Quinazoline and quinoline derivatives and medicinal agents based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes analgesic agent possessing the analgesic effect showing effectiveness against the pain by effect on nociceptors. As an active component the proposed analgesic agent comprises compound represented by the general formula (1) or its salt wherein X, Y, E, Q, A1, A2, R1, R3, R4, R5, R2A, R2C, R2D and R2B re determined in the invention claim.

EFFECT: valuable medicinal properties of agents.

3 tbl, 70 ex

 

The present invention relates to pharmaceutically useful new heterocyclic derivative or salts thereof and to pharmaceutical compositions containing them as active ingredient.

As an analgesic use narcotic analgesic (such as morphine), non-narcotic analgesic such as aspirin or indomethacin) or narcotic-antagonist analgesic (such as pentazocine). Narcotic analgesic exerts analgesic effects primarily through inhibition of Central pain transmission of excitation. Non-narcotic analgesic exerts analgesic effects primarily by inhibiting the production of peripheral leg pain substances. Narcotic-antagonist analgesic has analgesic action mechanism similar to the mechanism of action narcotic analgesic.

However, there is no analgesic that is effective against chronic pain, which is not suppressed by morphine, when allodynia involving shingles, or increased pain sensitivity, and it would be desirable to develop an excellent analgesic.

Nociceptin is a neuropeptide related to a variety of neural activity, including pain sensitivity in vivo. In the not-p is osadchey examination patent publication Japan No. 10-212290 described, that agonist and/or antagonist nociceptin may be effective in the treatment of mental disorders, neuropathies and disorders and is particularly effective for reducing anxiety and stress, depression, traumatic disorders, amnesia due to Alzheimer's or another dementia, symptoms of epilepsy, spasm, acute and/or chronic pain symptoms when stopping taking drugs to control water balance, excretion of Na+violations of arterial blood pressure and when the eating disorder, such as obesity.

As ones compounds influencing nociceptive receptor, known lofentanil, benzoylhydrazone naloxone and its derivative 2-accomidate (international publication WO 9854168). However, these compounds are still at the stage of basic research, and none of them is commercially available.

As compounds similar to the derived hintline in heterocyclic derivatives of compounds in accordance with the present invention, various known compounds (international Publication WO 9307124, the publication of the last examination of the Japan patent No. 2923742, 9720821, international Publication WO 9850370, international Publication WO 9909986 not passed examination patent publication Japan No. 47-2927, the International is owned Publication WO 9817267 and the like). Among them, in International Publication WO 9720821 described that the derived 2-acylaminopyrazoles has an inhibitory effect on subtype-Y5 neuropeptide Y(NPY) receptor and is effective to reduce the intensity increased sensitivity to pain or amnesia.

The present invention is to develop new compounds with excellent analgesic effect. More specifically the present invention relates to a new analgesic (painkiller tool)with analgesic effect, which is very effective against chronic pain or allodynia involving shingles, by affecting nociceptive (pain) receptor.

The present invention is achieved by the connection represented by the following General formula (1), which is the agonist and/or antagonist nociceptive receptor and has an excellent analgesic effect.

Accordingly, the present invention relates to a compound represented by the following General formula (1):

or its salts.

In the formula, X and Y are the same or different, and each represents a nitrogen atom or CH;

R1represents a hydrogen atom or alkyl;

And1and2are the same or different is mi, and each represents (1) a single bond or (2) divalent aliphatic hydrocarbon group which may be substituted and may include 1-3 bonds in any position (such aliphatic hydrocarbon group may contain one heteroatom selected from the group consisting of-NH-, O and S);

Q represents (1) a single bond, (2) optionally substituted 3-8-membered cycloalkenyl group, (3) optionally substituted fenelonov group, or (4) optionally substituted 4-to 8-membered divalent heterocyclic group;

R2A, R2Cand R2Dare the same or different, and each represents a hydrogen atom, alkyl or phenyl, R2Brepresents a hydrogen atom, alkyl, cyano, nitro or phenyl, or two nitrogen atom guanidino groups form a loop with one or two substituents R2B, R2Cand R2Dwith the formation of a saturated or unsaturated 5-or 6-membered ring;

or taken together form-N(R1)-A1-Q-A2-N(R2A)- with the formation of a 5-7-membered ring;

E represents (1) attilan, (2) -NRCO-, (3)

-NRCONH-, (4) -CONR-, (5) ethynylene, (6) -NRSO2or (7) aminoalkyl (where R represents hydrogen or optionally substituted alkyl);

R3represents an optionally substituted phenyl group is whether heterocyclic group;

R4and R5(1) are the same or different, and each represents a hydrogen atom, alkyl, alkoxy, aralkylated, halogen, nitro, hydroxy, alkoxycarbonyl, -NR6R7, -NR6COR7, -NR6SO2R7, -CONR6R7(in which R6and R7are the same or different, and each represents a hydrogen atom or alkyl), or (2) when they are adjacent to each other, together form-O(CH2)n(Where n represents an integer of 1 or 2) or-CH=CH-CH=CH-.

Preferably in the formula (1) each X and Y represents a nitrogen atom or CH;

R1represents a hydrogen atom or alkyl;

And1and2are the same or different, and each represents (1) a single bond or (2) alkylene, which can be substituted by alkyl, carbamoyl, monoalkylammonium, dialkylammonium, hydroxy, alkoxy or trifluoromethyl, and can contain 1-3 bonds of any provisions;

Q represents (1) a single bond, (2) 3-8-membered cycloalkenyl group which may be substituted by alkyl, alkoxycarbonyl, carbamoyl, monoalkylammonium, dialkylammonium or alkoxy, (3) fenelonov group which may be substituted by alkyl, alkoxy, alkoxycarbonyl, carbamoyl, Manouk what carbamoyl, dialkylammonium, sulfamoyl, monoalkylphenols, dialkylamino, amino, monoalkylamines, dialkylamino, nitro, halogen, cyano or trifluoromethyl, or (4) 4-8-membered divalent heterocyclic group which may be substituted by alkyl, alkoxy, alkoxycarbonyl, carbamoyl, monoalkylammonium, dialkylammonium, amino, monoalkylamines or dialkylamino;

R2A, R2Cand R2Dare the same or different, and each represents a hydrogen atom, alkyl or phenyl, R2Brepresents a hydrogen atom, alkyl, a cyano, a nitro-group or phenyl, or two nitrogen atom guanidino group cyklinowanie together with one or two substituents R2B, R2Cand R2Dwith the formation of a saturated or unsaturated 5-or 6-membered ring;

or taken together form-N(R1)-A1-Q-A2-N(R2A)- with the formation of a 5-7-membered ring;

E represents (1) attilan, (2) -NRCO-, (3) -NRCONH-, (4) -CONR-, (5) ethynylene, (6) -NRSO2or (7) aminoalkyl (in which R represents hydrogen or optionally substituted alkyl);

R3represents an optionally substituted phenyl group or heterocyclic group which may be substituted by alkyl, alkoxy, alkoxycarbonyl, carbamoyl, monoalkylammonium, dialkylammonium, sulfa what oil, monoalkylphenols, dialkylamino, alkylsulfonyl, N-(alkyl)alkylsulfonyl, amino, monoalkylamines, dialkylamino, nitro, halogen, cyano, hydroxy or trifluoromethyl, and

R4and R5(1) are the same or different, and each represents a hydrogen atom, alkyl, alkoxy, aralkylated, halogen, nitro, hydroxy, alkoxycarbonyl, -NR6R7, -NR6COR7, -NR6SO2R7, -CONR6R7(in which R6and R7are the same or different, and each represents a hydrogen atom or alkyl) or (2) when they are adjacent to each other, together form-O(CH2)n(Where n represents an integer of 1 or 2) or-CH=CH-CH=CH-.

More preferable compound represented by the General formula (1), where each X and Y represents a nitrogen atom, R1represents a hydrogen atom or alkyl, And1and2are the same or different, and each represents (1) a single bond or (2) optionally substituted alkylene, Q represents (1) a single bond, (2) optionally substituted 4-to 8-membered cycloalkenyl group, (3) optionally substituted fenelonov group, or (4) optionally substituted 5-7-membered divalent heterocyclic group, R2A, R2B, R2CThe R 2Dare the same or different, and each represents a hydrogen atom, alkyl or phenyl, or taken together form-N(R1)-A1-Q-A2-N(R2A- form a 5-7 membered ring, E represents (1) attilan, (2) -NRCO -, or (3) -CONR-, and R4and R5(1) are the same or different, and each represents a hydrogen atom, alkyl, alkoxy, aralkylated, halogen, nitro, hydroxy or alkoxycarbonyl, or (2) when they are adjacent to each other, together form-O(CH2)nO- (where n is an integer 1 or 2) or-CH=CH-CH=CH-.

Additional preferred compound represented by the General formula (1), where each X and Y represents a nitrogen atom, R1is hydrogen. And1and2are the same or different, and each represents (1) a single bond or (2) optionally substituted alkylene, Q represents (1) a single bond, (2) optionally substituted 5-7-membered cycloalkenyl group, (3) optionally substituted fenelonov group, R2A, R2B, R2Cand R2Dare the same or different, and each represents a hydrogen atom, alkyl or phenyl, E is a (1) attilan, (2) -NRCO-, and R4and R5are the same or different, and each represents an atom of odor is Yes, alkyl, alkoxy, aralkylated, halogen or nitro.

In addition, the present invention relates to pharmaceutical compositions, comprising any of the foregoing compounds or its salt, and more specifically to the analgesic.

Structural characteristics of the compounds of the present invention are the following: the presence of guanidinium moiety at the end of the substituent, -N(R1)-A1-Q-A2-in the 4-position khinazolinov or quinoline structure, or in the 1-position of the isoquinoline structure; or cyclization of two NH groups in guanidino group together with the Deputy then.

The connection according to the present invention which has the above-described characteristic feature is a new connection, which was not disclosed in the references. The connection according to the present invention operates on nociceptive receptor, thereby an excellent analgesic effect.

Hereinafter the present invention will be described in detail.

Examples of "alkyl" in the present invention can include linear or branched alkyl having from 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 5-isopentyl, n-hexyl, isohexyl and the like. In particular, preferred is an alkyl containing from 1 to 4 carbon atoms.

Por the measures "alkoxy" may include linear or branched alkoxy group, containing from 1 to 6 carbon atoms, for example methoxy, ethoxy n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentylamine, n-hexyloxy, isohexane and the like. In particular, it is preferable alkoxy containing from 1 to 4 carbon atoms.

Examples of "aralkylated" may include aralkylated containing 7 to 10 carbon atoms, such as benzyloxy, penetrate and the like. In particular, preferred is benzyloxy.

Examples of the "divalent aliphatic hydrocarbon group" include linear or branched alkylene containing from 1 to 6 carbon atoms (e.g. methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, 2-ethyltryptamine and 1-methyltyramine), linear or branched albaniles containing from 2 to 6 carbon atoms (for example, vinile or propylen) or a linear or branched akinyan containing from 2 to 6 carbon atoms (e.g., ethynylene). Such aliphatic hydrocarbon group may contain one heteroatom selected from the group consisting of NH, oxygen atom and sulfur atom.

Examples of alkylene "aminoaniline" may include alkylene listed in the "divalent aliphatic hydrocarbon group".

Examples of "cycloalkyl" may include cycloalkyl, with the holding from 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. This cycloalkyl may contain 1-2 substituent, and examples of such substituents may include alkyl, alkoxycarbonyl, carbarnoyl, monoalkylammonium, dialkylammonium or alkoxy. It may also contain unsaturated bond, and examples of cycloalkyl containing such unsaturated bond include cyclohexenyl, cycloheptenyl, cyclooctene and the like.

Examples of "halogen" may include fluorine atoms, chlorine, bromine and iodine.

Examples of the heterocyclic ring in the heterocyclic group and divalent heterocyclic group" may include a 4-8-membered monocyclic or condensed ring containing 1-2 heteroatoms selected from the group consisting of NH, oxygen atom and sulfur atom, and which may contain 1-4 bonds. Examples R3may include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl. This heterocyclic group may contain 1 or 2 substituent and examples of the substituents may include alkyl, alkoxy, alkoxycarbonyl, carbarnoyl, monoalkylammonium, dialkylammonium, sulfamoyl, monoalkylphenol, dialkylamino, alkylsulfonyl, N-(alkyl) alkyls is phenylamino, amino, monoalkylamines, dialkylamino, nitro, halogen, cyano, hydroxy or triptoreline. Examples of the heterocyclic ring in the heterocyclic group Q may include pyridine, pyrimidine, piperazine, homopiperazine, furan, thiophene and the like. Heterocyclic group Q may contain 1-2 substituent, and examples of such substituents may include alkyl, alkoxy, alkoxycarbonyl, carbarnoyl, monoalkylammonium, dialkylammonium, amino, monoalkylamines or dialkylamino.

"Fenelonov group may contain 1 or 2 substituent, and examples of such substituents may include alkyl, alkoxy, alkoxycarbonyl, carbarnoyl, monoalkylammonium, dialkylammonium, sulfamoyl, monoalkylphenol, dialkylamino, amino, monoalkylamines, dialkylamino, hydroxy, nitro, halogen, cyano and trifluoromethyl.

An example of a ring represented by-N(R1)-A1-Q-A2-N(R2A)- may include a 5-7 membered saturated ring, such as piperazine derivatives or homopiperazine.

Examples of the "salt" of the compound (1)covered by the present invention, may include a salt of an inorganic acid, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid or Hydrobromic acid, or salt of organic acid such as acetic acid, tartaric acid, lactic who Isleta, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, toluensulfonate acid, naphthalenesulfonate acid or camphorsulfonic acid.

Examples of particularly preferred compounds may include dihydrochloride (1S,2R)-N-amidino-2-{[2(4-chlorobenzylamino)-6-methoxyquinazoline-4-yl]amino} cyclohexylamine, trihydrochloride N-amidino-2-[6-methoxy-4-{2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl)aminoethyl]phenethylamine, trihydrochloride CIS-4-guanidinate-CIS-2-methyl-N-{6-methoxy-2-[2-{2-pyridyl)ethynyl]hinzelin-4-yl}cyclohexylamine, trihydrochloride N-amidino-N'-{6-methyl-2-[2-(2-pyridyl)ethynyl] hinzelin-4-yl}-1,6-hexanediamine, dihydrochloride (1S,2R)-CIS-N-amidino-2-{[2-(4-chlorostyryl)-6-methoxyquinazoline-4-yl]amino} cyclohexylamine and trihydrochloride N-amidino-N'-{6-methoxy-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}-1,6-hexanediamine.

The connection according to the present invention can exist as CIS (Z-form) isomer or TRANS (E form) isomer, and each isomer and a mixture thereof are also included in the present invention.

Some compounds according to the present invention may have asymmetric carbon atoms and each optical isomer and the racemate is also included in the present invention. The optical isomer can be obtained, for example, the R, based on the racemate obtained as described above, using its basic properties, using optically active acid (tartaric acid, dibenzoyltartaric acid, almond acid, 10-camphorsulfonic acid and the like) in a known manner for the implementation of optical separation, or based on pre-obtained optically active compounds.

Connection (1) according to the present invention can be obtained, for example, in the following ways :

The method of obtaining And

(where X, Y, R1, R2AR2B, R2c, R2D, R3, R4, R5, A1, A2, Q and E have the values described previously. R2band R2care the same or different, and each represents a hydrogen atom, alkyl, phenyl, cyano, nitro or a protective group. L represents a leaving group.)

Examples of the protective group may include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl and the like. Examples of leaving groups can include pyrazole-1-yl, methylthio, methoxy, halogen and the like. The compound (2) is subjected to interaction with compound (3) in an amount of one equivalent to an excess quantity of the hydrocarbons, such as benzene and toluene, ethers such as dioxane and tetrahydrofuran, halogenated Ugledar the Dah, such as chloroform, methylene chloride and 1,2-dichloroethane, or in N,N-dimethylformamide at a temperature from 0°C to the boiling point of the used solvent for from a few hours to several days, followed by removing the protective groups R2band R2cwhen they are present as protective groups, using a known per se method, thus obtaining a compound (1). Particularly preferable to use pyrazole-1-yl as the leaving group L in the compound (3) and tert-butoxycarbonyl as a protective group, 1,2-dichloroethane as a solvent and to carry out the reaction at room temperature for from 1 to 48 hours, followed by removing the protecting hydrochloric acid.

The method of obtaining (where R2Bin the compound (1) is a hydrogen atom)

(where X, Y, R1, R2A, R2B, R2C, R2D, R4, R5, A1, A2, Q and E have the above values.

The compound (1a) can be obtained by interaction of the compound (2) with R2CR2DN-CN by a known method (J. Med. Chem., 18, 90, 1975, and the like).

The method of obtaining (where R2Din the compound (1) is a hydrogen atom)

(where X, Y, R1, R2A, R2B, R2C, R3, R , R5, A1, A2, Q and E have the above values.

The compound (1b) can be obtained by interaction of the compound (2) with R2B-N=C=N-R2Cby a known method (J. Am.Chem. Soc., 3673, 1962, and the like).

The method of obtaining D

(where X, Y, R1, R2A, R2B, R2C, R2D, R3, R4, R5, A1, A2, Q and E have the values described previously. R8represents alkyl).

The compound (1) can be obtained from compound (120) in a known manner (Synthesis, 6, 460, 1988, and the like). Alkyl as R8represents alkyl having from 1 to 4 carbon atoms, and preferably represents methyl.

The method of obtaining E

The compound (1A), which represents a connection (1)where E represents attilan, both X and Y are N, can be obtained by the following reaction:

(where R1, R2A, R2B, R2C, R2D, R3, R4, R5, A1, A2, R2b, R2cand Q have the above values).

The compound (13) is subjected to interaction with the amine (4) in an amount of one equivalent to excess amount in the presence of a base such as sodium hydride or N,N-diisopropylethylamine, in a solvent having a high t is mperature boiling, such as 1-pentanol, N,N-dimethylformamide or phenol, at a temperature of from 50°C to the boiling point of the used solvent for from a few hours to several days, followed by removing the protective groups R2band R2cwhen they are present as protective groups, using a known method, thus obtaining the compound (1A). Preferably, the interaction is carried out in phenol at 150-180°for 5-24 hours, followed by removal of protection by using hydrochloric acid, obtaining the compound (1A).

The method of obtaining F

The compound (1Z), which represents a connection (1)where E represents-NRCO-, and both X and Y are N, can also be obtained below reactionary way:

(where R, R1, R2A, R2B, R2C, R2D, R3, R4R5, A1, A2, R2b, R2cand Q have the above values).

Connection (37V) is subjected to interaction with compound (3) in an amount of one equivalent to an excess quantity of the hydrocarbons, such as benzene and toluene, ethers such as dioxane and tetrahydrofuran, halogenated hydrocarbons such as chloroform, methylene chloride and 1,2-dichloroethane, or in N,N-dimethylformamide at temperatures between 0&x000B0; C to the boiling point of the used solvent for from a few hours to several days, thus obtaining the compound (37A). Particularly preferable to use pyrazole-1-yl as the leaving group L in the compound (3), tert-butoxycarbonyl as a protective group and 1,2-dichloroethane as a solvent.

The compound (37A) is subjected to interaction with the acid chloride of the acid in an amount of one equivalent to an excess quantity of the hydrocarbons, such as benzene and toluene, ethers such as dioxane and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane and chloroform, in the presence of a base, such as triethylamine, N,N-diisopropylethylamine or pyridine, using, if necessary, a catalyst such as 4-dimethylaminopyridine, at a temperature from room temperature up to the boiling point of the used solvent for from a few hours to several days, followed by removing the protective groups R2band R2cwhen they are present as protective groups, using a known method, thus obtaining the compound (1Z).

Thus obtained compound (1) can be isolated and purified by the known methods such as concentration, the conversion of the liquid phase, separation, extraction Rast is orichalum, crystallization, recrystallization, fractional distillation or chromatography.

The original compound (2) can be obtained in accordance with the following reaction schema.

(a) When E is attilan, and both X and Y represent N in the compound (2):

(where R1, R2, R3, R4, R5And1And2and Q have the above meanings. R1represents a protective group).

Examples of the protective group may include tert-butoxycarbonyl, benzyloxycarbonyl and the like.

The compound (13) (obtained as described on page 13-15 in International Publication WO 9909986) is subjected to interaction with the amine (14) in an amount of one equivalent to an excess quantity of the hydrocarbons, such as benzene and toluene, ethers such as dioxane and tetrahydrofuran, alcohols such as ethanol and isopropanol, or in an organic solvent such as N,N-dimethylformamide, optionally in the presence of a base such as triethylamine or N,N-diisopropylethylamine, at a temperature of from room temperature to the boiling point of the used solvent for from several hours to several days, followed by removing the protecting hydrochloric acid, triperoxonane acid or by hydrogenation with COI is whether the palladium-on-carbon, thus obtaining the compound (2A). Especially preferably, the compound (13) was subjected to interaction with 1-2 equivalents of amine (14), in which R1represents a tert-butoxycarbonyl in toluene as solvent in the presence of triethylamine (tea) at 100-130°With in 24-48 hours, and then removing the protection was carried out by hydrochloric acid.

(b) When E is ethenylene, X represents CH, Y represents N in the compound (2):

(where R1, R2A, R3, R4, R5And1, A2, Q and R1have the above values).

To obtain the compound (19) using the known method (JACS 70, 4065 (1948); JACS 70, 2402 (1948); JOC 12, 456 (1947), and the like), based on the compound (16).

The compound (19) is subjected to interaction with the aldehyde (11) in a solvent such as acetic anhydride, acetic acid or triperoxonane acid at a temperature of from room temperature to the boiling point of the used solvent for 1-48 hours, preferably in acetic anhydride as solvent at 80 to 100°for 5-24 hours, thus obtaining a compound (20). The aldehyde (11) may be commercially available or can be obtained in a known manner.

The compound (20) is subjected to interaction with chlorinol the named agent, such as phosphorus oxychloride or pentachloride phosphorus, without using any solvent or in a solvent such as toluene, xylene or 1,2-dichloroethane, at a temperature of from room temperature to the boiling point of the used solvent or at a temperature of from room temperature to the boiling temperature used glorieuses agent in the case where no solvent is used, for 1-24 hours, thus obtaining a compound (21). By this method, if necessary, may contain a tertiary amine such as dimethylaniline or triethylamine.

The compound (21) is subjected to interaction with the amine (14) in an amount of one equivalent to excess amount, as described above in (a), and then, if necessary, conduct unprotect using a known method, obtaining the compound (2B). Especially preferably, the compound (21) interacted with 1-2 equivalents of amine (14), in which R1represents a tert-butoxycarbonyl in toluene as solvent in the presence of triethylamine at 100-130°With in 24-48 hours, giving the compound (22), which then remove protection using triperoxonane acid in methylene chloride.

(C) When E is ethenylene, X represents N and Y represents a CH in connection (2):

p>

(where R1, R2A, R3, R4, R5And1, A2, Q and R1have the above values).

Proceeding from compound 23 using the known method (J. Chem. Soc. Perkin Trans., 1, 1990, 1770), get a connection (24).

The compound (24) is subjected to interaction with 1-3 equivalents of selenium dioxide in ethers, such as dioxane and tetrahydrofuran, or alcohols, such as ethanol and isopropanol, at a temperature of from room temperature to the boiling point of the used solvent for from a few hours to several days, preferably in dioxane at 50 to 100°for 5-48 hours, thus obtaining a compound (25).

The compound (25) is subjected to interaction with compound (26) or a compound (27) in a solvent which does not participate in the reaction such as dioxane or tetrahydrofuran, in the presence of a base, such as n-utility, sodium hydride or hexamethyldisilazide sodium, at a temperature of from -78°C to the boiling point of the used solvent for from a few hours to several days, preferably tetrahydrofuran at a temperature from -20°C to room temperature for 1-5 hours, thus obtaining a compound (28).

Similarly to the technique described above in part (b), the compound (28) communicates with glorieusement, such as phosphorus oxychloride or pentachloride phosphorus within 1-24 hours, giving the compound (29). Compound (29) communicates with the amine (14) in an amount of one equivalent to excess amount, as described above in part (a), and then if necessary, conduct the removal of the protective groups known in itself by the way, obtaining the compound (2C).

(d) When E represents-NRCO-, and both X and Y represent N in the compound (2):

(where R, R1, R2A, R3, R4, R5, A1, A2, Q and R1have the values described previously. X represents a hydroxyl group, or amino group. R2represents a hydrogen atom or a protective group such as benzyl or 4-methoxybenzyl).

Compound (34) can be obtained from the compounds (31) and (32) in accordance with the known method (Japan patent No. 2923742).

Connection (34) is subjected to interaction with the amine (14) in an amount of one equivalent to excess amount of the same solvent as described above in part (a), optionally in the presence of a base such as triethylamine or N,N-diisopropylethylamine, at a temperature of from 0°C to the boiling point of the used solvent for from a few hours to several days, preferably in the presence of triethylamine in to the room temperature for 5-48 hours, while receiving the connection (35).

Compound (35) is subjected to interaction with the amine (36) in an amount of one equivalent to excess amount of the solvent having a high boiling point, such as diphenyl phenol or a simple ester, optionally in the presence of a base such as triethylamine or N,N-diisopropylethylamine, at a temperature of from room temperature to the boiling point of the used solvent for from a few hours to several days, or hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane and tetrahydrofuran, in the presence of a metal catalyst such as palladium acetate, ligand, such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, and a base, such as tert-piperonyl sodium, at a temperature of from room temperature to the boiling point of the used solvent for from a few hours to several days, followed by removing the protective group P2when it is present as a protective group, using the method of not exerting actions on R1obtain compound (37).

The compound (37) is subjected to interaction with the acid chloride of the acid in an amount of one equivalent to an excess quantity of the hydrocarbons, such as benzene and toluene, ethers such cardioxane and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane and chloroform, in the presence of a base, such as triethylamine, N,N-diisopropylethylamine or pyridine, optionally using a catalyst such as 4-dimethylaminopyridine, at a temperature of from room temperature to the boiling point of the used solvent for from a few hours to several days, thus obtaining the compound (38). To obtain the compound (2D) in the connection (38) remove a protective group using a known per se method. Particularly preferable to carry out communication using methylene chloride as a solvent in the presence of triethylamine using a catalytic amount of 4-dimethylaminopyridine at room temperature for 24-48 hours. The acid chloride of the acid may be commercially available or can be obtained in a known manner.

(e) When E represents-NHCO-, and both X and Y represent N in the compound (2):

(where R1, R2A, R3, R4, R5, A1, A2, Q and R1have the above values).

Based on the compound (39), to obtain compound (41) using the known method (see JOC, 27, 4672 (1962).

Compound (41) is subjected to shimodate with the amine (14) in an amount of one equivalent to excess amount similar to that described above in part (a), receiving a connection (42). Especially preferably the interaction of the compound (41) with 1-2 equivalents of amine (14) in toluene as solvent in the presence of triethylamine (tea) at 100-130°With in 24-48 hours.

Hydrolysis of the compound (42) in a known manner to receive a connection (43). Especially preferably the interaction of the compound (42) in ethanol in the presence of 1H. an aqueous solution of sodium hydroxide at a temperature of from room temperature to 60°C for 1-3 hours.

Compound (43) is subjected to interaction with diphenylphosphorylacetate (DPPA) in alcohols, such as ethanol and benzyl alcohol, in the presence of a base such as triethylamine or N,N-diisopropylethylamine, at a temperature of from room temperature to the boiling point of the used solvent for from a few hours to several days, thus obtaining the compound (44). Especially preferably the interaction of the compound (43) in boiling under reflux with ethanol in the presence of triethylamine in 24-48 hours.

Compound (44) hydrolyzing a known manner, which does not affect R1, thus obtaining the compound (45). Especially preferably the interaction of the compound (44) in methanol in the presence of potassium hydroxide at a temperature of from room tempera is URS to 60° C for 1-3 hours.

The compound (45) is subjected to interaction with the acid chloride of the acid in an amount of one equivalent to an excess quantity of the hydrocarbons, such as benzene and toluene, ethers such as dioxane and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane, in the presence of a base, such as triethylamine, N,N-diisopropylethylamine or pyridine, optionally using a catalyst such as 4-dimethylaminopyridine, at a temperature of from room temperature to the boiling point of the used solvent for from a few hours to several days, thus obtaining the compound (46). Particularly preferable to carry out communication using methylene chloride as a solvent in the presence of triethylamine using a catalytic amount of 4-dimethylaminopyridine at room temperature for 24-48 hours.

In the compound (46) in a known manner remove a protective group receiving the compound (2E). When R1represents a tert-butoxycarbonyl, it is preferable to carry out the interaction with triperoxonane acid in methylene chloride at room temperature for 1-5 hours. When R1is benzyloxycarbonyl is preferred Khujand is indeed hydrogenation in methanol in the presence of 5%palladium-on-carbon at room temperature under atmospheric pressure.

(f) When F is an ethynylene, and both X and Y represent N in the compound (2):

(where R1, R2A,R3, R4, R5And1, A2, Q and R1have the above values).

Based on the compound (35), using well-known by itself, the way (see Heterocycles, 24, 2311 (1986), and the like) to obtain the compound (200). In the connection (200) remove a protective group in a known manner, obtaining the compound (2F).

(g) When E is a-CONR-, and both X and Y represent N in the compound (2):

(where R, R1, R2A, R3, R4, R5, A1, A2, Q and R1have the above values).

On the basis of connection (43), using well-known by itself, the way amidation to obtain the connection (210). In the connection (210) then remove the protective group in a known manner, receiving the connection (2G).

(h) When E represents-NRSO2-and both X and Y represent N in the compound (2):

(where R, R1, R2A, R3, R4, R5, A1And2, Q and R1have the above values).

Connection (220) can be produced from compound (45), in accordance with the known method of sulfonmethane. In the connection (220) then removing the Ute protective group in a known manner, receiving connection (2N).

(i) When E is a-NRCONH-and both X and Y represent N in the compound (2):

(where R, R1, R2AR3, R4, R5, A1, A2, Q and R1have the above values).

On the basis of connection (45), isocyanate subjected to interact in a known manner, receiving the connection (230). In the connection (230) then remove the protective group in a known manner, receiving a connection (21).

The original compound (3) can be obtained in accordance with the known method (J. Org. Chem., 34, 616, 1969; Synthesis 6, 460, 1988, and the like).

The original compound (4) can be obtained in accordance with the following reaction scheme:

(where R1, R2aR2b, R2C, R2D, A1, A2, Q, L, and R1have the above values).

The compound (100) is subjected to interaction manner similar to the above method of obtaining And getting the original connection (4). This original connection (100) may be commercially available or can be obtained by using a known method.

The original connection (120) can be obtained in accordance with the following reaction schema.

(where R1, R2A, R2B, R3, R4, R5, A1, A2E, Q, X and Y have the above values).

Connection (110) is subjected to interaction with R2BN=C=S in an amount of one equivalent to excess amount of the solvent, as described above in the method of obtaining And, if necessary, in the presence of a base such as triethylamine or N,N-diisopropylethylamine, at a temperature of from room temperature to the boiling point of the used solvent for from a few hours to a few days, getting the original connection (120). Especially preferably the interaction in methylene chloride at room temperature for 1-24 hours.

In the above-described method of obtaining the amino group or hydroxyl group may optionally be protected commonly used protective groups, and after the interaction of the protective group can be removed at an appropriate stage in a way that is known in itself, such as treatment with acid or alkali, or catalytic hydrogenation. Examples aminosidine group may include benzyl, benzyloxycarbonyl, tert-butoxycarbonyl and TRIFLUOROACETYL. Examples hydroxylamino group may include methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, tetrahydropyranyl, tert-butyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl and the like.

The salt of compound (1)of the present invention can be obtained in a known manner. For example, the hydrochloride of compound (1) of the present invention can be obtained by treating compound (1) of the present invention with a solution of hydrogen chloride in alcohol or simple ethyl ether, followed by separation of precipitated precipitated crystals by filtration, or in the case where crystals do not precipitate, by concentrating the solution until precipitation of crystals, which then emit filtering.

Because the connection according to the present invention, represented by formula (1), as shown in the following examples, the tests associated with nociceptive receptor, having agonistic or antagonistic action, it is useful as an analgesic, anti-inflammatory agent, diuretic, anesthetic, anti-hypertensive agent, an overwhelming anxiety agent, agent, anti-obesity, controller hearing, antidepressant agent against dementia, agent, overcoming narcotic-analgesic stability.

When the compound of the present invention is administered as a drug, it can be administered to a mammal, including humans, by itself or in a mixture with a pharmaceutically acceptable nontoxic, inert carrier, for example in the form of a pharmaceutical composition containing the compound at a level from 0.1% to 99.5%, preferably from 0.5% on the 90%.

As a carrier you can use one or more auxiliary agents for the preparation of the formulation, such as solid, semisolid and liquid diluent. Preferably, the pharmaceutical composition is injected in a single preparative dosage forms. Because the connection of the present invention is water soluble, it can be used not only in the form of solid formulations, but also in the form of liquid formulations (for example, a composition for intravenous injection, infusion into the bladder, a syrup for oral administration). The pharmaceutical composition can be entered in the tissue or orally, topically (dermal) or rectally. Needless to say that using preparative dosage form, suitable for any of the above ways of doing. For example, preferred is oral or intravenous.

Although it is desirable that the dose as an analgesic can be selected depending on the condition of the patients, including age, body weight, the nature and degree of pain, as well as the route of administration, the daily dose as an active ingredient for an adult ranges from 1 mg to 1000 mg for an adult, preferably from 1 mg to 500 mg per adult human by oral administration, and typically from 1 mg to 100 mg per adult human, predpochtitel is from about 1 mg to 50 mg per adult human when administered intravenously. In some cases it may be sufficient to lower the dose or you may need a higher dose. Usually the dose is administered once or several times, divided into portions, or injected intravenously and continuously during the period from 1 to 24 hours.

Introduction to fabric can be realized when using a single liquid formulation of the dosage form, for example in the form of a solution or suspension of the composition for subcutaneous, intramuscular, into the urinary bladder or intravenous injection. Any of these compounds can be obtained by suspension or dissolution of a certain number of connections in a non-toxic liquid medium such as water or an oil medium that is compatible with the purpose of injection, followed by sterilization of the specified suspension or solution. Alternative a certain number of connections are placed in the ampoule, which is then sterilized together with its contents and then sealed. For reconstitution or mixing immediately before use powdered or lyophilized active ingredient provide additional ampoule or carrier. To obtain isotonic solution for injection it is possible to add a non-toxic salt or salt solution. You can also apply a stabilizer, a preservative, an emulsifier and the like.

The capsule can be obtained by filling a capsule such as a gelatin capsule, particles or powder, which previously were sprayed as described above, or granules obtained as described in the section for tablets. Well as possible before filling mix with the sprayed substance additives, such as lubricant, siaosi agent, such as colloidal silicon dioxide, talc, magnesium stearate, calcium stearate or solid polyethylene glycol. With the aim of increasing the availability of medicines if swallowed capsules can be added disintegrity or solubilizers agent, is the aka as carboxymethylcellulose, calcixerollic, nizkozameshhennoj hydroxypropylcellulose, croscarmellose sodium, carboxymethyl sodium, calcium carbonate or sodium carbonate.

Finely pulverized powder may be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surface-active substance, and then encapsulated in a gelatin shell with getting so soft capsules. The tablet is produced by preparing a powder mixture, turning it into granules or pieces of irregular shape, add disintegrant or lubricant, and then pressed into a pill. The powder mixture is obtained by mixing powdered appropriate substance with a diluent or base as described above, optionally together with a binder (for example, carboxymethylcellulose sodium, hydroxypropylcellulose, methylcellulose, hypromellose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol and the like), moderator dilution (for example, paraffin, wax, utverzhdennym castor oil and the like), a promoter of resorbtive (for example, Quaternary salt) or adsorbent (for example, bentonite, kaolin, calcium diphosphate and the like). The powder mixture can be granulated by wetting with a binder such the AK syrup, starch glue, Arabian gum, a solution of cellulose or polymer solution, and then forcibly put through a sieve. Instead of the above procedure granulating the powder, you can use another method in which the mixture is initially exposed to tabletiruemogo device with the formation of morphologically unfinished pieces, which are then crushed.

Thus obtained granules to prevent any clumping with each other can contain as lubricants stearic acid, stearates, talc, mineral oil and the like. Greased so the mixture is then pressed into tablets.

Thus obtained flat tablets may be film-coated or coated with sugar.

The active ingredient may be mixed with a liquid inert carrier, and then directly subjected to pressing into tablets without the use of the above-described method of granulating or conversion into pieces. You can also use transparent or semi-transparent protective film in the form of shellac sealing film, a film of sugar or polymeric material and a brilliant film of wax.

Other oral medications dosage forms such as solution, syrup and elixir can be retseptoriani in the form of single preparative drug is Orme, a certain amount of which contains a certain amount of drugs. The syrup obtained by dissolution of the compound in a flavored aqueous solution, while elixir is obtained using a non-toxic alcoholic media. The suspension obtained by dispersing the compounds in a non-toxic carrier. If necessary, can be added excipients, such as solubilizers agent, emulsifier (for example, ethoxylated isostearyl alcohols, esters of polyoxyethylenesorbitan), a preservative and flavoring (e.g. mint oil, saccharin).

If desired, a single oral formulation drug formulation can also be encapsulated. This recipe can be film-coated or embedded in a polymer or wax to obtain prolonged activity or slow release of the active ingredient.

Rectal administration can be accomplished with the use of a suppository, which is obtained by mixing the compounds with water-soluble or water-insoluble solid having a low melting point such as polyethylene glycol, cacao butter, higher esters (for example, myristyl palmiet), and mixtures thereof.

The best way of carrying out the invention

Hereinafter the present invention will be described bol is e detail with reference to examples of the preparation of typical starting compounds (Reference examples) examples of obtaining compounds according to the present invention (Examples)examples of compositions and examples of tests that it is not limited. Note that the optical rotation was measured at 20°C.

Reference example 1

N-tert-Butoxycarbonyl-1,6-hexanediamine

A solution of 5.9 g of 1,6-hexanediamine in 30 ml of tetrahydrofuran was combined with 30 ml of 2%aqueous sodium hydroxide solution and cooled to 0°C. This mixture was treated dropwise with a solution of 4.46 g of di-tert-BUTYLCARBAMATE in 30 ml of tetrahydrofuran and stirred for 15 hours, gradually warming to room temperature. The reaction solution was combined with water, extracted with ethyl acetate, dried over sodium sulfate and then concentrated. The residue was purified by chromatography on silica gel, obtaining 3.1 g of the target compound.

The following compounds were obtained in a manner analogous to the method used in referential example 1:

N-tert-Butoxycarbonyl-1,2-Ethylenediamine

N-tert-Butoxycarbonyl-1,3-propandiamine

N-tert-Butoxycarbonyl-1,4-butanediamine

N-tert-Butoxycarbonyl-1,5-pentanediamine

N-tert-Butoxycarbonyl-1,7-heptadien

N-tert-Butoxycarbonyl-1,8-octanediamine

N-tert-Butoxycarbonylmethyl

CIS-N-tert-Butoxycarbonyl-1,2-cyclohexanediamine

TRANS-N-tert-Butoxycarbonyl-1,2-cyclohexanediamine

CIS-N-tre is-Butoxycarbonyl-1,3-cyclohexanediamine

TRANS-N-tert-Butoxycarbonyl-1,3-cyclohexanediamine

CIS-N-tert-Butoxycarbonyl-1,4-cyclohexanediamine

TRANS-N-tert-Butoxycarbonyl-1,4-cyclohexanediamine

Reference example 2

(1S,2R)-2-tert-Butoxycarbonylamino-cyclohexylamin

Stage 1

(1R,2R)-N-tert-Butoxycarbonyl-2-benzyloxycarbonylamino

A solution of 3.0 g of (1R,2R)-2-benzyloxycarbonylamino in 30 ml of tetrahydrofuran was combined with 30 ml of 2%aqueous sodium hydroxide solution and cooled to 0°C. This mixture was treated dropwise with a solution of 4.46 g of di-tert-BUTYLCARBAMATE in 30 ml of tetrahydrofuran and stirred for 15 hours, gradually warming to room temperature. The reaction solution was combined with water and extracted with ethyl acetate. After drying over magnesium sulfate by concentrating the received of 4.45 g of the target compound.

Stage 2

(1R,2R)-N-tert-Butoxycarbonyl-2-hydroxycyclohexyl

A solution of 3.0 g of (1R,2R)-N-tert-butoxycarbonyl-2-benzyloxycarbonylamino in 100 ml of methanol was combined with 300 mg of 5%palladium-on-carbon and was first made at room temperature under atmospheric pressure. After 48 hours of palladium-on-carbon was filtered and the filtrate was concentrated. The residue was subjected to chromatography on silica gel (n-hexane:ethyl acetate = 2:1)to give 2.0 g of the target compound.

Stage 3

(1R,2S)-N-tert-Butoxycarbonyl the Il-2-preliminaryagreement

In an argon atmosphere a solution of 500 mg of (1R,2R)-N-tert-butoxycarbonyl-2-hydroxycyclohexanone in 20 ml of anhydrous tetrahydrofuran was combined with 913 mg of triphenylphosphine and 513 mg phthalimide, was treated dropwise 1,58 ml of 40%solution of diethyl ester of azodicarboxylic acid in toluene under ice cooling and stirred for 24 hours, allowing to slowly warm to room temperature. After removal of the solvent the residue was purified column chromatography on silica gel(n-hexane:ethyl acetate = 2:1)to give 550 mg of the target compound.

Stage 4

(1S,2R)-2-tert-Butoxycarbonyloxyimino

A solution of 2.50 g of (1R,2S)-N-tert-butoxycarbonyl-2-preliminaryagreement in 80 ml of ethanol was combined with 1,82 g of hydrazine hydrate is added and was heated at the boil under reflux for 3 hours. After removal of the solvent the residue was combined with 10%aqueous sodium hydroxide solution and was extracted with chloroform. After concentration the residue was purified column chromatography on silica gel (chloroform:methanol = 10:1)to give 1.60 g of the target compound.

The following compounds were obtained in a manner analogous to the method of reference example 2.

(1R,2S)-2-tert-Butoxycarbonyloxyimino

(1R,2S)-2-tert-Butoxycarbonylmethylene

(1S,2R)-2-tert-Butoxycarbonylmethylene

4-Amino-N-tert-butoxycarbonylamino

Reference example 3

1-tert-Butoxycarbonylamino-6-aminoheptane

Stage 1

6-tert-Butoxycarbonylamino-1-hexanol

A solution of 5.1 g of 6-amino-1-hexanol in 100 ml of chloroform was treated dropwise 10.4 g of di-tert-BUTYLCARBAMATE and was stirred for 12 hours. The reaction solution was concentrated and the residue was washed with n-hexane, obtaining 9,40 g of target compound as white crystals.

Stage 2

6-tert-Butoxycarbonylmethyl

A solution of 1.0 g of b-tert-butoxycarbonylamino-1-hexanol in 20 ml of methylene chloride was combined with 3 g of molecular sieves capacity of 4 Angstrom, 808 mg N-methylmorpholin-N-oxide and a catalytic amount of perruthenate of tetrapropylammonium and was stirred for 24 hours. The reaction solution was filtered through celite and concentrated. The residue was purified column chromatography on silica gel (n-hexane:ethyl acetate = 2:1)to give 660 mg of the target compound.

Stage 3

1-tert-Butoxycarbonylamino-6-hydroxylated

In an argon atmosphere a solution of 650 mg of 6-tert-butoxycarbonylmethyl in 10 ml of anhydrous tetrahydrofuran was cooled to -78°and treated dropwise 6.8 ml of methylacrylamide (1.0 M solution in tetrahydrofuran). After 2 hours the reaction solution was combined with water, extracted with ethyl acetate and dried. After the con is interevene the residue was purified column chromatography on silica gel (n-hexane:ethyl acetate = 2:1), getting 280 mg of the target compound.

Stage 4

1-tert-Butoxycarbonylamino-6-phthalimidomethyl

In an argon atmosphere a solution of 270 mg of 1-tert-butoxycarbonylamino-6-hydroxyethane in 7 ml of anhydrous tetrahydrofuran was combined with 367 mg of triphenylphosphine and 258 mg of phthalimide, was treated dropwise to 0.80 ml of 40%solution of diethyl ester of azodicarboxylic acid in toluene under ice cooling and stirred for 24 hours, allowing to slowly warm to room temperature. After removal of the solvent the residue was purified column chromatography on silica gel (n-hexane: ethyl acetate = 4:1)to give 321 mg of the target compound.

Stage 5

1-tert-Butoxycarbonylamino-6-aminoheptane

A solution of 321 mg of 1-tert-butoxycarbonylamino-6-phthalimidomethyl in 10 ml of ethanol was combined with 89 mg of hydrazine hydrate is added and heated at boiling under reflux for 4 hours. After removal of the solvent the residue was combined with 10%aqueous sodium hydroxide solution and was extracted with chloroform. After drying over sodium sulfate, followed by concentration the residue was purified column chromatography on silica gel (chloroform:methanol = 10:1)to give 202 mg of the target compound.

Reference example 4

CIS-4-Cryptanalytically

Stage 1

Hydrochloride methyl ester CIS-4-AMI is cyclohexanecarbonyl acid

A solution of 2.0 g of CIS-4-aminocyclohexanecarboxylic acid in 20 ml of methanol was combined with 3,57 ml chloride tiomila and was stirred for 3 hours. The reaction solution was concentrated and the residue was washed simple ethyl ether, receiving 2.64 g of the target compound as colorless crystals.

Stage 2

Methyl ester of CIS-4-(tert-butoxycarbonylamino) cyclohexanecarboxylic acid

A solution of 2.64 g of the hydrochloride of the methyl ester of CIS-4-aminocyclohexanecarboxylic acid in 30 ml of chloroform was combined with 1.52 g of triethylamine, and to this solution was added dropwise with 3.27 g of di-tert-BUTYLCARBAMATE. After 3 hours the reaction solution was combined with water, was extracted with chloroform and then dried over magnesium sulfate. The solvent is kept off and the residue was purified column chromatography on silica gel (chloroform)to give 3,62 g of target compound.

Stage 3

CIS-N-(tert-Butoxycarbonyl)-4-hydroxymethylglycinate

In an argon atmosphere a suspension of 1.29 g of sociallyengaged in 40 ml of anhydrous ethyl ether under ice cooling was treated dropwise with a solution 5,80 g of methyl ester of CIS-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid in 20 ml of anhydrous ethyl ether and was stirred for 3 hours, gradually giving the opportunity to warm to room temperature. The reaction process is cooled to 0° With, combined with a small amount of water to decompose the excess sociallyengaged. Insoluble matter was filtered through celite and the filtrate was concentrated, then the residue was washed with n-hexane, obtaining of 3.60 g of the target compound as colorless crystals.

Stage 4

CIS-N-(tert-Butoxycarbonyl)-4-phthalimidophenylmethecrylates

In an argon atmosphere a solution of 3.60 g of CIS-N-(tert-butoxycarbonyl)-4-hydroxyethylnitrosamine in 50 ml of anhydrous tetrahydrofuran was combined with 4.12 g of triphenylphosphine and 2,31 g phthalimide, was treated dropwise at 6.84 ml of 40%solution of diethyl ester of azodicarboxylic acid in toluene under ice cooling and stirred for 15 hours, allowing to slowly warm to room temperature. The solvent is kept off and the residue was purified column chromatography on silica gel (chloroform), receiving of 3.45 g of the target compound.

Stage 5

CIS-N-(tert-Butoxycarbonyl)-4-cryptanalytically

A solution of 3.45 g of CIS-N-(tert-butoxycarbonyl)-4-phthalimidophenylmethecrylates in 35 ml of ethanol was combined from 0.72 g of hydrazine hydrate is added and was heated at the boil under reflux for 5 hours. The solvent is kept off and the residue was combined with 10%aqueous sodium hydroxide solution and was extracted with chloroform. After concentration of RA is solution of the residue in 25 ml of methanol was combined with that of 1.17 g of triethylamine and 1.64 g of ethyl ether triperoxonane acid and was stirred for 15 hours. After concentrating the reaction solution, the residue was purified column chromatography on silica gel (chloroform:methanol = 40:1)to give 2.50 g of the target compound.

Stage 6

CIS-4-Cryptanalytically

A solution of 0.53 g of CIS-N-(tert-butoxycarbonyl)-4-cryptanalytically in methylene chloride was combined with 2 ml triperoxonane acid and was stirred for 2 hours. The reaction solution was podslushivaet the addition of saturated sodium hydrogen carbonate solution and then was extracted with chloroform. After drying over sodium sulfate received 0,19 g of the target compound as pale yellow oil.

The following compound was obtained by a method similar to that described in reference example 4.

CIS-2-Cryptanalytically

Reference example 5

TRANS-N-tert-Butoxycarbonyl-1,4-bis(aminomethyl)cyclohexane

Stage 1

Dimethyl ether of TRANS-1,4-cyclohexanedicarboxylic acid

Under ice cooling 25 ml of methanol was treated dropwise 6 ml of chloride tiomila and was stirred for 1 hour. This solution was combined with 3,44 g of TRANS-1,4-cyclohexanedicarboxylic acid and stirred at room temperature for 20 hours. After concentrating the reaction solution, the residue was combined with ice and podslushivaet by adding 10%water is th solution of sodium hydroxide. The mixture was extracted with chloroform, dried and then concentrated. The residue was washed with n-hexane, obtaining of 3.9 g of the target compound.

Stage 2

TRANS-1,4-Bis(hydroxymethyl)cyclohexane

In a stream of argon suspension 2,96 g sociallyengaged in 100 ml of anhydrous tetrahydrofuran was treated dropwise with a solution of 3.9 g of dimethyl ether of TRANS-1,4-cyclohexanedicarboxylic acid in anhydrous tetrahydrofuran at -20°and was stirred for 2.5 hours. The reaction solution was combined with ice water to complete the reaction and the insoluble matter was filtered through celite. After drying over magnesium sulfate, the residue was concentrated, receiving 2,80 g of target compound.

Stage 3

TRANS-1,4-Bis(phthalimidomethyl)cyclohexane

A solution of 1.60 g of TRANS-1,4-bis(hydroxymethyl)cyclohexane in 200 ml of toluene was combined from 6.98 g of triphenylphosphine, was treated dropwise to 3.92 g phthalimide and 11.58 ml of 40%solution of diethyl ester of azodicarboxylic acid in toluene under ice cooling and stirred for 18 hours. The residue was combined with water, was extracted with chloroform, dried and then concentrated. The residue was washed with ethyl ether and methanol, receiving of 3.53 g of the target compound.

Stage 4

TRANS-N,N-Di-tert-butoxycarbonyl-1,4-bis(aminomethyl) cyclohexane

Suspension 3.50 g of TRANS-1,4-bis(phthalimidomethyl) cycle the hexane in 50 ml of ethanol was combined with 4.35 g of hydrazine hydrate is added and was heated at the boil under reflux for 2 hours. The reaction solution was concentrated, combined with 20 ml of 10%aqueous sodium hydroxide solution and 30 ml of 1,4-dioxane was treated dropwise 6.50 g of di-tert-BUTYLCARBAMATE under ice cooling and then stirred at room temperature for 2 hours. After extraction with chloroform, the extract was dried and concentrated. The residue was washed with n-hexane and dried, obtaining 2,80 g of target compound.

Stage 5

TRANS-N-tert-Butoxycarbonyl-1,4-(aminomethyl)cyclohexane

A solution of 2.75 g of TRANS-N,N'-di-tert-butoxycarbonyl-1,4-bis(aminomethyl)cyclohexane in 40 ml of methylene chloride was combined with 5 ml of 4n. solution of hydrogen chloride in ethyl acetate was stirred at room temperature for 2 hours and then the reaction solution was concentrated. The resulting residue was combined with 40 ml of 10%aqueous sodium hydroxide solution and 20 ml of 1,4-dioxane was treated dropwise 0,90 g of di-tert-BUTYLCARBAMATE under ice cooling and stirred at room temperature for 2 hours. After extraction with chloroform, the extract was dried and concentrated. The residue was purified column chromatography on silica gel (chloroform:methanol = 20:1)to give 0.25 g of the target compound.

The following compound was obtained by a method similar to that described in reference example 5.

CIS-N-tert-Butoxycarbonyl-1,4-bis(aminomethyl is)cyclohexane

Example 1

The dihydrochloride, CIS-N-Amidino-2-[2-(4-chlorostyryl)-6-methoxyquinazoline-4-yl]aminocyclohexanone

Stage 1

CIS-N-tert-Butoxycarbonyl-2-[2-(4-chlorostyryl)-6-methoxyquinazoline-4-yl]aminocyclohexane

A solution of 391 mg of 4-chloro-2-(4-chlorostyryl)-6-methoxyquinazoline, 379 mg of CIS-2-(tert-butoxycarbonyl) aminocyclohexanone and 358 mg of triethylamine in 20 ml of toluene was combined with a catalytic amount of 4-dimethylaminopyridine and was heated at the boil under reflux for 20 hours. After distillation of the reaction solution, the residue was combined with water, was extracted with chloroform, dried over magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel (chloroform:methanol = 50:1)to give 580 mg of the target compound.

Stage 2

CIS-2-[2-(4-Chlorostyryl)-6-methoxyquinazoline-4-yl] aminocyclohexane

A solution of 520 mg of CIS-N-tert-butoxycarbonyl-2-[2(4-chlorostyryl)-6-methoxyquinazoline-4-yl]aminocyclohexanone in 10 ml of methanol was combined with 5 ml of 4n. solution of hydrogen chloride in ethyl acetate and spent interaction at 50°C for 24 hours. After removal of the solvent the residue was podslushivaet by adding 10%aqueous sodium hydroxide solution and was extracted with chloroform. After concentration the residue was purified column chromatography on silica gel (chloroform:meth is Nol = 10:1), getting 378 mg of the target compound.

Stage 3

CIS-N-[N,N'-Bis(tert-butoxycarbonyl)]amidino-2-[2-(4-chlorostyryl)-6-methoxyquinazoline-4-yl]aminocyclohexane

A solution of 400 mg of CIS-2-[2-(4-chlorostyryl)-6-methoxyquinazoline-4-yl]aminocyclohexanone in 5 ml of dichloroethane and 1 ml of N,N-dimethylformamide was combined with 273 mg of N,N'-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine and stirred at room temperature for 15 hours. The reaction solution was combined with water and extracted with ethyl acetate. The organic layer is then washed with water and saturated salt solution and dried over magnesium sulfate. After concentration the residue was purified column chromatography on silica gel (chloroform:methanol = 30:1)to give 580 mg of the target compound.

Stage 4

The dihydrochloride, CIS-N-amidino-2-[2-(4-chlorostyryl)-6-methoxyquinazoline-4-yl]aminocyclohexanone

A solution of 570 mg of CIS-N-[N,N'-bis(tert-butoxycarbonyl)] amidino-2-[2-(4-chlorostyryl)-6-methoxyquinazoline-4-yl] aminocyclohexanone in 8 ml of methanol and 8 ml of chloroform was combined with 5 ml of 4n. solution of hydrogen chloride in ethyl acetate and cooperated with 50°C for 48 hours. After concentrating conducted crystallization from ethyl acetate, getting 310 mg of the target compound as pale yellow crystals.

Cation FAB-mass spectrum (fast atom bombardment) mz: 451[M+H] +.

Elemental analysis data (for C24H27N6ClO·2HCl·H2O

The calculated value (%): 51,48 N: 5,94 N: 15,01

Value found (%): won with 51.75 N: 5,64 N: 15,01

Example 2

The dihydrochloride, CIS-N-amidino-2-[2-(4-chlorbenzoyl)-6-methoxyquinazoline-4-yl]aminocyclohexane

Stage 1

CIS-N-tert-Butoxycarbonyl-2-(2-etoxycarbonyl-6-methoxyquinazoline-4-yl]aminocyclohexane

The solution to 1.96 g of 4-chloro-2-etoxycarbonyl-6-methoxyquinazoline in 70 ml of toluene was combined with 1.58 g of CIS-2-tert-butoxycarbonyloxyimino and 0.74 g of triethylamine was heated at the boil under reflux for 15 hours. After concentrating the mixture was combined with water, was extracted with chloroform and dried. After removal of the solvent the residue was purified column chromatography on silica gel (chloroform)to give 2.70 g of the target compound.

Stage 2

CIS-N-tert-Butoxycarbonyl-2-(2-carboxy-6-methoxyquinazoline-4-yl]aminocyclohexane

A solution of 1.70 g of CIS-N-tert-butoxycarbonyl-2(2-etoxycarbonyl-6-methoxyquinazoline-4-yl)aminocyclohexanone in 5 ml of methanol was combined with 5 ml of 1N. an aqueous solution of sodium hydroxide and stirred at room temperature for 3 hours. After adjusting the pH to 5 by adding to the reaction solution 1N. an aqueous solution of potassium hydrosulfate, it then uh what was strayaway chloroform and dried. After removal of the solvent the residue was purified column chromatography on silica gel (chloroform:methanol = 10:1)to give 1.10 g of the target compound.

Stage 3

CIS-N-tert-Butoxycarbonyl-2(2-ethoxycarbonyl-6-methoxyquinazoline-4-yl)aminocyclohexane

A solution of 1.03 g of CIS-M-tert-butoxycarbonyl-2-(2-carboxy-6-methoxyquinazoline-4-yl)aminocyclohexanone in 10 ml of tetrahydrofuran was combined with 0,82 g diphenylphosphinite, 1,14 g of ethanol and 0.3 g of triethylamine and have interaction in 80°C for 72 hours. The reaction solution was concentrated and then combined with water, was extracted with chloroform and dried. After removal of the solvent the residue was purified column chromatography on silica gel (chloroform:methanol = 50:1)to give 800 mg of the target compound.

Stage 4

CIS-2-(2-Amino-6-methoxyquinazoline-4-yl)amino-N-tert-butoxycarbonyloxyimino

A solution of 300 mg of CIS-N-tert-butoxycarbonyl-2(2-ethoxycarbonyl-6-methoxyquinazoline-4-yl) aminocyclohexanone in 10 ml of methanol was combined with 50 mg of powdered potassium hydroxide and stirred at room temperature for 3 hours. The reaction solution was neutralized by adding saturated aqueous solution of ammonium chloride and then extracted with chloroform and dried. After removal of the solvent the residue was purified column of chromatographie the on silica gel (chloroform:methanol = 10:1), receiving 250 mg of the target compound.

Stage 5

CIS-N-tert-Butoxycarbonyl-2-[2-(4-chlorobenzylamino)-6-methoxyquinazoline-4-yl]aminocyclohexane

A solution of 68 mg of 4-chlorobenzylchloride and 200 mg diisopropylethylamine in 8 ml of methylene chloride was combined with 150 mg of CIS-2-(2-amino-6-methoxyquinazoline-4-yl)amino-N-tert-butoxycarbonyloxyimino and stirred at room temperature for 15 hours. The reaction solution was combined with water, was extracted with chloroform and dried. After removal of the solvent the residue was purified column chromatography on silica gel (chloroform:methanol = 30:1)to give 120 mg of the target compound.

Stage 6

CIS-2-[2-(4-Chlorobenzylamino)-6-methoxyquinazoline-4-yl]aminocyclohexane

A solution of 120 mg of CIS-N-tert-butoxycarbonyl-2-[2-(4-chlorobenzylamino)-6-methoxyquinazoline-4-yl] aminocyclohexanone in 5 ml of methylene chloride was combined with 2 ml triperoxonane acid and cooperated at room temperature for 1 hour. The reaction solution was podslushivaet by adding a saturated solution of sodium bicarbonate, extracted with chloroform and dried. After removal of the solvent the residue was purified column chromatography on silica gel (chloroform:methanol = 30:1)to give 80 mg of the target compound.

Stage 7

CIS-N-[N,N'-Bis(tert-butoxycarbonyl)]amidino-2-[2(4-chloro what benzoylamino)-6-methoxyquinazoline-4-yl]aminocyclohexane

A solution of 80 mg of CIS-2-[2-(4-chlorobenzylamino)-6-methoxyquinazoline-4-yl]aminocyclohexanone in 5 ml of dichloroethane and 1 ml of N,N-dimethylformamide were combined with 58 mg of N,N'-bis(tert-butoxycarbonyl) -1H-pyrazole-1-carboxamidine and stirred at room temperature for 15 hours. The reaction solution was combined with water and extracted with ethyl acetate. The organic layer was washed with water and saturated salt solution and then dried over magnesium sulfate. After concentration the residue was purified column chromatography on silica gel (chloroform:methanol = 30:1)to give 120 mg of the target compound.

Stage 8

The dihydrochloride, CIS-N-amidino-2[2(4-chlorobenzylamino)-6-methoxyquinazoline-4-yl]aminocyclohexane

A solution of 120 mg of CIS-N-[N,N'-bis(tert-butoxycarbonyl) ] amidino-2-[2-(4-chlorobenzylamino)-b-methoxyquinazoline-4-yl] aminocyclohexanone in 5 ml methanol and 5 ml of chloroform was combined with 3 ml of 4n. solution of hydrogen chloride in ethyl acetate and spent interaction at 50°C for 72 hours. After concentrating the spent processing a mixture of methanol-ethyl ether, receiving 22 mg of the target compound as pale yellow powder.

Cation FAB-Macc-spectrum m/z: 468[M+H]+.

Elemental analysis data (for C23H26ClN7O2·2hcl·3H2O)

The calculated value (%): 46,43 N: 5,76 N: 16,48

Found C is Uchenie (%): 46,45 N: 5,55 N: 16,25

Example 3

The dihydrochloride, CIS-N-acetamid-2-[2-(4-chlorostyryl-6-methoxyquinazoline-4-yl]aminocyclohexane

A solution of 50 mg of CIS-2-[2-(4-chlorostyryl)-6-methoxyquinazoline-4-yl]aminocyclohexanone in 8 ml of ethanol was combined with 76 mg of ethylacetamide and 123 mg of triethylamine was heated at the boil under reflux for 3 hours. After concentrating the reaction solution, the residue was purified column chromatography on silica gel (chloroform:methanol:aqueous ammonia = 100:10:1). A solution of 50 mg of the obtained CIS-N-acetamid-2-[2-(4-chlorostyryl)-6-methoxyquinazoline-4-yl]aminocyclohexanone in 3 ml of methanol was combined with 1 ml of 4n. hydrochloric acid in ethyl acetate and stirred for 30 minutes. After concentrating conducted crystallization in a simple ethyl ether, receiving 45 mg of the target compound as pale yellow crystals.

Elemental analysis data (for C25H28ClN5O·2HCl·1,5H2O)

Cation FAB-mass spectrum m/z: 450 [M+H]+

The calculated value (%): 65,28 N: 6,14 N: 12,18

Value found (%): 65,23 N: Of 5.92 N: 12,12

Example 4

Trihydrochloride CIS-4-guanidinate-N-{2[2(2-pyridyl)ethynyl]-6-methoxyquinazoline-4-yl}cyclohexylamine

Stage 1

CIS-4-Triptoreline-N-{2-[2-(2-pyridyl)ethynyl]-6-methoxyquinazoline-4-yl}cyclohexylamin

A solution of 140 mg of CIS-4-TRIFLUOROACETYL is indomethicillin in 15 ml of toluene was combined with 180 mg of 4-chloro-6-methoxy-2-[2-(2-pyridyl)ethynyl] hintline, 500 mg of triethylamine and 20 mg of 4-dimethylaminopyridine and was heated at the boil under reflux for 15 hours. After distillation of the reaction solution, the residue was combined with water and was extracted with chloroform. After drying over magnesium sulfate and concentration, the residue was purified column chromatography on silica gel (chloroform:methanol = 30:1)to give 140 mg of the target compound.

Stage 2

CIS-4-Aminomethyl-N-{2-[2-(2-pyridyl)ethynyl]-6-methoxyquinazoline-4-yl}cyclohexylamin

A solution of CIS-4-triptoreline-N-{2-[2-(2-pyridyl) ethynyl]-6-methoxyquinazoline-4-yl}cyclohexylamine in 45 ml of methanol and 5 ml of water was combined with 414 mg of potassium carbonate and stirred at room temperature for 15 hours. The reaction solution was combined with water, was extracted with chloroform and then dried over sodium sulfate and concentrated. The residue was purified column chromatography on silica gel (chloroform:methanol:aqueous ammonia = 100:10:1)to give 120 mg of the target compound.

Stage 3

Trihydrochloride CIS-4-guanidinate-N-{2-[2-(2-pyridyl)ethynyl-6-methoxyquinazoline-4-yl}cyclohexylamine

A solution of 120 mg of CIS-4-aminomethyl-N-{2[2(2-pyridyl) ethynyl]-6-methoxyquinazoline-4-yl}cyclohexylamine in 15 ml of dichloromethane and 3 ml of N,N-dimethylformamide was combined with 150 mg of N,N'bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine and stirred the at room temperature for 15 hours. The reaction solution was combined with water and extracted with ethyl acetate. The organic layer was washed with water and saturated salt solution and then dried over magnesium sulfate. After concentration the residue was purified column chromatography on silica gel (chloroform:methanol = 30:1). The obtained product was dissolved in 3 ml of methanol was combined with 3 ml of 4n. solution of hydrogen chloride in ethyl acetate and spent interaction at 50°C for 24 hours. The reaction solution was concentrated and then treated with a mixture of methanol-ethyl simple ether, receiving 84 mg of the target compound.

Cation FAB-mass spectrum m/z: 416 [M+H]+.

Appearance: yellow powder.

Example 5

The dihydrochloride of N-2-(2-imidazolyl)-N'-[2-(4-chlorostyryl)-6-methylpyrazole-4-yl]-1,4-cyclohexanediamine

100 mg of N-[2-(4-chlorostyryl)-6-methylpyrazole-4-yl]-1,4-cyclohexanediamine in 10 ml of methanol was combined with 82 mg of 1-tert-butoxycarbonyl-2-methylthio-2-imidazoline and was heated at the boil under reflux for 10 hours. The reaction solution was concentrated and the residue was purified column chromatography on silica gel (chloroform: methanol = 20:1) and obtained by purification of the product was combined with 7 ml of 4n. solution of hydrogen chloride in ethyl acetate and spent interaction at 50°C for 24 hours. After concentrating the spent processing the mixture of meta is ol-ethyl simple ether, receiving 80 mg of target compound. Appearance: white powder

Elemental analysis data (for C26H29ClN6·3HCl·5H2O)

The calculated value (%): 50,75 N: 6,06 N: 13,66

Value found (%): 51,15 N: 5,70 N: 13,47

Compounds of the following examples onset 6 to 48, 52-59, 61, 64-68 got a way similar to that described in example 1.

Example 6

The dihydrochloride of N-amidino-N'-[2-(4-chlorostyryl)hinzelin-4-yl]-1.4-butanediamine

Cation FAB-mass spectrum m/z: 395 [M+H]+

Appearance: pale yellow crystals

Example 7

The dihydrochloride of N-amidino-N'-[2-(4-chlorostyryl)hinzelin-4-yl]-1.5-pentanediamine

Cation FAB-mass spectrum m/z: 409 [M+H]+

Appearance: pale yellow powder

Elemental analysis data (for C22H25ClN6·2HCl·1,5H2O)

The calculated value (%): 51,93 N: 5,94 N: 16,52

Value found (%): 51,99 N: 5,76 N: 16,25

Example 8

The dihydrochloride of N-amidino-N'-[2-(4-chlorostyryl)-6-methylpyrazole-4-yl]-1,6-hexanediamine

Cation FAB-mass spectrum m/z: 437[M+H]+

Appearance: white powder

Example 9

The dihydrochloride of N-amidino-N'-[2(4-chlorostyryl)hinzelin-4-yl]-1,3-propandiamine

Cation FAB-mass spectrum m/z: 381[M+H]+

Appearance: pale red powder

Elemental analysis data (for C20H21ClN6·2HCl·H2O)

The calculated value (%): 50,91 N: ,34 N: 17,82

Value found (%): 50,79 H: 5,07 N: 18,30

Example 10

The dihydrochloride of N-amidino-N'-[2-(4-chlorostyryl)-6-methylpyrazole-4-yl]-1,4-butanediamine

Cation FAB-mass spectrum m/z: 409[M+H]+

Appearance: pale yellow powder

Example 11

The dihydrochloride of N-amidino-N'-[2(4-chlorostyryl)-6-methylpyrazole-4-yl]-1,5-pentanediamine

Cation FAB-mass spectrum m/z: 423[M+H]+

Appearance: white powder

Example 12

The dihydrochloride, CIS-N-amidino-2-[2-(4-chlorostyryl)-6-methylpyrazole-4-yl]aminocyclohexanone

Cation FAB-mass spectrum m/z: 435[M+H]+

Appearance: yellow powder

Elemental analysis data (for C24H27ClN6·3l)

The calculated value (%): 52,96 N: 5,55 N: 15,44

Value found (%): 52,60 N: 5,73 N: 15,77

Example 13

The dihydrochloride of (1R,2S)-N-amidino-2[2(4-chlorostyryl)-6-methylpyrazole-4-yl]aminocyclohexanone

Cation FAB-mass spectrum m/z: 435[M+H]+

Elemental analysis data (for C24H27ClN6·6l·2,5H2O)

The calculated value (%): 52,13 N: 6,20 N: 15,20

Value found (%): 52,40 N: 5,80 N: 15,43

Optical rotation [α]20D=+87,6° (C=1.0, methanol)

Example 14

The dihydrochloride of (1S,2R)-N-amidino-2-[2-(4-chlorostyryl)-6-methylpyrazole-4-yl]aminocyclohexanone

Cation FAB-mass spectrum m/z: 435 [M+H]+

Elemental analysis data (for C2 H27N6Cl·2HCl·2H2O)

The calculated value (%): 53,00 N: 6,12 N: 15,45

Value found (%): 52,95 N: 5,95 N: 15,40

Optical rotation [α]20D=-86,7° (C=1,1, methanol)

Example 15

The dihydrochloride of N-amino-N'-[6-tert-butyl-2-(4-chlorostyryl)hinzelin-4-yl]-1,6-hexanediamine

Appearance: pale red powder

Example 16

The dihydrochloride of N-amidino-N'-[2(4-chlorostyryl)-6-methoxyquinazoline-4-yl]-1,6-hexanediamine

Cation FAB-mass spectrum m/z: 453[M+H]+

Appearance: pale yellow powder

Elemental analysis data (for C24H29ClN6O·2HCl·H2O)

The calculated value (%): 53,00 N: 6,12 N: 15,45

Value found (%): 52,73 N: 5,99 N: 15,64

Example 17

The dihydrochloride of N-amidino-N'-[2-(4-chlorostyryl)-6,7-dimethylpyrazole-4-yl]-1,5-pentanediamine

Cation FAB-mass spectrum m/z: 437[M+H]+

Elemental analysis data (for C24H29ClN6·3HCl)

The calculated value (%): 52,76 N: 5,90 N: 15,38

Value found (%): 52,45 N: 6,12 N: 15,10

Example 18

The dihydrochloride of N-amidino-N'-[2-(4-chlorostyryl)-6-isopropylthiazole-4-yl]-1,6-hexanediamine

Cation FAB-mass spectrum m/z: 465 [M]+

Elemental analysis data (for C26H33ClN6·2hcl·1,4H2O)

The calculated value (%): 55,45 N: 6,77 N: 14,92

Value found (%): 55,50 N: 6,61 N: 14,82

the example 19

The dihydrochloride, CIS-N-amidino-N'-[2-(4-chlorostyryl)-6-methylpyrazole-4-yl]-1,4-cyclohexanediamine

Cation FAB-mass spectrum m/z: 435[M+H]+

Elemental analysis data (for C24H27ClN6·2hcl·2H2O)

The calculated value (%): 53,00 N: 6,11 N: 15,45

Value found (%): 53,50 N: Between 6.08 N: 14,92

Example 20

The dihydrochloride, CIS-N-amidino-2-[2-(4-chlorostyryl)-6,7-dimethylpyrazole-4-yl]aminocyclohexanone

Cation FAB-mass spectrum m/z: 449[M+H]+

Example 21

The dihydrochloride, CIS-N-amidino-3-[2-(4-chlorostyryl)-6-methylpyrazole-4-yl]aminocyclohexanone

Cation FAB-mass spectrum m/z: 435[M+H]+

Elemental analysis data (for C24H27ClN6·2hcl·2H2O)

The calculated value (%): 53,00 N: 6,12 N: 15,45

Value found (%): 52,52 N: 5,79 N: 15,23

Example 22

The dihydrochloride, TRANS-N-amidino-3-[2-(4-chlorostyryl)-6-methylpyrazole-4-yl]aminocyclohexanone

Cation FAB-mass spectrum m/z: 435[M+H]+

Example 23

The dihydrochloride of N-amidino-N'-{6-methoxy-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}-1,6-hexanediamine

Appearance: yellow crystals

Cation FAB-mass spectrum m/z: 420[M+H]+

Elemental analysis data (for C23H29N7O·3HCl·3H2O)

The calculated value (%): 47,39 N: 6,57 N: 16,82

Value found (%): 47,32 N: 6,29 N: 16,89

Example 24

Dihydrochloride the (1R,2S)-N-amidino-2[2(4-chlorostyryl)-6-methoxyquinazoline-4-yl]aminocyclohexanone

Appearance: pale yellow powder

Elemental analysis data (for C24H27ClN6O·2hcl·0,5H2O)

The calculated value (%): 54,09 N: 5,67 N: 15,77

Value found (%): 53,71 N: the ceiling of 5.60 N: 15,65

Optical rotation [α]20D=+81,7° (C=1,1, methanol)

Example 25

The dihydrochloride of (1S,2R)-N-amidino-2-[2-(4-chlorostyryl)-6-methoxyquinazoline-4-yl]aminocyclohexanone

Appearance: pale yellow powder

Cation FAB-mass spectrum m/z: 451 [M+H]+

Elemental analysis data (for C24H27ClN6O·2HCl·H2O)

The calculated value (%): 53,19 N: 5,77 N: 15,51

Value found (%): 53,37 N: 5,54 N: 15,61

Optical rotation [α]20D=-77,6° (C=0.6, methanol)

Example 26

The dihydrochloride of N-amidino-N'-[2(4-chlorostyryl)hinzelin-4-yl]-1,4-bis(aminomethyl)cyclohexane

Appearance: pale red powder

Cation FAB-mass spectrum m/z: 449[M+H]+

Elemental analysis data (for C25H29ClN6·2hcl·N2O)

The calculated value (%): 55,62 N: 6,16 N: 15,56

Value found (%): Of 55.64 N: 6,16 N: 15,02

Example 27

The dihydrochloride of N-amidino-N'-[2-(4-chlorostyryl)benzo[g]hinzelin-4-yl]-1,6-hexanediamine

Cation FAB-mass spectrum m/z: 473[M+H]+

Appearance: orange powder

Elemental analysis data (for C27H29ClN 6·3l·0,5H2O)

The calculated value (%): 54,84 N: 5,62 N: 14,21

Value found (%): 55,11 N: 5,65 N: 14,37

Example 28

The dihydrochloride, CIS-N-amidino-2-[2-(4-chlorostyryl)-6-isopropylthiazole-4-yl]aminocyclohexanone

Cation FAB-mass spectrum m/z: 464 [M+H]+

Elemental analysis data (for C26H31ClN6·2,0l·2H2O)

The calculated value (%): 54,60 N: 6,52 N: 14,69

Value found (%): 54,82 N: 6,20 N: 14,85

Example 29

The dihydrochloride of N-amidino-N'-[2(4-chlorostyryl)-6-methylpyrazole-4-yl]-1,4-bis(aminomethyl)cyclohexane

Cation FAB-mass spectrum m/z: 463[M+H]+

Elemental analysis data (for C26H31ClN6·2hcl·1,5H2O)

The calculated value (%): 55,47 N: 6,45 N: 14,93

Value found (%): 55,81 N: 6,52 N: 14,72

Example 30

The dihydrochloride, CIS-N-amidino-2-[2-(4-chlorostyryl)-6-hydroxyquinazoline-4-yl]aminocyclohexanone

Appearance: pale green powder

Cation FAB-mass spectrum m/z: 437[M+H]+

Elemental analysis data (for C23H25ClN6O·3Hl·1,5H2O)

The calculated value (%): 48,40 N: 5,30 N: 14,37

Value found (%): 48,18 N: The 5.45 N: 14,66

Example 31

Trihydrochloride CIS-N-amidino-2-{6-methyl-2-[2-(4-pyridyl; ethynyl]hinzelin-4-yl}aminocyclohexanone

Cation FAB-mass spectrum m/z: 402[M+H]+

Data element the analysis (for C 23H27N7·3HCl·6H2O)

The calculated value (%): 44,63 N: 6,84 N: 15,84

Value found (%): 45,00 N: 6,59 N: 15,65

Example 32

The dihydrochloride, CIS-N-Amidino-2-[2-(4-chlorobenzylamino)-6-methylpyrazole-4-yl]aminocyclohexanone

Cation FAB-mass spectrum m/z:452[M+H]+

Example 33

The dihydrochloride, CIS-N-amidino-2-[2-(4-chlorostyryl)-6-ethoxyquinoline-4-yl]aminocyclohexanone

Appearance: pale yellow powder

Cation FAB-mass spectrum m/z: 465[M+H]+

Elemental analysis data (for C25H29ClN6O·3HCl·H2O)

The calculated value (%): 51,19 N: 5,86 N: 13,90

Value found (%): 50,69 N: 5,79 N: 14,19

Example 34

Trihydrochloride CIS-N-amidino-2-(6-methoxy-2-[2-(3-pyridyl)ethynyl]hinzelin-4-yl]aminocyclohexanone

Cation FAB-mass spectrum m/z: 418 [M+H]+

Elemental analysis data (for C23H27N7O·3HCl·H2O)

The calculated value (%): 50,70 N: Of 5.92 N: 18,00

Value found (%): 50,57 N: 5,85 N: 17,98

Example 35

Trihydrochloride (1R,2S)-CIS-N-amidino-2{6-methoxy-2[2(3-pyridyl)ethynyl]hinzelin-4-yl}aminocyclohexanone

Cation FAB-mass spectrum m/z: 418[M+H]+

Example 36

Trihydrochloride (1S,2R)-CIS-N-amidino-2-(6-methoxy-2-[2-(3-pyridyl)ethynyl]hinzelin-4-yl]aminocyclohexanone

Cation FAB-mass spectrum m/z: 418[M+H]+

Example 37

D. the hydrochloride (1R,2S)-N-amidino-2[2(4-chlorostyryl)-6-methoxyquinazoline-4-yl]aminocyclopentane

Cation FAB-mass spectrum m/z: 437[M+H]+

Elemental analysis data (for C23H25ClN6O·2hcl·N2O)

The calculated value (%): 52,33 N: 5,54 N: 15,92

Value found (%): 52,72 N: 5,24 N: 16,07

Optical rotation [α]20D=-52,3° (C=1.0, methanol)

Example 38

The dihydrochloride of (1S,2R)-N-amidino-2-[2-(4-chlorostyryl)-6-methoxyquinazoline-4-yl]aminocyclopentane

Cation FAB-mass spectrum m/z: 437[M+H]4'

Elemental analysis data (for C23H25ClN6O·2hcl·N2O)

The calculated value (%): 52,33 N: 5,54 N: 15,92

Value found (%): 52,42 N: 5,34 N: 15,98

Example 39

Trihydrochloride CIS-N-amidino-2-(6-methoxy-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl]aminocyclohexanone

Cation FAB-mass spectrum m/z: 418[M+H]+

Elemental analysis data (for C23H27N7O·3HCl·H2O)

The calculated value (%): 50,70 N: Of 5.92 N: 18,00

Value found (%): 50,58 N: 5,75 N: 18,10

Example 40

Trihydrochloride (1R,2S)-CIS-N-amidino-2-{6-methoxy-2[2(2-pyridyl)ethynyl]hinzelin-4-yl}aminocyclohexanone

Cation FAB-mass spectrum m/z: 418[M+H]+

Example 41

Trihydrochloride (1S,2R)-CIS-N-amidino-2-{6-methoxy-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}aminocyclohexanone

Cation FAB-mass spectrum m/z: 418 [M+H]+

Example 42

Trihydrochloride CIS-N-amidino-2-{6-m the toxi-2[2(4-pyridyl)ethynyl]hinzelin-4-yl}aminocyclohexanone

Cation FAB-mass spectrum m/z: 418 [M+H]+

Example 43

The dihydrochloride, CIS-N-amidino-2-[6-methoxy-2-(2-methoxystyrene)hinzelin-4-yl]aminocyclohexanone

Cation FAB-mass spectrum m/z: 447[M+H]+

Elemental analysis data (for C25H30N6O2·3l)

The calculated value (%): 54,01 N: 5,98 N: 15,12

Value found (%): 54,11 N: 6,22 N: 15,14

Example 44

Trihydrochloride CIS-N-amidino-N'(6-methoxy-2[2(2-pyridyl)ethynyl]hinzelin-4-yl]-1,4-bis(aminomethyl)cyclohexane

Appearance: orange powder

Cation FAB-mass spectrum m/z: 446[M+H]+

Example 45

Trihydrochloride TRANS-N-amidino-N'-{6-methoxy-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}-1,4-bis(aminomethyl)cyclohexane

Appearance: orange powder

Cation FAB-mass spectrum m/z: 446[M+H]+

Example 46

Trihydrochloride N-amidino-N'-{6-methyl-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}-1,6-hexanediamine

Cation FAB-mass spectrum m/z: 404 [M+H]+

Elemental analysis data (for C23H29N7·3l·2H2O)

The calculated value (%): 50,33 N: 6,61 N: 17,86

Value found (%): 50,93 N: 6,69 N: 17,26

Example 47

Trihydrochloride N-amidino-N'-{6-methyl-2[2(2-pyridyl)ethynyl]hinzelin-4-yl}-1,8-octanediamine

Appearance: yellow powder

Cation FAB-mass spectrum m/z: 432[M+H]+

Elemental analysis data (for C25H33 7·3l·N2O)

The calculated value (%): 53,72 N: 6,85 N: comprised 17.54

Value found (%): 53,83 N: 7,03 N: 17,03

Example 48

Trihydrochloride N-amidino-6-{6-methoxy-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}aminoethylamino

Appearance: yellow powder

Cation FAB-mass spectrum m/z: 434 [M+H]+

Elemental analysis data (for C24H31N7O·3HCl·1,5H2O)

The calculated value (%): 65,28 N: 6,14 N: 12,18

Value found (%): 65,23 N: Of 5.92 N: 12,12

Example 49

The dihydrochloride of N-[2-(4-chlorostyryl)hinzelin-4-yl]-N'-(2-pyrimidyl)piperazine

Specified in the title compound was obtained as pale yellow powder in a manner analogous to the method of example 3.

Cation FAB-mass spectrum m/z: 429[M+H]+

Elemental analysis data (for C24H21ClN6·3HCl)

The calculated value (%): 56,33 N: 6,47 N: 11,43

Value found (%): 56,05 N: Of 6.31 N: 11,36

Example 50

The dihydrochloride, CIS-N-[2-(4-chlorostyryl)6-methoxyquinazoline-4-yl]-2-guanidinonaltrindole

Specified in the title compound was obtained in a manner analogous to the method of example 4.

Cation FAB-mass spectrum m/z: 465[M+H]+

Elemental analysis data (for C25H29ClN6O·3HCl)

The calculated value (%): 52,28N: 5,62 N: 14,63

Value found (%): 52,24 N: 5,66 N: 14,27

Example 51

The dihydrochloride of N-2-(2-imidazole the Nile)-N' [2-(4-chlorostyryl)-6-methylpyrazole-4-yl]-1,6-hexanediamine

Specified in the title compound was obtained as a white powder in a manner analogous to the method of example 5.

Melting point: 305°

Example 52

The dihydrochloride of N-[2-(4-chlorostyryl)hinzelin-4-yl]-1,2-academia

Appearance: pale red powder

Cation FAB-mass spectrum m/z: 367[M+H]+

Elemental analysis data (for C19H19ClN6·2hcl·N2O)

The calculated value (%): 49,85 N: 5,06 N: 18,36

Value found (%): 49,97 N: equal to 4.97 N: 18,26

Example 53

The dihydrochloride of N-amidino-N'-[2-(4-chlorostyryl)hinzelin-4-yl]-1,6-hexanediamine

Appearance: white powder

Cation FAB-mass spectrum m/z: 423[M+H]+

Example 54

The dihydrochloride of N-amidino-N'-[2-(4-chlorostyryl)-6-methylinosine-4-yl]-1,6-hexanediamine

Appearance: pale yellow powder

Cation FAB-mass spectrum m/z: 436 [M+H]+

Elemental analysis data (for C25H30ClN5·2hcl·0,7N2O)

The calculated value (%): 57,58 N: 6,45 N: 13,43

Value found (%): 57,48 N: 6,32 N: 13,34

Example 55

The dihydrochloride of N-amidino-N'-[2-(4-chlorostyryl)quinoline-4-yl]-1,6-hexanediamine

Appearance: pale yellow powder

Cation FAB-mass spectrum m/z: 422 [M+H]+

Example 56

The dihydrochloride, CIS-N-amidino-2-[2-(4-chlorostyryl)-6-methylinosine-4-yl]aminocyclohexanone

Appearance: white powder

Cation FAB-mA the-range m/z: 434 [M+H] +

Elemental analysis data (for C25H28ClN5·2HCl·1,5H2O)

The calculated value (%): 56,24 N: 6,23 N: 13,12

Value found (%): 56,14 N: 6,02 N: 13,08

Example 57

The dihydrochloride, CIS-N-amidino-2-[2-(4-chlorostyryl)-6-methoxyquinoline-4-yl]aminocyclohexanone

Appearance: pale yellow powder

Cation FAB-mass spectrum m/z: 450[M+H]+

Elemental analysis data (for C25H28ClN5O·3HCl·H2O)

The calculated value (%): 52,01 N: 5,76 N: 12,13

Value found (%): 52,00 N: 5,59 N: 12,01

Example 58

The dihydrochloride, CIS-N-amidino-2-[3-(4-chlorostyryl)isoquinoline-1-yl]aminocyclohexanone

Appearance: pale yellow powder

Cation FAB-mass spectrum m/z: 420 [M+H]+

Example 59

Trihydrochloride N-amidino-4-{6-methyl-2-[2-(2-pyridyl)ethynyl] hinzelin-4-yl]aminomethyl-benzylamine

Appearance: white powder

Cation FAB-mass spectrum m/z: 424 [M+H]+

Elemental analysis data (for C25H25N7·3HCl·2H2O)

The calculated value (%): 52,78 N: 5,66 N: 17,23

Value found (%): 53,28 N: Are 5.36 N: 17,09

Example 60

Trihydrochloride N-(N-isobutyl-N'-phenyl)amidino-N'-{6-methoxy-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}-1,6-hexanediamine

Stage 1

N-[6-{6-Methoxy-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}amino]hexyl-N'-phenyl-thiourea

A solution of 135 mg of N-{methoxy-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}-1,6-hexanediamine in methylene chloride were combined with 58 mg of phenylisocyanate and stirred at room temperature for 2 hours. After distillation of the reaction solution, the residue was purified column chromatography on silica gel (chloroform:methanol = 50:1)to give 174 mg of the target compound.

Stage 2

N-[6-{6-Methoxy-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}amino]hexyl-N'-phenyl-S-methylisothiazoline

A solution of 10 mg of the compound from stage 1 in 3 ml of methylene chloride was combined with an excess of methyl iodide and stirred for 15 hours. After distillation of the reaction solution, the residue was purified column chromatography on silica gel (chloroform:methanol:aqueous ammonia = 10:1:0,1), receiving 11 mg of the target compound.

Stage 3

Trihydrochloride N(N-isobutyl-N'-phenyl)amidino-N'-{6-methoxy-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}-1,6-hexanediamine

A solution of 11 mg of the compound from stage 2 in 3 ml of ethanol was combined with an excess of isobutylamine and was heated at the boil under reflux for 15 hours. After distillation of the volatile components from the reaction solution, the residue was purified column chromatography on silica gel (chloroform: methanol: aqueous ammonia =10:1:0,1) and then was treated with 4n. a solution of hydrogen chloride in ethyl acetate, receiving 13 mg of the target compound.

Cation FAB-mass spectrum m/z: 552 [M+H]+

Connections the following example 62 example 63 was obtained in a manner analogous to the method of example 60.

Example 61

Trihydrochloride 2 guanidinoacetate-N - {6-methyl-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}ethylamine

Appearance: pale yellow powder

Cation FAB-mass spectrum m/z: 392 [M+H]+

Example 62

Trihydrochloride N-(N-methyl-N'-phenyl)amidino-N'-{6-methoxy-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}-1,6-hexanediamine

Appearance: pale yellow powder

Cation FAB-mass spectrum m/z: 510[M+H]+

Example 63

Trihydrochloride N-(N-ethyl-N'-methyl)amidino-N'-{6-methoxy-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl)-1,6-hexanediamine

Cation FAB-mass spectrum m/z: 462[M+H]+

Example 64

Trihydrochloride 2 guanidinopropionic-N-{6-methyl-2[2(2-pyridyl)ethynyl]hinzelin-4-yl}ethylamine

Appearance: yellow powder

Cation FAB-mass spectrum m/z: 406[M+H]+

Example 65

Trihydrochloride 3 guanidinoacetate-N-{6-methyl-2[2(2-pyridyl)ethynyl]hinzelin-4-yl}Propylamine

Appearance: pale yellow powder

Cation FAB-mass spectrum m/z: 406 [M+H]+

Example 66

Trihydrochloride N-amidino-2-{6-methoxy-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}aminoethyl-phenethylamine

Appearance: yellow powder

Cation FAB-mass spectrum m/z: 468[M+H]+

Elemental analysis data (for C27H29N7O·3HCl)

The calculated value (%): 56,21 N: 5,59 N: 16,99

Value found (%): 55,92 N: 5,59 N: 16.28 per

Example 67

Trihydrochloride TRANS-4-guanidinate-CIS-2-methyl-N-{6-methoxy-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}cyclohexylamin

Appearance: yellow then the shock

Cation FAB-mass spectrum m/z: 446[M+H]+

Elemental analysis data (for C25H31N7O·3Hl·N2O)

The calculated value (%): 49,31 N: 6,62 N: 16,10

Value found (%): 49,60 H: 6.42 Per N: 16,01

Example 68

Trihydrochloride CIS-4-guanidinate-CIS-2-methyl-N-{6-methoxy-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}cyclohexylamine

Appearance: yellow powder

Cation FAB-mass spectrum m/z: 446[M+H]+

Elemental analysis data (for C25H31N7O·3l·2,5H2O)

The calculated value (%): 50,05 N: 6,55 N: 16,34

Value found (%): 49,87 N: 6,30 N: 16,22

Example 69

The dihydrochloride of (1R,2S)-N-amidino-2(2(4-chlorobenzylamino)-6-methoxyquinazoline-4-yl)aminocyclohexanone

Stage 1

(1R,2S)-N-tert-Butoxycarbonyl-2(2-chloro-6-methoxyquinazoline-4-yl)aminocyclohexane

A solution of 710 mg of 2,4-dichloro-6-methoxyquinazoline in 20 ml of methylene chloride was combined with 471 mg of triethylamine and 750 mg of (1S,2R)-2-tert-butoxycarbonyloxyimino and stirred at room temperature for 48 hours. After concentrating the mixture was combined with water, was extracted with methylene chloride and dried. After removal of the solvent the residue was purified column chromatography on silica gel (chloroform:methanol = 20:1)to give 1.20 g of the target compound.

Stage 2

(1R,2S)-N-tert-Butoxycarbonyl-2[2(4-meth is cibenzoline)-6-methoxyquinazoline-4-yl]aminocyclohexane

In an argon atmosphere a solution of 1.75 g of (1R,2S)-N-tert-butoxycarbonyl-2-(2-chloro-6-methoxyquinazoline-4-yl) aminocyclohexanone and 1.47 g of 4-methoxybenzylamine in 100 ml of anhydrous toluene was combined with 97 mg of palladium acetate, 268 mg of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 1.03 g of tert-butoxide sodium and stirred at 70°C for 5 hours. The reaction solution was concentrated and then combined with water, was extracted with chloroform and dried. After removal of the solvent the residue was purified column chromatography on silica gel (chloroform:methanol = 20:1), receiving of 1.62 g of the target compound.

Stage 3

(1R,2S)-N-[N,N'-Bis(tert-butoxycarbonyl)]amidino-2-[2-(4-methoxybenzylamine)-6-methoxyquinazoline-4-yl]aminocyclohexane

A solution of 1.70 g of (1R,2S)-N-tert-butoxycarbonyl-2-[2(4-methoxybenzylamine)-6-methoxyquinazoline-4-yl] aminocyclohexanone in 30 ml of methylene chloride was combined with 10 ml triperoxonane acid under ice cooling and stirred for 2 hours. The reaction solution was neutralized with a saturated solution of sodium bicarbonate, extracted with methylene chloride and dried. After removal of the solvent solution of the residue in 30 ml of methylene chloride was combined with 1.18 g of N,N'-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine and stirred at room temperature for 15 hours. The reaction solution was combined with water, ek who was tragically methylene chloride and dried. After removal of the solvent the residue was purified column chromatography on silica gel (chloroform:methanol = 20:1)to give 1.86 g of the target compound.

Stage 4

(1R,2S)-N-[N,N'-Bis(tert-butoxycarbonyl)]amidino-2-(2-amino-6-methoxyquinazoline-4-yl)aminocyclohexane

A solution of 1.76 g of (1R, 2S)-N-[N,N'-bis(tert-butoxycarbonyl)]amidino-2-[2-(4-methoxybenzylamine)-6-methoxyquinazoline-4-yl] aminocyclohexanone in 80 ml of methylene chloride was combined with 3,17 g N-methylmorpholin-N-oxide and 95 mg of perruthenate of tetrapropylammonium and was stirred for 9 hours. The reaction solution was combined with water, was extracted with methylene chloride and dried. After removal of the solvent the residue was purified column chromatography on silica gel (chloroform:methanol = 10:1)to give 0.95 g of the target compound.

Stage 5

(1R,2S)-N-[N,N'-Bis(tert-butoxycarbonyl)]amidino-2-[2-(4-chlorobenzylamino)-6-methoxyquinazoline-4-yl]aminocyclohexane

A solution of 366 mg of N,N-diisopropylethylamine in 10 ml of methylene chloride was combined with 60 mg of 4-dimethylaminopyridine and 0,156 ml 4-chlorobenzylchloride. This mixture was treated dropwise with a solution of 500 mg of (1R,2S)-N-[N,N'-bis(tert-butoxycarbonyl)]amidino-2-(2-amino-6-methoxyquinazoline-4-yl) aminocyclohexanone in 10 ml of methylene chloride and stirred at room temperature for 3 hours. The reaction solution was combined with water, extrai is ovali methylene chloride and dried. After removal of the solvent the residue was purified column chromatography on silica gel (chloroform:methanol = 30:1)to give 560 mg of the target compound.

Stage 6

The dihydrochloride of (1R,2S)-N-amidino-2{[2-(4-chlorobenzylamino)-6-methoxyquinazoline-4-yl]amino}cyclohexylamine

A solution of 450 mg of (1R,2S)-N-[N,N'-bis(tert-butoxycarbonyl)]amidino-2-[2-(4-chlorobenzylamino)-6-methoxyquinazoline-4-yl] aminocyclohexanone in 5 ml methanol and 5 ml of chloroform was combined with 5 ml of 4n. solution of hydrogen chloride in ethyl acetate and spent interaction at 50°C for 72 hours. After concentrating the spent processing a mixture of methanol-simple ethyl ester, getting 260 mg of the target compound as a colorless powder.

Cation FAB-mass spectrum m/z: 468[M+H]+

Elemental analysis data (for C23H26ClN7O2·2hcl·1,5H2O)

The calculated value (%): 48,64 N: 5,50 N: 17,26

Value found (%): 48,87 N: 5,38 N: 17,29

Optical rotation [α]20D=+64,97 (C=1.0, methanol)

Connection the following example 70 was obtained in a manner analogous to the method of example 69.

Example 70

The dihydrochloride of (1S,2R)-N-amidino-2-{[2-(4-chlorobenzylamino)-6-methoxyquinazoline-4-yl]amino}cyclohexylamine

Cation FAB-mass spectrum m/z: 468[M+H]+

Elemental analysis data (for C23H26ClN7O2•2hclȢ 3H2O)

The calculated value (%): 46,43 N: 5,76 N: 16,48

Value found (%): 46,41 N: 5,56 N: 16,50

Optical rotation [α]20D=+65,98° (C=1.0, methanol)

The test example 1

The analysis of binding nociceptive receptor

Suspension cell membranes obtained from expressing nociceptin human cells, obtained in such a way that it contains from 5 to 10 μg/ml of membrane protein in Tris-buffer (50 mm Tris-HCl (pH 7.8), 5 mm MgCl2, 1 mm EGTA, 0.1% BSA). To this suspension was added a [3N]nociceptin (diluted to a final concentration of 0.08 nm Tris-buffer) and the test substance and the mixture is incubated at 25°C for 60 minutes. Using a cell harvester and wash buffer [50 mm Tris-HCl (pH 7.8), 4°] membranes were isolated on a GF/B filter, which was pre-treated with 0.3% PEI and then further washed 4 times. The filter was transferred into a vial, to which was added the scintillator, and measured the radioactivity using a liquid scintillation counter. Note that the nonspecific binding was considered as binding in the presence of 10 μm nociceptin, and specific binding was obtained by subtracting the nonspecific binding from the total binding. The ratio of inhibition of binding in the presence of the analyte of interest received is IC50and ZAT is used together with the value of K dfor [3N]nociceptin to calculate the values of Kifor the investigated substances. The results are presented in table 1.

Table 1
The test substance

(Example no.)
The affinity to nociceptive receptors Ki(µm)
20,006
40,008
160,009
230,003
440,007
460,003
660,004
680,003

The test example 2

The analysis of binding μ-receptor

The drug expressing μ-receptor cell membrane person (Receptor Biology) received in such a way that it contained an 8.5 μg/ml of membrane protein in Tris-buffer (50 mm Tris-HCl (pH of 7.8), 5 mm MgCl2, 1 mm EGTA, 0.1% BSA). To this suspension was added a [3N] diprenorphine (diluted to a final concentration of 0.13 nm Tris-buffer) and the test substance and the mixture is incubated at 25°C for 90 minutes. Using a cell harvester and wash buffer [50 mm Tris-HCl (pH 7,8), 4°] membranes were isolated on a GF/B filter, which has previously been treated with 0.3% PEI, then further washed 4 times. Filter Perrin is a force for stability in the ampoule, which was added to the scintillator, and measured the radioactivity using a liquid scintillation counter. Note that the nonspecific binding was considered as binding in the presence of 100 μm naloxone, and specific binding was obtained by subtracting the nonspecific binding from the total binding. The ratio of inhibition of binding in the presence of the analyte of interest received is IC50and then used together with the value of Kdfor [3N] diprenorphine to calculate the values of Kifor the investigated substances. The results are presented in table 2.

Table 2
The test substance (Example no.) The affinity to μ-receptor Ki(µm)
20,193
40,063
160,038
230,019
440,030
460,023
660,022
68to 0.032

As can be seen from table 1 and table 2, each connection of the present invention had excellent binding effect against nociceptive receptor.

Example test 3

Test more than what's convulsing with acetic acid in mice

Ten male mice (Slc:ddY, 4-5 weeks of age) were prescribed to each group. The skin on the back of each mouse grafted to the side length of approximately 3 cm and after acclimatization for 30 minutes or longer was put in position around the L3-L4 27G needle attached to the tip of the silicone tubes associated with microspace through which injected 5 μl of a solution of a medicinal product, holding thus the introduction spinal podavlennoe space. The test substance was dissolved in saline and injected at a rate of 10 nmol/animal. In the control group similarly injected with saline.

The mouse, which did not give food the day before the experiment, were placed in the camera (20×20×15 cm), where she was given the opportunity to acclimate for 30 minutes or longer, and then she was injected intraperitoneally with a needle 27G 100 μl per 10 g of body weight of 0.6% solution of acetic acid. The number of convulsive reactions with stretching of the abdominal cavity was calculated for 20 minutes after injection of acetic acid and the obtained data were presented as mean value ± standard error. Only data were tested for significant difference using a t-test between the two groups of control and processing group, or by one-way analysis of variance among the different groups with the settlement of edusim test of multiple comparisons Dannette (Dunnett), and a significant difference was considered as taking place when p<0,05. The results are presented in table 3.

Table 3

Test painful cramps with acetic acid in mice

(Number of seizures)

Vnutriobolochechnoe introduction

Animal No.
SalinePR

10 nmol
PR

10 nmol
PR

10 nmol
PR

10 nmol
10121806
2191128416
3300001
41813014
518130912
623181407
74120130
82710060
916003 0
10026100
1132
120
1325
1420
1533
Average17,67of 7.906,904,50the ceiling of 5.60
Standard error3,00to 2.063,111,522,02

As can be seen from table 3, it was found that each connection of the present invention reduces the number of significant convulsive reactions, thereby manifesting the analgesic (pain relieving) effect.

Example composition 1

100 g of Compound of example 70, 292 g of D-mannitol, 120 g of corn starch and 28 g nitrosamines hydroxypropylcellulose was placed in a fluidized bed granulator (STREA; PAUREC) and was grained with raspy is the group of a certain quantity of a 5%aqueous solution of hydroxypropylcellulose. After drying, and then grinding using a grinding/milling device (COMIL, PAULEC) was mixed with a certain amount of stearate using a mixer (BOHRE container mixer model M, KOTOBUKI-GIKEN) and the mixture was subjected to the action of the rotor teletrauma pressing machine (CORRECT 12HUK; KIKUSUI) for forming tablets of 7 mm diameter each weighing 140 mg per tablet so that the tablet containing 25 mg of the compound of the present invention.

Example composition 2

75 g of Compound of example 70, 180 g of lactose, 75 g of corn starch and 18 g croscarmellose calcium was placed in a mixing granulator (vertical granulator VG-01), combined with a certain amount of a 5%aqueous solution of hydroxypropylmethylcellulose and was granulated, and then dried using a granulating drying in a fluidized bed (STREA; PAUREC), and then crushed using chopping/grinding device (COMIL, production PAULEC). 120 mg of the Crushed material was filled in a capsule No. 3 using the device for filling capsules (capsule filling device; SHIONOGI QUALICAPS), thus receiving a capsule containing 25 mg of the compound of the present invention.

An example of a structure of 3

Was weighed 2.5 g of the compound of example 70 and 4.5 g of sodium chloride was combined with 450 ml of water for injection and stirred dissolved and Dov is Dili to pH 6.5 using solutions of 0.1 mol/l hydrochloric acid and 0.1 mol/l sodium hydroxide. Then add water for injection to achieve a total number of 500 ml. of the resulting solution was filtered under pressure through a membrane filter (pore size: 0.22 μm), and then brown vials with a capacity of 5 ml was filled with 5.3 ml of the composition in aseptic conditions, thus obtaining a composition for injection containing 25 mg of the compound of the present invention. The procedure to obtain by filling was performed in aseptic conditions.

Example of part 4

of 99.75 g UITEPSOL N-15 (produced by HIRTH) was dissolved at 45°and combined with 0.25 g of the compound of example 70 and dispersively using hashing. This mixture while it was still hot, carefully to prevent sedimentation was introduced in the form 1 g suppository, utverjdali and removed from the mold, thus obtaining the suppository contains 25 mg of the compound of the present invention.

Industrial applicability

Because the connection of the present invention has an excellent ability of binding to nociceptive receptor, it can safely be used over an extended period of time against pain-causing diseases, such as pain, migraine, rheumatoid arthritis and neuralgia, and as an agent for overcoming resistance to morphine or the like.

1. The connection represented by the th following General formula (1):

where X and Y are the same or different, and each represents a nitrogen atom or CH;

R1represents a hydrogen atom or alkyl;

And1and2are the same or different, and each represents (1) a single bond or (2) divalent aliphatic hydrocarbon group which may be substituted and may contain 1-3 bonds in any position (such aliphatic hydrocarbon group may contain one heteroatom selected from the group consisting of-NH and Oh);

Q represents (1) a single bond, (2) optionally substituted 3-8-membered cycloalkenyl group, or (3) optionally substituted fenelonov group;

R2A, R2Cand R2Dare the same or different, and each represents a hydrogen atom, alkyl or phenyl, R2Brepresents a hydrogen atom, alkyl, cyano, nitro or phenyl, or two nitrogen atom guanidino groups form a loop with one or two substituents R2B, R2Cand R2Dwith the formation of a saturated or unsaturated 5 - or 6-membered ring;

or taken together form-N(R1)-A1-Q-A2-N(R2A)- with the formation of a 5-7-membered ring;

E represents (1) attilan, (2) -NRC-, (3) -NRCONH-, (4) -CONR-, (5) or ethynylene (7) aminoalkyl (where R represents hydrogen or optionally substituted alkyl);

R3represents an optionally substituted phenyl group or a 4-to 8-membered monocyclic or condensed ring containing 1-2 heteroatoms selected from the group consisting of NH, oxygen and sulfur, and may have 1-4 bonds, and

R4and R5(1) are the same or different, and each represents a hydrogen atom, alkyl, alkoxy, halogen, nitro, hydroxy, alkoxycarbonyl, -NR6R7, -NR6COR7, -CONR6R7(in which R6and R7are the same or different, and each represents a hydrogen atom or alkyl), or (2) when they are adjacent to each other, together form-O(CH2)nO- (where n is an integer 1 or 2) or-CH=CH-CH=CH-,

or its salt.

2. The compound according to claim 1, where a1and/or And2are alkylene, which can be substituted by the Deputy selected from the group consisting of alkyl, carbamoyl, monoalkylammonium, dialkylamino, hydroxy, alkoxy and trifloromethyl.

3. The compound according to claim 1, where a1and/or And2are alkylene, which can be substituted by the Deputy selected from the group consisting of the of Lila, hydroxy, alkoxy and trifloromethyl.

4. The compound according to claim 1, where Q is a 4-8-membered cycloalkenyl group which may be substituted by the Deputy selected from the group consisting of alkyl, alkoxycarbonyl, carbamoyl, monoalkylammonium, dialkylamino and alkoxy.

5. The compound according to claim 1, where Q is a 5-7-membered cycloalkenyl group which may be substituted by the Deputy selected from the group consisting of alkyl, alkoxycarbonyl and alkoxy.

6. The compound according to claim 1, where Q is fenelonov group which may be substituted by the Deputy selected from the group consisting of alkyl, alkoxy, alkoxycarbonyl, carbamoyl, monoalkylammonium, dialkylamino, sulfamoyl, monoalkylphenol, dialkylamino, amino, monoalkylamines, dialkylamino, nitro, halogen, cyano and trifloromethyl.

7. The compound according to claim 1, where Q is fenelonov group which may be substituted by the Deputy selected from the group consisting of alkyl, alkoxy, alkoxycarbonyl, carbamoyl, monoalkylammonium, dialkylamino, amino, monoalkylamines, dialkylamino, nitro, halogen, cyano or trifloromethyl.

8. The compound according to claim 1, where Q is fenelonov group which may be substituted by the Deputy selected from the group consisting of alkyl is, alkoxy, alkoxycarbonyl, amino, monoalkylamines, dialkylamino, nitro, halogen, cyano or trifloromethyl.

9. The compound according to claim 1, where R3represents a phenyl group or a 4-to 8-membered monocyclic or condensed ring containing 1-2 heteroatoms selected from the group consisting of NH, oxygen and sulfur, and may have 1-4 bonds, which can be substituted by the Deputy selected from the group consisting of alkyl, alkoxy, alkoxycarbonyl, carbamoyl, monoalkylammonium, dialkylamino, sulfamoyl, monoalkylphenol, diallylsulfide, alkylsulfonyl, N-(alkyl)alkylsulfonyl, amino, monoalkylamines, dialkylamino, nitro, halogen, cyano, hydroxy and trifloromethyl.

10. The compound according to claim 1, where R3represents a phenyl group or a 4-to 8-membered monocyclic or condensed ring containing 1-2 heteroatoms selected from the group consisting of NH, oxygen and sulfur, and may have 1-4 bonds, which can be substituted by the Deputy selected from the group consisting of alkyl, alkoxy, alkoxycarbonyl, amino, monoalkylamines, dialkylamino, nitro, halogen, cyano, hydroxy and trifloromethyl.

11. The compound according to claim 1, where-N(R1)-A1-Q-A2-N(R2Ais a 5-7-membered ring.

12. The compound according to claim 1, where in the General forms of the Le (1) each of X and Y represents a nitrogen atom, R1represents a hydrogen atom or alkyl, And1and2are the same or different, and each represents (1) a single bond or (2) optionally substituted alkylene, Q represents (1) a single bond, (2) optionally substituted 4-to 8-membered cycloalkenyl group, or (3) optionally substituted fenelonov group, R2A, R2B, R2Cand R2Dare the same or different, and each represents a hydrogen atom, alkyl or phenyl, or taken together form-N(R1)-A1-Q-A2-N(R2A- form a 5-7 membered ring, E represents (1) attilan, (2) -NRCO -, or (3) -CONR-, and R4and R5(1) are the same or different, and each represents a hydrogen atom, alkyl, alkoxy, halogen, nitro, hydroxy or alkoxycarbonyl, or (2) when they are adjacent to each other, together form-O(CH2)nO- (where n is an integer 1 or 2) or-CH=CH-CH=CH-.

13. The compound according to claim 1, where in the General formula (1) each of X and Y represents a nitrogen atom, R1represents a hydrogen atom, And1and2are the same or different, and each represents (1) a single bond or (2) optionally substituted alkylene, Q represents (1) a single bond, (2) optionally substituted 5-7 member is nnow cycloalkenyl group, (3) optionally substituted fenelonov group, R2A, R2B, R2Cand R2Dare the same or different, and each represents a hydrogen atom, alkyl or phenyl, E is a (1) ethenylene or (2) -NRCO-, and R4and R5are the same or different, and each represents a hydrogen atom, alkyl, alkoxy, halogen or nitro.

14. The compound according to claim 1, where in the General formula (1) each of X and Y represents a nitrogen atom, R1represents a hydrogen atom, And1and2are the same or different, and each represents a single bond or optionally substituted alkylene, Q represents a single bond or optionally substituted 5-6-membered cycloalkenyl group, R2A, R2B, R2Cand R2Dare the same or different, and each represents a hydrogen atom or alkyl, or taken together form-N(R1)-A1-Q-A2-N(R2A)- with the formation of a 5-6-membered ring, E represents ethenylene or-NRCO-, and R4and R5are the same or different, and each represents a hydrogen atom, alkyl or alkoxy.

15. The compound according to claim 1, where the compound is a compound selected from the group consisting of dihydrochloride of (1S,2R)-N-amidino-2-{[2-(4-chlorobenzylamino)-6-methoxyquinazoline-4-the l]amino}cyclohexylamine, trihydrochloride N-amidino-2-[6-methoxy-4-{2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl)aminoethyl]phenethylamine, trihydrochloride CIS-4-guanidinate-CIS-2-methyl-N-{6-methoxy-2-[2-{2-pyridyl)ethynyl]hinzelin-4-yl}cyclohexylamine, trihydrochloride N-amidino-N'-{6-methyl-2-[2-(2-pyridyl)ethynyl]hinzelin-4-yl}-1,6-hexanediamine, dihydrochloride (1S,2R)-CIS-N-amidino-2-{[2-(4-chlorostyryl)-6-methoxyquinazoline-4-yl]amino} cyclohexylamine and trihydrochloride N-amidino-N'-{6-methoxy-2-[2-(2-pyridyl) ethynyl]hinzelin-4-yl}-1,6-hexanediamine or their salts.

16. Pharmaceutical composition having an analgesic effect, comprising as active ingredient a compound represented by the General formula (1) according to claim 1 or its salt.

17. Analgesic agent comprising as an active ingredient the compound represented by General formula (1) according to claim 1 or its salt.

Priority signs of the radicals R2a, R2D, R2c, R2B- representing phenyl - from 02.11.2000. Priority signs of the radical R2Brepresenting CN, NO2; R4and R5-NR6COR7when R6=hydrogen from 31.03.2000 and 02.11.2000, at other values of radicals from 30.03.2001. Priority signs E, representing-NRCONH-, CONR-, ethynylene, aminoalkyl, -NRCO-, in which R represents optionally substituted alkyl - dated 30.03.2001. Priority signs-NRCO-, g is e R=H - from 31.03.2000 and 02.11.2000. Priority signs of the remaining radicals from 31.03.2000 and 02.11.2000.



 

Same patents:

FIELD: organic chemistry, chemical technology, herbicides, agriculture.

SUBSTANCE: invention relates to new sulfonamides of the formula (I):

and their salt wherein A represents substituted or unsubstituted benzene ring or 5-membered, or 6-membered substituted or unsubstituted heteroaromatic ring taken among the group comprising thienyl, pyrazolyl, imidazolyl, pyridyl wherein optional substitutes are taken among the group consisting of halogen atom, substituted or unsubstituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy-group, nitro-group, phenyl, phenoxy-group, benzoyl and (C1-C4)-alkylcarboxylate when any alkyl fragment in the latter indicated substituted is substituted with one or some halogen atoms, (C1-C4)-alkoxy-groups, cyano-group and phenyl; Q represents -O-, -S- or group of the formula: -CXX' wherein X and X' can be similar or different and each represents hydrogen atom, halogen atom, cyano-group, alkyl comprising 1-8 carbon atoms, or the group -ORa, -SRa; or one of X and X' represents hydroxy-group and another has values determine above; Ra means (C1-C8)-alkyl, phenyl; Rb means (C1-C8)-alkyl, phenyl; Y means nitrogen atom or the group CR9; R1 means unsubstituted (C1-C8)-alkyl or that substituted with halogen atom, cyano-group, phenyl or (C1-C4)-alkoxycarbonylamino-group, or it represents phenyl; R2 means hydrogen atom (H), (C1-C4)-alkyl; R3 and R4 can be similar or different and each represents (C1-C4)-alkyl, (C1-C4)-alkoxy-group, halogen atom; R9 means hydrogen atom (H) under condition that when Q represents oxygen atom (O) or -S- then ring A represents 5-membered substituted or unsubstituted heteroaromatic ring and determined above. Compounds of the formula (I) possess the herbicide activity that allows their using for eradication of weeds. Also, invention describes a method for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable properties of compounds.

9 cl, 5 tbl, 18 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds that inhibit binding ligands with α4β1-integrin (VLA-4) selectively. Compounds have the formula (I):

wherein W means unsubstituted phenyl or phenyl substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom, (C1-C4)-alkoxy-group and halogen alkyl; W1 means unsubstituted phenylene or phenylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, pyridylene, pyridylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, 2-oxopyrrolylene or thiazolylene; A means oxygen atom (O); R means -(CH2)n- wherein n = 1 or 2; X means -C(O)-; M is taken among the following groups: a)

wherein means divalent 5- or 6-membered heterocyclic radical wherein nitrogen atom is located in the joining point to X wherein Q represents -CH2-, -O- or -S-; R1, R2 and R3 are taken independently among the group involving: hydrogen atom (-H), hydroxyl group (-OH), quinolinyloxy-group, -NH2, mono- or dialkylamino-group, (C1-C6)-alkylsulfonylamino-, arylsulfonylamino-, naphthyloxy-, phenyloxy-group substituted optionally with di-(C1-C6)-alkylamine, (C1-C6)-alkyl, benzyloxymethyl, halogen atom, phenyl, (C1-C4)-alkoxy-group; or two adjacent R1, R2 and R3 taken in common can form alkylene- or alkylenenedioxy-group substituted optionally with 1-3 alkyl groups; R4 means hydrogen atom (H), lower alkyl; Y is taken among a bond, (C2-C8)-alkenylene group, (C2-C8)-alkynylene group, -C(O)-, -C(O)NH- and -(CH2)kY2 wherein k is taken among 1, 2 and 3; Y2 means a direct bond or divalent radical taken among -O-, -S-, -S(O)-, -S(O)2- and -NY3- wherein Y3 is taken among hydrogen atom (H), lower alkyl; Z means (C3-C8)-cycloalkylene, optionally substituted phenylene, pyridylene, piperidylene, piperazinylene; A1 means a direct bond, -(CH2)t-alkynyl wherein t is taken among 1, 2 and 3; R5 means -OH, lower alkoxy-group, , ; b) means wherein R11 is taken among , -NR12- wherein R12 is taken among hydrogen atom (-H), optionally substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl; Z3 is taken among a direct bond, (C1-C12)-alkyl wherein one or some carbon atoms can be replaced with -O- or -NR13- wherein R13 means hydrogen atom (-H), lower alkyl, wherein x = 0 or 1; y = 1, 2 or 3; R14 means hydrogen atom (-H), ; and when R11 means NR12 then Z3 is taken among: wherein 14Ra means hydrogen (H), halogen atom; , and ; Q2 means wherein R17 and R18 mean hydrogen atom (H), lower alkyl; or phenylene that can be substituted; L1 means -COOH or -COOR19 wherein R19 means lower alkyl. Compounds of the formula (I) inhibit activity of VLA-4-mediated adhesion of cells that allows their using in pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and compositions.

21 cl, 11 tbl, 283 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: organic chemistry, insecticides, chemical technology.

SUBSTANCE: invention describes derivative of 1-aryl-3-cyano-5-heteroarylalkylaminopyrazole of the general formula (1): wherein A means: (A-1) , (A-2) , (A-3) and (A-4) and wherein X represents C-halogen; R1 represents (C1-C4)-alkyl group or halogen-(C1-C4)-alkyl group; A represents any group among (A-1) - (A-4) wherein R4 represents hydrogen atom or (C1-C4)-alkyl group; n = 0, 1 or 2 under condition that R1 represents halogen-(C1-C4)-alkyl group with exception for perhalogenalkyl group when A represents (A-1) and n = 0, and that n doesn't equal 0 when A represents (A-4). Also, invention describes derivative of pyrazole of the formula (2): wherein A means: (A-1) and Y means: (Y-1) , (Y-2) and (Y-3) wherein X, R2, R3 and R4 have values given above; R5 represents hydrogen atom; A represents (A-1); Y means any group among (Y-1) - (Y-3); Z represents halogen atom that are intermediate compounds used for synthesis of the compound (1). Invention describes methods for preparing compounds of the formula (1) and (2) and insecticide comprising compound of the formula (1) as an active component. Insecticide shows high systemic activity, high safety and reduced harmful effect on environment in vicinity areas of its applying.

EFFECT: improved methods for preparing, valuable insecticide properties of compound.

11 cl, 9 tbl, 19 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new derivatives of acridine of the formula (1):

wherein R, R1, R2 and R3 mean hydrogen atom; Z means oxygen or sulfur atom; X means nitrogen atom or C-R5 wherein R5 means hydrogen atom; n = 2; m = 0; R4 means (C1-C3)-alkyl residue that can be substituted with aryl, (C4-C10)-heteroaryl and other substitutes, (C6-C10)-aryl and others, and to their pharmaceutically acceptable salts. Compounds of the formula (1) possess an anti-tumor activity and can be used as an active component of the medicinal agent.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

9 cl, 1 tbl, 20 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to substituted derivatives of N-benzylindol-3-yl-glyoxylic acid of the formula (1): wherein groups R, R1, R2, R3, R4 and Z have the following values: R means -NO2, -NH2, (C1-C6)-acylamino-, aroylamino-, nicotinoyl or isonicotinoyl, arylsulfonylamino-, succinimido- wherein this residue R can be substituted with (C1-C6)-group by choosing by carbon atom at positions 2, 3 and 4 of phenyl ring; R1 means hydrogen atom (H), (C1-C6)-alkyl that can be replaced with at least one phenyl group; R2 means pyridyl; R3 and R4 mean H; Z means oxygen (O), sulfur (S) atom. Compounds of the formula (1) possess an antitumor effect that allows their using in pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and compositions.

6 cl, 2 dwg, 3 tbl, 9 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new heteroaryl derivatives, in particular, derivatives of quinoline of he general formula (I): wherein R, R1, R2 and R3 are similar or different and mean independently of one another hydrogen atom, linear or branched (C1-C8)-alkyl, halogen atom, aryl-(C1-C8)-alkoxy-group, aryl. Except for, R and R1 or R2 and R3 can form six-membered aromatic ring condensed with quinoline residue; X means oxygen atom; p, Q mean in each case -CH2-; X means nitrogen atom; n = 2; m = 0; R4 means phenyl or pyridyl. Also, invention relates to their pharmaceutically acceptable salts, in particular, acid-additive salts. Compounds are useful as antitumor agents. Also, invention describes a method for preparing compounds and medicinal agent based on thereof.

EFFECT: improved preparing method, valuable medicinal properties of compounds and agent.

11 cl, 2 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted indole compounds of Mannich bases of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C10)-alkyl, unsubstituted phenyl or naphthyl bound through (C1-C2)-alkylene group or that monosubstituted at least with hydroxy group (-OH), halogen atom, -CF3, -CN, (C1-C6)-alkyl, (C1-C6)-alkoxy group; R2 means atoms H, F, Cl, Br, groups -CF3, -CN, -OR10, -CO(OR11), -CH2CO(OR12), -COR19, (C1-C10)-alkyl, unsubstituted phenyl or naphthyl, or that monosubstituted at least with -OH, halogen atom, -CF3, -CN, (C1-C6)-alkyl and (C1-C6)-alkoxy group; R3 means -CH(R13)N(R14)(R15); R4, R5, R6 and R7 can have similar or different values and mean atoms H, F, Cl, Br and groups -CF3, -CN, -NO2, -OR10 and others; R10 means H, -COR17, (C1-C6)-alkyl and others; R13 means unsubstituted phenyl or phenyl monosubstituted with at least (C1-C4)-alkyl, halogen atom, -CF3, -CN and -OH; R14 and R15 can have similar or different values and mean unbranched or branched (C1-C6)-alkyl, or R14 and R15 represent in common (CH2)n wherein n means a whole number from 3 to 6, or (CH2)O(CH2)2; R17 means (C1-C6)-alkyl; R19 means -NHR20, (C1-C6)-alkyl and others; R20 means H, (C1-C6)-alkyl and others, and/or their racemates, enantiomers, diastereomers and/or corresponding bases, and/or corresponding salts of physiologically acceptable acids with exception of racemates of some compounds given in claim 1. Also, invention describes method for their preparing and using as a medicinal agent possessing analgesic effect.

EFFECT: valuable medicinal properties of compounds.

42 cl, 2 dwg, 3 tbl, 103 ex

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):

wherein Y means lower alkylene; R1 means phenyl with 1 or 2 substitutes taken among group consisting of trihalogen-(lower)-alkyl, halogen atom, lower alkylamino-, di-(lower)-alkylamino- and nitro-group; R2 means phenyl or indolyl and each comprises 1 or 2 substitutes taken among group consisting of lower alkyl, trihalogen-(lower)-alkyl, lower alkylene dioxy-, hydroxy-group, hydroxy-(lower)-alkyl, lower alkoxy- lower alkylamino- and di-(lower)-alkylamino-group; R3 means hydrogen atom; R4 means morpholinyl-(lower)-alkyl comprising 1 or 2 substitutes taken among group consisting of ethyl, hydroxy-(lower)-alkyl, halogen-(lower)-alkyl and lower alkoxy-(lower)-alkyl, or morpholinyl-(lower)-alkynyl that can comprise 1 or 2 substitutes taken among group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo-(lower)-alkyl, lower alkoxy-(lower)-alkyl, hydroxy-(lower)-alkyl, carboxy-(lower)-alkyl, di-(lower)-alkyl-carbamoyl, lower alkoxycarbonyl and halogen-(lower)-alkyl. Also, invention relates to a method for preparing, pharmaceutical composition based on these compounds and a method for treatment of tachykinine-mediated diseases, such as respiratory diseases, ophthalmic, cutaneous, inflammatory diseases, and as analgetic agents. Describes compounds are antagonists of tachykinine.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 94 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

9 cl, 47 ex

The invention relates to a new inhibitor of serine proteases of the formula (I):

in which J is an R1, R1-SO2-, R3OOC-(CHR2)p- or (R2aR2b)N-CO-(CHR2)P-;D is an amino acid of formula-NH-CHR1-C(O) -, or-NR4-CH[(CH2)qC(O)OR1]-C(O)-; E is-NR2-CH2or fragment

R1selected from (1-12C)alkyl, (3-12C)cycloalkyl and (3-12C)cycloalkyl(1-6C)alkylene, groups which are optionally substituted (3-12C)cycloalkyl, and from (14-20C)(biaryl)alkyl; each of R2, R2Aand R2bindependently selected from H, (1-8C)alkyl, (3-8C)cycloalkyl and (6-14C)aryl; R3has the same values, which is defined for R2; R4represents H; X and Y are CH; m is 1 or 2; p is 1, 2 or 3; q is 1, 2 or 3; t is 2, 3 or 4; or N-alkoxycarbonyl-substituted derivative; and/or its pharmaceutically acceptable salt additive and/or MES
Up!