WO1996027592A1 - Polymorphic b form of (e)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-diethyl-4-oxobutanoic acid - Google Patents
Polymorphic b form of (e)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-diethyl-4-oxobutanoic acid Download PDFInfo
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- WO1996027592A1 WO1996027592A1 PCT/EP1996/000729 EP9600729W WO9627592A1 WO 1996027592 A1 WO1996027592 A1 WO 1996027592A1 EP 9600729 W EP9600729 W EP 9600729W WO 9627592 A1 WO9627592 A1 WO 9627592A1
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- thiazolyl
- cyclobutyl
- ethenyl
- phenyl
- amino
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
Definitions
- the invention relates to a new crystalline form of (E) -4- [ [3- [2- (4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]- amino] -2, 2-diethyl-4-oxobutanoic acid, herein designated as "Polymorphic Form B or Polymorph B", and salts thereof with pharmaceutically acceptable bases, which are useful as bronchopulmonary agents, for example, in the relief of asthma and allergic reactions.
- the invention relates to pharmaceutical compositions and methods of making and using the referred to Polymorph B of (E) -4- [ [3- [2- (4- cyclobutyl-2-thiazolyl)ethenyl] -phenyl]amino] -2,2- diethyl-4-oxobutanoic acid.
- the invention also relates to a process for preparing polymorphic Form B comprising agitating polymorphic Form A in the presence of Polymorphic Form B seed.
- Pop/Ul 8.12.95 4-oxobutanoic acid can be prepared in new crystalline form, herein designated as "Polymorphic Form B or Polymorph B” , having more advantageous handling properties in the preparation of pharmaceutical compositions.
- the invention provides (E) -4- [ [3- [2- (4- cyclobutyl-2-thiazolyl)ethenyl] phenyl]amino] -2,2- diethyl-4-oxobutanoic acid in Polymorphic Form B, which is useful as a bronchopulmonary agent, for example, in the relief of asthma and allergic reactions.
- Polymorph B possesses better flow characteristics than Polymorph A and is thermodynamically more stable than Polymorph A. Thus, Polymorph B is easier to handle (remove from vessel and transfer to filter) , filter and dry than Polymorph A. Polymorph B is also easier to feed and micronize. Hence, the methods for its manufacture are more easily validated than that of Polymorph A.
- Polymorph B may be characterized by its powder X-ray diffraction pattern and/or single crystal X-ray diffraction pattern hereinafter described in greater detail .
- the powder X-ray diffraction pattern of Polymorph A and Polymorph B was obtained by completely and uniformly filling the sample holder of the Scintag XDS2000 with the sample utilizing a spatula. The sample was then irradiated with the Scintag XDS2000 and d spacings were determined based on Debye Scherrer equation under the conditions described in Table I.
- the X-ray powder diffraction pattern of the micronized form of Polymorph A and B are given in Tables II and III which follow. The patterns are given in terms of 'd' spacings and relative intensities.
- the intensity data for Polymorph B were measured on an Enraf-Nonius CAD4 diffractometer (graphite- monochromated Cu KCX radiation, G)-2 ⁇ scans) .
- the size of the crystal used for the data collection was approximately 0.06 x 0.10 x 0.25 mm.
- the data were corrected for absorption. Of the 2212 independent reflections for ⁇ 50°, 621 were considered observed [Intensity (I) > 3.0 ⁇ (I)] .
- the structure of Polymorph B was solved by a multiple-solution procedure and was refined by full matrix least squares. In the final refinement, the heteroatoms were refined anisotropically and the carbon atoms were refined isotropically. The hydrogen atoms were included in the structure-factor calculations, but their parameters were not refined.
- the X-ray data for both the Polymorph A and Polymorph B Forms is summarized in terms of a unit cell in Table IV.
- Z is the number of molecules in the unit cell.
- Polymorph B can be prepared as hereinafter described in Schemes I and II.
- (E) -4- [ [3- [2- (4-cyclobutyl-2- thiazolyl)ethenyl)phenyl] amino] -2, 2-diethyl-4-oxobutanoic acid, the compound of formula I, is made by the reaction of (E)-3-[2- (4-cyclobutyl-2-thiazolyl) ethenyl]benzeneamino, the compound of formula II, with 2,2 diethylsuccinic anhydride (formula III) preferably with agitation until crystallization is complete in a suitable solvent.
- Suitable solvents include any organic solvent which does not react with or bind chemically to (E) -3- [2- (4-cyclobutyl-2- thiazolyl) ethenyl]benzeneamino, 2,2 diethylsuccinic anhydride or (E) -4- [ [3- [2- (4-cyclobutyl-2- thiazolyl) ethenyl)phenyl] amino] -2 , 2-diethyl-4- oxobutanoic acid, such as, for example, dimethylformamide (DMF) , toluene, DMF/toluene combinations, iso-propyl alcohol (IPA) , tetrahydrofuran (THF) , IPA/THF combinations, preferably, IPA.
- a temperature in the range of from room temperature to reflux temperature is preferred.
- the compound of formula I is typically produced as Polymorph A. However, it can be produced as Polymorph B if seeds of Polymorph B are present.
- Polymorph B of (E) -4- [ [3- [2- (4-cyclobutyl-2 thiazolyl) ethenyl)phenyl]amino] -2,2-diethyl-4- oxobutanoic acid can be formed from Polymorph A by agitating Polymorph A in any organic solvent which shows a solubility for (E) -4- [ [3- [2- (4-cyclobutyl-2 thiazolyl) ethenyl)phenyl]amino] -2,2-diethyl-4-oxobutanoic acid and does not react chemically with or bind to (E) -4- [ [3- [2- (4-cyclobutyl-2 thiazolyl)ethenyl)phenyl] amino] -2,2- diethyl-4-oxobutanoic acid, preferably in the presence of Polymorph B seeds.
- the rate of conversion will depend on the rate of agitation, dilution, the temperature and the amount of Polymorph B seed that is present. Preferably, the rate of agitation should be about 500 rpm.
- Polymorph B seed is preferably present in an amount of from about 0.5% to 1% of Polymorph A, particularly preferred in an amount of 0.5% of Polymorph A.
- suitable solvents include tetrahydrofuran (THF) , isopropyl alcohol (IPA), dimethyl-formamide (DMF) , methyl tertiary butyl ether, acetonitrile, methanol, acetone, miscible combinations of the solvents listed and miscible combinations of DMF/toluene.
- THF/IPA is the preferred solvent, preferably in the ratio of from about 1:20 to about 15:85 THF to IPA, a ratio of 1:20 is particularly preferred.
- Polymorph B or a salt thereof or a composition containing a therapeutically effective amount of Polymorph B or a salt thereof can be administered by methods well known in the art. More particularly, Polymorph B or a salt thereof can be administered either singly or in combination with other pharmaceutical agents, for example, antihistamines, mediator release inhibitors, methyl xanthines, beta agonists or antiasthmatic steroids such as prednisone and prednisoline.
- the foregoing pharmaceutical composition can be administered orally, parenterally, rectally or by inhalation, for example, in the form of an aerosol, micropulverized powder or a nebulized solution.
- the foregoing pharmaceutical composition can be administered in the form of tablets, capsules, for example, in admixture with talc, starch, milk sugar or other inert ingredients, that is, pharmaceutically acceptable carriers, or in the form of aqueous solutions, suspensions, elixirs or aqueous alcoholic solutions, for example, in admixture with sugar or other sweetening agents, flavoring agents or colorants, thickeners and other conventional pharmaceutical excipients.
- the foregoing pharmaceutical composition can be administered in solutions or suspensions, for example, as an aqueous or peanut oil solution or suspension using excipients and carriers conventional for this mode of administration.
- the foregoing pharmaceutical composition can be dissolved in a suitable pharmaceutically acceptable solvent, for example, ethyl alcohol or combinations of miscible solvents, and mixed with a pharmaceutically acceptable propellant.
- a suitable pharmaceutically acceptable solvent for example, ethyl alcohol or combinations of miscible solvents
- Such aerosol compositions are packaged for use in a pressurized container fitted with an aerosol valve suitable for release of the pressurized compositions.
- the aerosol valve is a metered valve, that is one which on activation releases a predetermined effective dose of the aerosol composition.
- Polymorph B or salt thereof to be administered and the frequency of administration will be dependent on the route of administration, as well as on the severity of the condition, age of the mammal to be treated and the like.
- Oral doses of Polymorph B or a salt thereof contemplated for use by human adults in practicing the invention are in the range of from about 5 to about 1000 mg per day, preferably about 5 to about 250 mg either as a single dose or in divided doses.
- the batch was cooled at 3°C/minute to -5°C and then filtered.
- the reactor and filter cake were rinsed with acetone and then dried overnight under vacuum with a slight nitrogen purge at 40°C.
- the product was analyzed to be Polymorph B by powder X-Ray diffraction.
- a 10.2 wt% solution of dimethylformamide (DMF) in toluene was made by combining 44.9 grams of anhydrous DMF with 393.0 grams of toluene. To 250 grams of the above solution was added 20.6 grams of 2,2 diethylsuccinic anhydride. The mixture was charged to a 1 liter resin kettle reactor with temperature, agitation and metering control and a nitrogen blanket. The agitation was set at 600 RPM and the reactor temperature was raised to 61°C at a rate of 75°C/hour. To the remaining DMF/toluene was added 25.2 grams of (E) -3- [2- (4-cyclobutyl-2- thiazolyl) ethenyl]benzeneamine.
- DMF dimethylformamide
- Polymorph B Immediate crystallization was observed.
- the batch was then cooled at 5°C/hour to -5°C and filtered through a course fritted disc filter.
- the filter cake was washed with 381.5 grams of methyl tertiary butyl ether.
- the filter cake was dried overnight in a vacuum over a slight nitrogen purge at 40°C to give 36 grams of Polymorph B (99.8 weight% by HPLC) .
- the results on the polymorphic form were confirmed by X-Ray diffraction.
- (THF/IPA) solution was prepared by mixing 501 grams of anhydrous IPA and 25 grams of anhydrous THF and drying the solution over 50 grams of 4 A (angstorm) molecular sieves.
- a solution of 25 grams of (E)-3-[2- ⁇ 4- cyclobutyl-2-thiazolyl)ethenyl]benzeneamine in 263 grams of the 1/20 THF/IPA prepared above was added to a 1 liter glass reactor with a temperature, agitation and metering control and a nitrogen blanket. The agitation was set at 750 RPM and the reactor temperature was raised to 45°C at a rate of 50°C/hour.
- Step 2 (2) Fill solution from Step 1 into a suitable glass bottle, insert valve and crimp to seal container.
- Step 2 (2) Fill the concentrated suspension from Step 1 into a suitable can and place in valve and crimp to seal container.
- a suitable valve may be used to deliver 25 to 100 microliters in volume.
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Abstract
The invention relates to a new crystalline form of (E)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]-amino]-2,2-diethyl-4-oxobutanoic acid, herein designated as 'Polymorphic Form B or Polymorph B', and salts thereof with pharmaceutically acceptable bases, which are useful as bronchopulmonary agents, for example, in the relief of asthma and allergic reactions. In another aspect, the invention relates to pharmaceutical compositions and methods of making and using Polymorph B.
Description
Polymorphic B form of (E) -4- f T3- \2 - (4-cvclobutvl-2- thiazolvl)ethenvllphenvllaminol-2.2-diethvl-4-oxobutanoic acid
The invention relates to a new crystalline form of (E) -4- [ [3- [2- (4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]- amino] -2, 2-diethyl-4-oxobutanoic acid, herein designated as "Polymorphic Form B or Polymorph B", and salts thereof with pharmaceutically acceptable bases, which are useful as bronchopulmonary agents, for example, in the relief of asthma and allergic reactions.
In another aspect, the invention relates to pharmaceutical compositions and methods of making and using the referred to Polymorph B of (E) -4- [ [3- [2- (4- cyclobutyl-2-thiazolyl)ethenyl] -phenyl]amino] -2,2- diethyl-4-oxobutanoic acid.
The invention also relates to a process for preparing polymorphic Form B comprising agitating polymorphic Form A in the presence of Polymorphic Form B seed.
A crystalline form of (E) -4- [ [3- [2- (4-cyclobutyl-2- thiazolyl) ethenyl] -phenyl]amino] -2, 2-diethyl-4- oxobutanoic acid, which is herein designated as "Polymorphic Form A or Polymorph A", is described and claimed in U.S. Patent No. 5,001,140. Polymorph A, as described in U.S. Patent No. 5,001,140, is an inhibitor of bronchoconstriction and is therefore useful as a bronchopulmonary agent, for example, in the relief of asthma and allergic reactions.
It has now been discovered that (E) -4-[ [3- [2- (4- cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino] -2,2-diethy1- 4-oxobutanoic acid can be prepared in new crystalline
Pop/Ul 8.12.95
4-oxobutanoic acid can be prepared in new crystalline form, herein designated as "Polymorphic Form B or Polymorph B" , having more advantageous handling properties in the preparation of pharmaceutical compositions. The invention provides (E) -4- [ [3- [2- (4- cyclobutyl-2-thiazolyl)ethenyl] phenyl]amino] -2,2- diethyl-4-oxobutanoic acid in Polymorphic Form B, which is useful as a bronchopulmonary agent, for example, in the relief of asthma and allergic reactions.
Polymorph B possesses better flow characteristics than Polymorph A and is thermodynamically more stable than Polymorph A. Thus, Polymorph B is easier to handle (remove from vessel and transfer to filter) , filter and dry than Polymorph A. Polymorph B is also easier to feed and micronize. Hence, the methods for its manufacture are more easily validated than that of Polymorph A.
Polymorph B may be characterized by its powder X-ray diffraction pattern and/or single crystal X-ray diffraction pattern hereinafter described in greater detail .
PΦ fler X-ray Diffraction
The powder X-ray diffraction pattern of Polymorph A and Polymorph B was obtained by completely and uniformly filling the sample holder of the Scintag XDS2000 with the sample utilizing a spatula. The sample was then irradiated with the Scintag XDS2000 and d spacings were determined based on Debye Scherrer equation under the conditions described in Table I.
Table I. Parameters for Powder X-Ray Diffraction
Instruments and Conditions (Equivalent instrumentation may used. )
Instrument Scintag XDS2000 Theta:Theta system
X-ray Target Copper (λ = 1.54 A)
Voltage 45 kV
Current 40 mA
Detector Germanium solid state cooled by liquid nitrogen detector
Two-Theta Range 54<
Scan Type Continuous
Chopper Increment 0.02°
Divergent Beam Slit 2.0 mm
Divergent Beam Scatter Slit 4.0 mm
Receiving Beam Scatter Sli 0.5 mm
Receiving Beam Slit 0.2 mm
Atmosphere Air
The X-ray powder diffraction pattern of the micronized form of Polymorph A and B are given in Tables II and III which follow. The patterns are given in terms of 'd' spacings and relative intensities.
Table II. Powder X-Ray Diffraction Data for Micronized
Polymorph A d{A) Intensity d(A) Intensity
2.22 vw
2.17 vw
2.11 vw 2.06 vw
intensity > 75% intensity 25% - 75%
intensity 10% - 25%
vw very weak intensity < 10%
Table III. Powder X-Ray Diffraction Data for Micronized Polymorph B
d(A) Intensity
11.68 vw 8.79 vw
6.77 vw
6.62 s 6.49 vw 5.92 vw
5.77 vw 5.63 w 5.31 vw
5.08 vw
4.94 vw
4.68 w
4.49 vw
4.38 vw
4.26 vw
4.12 vw
3.93 vw
3.89
vw
Single Crystal X-rav Diffraction
The intensity data for Polymorph B were measured on an Enraf-Nonius CAD4 diffractometer (graphite- monochromated Cu KCX radiation, G)-2θ scans) . The size of the crystal used for the data collection was approximately 0.06 x 0.10 x 0.25 mm. The data were corrected for absorption. Of the 2212 independent reflections for θ< 50°, 621 were considered observed [Intensity (I) > 3.0σ(I)] .
The structure of Polymorph B was solved by a multiple-solution procedure and was refined by full matrix least squares. In the final refinement, the heteroatoms were refined anisotropically and the carbon atoms were refined isotropically. The hydrogen atoms were included in the structure-factor calculations, but their parameters were not refined. The final discrepancy indices are R=0.080 and Rw=0.080 for the 618 observed reflections. R is the ratio of the sum of the differences between the observed and theoretical structure factors to the sum of the observed structure factors. The final difference map has no peaks greater than +.0.3 e A-3. The X-ray data for both the Polymorph A and Polymorph B Forms is summarized in terms of a unit cell in Table IV.
Table IV. Single Crystal X-ray Data for Polymorph A and B at 295°K
Polymorphic Form A B
Z is the number of molecules in the unit cell.
Polymorph B can be prepared as hereinafter described in Schemes I and II.
SCHEME I
(E) -4- [ [3- [2- (4-cyclobutyl-2- thiazolyl)ethenyl)phenyl] amino] -2, 2-diethyl-4-oxobutanoic acid, the compound of formula I, is made by the reaction of (E)-3-[2- (4-cyclobutyl-2-thiazolyl) ethenyl]benzeneamino, the compound of formula II, with 2,2 diethylsuccinic anhydride (formula III) preferably with agitation until crystallization is complete in a suitable solvent. Suitable solvents include any organic solvent which does not react with or bind chemically to (E) -3- [2- (4-cyclobutyl-2- thiazolyl) ethenyl]benzeneamino, 2,2 diethylsuccinic anhydride or (E) -4- [ [3- [2- (4-cyclobutyl-2- thiazolyl) ethenyl)phenyl] amino] -2 , 2-diethyl-4- oxobutanoic acid, such as, for example, dimethylformamide (DMF) , toluene, DMF/toluene combinations, iso-propyl alcohol (IPA) , tetrahydrofuran (THF) , IPA/THF combinations, preferably, IPA. A temperature in the range of from room temperature to reflux temperature is preferred. The compound of formula I is typically produced as
Polymorph A. However, it can be produced as Polymorph B if seeds of Polymorph B are present.
The conversion of Polymorph A to Polymorph B is set forth in Scheme II below.
SCHEME II
Solvent, Agitation, Temperature Polymorph A »*- Polymorph B
Seeds of Form B
Polymorph B of (E) -4- [ [3- [2- (4-cyclobutyl-2 thiazolyl) ethenyl)phenyl]amino] -2,2-diethyl-4- oxobutanoic acid can be formed from Polymorph A by agitating Polymorph A in any organic solvent which shows a solubility for (E) -4- [ [3- [2- (4-cyclobutyl-2 thiazolyl) ethenyl)phenyl]amino] -2,2-diethyl-4-oxobutanoic acid and does not react chemically with or bind to (E) -4- [ [3- [2- (4-cyclobutyl-2 thiazolyl)ethenyl)phenyl] amino] -2,2- diethyl-4-oxobutanoic acid, preferably in the presence of Polymorph B seeds. The rate of conversion will depend on the rate of agitation, dilution, the temperature and the amount of Polymorph B seed that is present. Preferably, the rate of agitation should be about 500 rpm. Polymorph B seed is preferably present in an amount of from about 0.5% to 1% of Polymorph A, particularly preferred in an amount of 0.5% of Polymorph A. Examples of suitable solvents include tetrahydrofuran (THF) , isopropyl alcohol (IPA), dimethyl-formamide (DMF) , methyl tertiary butyl ether, acetonitrile, methanol, acetone, miscible combinations of the solvents listed and miscible
combinations of DMF/toluene. The combination of THF/IPA is the preferred solvent, preferably in the ratio of from about 1:20 to about 15:85 THF to IPA, a ratio of 1:20 is particularly preferred.
Polymorph B or a salt thereof or a composition containing a therapeutically effective amount of Polymorph B or a salt thereof can be administered by methods well known in the art. More particularly, Polymorph B or a salt thereof can be administered either singly or in combination with other pharmaceutical agents, for example, antihistamines, mediator release inhibitors, methyl xanthines, beta agonists or antiasthmatic steroids such as prednisone and prednisoline. The foregoing pharmaceutical composition can be administered orally, parenterally, rectally or by inhalation, for example, in the form of an aerosol, micropulverized powder or a nebulized solution. For oral administration, the foregoing pharmaceutical composition can be administered in the form of tablets, capsules, for example, in admixture with talc, starch, milk sugar or other inert ingredients, that is, pharmaceutically acceptable carriers, or in the form of aqueous solutions, suspensions, elixirs or aqueous alcoholic solutions, for example, in admixture with sugar or other sweetening agents, flavoring agents or colorants, thickeners and other conventional pharmaceutical excipients.
For parenteral administration, the foregoing pharmaceutical composition can be administered in solutions or suspensions, for example, as an aqueous or peanut oil solution or suspension using excipients and carriers conventional for this mode of administration. For administration as aerosols, the foregoing pharmaceutical composition can be dissolved in a suitable pharmaceutically acceptable solvent, for example, ethyl
alcohol or combinations of miscible solvents, and mixed with a pharmaceutically acceptable propellant. Such aerosol compositions are packaged for use in a pressurized container fitted with an aerosol valve suitable for release of the pressurized compositions.
Preferably, the aerosol valve is a metered valve, that is one which on activation releases a predetermined effective dose of the aerosol composition.
In the practice of the invention, the dose of
Polymorph B or salt thereof to be administered and the frequency of administration will be dependent on the route of administration, as well as on the severity of the condition, age of the mammal to be treated and the like. Oral doses of Polymorph B or a salt thereof contemplated for use by human adults in practicing the invention are in the range of from about 5 to about 1000 mg per day, preferably about 5 to about 250 mg either as a single dose or in divided doses.
The examples which follow further illustrate the invention. The synthesis of Polymorph A of (E) -4- [ [3- [2- (4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino] -2,2- diethyl-4-oxobutanoic acid is disclosed in U.S. Patent No. 5,001,140.
EXAMPLE 1
Conversion of Polymorph A to Polymorph B bv Stirring in Isopropyl Alcohol Without Seeding
To a one liter flask was added 700.95 grams of isopropyl alcohol and 10.08 grams of Polymorph A. The batch temperature was set and controlled at 25°C. Agitation was maintained at 450 RPM. Polymorph A had converted to less than 5% Polymorph B after 7 hours of
stirring. All of the Polymorph A had converted to Polymorph B after 24 hours of stirring. The results on the polymorphic form were confirmed by powder X-Ray diffraction.
EXAMPLE 2
Conversion of Polymorph A to Polvmorph B by Stirring in Isopropyl Alcohol With 1 % Polvmorph B Seeds Added
To a one liter flask was added 550 grams of isopropyl alcohol, 50.36 grams of Polymorph A and 0.50 grams of Polymorph B. The batch temperature was set and maintained at 25°C. Agitation was maintained at 600 RPM. All of the Polvmorph A had converted to Polymorph B at the end of 4.2 hours of agitation. The results on the polymorphic form were confirmed by powder X-Ray diffraction.
EXAMPLE 3
Recrvstallization of Polvmorph A to Polvmorph B from 11.9 weight% Dimethylformamide/Acetone Seeded with Micronized Polvmorph B to Induce Crystallization
To a one liter flask was added 57.3 grams of dimethyl formamide, are added 427.9 grams of acetone and 20.1 grams of Polymorph A. Agitation was maintained at 750 RPM. The batch temperature set-point was set at 25°C and the batch was maintained at this temperature for 40 minutes. The batch was then heated to 53°C over 1 hour. The batch was held at 53°C for approximately 105 minutes and then heated to approximately 59°C over 10 minutes. The batch was in total solution at 58.5°C. The batch was held at 59°C for approximately 30 minutes and then cooled to 40.7°C over 2 hours. It was held at 40.7°C for 1
hour. The batch remained in solution. The batch was then seeded with 0.116 grams of micronized Polymorph B. Immediate crystallization was observed. The batch was cooled at 3°C/minute to -5°C and then filtered. The reactor and filter cake were rinsed with acetone and then dried overnight under vacuum with a slight nitrogen purge at 40°C. The product was analyzed to be Polymorph B by powder X-Ray diffraction.
EXAMPLE 4
Preparation of Polvmorph B in 10.2 wt.% Dimethyl formamide/Toluene. Reaction and Crystallization Procedure
A 10.2 wt% solution of dimethylformamide (DMF) in toluene was made by combining 44.9 grams of anhydrous DMF with 393.0 grams of toluene. To 250 grams of the above solution was added 20.6 grams of 2,2 diethylsuccinic anhydride. The mixture was charged to a 1 liter resin kettle reactor with temperature, agitation and metering control and a nitrogen blanket. The agitation was set at 600 RPM and the reactor temperature was raised to 61°C at a rate of 75°C/hour. To the remaining DMF/toluene was added 25.2 grams of (E) -3- [2- (4-cyclobutyl-2- thiazolyl) ethenyl]benzeneamine. The (E)-3-[2-(4- cyclobutyl-2-thiazolyl)ethenylIbenzeneamine was uniformly metered in over 1 hour to the reactor. The addition vessel was rinsed with approximately 10 mis of anhydrous toluene. At the end of the addition, the batch was still in solution. It was then seeded with 0.1 grams of
Polymorph B. Immediate crystallization was observed. The batch was then cooled at 5°C/hour to -5°C and filtered through a course fritted disc filter. The filter cake was washed with 381.5 grams of methyl tertiary butyl ether. The filter cake was dried overnight in a vacuum over a slight nitrogen purge at
40°C to give 36 grams of Polymorph B (99.8 weight% by HPLC) . The results on the polymorphic form were confirmed by X-Ray diffraction.
EXAMPLE 5
Preparation of Polvmorph B in 1/20 Tetrahvdrofuran/Isopropvl Alcohol. Reaction and Precipitation Procedure
A 1/20 (w/w) tetrahydrofuran/isopropyl alcohol
(THF/IPA) solution was prepared by mixing 501 grams of anhydrous IPA and 25 grams of anhydrous THF and drying the solution over 50 grams of 4 A (angstorm) molecular sieves. A solution of 25 grams of (E)-3-[2-{4- cyclobutyl-2-thiazolyl)ethenyl]benzeneamine in 263 grams of the 1/20 THF/IPA prepared above was added to a 1 liter glass reactor with a temperature, agitation and metering control and a nitrogen blanket. The agitation was set at 750 RPM and the reactor temperature was raised to 45°C at a rate of 50°C/hour. To the reactor was then metered in over 2 hours a solution of 20 grams of 2,2 diethylsuccinic anhydride in 232 grams of 1/20 THF/IPA as prepared above. The batch was seeded with 0.19 grams of Polymorph B, 45 minutes into the metering period. At the end of the 2 hour metering period, the pump and the line were flushed with approximately 10 mis of anhydrous isopropyl alcohol. The batch was then stirred overnight at 45°C. An additional 5.35 grams of 2,2 diethylsuccinic anhydride was added to the reactor via a charging port. The batch was filtered through a fritted disc funnel the filter cake was washed with 163 grams of cold isopropyl alcohol . The filter-cake was dried over two days under house vacuum under a nitrogen purge at 40°C. The product assayed at 99.7 area% by HPLC and was determined to be Polymorph B by powder X-Ray diffraction.
EXAMP E $
Tablet Formulation (Wet Granulation)
Item
Preparation of Tablets
(1) Mix Items 1, 2, 3 and 4 and granulate with water.
(2) Dry the granulation at 50° C.
(3) Pass the granulation through suitable milling equipment.
(4) Add Item 5 and mix for three minutes; compress on a suitable press.
EXAMPLE 7
Capsule Formulation
Preparation of Tablets
(1) Mix Items 1, 2 and 3 and wet granulate with water. Dry at 45° C overnight.
(2) Mill through suitable screen using appropriate milling equipment.
(3) Add Items 4 and 5 and mix for five minutes.
EXAMPLE 9
Capsule Formulation
Ingredients mq/ςapsu,le
1. Polymorph B 0.01 0.5 5.0 25.0
2. Lactose Hydrous 168.99 168.5 159.0 123.0
3. Corn Starch 20.0 20.0 25.0 35.0
4. Talc 10.0 10.0 10.0 15.0
5. Magnesium Stearate 1.0 1_ 2 1_J2 1.0
Total 200.0 200.0 200.0 200.0
Preparation of Capsules
(1) Mix Items 1, 2 and 3 in a suitable mixer for 30 minutes .
(2) Add Items 4 and 5 and mix for 3 minutes
(3) Fill into suitable capsule.
EXAMPLE 9
Wet Granulation Formulation
Ingredients mg/capsule
1. Polymorph B 0.01 0.5 5.0 25.0
2. Lactose Anhydrous DTG 106.99 106.5 102.0 118.0
3. Avicel PH 102 15.0 15.0 15.0 25.0
4. Modified Starch 7.0 7.0 7.0 10.0
5. Magnesium Stearate 1.0 1.0 1.0 2d
Total 130.0 130.0 130.0 130.0
Preparation of Capsules
(1) Dissolve Item 1 in a suitable solvent such as alcohol.
(2) Spread the solution in step 1 over Item 2, dry.
(3) Add Items 3 and 4 and mix for 10 minutes.
.4) Add Magnesium Stearate and mix for 3 minutes and compress.
EXAMPLE α
Cream 0 ■ 5%
3% excess ^rlacel 165 2 ween 60
Preparation of Cream
(1) Dissolve Polymorph B in propylene glycol, add methyl paraben, propyl paraben and water and heat to 70° C.
(2) Melt petrolatum, glyceryl monostearate S.E. and cetyl alcohol. Heat to 70° C. Add polysorbate 60 and mix.
(3) Add solution in Step 2 to solution in Step 1 at 70° C and cool to room temperature while stirring.
EXAMPLE 11
Inhalation Aerosol Formulation ( Solut ion )
Item Ingredients % w/w
1 . Polymorph B 1 . 0
2. Ethyl Alcohol 30.0
3. Ascorbic Acid 0.5
4. Freon 12 54.8
5. Freon 114 13.7
Total 100%
Preparation of Aerosol
(1) Dissolve Items 1 and 3 in Item 2.
(2) Fill solution from Step 1 into a suitable glass bottle, insert valve and crimp to seal container.
(3) Pressure-fill a 80:20 mixture of Items 4 and 5 into the container.
NOTE: A suitable valve may be used to deliver 25 to 100 microliters in volume.
EXAMPLE 12
Inhalation Aerosol Formulation ( Suspension)
Item Ingredients % w/w
1 . Polymorph B 1 . 0
2. Sorbitan Trioleate 0.5
64.0
18.5
Preparation of Aerosol
(1) Mix Items 1 and 2 into 4 and homogenize.
(2) Fill the concentrated suspension from Step 1 into a suitable can and place in valve and crimp to seal container.
(3) Pressure-fill a 80:20 mixture of Items 3 and 5
NOTE: A suitable valve may be used to deliver 25 to 100 microliters in volume.
Claims
1. Polymorphic B Form of (E) -4- [ [3- [2- (4- cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino] -2 , 2-diethy1- 4-oxobutanoic acid characterized by the following single crystal x-ray diffraction data expressed in terms of unit cell dimensions and space group:
Space group P2^/n
Unit Cell Dimensions a (A) 6.930 b (A) 23.059 c (A) 13.606 β (°) 96.55
Z 4
wherein Z is the number of molecules in the unit cell.
2. The Polymorphic B Form of (E) -4- [ [3- [2- (4- cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino] -2 , 2-diethy1- 4-oxobutanoic acid characterized by the following x-ray powder diffraction pattern in terms of "d" spacings and relative intensities (s=strong, m=medium, w=weak, and v=very) :
d(A) Intensity 3.84 vw 3.76 vw 3.64 vw 3.55 s 3.43 vw 3.35 vw 3.30 vw 3.25 w 3.23 vw 3.21 vw 3.13 vw 3.10 w 2.88 vw 2.82 vw
2.75 vw
2.66 vw
2.51 vw 
2.38 vw
3. A pharmaceutical composition comprising an amount which is effective for treating bronchopulmonary constriction, of the Polymorphic B Form of (E) -4- [ [3- [2- (4-cyclobutyl-2-thiazolyl) ethenyl]phenyl]amino] -2,2- diethyl-4-oxobutanoic acid, characterized by the following single crystal x-ray diffraction data expressed in terms of unit cell dimensions and space group:
Space group P2]_/n Unit cell Dimensions a (A) 6.930 b (A) 23.059 c (A) 13.606 β (°) 96.55 Z 4 wherein Z is the number of molecules in the unit cell, or a salt thereof with a pharmaceutically acceptable base and an inert carrier material.
4. The pharmaceutical composition according to claim 3, wherein the effective amount is 5 to 1000 mg per day preferably 5 to 250 mg per day.
5. A process for preparing Polymorphic B Form of (E) -4- [ [3- [2- (4-cyclobutyl-2-thiazolyl) ethenyl)phenyl] - amino] -2, 2-diethyl-4-oxobutanoic acid which comprises agitating Polymorphic A Form of (E) -4- [ [3- [2- (4- cyclobutyl-2-thiazolyl)ethenyl)phenyl] amino] -2,2- diethyl-4-oxobutanoic acid preferably in the presence of Polymorphic B seed in any solvent which shows a solubility for (E) -4- [ [3- [2- (4-cyclobutyl-2- thiazolyl) ethenyl) phenyl]amino] -2, 2-diethyl-4- oxobutanoic acid and which does not react chemically with or bind to (E) -4- [ [3- [2- (4-cyclobutyl-2- thiazolyl) ethenyl) phenyl]amino] -2 , 2-diethyl-4- oxobutanoic acid.
6. The process for preparing Polymorphic B Form of E)-4-[[3-[2- (4-cyclobutyl-2-thiazolyl) ethenyl)phenyl] - amino] -2, 2-diethyl-4-oxobutanoic acid according to Claim 5, wherein the solvent is selected from the group consisting of isopropyl alcohol, tetrahydrofuran, dimethylformamide, methyl tertiary butyl ether, acetonitrile, methanol and acetone or is selected from the group consisting of miscible combinations of dimethylformamide, isopropyl alcohol, tetrahydrofuran, methyl tertiary butyl ether, acetonitrile, methanol, toluene and acetone.
7. The process for preparing Polymorphic B Form of E) -4- [ [3- [2- (4-cyclobutyl-2-thiazolyl) ethenyl)phenyl] - amino] -2,2-diethyl-4-oxobutanoic acid according to Claim 6, wherein the solvent is isopropyl alcohol or wherein the miscible combination of solvents is dimethylformamide and acetone, dimethylformamide and toluene or tetrahydrofuran and isopropyl alcohol.
8. The process of any one of Claims 5, 6 and 7 wherein the Polymorph B seed is present in an amount of from about 0.5 to 1 percent by weight Polymorph A present.
9. Polymorphic B form according to claims 1 or 2, whenever prepared by the process according to any one of claims 5 to 8 or by an obvious chemical equivalent thereof.
10. Polymorphic B form according to claims 1 or 2 for use in the treatment of bronchiopulmonary constriction, such as asthma or allergic reactions.
11. The use of compounds according to claims 1 or 2 for the treatment of bronchopulmonary constriction, such as asthma or allergic reactions, or for the production of corresponding medicaments.
12. The invention as hereinbefore described.
13. A method for treating bronchopulmonary constriction which comprises administering to a host requiring such treatment an effective amount of
Polymorphic B Form of (E) -4- [ [3- [2- (4-cyclobutyl-2- thiazolyl)ethenyl]phenyl]amino] -2, 2-diethyl-4- oxobutanoic, characterized by the following single crystal x-ray diffraction data expressed in terms of unit cell dimensions and space group: Space group P2^/n a (A) 6.930 b (A) 23.059 c (A) 13.606 β (°) 96.55
Z 4 wherein Z is the number of molecules in the unit cell.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU48792/96A AU4879296A (en) | 1995-03-03 | 1996-02-22 | Polymorphic b form of (e)-4-{{3-{2-(4-cyclobutyl-2-thiazolyl)ethenyl}phenyl}amino} -2,2-diethyl-4-oxobutanoic acid tanoic acid |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US39803295A | 1995-03-03 | 1995-03-03 | |
| US398,032 | 1995-03-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996027592A1 true WO1996027592A1 (en) | 1996-09-12 |
Family
ID=23573724
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1996/000729 WO1996027592A1 (en) | 1995-03-03 | 1996-02-22 | Polymorphic b form of (e)-4-[[3-[2-(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-diethyl-4-oxobutanoic acid |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU4879296A (en) |
| WO (1) | WO1996027592A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0355353A2 (en) * | 1988-07-15 | 1990-02-28 | F. Hoffmann-La Roche Ag | Cycloalkylthiazole derivatives |
-
1996
- 1996-02-22 AU AU48792/96A patent/AU4879296A/en not_active Abandoned
- 1996-02-22 WO PCT/EP1996/000729 patent/WO1996027592A1/en active IP Right Grant
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0355353A2 (en) * | 1988-07-15 | 1990-02-28 | F. Hoffmann-La Roche Ag | Cycloalkylthiazole derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| AU4879296A (en) | 1996-09-23 |
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