Amines to obtain drugs intended to prevent the proliferation of tumor cells

 

(57) Abstract:

The invention relates to medicine and relates to the use of CIS-N-cyclohexyl-N-ethyl-[-3-(3-chloro-4-cyclohexylphenol)- allyl]amine, or its pharmaceutically acceptable salt, or MES to obtain farbkomposition for the treatment of diseases caused by the proliferation of tumor or cancer cells, as well as farbkomposition intended for the treatment of these diseases. This composition has a high antitumor activity. 2 S. and 4 C.p. f-crystals, 2 ill., table 4.

The present invention relates to a new use of compounds having suitable binding affinity to the receptors on which is fixed CIS-N-cyclohexyl-N-ethyl-[3-(3-chloro-4-cyclohexylphenol)allyl] amine, as well as to new compounds with the same properties.

CIS-N-cyclohexyl-N-ethyl-[3-(3-chloro-4 - cyclohexylphenol)allyl] amine, known under the code name CM 31747 or SR 31747 and denoted below as "SR 31747", is described in European patent 376850, which States its immunosuppressive activity.

Found that SR 31747 prevents the proliferation of cancer cells and, therefore, exhibits antitumor activity.

Balearen, any product that can displace labeled with tritium SR 31747 from its receptors in tumor cells, prevents cell proliferation. In particular, it was found that compounds capable of displace labeled with tritium SR 31747 (below referred to as the "3H-SR 31747") from its receptor sites, possess anti-proliferative cellular activity.

Thus, according to one aspect of the present invention relates to the use of compounds able to displace labeled with tritium CIS-N-cyclohexyl-N-ethyl-[3-(3-chloro-4 - cyclohexylphenol)allyl]amine from its receptors, to pharmaceutical compositions intended for the provision of anti-cell proliferation. The ability contemplated for use according to the present invention compounds to displace labeled with tritium SR 31747 of its receptors can be easily identified by biochemical using 3H-SR 31747 and its fixation in the cells.

This determination can be performed using the selected accordingly tumor cells, preferably among the cell lines, which are easily proliferate in vitro, as, for example, cells of human myeloma, kidney cancer or lung of a person, or even when using the conditions, allowing you to obtain consistent and reproducible results, according to the context of the present invention is arbitrarily chosen line of tumor cells in the breast of man "MCF-7".

Also according to the context of the present invention randomly selects 3H-SR 31747, in which tritium is fixed on vanilinovoi communication, however, SR 31747 may be marked in any way, since the label is only used to monitor the displacement of the product from its receptors.

Determination of ability to displace3H-SR 31747 of its receptors in the cells, especially in the case of cell line MCF-7, carry out experiments on the total binding and specific binding.

According to the present invention, any product which is subjected to preliminary of the above operations can displace3H-SR 31747 of its receptors, can be used to produce pharmaceutical compositions against cell proliferation.

SR 31747, first, can displace 3H-SR 31747 of its receptors and has a high inhibitory activity against cell proliferation.

In particular, the object of the present invention is the use of the Lil]amine from its receptors, selected from the group consisting of:

(a) amines of the formula (I)

< / BR>
in which

R1means a hydrogen atom or a halogen atom;

R2means cyclohexyl;

R3means cycloalkyl with 3-6 carbon atoms;

R4means a hydrogen atom, alkyl with 1-6 carbon atoms or cycloalkyl with 3-6 carbon atoms;

A represents a group chosen among the following groups: -CO-CH2-, -CH(C1)-CH2-, -CH(OH)-CH2-, -CH2-CH2, -CH=CH-, -CC-;

b) pharmaceutically acceptable salts of joining amines of the formula (I);

b) amines of the formula (II)

< / BR>
in which

Aameans a group selected among the following groups:

-CO-CH2-, -CH(OH)-CH2-, -CH=CH-, -CC-;

R1ameans hydrogen or halogen;

R2ameans cyclohexyl;

d) pharmaceutically acceptable salts of joining acids amines of the formula II;

d) amines of the formula (III)

< / BR>
in which

R1bmeans a hydrogen atom or a halogen atom;

R2bmeans cyclohexyl;

R3bmeans a hydrogen atom or alkyl group with 1-3 carbon atoms;

R4bmeans an alkyl group with 1-3 carbon atoms, equal or different from the alkyl group which with the nitrogen atom, to which they are attached, a 5-7 membered heterocyclic group selected among piperidino, morpholino and pyrrolidino;

Abmeans the group-CH2CH2- or-CH=CH-;

e) pharmaceutically acceptable salts of joining acids amines of the formula (III);

g) amines of the formula (IV)

< / BR>
in which

Ar1means phenyl, naftalina, substituted phenyl or substituted naftalina group;

n means an integer number, including numbers from 1 to 4;

RB denotes an alkyl group, and in this case, Awithmeans of simple communication; and

RA and RC are the same or different, independently of one another mean a hydrogen atom or a group chosen among halogen atoms, alkyl, substituted by one or more halogen atoms of the alkyl and alkoxyl; or

RB and RC together form a bridge -(CH2)p- where p is 0, 1 or 2, and in this case, RA denotes hydroxyl or CNS group in position 5 containing aromatic cycle, or RA means a hydrogen atom or halogen in any position of the aromatic cycle; or

RB and RC together form a bridge-CH=, and communication, which he linked to the aromatic cycle is a simple relationship, and in this case, Awithoznaczenie 5 containing aromatic cycle; or

RB and RC together form a bond and then ANDwithmeans a group of the formula

< / BR>
moreover, the carbonyl is bound with oxygen and adjacent relationship ANDwithwith containing side chain carbon atom is a double bond, and in this case, RA means a hydrogen atom or a hydroxyl or CNS group;

when RB denotes an alkyl group, each of X and Y means a hydrogen atom or together with the containing carbon atom, they form a group C=O, and RD denotes a hydrogen atom or alkyl group;

when RB and RC form a bridge, each of X and Y means a hydrogen atom, and RD, which exists only when all links carrying its carbon atoms are simple links, means a hydrogen atom; provided that

the terms "alkyl" and "alkoxy" means a linear or branched saturated group with 1-6 carbon atoms;

the term "substituted" relating to phenyl and naftalina deputies, means that they can be substituted by 1-3 groups selected from among hydroxyl, alkyl, substituted by one or more atoms of halogen of the alkyl, alkoxyl and halogen;

3) pharmaceutically acceptable salts and solvate amines of the formula (IV);

and) amines of the formula (V)

< / BR>
W is ftil or phenyl, substituted by 1-3 groups selected from among hydroxyl, (C1-C6) - alkyl, alkoxyl, halogen and alkyl, and substituted by one or more atoms of halogen alkyl;

each of X' and Y' denotes a hydrogen atom or together they form oxoprop;

RE means (C1-C6)-alkyl group;

their isomers in individual form or in the form of a mixture;

C) pharmaceutically acceptable salts and solvate amines of the formula (V);

l) amines of the formula (VI)

< / BR>
in which

R3cmeans hydrogen or (C1-C3)-alkyl;

R1cand R2cidentical or different, chosen among hydrogen, hydroxyl, (C1-C3)-alkyl, (C1-C3)-alkoxyl, halogen and cyanopropyl;

V1and V2together form a double bond associated with the oxygen atom or hydroxyisopropyl N-OH, or they are connected to Ethylenedioxy - O-CH2-CH2-O-;

Admean valence bond, an oxygen atom, methylene group or ethylene group;

m' stands for zero, 1 or 2;

n' represents an integer from 1 to 5;

m) pharmaceutically acceptable salts of joining acids amines of the formula (VI);

n) amines of the formula VII

< / BR>
in which

m is aryl, chosen among phenyl, naphthyl and tanila, possibly mono - to trisemester halogen, trifluoromethyl, (C1-C3)-alkyl, (C1-C3- alkoxyl;

a) pharmaceutically acceptable salts of joining acids amines of the formula (VII);

p) amines of the formula (VIII)

< / BR>
in which

one of L and L' represents hydrogen and the other is chosen among hydrogen, fluorine, chlorine or nitro, or each of both L and L' represents a chlorine atom;

Z means:

(i) a group of structure (1)

< / BR>
in which

G1means (C1-C6)-alkyl or (C3-C7-cycloalkyl;

G2means (C1-C6)-alkyl, (C3-C6-cycloalkyl-(C1-C3)-alkyl, (C3-C7-cycloalkyl; phenyl, benzyl, finitely radical, possibly substituted in the benzene group of radical halogen, a methoxy group or a nitro-group;

or G1and G2together with the nitrogen atom to which they are bound, form containing one atom of nitrogen saturated with bridged or Spiro structure, a heterocycle with 5 to 10 carbon atoms; morpholinopropan; piperazinone, unsubstituted or substituted in position 4 (C1- C4)-alkyl, phenyl, benzyl or dryer is; group selected among 4-phenyl - 1,2,3,6-tetrahydropyridine-1-ilen radical, 4-phenylpiperidine, 4-benzylpiperidine, 4-phenotypegenotype, and the phenyl group of the above radicals may be substituted or substituted with halogen, a methoxy group or a nitro-group;

(ii) a group of structure (2)

< / BR>
in which

G3means hydrogen or hydroxyl;

G4means hydrogen;

or G3and G4together form one or two links so that together with the carbon atoms to which they are linked, they form vanilinovoi group or ethynylene group;

G5means a group selected among phenyl, benzyl, penicillinase radical, and the benzene group of the aforementioned radicals may be substituted or substituted by a halogen atom, a methoxy group or a nitro-group;

G6means a hydroxyl group or hydrogen;

G6and G7mean hydrogen or can form a connection;

or G5and G6together form n - Panteleeva group;

(iii) group structure (3)

< / BR>
in which

G3and G4have the above meanings;

Alk means (C1-C6)- alkyl or (C3-C6SUB>1-C3) -alkyl or a group chosen among phenyl, benzyl, 2-fenetylline radical, and the benzene group of the aforementioned radicals may be substituted or substituted with halogen, a methoxy group or a nitro-group;

or Alk and G8identical or different, mean (C4-C6)-alkyl group;

and G8does not imply (C3-C6-cycloalkyl, when L is hydrogen or fluorine atom or chlorine, L' is hydrogen and Alk means (C1-C6) -alkyl;

R) pharmaceutically acceptable salts and solvate amines of the formula (VIII).

Connection, the use of which is claimed according to the present invention, partially described in the literature.

In particular, amines of the formula (1) and their pharmaceutically acceptable salts are described in European patent 376850; the above amines can be obtained, as illustrated in this document, and allocated in the form of a Foundation, salt and/or solvate. Amines of formula (II) and their pharmaceutically acceptable salts are described in European patent 461986; the above amines can be obtained, as illustrated in this document, and allocated in the form of a Foundation, salt and/or solvate. Amines of formula (III) and their pharmaceutical what about this document, and allocated in the form of a Foundation, salt and/or solvate. Amines of formula (IV) and their pharmaceutically acceptable salts are described in European patent 702010; these amines can be obtained, as illustrated in this document, and allocated in the form of a Foundation, salt and/or solvate. Amines of formula (V) and their pharmaceutically acceptable salts are described in European patent 707004; the above amines can be obtained, as illustrated in this document, and allocated in the form of a Foundation, salt and/or solvate. Amines of formula (VI) and their pharmaceutically acceptable salts are described in European patent 581677; these amines can be obtained, as illustrated in this document, and allocated in the form of a Foundation, salt and/or solvate. Amines of formula (VII) and their pharmaceutically acceptable salts are described in international application 95/15948; these amines can be obtained, as illustrated in this document, and allocated in the form of a Foundation, salt and/or solvate.

Compounds of groups (n) and (p) of particular interest are new and constitute another aspect of the invention.

Thus, the invention also relates to new compounds which displace3H-SR 31747 of its receptors and the SS="ptx2">

More specifically, an object of the invention is an amine selected from the following compounds:

(A) compound of formula (VIII)

< / BR>
in which

one of L and L' represents hydrogen and the other is chosen among hydrogen, fluorine, chlorine or nitro, or both L and L' denote a chlorine atom;

Z means:

(i) a group of structure (1)

< / BR>
in which

G1means (C1-C6-alkyl or (C3-C7-cycloalkyl;

G2means (C1-C6)-alkyl, (C3-C6-cycloalkyl-(C1-C3)-alkyl, (C3-C7-cycloalkyl; phenyl, benzyl, finitely radical, possibly substituted in the benzene group, a halogen, a methoxy group or a nitro-group;

or G1and G2together with the nitrogen atom to which they are bound, form containing one atom of nitrogen saturated with bridged or Spiro structure of a heterocycle with 5 to 10 carbon atoms; morpholinopropan; piperazinone, unsubstituted or substituted in position 4 (C1- C4)-alkyl, phenyl, benzyl or penecillin radical, and the benzene group may be substituted with halogen, a methoxy group or a nitro-group; a group selected among 4-phenyl - 1,2,3,6-tetrahydropyridine is supplemented flax group of the above groups may be substituted or substituted with halogen, a methoxy group or a nitro-group;

(ii) a group of structure (2)

< / BR>
in which

G3means hydrogen or hydroxyl;

G4means hydrogen;

or G3and G4together form one or two links so that together with the carbon atoms to which they are linked, they form vanilinovoi group or ethynylene group;

G5means a group selected among phenyl, benzyl, penicillinase radical, and the benzene group of the aforementioned radicals may be substituted or substituted by a halogen atom, a methoxy group or a nitro-group;

G6means a hydroxyl group or hydrogen;

G6and G7mean hydrogen or can form a connection;

or G5and G6together form n - Panteleeva group;

and G6means a hydroxyl group, and G5and G7can form a link only when G5has a different meaning than possibly substituted benzyl or phenethyl;

(iii) group structure (3)

< / BR>
in which

G3and G4have the above meanings;

Alk means (C1-C6)- alkyl or (C3-C6)-alkenyl;

G8mean 1-substituted, (C3
or Alk and G8identical or different, mean (C4-C6)-alkyl group;

and G8does not imply (C3-C6- cycloalkyl, when L is hydrogen or fluorine atom or chlorine, L' is hydrogen and Alk means (C1-C6)-alkyl;

(B) a pharmaceutically acceptable salt and solvate of the compounds of the formula (VIII).

These new compounds of the formula (VIII) halogen preferably is chlorine or fluorine, and one of L and L' represents hydrogen and the other is fluorine, chlorine or nitro-group, or L and L' are identical and denote hydrogen or chlorine. These compounds are particularly preferred.

Especially preferred compounds are the compounds of formula (VIII) in which Z means:

(i') group structure (1')

< / BR>
in which

G'1means (C1-C6)-alkyl or (C3-C7- cycloalkyl;

G'2means (C1-C6)-alkyl, (C3-C7-cycloalkyl-(C1-C3)-alkyl, (C3-C7-cycloalkyl and ukazannyh radicals may be substituted or substituted with halogen, a methoxy group or a nitro-group;

or G'1and G'2together with the nitrogen atom to which they are bound, form morpholinopropan, pyrrolidinone, piperidine, hexahydroazepin or a group chosen among 4-phenyl-1,2,3,6-tetrahydropyridine-1-ilen radical, 4 - phenylpiperidine, 4-benzylpiperidine, 4-phenotypegenotype, and the phenyl group of the above groups may be substituted or substituted with halogen, a methoxy group or a nitro-group;

(ii') a group of structure (2')

< / BR>
in which

G'3and G'4mean hydrogen or together form a bond in the TRANS configuration or, preferably, Cys;

G'6and G'7mean hydrogen; and

G'5means phenyl or benzyl;

or G'5and G'6together form a 1,5-Panteleeva group;

(iii') group structure (3')

< / BR>
in which

G'3and G'4have the above meanings;

Alk" means (C1-C6)-alkyl;

G'8mean 1-adamantanol, phenyl, benzyl or 2-phenylethylene group;

or Alk" and G'8are the same and each means (C4-C6)-alkyl group;

and their pharmaceutically acceptable cm, that:

any functional derivative cyclopropanecarbonyl acid of formula (IX)

< / BR>
in which L and L' have the above values, enter into interaction with the amine of formula (X)

< / BR>
in which G1and G2have the above values, and then the thus obtained amide of the formula (XI)

< / BR>
subjected to restore to highlight the amines of formula (VIII) in which Z stands for a group of structure (1), in the form of free bases or pharmaceutically acceptable salts;

any compound of the formula (XII)

< / BR>
in which L and L' have the above values, enter into interaction with formaldehyde and an amine selected among the amines of formula (XIII) and (XIV)

< / BR>
< / BR>
and, if necessary, the thus obtained product of formula (VIII) in which Z stands for a group of structure (2) or (3) where G3and G4together form two links so that with the carbon atoms to which they are linked, they form ethynylene group, is subjected to hydrogenation using two or one mole of hydrogen to select an appropriate compound of formula (VIII) in which Z stands for a group of structure (2) or (3), respectively where both G3and G4means a hydrogen atom or together with durasol the resulting product of formula (VIII), in which Z represents a group of structure (2), where G5means phenyl, G6means hydroxyl and G7means hydrogen, is subjected to dehydration to isolate the compounds of formula (VIII) in which Z represents a group of structure (2), where G5means phenyl and G6and G7together form a bond, and the above compounds may be isolated in free base form or one of their pharmaceutically acceptable salts or one of their pharmaceutically acceptable solvate;

any acetophenone of the formula (XV)

< / BR>
in which L and L' have the above values, enter into interaction with formaldehyde and an amine of the above formula (XIII) or (XIV), and then the thus obtained product of formula (XVI)

< / BR>
in which L and L' have the above meanings and Z' represents a group of structure (2') or (3')

< / BR>
< / BR>
where Alk", G'5, G'6, G'7and G'8have the above meanings, is subjected to reduction reaction of ketogroup to highlight the corresponding compounds of formula (VIII) in which Z represents a group of structure (2) or (3) where G3means hydroxyl and G4means hydrogen, and then, if necessary, thus Anil, G6means hydroxyl and G7means hydrogen, is subjected to dehydration to obtain a compound of formula (VIII) in which Z represents a group of structure (2), where G5means phenyl and G6and G7together form a bond; and the above-mentioned compounds may be isolated in free base form or one of its pharmaceutically acceptable salts and, if necessary, the free base of formula (VIII) are converted into their pharmaceutically acceptable salts.

The interaction of the functional derivative of the acid of formula (IX) with an amine of formula (X) are carried out by classical methods for obtaining amides. As a functional derivative of the acid of formula (IX) you can use any commonly used in the chemistry of peptides connection, as, for example, acid chloride, anhydride or mixed anhydride, for example, with monoethylene ether carboxylic acid (obtained by reacting the acid of formula (IX) with etelcharge.com), activated complex ester or activated amidon. When the functional derivative using the acid chloride or anhydride, may be preferable to work in the presence of a tertiary amine, such as, for example, treefree amide to amine, using as reducing agent, the metal hydride, such as sociallyengaged or borane. The interaction between the acetylene derivative of the formula (XII) or acetophenone formula (XV) and amines of formula (XIII) and (XIV) in the presence of formaldehyde is carried out in a classical reaction conditions, manniche.

The recovery of the compounds of the formula (VIII) in which Z represents one of the groups of the structure (2) or (3) where3and G4form two communication carried out by hydrogenation using one mole of hydrogen to obtain the compounds of formula (VIII) (Z represents a group of structure (2) or (3) where G3+ G4form a bond CIS-configuration) or by using two moles of hydrogen to obtain a saturated compounds.

The recovery of the compounds of formula (XVI) for compounds of formula (VIII) in which Z represents one of the groups of the structure (2) or (3) where G3means hydroxyl and G4means hydrogen, carried out by classical methods. When you want to get a hydroxyl compound with a specific configuration at the chiral carbon atom, can be used stereospecific reducing agent.

When gidrauxilirovanne then derived on the structure (2) or (3), where G3and G4form a relationship, the spatial configuration plays no role and the recovery of the compounds of formula (XVI) can be carried out, for example, using sodium borohydride.

Possible dehydration of the compounds of formula (VIII) in which Z represents one of the groups of the structure (2) or (3) where G3means hydroxyl and G4means hydrogen, is carried out by heating in the presence of agents or devices that favor the removal and/or purification of water, for example, using the nozzle Dean-stark.

The thus obtained saturated compound of the formula (VIII) has the TRANS-configuration. This connection in turn can be gidrirovanie to obtain an amine of formula (VIII) in which Z represents one of the groups of the structure (2) or (3) where G3and G4mean hydrogen.

The source of the acid of formula (IX) and their functional derivatives, as well as amides of the formula (XI) are new products that can be obtained from 4-(4-cyclohexyl-3,5-L-L'-phenyl)-4-oxobutanoic acid.

More specifically, the acid of formula (IX) is obtained by recovery ketogroup 4- (4 - cyclohexyl-3,5-L-L'-phenyl)-4-oxobutanoic acid (where L and Yu turned into its lactone. This last glorious and converted into ester 4-chloro-4-(4-cyclohexyl-3,5-L-L'-phenyl) butane acid, which in turn by cyclization gives cyclopropanecarbonyl acid of formula (IX).

4-(4-Cyclohexyl-3,5-L-L'-phenyl)-4 - oxobutanoic acid (where L and L' have the above meanings) are obtained as follows:

when L and L' denote hydrogen, according to the method of N. P. Buu-Hoi and other Bull. Soc. Chim. France, 127 (1944);

when L is hydrogen, and L' denotes chlorine, according to the methodology F. Krausz, and others, Arzneim.-Forsh., 24, 1364-1367 (1974); BE 750233;

when L is hydrogen, and L' means the nitrogroup, according to the methodology BE 750233;

when L and L' denote chlorine, according to the methodology F. Krausz, and others, Arzneim.-Forsh., 24, 1364-1367 (1974);

when L is hydrogen, and L' denotes fluorine, by catalytic hydrogenation of 3-(4-cyclohexyl-3-fluoro)benzoylacrylic acid, in turn, is described in the Japan patent 75770/71 and the Federal Republic of Germany patent 2103749.

Thus, the acid of formula (IX) can be obtained by the method, according to which:

- 4-oxobutanoic acid of the formula (XVII)

< / BR>
in which L and L' have the above values, restore using alkali metal borohydride;

thus obtained 4-hydroxybutanoic acid Horny lactone of the formula (XIX)

< / BR>
is treated with thionyl chloride, highlighting in (C1-C4) alkanol, ester of formula (XX)

< / BR>
in which Alk' means (C1-C4)-alkyl;

thus obtained compound of formula (XX) cyclist by heating in the presence of potassium tert-butylate and allocate cyclopropanecarbonyl acid of formula (IX).

Acid of formula (IX), and their salts, functional derivatives, especially the acid chloride, the anhydride and the mixed anhydride with mono- (C1-C4) -alkylbis ether carboxylic acids, and amides of the formula (XI) are new products, which constitute another aspect of the present invention.

Thus, the present invention also relates to the compound of formula (XXI)

< / BR>
in which L and L' have the above meanings, and W denotes a hydroxyl group or a group of the structure-NG1G2where

G1means (C1-C6)-alkyl or (C3-C7-cycloalkyl;

G2means (C1-C6)-alkyl, (C3-C7-cycloalkyl, (C3-C6-cycloalkyl- (C1-C3)-alkyl; phenyl, benzyl, finitely radical, possibly substituted in the benzene group of radical halogen, metakit containing one nitrogen atom a saturated, having bridged or Spiro structure, a heterocycle with 5 to 10 carbon atoms; morpholinopropan, piperazinone, unsubstituted or substituted in position 4 (C1-C4)-alkyl, phenyl, benzyl or penecillin radical, and the benzene group may be substituted with halogen, a methoxy group or a nitro-group; a group selected among 4-phenyl-1,2,3,6 - tetrahydropyridine-1-ilen radical, 4 - phenylpiperidine, 4 - benzylpiperidine, 4 - phenotypegenotype, and phenyl groups of the above radicals can be substituted or substituted with halogen, a methoxy group or a nitro-group;

as well as salts of alkali metals, salts with secondary and tertiary amines and to functional derivatives of the acid of formula (XXI), where W stands for a hydroxyl group.

Among the alkali metal salts of compounds of formula (XXI), where W stands for hydroxyl group, particularly preferred is the sodium salt of (W = ONa), whereas among salts with secondary or tertiary amines are particularly preferred are salts of trimethylamine [W =-N+(CH3)3] and triethylamine [W = O-N+(C2H5)3] . Among the functional derivative of the acid forms of the particular acid chloride (W= chlorine), anhydride, mixed anhydrides from carboxylic or sulfonic acid, particularly those with mono-(C1-C4)-alkylbis ether carboxylic acid (W = O-COOAlk' where Alk' means (C1-C4)-alkyl, preferably ethyl) or n-toluensulfonate, and particularly preferred activated esters.

Especially preferred compounds of formula (XXI), in which the halogen is preferably chlorine or fluorine, one of L and L' represents hydrogen and the other denotes a fluorine, chlorine or nitro-group, or L and L' are identical and denote hydrogen or chlorine. Those preferred are such compounds in which, in formula (XXI), W stands for-OH, - ONa, O-N+(C2H5)3, Cl, O-COOAlk' [and Alk' means (C1-C4)-alkyl] or-NG1G2. According to biochemical and pharmacological research exposition of the compounds according to the invention in an environment with normal cells under conditions that inhibit proliferation of cancer cells, showed that the compounds do not act on such criteria as the integrity of cell structure and cell function or viability. Thus, these compounds have a high specification omicheskikh tumor cells in vitro and in vivo in mice. All the cells come from the international collection of type culture of ATSS. Cells MCF-7 is used to perform experiments on the binding.

Membranes prepared as follows: 109MCF-7 cell homogenized for 10 seconds in the transmitter station apparatus of thein 10 ml of Hepes buffer, pH = 7,4, containing: 210 mmol of D-mannitol, 70 mm sucrose, 1 mmol ethylenediaminetetraacetic acid, 0.3 mmol of phenylmethylsulfonyl. The homogenate was centrifuged at acceleration 650 g for 15 minutes, then the supernatant is taken and centrifuged for 1 hour at acceleration 100 000 g. The precipitate after centrifugation again suspended in buffer Tris-HCI, pH of 7.4, to a concentration of 1 mg/ml and stored at -70oC.

Full linking is carried out in vitro capacity of 5 ml, which is injected:

50 ál of a suspension of membranes containing 10-50 μg of protein;

- 175 μl of 50 mm Tris buffer, pH 7,4;

to 25 μl of 20 nm3H-SR 31747 in 50 mm Tris buffer, pH of 7.4, + 0,1% bovine serum albumin.

The nonspecific binding is carried out by adding 25 μl of 10-5M SR 31747 in the above-described solution (final volume 250 µl), followed by incubation for 30 minutes at a temperature of 25o

Used according to the invention compounds and new compounds show activity at IR50from 10-10up to 10-6the mole.

From other types of cells cultivated, usually in the medium of RPMI to which was added 10% fetal calf serum, the following cell lines: human myeloma U266 and RPMI 8226; carcinoma of human kidney 293; lung carcinoma human A; carcinoma human breast MCF-7, and MCF-7 lymphocytic leukemia person.

Antitumor activity determined by the colorimetric method using MTT { 3-(4,5 - dimethylthiazol-2,5-diphenyl) tetrazolium}, as described by Mosmann T., Journ. of Imm. Methods, 65, 55 (1983).

This colorimetric quantitative analysis allows us to quantitatively determine the antitumor activity of a solution containing used according to the invention the connection.

According to the used Protocol studies are sowing suspended cells (such as cells of a myeloma) 2,105 cells/ml per well with a capacity of 1 ml in a certain environment. Sowing adhesive cells (such as cells MCF - 7) produced by 5,104 cells/ml per well with a capacity of 1 ml of times and replace the specific environment. Certain environment meets the following medium: RPMI + 10 µg/ml insulin + 10 μg/ml human transferrin.

To implement this experience in the cells incubated in the presence of a solution containing the used connection for 5 days, then in the culture medium was added MTT.

Choose a time of 5 days, corresponds to the optimal exposure time. After cultivation for 5 days to determine cell proliferation using the above test. Measure the optical density at 570 nm. Blue colouring appears in the wells where cells are still viable. The intensity of colour developed is proportional to the number of living cells.

The results obtained are presented in table A.

The table shows that even low concentrations, such as 1 nmol 1 ámol, are sufficient to induce cessation of growth by 50%, and this effect reached in the case of all investigated tumor cells.

Established in vitro effect of inhibiting cell line MCF-7 was studied in vivo in a naked mouse by intraperitoneal injection in doses of 3 to 100 mg/kg on the model according to Neri S. and others, Cancer Research, 50, 5892-5897 (1990); and according Berebbi M., the growth in vitro and in vivo epithelial tumor cells of the breast and prostate.

The study is to assess the potential antitumor effects of SR 31747 on the growth of varieties of lines

cancerous epithelial cells of the mammary gland. A study carried out in vitro on cell cultures and in vivo after inoculation lines of tumor cells of the breast atonicheskoy "Nude" mouse.

Used cell lines are the following:

Hormonecuticura cell line MCF-7 is derived from the pleural allocation from mammary adenocarcinoma. Antiestrogenicity cells MCF-7LY2 obtained from cell line MCF-7 by selective exposure (pressure) in the presence of antiestrogen high affinity. Cell line MCF-7LCC1 and MCF - 7LCC2 are formed in naked mice after inoculation of MCF-7 cells. Both cell lines are estrogenozavisimymi. Cells MCF-7LCC2 are also antiestrogenicity. Cell line MCF-7AZTD5 comes from the line of MCF-7 cells after stable transfection with the oncogene H-ras. Cells MCF-7AZTD5 in vitro are antiestrogenicity. The combination of these cell lines incubated in a mixture of DMEM (modified by way of Dulbecco Wednesday Needle) / F 12 (volume ratio 1/1) containing 10% incomplete fetal calf serum and 16 exitmessage. Tumor epithelial cells in the breast MDA-MB are estrogenic and antiestrogen-insensitive. They are cultivated in the medium L-15 supplemented with 10% fetal calf serum, 1% essential amino acids, and 10 μg/ml human insulin.

The line of epithelial cells LnCaP, RS and DU145 come from prostatic adenocarcinoma. Only LnCaP cells are sensitive to hormones. All three cell lines were cultured in RPMI medium, supplemented with 10% fetal calf serum.

All cell line is maintained at a temperature of 37oWith in a humid atmosphere of a mixture of air with CO2(in the ratio of 95%/5%), except cells MDA-MB231, which are cultivated in the absence of CO2. The cell line is regularly inspected for the absence of Mycoplasma.

Inoculation and treatment of animals is as follows.

Used animals are ovariectomized or not females animicheskih "Nude" mice at the age of four weeks (R. Janvier). Before inoculation of the cells that are sensitive to hormones, breast cancer (MCF-7, MCF-7AZTD5) animals injected subcutaneously with 10 μl of 10-5M ethanol solution of estradiol. Processing resume three times during the week. One Milli subcutaneously in each of the thighs. The next day, animals injected with 200 µl of solution for injection (ethanol/tween 80/physiological serum in a volume ratio 1/1/18) containing various reagents in predetermined concentrations. Injections carry out IPR and renew every day.

RESULTS

In vitro effect of SR 31747 on the proliferation of various tumor lines the epithelial cells of the breast

The results related to the effects of SR 31747 on the proliferation of epithelial cells of the mammary gland under cultivation are presented in table B. the Activity of SR 31747 appreciate the presence of various concentrations of serum. In the presence of low concentrations of serum connection SR 31747 exerts an inhibitory effect on the proliferation of all tested lines of epithelial tumor cells. Increased amounts of serum in the culture media partially or completely suppress the inhibitory effect of SR 31747 on cell growth.

For a given concentration of serum ability SR 31747 to inhibit proliferation also varies depending on the cell line. In the presence of 0.1% fetal calf serum (FCS), which allows to simultaneously maintain twitteling hormone cell lines MCF-7 (MCF-7, MCF-7AZ, MCF-7 NT), varies from 210-9mol up to 710-8mol. Similar values IR50also get for cells MDA-MB231 and MCF-7LCC. In contrast, the cell line MCF-7AZTD5 and MCF-7LY2 have greater sensitivity to the inhibitory effect of SR 31747, as certain IR50are respectively 210-10mol and 510-12the mole.

In all cases, almost complete inhibition of cell proliferation observed in the presence of 10-6mol and sometimes 10-7mol SR 31747, apparently represent cytotoxic effects.

The results also show that SR 31747 not able to reverse the stimulatory effect of estradiol on sensitive hormones cell line MCF-7.

The impact of in vivo SR 31747 on the frequency and size of tumors developing after inoculation lines of epithelial tumor cells of the breast "Nude" mouse:

In Fig. 1 and 2 presents the impact of SR 31747 on tumor developing in ovariectomized "Nude" mouse cell line MDA-MB231.

Each mouse is injected into each hip (or 2 point inoculation in the mouse) 5106cells MDA-MB231. Animals are then treated daily administered intraperitoneally, and enter the generated tumors) and the size of the fully developed tumors determined at different points in time during processing. At the end of treatment (day 92) kill animals and weighed. Tumors removed and weighed.

The figure shows the trend of SR 31747 to reduce the size, weight and frequency of developing cells MDA-MB231 tumors in ovariectomized "Nude" mice. However, differences at the level of the size and weight of tumors between control groups and groups that impose SR 31747, are not representative due to the large variability observed in the breast of each group.

Thus in vitro SR 31747 exerts an antiproliferative effect on the proliferation of the population of the studied tumor epithelial cells of the mammary gland. This impact is particularly evident in the presence of low concentrations of serum and varies depending on the studied cell lines. If, in most cases, IR50measured with 0.1% fetal calf "serum vary from 210-9mol to 210-8the mole, however, see the extreme sensitivity of the cells MCF-7LY2 to SR 31747.

See the General trend of SR 31747 to simultaneously reduce the size, weight and frequency of developing cells MDA-MB231 tumors.

The present invention also relates to methods for meniu radioactively labeled, for example, using 123I18F,11C,13N compounds, receptors, on which is fixed 3H-SR 31747. In fact, the high density of these receptors in tumor cells leads to the conclusion that they can be preferably used for fixing the radio, using the methods of the PET (positron emission tomography) and SPECT (single photon emission computed tomography).

Therefore, the present invention also relates to the use of radioactively labeled a well-known specialist isotopes compounds as the agent image to radiomarkers.

Additionally, there may be used other ways of obtaining images, mediated by complex radioactively labeled antibody-antigens.

Such methods include, but are not restrictive, in the SPECT method or in a method called PET.

The use of compounds according to the invention includes obtaining drugs for treatment, which includes targeted delivery of radioactively labeled products as releasing radiation substances in the vicinity of the tumor or the tumor using the above ways to expose the tumor cells to radiation, enitirely above radioactively labeled products.

The use of compounds according to the invention may also include the step of radiation therapy, where cells that are in contact with the compounds that are exposed to ionizing radiation, including, for example, gamma rays, beta rays, x-rays or alpha particles, which can occur from an external source, as in the case of x-rays or gamma rays, or may be directly administered to a patient with the help of radionuclides, as described, for example, in Principles of Radiation Therapy in Cancer, Principles and Practice of Oncology, edited by Devita V. T. and others, 4th edition, J. B. Lippincott Co., Philadelphia, 1993, 15, 248-275.

These compounds can also be entered in combination with other anticancer active principles, well known to the specialist.

According to the illustrated earlier biochemical and pharmacological studies of best efficiency are the following connections:

N-benzyl-N-methyl[3-(3-chloro-4-cyclohexylphenol)propyl]amine;

1-(3-nitro-4-cyclohexylphenol)-3-(4-phenylpiperidine) propan-2-ol;

TRANS-3-[3-(3-nitro-4-cyclohexylphenol) allyl]-4-phenyl-piperidine;

1-[3-(3-chloro-4-cyclohexylphenol)prop-2-inyl]-4 - Hairdryer shall fenil) propyl]-4 - phenylpiperidine;

CIS-3-[3-(3-chloro-4-cyclohexylphenol)allyl]-3-azaspiro [5.5]undecane;

3-[3-(3-chloro-4-cyclohexylphenol)propyl]-3-azaspiro [5. 5]undecane;

CIS-N-adamantane-1-yl-N-ethyl-[3-(3-chloro - 4-cyclohexylphenol)allyl]amine;

4-benzyl-1-[3-(3-chloro-4-cyclohexylphenol)propyl]piperidine;

1-(3-chloro-4-cyclohexylphenol)-3-(4-phenylpiperidine) propan-1-ol;

N-cyclohexyl-N-ethyl-[3-(4-cyclohexylphenol)propyl] amine;

CIS-N-ethyl-N-phenyl-[3-(3-chloro-4-cyclohexylphenol)allyl] amine;

N-phenethyl-N-methyl-1-[3-(3-chloro-4-cyclohexylphenol) propyl]amine;

CIS-N-cyclohexyl-N-ethyl-[3-(4-cyclohexylphenol)allyl] amine;

N-cyclohexyl-N-ethyl-[3-(3,5-dichloro-4 - cyclohexylphenol)allyl]amine;

TRANS-N,N-dihexyl-[3-(3-chloro-4-cyclohexylphenol)allyl] amine;

CIS-N-cyclohexyl-N-ethyl-[3-(3-chloro-4-cyclohexylphenol)allyl]amine;

TRANS-N-cyclohexyl-N-ethyl-[3-(3-chloro-4 - cyclohexylphenol)allyl] amine;

N-cyclohexyl-N-ethyl-[3-(3-chloro-4-cyclohexylphenol) propyl]amine,

1-[3-(3-chloro-4-cyclohexylphenol)allyl]azepin;

TRANS-N,N-DICYCLOHEXYL-3-[(3-chloro-4-cyclohexylphenol) allyl]amine;

N-cyclohexyl-N-ethyl-[3-(3-chloro-4-cyclohexylphenol)prop - 2-inyl]amine;

1-(3-chloro-4-cyclohexylphenol)-3-(cyclohexylmethyl-amino) propane-1-it;

1-(3-chloro-4-cyclohexylphenol)-3-(p-4-cyclohexylphenol)propyl] morpholine;

4-[(3-chlorhexidine)but-2-enyl]morpholine;

4-[4-(3-chloro-4-cyclohexylphenol) butyl] morpholine

or one of their pharmaceutically acceptable salts or one of their pharmaceutically acceptable solvate.

Compounds capable of displace3H-SR 31747 of its receptors, can be used in the treatment of all pathological processes that result in the proliferation of tumor cells. This proliferation of the cells can be either sensitive or insensitive to hormones.

More specifically, the clinical application for which it is possible to envisage the use of these compounds include diseases resulting from cell proliferation, in particular such as glioblastoma, neuroblastoma, lymphoma, myeloma, leukemia, carcinoma of the colon; colon, epithelial, hepatic carcinoma; lung cancer, breast cancer, ovarian cancer, pancreatic cancer or prostate.

For these purposes, the compounds capable of displace 3H-SR 31747 of its receptors, namely compounds of formulas (I)-(VIII), as well as their pharmaceutically acceptable salts can be used to produce pharmaceutical compositions, injected oral, sublingual, transcutaneous who etani with pharmaceutically inert filler.

More preferably, according to another of its aspects the present invention relates to pharmaceutical compositions containing as an active start compound of formula (VIII) or one of its pharmaceutically acceptable salts.

Both organic and inorganic acids can be used to obtain salts of joining acids amines of the formula (VIII), which are non-toxic and pharmaceutically acceptable, especially such as sulphuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, Panova, ethicality, methansulfonate, amber, cyclohexylsulfamate, fumaric, maleic and benzoic acid.

In regard to the introduction of oral or sublingual, especially use simple or index of tablets, gelatin capsules with the medicine; granules, in some cases with a slow release of the medication; droplets or liposomes. In regard to administration intravenously, subcutaneously or intramuscularly, use sterile or sterilizable solutions, particularly for venous perfusion, whereas for the introduction of percutaneous you can implement conventional plasters. For local use m the present invention can be obtained by conventional means, well known in the field of pharmaceutical technology.

The active principle may be incorporated in excipients usually used in these pharmaceutical compositions, such as talc, gum Arabic, lactose, starch, magnesium stearate, aqueous or non-aqueous fillers, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing the components, or emulsifying agents, preservatives, etc.

The pharmaceutical compositions according to the invention preferably may contain a compound of the formula (VIII) or one of its pharmaceutically acceptable salts joining in combination with one or more other known and commonly used for the same therapeutic indications drugs.

The number you enter in the day of the beginning of the current according to the method of the present invention depends on the particular therapeutic indications, the severity of treatable medical conditions, as well as from the weight of the patient and route of administration.

For a systematic introduction of the total dose in the case of a person usually varies from 1 to 100 mg per day, for example, is 2 to 50 mg, and more acceptable is 0 and 50 mg of the product). These single dose is usually injected once or a few times a day, preferably 1-3 times a day.

For local applications, the pharmaceutical compositions typically contain of 0.0001-10% and preferably from 0.01 to 5% active start.

The following examples illustrate the invention without limiting its scope. In these examples, the melting point is determined in the device with a Kofler heating.

Obtaining acetylene derivatives for the synthesis of CIS-compounds

Sample preparation 1

Derived semicarbazone

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73,6 g (0.66 mol) of semicarbazide and a 54.2 g (0.66 mol) of sodium acetate are dissolved in 600 ml of distilled water, then the mixture is intensively mixed and at room temperature quickly add a solution to 142.1 g (0.6 mol) of 3-chloro-4 - cyclohexylacetophenone in 600 ml of ethanol. After that, the reaction mixture is heated at a temperature of 50oC for two hours, during the night stirred at room temperature, then the resulting crystals are filtered under vacuum, washed with water, acetone, diethyl ether, dried in vacuum, obtaining 169, 5mm g of white crystals; yield = 96%.

Example preparation of 2

oC for 1 hour, then for two hours at a temperature of 80oC and receive the intermediate selenodesy. Then the oil bath temperature was raised to 150oC and the reaction mixture is heated for 3.5 hours until the termination of nitrogen excretion, i.e., before complete decomposition of selenadiazoles. Acetic acid is then removed in vacuo, the residue is successively treated with 600 ml of diethyl ether, filtered off, washed four times with water, once with aqueous 5% sodium hydroxide solution, twice with water, dried over sodium sulfate, then evaporated in vacuum. N the residue is distilled under a pressure of 10-2mm RT. tbsp. at a temperature of 85-100oC, receiving 24.8 g of colorless oil.

Getting ketopropionic by reaction of manniche for the synthesis of hydroxylated precursors TRANS-compounds

Example preparation of 3

1-(3-Nitro-4-cyclohexylphenol)-3-(4 - phenylpiperidine)propanone

In 100 ml of 1,2-dimethoxyethane dissolving 12.3 g of 3-nitro-4-cyclohexylacetophenone, 9,85 g of 4-phenylpiperidine, 7.5 g of paraformaldehyde and 1.5 ml of concentrated hydrochloric acid, then the reaction mixture under stirring for 6 hours, then boiled with a reflux the t residue, which sequentially washed with ethyl acetate and then diethyl ether, receiving 17 g of target compound.

Example 1

3-[3-(3-Chloro-4-cyclohexylphenol)prop-2-inyl] -3 - azaspiro [5.5]underagegallery

4,85 g (0,022 mol) obtained in example of preparation 2 connections and 0.5 g of CuCl2dissolved in 25 ml of 1,2-dimethoxyethane. Then add dropwise a solution of 2.7 g of 35% formaldehyde and 3.74 g of 3-azaspiro[5.5]undecane in 20 ml of 1,2-dimethoxyethane. After the addition the reaction mixture is heated at a temperature of 70oC for 30 minutes, remove the solvent in vacuo, then treated with diethyl ether, the ether phase is washed with aqueous 5% sodium hydroxide solution, a saturated solution of sodium chloride, and dried over magnesium sulfate. The hydrochloride crystallized from ethyl acetate, gaining 7.6 g of the target product; so pl. = 241oC.

Example 2

CIS-3-[3-(3-Chloro-4-cyclohexylphenol)allyl] -3 - azaspiro[5.5]underagegallery

3 g of the hydrochloride of acetylene compounds obtained according to the preceding example 1, treated with an aqueous 10% sodium hydroxide solution. The oil obtained after extraction with diethyl ether, washed with a saturated solution of sodium chloride, dried, is added 5 ml of methanol, then add 0.2 g Pd/BaSO4and the reaction mixture hydronaut at room temperature and atmospheric pressure. The catalyst is filtered off through silica, the filtrate was concentrated in vacuo, then the residual oil chromatographic on a column of silica, elwira a mixture of dichloromethane/methanol in a volume ratio 98/2. Concentration of the pure fractions gives the hydrochloride, which is recrystallized from ethyl acetate; yield = 44%; so pl. = 238oC.

Examples 3 and 4

Described in example 1 methodology and entering into interaction 4-cyclohexyl-3,5-Lalor-1-ethynylbenzene respectively with 4-phenylpiperidine and cyclohexylethylamine in the presence of formaldehyde, respectively, received the following connections:

- 4-phenyl-1-[3-(3,5-dichloro-4-cyclohexylphenol) prop-2-inyl] piperidinedione; so pl. = 250oC (example 3);

- N-cyclohexyl-N-ethyl-3-(3,5-dichloro-4 - cyclohexylphenol)prop-2 - inlingerie (example 4).

Examples 5-10

Following the method of example 1 by reacting 3-chloro-4-cyclohexyl-1-ethynylbenzene respectively with ethylvanillin, 1-adamantylamine, benzylmethylamine, (2-phenyl - ethyl) - methylamine, 4-benzylpiperidine and 4-hydroxy-4-phenyl - piperidin cyclohexylphenol) prop-2-inlingerie (example 5);

- N-(1 - substituted)-N-ethyl-3-(3-chloro-4-cyclohexylphenol)prop-2 - inlingerie (example 6);

- N-benzyl-N-methyl-3-(3-chloro-4-cyclohexylphenol)prop-2-inlingerie (example 7);

- N-methyl-N-(2-phenylethyl)3-(3-chloro-4-cyclohexylphenol) prop-2 - inlingerie (example 8);

- 4-benzyl-1-[3-(3-chloro-4 - cyclohexylphenol) prop-2-inyl]piperidinedione (example 9); and

- 4-hydroxy-4-phenyl-1-[3- (3-chloro-4-cyclohexylphenol) prop-2 - inyl]piperidinedione (example 10).

Examples 11 and 12

Described in example 1 method, by reacting 4-cyclohexyl-1-ethynylbenzene respectively with cyclohexylethylamine and 4-phenylpiperidine in the presence of formaldehyde receive the following connections:

- N-cyclohexyl-N - ethyl-3-(4-cyclohexylphenol)prop-2-inlingerie (example 11);

- 4-phenyl-1-[3-(4-cyclohexylphenol)prop-2 - inyl] piperidinedione (example 12).

Examples 13-16

Described in example 2, the method by hydrogenation of acetylene derivatives obtained according to examples 4-6 and 11 receive CIS-propanamine presented in table I.

Example 17

1-(3-Nitro-4-cyclohexylphenol)-3-(4-phenylpiperidine)propanol

13.8 g of the ketone obtained according to example is sodium borohydride and the reaction mixture was kept at a temperature of -10oC for 10 minutes, then leave to stand for increasing the temperature to room. The precipitation is filtered off and washed with methanol, getting 9.5 g of the target product; so pl. = 148-150oC.

Example 18

TRANS-1-[3-[3-Nitro-4-cyclohexylphenol)allyl] ] -4-phenyl-piperidineacetic

10.6 g of the alcohol obtained according to example 17, and 10.4 g of p-toluenesulfonic acid are dissolved in 300 ml of xylene, and then the reaction mixture is refluxed for 6 hours under stirring and using nozzles Dean-stark for collecting the released water. The solvent is evaporated in vacuo, then the residual oil is successively treated with ethyl acetate, an ethyl acetate phase is washed with water to 0.5 N. the sodium hydroxide solution, water, dried over magnesium sulfate and concentrated in vacuo to a volume of 50 ml of solvent, through which pass through ozonation gaseous hydrogen chloride. Concentrated in vacuo and the residue was washed with diethyl ether, receiving 8 g target hydrochloride; so pl. = 225-233oC.

Example 19

3-(N-Ethyl-N-phenyl)amino-1-(3-chloro-4 - cyclohexyl)phenyl-preanalytical

(a) described in example of preparation 3 the technique of 3-chloro-4-cyclohex-(N-ethyl-N-phenylamino)propanone.

b) described in example 17 method, by restoring obtained in stage (a) of the ketone with sodium borohydride obtain the target product as hydrochloride; so pl. = 219oC.

Example 20

3-[3-(3-Chloro-4-cyclohexylphenol)propyl]-3 - azaspiro [5.5]underagegallery

3 g of the hydrochloride of acetylene compounds obtained according to example 1, treated with an aqueous 10% sodium hydroxide solution. The oil obtained after extraction with diethyl ether, washed with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residual oil then bring in 100 ml of ethyl acetate and added with 5 ml of methanol, then add 0.2 g Pd/BaSO4and the reaction mixture hydronaut at room temperature and atmospheric pressure. The catalyst is filtered off through celite, the filtrate was concentrated in vacuo. The resulting residue is treated with a minimal amount of methanol in the presence of 50 ml of 2 N. hydrochloric acid, then extracted with dichloromethane, the extract washed with 2 N. hydrochloric acid, a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo, obtaining 2 g of the target hydrochloride; so pl. = 266o

Example 27

1-[3-(3-Chloro-4-cyclohexylphenol)propyl] -4 - phenyl-1,2,3,6-tetrahydropyrimidine

1 g obtained according to example 26 compound and 0.51 g of p-toluenesulfonic acid are dissolved in 25 ml of xylene. The reaction mixture is refluxed for two hours, then concentrated in vacuo. The residue is treated with 10% sodium hydroxide solution, then extracted with dichloromethane, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo, gaining 0.7 g of the target hydrochloride; so pl. = 210oC.

Example 28

a) 4-(3-Chloro-4-cyclohexylphenol)-4 - hydroxybutanoic acid

20 g of 4-(3-Chloro-4-cyclohexylphenol)-4 - oxobutanoic acid are dissolved in 100 ml of tetrahydrofuran, and 8.6 ml of an aqueous sodium hydroxide solution and add 100 ml of methanol. The reaction mixture is cooled to a temperature of 0-5oC, then add 3.8 g sodium borohydride and the mixture was incubated over night at room temperature. This reaction mixture is poured into 8 l of water, then add 85 ml concentra fenil)dihydrofuran-2-he

Obtained according to stage (a) compound is dissolved in 300 ml of toluene and the reaction mixture is refluxed with adapter Dean-stark removal of water. Then concentrate the solvent under vacuum, obtaining the target lactone; output = 16 g; so pl. = 60oC.

C) Methyl ester of 4-chloro-4-(3-chloro-4-cyclohexylphenol) butane acid

2,78 g obtained in stage (b) of the lactone is dissolved in 30 ml of benzene and then added dropwise 2.2 ml of thionyl chloride and the reaction mixture is refluxed for three hours. Thereafter, this reaction mixture contribute to the cooled solution of gaseous hydrogen chloride in methanol and the mixture is stirred over night at room temperature, then concentrate it under vacuum and obtain 3.5 g of the target chlorinated derivative.

g) 2-(3-Chloro-4-cyclohexylphenol)cyclopropanecarbonyl acid

3 g obtained according to stage (C) of ester dissolved in 10 ml of tert-butanol, then add 1.5 g of potassium tert-butylate and the mixture is refluxed for four hours. Then, after cooling, add 50 ml of water and extracted with diethyl ether. Then, after concentration will dissolve the, then this reaction mixture is refluxed for two hours. After cooling, the solution was added water, acidified by adding 6 N. hydrochloric acid and extracted with diethyl ether, dried and concentrated in vacuo, gaining 1.4 g of the target acid.

Examples 29-32

(a) described in example 28 (a) the method of 4-(4-cyclohexylphenol)-4-oxobutanoic acid, 4-(4 - cyclohexyl-3,5-dichlorophenyl)-4-oxobutanoic acid, 4-(4 - cyclohexyl-3-forfinal)-4-oxobutanoic acid and 4-(4 - cyclohexyl-3-nitrophenyl)-4-oxobutanoic acid by restoring using sodium borohydride receive the following connections:

- 4-(4-cyclohexylphenol)-4-hydroxybutanoic acid (example 29);

- 4-(4-cyclohexyl-3,5-dichlorophenyl)-4 - hydroxybutanoic acid (example 30);

- 4-(4-cyclohexyl-3 - forfinal)-4-hydroxybutanoic acid (example 31);

and therefore

- 4-(4-cyclohexyl-3-nitrophenyl)-4 - hydroxybutanoic acid (example 32).

b) described in example 28 (b) the method of hydroxybutanoic acids obtained according to the above examples 29 (a) 32 (a), by heating or boiling under reflux in toluene in use the EP 29 b);

- 5-(4-cyclohexyl-3,5-dichlorophenyl)dihydrofuran-2-he (example 30);

- 5-(4-cyclohexyl-3-forfinal)dihydrofuran-2-he (example 31 b);

and therefore

- 5-(4-cyclohexyl-3-nitrophenyl)dihydrofuran-2-he (example 32 (b).

C) described in example 28 (C) the method by reacting lactones obtained according to the above examples 29 (b) - 32 (b), with thionyl chloride, then with a solution of hydrogen chloride in methanol receive the following connections:

- methyl- [4-chloro-4-(4-cyclohexylphenol)]butyrate (example 29);

- methyl-[4 - chloro-4-(4-cyclohexyl-3,5-dichlorophenyl)] butyrate (example 30);

- methyl-[4-chloro-4-(4-cyclohexyl-3-forfinal)]butyrate (example 31);

and therefore

- methyl-[4-chloro-4-(4-cyclohexyl-3 - nitrophenyl)]butyrate (example 32).

g) described in example 28 (g) the method by heating obtained according to the above examples 29(b) - 32 (V) esters in tert-butanol in the presence of potassium tert-butylate receive the following connections:

- 2-(4-cyclohexylphenol)cyclopropanecarbonyl acid (example 29 g);

- 2-(4-cyclohexyl-3, 5-dichlorophenyl) cyclopropanecarbonyl acid (example 30 g);

- 2-(4-cyclohexyl-3 - forfinal) cyclopropanecarbonyl acid (example 3SS="ptx2">

Example 33

a) the acid chloride of 2-(3-chloro-4 - cyclohexylphenol)cyclopropanecarbonyl acid

4 g obtained according to example 28 acid and 3.7 ml of thionyl chloride dissolved in 50 ml of carbon tetrachloride. The reaction mixture is refluxed for three hours, then concentrated in vacuo, receiving 5.9 g of the target carboxylic acid in the form of butter.

b) N-Cyclohexyl-N-ethyl-2-(3 - chloro-4-cyclohexylphenol)cyclopropanecarboxamide

3 g the above carboxylic acid is dissolved in 50 ml of carbon tetrachloride, then add a solution of 2.9 g of cyclohexylethylamine in 50 ml of carbon tetrachloride and the reaction mixture was stirred at room temperature for 20 hours. After this, the solution washed with water until neutral pH. Get 5,16 g of amide in the form of butter.

Examples 34-37

a) From cyclopropanecarboxylic acid, obtained as described in examples 29 (d) 32 (d), by reacting with thionyl chloride as described in example 33 (a) method will receive the following connections:

the acid chloride of 2-(4 - cyclohexylphenol)cyclopropanecarboxylic acid (example 34 (a);

the acid chloride of 2-(4-cyclohexyl-3,5-dichlorophenyl) cyclopropanecarboxylic acid (approx is therefore, its

the acid chloride of 2-(4-cyclohexyl-3 - nitrophenyl)cyclopropanecarboxylic acid (example 37 (a).

b) described in example 33 (b) the method by reacting acid chlorides of the acids obtained according to examples 34 (a) 37 (a), as described above, with cyclohexylethylamine receive the following connections:

- N-cyclohexyl-N-ethyl-2-(4 - cyclohexylphenol)cyclopropanecarboxamide (example 34 b);

- N-cyclohexyl-N-ethyl-2-(4-cyclohexyl - 3,5-dichlorophenyl) cyclopropanecarboxamide (example 35 (b);

- N-cyclohexyl-N-ethyl-2-(4 - cyclohexyl-3-forfinal)cyclopropanecarboxamide (example 36 (b);

- N-cyclohexyl-N-ethyl-2-(4-cyclohexyl-3-nitrophenyl) cyclopropanecarboxamide (example 37 (b).

Example 38

[2-(3-Chloro-4 - cyclohexylphenol)cyclopropylmethyl]cyclohexylethylamine chloride

5 g obtained according to example 33 amide is dissolved in 50 ml diethyl ether, then add the suspension 0,99 g Li-aluminiumhydride in diethyl ether and the reaction mixture is stirred for three hours at room temperature, then poured into aqueous 5% sodium hydroxide solution. After that the reaction mixture is extracted with diethyl ether, then decanted, dried over magnesium sulfate and prop.

Example 39

(a) described in example of preparation 3 the technique of 3-chloro-4-cyclohexylacetophenone by reacting with di - n-hexylamino and formaldehyde receive 1-(3-chloro-4 - cyclohexylphenol)-3-digoxinamiodarone.

b) described in example 17 method, by restoring obtained in stage (a) of the ketone with sodium borohydride receive 3-digoxigenin-1-(3-chloro-4-cyclohexylphenol)propanol.

C) described in example 18 method by dehydration obtained in stage (b) of the alcohol produced N-TRANS-[3-(3-chloro-4 - cyclohexylphenol)allyl]digoxigenin; so pl. = 128oC.

Examples 40-52

Of the acid chloride of 2-(3-chloro-4 - cyclohexylphenol)cyclopropanecarbonyl acid, obtained as described in example 33 (a) the method by interacting respectively with diethylamino, vexillium, (1-substituted)ethylamine, ethylvanillin, benzylmethylamine, methyl-(2-phenylethyl) amine, morpholine, piperidine, 4-phenyl - 1,2,3,6-tetrahydropyridine, 4-phenylpiperidine, 4 - benzylpiperidine, 4-(2-phenylethyl) piperidine, 3 - azaspiro[5.5] undecane, and following the instructions of example 33 (b)receive the following connections:

- N, N-diethyl-2-(3-chloro-4 - cyclohexylphenol)cyclepro
- N-(1-substituted)-N-ethyl-2-(3-chloro-4 - cyclohexylphenol) cyclopropanecarboxamide (example 42);

N - ethyl - N-phenyl-2-(3-chloro-4-cyclohexylphenol)cyclopropanecarboxamide (example 43);

- N-benzyl-N-methyl-2-(3-chloro-4-cyclohexylphenol) cyclopropanecarboxamide (example 44);

- N-methyl-N-(2-phenylethyl) -2-(3 - chloro-4-cyclohexylphenol)cyclopropanecarboxamide (example 45);

- 4- [2-(3-chloro-4-cyclohexylphenol)cyclopropyl]carbonyl-morpholine (example 46);

- 1-[2-(3-chloro-4-cyclohexylphenol)cyclopropyl] carbonyl-piperidine (example 47);

- 1-[2-(3-chloro-4 - cyclohexylphenol)cyclopropyl]carbonyl-4-phenyl-1,2,3,6 - tetrahydropyridine (example 48);

- 1-[2-(3-chloro-4 - cyclohexylphenol)cyclopropyl]carbonyl-4-phenylpiperidine (example 49);

- 1-[2-(3-chloro-4-cyclohexylphenol)cyclopropyl]carbonyl-4 - benzylpiperidine (example 50);

- 1-[2-(3-chloro-4-cyclohexylphenol) cyclopropyl] carbonyl-4-(2-phenylethyl)piperidine (example 51);

- 3- [2-(3-chloro-4-cyclohexylphenol)cyclopropyl]carbonyl-3 - azaspiro[5.5] undecane (example 52).

Examples 53-65

Described in example 38 methodology, by restoring the amides obtained according to examples 40-52 receive the following connections:

- N,N-diethyl-2-(3-chloro-4 - cyclohexylphenol)cyclopropylmethanol (example 53);

- N,N-hexylphenyl)cyclopropylmethanol (example 55);

N - ethyl-N-phenyl-2-(3-chloro-4-cyclohexylphenol) cyclopropylmethanol (example 56);

- N-benzyl-N-methyl-2-(3-chloro-4 - cyclohexylphenol)cyclopropylmethanol (example 57);

- N-methyl-N- (2-phenylethyl)-2-(3-chloro-4-cyclohexylphenol) cyclopropylmethanol (example 58);

- 4-[2-(3-chloro-4-cyclohexylphenol) cyclopropyl] methylmorpholin (example 59);

- 1-[2-(3-chloro-4 - cyclohexylphenol) cyclopropyl]methylpiperidine (example 60);

- 1-[2-(3-chloro-4-cyclohexylphenol) cyclopropyl] methyl-4-phenyl-1,2,3,6-tetrahydropyridine (example 61);

- 1-[2-(3-chloro-4 - cyclohexylphenol) cyclopropyl]methyl-4-phenyl-piperidine (example 62);

- 1-[2-(3-chloro-4-cyclohexylphenol)cyclopropyl]methyl-4-benzyl - piperidine (example 63);

- 1-[2-(3-chloro-4-cyclohexylphenol) cyclopropyl] methyl-4-(2-phenylethyl)piperidine (example 64);

- 3-[2- (3-chloro-4-cyclohexylphenol)cyclopropyl]methyl-3 - azaspiro[5.5]undecane (example 65).

Example 66

N-Cyclohexyl-N-ethyl-2-(3-chloro-4 - cyclohexylphenol)cyclopropanecarboxamide

a) To a solution of 3.4 g (12.2 mmol) of 2-(3-chloro-4-cyclohexylphenol) cyclopropanecarbonyl acid and 1.25 g (12.3 mmol) of triethylamine in 50 ml of dioxane, cooled to a temperature of - 5oC add to 1.34 g (12.3 mmol) of ethylchloride, kept at this internal temperature wivout trietilenglikole and use the solution so obtained mixed anhydride of 2-(3-chloro-4-cyclohexylphenol)cyclopropanecarbonyl acid monoethylene ether carboxylic acids.

To the thus obtained solution of the mixed anhydride add a solution of 1.56 g of cyclohexylethylamine in 30 ml of tetrahydrofuran and the reaction mixture is stirred for 8 hours at room temperature. Then the solution is washed with water, dried him, and the solvent is evaporated. Thus get N-cyclohexyl-N-ethyl-2-(3-chloro-4-cyclohexylphenol) cyclopropanecarboxamide.

1. The use of CIS-N-cyclohexyl-N-ethyl-[3-(3-chloro-4-cyclohexylphenol)allyl] amine, or its pharmaceutically acceptable salt, or MES to obtain a pharmaceutical composition prescribed for the treatment of diseases caused by proliferation of tumor or cancer cells.

2. Application under item 1, characterized in that the cell proliferation is hormonecontaining.

3. Application under item 1, characterized in that the cell proliferation is gormonorezistentnost.

4. Use PP.1-3, to obtain a pharmaceutical composition intended for the treatment of glioblastoma, for neuroblastoma, lymphoma, myeloma, leukemia, and carcinoma of the colon, colon, epithelial, hepatic carcinoma, lung carcinoma, breast cancer, ovarian cancer, pancreatic cancer or pratia tumor or cancer cells, including CIS-N-cyclohexyl-N-ethyl-[3-(3-chloro-4-cyclohexylphenol)-allyl]-amine, or pharmaceutically acceptable salt, or MES.

6. The pharmaceutical composition under item 1, characterized in that it is intended for the treatment of glioblastoma, for neuroblastoma, lymphoma, myeloma, leukemia, and carcinoma of the colon, colon, epithelial, hepatic carcinoma, lung carcinoma, breast cancer, ovarian cancer, pancreatic cancer or prostate.

 

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R1-Q1-X-Q2-R2(I)

in which Q1, Q2in each case, independently of one another are either absent or represent-NH-(CH2)n-CO-,

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R3- R5-R4, -R6-R4or-R7-R4< / BR>
R4is a HE, NH2, SH or COOH,

R5- alkylene containing 1-6 carbon atoms,

R6- alkaliphiles containing 7 to 14 carbon atoms,

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R8-H, a or alkylether containing 7-12 carbon atoms,

A is alkyl containing 1-6 carbon atoms,

R10- alkanoyl containing 1-18 carbon atoms, which is unsubstituted or contains one Deputy from among COOH, COOA, SR11or NR12R12,

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R16is arkanoid, which contains 7-19 carbon atoms and which is not substituted or substituted in the aryl fragment of one, two or three deputies, including Hal, alkoxygroup containing 1-6 carbon atoms, or HE, and in which the aryl fragment may also represent a group:

< / BR>
E - CH2or,

D is carbonyl or [C(R17R17')]m,

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Het is a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle which contains from 1 to 4 atoms of N, O and/or S, attached cherepy, including Hal, A, R3, NR4R4', CN, NO2and/or carbonyl oxygen,

n- 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 and

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