WO2008051440A1 - Crystal modifications -3- (1h-ind0l-3-yl) -4- [2- (4-methyl-piperazin-1-yl) -quinazolin-4-yl] -pyrrole-2, 5-d ione - Google Patents

Crystal modifications -3- (1h-ind0l-3-yl) -4- [2- (4-methyl-piperazin-1-yl) -quinazolin-4-yl] -pyrrole-2, 5-d ione Download PDF

Info

Publication number
WO2008051440A1
WO2008051440A1 PCT/US2007/022241 US2007022241W WO2008051440A1 WO 2008051440 A1 WO2008051440 A1 WO 2008051440A1 US 2007022241 W US2007022241 W US 2007022241W WO 2008051440 A1 WO2008051440 A1 WO 2008051440A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
pyrrole
piperazin
quinazolin
indol
Prior art date
Application number
PCT/US2007/022241
Other languages
French (fr)
Inventor
Piotr Karpinski
Stéphanie MONNIER
Elias Ndzie
Dimitris Papoutsakis
Paul Allen Sutton
Original Assignee
Novartis Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=38921707&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2008051440(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to AU2007309558A priority Critical patent/AU2007309558B2/en
Priority to CA002666965A priority patent/CA2666965A1/en
Priority to NZ576241A priority patent/NZ576241A/en
Priority to RU2009118816/04A priority patent/RU2481341C2/en
Priority to BRPI0717461-6A2A priority patent/BRPI0717461A2/en
Priority to US12/445,371 priority patent/US8865897B2/en
Priority to MX2009004048A priority patent/MX2009004048A/en
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to JP2009533377A priority patent/JP5302199B2/en
Priority to CN2007800383914A priority patent/CN101522664B/en
Priority to EP07839661A priority patent/EP2102195A1/en
Publication of WO2008051440A1 publication Critical patent/WO2008051440A1/en
Priority to IL197962A priority patent/IL197962A/en
Priority to TNP2009000147A priority patent/TN2009000147A1/en
Priority to NO20091970A priority patent/NO20091970L/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to particular forms of the acetate salt of 3-(lW.-indol-3-yl)-4-[2- (4-methyl-piperazin-1-yl)-quinazoli ⁇ -4-yl]-pyrrole-2,5-dione, comprising amorphous form and certain crystals, processes for the preparation thereof, pharmaceutical compositions containing such amorphous and crystal form, and their use in diagnostic methods or preferably for the therapeutic treatment of warm-blooded animals, especially humans, or their use for the preparation of pharmaceutical preparations for use in diagnostic methods or preferably for the therapeutic treatment of warm-blooded animals, especially humans.
  • amorphous form, crystal forms e.g. polymorphs, or pseudopolymorphs, such as solvates of hydrates
  • crystal forms e.g. polymorphs, or pseudopolymorphs, such as solvates of hydrates
  • A, B, C or D crystal forms or the solvate form S Al which have very advantageous properties.
  • Such forms show improved stability and purity and thus e.g. easier handling in plant and open up new possibilities for improved formulation of pharmaceutical compositions for 3-(7.H.-indol-3- 50354A
  • crystal of the invention encompasses the amorphous form, crystal forms, e.g. polymorphs, and pseudo-polymorphs, e.g. solvate and hydrate, of the 3-(lH.-indol-3-yl)-4-[2-(4-methyl-p ⁇ erazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5- dione acetate.
  • crystal of the invention are form A, form B, form C , form D, and form S Al .
  • the present invention provides a amorphous form, crystal forms, e.g. polymorphs, and pseudo-polymorphs, e.g. solvate and hydrate, of the 3-(lf/.-indol-3-yl)-4-[2-(4-methyl- piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate, in particular the form A, B, as defined herebelow, the form S A , or mixture thereof, preferably form B or mixture of form A and B.
  • the amorphous and crystalline forms of 3-(7.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)- quinazolin-4-ylJ-pyrrole-2,5-dione acetate are preferably essentially pure.
  • the term essentially pure in accordance with the present invention is means that the sum of related substances is less than 1%, preferably less than 0.75%, more preferably less than 0.5% and that the residual solvents and water are less than 1%, preferably less than 0.75%, more preferably less than 0.5% and still more preferably less than 0.25% by weight.
  • the crystalline form of 3-(lH.-indol-3-yl)-4-[2-(4-methyl- piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate is not hydrated, i.e. the anhydrate.
  • the anhydrate can e.g. be prepared by dehydration of the monohydrate under suitable conditions.
  • a crystalline form of 3- (1. H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-qu ⁇ nazolin-4-yl]-pyrrole-2,5-dione acetate e.g. form A or B, which is anhydrous.
  • solvate of 3-(1.H.- indol-3-yl)-4-[2-(4-methyl-piperaz ⁇ n-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate e.g. obtained in solvant such as acetone, ethanol, tertahydrofrurane, acetonitrile, methanol or 50354A
  • the present invention provides the hydrate form of 3-(7.H.-indol- 3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate is a solvate, e.g. monohydrate form.
  • a crystalline form of 3- (y.Ay.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quina2olin-4-yl3-pyrrole-2,5-dione acetate e.g. the crystal form A, B, C or D, as hereinbelow described, or mixture thereof.
  • Fig. 1 shows the X-ray Powder Diffraction Diagram of Form A of the acetate anhydrate salt of 3-(f.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione.
  • X-ray powder diffraction patterns are measured using a Bruker STOE instrument with CuK alpha radiation source.
  • Fig. 2 shows the FT-IR spectrum of Form A.
  • FT-IR spectrum is recorded in Nujol mull between 2 KBr plates using a Bruker Vertex. The sample is tested as is using ATR (attenuated total reflectance) sampling device.
  • ATR attenuated total reflectance
  • Fig. 3 shows the FT-Raman spectrum of Form A.
  • the FT-Raman spectrum is recorded using a Bruker RFS 100 instrument.
  • Fig. 4 shows a microscopic view of Form A.
  • Fig. 5 shows the X-ray diffraction diagram of form B of the acetate anhydrate salt of 3-(1.H.- indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione.
  • the angle of diffraction is plotted on the horizontal axis (x-axis) and the peak intensity on the vertical (y-axis).
  • X-ray powder diffraction patterns are measured using a Bruker STOE instrument with CuK alpha radiation source,). '
  • Fig. 6 shows the FT-IR spectrum of Form B.
  • FT-IR spectrum is recorded in Nujol mull between 2 KBr plates using a Bruker Vertex. The sample is tested as is using ATR ( criznous total reflectance) sampling device. 50354A
  • Fig. 7 shows the FT-Raman spectrum of Form B.
  • the FT-Raman spectrum is recorded using a Bruker RFS 100 instrument.
  • Fig. 8 shows a microscopic view of Form B.
  • Fig. 9 shows a X-ray powder diffraction pattern of amorphous form.
  • Fig. 10 shows a FT-IR Spectrum of amorphous form.
  • Fig. 11 shows a FT-RAMAN Spectrum of amorphous form.
  • Form B is slightly hygroscopic with maximum water uptake of 0.7% at 80%r.h.
  • the melting onset temperature of form B is about 220 0 C, e.g. about 190 0 C.
  • the XRPD X-ray Powder Diffraction shows a strong diffraction peak at an angle of about 9.7° 2theta. 50354A
  • Form B may be characte ⁇ zed by the following major IR bands: Main IR bands: 1754; 1711; 11574; 1486; 1462; 1378; 1248; 1086; 976; 770; 723; 661; 622cr ⁇ 1 .
  • Form B may be characte ⁇ zed by the following main RAMAN bands: 3064; 1754; 1711; 1625; 1574; 1485, 1445; 1388; 1334; 1309; 1246; 1212; 664; 645cm "1
  • Form B is orange.
  • the melting onset temperature of form A is about 180 0 C 1 e.g. 182°C.
  • the X-ray diffraction pattern depicted in FIG. 4 for Form A is summarized in Table 3.
  • the XRPD shows a strong diffraction peak at about 21.5° 2Theta, e.g. 21.4° 2Theta.
  • Form A may be distinguished from form B in particular by at least one of the following XRPD diffraction peaks: about 11.6°, about 12.0° and about 21.5° 2Theta.
  • Form A may be characterized by the following major IR bands: 1757; 1710; 1631; 1552; 1378; 1145; 1084; 1005; 979; 777; 750, 660; 642; 623 cm "1 ..
  • Form A may be characterized by the following main RAMAN bands: 3076; 1756; 1632; 151; 1495; 1380, 1347; 1310; 1249; 1222; 660; 643; 255cnT 1 .
  • Form A is yellow. 50354A
  • a crystalline form exhibiting at least one of the following major IR bands: 1711; 11574; 1486; 1462; 1378; 1248; 1086; 976; 770; 723; 661; 622cm "1 .
  • a crystalline form exhibiting at least one of the following main RAMAN bands: 3064; 1754; 1711; 1625; 1574; 1485, 1445; 1388; 1334; 1309; 1246; 1212; 664; 645cr ⁇ V 1 .
  • a crystalline form exhibiting at least one of the following major IR bands: 1757; 1710; 1631; 1552; 1378; 1145; 1084; 1005; 979; 777; 750, 660; 642; 623 cm 1 .
  • a crystalline form exhibiting at least one of the following main RAMAN bands: 3076; 1756; 1632; 151 ; 1495; 1380; 1347; 1310; 1249; 1222; 660; 643; 255cm '1 .
  • the melting onset temperature of amorphous form is comprised between about 100 and about 110 0 C 1 .
  • Amorphous form of 3-(l/-/.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quina2olin-4-yl]-pyrrole- 2,5-dione acetate is orange.
  • the invention also includes a process for the preparation of the crystals of the invention which comprises the step of forming a solution of 3-(f.H.-indol-3-yl)-4-[2-(4-methyl-piperazin- 1-yl)-quinazolin-4-yl]-pyrro!e-2,5-dione acetate and crystallizing the acetate from solution by precipitation or recrystallization.
  • the process for the preparation of the crystals of the invention comprises the step of reacting 3-(7./-/.-indol-3-yl)-4-[2-(4-methyl-piperazin-1- yl)-quinazolin-4-yl]-pyrrole-2,5-dione in free base form with acetic acid and recovering from the reaction mixture the resultant salt, and the step of reacting an appropriate inert solvent such as acetone, acetonitrile, ethanol, ethyl acetate, heptane, t-butyl methyl ether, methylene chloride, 2-propanol, /-propyl acetate, toluene, E95, or a mixture EtAC/ethanol, e.g. 75/25 vol% or 50/50 vol%.
  • Preferred solvent is acetone.
  • Crystallization-inducing conditions normally involve the use of an appropriate crystallization- inducing solvent, such as acetone, acetonitrile, ethanol, ethyl acetate, heptane, or t-butyl methyl ether, methylene chloride, 2-propanol, /-propyl acetate, toluene, E95 or a mixture EtAC/ethanol, e.g. 75/25 vol% or 50/50 vol%.
  • an appropriate crystallization- inducing solvent such as acetone, acetonitrile, ethanol, ethyl acetate, heptane, or t-butyl methyl ether, methylene chloride, 2-propanol, /-propyl acetate, toluene, E95 or a mixture EtAC/ethanol, e.g. 75/25 vol% or 50/50 vol%.
  • Preferred solvants are acetone, ethyl acetate, heptane, t-butyl methyl ether, methylene chloride, 2-propanol, /-propyl acetate, toluene, and mixture EtAC/ethanol, e.g. 75/25 vol% or 50/50 vol%
  • 3-(7./-/.-indol-3-yl)-4-[2- (4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione is dissolved in the solvent at ambient temperature.
  • the solution may be produced by dissolving in a solvent any one or more of amorphous forms of 3-(f .H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]- pyrrole-2,5-dione, and solvates thereof, such as hydrate. Crystals may then be formed by 50354A
  • the dissolution and crystallization may be carried out in various conventional ways.
  • free base may be dissolved in a solvent or a mixture of solvents in which it is readily soluble at ambient temperatures but in which it acetate salt is only sparingly soluble at the same temperatures.
  • Dissolution of the free base at elevated temperature followed by cooling after salt formation can also help the acetate salt crystals crystallize out of solution.
  • Mixed solvents comprising a good solvent in which 3-(lH-indol-3-yl)-4-[2-(4-methyl- piperazin-1-yl)-quinazolin ⁇ 4-yl]-pyrrole-2,5-di ⁇ ne is readily soluble, preferably, in amounts of at least 10% by weight at 20 0 C, and a poor solvent in which it is more sparingly soluble, preferably in amounts of not more than about 0.1% by weight at 20 0 C, may also be employed provided that crystallization from the mixture at a reduced temperature of normally at least about 0° C, is possible using the selected solvent mixture.
  • seeds of crystalline material to the solution in order to induce crystallization.
  • the crystalline forms of 3-(?.H.-indol-3-yl)-4-t2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate, e.g. the anhydrous forms, have a high crystallinity.
  • a crystal form is defined herein as having a "high crystallinity” or being “crystallographically pure” when it contains at most about 0.5% (w/w), e.g. at most about 0.1% (w/w) of other form.
  • crystallinity e.g. at most about 0.5% (w/w) of other form.
  • crystallographically pure Form A or B contains about 0.5% (w/w) or less, e.g. about 0.1% (w/w) or less of another crystallographic form and/or amorphous form.
  • the present invention provides pharmaceutical composition
  • such a composition is a high dose formulation of including e.g. at least 50 mg, preferably at least 100 mg, more preferably at least 250 mg 3-(lH.-indof-3-yl)- 50354A
  • such a composition is an oral formulation, comprising e.g. 0.5 mg to 2000 mg 3-(f.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1- yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate and a suitable pharmaceutical carrier or diluent.
  • the crystals of the invention are, therefore, useful in the treatment and/or prevention of diseases or disorders mediated by T lymphocytes and/or PKC, e.g. acute or chronic rejection of organ or tissue allo- or xenografts or T-cell mediated inflammatory or autoimmune diseases, e.g. atherosclerosis, vascular occlusion due to vacular injury such as angioplasty, restenosis, hypertension, heart failure, chronic obstructive pulmonary disease, CNS diseases such as Alzheimer disease or amyotrophic lateral sclerosis, cancer, infectious diseases such as AIDS, septic shock or adult respiratory distress syndrome, ischemia/reperfusion injury e.g.
  • crystals of the invention are also useful in the treatment and/or prevention of T- cell mediated acute or chronic inflammatory diseases or disorders or autoimmune diseases e.g.
  • rheumatoid arthritis osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroidis, multiple sclerosis, myasthenia gravis, diabetes type I or Il and the disorders associated therewith, respiratory diseases such as asthma or inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, cutaneous manifestations of immunologically- mediated disorders or illnesses, inflammatory and hyperproliferative skin diseases (such as psoriasis, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis), inflammatory eye diseases, e.g. Sjoegren's syndrome, keratoconjunctivitis or uveitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis.
  • respiratory diseases such as asthma or inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, cutaneous manifestations of immunologically-
  • the present invention further provides:
  • composition comprising the crystal of the invention, e.g. 3-(7./7.- ⁇ ndol-3- yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate in amorphous form, crystalline form, e.g. Form A or Form B, or pseudocrystalline form, e.g. Form S A together with at least one pharmaceutically acceptable carrier or diluent;
  • crystals of the invention e.g. 3-(7. ⁇ /.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)- quinazolin-4-yl]-pyrrole-2,5-dione acetate in amorphous, crystalline or pseudocrystalline 50354A
  • Form A , B, C , D or S A preferably Form A, B or mixture thereof, for use as a pharmaceutical;
  • the crystals of the invention e.g. 3-('/.H.-indol-3-yl)-4-[2-(4-methyl-pipera2in-1-yl)- quinazolin-4-yl]-pyrrole-2,5-dione acetate in amorphous, crystalline or pseudocrystalline form, e.g. Form A , B, C, D or S A , preferably Form A, B or mixture thereof, for use in the preparation of a medicament;
  • crystals of the invention e.g. 3-(?.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)- quinazolin-4-yl]-pyrrole-2,5-dione acetate in amorphous, crystalline or pseudocrystalline form, e.g. Form A, B, C, D or S A whenever prepared by a process as defined above;
  • crystals of the invention e.g. 3-(LH.-indol-3-yl)-4-[2-(4-methyl-piperazin-1- yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate in amorphous, crystalline or pseudocrystalline form, e.g. Form A, B, C, D or S A , in the preparation of a medicament for the treatment or prevention of diseases susceptible of therapy, such as diseases or disorders mediated by T lymphocytes and/or PKC, e.g. acute or chronic rejection of organ or tissue allo- or ' xenografts or T-cell mediated inflammatory or autoimmune diseases; and
  • a method for the prevention or treatment of diseases or disorders mediated by T lymphocytes and/or PKC such as acute or chronic rejection of organ or tissue allo- or xenografts or T-cell mediated inflammatory or autoimmune diseases, comprising administration of a therapeutically effective amount of the crystals of the invention, e.g. 3- ( ⁇ ./y.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate in amorphous, crystalline or pseudocrystalline form, e.g. Form A, B or S A , to a subject in need of such treatment.
  • diseases or disorders mediated by T lymphocytes and/or PKC such as acute or chronic rejection of organ or tissue allo- or xenografts or T-cell mediated inflammatory or autoimmune diseases
  • the crystal of the invention may be administered as the sole active ingredient or together with other drugs in immunomodulating regimens or other antiinflammatory agents e.g. for the treatment or prevention of allo- or xenograft acute or chronic rejection or inflammatory or autoimmune disorders.
  • they may be used in combination with cyclosporines, or ascomycines or their immunosuppressive analogs or derivatives, e.g. cyclosporin A, cyclosporin G, FK-506, ABT-281, ASM 981; an mTOR inhibitor, e.g.
  • rapamycin 40-O-(2-hydroxy)ethyl-rapamycin etc.
  • corticosteroids cyclophosphamide
  • azathioprene methotrexate
  • an accelerating lymphocyte homing agent e.g. FTY 720
  • leflunomide or analogs thereof an accelerating lymphocyte homing agent, e.g. FTY 720; leflunomide or analogs thereof
  • mizoribi ⁇ e mycophenolic acid
  • mycophenolate mofetil 15-deoxyspergualine or analogs thereof
  • immunosuppressive monoclonal antibodies 50354A
  • Crystalline form of the invention e.g. Form A or B, may also be administered together with an antiproliferative drug, e.g. a chemotherapeutic drug, e.g. in cancer treatment, or with an anti-diabetic drug in diabetes therapy.
  • an antiproliferative drug e.g. a chemotherapeutic drug, e.g. in cancer treatment, or with an anti-diabetic drug in diabetes therapy.
  • a method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of the crystal of the invention, e.g. 3-(1.H.- indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate in amorphous, crystalline or pseudocrystalline form, e.g. Form A 1 B, C, D or S A , and a second drug substance, said second drug substance being an immunosuppressant, immunomodulatory, anti-inflammatory, antiproliferative or anti-diabetic drug, e.g. as indicated above.
  • a therapeutically effective amount of the crystal of the invention e.g. 3-(1.H.- indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-d
  • a therapeutic combination e.g. a kit, comprising a) the crystal of the invention, e.g. 3-(1.H.- indol-3-yl)-4-[2-(4-methyl-pipera2in-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate in amorphous, crystalline or pseudocrystalline form, e.g. Form A, B, C, D or S A , and b) at least one second agent selected from an immunosuppressant, immunomodulatory, antiinflammatory, antiproliferative and anti-diabetic drug.
  • Component a) and component b) may be used concomitantly or in sequence.
  • the kit may comprise instructions for its administration.
  • a preferred crystalline form according to the invention is e.g. the Form B or A, more preferably the Form B.
  • aqueous layer is extracted with ethyl acetate (50 ml).
  • the organic layer is extracted twice with 5% aqueous sodium bicarbonate (2x50ml), followed by concentration to 40 ml residual volume.
  • ethyl acetate (50 ml) is added and subsequently is distilled off. This procedure is carried out four times.
  • etha ⁇ ol is added (30 ml).
  • the red solution is heated to 70 0 C over a period of 30 minutes and acetic acid (4g) is added. After seeding the reaction is stirred at 70 0 C for 90 minutes.
  • the mixture is cooled to 30 0 C over a period of 60 minutes and is stirred additionally for 30 minutes before it is cooled to 20°C over a period of 90 minutes.
  • the suspension is filtered, washed once with TBME (15ml) and once with a mixture TBME (13.5ml) - ethanol (1.5ml). After drying at 5O°C under reduced pressure for 2h, the product is obtained in 87.7% yield as an orange crystalline solid.
  • the orange powder is dried at 40 °C under vacuum (5 mbar) for 10 to 12 hours to yield 14.4 g of an orange solid exhibiting a XRD pattern which corresponds to that of polymorph B of -(lH.-indol-3-yl)-4-[2- (4-methyl-piperazin-1-yl)-quinazoli ⁇ -4-yl]-pyrrole-2,5-dione acetate salt.
  • acetic acid is dissolved in 0.1 ml of methanol and added drop-wise to the drug substance solution.
  • the reaction mixture is cooled to ambient and stirred overnight affording precipitation of the acetate salt as an orange powder.
  • the suspension is cooled to ambient and the solid is recovered by vacuum filtration, followed by washing with small amounts of methanol (2 x 0.25 ml).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Transplantation (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to a new crystalline form of the acetate salt of, 3-(1.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione, which may be used for example for transplantation.

Description

CRYSTAL MODIFICATIONS OF -3- (1H-INDOL-3-YL) -4- [2- (4-METHYL-PIPERAZIN-l-YL)
-QUINAZOLIN-4-YL] -PYRROLE-2 , 5-D IONE
The present invention relates to particular forms of the acetate salt of 3-(lW.-indol-3-yl)-4-[2- (4-methyl-piperazin-1-yl)-quinazoliπ-4-yl]-pyrrole-2,5-dione, comprising amorphous form and certain crystals, processes for the preparation thereof, pharmaceutical compositions containing such amorphous and crystal form, and their use in diagnostic methods or preferably for the therapeutic treatment of warm-blooded animals, especially humans, or their use for the preparation of pharmaceutical preparations for use in diagnostic methods or preferably for the therapeutic treatment of warm-blooded animals, especially humans.
3-( lH.-indol-3-yl)-4-[2-(4-methyl-piperazin-1 -yl)-quinazolin-4-yl]-pyrrole-2,5-dione can be represented by the following formula
Figure imgf000002_0001
and is known from WO2002/38561 (example 56), the entire disclosure of which is incorporated by reference, and can be synthesized as described therein.
It has now been surprisingly found that amorphous form, crystal forms, e.g. polymorphs, or pseudopolymorphs, such as solvates of hydrates, may under certain conditions be found in the acetate salt of this compound, which are described hereinafter e.g. as A, B, C or D crystal forms or the solvate form SAl and which have very advantageous properties. Such forms show improved stability and purity and thus e.g. easier handling in plant and open up new possibilities for improved formulation of pharmaceutical compositions for 3-(7.H.-indol-3- 50354A
- 2 -
yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate, such as e.g. high dose formulations.
For the purpose of the present invention, the term "crystal of the invention" encompasses the amorphous form, crystal forms, e.g. polymorphs, and pseudo-polymorphs, e.g. solvate and hydrate, of the 3-(lH.-indol-3-yl)-4-[2-(4-methyl-pφerazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5- dione acetate. Examples of crystal of the invention are form A, form B, form C , form D, and form SAl.
The present invention provides a amorphous form, crystal forms, e.g. polymorphs, and pseudo-polymorphs, e.g. solvate and hydrate, of the 3-(lf/.-indol-3-yl)-4-[2-(4-methyl- piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate, in particular the form A, B, as defined herebelow, the form SA, or mixture thereof, preferably form B or mixture of form A and B.
The amorphous and crystalline forms of 3-(7.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)- quinazolin-4-ylJ-pyrrole-2,5-dione acetate are preferably essentially pure. The term essentially pure in accordance with the present invention is means that the sum of related substances is less than 1%, preferably less than 0.75%, more preferably less than 0.5% and that the residual solvents and water are less than 1%, preferably less than 0.75%, more preferably less than 0.5% and still more preferably less than 0.25% by weight.
In another preferred embodiment the crystalline form of 3-(lH.-indol-3-yl)-4-[2-(4-methyl- piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate is not hydrated, i.e. the anhydrate. The anhydrate can e.g. be prepared by dehydration of the monohydrate under suitable conditions.
In another preferred embodiment of the invention, there is provided a crystalline form of 3- (1. H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quιnazolin-4-yl]-pyrrole-2,5-dione acetate, e.g. form A or B, which is anhydrous.
In yet another preferred embodiment of the invention, there is provided a solvate of 3-(1.H.- indol-3-yl)-4-[2-(4-methyl-piperazιn-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate, e.g. obtained in solvant such as acetone, ethanol, tertahydrofrurane, acetonitrile, methanol or 50354A
- 3 -
water (hydrate). In particular the present invention provides the hydrate form of 3-(7.H.-indol- 3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate is a solvate, e.g. monohydrate form.
In another preferred embodiment of the invention, there is provided a crystalline form of 3- (y.Ay.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quina2olin-4-yl3-pyrrole-2,5-dione acetate, e.g. the crystal form A, B, C or D, as hereinbelow described, or mixture thereof.
Figures
Fig. 1 shows the X-ray Powder Diffraction Diagram of Form A of the acetate anhydrate salt of 3-(f.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione. X-ray powder diffraction patterns are measured using a Bruker STOE instrument with CuK alpha radiation source.
Fig. 2 shows the FT-IR spectrum of Form A. FT-IR spectrum is recorded in Nujol mull between 2 KBr plates using a Bruker Vertex. The sample is tested as is using ATR (attenuated total reflectance) sampling device.
Fig. 3 shows the FT-Raman spectrum of Form A. The FT-Raman spectrum is recorded using a Bruker RFS 100 instrument.
Fig. 4 shows a microscopic view of Form A.
Fig. 5 shows the X-ray diffraction diagram of form B of the acetate anhydrate salt of 3-(1.H.- indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione. In the X-ray diagram, the angle of diffraction is plotted on the horizontal axis (x-axis) and the peak intensity on the vertical (y-axis). X-ray powder diffraction patterns are measured using a Bruker STOE instrument with CuK alpha radiation source,). '
Fig. 6 shows the FT-IR spectrum of Form B. FT-IR spectrum is recorded in Nujol mull between 2 KBr plates using a Bruker Vertex. The sample is tested as is using ATR (attentenous total reflectance) sampling device. 50354A
- A -
Fig. 7 shows the FT-Raman spectrum of Form B. The FT-Raman spectrum is recorded using a Bruker RFS 100 instrument.
Fig. 8 shows a microscopic view of Form B.
Fig. 9 shows a X-ray powder diffraction pattern of amorphous form.
Fig. 10 shows a FT-IR Spectrum of amorphous form.
Fig. 11 shows a FT-RAMAN Spectrum of amorphous form.
Form B
Form B is slightly hygroscopic with maximum water uptake of 0.7% at 80%r.h.
Table 1.
Relative humidity % Moisture Sorption at 25
45 0.4
55 0.5
75 0.6
85 0 7
95 0.6 hygroscopic slightly
XRPD pattern after DVS no change
Differential Scanning Calorimery (DSC). the melting onset temperature of form B is about 220 0C, e.g. about 1900C.
The X-ray diffraction pattern depicted in FIG. 1 for Form B is summarized in Table 2 which lists most significant diffraction peaks.
The XRPD (X-ray Powder Diffraction) shows a strong diffraction peak at an angle of about 9.7° 2theta. 50354A
- 5 -
Table 2.
2-theta d-spacings (A) Relative
(deg) intensity
8.4 10.50 Low
9.7 9 07 Strong
13 9 6 35 Low
16.8 5.24 Low
17.3 5 11 Low
188 4 71 Low
19 0 4 66 Low
19.9 4.45 Medium
20.5 4.31 Medium
25 9 342 Medium
27.1 3.28 Medium
27.4 324 Low
27 8 320 Low
282 3 15 Low
35.0 2 56 Strong
Form B may be characteπzed by the following major IR bands: Main IR bands: 1754; 1711; 11574; 1486; 1462; 1378; 1248; 1086; 976; 770; 723; 661; 622crτϊ1.
Form B may be characteπzed by the following main RAMAN bands: 3064; 1754; 1711; 1625; 1574; 1485, 1445; 1388; 1334; 1309; 1246; 1212; 664; 645cm"1
Form B is orange.
Form A
The melting onset temperature of form A is about 1800C1 e.g. 182°C.
The X-ray diffraction pattern depicted in FIG. 4 for Form A is summarized in Table 3. The XRPD shows a strong diffraction peak at about 21.5° 2Theta, e.g. 21.4° 2Theta.
Table 3 5O354A
- 6 -
2-theta d-spacings (A) Relative
(deg) intensity
8.5 10.28 Low
11.2 7.87 Low
11.6 7.56 Medium
12.1 7.27 Medium
12.6 7.01 Low
14.5 6.09 Strong
17.1 5 17 Strong
17.3 5.14 Strong
17.7 4.97 Strong
19.2 4.61 Medium
19.7 4.48 Medium
20.3 4.36 Medium
20.8 4.26 Medium
21.5 4.11 Strong
22.9 3.87 Low
24.6 3.61 Low
24.9 3 55 Low
26.2 3.38 Medium
34.7 2.57 Medium
Form A may be distinguished from form B in particular by at least one of the following XRPD diffraction peaks: about 11.6°, about 12.0° and about 21.5° 2Theta.
Form A may be characterized by the following major IR bands: 1757; 1710; 1631; 1552; 1378; 1145; 1084; 1005; 979; 777; 750, 660; 642; 623 cm"1..
Form A may be characterized by the following main RAMAN bands: 3076; 1756; 1632; 151; 1495; 1380, 1347; 1310; 1249; 1222; 660; 643; 255cnT1.
Form A is yellow. 50354A
- 7 -
In one preferred embodiment there is provided a crystalline form exhibiting at least one of the following major IR bands: 1711; 11574; 1486; 1462; 1378; 1248; 1086; 976; 770; 723; 661; 622cm"1.
In another preferred embodiment there is provided a crystalline form exhibiting at least one of the following main RAMAN bands: 3064; 1754; 1711; 1625; 1574; 1485, 1445; 1388; 1334; 1309; 1246; 1212; 664; 645crτV1.
In yet another preferred embodiment there is provided a crystalline form exhibiting at least one of the following major IR bands: 1757; 1710; 1631; 1552; 1378; 1145; 1084; 1005; 979; 777; 750, 660; 642; 623 cm 1.
In a further preferred embodiment there is provided a crystalline form exhibiting at least one of the following main RAMAN bands: 3076; 1756; 1632; 151 ; 1495; 1380; 1347; 1310; 1249; 1222; 660; 643; 255cm'1.
Amorphous
The melting onset temperature of amorphous form is comprised between about 100 and about 1100C1.
Amorphous form of 3-(l/-/.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quina2olin-4-yl]-pyrrole- 2,5-dione acetate is orange.
Form C
X-ray diffraction pattern:
Caption Legend Angle d value Intensity Intensity %
2-Theta° Angstrom Count : % d=11.12392 7.941 11.12392 18.5 25.2 d=7.30123 12.1127.30123 55.9 76.0 d=6.72964 13.1456.72964 72.4 98.4 d=5.56453 15.9145.56453 73.5 100.0 d=4.50771 19.6784.50771 27.9 38.0 d=3.71260 23 .9493.71260 27.5 37.4 50354A
- 8 -
d=3.36244 26.4863.36244 18.4 25.0 d=3.08551 28.9133.08551 17.8 24.1 d=5.89980 15.0045.89980 14.3 19.4 d=4.33943 20.4494.33943 18.6 25.3
Form D
X-ray diffraction pattern:
Caption Legend Angle d valuelntensity Intensity %
2-Theta ° Angstrom Count % d=12.57863 .022 12.57863 13.3 21.1 d=9.38691 .414 9.38691 7.89 12.5 d=7.56740 1.684 7.56740 38.6 61.0 d=7.00101 2.633 7.00101 38.3 60.6 d=6.52871 3.551 6.52871 41.7 66.1 d=6.19280 4.290 6.19280 15.9 25.2 d=5.65533 5.657 5.65533 15.7 24.8 d=5 43397 6.299 5.43397 16.5 26.1 d=4.90500 8.070 4.90500 36.9 58.3 d=4.82526 8.371 4.82526 37.4 59.1 d=4.61467 9.218 4.61467 46.7 73.8 d=4.38054 0.255 4.38054 15.6 24.7 d=4.19701 1.151 4.19701 35.0 55.4 d=4.08436 1.741 4.08436 63.2 100.0 d=3.92054 2.662 3.92054 27.1 42.9 d=3 84973 3.084 3.84973 18.6 29.4 d=3.78031 3.514 3.78031 18.2 28.8 d=3.57714 4.870 3 57714 20.4 32.3 d=3.36272 6.484 3.36272 21.3 33.7 d=3.23975 7.509 3.23975 24.2 38.3 d=3.18739 7.970 3.18739 17.1 27.1 d=3.14160 8.386 3.14160 19.9 31.5 d=2.89173 0.897 2.89173 15.6 24.7 50354A
- 9 -
d=2.52207 5.566 ' 2.52207 12.7 20.1 d=2.40324 37.3882.40324 10.5 16.7 d=8.44175 10.471 8.44175 10.7 16.9 d=8.18454 10.801 8.18454 10.0 15.9 d=3.51031 25.3523.51031 24.7 39.1
The invention also includes a process for the preparation of the crystals of the invention which comprises the step of forming a solution of 3-(f.H.-indol-3-yl)-4-[2-(4-methyl-piperazin- 1-yl)-quinazolin-4-yl]-pyrro!e-2,5-dione acetate and crystallizing the acetate from solution by precipitation or recrystallization. In particular, the process for the preparation of the crystals of the invention comprises the step of reacting 3-(7./-/.-indol-3-yl)-4-[2-(4-methyl-piperazin-1- yl)-quinazolin-4-yl]-pyrrole-2,5-dione in free base form with acetic acid and recovering from the reaction mixture the resultant salt, and the step of reacting an appropriate inert solvent such as acetone, acetonitrile, ethanol, ethyl acetate, heptane, t-butyl methyl ether, methylene chloride, 2-propanol, /-propyl acetate, toluene, E95, or a mixture EtAC/ethanol, e.g. 75/25 vol% or 50/50 vol%. Preferred solvent is acetone.
In accordance with the present invention a process for the crystallization of 3-(lH.-indol-3- yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate is provided. The precise conditions under which crystals are formed may now be empirically determined and a number of methods are suitable in practice, including the crystallization conditions as described in Examples 1 to 8.
Crystallization-inducing conditions normally involve the use of an appropriate crystallization- inducing solvent, such as acetone, acetonitrile, ethanol, ethyl acetate, heptane, or t-butyl methyl ether, methylene chloride, 2-propanol, /-propyl acetate, toluene, E95 or a mixture EtAC/ethanol, e.g. 75/25 vol% or 50/50 vol%. Preferred solvants are acetone, ethyl acetate, heptane, t-butyl methyl ether, methylene chloride, 2-propanol, /-propyl acetate, toluene, and mixture EtAC/ethanol, e.g. 75/25 vol% or 50/50 vol% Conveniently, 3-(7./-/.-indol-3-yl)-4-[2- (4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione is dissolved in the solvent at ambient temperature. The solution may be produced by dissolving in a solvent any one or more of amorphous forms of 3-(f .H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]- pyrrole-2,5-dione, and solvates thereof, such as hydrate. Crystals may then be formed by 50354A
- 10 -
conversϊon from free base to the salt, crystallization taking place at a temperature of between about 0° C as above and 400C, preferably at ambient temperature.
The dissolution and crystallization may be carried out in various conventional ways. For instance, free base may be dissolved in a solvent or a mixture of solvents in which it is readily soluble at ambient temperatures but in which it acetate salt is only sparingly soluble at the same temperatures. Dissolution of the free base at elevated temperature followed by cooling after salt formation can also help the acetate salt crystals crystallize out of solution. Mixed solvents comprising a good solvent in which 3-(lH-indol-3-yl)-4-[2-(4-methyl- piperazin-1-yl)-quinazolin~4-yl]-pyrrole-2,5-diαne is readily soluble, preferably, in amounts of at least 10% by weight at 200C, and a poor solvent in which it is more sparingly soluble, preferably in amounts of not more than about 0.1% by weight at 200C, may also be employed provided that crystallization from the mixture at a reduced temperature of normally at least about 0° C, is possible using the selected solvent mixture.
It is preferred to add "seeds" of crystalline material to the solution in order to induce crystallization.
Furthermore, there is provided a process for the conversion of crystal form A to crystal form B , e.g. for preparing the form B from the form A.
In accordance with a preferred embodiment of the present invention, the crystalline forms of 3-(?.H.-indol-3-yl)-4-t2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate, e.g. the anhydrous forms, have a high crystallinity.
A crystal form is defined herein as having a "high crystallinity" or being "crystallographically pure" when it contains at most about 0.5% (w/w), e.g. at most about 0.1% (w/w) of other form. Thus e.g. "crystallographically pure Form A or B" contains about 0.5% (w/w) or less, e.g. about 0.1% (w/w) or less of another crystallographic form and/or amorphous form.
In one aspect the present invention provides pharmaceutical composition comprising an effective amount of the crystal of the invention, e.g. form A, form B or mixture thereof, preferably Form B in substantially pure form.
In a preferred embodiment, such a composition is a high dose formulation of including e.g. at least 50 mg, preferably at least 100 mg, more preferably at least 250 mg 3-(lH.-indof-3-yl)- 50354A
- 11 -
4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate and a suitable pharmaceutical carrier or diluent. In another preferred example, such a composition is an oral formulation, comprising e.g. 0.5 mg to 2000 mg 3-(f.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1- yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate and a suitable pharmaceutical carrier or diluent.
The crystals of the invention are, therefore, useful in the treatment and/or prevention of diseases or disorders mediated by T lymphocytes and/or PKC, e.g. acute or chronic rejection of organ or tissue allo- or xenografts or T-cell mediated inflammatory or autoimmune diseases, e.g. atherosclerosis, vascular occlusion due to vacular injury such as angioplasty, restenosis, hypertension, heart failure, chronic obstructive pulmonary disease, CNS diseases such as Alzheimer disease or amyotrophic lateral sclerosis, cancer, infectious diseases such as AIDS, septic shock or adult respiratory distress syndrome, ischemia/reperfusion injury e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, or traumatic shock. The crystals of the invention are also useful in the treatment and/or prevention of T- cell mediated acute or chronic inflammatory diseases or disorders or autoimmune diseases e.g. rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroidis, multiple sclerosis, myasthenia gravis, diabetes type I or Il and the disorders associated therewith, respiratory diseases such as asthma or inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, cutaneous manifestations of immunologically- mediated disorders or illnesses, inflammatory and hyperproliferative skin diseases (such as psoriasis, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis), inflammatory eye diseases, e.g. Sjoegren's syndrome, keratoconjunctivitis or uveitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis.
In accordance with the foregoing the present invention further provides:
- a pharmaceutical composition comprising the crystal of the invention, e.g. 3-(7./7.-ιndol-3- yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate in amorphous form, crystalline form, e.g. Form A or Form B, or pseudocrystalline form, e.g. Form SA together with at least one pharmaceutically acceptable carrier or diluent;
- the crystals of the invention, e.g. 3-(7.Λ/.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)- quinazolin-4-yl]-pyrrole-2,5-dione acetate in amorphous, crystalline or pseudocrystalline 50354A
- 12 -
form, e.g. Form A , B, C , D or SA, preferably Form A, B or mixture thereof, for use as a pharmaceutical;
- the crystals of the invention, e.g. 3-('/.H.-indol-3-yl)-4-[2-(4-methyl-pipera2in-1-yl)- quinazolin-4-yl]-pyrrole-2,5-dione acetate in amorphous, crystalline or pseudocrystalline form, e.g. Form A , B, C, D or SA , preferably Form A, B or mixture thereof, for use in the preparation of a medicament;
- the crystals of the invention, e.g. 3-(?.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)- quinazolin-4-yl]-pyrrole-2,5-dione acetate in amorphous, crystalline or pseudocrystalline form, e.g. Form A, B, C, D or SA whenever prepared by a process as defined above;
- the use of the crystals of the invention, e.g. 3-(LH.-indol-3-yl)-4-[2-(4-methyl-piperazin-1- yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate in amorphous, crystalline or pseudocrystalline form, e.g. Form A, B, C, D or SA, in the preparation of a medicament for the treatment or prevention of diseases susceptible of therapy, such as diseases or disorders mediated by T lymphocytes and/or PKC, e.g. acute or chronic rejection of organ or tissue allo- or ' xenografts or T-cell mediated inflammatory or autoimmune diseases; and
- a method for the prevention or treatment of diseases or disorders mediated by T lymphocytes and/or PKC such as acute or chronic rejection of organ or tissue allo- or xenografts or T-cell mediated inflammatory or autoimmune diseases, comprising administration of a therapeutically effective amount of the crystals of the invention, e.g. 3- (^./y.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate in amorphous, crystalline or pseudocrystalline form, e.g. Form A, B or SA, to a subject in need of such treatment.
The crystal of the invention, e.g. Form A or B, may be administered as the sole active ingredient or together with other drugs in immunomodulating regimens or other antiinflammatory agents e.g. for the treatment or prevention of allo- or xenograft acute or chronic rejection or inflammatory or autoimmune disorders. For example, they may be used in combination with cyclosporines, or ascomycines or their immunosuppressive analogs or derivatives, e.g. cyclosporin A, cyclosporin G, FK-506, ABT-281, ASM 981; an mTOR inhibitor, e.g. rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; an accelerating lymphocyte homing agent, e.g. FTY 720; leflunomide or analogs thereof; mizoribiπe; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualine or analogs thereof; immunosuppressive monoclonal antibodies, 50354A
- 13 -
e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD 1 1a/CD18, CD7, CD25, CD 27, B7, CD40, CD45, CD58, CD 137, ICOS, CD 150 (SLAM), OX40, 4-1 BB or their ligands, e.g. CD154; or other immunomodulatory compounds, e.g. a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g. an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA4lg (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEΞA29Y, or other adhesion molecule inhibitors, e.g. mAbs or low molecular weight inhibitors including LFA-1 antagonists, Selectin antagonists and VLA-4 antagonists. Crystalline form of the invention, e.g. Form A or B, may also be administered together with an antiproliferative drug, e.g. a chemotherapeutic drug, e.g. in cancer treatment, or with an anti-diabetic drug in diabetes therapy.
In accordance with the foregoing the present invention provides in a yet further aspect:
- A method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of the crystal of the invention, e.g. 3-(1.H.- indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate in amorphous, crystalline or pseudocrystalline form, e.g. Form A1 B, C, D or SA, and a second drug substance, said second drug substance being an immunosuppressant, immunomodulatory, anti-inflammatory, antiproliferative or anti-diabetic drug, e.g. as indicated above.
- A therapeutic combination, e.g. a kit, comprising a) the crystal of the invention, e.g. 3-(1.H.- indol-3-yl)-4-[2-(4-methyl-pipera2in-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate in amorphous, crystalline or pseudocrystalline form, e.g. Form A, B, C, D or SA, and b) at least one second agent selected from an immunosuppressant, immunomodulatory, antiinflammatory, antiproliferative and anti-diabetic drug. Component a) and component b) may be used concomitantly or in sequence. The kit may comprise instructions for its administration.
A preferred crystalline form according to the invention is e.g. the Form B or A, more preferably the Form B.
The amorphous and crystalline forms of the present invention are synthesized in accordance with the following examples which are illustrative without limiting the scope of the present invention. 50354A
- 14 -
EXAMPLE 1:
Preparation of polymorph A
2-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-acetamide (4.7 mg, 16.3 mmol) and 3- indoleglyσxylic acid methyl ester (4.35 mg, 1.3 eq.) are dissolved in THF (55 ml_). To the suspension is added dropwise a 20% solution of t-BuOK in THF (46.5 g, 5.1 eq.) at -5°C. The mixture is stirred at 0-50C for 8h and the conversion is checked by a PSC. After the conversion is complete, the reaction mixture is quenched with a mixture of 10% sodium chloride in water (50 ml) and acetic acid (5g). Subsequent the aqueous layer is extracted with ethyl acetate (50 ml). The organic layer is extracted twice with 5% aqueous sodium bicarbonate (2x50ml), followed by concentration to 40 ml residual volume. To the residue ethyl acetate (50 ml) is added and subsequently is distilled off. This procedure is carried out four times. To the distillation residue (40 ml) ethaπol is added (30 ml). The red solution is heated to 700C over a period of 30 minutes and acetic acid (4g) is added. After seeding the reaction is stirred at 700C for 90 minutes. The mixture is cooled to 300C over a period of 60 minutes and is stirred additionally for 30 minutes before it is cooled to 20°C over a period of 90 minutes. After 14h at 200C the suspension is filtered, washed once with TBME (15ml) and once with a mixture TBME (13.5ml) - ethanol (1.5ml). After drying at 5O°C under reduced pressure for 2h, the product is obtained in 87.7% yield as an orange crystalline solid. 1H NMR (DMSO, 400 MHz) δ 1.92 (s, 3H), 2.13 (s, 3H), 2.17 (m, 4H), 2.51 (m, 1H), 3.69 (m, 4H), 6.35 (d, J = 8.0 Hz, 1H), 6.64 (dd, J = 7.8, 7.4 Hz, 1 H), 7.02 (dd, J = 7.6, 7.4 Hz1 1H)1 7.10 (dd, J = 7.8, 7.2 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H)1 7.63-7.73 (m, 2H), 8.13 (s, 1H), 11.29 (br s, 1H), 12.01 (br s, 1H).
EXAMPLE 2:
Synthesis of acetate salt, polymorph A:
40 mg of solid 3-(f.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quina2olin-4-yl]-pyrrole-2,5- dione are suspended in 0.75ml of 2-propanol and the mixture is heated to 500C affording an almost clear solution. An equimolar amount of acetic acid is dissolved in 0.1 ml of 2-propanol and added drop-wise to the drug substance solution. The mixture is stirred at 500C for 1 to 2 hours and during this time the acetate salt precipitated out as a yellow powder. The 50354A
- 15 -
suspension is cooled to ambient and the solid is recovered by vacuum filtration, followed by washing with small amounts of 2-propanol (2 x 0.25 ml).
EXAMPLE 3:
Synthesis of acetate salt, polymorph B:
220 mg of solid S-Cl/V.-indol-a-yO^-^-C^methyl-piperazin-i-yO-quinazolin^-yll-pyrrole^.δ- dione were suspended in 2.5 ml of ethyl acetate and the suspension is heated to 50°C producing an almost clear solution. An equimolar amount of acetic acid is dissolved in 0.25 ml of ethyl acetate and added drop-wise to the drug substance mixture. The mixture is stirred at 500C for 1 to 2 hours and during this time the acetate salt precipitated out as an orange powder. The suspension is cooled to ambient and the solid is recovered by vacuum filtration, followed by washing with small amounts of ethyl acetate (2 x 0.25 ml).
EXAMPLE 4:
Conversion of Form A to form B
25.0 g of solid -(7.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazoliπ-4-yl]-pyrrole-2,5- dione acetate salt form A are suspended in 200 ml of a 75/25 (vol/vol) ethyl acetate/ethanol mixture and heated up to 65 °C. Addition of 30 ml of de-ionized water allows the dissolution of the solid and 100 ml of ethyl acetate are added at this temperature to yield a clear solution which is subsequently cooled down from 65 0C to 5 "C. On cooling 50 ml of ethyl acetate are first added at 41 0C and further 50 ml of ethyl acetate at 14 0C, the solution is seeded at this temperature with 0.5g of solid -(7.f/.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazoliπ-4-yl]- pyrrole-2,5-dione acetate salt form B. A thick orange suspension is obtained at 5 0C and kept under stirring at this temperature for 10 to 12 hours: The solid is recovered by filtration and the cake washed with 30 ml 75/25 (vol/vol) ethyl acetate/ethanol mixture. The orange powder is dried at 40 °C under vacuum (5 mbar) for 10 to 12 hours to yield 14.4 g of an orange solid exhibiting a XRD pattern which corresponds to that of polymorph B of -(lH.-indol-3-yl)-4-[2- (4-methyl-piperazin-1-yl)-quinazoliπ-4-yl]-pyrrole-2,5-dione acetate salt.
EXAMPLE 5:
Synthesis of acetate salt, polymorph C: 40 mg of solid AEB071 are suspended in 0.75ml of methanol and the mixture is heated to 400C affording an almost clear solution. An equimolar 50354A
- 16 -
amount of acetic acid is dissolved in 0.1 ml of methanol and added drop-wise to the drug substance solution. The reaction mixture is cooled to ambient and stirred overnight affording precipitation of the acetate salt as an orange powder. The suspension is cooled to ambient and the solid is recovered by vacuum filtration, followed by washing with small amounts of methanol (2 x 0.25 ml).
EXAMPLE 6:
Synthesis of acetate salt, polymorph P: 40 mg of solid AEB071 are suspended in 0.75ml of ethyl acetate and the mixture is heated to 400C affording an almost clear solution. An equimolar amount of acetic acid and 20 μLt of methanol (2.2% vv with respect to ethyl acetate) are dissolved in 0.1 ml of ethyl acetate and added drop-wise to the drug substance solution. The reaction mixture is stirred at 400C for 1 to 2 hours affording precipitation of the acetate salt as an orange powder. The suspension is cooled to ambient and the solid is recovered by vacuum filtration, followed by washing with small amounts of ethyl acetate (2 x 0.25 ml).
EXAMPLE 7:
Synthesis of acetate salt acetone solvate, polymorph S^: 40 mg of solid 3-(f./-/.-indol-3-yl)-4- [2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione are suspended in 0.75ml of acetone affording an almost clear solution at ambient. An equimolar amount of acetic acid is dissolved in 0.1 ml of acetone and added drop-wise to the drug substance solution. The reaction mixture is stirred at ambient for 1 to 2 hours affording precipitation of the acetate salt as an orange powder. The solid is recovered by vacuum filtration, followed by washing with small amounts of acetone (2 x 0.25 ml).
EXAMPLE 8:
Synthesis of amorphous form: 4 g of solid 3-(7.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)- quinazolin-4-yl]-pyrrole-2,5-dione acetate in Form B are dissolved in 400ml of acetone and spray-dried.

Claims

50354A- 17 -Claims:
1. Crystalline form of 3-(?.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1 -yl)-quinazolin-4-yl]- pyrrole-2,5-dione acetate.
2. A crystalline form according to claim 1 which is anhydrate.
3. A crystalline form according to claim 1 or 2 which is Form A , Form B, Form SA or mixture thereof.
4. A crystalline form according to claim 1 or 2 exhibiting a strong diffraction peak at an angle of about 9.7° 2theta.
5. A crystalline form according to claim 1 or 2 exhibiting a strong diffraction peak at an angle of about 21.5° 2Theta.
6. A crystalline form according to claim 1 which is a solvate or hydrate.
7. A crystalline form according to any preceding claim having a high crystallinity.
8. A crystalline form according to any preceding claim in essentially pure form.
9. Use of a crystalline form according to any one of the claims 1 to 8, or a mixture thereof, for the preparation of a pharmacological agent for the prevention or treatment of diseases or disorders mediated by T lymphocytes and/or PKC, such as acute or chronic rejection of organ or tissue allo- or xenografts or T-cell mediated inflammatory or autoimmune diseases.
10. Processes for the preparation of the crystal form according to any one of the claims 1 to 8 comprising forming a solution of 3-(7.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)- quinazolin-4-yl]-pyrrole-2,5-dione acetate and crystallizing the acetate from solution by precipitation or recrystallization.
PCT/US2007/022241 2006-10-20 2007-10-18 Crystal modifications -3- (1h-ind0l-3-yl) -4- [2- (4-methyl-piperazin-1-yl) -quinazolin-4-yl] -pyrrole-2, 5-d ione WO2008051440A1 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
EP07839661A EP2102195A1 (en) 2006-10-20 2007-10-18 Crystal modifications -3- (1h-ind0l-3-yl) -4- [2- (4-methyl-piperazin-1-yl) -quinazolin-4-yl]-pyrrole-2, 5-d ione
MX2009004048A MX2009004048A (en) 2006-10-20 2007-10-18 Crystal modifications -3- (1h-ind0l-3-yl) -4- [2- (4-methyl-piperazin-1-yl) -quinazolin-4-yl] -pyrrole-2, 5-d ione.
NZ576241A NZ576241A (en) 2006-10-20 2007-10-18 Crystalline forms of -3-(1H-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate
RU2009118816/04A RU2481341C2 (en) 2006-10-20 2007-10-18 Crystalline modifications of 3-(1h-indol-3-yl)-4-(4-methylpiperazin-1-yl)quinazolin-4-yl)pyrrol-2,5-dione
BRPI0717461-6A2A BRPI0717461A2 (en) 2006-10-20 2007-10-18 -3- (1H-INDOL-3-IL) -4- [2- (4-METHYL-PIPERAZIN-1-IL) -QUINAZOLIN-4-IL] -PIRROL-2,5-DIONA CRYSTAL MODIFICATIONS
US12/445,371 US8865897B2 (en) 2006-10-20 2007-10-18 Crystal modifications-3-(1H-indol-3-yl)-4- [4-methyl-piperazin-1-yl)-quinazolin-4-yl] -pyrrole-2, 5-D ione
JP2009533377A JP5302199B2 (en) 2006-10-20 2007-10-18 Crystalline form of 3- (1H-indol-3-yl) -4- [2- (4-methyl-piperazin-1-yl) -quinazolin-4-yl] -pyrrole-2,5-dione
AU2007309558A AU2007309558B2 (en) 2006-10-20 2007-10-18 Crystal modifications -3- (1H-indol-3-yl) -4- [2- (4-methyl-piperazin-1-yl) -quinazolin-4-yl] -pyrrole-2, 5-dione
CA002666965A CA2666965A1 (en) 2006-10-20 2007-10-18 Crystal modifications of -3-(1h-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione
CN2007800383914A CN101522664B (en) 2006-10-20 2007-10-18 Crystal modifications -3- (1h-ind0l-3-yl) -4- [2- (4-methyl-piperazin-1-yl) -quinazolin-4-yl] -pyrrole-2, 5-d ione
IL197962A IL197962A (en) 2006-10-20 2009-04-05 Crystalline form of -3-(1h-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione acetate, pharmaceutical composition comprising it, process for its preparation and use thereof for the preparation of a pharmacological agent
TNP2009000147A TN2009000147A1 (en) 2006-10-20 2009-04-17 Crystal modifications -3-(1h-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-d ione
NO20091970A NO20091970L (en) 2006-10-20 2009-05-20 Crystal modifications of 3- (1,1H-indol-3-yl) -4- [2- (4-methyl-piperazin-1-yl) -quinazolin-4-yl] -pyrrol-2,5-dione

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US85338406P 2006-10-20 2006-10-20
US60/853,384 2006-10-20

Publications (1)

Publication Number Publication Date
WO2008051440A1 true WO2008051440A1 (en) 2008-05-02

Family

ID=38921707

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2007/022241 WO2008051440A1 (en) 2006-10-20 2007-10-18 Crystal modifications -3- (1h-ind0l-3-yl) -4- [2- (4-methyl-piperazin-1-yl) -quinazolin-4-yl] -pyrrole-2, 5-d ione

Country Status (23)

Country Link
US (1) US8865897B2 (en)
EP (1) EP2102195A1 (en)
JP (1) JP5302199B2 (en)
KR (1) KR20090073231A (en)
CN (2) CN103265533A (en)
AR (1) AR063491A1 (en)
AU (1) AU2007309558B2 (en)
BR (1) BRPI0717461A2 (en)
CA (1) CA2666965A1 (en)
CL (1) CL2007003006A1 (en)
EC (1) ECSP099344A (en)
IL (1) IL197962A (en)
MA (1) MA30886B1 (en)
MX (1) MX2009004048A (en)
MY (1) MY158026A (en)
NO (1) NO20091970L (en)
NZ (1) NZ576241A (en)
PE (1) PE20081133A1 (en)
RU (1) RU2481341C2 (en)
TN (1) TN2009000147A1 (en)
TW (1) TWI399374B (en)
WO (1) WO2008051440A1 (en)
ZA (1) ZA200902048B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008112479A1 (en) * 2007-03-09 2008-09-18 Novartis Ag Salts of 3- (1h-ind0l-3-yl) -4- [2- (4-methyl-piperazin-i-yl) -quinazolin-4-yl] -pyrrole-2, 5-di one

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9005409B2 (en) 2011-04-14 2015-04-14 Tel Nexx, Inc. Electro chemical deposition and replenishment apparatus
US9017528B2 (en) 2011-04-14 2015-04-28 Tel Nexx, Inc. Electro chemical deposition and replenishment apparatus
US9303329B2 (en) 2013-11-11 2016-04-05 Tel Nexx, Inc. Electrochemical deposition apparatus with remote catholyte fluid management

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002038561A1 (en) * 2000-11-07 2002-05-16 Novartis Ag Indolylmaleimide derivatives as protein kinase c inhibitors

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0504203D0 (en) * 2005-03-01 2005-04-06 Novartis Ag Organic compounds
MY148901A (en) 2007-06-18 2013-06-14 Sanofi Aventis Pyrrole derivatives as p2y12 antagonists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002038561A1 (en) * 2000-11-07 2002-05-16 Novartis Ag Indolylmaleimide derivatives as protein kinase c inhibitors

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008112479A1 (en) * 2007-03-09 2008-09-18 Novartis Ag Salts of 3- (1h-ind0l-3-yl) -4- [2- (4-methyl-piperazin-i-yl) -quinazolin-4-yl] -pyrrole-2, 5-di one
RU2487128C2 (en) * 2007-03-09 2013-07-10 Новартис Аг 3-(1h-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione salts

Also Published As

Publication number Publication date
IL197962A (en) 2013-08-29
PE20081133A1 (en) 2008-09-16
AR063491A1 (en) 2009-01-28
KR20090073231A (en) 2009-07-02
NZ576241A (en) 2012-05-25
CN101522664B (en) 2013-06-12
CN103265533A (en) 2013-08-28
AU2007309558B2 (en) 2012-05-24
MX2009004048A (en) 2009-04-27
US20100041884A1 (en) 2010-02-18
JP2010506927A (en) 2010-03-04
ZA200902048B (en) 2010-01-27
CN101522664A (en) 2009-09-02
JP5302199B2 (en) 2013-10-02
EP2102195A1 (en) 2009-09-23
RU2481341C2 (en) 2013-05-10
MA30886B1 (en) 2009-11-02
US8865897B2 (en) 2014-10-21
RU2009118816A (en) 2010-11-27
BRPI0717461A2 (en) 2013-10-08
NO20091970L (en) 2009-05-20
TN2009000147A1 (en) 2010-10-18
ECSP099344A (en) 2009-06-30
TW200829572A (en) 2008-07-16
MY158026A (en) 2016-08-30
TWI399374B (en) 2013-06-21
CL2007003006A1 (en) 2008-05-23
AU2007309558A1 (en) 2008-05-02
CA2666965A1 (en) 2008-05-02
IL197962A0 (en) 2009-12-24

Similar Documents

Publication Publication Date Title
US20210292276A1 (en) Polymorphic forms of belinostat and processes for preparation thereof
US20210387952A1 (en) Solid state forms of daprodustat and process for preparation thereof
JP2011508767A (en) Process for the synthesis of bosentan, its polymorphic forms and its salts
US20210292479A1 (en) Solid state forms of sugammadex sodium
US20230028566A1 (en) Crystalline Form of a 7H-Benzo[7]Annulene-2-Carboxylic Acid Derivative
US10144708B2 (en) Crystalline arylalkylamine compound and process for producing the same
US8865897B2 (en) Crystal modifications-3-(1H-indol-3-yl)-4- [4-methyl-piperazin-1-yl)-quinazolin-4-yl] -pyrrole-2, 5-D ione
US20210163498A1 (en) Solid state forms of lorlatinib and their preparation
CN112759545B (en) 3- (dimethylamino methyl) piperidine-4-alcohol derivative and preparation method and pharmaceutical application thereof
WO2020168144A1 (en) Solid state forms of n-[2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-2(lh)- isoquinolinyl)ethyl] phenyl }-2h-tetrazol-5-yl)-4,5-dimethoxyphenyl] -4- oxo-4h-chromene-2-carboxamide and of its mesylate salt
WO2020053795A2 (en) Process for the preparation of acalabrutinib and its intermediates
WO2022040111A2 (en) Solid state forms of erdafitinib salts and processes for preparation of erdafitinib
EP3947386A1 (en) Solid state forms of acalabrutinib
WO2019099761A1 (en) Solid state forms of elafibranor
RU2487128C2 (en) 3-(1h-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione salts
JPH0967347A (en) Cyclic amine derivative and medicinal composition containing the same
US20090030207A1 (en) Polymorphs of Dolasetron base and process for preparation thereof

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200780038391.4

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07839661

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2007309558

Country of ref document: AU

Ref document number: 2007839661

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2090/DELNP/2009

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 12009500642

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: 197962

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 12445371

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 2009040516

Country of ref document: EG

Ref document number: 576241

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: MX/A/2009/004048

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2666965

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2009533377

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2007309558

Country of ref document: AU

Date of ref document: 20071018

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: DZP2009000288

Country of ref document: DZ

WWE Wipo information: entry into national phase

Ref document number: 09050686

Country of ref document: CO

WWE Wipo information: entry into national phase

Ref document number: 1020097010201

Country of ref document: KR

ENP Entry into the national phase

Ref document number: 2009118816

Country of ref document: RU

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: PI0717461

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20090420