Cocrystalline form of niflumic acid with isonicotinamide ot caffeine

FIELD: chemistry.

SUBSTANCE: invention relates to novel cocrystals of niflumic acid with isonicotinamide or caffeine, where molar ratio of niflumic acid with isonicotinamide or caffeine constitutes 1:1, and cocrystal of niflumic acid with isonicotinamide has entothermic peak from 152 to 162°C according to the data of measurement by means of differential scanning calorimetry and peaks at 2θ(°) 6.3, 7.4, 12.5, 14.5, 19.2, 23.2, 25.0 by the data of measurement of X-ray radiation difraction on powder, and cocrystal of niflumic acid with caffeine has endothermic peak from 155 to 165°C by the data of measurements by means of differential scanning calorimetry and peaks at 2θ(°) 9.7, 12.0, 13.26, 14.3, 17.0, 18.1, 22.5, 26.2 and 26.9 by the data of measurement of X-ray radiation diffraction on powder.

EFFECT: increase of solubility in water in comparison with indices of niflumic acid solubility in pure form.

12 dwg, 2 ex

 

Introduction

The invention relates to the pharmaceutical industry, namely to new skristall niflumova acid, suitable for the manufacture of pharmaceutical products.

The level of technology

2-[[3-(Trifluoromethyl)phenyl]amino]-3-piridinkarbonovaya acid, also referred to as niflumova acid,

is known pharmaceutical ingredient (API), which has anti-inflammatory, analgesic, antipyretic action, and reduces platelet aggregation. Niflumova acid can be used in rheumatoid arthritis (infectious-allergic disease from the group of collagenoses, characterized by chronic progressive inflammation of the joints), osteoarthritis (disease of the joints), Ankylosaurus spondylitis (a disease of the spine), acute gouty arthritis (acute inflammation of a joint due to deposits in the tissues of the joint, uric acid salts). Used in the treatment of diseases of the soft tissues of the musculoskeletal system, such as bursitis (inflammation of the joint capsule), tendonitis (malnutrition tissue tendons, accompanied by signs of inflammation), epicondylitis (inflammation of the limited portion of the humerus, which is the site of attachment of muscles and tendons). Relieves pain syndromes of bone fractures, Vivi the Ah joints, sprains of ligaments and muscles, soft tissue lesions, periostitis (inflammation of the periosteum); pain syndromes after surgery: estracce (removal) of the teeth, and other dental procedures. Used in obstetric interventions: the introduction and removal of intrauterine device; gynecological diseases: adnexitis (inflammation of the uterus), parametritis (inflammation oculomotoric spaces). It is also used in diseases of ear, throat, nose; sinusitis (inflammation of the sinuses), pharyngolaryngitis (combined inflammation of the larynx and pharynx), otitis media (inflammation of the middle ear Department); acute superficial thrombophlebitis. Reduces the permeability of capillaries, complementary mechanism stabilizes and prevents the release in the cytoplasm and in the extracellular space of lysosomal enzymes, inhibits the production of high energy phosphates (especially ATP). It inhibits cyclooxygenase and inhibits the synthesis of prostaglandins and inhibits platelet aggregation. Although the most significant feature of medicinal compounds, such as niflumova acid is therapeutic effectiveness, not less important from the point of view of pharmacokinetic metrics are of the form of the proposed drug product. For example, an amorphous form, salt, cocrystal, amorfnye modifications because they have different physical and chemical properties that affect pharmaceutical API parameters such as storage stability, compressibility and others. One of the determining factors of bioavailability are solubility and kinetic indicators of dissolution because of the low solubility of pharmaceutical compounds in biological fluids leads to low efficiency of the drug and increased side effects. So use niflumova acid can cause nausea, vomiting, diarrhea, stomach pain. Other side effects include dyspepsia, anorexia, with long-term use, such as ulcers of the stomach and/or duodenum 12, melena. In some cases, after several years of treatment with high doses bone fluorosis. Local reactions: redness, itching, rash, burning sensation. When the rash at the site of application of the cream or gel is necessary to stop treatment. Therefore, the increase in solubility of the drug is an urgent technical problem.

There are various ways to increase the speed and level of solubility of drug compounds:

- fine grinding to create a greater surface area of the dissolved compounds [Chaumeil, J. C. Micronisation: a method of improving the Bioavailability of poorly soluble drugs // Methods Find. Exp. Clin. Pharmcol. - 1998 - 20(3) - P. 211-215],

- used the e salts studied objects with improved solubility [S. Agharkar, Lindenbaum, S., Higuchi T. Enhancement of solubility of drug salts by hydrophilic counter-ions: properties of organic salts of an anti-malarial drug // J. Pharm. Sci. - 1976 - 65(5) - P. 747-749],

- dissolution in the complex [Amin K., Dannenfelser, R.-M., Zielinski J., Wang B. Lyophilization of polyethylene glycol mixtures // J. Pharm. Sci. - 2004 - 93(9) - P. 2244-2249] and micellar solvents [Torchillin V. R. Micellar nanocarriers: pharmaceutical perspectives // Pharm. Res. - 2007 - 24(1) - p 1-16],

- the formation of supramolecular complexes with cyclodextrins [Rajewski, R. A., Stella V. J. Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery // J. Pharm. Sci. - 1996 - 85(11) - P. 1142-1169],

- the use of phospholipid vesicles filled with a lipophilic compounds [Humberstone A. J., Charman W. N. Lipid-based vehicles for the oral delivery of poorly soluble drugs // Adv. Drug Deliv. Rev. - 1997 - 25(1) - P. 103-128].

However, the known methods have disadvantages that limit their use. So, although the fine grinding increases the dissolution rate of drugs, but it does not increase the equilibrium solubility of the substance. Often for drug compounds increased van der Waals interactions between small particles and the electrostatic attraction lead to the reduction of effective surface area, dissolution and, thus, is limited to the limit of their biological activity.

The increase in solubility of drug compounds by creating its salts is unacceptable, as in the pharmaceutical industry are mainly used clubionidae and neutral the basic molecule, and salt in this class of compounds not included.

The use of complex and micellar solvents suggests acceptable solubility and compatibility of molecules of medicinal compounds with the solvent, which is not always attainable.

The increase in solubility by the formation of complexes with cyclodextrins, as well as the use of phospholipid vesicles applicable for drug compounds prolonged action, however, rarely require medication quick actions, such as non-steroidal anti-inflammatory agents.

It is also known that to increase the solubility can be achieved through education cocrystalline form API component contributing to the increase of dissolution. Societally represent supramolecular systems, where one component is poorly soluble active pharmaceutical ingredient, i.e. the molecule drug compounds, whereas the second component molecule is highly soluble compounds, which are completely absorbed by the body and is involved in enzymatic processes [Lara-Ochoa F. and Espinosa-Pérez G. Cocrystals definitions // Supramolecular Chemistry. - 2007 - 19(8) - P. 553-557].

Societally used in the pharmaceutical industry, are attractive because they give the possibility of new crystal forms of active pharmaceutical ingredi the NTA with special properties, such as improved solubility, thermal stability, improved mechanical properties, etc. While the choice of components cocrystal much easier to say, "fine tuning" of the physical properties of cocrystal.

The literature describes only one cocrystal niflumova acid - PP [L. Fábián, Hamill n, Eccles, K. S., H. A. Moynihan, A. R. Maguire, L. McCausland, Lawrence S. E., Cocrystals of Fenamic acids with Nicotinamide. Crystal Growth &Design 2011, 11, p.3522-3528].

However, in the work of Fabian al. does not mention any increase in the solubility of niflumova acid in the obtained cocrystal, so the use of this cocrystal in the pharmaceutical industry is inappropriate.

As components cocrystalline form niflumova acid were selected isonicotinamide and caffeine. It is known that isonicotinamide increases transcriptionally silent loci regulated by Sir2, which leads to slower aging. Caffeine is a stimulant medicine used in the composition of funds from headaches, migraines, and as a stimulator of respiration and cardiac activity for colds, to improve mental and physical performance, to eliminate sleepiness.

Thus, societally niflumova acid with isonicotinamide or caffeine can be used in a pharmaceutical is X.

The invention

The technical problem of the invention consists in the search cocrystalline form niflumova acid with isonicotinamide or caffeine, allowing to increase its solubility and is suitable for use in the pharmaceutical industry.

The invention consists in the following.

Cocrystalline form niflumova acid with isonicotinamide or caffeine, where the molar ratio of niflumova acid with isonicotinamide or caffeine is 1:1, and cocrystal niflumova acid with isonicotinamide has an endothermic peak from 152 to 162°C as measured using differential scanning calorimetry and peaks at 2θ(°) 6.3, 7.4, 12.5, 14.5, 19.2, 23.2, 25.0 by measuring the diffraction of x-rays on the powder, and cocrystal niflumova acid with caffeine has an endothermic peak of from 155 to 165°C as measured using differential scanning calorimetry and peaks at 2θ(°) 9.7, 12.0, 13.26, 14.3, 17.0, 18.1, 22.5, 26.2 and 26.9 by measuring the diffraction of x-rays on the powder.

The claimed invention allows to obtain the following advantage of increasing the solubility in water of 1.7 with isonicotinamide and 1.4 times with caffeine compared with the figures of the solubility of niflumova acid in pure form. Data on solubility were obtained for aquatic plants is ora at room temperature on the unit for measuring the solubility of solid compounds by the method of isothermal saturation. Samples were taken at points approximately 0.1, 0.15, 0.2, 0.25, 0.33, 0.5, 0.6, 0.75, 1, 1.25, 1.4, 1.75, 2, 2.5, 3, 3.5 hours and analyzed using a spectrophotometer VARIAN CARY 50 UV spectral range, the operating range of wavelengths λ=190÷400 nm.

Declared new cocrystalline form - stable crystalline solid substances do not break, not exposed to moisture and easy to prepare stable pharmaceutical preparations.

The structure of the claimed cocrystal proved in two ways, in the aggregate, sufficient to assert that the formation of new connections:

diffraction of x-rays (XPRD),

differential scanning calorimetry (DSC).

In Fig.1 presents a typical profile XPRD of cocrystal niflumova acid:isonicotinamide (1:1).

In Fig.2 presents a typical profile XPRD of cocrystal niflumova acid:caffeine (1:1).

In Fig.3 shows a typical profile XPRD niflumova acid in pure form.

In Fig.4 shows a typical profile XPRD of isonicotinamide in its purest form.

In Fig.5 presents a typical profile XPRD caffeine in its pure form.

In Fig.6 shows a typical DSC thermogram of cocrystal niflumova acid:isonicotinamide (1:1).

In Fig.7 shows a typical DSC thermogram of cocrystal niflumova acid:caffeine (1:1).

In Fig.8 shows a typical DSC thermogram is flamboy acid in pure form.

In Fig.9 shows a typical DSC thermogram of isonicotinamide in its purest form.

In Fig.10 shows a typical DSC thermogram of caffeine in its pure form.

In Fig.11 presents data on the solubility for cocrystal niflumova acid:isonicotinamide (1:1) and its components in pure form.

In Fig.12 presents data on the solubility for cocrystal niflumova acid:caffeine (1:1) and its components in pure form.

Information verifying the playback inventions

To get the claimed cocrystal used the following substances:

- niflumova acid is a manufacturing company "Sigma-Aldrich", lot N0630, CAS 4394-00-7, ReagentPlus®;

- isonicotinamide is a manufacturing company "Sigma-Aldrich", lot I17451, CAS 1453-82-3, purity 99%;

- caffeine is a manufacturing company "Sigma-Aldrich", lot C0750, CAS 58-08-2, ReagentPlus®;

- Methanol - analytical reagent manufacturer Labscan, Hemmed;

- Acetone (dimethylketone), "analytical grade", GOST 2603-79, "Hemmed".

New Secretary niflumova acid substantially characterized by the results XPRD shown in Fig.1-5, and substantially describes the data of the DSC thermograms shown in Fig.6-10. Get claimed cocrystalline form in the solid phase.

Example 1

The mixture 34.90 mg (0,124 mmol) of niflumova acid and 15.10 mg (0,124 mmol) isonicotinamide put in agate mesh is for grinding in the planetary micromelia, to the mixture was added 0.05 ml of ethanol (according to the ratio of 1 µl of solvent per 1 mg of the mixture). In the cell were placed 10 agate beads with a diameter of 3 mm, the Process by grinding at a speed of 600 rpm was continued twice for half an hour with a break of 5 minutes. After mincing, the cell was left in a fume hood to evaporate the remaining solvent. The remaining powder was cocrystal niflumova acid:isonicotinamide (1:1), which was confirmed by the data XPRD and DSC. The resulting profile XPRD final product substantially corresponds to that shown in Fig.1. Received the DSC thermogram of the final product is substantially equal to that shown in Fig.6.

Example 2

The mixture 29.62 mg (0,105 mmol) of niflumova acid and 20.38 mg (0,105 mmol) of caffeine was placed in agate cell for grinding in the planetary micromelia, to the mixture was added 0.05 ml of ethanol (according to the ratio of 1 µl of solvent per 1 mg of the mixture). In the cell were placed 10 agate beads with a diameter of 3 mm, the Process by grinding at a speed of 600 rpm was continued twice for half an hour with a break of 5 minutes. After mincing, the cell was left in a fume hood to evaporate the remaining solvent. The remaining powder was cocrystal niflumova acid:isonicotinamide (1:1), which was confirmed by the data XPRD and DSC. The obtained XRD profile of the final product substantially corresponds to what is shown in Fig.2. Received the DSC thermogram of the final product is substantially equal to that shown in Fig.7.

Declared Secretary niflumova acid can be used for the production of tools for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gouty arthritis; treatment of diseases of the soft tissues of the musculoskeletal system, such as bursitis, tendonitis, epicondylitis and other

Cocrystalline form niflumova acid with isonicotinamide or caffeine, where the molar ratio of niflumova acid with isonicotinamide or caffeine is 1:1, and cocrystal niflumova acid with isonicotinamide has an endothermic peak from 152 to 162°C as measured using differential scanning calorimetry and peaks at 2θ(°) 6.3, 7.4, 12.5, 14.5, 19.2, 23.2, 25.0 by measuring the diffraction of x-rays on the powder, and cocrystal niflumova acid with caffeine has an endothermic peak of from 155 to 165°C as measured using differential scanning calorimetry and peaks at 2θ(°) 9.7, 12.0, 13.26, 14.3, 17.0, 18.1, 22.5, 26.2 and 26.9 by measuring the diffraction of x-rays on the powder.



 

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15 cl, 72 ex, 9 tbl, 6 dwg

FIELD: chemistry.

SUBSTANCE: in formula (I') , R5 is any group selected from a group comprising C1-C6 alkoxy group, which can be substituted with one group selected from a group of β substitutes, phenyloxy group which can be substituted with one group selected from a group of γ substitutes, C1-C6 halogenalkoxy group and C3-C6 cycloalkyloxy group; R6 is a substitute in a benzene ring which is selected from a group of α substitutes; R7 is a hydrogen atom, C1-C6 halogenalkyl group, C1-C6 hydroxyalkyl group which can be substituted with a hydroxy-protective group, C1-C6 alkyl group which can be substituted with one group selected from a group of β substitutes, or a phenyl group which can be substituted with one hydroxy group; m equals 1; n equals 1 or 2; numbers in each benzene ring denote the number of the position of each substitute; the group of substitutes includes hydroxyl groups, nitro groups, cyano groups, C1-C6 dialkylamino groups, acetamide groups, halogen atoms, C1-C6 alkyl groups, which can be substituted with one group selected from a group of β substitutes, C1-C6 halogen alkyl groups, C3-C10 cycloalkyl groups, 6-member heterocyclic groups with an N atom or O atom as a heteroatom, C3-C6 cycloalkenyl groups, phenyl group which can be substituted with one group selected from a group of γ substitutes, 5-6-member heteroaryl groups with 1-3 N atoms as heteroatoms which can be substituted wit one or more groups selected from a group of γ substitutes, C1-C6 alkoxy groups, C1-C6 halogenalkoxy groups, C3-C10 cycloalkoxy groups, phenyloxy group, C1-C6 alkylthio groups, C1-C6 halogenalkylthio groups, C1-C6 alkylsulphonyl groups and C1-C6 alkylcarbonyl groups; the group of β substitutes includes C1-C6 alkoxycarbonyl groups, C3-C10 cycloalkyl groups which can be substituted with one group selected from a group of γ substitutes, C3-C6 cycloalkenyl groups, C6-C10 aryl groups which can be substituted with one or more groups selected from a group of γ substitutes, 5-6-member heteroaryl groups with one N, O or S heteroatom, 9-member heteroaryl groups with two heteroatoms selected from N and S, C1-C6 alkoxy group and C6-C10 aryloxy group; and the group of γ substitutes include cyano groups, C1-C6 dialkylamino groups, C1-C6 cyclic amino groups, halogen atoms, C1-C6 alkyl groups, C3-C10 cycloalkyl grous, C1-C6 halogenalkyl groups, C1-C6 alkoxy groups and C1-C6 alkylenedioxy groups. The invention also relates to compounds or pharmaceutically acceptable salts thereof, selected from: 4-(2-cyclopropylethoxy)-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide, 4-(2-cyclopropylethoxy)-N-(2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide, 4-(2-cyclopropylethoxy)-N-(2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}-vinyl)-benzamide. Other compounds are given in the formula of invention. The invention also relates to a pharmaceutical composition which can inhibit bone resorption, which contains the disclosed compound, to use of the disclosed compound as a medicinal agent for inhibiting bone resorption, for preparing a medicinal agent for lowering concentration of calcium in the blood, for preparing a medicinal agent for inhibiting reduction of bone mass, to a medicinal agent for inhibiting bone resorption in form of the disclosed compound, to a method of inhibiting bone resorption, a method of lowering concentration of calcium in the blood, a method of inhibiting reduction of bond mass, involving addition of an effective amount of the disclosed compound.

EFFECT: more effective use of the compounds.

22 cl, 6 tbl, 116 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel anthranilic acid derivatives having inhibitory effect on production of matrix metalloprotease 13 of formula 1 , where R1 is a hydrogen atom or carboxy protective group selected from C1-3alkyl; R2 is phenyl, C3-6cycloalkyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-3 heteroatoms selected from N, O, S, which can be condensed with phenyl, which can be optionally substituted with C1-6alkyl, C1-6alkoxy, acetyl, acetoxy, halogen, halogenC1-6alkyl, nitro group, hydroxyl group, CN, amino group, phenyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-4 heteroatoms selected from N, O, S, which can be disubstituted with C1-6alkyl; R3 is phenyl, C3-6cycloalkyl, C5cycloalkenyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-3 heteroatoms selected from N, O, S, which can be condensed with phenyl (except benzoxazole), which can be optionally substituted with C1-6alkyl, C1-6alkoxy, phenyl, acetyl, halogen, halogenC1-6alkyl, halogenC1-6alkoxy, nitro group, hydroxyl group, hydroxyC1-6alkyl, CN, acetylamino, ketone, phenoxy, benzoyl, benzyl, amino group, which can be disubstituted with C1-6alkyl, carboxy group, C1-6alkylsufonyl group or pyrrolyl; X1 is a carbonyl group or sulfonyl group; X2 is a C1-3alkylene, C2-3alkenylene or C2-3alkynylene group which can be optionally substituted with C1-3alkyl, or a bond; provided that when X1 is a sulfonyl group and X4 is a bond, X2 is a C1-3alkylene, C2-3alkenylene or C2-3alkynylene group which can be optionally substituted with C1-3alkyl; X3 is an oxygen atom or a bond; and X4 is a group with general formula -X5-X6- or -X6-X5-, where the bond on the left side of each formula is bonded to R3; and X5 is an oxygen atom, a sulphur atom, an imino group which can be optionally protected or a bond; X6 is a C1-4alkylene, C2-3alkenylene or C2-3alkynylene group or a bond, as well as to their pharmaceutically acceptable salts. The invention also relates to a matrix metalloprotease 13 production inhibitor and a therapeutic agent for making a medicinal agent for treating rheumatoid arthritis.

EFFECT: possibility of making a medicinal agent for treating rheumatoid arthritis.

8 cl, 7 tbl, 633 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I), (values of radicals are described in formula of invention) or its pharmaceutically acceptable salts, to methods of its production, pharmaceutical composition, which contains it. Application of invention is described for manufacturing of medicinal agent intended for provision of inhibiting action in respect to HDAC in warm-blooded animal, in production of agent used for treatment of malignant tumor. Method is also described for provision of inhibiting action in warm-blooded animal.

EFFECT: compounds have inhibiting activity in respect to HDAC.

15 cl, 17 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to sulphonamide compounds of formula or pharmaceutically acceptable salts thereof, wherein A is phenyl, optionally substituted with 1 or 2 halogen atoms, C1-6 alkyl group, trifluoromethyl group, C1-6 alkoxy group or -SCH3 group, thiophenyl, optionally substituted with a C1-C6 alkyl group or a halogen atom, pyridinyl, optionally substituted with a halogen atom, naphthalenyl or dihydroindenyl; R1 denotes the following formulae or [in formulae (R1a) and (R1b) Ar1 denotes the following formulae , or (each R5 and R6 independently denotes a hydrogen atom, a halogen atom, a C1-6 alkyl group optionally substituted with up to three halogen atoms, C1-6 lower alkoxy group optionally substituted with up to three halogen atoms); Ar2 denotes the following formulae , or (each R7 and R8 independently denotes a hydrogen atom, a hydroxyl group, a halogen atom, a C1-6 alkyl group optionally substituted with up to three halogen atoms or a C1-6 lower alkoxy group optionally substituted with up to three halogen atoms, an amine group, a nitro group, a C2-6 acyl group, or R7 and R8 together form -CH2CH2O-; R9 is a hydrogen atom or - J-COOR10; J is a covalent bond, alkylene containing 1 to 5 carbon atoms, alkenylene containing 2 to 5 carbon atoms or alkynylene containing 2 to 5 carbon atoms, where one carbon atom in said alkylene groups can be substituted with an oxygen atom, a sulphur atom, NR11, CONR11 or NR11CO in any chemically acceptable position; R11 is a hydrogen atom; and R10 is a hydrogen atom); and p equals 0 or 1]; R2 is a C1-6 alkyl group; each R3 and R4 is independently a C1-6 alkyl group; * denotes an asymmetric carbon atom; and m equals an integer from 1 to 3. The invention also relates to a medicinal agent for stimulating PTH secretion.

EFFECT: obtaining novel compounds which can be used in medicine to prevent or treat primary or secondary osteoporosis.

29 cl, 15 tbl, 14 ex

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