UA82095C2 - Pharmaceutical composition comprising a p2x7-receptor antagonist, tumour necrosis factor alpha, and method for treatment of inflammatory disorder - Google Patents

Abstract

The invention provides a pharmaceutical product or kit comprising a first active ingredient which is a P2Xreceptor antagonist which P2Xreceptor antagonist is an adamantyl derivative and a second active ingredient which is a tumour necrosis factor(ТМF) inhibitor, for use in the treatment of inflammatory disorders.

Description

Description of the invention

The present invention relates to a combination of a pharmaceutically active substance for use in the treatment of inflammatory conditions/disorders, especially rheumatoid arthritis.

Chronic inflammatory disorders such as rheumatoid arthritis are polygenic, multifactorial, and involve multiple inflammatory and immune mechanisms. Treatment of these disorders is largely empiric with a variety of therapeutic agents applied with poor understanding of the mechanisms involved. Recent research suggests that two inflammatory mediators, cytokine I-1 and TMEaprsra (TMEo), may play key roles in the inflammatory process in rheumatoid arthritis.

It would be desirable to develop new pharmaceuticals for use in the treatment of inflammatory conditions/disorders.

According to the presented invention, a pharmaceutical product is proposed, which contains in combination the preparation of the first active ingredient, which is an antagonist of the P2X receptor; where the antagonist of the P2X receptor"; - a derivative of adamantyl, and the preparation of the second active ingredient, which is an inhibitor of tumor necrosis factor A (TMEo), for simultaneous, sequential or separate use in treatment.

In the next aspect, the invention relates to a kit containing the preparation of the first active ingredient - the P2X receptor antagonist»7, where the P2X receptor antagonist is an adamantyl derivative, the preparation of the second active ingredient - tumor necrosis factor A inhibitor (TMEo) and instructions for simultaneous, sequential or 720 separate administration of drugs to a patient who needs it.

The P2X receptor, (formerly known as the P27 receptor) is a ligand-gated ion channel that is present in a variety of cell types, mainly those known to be involved in the inflammatory/immune process, especially macrophages, mast cells, and lymphocytes (TT and IN). It is known that activation of the P2X7 receptor by extracellular nucleotides, especially adenosine triphosphate, among other things, leads to the release of interleukin-1p (1--1p). Go)

An antagonist of the P2X receptor is a compound or other substance capable of preventing either complete or partial activation of the P2X receptor."

Methods of studying the antagonism of the P2X7 receptor are known in the art, for example from (MO 01/42194), which describes studies based on the observation that when the P2X7 receptor is activated by using a receptor agonist in the presence of ethidium bromide (a fluorescent DNA probe), observed an increase in the fluorescence of Ф» of intracellular DNA-bound ethidium bromide when. Therefore, the increase in fluorescence can be used as a measure of the activation of the P2X7 receptor, thereby quantifying the effect of a compound or substance on the P2X receptor." everything

In MO 01/421941) the research was carried out using a 96-cell microtiter plate with a flat bottom and filling the cells with 250 μl of the test solution, which contains 200 μl of a suspension of TME-1 cells (2.5x105 cells/ml), containing 107 M ethidium bromide, 25 μl of a solution of high potassium buffer containing 107

M of benzoylbenzoyl adenosine triphosphate (BBATP, a known P2X receptor agonist) and 25 μl of a buffer solution with a high potassium content containing 3x107 M of the test compound. The tablet was covered with a plastic sheet and incubated at 372C for one hour. Then the tablet was read with a fluorescent tablet reader pt) with Regkip-EIteg, excitation 52 Ohm, emission 595 nm, slit width: Zbuzh. 15nm, Amis. 2 Ohm For comparison in test a, BBATP (P2X receptor 7 agonist) and pyridoxal 5-phosphate (P2X receptor "antagonist")7 are used separately as a control. From the obtained data, the RiKeo number for the test compound was calculated. This number represents the negative logarithm of the concentration of the test compound required to reduce BBATP agonist activity by 50965.

A riQo value greater than 5.5 is, of course, a sign of an antagonist. (ee) Examples of P2X receptor antagonists that may be used in accordance with the present invention include compounds described in (MO 00/61569, MO 01/42194, MO 01/44170 and MO 03/41707), the full contents of which are covered herein links av | More specifically, in the first embodiment of the present invention, the P2X receptor antagonist is a compound of the formula

F (SYA - yes A (l

Ф) yiv v" yuyu i 60 die (g where t is equal to 1, 2 or 3; 65 each 2 independently represents a hydrogen or halogen atom;

Ag represents C(O)MH or MHCss);

Huh? represents the group and m ; xx

For and oh I'm with

Xe represents a bond, an oxygen atom or a CO group, (CH 52)4-6, СНе, (СНо)--6О, О(СН»)4-в, О(СН»)»вО,

О(СНО)»зО(СНо)М-, СОН), (СН) зО(СНо)3, (СНо)зО(СНо)»зО, MA, (СНОМ, МмА(СН) в, (СН2)uzМмА ЗАСН ). в, О(СНо)р ема, О(СНо)»зМА(СН») 3, (СН) ЗМ аСН)» зо, MARаСН» в, ма за(СсHO)»зОо(СН2)і 3, СОМАРа, MAbaso , 5(0), 8(О)0СН», СНоВ(О)», 502МА 2 or МАра80»5. n equals 0, 1 or 2;

ЕК" represents a hydrogen atom or C--C6 alkyl; one of K72 and va represents halogen, cyano, nitro, amino, hydroxyl, or they are selected from the group: () C--Cv alkyl, and SM as a variant, substituted, at least , one C3-C6 cycloalkyl, (ii) C3-C6 cycloalkyl, (ii) C3-C6 alkyloxyl, optionally substituted with at least one C3-C6 cycloalkyl and (im) C3--C6 cycloalkyloxyl, each of these groups, as an option, is replaced by one or more fluorine atoms, and the other from Ka and Za represents a hydrogen or halogen atom; Vla represents a 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system that contains one or two nitrogen atoms and, optionally, an oxygen atom, a heterocyclic ring system, optionally substituted with one or more substituents independently selected from the group: fluorine, hydroxyl, carboxyl, cyano, C-Cv alkyl, C4.Cv hydroxy-alkyl, -chK Zav a, (СНО) Mav and "СОМ ав "8, o or Ka represents a 3- - 8--linked saturated carbocyclic ring system substituted by one or more substituents substituents independently selected from the group: -Mv avta, (СНо)MAezava and -SOMEZava, the ring system, as an option, is additionally substituted by one or more substituents independently selected from the group: fluorine, hydroxyl and C.Cv alkyl; g-1,2,3,4, 5 or 6; va represents a hydrogen atom or C.-Cv alkyl or C.-Cv cycloalkyl; « ba and Ka each independently represent a hydrogen atom or C-Cv alkyl, Co-Cv hydroxyalkyl or C3-Cv c-v c cycloalkyl, or ba and B/a together with the nitrogen atom to which they are attached form 3- - 8 --lenne c saturated heterocyclic ring; ," provided that a) when A? represents С(О)МН, and B 72 represents an unsubstituted 3- - 8--lene saturated aliphatic heterocyclic ring system containing one nitrogen atom, then X2 is not a bond, and so (B) when A? represents С(О)МН, and Xa represents the group (СН 2)4.6 or Ф(СН»).4 in, then K72 does not represent ko unsubstituted imidazolyl, unsubstituted morpholinyl, unsubstituted piperidinyl or unsubstituted pyrrolidinyl, and (c) when AND? represents MHC(O), and B 72 represents an unsubstituted 3- - 8--lene saturated aliphatic o 50 heterocyclic ring system containing one nitrogen atom, then X? is not a connection, and (se) (4) when A? represents the Ministry of Emergency Situations (O), and X? represents O(CH"). c, МН(СН»)..6 or ЗСН», then K72 does not represent sl unsubstituted 1-piperidinyl or unsubstituted 1-pyrrolidinyl and (e) when A? represents MHCs(O), and X represents O(CH2)» ZMH(CH»), then K72 does not represent imidazolyl; or a pharmaceutically acceptable salt or solvate thereof.

Compounds of formula (I) are described in UMO 00/61569.

In the second embodiment of the presented invention, the P2XU receptor antagonist is a compound of the formula

F) ko 60 b5 nridshvish | in! (Where 0? represents СН» or СНоСН»;

EP represents C(OOMH or MHCs(C); 2" and EP, each independently, represents a hydrogen or halogen atom, or amino, nitro, C-C 6 alkyl or trifluoromethyl;

VZ? represents the group of the formula l B» cm 2 uh ; In o

oh

X? represents oxygen or sulfur, or the group MH, ZO or 505; Io)

IN? represents oxygen or sulfur, or the MAE group "2, 80 or 50"; b 75 represents the group -OH, -ZH, -СО оН, C. C. Alkoxyl, C. C. alkylthio, C. C. alkylsulfinyl, C. C. alkylsulfonyl, -MEbev", -C(O)MAZRAZ, imidazolyl, 1-methylimidazolyl, -М(Б95)32(03)-Си Св alkyl, Си.Св i- alkylcarbonyloxy, Си.Св alkoxycarbonyloxy, -ОС(О)МА in, -ОоСснНоОС(ОВ"?, -ОСНоОС(ООВ"? or SM -ов(ФфОосНноОК ов; со

IN? represents Co-Cv alkyl;

Ve represents S. Sv alkyl; вв, ве, ВВ, ве, ов, 2 | BZ, each independently, represent a hydrogen atom, or C..Cv alkyl, as a variant substituted by at least one hydroxyl; also represents a hydrogen atom, or C 4.Ce alkyl, as a variant, substituted by at least one substituent, - c independently selected from the group: hydroxyl and Si. St. Alkoxyl; and

ВВ вв | 'bv each independently, represent Si. Sat alkyl; provided that (u) when ER? represents the Ministry of Emergency Situations (O), in» p

X? represents O, 5 or MH, and U? represents O, then 7? represents -ME URE? where is BU? represents a hydrogen atom, and ee represents either a hydrogen atom or C. Se is an alkyl substituted by at least one hydroxyl group, and (ii) when E? represents the Ministry of Emergency Situations (O), X? represents O, 5 or MH, U? represents MN, and VR? represents (oh)

СНоСН", then 75 does not represent -OH or imidazolyl; wherein or a pharmaceutically acceptable salt or solvate thereof. o Compounds of formula (II) are described in UMO 01/42194.

In the third embodiment of the presented invention, the antagonist of the P2XU receptor is a compound of the formula se) "(pl (F) ko bo b5 where Z g . schchi d A I where OO represents CH" or СНЬЧН";

ES represents С(О)МН or МНС(О);

Bc and B2C, each independently, represent hydrogen, halogen, amine, nitro, C1-C8 alkyl or trifluoromethyl, but All 22 cannot both simultaneously represent hydrogen; high school

Sun represents the group of the formula o ya Bo

X Io) i ( y y; b"

Sun represents S. Sv alkyl; ("in")

Hoprepresents oxygen or sulfur, or group MA 72, 50 or 50"; si to represents hydrogen, or to represents C.-Salkyl or C.sub.-Ce alkenyl, each of which may optionally be substituted with at least one substituent selected from the group: halogen, hydroxyl, (di)-Si. Sv-alkylamino, so -u5.r be s . "» | and and and a 5- or b-membered heteroaromatic ring, as containing from 1 to 4 heteroatoms independently selected from the group: nitrogen, oxygen and sulfur, this heteroaromatic ring may itself optionally be substituted with at least , by one substituent selected from the group: halogen, hydroxyl and C.i.Cv alkyl; co U represents oxygen or sulfur, or the group MH, 5O or 50"; o 29C represents the group -K 7272, where B/- represents Co- Alkyl, and 77 represents -OH, -СО2Н, -MA Zore, 50. -С(О)MA eV 112 or -ШВК122)С(0)- C). Alkyl, and, in the case where 7 represents oxygen or sulfur, or the i-th MH group, all in addition represents hydrogen, C 4.Cv alkyl, C.Cv alkyl carbonyl, C.Ce alkoxycarbonyl, "(pl -k(Oo)me edee, "СНооСс(О)В бе, -СНоОС(ОЙУВ 7172 or -С(00ОСНоОК Бе; вс, вес, рос, where and В 2с, each independently, represent a hydrogen atom or Ct-Cb alkyl; ze represents hydrogen, C3-Cv cycloalkyl, C3-Cv cycloalkylmethyl or ve represents C-C-C alkyl optionally substituted with at least one substituent, selected from the group: hydroxyl and Si Svalkoxyl; and

GF) Be, de, db, de and 82 each independently represent C..Cv alkyl;

Ф on the condition that if E?9 is С(О)МН, Хо-О, МН or MШ(СС.. Св alkyl), then Вс is not a hydrogen atom or unsubstituted

C.Sv alkyl; 60 or a pharmaceutically acceptable salt or solvate thereof.

The best compounds of the formula (IM) are those where KOS represents, as an option, a substituted C 4.Sbv alkyl, the best substituent is -U9v6bs. When Os - is substituted by a 5- or b-membered heteroaromatic ring containing from 1 to 4 heteroatoms, then the best number of heteroatoms in the ring does not exceed 2.

Compounds of the formula (IM) are described in UMO 01/44170. 65 In the fourth embodiment of the present invention, the P2XU receptor antagonist is a compound of the formula

(dreams: A - AR ch

NE where t is equal to 1, 2 or 3; each VZ independently represents a hydrogen or halogen atom;

АЗ represents С(О)МН or МНС(С);

Ag represents the group

In de for i shcha d' And I o os zy Ot

She; -- she is 30. b" ve in in F p

ШЙ (IN THE COMBINATION of ayu, one of BZ and Ba represents a halogen, nitro, amine, hydroxyl, or they are selected from the group: (i) C..Ce alkyl, as an option, substituted by at least one halogen, (its) Cz -Cv cycloalkyl, (iii) CiCv alkoxyl, as an option, substituted by at least one halogen and (im) C3-Cv cycloalkyloxyl, and the other from KU ii KZZZ represents hydrogen /- c or halogen; "from ВЗ represents the group п and со Х M (ав) n " и ХХ: (se) sl ХУ represents oxygen or sulfur, or the group »М-В89; n is equal to 0 or 1; da represents C 4.Cv alkyl, which can be, as an option, substituted, at least one substituent selected from the group: hydroxyl, halogen, and CiCe alkyl;

Вб and ВЯ, each independently, represent a hydrogen atom, C 4.Св alkyl (as an option, substituted,

Ф, at least one substituent selected from the group: hydroxyl, halogen, C..Cv alkyl and (di)-C.C. alkylamine

KkZz (itself optionally substituted by at least one hydroxyl)), or

C3-C8 cycloalkyl (optionally substituted with at least one substituent selected from the group: hydroxyl, 60 halogen, and C1-C6 alkyl); and c represents a hydrogen atom or C 4 C 10 alkyl, which may optionally be substituted by at least one substituent selected from the group: hydroxyl, halogen, and C 10 alkyl; provided: (a) if n-0, then AU is МНСс(О) and because (B) when n-1, ХУ is oxygen and AU is СЙОМН, then 299 and КЗ do not represent a hydrogen atom at the same time, or do not represent at the same time unsubstituted C. Svalkil, or when one of the car and wa represents a hydrogen atom, then the other of KZ and KZ does not represent unsubstituted Si. St alkyl; and (c) when n-1, ХУ - oxygen, sulfur or "МН, and АЗ - МНССО), then E99 and KZ do not simultaneously represent 2 hydrogen atoms or do not simultaneously represent unsubstituted C. Св alkyl, or when one of a and KZ represents a hydrogen atom, then the other of both and BZ do not represent unsubstituted C... Ce alkyl or -СНСНООН; or a pharmaceutically acceptable salt or solvate thereof.

Compounds of formula (MI) are described in UMO 03/41707. 16 In the next aspect of the present invention, the P2X7 receptor antagonist is a compound of the formula - copper. x in sp) In m d" s o (XI) Fu where t is equal to 1, 2 or 3; b

Ag represents C(O)MH or MHCs(O);

Uue represents M or CH; at

X" represents a bond, CO, (CH2)1-6; O(CH»2) 1-6; (CH2)1-6MH(CH2) 6 (CH2)i-6O(CH»2) 6; МН (CH»2) 4-6; c 72 represents ME Ue; co represents halogen, cyano, nitro, amino, hydroxyl, C4-C6 alkyl or C3-C6 cycloalkyl, which alkyl or cycloalkyl can be as optionally substituted with one or more fluorine atoms; He and Kg each independently represent a hydrogen atom, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, which alkyl or cycloalkyl may optionally be substituted with one or more groups selected from the group : hydroxyl, « 70 halogen or C.i.Cb alkoxyl, - c or 2 and Be, together with the nitrogen to which they are attached, form a 3- - 9--membered saturated mono- or c bicyclic heterocyclic ring, which contains from 1 up to 2 nitrogens and optionally an oxygen atom, this "heterocyclic ring may optionally be substituted with one or more substituents selected from the group consisting of: hydroxyl, halogen, or C 1 -C 6 alkyl; or a pharmaceutically acceptable salt or solvate thereof. ( ос) Compounds of formula (XI) can be obtained chemically according to or analogously described in the references cited above.

In a further aspect of the presented invention, the P2X receptor antagonist represents: )-benzamide, so 20 2-Chloro-5-I3-KZ-hydroxypropyl)amino|propyl|-M-(tricycloyl|3.3.1.1|)dec-1-ylmethyl benzamide,

B-2-Chloro-5-3-(2-hydroxy-1-methylethyl)amino|propyl|-M-(tricyclo|3.3.1.1Zldec-1-ylmethyl)-benzamide, «sl 2-Chloro-5-( 2-(2-Hydroxyethyl)amino|ethoxy|-methylyl-N-(tricycloyl|3.3.1.13.7dec-1-ylmethyl)-benzamide. 2-Chloro-5-|3-III-"methylamino)propoxy|propyl |-M-(tricyclo|3.3.1.1 Z.LPdec-1-ylmethyl)benzamide, 2-Chloro-5-|3-(3-hydroxypropylamino)-propoxy|-M-(tricyclo|3.3.1.1 Z.7dec- 1-ylmethyl)-benzamide, 2-Chloro-5-(2-(3-hydroxypropylamino)ethylamino|-M-(tricyclo!|3.3.1.1 Z.LZdec-1-ylmethyl)-benzamide, (F) 2-Chlor -5-(2-(3-hydroxypropylsulfonyl)ethoxy|-M-(tricyclo|3.3.1.1Z.LPdec-1-ylmethyl)-benzamide,

Ho) 2-Chloro-5-(2-(2-(2-hydroxyethyl)amino|ethoxy|)ethoxy|-M-(tricyclo|3.3.1.1Zldec-1-ylmethyl)-benzamide, 2-Chloro-5- C2-(2-(methyl-1H-imidazol-4-ylethylamino)ethyl|amino|-M-(tricycloi|3.3.1.1Zldec-1 -yl 60 methyl)-benzamide, 2-Chloro-5-piperazine-1 - ylmethyl-M-(tricyclo|3.3.1.1 |dec-1 -ylmethyl|-benzamide, 2-Chloro-5-(4-piperidinyloxy)-M-(tricyclo!|3.3.. 1.13.7dec-1-ylmethyl)- benzamide, 2-Chloro-5-(2,5-diazabicyclo|2.2.1|hept-2-ylmethyl)-M-(tricycloyl3.3.1.1|dec-1-ylmethyl)-benzamide, 2-Chloro-5- (piperidin-4-ylsulfinyl)-M(tricyclo|3.3.1.1 ZZdec-1-ylmethyl)-benzamide, because 5-Chloro-2-3-(3-hydroxypropyl)amino|propyl|-M-(tricyclo|3.3. 1.1 Z7dec-1-ylmethyl)-4-pyridinecarboxamide,

2-Chloro-5-(3-((12)-2-hydroxy-1-methylethyl|amino|propyl|-M-(tricyclo|3.3.1.1 57 dec-1-ylmethyl)-3-pyridinecarboxamide, 5-Chlor -2-(3-ethylamino)propyl|-M-(tricyclo|3.3.1.1Z.Ldec-1-ylmethyl)-4-pyridinecarboxamide, 5-Chloro-2-I(3-((2-hydroxyethyl)amino |propyl|-M-(tricyclo|3.3.1.1 Z.LPdec-1-ylmethyl)-4-pyridinecarboxamide, 5B-Chlor-2-IZ-I(25)-2-hydroxypropylamino|propyl|-M-(tricyclo! |3.3.1.1 Zldec-1-ylmethyl)-4-pyridinecarboxamide,

M-(2-Methyl-5-(9-oxa-3,7-azabicycloi|3.3.1|non-3-ylcarbonyl)phenyl|-tricycloi|3.3.1.1 Z.Zdecan-1-acetamide, or a pharmaceutically acceptable salt or a solvate of any of these.

Pharmaceutically acceptable salts include, where applicable, acid addition salts derived from 70 pharmaceutically acceptable inorganic and organic acids such as chloride, bromide, sulfate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2 - or 4-methoxybenzoate, 4-hydroxybenzoate, p-toluenesulfonate, methanesulfonate, ascorbate, acetate, succinate, lactate, glutarate. gluconate, tricarballylate, hydroxynaphthalene carboxylate or oleate; and salts derived from pharmaceutically acceptable inorganic and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, cuprum, 72 ferrum(I), ferrum(I), lithium, magnesium, manganese(I), manganese(II), potassium, sodium, zinc, and bismuth ammonium, calcium, magnesium, potassium and sodium salts are preferred. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, cyclic amines such as arginine, betaine, choline and the like. Examples of pharmaceutically acceptable solvates include hydrates.

Examples of P2X receptor antagonists) that can be used in the present invention include: 2-Chloro-5-(2-(2-hydroxy-ethylamino)-ethylamino|-methylI-M-(tricyclo|3.3.1.1 Z.dec-1 -ylmethyl)-benzamide, dihydrochloride 2-Chlor-5-I3-KZ-hydroxypropyl)amino|propyl|-M-(tricycloi|3.3.1.1|dec-1-methyl)-benzamide, hydrochloride (K)-2-Chlor -5-I3-(2-hydroxy-1-methylethyl)amino|propyl|-M-(tricyclo|3.3.1.1Z.7dec-1-ylmethyl)-benzamide, hydrochloride c » 2-Chlor-5-C2-K2 -hydroxyethyl)amino|ethoxy|methyl|-M-(tricycloyl|3.3.1.1Z.Ldec-1-ylmethyl)-benzamide, acetate (o) (111) salt 2-Chloro-5-(3-(Z-( methylamino)propoxy|propyl|-M-(tricyclo!|3.3.1.1 Z.Ldec-1-ylmethyl)benzamide, hydrochloride 2-Chloro-5-|3-(3-hydroxy-propylamino)-propoxy|-M-( tricyclo(3.3.1.1Z.Pdec-1-ylmethyl)-benzamide, hydrochloride -benzamide, acetate (1:11) salt F 2-Chloro-5-12-(3-hydroxypropylsulfonyl)ethoxy|-M-(tricyclo!|3.3.1.1Z.Pdec-1-ylmethyl)-benzamide o 2-Chlor -2-(2-((2-g hydroxyethyl)amine|iethoxy|)ethoxy|-M-(tricyclo|3.3.1.1Z.Ldec-1-ylmethyl)-benzamide, hydrochloride with 2-Chloro-5-C2-(2-(1-methyl-1H-imidazole) -4-yl)ethylamino)ethylamino|-M-(tricyclo!/3.3.1.1 57 3o |dec-1-ylmethyl)-benzamide (he) 2-Chloro-5-piperazin-1 -yl methyl-M-"tricyclo !/3.3.1.197) dec-1 -ylmethyl)-benzamide, dihydrochloride 2-Chloro-5-(4-piperidinyloxy)-M-(tricyclo|3.3.1.1 3.7dec-1-ylmethyl)-benzamide, hydrochloride 2- Chloro-5-(2,5-diazabicyclo|2.2.1Hept-2-ylmethyl)-M-(tricycloil|3.3.1.1Z.7dec-1-ylmethyl)-benzamide, hydrochloride « 2-Chloro-5-(piperidine- 4-ylsulfinyl)-M-(tricyclo|3.3.1.1 U L3dec-1-ylmethyl)-benzamide with 5-Chloro-2-3-(3-hydroxypropyl)amine|Ipropyl|-M-(tricycloi|3.3.1.1 Z.Ldec-1-ylmethyl)-4-pyridinecarboxamide, c 2-Chloro-5-I3-((1)-2-hydroxy-1-methylethyl|amino|propylI|-M-(tricyclo|3.3.1.1 5.7 " » |dec-1-ylmethyl)-3-pyridinecarboxamide, 5-Chloro-2-(3-"ethylamino)propyl|-M-(tricyclo|3.3.1.1 Z.Ldec-1-ylmethyl)-4-pyridinecarboxamide, hydrochloride 5-Chloro-2-I3-((2-hydroxyethyl)amino|propyl|-M-(tricyclo)/3.3.1.1 Z.Lde c-1-ylmethyl)-4-pyridinecarboxamide, (ee) hydrochloride t 5-Chlor-2-I3-I((25)-2-hydroxypropylamino|propyl-M-(tricyclo(|3.3.1.1 Z7dec-1-ylmethyl )-4-pyridinecarboxamide, dihydrochloride and o M-(2-Methyl-5-(9-oxa-3,7-diazabicyclo|3.3.1|non-3-ylcarbonyl)phenyl|-tricycloyi3.3.1.1 Z.Pdecane -1-acetamide, "se 20 hydrochloride.

The P2X receptor antagonist used in the present invention is able to exist in a stereoisomeric form. It is understood that the invention covers all geometric and optical isomers of the active ingredient and mixtures thereof, including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.

The second active ingredient in the product or kit of the present invention is an inhibitor of factor o. 59 tumor necrosis (TMEo). A TMEo inhibitor is a compound or other substance capable of inhibiting the activity of TMEo,

F! in whole or in part. A detailed description of the compounds or substances that can be used in the present invention as inhibitors of TMEo can be found, for example, in the published International Application for (patent MoUUO 0 98/05357|, the full content of which is covered here by reference. In the embodiment of the invention, the inhibitor of the factor o. tumor necrosis factor (TMEo) - a receptor molecule capable of binding to TMEo Such receptor molecules are known in the art and a detailed description of receptor molecules that can be used in the present invention can be found, for example, on pages 32-35 of |MUO 98/053571.

An example of a receptor molecule that gives particularly good results in the presented invention is etanercept (E(apexer) (Ehrep Orip. RIaptasoiyeg. (2001) 2(7); 1137-1148). Etanercept is a condensed protein consisting of an extracellular ligand of the binding part of the human tumor necrosis factor receptor associated with human IDS Es-ch-astin. It was created by recombinant DNA technology in a Chinese Hamster Ovary (CHO) cell expression system. It is believed that etanercept attenuates the biological activity of the pro-inflammatory cytokine - tumor necrosis factor (TME) by binding the protein and blocking its interaction with

TME-receptors on the cell surface. Etanercept is sold by Atdep and M/ue(y RPpagptaseciisaiz under the trade name "Enbrel". A further example of a TMEo inhibitor, which is a receptor molecule and which can be used according to the present invention, is Pegsanercept, a PEGylated soluble receptor of the TMEo inhibitor IAPy. KNeit. (2003) 48, 51211.

In another embodiment of the invention, the tumor necrosis factor inhibitor (TMEo) is an anti-TMEo antibody. Examples of anti-TME antibodies according to the present invention include monoclonal, chimeric, humanized, cross-coated and recombinant antibodies and fragments thereof capable of inhibiting the activity of TMEo in whole or in part. Such antibodies are known in the art and are described, for example, on pages 13-32 of MO 98/05357. Specific examples of anti-TMEo antibodies that can be used in the present invention are monoclonal antibodies

Infliximab and Adalimab (02E7). Infliximab is a chimeric IdSiC monoclonal antibody composed of a human constant region and a mouse variable region and is sold by Sepiosog under the trade name "Remicade".

Adalimamab (02E7) is a recombinant human IdsiI monoclonal antibody obtained using bacteriophage detection technology, which gives an antibody with human-derived variable regions of heavy and light chain regions and human IdsC1:K constant regions. Adalimamab (02E7) is sold by Arroy

And aroghaiogies under the trade name "Humira. A further example of an anti-TMEro antibody fragment that can be used according to the present invention is SOR-870, a PEGylated humanized antibody fragment that binds with high affinity to TME»o, ISig. Orip. Ipmeviid. Ogydv , (2003) 4: 588-592.

In the next embodiment of the invention, the tumor necrosis factor inhibitor. (TMEo) can bind the TMEo receptor, and includes antibodies against the TMEo receptor.

The selection of active ingredients according to the invention has been found to be advantageous in that it results in a beneficial anti-inflammatory effect and thus can be used to treat various acute and chronic inflammatory conditions/disorders such as rheumatoid arthritis. Treatment of inflammatory disorders may include reducing swelling and/or alleviating pain associated with the condition. In this regard, the products of the present invention have been shown to be particularly superior in reducing or alleviating pain caused by inflammatory disorders, particularly rheumatoid arthritis.

A further preferred aspect of the present invention is the possibility of effective treatment of the disease with lower doses of the TMEo inhibitor than with the use of the TMEo inhibitor alone. It is important that the application of Ge"! of biological therapeutic agents, such as TME inhibitors, may leave patients' ability to resist infections. In addition, anti-TME therapies such as etanercept have been found to have the added complication of having a long "washout" period before the drug is cleared from the system. Co-administration with a se antagonist P2X7, which allows to reduce the dose of a TMEo inhibitor, without impairing efficacy, reduces the se requirements for this safety and potentially allows the use of anti-TME o-Therapy in patient populations for which their use is considered unacceptable.

In the best embodiment of the presented invention, the second active ingredient is a tumor necrosis factor inhibitor (TMEo) Etanercept and the first active ingredient is a P2X receptor antagonist selected from the group: "2-Chloro-5-(2-(2-hydroxy-ethylamino) -ethylamino|-methylI-M-(tricyclo|3.3.1.1 Z.dec-1-ylmethyl)-benzamide, - c 2-Chlor-5-I3-K(3-hydroxypropyl)amino|propyl|-M-(tricyclo |3.3.1.1|dec-1-ylmethyl)-benzamide, "» (2K)-2-Chloro-5-3-(2-hydroxy-1-methylethyl)amino|propy|-M-(tricyclo|3.3.1.1 Z.LPdec-1-ylmethyl) "benzamide, " 2-Chloro-5-(2-(2-hydroxyethyl)amino|ethoxy|methyl-y/-(tricycloyl|3.3.1.1 Z.7dec-1-ylmethyl)- benzamide, 2-Chloro-5-(3-(3-(methylamino)propoxy|propyl|-M-(tricyclo!|3.3.1.1 Z.Ldec-1-ylmethyl)benzamide, so that 2-Chloro-5-( 3-(3-hydroxy-propylamino)-propoxy|-M-(tricyclo|3.3.1.1 37dec-1-ylmethyl)-benzamide, 2-Chloro-5-(2-(3-hydroxypropylamino)ethylamino|-M-( tricyclo!|3.3.1.1 Z.L3dec-1-ylmethyl)-benzamide, co 2-Chloro-5-(2-(3-hydroxypropylsulfonyl)ethoxy1|-M-(tricycloil|3.3.1.1 2.7dec-1-ylmethyl) -benzamide, about 2 -Chloro-5-(2-(2-((2-hydroxyethyl)amino|ethoxy|ethoxy|-M-(tricyclo!Y3.3.1.13.7dec-1-ylmethyl)-benzamide, 2-Chloro-5 -(C2-C2-(1-methyl-1H-imidazole)ethylamine, ethylamino|-M-(tricyclo!/3.3.1.13.7Pdec-1-ylmethyl)-benzamide, and 2-Chloro-5-piperazine-1 -ylmethyl-M-(tricyclo|3.3.1.1)dec-1-ylmethyl)-benzamide, 37 sp 2-Chloro-5-(4-piperidinyloxy)-M-(tricyclo|3.3.1.1 Udec-1 -ylmethyl)- benzamide, 2-Chloro-5-(2,5-diazabicyclo|2.2.1|hept-2-ylmethyl)-M-(tricycloyl3.3.1.1|dec-1-ylmethyl)-benzamide, 2-Chloro-5- (piperidin-4-ylsulfinyl)-M-(tricyclo|3.3.1.1Z.Ldec-1-ylmethyl)-benzamide, 59 5-Chlor-2-I3-((3-hydroxypropyl)amino|propyl|-M-( tricyclo|3.3.1.1 Z.7Pdec-1-ylmethyl)-4-pyridinecarboxamide,

HF) 2-Chloro-5-I3-((1)-2-hydroxy-1-methylethyl|amino|propyl|-M-tricyclo|3.3.1.1 5.7 dec-1-ylmethyl)-3-pyridinecarboxamide o 5-Chlor -2-IZ-"ethylamino)propyl)|-M-(3.3.1.1Z.Ldec-1-ylmethyl)-4-pyridinecarboxamide, in 5-Chloro-2-I3-(2-hydroxyethyl)amino|propyl|- M-(tricyclo|3.3.1.1 Z.LPdec-1-ylmethyl)-4-pyridinecarboxamide, 5-Chloro-2I3-((25)-2-hydroxypropylamino|propyl|-M-(tricyclo|3.3.1.1 Z.LPdec -1-ylmethyl)-4-pyridinecarboxamide,

M-(2-Methyl-5-(9-oxa-3,7-diazabicyclo|3.3.1|non-3-ylcarbonyl)phenyl|-tricycloil|3.3.1.1 C.7Pdecane-1-acetamide or a pharmaceutically acceptable salt or solvate of any of these In particular, the products of this embodiment can be used to reduce or alleviate pain caused by inflammatory disorders, particularly rheumatoid arthritis.

The first and second active ingredients are used simultaneously (other than in a mixture), sequentially or separately for the treatment of inflammatory conditions. Sequentially - means that the first and second active ingredients are used, in any sequence, one immediately after the other. They still have the desired effect if they are used separately.

The first and second active ingredients are conveniently administered orally or parenterally (eg, intravenously, subcutaneously, intramuscularly, intra-articularly or by inhalation) using conventional systemic dosage forms such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions. emulsions and sterile injectable aqueous or oily solutions or suspensions. These dosage forms typically include one or more pharmaceutically acceptable ingredients, which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilizers, buffering agents, emulsifiers, viscosity regulators, surfactants, preservatives, flavoring agents and dyes. It is clear to experts that the most appropriate way of using active ingredients depends on a number of factors. However, in general, oral administration of the first active ingredient is preferred, while subcutaneous administration of the second active ingredient is preferred.

For the above-mentioned therapeutic use, the dosages should, of course, vary with the use of the first and second active ingredients, the route of administration, the treatment required and the condition or disorder established. However, in general, suitable results are obtained when the total combined dosage of the first and second active ingredients is in the range of from 10 to 2000 milligrams (mg), especially from 10, 20, 30, 40, 50, 100, 150, 200 or 300 to 1800, 1500, 1200, 1000, 800, 600, 500 or 40Omg.

The pharmaceutical product or kit of the invention can be administered as divided doses. When used in divided doses, the first and second ingredients can be used at different frequencies. However, in general, the frequency of use of each active ingredient should independently range from one dose every 7 days to 4 doses per day.

In an embodiment of the present invention, the dosage of the first active ingredient in the pharmaceutical product or kit is in the range from 5 to 1000 mg, preferably from 20, 50, 100, or 200, to 800, 600, 500 or 400 mg per day, this daily dose can be used as divided doses from 1 to 4 times a day, preferably once or twice a day; and the dose of the second active ingredient is in the range from 1 to 100Omg, preferably from 5, 10 or 20 - 80, 50 or 4Omg, these doses are used with a frequency ranging from one dose every 7 days to one dose against

The dosage regimen according to this embodiment can particularly be used when the first active ingredient is delivered orally or by inhalation, and the second active ingredient is administered by subcutaneous injection.

The subcutaneous injection of the second active ingredient and dosage regimen of this embodiment would be particularly applicable when the second active ingredient is etanercept. at

The present invention also relates to the use of a pharmaceutical product or kit according to the invention in the manufacture of a medicament for the treatment of an inflammatory disorder. with

Also, the present invention relates to a method of treating an inflammatory disorder, which consists in the simultaneous, sequential or separate administration of: (a) a (therapeutically effective) dose of the first active ingredient, which is a P2X receptor antagonist, this P2X receptor antagonist is an adamantyl derivative ; (B) a (therapeutically effective) dose of the second active ingredient, which is a tumor necrosis factor (TME0) inhibitor, to a patient in need thereof. -о с In the context of the presented description, the term "treatment also includes "prophylaxis, unless otherwise specified. The terms "therapeutic" and "therapeutically" shall be interpreted accordingly. Prophylaxis is intended to be particularly appropriate for the treatment of persons who have previously suffered from, or are believed to be at increased risk for, the condition or disorder in question. Persons at risk of developing a particular condition or disorder generally include those , who have a family history of the condition or disorder, or

Go! those identified by genetic testing or screening as particularly susceptible to developing a condition or disorder. where the invention further relates to a triple combination therapy for the treatment of any one of the group: o rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, inflammatory bowel disease, COPD, asthma, allergic rhinitis or cancer, or neurodegenerative diseases such as multiple sclerosis , Alzheimer's disease, or stroke. For the treatment of rheumatoid arthritis, the pharmaceutical product or kit of the invention can be combined with "biological agents" such as 1-1 receptor antagonists (eg, Anakinra) and 1-1 blocker, receptor

E1-18, anti-CO20 AB, anti-CO20 AB, anti-1II -15AB and STI A4Id.

Suitable agents for use in combination with the pharmaceutical product or kit of the invention include standard nonsteroidal anti-inflammatory agents (NSAIDs) such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as then mefenamino-va

F) acid, indomethacin, sulindac, apazone, pyrazolones like phenylbutazone, salicylates like aspirin. Cyclo-oxygenase-inhibiting nitric oxide donors (DMOs) and "disease-modifying agents" (DMOs) such as cyclosporin A, leflunomide, ciclesonide, hydroxychloroquine, a-penicillamine, auranofin, can also be used because gold parenterally or orally

In addition, the presented invention relates to a combination of a pharmaceutical product or a kit of the invention together with an inhibitor of leukotriene biosynthesis, an inhibitor of Bb-lipoxygenase (5-10) or an antagonist of activating protein 5-lipoxygenase (PGAR), selected from the group: zileiton; AVT-761; fenleyton; tepoxalin;

Arrots-79175; Arroyo-85761; M-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6b-di-tert-butylphenol hydrazone; 65 methoxytetrahydropyrans, such as Zeneca 20-2138; compound 5B-210661; compounds of pyridinyl-substituted 2p-cyanonaphthalene compounds, such as 1-739,010; 2-cyanoquinoline compounds, such as 1-746,530; indole and quinoline compounds, such as MK-591, MK-886 and VAM x1005.

The present invention, in addition, relates to a pharmaceutical product or a kit of the invention together with a receptor antagonist for leukotrienes TV4, ITS, 104 and I TE4, selected from the group: phenothiazine-3-ones, such as 1-651,392; amidino compounds, such as СО5-25019c; benzoxalamines, such as ontazolast; benzene carbohymidamides, such as VEI 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, ver-lukast (MK-679),

KOo-12525, KO-245913, iralukast (СОР45715А) and VАУхХ7195.0

The present invention also relates to a pharmaceutical product or a kit of the invention together with a POE4 inhibitor, including inhibitors of the POE40 isoform. 70 The present invention further relates to a pharmaceutical product or kit of the invention together with antihistamine receptor antagonists Ni including cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine and chlorpheniramine.

The present invention, in addition, relates to a pharmaceutical product or kit of the invention together with an antagonist of the gastroprotective receptor H" or proton pump inhibitors (such as omeprazole).

The present invention further relates to a pharmaceutical product or kit of the invention together with a vasoconstrictor sympathomimetic agent of an o4- and or-adrenoceptor agonist, including propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride and ethylnorepinephrine hydrochloride .

The present invention further relates to a pharmaceutical product or kit of the invention together with anticholinergic agents, including ipratropium bromide; tiotropium bromide; oxytropium bromide; pirenzepine; and telenzepin.

The present invention further relates to a pharmaceutical product or kit of the invention together with methylxanthines, including theophylline and aminophylline; sodium cromoglicate; or a muscarinic receptor antagonist (M1, M2 and M3Z). Ha

The present invention, in addition, relates to a pharmaceutical product or a kit of the invention together with modulators of chemokine receptor function, such as SSKI, SSKI2, SSKI2A, SSKI25, SSZ, SSkKa, SSk5, SS, and) cSSKk7, SSkKV8, ССО, ССКИ1О and ССКИ1 (for the C-C family); SHSKI, SHSKZ, SHOSKA and SHOK5 (for the family

С-Х-С) and СХЗСКИ1 for the С-Х3-С family.

The present invention also relates to a pharmaceutical product or kit of the invention together with an insulin-like growth factor type 1 (ISE-1) mimetic.

The present invention, in addition, relates to a pharmaceutical product or a kit of the invention together with F means selected from the group: (a) tryptase inhibitors; (B) antagonists of platelet activating factor (PAP); "with (c) inhibitors of interleukin-converting enzyme (ICE); (4) IMRON inhibitors; (e) inhibitors of aggregation of molecules, including antagonists of MI A-4; (Her) cathepsins; (d) glucose-b-phosphate dehydrogenase inhibitors; (j) antagonists of the kinin-B receptor. and Vo; (І)) anti-gout drugs, for example, colchicine; (Y) xanthine oxidase inhibitors, for example, allopurinol; (K) uricosuric agents, such as probenecid, sulfinpyrazone, and benzbromarone; (I) a means of increasing the secretion of growth hormone; (t) growth transforming factor (GTR); (n) platelet-derived growth factor (ROSE); (o) fibroblast growth factor, for example, basic fibroblast growth factor (BEC); (p) granulocyte-macrophage colony stimulating factor (ZM-SZE); (4) capsaicin cream; (d) antagonists of the Tachykinin MK receptor. and MK", selected from the MKR-608S group; 5B8-233412 (talnetant); and O-4418; and (c) elastase inhibitors selected from the group: OT-77 and 7270-0892 (NO inhibitors of nitric oxide-induced synthase a (NOB) or (0) chemoattractant receptor homologous molecule expressed by TNI2 cells ("SvtH" antagonists) .

The pharmaceutical product or kit of the invention can also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable agents for use in combination include (ee) standard nonsteroidal anti-inflammatory drugs (NSAID below) such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid , about indomethacin, sulindac, arazone, pyrazolone, like phenylbutazone, salicylates like aspirin, inhibitors of induced AV | nitric oxide synthase (IIMO5 inhibitors) and cyclooxygenase inhibitory nitric oxide donor (NOS) analgesics (such as paracetamol and tramadol), cartilage-preserving agents such as diacerein, doxycycline and glucosamine, and hyaluronic acids such as hyalgan and son-in-law c The pharmaceutical product or kit of the invention can also be used in combination with existing therapeutic agents for the treatment of inflammatory bowel diseases (ulcerative colitis and Crohn's disease).

Agents suitable for use include 5-amino salicylates, thiopurines, azathioprine, and b-mecaptorurin.

The pharmaceutical product or kit of the invention can also be used in combination with anticancer agents such as endostatin and angistatin or cytotoxic drugs such as adriamycin, daunomycin, iF) cis-platinum, etoposide, taxol, taxotere and farnesyl transferase inhibitors, inhibitors Meokt, and

With antimetabolites, such as antineoplastic agents, especially antimitotic drugs, including vinca alkaloids, such as vinblastine and vincristine. 60 The pharmaceutical product or kit of the invention can also be used in combination with antiviral agents such as Viracept, A7T, acyclovir and famciclovir, and antiseptic compounds such as Valant.

The pharmaceutical product or kit of the invention can also be used in combination with calcium channel blockers, lipid-lowering agents such as fibrates, beta-blockers, ACE inhibitors, angiotensin-2 receptor antagonists, and platelet aggregation inhibitors. 65 The pharmaceutical product or kit of the invention can also be used in combination with means for

Central nervous system, such as antidepressants (such as sertraline), drugs against Parkinson's disease (such as deprenyl, 1-dopa,

Requip, Mirapex, MAOI inhibitors, such as selegin and rasagiline, sotR inhibitors, such as Tasmar, A-2 inhibitors, dopamine resorption inhibitors, MMOBA antagonists, nicotine agonists, agonists

Dopamine and neuronal nitric oxide synthase inhibitors and anti-Alzheimer's drugs such as doneprezil, tacrine, propentofylline or metrifonate.

The pharmaceutical product or kit of the invention can also be used in combination with anti-osteoporosis agents from the group: roloxifene, droloxifene, lasofoxifene or fosomax and immunosuppressant agents such as

EC-506, ramamycin, cyclosporine and azathioprine.

The presented invention is further illustrated by references and examples. The following P2OX 7/o antagonists were used in the examples: 1. M2-Methyl-5-(9-oxa-3,7-azabicyclo|3.3.1|non-3-ylcarbonyl)phenyl|-tricyclo!|3.3.1.12.7 |-decane-1-acetamide, hydrochloride

Fe s o s y

N. (2) o s so

P2X antagonist; 1. (M-(2-Methyl-5-(9-oxa-3,7-azabicyclo|3.3.1|Inon-3-ylcarbonyl)phenyl|-tricyclo|3.3.1.1 37decane-1-acetamide, hydrochloride) was obtained in the following way." a). 3-(4-Methyl-3-nitrobenzoyl)-7-(phenylmethyl)-9-oxa-3,7-diazabicyclo|3.3.1Inonane.

Oxalyl chloride (9.bml) in dichloromethane (30ml) was added dropwise over 45 minutes to an ice-cooled solution of 4-methyl-3-nitro-benzoic acid (10.0g) in dichloromethane (320ml) containing DMF (0.0ml) , h» The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. Hydrochloric acid was dissolved in tetrahydrofuran (320 mL) and cooled in an ice bath before adding

3-(phenylmethyl)-9-oxa-3,7-azabicyclo|3.3.1|Inonane dihydrochloride (16.0 g) (obtained as described in MUO 01/028992) was then added in portions of M,M-diisopropylethylamine (Zvml). The reaction mixture was stirred for 18 hours, then diluted with ethyl acetate (b00ml) and washed with water (2 x 200ml) and saturated sodium hydrogencarbonate (aqueous) (3x50ml), then dried over magnesium sulfate, filtered and concentrated to give the sub-title compound (18.5g) . o - .) t/2 : 382 "sl c) 3-(33-amino-4-methylbenzoyl)-7-(phenylmethyl)-9-oxa-3,7-diazabicyclo|3.3.1 Inonane

Reduced iron powder (7.9g) and ammonium chloride (7.5g) in ethanol/water (3:1, 320ml) at 7093 were added over 15 minutes with stirring to a solution of the product of step a) (18.0g). The reaction mixture was heated to reflux for 2 hours, then filtered and concentrated in vacuo. The residue was transferred to ethyl acetate ml) washed with water (2x15Oml), the organic phase was dried with magnesium sulfate and

Gee! (400ml) (2x150ml) and concentrated in vacuo to give the sub-title compound (14.5G). t/g2 x 352 60 s) 3-(2-Methyl-5-|(7-(phenylmethyl)-(9-oxa-3,7-diazabicyclo|3.3.1|non-3-ylcarbonyl)phenyl|-tricyclo |3.3.1.1 ZLdecane-1-acetamide

Obtained by the method of step a), using 1-adamantanoacetic acid and the product of step b).

Recrystallization (ethyl acetate) gave the sub-title compound. b5 pt/2528 4). M-(2-Methyl-5-(9-oxa-3,7-diazabicyclo|3.3.1|non-3-ylcarbonyl)phenyl|-tricycloi|3.3.1.13.7)decane-1-acetamide, hydrochloride

AM NOI in 1,4-dioxane (ml) was added to a solution of the product of step c) (13.0g) in ethyl acetate (000ml). The resulting precipitate was separated by filtration, then suspended in ethanol (000ml) and 395 palladium on charcoal (1.2g ). The reaction mixture was stirred under atmospheric hydrogen pressure for 36 hours. Methanol was added under a nitrogen atmosphere, then the catalyst was removed by filtration and the filtrate was concentrated in vacuo. 70 Recrystallization (isopropanol:methanol 25:1, 800ml) gave the title compound (9.1g). t/2 438 (MANU vn (400MHz o, SIE-DMSO, Meji, 9022) 9.06 (1TN, 5), 7.64 (1Н, 8), 7.25 (1Н, t), 7.19 (IN, t), 4.15 (2Н . 12H, t).

Example 1

Pharmacological study to determine the effect of the TME inhibitor o/P2X antagonist combination (without the addition of the P2X»7 agonist).

Human peripheral blood monocytes were obtained from the blood of healthy volunteers collected in EDTA blood tubes. Monocytes were isolated by sequential gradient centrifugation and washing, obtaining a pure cell population. Then lipopolysaccharide (IRB5) was added to the suspension of cells in tissue culture and incubated for 4-12 hours at 372C. Then TMEo inhibitor and/or Antagonist P2X; or filler was added to the cells.

After incubation, samples of cell supernatants were transferred to a 96-well plate for subsequent cytokine and mediator measurements. The formation of inflammatory mediators was measured in the supernatant layers of cells by the determination and specific EGISA-study of cytokines II-1, /-18, TMERa and other mediators, including POE2, MO and matrix metalloproteinases (MMP). The levels of mediators were determined in the presence of only a P2X receptor antagonist, or in the presence of only a TME0 inhibitor, or in the presence of a combination of a P2X receptor antagonist and an inhibitor

TMEo. The effect of antagonists / Inhibitor TMEo alone and in combination was compared. Statistically probable levels of 3o inhibitory activity against a single mediator (11-14 or TMERo) or against multiple mediators. FU with the combination of P2X antagonist / TMEco inhibitor, in comparison with those achieved by the P2X 7 antagonist or TMEo inhibitor alone, is an indicator of increased efficiency in the treatment of diseases. and

Example 2 se

Pharmacological study to determine the effect of the combination TME co-inhibitor/P2X7 antagonist (with the addition of the co-agonist P2X»7).

Human peripheral blood monocytes obtained from the blood of healthy volunteers were collected in EDTA blood tubes. Monocytes were isolated by sequential gradient centrifugation and washing, obtaining a pure cell population. Then lipopolysaccharide (I P5) was added to the cell suspension in tissue culture and everything was incubated for 4-12 hours at 3720. Then, after adding the P2X receptor agonist, B2ATP, test mixtures were added. Test mixtures may contain an excipient such as a control, a P2X7 receptor antagonist, or a combination of antagonists. P2X receptor, together with the TMEo inhibitor. After incubation, samples of cell supernatants were transferred to a "" 96-well plate for subsequent cytokine and mediator measurements.

The formation of inflammatory mediators was measured in the supernatant layers of cells by a specific EGISA study for cytokines 1-1, 1-18, TMERo and for other mediators, including POE2, MO and matrix metalloproteinases o (MMP). The levels of mediators were determined in the presence of only the P2X7 receptor antagonist or in the presence of a combination of the P2X receptor antagonist and the TMEco inhibitor. The effect of the P2X antagonist, alone and in combination with the TMEo inhibitor, was compared. Statistically probable levels of inhibitory activity against a single mediator (T1-1 or TMEo) or multiple mediators by the combination of P2X.,-antagonist / TMEo inhibitor in comparison with that achieved with "so 20 P2X antagonist. alone - an indicator of increased efficiency in the treatment of diseases.

Example C sp Determination of the anti-inflammatory activity of the combination TME inhibitor / P2X7 antagonist in relation to rat arthritis induced by streptococcal cell walls.

Streptococcal cell wall-induced arthritis (SWIA) was induced in the left ankle of female Lewis rats. 22 Animals were sensitized by intra-articular injection of Bmcg (in 2 omcl) ZSMU (ee Iarogaigiev) in the left ankle. Ankle swelling was assessed 3 days after injection and non-responding animals (animals with no ankle swelling) were discarded. Responding animals were included in the test group. co Arthritis was induced 21 days after sensitization by intravenous (im) injection of ZSMU (100 μg in 500 μl of physiological solution). Animals were monitored and evaluated for 6 days after induction. 60 rats were placed on sawdust and provided with food and water ad libitum.

In this example, the P2X71 antagonist was dosed orally at 3 mg/kg (4 ml/kg). The compound was dosed as a suspension in 195 (w/v) methylcellulose in deionized water and obtained as a fresh extract. Dosing was started 1 day before induction of arthritis and continued for 6 days after induction. Etanercept (0.5 mg/kg) was administered by subcutaneous injection (ml/kg) 1 day before induction of arthritis and then on days 1, 3 and 5 after induction. Because the diameters of the ankle were measured with a caliper with a vernier relative to the day -1. Mechanical thresholds were assessed using von Frey villi at -1, 1, 3 and 5 days. Fibers were applied with increasing weight to the ankle on the pads of both legs. The first fiber that induces the withdrawal reaction is considered threshold.

The effect on swelling of the ankle and the mechanical threshold were calculated by the plane under the curve (AS), as the sum of the differences from the value of a separate day -1. The size and direction of the interaction were calculated, and data analysis was performed using AMOMA according to Dunnett's test on AS data (ZAZ version 8.01). The results are summarized below in Table: i

Etanercept Interaction test p-0.0857

AND

From the above results, it can be seen that the combination of the P2X71 antagonist and Etanercept showed a positive interaction in terms of producing a significantly greater reduction in the mechanical threshold than could be expected on the basis of their separate application. The finding that the two drugs have a positive effect on the von Frey threshold in a combination that does not show an additional benefit on ankle swelling suggests that this combination of drugs has a strong and unexpected positive effect on pain in the inflamed joint. 1. The experiment is based on the one described in Sagizop KR, DasorzeV RV; Comparison of adjuvant- and streptococcal cell wall-induced arthritis in the rat, Mogdap OMU, Magzgpai! IA, ediuge; Model of IP mimo inflammation.

Vaze!: Vigkpaizeg Megiazd; 1999. p

Claims (14)

The formula of the invention i) 1. A pharmaceutical product, which contains in combination the preparation of the first active ingredient, which is an antagonist of the P2XU receptor, which is a compound of the formula (XI), and the preparation of the second active ingredient, which is an inhibitor of tumor necrosis factor A (TME p. ), for simultaneous, sequential or separate use in b therapy, where the P2X7 receptor antagonist is a compound of the formula (XI) k-l o - s ikh X ia so No "- s i SK Iz" where t equals 1, 2 or 3; AND? represents С(О)МН or МНСсс); 415 Uue represents M or CH; со Xe represents a bond, СО, (СНао)4-в, О(СН») 4-6, "(СН2)и-6МН(СН") с, (СН) вО(СНо) 46, МН(СНО ) 4 in; 72 represents MA ge ze; which represents halogen, cyano, nitro, amino, hydroxyl, C 1-C alkyl or C 3-C cycloalkyl, where this alkyl or cycloalkyl may optionally be substituted by one or more fluorine atoms; co 20 Be and Be, each independently, represent a hydrogen atom, C 1-C alkyl or C 3-C cycloalkyl, this alkyl or cycloalkyl may optionally be substituted by one or more groups selected from the group: hydroxyl, "sp halogen or C. -Svalcoxyl, or 22 and KZe, together with the nitrogen to which they are attached, form a 3-9--membered saturated mono- or dicyclic heterocyclic ring, which contains from 1 to 2 nitrogens and, optionally, an oxygen atom, this 22 heterocyclic ring may be, as an option, substituted by one or more substituents selected from the group: o hydroxyl, halogen or C.-Svalcoxyl; or a pharmaceutically acceptable salt or solvate thereof. ko 2. The product according to claim 1, where the P2X7 receptor antagonist is: 2-chloro-5-((2-(2-hydroxyethylamino)ethylamino|methylI-M-(tricyclo|3.3.1.1 Z.Ldec-1-ylmethyl)benzamide , 60 2-chloro-5-I3-((3-hydroxypropyl)amino|propyl|-M-(tricycloyl|3.3.1.1)dec-1-ylmethyl)benzamide, (K)-2-chloro-5-(3 -(2-hydroxy-1-methylethyl)amino|propyl|-M-(tricyclo|3.3.1.1Z.7dec-1-ylmethyl)benzamide, 2-chloro-5-((2-(2-hydroxyethyl)iamino| ethoxy|methyl-M-(tricycloI3.3.1.137Pdec-1-ylmethyl)benzamide, 2-chloro-5-13-(3-"methylamino)propoxy|propyl|-M-(tricyclo|3.3.1.137dec -1-ylmethyl)benzamide, 65 2-chloro-5-I3-(3-hydroxypropylamino)propoxy|-M-(tricyclo!I3.3.1.1Z.Pdec-1-ylmethyl)benzamide, 2-chloro-5- (2-(3-hydroxypropylamino)dethylamino|-M-(tricycloyl|3.3.1.1Z.LZdec-1-ylmethyl)benzamide, 2-chloro-5-piperazin-1-ylmethyl-M-(tricyclo|3.3.1.1)dec-1-ylmethyl)benzamide, 2-chloro-5-(2,5-diazabicyclo|2.2.1)hept-2- ylmethyl)-M-(tricyclo|3.3.1.1)dec-1-ylmethyl)benzamide, B-chloro-2-3-(3-hydroxypropyl)amino|propyl|-M-(tricyclo!|3.3.1.1 З7dec-1 -ylmethyl)-4-pyridinecarboxamide, 5-chloro-2-3-(ethylamino)propyl|-M-(tricyclo|3.3.1.1Z.Ldec-1-ylmethyl)-4-pyridinecarboxamide, B-chloro-2-IZ -K2-hydroxyethyl)amino|propyl|-M-(tricycloyl|3.3.1.1Z.Ldec-1-ylmethyl)-4-pyridinecarboxamide, 5-chloro-2-I3-((25)-2-hydroxypropylamino|propyl| -M-(tricycloyl|3.3.1.1 ZLdec-1-ylmethyl)-4-pyridinecarboxamide, M-(2-methyl-5-(9-oxa-3,7-azabicycloyl|3.3.1|non-3-ylcarbonyl) phenyl|gricycloil|3.3.1.1 Z.Ldecane-1-acetamide, or a pharmaceutically acceptable salt or solvate of any of these. Q. The product according to claim 1 or 2, where the second active ingredient is a receptor molecule capable of binding to TME with... 4. The product according to claim 3, where the second active ingredient is etanercept. 5. The product according to claim 1 or 2, where the second active ingredient is an anti-TME 95 antibody... 6. The product according to claim 5, where the second active ingredient is selected from Infliximab and Adalimumab (02E7). 7. A kit containing the preparation of the first active ingredient - the P2X receptor 7 antagonist, where the P2X receptor antagonist is an adamantyl derivative, and the preparation of the second active ingredient - tumor necrosis factor A inhibitor (TME 3), and instructions for simultaneous, sequential or separate use drugs to a patient in need thereof, where the P2X 7 receptor antagonist is a compound of formula (Xi) as defined in claim 1. 8. The kit according to claim 7, where the P2X receptor antagonist is: 2-chloro-5-((2-(2-hydroxyethylamino)ethylamino|methylI-M-(tricyclo!/3.3.1.1 ZPdec-1-ylmethyl)benzamide, 2-chloro-5-I3-((3-hydroxypropyl)amino|propyl|-M-(tricycloyl|3.3.1.1)dec-1-ylmethyl)benzamide, (c)-2-chloro-5-I3-(2 -hydroxy-1-methylethyl)amino|propyl|-M-(tricyclo|3.3.1.1 ZLdec-1-ylmethyl)benzamide, 2-chloro-5-((2-(2-hydroxyethyl)amino|)ethoxy|methyl| -M-(tricyclo|3.3.1.1 ZULZdec-1-ylmethyl)benzamide, Ha 2-chloro-5-3-3-(methylamino)propoxy|propyl|-M-(tricyclo|3.3.1.1 ZULZdec-1-ylmethyl) benzamide, o 2-chloro-5-I3-(3-hydroxypropylamino)propoxy|-M-(tricyclo!I3.3.1.1Z.Pdec-1-ylmethyl)benzamide, 2-chloro-5-(2-(3 -hydroxypropylamino)deethylamino)-M-(tricyclo!|3.3.1.1 Z.dec-1-ylmethyl)benzamide, 2-chloro-5-piperazin-1-ylmethyl-M-(tricyclo|3.3.1.1)dec-1- ylmethyl)benzamide, 2-chloro-5-(2,5-diazabicyclo|2.2.1)hept-2-ylmethyl)-M-(tricycloyl|3.3.1.1)dec-1-ylmethyl)benzamide, o 3o 5-chloro -2-3-(3-hydroxypropyl)amino|propyl|-M-(tricyclo!|3.3.1.137dec-1-ylmethyl)-4-pyridinecarbox amide, He») 5-chloro-2-3-(ethylamino)propyl|-M-(tricyclo!|3.3.1.1 ZLZdec-1-ylmethyl)-4-pyridinecarboxamide, o 5-chloro-2-I3-(( 2-hydroxyethyl)amino|propyl|-M-(tricyclo|3.3.1.1Z.7|dec-1-ylmethyl)-4-pyridinecarboxamide, 5-chloro-2-I3-((25)-2-hydroxypropylamino|Ipropyl |-M-(tricyclo!/3.3.1.1 ZLPdec-1-ylmethyl)-4-pyridinecarboxamide se zy and (se) M-(2-methyl-5-(9-oxa-3,7-diazabicyclo|3.3.1 |non-3-ylcarbonyl)phenyl|tricyclo|3.3.1.1 Z.decane-1-acetamide, or a pharmaceutically acceptable salt or solvate of any of these compounds. 9. The kit according to any of claims 7 or 8, where the second active ingredient is a receptor molecule capable of "binding to TME o... 10. Kit according to claim 9, where the second active ingredient is etanercept. - with 11. Kit according to claim 7 or 8, where the second active ingredient is an anti-TME antibody. "» 12. Kit according to claim 11, wherein the second active ingredient is selected from Infliximab and Adalimumab (02E7). " 13. The use of a pharmaceutical product or kit according to any of the previous items in the production of a medication for the treatment of an inflammatory disorder. 14. Use according to claim 13, wherein the inflammatory disorder is rheumatoid arthritis. (ог) 15. A method of treating an inflammatory disorder, in which the following is administered simultaneously, sequentially or separately: t a) a (therapeutically effective) dose of the first active ingredient - a P2X receptor antagonist; where the P2X receptor antagonist is an adamantyl derivative, which is a compound of the formula ( XI), as defined in claim 1; and (a) B) (therapeutically effective) dose of the second active ingredient - factor c inhibitor. tumor necrosis (TME "with 20 in ) to a patient who needs it. c 16. The method according to claim 15, where the inflammatory disorder is rheumatoid arthritis. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2008, M 05, 11.03.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. F) ko 60 b5