EA022290B1 - Anthraquinone dioximes and uses thereof - Google Patents

Abstract

Anthraquinone dioximes and their derivatives of formulae (I) and (III) are disclosed for use in treatment of diseases, especially cancer, such as colon and colorectal cancer. A pharmaceutical composition based on these compounds is also described.

Description

The application for this patent is a partial continuation of the application PCT / CH2008 / 006015, filed May 9, 2008, which claims the priority of provisional patent application US 60/928592, filed May 10, 2007, and provisional patent application US 60/999153 filed October 15, 2007, the contents of which are incorporated into this application in its entirety.

FIELD OF THE INVENTION

The present invention relates to the field of antitumor therapy using anthraquinondioximes.

BACKGROUND OF THE INVENTION

The νηί / beta-catenin signaling pathway is recognized as one of the key signaling pathways in cancer and as an effective target for therapeutic intervention in many types of tumors, especially colon tumors.

Cells of multicellular organisms have the ability to transmit and recognize signals of each other, sometimes at considerable distances. This signaling can be accomplished by generating signaling molecules produced by one of the cells, which then bind to specific receptors on the other cell. Similar signal transmission pathways are involved in the development of various diseases, including cancer. Νηΐ signal transmission due to receptor binding, followed by increased levels of intracellular β-catenin, is considered a canonical signaling pathway. Proteins \ Yn1 form a family of highly conserved secreted signaling molecules that regulate intercellular interactions and participate in the pathogenesis of cancer. Proteins \ νηΙ bind to receptors of the Pn // 1eb and LKP families on the cell surface. Through several translating components in the cytoplasm, their signal is transmitted to β-catenin, which then enters the nucleus and forms a complex with TCP, which leads to the activation of transcription of the target νηΐ genes.

When a signal is transmitted along this pathway, the νηΐ polypeptides are either located on the surface of the signal-transmitting cell, or are released by the cell and eventually come into contact with specific receptors on the surface of another cell. These receptors on the surface of the target cells include the Pn // 1eb / BKR receptor (LKP = Lb-receptor-bound protein), and they transmit the received signal to intracellular proteins, such as β-catenin, whose level in the stationary state usually remains relatively low, due to constant decay (usually mediated by proteosomes). This process is regulated by a complex containing ΟδΚ-3 / APC / axin proteins (ΟδΚ-3 = glycogen synthesis kinase and APC = colon adenomatous polyposis protein). The result of νηΐ binding on the surface of the target cell is the inhibition of β-catenin destruction, as a result of which the amount of the latter increases, it enters the nucleus and connects with transcription regulators, activating genes.

It was found that mutations that contribute to the constitutive activation of the νηΐ signaling pathway can lead to cancer [for a review see Bodan anb икikke, Thé νηΐ δφηαΐίηβ Rabshau ίη Eeeeehr apb Egkeake in Αηη. Keu. Ce11 Eee. ΒίοΙ., 20: 781-810 (2004)]. For example, mutations in Αχίη2 can cause an individual to be predisposed to colon cancer (Largat e1 a1., At. Н. Nit. Oe ^ b, 74: 1043-50 (2004)). As another similar example, familial adenomatous polyposis (PAP), i.e. hereditary disease, characterized by numerous polyps in the colon and rectum, is often caused by shortening of the APC (another protein involved in the νηΐ signaling pathway), which contributes to the abnormal activation of the νηΐ signaling pathway [see, CT / Ig e1 a1., Zaepse. 253: 661-665 (1991)]. Mutations in APC and β-catenin have also been found in cancer of the rectum and other types of tumors (for a review, see Og1e8 e1 a1., Vusyt. Vyuruk. Ac1a, 1653: 1-24 (2003)). In addition, mutations in axin were detected in hepatocarcinoma carcinomas, causing a loss of its function [see ZAYU e1 a1., No.-H. Oe ^ b, 24: 245-50 (2000)]. Thus, any mutations and other phenomena in the cell that lead to disruption of the νηΐ signaling pathway and regulation of β-catenin levels seem to play an important role in the onset of cancer.

Since the cases of carcinogenesis described above were associated with elevated levels of β-catenin (i.e. situations in which β-catenin levels were independent of νηΐ), low molecular weight organic compounds and other agents that contribute to the restoration of this dependence or otherwise lower β-catenin levels , could be useful for weakening the cancer process and find application as antineoplastic agents. The present invention provides such agents in the form of disulfonamide derivatives of fluorene, anthracene, xanthene, dibenzosuberone and acridine, which lower the levels of beta-catenin in tumor cells.

Structurally related derivatives of fluorene and anthracene with sulfonamide groups substituted with aromatic amines (see, for example, YZ 2004/0019042) are known as inhibitors of P2X2 and P2X2 / 3 containing receptors, and it has been found that they are applicable in the treatment and prevention disorders such as excessive bladder activity, urinary incontinence, or pain. However, the present invention has shown that new structurally related compounds useful as modulators of the νηΐ / β-catenin signaling pathway can be obtained. It is known that β-catenin is a regulator of the νηΐ signaling pathway (see νίΙΚΠ apb Yikke, SiggeSh Θρίηίοη ίη OeneI ^

- 1 022290 apb Oeue1ortep1, 8: 95-102 (1998)).

Summary of the invention

The present invention relates to low molecular weight organic compounds of the anthraquinondioxime family that are useful in the treatment of cancer, which impede the signaling pathway and reduce the levels of beta-catenin in cancer cells, as well as methods for their synthesis. In specific embodiments, the implementation of these compounds include disulfonamide derivatives of anthraquinondioxime that lower beta-catenin levels in tumor cells.

The compounds of the present invention have the structure represented by formula (III)

where K _A means hydrogen;

K ₇ and K _{8 are} independently selected from H and 8Θ ₂ ΝΚ. ₇ , Κ · |. where one of K ₇ and K ₈ represents a hydrogen atom, and where

ΝΚ ₁ Κ ₂ and ΝΚ3Κ4 independently represent a 6-15 membered heterocycloalkyl containing one nitrogen atom in the ring, which is a saturated monocyclic ring or a fused, bridging or spirobicyclic ring system and may optionally be substituted with 1-4 substituents selected from cyano , hydroxy, carboxy, amino, acetyl, formyl, C ₁ -C ₅ alkyl, C ₁ -C ₅ mono- or di-C1-C ₅ -alkylamino-C1-C ₅ -alkyl, phenyl, 0-C ₅ alkoxy, phenoxy, or any combination of the substituents listed;

or its pharmaceutically acceptable salts, stereoisomers or geometric isomers.

In specific embodiments, the implementation of the compounds of the present invention include a compound having the following formula

or its pharmaceutically acceptable salt, stereoisomer or geometric isomer and a compound having the following formula

or a pharmaceutically acceptable salt, stereoisomer or geometric isomer thereof.

The compounds shown in table. 1-4, and these compounds are encompassed by the present invention either individually or in any combination thereof. Thus, the present invention includes any of these compounds individually, or any combination of these compounds, or all of these compounds, as well as the use of any of them, or all of these compounds in any combination for the treatment of cancer by any mechanism. Each of the compounds mentioned is itself an embodiment of the invention, and any combination of these embodiments is itself a separate embodiment of the invention.

In addition, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (III) in a pharmaceutically acceptable carrier, including individual compositions of any of these compounds or compositions of any combination of these 2,22290 compounds. Each of these compositions per se is an embodiment of the invention, and any combination of these embodiments per se is a separate embodiment of the invention.

In addition, the present invention relates to a method for preventing, treating or alleviating cancer or tumor metastases in a mammal, comprising administering to said mammal an effective amount of a compound of formula (III).

Including the invention covers the use of the compounds of table. 1-4 for the treatment of cancer. The use of each of these compounds per se is an embodiment of the invention, and any combination of these embodiments per se is a separate embodiment of the invention.

Definitions

Unless explicitly stated otherwise, the following terms have the indicated meanings.

Acyl or carbonyl means a radical formed by the removal of a hydroxy group from a carboxylic acid (i.e., K — C (= O) -). Preferred acyl groups include acetyl, formyl and propionyl, with acetyl being most preferred.

Alkyl means a saturated hydrocarbon radical comprising from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 5 carbon atoms, most preferably from 1 to 3 carbon atoms, which may be branched or unbranched. Non-limiting examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like, with methyl, ethyl, n-propyl and isopropyl are particularly preferred examples.

The term alkenyl, alone or in combination with other terms, refers to an optionally substituted linear or optionally substituted branched hydrocarbon radical comprising one or more carbon-carbon double bonds and containing from 2 to 15 carbon atoms, preferably from 2 to 10, more preferably from 2 to 5 carbon atoms, more preferably from two to about eighteen carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, butenyl, 1,3-butadienyl and the like.

The term alkynyl, alone or in combination with other terms, refers to an optionally substituted linear or optionally substituted branched hydrocarbon radical comprising one or more carbon-carbon triple bonds and containing from 2 to 15 carbon atoms, preferably from 2 to 10, more preferably from 2 to 5 carbon atoms, more preferably from two to about twelve carbon atoms, from two to about six carbon atoms, and also from two to about four carbon atoms. Examples of alkynyl radicals include ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiinyl and the like.

Preferred branched alkyl, alkenyl and alkynyl chains include one or two branches, preferably one branch, and each of them may be unsubstituted or substituted with 1-4 substituents, preferably not more than 3 substituents, more preferably 2 substituents and most preferably one substituent. Preferred substituents are hydrocarbon residues, halogens (preferably P, C1, Br and I), hydroxy, aryloxy (e.g. phenoxy), heteroaryloxy, acyloxy (e.g. acetoxy), carboxy, aryls (e.g. phenyl), heteroaryls, cycloalkyls, heteroalkyls , heterocycloalkyls, spirocycles, amino, amido, acylamino, keto, thioketo, cyano, or any combination of these substituents. Preferred hydrocarbon residues are methyl, ethyl, propyl, isopropyl, butyl, vinyl, allyl, butenyl and ethoxymethylene.

The term lower alkyl means short chain alkyl, for example, alkyl containing from one to about six carbon atoms.

Also, in the text of the present invention, the lower alkyl, alkenyl or alkynyl moiety (e.g. lower alkyl) is a chain comprising from 1 to 10, preferably from 1 to 8 carbon atom in the case of alkyl, and from 2 to 10, preferably from 2 to 8 carbon atoms in the case of alkenyl or alkynyl.

The term alkoxy means an oxygen atom having a hydrocarbon chain as a substituent, wherein the hydrocarbon chain is alkyl or alkenyl (i.e., —O-alkyl or —O-alkenyl). Examples of alkoxy substituents include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, allyloxy and the like.

Aryl means an aromatic hydrocarbon cycle. Aryl moieties are monocyclic or fused bicyclic systems. Monocyclic aryl rings contain 6 carbon atoms in a ring. Monocyclic aryls are also called phenyl rings. Bicyclic aryls contain from 8 to 17 carbon atoms, preferably from 9 to 12 carbon atoms. Bicyclic aryls include cyclic systems where one of the rings is aryl and the other is aryl, cycloalkyl or heterocycloalkyl. Preferred bicyclic aryls include 5-, 6- or 7-membered rings fused to 5-, 6- or 7-membered rings. Aryl rings may be unsubstituted or may be substituted with 1-4 substituents. Aryls may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy, alkoxy, heteroalkyloxy, carbamoyl, haloalkyl, methylenedioxy, heteroaryloxy or any combination. Preferred aryl rings include naphthyl, tolyl, xylyl and phenyl. The most preferred aryl cyclic substituent is phenyl.

The aryloxy group is an oxygen atom which has an aryl substituent (i.e., -O-aryl). Preferred aryloxy groups include, for example, phenoxy, naphthyloxy, methoxyphenoxy and methylenedioxyphenoxy.

The term cycloalkyl refers to a saturated hydrocarbon ring that is not aromatic. Cycloalkyls are monocyclic or fused, spiro or bridged bicyclic or polycyclic systems. Monocyclic cycloalkyls contain from about 3 to about 12 carbon atoms in the cycle, preferably from 3 to 7 carbon atoms. Bicyclic cycloalkyls contain from 7 to 17 carbon atoms, preferably from 7 to 12 carbon atoms. Preferred bicyclic cycloalkyls include 4-, 5-, 6- or 7-membered rings fused to 5-, 6- or 7-membered rings. Cycloalkyls may be unsubstituted or may be substituted with 1-4 substituents. Cycloalkyls may be substituted with halogens, cyano, alkyls, heteroalkyls, haloalkyls, phenyls, keto groups, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, or any combination of these substituents. Preferred cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.

The term lower alkenyl or lower alkynyl refers, respectively, to an alkenyl or alkynyl radical, the carbon chain of which contains from two to about six carbon atoms, and does not include substituents.

G halogen means fluoro, chloro, bromo or iodo; preferred halogens are fluoro, chloro and bromo; more preferred halogens are typically chlorine and fluorine, especially fluorine.

The term heteroatom refers to nitrogen, sulfur or oxygen atoms. Groups containing more than one heteroatom may contain various heteroatoms.

The term heteroalkyl refers to a hydrocarbon containing a saturated or unsaturated chain and at least one heteroatom, the two heteroatoms being not adjacent. Heteroalkyl chains contain from 2 to 15 atoms (carbon and heteroatoms), preferably from 2 to 10, more preferably from 2 to 5. For example, heteroalkyls include alkoxy groups (i.e., -O-alkyl or O-heteroalkyl). Heteroalkyl chains may be linear or branched. Preferred branched heteroalkyls include one or two branches, preferably one branch.

Preferred heteroalkyls are saturated.

Unsaturated heteroalkyls include one or more carbon-carbon double bonds and / or one or more carbon-carbon triple bonds. Preferred unsaturated heteroalkyls include one or two double bonds or one triple bond, more preferably one double bond.

Heteroalkyl chains may be unsubstituted or they may be substituted with 1-4 substituents. Preferred substituted heteroalkyls are mono-, di- or trisubstituted. Heteroalkyl may be substituted with lower alkyl, haloalkyl, halogen, hydroxy, acyloxy, carboxy, amino, acylamino, amido, keto, thioketo, cyano and any combination of these groups. If the group is described, for example, as an alkyl derivative, for example, -ethylpyridine, the dash indicates the attachment point of the substituent. So, for example, -ethylpyridine means the addition of ethylpyridine to the rest of the molecule through the ethyl fragment of the group, while ethylpyridine- means addition through the pyridine ring.

Heteroaryl is an aromatic ring containing carbon atoms and from 1 to about 6 heteroatoms. Heteroaryl rings are monocyclic or fused bicyclic systems. Monocyclic heteroaryl rings contain from about 5 to about 9 atoms (carbon and heteroatoms), preferably 5 or 6 atoms. Bicyclic heteroaryls contain from 8 to 17 atoms, preferably from 8 to 12 atoms. Bicyclic heteroaryls include cyclic systems in which one cycle is heteroaryl, the other cycle is aryl, heteroaryl, cycloalkyl or heteroalkyl, heterocycloalkyl. Preferred bicyclic heteroaryl ring systems include 5-, 6-, or 7-membered rings fused to 5-, 6-, or 7-membered rings. Heteroaryl rings may be unsubstituted or may be substituted with 1-4 substituents. Heteroaryl may be substituted with halogens, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy, heteroaryloxy, or any combination of these substituents. Preferred heteroaryl rings include, but are not limited to, the following groups:

- 4,022,290

Condensed heteroaryl radicals can contain from two to four condensed rings, and if the ring attached to the rest of the molecule is heteroaromatic, other individual rings in the condensed ring system may be aromatic, heteroaromatic, alicyclic or heterocyclic. The term heteroaryl also includes monoheteroaryls or fused heteroaryls containing from five to about twelve atoms of the cyclic skeleton, as well as heteroaryls containing from five to about ten atoms of the cyclic skeleton. The term lower heteroaryl refers to heteroaryls containing from five to about ten atoms of a cyclic skeleton, for example, pyridyl, thienyl, pyrimidinyl, pyrazinyl, pyrrolyl or furanyl.

Heteroaryloxy means an oxygen atom that has a heteroaryl substituent (i.e., -O-heteroaryl). Preferred heteroaryloxy groups include (for example) pyridyloxy, furanyloxy, (thiophene) oxy, (oxazole) oxy, (thiazole) oxy, (isoxazole) oxy, pyrimidinyloxy, pyrazinyloxy and benzothiazolyloxy.

Heterocycloalkyl is a saturated or unsaturated ring containing carbon atoms and from 1 to 4 (preferably 1 to 3) heteroatoms. Heterocycloalkyls are not aromatic. Heterocycloalkyls are monocyclic or are fused, bridged or spirobicyclic systems. Monocyclic heterocycloalkyl groups contain from about 3 to about 9 cyclic atoms (including both carbon atoms and heteroatoms), preferably from 5 to 7 cyclic atoms. Bicyclic heterocycloalkyl groups contain from 7 to 17 cyclic atoms, preferably from 7 to 12 cyclic atoms. Bicyclic heterocycloalkyl systems contain from about 7 to about 17 cyclic atoms, preferably from 7 to 12 cyclic atoms. Bicyclic heterocycloalkyl groups may be fused, spiro, or bridged ring systems. Preferred bicyclic heterocycloalkyl groups include 5-, 6- or 7-membered rings fused to 5-, 6- or 7-membered rings. Heterocycloalkyl groups may be unsubstituted (i.e., include hydrogen atoms as substituents of cyclic atoms) or substituted (either by carbon atoms, or heteroatoms, or by atoms of both types) 1-4 substituents selected from methyl, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, alkyl, heteroalkyl, phenyl, alkoxy, aryloxy, or any combination of the above substituents. Preferred substituents of heterocycloalkyl groups include methyl, ethoxyl and halogens. A heterocycloalkyl group may be attached as a substituent to the rest of the molecule through any chemically possible atom of said heterocycloalkyl. Preferred heterocycloalkyl groups include, but are not limited to, the following moieties:

- 6,022,290

The term “member cycle” can encompass any cyclic structure, including aromatic, heteroaromatic, alicyclic, heterocyclic and polycyclic fused ring systems, as described below. The term “member” means the number of skeletal atoms that form a cycle. Thus, for example, pyridine, pyran or pyrimidine are six-membered rings, and pyrrole, tetrahydrofuran and thiophene are five-membered rings.

The term alkylaryl, alone or in combination with other terms, refers to the aryl substituent as defined above, in which one H atom is substituted by an alkyl radical, which is also defined above, for example tolyl, xylyl, and the like.

The term arylalkyl or aralkyl, alone or in combination with other terms, refers to an alkyl radical as defined above in which one H atom is replaced by an aryl radical as defined above, for example benzyl, 2-phenylethyl and the like.

The term heteroarylalkyl refers to an alkyl radical as defined above, in which one H atom is substituted by a heteroaryl radical as defined above, each of which may be optionally substituted, with an aryl group attached to the rest of the molecule and an alkyl

- 7 022290 group is the terminal fragment.

The term alkyl heteroaryl refers to an alkyl radical as defined above, in which one H atom is substituted by a heteroaryl radical as defined above, each of which may be optionally substituted, wherein the alkyl group is attached to the rest of the molecule and the heteroaryl group is an end fragment.

The term alkylthio, alone or in combination with other terms, refers to an alkylthio group, i.e. alkyl-8-, where the term alkyl is as previously defined.

The term arylthio, alone or in combination with other terms, refers to an arylthio group, i.e. aryl-8-, where the term aryl is as previously defined.

The term heteroarylthio refers to the group heteroaryl-8-, where the term heteroaryl is as previously defined.

The term acyloxy refers to the ester group OC (O) K, where K is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocycle, arylalkyl or heteroarylalkyl, where alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocycle, arylalkyl or heteroarylalkyl may be optionally substituted.

The term carboxy esters refers to the moiety —C (O) OK, where K is alkyl, aryl or arylalkyl, wherein alkyl, aryl or arylalkyl may be optionally substituted.

The term carboxamido refers to the —C (O) MKK ′ fragment, where nitrogen is attached to the carbonyl carbon atom and each of the substituents K and K ′ is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, alicyclic, heterocycle, arylalkyl and heteroarylalkyl wherein said alkyl, aryl, heteroaryl, alicyclic, heterocycle or arylalkyl may be optionally substituted.

The term alkylamino refers to the group -ΝΗΚ ', where K is independently selected from among alkyls.

The term dialkylamino refers to the group -ΝΡΡ '. where K and K 'are alkyl.

The term sulfide refers to a sulfur atom covalently bonded to two atoms; the formal oxidation state of said sulfur atom is (II).

The term thioether is interchangeable with the term sulfide.

The term sulfoxide refers to a sulfur atom covalently bonded to three atoms, at least one of which is an oxygen atom; the formal oxidation state of said sulfur atom is (IV).

The term sulfone refers to a sulfur atom covalently bonded to four atoms, at least two of which are oxygen atoms; the formal oxidation state of said sulfur atom is (VI).

The term optional or does not necessarily mean that the event or circumstance mentioned after it can take place, but not necessarily, and that this description includes situations where the event or circumstance takes place, as well as situations where the event or circumstance does not take place. For example, the phrase aryl is optionally substituted with one or two alkyls, meaning that alkyl may be present, but optionally, with one alkyl or two alkyls present, and this description includes situations where aryl is substituted with one or two alkyls and a situation where aryl is not substituted by alkyl.

Independently selected groups are groups present in the same structure, which optionally represent the same substituent. For example, if two substituents are represented by the designation NOK _Α , and each K _{A is} said to be independently selected from H, methyl, ethyl, etc., this means that if one substituent K _A is methyl, the other K _A can be methyl, but could be H or ethyl (or any other substituent indicated). Typical options for the substituents are presented in table. 2.

Some of the compounds of the present invention may contain one or more chiral centers and, therefore, can exist in enantiomeric and diastereomeric forms. The scope of the present invention includes all isomers themselves, as well as mixtures of cis and trans isomers, mixtures of diastereomers and, in addition, racemic mixtures of enantiomers (optical isomers). In addition, it is possible to separate the various forms using well-known methods, and some embodiments of the present invention may be purified enantiomers or diastereomers or mixtures enriched in this enantiomer or diastereomer.

The term pharmacological composition refers to a mixture of one or more of the compounds described in the present invention, or their pharmaceutically acceptable salts with other chemical components, such as pharmaceutically acceptable carriers and / or excipients. The objective of the pharmacological composition is to facilitate the administration of the compound to the body.

The phrase pharmaceutically acceptable carrier in the present invention means a pharmaceutically acceptable material, composition or carrier, for example a liquid or solid excipient, diluent, excipient, solvent or encapsulating material, involved in the transfer or transport of the target agent from one organ or part of the body to another organ or part body. Each carrier must be acceptable in the sense of compatibility with other ingredients of the formulation and no harm to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include (1) sugars, for example lactose, glucose, and sucrose; (2) starches, for example corn starch and potato starch; (3) cellulose and its derivatives, for example sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) fillers, for example cocoa butter and suppository waxes; (9) oils, for example peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, for example propylene glycol; (11) polyols, for example glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, for example ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, for example magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffered solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations. A physiologically acceptable carrier should not cause significant irritation to body tissues and should not invalidate the biological activity of the administered compound and its beneficial properties.

The term “excipient” refers to an inert substance added to a pharmacological composition to further facilitate administration of a compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

As used herein, the term “therapeutic effect” includes, but is not limited to, completely or partially suppressing the growth of cells characteristic of a proliferative disorder, such as colon cancer. The therapeutic effect may also include alleviating one or more symptoms of the disease in addition to cell growth or cell mass size and may include 1) a reduction in the number of cells; 2) reduction in cell size; 3) inhibition (i.e., slowing down, preferably stopping) of cell infiltration (i.e. the formation of metastases) in the surrounding organs; 4) inhibiting or slowing down cell growth; and / or 5) alleviating one or more symptoms associated with a disease such as cancer. It is believed that any amount or dose of the compounds disclosed in the present invention that lead to such a therapeutic effect is a therapeutically effective dose or therapeutically effective amount of said compound.

For cancer, the phrase effective amount means an amount sufficient to elicit the desired response or to alleviate a symptom or symptom, in relation to the progression, size or growth of both metastases and the primary tumor. Representative mammalian recipients of the compounds of the present invention include mice, rats, cats, dogs, and primates, including humans. The effective amount for a particular patient may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage, as well as the severity of side effects. Preferably, this effect will consist in changing the desired quantitative parameter by at least about 10%, preferably at least 20, 30, 50, 70, or even 90% or more. When used as part of a combination, the effective amount depends on the components included in the combination, and the effect is not limited to the action of the individual components themselves.

A solvate is a complex formed by a combination of a solute (e.g., a metalloprotease inhibitor) and a solvent (e.g., water). See 1. Notd e1 a1., Thieu Wap ΝοδϋΉηά S’yepY51'5 Eyyopatu, p. 650 (1953).

The terms optical isomer, geometrical isomer (e.g., cis and / or trans-isomer), a stereoisomer and have the generally accepted meaning diastereomer (see., E.g., in \\ '1eu'5 S'opyepzezy Syenisa1 Eyuyopatu, 11 ⁴¹¹ Eu.). The specific protected forms and other derivatives of the compounds of the present invention given by way of illustration are not limiting. The use of other suitable protecting groups, salt forms, prodrugs, etc. is within the competence of a specialist in this field of technology.

The term prodrug means a form of a medicinal product, which, before becoming an active or fully active pharmacological agent, must undergo a chemical transformation under the influence of metabolic processes. A prodrug is inactive or less active in the form in which it is taken orally, absorbed, or in another form intended for administration. For example, a prodrug can undergo digestion by bacteria in the digestive system to form products, at least one of which will become active as a medicine. Alternatively, the prodrug may be administered systemically, for example, by intravenous injection, and then metabolized to one or more active molecules.

The term Yuyu in the present description refers to the amount, concentration or dosage of a particular test compound at which 50% inhibition of the maximum reaction is achieved in the assay in which this reaction is measured. In some embodiments of the present invention, the 'TCo of the compound of the present invention for normal cells may be greater than that for cells exhibiting proliferative disorder, such as breast cancer cells. The obtained value depends on the analysis method used.

- 9,022,290

Standard refers to positive or negative control. The term negative control in this case refers to normal cells, as opposed to cancer cells, for example, samples in which the activity of the Αηί / β-catenin signaling pathway corresponding to a normal cell is observed. A negative control may also include a sample in which there is no such signaling pathway. In contrast, the positive control does not demonstrate this signaling pathway, preferably to the same extent that corresponds to the overexpression found in proliferative disorders, such as breast cancers. Control samples can be cells or tissue samples, or, in another case, contain a purified ligand (or not contain a ligand), immobilized or not. In some embodiments, one or more control samples may be in the form of diagnostic strips.

By selective targeting is meant the effect on one type of cell to a greater extent than on the other, for example, cancer cells compared to non-cancerous cells.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound having the structure depicted by formula (III)

where K _A means hydrogen;

K ₇ and K _{8 are} independently selected from H and §Ο ₂ ΝΚ ₃ Κ ₄ , where one of K ₇ and K ₈ represents a hydrogen atom, where

ΝΚιΚ ₂ and ΝΚ ₃ Κ ₄ independently represent a 6-15 membered heterocycloalkyl containing one nitrogen atom in the ring, which is a saturated monocyclic ring or a fused, bridging or spirobicyclic ring system and may optionally be substituted with 1-4 substituents selected from cyano, hydroxy, carboxy, amino, acetyl, formyl, C ₁ -C ₅ -alkyl, C ₁ -C ₅ -mono or di-C ₁ -C ₅ -alkylamino-C ₁ -C ₅ -alkyl, phenyl, C ₁ -C ₅ alkoxy, phenoxy, or any combination of the above substituents;

or its pharmaceutically acceptable salts, stereoisomers or geometric isomers.

In preferred embodiments, at least one of the groups _{K, A} is H, or both groups are H. In another preferred embodiment of formula (III) fragments ΝΚ ₁ Κ ₂ and ₃ ΝΚ Κ ₄ are independently selected from groups of formula (IV)

formula (IV);

where Ζ means (SK ₁₇ K ₁₈ ) _t and t = 1-4;

K ₉ , K ₁₀ , K ₁₁ , K ₁₂ , K ₁₃ , K ₁₄ , K ₁₅ , K ₁₆ , K ₁₇ and K ₁₈ independently represent H, methyl, ethyl, propyl, butyl, methoxy or ethoxy.

In one embodiment, the compound of the present invention has the structure represented by formula (V)

where the fragments ΝΚ ₁ Κ ₂ and ΝΚ ₃ Κ ₄ independently represent 6-12 membered heterocycloalkyls containing one nitrogen atom in the ring, and where the K groups correspond to the definitions given for formula (II).

In preferred embodiments, at least one group _KA represents H or the two groups K _A are H. In another preferred embodiment, the fragments ₁ ΝΚ Κ ₂ and ₃ ΝΚ Κ ₄ are independently selected from groups of formula (VI)

- 10 022290

where Ζ means (SK ₁₇ K ₁₈ ) _t and t = 1-4;

K ₉ , K ₁₀ , Kp-K ₁₂ , K ₁₃ , K ₁₄ , K ₁₅ , K ₁₆ , K ₁₇ and K ₁₈ independently represent H, methyl, ethyl, propyl, butyl, methoxy or ethoxy.

In preferred embodiments, ΝΚ ₁ Κ ₂ and ΝΚ ₃ Κ ₄ is piperidine substituted with 1-2 methyl substituents or each of ΝΚ ₁ Κ ₂ and ΝΚ ₃ Κ ₄ is azepane.

In one embodiment, the compound of the present invention has the structure of the compound shown in table. 1, so that each of these structures in itself is a separate embodiment of the invention. In preferred examples of such embodiments, the invention specifically relates to compounds selected from compounds 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 122, 1-26, 1-37, 1 -44, 1-45, 1-46, 1-49, 1-51, 1-56, 1-77, 1-95 tab. one.

In another preferred embodiment, the compound of the present invention has the structure of the compounds of table 3. Specific examples of these preferred embodiments are compounds 3-1, 3-2, 3-3, 3-4, 3-7, 3-8, 3-11 , 3-13, 3-14, 3-16, 3-21, 3-28, 3-38, 3-39 and 340 tab. 3.

Other preferred embodiments of the compounds of the present invention are compounds having the structures shown in table. 2 and / or 4.

In specific embodiments of the present invention, any of the compounds shown above, including combinations of these compounds, or combinations of one or more of these compounds with one or more additional therapeutic agents, preferably anti-cancer agents (for example, used in Example 12), are used in the treatment of any or all cancer diseases mentioned in the invention, for example, one or more diseases of the colon cancer, adenocarcinoma, colorectal cancer, colo ektalnogo cancer, breast cancer, lung cancer, ovarian cancer, polypoid adenomatosis and hepatocellular carcinoma, wherein a colon cancer and colorectal cancer are particularly preferred.

One preferred embodiment of the present invention is 2,7-bis (azepan-1-ylsulfonyl) anthracene-9,10-dione dioxime

One of the preferred embodiments of the present invention is 2,7-bis (azocan-1-ylsulfonyl) anthracene-9,10-dione dioxime

One preferred embodiment of the present invention is 2 ((3K, 5§) -3,5-dimethylpiperidin-1-ylsulfonyl) -7 ((3K, 5K) -3,5-dimethylpiperidin-1-ylsulfonyl) anthracene-9 10-dione dioxime

One preferred embodiment of the present invention is 2,6-bis (4-ethoxypiperidin-1-ylsulfonyl) anthracene-9,10-dione dioxime

- 11 022290

One of the preferred embodiments of the present invention is 2,6-bis (azepan-1-ylsulfonyl) anthracene-9,10-dione dioxime

One preferred embodiment of the present invention is 2,6-bis (azocan-1-ylsulfonyl) anthracene-9,10-dione dioxime

One preferred embodiment of the present invention is 2,6-bis ((3K, 5K) -3,5-dimethylpiperidin-1-ylsulfonyl) anthracene-9,10-dione dioxime

In addition, the present invention relates to compositions of compounds, including their pharmaceutically acceptable salts, having the structure defined by the above formulas (I) (VI) (with the substituents disclosed in the present invention), preferably the compounds of table. 1-4, in a therapeutically effective amount in a pharmaceutically acceptable carrier.

The compounds included in these compositions may also contain a multicyclic cycloalkyl or heterocycloalkyl bridge structure (as in Tables 1-4), comprising a total of up to 12 atoms and up to 4 heteroatoms selected from N and O.

In addition, the present invention relates to therapeutic compositions of any of the compounds of the present invention, for example, compounds of the table. 1-4.

The compounds of the present invention may take the form of their pharmaceutically acceptable salts, esters, amides, stereoisomers, geometric isomers, solvates or prodrugs. If the compound of the present invention is a stereoisomer, this stereoisomer may be an enantiomer or a diastereomer. If said compound is an enantiomer (or contains a chiral center, for example, a chiral carbon atom), the form of the compound used for pharmaceutical purposes may include any enantiomer or racemate, although one of these enantiomers may be preferred, for example, if is an active form or is more active than another enantiomer. If said compound of the present invention is a geometric isomer (for example, includes a pair of carbon atoms with substituents attached in a cis or trans configuration), either the cis or trans form may be preferred for pharmaceutical use, although in the methods of the present invention mixtures of cis and transform can be used, provided that they have the desired pharmaceutical effect.

A pharmaceutically acceptable salt is a cationic salt formed by any acidic (e.g., carboxyl) group of the compound, or an anionic salt formed by any basic (e.g., amino) group of the compound. Many of these salts are known in the art, as indicated, for example, in AO 87/05297 Οοΐιηδίοη s1 a1., Published September 11, 1987, incorporated herein by reference). Examples of suitable salts formed by acids include acetates, adipates, alginates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, citrates, camphorosulfates, digluconates, dodecyl sulfates, ethanesulfonates, formates, sulfonates, formates, sulfonates, glycolates, hemisulphates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, palmitates, p ectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, tosylates and undecanoates. Preferred cationic salts include alkali metal salts (e.g. sodium and potassium) and alkaline earth metals (e.g. magnesium and calcium) and organic base salts. Preferred salts with anions include halides (e.g., chlorides), sulfonates, carboxylates, phosphates, and the like.

The present invention also contemplates the quaternization of any basic nitrogen-containing group of compounds disclosed in the present invention. Using such quaternization, water- or oil-soluble or dispersible products can be obtained.

In another aspect, the present invention relates to compositions of any of the compounds of the present invention, in which the compound is preferably in a pharmaceutically acceptable carrier and in a therapeutically effective amount. These compositions typically should include an amount of a compound of the present invention that is not toxic (i.e., an amount that is safe for therapeutic use).

In addition, the present invention encompasses metabolites of any new compounds of the present invention, where these metabolites are second compounds resulting from one or more of the ίη νίνο metabolic reactions that occur with the first compound, after administration of this first compound to a mammal, wherein said first compound is new the compound of the present invention. In preferred embodiments, said first compound is any of the compounds disclosed in the present invention and having the structure defined by formulas (Ι) - (νΐ), with substituents disclosed for these formulas, and even more preferably any of the compounds of the table. 1-3 or 4, including all pharmaceutically acceptable salts thereof.

Selected examples of the compounds of the present invention include, but are not limited to, any or all of the compounds of the table. 1-4, including all pharmaceutically acceptable salts thereof, as well as metabolites of any of these compounds, which are formed in the body of a normal mammal, especially a human, and metabolism of these compounds occurs after the administration of the compounds to the specified mammal as a therapeutic agent. Any and all of these compounds are specifically claimed for use in any and all methods of the present invention. In each of the structures shown, the ligand is attached via an atom marked with an asterisk (*). For example, in table. 1 (anthraquinone dioximes) a sulfur atom of the formula shown (i.e., a structure nucleus) is attached to the group K shown through a nitrogen atom marked with an asterisk in the column K of the table; the same is true for other tables.

- 13,022,290

Table 1

Compound Η molar mass 1-1 Ό 532.6 1-2 Ck 560.6 1-3 Ό 536.5 1-4 'nine 560.6 1-5 Ό 560.6 1-6 γ 588.7 1-7 X 676.7 1-8 Ό Ν Η 562.6 1-9 Ο 590.7 1-10 • ςτ 604.7 1-11 Ό 590.7 1-12 ΗΝ ' ^Λχ ^ ^Λ ' Ν ' ^Λχ 622.7

- 14,022,290

- 15,022,290

1-29 • ΗΝ 664.8 1-30 * Ν 0 724.9 1-31 * ^ην ΑΣΗγ 672.8 1-32 • ΗΝ— / ^- 588.7 1-33 • ΗΝ-0 560.6 1-34 'Ο 588.7 1-35 _ / ° Ά 762.8 1-36 νΑ 0 618.6 1-37 Ό 700.9 1-38 Ό Η 0 646.7 1-39 όο 640.8 1-40 • with 640.8 1-41 • ΗΝ ^- 636.7 1-42 ° Ό 684.8

- 16,022,290

1-43 € υθ 712.8 1-44 644.8 1-45 588.7 1-46 Ό 672.8 1-47 ο 754.9 1-48 668.8 1-49 616.7 1-50 ΌΟ 640.8 1-51 and 588.7 1-52 όο Η ..... 640.8 1-53 Ό 564.6 1-54 τ 640.8 1-55 Η 668.8 1-56 Α 672.8 1-57 628.7

- 17 022290

1-58 750.9 1-59 • α Ρ 604.5 1-60 620.8 1-51 837.01 1-62 Ο> 640.8 1-63 ; ^ν Ο 588.7 1-64 ^ΉΝ > 620.6 1-65 χΛ Υ 843.1 1-66 -> Ν _Χ 815.1 1-67 „Η • ΚΝ. one % 668.8 1-68 * Ν ^ Υ ΟγΜ it 620.6 1-69 0 508.6

- 18,022,290

- 19,022,290

1-80 * ^ΗΝ ~ χ ~ ^ϊ ^ ^/ 'Η 696.9 1-81 ™ Ό 576.6 1-82 • ΗΝ- ^ θ 588.7 1-83 • φο 718.8 1-84 X 839.1 1-85 V 564.7 1-86 676.9 1-87 733.03 1-88 508.6 1-89 536.6 1-90 ΉΝ ^Ζ ~ ^Χ · ^ΖΧ - ^{/ Χ} 564.7 1-91 * ΗΝ 536.6 1-92 ΗΝ ' ^Χ Υ ^Χ ^ 564.7 1-93 Υ 668.6 1-94 .Λ 712.7 1-95 620.7 1-96 Υ 616.7 1-97 „„ 'Ώ- 720.9 1-98 .Υ Ρ 764.9 1-99 ..Υ © χ- · \ ^ ΟΗ 817.1

- 20 022290

table 2

Compound TO Κι "G molar mass 2-1 About ⁿ .about- -about- 590.7 2-2 I 0 ~ ^Ν - I .Ο ~ ^Ν > 730.9 2-3 I 759.03 2-4 At G i ABOUT G i ην ^ ν ^^ - ^, ν О 899.2 2-5 • ν '/ . Ό— * Oh ~ 618.7 2-6 0 " 730.9

- 21 022290

2-7 Ό • ο ^ I • OchH \ X 817.1 2-8 θ ' " ' ^νΧΧ ΝΗ ₂ - '' 'ΝΗϊ 702.9 2-9 0 to Ο - ^^ ΝΗ ₂ 674.8 2-10 V .Ο '' '' _ο .0 ^ .Ο 783.05 2-11 • Ο '' ' Ν-Λ .Ο '-' '' · \ ΝΛ 811.1 2-12 ΐ / .Ο • Ο ^ ζ-. .Ο 839.1 2-13 Ο-  0 ^ I -Ο '' ”' I h / c 702.9 2-14 Ο- »0 χ I • 0 ^ I \ χΝ ₄ 730.9 2-15 α • Ο ^ „Ο .ο 755 2-16 • ο '' '' ^Ν Ά -Ο ^ '' ΝΛ 783.1 2-17 Ο- * Π .ο ‘Ον / Ή XX 811.1 2-18 Ό ΗΗ ^, Ν, Ο I g ΗΝ ^ Ν 0 I 899.2 2-19 Ν''Λ to ΗΝ ^ Ν. 0 I to ΗΝ ^ Ν 0 * I 931.2 2-20 • α '^ *' ^ν ΝΗ ₂ • θ y-h νη ₂ 702.9

- 22 022290

2-21 X G 0 I G i 0 * 871.1 2-22 ’B G ΗΝ ^ Ν ^ 0 I G i ΗΝ ^ Ν ^^ χ- ^ Ν 0 * 959.1 2-23 Ό G ΗΝγ, Ν ^ Ο I Ν G! ΗΝγΝ ^ - ^, Ν Ο • 927.2 2-24 Ό »0%. I / 'φ • Ο ^ χ ^, Ν 759.03 2-25 φ Η * θ'-i. I 0 Ν 811.1 2-26 Ό G ΗΝ- ^ Ν ^ Ο I •it 715.9 2-27 • at • O - ^ - ^ UN ₂ •it 645.8 2-28 Ό •it 645 8

- 23 022290

Table 3

Compound TO molar mass 3-1 nine 560.6 3-2 Ό 560.6 3-3 Ό 532.6 3-4 γ 588.7 3-5 676.7 3-6 Ό ' 590.7 3-7 about 560.6 3-8 and 588.7 3-9 640.8 3-10 ° Ό 684.8 3-11 • OA 644.8 3-12 668.8

- 24,022,290

3-13 588.7 3-14 Ό 588.7 3-15 SJ ό 837.01 3-16 Cx 616.7 3-17 W) 712.8 3-18 ' ^ΗΝ Ύ \ 664.8 3-19 * ΗΝ Λ 720.9 3-20 b Η 640.8 3-21 Ό 616.7 3-22 Ή 628.7 3-23 Ό θ ’ 564.6 3-24 Μ ^U SS Η 640.8 3-25 • χ 592.6 3-26 • η 744.8

- 25,022,290

3-27 BUT 686.8 3-28 V 588.7 3-29 696.9 3-30 668.8 3-31 L 718.7 3-32 508.6 3-33 692.8 3-34 620.8 3-35 Στ 644.8 3-38 668.8 3-37 664.8 3-38 ό 560.6 3-39 about, 620.7 3-40 Ά 592.6 3-41 620.7 3-42 648.7 3-43 'Ν' '' '' '' Α ' 564.7 3-44 ^Η Ά ( 672.8 3-45 664.8 3-46 Ν-che 668.8

- 26,022,290

Table 4

Compound TO, to ₃ molar mass 4-1 • 04- n I 758.1 4-2 • 04 n one 744.0 4-3 •BUT n one 754.0 4-4 • 04 n ABOUT? 772.1 4-5 BUT n one 754.0 4-6 04 n • \ x-OH 717.0 4-7 • 04 n 761.1 4-8 • 04 n 783.0 4-9 BUT n 740.0 4-10 n 718.9 4-11 • t n ^ _0Η 745.0

In accordance with the foregoing, the present invention is directed to the use of the compounds of the present invention as active ingredients of drugs, in particular drugs useful in the treatment of tumors. Thus, the compounds of the present invention will be included in pharmaceutical compositions containing, for example, compounds of formula (I) as active ingredients in a mixture with pharmaceutically acceptable carriers and excipients, including any pharmaceutical agents that do not themselves produce antibodies that cause harm to the individual taking the composition that may be administered without exerting an unacceptable toxic effect. Pharmaceutically acceptable carriers include, but are not limited to, liquids, such as water, saline, glycerin, ethanol, and the like, including carriers that are suitable for nasal delivery and delivery via other parts of the respiratory tract, or via visual system. A detailed discussion of pharmaceutically acceptable carriers, diluents, and other excipients is provided in KEMΙΝΟΤΟΝ'δ RNAKMASETYUL §SIENSE§ (Meyk Rieb. So., N.1. SiggsSh ούίΐίοη). The use of these carriers is well known to those skilled in the art and will not be described in more detail in the text.

In addition, as described above, the present invention relates to a method for preventing or treating a disease associated with a change in expression levels of certain sets of genes in mammals, comprising administering to said mammal an effective amount of a compound of the present invention.

The compounds of the present invention have, for example, the effect of reducing the size and / or number of tumors, in particular, primary tumors in mammals, including humans, who need such treatment. A statistically significant change in the number of cells of the primary tumor or metastasis will typically be at least about 10%, preferably 20, 30, 50, 70, 90% or more.

In accordance with the present invention, the agents described in the present invention can be combined with other methods of treating the medical conditions described in the invention, for example, other types of chemotherapy, radiation treatment, immunotherapy, surgical treatment, etc. In addition, the compounds of the present invention can also be administered in combination with agents such as analgesics, diuretics, antidiuretics, antiviral agents, antibiotics, food additives, anemia agents, blood coagulation agents, bone agents, and psychiatric and psychological agents .

- 27 022290

The determination of a suitable dose for treatment is carried out by the clinician, using, for example, parameters or factors known in the art in order to carry out treatment or predict treatment. Introduction, as a rule, begins with an amount that is slightly less than the optimal dosage, and then increase the dosage in small steps, until the desired or optimal result is achieved with respect to any negative side effects.

The specific doses of the compound administered by the present invention to achieve a therapeutic and / or prophylactic effect will certainly be determined by the particular circumstances of the disease, including, for example, the particular compound administered, the route of administration, the condition being treated and the individual being being treated. A typical daily dose (administered as one or more doses) will be from about 0.01 to about 50-100 mg / kg body weight of the active compound of the present invention. Preferred daily dosages will typically be from about 0.05 mg / kg to about 25 mg / kg and optimally from about 0.1 mg / kg to about 10 mg / kg. Factors such as excretion rate, half-life, and maximum tolerated dose (ΜΤΌ), which are not specifically indicated in the present description, can be easily determined by an ordinary person skilled in the art using standard techniques.

An effective amount of a therapeutic agent will regulate symptoms, typically at least about 10%; usually at least about 20%; preferably at least about 30%, or more preferably at least about 50%. Alternatively, the regulation of migration will mean that the therapeutic agent affects the migration or transfer of various types of cancer cells. This will lead, for example, to statistically significant and quantifiable changes in the number of affected cells. This effect may consist in reducing the number of target cells that attach to a target area over a certain period of time. In addition, the progression, size, or growth of the primary tumor can be monitored.

In another aspect, the present invention relates to a method for preventing or treating a disorder modulated by altered gene expression, for example, one or more cancers, cardiovascular disorders, arthritis, osteoporosis, inflammation, periodontal diseases and skin diseases, comprising administering to a mammal in need thereof treating or preventing a therapeutically effective amount of a compound of the present invention.

In a preferred embodiment, the present invention relates to a method for the prophylaxis, treatment or alleviation of cancer or tumor metastases in a mammal, comprising administering to said mammal an effective amount of a compound of the present invention, said mammal being preferably human.

The compounds of the present invention can also be administered in combination (simultaneously or sequentially) with other chemotherapeutic agents. Such combined administration preferably results in a synergistic effect. In one preferred embodiment of the method of the present invention, the compound of the present invention is administered with an agent such as a ΗΜΟ CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitor, e.g. atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, etc. P. (used in the treatment of cardiovascular disorders (e.g. atherosclerosis), as described in AO 2006/083214). Other preferred co-administration agents include 5-fluorouracil and oxaliplatin. The techniques for such co-administration are given in Example 12 (see data in Table 8).

The compounds of the present invention will typically exhibit a therapeutic effect by modulating one or more genes present in a cell, in particular a mammalian cell, for example a cancer cell, preferably a colon cancer cell, most preferably an adenocarcinoma. Thus, the compounds of the present invention can be used to determine or differentiate a set of genes by determining the modulation of such a set of genes with one or more compounds of the present invention. For example, if it is found that a set of genes undergoes upregulation in cancer cells, but does not undergo similar regulation in normal cells, in particular normal cells of the same tissue or organ to which the cancer cells belong, the set of genes can be determined by their usual ability to undergo modulation (based on changes in gene expression, for example, changes in transcription rate or the amount of transcribed RNA, or the amount of polypeptide generated as a result of said expression) m contacting these genes or cells containing these genes with one or more compounds of the present invention. Obviously, the degree of this modulation may be related to the amount of said compound or compounds used for contact. Said modulation may include increased expression of all defined genes (i.e., genes of said set), decreased expression of all set genes, or increased expression of some of the set genes and decreased expression of others. Therefore, a gene that has not undergone modulation by the test compound (a compound introduced into contact with the genes or cells containing them) is not considered a member of the kit.

Thus, the present invention relates to a set of genes, where the expression of each member

- 28 022290 of the specified set of genes is modulated by bringing into contact of the specified set of genes with the compound of the present invention. In specific embodiments, the expression of each member of the specified set of genes increases as a result of said contacting or decreases as a result of said contacting. In another preferred embodiment, this set of genes is in the cell. The specified set of genes will usually be associated with a specific disease process, such as, for example, a set of genes, all of whose components are modulated by the compound of the present invention, where this compound has a specific therapeutic effect, for example, is an antineoplastic agent. This set of genes is shown in table. 5. Any subset of the genes of the table. 5 may also form a set of genes encompassed by the present invention.

Table 5

No. gene Gene name one transcription activating factor 3 2 nucleoprotein ΑΗΝΑΚ 2 3 C2 member, Aldo-keto reductase 1 family (dihydrodiol dehydrogenase 2; bile acid binding protein; 3- alpha hydroxysteroid dehydrogenase;) 4 containing the main domain spiral-loop-spiral, class at 2 5 CE2000 molecule b chemokine ligand (CC motif) 20 7 open reading frame 15 of the 13th chromosome 8 cytidine deaminase nine dehydrogenase / reductase (5VK family) member 9 10 DNA damage induced transcript 3

- 29 022290

eleven homolog Epal (NZr40), subfamily B, member 9 12 homolog Epal (NZr40), subfamily C, member 12 thirteen BORA decarboxylase (aromatic L-decarboxylase amino acids) 14 double specificity phosphatase 1 fifteen double specificity phosphatase 5 fifteen epithelial membrane protein 3 17 protein similar to OAVA (A) receptor-associated protein one eighteen protein similar to OAVA (A) receptor-associated protein 3 nineteen growth and differentiation factor 15 twenty ΘΤΡ-binding protein overexpressed in skeletal muscle 21 lymphoid specific helicase 22 gem-oxygenase (recyclizing) 1 23 histone cluster 2, H2bе 24 hypothetical protein MOS14376 25 11.8 26 20 KDa interferon-stimulated exonuclease gene 27 interleukin 32 28 interleukin 8 29th laminin alpha 3 thirty regulator of lysosomal migration 31 ΝΑΒΡΗ oxidase 1 32 optineurin 33 protein phosphatase 1 regulatory (inhibitory) subunit 15a 34 putative inducible ΡΤΕΝ kinase 1 35 gene family of homologs Eaz, member P (in filopodia) 36 containing sclerostin domain 1 37 sequestosome 1 38 small proline rich protein 1A 39 small proline-rich protein 1B (cornifin)

40 small proline rich protein 3 41 carrier of dissolved substances Ί family, (carrier cationic amino acids, system +), member 11 42 5RS25, 1GOS80 component of the kinetochore complex, homolog (5.segeu! Z1ae - baker's yeast) 43 protein 2 associated with 3-phase kinase (p45) 44 Tubulin, alpha 1a

In another aspect, the present invention relates to a method for preventing, treating or alleviating cancer or tumor metastases in a mammal, comprising administering to said mammal an effective amount of a compound that modulates the expression of one or more genes of the table. 5. Such compounds have the structure represented by formula (III) with the substituents described for these formulas in the present invention, and even more preferably are any of the compounds of table. 1-3 or 4, including all pharmaceutically acceptable salts thereof.

In addition, the present invention relates to a method for alleviating cancer or tumor metastases in a mammal, comprising administering to said mammal an effective amount of a compound of the present invention. In particular, it is intended to use the compounds of table. 1. In some embodiments, said cancer is a sarcoma, or

- 30,022,290 said cancer is a carcinoma. Specific cancers covered by the methods of the present invention include, but are not limited to, one or more diseases of the colon cancer, adenocarcinoma, colon cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, adenomatous polyposis, and hepatocellular carcinomas, where colon cancer and colorectal cancer are preferred embodiments.

In addition, the present invention provides convenient methods for the synthesis of compounds of formula (I) corresponding to the general synthesis procedure shown in Scheme 1. The starting sulfonyl chlorides can be obtained by direct chlorosulfonylation of the corresponding aromatic systems or by chlorination of suitable sulfonic acid derivatives. Compounds 1 are reacted with 6- or 7-membered cyclic amines to give secondary sulfonamides 2. Compounds can be further converted to derivatives 3, which in some cases serve as prodrugs with modified physicochemical and pharmacological properties, for example, water solubility, modified ability contact proteins, plasma resistance, toxicity and others.

Examples

Most of the compounds disclosed in the present invention were obtained from the corresponding sulfonyl chloride derivatives in accordance with the general synthesis procedure shown in Scheme 1.

The following diagrams and examples are intended to illustrate the invention, and not to limit its scope, which is defined by the attached claims.

Example 1. 2,7-bis- (Azocan-1-ylsulfonyl) anthracene-9,10-dione.

Anthraquinone-2,7-disulfonyl chloride (1215 mg, 3 mmol) was dissolved in 100 ml of ISM. The solution was cooled to -50 ° C. To this solution was added 1 ml (8 mmol) of heptamethyleneimine and then 1 ml of diisopropylethylamine. The reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was treated with 1N. HCl, filtered, washed with water and dried. The crude product was crystallized from chloroform-hexane to give 1.014 g (91%) of a yellow material, which was the desired compound.

'H NMR (SIS1 ₃ ): 8.70 (2H, d, C1 and C8), 8.47 (2H, d, C4 and C5), 8.22 (2H, dd, C3 and C6), 3.22 (8H, m), 1.70 (20H, m).

Example 2. 2,7-bis- (Azocan-1-ylsulfonyl) anthracene-9,10-dione dioxime (1-22).

The product of example 1 (1.0 g, 1.706 mmol), 5 ml of pyridine and hydroxylamine hydrochloride (1.5 g, 21.5 mmol) was stirred at 95 ° C for 36 hours. The pyridine was evaporated and the residue was stirred with 1N. HC1 (50 ml) for several minutes. The white product was collected by filtration, washed with water and dried. After this, the crude product was crystallized from a mixture of ISM-hexane, receiving 970 mg

- 31 022290 (97%) of compound 1-22 of white color.

Ή NMR (SIS1 ₃ ): 9.05 (1H, dd), 8.75 (1H, dd), 8.35 (1H, dd), 8.05 (1H, dd), 7.90 (2H, m ), 3.20 (8H, m), 1.70 (20H, m).

Example 3. Disodium salt of 2,7-bis- (azocan-1-ylsulfonyl) anthracene-9,10-dione dioxime (222 2Να).

A mixture of compound 1-22 (620 mg, 1.0 mmol), 35 ml of ISM and 2.2 ml of 1 M sodium ethoxide in ethanol was stirred under heating until a clear solution was formed. 100 ml of ether was added to this solution, and the mixture was sonicated for 5 minutes. The product as a yellow solid was collected by filtration, washed with ether and dried, yielding 660 mg (100%) of the title compound.

Example 4. Tetrahydrochloride 9,10-bis- (No.- (3-dimethylamino) propyl-M-ethylcarbamimidoyloxyimino) -2,7-bis- (azocan-1-ylsulfonyl) -9,10-dihydroanthracene (3-18).

Compound 1-22 (442 mg, 0.75 mmol), 4 ml of anhydrous chloroform and 400 mg of BIAS were stirred at 60 ° C for 1 h. The reaction mixture was condensed and chromatographed by HPLC. The pooled fractions containing the desired product (MH ⁺ = 899) were acidified by the addition of 5 ml of 1N. HC1 and evaporated to dryness. The product was dissolved in distilled water and lyophilized to give 530 mg (68%) of the title compound of white color.

Example 5. 9.10-bis - [(3-Aminopropyl) oxyimino] -2,7-bis- (azocan-1-ylsulfonyl) -9,10 dihydroanthracene (2-24).

To a solution of compound 1-22χ2Να (320 mg, 0.5 mmol) in DMSO (2 ml) was added tert-butyl 3bromopropylcarbamate (180 mg, 0.75 mmol) and the mixture was stirred at room temperature for 1 h. To the reaction mixture was added water and the precipitated products were extracted with ethyl acetate. The extract was dried with sodium sulfate, evaporated and the residue was stirred with 4n. HCl / dioxane (5 ml) for 1 h. The solvent was evaporated, the residue was dissolved in methanol and purified by preparative HPLC. Fractions containing the main product were acidified with hydrochloric acid and evaporated. The residue was dissolved in water and lyophilized to give the title compound as dihydrochloride (170 mg, two stages yield 44%). MS 703 (MH +).

Example 6. 10- (3-Aminopropyl) oximino-9-gyroxyimino-2,7-bis- (azocan-1-ylsulfonyl) -9,10 dihydroanthracene (2-28).

The title compound was isolated as the second main product in Example 5. Yield 2 stages 20%. MS 646 (MH +).

- 32,022,290

Scheme 4

Example 7. W ² , M ⁷ -bis- (4-1ret-butylcyclohexyl) -9,10-dioxo-9,10-dihydroanthracene-2,7disulfonamide.

Anthraquinone-2,7-disulfonyl chloride (10 g, 24.7 mmol) was dissolved in 200 ml of an ESM (dichloromethane). The solution was cooled to -50 ° C. To this solution was added 4-tert-butylcyclohexanamine (8.43 g, 54 mmol) and then triethylamine (8.6 ml, 61.7 mmol). The reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated, the residue was treated with MeOH, filtered off and dried, yielding 15 g (95%) of the product as a yellow powder.

Example 8. W ² , M ⁷ -bis- (4-tert-butylcyclohexyl) -H ² - (3- (dimethylamino) propyl) -9,10-dioxo-9,10 dihydroanthracene-2,7-disulfonamide and M ² , M ⁷ -bis- (4-tert-butylcyclohexyl) -M ² , M ⁷ -bis- (3 (dimethylamino) propyl) -9,10-dioxo-9,10-dihydroanthracene-2,7-disulfonamide.

NaN (95.0%, 697 mg, 27.58 mmol) was added to an ice-cold solution of sulfonamide (product of Example 7, 6.82 g, 10.61 mmol) in anhydrous DMF (100 ml) under argon atmosphere. This solution was stirred for 5 minutes and then 3-chloro-H, Y-dimethylpropan-1-amine hydrochloride (2.18 g, 13.8 mmol) was added. After 10 minutes, the reaction mixture was transferred to an oil bath preheated to 40 ° C. and stirred for 3 days. LCMS showed the presence of monoalkylated and bisalkylated products (65:25) in a mixture with unreacted starting material. After cooling, 1N was added to the reaction mixture. NaOH and was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and the filtrate was evaporated under reduced pressure. The crude mixture was purified by silica gel column chromatography. The unreacted starting material was isolated from the column by eluting with 40% ENAc in hexane. Pure monoalkylated product (LCMS, MS 728.0 (MH +)) was obtained by eluting with pure EJAc, and a bisalkylated product (LCMS, MS 813.2 (MH +)) was isolated using 5% triethylamine in EJAc as eluent. The collected fractions were evaporated to dryness under reduced pressure to give the title products (3.02 g, 53%) and (1.10 g, 17%).

Example 9. L ² , M ⁷ -bis- (4-tert-butylcyclohexyl) -H ² - (3- (dimethylamino) propyl) -9,10-bis (hydroxyimino) -9,10-dihydroanthracene-2,7- disulfonamide (4-1).

Dioxime (4-1) was prepared according to the general procedure using monoalkylated sulfonamide (product of Example 8, 2 g, 2.7 mmol), excess hydroxylamine hydrochloride (2.7 g, 27.5 mmol) and pyridine (50 ml) at 95 ° C for 36 hours. After cooling, the excess hydroxylamine was removed by filtration, washed with pyridine and the filtrate was evaporated to dryness under reduced pressure. An excess of 1N was added to the resulting product. aqueous HC1, oxime precipitated and was separated by filtration, collecting and drying a colorless precipitate. Oxime (4-1) was additionally purified by crystallization or HPLC to give it as a colorless salt with HCl (1.42 g, 65%).

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Ή NMR (DMSO-a ₆ ) δ: 13.04-13.01 (m, 1H), 12.94-12.89 (m, 1H), 10.48 (br.s, 1H), 9.18 -9.07 (m, 1H), 8.87-8.78 (m, 1H), 8.40-7.78 (m, 4H), 3.75-3.05 (m, 16 N), 2.72 (s, 6H); 1.96-0.76 (m, 28H).

Example 10. The activity of inhibiting the growth of NT-29.

To determine the survival of cell line cells, an analysis of the activity of ARN (acid phosphatase) was used, which is based on a quantitative determination of the activity of cytosolic acid phosphatase (Soppo11u e! A1., 1986; Er1sPg1sP e! A1., 2007; Magyp & C1upe8, 1993). Intracellular acid phosphatases in living cells hydrolyze p-nitrophenyl phosphate to p-nitrophenol. Its absorption at 405 nm is directly proportional to the number of cells in the range of 10 ³ -10 ⁵ cells in the form of a monolayer. NT-29 cells were grown in standard flat-bottomed 96-well microtiter plates and allowed them to grow to the wall for 24 hours before being treated with the test compounds. 72 h after treatment with the test compound, the cells were washed with ΡΒδ, 100 μl of assay buffer (0.1 M sodium acetate, 0.1% TgPop X-100, with the addition of immunologically pure p-nitrophenyl phosphate, P1egse Wu1esy. 1is., RosIoM, was added. 1b υδΑ) per well and incubated for 90 min at 37 ° C. After incubation, 10 μl of 1N was added to each well. ΝαΟΗ and we measured the absorption in each well at 405 nm for 10 min on a Rikui Ishue8a1 M1gor1a1e Apa1u / eg instrument (Raskagb, MegShey, ST, υδΑ). The results are shown in table. 6.

Table 6

Inhibition of cell growth

Compound No. Re-at-at Compound No. Result Compound No. result 1-1 ++ 1-78 ++ 3-1 +++ 1-2 +++ 1-79 +++ 3-2 +++ 1-3 ++ 1-80 ++ 3-3 +++ 1-4 +++ 1-81 ++ 3-4 +++ 1-5 +++ 1-82 ++ 3-7 +++ 1-6 +++ 1-83 +++ 3-8 ++ 1-9 + 1-84 +++ 3-9 +++ 1-10 ++ 1-85 +++ 3-10 +++ 1-13 ++ 1-86 +++ 3-11 +++ 1-14 + 1-87 +++ 3-12 +++ 1-15 ++ 1-88 +++ 3-13 +++ 1-16 ++ 1-89 ++ 3-14 +++ 1-19 + 1-90 +++ 3-15 + 1-26 +++ 1-91 ++ 3-16 +++ 1-27 +++ 1-92 ++ 3-17 +++ 1-28 +++ 1-93 +++ 3-18 +++ 1-29 +++ 1-95 +++ 3-19 +++ 1-31 1-96 +++ 3-20 +++ 1-34 + 1-97 +++ 3-21 +++ 1-37 +++ 1-98 + 3-22 +++ 1-39 +++ 1-99 +++ 3-24 ++

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1-40 +++ 2-1 ++ 3-26 ++ 1-41 +++ 2-2 +++ 3-28 +++ 1-42 +++ 2-3 +++ 3-29 +++ 1-43 +++ 2-4 +++ 3-32 +++ 1-44 +++ 2-5 ++ 3-33 +++ 1-45 +++ 2-6 +++ 3-34 +++ 1-46 +++ 2-8 ++ 3-37 4CH- + 1-48 +++ 2-9 ++ 3-39 + 4 + 1-49 +++ 2-10 ++ 3-41 ++ 1-50 +++ 2-11 ++ 3-42 +++ 1-51 ++ 2-12 + 4 3-43 +++ 1-52 ++ 2-13 +++ 3-44 +++ 1-55 ++ 2-14 +++ 3-45 +++ 1-56 +++ 2-15 ++ 3-46 +++ 1-57 ++ 2-16 +++ 4-1 +++ 1-59 ++ 2-17 ++ 4-2 +++ 1-60 +++ 2-18 +++ 4-3 +++ 1-62 ++ 2-20 ++ 4-4 +++ 1-65 +++ 2-21 ++ 4-5 1-66 +++ 2-22 + 4-6 +++ 1-67 +++ 2-23 +++ 4-8 + 1-69 ++ 2-24 +++ 4-9 +++ 1-71 +++ 2-25 ++ 4-10 ++ 1-74 +++ 2-26 +++ 4-11 4 - ++ 1-75 +++ 2-27 +++ 1-76 ++ 2-28 +++ 1-77 ++

Symbols in the table. 6 mean the following results: +++ (good inhibition), ++ (moderate inhibition) and + (poor inhibition). The ranges of values for these results are: +++ (1C ₅₀ 1 μM or less), ++ (1C ₅₀ 1 to 5 μM) and + (1C ₅₀ more than 5 μM).

Example 11. Experiment ίη νίνο: study of efficacy against xenograft.

Female pi / pi mice (20-30 g, aged 7-9 weeks) were placed in ventilated racks and were given filtered acidified water and sterile laboratory food without restrictions. Before testing, the mice were allowed to adapt for 1 week. Before the administration of the test compounds to animals with tumors, a study was conducted on intact animals to determine the maximum dose for a 5-week administration schedule. To this end, mice were injected with ΙΡ preparations or orally once a day for one week and their body weight was determined twice a week for two weeks. A loss of 20% or more of body weight was considered lethal, and higher doses were considered doses that caused significant mortality according to experiments on weight loss [see Etegwop e! A1., Sapseg Keveagss (1995), 55, 603-609; Μοήοη e! A1., YaShge Ρτοΐοεοίβ, (2007) 2 (2) 247250].

Tumor development was caused by a single subcutaneous injection of the grown tumor cells at a point located in the lower part of the left side of the animal. Then the mice were divided by body weight, grouping 5 mice per cell and microchips were introduced into their organisms for constant identification. For each group, a narrow range of body mass ± 1 g and tumor size was established. Studies on the effectiveness of drugs were carried out in a dosage range that included the previously determined highest dose. The tumor volume in each mouse was determined by measuring two sizes using a caliper and calculating using the formula length width) ² Tumor volume = - ---------- The total tumor growth was expressed as T / C ratio, where the tumor volume in late administration of test compounds (T) was divided by tumor volume at the end of vehicle (C) administration. The compounds shown in table. 7 demonstrated inhibition of tumor growth compared to the control used in this study.

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Table 7

Line cells Compound No. Dose Carrier Way introductions Co1o-205 1-10 10 RUR / glucose IV Co1o-205 1-10 75 RUR / glucose RO Co1o-205 1-25 fifteen RUR / glucose IV Co1o-205 3-2 40 ρνΡ / g l yukose ΙΡ Co1o-205 3-2 40 ρνΡ / glucose IV Co1o-205 3-2 thirty RUR / glucose ΙΡ Co1o-205 3-2 40 RUR / glucose IV Co1o-205 1-10 fifteen RUR / glucose IV Co1o-205 3-2 thirty RUR / glucose RO H4 6 0 3-2 40 ρνΡ / glucose IV H460 3-2 thirty RUR / glucose ΙΡ NT-29 1-22 75 glucose RO NT-29 1-6 fifty glucose RO NT-29 1-8 25 glucose ΙΡ NT-29 1-22 75 glucose RO NT-29 1-6 25 glucose RO NT-29 1-22 fifty glucose RO NT-29 2-14 5 glucose ΙΡ NT-2 9 1-22 75 glucose RO NT-29 1-28 75 glucose RO NT-2 9 1-6 fifty glucose RO NT-29 1-8 fifty glucose ΙΡ NT-2 9 1-6 fifty glucose RO NT-29 3-2 40 RUR / glucose IV NT-29 3-2 thirty RUR / glucose RO NT-29 1-5 75 glucose RO NT-29 1-6 75 glucose RO NT-2 9 1-8 25 glucose ΙΡ NT-29 3-4 fifty glucose RO

Example 12. Combined chemotherapy.

The efficacy of a set of chemotherapeutic agents in colon cancer models (HT29 and 8A480) was assessed to determine whether the combination of these drugs with compound 3-2 can act synergistically from the point of view of inducing cancer cell death. Using the statistical model developed by Failures and Ta1au (1981) (SepaPa / eb ctab baaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa ... ίπΗίόίΙοΓδ ίη Eigoreap 1oita1 o £ B | osnet151gu. 115: 207-216), 4 drugs were revealed that showed synergy with compound 3-2 (Table 8). Combination coefficients were calculated for each combination of drugs, and a combination coefficient of less than 1.09 indicated synergy, and a value of less than 0.5 indicated strong synergy. The combined use together with lovastatin, fluvastatin, oxaliplatin and 5-RI gave a synergistic effect of inducing the death of cancer cells.

Table 8

Medicinal means Raman index Result Lovastatin 0.62 Synergy Fluvastatin 0.72 Moderate synergy Oxaliplatin 0.25 Strong synergy 5-gi 0.24 Strong synergy

Claims (7)

1. The compound of formula (III) FORMULA OF THE INVENTION wherein K _A is hydrogen; K ₇ and K _{8 are} independently selected from H and δΟ ₂ ΝΡ ₃ Ρ ₄ . where one of K ₇ and K ₈ represents a hydrogen atom, where ΝΚ ₁ Κ ₂ and ΝΚ ₃ Κ4 independently represent a 6-15 membered heterocycloalkyl containing one nitrogen atom in the ring, which is a saturated monocyclic ring or a fused, bridging or spirobicyclic ring system and may optionally be substituted with 1-4 substituents selected from cyano, hydroxy, carboxy, amino, acetyl, formyl, C ₁ -C ₅ -alkyl, C ₁ -C ₅ -mono- or di-C ₁ -C ₅ -alkylamino-C ₁ -C ₅ -alkyl, phenyl, C ₁ -C ₅ alkoxy, phenoxy or any combination of the above substituents; or its pharmaceutically acceptable salts, stereoisomers or geometric isomers. 2. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 in a pharmaceutically acceptable carrier. 3. A method of preventing, treating or alleviating cancer or tumor metastases in a mammal, comprising administering to said mammal an effective amount of a compound according to claim 1. 4. The compound according to claim 1, where each of ΝΚ ₁ Κ ₂ and ΝΚ ₃ Κ ₄ is piperidine substituted with 12 methyl substituents. 5. The compound according to claim 1, where each of ΝΚιΚ ₂ and ΝΚ ₃ Κ ₄ represents azepan. 6. A compound having the following formula or a pharmaceutically acceptable salt, stereoisomer or geometric isomer thereof. 7. A compound having the following formula or a pharmaceutically acceptable salt, stereoisomer or geometric isomer thereof.