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WO2008101613A1 - Nouvelle forme polymorphe de 2-(4-fluorophényl) -4-3-hydroxy-3-méthyl-1-butoxy-5-[4-méthylsulfonyl)phényl]-3(2h)-pyridazinone (fhmp) - Google Patents

Nouvelle forme polymorphe de 2-(4-fluorophényl) -4-3-hydroxy-3-méthyl-1-butoxy-5-[4-méthylsulfonyl)phényl]-3(2h)-pyridazinone (fhmp) Download PDF

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Publication number
WO2008101613A1
WO2008101613A1 PCT/EP2008/001040 EP2008001040W WO2008101613A1 WO 2008101613 A1 WO2008101613 A1 WO 2008101613A1 EP 2008001040 W EP2008001040 W EP 2008001040W WO 2008101613 A1 WO2008101613 A1 WO 2008101613A1
Authority
WO
WIPO (PCT)
Prior art keywords
modification
compound
formula
diseases
fhmp
Prior art date
Application number
PCT/EP2008/001040
Other languages
German (de)
English (en)
Inventor
Alfons Grunenberg
Franz-Josef Mais
Hartwig Müller
Birgit Keil
Original Assignee
Bayer Animal Health Gmbh
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 Bayer Animal Health Gmbh filed Critical Bayer Animal Health Gmbh
Publication of WO2008101613A1 publication Critical patent/WO2008101613A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C07D237/16—Two oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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

  • the present invention relates to a novel polymorphic form of FHMP, processes for their preparation, medicaments containing them and their use in the control of diseases.
  • FHMP is described in WO 99/10331 and also in WO 00/24719 and corresponds to the compound of the formula (I):
  • the compound is a COX-2 inhibitor which is particularly suitable for the treatment of inflammatory diseases, pain or pain and fever.
  • Other indications include, for example: inflammatory joint diseases, rheumatoid arthritis, osteoarthritis, Bechterew's disease, osteoporosis, dysmenorrhea, asthma, premature labor, adhesions, especially of the pelvis and cancers (eg colon cancer).
  • the compound of formula (T) can be prepared in the manner described in WO 99/10331 and WO 00/24/719.
  • the compound of the formula (I) is obtained in a crystal modification, which is referred to below as modification II.
  • Modification II has one by means of differential
  • the present invention relates to the compound of the formula (I) in the modification I.
  • the modification I is thermodynamically stable and stable even after processing via suspensions, it is therefore particularly suitable for use in pharmaceutical formulations such. As suspensions or creams, but also in other preparations which are prepared via suspended active ingredient, such as. B. in the aqueous granulation or wet grinding.
  • the present invention furthermore relates to pharmaceutical formulations which contain FHMP of the formula (T) in the modification I as the active substance.
  • the formulation may contain one or more pharmaceutically acceptable excipients, such as. As binders, solvents, fillers, etc. included.
  • Modification I of the compound of the formula (T) has a clearly distinguishable X-ray diffractogram, IR spectrum, NER spectrum, FIR spectrum and Raman spectrum compared to the previously known modification (FIGS. 2-6).
  • the compound of formula (I) in the modification I melts at 141 0 C and is thus clearly distinguishable from modification II (melting point 136 ° C).
  • a pharmaceutical formulation mainly contains the compound of the formula (I) in the modification I and no major proportions of another form such as for example another modification of the compound of the formula (T).
  • the drug contains more than 90% by weight, more preferably more than
  • Another object of the present invention is the use of the compound of formula (I) in the modification I for the treatment of diseases.
  • Preference is given to a use for the treatment and prophylaxis of inflammatory diseases, pain or pain, fever, inflammatory joint diseases, rheumatoid arthritis, osteoarthritis, Bechterew's disease, osteoporosis, dysmenorrhea, asthma, preterm labor, adhesions (especially of the pelvis) and Cancers (eg colon cancer).
  • Particularly preferred is the treatment of pain or pain as well as inflammatory
  • Another object of the present invention is the use of the compound of formula (I) in the modification I for the preparation of a medicament for the treatment of diseases, in particular the above-mentioned diseases, particularly preferably pain or pain as well as inflammatory diseases.
  • Another object of the present invention is a method for the treatment of diseases, in particular the aforementioned diseases, using an effective amount of the compound of formula (I) in the modification I.
  • the compound of the formula (I) in the modification I can be suitably applied; In principle, all possible types of application come into question, such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, cojunctival, otic or as an implant or stent. Particularly preferred is oral administration.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the prior art is capable of rapidly and / or modifying the compound of formula (I) in the modification I-releasing forms of administration, e.g. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules) in the oral cavity , Dragees, granules, pellets, powders, suspensions or aerosols.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
  • capsules for example hard or soft gelatin capsules
  • Parenteral administration can be carried out bypassing a resorption step (eg intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or using absorption (for example intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
  • a resorption step eg intravenously, intraarterially, intracardially, intraspinally or intralumbarly
  • absorption for example intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of suspensions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, nebulizers
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shaking mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (such as patches)
  • pastes scattering powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients include, among others, excipients, solvents, emulsifiers and dispersants or wetting agents, binders, stabilizers (eg antioxidants), preservatives, dyes, flavors, flavorings and / or perfumes.
  • Another object of the present invention sin ⁇ drugs containing at least the compound of formula (I) in the modification I, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients such as binders, fillers, etc., as well as their use in the previously mentioned purposes.
  • the compound of formula (I) can also be used in animals. Called were useful, breeding, zoo, laboratory, experimental and hobby animals.
  • the livestock and breeding animals include mammals such as e.g. Cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, fur animals such as e.g. Mink, chinchilla, raccoon, birds, e.g. Chickens, geese, turkeys, ducks, pigeons, bird species for home and zoo keeping. It also includes farmed and ornamental fish.
  • mice To laboratory and experimental animals belong z. As mice, rats, guinea pigs, golden hamsters, dogs and cats.
  • the hobby animals include z. Dogs and cats.
  • Particularly preferred is the use in pets, especially the dog.
  • Active substance, method of preparation and time or interval to which the application takes place may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.
  • the new modification I of the FHMP can be used and used in the same way as has already been described in the prior art for FHMP.
  • Another object of the present invention is a process for the preparation of the compound of formula (I) in the modification I, by suspending the compound of formula (I) in the modification II in an inert solvent and until the desired degree of conversion is stirred or shaken in the modification I. The resulting crystals are isolated and dried. This gives the compound of formula (T) in the modification I. It is preferably carried out at a temperature of 15 to 35 ° C, particularly preferably at 20 to 30 0 C.
  • Suitable inert solvents for the process described above are, in particular: lower alcohols, in particular C 1 -C 6 -alkanols, such as, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, 1 pentanol;
  • lower alcohols in particular C 1 -C 6 -alkanols, such as, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, 1 pentanol;
  • Ketones in particular di- t QG -Alkylketone such as acetone,
  • cyclic five- or six-membered ethers such as tetrahydrofuran or 1,4-dioxane
  • aromatic solvents such as toluene
  • solvents or solvent mixtures may additionally contain water.
  • Preferred of these solvents are ethyl acetate, tetrahydrofuran, ethanol or mixtures thereof.
  • thermograms were measured using a differential scanning calorimeter DSC 7 or
  • Example 3 Approx. 150 mg of FHMP in Mod. II are suspended in 5 ml of toluene: n-heptane (1: 4) and stirred at 7O 0 C at reflux. After one week, the suspension is filtered and the residue is dried at room temperature at ambient humidity. It is examined by X-ray diffractometry and corresponds to the title compound in Mod. I.
  • Fig. 1 DSC and TGA thermograms of FHMP
  • FIG. 3 IR spectra of FHMP (mod. I above, mod. II below)
  • FIG. 4 Raman spectra of FHMP (mod. I above, mod. II below)
  • FIG. 5 FER spectra of FHMP (mod. I above, mod. II below)
  • FIG. 6 NIR spectra of FHMP (mod. I above, mod. II below)

Landscapes

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

Abstract

L'invention concerne une nouvelle forme polymorphe de FHMP, un procédé pour sa préparation, des médicaments la contenant, et son utilisation pour lutter contre des maladies.
PCT/EP2008/001040 2007-02-23 2008-02-12 Nouvelle forme polymorphe de 2-(4-fluorophényl) -4-3-hydroxy-3-méthyl-1-butoxy-5-[4-méthylsulfonyl)phényl]-3(2h)-pyridazinone (fhmp) WO2008101613A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102007008840.1 2007-02-23
DE102007008840A DE102007008840A1 (de) 2007-02-23 2007-02-23 Neue polymorphe Form von 2-(4-Fluorophenyl)-4-3-hydroxy-3-methyl-1-butoxy)-5-[4-methylsulfonyl)phenyl]-3(2H)-pyridazinon (FHMP)

Publications (1)

Publication Number Publication Date
WO2008101613A1 true WO2008101613A1 (fr) 2008-08-28

Family

ID=39410305

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2008/001040 WO2008101613A1 (fr) 2007-02-23 2008-02-12 Nouvelle forme polymorphe de 2-(4-fluorophényl) -4-3-hydroxy-3-méthyl-1-butoxy-5-[4-méthylsulfonyl)phényl]-3(2h)-pyridazinone (fhmp)

Country Status (2)

Country Link
DE (1) DE102007008840A1 (fr)
WO (1) WO2008101613A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102007020689A1 (de) 2007-05-03 2008-11-06 Bayer Healthcare Ag Neue polymorphe Form von 2-(4-Fluorophenyl)-4-3-hydroxy-3-methyl-1-butoxy-5-[4-methylsulfonyl)phenyl]3/2H)-pyridazinon (FHMP)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999010331A1 (fr) * 1997-08-22 1999-03-04 Abbott Laboratories Arylpyridazinones inhibitrices de la biosynthese de la prostaglandine endoperoxyde h synthase
WO2000024719A1 (fr) * 1998-10-27 2000-05-04 Abbott Laboratories Inhibiteurs de la biosynthese de la prostaglandine endoperoxyde h synthase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999010331A1 (fr) * 1997-08-22 1999-03-04 Abbott Laboratories Arylpyridazinones inhibitrices de la biosynthese de la prostaglandine endoperoxyde h synthase
WO2000024719A1 (fr) * 1998-10-27 2000-05-04 Abbott Laboratories Inhibiteurs de la biosynthese de la prostaglandine endoperoxyde h synthase

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