GB2462893A - Preparation of and compositions comprising N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylaminomethyl]-benzamide (MS-275) polymorph B - Google Patents

Abstract

Preparation of and compositions comprising N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylaminomethyl]-benzamide (MS-275) polymorph B Process for the production of N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylaminomethyl]-benzamide (MS-275) polymorph B of formula (I), wherein the preparation involves dissolving crude 3-pyridylmethyl N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylaminomethyl]-benzamide in water, the temperature of the resulting solution is maintained below 5°C as dilute hydrochloric acid is added. Charcoal is added and the reaction mixture is stirred for 1 to 20 hrs below 5°C. The mixture is filtered and the charcoal is washed with water. The temperature of the reaction mixture is maintained below 5°C as the pH is adjusted to ≥ 8 with dilute sodium hydroxide. The precipitated N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylaminomethyl]-benzamide is washed with water and ethanol and is then dried. The precipitate is suspended in a mixture of ethanol and water and heated to a temperature of 40-90°C for 1 to 10 hrs. The mixture is cooled and the precipitate is washed with water and ethanol and dried at a temperature between 30-60°C to yield pure N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylaminomethyl]-benzamide (MA-275) polymorph B. Compositions comprising and the use of N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylaminomethyl]-benzamide (MS-275) polymorph B as a medicament for the treatment of diseases including malignant tumours, autoimmune diseases, dermatological diseases and parasitism is outlined.

Description

benzamide (MS-275) polymorph B The invention refers to the crystalline Polymorph B of N-(2-aminophenyl)-4-[N- (pyridine-3-yl)methoxycarbonylaminomethyllbeflzamide (MS-275), the process for the production, and the use of said compound as a medicament for the treatment of selected diseases.

In EP 0 847 992 Al benzamide derivatives as medicament for the treatment of malignant tumors, autoimmune diseases, dermatological diseases and io parasitism are described. In particular, these derivatives are highly effective as anticancer drugs, preferred for the haematological malignancy and solid tumors.

Especially N-(2-a m inophenyl)-4-[N-(pyridine-3-yI)methoxycarbonylaminomethyll-benzamide is mentioned in Example 48 on page 57 in said application.

Said compound has a melting point (mp) of 159-160 °C.

The IR spectrum shows the following bands: lR(KBr) cm1: 3295, 1648, 1541, 1508, 1457, 1309, 1183, 742.

In EP 0 974 576 BI a method for the production of monoacylated phenylenediamine derivatives, especially N-(2-aminophenyl)-4-{N-(pyridine-3-yl)methoxycarbonylaminomethyl]benzamide is described, Said compound, (see for example page 13, lines 5 -9) has a melting point (mp) of 159 -160 °C.

In J. Med. Chem. 1999, 42, 3001-3003, the synthesis of new benzamide derivatives and the inhibition of histone deacetylase (HDAC) is decribed.

Especially the compound N-(2-aminophenyl)-4-[N-(pyridine-3-yI) meth-oxycarbonylaminomethyl] benzamide (MS-275) has been described.

In WO 01/121 93 Al a pharmaceutical formulation comprising N-(2-aminophenyl)-4-[N-(pyridine-3-yl) methoxycarbonylamino-methyljbenzamide (MS-275) is described, In WO 01/16106 a MS-275 formulation, having an increased solubility and an improved oral absorptivity for berizamide derivatives, and pharmaceutically acceptable salts thereof are described.

None of the state of the art documents refer to a polymorph B of N-(2 and no physicochemical features of said compound are known.

In the course of process development (scale up and modified purification process, higher purity of the product) it has now surprisingly been found that the io known form of N-(2-aminophenyl)-4[N(pyridine-3-yl)methoxycarbOflylamiflO-methyl] benzamide which is described in the above mentioned state of the art, is not the thermodynamically most stable polymorph of said compound, at least not in the relevant temperature range below 60°C, but is polymorph A of N(2-aminophenyl)-4[N-.(pyridine-3-yl)methoxycarbonylamino-methyl] benzamide.

This generates problems of not using the thermodynamically most stable polymorph of N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamiflO-methyl] benzamide for drug development when using polymorph A. This bears for example the risk that the polymorph A form of N-(2aminophenyt)-4-{N- (pyridine-3-yl)methoxycarbonylaminomethyl]benzamide transforms partly or completely into the polymorph B form of N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamino-methyl} benzamide (e.g. during storage as drug substance as well as drug product).

In addition, it was not possible to establish a reliable manufacturing process for polymorph A as pure polymorphic phase at larger scale.

An additional problem is the reliable manufacture of polymorph A with high chemical purity.

These problems are now solved by the thermodynamically most stable polymorph of N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamino-methyl} -benzamide, the polymorph B. The inventive N-(2-ami nophenyl)-4-[N-(pyridi ne-3-yl)methoxycarbonylamino methyl]benzamide polymorph B of formula I (I), can be obtained via a process, which comprises the following process steps: a) crude 3-pyridylmethyl N-(2-aminophenyl)-4-[N-(pyridine-3-yl) methoxycarbonylaminomethylj-benzamide is dissolved in water and diluted hydrochloric acid is added to the reaction mixture, at a constant internal reaction vessel temperature below 5°C, and b) to said reaction mixture charcoal is added and the reaction mixture is then permanently stirred for I to 20 hours at a constant temperature below 5°C, and c) is filtered to remove the charcoal from the solution and is rinsed with water, and d) while keeping the internal vessel temperature below 5°C the p1-I of the reaction mixture is adjust to �= 8 with a diluted sodium hydroxide solution, and e) the resulting precipitated N-(2-aminophenyi)-4-[N-(pyridine-3-yl) methoxycarbonylaminomethylj-benzamicle is washed with water and ethanol, and is dried, and f) the precipitate is suspended into a mixture of ethanol and water and is heated up to a temperature of 40 -90°C for I to 10 hours, and g) after cooling down the mixture, the resulting precipitate is rinsed with water and ethanol to give the pure N-(2-aminophenyl)-4-[N-(pyridifle-3-yl) methoxycarbonylaminomethyll-beflZamide polymorph B which is subsequently dried at a temperature between 30-60 °C.

The inventive process is also an object of the instant invention The crude N-(2-am inophenyl)-4-[N-(pyrid ine-3-yl)methoxycarbonylaminomethyl]-benzamide polymorph B of step a) can be produced according to the method described in example 6 of EP 0974 576 BI.

The inventive N-(2-aminophenyl)-4-[N-(pyridine-3-yl) methoxycarbOflylamiflo-methylJ-benzamide polymorph B, produced according to the instant process might have a purity of at least 94%, preferred of at least 96%, more preferred of is at least 98%, much more preferred of at least 99%, most preferred of at least 99.5%.

For example, a higher purity can be achieved by repeating step b) and step c) of the above mentioned process if after passing step c), an insufficient purity of the N-(2-aminophenyl)-4-[N-(pyridine-3-yI) methoxycarbo-nylamino-methyfl-benzamide is determined.

The polymorph B of N-(2-aminophenyl)-4-(N-(pyridine-3.yl)methoxycarbonyl-aminomethyl] benzamide is an anhydrous form and has a melting point (mp) of 156-158°C.

In addition, a third anhydrous form, the polymorph C of N-(2-aminophenyl)-4-[N- (pyridine-3-yl)methoxycarbo-nylamino-methyl]-benzamide was found, which is characterized by its melting point of 152 -155 °C.

The polymorph C of N-(2-aminophenyl)-4-[N-(pyridine-3-yl) methoxycarbo-nylamino-methylj-benzamide is thus also an object of the invention.

Beside the melting points, polymorph A, polymorph B und poiymorph C are also be distinguishable by the positions of the reflections in the X-ray powder diffraction (XRPD) pattern (see Example 2).

The three different polymorphs can further be distinguished by their characteristic bands in the FT-Reman spectra (see Example 3).

A differentiation between the present state of the art, polymorph A, and the new polymorph B of N-(2-am I nophenyl)-4-[N-(pyridine-3-yl)methoXycarbOflYlaminO-methyl]-benzamide is also possible by IR spectroscopy (see Example 4).

The polymorph B is the thermodynamically most stable polymorph of N-(2-at least in the relevant temperature range below 600, which is therefore the preferred form for the use as medicament.

Thus, the crystalline N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxyCarbOnYl-amino-methyl] -benzamide polymorph B is characterized in that its X-ray diffractogram has a reflection at 2Theta = 21.1°.

Further, the crystalline N-(2-aminophenyt)-4-[N-(pyridine-3-yl)methoxycarbonYl-amino-methyl] -benzamide polymorph B is characterized in that its X-ray diffractogram has reflections at 2Theta = 21.1°, 20.4° and 27.4°.

Additional characterization is given by the Reman spectrum, wherein the crystalline N-(2-ami nopheny! )-4-[N-(pyridi ne-3-yI)methoxycarbonylami no-methyl]-benzamide polymorph B has its a bands at 902 cm1, 3036 cm1, 1639 cm1 and 916 cm1.

The I R-spectrum of polymorph B of N-(2-aminophenyl)-4-[N -(pyridi ne-3-yl-methoxycarbonylami no-methylj-benzamide shows the following characteristic bands: IR (KBr) cm1: 3350, 3216, 1527, 1706, 1642, 1263, 752.

Thus, the characteristics of the pure crystalline N-(2-aminophenyl)-4-[N- (pyridine-3yl)methoxycarbonylamino-methyl}-benZamide polymorph B are its X-ray diffractogram which has a reflection at 2Theta = 21.1°, 204° and 27.4°, and its FTRaman spectrum which has bands at 902 cm, 3036 cm1, 1639 cm1 and 916 cm1, and its IR (KBr) spectrum with bands at 1642 cm1, 1527 cm1 and 751 cm1.

Due to the fact that the polymorph B is the thermodynamically most stable polymorph of MS-275, at least in the relevant temperature range below 60°, its io manufacture in highly pure form at larger scale is easier than the manufacture of polymorph A of MS-275.

The N-(2aminopheflyl)-4-[N-(pyridine-3yl)methOXYCarbOnylaminOmethYl]-benzamide polymorph B can be used for the treatment of different diseases, as well as in established test systems.

For example, N-(2-aminophenyl)-4-[N-(pyridine3-yl)methoxycarbonylamino-methyl]benzamide polymorph B can be used as medicament for the treatment of malignant tumors, auto -immune diseases, dermatological diseases and parasitism.

The term "malignant tumors" comprises hematologic malignancy such as acute leukaemia, malignant lymphoma, multiple myeloma and macroglobulinemia as well as solid tumors such as colon cancer, cerebral tumor, head and neck tumor, breast carcinoma, pulmonary cancer, oesophageal cancer, gastric cancer, hepatic cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, nesidioblastoma, renal cell carcinoma, adrenocortical cancer, urinary bladder carcinoma, prostatic cancer, testicular tumor, ovarian carcinoma, uterine cancer, chorionic carcinoma, thyroid cancer, malignant carcinoid tumor, skin cancer, malignant melanoma, osteogenic sarcoma, soft tissue sarcoma, neuroblastoma, Wilms tumor and retinoblastoma.

The term "autoimmune diseases" comprises rheumatism, diabetes, systemic lupus erythematodes, human autoimmune lymphocytic lymphadenopathy, immunoblastic lymphadenopathy, Crohn disease and ulcerative colitis.

The term "dermatologic diseases" comprises psoriasis, acne, eczema and atopic dermatitis.

The term "parasitism" includes diseases such as malaria caused through vermi nation.

The invention thus further comprises the use of N-(2-aminophenyl)-4-[N- (pyridine-3-yl)methoxycarbonylam i no-methyl]-benzam ide polymorph B for the treatment of said diseases, as well as the use of of N-(2-aminophenyl)-4-[N- (pyridine-3-yl)methoxycarbonylamino-methyl}-benzamide polymorph B for the production of a medicament for the treatment of said diseases.

The use of N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamino-methyl] -benzamide polymorph B as medicament for the treatment of malignant tumors is preferred.

The manufacture of the medicaments/formulations may be performed according to methods known in the art. Commonly known and used adjuvants, as well as further suitable carriers or diluents may be used.

Suitable carriers and adjuvants may be such as recommended for pharmacy, cosmetics and related fields in: Ullmann S Encyclopedia of Technical Chemistry, Vol. 4, (1953), pp. 1-39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), p. 918ff; H.v.Czetsch-Lindenwald, "Hilfsstoffe für Pharmazie und angrenzende Gebiete"; Pharm. md. 2, 1961, p.72ff; Dr. H.P. Fiedler, Lexikon der Hllfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, Cantor KG, Aulendorf in Wurttemberg, 1971, which are hereby incorporated by reference.

Said medicaments and formulations are also an object of the instant invention.

For a therapeutical effect the sensible dosis is different and depends on the concentration in the pharmaceutical composition, the host, the form of application and the intensity of the disease which is treated.

The invention also comprises pharmaceutical compositions, which can be prepared by known methods of preparing galenics for oral, enteral, parenteral, e.g. intravenous, intraperitoneal, intramuscular, subcutaneous or percutaneous application. The inventive combination can also be implanted into tissue.

Thus, the invention comprises the use of the N-(2-aminophenyl)-4-[N-(pyridine- 3-yl)methoxycarbonylamino-methyl}-benzamide polymorph B composition for enteral administration, such as nasal, buccal, rectal or, expecially, oral administration, and for parenteral administration, such as intravenous, is intramuscular or subcutaneaous administration, to warm-blooded animals, especially, humans, are especially preferred. The compositions comprise the N- (2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamlno-methyl]-benzamide polymorph B alone or, preferably, together with a pharmaceutically acceptable diluent and! or carrier. The dosage of the active ingredient depends upon the disease to be treated and upon the species, gender, age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration.

Preferred amounts of N-(2-am i nophenyl)-4-[N-(pyridine-3-yl)methoxycarbonyl-aminomethylj-benzamide polymorph B are in the range of 0.0001 to 100 mg/kg per day, preferred 0.001 to 10 mg/kg per day, more preferred 0,01 to 1 mg/kg per day and most preferred 0.05 to 0.5 mg/kg per day.

Depending on the amount, necessary for the treatment of a patient it might be useful to apply a defined amount of active compound on one or on several days in the same or different dose.

N-(2-aminophenyl)-4-[N-(pyridi ne-3-yl)methoxycarbonyl-ami nomethyl]-benzamide polymorph B can also be used prophylactically or especially therapeutically, to a process for the preparation of a composition (especially in the form of compositions for the treatment of tumors) and to a method of treating of a number of diseases, especially tumor diseases, more especially those mentioned hereinabove.

In the preferred embodiment, the N-(2-aminophenyl)-4-[N-(pyridifle-3-yl)methoxycarbonyl-aminomethyl] -beflZamide polymorph B is suitable for administration to a warm-blooded animal, especially humans or commercially useful mammals suffering form a disease especially a neoplastic disease, and comprises an effective quantity of said compound for the treatment of the disease, together with at least one pharmaceutically acceptable carrier.

The N(2aminophenyl)4-[N-(pyridine-3-yI)methOXYCarbOnyl-amiflOmethYl1-benzamide polymorph B can also be administered in the form of tablets, film coated tablets, wafers, suppositories, pills, dragees, gel capsules, granules, suppositories, implants, injectable sterile aqueous or oily solutions, suspensions or emulsions, ointments, creams, gels, patches for transdermal administration, formulations suitable for administration by inhalation, for instance nasal sprays.

As combination with at least one pharmaceutically acceptable carrier, said zo combination comprises the N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonyl-aminomethyl} -benzamide polymorph B from approximately 0.1% to approximately 95%, single-dose administration forms comprising in the preferred embodiment from approximately 1% to approximately 20% active ingredient. Unit dose forms are, for example, coated and uncoated tablets, ampoules, vials, suppositories or capsules. Further dosage forms are, for example, ointments, creams, pastes, foams, tinctures, lip-sticks, drops, sprays, dispersions, etc. Examples are capsules containing from about 0.05 mg to about 1.0 g active ingredients.

For the preparation of the pharmaceutical compositions for oral administration, the active agents suitable for the purposes of the present invention as defined above can be admixed with commonly known and used adjuvants and carriers such as for example, gum arabic, talcum, starch, sugars like e.g. mannitose, methyl cellulose, lactose, gelatin, surface-active agents, magnesium stearate, aqueous or non-aqueous excipients, paraffin derivatives, crosslinking agents, dispersants, emulsifiers, lubricants, conserving agents and flavoring agents (e.g., ethereal oils).

In the pharmaceutical composition, the N-(2-aminophenyl)-4-[N-(pyridifle-3-yl)methoxycarbonyl-aminomethyl} -benZamide polymorph B may be dispersed in a microparticle, e.g. a nanoparticulate, composition. The

benzamide polymorph B can thus be combined with one or more of those physiologically acceptable pharmaceutical adjuvants and carriers to give an acceptable formulation as medicament.

Further pharmacologically effective adjuvants and carriers are, for example, is described in Remington's Pharmaceutical Science, 15th ed. Mack Publishing Company, Easton Pennsylvania (1980), which is hereby incorporated by reference In order to further enhance the bloavailability of the N-(2-aminophenyl)-4-[N- (pyridine-3-yI)methoxycarbonylaminomethyll-beflZamide polymorph B, the compound suitable for the purposes of the present invention as defined above can also be formulated as cyclodextrin clathrates by reacting them with a-, 1-or y-cyclodextrines or derivatives thereof according to the method as disclosed in For parenteral administration the N-(2-aminophenyl)-4-[N-(pyridine-3-yI)methoxycarbonylam ino-methyl-benzamide polymorph B suitable for the purposes of the present invention as defined above can be dissolved or suspended in a physiologically acceptable diluent, such as e.g., oils with or without solubilizers, surface-active agents, dispersants or ernulsifiers. As oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used.

The N-(2-ami nopheny1)4[N(pyridine-3-YmethOXYcarbOflYlami riomethyl] benzamide polymorph B according to the present invention can also be administered via a depot injection or an implant preparation, optionally for sustained delivery of the active agent(s).

Implants can comprise as inert materials e.g. biologically degradable polymers or synthetic silicones such as e.g. silicone rubber.

For percutaneous applications, the N-(2-aminophenyl)-4-[N-(pyridine-3-yl) methoxycarbonylamino-methylj-benZamide polymorph B may also be formulated into adhesives, The preferred mode of administration is oral administration.

Formulations comprising the N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylaminomethyl] -benzamide polymorph B can be prepared in a manner known perse, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.

Preference is given to the use of solutions of the N-(2-aminophenyl)-4-[N- (pyridine-3yl)methoxycarbonyIaminomethYI1-beflZamide polymorph B, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilized compositions comprising the active ingredients alone or together with a carrier, for example mannitol, can be made up before use. The pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per Se, for example by means of conventional dissolving and lyophilizing processes. The said solutions or suspensions may comprise visosityincreasing agents, typically sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatins, or also solubilizers, for example Tween 80 [polyoxyethylene(20)sorbitan mono-oleate; trademark of ICI Americas, Inc. U SAI.

Suspensions in oil comprise as the oil component the vegetable, synthetic, or S semi-synthetic oils customary for injection purposes. ln respect of such, special mention may be made of liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22, expecially from 12 to 22, carbon atoms, for example lauric acid, tripdecylic acid, myristic acid, pentadecylic acid, palrnitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleaic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, if desired with the addition of anti-oxidants, for example vitamine E, R-carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a monovalent or polyvalent, for example a is mono-, di-or trivalent, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or the isomers thereof, but especially glycol and glycerol. As fatty acid esters, therefore, the following are mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, ,,Labrafil M 2375" (polyoxyethylene glycerol trioleate from Gattefossé, Paris), ,,Labrafil M 1944 CS" (unsaturated polyglycolized glycerides prepared by alcoholysis of apricot kernel oil and consisting of glycerides and polyethylene glycol ester; Gattefossé, France), Labrasol" (saturated polyglycolized glycerides prepared by alcoholysis of TCM and consistitn of glycerides and polyethylene glycol ester; Gattefossé, France), and/or,,Miglyol 812" (triglyceride of saturated fatty acids of chain length C8 to 012 from HUls AG, Germany), but especially vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more expecially groundnut oil.

The manufacture of injectable preparations is usually carried out under sterile conditions, as is filling, for example into ampoules or vials, and the sealing of the containers.

Pharmaceutical compositions for oral administration can be obtained, for example, by combining the N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonyl-aminomethyl] -benzamide polymorph B with one or more solid carriers, if desired granulating a resulting mixture, and processing the mixture of granules, if desired or necessary, by the inclusion of additional excipients, to form tablets or tablet cores.

Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl-cellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.

Additional excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.

Tablet cores can be provided with suitable, optionally enteric, coatings through the use of, inter al/a, concentrated sugar solutions, which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethzlene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixture, or for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetly cellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of the N-(2-aminophenyl)-4- [N-(pyridine-3-yl)methoxycarbonylaminomethyl]-benzamide polymorph B. Pharmaceutical compositions for oral administration also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and plasticizer, such as glycerol or sorbitol. The hard capsules may contain the N-(2-aminophenyl)-4-[N-(pyridine-3-yl) methoxycarbonylaminomethylj-benzamide polymorph B in the form of granules, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers, In soft capsules, the N-(2-aminophenyl)-4-[N-(pyridifle- 3-yl)methoxycarbonytam i nomethyl-benzamide polymorph B is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.

io Other oral dosage forms are, for example syrups prepared in customary manner which comprise the active ingredient, for example, in suspended form and in a concentration of about 5% to 20%, preferably about 10%, or in similar concentration that provides a suitable single dose, for example, when administered in measures of 5 or 10 ml. Also suitable are, for example, powdered or liquid concentrates for the preparation of shakes, for example in milk. Such concentrates may also be packaged in single-dose units.

Pharmaceutical compositions suitable for rectal administration are, for example, suppositories that consist of a combination of the N-(2-aminophenyl)-4-[N- (pyridine-3-yl)methoxycarbonylaminomethylj-benzamide polymorph B and a suppository base. Suitable suppository bases are, for example, naturral or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

For parenteral administration, aqueous solutions of the N-(2-aminophenyl)-4-[N- (pyridine-3-yl)methoxycarbonylaminomethylj-benzamide polymorph B in water-soluble form, for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers, are especially suitable, The N(2.aminophenyl)-4-{N(pyridine-3-yl)methoxyCarbOflyl-aminomethyl] -benzamide polymorph B, optionally together with excipients, can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents.

Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.

Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or micro-bicides, such as sorbic acid or benzoic acid.

The present invention relates especially also to the use of the combination, as such or in the form of a pharmaceutical formulation with at least one io pharmaceutically acceptable carrier for the therapeutic and also prophylactic management of one or more of the diseases mentioned hereinabove, especially a neoplastic disease.

Optionally, the N-(2-aminophenyl)-4-[N-(pyridine-3-yl) methoxycarbonylamino-methyl3-benzamide polymorph B can be combined with one or more pharmacologically active agents.

For example, the compounds of this invention can be combined with known anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolernia, anti-dyslipidemia, anti-diabetic or antiviral agents, and the like, as well as with admixtures and combinations thereof.

A combination of the N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonyl-amino-methyl] -benzamide polymorph B together with cytotoxic agents is preferred.

The additional pharmaceutical agent can be aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin (exemestan), 5-azacytidine, azathioprine, BCG or twice BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabne, carboplatin, casodex, cefesone, celmoleukin, cerubidine, chiorambucil, cisplatin, cladribine, 2-cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadron phosphate, delestrogen, denileukin diftitox, depo-medrol, deslorelin, dexrazoxane, diethylstilbestroi, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend, epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, erlotinib (Tarceva), estrace, estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyoL etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim, finasteride, fligrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosteabine, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron HCI, histrelin, hycamtin, hydrocortone, eyrthro-hydroxynonyladeni ne, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferon alfa-2A, interferon alfa-2B, interferon alfa-ni, interferon alfa-n3, interferon beta, interferon gamma-la, interleukin-2, intron A, iressa, irinotecan, kytril, lentinan sulphate, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolinic acid calcium salt, levothroid, Levoxyl, lomustine, lonidamine, marinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, meiphalan, menest, 6-mercaptopurine, Mesna, methotrexate, metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide, nolvadex, NSC-631 570, OCT-43, octreotide, ondansetron HCI, orapred, oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin, picibanhl, pilocarpine HCI, pirarubicin, plicamycin, porfimer sodium, predniniustine, prednisolone, prednisone, premarin, procarbazine, procrit, raltitrexed, rebif, rhenium-i 86 etidronate, rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine, sizofiran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy, streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin, tasonermin, tastolactone, taxotere, teceleukin, temozolomide, teniposide, testosterone propionate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumoma b, trastuzu mab, treosulfan, treti noin, trexall, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinbiastine, vincristine, vindesine, vinorelbine, virulizin, zinecard, zinostatin stimalamer, zofran, ABI-007, acolbifene, actimmune, affinitak, aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, BAY 43-9006 (sorafenib), avastiri, CCL-779, CDC-501, celebrex, cetuximab, crisnatol, cyproterone acetate, decitabine, DN-I 01, doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochioride, histrelin hydrogel Implant, holmium-I 66 DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyhole io limpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafarnib, miproxifene, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem, pactitaxel polyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1549, raloxifene, ranpirnase, 13-cis -retinoic acid, satraplatin, seocalcitol, T-138067, is tarceva, taxoprexin, thymosin alpha I, tiazofurine, tipifarnib, tirapazamine, TLK- 286, toremifene, TransMlD-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-I 00, zoledronic acid or combinations thereof.

The additional pharmaceutical agent can also be gemcitabine, paclitaxel, cisplatin, carboplatin, sodium butyrate, 5-FU, doxirubicin, tamoxifen, etoposide, trastumazab, gefitinib, intron A, rapamycin, 17-AAG, U0126, insulin, an insulin derivative, a PPAR ligand, a sulfonylurea drug, an u-glucosidase inhibitor, a biguanide, a FTP-lB inhibitor, a DPP-IV inhibitor, a II-beta-HSD inhibitor, GLP- 1, a GLP-I derivative, GIP, a GIP derivative, PACAP, a PACAP derivative, secretin or a secretin derivative.

Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 1h Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucii, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilmans The Pharmacological Basis of Therapeutics (Ninth Edition), editor MoUnoff et al. publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylsilibestrol, 2',2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine, ethinyl estradiol, 5-fl uorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, is flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphala n, mitotane, pachtaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine, Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan.

Generally, the use of cytotoxic and/or cytostatic agents in combination with the N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonyl-amino-methyl] -benzamide polymorph B of the present invention will serve to: i) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone, ii) provide for the administration of lesser amounts of the administered chemo-therapeutic agents, iii) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, iv) provide for treating a broader spectrum of different cancer types in mammals, especially humans, v) provide for a higher response rate among treated patients, vi) provide for a longer survival time among treated patients compared to standard chemotherapy treatments, vii) provide a longer time for tumor progression, and/or yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.

The instant invention further comprises the combination of the N-(2-amino-phenyl)-4-[N-(pyridine-3-yl) methoxycarbonylamino-methylj-benzamide polymorph B together wit one ore more regiments of cytotoxic agents, for example, Folfox4 (fluorouracil/ leucovorin/ oxaliplatin); Folfiri (leukovorin, 5-fluorouracil, irinotecan); DHAP (cisplatin! cytarabine/ dexamethasone), CEOP (cyclophosphamide! eprirubicin! vincristine! prednisone), CHOP (cyclophosphamid, doxorubicin, vincristine and prednisone), FLAG (fludarabine! cytarabine/ filgrastim), M & P (mitoxantrone + prednisone; or melhalan + prednisone), ABMC (doxorubicin/ carmustine! melphalan/ cyclophosphamide), ICE (ifosfamide, carboplatin and etoposide), DVP (daunorubicin, vincristine and prednisone), ATRA (all-trans retinoic acid), ABVD (bleomycin, dacarbazin, doxorubicin and vincristine), COP (cydophosphamide, vincristine and prednisone), VAD (vincristine, adriamycin and dexametasone) and MOPP (mechlorethamine, prednisone, procebazine and vincristine).

The cytotoxic agents itself or from the regimens are either commercially available or can be prepared by standard literature procedures.

The N-(2-ami nophenyl)-4-{N(pyridine-3.yl)methOXYCarbOnYlami nomethyl)-benzamide polymorph B can be applied in an pharmaceutically effective amount together with one or more of these cytotoxic agents simultaneously, separately io or sequentially.

The amounts (a pharmaceutically effective amount") of the combined active agents to be administered vary within a broad range and depend on the condition to be treated and the mode of administration. They can cover any is amount efficient for the intended treatment. Determining a "pharmaceutically effective amount" of the combined active agent is within the purview of a person skilled in the art.

Those combinations which comprise the N-(2-aminophenyl)-44N-(pyridifle-3-yl)methoxy-carbonylaminomethyl] -benZamide polymorph B together with cytotoxic and! or cytostatic agents are also matter of the instant invention.

Examples

Example I

Process for the production of N 42-ami nophenyl)-4-IN-(pvridi ne-32yjE methoxycarbonVlaminomethVl1beflZamlde, polymorph B form.

kg of crude 3-pyridylmethyl N-(2aminophenyl)-4-[N-(PY1idine-3-yl) methoxycarbonylaminOmethyll-beflZamide (MS-275, crude) was transferred into a reaction vessel and approximately 300 kg of water have been added. To that reaction mixture approximately 18 kg of hydrochloric acid, 36% (wlw), diluted in approximately 66 kg of water have been added, while keeping the internal temperature constantly below 5°C. Under permanent control of the internal temperature, 15 kg charcoal was added and the reaction mixture was stirred for approximately 10 hours.

After that reaction time the reaction solution was filtered to remove the charcoal from the solution and was accordingly rinsed with approximately 90 kg of water.

The purity of N-(2-aminophenyl)-4-IN-(PYridi ne-3-yl)methoxycarbonylami no-methyl]-benzamide was determined. If the purity was insufficient again 15kg charcoal was added to the filtrate and stirred for further 10 hours, and again the reaction solution was filtered to remove the charcoal from the solution and was accordingly rinsed with approximate'y 90 kg of water.

While keeping the internal temperature below 5°C the pH of the reaction mixture was adjust to �= 8 by using a diluted sodium hydroxide solution. After said treatment the N-(2-am inophenyl)-4-[N-(pyrid i ne-3-yl)methoxycarbonylaminomethYl]-benZamide product, which has been precipitated was washed with approximately 120 kg water and with approximately 68 kg ethanol.

The precipitate was then dried at a temperature between 30-60 °C. After the precipitate was dried, it was suspend in a mixture of 5-fold (e.g. approximately 63 kg) ethanol and of 7-fold (e.g. approximately 111 kg) water, and was heated up to 40-90CC for 5 hours. After that reaction time the reaction mixture was cooled down. The precipitate was rinse with approximately 120 kg of water and with approximately 52 kg of ethanol.

The N-(2aminophenyl)-4-[N-(pyridine-3-Yl)methoxycarbonylam inomethyl)-benzamide product was dried at a temperature between 30-60 C. Yield: 9 kg -24 kg (30 % -80% of theory) Melting Point:: 156 -158 °C

Example 2

Analysis of the N(2aminophenyI)-4-1N-(PVridifle-3-VRmethOXVCarb0nYl aminomethyl1.benzamide polymorphs by X-ray powder diffracti The X-ray powder diffraction data were recorded at room temperature using germanium-monochromatized CuKal-radiation (2. = 1.5406 A). The 2Theta scans were performed using the small linear position sensitive detector with an angular resolution of 0.08° between 3°�= 2Thet �= 35° (stepwidth 0.5°), at room temperature.

The 2 Theta values of the strongest reflections of the three polymorphs in the X-ray powder pattern are given in the following Table 1.

Table I

I°'°i lymphBPrC 18.8 -18.1 18A 19.1 19.4 18.8 20.9 20,0 19.2 22.6 20.4 20.0 26.4 21.1 22.0 26.7 22.1 22.3 27,2 25.8 23.2 27.4 23.4 One of ordinary skill in the art will appreciate that an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions. In particular, it is generally known that intensities in an X-ray diffraction pattern may fluctuate depending upon crystal habitus of the material and measurement conditions employed. Additionally, a measurement error of diffraction angle Theta for a conventional X-ray diffraction pattern at a given temperature is typically about � 0.1, and such degree of measurement error should be taken into account as pertaining to the diffraction angles.

Consequently, any crystal form that provides X-ray diffraction patterns that is substantially identical as to those disclosed in the accompanying Figures falls within the scope of the present invention.

Example 3

Analysis ami nomethyll-benZamide polymorphs by FT-Raman spectroscopy The FT-Raman spectra were recorded using a resolution of 2 and 64 sans at a laser power of 250 mW.

The results of the Reman analysis are shown in Table 2. The data show the wave numbers (cm1) of characteristic bands in the FT-Raman spectra of Polymorph A, Polymorph B and Polymorph C.

Table 2

rphAPOIVmOrPhBP01Vm0rP 3061 3075 3076 3048 3063 3050 1613 1639 1629 1262 1613 1613 1041 1328 1329 1034 1299 1311 936 1293 1297 908 1040 1040 893 1033 908 776 916 783 902 775 According to a person ordinary skilled in the art, the acceptable tolerance for the wave number shift is � 2 cm1 dependent on the used equipment and measurements conditions.

Example 4

Analysis of the aminomethyll-benZamide polymorph B by IR spectroscopy The IR spectrum (KBr pellet) was recorded on NICOLET 20 SX. The major infrared bands and their assignments are summarized in the following table.

to Table 3

wavenumber (cm1) group assignment MJ-4 frt'hinri irnir[ nd 1706 0=0 stretching of carbamate 1642 0=0 stretching of amide I 527 C=N stretching of pyridirie ring 1263 C-0 bending of carbamate 752 C-H bending of aromatic rings

Description of the figures

Fig. I shows the X-ray powder diffraction pattern of Polymorph A of N-(2- aminopheny-4-[N-(pyridi ne-3-yI)methoxycarboflYlami nomethyl]benzamide (MS-275).

Fig. 2 shows the X-ray powder diffraction pattern of Polymorph B of N-(2- aminophenyl (MS-275).

Fig. 3 shows the X-ray powder diffraction pattern of Polymorph C of N-(2- aminophenyl benzamide (M S-275).

Fig. 4 shows the Raman spectrum of Polymorph A of N-(2-aminopheflYl)-4-EN- (pyrLdine-3-yl)methoxycarbonylamiflomethYllbenzamide (MS-275).

Fig. 5 shows the Raman spectrum of Polymorph B of N(2-aminophenYD-4-[N- (pyridine3yl)methOxyCarbOflyiamifl0methY1]beflZamid0 (MS-275).

is Fig. 6 shows the Raman spectrum of Polymorph C of N(2aminophenYD-4-[N- (pyridi ne-3-yl)methoxycarbonylam i nomethyl]benzamide (MS-275).

Fig. 7 shows the IR spectrum (KBr peltet) of Polymorph B of N-(2-aminophenYl)- 4[N(pyridine3yI)methoXyCarbOnYIamiflOmethY1Ib0flZamide (MS-275), and the major infrared bands and their assignments.

Claims (7)

1. What is claimed is: 1. Crystalline N-(2-aminophenyl)-4-[N -(pyridine-3-yl)methoxycarboflYlaminO-niethyl}-benzamide polymorph B of formula (1).
2. 2. Process for the production of the crystalline N-(2-aminophenyl)-4-[N-i0 (pyridine-3-yl)methoxycarbonylaminomethylj-benzamide polymorph B compound of formula (I), characterized in that a) crude 3-pyridyl methyl N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxy-carbonylami nomethylj-benzamide is dissolved in water and diluted hydrochloric acid is added to the reaction mixture, at a constant internal reaction vessel temperature below 5°C, and b) to said reaction mixture charcoal is added and the reaction mixture is then permanently stirred for I to 20 hours at a constant temperature below 5°C, and c) is filtered to remove the charcoal from the solution and is rinsed with water, and d) while keeping the internal vessel temperature below 5°C the pH of the reaction mixture is adjust to �= 8 with a diluted sodium hydroxide solution, and e) the resulting precipitated N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylaminomethyl} -benzamide is washed with water and ethanol, and is dried, and f) the precipitate is suspended into a mixture of ethanol and water and is heated up to a temperature of 40 -90°C for I to 10 hours, and g) after cooling down the mixture, the resulting precipitate is rinsed with water and ethanol to give the pure N-(2-aminophenyl)-4-[N-(pyridine-3-yl) methoxycarbonylaminomethylj-benzamide polymorph B which is subsequently dried at a temperature between 30-60 °C.
3. 3. Process according to claim 1, characterized in that step b) and step c) is repeated if the purity of N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbo-nylamino-methyl] -benzamide after step c) is insufficient,
4. 4. Crystalline N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamiflO-methyl] -benzamide polymorph B according to claim 1, characterized that it is produced according to claims 2 and 3.
5. 5. Crystalline N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamino-methyl] -benzamide polymorph B according to any of the preceding claims, characterized in that its X-ray diffractogram has a reflection at 2Theta 21.1°.
6. 6. Crystalline N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoXYCarbOnYlaminO-methyI] -benzamide polymorph B according to any of the preceding claims, characterized in that its X-ray diffractogram has reflections at 2lheta = 21.1, 20,4 and 27.4°.
7. 7. Crystalline N-(2-aminophenyl)-4-[N-(pyridine-3-yl) methoxyCarbOflYlamiflO-methylj-benzamide polymorph B according to any of the preceding claims, characterized in that the Raman spectrum has a band at 902 cm1. l08. Crystalline N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxyCarbOnYlaminO-methyl] -benzamide polymorph B according to any of the preceding claims, characterized in that the Raman spectrum has bands at 902 cm1, 3036 cm1, 1639 cm1 and 916 cm* 9. Crystalline N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarboflylamino-methyl] -benzamide polymorph B according to any of the preceding claims, characterized in 10. Crystalline N-(2-aminophenyl)-4-[N-(pyridine-3-yl) methoxycarbonylamino-methylj-benzamide polymorph B according to any of the preceding claims, characterized in that its X-ray diffractogram has a reflection at 2Theta = 21.10 and the Raman spectrum has bands at 902 cm1, 3036 cm1, 1639 cm1 and 916 cm1, and the lR (KBr) spectrum has bands at 1642 cm1, 1527 cm1 and 751 cm1.11. Use of methyl]benzamide polymorph B for the production of a medicament for the treatment of malignant tumors, auto -immune diseases, dermatological diseases and parasitism.12. A composition comprising the N-(2-aminophenyl)-4-[N-(pyridine-3-Yl)methoxy-carbonylamino-methyl] -benzamide polymorph B alone or in combination with a pharmaceutically acceptable diluent and! or carrier.13. A combination comprising the N(2aminophenyl)4-IN(pyridine-3-Yl)methoXY-carbonylaminomethylj-benzamide polymorph B together with one or more cytotoxic or cytolytic agents.14.A combination according to claim 13, characterized in that the N-(2-polymorph B is applied simultaneously, separately or sequentially from the cytotoxic or cytolytic agents