Derivatives of 10,11-metadimension, chemosensitizers composition, method of overcoming resistance to anticancer drugs and the treatment of neoplastic diseases

 

(57) Abstract:

The invention relates to pharmaceutically active agents. Describes derivatives of 10,11-MetaDimension General formula I, where denotes-CH2-CH2; -CH2-CHRa-CH2where Radenotes H, HE, or lower acyloxy; or-CH2-Ra-CHRb-CH2where one of Raor Rbdenotes H,HE, or lower acyloxy, and the other denotes H, R' denotes H, F, CL or Br, R2denotes H, F, Cl or Br; R3denotes heteroaryl consisting of two condensed rings containing 1 to 3 heteroatoms selected from N, O or S, or their pharmaceutically acceptable salts. These compounds exhibit anti-tumor activity and are suitable for the treatment of cancer, in particular for increasing the effectiveness of existing cancer chemotherapy and for the prevention of resistance to many drugs. Also describes a way of overcoming the resistivity to anticancer drugs and the treatment of neoplastic diseases. 4 C. and 13 C.p. f-crystals.

The invention relates to pharmaceutically active agents. These agents are suitable, for example, for the treatment of cancer, in particular for increasing the efficiency of the tov. More specifically, the invention relates to a number of derivatives of 10,11-MetaDimension. The invention also relates to pharmaceutical compositions and methods of chemosensitization, for example, for the treatment of cancer, including overcoming resistance to many drugs, applications of new agents to obtain pharmaceutical compositions comprising such agents, and to methods for their preparation.

Art

One of the problems encountered in cancer chemotherapy is the development of resistance to treatment. The tumors that at the beginning respond well to a particular drug or drugs, often develop a tolerance to the medication(s). This condition, called resistance to many medicinal drugs, described in detail Kuzmich and Tew in Detoxication Mechanisms and Tumor Cell Resistance to Anticancer Drugs, in particular, in section VII, "The Multidrug-Resistant Phenotip (MDR)", Medical Research Reviews, T. 11, N 2, 185-217, in particular, pages 208-213 (1991); and Georges, Sharom and Ling in Multidrug Resistance and Chemosensitization: Therapeutic Implications for Cancer Chemotherapy", Advances in Pharmacology, T. 21, 185-220 (1990).

Certain active agents, called chemosensitizers agents or potentiating agents have been proposed as AG and various disadvantages. They included, for example, verapamil (blocker occurrence of calcium, which lowers blood pressure and has been found effective in vitro for the treatment of drug-resistant malaria), steroids, triptorelin (CNS agent), ventolin and reserpine ( -2-blocker of some functions of the Central nervous system). Thus, a need remains in the active agents for the treatment, i.e., reversion, inhibition and/or prevention of resistance to many drugs, preferably with minimal unwanted side effects or their absence.

Chemosensitizing agents interact with P-glycoprotein pump to drain the drugs found in cell membranes, particularly in tumor cells with resistance to multiple drugs, cells of the gastrointestinal tract and the endothelial cells forming the brain blood barrier. Blocking the pump, chemosensitizing agents inhibit the outflow of drugs used in cancer chemotherapy, tumor cells and can increase the absorption of nutrients or active agents through the gastrointestinal tract and the penetration of active agents through the brain blood barrier.

In U.S. patent 5112817 Fukazawa and others describe is intended for the treatment of resistance to many drugs. One of the described in this patent initially promising active agents is MS-073, having the following structure:

< / BR>
Despite the high activity shown in experiments in vitro, MS-073, as it turns out, has poor oral bioprosthetic and disadvantages associated with instability in the solution. Other compounds in this series, such as derived biphenyltetracarboxylic, MS-209, as was found has the best stability and oral bioprosthetic, however, this is achieved by introducing a higher effective doses. Thus, there is the problem of developing a potentiating means anticancer drug with activity MS-073, and good oral bioregionally and stability. The purpose of the present invention are solutions to these problems.

Brief description of the invention

One of the objects of the present invention are derivatives of 10,11-MetaDimension, i.e. the compounds of formula I:

< / BR>
where A denotes-CH2-CH2-, -CH2-CHRa-CH2- or-CH2-CHRa-CHRb-CH2- where one of Raor Rbdenotes H, OH or lower acyloxy, and the other represents H;

R1denotes H, F, Cl or B is F config, Cl, Br, CF3, CN, NO2or OCHF2;

and their pharmaceutically acceptable salts.

A preferred aspect of the invention relates to certain compounds of formula I and, in particular, to its simple isomers, more specifically, includes connection, where A denotes-CH2-CHRa-CH2- where Rarepresents OH, R1denotes F, R2denotes F and R3means chinosol. Most preferred is (2R)-anti-isomer.

Another object of the invention is a pharmaceutical composition comprising a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt. In a preferred embodiment, such pharmaceutical composition may also include a pharmaceutically acceptable excipient.

Another object of the invention is a method of treatment by introducing a mammal in need of such treatment, the compounds of formula I or its pharmaceutically acceptable salt or the use of the compounds of formula I or its pharmaceutically acceptable salt to obtain a pharmaceutical composition in the amount therapeutically effective for potentiation effectiveotraditional agents are antimetabolites, such as 6-mercaptopurine, 5-fluorouracil, citizenoriented and its metabolites and derivatives of these agents. Other anti-cancer chemotherapeutic agents are antifolates, such as methotrexate, or agents derived from natural products, for example, obtained from wincolmlee, such as vinblastine, vincristine and colchicine; adriamycin, daunorubicin, doxorubicin, teniposide, or etoposide. Such anti-cancer chemotherapeutic agents also include platypodinae anticancer drugs such as cisplatin and carboplatin. In addition, the agents according to the present invention can be administered in conjunction with cyclophosphamide, bisolvon, procarbazine, dacarbazine, carmustine, lomustine, mechlorethamine, hlorambuzila, hydroxyurea, melphalan, mitotane, Taxol and spirogermanium. Most often resistant to many drugs observed in relation to wincolmlee, of anthracyclines daunorubicin, doxorubicin and adriamycin; and etoposide and teniposide; less likely to antimetabolites and other chemotherapeutic agents.

Another object of the invention is a method of treatment of drug resistance in the mammal by introducing mlikovsky acceptable salt. One variant on this subject matter includes a method of treating resistant to malaria drugs. In a preferred embodiment of the invention a method of treating resistant to many drugs of cancer in a mammal exhibiting clinical resistance to anticancer chemotherapeutic agent, is a joint introduction of modifying the resistance amount of the compound or salt of formula I with a therapeutically effective amount of an anticancer chemotherapeutic agent to which manifested resistance.

Another object of the invention is a method of chemosensitization to improve oral bioprosthetic pharmaceutically active agent, comprising the administration to a mammal, optionally, compounds or salts of formula I in a quantity sufficient to increase the penetration of the active agent through the brain blood barrier or the gastrointestinal tract.

Another object of the invention is a method of obtaining compounds of formula I.

Detailed description of the invention

Definitions and General options

The definitions below are intended to illustrate and define the values and volume razlicitu saturated monovalent radical, containing only carbon and hydrogen and which may be cyclic, branched or remotemachine radical. Examples for this term are such radicals as methyl, ethyl, tert.-butyl, pentyl, neopentyl, heptyl and substituted.

The term "lower alkyl" refers to a cyclic, branched or remotemachine monovalent alkyl radical having from one to six carbon atoms. Examples for this term are such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.-butyl, isobutyl or 2-methylpropyl), cyclopropylmethyl, isoamyl, n-amyl, and hexyl.

The term "alkylene" denotes fully saturated divalent radical containing only carbon and hydrogen, which may be branched or remotemachine radical. Examples for this term are such radicals, such as methylene, ethylene, n-propylene, tert.-butylene, isopentyl and n-heptylene.

The term "lower alkylene" refers to divalent alkyl radical having from one to six carbon atoms. Examples for this term are such radicals, such as methylene, ethylene, n-propylene, isopropylene, n-butylene, tert. -butylene, isobutylene or 2-methylpropene), isoamylene, pentile the LASS="ptx2">

The term "aryl" refers to monovalent unsaturated aromatic carbocyclic radical, typically containing 6 to 16 carbon atoms having a single ring (e.g. phenyl) or two condensed rings (e.g., naphthyl), which (radical) may not necessarily be independently mono-, di - or tri-substituted by fluorine, chlorine, bromine, trifluoromethyl, cyanide, nitrogen and/or dipterocarps.

The term "heteroaryl" refers to monovalent unsaturated aromatic heterocyclic radical, usually containing 2-12 carbon atoms, having in the ring at least one heteroatom, usually from 1 to 3 heteroatoms, such as N, O or S. the Heteroaryl radical can usually have the same ring as, for example, pyridyl, or two condensed rings, such as, for example, hinely, benzofuranyl and benzofurazanyl.

The term "halo" refers to fluorine, bromine, chlorine or iodine.

"Optional" or "optionally" means that the described action or circumstance can take place or it may not be present and that the description includes instances where the specified action or circumstance occurs and instances in which it does not.

"Pharmaceutically acceptable salt" may be robobasket anion such acid additive salt. The selected salt and/or the anion should not be biologically or otherwise undesirable.

Anions derived from inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid (forming sulfate and bisulfate salts), nitric acid, phosphoric acid, etc. and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, salicylic acid, p-toluensulfonate, hexanoic acid, heptane acid, cyclopentylpropionic acid, lactic acid, o-(4-hydroxybenzoyl)benzoic acid, 1,2-ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonate, camphorsulfonate acid, 4-methylbicyclo[2.2.2]Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 4,4'-Methylenebis(3-hydroxy-2-naphthoic acid, 3-phenylpropionate acid, trimethylarsine Ki the Ki-2-naphthoic acid, stearic acid, Mukanova acid, etc.

The term "treatment" or "treating" means any treatment of a disease in a mammal, including:

(1) preventing the disease, i.e., leading to the clinical symptoms of the disease did not develop;

(2) inhibiting the disease, i.e., the termination of development of clinical symptoms; and/or

(3) facilitation of the disease, i.e. causing regression of clinical symptoms.

The term "effective amount" means a dosage sufficient to provide treatment for this state of the disease, which is treatable. It can vary depending on the patient, the disease and provide treatment.

The term "co-administration" refers to the introduction of more than one active agent as part of any medical scheme regardless of whether they are at the same time or at different times.

"The structure of formula I" refers to the General structure of the compounds according to the invention. Chemical bond indicated by a wavy line, for example, in formula II, show non-specific stereochemistry, for example, in position 5 dibenzosuberane, i.e., a carbon that is attached to the piperazine group.

"Isomerism" refers to compounds having the and properties.

"Stereoisomer" refers to one of the two chemical compounds having the same molecular weight, chemical composition and structure, but the atoms are grouped in different ways. This means that certain identical chemical parts have different orientation in space and, consequently, in their pure form have the ability to reject the plane of polarized light. However, some of the pure stereoisomers can be so small optical deviation that it cannot be detected by modern devices.

"Optical isomerism" describes one type of stereoisomer, which is manifested in the fact that the isomer, pure or in solution, rejects the plane of polarized light. The cause in many cases is the merger of four different chemical atoms or groups at least one carbon atom in the molecule. These isomers can be identified as d-, l - or d, l-pair or D-, L - or D,L-pair; or (R)-, (S)- or (R,S)-pair depending on what the item is used.

The compounds of formula I exist in two isomeric configurations, defined by the relationship 10,11-methane - and 5-piperazinil-substituents in dibenzosuberane (see, for example, the structure, the pre is eaten both oriented in the same direction with respect to dibenzosuberane (for example, both up or both down), isomeric form is called "sin". When 10,11-methane - and 5-piperazinil-substituents are oriented in opposite directions relative to dibenzosuberane (for example, one up and one down), isomeric form is called "anti".

Certain compounds of formula I can have an asymmetric center in the group, denoted by "A", where Raor Rbare not hydrogen. These compounds can exist in two stereochemical forms, referred to as (+) and (-) or called (R)- and (S)- or as a mixture of two stereoisomers. The description uses the notation (R)- and (S)-.

Although described and shown a particular stereoisomers, the scope of the present invention includes the individual stereoisomers and their mixtures, racemates, etc.

Nomenclature

The compounds of formula I are named and listed as described below with reference to formula II.

< / BR>
For example, the compound where R1and R2denote chlorine, Radenotes hydroxyl and phenyl group (R3in the formula (I) substituted by NO2in position 3, is called (3R, S)-anti, SYN-1-{ 4-[4-(10,11-dichlorocyclopentane-5-yl)piperazine-1-yl]-3-hydroxyethoxy}-3-nitrobenzene.

The preferred compound of the present invention, is depicted below as formula III:

< / BR>
which is a compound of formula I, where R1and R2denote F, A denotes the (2R)-hydroxypropyl and R3means chinolin attached in position 5 to oxygen, is called (2R)-anti-5-{3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl] -2-hydroxypropoxy} quinoline. In contrast, according to the nomenclature of Chemical Abstracts compound of formula III is called 1-(4-anti(1,1-debtor-1a,10b-dihydrobenzo[a,e]cyclopropa [c]cyclohepten-6-yl)piperazine-1-yl)-(2R)-3-(5-hinomisaki)-2-propanol (numbering presented in formula III, is not used in the nomenclature system Chemical Abstracts). Since any item system adequately describes compounds of the present invention, the first of these two systems Buhl", "inert organic solvent" or "inert solvent" mean a solvent inert under the conditions described in this reaction [they include, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, etc.]. If not specified, the solvents used in the reactions of the present invention are inert organic solvents.

The term "D. K." means adding a quantity sufficient to achieve a given purpose, for example, bringing the solution up to the desired volume (i.e. 100%).

Unless otherwise stated, are given in the description of the reactions take place at atmospheric pressure in the temperature range of 5oC to 100oC (preferably from 10oC to 50oC; most preferably at "room" temperature, or the temperature "environment", i.e., at 20oC). However, it is clear that some of the reactions using temperature range chemical reaction can proceed at temperatures above or below the specified temperature ranges. In addition, unless otherwise indicated, time and reaction conditions are seen as closer IMEMO 5oC to about 100oC (preferably from about 10oC to about 50oC; most preferably at about 20oC) during the period of time from about 1 hour to about 10 hours (preferably about 5 hours). The settings specified in the examples, be considered as a specific, but not rough.

Isolation and purification of the compounds and intermediates described below, can be performed, if required, using any suitable method of separation or purification, such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, or a combination of these methods. Specific illustrations of suitable separation methods, and selection is described in the examples below. But, of course, can be used by other equivalent methods of division and separation.

The synthesis of compounds of formula I

The compounds of formula I can be obtained in accordance with methods described in U.S. patent 5112817 included in the present description by reference, by replacing dibenzosuberone optionally substituted 10,11-MetaDimension obtained, for example, as is. Series of Potent Antidepressants", J. Med. Chem., 1974, T. 17, N 1, 72-75, which is incorporated into this description by reference. Various syntheses of compounds of formula I described below with reference to reaction schemes 1, 2 and 3.

A key role in the synthesis of compounds of formula I plays 1-[10,11-methandienone-5-yl] piperazine following formula 4, which optionally can be substituted in positions 10 and 11. This key intermediate product combine or condense with a reagent that contains or is transformed into A group-O-R3for inclusion in the compounds of formula I; or a reagent, which contains essentially A group-epoxide or its derivative, A group'-O-R3or turns to her for inclusion in the compounds of formula I. Such transformations include, for example, acylation of the hydroxy-group present in the group A', to receive alloctype, or remove alloctype in the group A', or the transformation of the A-epoxide with R3-OH in the compound of formula I. In this transformation, when R3-OH added to the A-epoxide, the epoxide ring is opened, forming the hydroxy-group adjacent to the carbon atom to which is attached-OR3.

A brief description of the reaction schemes

Reaction scheme 3 illustrates the synthesis of compounds of formula I, where Rbdenotes OH.

Used in the reaction schemes, the substituents A, R1, R2, R3, Raand Rbhave the same values, which are listed in "Summary of the invention". Deputy "X" denotes halogroup; n is 1 or 2; and m is 1, 2, 3, or 4.

Raw materials

Compound 5H-dibenzo[a,d]cyclohepten-5-he (also known as dibenzo[a, d] -5H-cyclohepten-5-one or dibenzosuberone) is commercially available, for example, is made by Aldrich Chemical Company, Milwaukee, WI. Other reagents, such as epibromohydrin and 1-bromo-3,4-epoxybutane, are also commercially available or can be easily obtained by specialists in the art using commonly used methodology of synthesis. (Reaction scheme 1, see end of text).

Obtaining compounds of formula I

The acetate solution (such as chlorodifluoroacetate sodium, methyltrichlorosilane, ethyltrichlorosilane; depending on the desired substituents for R1and R2in Rast) to a solution of dibenzosuberenone (for example, in diglyme) under stirring in nitrogen atmosphere, maintaining the reaction temperature at the level of 160-165oC. (Can be used for other temperature regimes of the reaction depending on the reagents, as described Ciganek, etc. and Coyne and Cusic). The reaction mixture is brought to room temperature, then poured into water and extracted (for example, a simple ether). Desired 10,11-substituted-MetaDimension isolated and purified by conventional means, for example, washed with water organic (e.g., benzene) phase is dried (for example, Na2SO4), evaporated and the residue recrystallized (for example, ethanol and optionally repeatedly, for example, from acetone/hexane).

In contrast, the compounds of formula 2 where R1and R2various, such as H and Cl, respectively, can be obtained similar to that described in the journal J. Med. Chem., so 17, 72 (1974), which is incorporated into this description by reference. The compound of formula 2 where R1and R2both represent hydrogen, can be obtained similarly described by Coyne and Cusic in the article "Aminoalkyldibenzo[a, e] cyclopropa[c] cyclogepten Derivatives. A Series of Potent Antidepressants", J. Med. Chem., 1974, T. 17, N 1, 72-75, which was previously mentioned as references.

Getting soeding/methanol) is cooled (for example, in an ice bath) and add in parts reducing agent (for example, borohydride sodium). The reaction mixture is allowed to reach room temperature and stirred for 1-5 hours (preferably 2 hours), then poured into water. Product highlight (e.g., by filtering) and purified by conventional means (e.g., washed with water and dried) to obtain the corresponding 10,11-(optionally substituted)-metandienone.

Obtaining compounds of formula 3, where R is formyl

A solution of 10,11-(optionally substituted)-metandienone in a solvent (e.g. dioxane) is cooled (for example, in an ice bath), then halogenous [for example, by adding dropwise thionyl chloride, maintaining the elevated temperature (from 40 to 70oC, preferably 50oC) for 2-5 hours (preferably 4 hours)]. The reaction mixture is evaporated to dryness, obtaining a mixture of SYN - and anti-isomers of the corresponding 5-halo-10,11-(optionally substituted)-MetaDimension. This the halogenated suberin dissolved without further purification (e.g., acetonitrile), and introduce piperazine by nucleophilic substitution of the halide [for example, adding under stirring 1-piperazinecarboxamide (preferably 20 hours)] . The reaction mixture is evaporated to dryness and produce the desired product 1-[10,11-(optionally substituted)-methandienone-5-yl] -4-formylpiperazine and clean it in the usual ways [for example, the residue is divided between water NaHCO3and ethyl acetate, the organic phase is washed with water, dried (for example, K2CO3) and evaporated]. Individual SYN - and anti-isomers share, for example, with fast chromatography of the residue on silica gel (30% acetone/hexane).

Obtaining compounds of formula 4

A solution of 1-[10,11-(optionally substituted), metandienone-5-yl]-4-formylpiperazine and potassium hydroxide in a solvent (for example, 9:1 ethanol/H2O) is heated under reflux for 0.5-2 hours (preferably 1 hour), then cooled. The cooled reaction mixture is concentrated, dissolved in water, extracted (e.g., ethyl acetate), dried (for example, K2CO3) and the organic phase is evaporated, obtaining the appropriate 1-[10,11-(optionally substituted), metandienone-5-yl] piperazine.

Obtaining compounds of formula I

A solution of the compounds of formula 8 [for example, 1-(aryloxy or heteroaromatic)-2,3-epoxypropane or 1-(aryloxy or heteroaromatic)-3,4-Epoque is souber-5-yl] piperazine is heated under reflux in a solvent (for example, isopropanol) for 10 to 30 hours, preferably 20 hours). The desired product, the corresponding derived 10,11-MetaDimension formula I is isolated and purified by conventional means [for example, pariva dry and chromatographie on silica gel (for example, using a mixture of 70:30:1 ethyl acetate/hexane/triethylamine)]. (Reaction scheme 2, see end of text).

Obtaining compounds of formula 8

Arrowy or heteroallyl alcohol (such as benzofurazan-4-ol, quinoline-5-ol or 2-NITROPHENOL) is dissolved in a solvent (such as acetonitrile, THF or dimethylformamide), treated with a slight excess of a strong base (e.g. sodium hydride or tert.-butoxide potassium). The mixture is heated (for example, when 50oC) for 10 minutes to 2 hours (preferably 30 minutes). Add the compound of formula 6 (such as 1-chloro-2,3-epoxybutane, 1-bromo-2,3-epoxybutane, epibromohydrin, epichlorohydrin or tosyl or mesyl-derived) and the mixture is heated (for example, at 60oC for 1-5 hours, preferably 2 hours). The reaction mixture is poured into water and extracted (e.g., ethyl acetate). The organic phase is washed with water, dried over Na2SO4and evaporated, obtaining the appropriate 1-(aryloxy or giaut conventional methods [for example, chromatography on silica gel (50% ethyl acetate/hexane)].

The compounds of formula 8, such as 1-(5-hinomisaki)-2,3-epoxypropane, can be synthesized as described in the publication of Drug Design and Discovery, so 9, 69, (1992), which is incorporated into this description by reference.

Obtaining compounds of formula 9

As shown in reaction scheme 3 (see end of text), anion kilowog or heteroarylboronic alcohol of formula 5 is subjected to interaction with dihaloalkanes compound of formula 7, such as 1-bromo-2-chlorate, 1-bromo-3-chloropropane or 1-bromo-4-chlorobutane, in a solvent (such as acetone, THF or DMF) at a temperature in the range from room temperature to the boiling point of the used solvent, obtaining the relevant haloacetonitriles (or heteroaryl) compound of formula 9. This synthesis is described in U.S. patent 5112817 previously specified in the present description by reference.

Obtaining compounds of formula 10

As shown in reaction scheme 3, step 1, 1-[10,11-(optionally substituted)-methandienone-5-yl] piperazine of formula 4 is subjected to interaction with the compound of the formula 6 (for example, by connection, where n is equal to 2, as shown in reaction scheme 3; each reaction scheme 2), receiving the compound of formula 10 1-[10,11-(optionally substituted)-methandienone-5-yl]-4-(3,4-epoxybutene)piperazine.

Obtaining compounds of formula I, where Rbdenotes OH

As shown in reaction scheme 3, step 2, compound of formula 10 1-[10,11-(optionally substituted)-methandienone-5-yl] -4-(3,4-epoxybutene)piperazine is subjected to interaction with arrowy or heteroallyl alcohol (such as benzofurazan-4-ol, quinoline-5-ol or 2-NITROPHENOL) in the conditions described above to obtain a formula 1 (reaction scheme 1), obtaining the corresponding compound of formula I, where Rbdenotes OH.

Obtaining compounds of formula I, where Raor Rbdenotes lower acyloxy

The compounds of formula I, where Raor Rbdenotes lower acyloxy, get similarly described in U.S. patent 5112817 specified above as a reference, starting from the corresponding compounds of formula I, where Raor Rbdenotes OH (obtained as described above). For example, the compound of formula I, where Raor Rbdenotes OH, is subjected to the interaction with acylchlorides for the formation of the corresponding acyloxy connection.

Obtaining salts of salt. The transformation is carried out by treatment with a stoichiometric amount of the appropriate acid, such as hydrochloric acid (3 molar equivalent education trihydrochloride salt in the case of the compounds of formula I, including three basic nitrogen atom). If R3denotes phenyl, the compound of formula I has only two basic nitrogen atom and can absorb only two equivalents of the acid to produce an acid additive salt. If the substituent R3includes two basic nitrogen atom, the basis of the formula I can absorb four equivalent acid. The preferred acid salt additive according to the invention may include two or three equivalents of acid. More preferred are acid additive salts with three equivalents of acid. During the formation of the salt of the present invention is usually free base is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added to water, methanol or ethanol. The temperature maintained within the range of 0oC to 50oC. the Corresponding salt precipitates spontaneously or can be deduced from the solution with a less polar solvent the free base of formula I in accordance with the present invention the acid additive salts of compounds of formula I may be decomposed to the corresponding free bases by treatment with an excess of a suitable base, such as ammonia or sodium bicarbonate, typically in the presence of an aqueous solvent and at a temperature between 0oC and 50oC. the Free base of the produce by conventional means such as extraction with an organic solvent. It is obvious that a stoichiometric excess must be taken with regard to the number of equivalents of acid related base formula I.

Preferred free base of formula I include 2 or 3 of the basic nitrogen atoms. Base with 3 basic nitrogen atoms are most preferred.

The preferred methods and final stage

To obtain the corresponding derivative of 10,11-MetaDimension formula I combine 1-(aryloxy or heteroaromatic)-2,3-epoxypropane or 1-(aryloxy or heteroaromatic)-3,4-epoxybutane, or aryloxy or heteroarylboronic and 1-[10,11-(optionally substituted)-methandienone-5-yl]piperazine.

The compound of formula I, where Raor Rbdenotes OH, is subjected to the interaction with acylchlorides for the formation of the corresponding acyloxy connection.

The compound of formula 10 is subjected to interaction with alcohol3-OH to obtain the corresponding proshat interaction with a pharmaceutically acceptable acid for the formation of the corresponding acid additive salt.

Pharmaceutically acceptable acid additive salt of formula I is subjected to interaction with the basis for the formation of the corresponding free base of formula I.

Preferred compounds

Preferred are the compounds of formula I, where R1and R2denote fluorine. Also preferred are those compounds where A denotes the 2-hydroxypropyl. Also preferred are those compounds where R3denotes 5-chinolin or 4-benzofuranyl. Also preferred are those compounds in which the joint of the above-noted characteristics. Also preferred simple isomers.

Most preferred is the compound 5-{3-[4-(10,11-diversitydialogues-5-yl)piperazine-1-yl] -2 - hydroxypropoxy}-quinoline; in particular, its (2R)-anti-isomer.

Usefulness, testing and introduction

Total utility

Compounds of the present invention are chemosensitizers or potentiating agents, and they are also suitable as agents, modifying resistance. They are also suitable for the treatment of resistance to many drugs (i.e., after development of clinical resistance) and can also ª activity of anticancer agents, introduced for the first time. Compounds of the present invention is also suitable for the treatment of resistant malaria drugs.

Test

Activity in vitro chemosensitizers or potentiating agents, in particular, for the treatment of resistance to multiple drugs was determined by quantitative analysis of cell proliferation MTT, for example, using a modified quantitative analysis described T. Mosmann in "Rapid Colorimetric Assay for Cellular Growth and Survival: Application to proliferation and cytotoxicity assays", J. Immunol. Meth., so 65, 55 to 63 (1983). Another quantitative analysis of cell proliferation MTT described'alleu and others in the "Feasibility of Drug Screening with Panels of Human Tumor Cell Lines Using a Microculture Tetrasolium Assay", Cancer Research, so 48, 589-601 (1988).

Activity in vivo chemosensitizers or potentiating agents, in particular, for the treatment of resistance to many drugs, determine, for example, as described Slate and Mchelson in Drug Resistance Reversal Strategies: A Comparison of Experimental Data with Model Prediction", J. Natl. Cancer Inst., so 83, 1574-1580 (1991). Other methods of in vivo tests described Sato and others in the "Circumvention of Multidrug Resistance by a Newly synthesized unit Quinoline Derivative, MS-073, "Cancer Research, 51 so, 2420-2424 (1991); Tsuruo, etc. in the "Circumvention of Vincristine and Adriamycin Resistance in Vitro and in Vivo by Calcium Influx Blockers", Cancer Research, 43 so, 2905-2910, (1983); and Tsuruo and others in the "Overcoming of Vincristine Resistance in P388 Leukemia in Vivo and in Vitro throu conventional methods, for example, by measuring the amount of compound remaining in solution at different pH values and temperatures.

Introduction

The compounds of formula I is administered in a therapeutically effective dose, for example at a dose sufficient to provide treatment of the above disease States, usually through a joint appointment with the second active agent, preferably an anticancer chemotherapeutic agent, in particular selected from the group of the agents listed above, and most preferably with anti-cancer chemotherapeutic agent, which developed clinical resistance in a mammal to be treated. Introduction compounds according to the invention or their pharmaceutically acceptable salts can be carried out via any of the accepted forms of introduction for agents that serve similar purposes.

Although the dosage levels of the compounds of the present invention for a person still needs to be optimized, the usual daily dose is from about 0.01 to 4.0 mg/kg body weight, preferably approximately from 0.1 to 2.0 mg/kg body weight and most preferably from about 0.3 to 1.0 mg/kg of body weight. Thus, when administered to man the weight of the flax from 7.0 to 140 mg per day and most preferably from about 21 to 70 mg per day. The amount of active compound must, of course, depend upon the subject and disease state to be treated, the severity of the lesion, method and mode of administration (e.g. oral introduction the day before cancer chemotherapy and intravenous during cancer chemotherapy), and the opinion of the treating physician.

When using the compounds of the present invention for the treatment of the above conditions can be used in any pharmaceutically acceptable form of introduction. The compounds of formula I may be administered either separately or in combination with other pharmaceutically acceptable inert excipients, including solid, semi-solid, liquid or aerosol dosage forms, such as, for example, tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, or etc., For prolonged introduction connection with a predetermined rate, preferably in the form of standard doses suitable for a single administration of precise dosages of the compounds of formula I may also be administered in dosage forms with continuous or controlled-release, including the injection of substances slow suction, osmotic pumps, pills, transdermal the cue carrier or excipient and a compound of formula I or its pharmaceutically acceptable salt. In addition, these compositions may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. such as the above anti-cancer chemotherapeutic agents.

In General, depending on the intended form of administration, pharmaceutically acceptable composition may contain from about 0.1 wt.% to 90 weight. %, preferably about 0.5 wt.% up to 50 wt.% compounds or salts of formula I, and the rest are pharmaceutically suitable inert fillers, carriers, etc.

One of the preferred routes of administration for the state, described above, is oral using a normal daily dose, which is determined depending on the degree of destruction. For such oral administration form pharmaceutically acceptable non-toxic composition by incorporating any of the commonly used inert fillers, such as, for example, mannitol, lactose, starch, magnesium stearate, saccharin sodium, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate, etc., Such compositions include solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, form continuous the m way along with the active ingredient, the composition may comprise: a diluent such as lactose, sucrose, dicalcium phosphate, or etc.; lubricating substance, such as magnesium stearate or similar; and a binder such as starch, Arabic gum, gelatin, polyvinylpyrrolidone, cellulose and their derivatives, etc.

Liquid entered the pharmaceutical compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound, as shown above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc., for the education of a solution or suspension. If required, enter the pharmaceutical composition may also contain smaller amounts of nontoxic auxiliary substances such as wetting, emulsifying or soljubilizatory, sautereau pH agents, etc. , for example, acetate, sodium citrate, cyclodextrin derivatives, sorbitanoleat, natriuretic triethanolamine, triethanolamine etc., Modern methods for such dosage forms are known, or may be obvious to a person skilled in this technical field; for example, is to contain the active substance in a quantity sufficient to relieve symptoms of the subject to be treated.

Can be prepared dosage forms or compositions containing active ingredient in the range of 0.005% to 95% with the addition of the missing to balance quantity at the expense of non-toxic carrier.

For oral administration of pharmaceutically acceptable non-toxic composition is prepared by incorporating any commonly used inert filler, such as, for example, pharmaceutically pure mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, croscarmellose sodium, glucose, sucrose, magnesium carbonate, saccharin sodium, etc., Such compositions can be in the form of solutions, suspensions, tablets, capsules, powders, forms, continuous-release, etc., Such compositions can contain 0,01%-95% of active ingredient, preferably about 0.1-50%.

For solid dosage form a solution or suspension, for example, propylene or ethylene carbonate resulting or mixtures thereof, vegetable oils or triglycerides, preferably include a gelatin capsule. Such solutions and methods for their preparation and inclusion in gelatin capsules is described in U.S. patent 4328245; 4409239 and 4410545. For your pharmaceutically acceptable liquid carrier, for example water, to facilitate standardization in the introduction.

In contrast, liquid or semi-solid oral forms may be obtained by dissolving or dispersing the active substance or salt in vegetable oils, glycols, triglycerides, esters of propylene glycol (e.g. propylene carbonate, ethylene carbonate resulting and their mixtures, etc., and incorporating these solutions or suspensions in hard or soft gelatin capsule shell.

Other suitable forms include such a set, which is described in U.S. patents Re. 28819 and 4358603.

Another advantage of the present invention is suitable for oral and parenteral introduction due to the very high stability characteristics, which were found for compounds of formula I, which was a problem for MS-073.

Under parenteral appointment typically involve the injection is subcutaneous, intramuscular or intravenous. Injectables can be prepared in conventional forms, in the form of liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable inert fillers are, napinka compositions for injection may also contain smaller amounts of non-toxic additives, such as wetting or emulsifying agents, sautereau pH agents that increase the solubility of the agents, etc., such as, for example, sodium acetate, sorbitanoleat, triethanolamine, cyclodextrins, etc.

In the most modern approach for parenteral injection is used, the implantation system with slow release, or continuous-release, which allows to maintain a constant level of dosage. See, for example, U.S. patent 3710795.

Percentage concentration of the active substance included in such parenteral compositions, to a large extent depends on their specific nature, as well as active substances and the needs of the subject. However, usually adopted percent concentration of active ingredient in the solution is from 0.01% to 10%, and they should be higher if the composition is solid, which, in turn, must be diluted to the above percentage concentrations. Preferably, the composition is comprised between 0.2-2% of the active agent in solution.

May also be entered nasal solutions of the active substances, individually or in combination with other pharmaceutically acceptable inert fillers.

Form asset is estomago using a spray gun, or in the form of ultrafine powder for injection, individually or in combination with an inert carrier such as lactose. In this case, particles of the composition have diameters less than 50 microns, preferably less than 10 microns.

Examples

The following preparations and examples are given in order to provide an opportunity for professionals in the art to more clearly understand and implement the present invention. They should not be construed as limiting the scope of the invention but merely as illustrating and explaining it.

Example 1

10.11-differenceswere

1A. Formula 1, where R1and R2denote F

The solution chlorodifluoroacetate sodium (350 g) in diglyme (1400 ml) dropwise with stirring of the upper layer and in nitrogen atmosphere for 6 hours was added to a solution of dibenzosuberenone (25 g) in diglyme (500 ml), maintaining the reaction temperature at the level of 160-165oC. the Cooled reaction mixture was poured into water (1.8 l) and was extracted with ether (1.8 l). The organic phase is washed with water, dried over Na2SO4and was evaporated. The residue was recrystallize from ethanol, then from a mixture of acetone/hexane, receiving 14 g of 10,11-deformationsvetsaren, tPL149,6o

1B. Formula 1 with different R1and R2< / BR>
In accordance with the procedure described in part a, and substituting chlorodifluoroacetate sodium following substances:

A. methyltrichlorosilane,

B. methylcaprolactam, and

century dichlorphenamide sodium,

received, respectively, the following connections:

A. 10,11-dichlorocyclopentane,

B. 10,11-dibromothiophene, and

century 10,11-chlorophenothiazine.

Example 2

10,11-diftormetilirovaniya

2A. Formula 3, where R1and R2denote F

A solution of 10,11-deformationsvetsaren (20.4 g) in THF/MeOH (1:2, 900 ml) was cooled in an ice bath. In parts was added borohydride sodium (12 g). The cooling bath was removed, the reaction mixture was stirred at ambient temperature for 2 hours and poured into water. The product was filtered, washed with water and dried, obtaining 20 g of 10,11-differenceswere, tPL230,1-230,6oC.

2B. Formula 2 with different R1and R2< / BR>
In accordance with the procedure described in part a, and substituting 10,11-differenceswere the following substances:

A. 10,11-dichlorohydroquinone,

B. 10,11-dibromohydroquinone,

the blowing connection:

A. 10,11-dichloroindophenol,

B. 10,11-dibromothiophene,

century 10,11-MetaDimension, and

he 10,11-chloroformmethanol.

Example 3

SYN - and anti-1-(10,11-diversitydialogues-5-yl)-4-formylpiperazine

3A. Formula 3, where R1and R2denote F and R denotes formyl

To a solution of 10,11-differenceswere (5,2 g) in dioxane (70 ml), cooled in an ice bath, was added dropwise thionyl chloride (4.5 ml). The temperature was raised to 50oC and maintained for 4 hours. The reaction mixture was evaporated to dryness, obtaining a mixture of SYN - and anti-5-chloro-10,11-deformationsvetsaren (5.7 g), which was dissolved in acetonitrile (200 ml), was added 1-piperazinecarboxamide (10 ml). The mixture was stirred in a dry nitrogen atmosphere at 100oC (bath temperature) for 20 hours and then evaporated to dryness. The residue was divided between aqueous NaHCO3and ethyl acetate. The organic phase is washed with water, dried over K2CO3and was evaporated. With fast chromatography of the residue on silica gel (30% acetone/hexane) received SYN-1-(10,11-diversitydialogues-5-yl)-4-formylpiperazine (2.4 g), tPL213oC and anti-1-(10,11-diversitydialogues-5-yl)-4-formylpiperazine (2,6 fool, described in part a, and substituting 10,11-diftormetilirovaniya the following substances:

A. 10,11-dichloromethanicum,

B. 10,11-dibromohydroquinone,

century 10,11-MetaDimension, and

he 10,11-chloroformmethanol,

received, respectively, the following connections:

A1. anti-1-(10,11-dichlorocyclopentane-5-yl)-4-formylpiperazine, tPL205oC,

A2. SYN-1-(10,11-dichlorocyclopentane-5-yl)-4-formylpiperazine

B1. anti-1-(10,11-dibromothiophene-5-yl)-4-formylpiperazine,

B2. SYN-1-(10,11-dibromothiophene-5-yl)-4-formylpiperazine

B1. anti-1-(10,11-methandienone-5-yl)-4-formylpiperazine, tPL195oC,

B2. SYN-1-(10,11-methandienone-5-yl)-4-formylpiperazine,

G1. anti-1-(10,11-chloroformmethanol-5-yl)-4-formylpiperazine, and

G2. SYN-1-(10,11-chloroformmethanol-5-yl)-4-formylpiperazine.

Example 4

Anti-1-(10,11-diversitydialogues-5-yl)piperazine

4A. Formula 4 where R1and R2denote F

A solution of anti-1-(10,11-diversitydialogues-5-yl)-4-formylpiperazine (2.55 g) and potassium hydroxide (3.0 g) in ethanol/water (9:1, 100 ml) was heated under reflux for 1 hour, then cooled. Ohla the SUB>CO3. The dried organic phase was evaporated and received anti-1-(10,11-diversitydialogues-5-yl)piperazine (2.35 g), tPL131oC.

4B. Formula 4 with different R1and R2< / BR>
In accordance with the procedure described in part a, and substituting anti-1-(10,11-diversitydialogues-5-yl)-4-formylpiperazine the following substances:

A. SYN-1-(10,11-diversitydialogues-5-yl)-4-formylpiperazine,

B. anti-1-(10,11-dichlorocyclopentane-5-yl)-4-formylpiperazine,

century SYN-1-(10,11-dichlorocyclopentane-5-yl)-4-formylpiperazine,

, anti-1-(10,11-dibromothiophene-5-yl)-4-formylpiperazine,

doctor SYN-1-(10,11-dibromothiophene-5-yl)-4-formylpiperazine,

E. anti-1-(10,11-methandienone-5-yl)-4-formylpiperazine,

W. SYN-1-(10,11-methandienone-5-yl)-4-formylpiperazine,

C. anti-1-(10,11-chloroformmethanol-5-yl)-4-formylpiperazine, and

I. SYN-1-(10,11-chloroformmethanol-5-yl)-4-formylpiperazine;

received, respectively, the following connections:

A. SYN-1-(10,11-diversitydialogues-5-yl)piperazine, tPL225,5oC,

B. anti-1-(10,11-dichlorocyclopentane-5-yl)piperazine, tPL199oC,

century SYN-1-(10,11-dichlormethanhaltige-5-yl)piperazine,

E. anti-1-(10,11-methandienone-5-yl)piperazine, tPL103oC,

W. SYN-1-(10,11-methandienone-5-yl)piperazine,

C. anti-1-(10,11-chloroformmethanol-5-yl)piperazine,

I. SYN-1-(10,11-chloroformmethanol-5-yl)piperazine.

Example 5

1-(4-benzofurazanyl)-2,3-epoxypropan

5A. Formula 8, where R3means benzofurazanyl and n is 1

Sodium hydride (620 mg; 60% dispersion in oil) was added in parts to benzofurazan-4-Olu (1,74 g) in dimethylformamide (30 ml). The mixture was stirred at 50oC for 30 minutes. Added epibromohydrin (1.6 ml) and the mixture was stirred at 60oC for 2 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic phase is washed with water, dried over Na2SO4and was evaporated. The residue was chromatographically on silica gel (50% ethyl acetate/hexane) and was obtained 1-(4-benzofurazanyl)-2,3-epoxypropane (1.6 g), tPL75oC.

5B. Formula 8 with different R3and n

In accordance with the procedure described in part a, and substituting benzofurazan-4-ol and epibromohydrin the following substances:

A. the quinoline-5-I and 1-chloro-3,4-epoxybutane,

B. 2-NITROPHENOL and epibromohydrin,

century 2-chlorophenol and epipo the E. the quinoline-5-I and epibromohydrin;

received, respectively, the following connections:

A. 1-(5-hinomisaki)-3,4-epoxybutane,

B. 1-(2-nitrophenoxy)-2,3-epoxypropane,

C. 1-(2-chlorophenoxy)-2,3-epoxypropane,

, 1-(2-deformationally)-2,3-epoxypropane,

D. 1-(3-pyridyloxy)-2,3-epoxypropane, and

E. 1-(5-hinomisaki)-2,3-epoxypropane.

5V. Formula 9 with various R3and n

In accordance with the procedure described in part a, and substituting benzofurazan-4-ol and epibromohydrin the following substances:

A. the quinoline-5-I and 1-bromo-3-chloropropane,

B. the quinoline-5-I and 1-bromo-4-chlorobutane, and

century 2-NITROPHENOL and 1-bromo-3-chloropropane,

received, respectively, the following connections:

A. 1-(5-hinomisaki)-3-chloropropane,

B. 1-(5-hinomisaki)-4-chlorobutane, and

C. 1-(2-nitrophenoxy)-3-chloropropane.

Example 6

(2R, S)-anti-5-{ 3-[4-(10,11-dichlorocyclopentane-5-yl)-piperazine-1 - yl]-2-hydroxypropoxy}quinoline

6A. Formula 1, where R1and R2denote F, A denotes the (2R,S)-hydroxypropyl and R3denotes 5-chinolin

A solution of 1-(5-hinomisaki)-2,3-epoxypropane (586 mg) and anti-1-(10,11-diversitydialogues-5-yl)piperazine (950 mg) in isopropanol (20 ml) was heated to reverse agile (70:30:1 ethyl acetate/hexane/triethylamine), receiving (2R, S)-anti-5-{3-[4-(10,11-dichlorocyclopentane-5-yl)-piperazine-1 - yl]-2-hydroxypropoxy}quinoline (1,33 g), which was turned into trihydrochloride salt, tPLof 193.5oC, by interacting with 3 molar equivalent of HCl.

6B. Isomers of formula I with various R1, R2, R3and A

In accordance with the procedure described in part a, and substituting anti-1-(10,11-diversitydialogues-5-yl)piperazine and 1-(5-hinomisaki)-2,3-epoxypropan the following substances:

A. SYN-1-(10,11-diversitydialogues-5-yl)piperazine and 1-(5-hinomisaki)-2,3-epoxypropanol,

B. anti-1-(10,11-diversitydialogues-5-yl)piperazine and (2R)-1-(5-hinomisaki)-2,3-epoxypropanol,

century anti-1-(10,11-diversitydialogues-5-yl)piperazine and (2S)-1-(5-hinomisaki)-2,3-epoxypropanol,

, SYN-1-(10,11-diversitydialogues-5-yl)piperazine and (2R)-1-(5-hinomisaki)-2,3-epoxypropanol,

doctor SYN-1-(10,11-diversitydialogues-5-yl)piperazine and (2S)-1-(5-hinomisaki)-2,3-epoxypropanol,

E. anti-1-(10,11-dichlorocyclopentane-5-yl)piperazine and 1-(5-hinomisaki)-2,3-epoxypropanol,

W. anti-1-(10,11-dichlorocyclopentane-5-yl)piperazine and (2R)-1-(5-hinomisaki)-2,3-epoxypropanol,

C. anti-1-(10,11-dichlorocyclopentane-5-is-(5-hinomisaki)-2,3-epoxypropanol,

K. anti-1-(10,11-diversitydialogues-5-yl)piperazine and 1-(4-benzofurazanyl)-2,3-epoxypropanol,

L. SYN-1-(10,11-diversitydialogues-5-yl)piperazine and 1-(4-benzofurazanyl)-2,3-epoxypropanol,

M. anti-1-(10,11-dichlorocyclopentane-5-yl)piperazine and 1-(4-benzofurazanyl)-2,3-epoxypropanol,

N. anti-1-(10,11-diversitydialogues-5-yl)piperazine and 1-(2-nitrophenoxy)-2,3-epoxypropanol,

O. anti-1-(10,11-diversitydialogues-5-yl)piperazine and 1-(2-chlorophenoxy)-2,3-epoxypropanol,

p. anti-1-(10,11-diversitydialogues-5-yl)piperazine and 1-(2-deformationally)-2,3-epoxypropanol,

R. anti-1-(10,11-diversitydialogues-5-yl)piperazine and 1-(3-pyridyloxy)-2,3-epoxypropanol,

C. anti-1-(10,11-diversitydialogues-5-yl)piperazine and 1-(5-hinomisaki)-3-chloropropanol,

so anti-1-(10,11-diversitydialogues-5-yl)piperazine and 1-(5-hinomisaki)-4-chlorobutanol,

. anti-1-(10,11-diversitydialogues-5-yl)piperazine and 1-(2-nitrophenoxy)-3-chloropropanol, and

F. anti-1-(10,11-diversitydialogues-5-yl)piperazine and 1-(5-hinomisaki)-3,4-epoxybutane,

received, respectively, the following connections:

A. (2R, S)-SYN-5-{3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl]-Suber-5 - yl)piperazine-1-yl]-2-hydroxypropoxy}quinoline, tPL190oC (trihydrochloride),

C. (2S)-anti-5-{3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl]-2-hydroxypropoxy}quinoline, tPL195oC (trihydrochloride),

, (2R)-sin-5-{3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl] -2-hydroxypropoxy}quinoline, tPL193oC (trihydrochloride),

D. (2S)-sin-5-{3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl] -2-hydroxypropoxy}quinoline, tPL188,5oC (trihydrochloride),

that is, (2R,S)-anti-5-{3-[4-(10,11-dichlorocyclopentane-5 - yl)piperazine-1-yl]-2-hydroxypropoxy}quinoline, tPL195oC (trihydrochloride),

W. (2R)-anti-5-{3-[4-(10,11-dichlorocyclopentane-5 - yl)piperazine-1-yl]-2-hydroxypropoxy}quinoline, tPL218oC (trihydrochloride),

C. (2S)-anti-5-{3-[4-(10,11-dichlorocyclopentane-5 - yl)piperazine-1-yl]-2-hydroxypropoxy}quinoline, tPL215oC (trihydrochloride),

I. (2R,S)-anti-5-{3-[4-(10,11-methandienone-5-yl)piperazine - 1-yl]-2-hydroxypropoxy} quinoline, tPLin the range 87,4-99,3oC; MS: molecular ion = 491,

K. (2R,S)-anti-4-{3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl]-2-hydroxypropoxy}benzofurazan, tPL186oC (dihydrochloride),

L. (2R, S)-SYN-4-{3-[4-(10,11-diversitydialogues-5 - yl)piperonylpiperazine-5 - yl)piperazine-1-yl]-2-hydroxypropoxy}benzofurazan,

N. (2R,S)-anti-1-{3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl]-2-hydroxypropoxy}-2-nitrobenzene,

O. (2R,S)-anti-1-{3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl]-2-hydroxypropoxy}-2-chlorobenzene,

p. (2R,S)-anti-1-{3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl]-2-hydroxypropoxy}-2-deformational,

R. (2R,S)-anti-3-{3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl]-2-hydroxypropoxy}pyridine,

C. (2R,S)-anti-5-{3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl]propoxy}quinoline,

so (2R,S)-anti-5-{4-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl]butoxy}quinoline,

. (2R,S)-anti-5-{3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl]propoxy}-2-nitrobenzene, and

F. (2R,S)-anti-5-{3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl]-3-hydroxybutane}quinoline.

Example 7

This example illustrates obtaining typical pharmaceutical composition for oral administration containing an active substance of the formula I, for example, (2R)-anti-5-{3-[4-(10,11-diversitydialogues-5-yl)piperazine-1 - yl]-2-hydroxypropoxy}quinoline.

Ingredients Quantity per tablet, mg

Active substance - 200

Lactose, spray dried - 148

Magnesium stearate - 2
by trihydrochloride salt, you need to 243 mg of salt.

Other compounds of formula I, such as is obtained in accordance with the methods described in examples 1-6 can be used as active substances for obtaining the compositions of this example for oral administration.

Example 8

This example shows which other typical pharmaceutical composition for oral administration containing an active substance of the formula I, for example, (2R)-anti-5-{ 3-[4-(10,11-diversitydialogues-5-yl)piperazine-1 - yl]-2-hydroxypropoxy}quinoline.

Ingredients Quantity per tablet, mg

Active substance - 400

Corn starch - 50

Lactose - 145

Magnesium stearate - 5

The above ingredients are mixed until homogeneous and pressed into the form of a set of individual tablets. If you are using trihydrochloride salt requires 486 mg of salt.

Other compounds of formula I, such as is obtained in accordance with the methods described in examples 1-6 can be used as active substances for obtaining the compositions of this example for oral administration.

Example 9

This example illustrates obtaining typical pharmaceutical compazine-1-yl] -2-hydroxypropoxy}quinoline.

Suspension for oral administration is prepared on the basis of the following composition:

Ingredients - Number

Active substance - 1.0 g

Fumaric acid 0.5 g

Sodium chloride, 2.0 grams

Methylparaben 0.1 g

Granulated sugar - 25,5 g

Sorbitol (70% solution) - is 12.85 g

Veegum K (Vanderbilt Co.) - 1.0 g

Corrigent - a 0.035 ml

Dyes - 0.5 g

Distilled water - D. K. to 100 ml

If to obtain a suspension is used trihydrochloride requires 1,215 g of salt. Other compounds of formula I, such as is obtained in accordance with the methods described in examples 1-6 can be used as active substances for obtaining the compositions of this example for oral administration.

Example 10

This example illustrates obtaining typical pharmaceutical compositions containing the active substance of the formula I, for example, (2R)-anti-5-{ 3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl] -2-hydroxypropoxy}quinoline.

Injectable drug, buffered to pH 4, is prepared on the basis of the following composition:

Ingredients - Number

Active substance: 0.2 g

Buffer solution of sodium acetate (0.4 M) - 2.0 ml

HCl (1N) - D. K. to pH 4

Water (SW is uflorida salt, you need 0,243 g of salt. Other compounds of formula I, such as is obtained in accordance with the methods described in examples 1-6 can be used as active substances for obtaining injectable compositions of this example.

Example 11

This example illustrates obtaining typical pharmaceutical compositions containing the active substance of the formula I, for example, (2R)-anti-5-{ 3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl] -2-hydroxypropoxy}quinoline.

A suppository of total weight 2.5 g is prepared on the basis of the following composition:

The active substance is 500 mg

Witepsol H-15*- balance

(*triglycerides of saturated fatty acids of vegetable origin; product firms Riches-Nelson, Inc., New York, N. Y.).

If you are using trihydrochloride salt requires 607 mg of salt. Other compounds of formula I, such as is obtained in accordance with the methods described in examples 1-6 can be used as active substances for obtaining suppozitornyj compositions of this example.

Example 12

Determination of stability at acidic pH

The test compound (15 mg) was dissolved in 3 ml of 0.01 N. HCl (pH 2) and incubated at 37o1/2:

MS-073 (U.S. patent 5112817), t1/2= 15 min,

(2R, S)-anti-5-{ 3-[4-(10,11-methandienone-5-yl)piperazine-1 - yl]-2-hydroxypropoxy}quinoline, t1/2= 2.5 h,

(2R, S)-5-{3-[4-(10,11-diversitydialogues-5-yl)piperazine-1 - yl]-2-hydroxypropoxy}quinoline, t1/272 h, and

(2R, S)-anti-5-{ 3-[4-(10,11-chlormethiazole-5-yl)piperazine-1 - yl] -2-hydroxypropoxy}quinoline, t1/272 hours

When testing the specified connection method according to the present invention exhibit greater stability at acidic pH compared to MS-073.

Example 13

The definition of activity in vitro using quantitative analysis MTT

This method is a modification of the analysis, described in Mosmann, T. Rapid Colorimetric Assay For Cellular Growth And Survival: Application to proliferation and cytotoxity assays", J. Immunol. Meth., so 65, 55 to 63, (1983).

Strain cells (0.3 ml) containing resistant to many Lakers is on Wednesday (2.7 ml), containing the test compound or the control medium in the presence or in the absence of adriamycin (1 μg/ml). Aliquots (0.1 ml) of cell suspension is then placed in eight holes on each of the three 96-well plates for micrometrology. After incubation in a tissue culture incubator at 37oC take one tablet in each of the following time points: 24 hours, 48 hours and 72 hours. After removal from the incubator into each well of the tablet, which is then returned to the incubator for 3 hours, add 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium, MTT (10 μl of a solution of the strain with a concentration of 5 mg/ml in phosphate buffered saline solution).

Crystals formazan formed in the activity of mitochondrial enzymes in living cells, solubilizing by removing the medium and adding DMSO (150 μl/well) with stirring carried out on the orbital vibrator. A570 (the corresponding wavelength of 650 nm) is read by the reader Molecular Devices microplate and the results expressed as percent of control media or to control adriamycin daily or in the form of a graph in time A570.

Compounds of the present invention show and is Suber-5-yl)piperazine-1 - yl] -2-hydroxypropoxy} quinoline more than 3 times more MS-73; the corresponding (2S)-anti-isomer is approximately 1.7 times more active than MS-73, and (2R,S)-anti-a mixture of approximately 1.6 times more active than MS-73.

Example 14

The definition of activity in vivo using quantitative analysis of MDR (resistance to many drugs)

This method is a modification of the analysis described Slate and Michelson in Drug Resistance Reversal Strategies: A Comparison of Experimintal Data With Model Predictions", J. Natl. Cancer Inst., so 83, 1574-1580 (1991).

Mice (B6D2F1, 7-8 weeks females, weighing approximately 20 g, Jackson laboratory) were selected at random, weighed and divided into groups of 6-7 animals in each. In the beginning of the experiment (day 0) of each mouse was injected intraperitoneally resistant to many drugs murine leukemia cells P388/ADR, 2,4 107cells/ml two hours Later, each mouse implanted intraperitoneally 7 days minimalis Alzet model 2001, Alza Corporation, Palo Alto, CA) containing vehicle (DMSO/SFR) plus adriamycin (3 mg/kg/day), one of the test compound (30 mg/kg/day) or adriamycin plus the test compound (0.3, 3, 10 and 30 mg/kg/day). The condition of the mice was monitored daily and recorded mortality, starting with the 7 days. Longer survival compared to the group is inane of the present invention are active when ispitivanje the specified method. More specifically, the compound (2R)-anti-5-{3-[4-(10,11-diversitydialogues-5-yl)piperazine-1 - yl] -2 hydroxypropoxy} quinoline more than 4 times more MS-73; and the corresponding (2S)-anti-isomer is approximately 1.3 times more active than MS-73.

In addition, the analysis in respect of uterine sarcoma human connection (2R)-anti-5-{3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl]-2-hydroxypropoxy}quinoline 3 times more active than MS-73.

Example 15

The toxicity of the compounds of the formula I

Mice received (2R)-anti-5-{ 3-[4-(10,11-diversitydialogues-5 - yl)piperazine-1-yl] -2-hydroxypropoxy}quinoline intravenous injection of a test dose of a substance once a day for two weeks, doses of 0 (vehicle: 5 weight. % by volume of mannitol in purified water), 10, 30 and 100 mg/kg, All mice in groups 0, 10 and 30 mg/kg survived. All mice treated with 100 mg/kg, showed muscle spasm, and they died after a single application dose. The cause of death has not been determined.

1. Derivatives of 10,11-MetaDimension formula 1

< / BR>
where a denotes-CH2-CH2-, -CH2-Rand-CH2- where Randdenotes H, HE, or lower acyloxy, or-CH2-Rand-CH2Rb-CH2- oznachaet N, F, Cl or Br;

R2denotes H, F, Cl or Br;

R3denotes heteroaryl consisting of two condensed rings containing 1 to 3 heteroatoms selected from N, O or S,

or their pharmaceutically acceptable salts.

2. The compound or salt according to p. 1, where R3means chinolin or benzofurazanyl.

3. The compound or salt according to p. 2, where R3denotes 5-chinolin.

4. The compound or salt according to PP.1 to 3, where Randor RbIT denotes.

5. The compound or salt according to p. 4, where a denotes-CH2-Rand-CH2and RandIT denotes.

6. Connection on p. 1 having the formula

< / BR>
or its pharmaceutically acceptable salt.

7. Connection on p. 1 having the formula

< / BR>
or its pharmaceutically acceptable salt.

8. Connection on p. 1 having the formula

< / BR>
or its pharmaceutically acceptable salt.

9. Derivatives of 10,11-MetaDimension or their salts on PP.1 - 8 with chemosensitizing activity.

10. Derivatives of 10,11-MetaDimension formula I or their pharmaceutically acceptable salts under item 1, characterized in that they receive: (a) the condensation of the compounds of formula 4
2-Rand-CH2where RandIT denotes,

with the subsequent transformation if necessary, their pharmaceutically acceptable salts, or by condensation of compounds of formula 4

< / BR>
with the compound of the formula 9

X-(CH2)mOR SIG3,

where R1, R2, R3have the above values, m = 2, 3, or 4, and X denotes halogen,

obtaining the compounds of formula I, And indicates in which-CH2-CH2-, -CH2-CH2-CH2or-CH2-CH2-CH2-CH2or their pharmaceutically acceptable salts; (b) condensation of the epoxide of formula 10

< / BR>
where R1and R2have the above values,

with the compound of the formula R3HE, where R3has the above value, obtaining the compounds of formula I in which R1, R2and R3have the above meanings and a represents a radical-CH2-Rand-Rb-CH2- where Randmeans hydrogen, and Rbmeans IT; (b) reaction of compounds of formula I, where Randor RbIT refers, with the lowest allelochemical formula R'-C(O)-X, where R' represents lower alkyl and X represents halogen or Rbdenotes lower acyloxy; (g) the interaction of the compounds of formula I with a pharmaceutically acceptable acid for the formation of the corresponding acid additive salt or (d) by the interaction of the acid additive salts of the compounds of formula I with a base for the formation of the corresponding free base of formula I.

11. Derived 10,11-MetaDimension formula I on p. 10, which represents a 5-{3-[4-(10,11-diversitydialogues-5-yl)piperazine-1-yl] -2-hydroxypropoxy} -quinoline, characterized in that it is produced by condensation of 1-(5-hinomisaki)-2,3-epoxypropane with 1-(10,11-diversitydialogues-5-yl)-piperazine.

12. 5-{3-[4-(10,11-diversitydialogues-5-yl)piperazine-1-yl]-2-hydroxypropoxy} -quinoline under item 10, characterized in that it is isolated in the form of (2R)-antisolar.

13. Chemosensitizers composition containing the active agent and pharmaceutically acceptable carrier, wherein the active agent contains a compound of General formula I or its salt PP.1 - 8 in therapeutically effective amounts.

14. Chemosensitizers composition on p. 13, characterized in that it additionally contains anticancer chemotherapy and lecapitaine, showing clinical resistance to anticancer chemotherapeutic agent, an active chemosensitizing agent, characterized in that as chemosensitizing agent connection is used for PP.1 to 9, in an effective amount.

16. The method according to p. 15, characterized in that the introduction of chemosensitizing compound or its salt according to PP.1 to 9 and 13 is carried out simultaneously, separately or sequentially a therapeutically effective amount of an antitumor chemotherapeutic agent, the resistance which must be overcome.

17. The method of treatment of neoplastic diseases, comprising the administration to a mammal an antitumor chemotherapeutic drugs and chemosensitizing agent, characterized in that as chemosensitizing agent use connections on PP.1 to 9, which is administered in an effective amount together with the anticancer drug.

 

Same patents:

- aminohydroxylation and carboxylic acid" target="_blank">

The invention relates to new compounds of General formula I, where Q, A, R1n, m are listed in the value formula

The invention relates to a derivative of 7- (alkoxycarbonyl-substituted) -10-hydroxy-taxan following formula 3b:

< / BR>
in which R1, R2, R4, R5, R6and R14defined above

The invention relates to benzothiophene compounds of formula I, where R1-H, - OH, -O(C1-C4alkyl), - EA6H5-, OCO(C1-C6alkyl), or-OSO2(C2-C6alkyl);

R2IS-H, -OH, -O(C1-C4alkyl), EA6H5, CCA(C1-C6alkyl) , -OSO2(C2-C6alkyl), or halogen; R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1 hexamethyleneimino; n = 2 or 3; Z Is-O - or-S-, or their pharmaceutically acceptable salts

The invention relates to new substituted heterocyclic compounds, process for the preparation of these compounds and pharmaceutical compositions containing them as active substances

The invention relates to new Amida condensed terracarbon acid of General formula I, where G is Q(C)k-W-(C)m-Z, Q is phenyl, 2-, 3-, 4-pyridyl, which may be substituted; T is halogen, hydrogen, hydroxyl, amino, C1-C6alkoxy; W is-O-, -N-, -S-, CR7R8where R7and R8the same or different and represent H, C1-C6alkyl; X is hydrogen; Z is hydroxyl, C1-C6alkoxy, C3-C7cycloalkylation, NH2and other, NR9COR10where R9and R10the same or different represent H, C1-C6alkyl, etc

The invention relates to an improved method for producing a magnesium salt of substituted sulfinil-heterocyclic compounds containing imidazole group corresponding to the formula (I), where Ar represents (a) or (b); Z represents a (c) or (d), and X is an (e) or (f), where N inside the benzene ring of the benzimidazole group means that one of the carbon atoms of substituted radicals R7-R10may may be replaced by a nitrogen atom without any substituents; R1, R2and R3are the same or different and selected from hydrogen, alkyl, alkylthio, alkoxy, possibly substituted by fluorine, alkoxyalkane, dialkylamino, piperidino, morpholino, halogen, phenylalkyl, funeralcare, where alkyl and alkoxygroup can be branched or linear and may contain cyclic alkyl groups, such as cycloalkylcarbonyl; R4and R5are the same or different and selected from hydrogen, alkyl and aralkyl; R6is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy; R7-R10are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, halogenoalkane, alkylcarboxylic, alkoxycarbonyl, ACS is ü optionally substituted; R11represents hydrogen or forms alkylenes circuit with R3and R12and R13are the same or different and selected from hydrogen, halogen, alkyl or alkoxygroup where alkoxygroup can be branched or normal C1- C9-chains, and alkyl and alkoxygroup may contain cyclic alkyl groups, such as cycloalkenyl, which replaced sulfinil-getall formula I are mixed together with a weak base selected from the group consisting of organic amines and ammonia, and a source of magnesium selected from the group consisting of magnesium acetate, magnesium nitrate, magnesium sulfate, carbonates of magnesium and magnesium chloride

-alaninemia and their derivatives, method for the treatment glycolipoprotein diseases, the prevention of ischemic myocardial damage, the pharmaceutical composition" target="_blank">

The invention relates to derivatives of indole-2-carboxamide that can be used as inhibitors of glycogen phosphorylase, and to methods of treatment of glycogenolysis-dependent diseases or conditions using these compounds and pharmaceutical compositions containing these compounds

The invention relates to new derivatives of azetidinone General formula (I) in which R, R1, Ar1-Ar3X, Y, m, n, q and r are specified in the claims values, and their pharmaceutically acceptable salts, which are the active ingredient of the pharmaceutical composition with anti-atherosclerotic or hypocholesterolemic activity

The invention relates to new niftystories compounds of formula I, where R1and R2- H, -OH, -O(C1-C4alkyl), -OCOC6H5, -OCO(C1-C6alkyl), -OSO2(C4-C6alkyl); R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, 1 hexamethyleneimino; intermediate compounds, which are suitable for easing symptoms of postmenopausal syndrome, including osteoporosis, hyperlipemia and estrogenzawisimy cancer, and inhibition of uterine fibroids, endometriosis and proliferation of aortic smooth muscle cells
Up!