DE102007020689A1 - Novel polymorphic form of 2- (4-fluorophenyl) -4-3-hydroxy-3-methyl-1-butoxy-5- [4-methylsulfonyl) phenyl] 3 / 2H) -pyridazinone (FHMP) - Google Patents

Abstract

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.

Description

The present invention relates to a novel polymorphic form of FHMP, Process for their preparation, medicines containing them and their use in the control of diseases.

FHMP will be in WO 99/10331 and also in WO 00/24719 and corresponds to the compound of the formula (I):

According to WO 99/10331 and WO 00/24/719 If the compound is a COX-2 inhibitor, which is particularly suitable for the treatment of inflammatory diseases (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 the formula (I) can be applied to the in WO 99/10331 and WO 00/24/719 be prepared manner described. In this case, the compound of the formula (I) is obtained in a crystal modification, which is referred to below as modification II. Modification II has a melting point of 136 ° C., determined by differential scanning calorimetry (Example 451 in WO 99/10331 respectively. WO 00/24719 : 133-134 ° C) and a characteristic X-ray diffractogram, IR spectrum, Raman spectrum, FIR spectrum and NIR spectrum (Tab. 1-6, 1 - 6 ). It has now been found that modification II has a low water solubility and therefore not suitable for use in pharmaceutical formulations, such. As solid and semi-solid preparations, where it depends on a high water solubility and crystallinity.

Further Crystal modifications or forms of the compound of the formula (I) are also the subject of pending patent applications.

Surprisingly another modification was found at 123 ° C melts and is referred to below as modification III.

object of the present invention is the compound of formula (I) in of modification III.

The Modification III is crystalline and has opposite known modification II a higher water solubility on. It is therefore particularly suitable for use in pharmaceutical formulations where there is good solubility and high bioavailability is the subject of the present invention Invention are also pharmaceutical formulations, the FHMP of the formula (I) in the modification III as the active substance. The formulation may be one or more pharmaceutically acceptable Auxiliaries, such. As binders, solvents, fillers etc. included.

Modification III of the compound of the formula (I) has a clearly distinguishable X-ray diffractogram, IR spectrum, NIR spectrum, FIR spectrum and Raman spectrum ( 2 - 6 ). The compound of formula (I) in the modification III melts at 123 ° C and is thus clearly distinguishable from modification II (melting point 136 ° C).

The Compound of the formula (I) according to the invention in of modification III is used in pharmaceutical formulations in high purity used. For stability reasons contains a pharmaceutical formulation mainly the compound of formula (I) in the modification III and none larger proportions of another form such as another modification of the compound of formula (I). Prefers if the product contains more than 90% by weight, more preferably more than 95% by weight of the compound of the Formula (I) in the modification III based on the total amount of contained compound of formula (I).

Another The present invention is the use of the compound of the formula (I) in the modification III for the treatment of diseases. Preferred is a use for the treatment and prophylaxis of inflammatory diseases, pain or pain, fever, inflammatory joint disease, Rheumatoid arthritis, osteoarthritis, Bekhterev's disease, osteoporosis, Dysmenorrhea, asthma, preterm labor, adhesions (especially of the pelvis) and cancers (eg colon cancer). Especially the treatment of pain or pain is preferred as well as inflammatory diseases.

Another The present invention is the use of the compound of the formula (I) in the modification III for the manufacture of a medicament for the treatment of diseases, in particular of the abovementioned diseases, particularly preferred pain or pain as well as inflammatory diseases.

Another The subject of the present invention is a method of treatment of diseases, in particular the aforementioned diseases, using an effective amount of the compound of the formula (I) in the modification II.

The Compound of formula (I) in the modification III can be converted to suitable Be applied manner; There are basically all sorts of things Application types in question, such. Oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic or as an implant or stent. Especially preferred is the oral application.

For These routes of administration can be the inventive Compounds are administered in suitable administration forms.

For The oral administration are functioning according to the prior art rapidly and / or modifies the compound of formula (I) in the Modification III donating application forms such. B. tablets (uncoated or coated tablets, for example with enteric or delayed dissolving or insoluble coatings that release control the compound of the invention), rapidly disintegrating tablets or films / wafers in the oral cavity, Films / lyophilisates, capsules (for example hard or soft gelatin capsules), Dragees, granules, pellets, powders, suspensions or aerosols.

The Parenteral administration can bypass a resorption step happen (eg intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with involvement of absorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Suitable for parenteral administration themselves as application forms u. a. Injection and infusion preparations in the form of suspensions, lyophilisates or sterile powders.

For the other routes of administration are suitable for. B. Inhalation medicines (including powder inhalers, nebulizers), lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, Ear or eye preparations, vaginal capsules, aqueous Suspensions (lotions, shake mixtures), lipophilic suspensions, Ointments, creams, trandermal therapeutic systems (such as Patches), pastes, scattering powders, implants or stents.

The Compounds according to the invention can converted into the mentioned application forms become. This can be done in a conventional manner by mixing with inert, Non-toxic, pharmaceutically suitable excipients happen. These adjuvants include u. a. Carriers, Solvents, emulsifiers and dispersing or wetting agents, Binders, stabilizers (eg antioxidants), preservatives, Dyes, flavors, flavors and / or perfumes. Another The present invention relates to medicaments which are at least the compound of the formula (I) in the modification III, usually together with one or more inert, non-toxic, pharmaceutical suitable excipients such as binders, fillers, etc., as well as their use for the purposes mentioned above.

Next In humans, the compound of formula (I) can also be used in humans used in animals. Called utility, breeding, zoo, Laboratory, experimental and hobby animals.

For the breeding and breeding animals include mammals such. B. cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, fur animals such. As mink, chinchilla, raccoon, birds such. As chickens, geese, turkeys, ducks, pigeons, bird species for home and zookeeping. Furthermore belong plus farmed and ornamental fish.

To Laboratory and experimental animals belong z. Mice, Rats, guinea pigs, golden hamsters, dogs and cats.

To the hobby animals belong z. Dogs and cats.

Especially preferred is the application in pets, especially the dog.

in the Generally, it has proven to be beneficial per day amounts from about 0.1 to 100 mg / kg, preferably from about 0.2 to 50 mg / kg, particularly preferably 1 to 40 mg / kg of body weight to achieve to deliver effective results.

Nevertheless it may be necessary, if necessary, of the quantities mentioned to deviate, depending on body weight, Application route, individual behavior towards the Active substance, method of preparation and time or interval, too which the application takes place. So it can in some cases be sufficient, with less than the aforementioned minimum quantity while in other cases the said upper limit must be exceeded. In case of application larger quantities may be recommended, this one in several single doses to distribute over the day.

in principle the new modification III of the FBMP can be used in the same way and used, as already known in the art FHMP is described.

Also The invention relates to a process for the preparation of the compound of the formula (I) in the modification III, in which the compound of the formula (I) in the modification I in an inert solvent dissolves and by evaporation of the solvent as Modified III. This gives the connection of the formula (I) in the modification III. The drying usually takes place to the mass constancy.

Suitable inert solvents are 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-C ₁ -C ₄ -alkyl ketones, such as acetone; straight-chain, branched or cyclic alkanes, preferably having 1 to 8 carbon atoms, such as n-pentane, n-hexane, cyclopentane, cyclohexane, cyclic five- or six-membered ethers, such as tetrahydrofuran or 1,4-dioxane, aromatic solvents, such as toluene; Ethyl acetate. or acetonitrile, or mixtures of said solvents, wherein the solvents or solvent mixtures may additionally contain water.

From these solvents are preferably ethyl acetate, tetrahydrofuran, Ethanol or mixtures thereof. Very particular preference is tetrahydrofuran.

Prefers the compound of formula (I) is prepared in the modification III, in that the compound of the formula (I) in the modification I in a dissolved inert solvent and at temperatures below room temperature at normal pressure until complete Evaporation of the solvent is dried. You get so the compound of formula (I) in the modification III. Prefers if the drying is carried out at a temperature of 0 ° C to -30 ° C, especially preferred at -10 ° C to -20 ° C carried out.

Modification I of the compound of formula (I) and its preparation is the subject of our co-pending German patent application with the file number 10 2007 008 840.1 , Modification I is characterized among others by a melting point of 141 ° C (DSC); a reflex in the X-ray diffraction pattern at a 2-theta angle of 19.8 and a band at 7037 cm ^-1 in the NIR spectrum. The modification I of the compound of the formula (I) can be prepared by suspending the compound of the formula (I) in the modification II in an inert solvent and stirring or shaking it until the desired degree of conversion to the modification I is reached. The resulting crystals are isolated and dried. This gives the compound of formula (I) in the modification I. It is preferably carried out at a temperature of 15 to 35 ° C, particularly preferably at 20 to 30 ° C.

Suitable inert solvents for the preparation of modification I 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; Ketones, in particular di-C ₁ -C ₄ -alkyl ketones such as acetone, straight-chain, branched or cyclic alkanes, preferably having 1 to 8 carbon atoms, such as n-pentane, n-hexane, cyclopentane, cyclohexane, cyclic five- or six-membered ethers, such as Tetrahydrofuran or 1,4-dioxane, aro matic solvents such as toluene, or ethyl acetate, or mixtures of said solvents, wherein the solvent or Lösungsmittelgemsiche may additionally contain water.

From these solvents are preferably ethyl acetate, tetrahydrofuran, Ethanol or mixtures thereof.

The Percentages in the following tests and examples are provided not stated otherwise, weight percentages; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions each refer to the volume.

Examples

The Thermograms were determined using differential scanning Calorimeters DSC 7 resp. Pyris-1 and Thermogravimetric Analyzer TGA 7 of Fa. Perkin Elmer received. The X-ray diffractograms were registered in a Stoe transmission diffractometer. The IR, FIR, NIR and Raman spectra were performed with Fourier IR spectrometers IFS 66v (IR, FIR), IFS 28 / N (NIR) and RFS 100 (Raman) from Bruker added.

The production of Mod II of FHMP is in WO 99/10331 described.

manufacturing of FHMP in modification I of modification II

Comparative Example 1

Approximately 70 mg of FHMP in Mod. II are suspended in 0.5 ml of ethanol and shaken at 25 ° C. After a week, the Suspension filtered and the residue at room temperature dried at ambient humidity. It is examined thermoanalytically and corresponds to the title compound in Mod. I.

Comparative Example 2

Approximately 120 mg of FHMP in Mod II are dissolved in 0.5 ml of tetrahydrofuran and the clear solution shaken at 25 ° C. The precipitated after about 1 day drug is still 5 days at 25 ° C. shaken, then filtered off and at room temperature Ambient humidity dried. He becomes X-ray diffractometric examined and corresponds to the title compound in the Mod I.

Comparative Example 3

Approximately 150 mg of FHMP in Mod. II are dissolved in 5 ml of toluene: n-heptane (1: 4) suspended and stirred at 70 ° C at reflux. After one week, the suspension is filtered and the residue dried at room temperature at ambient humidity. He becomes X-ray diffractometric examined and corresponds to the title compound in the Mod I.

Comparative Example 4

Approximately 150 mg of FHMP in Mod. II are suspended in 5 ml of ethanol: water (1: 4) and stirred at 50 ° C at reflux. To one week, the suspension is filtered and the residue dried at room temperature at ambient humidity. He becomes X-ray diffractometric examined and corresponds to the title compound in the Mod I.

Comparative Example 5

Approximately 0.1 g of FHMP in Mod. II are suspended in 1 ml of ethanol: water (1: 1) and shaken at 25 ° C. The next Day is the suspension with a spatula tip FHMP in the mod. I inoculated and continued to stir. After a week, the Suspension filtered and the residue at room temperature dried at ambient humidity. It is examined thermoanalytically and corresponds to the title compound in Mod. I.

Production of FHMP in the Modification III

example 1

Approximately 100 mg of FHMP in Mod. I are dissolved hot in about 8 ml of tetrahydrofuran. The solution is allowed to stand in the freezer until the Solvent has evaporated. The residue will be X-ray diffractometry and corresponds to the title compound in Mod. III.

FHMP of the modification III was characterized by various methods, the results are given in Tables 1 to 6. Tab. 1: Differential scanning calorimetry and thermogravimetry Modification II Modification III Melting point [° C] 136 123 Mass loss [%] ≤ 0.2 ≤ 1 Tab. 2: X-ray diffractometry Modification II [2 Thea] Modification III [2 theta] 7.8 8.3 13.8 9.0 15.6 12.8 18.1 13.8 18.4 14.2 21.7 16.5 23.4 16.9 23.7 17.4 24.7 17.6 24.9 18.1 25.7 19.9 26.1 20.6 26.8 22.4 26.9 23.8 27.2 24.0 27.8 24.3 28.2 26.5 28.9 29.7 Tab. 3: IR spectroscopy peak maxima Modification II [cm ^-1 ] Modification III [cm ^-1 ] 520 532 538 544 548 652 648 775 687 815 725 834 735 913 776 931 828 959 840 975 908 1003 926 1095 938 1101 964 1141 990 1148 1017 1179 1096 1220 1102 1256 1145 1307 1179 1376 1231 1506 1258 1598 1291 1606 1301 1649 1313 2890 1342 2967 1376 3501 1507 1604 1615 1649 2926 2979 3521 Tab. 4: Raman spectroscopy peak maxima Modification II [cm ^-1 ] Modification III [cm ^-1 ] 85 102 113 122 178 253 213 397 247 422 320 553 394 630 407 685 417 719 627 736 633 761 688 816 726 893 737 1089 771 1140 817 1255 1144 1291 1260 1313 1282 1336 1292 1389 1318 1405 1342 1488 1385 1507 1404 1525 1507 1598 1529 1614 1596 1648 1604 2879 1616 2923 1652 2946 2926 2975 2979 2999 3009 3075 3063 3070 3094 Tab. 5: FIR spectroscopy peak maxima Modification II [cm ^-1 ] Modification III [cm ^-1 ] 114 90 142 124 187 162 216 193 248 225 321 247 362 277 376 305 393 324 417 338 429 364 444 373 474 394 481 401 423 435 447 471 488 493 Tab. 6: NIR spectroscopy peak maxima Modification II [cm ^-1 ] Modification III [cm ^-1 ] 4048 4084 4079 4172 4160 4244 4326 4310 4408 4338 4482 4410 4579 4580 4671 4665 4695 4787 4874 4859 5164 4896 5795 5782 5848 5835 5961 5949 6020 6015 6878 6573 6805 7246 8835

Characters:

1 : DSC and TGA Thermograms of FHMP (Diagrams above: Mod II, Diagrams below: Mod III)

2 : X-ray diffractograms of FHMP (Mod III above, Mod II below)

3 : IR spectra of FHMP (Mod III above, Mod II below)

4 : Raman spectra of FHMP (Mod III above, Mod II below)

5 : FIR spectra of FHMP (Mod III above, Mod II below)

6 : NIR spectra of FHMP (Mod III above, Mod II below)

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• WO 99/10331 [0002, 0003, 0004, 0004, 0037]
• WO 00/24719 [0002, 0004]
• WO 00/24/719 [0003, 0004]
• - DE 102007008840 [0032]

Claims (12)

Compound of the formula (I)

in modification III. Compound of the formula (I) in the modification III, the one determined by differential scanning calorimetry melting point of 123 ° C. Compound of the formula (I) in the modification III, in X-ray diffraction a reflex at a 2-theta angle of 9.0. Compound of formula (I) in the modification III, which has a band at 6805 cm ^-1 in the NIR spectrum. Process for the preparation of the compound of the formula (I) in the modification III, wherein the compound of formula (I) in the modification I in an inert solvent dissolves and by evaporation of the solvent as Modified III. Compound of the formula (I) in the modification II, for the treatment of diseases. Use of the compound of formula (I) in the modification III for the manufacture of a medicament for the treatment of diseases. Use of the compound of formula (I) in the modification III for the preparation of a medicament according to claim 6 for the treatment of inflammatory diseases (inflammatory diseases), pain or pain, fever, inflammatory Joint diseases, rheumatoid arthritis, osteoarthritis, Bechterew's disease, Osteoporosis, dysmenorrhoea, asthma, preterm labor, adhesions (especially the pelvis) and cancers (eg colon cancer). Medicaments containing the compound of the formula (I) in the modification III. Medicament according to claim 8, containing one or more pharmaceutically suitable excipients. Method for the treatment of diseases, in which To give the patient an effective amount of the compound of the formula (I) administered in the modification III. A method according to claim 10 to Treatment of inflammatory diseases (inflammatory diseases), pain or pain, fever, inflammatory Joint diseases, rheumatoid arthritis, osteoarthritis, Bechterew's disease, Osteoporosis, dysmenorrhoea, asthma, preterm labor, adhesions (especially the pelvis) and cancers (eg colon cancer).