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US20120035175A1 - Novel salts as Anti-Inflammatory, Immunomodulatory and Anti-Proliferatory Agents - Google Patents

Novel salts as Anti-Inflammatory, Immunomodulatory and Anti-Proliferatory Agents Download PDF

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US20120035175A1
US20120035175A1 US13/174,900 US201113174900A US2012035175A1 US 20120035175 A1 US20120035175 A1 US 20120035175A1 US 201113174900 A US201113174900 A US 201113174900A US 2012035175 A1 US2012035175 A1 US 2012035175A1
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salt
hydrate
char
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acid
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Aldo Ammendola
Julia Diederichs
Johann Leban
Daniel Vitt
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4SC AG
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    • C07C233/59—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
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    • C07C233/60—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated

Definitions

  • the present invention relates to novel salts of compounds that can be used as anti-inflammatory, immunomodulatory and antiproliferatory agents.
  • the invention refers to new salts of compounds which inhibit dihydroorotate dehydrogenase (DHODH), a process for their manufacture, pharmaceutical compositions containing them and to their use for the treatment and prevention of diseases, in particular their use in diseases where there is an advantage in inhibiting dihydroorotate dehydrogenase (DHODH).
  • DHODH dihydroorotate dehydrogenase
  • RA Rheumatoid arthritis
  • WO 2003/006425 describes certain specific compounds which are reported to be useful for treatment and prevention of diseases where there is an advantage in inhibiting dihydroorotate dehydrogenase (DHODH).
  • DHODH dihydroorotate dehydrogenase
  • the specific salts according to the present invention are not disclosed.
  • WO 99/38846 and EP 0 646 578 disclose compounds which are reported to be useful for treatment of RA.
  • Leflunomide has immunomodulatory as well as anti-inflammatory properties [EP 217206, DE 2524929].
  • the mechanism of action is based upon the inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme of the pyrimidine biosynthesis.
  • DHODH dihydroorotate dehydrogenase
  • DHODH catalyzes the synthesis of pyrimidines, which are necessary for cell growth.
  • An inhibition of DHODH inhibits the growth of (pathologically) fast proliferating cells, whereas cells which grow at normal speed may obtain their required pyrimidine bases from the normal metabolic cycle.
  • the most important types of cells for the immuno response, the lymphocytes use exclusively the synthesis of pyrimidines for their growth and react particularly sensitively to DHODH inhibition.
  • Substances that inhibit the growth of lymphocytes are important medicaments for the treatment of autoimmune diseases.
  • the DHODH inhibitor leflunomide is the first medicament of this class of compounds (leflunomides) for the treatment of rheumatoid arthritis.
  • WO 99/45926 is a further reference that discloses compounds which act as inhibitors of DHODH.
  • JP-A-50-121428 discloses N-substituted cyclopentene-1,2-dicarboxylic acid monoamides as herbicides and their syntheses.
  • N-(4-chlorophenyl)-1-cyclopentene-1,2-dicarboxylic acid monoamide is produced by reacting 1-cyclopentene-1,2-dicarboxylic anhydride with 4-chloroaniline.
  • solubility of a compound is an important characteristic in drug discovery, as it serves as a starting point for formulation development. Furthermore, after oral administration, the resorption of a drug from the intestines into the circulation is at least in part dependent on its solubility. Only dissolved substances can be resorbed, so that an increase in solubility can be expected to result in a better uptake of a compound in the gastrointestinal tract, i.e. a better oral bioavailability and hence improved pharmacokinetic properties. It is desirable to provide compounds having enhanced bioavailability in order to improve their use as pharmaceutical compound for oral application.
  • the present invention is therefore directed to a salt selected from the group comprising the N-methyl-D-glucamine salt (NMG), the diethylamine salt (IDEA) salt, the magnesium salt, the tromethamine salt, the choline salt, the L-arginine salt, the zinc salt, and the 4-(2-hydroxyethyl)morpholine (HEM) salt of compounds of the general formula (I)
  • E is preferably an unsubstituted phenylene group or a phenylene group which is substituted with one or more groups independently selected from halogen, nitro or alkoxy; more preferably E is a phenylene group which is substituted with one fluorine or chlorine atom, one methoxy group or with four fluorine atoms. Even more preferably, E is a phenylene group which is substituted with one or four fluorine atoms, yet even more preferably one fluorine atom.
  • Y is preferably an optionally substituted phenyl, pyridine or benzothiophene group. More preferably, Y is an unsubstituted phenyl group or a phenyl group which is substituted with one or more groups independently selected from halogen, alkyl, alkoxy, haloalkoxy, haloalkyl or CN. Even more preferably E is a phenyl group which is substituted with one or more groups independently selected from fluorine, chlorine, CN, methoxy, ethoxy, trifluoromethyl or trifluoromethoxy. Yet even more preferably, E is a phenyl group which is substituted with one or more groups independently selected from methoxy or trifluoromethoxy, yet even more preferably methoxy.
  • the salts according to the present invention are selected from the N-methyl-D-glucamine salt (NMG) or the diethylamine salt (DEA) salt.
  • NMG N-methyl-D-glucamine salt
  • DEA diethylamine salt
  • Said salts in addition to their increased solubility, show favourable characteristics with respect to their hygroscopicity, which is desirable from the viewpoint of formulating the compounds into a medicament.
  • An alkyl group is preferably a saturated linear or branched chain of 1 to 6 carbon atoms, preferably a methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl or hexyl group, a methyl, ethyl, isopropyl or t-butyl group being more preferred, a methyl or ethyl group being even more preferred, a methyl group being yet even more preferred.
  • An alkoxy group denotes an O-alkyl group, the alkyl group being as defined above.
  • a haloalkyl group denotes an alkyl group which is substituted by one or more halogen atoms, the alkyl group being as defined above; a trifluoromethyl being preferred.
  • a haloalkyloxy group denotes an alkoxy group which is substituted by one or halogen atoms, the alkoxy group being as defined above; a OCF 3 being preferred.
  • Halogen is preferably chlorine, bromine, fluorine or iodine, fluorine, chlorine or bromine being preferred, fluorine being more preferred.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the specific salts of the compounds of formula (I) as described above or, together with a pharmaceutically acceptable diluent or carrier therefore.
  • the present invention also provides a method for the treatment or prophylaxis of a condition where there is an advantage in inhibiting dihydroorotate dehydrogenase (DHODH) which comprises the administration of an effective amount of a specific salt of the compounds of formula (I) as described above or a.
  • DHODH dihydroorotate dehydrogenase
  • the invention is also directed to the use of a specific salt of the compounds of formula (I) as described above for the production of a medicament for the prevention and treatment of diseases, where inhibition of the pyrimidine biosynthesis is of benefit.
  • the present invention also encompasses hydrates of the salts according to the present invention, which specifies that crystals obtainable from said salts contain water in specific sthoichiometric or substoichiometric amounts, such as for example 0.5, 1 or 2 water molecules per molecule of the compound of formula (I) or formula (Ia) as described herein,
  • the present invention provides methods for preparing the compounds of the invention such as desired amides of the formula (I), as well as for the specific salts thereof as described above.
  • a first method for synthesis of amides of formula (I) comprises the step of reacting an acid anhydride of formula (II) with an amine of the formula (III).
  • a second method of the invention for preparing the compounds of formula (I) comprises the step of reacting an amine of the formula (IV) with an aryl-boronic acid of the general formula (V) (HO) 2 B-E[D-(CHR 3 ) n ] q —Y [M. P. Winters, Tetrahedron Lett, 39, (1998), 2933-2936].
  • a third method of the invention for preparing the compounds of formula (I) comprises the step of reacting an halogen derivative of the formula (VI) with an arylboronic acid of the general formula (VII) [N. E. Leadbeater, S. M. Resouly, Tetrahedron, 55, 1999, 11889-11894].
  • Q is a halogen group such as chlorine, bromine, fluorine or iodine, bromine being preferred.
  • the salts of the present invention are the abovementioned salts derived from a compound selected from the group comprising the compounds 1 to 76 below:
  • the salts of the present invention are the abovementioned specific salts wherein the compound of formula (I) is selected from the group comprising the compounds shown below in table 1:
  • 35 ⁇ 1.84 (mC, 2H, CH2), 2.71 (mC, 2H, CH2), 2.80 (mC, 2H, CH2), 3.93 (s, 3H, O—CH3), 7.26-7.35 (m, 3H, CHAr), 7.57 (mC, 1H, CHAr), 7.67 (s, 1H, CHAr), 7.74 (mC, 1H, CHAr), 8.23 (mC, 1H, CHAr), 10.33 (s, 1H, NH). 421 422 [M + H]+ A N.D. N.D.
  • N.D. N.D. 46 ⁇ 1.19 (s, 3H, O—CH2—CH3), 1.74 (mC, 2H, CH2), 2.54 (mC, 2H, CH2), 2.65 (mC, 2H, CH2), 3.95 (mC, 2H, O—CH2—CH3), 6.75-6.78 (m, 1H, CHAr), 7.04-7.38 (m, 3H, CHAr), 7.43-7.48 (m, 2H, CHAr), 7.87-7.93 (m, 1H, CHAr), 10.41 (s, 1H, NH), 12.90 (s, 1H, OH).
  • a A 57 ⁇ (CD3OD) 1.97 (mC, 2H, CH2), 2.33 (s, 3H, CH3), 2.84 (mC, 2H, CH2), 2.94 (mC, 2H, CH2), 3.78 (s, 3H, O—CH3), 6.96-7.06 (m, 2H, CHAr), 7.25-7.35 (m, 4H, CHAr), 7.50 (mC, 1H, CHAr).
  • the compounds of formula (I) may be obtained via various methods, including the method described in JP-A-50-121428. In preferred embodiments of the methods of the invention the two following methods of synthesis are used.
  • Method 1 In a first step the cycloalkene-1,2-dicarboxic acids can be obtained from the corresponding ⁇ , ⁇ ′-dibromo alkanedicarboxylic acids as described by R. N. Mc Donald and R. R. Reitz, J. Org. Chem. 37, (1972) 2418-2422, Cyclopentene-1,2-dicarboxylic acid can also be obtained in large amounts from pimelic acid [D. C. Owsley and J. J. Bloomfield, Org. Prep. Proc. Int. 3, (1971) 61-70; R. Willmaschiner, J. Chem. Soc. (1926), 655-663].
  • Dicarboxylic acids substituted in or on the ring system can be synthesized in general via the cyanhydrine synthesis [Shwu-Jiüan Lee et. al., Bull. Inst. Chem. Academia Sinica Number 40, (1993), 1-10 or B. R. Baker et al., J. Org. Chem. 13, 1948, 123-133; and B. R. Baker at al., J. Org. Chem. 12, 1947, 328-332; L. A. Paquette et. al., J. Am. Chem. Soc. 97, (1975), 6124-6134].
  • the dicarboxylic acids can then be converted into the corresponding acid anhydrides by reacting them with acetic acid anhydride [P. Singh and S. M. Weinreb, Tetrahedron 32, (1976), 2379-2380].
  • Biarylaniline can be synthesized in general via the palladium coupling [G. W. Kabalka et al., Chem.Commun., (2001), 775; A. Demeter, Tetrahedron Lett. 38; (1997), 5219-5222; V. Snieckus, Chem.Commun. 22, (1999), 2259-2260].
  • the salts of the present invention can be used for a variety of human and animal diseases, preferably human diseases, where inhibition of the pyrimidine metabolism is beneficial.
  • Such diseases are:
  • the salts according to the invention and medicaments prepared therewith are generally useful for the treatment of cell proliferation disorders, for the treatment or prophylaxis, immunological diseases and conditions (as for instance inflammatory diseases, neuroimmunological diseases, autoimmune diseases or other).
  • the salts of the present invention are also useful for the development of immunomodulatory and anti-inflammatory medicaments or, more generally, for the treatment of diseases where the inhibition of the pyrimidine biosynthesis is beneficial.
  • the salts of the present invention are also useful for the treatment of diseases which are caused by malignant cell proliferation, such as all forms of hematological and solid cancer. Therefore the compounds according to the invention and medicaments prepared therewith are generally useful for regulating cell activation, cell proliferation, cell survival, cell differentiation, cell cycle, cell maturation and cell death or to induce systemic changes in metabolism such as changes in sugar, lipid or protein metabolism.
  • cell generation poiesis including blood cell growth and generation (prohematopoietic effect) after depletion or destruction of cells, as caused by, for example, toxic agents, radiation, immunotherapy, growth defects, malnutrition, malabsorption, immune dysregulation, anemia and the like or to provide a therapeutic control of tissue generation and degradation, and therapeutic modification of cell and tissue maintenance and blood cell homeostasis.
  • diseases and conditions include but are not limited to cancer as hematological (e.g. leukemia, lymphoma, myeloma) or solid tumors (for example breast, prostate, liver, bladder, lung, esophageal, stomach, colorectal, genitourinary, gastrointestinal, skin, pancreatic, brain, uterine, colon, head and neck, and ovarian, melanoma, astrocytoma, small cell lung cancer, glioma, basal and squameous cell carcinoma, sarcomas as Kaposi's sarcoma and osteosarcoma), treatment of disorders involving T-cells such as aplastic anemia and DiGeorge syndrome, Graves' disease.
  • hematological e.g. leukemia, lymphoma, myeloma
  • solid tumors for example breast, prostate, liver, bladder, lung, esophageal, stomach, colorectal, genitourinary, gastrointestinal, skin,
  • Leflunomide was previously found to inhibit HCMV replication in cell culture.
  • Ocular herpes is the most common couse of infectious blindness in the developed world. There are about 50,000 cases per year in the US alone, of which 90% are recurences of initial infections. Recurrences are treated with antivirals and corticosteroids. Cytomegalovirus another herpes virus is a common couse of retinal damage and blindness in patients with aids.
  • the compounds of the present invention can be used alone or in combination with other antiviral compounds such as Ganciclovir and Foscarnet to treat such diseases.
  • the salts of the present invention can further be used for diseases that are caused by protozoal infestations in humans and animals.
  • Such veterinary and human pathogenic protozoas are preferably intracellular active parasites of the phylum Apicomplexa or Sarcomastigophora, especially Trypanosoma, Plasmodia, Leishmania, Babesia and Theileria, Cryptosporidia, Sacrocystida, Amoebia, Coccidia and Trichomonadia.
  • These active substances or corresponding drugs are especially suitable for the treatment of Malaria tropica, caused by Plasmodium falciparum , Malaria tertiana, caused by Plasmodium vivax or Plasmodium ovale and for the treatment of Malaria quartana, caused by Plasmodium malariae .
  • Toxoplasmosis caused by Toxoplasma gondii
  • Coccidiosis caused for instance by Isospora belli
  • intestinal Sarcosporidiosis caused by Sarcocystis suihominis
  • dysentery caused by Entamoeba histolytica
  • Cryptosporidiosis caused by Cryptosporidium parvum
  • Chargas' disease caused by Trypanosoma cruzi
  • sleeping sickness caused by Trypanosoma brucei rhodesiense or gambiense
  • the cutaneous and visceral as well as other forms of Leishmaniosis caused by Toxoplasmosis, caused by Toxoplasma gondii
  • Coccidiosis caused for instance by Isospora belli
  • intestinal Sarcosporidiosis caused by Sarcocystis suihominis
  • dysentery caused by Entamoeba histolytica
  • Cryptosporidiosis caused by Cryptosporidium parvum
  • veterinary pathogenic protozoa like Theileria parva , the pathogen causing bovine East coast fever, Trypanosoma congolense congolense or Trypanosoma vivax vivax, Trypanosoma brucei brucei , pathogens causing Nagana cattle disease in Africa, Trypanosoma brucei evansi causing Surra, Babesia bigemina , the pathogen causing Texas fever in cattle and buffalos, Babesia bovis , the pathogen causing European bovine Babesiosis as well as Babesiosis in dogs, cats and sheep, Sarcocystis ovicanis and ovifelis pathogens causing Sarcocystiosis in sheep, cattle and pigs, Cryptosporidia, pathogens causing Cryptosporidioses in cattle and birds, Eimeria and Isospora species, pathogens causing Coccidios
  • the use of the compounds of the present invention is preferred in particular for the treatment of Coccidiosis or Malaria infections, or for the preparation of a drug or feed stuff for the treatment of these diseases.
  • This treatment can be prophylactic or curative.
  • the compounds of the present invention may be combined with other anti-malaria agents.
  • the salts of the present invention can further be used for viral infections or other infections caused for instance by Pneumocystis carinii.
  • the diseases or medical conditions to be treated or prevented by the calcium salts according to the present invention are selected from the group comprising graft versus host and host versus graft reactions, rheumatoid arthritis, multiple sclerosis, lupus erythematosus, inflammatory bowel disease, and psoriasis.
  • the specific salts of the compounds of the formula (I) according to the present invention can be administered to animals, preferably to mammals, and in particular to humans, dogs and chickens as therapeutics per se, as mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and which as active constituent contain an effective dose of at least one of the aforementioned specific salts of the compound of the formula (I) according to the present invention, in addition to customary pharmaceutically innocuous excipients and additives.
  • the therapeutics can be administered orally, e.g. in the form of pills, tablets, coated tablets, sugar coated tablets, hard and soft gelatin capsules, solutions, syrups, emulsions or suspensions or as aerosol mixtures. Administration, however, can also be carried out rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injections or infusions, or percutaneously, e.g. in the form of ointments, creams or tinctures.
  • the pharmaceutical composition can contain further customary, usually inert carrier materials or excipients.
  • the pharmaceutical preparations can also contain additives, such as, for example, fillers, extenders, disintegrants, binders, glidants, wetting agents, stabilizers, emulsifiers, preservatives, sweetening agents, colorants, flavorings or aromatizers, buffer substances, and furthermore solvents or solubilizers or agents for achieving a depot effect, as well as salts for changing the osmotic pressure, coating agents or antioxidants. They can also contain the aforementioned salts of two or more compounds of the formula (I) and also other therapeutically active substances.
  • the salts of the present invention can be used alone or in combination with other active compounds—for example with medicaments already known for the treatment of the aforementioned diseases, whereby in the latter case a favorable additive, amplifying effect is noticed.
  • Suitable amounts to be administered to humans range from 5 to 500 mg.
  • pharmaceutically inert inorganic or organic excipients can be used.
  • pills tablets, coated tablets and hard gelatin capsules, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc.
  • Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc.
  • Suitable excipients for the production of solutions and syrups are, for example, water, sucrose, invert sugar, glucose, polyols etc.
  • Suitable excipients for the production of injection solutions are, for example, water, alcohols, glycerol, polyols or vegetable oils.
  • the dose can vary within wide limits and is to be suited to the individual conditions in each individual case.
  • the appropriate dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, however, satisfactory results are achieved at dosage rates of about 1 to 100 mg/kg animal body weight preferably 1 to 50 mg/kg.
  • Suitable dosage rates for larger mammals, for example humans are of the order of from about 10 mg to 3 g/day, conveniently administered once, in divided doses 2 to 4 times a day, or in sustained release faun.
  • a daily dose of approximately 10 mg to 5000 mg, preferably 50 to 500 mg, per human individual is appropriate in the case of the oral administration which is the preferred for in of administration according to the invention. In the case of other administration forms too, the daily dose is in similar ranges.
  • FIG. 1 Reduction of human lymphocyte cell proliferation caused by 2-(Biphenyl-4-ylcarbamoyl)-cyclopent-1-enecarboxylic acid used in a concentration of 100 ⁇ M;
  • FIG. 2 Powder Xray diffraction pattern of vidofludimus free acid.
  • FIG. 3 The upper line shows the Raman spectrum of the NMG salt produced as described in example 4, the lower spectrum pertains to vidofludimus free acid. The spectra have been scaled and offset in y-direction for comparison.
  • FIG. 4 Optical microscopy of the NMG salt without crossed and with crossed polarizers. The picture shows that the sample consists of very small crystalline particles.
  • FIG. 5 Powder Xray diffraction pattern of the NMG salt. The sharp peaks demonstrate that crystalline material was obtained.
  • FIG. 6 Raman spectrum of the DEA salt (top trace) and for comparison of the vidofludimus free acid (lower trace). The differences in the spectra support the notion that salt formation led to a new crystal structure.
  • FIG. 7 Optical microscopy image of the DEA salt through crossed polarizers
  • FIG. 8 XRPD of the DEA salt.
  • FIG. 9 Raman spectra of two different Arg salt preparations (top and middle trace). For comparison, the Raman spectrum of vidofludimus acid is shown in the bottom trace; it differs significantly from the salt spectra.
  • FIG. 10 Optical microscopy image through crossed polarizers of the arginine salt, suggesting that the material is crystalline.
  • FIG. 11 PXRD of the arginine salt.
  • FIG. 12 Raman spectrum of the choline salt (top trace) and vidofludimus acid (bottom).
  • FIG. 13 Optical microscopy image through crossed polarizers of the choline salt, suggesting that the material is crystalline.
  • FIG. 14 PXRD of the choline salt.
  • FIG. 15 Raman spectrum of HEM salt (top and middle trace, two different preparations) which differs from vidofludimus acid Raman spectrum (bottom)
  • FIG. 16 Optical microscopy image through crossed polarizers of the HEM salt, suggesting that the material is crystalline.
  • FIG. 17 PXRD spectrum of the HEM salt, confirming its crystalline nature.
  • 1 H-NMR 1 H-NMR spectra were recorded using a Bruker DPX300 spectrometer with a proton frequency of 300.13 MHz, a 30° excitation pulse, and a recycle delay of 1 s. 16 scans were accumulated, D 2 O; MeOD or d6-DMSO was used as the solvent.
  • Solubility was determined by a stepwise addition of 0.05 mL portions of solvent to a suspension of 10 mg of sample in 0.05 mL of solvent. If the substance was not dissolved by addition of a total of 10 mL solvent, the solubility is indicated as less than 1 mg/mL.
  • DSC Differential scanning calorimetry was carried out with a Perkin Elmer DSC-7 instrument (closed gold sample pan under N 2 atmosphere). The sample are heated up to the melting point at a rate of 10K/min), then cooled down (cooling rate 200K/min) and afterwards heated up again at a rate of 10K/min.
  • DVS Surface Measurement Systems Ltd. DVS-1 water vapour sorption analyzer.
  • the sample is placed on a platinum sample pan and allowed to equilibrate at a given relative humidity (r.h.), usually 50% r.h.
  • a pre-defined humidity program was started with a scanning rate of 5% r.h. change per hour.
  • First step from 50% r.h. to 0% r.h. (in case of a possibly hydrate as starting material 50 to 95% r.h.)
  • second step from 0% to 95% r.h. (in case of a possibly hydrate as starting material 95 to 0% r.h.)
  • FT-Raman spectroscopy FT-Raman spectra were recorded on a Bruker RFS 100 FT-Raman system with a near infrared Nd:YAG laser operating at 1064 nm and a liquid nitrogen-cooled germanium detector. For each sample, a minimum of 64 scans with a resolution of 2 cm ⁇ 1 were accumulated. 300 mW nominal laser power was used. The FT-Raman data are shown in the region between 3500 to 100 cm ⁇ 1 . Below 100 cm ⁇ 1 the data are unreliable due to the Rayleigh filter cut-off.
  • Optical Microscopy Leitz Orthoplan 110680 microscope equipped with a Leica DFC280 camera and IM50 v.5 image-capturing software: Images were recorded with or without crossed polarizers and with 4 ⁇ , 10 ⁇ , or 25 ⁇ magnification.
  • Powder X-ray diffraction Bruker D8; Copper K a radiation, 40 kV/40 mA; LynxEye detector, 0.02 °2 ⁇ step size, 37 s step time.
  • Sample preparation The samples were generally measured without any special treatment other than the application of slight pressure to get a flat surface. Silicon single crystal sample holders were used (0.1, 0.5 or 1 mm deep). The samples were rotated during the measurement.
  • Raman microscopy Renishaw in Via Reflex Raman System. Stabilized diode laser with 785 nm excitation and an NIR enhanced Peltier-cooled CCD camera as the detector. Measurements were carried out with a long working distance 20 ⁇ objective. Wavenumber range 2000-100 cm ⁇ 1 , 10 s detection time, three accumulations per spectrum.
  • TG-FTIR Thermogravimetric measurements were carried out with a Netzsch Thermo-Microbalance TG 209 coupled to a Bruker FTIR Spectrometer Vector 22 or IFS 28 (sample pans with a pinhole, N2 atmosphere, heating rate 10° C./min, range 25° C. to 350° C.).
  • HPLC was performed with a Dionex UltiMate® 3000 liquid chromatograph comprising a solvent Rack, a vacuum degasser, a binary pump (mikro), a static mixer (500 ⁇ l), an autosampler, a 25 ⁇ l sample loop, a 100 ⁇ l syringe, a column oven and a DAD detector (semimicro measuring cell), which was set up for UV analysis. Data analysis was done with Chromeleon® 6.80 SP3. Compounds were separated at 30° C. on a Phenomenex OnyxTM Monolithic C18 50 ⁇ 2 mm column. The injection volume was 2 ⁇ l and the detection wavelength was 305 nm.
  • the standard assay mixture contained 50 ⁇ M decyclo ubichinone, 100 ⁇ M dihydroorotate, 60 ⁇ M 2,6-dichloroindophenol, as well as 20 mU DHODH.
  • the volume activity of the recombinant enzyme used was 30 U/ml. Measurements were conducted in 50 mM TrisHCl (150 mM KCl, 0.1% Triton X-100, pH 8.0) at 30° C. in a final volume of 1 ml. The components were mixed, and the reaction was started by adding dihydroorotate. The course of reaction was followed by spectrophotometrically measuring the decrease in absorption at 600 nm for 2 mM.
  • PBMC Human peripheral blood mononuclear cells
  • PBMC Human peripheral blood mononuclear cells
  • PHA phytohemagglutinin
  • Vidofludimus was added in dimethyl sulfoxide (DMSO, final concentration: 0.1 Vol %) to final concentrations ranging from 20 nM to 50 ⁇ M.
  • DMSO dimethyl sulfoxide
  • IC 50 Half maximal inhibition
  • Sample B About 1 ⁇ 5 of the solid produced as Sample A was suspended in 500 ⁇ L of 1,4-dioxane/TBME (tert-butylmethylether) (1:1) and stirred for 3 days at 25° C. Partially crystalline material (Sample B) was obtained.
  • sample A produced above was suspended in 2 mL of 1,4-dioxane/TBME and seeded with Sample B. The suspension was stirred for seven days at 25° C. The solid was recovered by vacuum filtration and washed with 1,4-dioxane/TBME, The sample was dried for 15 min under vacuum. The material was shown to be crystalline using the methods described in the following.
  • the Raman spectrum of the newly formed compound demonstrated differences to that of the free acid (see FIG. 3 for both spectra.).
  • a Raman spectrum that is not simply the superposition of the free acid, the salt former and the solvent spectra e.g., a Raman spectrum where new peaks or shifted peaks are observed, may correspond to a salt.
  • Peak shifts could also be due, in principle, to complexation of the free acid and salt former as an amorphous product, to polymorphs of either the free acid or salt former, to impurities, or to degradation products. Therefore, the integrity of the molecular structure was confirmed by 1 H-NMR (not shown)).
  • the powder X-ray diffraction shown in FIG. 5 show that crystalline material was obtained, however with a pattern different from that of the free acid (see FIG. 2 ), With light microscopy the crystals were visualized ( FIG. 4 ), DSC (differential scanning calorimetry) demonstrated a melting point of about 143° C., TG-FTIR (thermogravimetric analyzer-coupled Fourier-Transform Infrared) indicates that probably a hydrate was formed (0.8% water) and dynamic vapor sorption yielded 0.3% water uptake at about 85% r.h. and 0.5% water uptake at 95% r.h. (reversible).
  • TG-FTIR thermogravimetric analyzer-coupled Fourier-Transform Infrared
  • the elemental composition analysis data is shown in the table below; the data is consistent with a 1:1 salt that contains water.
  • the Raman spectrum of the newly formed compound demonstrated differences to that of the free acid (see FIG. 6 for both spectra).
  • further analysis was performed to confirm the integrity of the molecular structure (1H-NMR).
  • PXRD also confirmed formation of a new crystalline structure (see FIG. 8 ).
  • the salt was further characterized by light microscopy ( FIG. 7 ), DSC (melting point around 161° C.), TG-FTIR (probably nonsolvated form) and dynamic vapor sorption (0.2% water uptake at about 85% r.h., 0.5% water uptake at 95% r.h., reversible).
  • 298.0 mg of vidofludimus free acid was suspended in 34 mL of acetone at 50° C. A small amount of the material was not dissolved. 146.4 mg of L-arginine was dissolved in 1.0 mL of water, and slowly added to the suspension. The vessel containing the salt former solution was rinsed with 100 ⁇ L of water; this solution was also added to the vidofludimus acid suspension. Precipitation was observed. After sonication and stirring for a few minutes at 50° C., an amorphous film at the bottom of the vessel was observed. The sample was treated for 10 min with ultrasound and afterwards stirred at 25° C. After 1 h precipitation alongside the amorphous film was observed. The suspension was stirred overnight at 25° C.
  • the white solid was recovered by filter centrifugation with a 0.2- ⁇ m PTFE centrifuge filter and washed with 500 ⁇ L of acetone. The material was dried for a few minutes under vacuum at 25° C. The crystallinity of the material was determined as described in the following.
  • Elemental composition analysis is summarized in the table below and corresponds to a 1:1 salt.
  • the Raman spectrum of the newly formed arginine salt demonstrated differences to that of the free acid (see FIG. 9 ). As noted already in the previous examples, further analysis was performed to confirm the integrity of the molecular structure (1H-NMR). PXRD also confirmed formation of a new crystalline structure ( FIG. 11 ). The salt was further characterized by light microscopy (see FIG. 10 ), DSC (melting point around 156° C.), TG-FTIR (probably acetone solvate) and dynamic vapor sorption (1.7% water uptake at about 85% r.h., >12% water uptake at 95% r.h., irreversible).
  • vidofludimus acid was dissolved in 18 mL of DCM/MeOH (3:1) (sonication for 3 minutes). 239 ⁇ L of choline solution ( ⁇ 45% in methanol) was slowly added. The color of the solution changed from yellow to light yellow. The solution was stirred overnight at 25° C. The solution was evaporated under nitrogen flow at 25° C. The yellow solid was suspended in 200 ⁇ L of DCM/MeOH (3:1). The suspension was stirred for 2 days at 25° C. The solid was recovered by filtration and washed with DCM/MeOH (3:1). The material was dried for 15 min under vacuum. The crystallinity of the material was determined as described in the following.
  • Elemental composition analysis is summarized in the table below and corresponds to a 1:1 salt that contains water.
  • the Raman spectrum of the newly formed choline salt demonstrated differences to that of the free acid (see FIG. 12 for both spectra). As noted already in the previous examples, further analysis was performed to confirm the integrity of the molecular structure (1H-NMR). PXRD also confirmed formation of a new crystalline structure (see FIG. 14 ).
  • the salt was further characterized by light microscopy (see FIG. 13 ), DSC (melting point around 138° C.), TG-FTIR (probably hemihydrate) and dynamic vapor sorption (ca. 2% water for hemi-hydrate and 0.4% water uptake at about 85% r.h., 1.2% water uptake at 95% r.h., almost reversible).
  • vidofludimus acid was suspended in 35 mL of acetone at 50° C. A small amount of material was not dissolved.
  • 102 ⁇ L of 4-(2-hydroxyethyl)morpholine was mixed with 1.5 mL of acetone and slowly added to the FA suspension. The suspension became a solution and its color changed from yellow to light yellow.
  • the solution was filtered with a 0.2- ⁇ m PTFE filter. The solution was partially evaporated under nitrogen flow at 25° C. and precipitation was observed. The suspension was stirred overnight at 25° C. and afterwards partially evaporated again. The white solid was recovered by filter centrifugation with a 0.2- ⁇ m PTFE centrifuge filter and washed with 500 ⁇ L of acetone.
  • the material was dried for a few minutes under vacuum at 25° C.
  • the crystallinity of the material was determined as described in the following.
  • Elemental composition analysis is summarized in the table below and corresponds to a 1:1 salt that contains water.
  • the Raman spectrum of the newly formed HEM salt demonstrated differences to that of the free acid (see FIG. 15 for both spectra).
  • further analysis was performed to confirm the integrity of the molecular structure (1H-NMR).
  • PXRD also confirmed formation of a new crystalline structure (see FIG. 17 )
  • the salt was further characterized by light microscopy (see FIG. 16 ), DSC (melting point around 152° C.), TG-FTIR (probably nonsolvated form, 0.1% water) and dynamic vapor sorption (ca. 0.7% water uptake at about 85% r.h., 1.5% water uptake at 95% r.h., almost reversible).
  • aqueous solubility of the respective compound was determined by HPLC, and the pH of the resulting saturated solution was measured.
  • a suspension was prepared and equilibrated for 24 hours at 25° C. The suspension was filtered, the filtrate was diluted and analysed by HPLC. The data illustrates that not all salts led to increase in solubility.
  • Oral bioavailabilities of Vidofludimus free acid, the N-methyl-D-glucamine salt and the diethylamine salt were compared in male Wistar rats.
  • the free acid or the aforementntioned salts were filled into gelatine capsules and the animals received a single administration at a dose level of approximately 10 mg free acid equivalents per kilogram body weight.
  • Four male Wistar rats (body weight range: 250-275 g) per group were treated with either Vidofludimus free acid the aforementioned salts.
  • the capsules were administered into the oesophagus of the animals using an application device.
  • Venous blood samples were taken from the animals under isoflurane anaesthesia at the following time points after administration: 30 min; 1 h; 2 h; 4 h; 6 h; 8 h; 24 h; 28 h; 32 h and 48 h. Coagulation was inhibited using Na-heparin and plasma was generated by centrifugation of the blood samples. Plasma samples were analyzed for Vidofludimus by LC-MS/MS and pharmacokinetic parameters calculated according to the mixed log linear trapezoidal method.
  • the compounds were stored for 18 months at ambient conditions (20-25° C., 30-60% relative humidity) and subsequently analysed by HPLC for purity.

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