WO2007109434A1 - Besylate salt form of 1- (5-tert-butyl-2-p-t0lyl-2h-pyraz0l-3-yl) -3- (4- (6- (morpholin-4-yl-methyl) -pyrid in- 3 -yl) -naphthalen- 1-yl) -urea and polymorphs thereof - Google Patents

Besylate salt form of 1- (5-tert-butyl-2-p-t0lyl-2h-pyraz0l-3-yl) -3- (4- (6- (morpholin-4-yl-methyl) -pyrid in- 3 -yl) -naphthalen- 1-yl) -urea and polymorphs thereof Download PDF

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WO2007109434A1
WO2007109434A1 PCT/US2007/063637 US2007063637W WO2007109434A1 WO 2007109434 A1 WO2007109434 A1 WO 2007109434A1 US 2007063637 W US2007063637 W US 2007063637W WO 2007109434 A1 WO2007109434 A1 WO 2007109434A1
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Prior art keywords
butyl
methyl
type
naphthalen
tert
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PCT/US2007/063637
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French (fr)
Inventor
Magnus Carl Arne Eriksson
Xiaohui Mei
Earl Michael Spinelli
Richard J. Varsolona
Zeren Wang
Deliang Zhou
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Boehringer Ingelheim International Gmbh
Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Publication of WO2007109434A1 publication Critical patent/WO2007109434A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to a besylate salt form and polymorphs of l-[5-tert-butyl-2-p- tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-l-yl]- urea and process of making same.
  • Aryl- and heteroaryl-substituted ureas have been described as inhibitors of cytokine production.
  • One such compound, l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6- (morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-l-yl]-urea is in WO 00/55139, US patent 6,358,945 and US publication US-2003-0060455.
  • These inhibitors are described as effective therapeutics in cytokine-mediated diseases, including inflammatory, cancer and autoimmune diseases.
  • Fig. 1 Shows dissolution of the BS, CL, BF and TS forms in 900 ml SGF/pH 1.2; 37
  • Fig. 2 Shows dissolution of the BS, CL, BF and TS forms in 900 ml SIF/pH 6.5; 37
  • Fig. 3 Shows dissolution of the BS, CL, BF and TS forms in 100 ml HCl/pH 2.0/0.1 M
  • Fig. 4 Shows dissolution of the BS, CL, BF and TS forms in 100 ml 0.02 M phosphate pH 3.0/0.1 M NaCl; 37 °C/paddle/50 rpm.
  • Fig. 5 Shows dissolution of the BS and BF in 900 ml HCl/pH 2.0 buffer/0.1 M NaCl;
  • Fig. 6 Shows dissolution of the BS and BF in 900 ml 0.02 M phosphate pH 3.0/0.1M
  • Fig. 7 Shows dissolution of the BS and BF in 900 ml HCl/pH 2.0 buffer/0. IM NaCl;
  • Fig. 8 Shows dissolution of the BS and BF in 900 ml 0.02 M phosphate pH 3.0/0.1M NaCl; 37 °C/paddle/50 rpm.
  • Fig. 9 Shows XRPD data of the Type F Polymorph-THF solvate.
  • Fig. 10 Shows XRPD data of the dried (dcsolvated) THF solvate.
  • Fig. 11 Shows XRPD data of the Type A anhydrous polymorph.
  • Fig. 12 Shows XRPD data of the Type B anhydrous polymorph.
  • BS shall be understood as the free base form of the subject compound.
  • CL shall be understood as the hydrochloride salt form of the subject compound.
  • BF shall be understood as the benzenesulfonic acid (besylate) salt form of the subject compound.
  • TS shall be understood as the toluenesulfonic acid (tosylate) salt form of the subject compound.
  • SGF shall be understood as Simulated Gastric Fluid (HCl/NaCl, 34 mM NaCl, pH 1.2)
  • SIF shall be understood as Simulated Intestinal Fluid (29 mM KH 2 PO 4 , 103.3 mM KCl,
  • XRPD shall be understood as X-ray powder diffraction
  • the criteria for salt selection was based on crystallinity, dissolution, stability and hygroscopicity.
  • the relative dissolution rates are shown in Figures 1-8.
  • the relative solubilities, stabilities and hygroscopicities are shown in the following tables.
  • the besylate salt surprisingly possessed improved dissolution properties over other salts, especially apparent at pH 3 and above.
  • RH relative humidity l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3- yl)-naphthalen-l-yl]-urea TS: Stability
  • RH relative humidity It is yet another object of the invention to provide l-[5-tert-butyl-2-p-tolyl-2H-pyrazol- 3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-l-yl]-urea BF type B polymorph, and a process of making the same, said process comprising:
  • non-solvating polar acetate and ketone solvents such as Methyl Acetate, Ethyl Acetate, Isopropyl Acetate, and n-Butyl Acetate; Acetone, methyl ethyl ketone and methyl isobutyl ketone; preferred solvents are n-Butyl Acetate and Acetone, to the isolated compound Besylate THF desolvated form;
  • Type F Polymorph may also be identified by reflections:
  • Type A anhydrous polymorph :
  • Type A anhydrous Polymorph may also be identified by reflections:
  • Type B anhydrous polymorph may also be identified by reflections: 1.) reflections: 8.9, 14.2 and 19.5 degrees 2 theta;
  • reflections 8.9, 11.2 and 13.2 degrees 2 theta; 3.) reflections: 8.9, 11.2 and 19.5 degrees 2 theta; or 4.) reflections: 8.9, 11.2 and 20.6 degrees 2 theta.
  • the remaining benzenesulfonic acid stock solution (3.95 kg) was added to the reactor at linear rate over 2 h while maintaining the temperature at 35 0 C. It was found preferable to add the benzenesulfonic acid solution directly into the vortex of the stirring slurry to prevent a yellow discoloration during the salt formation.
  • the benzenesulfonic acid solution addition vessel was rinsed with 482 mL of THF and the rinse was added to the 22 L reactor.
  • the resulting slurry was cooled to 20 0 C linearly over 1 h and allowed to stir overnight.
  • the solids were collected by filtration and washed with about 3 L of THF to give I BF Type F (See Figure 9).
  • the wet cake was dried under vacuum with a nitrogen flow at 80 0 C for 24 h to give 1.18 kg of I BF Type F dried (See Figure 10). At this point the THF level was less than 1.0 weight %.
  • the resulting Type B slurry in n-butyl acetate was cooled at a linear rate to 20 0 C over 4 h.
  • the solids were collected by filtration and washed with about 3.6 L of n-butyl acetate.
  • the washed solids were dried at about 70 0 C under vacuum with a nitrogen flow for 24 h to give 1.15 kg of I BF Type B (See Figure 12).

Abstract

Disclosed is a 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea besylate salt form, polymorph and process of making same.

Description

BESYLATE SALT FORM OF - ( 5-TERT-BUTYL-2-P-TOLYL-2H-PYRAZOL-3-YL) -3- (4- (6- (M0RPH0LIN-4-YL-METHYL) -PYRID IN- 3 -YL) -NAPHTHALEN- 1-YL) -UREA AND POLYMORPHS THEREOF
APPLICATION DATA This application claims benefit to US provisional application serial no. 60/743,515 filed March 17, 2006.
BACKGROUND OF THE INVENTION
1. TECHNICAL FIELD
This invention relates to a besylate salt form and polymorphs of l-[5-tert-butyl-2-p- tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-l-yl]- urea and process of making same.
2. BACKGROUND INFORMATION
Aryl- and heteroaryl-substituted ureas have been described as inhibitors of cytokine production. One such compound, l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6- (morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-l-yl]-urea, is in WO 00/55139, US patent 6,358,945 and US publication US-2003-0060455. These inhibitors are described as effective therapeutics in cytokine-mediated diseases, including inflammatory, cancer and autoimmune diseases.
Figure imgf000002_0001
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3- yl)-naphthalen-l-yl]-urea (referred to hereafter as "the subject compound or compound I").
It is therefore desirable for formulation development to provide the subject compound with improved properties such as dissolution rate, crystallinity and hygroscopicity. It is also desirable to produce and isolate polymorphic forms with improved properties such as thermostability. BRIEF SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide a new besylate salt form of the subject compound.
It is a further object of the invention to provide one or more polymorphs with properties suitable for a drug product.
It is yet another object of the invention to provide processes of making said salt forms and polymorphs.
DESCRIPTION OF FIGURES
In each of the dissolution experiments represented by Figures 1-8, 50 mg of the free base or salt were mixed with 350 mg lactose and added to the amount of solvent and the conditions indicated for each figure. Samples were taken and analyzed at the time points shown in each figure.
Fig. 1: Shows dissolution of the BS, CL, BF and TS forms in 900 ml SGF/pH 1.2; 37
°C/paddle/50 rpm. Fig. 2: Shows dissolution of the BS, CL, BF and TS forms in 900 ml SIF/pH 6.5; 37
°C/paddle/50 rpm.
Fig. 3: Shows dissolution of the BS, CL, BF and TS forms in 100 ml HCl/pH 2.0/0.1 M
NaCl; 37 °C/paddle/50 rpm.
Fig. 4: Shows dissolution of the BS, CL, BF and TS forms in 100 ml 0.02 M phosphate pH 3.0/0.1 M NaCl; 37 °C/paddle/50 rpm.
Fig. 5: Shows dissolution of the BS and BF in 900 ml HCl/pH 2.0 buffer/0.1 M NaCl;
37 °C/paddle/50 rpm.
Fig. 6: Shows dissolution of the BS and BF in 900 ml 0.02 M phosphate pH 3.0/0.1M
NaCl; 37 °C/paddle/50 rpm. Fig. 7: Shows dissolution of the BS and BF in 900 ml HCl/pH 2.0 buffer/0. IM NaCl;
37 °C/paddle/50 rpm.
Fig. 8: Shows dissolution of the BS and BF in 900 ml 0.02 M phosphate pH 3.0/0.1M NaCl; 37 °C/paddle/50 rpm. Fig. 9: Shows XRPD data of the Type F Polymorph-THF solvate. Fig. 10: Shows XRPD data of the dried (dcsolvated) THF solvate. Fig. 11: Shows XRPD data of the Type A anhydrous polymorph. Fig. 12: Shows XRPD data of the Type B anhydrous polymorph.
DETAILED DESCRIPTION OF THE INVENTION
All terms as used herein in this specification, unless otherwise stated, shall be understood in their ordinary meaning as known in the art unless otherwise specified. Other more specific definitions are as follows:
BS shall be understood as the free base form of the subject compound.
CL shall be understood as the hydrochloride salt form of the subject compound.
BF shall be understood as the benzenesulfonic acid (besylate) salt form of the subject compound. TS shall be understood as the toluenesulfonic acid (tosylate) salt form of the subject compound.
SGF shall be understood as Simulated Gastric Fluid (HCl/NaCl, 34 mM NaCl, pH 1.2)
SIF shall be understood as Simulated Intestinal Fluid (29 mM KH2PO4, 103.3 mM KCl,
3 mM Sodium Taurocholate, 0.75 mM Lecithin, pH 6.5) XRPD shall be understood as X-ray powder diffraction
I. The Besylate Salt.
In one aspect of the invention, there is provided a l-[5-tert-butyl-2-p-tolyl-2H-pyrazol- 3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-l-yl]-urea besylate salt form and a process of making the same, comprising:
Adding the subject compound to a mixture of benzenesulfonic acid in a polar organic solvent such as THF, to produce the compound besylate salt form solvate: Benzenesulfonic Acid
Figure imgf000005_0001
Figure imgf000005_0002
(besylate solvate form); preparing under desolvating conditions, preferably by drying in a vacuum oven, the desolvated form and thereby isolating the desolvated form of the compound besylate salt form:
Figure imgf000005_0003
(desolvated besylate salt form).
The criteria for salt selection was based on crystallinity, dissolution, stability and hygroscopicity. The relative dissolution rates are shown in Figures 1-8. The relative solubilities, stabilities and hygroscopicities are shown in the following tables. As seen in the Figures, the besylate salt surprisingly possessed improved dissolution properties over other salts, especially apparent at pH 3 and above. l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3- yl)-naphthalen-l-yl]-urea BS and Salts: apparent solubility in SGF and SIF @ 37°C is summarized in the following table:
Figure imgf000006_0001
Stability properties of the BF salt vs BS, and CL and TS salt forms can be seen in the following tables: l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3- yl)-naphthalen-l-yl]-urea BS: Stability
Figure imgf000006_0002
RH = relative humidity DI = deionized l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3- yl)-naphthalen-l-yl]-urea CL: Stability
RH = relative humidity
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3- yl)-naphthalen-l-yl]-urea BF: Stability
Figure imgf000007_0002
RH = relative humidity l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3- yl)-naphthalen-l-yl]-urea TS: Stability
Figure imgf000008_0001
RH = relative humidity
Hygroscopicity of 1 -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)-naphthalen-l-yl]-urea BS and the Salts can be seen in the following table:
Figure imgf000008_0002
RH = relative humidity It is yet another object of the invention to provide l-[5-tert-butyl-2-p-tolyl-2H-pyrazol- 3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-l-yl]-urea BF type B polymorph, and a process of making the same, said process comprising:
providing the desolvated form of l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6- (morpholin-4-yl-methyl)pyridin-3 -yl)-naphthalen- 1 -yl] -urea BF described above;
adding non-solvating polar acetate and ketone solvents such as Methyl Acetate, Ethyl Acetate, Isopropyl Acetate, and n-Butyl Acetate; Acetone, methyl ethyl ketone and methyl isobutyl ketone; preferred solvents are n-Butyl Acetate and Acetone, to the isolated compound Besylate THF desolvated form;
seeding with about a 2 % seed level of l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4- (6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-l-yl]-urea BF Type B which is prepared in n-Butyl Acetate;
monitor for conversion to Type B, preferably by XRPD.
XRPD DATA Compound (I) BF Reflections:
Type F Polymorph- THF solvate :
Identifying reflections: 4.0, 5.7, 8.1, 13.6, 17.9, and 19.9 degrees 2 theta. As will be appreciated by those skilled in the art, Type F Polymorph may also be identified by reflections:
1.) reflections: 13.6, 17.9 and 19.9 degrees 2 theta;
2.) reflections: 5.7, 8.1 and 17.9 degrees 2 theta; or
3.) reflections: 4.0, 8.1 and 13.6 degrees 2 theta
Type F Dried Polymorph- Dried THF solvate:
Identifying reflections: 4.0, 8.0, 8.4, 9.3, and 18.1 degrees 2 theta. As will be appreciated by those skilled in the art ,Type F Dried Polymorph- Dried THF solvate may also be identified by reflections:
1.) reflections: 4.0, 8.0 and 8.4 degrees 2 theta; or
2.) reflections: 4.0, 8.0, and 18.1 degrees 2 theta.
Type A anhydrous polymorph :
Identifying reflections: 7.1, 7.4, 8.5, 11.8, 14.2, 17.0, 17.9, 19.7, 20.3, 22.0, 22.7 and 26.2 degrees 2 theta.
As will be appreciated by those skilled in the art, Type A anhydrous Polymorph may also be identified by reflections:
1.) reflections: 7.1, 8.5 and 11.9 degrees 2 theta; 2.) reflections: 7.4, 11.9 and 14.2 degrees 2 theta; 3.) reflections: 8.5, 17.0, and 22.7 degrees 2 theta; or 4.) reflections: 7.4, 11.9 and 22.7 degrees 2 theta.
Type B anhydrous polymorph
Identifying reflections: 8.9, 11.2, 13.2, 14.2, 17.6, 19.5, 19.8, and 20.6 degrees 2 theta. As will be appreciated by those skilled in the art, Type B anhydrous polymorph may also be identified by reflections: 1.) reflections: 8.9, 14.2 and 19.5 degrees 2 theta;
2.) reflections: 8.9, 11.2 and 13.2 degrees 2 theta; 3.) reflections: 8.9, 11.2 and 19.5 degrees 2 theta; or 4.) reflections: 8.9, 11.2 and 20.6 degrees 2 theta.
EXAMPLES
Preparation of Compound I BF Type F and Type F dried.
Compound I (955 g) and tetrahydrofuran (THF) (9.2 L) were added to a 22 L reactor at 20-25 0C under nitrogen. The mixture was warmed to 35 0C with stirring to obtain a complete solution. A stock solution of benzenesulfonic acid was prepared by dissolving 270.9 g of solid anhydrous benzenesulfonic acid in 5.17 L of THF. To the solution of compound I was added 443 g of the benzenesulfonic acid stock solution. A seed slurry of compound I Type F (system composition = 20 mg of I BF type F/mL THF) was added to the 22 L reactor to yield a relatively thin slurry. The remaining benzenesulfonic acid stock solution (3.95 kg) was added to the reactor at linear rate over 2 h while maintaining the temperature at 35 0C. It was found preferable to add the benzenesulfonic acid solution directly into the vortex of the stirring slurry to prevent a yellow discoloration during the salt formation. The benzenesulfonic acid solution addition vessel was rinsed with 482 mL of THF and the rinse was added to the 22 L reactor. The resulting slurry was cooled to 20 0C linearly over 1 h and allowed to stir overnight. The solids were collected by filtration and washed with about 3 L of THF to give I BF Type F (See Figure 9). The wet cake was dried under vacuum with a nitrogen flow at 80 0C for 24 h to give 1.18 kg of I BF Type F dried (See Figure 10). At this point the THF level was less than 1.0 weight %.
Preparation of Compound I BF Type B
Compound I BF Type F dried (1.178 kg) and n-butyl acetate (16.5 L) were added to a 22 L reactor. The stirred slurry was heated to 900C over 30 min. The slurry was stirred and seeded with about 80 mL of a slurry of I BF Type B in n-butyl acetate at a concentration of about 300 mg/mL. (The seed slurry may be independently prepared from I BF Type F in n -butyl acetate at 90 0C). The seeded slurry was stirred at 900C for 6 h. Over this time period the I BF Type F dried converted to I BF Type B. The resulting Type B slurry in n-butyl acetate was cooled at a linear rate to 200C over 4 h. The solids were collected by filtration and washed with about 3.6 L of n-butyl acetate. The washed solids were dried at about 700C under vacuum with a nitrogen flow for 24 h to give 1.15 kg of I BF Type B (See Figure 12).
Preparation of Compound I BF Type A
1.46 g of amorphous Compound I BF and 23 mL of n-butanol was added to a 50 mL reactor. The contents were heated to about 68 0C to dissolve the solids. The hot solution was seeded with Compound I BF n-butanol solvate. The resulting slurry was cooled to ambient temperature and allowed to stir overnight. The slurry was filtered and the resulting wet cake was washed with n-heptane. The washed solids were dried under a nitrogen atmosphere for 30 minutes at ambient temperature to produce 1.116g of Compound I BF n-butanol solvate. A portion of the Compound I BF n-butanol solvate was dried at 118 0C under vacuum with a nitrogen purge for 45 minutes to produce 0.71 g of Compound I BF Type A.

Claims

Claims
1. 1 -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3- yl)-naphthalen-l-yl]-urea besylate salt.
2. A process of making l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin- 4-yl-methyl)pyridin-3-yl)-naphthalen-l-yl]-urea besylate salt form comprising:
adding the subject compound to a mixture of benzenesulfonic acid in a polar organic solvent such as THF, to produce the compound besylate salt form solvate:
Benzenesulfonic Acid
Figure imgf000012_0001
Figure imgf000012_0002
(besylate solvate form); preparing under desolvating conditions, preferably by drying in a vacuum oven, the desolvated form and thereby isolating the desolvated form of the compound besylate salt form:
Figure imgf000013_0001
(desolvated besylate salt form).
3. A polymorph of l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)-naphthalen-l-yl]-urea selected from
Type F Polymorph- THF solvate with identifying reflections: 4.0, 5.7, 8.1, 13.6, 17.9, and 19.9 degrees 2 theta;
Type F Dried Polymorph- Dried THF solvate with identifying reflections: 4.0, 8.0, 8.4,
9.3, and 18.1 degrees 2 theta;
Type A anhydrous polymorph with identifying reflections: 7.1, 7.4, 8.5, 11.8, 14.2,
17.0, 17.9, 19.7, 20.3, 22.0, 22.7 and 26.2 degrees 2 theta; and
Type B anhydrous polymorph with identifying reflections: 8.9, 11.2, 13.2, 14.2, 17.6,
19.5, 19.8, and 20.6 degrees 2 theta.
PCT/US2007/063637 2006-03-17 2007-03-09 Besylate salt form of 1- (5-tert-butyl-2-p-t0lyl-2h-pyraz0l-3-yl) -3- (4- (6- (morpholin-4-yl-methyl) -pyrid in- 3 -yl) -naphthalen- 1-yl) -urea and polymorphs thereof WO2007109434A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000055139A2 (en) * 1999-03-12 2000-09-21 Boehringer Ingelheim Pharmaceuticals, Inc. Heterocyclic urea and related compounds useful as anti-inflammatory agents
WO2002083642A1 (en) * 2001-04-13 2002-10-24 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
WO2004014387A1 (en) * 2002-08-13 2004-02-19 Boehringer Ingelheim Pharmaceuticals, Inc. COMBINATION THERAPY WITH p38 MAP KINASE INHIBITORS AND THEIR PHARMACEUTICAL COMPOSITIONS

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000055139A2 (en) * 1999-03-12 2000-09-21 Boehringer Ingelheim Pharmaceuticals, Inc. Heterocyclic urea and related compounds useful as anti-inflammatory agents
WO2002083642A1 (en) * 2001-04-13 2002-10-24 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
WO2004014387A1 (en) * 2002-08-13 2004-02-19 Boehringer Ingelheim Pharmaceuticals, Inc. COMBINATION THERAPY WITH p38 MAP KINASE INHIBITORS AND THEIR PHARMACEUTICAL COMPOSITIONS

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