WO1999018111A1 - Polymorphe antifongique cristallin d'ester de glycine - Google Patents

Polymorphe antifongique cristallin d'ester de glycine Download PDF

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Publication number
WO1999018111A1
WO1999018111A1 PCT/US1998/020475 US9820475W WO9918111A1 WO 1999018111 A1 WO1999018111 A1 WO 1999018111A1 US 9820475 W US9820475 W US 9820475W WO 9918111 A1 WO9918111 A1 WO 9918111A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
triazol
compound
polymorph
crystalline
Prior art date
Application number
PCT/US1998/020475
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English (en)
Inventor
William Leong
Original Assignee
Schering Corporation
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
Application filed by Schering Corporation filed Critical Schering Corporation
Priority to AU95929/98A priority Critical patent/AU9592998A/en
Publication of WO1999018111A1 publication Critical patent/WO1999018111A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms

Definitions

  • This invention relates to a crystalline polymorph of (-)-2S-[4-[4- [4-[4-[[(R-CIS)-5-(2 / 4-difluorophenyl)tetrahydro-5-(lH-l / 2 / 4-triazol-l- ylmethy ⁇ -S-furanylJmethoxylphenylJ-l-piperazinylJpheny /S-dihydro- ⁇ - oxo-lH-l,2,4-triazol-l-yl]-l(S)-methylbutyl aminoacetate represented by the formula I (hereinafter "the compound of formula I”)
  • compositions containing such a polymorph and methods of using such a polymorph to treat fungal infections in mammals.
  • the compound of formula I can exist in the form of a crystalline polymorph, having distinctly different physical properties compared to the amorphous form.
  • this invention provides a crystalline polymorph of (-)-2S-[4-[4-[4-[4-[4-[4-[[[(R-CIS)-5-(2,4-difluorophenyl)tetrahydro-5-(lH-l,2,4- triazol-l-ylmethyl)-3-furanyl]methoxy]phenyl]-l-piperazinyl]phenyl-4,5- dihydro-5-oxo-lH-l,2,4-triazol-l-yl]-l(S)-methylbutyl aminoacetate represented by the formula I
  • This invention further provides pharmaceutical composition containing the crystalline polymorph of the compound of formula I and methods of treating and /or preventing fungal infections using such crystalline polymorph
  • Figure 1 presents a characteristic x-ray powder diffraction pattern of the cyrstalline polymorph of the compound of formula I [Vertical Axis: Intensity(CPS, counts(square root) ) Horizontal Axis: Two Theta(degrees)].
  • Figure 2 presents a characteristic infrared spectrum of the crystalline polymorph of the compound of formula I in a potassium bromide pellet [Vertical Axis; Transmittance(Percent); Horizontal Axis: wavenumber (cm ' ⁇ J"
  • Figure 3 presents a characteristic differential scanning calorimetry therogram of the crystalline polymorph of the compound of formula I [ on a DuPont 2100 :Thermal Analysis under a nitrogen atmosphere; 10° C /min scan rate; single endotherm, onset temperature: 186.33° Vertical Axis;Heat Flow in cal/sec/g; Horizontal Axis:Temperature in degrees centigrade] .
  • Figure 4 presents a characteristic ⁇ H nmr spectrum of the crystalline polymorph of the compound of formula I(Varian XL400)in CDCI3 at 400 MHz with TMS as an internal standard.
  • the crystalline polymorphic form of the compound of formula I may be formed by crystallizing the compound of formula I (as the free base) using a solvent system such as acetonitrile, tetrahydrofuran ("THF"), THF in combination with heptane or isopropyl acetate in a v/v ratio of 1.5:1 to:1.5, preferably about 1:1; and methylene chloride in combination with hexane in a volume/volume (v/v) ratio of 0.2:1 to 0.75:1, preferably about 0.25:1.
  • THF tetrahydrofuran
  • methylene chloride in combination with hexane in a volume/volume (v/v) ratio of 0.2:1 to 0.75:1, preferably about 0.25:1.
  • the solvent or solvent system were typically healed to reflux and slowly cooled to room temperature (20°-25°C) or even 0° (with THF or THF/heptane for 1-3 days.
  • the infrared spectra were obtained on a Mattson Galaxy 6021 FTIR spectrometer.
  • the potassium bromide pellets were prepared in accordance with the USP procedure ⁇ 197K>,U.S. Pharmacopeia, National Formulary, USP XXIII, NF XVIII.
  • the x-ray powder diffraction patterns were measured on a Philips APD3720 automated diffractometer system (model PW 1800).
  • the radiation source was copper (K-alpha) and the long fine focus tube connected to a Philips XRG 3100 x-ray generator operated at 45 KV and 40 mA.
  • the take-off angle was 6 degrees and a graphite monochromator as used.
  • a scintillation detector was employed and data was acquired with a scan rate of 0.025 degrees per second, a step size of 0.010 and a step time of 40 seconds per degree.
  • compositions of this invention may contain in addition to an anti-fungally effective amount of crystalline polymorph of the compound of formula I as the active ingredient, inert pharmaceutically acceptable carriers that may be solids or liquids.
  • Solid form compositions include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances which may also act as diluants, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegration agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from about 5 to about 20 percent of the active ingredient.
  • Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methycelluloseose, sodium carboxymethyl-cellulose, a low melting wax. cocoa butter and the like.
  • compositions is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly, caches are included. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for topical administration. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by adding the active component in water and adding suitable colorants, flavors, stabilizing, sweetening, solubilizing and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can e made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.
  • Topical formulation useful for nasal or ophthalmic administration are also contemplated.
  • Topical formulation suitable for nasal administration may be solutions or suspensions.
  • Ophthalmic formulations may be solutions, suspension or ointments.
  • Ointments usually contain lipophilic carriers such as mineral oil and /or petrolatum.
  • Solution for ophthalmic administration may contain sodium chloride, acid and/or base to adjust the pH as well as purified water and preservatives, which normally contains a non-toxic, pharmaceutically acceptable topical carrier may be applied daily to the affected skin until the condition has improved.
  • the anti-fungally effective amount of the crystalline polymorph of the compound of formula I for topical administration varies from 0.1 to 20% by weight of the total pharmaceutical composition, which normally contains one or more non-toxic, pharmaceutically acceptable topical carriers; the pharmaceutical composition may be applied daily to the affected area of the skin until the fungal infection has been irradiated
  • the preferred amount varies from 0.5 to 10% by weight of the total pharmaceutical composition.
  • the anti-fungally effective amount of the crystalline polymorph of the compound of formula I for oral administration varies from about 1 to 30 mg/day, more preferably about 1 to 20 mg/day and most preferably about 1 to 10 mg/day in single or divided doses.
  • Parenteral forms to be injected intravenously, intramuscularly, or subcutaneously are usually in the form of a sterile soluon, and may contain salts or glucose to make the solution isotonic.
  • parenteral dosage for humans for antifungal use ranges from about 0.25 mg per kilogram of body weight per day to about 20 mg kilogram of body weight per day being preferred.
  • the compounds of this invention are prepared in accordance with the following Examples using commercially available starting materials.
  • the layers were separated and the organic layer was washed sequentially with 0.65 L of IN sulfuric acid, 4 L of 9% aqueous sodium bicarbonate solution and 3.75 L of an 18% aqueous sodium chloride solution.
  • the organic layer was treated with 0.1 kg of darco and 0.1 kg of supercel, filtered, and then diluted into 70 L of warm isopropyl alcohol.
  • the volume of the solution was reduced to 40 L by distillation, diluted with 20 L of isopropyl alcohol, then reduced to 40 L of volume by distillation. While maintaining the temperature at about 60°C, about 11.5 L of acetone was added to the solution and the mixture was cooled slowly to about 0 to 5°C for a period of 6 hours.
  • the crystals were collected by filtration, then slurried into 40 L of isopropyl alcohol, heated to about 80°C, and cooled to about 60°C. About 4 L of acetone was added to the solution and the solution was cooled slowly to about 0 to 5°C for a period of 6 hours. The white crystals were collected by filtration and dried in an oven at 50-55°C for 12 hours to yield 2.1 kg of product, mp 74- 76°C.
  • Example 2 To 0.8 kg of the product of Example 2 was added 32 L of acetonitrile at room temperature. The agitated mixture was refluxed at 80-82°C until a clear solution was obtained. The solution was cooled to 65-70°C, held at that temperature, filtered, and then concentrated to about 8 L of volume, the solution was cooled to 20 to 25°C over a two hour period, held at 20-25°C for about 16 hours, and then filtered to collect the crystalline product. The filtrate was washed with 2.4 L of acetonitrile and then dried in vacuum oven at 55-60°C for 24 hours to yield 0.7 kg of crystalline product, mp 187- 189°C.
  • Example 2 To 12.5 mL of methylene chloride was added 2.5 g of the product of Example 2 at room temperature. The agitated mixture was heated to reflux until a clear solution was obtained. The solution was added to 50 mL of refluxing hexane. The solution was distilled to remove methylene chloride, cooled to room temperature, and then filtered to collect the crystalline product. The filtrate was dried in vacuum oven at 85°C for 24 hours to yield 2.0 g of crystalline product.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention porte sur la forme cristalline polymorphe du (-)-2S-[4-[4- [4-[4-[ [(R-CIS)-5-(2, 4-difluorophényl) tétrahydro-5-(1H-1, 2,4-triazol-1- ylméthyl)-3-furanyl] méthoxy]phényl] -1-pipérazinyl] phényl-4,5-dihydro-5- oxo-1H-1, 2,4-triazol-1-yl] -1(S)-méthylbutyl aminoacétate de formule (I), des préparations pharmaceutiques le contenant, et sur ses procédés d'utilisation pour le traitement de mycoses chez les mammifères.
PCT/US1998/020475 1997-10-07 1998-10-05 Polymorphe antifongique cristallin d'ester de glycine WO1999018111A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU95929/98A AU9592998A (en) 1997-10-07 1998-10-05 Crystalline antifungal glycine ester polymorph

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US94647497A 1997-10-07 1997-10-07
US08/946,474 1997-10-07

Publications (1)

Publication Number Publication Date
WO1999018111A1 true WO1999018111A1 (fr) 1999-04-15

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Application Number Title Priority Date Filing Date
PCT/US1998/020475 WO1999018111A1 (fr) 1997-10-07 1998-10-05 Polymorphe antifongique cristallin d'ester de glycine

Country Status (2)

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AU (1) AU9592998A (fr)
WO (1) WO1999018111A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0228125A1 (fr) * 1985-12-23 1987-07-08 Janssen Pharmaceutica N.V. Dérivés de [[[(phényl-4 pipérazinyl-1)-4 phénoxyméthyl]-4 dioxolanne-1,3yl-2]-4 méthyl]1H-imidazoles et 1H-triazoles-1,2,4
WO1995017407A1 (fr) * 1993-12-21 1995-06-29 Schering Corporation Tetrahydrofuranes antifongiques
WO1996038443A1 (fr) * 1995-06-02 1996-12-05 Schering Corporation Antifongiques au tetrahydrofurane

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0228125A1 (fr) * 1985-12-23 1987-07-08 Janssen Pharmaceutica N.V. Dérivés de [[[(phényl-4 pipérazinyl-1)-4 phénoxyméthyl]-4 dioxolanne-1,3yl-2]-4 méthyl]1H-imidazoles et 1H-triazoles-1,2,4
WO1995017407A1 (fr) * 1993-12-21 1995-06-29 Schering Corporation Tetrahydrofuranes antifongiques
WO1996038443A1 (fr) * 1995-06-02 1996-12-05 Schering Corporation Antifongiques au tetrahydrofurane

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Publication number Publication date
AU9592998A (en) 1999-04-27

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