UA66361C2 - QUINOLINE AND QUINPXALINE COMPOUNDS WHICH INHIBIT PLATELET-DERIVED GROWTH FACTOR AND/OR p56 - Google Patents

Abstract

This invention is directed to quinoline/quinoxaline compounds which inhibit platelet-derived growth factor tyrosine kinase and/or Lck tyrosine kinase, to pharmaceutical compositions comprising these compounds, and to the use of these compounds for treating a patient suffering from or subject to disorders/conditions involving cellular differentiation, proliferation, extracellular matrix production or mediator release and/or T cell activation and proliferation.

Description

Description of the invention

This invention relates to the inhibition of cell proliferation and/or cell matrix production, and/or 2 cell movement (chemotaxis) and/or T-cell activation and proliferation by using quinoline and quinoxaline compounds that are useful protein tyrosine kinase (TPK) inhibitors.

Cellular signaling occurs through a system of interactions that includes cell-to-cell contact, cell-to-matrix contact, or extracellular receptor-to-substrate contact. The extracellular signal is often transmitted to other parts of the cell through tyrosine kinase-mediated phosphorylation, which affects 70 substrate proteins across the cell membrane associated with the signal-transducing complex. An example of tyrosine kinase enzymes involved in cellular signaling is a specific set of enzyme receptors, such as the insulin receptor, the epidermal growth factor receptor (EGF-B) or the platelet-derived growth factor receptor (PGF-K). Autophosphorylation of the enzyme is required for efficient enzymatic phosphorylation of substrate proteins containing tyrosine residues. These substrates are known to be responsible for a variety of 72 cellular events, including cell proliferation, cell matrix production, cell migration, apoptosis, etc.

It is clear that uncontrolled cell reproduction, matrix overproduction, or poorly regulated programmed cell death (apoptosis) causes many disease states. These disease states involve a variety of cell types and include diseases such as leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, fibrosis, atherosclerosis, and restenosis occurring after coronary, femoral, or renal angioplasty, or fibroproliferative disease such as arthritis, fibrosis of the lung, kidney and liver.

In addition, conditions for unregulated cell proliferation are created after coronary bypass surgery.

Inhibition of tyrosine kinase activity is believed to be useful in regulating uncontrolled cell reproduction, matrix remodeling, or poorly regulated programmed cell death (apoptosis). Gee)

It is also known that certain tyrosine kinase inhibitors can interact with more than one type of tyrosine kinase enzyme. Several tyrosine kinase enzymes are very important for the normal functioning of the body.

For example, it would be desirable to inhibit the action of insulin in most normal cases. Thus, compounds that inhibit the tyrosine kinase activity of the ROSE-K receptor at concentrations below those effective in inhibiting the insulin receptor kinase could provide valuable agents for the selective treatment of diseases characterized by cell proliferation and/or cell matrix production and /or cell movement (chemotaxis), such as restenosis. at

This invention relates to modulation and/or inhibition of cell signaling, cell proliferation, extracellular matrix production, chemotaxis, regulation of abnormal cell growth, and cell inflammatory response. More specifically, this invention relates to the use of substituted quinoxalines having the ability to selectively inhibit differentiation, proliferation or mediator release by effectively inhibiting platelet-derived growth factor receptor tyrosine kinase activity (ROSBE-K) and/or /sk tyrosine kinase activity. "

In a number of literature sources, tyrosine kinase inhibitors are described, which selectively act on 50 receptor tyrosine kinase enzymes, such as ESE-K or ROSBE-K, or non-receptor cytosolic tyrosine kinases, such as y-ari, robisk or c-zgse. In recent reviews of Zrada apa Muegz (Ehr. Raiepiz 1995, 5(8), 805) and Vgiddez (Ehr.

From Raiepiz 1995, 5(12), 1245) a brief description of the literature on tyrosine kinase inhibitors and inhibitors selective for ESE-K, respectively, is given. In addition, I am/ apa I udop gave a brief report on the antitumor activity of tyrosine kinase inhibitors (Etegoaipa Ogydv: Te Rgozresi Rog Itrgomeid Meadisipez 1996, 241-260).

Known inhibitors of the tyrosine kinase activity of ROSP-K include the quinoline-based inhibitors described

Me Madiige eyi aYi). (9. May. Spet., 1994, 37, 2129) and ru OoMe ei aiYi. (). May Spet., 1994, 37, 2627). Class

Ge») of phenylaminopyrimidine-based inhibitors was recently described by Tgahieg ei ai. in ER 564409 and Lttegtap, ..; apa Tgahieg, R. ei aI. (Viogd. May 5. Spet. Gen. 1966, 6(11), 1221-1226) and Vyspatspedeg, E. ei aiYi. (Rgod. Mai. o Asaid. Zsi. 1995, 92, 2558). Despite progress in this area, there are still no agents from these classes of compounds that have been approved for use in humans for the treatment of proliferative diseases.

The relationship between the multifactorial restenosis disease and ROSE and ROSB-K is sufficiently described in the scientific - . and with. And: literature However, recent developments in the study of fibrosis of the lungs (Apiopiades, N.M. ei aiYi. 9U. Siip. Ipmevi. 1990, 86, 1055), kidneys and liver (Reieggop, T. Neraiysiodu, 1993, 17, 486) showed that important ROSE and ROSE-K also play a role in these diseases. For example, glomerulonephritis is the main cause of renal 52 failure, and, as shown by ZPCI; her and her 1988, 255, Eb74) and Riioede eyi aYi. 1991, 86, 334), ROSRE was

GF) has been identified as a potent mitogen for mesangial cells. As reported by TPogpiop, 5.S.; her aI. (Siip. Ehr. Ittyp. 1981, 86, 79), TMP-alpha and ROSE (obtained from people with rheumatoid arthritis) are the main cytokines involved in the process of proliferation of synovial cells. In addition, specific types of tumor cells have already been identified (see Ziimeg, V., Viobasioge, 1992, 3, 217), such as glioblastoma and Kaposi's sarcoma 60 (Carosi), which overexpress the ROSE protein or the receptor, leading to uncontrolled growth of tumor cells through an autocrine or paracrine mechanism. Thus, it is expected that the ROSE tyrosine kinase inhibitor will be useful for the treatment of various, apparently unrelated human disease states, which can be characterized by the involvement of ROSE and/or ROSBE-K in their etiology.

The role of various non-receptor tyrosine kinases, such as p5b sk (hereinafter "sk, in conditions that refer to bo inflammatory, including activation and proliferation of T cells, has already been described by Napke, ei a). (Ipiatt. Kev. 1995, 44,

357) and Voiep apa Vgoidde (App. Keu. Ittipoi, 1997, 15, 371). These inflammatory conditions include allergy, autoimmune disease, rheumatoid arthritis, and transplant rejection. Another recent review briefly described different classes of tyrosine kinase inhibitors, including compounds with inhibitory activity against ISK ((goipamaijeg, ei ai. Rgodgezz ip Meadisipa! Spetivighu, 1996, 33, 233). Inhibitors of ISK tyrosine kinase activity include some natural products that are usually non-selective inhibitors of tyrosine kinases, such as staurosporine, genistein, some flavones, and erbstatin. Damnacanthol has recently been reported to be an ISK inhibitor (RGakupek, ei ai, Viospetizigu, 1995, 34, 12404). Examples of synthetic ISK inhibitors include : a series of dihydroxy-isoquinoline inhibitors that, as reported (VygkKe, ei aiYi, U. Mei. Spet. 1993, 36, 425), have /o activity at low concentrations ranging from micromolar to submicromolar, and a quinoline derivative that, was found to be much less active against Isc (IC 50-61µM).Researchers also discovered a number of 4-substituted quinazolines that inhibit IscCC at low concentrations ranging from micromolar to submicron omolarny (Muegv ei ai, UMO 95/15758 and Muegz ei aiY, Visogda. Honey. Spent And ek. 1997, 7, 417). Researchers from the company Riegeg (Napke, ei ai, U. Vioi. Spet. 1996, 271, 695) discovered two specific pyrazolopyrimidine inhibitors, known as PP and PP2, which have activity at a low nanomolar concentration in relation to Isk and Bup. (another kinase of the 5gs family). Isk inhibitors related to compounds based on quinoline or quinoxaline have not been reported. Therefore, it is expected that a quinoline or quinoxaline inhibitor of tyrosine kinase I sk activity may be useful in the treatment of various non-familial human disease states, which can be characterized by the involvement of tyrosine kinase 1 sk signaling in their etiology.

This invention relates to a compound of formula I:

Ks

Ki her TV

And Z

--

Ka m (0) o de

Kia means optionally substituted alkyl, hydroxy, acyloxy, optionally substituted alkyloxy, optionally substituted cycloalkyloxy, optionally substituted oxaheterocyclyloxy, optionally substituted heterocyclylcarbonyloxy or halogen; oh

El means hydrogen, optionally substituted alkyl, hydroxy, acyloxy, optionally substituted alkoxy, Geo) optionally substituted cycloalkyloxy, optionally substituted oxaheterocyclyloxy, optionally substituted heterocyclylcarbonyloxy or halogen; oh

Ec means hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted (se) heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocyclylcarbonyloxy, halogen, cyano, K5KeM- or acylicBM-; "

EK" means y - - x C" ;" "O. Sn Z

Az or gia Ez means hydrogen, ortho- or parafluoro, meta-lower alkyl, lower alkoxy; halogen or carbamoyl; b Ku means hydrogen or lower alkyl;

Kv and Ke are independently hydrogen or alkyl, or Kb and Kb, taken together with the nitrogen atom to which K and K o are attached, form azaheterocyclyl; bu 70 7a means M or CH; and 25 is MH or O, -6, or its M-oxide, hydrate, solvate, prodrug, or salt, provided that Ka and Ki are not both optionally substituted alkyl.

This invention also relates to a pharmaceutical composition containing a pharmaceutically effective amount of a compound of formula | and a pharmaceutically acceptable carrier. This invention further relates to intermediates,

HF) suitable for obtaining compounds of formula I, methods of obtaining intermediate compounds and compounds of formula | and application of the compound of formula I! for the treatment of a patient suffering from or subject to disorders or conditions involving cellular differentiation, proliferation, accurate matrix production or mediator release. 6o The terms used above and throughout the description of the invention have, unless otherwise indicated, the following meanings.

Definition "Patient" means a mammal, including a human. "Effective amount" means the amount of the compound according to the present invention, effective in inhibiting the activity of the tyrosine kinase ROSB-K and the activity of the ISK tyrosine kinase, which provides the necessary therapeutic effect.

"Alkyl" refers to an aliphatic hydrocarbon group that may be branched or unbranched and have from about 1 to about 10 carbon atoms. A preferred alkyl is "lower alkyl" having from about 1 to about 3 carbon atoms, with methyl being more preferred. Branched chain means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to the linear alkyl chain. The alkyl group is also optionally substituted by alkoxy, halogen, carboxy, hydroxy, or KBKeM- (where Kb and Co are independently hydrogen or alkyl or Kb and Kv, taken together with the nitrogen atom to which K 5 and Ko are attached, form azaheterocyclyl) , and more preferably optionally substituted by fluorine.

Examples of alkyl include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, tert-butyl, amyl and hexyl. "Cycloalkyl" means a non-aromatic monocyclic ring system having from about 3 to about 7 carbon atoms. Preferred monocyclic cycloalkyl include cyclopentyl, cyclohexyl and cycloheptyl; cyclohexyl and cyclopentyl are more preferred. "Aryl" means an aromatic carbocyclic radical containing from about b to about 10/5 carbon atoms. An example of aryl is phenyl or naphthyl or phenyl or naphthyl substituted with one or more substituents of the aryl group, which may be the same or different, and the substituent of the aryl group includes hydrogen, hydroxy, halogen, alkyl, alkoxy, carboxy, alkoxycarbonyl or U m2 MсОо -, where are you! and m? independently means hydrogen or alkyl. "Heteroaryl" means an approximately 5- to 10-membered aromatic monocyclic or polycyclic hydrocarbon ring system in which one or more of the carbon atoms is an element(s) other than carbon, such as nitrogen, oxygen, or sulfur. Heteroaryl may also be substituted with one or more of the aforementioned "aryl substituents". An example of a heteroaryl group includes substituted pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, imidazo|2,1-b)hiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl , imidazolyl and isoquinolinyl. Ha "Heterocyclyl" means an approximately 4-7-membered monocyclic ring system in which one or more atoms in the ring system are element(s) (other than carbon and selected from nitrogen, oxygen or sulfur. i9)

The presence of "aza" or "oxa" as a prefix before the heterocyclyl means that at least nitrogen or oxygen, respectively, is present as a ring atom. Examples of monocyclic heterocyclic groups include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. Examples of heterocyclyl moieties include quinuclidyl, pentamethylene sulfide, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, o tetrahydrofuranyl, or 4-piperidinopiperidine. co "Heterocyclylcarbonyloxy" means a heterocyclyl-"C(O)O-group in which the heterocyclyl has the above meanings. An example of a heterocyclylcarbonyloxy group is 1,471-bipiperidin-1'-ylcarbonyloxy (4-piperidinopiperidin-1-ylcarbonyloxy). Ge) "Acyl" means an H-CO- or alkyl-CO- group in which the alkyl group is as described above. Preferred acyls contain lower alkyl. Examples of acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and caproyl. "Alkoxy" means an alkyl-O group in which the alkyl group is as described above. Preferred alkoxy is "lower alkoxy" having from about 1 to about 3 carbon atoms; methoxy is more preferred. c Alkoxy may be optionally substituted with one or more groups including alkoxy, carboxy, 6-alkylcarbonyl, carboxyaryl, or CoBKeM- (where Kb and Co are as defined above). Examples of "" alkoxy include methoxy, ethoxy, n-propoxy, isoprolox, n-butoxy, heptoxy, 2-(morpholin-4-yl)ethoxy, and 2-(ethoxy)ethoxy. "Cycloalkyloxy" means a cycloalkyl-O-group, in which the cycloalkyl group is as described above. Examples of a cycloalkyloxy group are cyclopentyloxy or cyclohexyloxy. "Heterocyclyloxy" means a heterocyclyl-O group in which the heterocyclyl group is as described above. b Examples of a heterocyclyloxy group include pentamethylenesulfidoxy, tetrahydropyranyloxy, oz tetrahydrothiophenyloxy, pyrrolidinyloxy or tetrahydrofuranyloxy. "Aryloxy" means an aryl-O group in which the aryl group is as described above. b "Heteroaryloxy" means a heteroaryl-O group in which the heteroaryl group is as described above. - M "Acyloxy" means an acyl-O group, wherein the acyl group is as described above. "Carboxy" means a HO(O)C-(carboxylic acid) group. "KBKeM-" means a substituted or unsubstituted amino group, wherein K 5 and K e are as defined above Examples

Groups include amino (HBM), methylamino, ethylmethylamino, dimethylamino, and diethylamino. "KBKeMSO-" means a substituted or unsubstituted carbamoyl group in which K 5 and K e are as defined above.

F, Examples of the group are carbamoyl (HMSO-) and dimethylaminocarbamoyl (MeMSO-). co "AcylkKBM-" means an acylamino group in which Kb and acyl are as defined above. "Halogen" means fluorine, chlorine, bromine or iodine. Fluorine, chlorine or bromine are preferred, and fluorine or chlorine is more preferred. "Prodrug" means a form of a compound of formula I, suitable for administration to a patient, which does not cause toxicity, irritation, allergic reaction and the like and is effective for a particular use; such forms include ketal, ester, and zwitterone forms. The prodrug is transformed into the original compound of the above formula, for example, by hydrolysis in the blood. A detailed description is given in the work T. 65 Nidispi apa M. 5(eiMya, Rgogagnde az Mome! OeiYimegu Zuvietv, Moi. 14 oi (She A.S.5. Zutrovisht Zegiev, and in the work of Eduzhag V. Kospe, ed., Viogemegvirie Saigtiegz ip Ogyd Oezidp, Ategisap RIagtaseciisa! Azzosiaiop apa

Regdatop Rgezz, 1987; both materials are incorporated herein by reference. "Solvate" means the physical association of a compound of the present invention with one or more solvent molecules. This physical association includes various degrees of ionic and covalent bond formation, including hydrogen bond formation. In some cases, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattices of a crystalline solid. The term "solvate" includes both solution solvates and isolated solvates. Typical solvates include ethanolates, methanolates and similar compounds. A "hydrate" is a solvate in which the solvent molecule(s) is/are H2O.

Preferred embodiments of the invention 70 A preferred compound according to the present invention is a compound of formula I, in which Ka means optionally substituted lower alkoxy, optionally substituted monocyclic cycloalkyloxy, optionally substituted heterocyclylcarbonyloxy or optionally substituted monocyclic oxaheterocyclyloxy; more preferably

Kia means optionally substituted lower alkoxy or optionally substituted monocyclic oxaheterocyclyloxy, and even more preferably Ka means methoxy, ethoxy, 2-(ethoxy)ethoxy, 75. 2-(4-morpholinyl)ethoxy or furanyloxy.

Another preferred compound according to the present invention is a compound of formula !, wherein Kyl is hydrogen, optionally substituted lower alkoxy, optionally substituted monocyclic cycloalkyloxy, optionally substituted heterocyclylcarbonyloxy or optionally substituted monocyclic oxaheterocyclyloxy, more preferably K. R represents hydrogen or optionally substituted lower alkoxy, and even more preferably R represents methoxy or ethoxy.

A further preferred compound according to the present invention is a compound of formula I, wherein Ka and Cl are lower alkoxy, and the more preferred lower alkoxy is methoxy or ethoxy.

The next preferred compound according to the present invention is a compound of formula I, in which K/s is hydrogen or optionally substituted lower alkoxy, and more preferably K is hydrogen, methoxy or ethoxy. c 25 The next preferred compound according to the present invention is a compound of the formula I, in which Ko means o "z. "- z o The next preferred compound according to the present invention is a compound of the formula I, in which Ko means (Ce)

MS" so vn" at 35! | (Se)

A further preferred compound according to the present invention is a compound of formula I, wherein Kz is hydrogen, ortho- or parafluoro or metamethyl, trifluoromethyl, methoxy, fluoro, chloro, bromo or carbamoyl.

A further preferred compound according to the present invention is a compound of formula I, wherein Ki is hydrogen, di or methyl. -at

The next preferred compound according to the present invention is the compound c of formula I, in which 74 is M. :c» The next preferred compound according to the present invention is the compound of formula I, in which 74 is CH.

The next preferred compound according to the present invention is a compound of formula I, in which 7 is MH.

The next preferred compound according to the present invention is a compound of formula I, in which 7 is 0. b» Preferred compounds according to the present invention include: 2-anilino-6-quinoxalinol; (o) 2-(K)-o-methylbenzylamino)-6,7-diethoxyquinoxaline; 2-anilino-6-isopropoxyquinoxaline; 2-phenoxy-6b-methoxyquinoxaline; (o) (3-bromobenzyl)-(6,7-dimethoxyquinoxalin-2-yl)amine; also 2-(3-carbamoylphenylamino)-6-methoxyquinoxaline; 2-(2-fluorophenylamino)-6,7-diethoxyquinoxaline; 2-(3-trifluoromethylphenylamino)-6, 7-diethoxyquinoxaline; 5 Phenyl-1β-(tetrahydrofuran-3(K)-yloxy)quinoxalin-2-ylamine;

Benzyl-(6,7-dimethoxyquinoxalin-2-yl)amine;

HF) 2-(5)-o-methylbenzylamino)-6,7-diethoxyquinoxaline;

GI 2-benzylamino-6,7-diethoxyquinoxaline; (b-methoxyquinoxalin-2-yl)-(3-methylphenyl)amine; b-methoxy-2-phenylaminoquinoxaline; 2-anilino-b-ethoxyquinoxaline; 2-(3-methoxyphenylamino)-6,7-diethoxyquinoxaline; 2-(4-fluorophenylamino)-6, 7-diethoxyquinoxaline; 6,7-diethoxy-2-phenoxyquinoxaline; 65 2-phenylamino-6, 7-diethoxyquinoxaline; (6,7-dimethoxyquinoxalin-2-yl)-(3-fluorophenyl)amine,

2-(3-fluorophenylamino)-6,7-diethoxyquinoxaline; (3-bromophenyl)-(6,7-dimethoxyquinoxalin-2-yl)amine; (6,7-dimethoxyquinoxalin-2-yl)phenylamine; and (3-chlorophenyl)-(6,7-dimethoxyquinoxalin-2-yl)amine.

More preferred compounds are the following:

Phenyl(|((b-(tetrahydrofuran-z(K)-yloxy)quinoxalin-2-yl|amine;

Benzyl-(6,7-dimethoxyquinoxalin-2-yl)amine; 2-(5)-o-methylbenzylamino)-6,7-diethoxyquinoxaline; 70 2-benzylamino-6,7-diethoxyquinoxaline; (b-methoxyquinoxalin-2-yl)-(3-methylphenyl)amine; 6-Methoxy-2-phenylaminoquinoxaline; 2-anilino-b-ethoxyquinoxaline; 2-(3-methoxyphenylamino)-6,7-diethoxyquinoxaline; 2-(4-fluorophenylamino)-6,7-diethoxyquinoxaline; 6,7-diethoxy-2-phenoxyquinoxaline; 2-phenylamino-6, 7-diethoxyquinoxaline; (6,7-dimethoxyquinoxalin-2-yl)-(3-fluorophenyl)amine; 2-(3-fluorophenylamino)-6,7-diethoxyquinoxaline; (3-bromophenyl)-(6,7-dimethoxyquinoxalin-2-yl)amine; (6,7-dimethoxyquinoxalin-2-yl)phenylamine; and (3-chlorophenyl)-(6,7-dimethoxyquinoxalin-2-yl)amine.

It is to be understood that the present invention encompasses all suitable combinations of the individual preferred groups mentioned herein. with

The compounds according to the present invention can be obtained using methods known from the literature, from known compounds or easily obtained intermediate compounds. Examples of common techniques are given below. at

In addition, compounds of formula I are prepared in accordance with schemes I-MI, where the variables have the values described above, except for those variables that a specialist in this field of chemistry assessed as incompatible with the described method.

Scheme | "--

Ace | nose is),

K M S V o notes kn - clean

In M in 2 (Se) and Za. du Scheme /Y - s As all. » "Kk t ra NOV" Ah M on; I sing - Man, TNE t b Ka M Via M

Ф Scheme of c. at school! You are

K M s - t MA» Kv u MnA notes kn - pure

Ka M Kk iy i ia.

F) name)

Scheme /Yi bo A vs

Kkt ra NOV» Ah M on; I sing 2 stops M b5 ka Aa M

Scheme Sh

Kv o yav Ya re - h y sh

Ka M Y Z Va

I) N», ROS 2) maskvn,, meon

Ki

N

In M | And Ten- z - va M v,

Scheme of IU

What is Zarya TV?

Ka m 15 11,, dis her | 2) Ma-Vybukat Z-VIMAR, cat. that bisbibenzyl idenadeton-ra (Ra(yba)") is her

Ve, and (Se)

WITH.

Ks

I « t yy - same V. s Va M ! :z" (e)) (e)) (95) bo 50 -Z (F. ko bo b5

Scheme Sh

Kv o

Kv in MO, re - x and sh

Ka M Y Z Va

I) N», ROS 2) maskvn,, meon

Ki

N

In M | I s» ber-- z - va M v,

Scheme of IU

What is Zarya TV?

Ka m 15 11,, dis her | 2) Ma-Vybukat Z-VIMAR, cat. that bisbenbenzyl idenadetone-pRa (Ra(yba)") is her

Ve, and (Se)

WITH.

Ks i « t iy - re V s Va M ! x" (e)) (e)) (95) bo 50 -Z (F. ko bo b5

Scheme U

Ass

Viv Mo;

Te NOV 4. - . and M Univ., ra/s 2U NOMO, NS. 3) gr, OEA

Ka l ok; and: a

Ka M

MI scheme

Ass

ЕК ге гьКо s t o

Via m where 1a, Kv or Ku, means lower alkoxy 1) MabEi 2) base, K4Wt or «- zo KOH, RIZP, BOTH where E, 4 means optionally substituted alkyl, optionally substituted cycloalkyl or optionally x , substituted oxaheterocyclyl co or !

Viv SOSI ix, where Ku means acyl or optionally involved "co heterocyclyl

Don't go dn «-ts Ka. M. . khz c. where Kz, Ki, or Bc corresponding to the above lower alkoxy now means acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted oxaheterocyclyloxy (2) or optionally substituted heterocyclylcarbonyloxy (22) (95)

FU o - M ko 60 65

Scheme U

Ass

Viv Mo;

Te NOV 4. - . and M Univ., ra/s 2U NOMO, NS. 3) gr, OEA

Ka l ok; and: a

Ka M

MI scheme

Ass

ЕК ге гьКо s t o

Via m where 1a, Kv or Ku, means lower alkoxy 1) MabEi 2) base, K4Wt or «- zo KOH, RIZP, BOTH where E, 4 means optionally substituted alkyl, optionally substituted cycloalkyl or optionally x , substituted oxaheterocyclyl co or !

Viv SOSI ix, where Ku means acyl or optionally involved "co heterocyclyl

Don't go dn «-ts Ka. M. . khz c. where Kz, Ki, or Bc corresponding to the above lower alkoxy now means acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted oxaheterocyclyloxy (2) or optionally substituted heterocyclylcarbonyloxy (22) (95)

FU o - M ko 60 65

Scheme MI! - NO M SI Czech Moss I) NU Ra Fe Y ih 2) Ethylglyoxalate Meo M

Me A MO" 3) ROSI, me M. s ; x ov, base, Ka VG or

KIN, RIZR, BEAD where VK.4 means optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted viv Chi si oxaheterocyclyl LO I or p 20. Vu.SOSsi Meo y de Ku: means acyl or optionally substituted heterocyclyl meo. M si

Huh

Ka M s o de Kia ii Kui і means acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted oxaheterocyclyloxy or optionally substituted heterocyclylcarbonyloxy - then 1. General methods: so 2. Interaction of 2-chlorosubstituted quinoxaline and amines or anilines c

A mixture of 2-chloro-6,7-dimethoxyquinoxaline (Teq.) and an amine (about 1-eq.) is heated at a temperature of about 160-180" for about three hours to overnight. The dark brown residue is dissolved in ise) a mixture of methanol -methylene chloride (0950-1090) and chromatographed on silica gel eluting with He hexane-ethyl acetate or methanol-methylene chloride (095-10095) to give the target product. The target product can be further purified by recrystallization from methanol, methylene chloride or a mixture of methanol -water. 2. Interaction of 2-chloro-substituted quinoxaline and alcohols or phenols "

A suspension of alcohol or mercaptan (Eq.) and sodium hydride (approx. 1-Eq.) in anhydrous DMF/THF -ptv) c (0095-5095) is refluxed for 1 hour, after which 2-chloro-6 ,7-dimethoxyquinoxaline (T1eq.). The resulting mixture is boiled under reflux for ;" approximately one to four hours. The suspension is neutralized to approximately pH 5-8 and distributed between methylene chloride and brine. The residue after concentration of methylene chloride is chromatographed on silica gel, eluting with a mixture of hexane-ethyl acetate or methanol-methylene chloride (0905-1090), to obtain the target product.

He» 3. Reaction of reductive amination with aminoquinolines and aldehydes or ketones

Appropriately substituted 3-aminoquinoline (Eq.) is mixed with Eq. of the corresponding aldehyde or ketone

Me, in methanol (or other suitable solvent mixture) until TLC shows the completion of imine formation. oo Add excess MasmMmVnH or Mavn, or other suitable reducing agent, and stir the mixture until 5p TLC shows complete use of the imine intermediate. The mixture is concentrated and the residue is chromatographed on

Me. silica gel with a mixture of hexane-ethyl acetate (0-10095) or chloroform-methanol (0-2095), to obtain the target product. 4. Interaction of 3-amino substituted quinolines and bromophenyl compounds

An appropriately substituted 3-aminoquinoline (1 eq.) is mixed with about 1.4 eq. of a strong base, such as sodium tert-butoxide, Eq. of the corresponding bromophenyl compound and catalytic amounts of 2,2-bis(diphenylphosphino)-1,1-binaphthyl (5-VIMAR) and bis(idibenzylideneacetone)ipalladium (Ra(ara)") in an inert (F, organic solvent such as toluene , under an inert gas such as argon, and heated to about 807°C overnight. The mixture was cooled, diluted with a solvent such as ether, filtered, concentrated, and chromatographed with 5095 E(oAc-hexane) to give the target product. 5. Formation of a simple ether from 3-hydroxy-substituted quinolines under the conditions of the Mitsunobu (Miizypovy) reaction

A solution of appropriately substituted hydroxyquinoxaline (at approximately 0-257C) in THF is treated with eq. of each of the desired alcohols, triphenylphosphine and finally diethylazodicarboxylate (OEAB) or a suitable equivalent. The progress of the reaction is monitored by TLC and upon completion of the reaction (from approximately 1 to approximately 24 hours) the mixture is concentrated and the residue is chromatographed on silica gel to obtain the target product. 65 6. Dealkylation of quinoline or quinoxaline substituted by lower alkoxy followed by alkylation

The corresponding quinoline or quinoxaline substituted with a lower alkoxy (dec.) in DMF is treated with an excess of sodium ethanethiolate (usually about 2 or more equivalents) and the reaction mixture is stirred under heating for about 1-24 hours. The mixture is partitioned between water and ethyl acetate. Extractive work-up followed by chromatography, if necessary, gives the corresponding target product: hydroxy-substituted quinoline or quinoxaline.

A hydroxy-substituted quinoline or quinoxaline can be alkylated using the Mitsunobu reaction conditions detailed above. Alternatively, simple alkylation using methods well known in the art of chemistry with a reactive alkyl or benzyl halide using Mann or another suitable base in a suitable solvent gives the target alkylated product. 70 7. Oxidation of nitrogen in quinoline or quinoxaline to the corresponding M-oxide

The imine (-M-) moiety in a quinoline or quinoxaline compound of formula (I) can be converted into the corresponding compound in which the imine moiety is oxidized to the M-oxide, preferably by interaction with a per-acid, for example peracetic acid in acetic acid or m-chloro -peroxybenzoic acid in an inert solvent such as dichloromethane at a temperature ranging from about room temperature to /5 boiling point, preferably at an elevated temperature.

The compounds of the present invention can be used in the form of the free base or free acid or in the form of a pharmaceutically acceptable salt thereof. All forms are covered by the scope of this invention.

When the compounds according to the present invention are substituted with a basic group, acid addition salts are formed, which is a more convenient form for use; the practical use of a compound in the form of a salt, strictly speaking, is equivalent to the use of a compound in the form of a free base. Acids that can be used to prepare acid addition salts include mainly those that, when bound to a free base, form pharmaceutically acceptable salts, that is, salts whose anions are not toxic to the patient in pharmaceutical doses of the salts, due to which beneficial inhibitory effects on ROS are characteristic of the free base and do not cause harmful side effects caused by anions. Although pharmaceutically acceptable salts of these basic compounds are preferred, not all acid-addition salts are useful as a source of the free base form, even if the particular salt per se is only required as an intermediate, as, for example, in the case where the salt is prepared only for the purposes of i) purification and identification or when it is used as an intermediate to obtain a pharmaceutically acceptable salt by ion exchange methods. Pharmaceutically acceptable salts included in the scope of this invention are salts derived from the following acids: mineral acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, and sulfamic acid, and organic acids, such as acetic acid, citric acid acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, x, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid (succinic acid, quinic acid and the like. Suitable acid addition salts include the following: hydrohalides, such as the hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartrate, ise)

335 Malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-p-hydroxynaphthoate, gentisates, co-mesylates, isethinoates and di-p-toluene tartrate methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.

According to another feature of this invention, acid-addition salts of compounds according to this invention are obtained by the interaction of a free base with a corresponding acid using or adapting known methods. "

For example, acid-addition salts of compounds according to the present invention are obtained either by dissolving the free base shsh s in an aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid, and by separating the salt by evaporating the solution, or by the interaction of the free base and the acid in an organic solvent, "» and in this case the salt is released directly or it can be obtained by concentrating the solution.

The compounds according to the present invention can be regenerated from acid-addition salts by

Gee! application or adaptation of known methods. For example, the original (parent) compounds according to the present invention can be regenerated from their acid addition salts by treatment with an alkali, for example, with an aqueous solution of sodium bicarbonate or an aqueous solution of ammonia.

Ge) In the case of the compound according to the present invention, substituted by an acid group, 5p base-additive salts can be formed, which is a more convenient form for use; practical application of the compound in the form

Fo salt, strictly speaking, is equivalent to the use of the compound in the form of a free acid. The bases that can be - used for the preparation of base-addition salts include mainly those that, when combined with a free acid, give pharmaceutically acceptable salts, that is, salts whose cations are not toxic to the animal body in pharmaceutical doses of the salts, due to which the inhibitory effect is useful action on РОСРЕ, characteristic of a free acid, is not accompanied by harmful side effects caused by cations.

Pharmaceutically acceptable salts, including, for example, salts of alkali and alkaline earth metals, within the scope of this invention are salts derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, trimethylammonia, triethylammonia, ethylenediamine, n-methylglucamine, lysine, arginine, ornithine, choline, bo MM'-dibenzylethylenediamine, chlorprocaine, diethanolamine, procaine, n-benzylphenethylamine, diethylamine, piperazine, tris( hydroxymethyl)aminomethane, tetramethylammonium hydroxide and the like.

Metal salts of the compounds according to the present invention can be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the selected metal in an aqueous or organic solvent with the compound in the form of a free acid. The aqueous solvent used may be water or a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate. Such reactions are usually carried out at ambient temperature, but if necessary, they can be carried out under heating.

Salts of compounds with amines according to the present invention can be obtained by contacting the amine in an aqueous or organic solvent with the compound in the form of a free acid. Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile, or ketones such as acetone. Salts with amino acids can be obtained in a similar way.

The compounds according to the present invention can be regenerated from basic additive salts by applying or adapting known methods. For example, the parent compounds of the present invention can be regenerated from their base-addition salts by treatment with an acid, such as hydrochloric acid.

In addition to being useful per se as active compounds, the salts of the compounds of the present invention are also useful for purifying the compounds, for example using the difference in solubility between the salts and the parent compounds, by-products and/or starting materials, by methods well known to those skilled in the art. field of chemistry.

Compounds according to the present invention may contain asymmetric centers. These asymmetric centers can independently have a K or 5 configuration. For specialists in this field of chemistry, it is also obvious that some compounds of formula I! can have geometric isomerism. Geometric isomers include cis- and transform compounds according to the present invention, that is, compounds having alkenyl fragments or substituents in the ring systems. In addition, bicyclic ring systems include endo- and exoisomers. This invention covers individual geometric isomers, stereoisomers, enantiomers and their mixtures.

Such isomers can be isolated from their mixtures by applying or adapting known methods, for example, chromatography and recrystallization methods, or can be obtained separately from the corresponding isomers of their intermediate compounds, for example, by applying or adapting the methods described in this description.

Starting materials and intermediate compounds are obtained by applying or adapting known methods, i) such as those described in the reference examples, or their obvious chemical equivalents, or methods described according to the invention in this description.

The present invention is further illustrated by examples that do not limit its scope and describe the preparation of the compounds according to the present invention.

In addition, the following examples represent methods used for the synthesis of compounds according to the present invention. co

Example 1 2-(33-fluorophenylamino)-6,7-diethoxyquinoxaline

2 ml of m-fluoroaniline is added to 0.25 g (0.989 mmol) of 2-chloro-6,7-diethoxyquinoxaline. This mixture is heated in an atmospheric atmosphere overnight to 1207°C. The resulting mixture is chromatographed (CH2CI12:EUN-Z30:1) to obtain a partially purified product. This solid is triturated with ethyl acetate to obtain 0.175 g of the product in the form of a brown yellow solid, yield 54.195 (mp 19372). Elemental analysis. Calculated for

SivNivM3025E"0.25H50: C, 65.15; H, 5.62; M, 12.66. Found: C, 65.30; H, 5.30; M, 12.41.

Example 2 2-anilino-b-methoxyquinoxaline hydrochloride "

Aniline (1.3 ml, 14.3 mmol) was added to 2-chloro-b-methoxyquinoxaline (0.93 g, 4.8 mmol) in an argon atmosphere. The reaction mixture is heated at 120°C for 2 hours, and then at 1507°C for 1.5 hours. The mixture is cooled and CH 25Si is added. The resulting suspension is stirred and an orange solid substance; filtered off, washed with a mixture of CHClCl-EC2O and then intensively stirred in HNO for 40 minutes, filtered and washed with EBO to obtain a light yellow solid.

The following compounds are obtained in a similar way from the corresponding starting material.

He» 2-(3-carbamoylphenylamino)-b6-methoxyquinoxaline, m.p. 2477" p. Elemental analysis. Calculated for

SivNniaMyO0570.25Н20: C, 64.31; N, 4.89; M, 18.75. Found: C, 64.24; H, 5.04; M, 18.75;

Me. 2-(2-fluorophenylamino)-6,7-diethoxyquinoxaline, m.p. 18473. Elemental analysis. Calculated for C 8NivEMa30O»9: oo C, 66.04; H, 5.54; R, 5.80; M, 12.84. Found: C, 65.75; H, 5.61; M, 12.68; 2-(3-trifluoromethylphenylamino)-6,7-diethoxyquinoxaline, m.p. 158" p. Elemental analysis. Calculated for

Me. SioNivEzMa3O»: C, 60.47; N, 4.81; RE, 15.10; M, 11,14. Found: C, 60.27; N, 4.84; M, 10.97; as (b-methoxyquinoxalin-2-yl)-(3-methylphenyl)amine, m.p. 133-135" S. Elemental analysis. Calculated for

SivNi5M3O: C, 7243; NN, 5.0; M, 1584. Found: C, 7243; NN, 579; M, 15.77; b-methoxy-2-phenylaminoquinoxaline, m.p. 152-1537S. Elemental analysis. Calculated for C15NezMz3O: C, 71.70; H, 5.21; M, 16.72. Found: C, 71.70; H, 5.16; M, 16.80; 2-anilino-b-ethoxyquinoxaline, m.p. 118-1207S. Elemental analysis. Calculated for C 16Ni5M3070.63NiO: C, (F) 69.48; H, 5.92; M, 15,19. Found; C, 69.24; H, 5.97; M, 15.14; ka 2-(3-methoxyphenylamino)-b, 7-diethoxyquinoxaline, m.p. 173" p. Elemental analysis. Calculated for

SioN»aiM3Oz: C, 67.24; H, 6.24; M, 12.38. Found: C, 67.02; H, 6.23; M, 12.21; in 2-(4-fluorophenylamino)-6,7-diethoxyquinoxaline, m.p. 2427" S. Elemental analysis. Calculated for

SivNivEM30500.50Н50: C, 64.27; H, 5.69; M, 12.49. Found: C, 64.21; H, 5.39; M, 12.24; 2-phenylamino-6b,7-diethoxyquinoxaline, m.p. 2397; (6,7-dimethoxyquinoxalin-2-yl)-(3-fluorophenyl)amine, m.p. 99-1007C. Elemental analysis. Calculated for

Si6NIAEMzO»z: C, 64.21; N, 4.71; R, 6.35; M, 14.04. Found: C, 64.35; N, 4.61; M, 13.84; 65 2-(3-fluorophenylamino)-6,7-diethoxyquinoxaline, m.p. 1937C. Elemental analysis. Calculated for

SivNivEM30500.25Н50: C, 65.15; H, 5.62; M, 12.66. Found: C, 65.30; H, 5.30.

(3-bromophenyl)-(6,7-dimethoxyquinoxalin-2-yl)amine, m.p. 197-198" S. Elementary analysis. Calculated for

SivNiAVgM3O»: C, 53.35; H, 3.92; Hg, 22,18; M, 11.67. Found: C, 53.39; H, 3.82; M, 11.64; (6,7-dimethoxyquinoxalin-2-yl)uphenylamine, m.p. 88-90"C. Elemental analysis. Calculated for C 16H/5Mz3O": C, 68.31; H, 5.37; M, 14.94. Found: C, 68.02; H, 5.52; M ,14.91; and (3-chlorophenyl)-(6,7-dimethoxyquinoxalin-2-yl)amine, m.p. 187-188"C. Elemental analysis. Calculated for

SivNIASIMa3O»: C, 60,86; N, 4.47; SI, 11.23; M, 13.31. Found: C, 60.85; H, 4.59, M, 12.36.

Example C 2-benzylamino-6,7-diethoxyquinoxaline

2 ml of benzylamine is added to 0.3 g (1.19 mmol) of 2-chloro-6,7-diethoxyquinoxaline. This mixture is heated in a nitrogen atmosphere overnight to 120°C. The resulting mixture is distributed between CH 2SiI and a saturated solution

Manso»z. The organic layer is concentrated and the residue is chromatographed (СНоСИЕУН-З0:1) to obtain 0.337 g of the product in the form of a yellow solid with a yield of 87.6905 (m.p. 136"C). Elemental analysis. Calculated for

SioN»aiM3O»: C, 70.57; H, 6.54; M, 12.99. Found: C, 70.54; H, 6.66; M, 12.80.

The following compounds are obtained in a similar way from the corresponding starting materials. (3-bromobenzyl)-(6,7-dimethoxyquinoxalin-2-yl)damine, m.p. 199-206"S. Elemental analysis. Calculated for

C.7NivVgM3O»: C, 54.56; N, 4.31; Vg, 21.35; M, 11.23. Found: C, 49.90; H, 4.00; M, 10.14;

Benzyl-(6,7-dimethoxyquinoxalin-2-yl)amine, m.p. 210-2147S. Elementary analysis. Calculated for

С.17Н47М3О»: С, 69.14; H, 5.80; M, 14,23. Found: C, 61.78; H, 5.47; M, 12.64; and 2-benzylamino-6,7-diethoxyquinoxaline, m.p. 136"C. Elemental analysis. Calculated for C 419H24M3O": C, 70.57; H, 6.55; M, 12.99. Found: C, 70.54; H, 6.66; M, 12.80 .

Example 4 2-(K)-o-methylbenzylamino)-6,7-diethoxyquinoxaline

2 ml of (K)-(x)-o-methylbenzylamine is added to 0.3 g (1.19 mmol) of 2-chloro-6,7-diethoxyquinoxaline. This mixture is heated in a nitrogen atmosphere for three days to 120°C. The resulting mixture is distributed between SNESII"z and a saturated solution of ManHsSoO". substance with a yield of 29.495 (m.p. 55-56"C). Elemental analysis. Calculated for Со0НозМ302510.25Н20: C, 70.26; N, 6.93; M, 12.29. Found: C, 70.56; H, 6.80; M, 12.35. at

The following compound is obtained in a similar way from the corresponding starting materials. 2-(5)-α-methylbenzylamino)-6,7-diethoxyquinoxaline, m.p. 55-58" S. Elemental analysis. Calculated for

СгоНозМ30200.25Н50: C, 70.26; N, 6.93; M, 12.29. Found: C, 70.49; H, 6.89; M, 12,23. -

Example 5 2,7-biscyclohexyloxy-b-methoxyquinoxaline

Cyclohexanol (0.7 ml, 6.7 mmol) was added dropwise to a solution of Man (0.32 g, vmMol) in DMF (5 ml) in the atmosphere. The mixture is stirred at room temperature for 25 minutes, after which 2-chloro-6,7-dimethoxyquinoxaline is added in portions. The reaction mixture is stirred for 15 minutes at room temperature, 2 hours at 907 and 1 hour at 1107C. The mixture is cooled, quenched by adding HO. The organic layer is washed with water brine, dried (Ma5O)) and chromatographed (1095 E(SO/hexane) to obtain a waxy white solid (Ce) (m.p. 75-787"С). Elemental analysis. Calculated for С 24Но8М»Оз: С, 70.76, H, 7.92, M, 7.86.

Found: C, 70.81; N, 7.79; M, 7.70.

The following compound is prepared in a similar manner from the appropriate starting materials. "2-phenoxy-6b-methoxyquinoxaline, m.p. 79-81; and 6,7-diethoxy-2-phenoxyquinoxaline, m.p. 130-1317S. Elemental analysis. Calculated for C/8Ni8M2Oz: C, 69.66; H, 5.85; M, 9.03. Found: C, 69.53; H, 5.82; M, 8.91. - c Example 6 Cyclohexyl-(6b,7-dimethoxyquinoxalin-2-ylmethyl)amine a To 0.067M solution of 6,7-dimethoxy-2-quinoxalinecarboxaldehyde in a mixture (2:11) Meon-1,2-dichloroethane (7.5ml , "» 0.bmMol) add cyclohexylamine (0.1 µM, 0.9 mmol). The reaction mixture is stirred at room temperature overnight, after which MavN (0.038 g, µM) is added and the reaction mixture is stirred overnight. The mixture is then concentrated and chromatographed (5095 EtOAc/hexane approx. 595 Meon in (o) EAac/hexane). The oil was dissolved in an EtOAc/hexane mixture and treated with HCl in EUN). The resulting solution was concentrated and the solid triturated to give a white solid after drying in vacuo at 60906 (pl. 185-190", layout.). Elemental analysis. Calculated for С.47Н2зМ3О2О NS: С, 60.44; H, 7.16;

Ge) M, 12.44. Found: C, 60.48; H, 6.88; M, 12.07. b» 50 Example 7 Cyclohexyl-(b-methoxy-7-morpholin-4-yl-quinoxalin-2-yl)amine

They use the method described in Vispmaia, ei aiYi, 9. At. Spent os, 1996, 118, 7215. Morpholine (0.1g, 0.3mMol, tert-butoxide sodium (0.04g, 0.42mmol) 5-(-)-VIMAR (cat., 0.001g) and Ra(ara)" (cat., 0.001g). The reaction mixture is heated to 807C overnight. The mixture is cooled, diluted Eb2O, filtered, concentrated, and chromatographed (5090 EtOAc/hexane). The product was recrystallized from EtOAc/hexane to give (in two batches) a yellow solid (mp 194-1967C). Elemental analysis. Calculated for SiONovMa4O: C, 66.64; H, 7.65; M, 16.36. Found: C, 66.60; H, 7.60; M, 16.51. co Example 8 3-cyclohexyloxy-6,7-dimethoxyquinoline

3-hydroxy-β6,7-dimethoxyquinoline (0.237g, 1.15mmol), cyclohexanol (0.347g, 3.4bmmol), RizR (0.908g, 3.4bmmol) are added to the THF solution (30ml) at 0"C. Diethyl azodicarboxylate was added portionwise until the solution turned dark red (0.663g, 3.81mmol). After 4 hours, the solution was concentrated and the residue was chromatographed (5095 EUdAs in hexane). The product was recrystallized from isopropanol/hexane to give the hydrogen chloride salt as a white of a solid substance (m.p. 229-232"C, decomp.).

Example 9 2-anilino-6-quinoxalinol 65 By the method described in Rezigia, (5.1: Mighipdiop, K.M. Tei Gay. 1970, 1327, arylmethyl ether is converted into a phenol derivative. To 2-anilino-b-methoxyquinoxaline (0, 27g, 1.07mMol) under an argon atmosphere in DMF is added the sodium salt of ethanethiol (0.19g, 2mMol). The reaction mixture is heated to 1107C overnight. The mixture is concentrated and partitioned between anise and H»O/590 tartaric acid mixture so that the pH of the aqueous layer becomes approximately 4. The organic layer is washed with water (4 times) and then with 2.595 Mah (4 times). The main layers are combined, washed with EtOAc (2 times), acidified again with 595 N tartaric acid and repeatedly washed in portions

EUAs. The organic layers are combined, washed with brine, dried (MA»ZO)) and concentrated. The resulting solid is chromatographed (5090 EtOAc/hexane). By grinding the product with EGO, a sample for analysis is obtained in the form of a yellow powder (m.p. 211-213"С). Elemental analysis. Calculated for С45Н14М30: С, 70.88;

N, 4.67; M, 17.71. Found: C, 70.64; N, 4.85; M, 17.58. 70 Example 10 Phenyl-I|b-(tetrahydrofuran-3(K)-yloxy)quinoxalin-2-yl|Iamine

2-anilino-b-quinoxalinol (0.23g, 0.97mMmol) is added to the THF solution at 0"C in an argon atmosphere.

Add portions of (5)-()-3-hydroxytetrahydrofuran (0.08 bml, 1.3 mmol) and triphenylphosphine (0.31 g, 1.2 mmol). Add CEAO (0.18 ml, 1.2 mmol) in portions. The reaction mixture is allowed to warm to room temperature and stirred for 1.5 hours. The mixture is concentrated and partitioned between EtOAc and H2O. The organic layer 7/5 is washed with water, brine, dried (M9ZO) and concentrated. The resulting yellow oil is chromatographed (5090

EtOAc/hexane) and dissolved in EGOO/IPA (isopropanol). A solution of NCI/EC 2O is added dropwise and the resulting red-orange powder is dried in a vacuum. The powdered product is converted into a free-base form by mixing in Meon from a washed (Z3xH»O, 5xMeon) basic ion exchange resin. The mixture is stirred

30 minutes, filtered, concentrated and recrystallized from a mixture of Е(ХАс/hexa), obtaining (in two batches) the product (m.p. 173-1757С). Elemental analysis. Calculated for С8Н47М3О»: С, 70.35; 5.57; M, 13.67. Found: C, 70.19; H, 5.60; M, 13.66.

Example 11 2-anilino-b-isopropoxyquinoxaline hydrochloride

To Man (0.033 g, 0.84 mmol) in an atmosphere of argon, add a little DMF. Add portions of 2-aniline-6-quinoxalinol (0.1 g, O0.42 mmol) in 1.5 ml of DMF. After 30 minutes, 2-bromopropane is added dropwise and the resulting solution is heated to 507C for 1.5 hours. The cooled reaction mixture is quenched with water and distributed between

EtOAc and HNO, washed with HNO (3 times), brine, dried (Ma5O)) and concentrated. The resulting residue i) is chromatographed (3090 E(UAc/hexane) to obtain 0.05 g of the dialkylated product and 0.1 g of the compound indicated in the title. An analytical sample of the hydrogen chloride salt is obtained by adding IPA/HCI to the ET2OL/LPA solution of the free base to obtain the hydrochloride salt ( t.pl. 205-2107C, schedule.) Elemental analysis. Calculated for "-

SitNitM3O NS C, 64.65; H, 5.74; M, 13.91. Found: C, 64.51; N, 5.90; M, 13.09.

Example 12 3-cyclohexyloxy-6,7-dimethoxychymoxaline 1-oxide so

A mixture of 2-cyclohexyloxy-b,7-dimethoxyquinoxaline (110 mg, 0.38 mmol) and metachlorobenzoic peracid c (7095, 11 mg, 0.46 mmol) and 10 ml of methylene chloride was stirred at room temperature during the day. After filtration, the solution is concentrated and the residue is chromatographed on silica gel (2095 ethyl acetate-hexane) with ise) to give the target product (m.p. 167-169). Similarly, trans-4-(6,7-dimethoxy-4-oxyquinoxalin-2-ylamino) cyclohexanol (m.p. 220-2227С) is obtained. Elemental analysis.

Calculated for С16Н23М30400.2Н20: С, 59.42; H, 6.69; M, 12.99. Found: C, 59.43; H, 6.64; M, 12.95.

Example 1 of obtaining the intermediate compound 4-bromo-5-methoxybenzene-1,2-diamine hydrochloride "

595 Pa/C (0.5 g) was added to a solution of EtOAc (5 Oml) and 5-bromo-4-methoxy-2-nitrophenylamine (2.5 g, 1 Omol) in an argon atmosphere. The reaction mixture is hydrogenated at a pressure of 10 psi (3.5 kg/cm 7 ) for 1 hour. The mixture is filtered through Celite into a solution of NSILRA/EIHUAc and the Celite layer is washed with additional E(Ac. The precipitate obtained is filtered to obtain a white solid.

Example 2 preparation of the intermediate compound 7-bromo-b-methoxyquinoxalin-2-ol and

He») b-bromo-7-methoxyquinoxalin-2-ol

To the MeonH solution (15 ml) in an argon atmosphere, Mmaon granules (0.86 g,

Pho B5imMol) and 4-bromo-5-methoxybenzene-1,2-diamine dihydrochloride (2.7g, 9.3mMmol). The mixture is stirred for 10 minutes, after which a solution of 4595 ethylene glyoxalate in toluene (2.7 g, 12 mmol) is added in portions. The reaction mixture is boiled under reflux for 1 hour, after which it is cooled. Add water and then filter the suspension. The resulting solid is washed successively with NaO, Meon, IRA and EBO to obtain a yellow powder.

Example From the preparation of the intermediate compound 7-bromo-2-chloro-6-methoxyquinoxaline and 6-bromo-2-chloro-7-methoxyquinoxaline

To a mixture of 7-bromo-b-methoxyquinoxalin-2-ol and b-bromo-7-methoxyquinoxalin-2-ol (1g, 3.9Ummol) add

F, ROSI" (B5ml). The reaction mixture was refluxed for 1 hour, poured into ice water, filtered and then washed with water to give a light reddish brown solid.

The ratio of 7-bromo-2-chloro-b-methoxyquinoxaline: b-bromo-2-chloro-7-methoxyquinoxaline is approximately 7:1 60 according to analysis by the IN NMR method.

Example 4 of obtaining the intermediate compound 5-chloro-4-methoxy-2-nitroaniline

To a solution of M-I-((5-chloro-4-methoxy-2-nitrophenyl)acetamide (2g, 8.2mMmol) in 5% HCl (20ml) add 1,4-dioxane (10ml) and stir the mixture at 60°C. C for 1.5 hours. The reaction mixture was concentrated and partitioned between EtOAc and 2 N. Fat. The aqueous layers were washed with EtOAc (3 times), brine, dried (Mo509 ud), adsorbed on silica gel and chromatographed (7095 E(OAc/hexane) with obtaining an orange powder.

Example 5 of obtaining the intermediate product 4-chloro-5-methoxybenzene-1,2-diamine dihydrochloride

To a solution of EtOAc (25 ml) and 5-chloro-4-methoxy-2-nitrophenyl-amine (1.6 g, 7.9 mmol) in an atmosphere of argon, add 5905 Ra/cС (0.5 g). The reaction mixture is hydrogenated at a pressure of 5 BOlbs/sq.in (3.5 kg/cm 2 ) for 1 hour.

The mixture is filtered in a nitrogen atmosphere through Celite into a solution of zinc. NSIBO in EtOAc and the Celite layer is washed with additional EtOAc. The resulting precipitate is filtered to obtain a white solid.

Example 6 of obtaining the intermediate compound 7-chloro-6-methoxyquinoxalin-2-ol and 70 b-chloro-7-methoxyquinoxalin-2-ol

TEA (triethanolamine) (2.5 ml, 14 mmol) was added to a solution of 4-chloro-5-methoxybenzene-1,2-diamine dihydrochloride (1.8 g, 7.2 mmol) in EtOAc (15 mL) under an argon atmosphere at 0"C. The mixture stirred for 20 minutes, then a solution of 4595 ethylene glyoxalate in toluene (2.1 g, 9.3 mmol) was added portionwise. The reaction mixture was warmed to room temperature, refluxed for 1.5 hours, then cooled. 75 Water was added and then the suspension is filtered and washed sequentially with H 20, IPA and EBO to obtain a light yellow powder.The product is azeotroped several times with toluene and dried in a vacuum before use.

Example 7 preparation of the intermediate compound 2,7-dichloro-6-methoxyquinoxaline and 2,6-dichloro-7-methoxyquinoxaline

To a mixture of /7-chloro-b-methoxyquinoxalin-2-ol and b-chloro-7-methoxyquinoxalin-2-ol (1 g, 4.7 mmol) using a chlor-calcium (Sasi 5) tube, add ROCI 3 (bBml). The reaction mixture is refluxed for 30 minutes, poured into a cold saturated solution of MansSoO»z, filtered and then washed with water to obtain a solid. The ratio of 2,7-dichloro-b-methoxyquinoxaline:Ga 2,6-dichloro-7-methoxyquinoxaline is approximately 6:1 according to analysis by the IN NMR method. at

Compounds of formula I, as described above, inhibit cell proliferation and/or cell matrix production and/or cell movement (chemotaxis) by inhibiting the activity of tyrosine kinase ROSE-K. Uncontrolled cell proliferation, matrix overproduction, or poorly regulated programmed cell death (apoptosis) cause many disease states. A wide variety of cell types are involved in these disease states, and they include diseases such as leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, bone diseases, fibrosis, atherosclerosis, and restenosis that occurs after angioplasty of the coronary, femoral, or renal arteries, or fibroproliferative diseases such as arthritis, fibrosis of the lungs, kidneys and liver. co

In particular, ROSE and ROSBE-K have been reported to be involved in some types of cancers and tumors, such as brain cancer, ovarian cancer, colon cancer, prostate cancer, lung cancer, Kaposi's sarcoma, and malignant melanoma. In addition, conditions for cell proliferation with (Ce) impaired regulation are created after coronary bypass surgery. Inhibition of tyrosine kinase activity is believed to be useful in regulating uncontrolled cell reproduction, matrix remodeling, or poorly regulated programmed cell death (apoptosis). "

This invention relates to modulation and/or inhibition of cell signaling, cell proliferation, cell matrix production, cell movement (chemotaxis), regulation of abnormal cell growth, and cell inflammatory response. More specifically, this invention relates to the use of substituted quinolines and α-quinoxalines, which have the ability to selectively inhibit differentiation, proliferation, matrix production, "» chemotaxis or mediator release by effectively inhibiting the activity of platelet-derived growth factor receptor tyrosine kinase (ROSB-K).

Initiation of autophosphorylation, i.e. phosphorylation of the growth factor receptor itself, and (o) phosphorylation of host intracellular substrates is a biochemical process involved in cell signaling, cell proliferation, matrix production, chemotaxis, and mediator release.

Due to their effective inhibition of tyrosine kinase I activity, the compounds of the present invention are also (95) useful in the treatment of transplant resistance and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus, in transplant rejection, in the condition named "graft against host" in hyperproliferative disorders, such as tumors and psoriasis, and in diseases in which cells accept pro-inflammatory signals, such as asthma, inflammatory bowel disease, and pancreatitis. For the treatment of transplant resistance, the compounds of the present invention can be used either prophylactically or in response to an adverse human reaction to a transplanted organ or tissue. When used prophylactically, a compound of the present invention is administered to a patient either in the transplanted tissue or organ prior to the transplant operation. Prophylactic treatment may also include the administration of the drug after the transplant operation, but before any signs of an adverse reaction to the transplant are detected. When administered in response to an adverse reaction, a compound of the present invention is administered directly to a patient to counteract transplant resistance after the appearance of outward signs of resistance.

According to another aspect of the present invention, there is provided a method of treating a patient suffering from or susceptible to conditions that can be attenuated or reversed by administration of an inhibitor of tyrosine kinase activity

ROSE-K and/or activity of tyrosine kinase I cK, for example, the conditions described above, which includes administering to the patient an effective amount of a compound of formula I or a composition containing a compound of formula I, or a pharmaceutically acceptable salt thereof.

As used herein, the term "treatment" includes both prophylactic therapy and treatment of underlying conditions.

The present invention covers pharmaceutical compositions containing a pharmaceutically acceptable amount of at least one of the compounds of formula | together with a pharmaceutically acceptable carrier such as an excipient, diluent, coating and excipient.

In practice, compounds or compositions for treatment according to the present invention may be administered by any of a number of suitable routes, such as by inhalation, topically, parenterally, rectally, or orally; the oral route of administration is more preferred. More specific routes of administration include intravenous, intramuscular, subcutaneous, intraocular, intraarticular, colonic, 70 peritoneal, transepithelial, including transdermal, ophthalmic, sublingual, transbuccal, dermal, ocular, nasal inhalation by insufflation, and aerosol.

The compounds of formula I can be presented in forms that allow administration by the most appropriate route, and the invention also relates to pharmaceutical compositions containing at least one compound according to the present invention, suitable for use as a medicinal product for a patient. These compositions may be prepared by conventional methods using one or more pharmaceutically acceptable excipients or excipients. Excipients include, but are not limited to, diluents, sterile aqueous media, and various non-toxic organic solvents. The compositions may be in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, solutions for injection, elixirs or syrups and may contain one or more substances selected from the group consisting of sweetening agents such as 20 sucrose, lactose, fructose, saccharin or Nutrasvit (Miigasmueeke), corrigents such as peppermint oil, wintergreen oil or cherry or orange corrigents, colors or stabilizers such as methyl- or propylparaben, to obtain pharmaceutically acceptable preparations.

The choice of the carrier and retention of the active substance in the carrier is usually determined according to the solubility and chemical properties of the product, the specific method of administration and precautionary measures used in pharmaceutical practice. For example, fillers such as lactose, sodium citrate, calcium carbonate, i) dicalcium phosphate and disintegrants such as starch, alginic acids and some complex silica gels can be used for the production of tablets, lozenges, pills, capsules and similar preparations. , combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc.

For the preparation of capsules, it is advisable to use lactose and a liquid carrier, such as high-molecular "-

From Ppolyethylene glycol. Various other materials may be present as coatings or for some other change in the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar, or both. When using aqueous suspensions, they may contain emulsifying substances or substances that contribute to the formation of a suspension. Diluents such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerin, and chloroform or mixtures thereof may also be used. except ise)

Therefore, the active compound can be included in compositions and preparations with extended action. "at

When administered orally, the active compound may be administered, for example, with an inert diluent or with an digestible edible carrier, may be incorporated into hard or soft gelatin capsules, may be compressed into tablets, or may be administered directly with food or combined with an excipient. and used in the form of tablets that are swallowed, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers and the like. for parenteral administration use emulsions, suspensions or solutions of compounds according to this

And the invention in vegetable oil, for example, sesame, peanut or olive oil, or water-organic oils? solutions such as water and propylene glycol in injectable organic esters such as ethyl oleate and sterile aqueous solutions of pharmaceutically acceptable salts. Injectable forms should be so fluid that they can be easily injected with a syringe, and the proper fluidity could be ensured, for example, by the use of a coating such as lecithin, by providing the required particle size in the case of dispersion, and by the use of surface- active substances.

Me. Prolonged absorption of injectable compositions can be ensured by the use of agents that delay absorption, for example, aluminum monostearate and gelatin. Salt solutions of the products according to the present invention are particularly suitable for administration by intramuscular or subcutaneous injection. Solutions

Me, the active compound in the form of a free base or a pharmacologically acceptable salt may be suitable in water,

Kk suitably mixed with a surfactant such as hydroxypropyldelulose. Dispersion in glycerol, liquid polyethylene glycols and their mixtures and in oils can also be prepared. Aqueous solutions, including solutions of salts in pure distilled water, may be used for intravenous administration provided that their pH is properly adjusted, that appropriate buffering properties are added to them, and that they are made isotonic with sufficient glucose or sodium chloride, and that they are sterilized

F) by heating, irradiation, microfiltration and/or with the help of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. Sterile injectable solutions are prepared by introducing the active compound in the required amount into a suitable solvent with the various other components listed above, as needed, followed by filtration sterilization. Typically, dispersions are prepared by introducing various sterilized active components into a sterile carrier containing the main dispersion medium and other necessary components from those specified above. In the case of sterile powders for the preparation of sterile injectable solutions 65, the preferred methods of preparation are vacuum drying and lyophilization, which provide a powder of the active ingredient plus any other necessary ingredient from a previously sterile filtered solution.

For local administration, gels (water or alcohol based), creams or ointments containing the compounds of the present invention may be used. The compounds of the present invention may also be incorporated into a gel or matrix base for patch application, which would allow for controlled release of the compound across the transdermal barrier.

For administration by inhalation, the compounds of the present invention may be dissolved or suspended in a suitable carrier for use in a nebulizer or suspension, or solutions in aerosol form, or may be absorbed or adsorbed on a suitable solid carrier for use in a dry powder inhaler. 70 Solid compositions for rectal administration include suppositories prepared according to known methods and containing at least one compound of formula I.

Compositions according to the present invention can also be prepared to provide resistance to rapid removal through the walls of a vessel (artery or vein) by convection and/or diffusion, due to which the time of stay of viral particles in the desired site of action is increased. For sustained release, a 7/5 Periadventitous Depot containing a compound of the present invention may be used. One such suitable depot for the administration of a compound of the present invention may be a copolymer matrix, such as ethylene-vinyl acetate or a polyvinyl alcohol gel, surrounded by a shell of Silastik (Ziazeis). Alternatively, a compound of the present invention may be delivered locally from a silicone polymer implanted in the adventitia.

An alternative method of minimizing washout of a compound of the present invention during percutaneous transvascular delivery involves the use of non-diffusible drug-releasing microparticles.

Microparticles can be composed of a wide variety of synthetic polymers, such as, for example, polylactide, or natural substances, including proteins and polysaccharides. Such microparticles provide the possibility of operational manipulation of variables, including the total dose of the drug and the kinetics of its release. Microparticles can be effectively introduced through the arterial or venous wall using a porous balloon catheter or balloon on a stent (dilator) and retained in the vessel wall and periadventitial tissue for at least about two weeks. Preparative forms and methods of i) local delivery of drugs to a specific place inside the blood vessel are described in the work of Keizep ei ai. (9.

At. Soy Sagao! 1994; 23; 1234-1244), included in this description as a reference.

The composition of the present invention may also contain a hydrogel prepared from any biocompatible or non-cytotoxic (homo or hetero) polymer, such as a hydrophilic polymer of polyacrylic acid, which can act as a drug absorbing sponge. Such polymers are already described, for example, in the ISE application)

MO 93/08845, which is included in this description as a reference. Some of them, such as, in particular, those obtained from ethylene and/or propylene oxide, are commercially available.

When using compounds according to the present invention for the treatment of pathologies associated with re) hyperproliferative disorders, these compounds can be administered by various routes. For the treatment of restenosis, compounds of the present invention are administered directly into the blood vessel wall using an angioplasty balloon coated with a hydrophilic film (e.g., hydrogel) that is impregnated with the compound, or by any other catheter containing an infusion chamber for the compound. , which, thus, can be accurately brought to the place to be treated, and makes it possible to effectively "

Release the compound precisely at the location of the cells where the treatment is needed. This method of administration provides the possibility of rapid introduction of the compound into contact with the cells in need of treatment.

The method of treatment according to the present invention preferably consists in the introduction of the compound according to the present invention into the place to be treated. For example, the composition containing the hydrogel can be applied directly to the surface of the tissue to be treated, for example, during surgery. Easy

INTRODUCE the hydrogel to the required place inside the vessel by coating a catheter, such as a balloon b catheter, and delivering it to the vessel wall, preferably during angioplasty. It is especially appropriate to introduce a saturated hydrogel in the place to be treated using a balloon catheter. When promoting

Me, the catheter in the direction of the intended vessel, the balloon can be equipped with a protective shell to minimize the washout of the drug after inserting the catheter into the bloodstream.

Another embodiment of the present invention relates to the administration of the compound using perfusion balloons.

Me, These perfusion balloons, which provide the ability to maintain blood flow and thereby reduce the risk of myocardial ischemia when the balloon is inflated, also provide the ability to deliver the compound to the desired site at normal pressure for a relatively long time (more than twenty minutes), which may be necessary for its optimal action. Alternatively, a channelized balloon catheter can be used ("channelized balloon catheter for angioplasty", Mapwiei Meisa!, Voviop Zsiepiyis Sogr., U/agegomp,

MA). The latter consists of a traditional balloon covered with a layer of 24 perforated channels, which

Ф) are poured thanks to an independent lumen through an additional infusion hole. Various types of balloon catheters, such as double balloon, porous balloon, microporous balloon, channeled balloon, stented balloon, and hydrogel catheter, all of which can be used in the practical implementation of the invention, are described in the work of Keivzep et al. (1994), which is incorporated herein by reference. The use of a perfusion balloon catheter is especially preferable, as it provides both the ability to keep the balloon inflated for a long period of time while maintaining the properties of easy sliding, and the specific localization of the hydrogel at the same time.

Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of the present invention and a poloxamer such as Poloxamer (Roiochateg) 407 non-toxic biocompatible polyol commercially available (BA5ZE, Ragvirrapu, M.)).

Poloxamer impregnated with a compound according to the present invention can be applied directly to the surface of the tissue to be treated, for example during surgery. Poloxamer has, in fact, the same advantages as a hydrogel, although it has a lower viscosity.

The use of a channel balloon catheter with poloxamer impregnated with a compound according to the present invention has a particular advantage. In this case, it is simultaneously possible to keep the balloon inflated for a long period of time while maintaining the properties of easy sliding and specific localization of the poloxamer.

The percentage content of the active ingredient in the compositions can be changed, and it is necessary that it be 7/0 present in the amount that provides the required dose. Obviously, multiple unit dosage forms can be administered at approximately the same time. The dose used can be determined by a doctor or qualified medical professional and depends on the desired therapeutic effect, the method of administration, the duration of treatment and the condition of the patient. For adults, doses are usually from about 0.001 to about 50, preferably from about 0.001 to about 0.001 to about 0.001 to about 0.001 mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably from 0.1 to 70, more preferably from 0.5 to 10 mg/kg of body weight per day for oral administration and from about 0.001 to 10, preferably 0.01-10 mg/kg of body weight per day for intravenous administration. In each specific case, doses are determined according to the characteristics of the patient to be treated, such as age, weight, general health and other characteristics that may affect the effectiveness of the compound according to the present invention.

The compounds of the composition according to the present invention can be administered as often as necessary to achieve the desired therapeutic effect. Some patients may respond quickly to a higher or lower dose, and much lower maintenance doses may be sufficient for them. For other patients, long-term treatment at the rate of 1-4 doses per day may be necessary, according to the physiological needs of each specific patient. As a rule, the active product can be administered orally 1-4 times a day. But, of course, for other patients, it may be necessary to prescribe no more than one or two doses per day. (8)

The compounds of the present invention can also be used in combination with other therapeutic agents or in combination with the application of therapeutic methods to certain pharmacological conditions that can be alleviated by the use of such compounds of formula I. The compounds of the present invention can be used for treatment of restenosis after angioplasty using any device such as balloon, excision, or laser procedures. The compounds according to the present invention can be used for the treatment of restenosis after stent placement in the circulatory system either 1) for the primary treatment of vascular occlusion, or 2) in the event that angioplasty using some device is not able to ensure patency of the artery. The compound can be used orally, ise) c5 parenterally, by local application with the introduction of a special device or in the form of a properly manufactured coating on an expander (stent).

The compounds of the present invention can be used to treat restenosis in combination with any anticoagulant, antiplatelet, antithrombotic or profibrinolytic agent. Often, patients are treated before, during, and after surgery with agents of these classes to safely perform surgery or to prevent the adverse effects of thrombus formation. Some examples of classes of agents known as anticoagulant, antiplatelet, antithrombotic or profibrinolytic agents,

And include any heparin preparations, low molecular weight heparins, pentasaccharides, antagonists, etc.? fibrinogen receptors, thrombin inhibitors, Xa factor inhibitors or Miia factor inhibitors.

The compounds of the present invention can be used in combination with any hypotensive agent or cholesterol or lipid regulating agent in the treatment of restenosis or atherosclerosis in parallel with the treatment of high blood pressure or atherosclerosis. Some examples of agents suitable for treating high blood pressure include compounds of the following classes: beta-blocker, ACE inhibitors (an enzyme that

Me, converts angiotensin, ACE), calcium channel antagonists and alpha-receptor antagonists. Some examples of 2) agents suitable for the treatment of elevated cholesterol levels or dysregulated lipid levels include 50 bpoluks known as NMOSO reductase inhibitors, compounds of the fibrate class.

Me. The compounds of the present invention can be used to treat various forms of cancer either alone or in combination

Kk in combination with known compounds for the treatment of cancer.

It is understood that the present invention encompasses combinations of compounds according to the present invention with one or more of the above-mentioned drugs. 5B Compounds within the scope of this invention show significant pharmacological activity in tests described in the literature, the results of which are believed to correlate with pharmacological activity in humans and other mammals.

F) The following results of ip migo and ip mimo pharmacological tests are typical for the characterization of compounds according to each invention.

Pharmaceutical Compositions and Pharmacological Tests The compounds of the present invention exhibit significant activity as inhibitors of protein tyrosine kinases and have therapeutic value as cellular antiproliferative agents for the treatment of certain conditions including psoriasis, atherosclerosis and restenosis. Compounds of the present invention modulate and/or inhibit cell signaling and/or cell proliferation and/or matrix production, chemotaxis and/or cellular inflammatory response and may be used to prevent or delay the onset or recurrence of or treat such conditions.

To determine the effectiveness of the compounds according to the present invention, the following pharmacological tests are used, which are accepted in this field of medicine and are known to correlate with pharmacological activity in mammals. Compounds of the present invention have been tested and the results obtained in various tests are believed to be consistent with beneficial activity as a mediator of cell differentiation. The results

THOSE tests, one must think, provide sufficient information to specialists in the field of pharmacology and medicinal chemistry, to determine the parameters of the use of the investigated compounds in one or more therapeutic methods described in this description. 1. Analysis of autophosphorylation of ROSB-K tyrosine kinase by the EGISA method

The analysis specified in the title is performed as described in Section a). (IN). Honey. Seth 1994, 37, 2627) that 7/0 is incorporated herein by reference, except that a cell lysate derived from human aortic smooth muscle cells (HAM5C) is used as described below. 2. General technique of mitogenesis analysis.

Human aorta smooth muscle cells (passage 4-9) are placed in the wells of a 9b-well plate in a nutrient medium with a concentration of bOO cells/well and allowed to grow for 2-3 days. At approximately 80965 confluence, growth is 7/5. Cells are stopped with serum-free medium (ZEM).

After 24 hours of serum deprivation, the medium is removed and replaced with the tested compound in the medium, ZEM (200 μl per well). The compounds are dissolved in OM5O (DMSO) cell culture at a concentration of 10 mM and additional dilutions are made in ZEM.

After 30 minutes of pre-incubation with the compound, the cells are stimulated with ROS at a concentration of 1 TOng/mol.

Determination is carried out in duplicate with stimulated and unstimulated wells at each concentration of the compound.

After four hours, add 1 μCi of ZN thymidine/well. Cultivation is completed 24 hours after adding the growth factor. Cells are lifted by trypsin and collected on filter paper using an automated cell harvester (UMaMyas MaspP9b). The filter paper is analyzed using a scintillation counter (UMaiias Veyaria(e)) to detect the label introduced into the DNA.

Z. Analysis of chemotaxis and9)

Id ATSS is obtained by human aortic smooth muscle cells (NASMS) at earlier passages. Cells are cultured in Siopeisv ZtoOM 2 ZipdieOtsoi (use medium and cells at passages 4-10). When the cells are confluent at 8090, a fluorescent probe, calcein AM (5 mM, Moiiesciag Rgobe) is added to the medium, and the cells are incubated for 30 minutes. After washing with a saline solution with NEREZ buffer, the cells are raised with trypsin and neutralized with buffer MCOV 131 (cSirso) with 0.195 VZA (bovine serum albumin), 10 mM glutamine and 1090 fetal bovine serum. After centrifugation, the cells are washed again and resuspended in the same buffer without fetal bovine serum at a concentration of 30,000 cells per 5 Oml. Cells are incubated at different concentrations of compounds of formula I! (final concentration in DMSO - 195) for 30 minutes at 3770.

To study chemotaxis, we use modified Boyden chambers with 96 wells (Meygorgobe, Ips.) and a polycarbonate membrane with a pore size of 8 nm (Rogeiisv, SA.. The membrane is covered with collagen (Zidta C3657,

O, Tmg/ml). In the lower chamber, put ROSE-rD (Zng/ml) in a buffer with a compound of formula I! and without her. Cells (30,000) with and without inhibitor are placed in the upper chamber. Cells are incubated for 4 hours. The filter membrane is removed and the cells located on the upper side of the membrane are removed. After drying, determine the fluorescence on the membrane using Suoysog I! (Miiiroge) at excitation and emission wavelengths of 485 and 53 Ohm, respectively. In each experiment, the average cell migration is obtained from six replicates. The percentage of inhibition is determined by control values with DMSO treatment. According to five evaluations, "» calculate the concentration-dependent inhibition, the value of IC so. The results are expressed as the average value of x

RMS (root mean square error of measurement) from five such experiments.

Purification of the ESRE receptor is based on the method of Yarden and Schlessinger (Uagaep apa Zspiezvipdeg). Cells (o) A431 are cultivated in containers with an area of 80 cm2 until confluence (2x10 7 cells per container). Cells are washed twice with PB5 (phosphate-buffered saline) and collected using 11.0 mmol EOTA containing PB5 for 1 hour at 37"C and centrifuged at 60049 for 10 minutes. Cells are solubilized in iml per 2x107 cells (65 ) of cold solubilization buffer (HomMol Nerez buffer, pH 7.6, 195 Top X-100, 150mMol Mass, 5bmMol

Fu 50 ESTA, imMole PM5E, B5Omg/ml aprotinin, 25mMol benzamidine, mg/ml leupepsin inhibitor and 1Omg/ml soybean trypsin inhibitor) for 20 minutes at 4"C. After centrifugation at 1000009 for 30-3 minutes, the supernatant is loaded onto M/ cA-agarose column (100 ml of packed resin per 2x10" cells) and shaken for 2 hours at 47C. The unabsorbed material is removed and the resin is washed twice with NTM buffer (5 BOmMol Nerev buffer, pH 7.6, 0.195 Tgyop X-100, 150mMol Masi), twice with NTM buffer containing 1 M Masi, and twice with NTMO buffer (50 Nerez buffer / pH 7.6, 0.195 Top X-100, 150mmol Massi and 1095

GF! glycerin). The ESE receptor is periodically eluted with NTMO buffer containing 0.5 M M-acetyl-O-glucosamine (200 ml per 2x107 cells). The eluted material is stored in aliquots at -707C and before use is diluted with TMTMO buffer (50 mmol Ttgiz-Mez buffer, pH 7.6, 0.195 Top X-100, 150 mmol Mass and 1095 glycerol). 5. Inhibition of autophosphorylation-Est-Kbo A431 cells are cultured until confluent on Petri dishes with fibronectin-coated human tissue culture. After washing twice with ice-cooled PB5 solution, the cells are lysed by adding 50 Oml/well of lysis buffer (5HOmmol Nerez, p 7.5, 150mmol Masi, 1.5mmol MasIi, tTmMol

ESTA, 1095 glycerol, 195 Triton X-100, tmMole PM5E, mg/ml aprotinin, tmg/ml leupeptin) and incubated for 5 minutes at 4"C. After stimulation of ESE (50Omg/ml, 10 minutes at 37"C) immunoprecipitation of 65 using anti ESE-K (AB 108) and autophosphorylation reaction of the sample (5 Oml aliquot, ZmKi (d-2RIATP) in the presence of 2 or 100 mM of the compound according to the present invention for 2 minutes at 4"C. The reaction is stopped by adding hot electrophoretic sample buffer. 5ZOA-RACE analysis (7.590 eL) is performed followed by autoradiography and reaction results are quantified by densitometric scanning of X-ray films. a. Cell culture

Cells marked with NEK 14 and K7/21A are obtained by transfection of MINZTZ cells (clone 2.2) (from C. Eguipa,

MCI, MIN) that do not contain endogenous ESE receptors, with cDNA links of the wild-type ESE receptor or a mutant ESE receptor that lacks tyrosine kinase activity (in which Lys 721 in the ATP binding site 70 is replaced by an Ala residue, respectively) . All cells were cultured in OMEM with 1095 calf serum (Nussiope,

It is odap, (ap). b. Selectivity in relation to RKA and RKS is determined using commercial kits a. Riegse colorimetric set for RKA analysis, bZriphute format

Short protocol: 1 RKA enzyme (bovine heart)/analytical tube peptide substrate (dye-labeled) Kemptide 45 minutes at 307"C

Spectral absorption capacity at 57O0nm

B. Riegse colorimetric kit for RKS analysis, Zriplgute format

Short protocol: 0.025) RSC enzyme (rat brain)/peptide substrate (dye-labeled) analytical tube

Neurogranin 30 minutes at 307C

Absorbance at 57 Ohm 7. Measurement of inhibitory activity against tyrosine kinase p5bek

The inhibitory activity against the tyrosine kinase p5bekK is determined according to the method disclosed in the patent of

US Mo. 5714493, incorporated herein by reference. Alternatively, inhibitory activity against tyrosine kinase is determined by the following method. Substrate (tyrosine-containing substrate, and)

Viok-(rVAia)z-Guz-Ma!-sish-I uv-Pe-s1u-siy-s1u-TNg-Tug-sIn-MaI-MaI-Tug-Guv-"МН 2), recognized robisk, μm) first phosphorylate in the presence or absence of a given concentration of the tested compound by a given amount of enzyme (the enzyme is produced by expressing the rBbik gene in a yeast construct), purified from cloned yeast (purification of the enzyme is carried out by the following classical methods), in the presence of ATP so (TOnkM), Maosi" (2 .5mM), Masi (2.5mM), Masi (25mM), OT (0.4mM) in Nerez 50OmM, pH 7.5, for 10 minutes at ambient temperature. The total volume of the reaction mixture is 5 Ωcl and the reactions are carried out with CO in a black fluroplate with 96 wells. The reaction is stopped by adding 150 μl of stop buffer (100 mM Nerez, pH 7.5, KE 400 mM, EOTA 13 mM, B5A g/l), containing an antibody for tyrosine, labeled with europium cryptate (RU20-K), at 0.mkg/ml and allophycocyanin-labeled streptavidin (XI 665) at 4 μg/mol. Labeling of streptavidin and antibodies |se) for tyrosine was carried out in Siv-Vio Ipiegpaiopai! (France). The mixture was calculated using a RasKag counter

Oizsomeg capable of measuring the transfer of homogeneous fluorescence with time resolution (excitation at 337 nm, reading at 62 Ohm and bb5 nm). The ratio of the signal at 6bbo5nm to the signal at 62Ohm is an indicator of the concentration of phosphorylated tyrosine. The control is obtained by replacing the enzyme with a buffer. The characteristic signal is the difference between the ratio obtained without inhibitor and the ratio with the control. Calculate ts characteristic signal in percentage. Calculate the ISvo for 10 concentrations of the inhibitor in duplicate, using the software "Xi. The reference compound is staurosporine (Zidta), which has the ICvo-ZOzh6bnm (n-20). " The results obtained by the experimental methods described above prove that the compounds according to the given according to the invention have a useful inhibitory activity against the protein tyrosine kinase of the NOSE receptor and an inhibitory ability against the tyrosine kinase rBbk | therefore have therapeutic value. The results described above

Me pharmacological tests can be used to determine the dose and method of administration for a particular

Ge" of the therapeutic method. This invention can be implemented in other specific forms within its scope or essential features. b 50

Claims (32)

Formula of the invention - 1. Quinoline and quinoxaline compounds of the formula I: m Ya sho 1s o Khi ha ТВ» ime) ih bo t Ka M ih de Kia is an optionally substituted alkyl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted oxaheterocyclyloxy, optionally substituted heterocyclylcarbonyloxy or halogen; Ky is hydrogen, optionally substituted alkyl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted oxaheterocyclyloxy, optionally substituted heterocyclylcarbonyloxy, or halogen; X is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocyclyloxy, optionally substituted aryloxy , optionally substituted heteroaryloxy, optionally substituted heterocyclylcarbonyloxy, halogen, cyano, K 5KeM- or acylbich-; 70 EC" represents; "Z. Kz is hydrogen, ortho- or parafluoro or methane-lower alkyl, lower alkoxy, halogen or carbamoyl; Kb and Co are independently hydrogen or alkyl or Kb and Kv taken together with the nitrogen atom to which Kv and Ko are attached, form an azaheterocyclyl; 74 is M or CH; and 7 is MH or O, or an M-oxide, hydrate, solvate, prodrug, or salt thereof, provided that Ka and Cl are both optionally substituted alkyl. 2. The compound of formula 1 according to claim 1, in which K/a is optionally substituted lower alkoxy, optionally substituted monocyclic cycloalkyloxy, optionally substituted heterocyclylcarbonyloxy, or c optionally substituted monocyclic oxaheterocyclyloxy. 3. The compound according to claim 2, in which Ka is an optionally substituted lower alkoxy or optionally i) substituted monocyclic oxaheterocyclyloxy. 4. The compound according to item C, in which Ka is methoxy, ethoxy, 2-(ethoxy)ethoxy, 2-(4-morpholinyl)ethoxy or furanyloxy. "h- 5. The compound according to claim 1, in which K/j is hydrogen, optionally substituted lower alkoxy, optionally substituted monocyclic cycloalkyloxy, optionally substituted heterocyclylcarbonyloxy or optionally substituted monocyclic oxaheterocyclyloxy. co 6. The compound according to claim 5, in which R is hydrogen or optionally substituted lower alkoxy. 7. The compound according to claim 6, in which R is methoxy or ethoxy. i-th 8. The compound according to claim 1, in which Ka and K/j are lower alkoxy. Gee) 9. The compound according to claim 8, in which Ka and K/j represent methoxy or ethoxy. 10. Compound according to claim 1, in which K/; is hydrogen or optionally substituted lower alkoxy. 11. The compound according to claim 10, in which Ki; is hydrogen, methoxy or ethoxy. " 12. The compound according to claim 1, in which Kz is hydrogen, ortho- or parafluoro or metamethyl, trifluoromethyl, 70 methoxy, fluorine, chlorine, bromine or carbamoyl. - with 13. The compound according to claim 1, in which 74 is M. y 14. The compound according to claim 1, in which 74 is CH. and" 15. The compound according to claim 1, in which 75 is MH. 16. The compound according to claim 1, in which 75 is 0. 17. The compound according to claim 1, which is: Ge») 2-anilino-6-quinoxalinol; 2-anilino-6-isopropoxyquinoxaline; Fo 2-phenoxy-6b-methoxyquinoxaline; oz 2-(3-carbamoylphenylamino)-6-methoxyquinoxaline; 2-(2-fluorophenylamino)-6,7-diethoxyquinoxaline; b 2-(3-trifluoromethylphenylamino)-6, 7-diethoxyquinoxaline; - M phenyl-I(b-(tetrahydrofuran-z(K)-yloxy)quinoxalin-2-yl|amine; (b-methoxyquinoxalin-2-yl)-(3-methylphenyl)amine; b-methoxy-2-phenylaminoquinoxaline ; 2-anilino-b-ethoxyquinoxaline; 2-(3-methoxyphenylamino)-6,7-diethoxyquinoxaline; F, 2-(4-fluorophenylamino)-6,7-diethoxyquinoxaline; ko 6,7-diethoxy-2-phenoxyquinoxaline; 2- phenylamino-6b,7-diethoxyquinoxaline; in (6,7-dimethoxyquinoxalin-2-yl)-(3-fluorophenyl)amine; 2-(3-fluorophenylamino)-6,7-diethoxyquinoxaline; (3-bromophenyl)- (6,7-dimethoxyquinoxalin-2-yl)amine; (6,7-dimethoxyquinoxalin-2-yl)phenylamine and (3-chlorophenyl)-(6,7-dimethoxyquinoxalin-2-yl)amine, 65 or its M- oxide, hydrate, solvate, prodrug or pharmaceutically acceptable salt. 18. Compound according to claim 1, which is: phenyl-I(b-(tetrahydrofuran-z(K)-yloxy)quinoxalin-2-yl|amine; (b-methoxyquinoxalin-2-yl)-(3-methylphenyl)amine; b-methoxy-2-phenylaminoquinoxaline; 2 -anilino-b-ethoxyquinoxaline; 2-(3-methoxyphenylamino)-6,7-diethoxyquinoxaline; 2-(4-fluorophenylamino)-6,7-diethoxyquinoxaline; 6,7-diethoxy-2-phenoxyquinoxaline; 2-phenylamino-6 , 7-diethoxyquinoxaline; 70 (6,7-dimethoxyquinoxalin-2-yl)-(3-fluorophenyl)amine; 2-(3-fluorophenylamino)-6,7-diethoxyquinoxaline; (3-bromophenyl)-(6,7- dimethoxyquinoxalin-2-yl)amine; (6,7-dimethoxyquinoxalin-2-yl)phenylamine and (3-chlorophenyl)-(6,7-dimethoxyquinoxalin-2-yl)amine, or its M-oxide, hydrate, solvate, prodrug or 7/5 pharmaceutically acceptable salt. 19. The compound according to claim 1, which is phenyl-|b-(tetrahydrofuran-3(K)-yloxy)quinoxalin-2-ilyamine or its M-oxide, hydrate, solvate, prodrug or pharmaceutically acceptable salt. 20. The compound according to claim 1, which is (6,7-dimethoxyquinoxalin-2-yl)-(3-fluorophenyl)amine or its M-oxide, hydrate, solvate, prodrug or pharmaceutically acceptable salt. 21. The compound according to claim 1, which is (3-bromophenyl)-(6,7-dimethoxyquinoxalin-2-yl)iamine or its M-oxide, hydrate, solvate, prodrug or pharmaceutically acceptable salt. 22. The compound according to claim 1, which is (3-chlorophenyl)-(6,7-dimethoxyquinoxalin-2-yl)amine or its M-oxide, hydrate, solvate, prodrug or pharmaceutically acceptable salt. 23. A pharmaceutical composition containing a compound according to claim 1 and a pharmaceutically acceptable carrier. high school 24. The method of inhibiting the tyrosine kinase activity of the ROSE growth factor, which includes contacting the compound according to claim 1 with the composition containing the ROSBE tyrosine kinase. and) 25. A method of inhibiting the activity of tyrosine kinase ISK, which includes contacting the compound according to claim 1 with a composition containing tyrosine kinase I sk. 26. A method of inhibiting cell proliferation, differentiation or release of a mediator in a patient suffering from a disorder characterized by such proliferation and/or differentiation and/or release of a mediator, comprising administering to said patient a pharmaceutically effective amount of the compound according to claim 1 or its ise) of a pharmaceutically acceptable salt. with 27. The method according to claim 26, in which the disorder is leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, bone diseases, fibrotic diseases, arthritis, pulmonary fibrosis, kidney fibrosis, liver fibrosis, atherosclerosis ise) or restenosis after angioplasty of the coronary artery, femoral artery artery or renal arteries. "at 28. A method of treating a patient prone to a pathology associated with a hyperproliferative disorder, which includes administering to the specified patient a pharmaceutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 29. The method according to claim 28, in which the pathology associated with the hyperproliferative disorder is cancer, "susceptible to treatment by inhibition of ROSBE growth factor tyrosine kinase. from the village 30. The method according to claim 29, in which the cancer is brain cancer, ovarian cancer, colon cancer, cancer. prostate, lung cancer, Kaposi's sarcoma, or malignant melanoma. and?" 31. The method according to claim 28, in which the indicated pathology is restenosis. 32. The method according to claim 31, in which the compound according to claim 1 is administered by coating an expanding device (stent), where the coating contains the compound according to claim 1. 33. A method of treating inflammation in a patient suffering from it, which includes administration to the indicated patient of a pharmaceutically effective amount of the compound according to claim 1 or its pharmaceutically acceptable salt. Me, 34. Method of treatment of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, graft-versus-host disease, asthma, inflammatory bowel disease or pancreatitis, which includes 5 or administration to a patient in need of such treatment of a tyrosine kinase inhibitory compound according to claim 1. (22) as the Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2004, M 5, 15.05.2004. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. F) name) 60 b5