replace the preparation of Buddhist nun's phosphate H crystal form
1.0g bars of Rake is weighed for Buddhist nun in sample bottle, the mixed solvent of addition 25mL acetonitriles and 8mL ethanol, then by temperature
Degree rises to 80 DEG C and Ba Ruike is dissolved for Buddhist nun's phosphate.In 2 minutes, into the dissolved matter being slowly added to 4mL contains
The ethanol solution of 3.375mmol phosphoric acid, the solution obtained by this step is continued into stirring 2 hours at 80 DEG C.Then by solution
Cooling at room temperature (the temperature-reducing medium condition cooling for being passed through 25 DEG C) is placed in, separates out solid.Resulting precipitate is filtered, and
Vacuum drying, finally obtains off-white powder.During used reagent be analysis it is pure.
14 bars of Rakes of embodiment replace the preparation of Buddhist nun's phosphate H crystal form
1.0g bars of Rake is weighed for Buddhist nun in sample bottle, the mixed solvent of addition 24mL acetonitriles and 8mL ethanol, then by temperature
Degree rises to 85 DEG C and Ba Ruike is dissolved for Buddhist nun's phosphate.In 2 minutes, into the dissolved matter being slowly added to 4mL contains
The ethanol solution of 3.75mmol phosphoric acid, the solution obtained by this step is continued into stirring 2 hours at 85 DEG C.Then solution is put
Cooling (the temperature-reducing medium condition cooling for being passed through 30 DEG C) at room temperature, separates out solid.Resulting precipitate is filtered, and very
Sky is dried, and finally obtains off-white powder.During used reagent be analysis it is pure.
15 bars of Rakes of embodiment replace the preparation of Buddhist nun's phosphate H crystal form
1.0g bars of Rake is weighed for Buddhist nun in sample bottle, the mixed solvent of addition 25mL acetonitriles and 5mL ethanol, then by temperature
Degree rises to 65 DEG C and Ba Ruike is dissolved for Buddhist nun's phosphate.In 2 minutes, into the dissolved matter being slowly added to 4mL contains
The ethanol solution of 4.0mmol phosphoric acid, the solution obtained by this step is continued into stirring 2 hours at 65 DEG C.Then solution is put
Cooling (the temperature-reducing medium condition cooling for being passed through 20 DEG C) at room temperature, separates out solid.Resulting precipitate is filtered, and very
Sky is dried, and finally obtains off-white powder.During used reagent be analysis it is pure.
Embodiment 16 replaces Buddhist nun's phosphate H crystal form by XRPD figures to characterize Ba Ruike
To the same method as example 6, determine the Ba Ruike prepared according to the methods described of embodiment 11 and replace Buddhist nun's phosphate H
The XRPD collection of illustrative plates of crystal formation, 2 θ=7.94,12.401,13.539,14.278,15.957,16.779,17.52,19.403,
20.282nd, there is diffraction maximum at 22.259,24.617,26.04,27.144, as shown in Figure 6.Wherein 2 θ values error ranges for ±
0.2.After testing, 2 θ values error ranges can also be ± 0.15.Buddhist nun is replaced according to Ba Ruike prepared by embodiment 12-15 methods describeds
Phosphate H crystal form, its XRPD collection of illustrative plates and collection of illustrative plates shown in accompanying drawing 6 are essentially identical.
It will be understood by those skilled in the art that these diffraction maximums, which do not represent Ba Ruike, replaces diffraction shown by Buddhist nun's phosphate H crystal form
The detailed situation at peak.2 θ values of X-ray powder diffraction figure be can with machine and with the change in sample preparation and batch
Change and slight change between secondary, cited value is not intended as absolute value.It will also be appreciated that the relative intensity at peak may be with orientation
Effect and become, therefore the intensity shown in the XRPD traces contained by the present invention is exemplary, is not used to definitely relatively.
17 bars of Rakes of embodiment are investigated for the high-temperature stability of Buddhist nun's phosphate H crystal form
Take appropriate Ba Ruike to be placed in for Buddhist nun's phosphate H crystal form in 60 DEG C of baking ovens, the sample is taken out after 5 days and 10 days and carried out
XRPD tests (as shown in Figure 7), to investigate stability of crystal form of the Ba Ruike for Buddhist nun's phosphate H crystal form to temperature.As a result show, bar
Rake is stablized under the high temperature conditions for Buddhist nun's phosphate H crystal form.
18 bars of Rakes of embodiment replace the high humidity study on the stability of Buddhist nun's phosphate H crystal form
Take appropriate Ba Ruike to be placed in for Buddhist nun's phosphate H crystal form under 92.5% damp condition, take the sample after 5 days and 10 days
Go out to carry out XRPD tests (as shown in Figure 8), to investigate stability of crystal form of the Ba Ruike for Buddhist nun's phosphate H crystal form to humidity.As a result
Show, stability is general under conditions of high humidity for Buddhist nun's phosphate H crystal form by Ba Ruike.
19 bars of Rakes of embodiment are investigated for the light durability of Buddhist nun's phosphate H crystal form
Appropriate Ba Ruike is taken to be placed in for Buddhist nun's phosphate H crystal form under 4500lux intensity of illumination, by the sample after 5 days and 10 days
Product, which take out, carries out XRPD tests (as shown in Figure 9), to investigate stability of crystal form of the Ba Ruike for Buddhist nun's phosphate H crystal form to illumination.
As a result show, Ba Ruike stabilizations under illumination condition for Buddhist nun's phosphate H crystal form.
20 bars of Rakes of embodiment contrast for Buddhist nun's phosphate H crystal form and X bars of Rake of crystal formation for the phosphatic solubility of Buddhist nun
At 35 DEG C, the Ba Ruike of the gained of embodiment 11 is determined respectively for Buddhist nun's phosphate H crystal form and the crystalline substance of the gained of comparative example 1
X bars of Rake of type replaces Buddhist nun's phosphate as shown in Figure 10 in the water solubility of different time points, solubility curve, the results showed that, Ba Rui
Gram it is 2.9mg/mL or so for solubility of Buddhist nun's phosphate H crystal form in water, and stable water is maintained in minute
It is flat.X bars of Rake of crystal formation is 2.5mg/mL or so for solubility of Buddhist nun's phosphate in water.Ba Ruike exists for Buddhist nun's phosphate H crystal form
Solubility in water replaces solubility of Buddhist nun's phosphate in water more than X bars of Rake of crystal formation.
21 bars of Rakes of embodiment replace the preparation of Buddhist nun's phosphate I crystal
1.0g bars of Rake is weighed for Buddhist nun in sample bottle, the mixed solvent of addition 25mL acetonitriles and 8mL ethanol, then by temperature
Degree rises to 80 DEG C and Ba Ruike is dissolved for Buddhist nun's phosphate.In 2 minutes, into the dissolved matter being slowly added to 4mL contains
The ethanol solution of 3.375mmol phosphoric acid, the solution obtained by this step is continued into stirring 2 hours at 80 DEG C.Then by solution
In being slowly dropped to room temperature in 90 minutes, separate out solid.Resulting precipitate is filtered, and is dried in vacuo, finally obtains class
White solid.During used reagent be analysis it is pure.
22 bars of Rakes of embodiment replace the preparation of Buddhist nun's phosphate I crystal
1.0g bars of Rake is weighed for Buddhist nun in sample bottle, the mixed solvent of addition 25mL acetonitriles and 5mL ethanol, then by temperature
Degree rises to 85 DEG C and Ba Ruike is dissolved for Buddhist nun's phosphate.In 2 minutes, into the dissolved matter being slowly added to 4mL contains
The ethanol solution of 3.75mmol phosphoric acid, the solution obtained by this step is continued into stirring 2 hours at 85 DEG C.Then by solution in
Room temperature is slowly dropped in 100 minutes, separates out solid.Resulting precipitate is filtered, and is dried in vacuo, it is white to finally obtain class
Color solid.During used reagent be analysis it is pure.
23 bars of Rakes of embodiment replace the preparation of Buddhist nun's phosphate I crystal
1.0g bars of Rake is weighed for Buddhist nun in sample bottle, the mixed solvent of addition 24mL acetonitriles and 8mL ethanol, then by temperature
Degree rises to 65 DEG C and Ba Ruike is dissolved for Buddhist nun's phosphate.In 2 minutes, into the dissolved matter being slowly added to 4mL contains
The ethanol solution of 4.0mmol phosphoric acid, the solution obtained by this step is continued into stirring 2 hours at 65 DEG C.Then by solution in
Room temperature is slowly dropped in 80 minutes, separates out solid.Resulting precipitate is filtered, and is dried in vacuo, it is white to finally obtain class
Color solid.During used reagent be analysis it is pure.
Embodiment 24 replaces Buddhist nun's phosphate I crystal by XRPD figures to characterize Ba Ruike
To the same method as example 6, determine the Ba Ruike prepared according to the methods described of embodiment 21 and replace Buddhist nun's phosphate H
The XRPD collection of illustrative plates of crystal formation, 2 θ=8.818,10.442,12.901,14.901,16.076,16.88,17.54,18.677,
19.12nd, there is diffraction maximum at 19.44,20.596,21.699,22.422,23.181,24.539,25.779,27,28.461, such as
Shown in Figure 11.Wherein 2 θ values error ranges are ± 0.2.After testing, 2 θ values error ranges can also be ± 0.15.According to embodiment
Ba Ruike prepared by 22-23 methods describeds replaces Buddhist nun's phosphate H crystal form, and its XRPD collection of illustrative plates and collection of illustrative plates shown in accompanying drawing 11 are essentially identical.
It will be understood by those skilled in the art that these diffraction maximums, which do not represent Ba Ruike, replaces diffraction shown by Buddhist nun's phosphate I crystal
The detailed situation at peak.2 θ values of X-ray powder diffraction figure be can with machine and with the change in sample preparation and batch
Change and slight change between secondary, cited value is not intended as absolute value.It will also be appreciated that the relative intensity at peak may be with orientation
Effect and become, therefore the intensity shown in the XRPD traces contained by the present invention is exemplary, is not used to definitely relatively.
25 bars of Rakes of embodiment are investigated for the high-temperature stability of Buddhist nun's phosphate I crystal
Take appropriate Ba Ruike to be placed in for Buddhist nun's phosphate I crystal in 60 DEG C of baking ovens, the sample is taken out after 5 days and 10 days and carried out
XRPD tests (as shown in figure 12), to investigate stability of crystal form of the Ba Ruike for Buddhist nun's phosphate I crystal to temperature.As a result show,
Ba Ruike stablizes under the high temperature conditions for Buddhist nun's phosphate I crystal.
26 bars of Rakes of embodiment replace the high humidity study on the stability of Buddhist nun's phosphate I crystal
Take appropriate Ba Ruike to be placed in for Buddhist nun's phosphate I crystal under 92.5% damp condition, take the sample after 5 days and 10 days
Go out to carry out XRPD tests (as shown in figure 13), to investigate stability of crystal form of the Ba Ruike for Buddhist nun's phosphate I crystal to humidity.As a result
Show, stability is general under conditions of high humidity for Buddhist nun's phosphate I crystal by Ba Ruike.
27 bars of Rakes of embodiment are investigated for the light durability of Buddhist nun's phosphate I crystal
Appropriate Ba Ruike is taken to be placed in for Buddhist nun's phosphate I crystal under 4500lux intensity of illumination, by the sample after 5 days and 10 days
Product, which take out, carries out XRPD tests (as shown in figure 14), to investigate stability of crystal form of the Ba Ruike for Buddhist nun's phosphate I crystal to illumination.
As a result show, Ba Ruike stabilizations under illumination condition for Buddhist nun's phosphate I crystal.
28 bars of Rakes of embodiment contrast for Buddhist nun's phosphate I crystal and X bars of Rake of crystal formation for the phosphatic solubility of Buddhist nun
At 35 DEG C, the Ba Ruike of the gained of embodiment 21 is determined respectively for Buddhist nun's phosphate I crystal and the crystalline substance of the gained of comparative example 1
X bars of Rake of type replaces Buddhist nun's phosphate as shown in figure 15 in the water solubility of different time points, solubility curve, the results showed that, Ba Rui
Gram it is 3.6mg/mL or so for solubility of Buddhist nun's phosphate I crystal in water, and stable water is maintained in minute
It is flat.X bars of Rake of crystal formation is 2.5mg/mL or so for solubility of Buddhist nun's phosphate in water.Ba Ruike exists for Buddhist nun's phosphate I crystal
Solubility in water replaces solubility of Buddhist nun's phosphate in water more than X bars of Rake of crystal formation.
Comparative example 1 replaces Buddhist nun's phosphate by XRPD figures to characterize X bars of Rake of crystal formation
Method according to disclosed in Chinese invention patent CN 102026999 (WO 2009/114512) prepares X bars of crystal formation
Rake replaces Buddhist nun's phosphate.Determined through XRPD, collection of illustrative plates is as shown in figure 16.Resulting solid melts are 188 DEG C, and patent discloses class
Seemingly.
X bars of Rake of 2 crystal formation of comparative example is investigated for Buddhist nun's phosphate high-temperature stability
Take appropriate X bars of Rake of crystal formation to be placed in for Buddhist nun's phosphate in 60 DEG C of baking ovens, the sample is taken out after 5 days and 10 days and carried out
XRPD tests (as shown in figure 17), to investigate stability of crystal form of the X bars of Rake of crystal formation for Buddhist nun's phosphate to temperature.As a result show,
X bars of Rake of crystal formation is stablized under the high temperature conditions for Buddhist nun's phosphate.
X bars of Rake of 3 crystal formation of comparative example replaces Buddhist nun's phosphate high humidity study on the stability
Appropriate X bars of Rake of crystal formation is taken to be placed in for Buddhist nun's phosphate under 92.5% damp condition, by the sample after 5 days and 10 days
Take out and carry out XRPD tests (as shown in figure 18), to investigate stability of crystal form of the X bars of Rake of crystal formation for Buddhist nun's phosphate to humidity.Knot
Fruit shows that X bars of Rake of crystal formation is stablized under conditions of high humidity for Buddhist nun's phosphate.
X bars of Rake of 4 crystal formation of comparative example is investigated for Buddhist nun's phosphate light durability
Appropriate X bars of Rake of crystal formation is taken to be placed in for Buddhist nun's phosphate under 4500lux intensity of illumination, by the sample after 5 days and 10 days
Product, which take out, carries out XRPD tests (as shown in figure 19), to investigate stability of crystal form of the X bars of Rake of crystal formation for Buddhist nun's phosphate to illumination.
As a result show, X bars of Rake of crystal formation stabilization under illumination condition for Buddhist nun's phosphate.
In summary, Ba Ruike for Buddhist nun phosphate A crystal formations, H crystal form and I crystal under high temperature, high humidity and illumination condition all
It can keep stable, and solubility is better than existing crystal formation.As it is known to the person skilled in the art, improving solubility can improve
The bioavilability of medicine, and stable crystal formation also has advantage in the production process of pharmaceutical preparation.Because Ba Ruike is replaced
The stability that Buddhist nun phosphate A crystal formations, H crystal form and I crystal have, it can be protected in the medicine process of various solid dosages
It is fixed to keep steady, and can determine the crystal formation of the active constituents of medicine in the medicine finally obtained, can also obtain higher biological utilisation
Degree, will not occur the drug effect difference brought because of crystal transfer.
Those skilled in the art is it should be understood that although for illustrative purposes, this document describes the tool of the present invention
Body embodiment, but various modifications can be carried out to it without departing from the spirit and scope of the present invention.Therefore, it is of the invention specific
Embodiment and embodiment should not be considered as limiting the scope of the invention.The present invention is limited only by the appended claims.This Shen
Please in quote all documents be fully incorporated herein by reference.
Claims (14)
1. a kind of Ba Ruike of formula (I) replaces Buddhist nun's phosphate I crystal, it is characterised in that
Its XRPD collection of illustrative plates 2 θ=8.818,10.442,12.901,14.901,16.076,16.88,17.54,18.677,
19.12nd, there is diffraction maximum at 19.44,20.596,21.699,22.422,23.181,24.539,25.779,27,28.461, its
In 2 θ values error ranges be ± 0.2.
2. Ba Ruike as claimed in claim 1 replaces Buddhist nun's phosphate I crystal, it is characterised in that it has and Figure of description figure
11 substantially the same XRPD collection of illustrative plates.
3. prepare the method that Ba Ruike as claimed in claim 1 or 2 replaces Buddhist nun's phosphate I crystal, it is characterised in that including following
Step：
(1) added in Ba Ruike replaces Buddhist nun for the organic solvent of dissolving and obtain the dissolved matter that the Ba Ruike replaces Buddhist nun；Wherein,
The temperature of the organic solvent for being used to dissolve is higher than room temperature；
(2) organic solvent of phosphoric acid is added into the Ba Ruike in the dissolved matter of Buddhist nun, it is phosphatic for Buddhist nun obtains Ba Ruike
Dissolved matter；
(3) Ba Ruike is slowly dropped to room temperature for the temperature of the phosphatic dissolved matter of Buddhist nun, the Ba Ruike is replaced Buddhist nun's phosphoric acid
Salt out, obtain the Ba Ruike and replace the phosphatic precipitate of Buddhist nun；
(4) Ba Ruike is dried for the phosphatic precipitate of Buddhist nun, obtains Ba Ruike and replace Buddhist nun's phosphate I crystal.
4. method as claimed in claim 3, it is characterised in that also include entering the Ba Ruike for the phosphatic precipitate of Buddhist nun
The step of row filtering.
5. method as claimed in claim 3, it is characterised in that the organic solvent for being used to dissolve is in nitrile or alcohols
A kind of solvent or two or more solvents anticipate with the mixed solvent of arbitrary proportion.
6. method as claimed in claim 3, it is characterised in that
The nitrile organic solvent is acetonitrile；
The alcohol organic solvent is ethanol.
7. method as claimed in claim 3, it is characterised in that the organic solvent for being used to dissolve is the mixed of acetonitrile and ethanol
Bonding solvent.
8. method as claimed in claim 7, it is characterised in that the volume ratio of the acetonitrile and the ethanol is 3:1 to 5:
1。
9. method as claimed in claim 8, it is characterised in that the volume ratio of the acetonitrile and the ethanol is 25:8.
10. method as claimed in claim 3, it is characterised in that it is described be used for dissolve organic solvent temperature for 65 DEG C extremely
85℃。
11. method as claimed in claim 10, it is characterised in that the temperature of the organic solvent for being used to dissolve is 80 DEG C.
12. method as claimed in claim 3, it is characterised in that the organic solvent of the phosphoric acid is molten for the ethanol of phosphoric acid
Liquid.
13. method as claimed in claim 3, it is characterised in that the cool-down method in the step (3) is in 80-100 minutes
It is interior that the Ba Ruike is reduced to room temperature for the temperature of the phosphatic dissolved matter of Buddhist nun from the temperature higher than room temperature.
14. method as claimed in claim 3, it is characterised in that
The Ba Ruike is dried in vacuo for the phosphatic precipitate of Buddhist nun and obtains the Ba Ruike and replaces Buddhist nun's phosphate I crystal.
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| CN201610070654.0A CN105601635B (en) | 2016-02-01 | 2016-02-01 | Ba Ruike is for Buddhist nun phosphatic A crystal formations, H crystal form and I crystal and preparation method thereof |
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| CN201710779690.9A Pending CN107641125A (en) | 2016-02-01 | 2016-02-01 | Ba Ruike is for Buddhist nun's phosphate I crystal and preparation method thereof |
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| EP3327020A1 (en) | 2016-11-29 | 2018-05-30 | Sandoz Ag | Citrate salts of a janus kinase (jak) inhibitor |
| CZ2016816A3 (en) * | 2016-12-21 | 2018-07-04 | Zentiva, K.S. | Crystalline forms of 2-[1-Ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4yl)pyrazol-1yl]azetidin-3yl]-acetonitrile with phosphoric acid and the method of their preparation |
| CN108341818A (en) * | 2017-01-21 | 2018-07-31 | 南京华威医药科技开发有限公司 | Ba Ruike replaces Buddhist nun and its phosphatic novel crystal forms and preparation method thereof |
| EP3502114A1 (en) | 2017-12-20 | 2019-06-26 | Sandoz AG | Co-crystal of an orally available janus kinase inhibitor |
| CN111278828B (en) * | 2018-01-09 | 2021-08-31 | 广东东阳光药业有限公司 | Novel crystal form of Baratinib phosphate and preparation method thereof |
| WO2020163431A1 (en) | 2019-02-05 | 2020-08-13 | Teva Pharmaceuticals International Gmbh | Crystalline solid forms of baricitinib |
| TWI781345B (en) * | 2019-09-06 | 2022-10-21 | 台耀化學股份有限公司 | Crystalline form of baricitinib and method for preparation thereof |
| CN116751204A (en) * | 2023-06-14 | 2023-09-15 | 枣庄学院 | Baricitinib-gallic acid eutectic crystal and preparation method and application thereof |
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| WO2010039939A1 (en) * | 2008-10-02 | 2010-04-08 | Incyte Corporation | Janus kinase inhibitors for treatment of dry eye and other eye related diseases |
| CN101932582A (en) * | 2007-06-13 | 2010-12-29 | 因塞特公司 | Salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
| CN102026999A (en) * | 2008-03-11 | 2011-04-20 | 因塞特公司 | Azetidine and cyclobutane derivatives as JAK inhibitors |
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| CN101932582A (en) * | 2007-06-13 | 2010-12-29 | 因塞特公司 | Salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
| CN102026999A (en) * | 2008-03-11 | 2011-04-20 | 因塞特公司 | Azetidine and cyclobutane derivatives as JAK inhibitors |
| WO2010039939A1 (en) * | 2008-10-02 | 2010-04-08 | Incyte Corporation | Janus kinase inhibitors for treatment of dry eye and other eye related diseases |
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