The pharmaceutical composition inhibiting tumor growth

 

(57) Abstract:

The invention relates to medicine and relates to a pharmaceutical composition inhibiting tumor growth. The invention provides stability for at least 2 years at room temperature. The invention consists in that the pharmaceutical composition, inhibiting tumor growth, contains 8 - N/diethylaminoethyl/rebeccamycin of 0.1 - 50 mg, and water to 1 ml, pharmaceutically acceptable acid providing for a pH of 3 to 4. 5 C. p. F.-ly, 3 tables.

The invention relates to stable solutions of antitumor compounds 8-N-(diethylaminoethyl)rebeccamycin and preferred method of obtaining them.

In U.S. patent N 4785085 described rebeccamycin analogues, including 8-N-(diethylaminoethyl)rebeccamycin the following formula:

where n=2;

each of R1and R2is ethyl.

The connection relates to 6-(2-diethylaminoethyl)rebeccamycin. However, the connection is not sufficiently soluble in water to obtain an aqueous solution for injection. Instead of the solution it forms a suspension. Has been described a method of obtaining the acid additive salts and salts with bases, resulting in possible to increase the solubility rebeccae)rebeccamycin.

As for kislotoupornyh salts of 8-N-(diethylaminoethyl)rebeccamycin, including hydrochloride, the difficulty lies in the fact that the crystalline acid salt additive containing equimolar amounts of acid and base, adding water in sufficient concentration for use or dilution to pharmaceutical dosage forms, do not form sufficiently stable aqueous solutions. Long-term studies have revealed unusual physical instability during the period smaller than the period of time that is acceptable for pharmaceutical compositions, i.e., at least 2 years at room temperature. This unusual physical instability includes gelation, sedimentation, turbidity and the formation of liquid crystalline phases, which makes the solutions of crystalline salts unsuitable for practice or for dilution with water in obtaining solutions for injection.

The aim of the invention is to obtain an aqueous solution of 8-N-(diethylaminoethyl)rebeccamycin for injection or for dilution upon receipt of solutions for injection, almost chemically and physically stable for at least 2 years at room temperature.

The term "stable" means here the practice is from the light, for example, cutting off the light opaque material or by placing the solution in a container brown glass, if it additionally does not mean that the analysis shows the presence of at least 95 wt. 8-N-(diethylaminoethyl)rebeccamycin, originally dissolved in solution. The term "almost physically stable" means the absence of gel formation, sediment, turbidity, or liquid crystalline phase, or other entities, which can make the solution suitable for injection.

It has been discovered that the use of certain acids in certain quantities in combination with the desired concentrations of 8-N-(diethylaminoethyl)rebeccamycin in water leads to the production of stable aqueous solutions with the indicated concentrations of 8-N-(diethylaminoethyl)rebeccamycin. Acids are pharmaceutically acceptable acids, one molar equivalent of which solubilities 8-N-(diethylaminoethyl)rebeccamycin. Acid is used in amounts greater than the specified molar equivalent to achieve a pH below 4. The acid used in the number of molar equivalents, does not lead to a positive effect of the invention. Thus, by themselves, crystalline acid salt additive in the form of vadnagar have increased stability at low temperatures, for example, at temperatures of refrigerators and cooling used in the transportation, storage, etc.

Stable solutions according to the invention mainly consists of the following components: a) water, b) 8-N-(diethylaminoethyl)rebeccamycin in an effective dosage amount in concentrations up to 50 mg/ml water; (C) such pharmaceutically acceptable acid, the presence of which in the amount of molar equivalent will be solubilisate (b), and this acid is present in excess compared with the molar equivalent of giving a stabilizing pH in the range of 3-4.

The term "effective dosage amount" corresponds to the effective antitumor amount that is entered as such or after dilution.

The term "molar equivalent or molar equivalent" means that for the neutralization of 1.0 mol of 8-N-(diethylaminoethyl)rebeccamycin required to 1.0 molar equivalent of acid. Therefore, in the case diproton acids, such as tartaric acid, 1.0 mol of 8-N-(diethylaminoethyl)rebeccamycin requires 0.5 moles of acid to one molar equivalent of acid and more than 0.5 mol of acid to produce excess acid in comparison with the molar equivalent.

Consider first the stable solutions.

Water component must be suitable for the production of injection solutions, for example, this may be water for injection.

8-N-(diethylaminoethyl)rebeccamycin usually must be present in a concentration of not less than 0.1 mg/ml of water, often at a concentration of at least 1 mg/ml of water or at least 5 mg/ml of water, because these concentrations can give or can be diluted up to antitumor effective injectively concentrations. The upper limit is determined solubilities the action of the acid component (C) and solubility kislotoupornoj salt 8-N-(diethylaminoethyl)rebeccamycin with a molar equivalent of the specified acid. The concentration of 8-N-(diethylaminoethyl)rebeccamycin should be such that not proceeded crystallization upon cooling of the solution, usually 2-8 ° aboutC. Usually choose to dilution to the effective dose.

As noted above, the acid component (C) must be pharmaceutically acceptable. This means that the acid component (C) should not significantly increase the toxicity of the free base.

The acid component (C) is preferably such that the acid additive salt formed from the free base and the molar equivalent of the acid, had a solubility in water at room temperature greater than 25 mg/ml Pharmaceutically acceptable acid component (s), meeting this criterion solubility include, for example, L-(+)-tartaric, D, L-malic, -(-)-malic, citric, L-(+)-lactic, lactobionic acid, methanesulfonate, phosphoric, pyroglutamyl, succinic acid and sulphuric acid. Of these the most preferred L-(+)-tartaric acid.

As mentioned above, the acid component (C) is present in excess relative to the molar equivalent of (b), giving a pH in the range of about 3-4. The upper limit is about 4 required to obtain a stable solution, i.e., physically stable. Although the formulation with a pH below 3 is stable, however, such acid pH is undesirable from the standpoint of physiological acceptability. The presence of the preferred component (C) depredation use of tartaric acid as the component (C) in equimolar amounts with respect to 8-N-(diethylaminoethyl)rebeccamycin. If 8-N-(diethylaminoethyl)*, rebeccamycin is present at a concentration of 25 mg/ml of water, it gives a pH of 3.2. As is well known, the dilution of the composition with water is given to the increase in pH towards neutral value. It should be noted that the difference in frequency may cause slight pH measurement when the same concentration of the active ingredient.

As noted above, the preferred method of obtaining a solution is to obtain a suspension of 8-N-(diethylaminoethyl)rebeccamycin in water and subsequent addition of the acid component to the desired pH. This is followed by mixing, for example 5-15 h at room temperature. Any slight haze is easily removed by filtration.

In addition, the solution can be obtained by first adding the acid to the water, and then adding 8-N-(diethylaminoethyl)rebeccamycin or adding to the capacity of the acid and the active ingredient, then adding the water.

To increase the dissolution rate can be used known methods such as heating, intensive mixing, processing ultrasound, etc.

Solutions can also easily be obtained by adding an acid additive salt to the water (obtained from acid, bespec, which is present in an acid additive salt, or other acid meets the requirements of component (C).

When therapeutic treatment of mammals, such as animals, affected by a malignant tumor, the solutions according to the invention should be entered in an effective amount for inhibition of tumor growth, i.e., in a dosage amount effective for inhibiting tumor growth. As a rule, inhibiting tumor growth, the number lies in the range of about 0.1-100 mg/kg of body weight of animal per day. It is clear that the actual preferred dosage of the compound will vary widely depending on the condition treatable animal, location of tumor, its type and method of drug administration. Many factors affecting the activity antineoplastics agents will be considered by a specialist using this invention, including, for example, age, body weight, sex of the patient, diet, time of administration, method of excretion, condition of the patient and severity of the disease. The optimal way of introduction (or application) for a given set of conditions can be easily selected by a specialist using the usual tests for determining the dose.

Solutions can be ispolzovanny for introduction if injectisome number gives too high a dose. Thinning easily hold water for injection, USP saline, 5% dextrose, etc. Injectisome concentration usually lie in the range of 0.1-50 mg/ml based on the content of the free base in 1 ml of water.

The examples below illustrate typical variations of the present invention, but not limit its scope.

P R I m e R 1. The solution concentration of 12 mg/ml of free base per ml of water is obtained from 249,2 mg free base, i.e., 8-N-(diethylaminoethyl)rebeccamycin purity of 96.2% 54,0 mg of L-(+)-tartaric acid and 20 ml of sterile water for injection as follows. The free base is suspended in water. Then add the acid. Then spend the mixing vials of finglass, wrapped with aluminum foil to protect from light. The resulting slightly turbid solution was then filtered through a 0.2 μm Acrodisc filter CR, receiving a transparent yellow solution. The composition corresponds to the molar ratio of free base to acid is 1:1, the pH of the slurry is 3.6.

If you get the same solution, but using 520,15 mg free base and 112,6 mg of tartaric acid, the resulting solution contains 25 mg/ml (free base per ml of water), molar the free base per ml of water) solution obtained from the 10.40 g of 8-N-(diethylaminoethyl)rebeccamycin (purity 96%) of 2.26 g of L-(+)-tartaric acid and sterile water for injection USP, which the volume was adjusted to 1000 ml, as follows, 8-N-(diethylaminoethyl)rebeccamycin suspended (90% of need) in a portion of water for injection. Then add L-(+)-tartaric acid and the suspension is stirred overnight, getting slightly turbid solution. Then add water for injection to 1000 ml and the solution is aseptically filtered under nitrogen pressure, through the filter Gelnan Capsule (P N12120) and collected into a sterile container. The solution is aseptically transferred into fingersave capsules USP type 1 (10 ml/ampoule). The capsules are rinsed with sterile gazoobraznym with nitrogen and sealed. The solution contains tartaric acid and free base in a molar ratio of 1:1 and has a pH of 3.5.

Storage test for 4 weeks at temperatures of up to 56aboutWith not detecting a physical or chemical change, which indicates a possible date for at least 2 years when stored at 2-30aboutC and protect from light.

When administered intravenously by infusion of the resulting solution can be diluted, for example, up to 1 mg of the free base in 1 ml of water water for injection USP or 5% dextrose. Found that dilute solutions of physically stable for 24 hours at normal room conditions and lighting.

P is ω the ratio of the acid to the base, specified below. Solutions stored for 4 weeks at 56aboutC and protect from light, the results presented in table. 1.

The above results indicate the critical value of pH to achieve physical stability. In this test the physical stability no physical changes occur that involves physical stability for at least 2 years when stored at 2-30aboutC and protect from light.

The above solutions have also freezing (thawing, spending cycles from -20aboutWith up to room temperature 5 times a week). Solutions are defined as physically stable in the above test are also physically stable in this test, and this indicates that these solutions can be cool and even freeze without compromising quality.

P R I m e R 4. A solution of 8-N-(diethylaminoethyl)rebeccamycin obtained from tartaric acid, have anti-tumor activity against transplanted mouse leukemia P-338 according to the method Geran and other Cancer Chenother, Repts, 3,1-103 (1972). Selected methods include intraperitoneal (WB) introduction of the test compound to the female mice DF 1/18/22 g/ infected, vnutri) and it is 1 injection per day for 5 consecutive days. Using a solution of 8-N-(diethylaminoethyl)rebeccamycin with a concentration of 25 mg free base per ml of water and tartaric acid in a molar ratio of 1:1 with the free base receive doses so diluted that they were kept in 0.5 ml solution for WB injection in 0.2 ml for intravenous injections and below they are marked as "invention". The following results MST corresponds to an average survival time, days; T/is the average time of survival of the test animals divided by the mean survival time of control animals and multiplied by 100; AWC is the average weight change on day 5,, Mitomycin C are included for comparison. The following test results, the WB, which are presented in the table.2.

Results when tested with intravenous presented in table.3.

The results show that the solutions according to the invention, containing tartaric acid, have antineoplastic activity.

1. PHARMACEUTICAL COMPOSITION, INHIBITING TUMOR GROWTH, comprising of 8-N-(diethylaminoethyl) rebeccamycin and a solvent, wherein the solvent consists of water and pharmaceutically acceptable acid, Priya components:

8-N-(Diethylaminoethyl)-rebeccamycin, mg - 0,1 - 50,0

Water, ml - 1

Pharmaceutically acceptable acid providing for a pH of 3 to 4

2. The composition according to p. 1, characterized in that the acid is that acid additive salt with 8-N-(diethylaminoethyl) rebeccamycin has a solubility in water at room temperature is higher than 25 mg/ml

3. The composition according to p. 2, characterized in that the specified acid selected from the group consisting of -(+)-tartaric, D-(-)-malic, -(-)-malic, citric, -(+)-lactic, lactobionic acid, methanesulfonate, phosphoric, pyroglutamyl, amber and sulfuric acids.

4. The composition according to p. 2, characterized in that the specified acid selected from the group consisting of -(+)-tartrate, -(-)-malic, phosphoric, -(+)-lactic, succinic, lactobionic acid.

5. The composition according to p. 4, characterized in that the acid is(+)-tartaric acid.

6. The composition according to p. 5, wherein the -(+)-tartaric acid and 8-N-(diethylaminoethyl) rebeccamycin are present in equimolar amounts.

 

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The invention relates to new derivatives of benzimidazole, possessing valuable pharmacological properties, in particular a derivative of benzimidazole of General formula I

< / BR>
(I) where R1in position 4 means fluorine atom, chlorine or bromine, alkyl with 1-4 carbon atoms, cycloalkyl, vermeil, deformity or trifluoromethyl;

R2alkoxyl with 3-5 carbon atoms, substituted imidazolium in position 3, 4 or 5, alkoxyl with 2-5 carbon atoms, a substituted benzimidazole or tetrahydroimidazo in position 2, 3, 4 or 5, 2-(imidazol-1-yl)-ethoxyl provided that R4means 1H-tetrazolyl, alkylsulfonate with 1-4 carbon atoms, benzosulfimide or generalconclusions, unsubstituted or substituted at the nitrogen atom by alkyl with 1-6 carbon atoms, phenyl, cycloalkyl, phenylalkyl, cycloalkylation, bicyclohexyl or the biphenyl alluminare, in which the acyl radical is alkanoyl with 1-7 carbon atoms, alkoxycarbonyl with a total of 2-4 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, benzoyl, benzazolyl, generalkonsulin, naphthalenesulfonyl, cycloalkylcarbonyl, phenylalkanoic or Central electoral commissions substituents from the group includes fluorine atom, chlorine or bromine, methyl, methoxy, phthalimido, hemophthalmia, 2-carboxymethylamino or 2-carboxymethylamino, and one carbonyl group in phthalimidopropyl replaced by methylene, alkylamino or dialkylamino, one methylene group in hoofdlijnen may be substituted by one or two alkyl groups, and the phenyl nucleus may be optionally mono - or tizamidine the alkyl or alkoxyl, and the substituents may be the same or different and are wholly or partially gidrirovanny, unsubstituted or substituted by one or two alkyl groups or one tetramethylenebis or pentamethylene group 5-, 6 - or 7-membered, alkylamino or alkenylamine in which one methylene group may be replaced by a carbonyl or sulfonyl, imides bicycloalkyl-2,3-dicarboxylic acid and imine bicycloalkyl-2,3-dicarboxylic acid, where bicycloalkanes and bicycloalkanes part can contain 9 or 10 carbon atoms can be substituted by 1, 2 or 3 methyl groups, and endometrioma group may be replaced by oxygen atom, amidinopropane, unsubstituted or substituted by one or two alkyl groups is whether the two alkyl groups or tetramethylene or pentamethylene, maleinimide, unsubstituted or mono - or disubstituted by identical or different substituents from among alkyl and phenyl, linked through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup, oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and mentioned heteroaromatic rings in the carbon skeleton may be substituted by alkyl with 1-6 carbon atoms or phenylalkyl to 5-membered and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methylene group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom of the formed pyridine ring with the sulfur atom, or formed anilinophenol phenyl ring by one or two methyl groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroalkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene bridge, and available if needed in the imidazole ring NH group may be substituted by an alkyl group with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl, imidazolidinedione group, unsubstituted or substituted alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene, pyridazin-3-one and dihydropyridin-3-one, which is in position 2 can be substituted and,

the group R7-NR6CO NR5where R5a hydrogen atom, alkyl with 1-8 carbon atoms, cycloalkyl with 5-7 carbon atoms or phenylalkyl;

R6a hydrogen atom, alkyl with 1-8 carbon atoms, alkenyl with 3-5 carbon atoms, phenyl, phenylalkyl or cycloalkyl with 5-7 carbon atoms,

R7a hydrogen atom or alkyl with 1-6 carbon atoms,

one of the radicals R5, R6or R7may mean bicyclohexyl or diphenylol, R6and R7together with the enclosed nitrogen atoms means the unbranched alkalinising with 4-6 carbon atoms, or R5and R6ashamed mean alkylen with 2-4 carbon atoms, 1H, 3H-hinzelin-2,4-Dion-3-yl, pentamethylene-oxazoline-2-yl, or R1a hydrogen atom or is in position 5, 6 or 7 atoms fluorine, chlorine or bromine, an alkyl group with 1-4 carbon atoms, vermeil, deformity or trifluoromethyl; R2bound through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup and the oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and said heteroaromatics and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom, or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methine group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom formed piperidino ring sulfur atom, or formed anilinophenol phenyl ring, one or two methine groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroaromatic rings in the carbon skeleton may additionally be monogamist fluorine atom, chlorine or bromine, the alkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene my with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl,

R3a hydrogen atom, an alkyl group with 1-5 carbon atoms in which one methylene group may be replaced by oxygen atom or sulfur, or cycloalkyl with 3-5 carbon atoms,

R4carboxyl, cyano, 1H-tetrazolyl, 1-triphenyl-methyl-tetrazolyl, alkoxycarbonyl with the total number of carbon atoms 2-5, alkanesulfonyl, arylsulfonamides, triftormetilfullerenov, and if nothing else is specified, then the above alcoolica, alkyl and CNS part can contain 1-3 carbon atoms, and cycloalkyl part of 3-7 carbon atoms, and moreover, if (a) R1a hydrogen atom, R3N-propyl and R4carboxyl, R2in position 6 does not mean 3-methylimidazo[4,5-b]pyridine-2-yl or 3-n-hexyl-imidazo[4,5-b]pyridine-2-yl, or if (b) R1a hydrogen atom, R3n-propyl or n-butyl and R41H-tetraza the sawdust and R4carboxyl, R2in position 5 or 6 does not mean 1-methylbenzimidazole-2-yl or 6 position 1H-butylbenzothiazole-2-yl, 1,5-dimethylbenzimidazole-2-yl or 1-methyl-5-trifluoromethyl-benzimidazole-2-yl, or if g) R1a hydrogen atom, R3n-butyl and R4carboxy or 1H-tetrazolyl, R2in position 6 does not mean 1-methylbenzimidazole-2-yl, or if d) R1a hydrogen atom, R3n-butyl and R4carboxyl, R2in position 6 does not mean benzimidazole-2-yl, mixtures of them 1-, 3-isomers or individual isomers and hydrates and salts, in particular their physiologically tolerated salts with inorganic or organic acids or bases which are used, for example, as antagonists of angiotensin II, the method of obtaining derivatives of benzimidazole containing the substances, medicinal product and method of its production

The invention relates to medicine, in particular to pharmacology and Oncology

The invention relates to new derivatives of benzimidazole, with a strong pharmacological action, as well as to intermediate compounds for their production

The invention relates to new biologically active compounds, namely, the derivative of 4-aminophenol of the formula I

XNROR1where R1represents a group WITH/ABOUT/УZ;

Y represents a single bond, 0, NR7or; Z represents hydrogen, pyridyl; phenyl which may be substituted with halogen, nitro, lower alkoxy or carboxy; lower alkyl which may be substituted by hydroxy, lower acyloxy, carboxy, lower alkoxycarbonyl, CONR8R9, phenyl/lower/ alkoxy, phenyl, halogen, cyano or NR10R11;

R2, R3, R5and R6that may be the same or different, represent hydrogen, lower alkyl or alkenyl, lower alkoxy or halogen;

R4and R7that may be the same or different, represent hydrogen or lower alkyl;

X 4.5-dihydropyrazolo or pyrazolyl, which may be substituted WITH3-C6-cycloalkyl or phenyl which can be substituted by trihalomethyl;

R8, R9, R10, R11which may be the same or different, represent hydrogen, lower alkyl or benzyloxycarbonyl, or their N-alkyl
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