Derivatives of bis-benzo - or benzopyrano-cycloheptatriene, piperidylidene and piperazine and pharmaceutical composition based on them

 

(57) Abstract:

Usage: in medicine as antagonists of platelet activating factor and histamine. The inventive products: derivatives of bis-benzo - or benzopyrano-cycloheptatriene, piperidylidene and piperazine f-crystals of l, where Z is the group-CH2-Y-, where Y is CH2-, -O - or-S-, -CH=CH-, -O - or a bond, L is a N atom or the group N+-O-X - atom or the CH group, T is a nitrogen atom or a carbon atom , R1is hydrogen, lower alkyl, R2is hydrogen or halogen - - - the presence or absence of communication. Reagent 1. Connection f-ly ll. Reagent 2 connection f-lll ly. Reaction conditions: inert organic solvent in the presence of a base. 2 S. p. f-crystals, 6 PL.

The invention relates to a derivative of bis-benzo - or benzopyrano-piperidine, piperidylidene and piperazine, which are particularly useful as antagonists of platelet-activating factor and antihistamine, and their pharmaceutical compositions, methods of use of these derivatives and the way they are received.

The invention relates to new derivatives of bis-benzo - or benzopyrano-cyclohepta-piperidine, piperidylidene and piperazine of General formula (l)

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X is a nitrogen atom, a group CH or NR12where R12means an oxygen atom or methyl (experts it is clear that if R12methyl nitrogen has a positive charge and therefore there is a pharmaceutically acceptable counterion: suitable counterions are widely known, as examples of the halides (Br-I , J-, Cl-, F-), NaSO-4, KSO-4, alkyl-SO-3aryl-SO-3alkyl-COO-, aryl-COO-and the like);

R1, R2, R3and R4the same or different and independently from each other mean a hydrogen atom or halogen, trifluoromethyl, group OR11, -C(=O)R11, -SR11, -S(O)eR13where e is 1 or 2, -N(R11)2, -NO2, -CO(=O)R11, -CO2R11, -OCO2R13, -NR11C(= O)R11, cyano, alkyl, unsubstituted or substituted groups, OR11, -SR11, -N(R11)2and-CO2R11, aryl, alkenyl, unsubstituted or substituted by halogen, a group OR13or-CO2R11;

R1and R2together may form a benzene ring, precondensation to the ring t and/or R3and R4together can form benzoin the keel, unsubstituted or substituted by groups OR11, -SR11and-N(R11)2, R5together with R6can oznaczania S;

R7, R8and R9independent and mean a hydrogen atom or halogen, trifluoromethyl, nitro, cyano, groups OR11, -C(O)R11, -SR11, -S(O)eR13where e is 1 or 2, -N(R11)2, -CO2R11, -OCO2R13, -OCOR11where e is 1 or 2, -N(R11)2, -CO2R11, -OCO2R13, -OCOR11, alkyl, unsubstituted or substituted groups, OR11, -SR11, -N(R11)2and-CO2R11, aryl, alkenyl, unsubstituted or substituted by a halogen atom or a group-OR13or-CO2R11or alkenyl, m and n are 0, 1 or 3 so that the sum of m + n is 0, 1 or 3, and if m+n is 0, Y represents-O-, -S(O)e- where e denotes 0, 1 or 2, -NR11or a direct link, if m+n is equal to 1, Y represents-O-, -S(O)ewhere e denotes 0, 1 or 2, or-NR11if m+n is 3 then Y represents a direct bond;

R10a hydrogen atom or alkyl;

the radicals R11independent and mean a hydrogen atom, alkyl or aryl;

the radicals R13independent and mean alkyl or aryl;

indicate a hydrogen atom or lower alkyl;

j 1, 2 or 3;

T CH, C or N, and the dotted line associated with radical T, means a double bond, if the radical T denotes the carbon atom, as in the case of T=CH or N, the dashed line is absent, if the radical Z means the rest

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the dashed line between carbon atoms 5 and 6 may indicate a double bond, while in the case of the double bond of the radicals A and B are independent and mean a halogen atom or a group R11, OR13or-OC(O)R11and in case of its absence the radicals A and B are independent and mean H2, -(OR13)2, (alkyl and H, (alkyl)2(The-H and-OC(O)R11), (H-OR11O NOR14provided that if Z means

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X represents CH, T means C and the associated dashed line represents a double bond then L is N+O-or their pharmaceutically correct salt or MES.

The above radicals have the following preferred values.

R1, R2, R3and R4independent and mean a hydrogen atom or halogen, alkyl, N(R11)2and-OR11, R5and R6independent and mean a hydrogen atom or lower alkyl, R7and R6means a hydrogen atom, R9means an atom of water which in particular means a hydrogen atom, T denotes the nitrogen atom or carbon, L mean N-oxide (i.e., N+O-), and L in particular is in the para-position relative to the connection between the pyridine ring (the ring w and the remainder of the molecule proposed connection j is 1, R10means a hydrogen atom or lower alkyl.

According to one variant of the invention, the radical Z means a group of the formula

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Thus the new compounds have the following formula La

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where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, A, B, T and L have the above formula for l values. This option also relates to pharmaceutically acceptable salts or MES compounds of formula La.

In the case of formula La double bond between carbon atoms 5 and 6 is missing, both radicals A and B denote H2or one of them means (H and OH) on the same carbon atom or oznachaet, and other means of H2. The radicals R5and R6independent and mean a hydrogen atom or lower alkyl. R1, R2, R3and R4independent and mean a hydrogen atom or halogen, alkyl, N(R11)2and OR11. The radicals R7and R8means a hydrogen atom, and lower alkyl, in particular a hydrogen atom. T preferably means a nitrogen atom or carbon, L is preferably in the para-position relative to the connection between the pyridine ring and the rest of the molecule compounds, j means preferably 1, and R10preferably means hydrogen atom.

According to a preferred variant of the invention the new compounds have the following formula lb

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in which the dashed line may represent a double bond, X is CH, N or N+O-;

R7and R8independent and mean a hydrogen atom or halogen, alkyl, aryl, alkenyl, quinil, trifluoromethyl, group OR11, -SR11, -N(R11)2,

provided that L is N+O-if X is CH, T means C and is associated with T dashed line represents a double bond.

All other radicals of the formula Ib are those indicated above for formula I values.

These options invention also relates to pharmaceutically acceptable layers or MES compounds of formula Ib.

The compounds of formula Ib have the following preferred values. The double bond between carbon atoms 5 and 6 is absent, R1and R2independent and oznachaet R3in particular means a hydrogen atom, chlorine, bromine or fluorine at the specified position 8, and R4in particular means a hydrogen atom at the specified position 9.

Representatives of the compounds of formula Ib is

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According to another variant of the invention, the radical z means a group -(C(Ra)2)n-Y-(C(Ra)2)n-. Thus obtained compounds of formula Ij

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where these radicals are mentioned above in connection with formula I values. This variant of the invention also relates to pharmaceutically acceptable salts or MES compounds of formula Ij.

Radicals of the formula Ij have the following preferred values.

R1, R2, R3and R4independent and mean a hydrogen atom or halogen, alkyl and the group N(R11)2and OR11, R5and R6independent and mean a hydrogen atom or lower alkyl, R7and R8mean hydrogen atoms, R9means a hydrogen atom or halogen, trifluoromethyl, lower alkyl, group OR11, -SR11, -N(R11)2in particular a hydrogen atom, T denotes N or C, and T means C, if the associated castranova ring and the remainder of the molecule compounds j is 1, R10means a hydrogen atom, and R11means a hydrogen atom or lower alkyl.

According to a preferred variant of the invention a new connection has the following formula Ik

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in which X is CH, N or N+O-;

R7and R8independent and mean a hydrogen atom or halogen, alkyl, alkenyl, quinil, aryl, trifluoromethyl, group OR11, -SR11, -N(R11)2;

Z group-C(Ra)2-Y-, -Y-C(Ra)2, -Y-, where Y denotes-O-, -S - and-NR10group-CH2CH2CH2- or a direct bond, and T denotes C or N, and if the associated with the T dashed line represents a double bond, then T means C

Representatives of the compounds of the formula Ik are

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The object of the invention is also a pharmaceutical composition comprising at least one compound of formula l or its pharmaceutically acceptable salt, or MES in therapeutically effective amounts, if necessary in combination with a pharmaceutically acceptable carrier.

A further object of the invention is a method of treatment of allergic reactions or inflammation by giving PAC the m number.

Certain compounds according to the invention can exist in various isomeric forms, for example in the form of enantiomers and diastereoisomers, and conformational forms. The invention includes all isomers in pure form or as mixtures, including racemic mixtures. Enol forms are also covered by the invention. So, for example, substituted by hydroxyl pyridinoline groups may also be present in the keto-form

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The new compounds of formula l may be available in resolutional and solvated form, including hydrated forms, such as the hemihydrate. For the purpose of the invention solvated forms, for example in the case of the use of pharmaceutically acceptable solvents, such as, for example, water, ethanol and the like, are equivalent nonsolvated forms.

As indicated above, the pyridine and benzene ring structure in formula l can have one or more substituents R1, R2, R3and R4and with the radical L pyridine ring (W) may contain one or more substituents R7, R8and R9. In compounds in which one ring has more than one Deputy, the substituents may be the same the Oia. In addition, the line coming into the ring, means that the radicals R1, R2, R3, R4, R7, R8and R9can be in any available position. For example, the substituents R1and R2can be linked to the carbon atom at positions f, g, h or i, while the substituents R3and R4can be in any position a, b, c and d.

R5and R6associated with piperidinium, piperidylidene or piperazinone ring. These substituents may be the same or different values, and they can be associated with the same or a different carbon atom of this ring. For example, if R5and R6together oznachaet S, they are bound to the same carbon atom.

In the framework of this application to denote the N-oxides are NO groups, N _ O N-O and N+O-. Certain compounds of formula l are acidic in nature, for example such compounds, which have a carboxyl or phenolic hydroxyl group. These compounds can form pharmaceutically acceptable salts. As such examples are sodium, potassium, calcium, aluminum, gold and silver salts. In the scope of the invention also include salts with pharmaca like that.

Joining the main character can also form pharmaceutically acceptable salts, for example kislotoupornye salt. For example, the atoms pyrido-nitrogen may form a salt with a strong acid, whereas compounds with basic substituents, such as, for example, an amino group, can form salts with weaker acids. As examples of suitable acids for salt formation can be called hydrochloric, sulfuric, phosphoric, acetic, citric, slit, malonic, salicylic, maleic, fumaric, succinic, ascorbic, malic, methansulfonate acid, as well as other well-known mineral and carboxylic acids. Salt is produced by the interaction of the free base with the desired acid in sufficient to scale the number. The free base can be obtained by treatment of the salt diluted aqueous solution of a suitable base, such as, for example, a dilute aqueous solution of hydroxy sodium, potassium carbonate, ammonia and sodium bicarbonate. The free base is slightly different from the corresponding salts by certain physical properties, such as, for example, solubility in polar solvents. But for the purpose of the invention kislotno is bretania under alkyl (including the alkyl part of alkoxy, alkylamino, dialkylamino) refers to branched and unbranched carbon chain, which contains from one to twenty carbon atoms, preferably 1 to 7 carbon atoms. The term cycloalkyl denotes a saturated carbocyclic ring branched or unbranched nature, having from three to twenty carbon atoms, preferably from three to seven carbon atoms. Under alkenyl refers to branched and unbranched carbon chain with two to twelve carbon atoms, preferably 2-6 carbon atoms, having at least one carbon-carbon double bond, under quinil branched and unbranched carbon chain with 2 to 12 carbon atoms, preferably 2-6 carbon atoms, having at least one carbon-carbon triple bond, under the carbocyclic aryl group (preferably phenyl or substituted phenyl), having 6-14 carbon atoms and at least one phenyl or a condensed fenelonov ring, with all available, fed to the substitution of carbon atoms and carbocyclic groups are possible places of connection. While carbocyclic group may be substituted by at least one radical from the GRU is UB>eR13where R13means alkyl or aryl, and e is 1 or 2, -CF3, amino, alkylamino, dialkylamino, -COOR13and-NO2. Under lower alkyl refers to an unbranched or branched carbon chain containing 1-6 carbon atoms, preferably 1-3 carbon atoms, under the substituted phenyl phenyl group, in which 1-3 atoms of hydrogen are replaced by identical or different substituents from the group comprising halogen, alkyl, hydroxyl, alkoxy, phenoxy, cyano, cycloalkyl, alkenylacyl, alkyloxy, -SH, -S(O)eR13where R13means alkyl or aryl, and e is 1 or 2, -CF3, amino, alkylamino, dialkylamino, -COOR13and-NO2and under the halogen fluorine, chlorine, bromine and iodine.

Obtaining compounds of formula I.

The compounds of formula I with the above value of radicals can be obtained below way.

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Indicated in the reaction scheme of the original compound III has the following formula

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Compounds of General formula I can better be obtained by alkylation of unsubstituted piperidino formula II according to the above reaction scheme. However, the processing of the compounds of formula II corresponding pyridium compound of formula III, which changes the formula I. The reaction is usually carried out in an inert solvent, such as, for example, tetrahydrofuran or methylene fluoride, at a suitable temperature, usually at the boiling point, although it is possible to conduct the reaction at temperatures from 0oC to 80oC. Typically use a suitable base, such as, for example, triethylamine or pyridine. The need to use Foundation may disappear when the connection can act as its own basis. Source pyridyl formula III can be obtained by known methods from the corresponding alcohol (e.g methylchloride in triethylamine in the case J= OSO2CH3, triphenylphosphine in tetrabromide carbon in the case J=Br, thionyl chloride in the case of J=Cl).

Many compounds of General formula I can also be obtained by reductive amination of unsubstituted piperidine of formula II suitable pyridinecarboxamide formula IV according to the following scheme

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The reaction is usually conducted in the environment of the polar solvent, such as, for example, methanol or ethanol, and, if necessary, in the presence of a dehydrating agent such as, for example, molecular sieve with a size of pores 3A. The presence of a reducing agent, toulene intermediate Chippewa Foundation. The reaction is usually carried out at temperatures of about 0-100oC.

Some compounds of formula I can be obtained by restoring the corresponding amide of the formula V according to the following scheme

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For example, if the amide of formula V is subjected to processing by aluminium lithium or a suitable regenerating agent, the carbonyl function is restored by obtaining the compounds of formula I. the Reaction is usually carried out in an inert solvent at temperatures from about 0oC to temperature phlegmy. Usually used ethereal solvent, such as, for example, tetrahydrofuran or simple diethyl ether. This method can be applied only when the reducing agent should not affect other functional groups, such as, for example, esters and ketones. Substituted amide of the formula V can be obtained by acylation of compounds of formula II, a compound of formula VI in the presence of a base according to the following scheme

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In the compound of formula VI, J means the group that you want. If the compound of formula VI is galoyanized (i.e., J=halogen) or anhydride (i.e., J=O(CO)R', where R' may mean, for example, a group of the formula

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or Alki the materials of the VI with an amine of the formula II at room temperature. The reaction is usually carried out in an inert solvent, such as, for example, methylene chloride, tetrahydrofuran and toluene, in the presence of a base, such as, for example, triethylamine. If J denotes hydroxyl, to obtain the compounds of formula V requires the presence of an additional reagent, such as 1-(3-dimethylaminopropyl)3-ethyl-carbodiimide as hydrochloride, N,N-dicyclohexylcarbodiimide and N,N-carbonyldiimidazole. The corresponding N-oxides of the present compounds (for example, when X in formula I is the group of N+-O-) can be obtained by treating the corresponding compounds, in which T stands for carbon) with a suitable oxidizing agent in an inert solvent. Suitable oxidizing agents are 3-chlormadinone acid in the environment methylene chloride or peracetic acid in acetic acid medium. The reaction is usually carried out at low temperatures, for example at about -10oC, in order to reduce the formation of by-products to a minimum. But it is possible to conduct the reaction at temperatures from about 0oC to temperature phlegmy. If T denotes N, before oxidation of the nitrogen should be protected in the form of its salt or other complex nailey group (CO2R", where R" means alkyl or aryl) from the corresponding carbamate formula VII or acid hydrolysis (HCl/H2O/ temperature phlegmy) or basic hydrolysis (KOH/H2O/temperature phlegmy) according to the following scheme

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Depending on the values of the radical R of the compound of the formula VII can also be treated ORGANOMETALLIC reagent (e.g. CH3Li, when R" means alkyl as, for example, ethyl) or regenerating reagent (for example, zinc in the environment of acid, when R" means 2,2,2-trichlorethyl) in order to obtain the compound of formula II.

Compound of formula VII can be obtained from N-Olkiluoto (preferably N-methyl) compounds of formula VIII are widely known methods, for example described in U.S. patents NN 4 282 233 and 4 335 036.

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For example, the compound of formula VIII can be subjected to the interaction of the corresponding alkylchlorosilanes in an inert solvent, such as, for example, toluene, at a suitable temperature, for example at a temperature of approximately 50-100oC. thus obtain the connection formula VII. As you know, there are other known methods to convert the compounds of formula VIII to the compound of formula II. For example, the result is showing in the subsequent hydrolysis in aqueous basic or acidic conditions can be obtained compound of the formula II according to the following reaction scheme. This method is preferred in the case of substitution on piperidinium or piperazinovom ring.

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The formation of compounds of the formulae II and VIII in which Z stands for a group

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(A). The compounds of formula VIII, in which X represents nitrogen (i.e., the compounds of formula VIIIa).

Methods for obtaining compounds of formula VIIIa

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widely known (see for example, U.S. patents NN 3 326 924, 3 357 986, 3 409 621, 3 419 565, 4 804 666, 4 826 853, and published in the international application N WO 88/03138 and WO 90/13548). So, for example in international application N WO 88/03138 describes the synthesis of the starting compounds, which are saturated or ninasimone in positions 5, 6, have a simple or a double bond at the specified position 11 tricyclic ring system, have piperazinovogo group attached to position 11 tricyclic ring system, substituted at the carbon atoms in positions 5 and/or 6, and have different alternates 1, 2, 3 and/or 4 on tricyclic part of the proposed compounds. In the international application N WO 90/13548 describes the synthesis of the starting compounds in which the nitrogen atom of the tricyclic ring is N-oxidized, and/or which have substituents R1and/or R2on the pyridine ring of the tricyclic ring system. Scheme I is where X and T denote the nitrogen (i.e., the compounds of formula IIa).

The compounds of formula II can in General be obtained in the manner described above. However, the synthesis of compounds of formula IIa (in the case of T=N)

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preferably is carried out by known techniques, for example, described in U.S. patent No. 3 409 621 and in published international application N WO 88/03138. Scheme II illustrates the method of obtaining compounds of the formula IIa, in which X and T denote the nitrogen.

(C) Compounds of the formulae II and VIII, in which X is carbon (i.e., compounds IIb and VIIIb).

The synthesis of compounds of formula IIb and VIIIb

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already described in the patent literature, for example in U.S. patent N 3 014 991, as well as in the technical literature, for example in the Journal of Chem. 8, S. 829, 1965, Journal of Org. Chem. 50, S. 339, 1985. In General, many methods for obtaining the compounds of formulas VIIIa and IIa, can be used to obtain derivatives of formula VIIIb and IIb. So, for example, derivatives of piperazine (TN) all carbon tricyclic groups (CCI) can be obtained by alkylation described to obtain the corresponding pyridine derivatives in U.S. patent N 3 409 621 and in the international application N WO 88/03138.

Scheme III, V, where A, B, R1-R6and X have the above meaning, explain the above-mentioned methods. When Aviemore from the method, used to obtain the compounds of formula VIII.

Obtaining compounds of formula VIII in which Z stands for a group-C(Ra)2)n-Y-(C(Ra)2)n-.

(A) Compounds of formula VIII in which m + n means O, and Y represents a direct bond (i.e. the compound of formula VIIIc).

Methods for obtaining compounds of formula VIIIc

in which m + n means O, and Y represents a direct bond, is widely known. The method of obtaining such compounds in which X is nitrogen, described in the international application N WO 89/10369. Scheme VI explains obtain compounds of formula VIIIc, in which X represents nitrogen. Expert it is clear that the compounds in which X represents carbon, can also be obtained by the method described in international application N WO 89/10369. Scheme VII illustrates the method of obtaining compounds of formula VIIIc, in which X is carbon.

In General the compounds of formula II in which m + n means O, and Y represents a direct link, you can get the above techniques. However, the synthesis of compounds of formula IIc

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(where T denotes a nitrogen) is preferably carried out by various known methods, for example according to the U.S. patent N 3 409 621 and international stated the x2">

(B) Compounds of formula VIII in which m + n means O, and Y represents-O-, -S(O)e-, -OR11, -NR11- (i.e., the compounds of formula VIIId).

Methods for obtaining compounds of formula VIIId

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in which m + n means O, and Y represents-O-, -S(O)e- or-NR11previously described for derivatives in which X represents nitrogen, for example, in U.S. patents NN 3 803 153, 3 803 154 and 3 325 501 and in the international application N WO 89/10369. Scheme IX illustrates the method of obtaining compounds of formula VIIId, in which X represents nitrogen.

The synthesis of compounds of formula VIIId, in which X represents carbon, widely known in the patent and technical literature (see, for example, Collect. Czech. Chem. Comm. 54(5), page 1388 -1402, 1989,J. Med. Chem. 17, page 57, 1874; U.S. patent NN 3 391 143, 4 021 561, 4 086 350, 4 616 023, patent Germany N1670334, GDR patent N 2549841, Belgium patent N 707523 and 815078, patent Brazil N 1 153 977 and international application N WO 87/07894). Scheme X illustrates the method of obtaining compounds of formula VIIId, in which X is carbon.

In General the compounds of formula II in which m + n means O, and Y represents-O-, -S(O)e-, -NR11- you can obtain the above-described techniques. However, the synthesis of the compounds of formula IId

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in which T stands for nitrogen, preferably get different known the WO 88/03138 and WO 89/10369. Scheme XI illustrates the method of obtaining the compounds of formula IId, in which T stands for nitrogen.

(B) Compounds of the formula VIII in which m + n is 1 and Y is-O-, -S(O)e-, OR-NR11- (i.e., the compounds of formula VIIIe).

The synthesis of compounds of formula VIIIe

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in which m + n means O, and Y represents-O-, -S(O)e- or-NR11well - known and described, for example, in international application N WO 89/10369 for derivatives in which X represents nitrogen. Scheme XII illustrates the method of obtaining compounds of formula VIIe, in which X represents nitrogen.

The synthesis of compounds of formula VIIIe, in which X is carbon, is widely known (see, for example, Collect. Czech. Chem. Comm. 54(5), S. 1388 1402, 1989; J. Med. Chem. 17, S. 57, 1974, patents NN USA N 3 367 094, 4 021 561, 4 086 350 and 4 616 023; patent N Germany 1670-334, patents Belgium NN 707523 and 815078, French patent N 1 391 767 and international application N WO 87/07894. In General, these compounds can also be obtained similar to the method of obtaining compounds of formula VIIIe, in which X represents nitrogen. Scheme XIII illustrates the method of obtaining compounds of formula VIIIe, in which X is carbon.

In General the compounds of formula II in which m + n means O, and Y represents-O-, -S(O)e- or-NR11- can be obtained in the manner described above. Though the known methods, for example according to U.S. patent N 3 409 621, application Germany N 3906-920 international application N WO 87/07894, 88/03138 and 89/10369. Scheme XIV explains the method of obtaining compounds of formula IIe, in which T stands for nitrogen.

(G) Compounds of the formula VIII in which m + n means 3, and Y represents a direct bond (i.e., the compounds of formula VIIIf)/

The synthesis of compounds of formula VIIIf

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in which m + n means 3, and Y represents a direct bond, described in the literature for derivatives in which X represents nitrogen (see, for example, international application N WO 89/10369). Scheme XV illustrates the method of obtaining compounds of formula VIIIf.

Expert it is clear that the data of the international application N WO 89/10369 can also be used to obtain compounds of formula VIIIf, in which X is carbon.

In General, the compound of formula II in which m + n means 3, and Y represents a direct bond, can also be obtained in the manner described above. However, the synthesis of compounds of formula IIf

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in which T stands for nitrogen, preferably carried out by various known methods, for example according to U.S. patent N 3 409 621 or international applications N WO 88/03138 and 89/10369. Scheme XVI illustrates the method of obtaining compounds of formula IIf. Experts clearly, h is Todd, can be used to change the value of the Deputy known techniques. For example, the ketone can be converted to thioketone by processing pentasulfide or reagent Losson. The result of this treatment, the oxygen is replaced by sulfur. The reaction can be performed at room or elevated temperature in an environment of pyridine, toluene or other suitable solvent. The ketone can also be transferred to a derivative having alkyl or aryl. For this purpose, the ketone is subjected to processing by a Wittig reagent or other ORGANOMETALLIC reagent such as a Grignard reagent. While getting the appropriate olefin or alcohol. The obtained derivatives, in turn, can be converted to alkyl or aryl compounds.

It is sometimes desirable and/or necessary during the mentioned reactions to protect certain values radicals, for example, R1, R2, R3, R4, R5, R6, R7, R8and R9known to the specialist techniques. Used for this purpose conventional protective groups are described in T. C. Greene in "Protective Groups In Organic Synthesis", ed. John Wiley Sons, New York, 1981. So, for example, shown in the column of the table. 1 group can protect specified in column 2 of the table. 1 group the s group is removed by known techniques.

Pharmacological experiments.

The proposed compounds have the properties of an antagonist of platelet-activating factor and histamine. Therefore, they are useful when platelet-activating factor and/or histamine play a role in disease or disorders, that is, in the case of allergic diseases, such as, for example, asthma, allergic renit, respiratory distress syndrome, urticaria, and inflammatory diseases, such as, for example, rheumatoid arthritis and osteo-arthritis. So, for example, platelet-activating factor is an important mediator of processes such as platelet aggregation, reduction of smooth muscle, particularly in the lung tissue, eosinophil chemotaxis, vascular permeability and neutrophil activation. Additionally represent that platelet-activating factor plays a role in the hyperresponsiveness of the Airways.

Antagonistic against platelet-activating factor properties of new compounds can be illustrated using the following standard pharmacological studies. These studies are a standard experiments to determine the antagonistic against platelet-activating factor is regulating the platelet factor. The in vitro assays is a screening test, then, as experience in vivo mimics the clinical use of antagonist, platelet-activating factor in order to obtain data on which to judge the appropriateness of the clinical trial compounds.

A. in vitro Studies.

The experiment for the determination of platelet aggregation.

Platelet-activating factor causes aggregation of platelets in the result mechanism, in which the mediator acts as a receptor. So called platelet-activating factor aggregation is a simple and suitable analysis to identify antagonism of the compounds under study.

50 ml of blood of a healthy male was collected in 5 ml of anticoagulant solution containing 3.8% sodium citrate and 2% dextrose. The blood was centrifuged at 100 x g for 15 min, after which rich trombocyte poor plasma was obtained by centrifugation of platelet-rich plasma at 12 000 x g for 2 min using an apparatus of the type Beckman Microfuge Century platelet-Rich plasma was used within 3 hours after blood collection.

Platelet-activating factor was dissolved in a mixture of chloroform and methanol in a volumetric southdale in a polypropylene tube and dried in a stream of nitrogen gas. To the dried sample was added to 25 mm magnesium chloride and 0.1% serum albumin cattle. Received 1 mm solution was subjected to sonication for 5 minutes This basic solution was then diluted to appropriate concentrations using the above-mentioned buffer solution. Collagen and adenosine diphosphate were used in the form of trading solutions. The compounds were initially dissolved in dimethyl sulfoxide at a concentration of 50 mm and then further diluted with the help of the mentioned buffer solution to the appropriate concentration.

After adding platelet-activating factor to platelet-rich plasma begins platelet aggregation. Aggregation was determined using an appropriate device and compared the transmission of infrared light through platelet-rich plasma and platelet-poor plasma. As a device used dual aggregometer model 440 foreign companies Chrono-Log Corporation, Havertown, USA. to 0.45 ml of platelet-rich plasma was continuously stirred at a temperature of 37oC half pans of aggregometry. 50 μl of solutions of the investigated compounds or 50 ál of the used solvent was added to platelet-rich plasma and after dvuhminutniy concentration 1 5 10-8M By changing the concentration of platelet-activating factor agregating the reaction is maintained within the specified limits. The processes of incubation continued up to a maximum with increasing light transmission (usually 2 min). This increase in light transmission, indicating the implementation of platelet aggregation, was transferred to the computer through the interface AGGRO/LINK (model 810 aforementioned companies). It was calculated the slope of the change of light transmission, which determined the degree of aggregation. The inhibition was calculated by comparing the degree of aggregation is reached in the presence of the tested compound, the degree of aggregation observed in its absence. In each experiment as a positive control using a standard antagonist of platelet-activating factor, that is 8-chloro-6, 11-dihydro-11-(acetyl-4-piperidylidene)-5H-benzo[5, 6] cyclohepta[1, 2-b] pyridine.

Compounds that inhibited caused by platelet-activating factor aggregation, were investigated for activity against other agents of aggregation, such as, for example, collagen (0.2 mg/ml) and adenosine diphosphate (2 Microm). Compounds that did not show activity against these agents systems is received in the table. 2.

B. in vivo Studies: caused by agonist response.

Caused by spasmogens bronchospasm in Guinea pigs.

Male Guinea pigs weighing 450-550 g breed of Hartley not given food during the night and the next day they were anestesiologi giving 0.9 ml/mg intraperitoneally of DeLorean containing 0.1 g/ml of diallylbarbituric acid, 0.4 g/ml edilmesini and 0.4 g/ml urethane. In the left jugular vein was introduced cannula to give the investigated compounds. In the trachea was introduced cannula and carried out artificial respiration at 55 beats./min (volume 4 ml). Side lumen tracheal cannula was connected to a pressure sensor in order to continuously monitor the pressure of injection. Bronchosoothe was defined as the percentage increase pressure injection, the peak of which is achieved within 5 min after giving spasmogen. Animals were given intravenous or histamine (10 mg/kg), metafolin (10 µg/kg), 5-oxitriptan (10 µg/kg) or with 0.4 µg/kg platelet-activating factor in isotonic saline medium containing 0.25% serum albumin cattle. Each animal was given only one spasmogen. The effect of the compounds on bronchospasm expressed as a percentage of braking pressure increase injection is ptx2">

In these experiments we investigated the known compounds, labeled 1, 2, and proposed connection labeled 3-10.

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According to the table. 2 shows that the compounds of formula I possess the properties of an antagonist of platelet-activating factor and antihistamines, which correspond to different levels, i.e. certain compounds are antagonistic against platelet-activating factor activity, but more weak antihistaminic activity. Other compounds exhibit high antihistaminew activity, and their properties antagonist of platelet-activating factor weaker. But in General the proposed compounds exhibit higher activity antihistaminico funds than known compounds No. 1 and 2, which also exhibit the properties of antagonists of platelet-activating factor and histamine. Some of the suggested connections are as strong antagonists of platelet-activating factor, and strong antigistaminny means. Therefore, if necessary, each of these compounds can be used on these two qualities.

Emaciations acceptable carriers, which can be solid or liquid. Solid preparations are, for example, powders, tablets, dispersible granules, capsules, including starch capsules, and suppositories. The powders and tablets may contain about 5-70% of the active substance. Suitable solid carriers are widely known, such as magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders and capsules can be used as solid dosage forms for oral application.

Suppositories are prepared due to the fact that the low-melting wax, such as, for example, a mixture of glycerides of fatty acids or coconut oil, is first melted and the resulting melt is homogeneous dispersed by mixing the active substance. The resulting molten homogeneous mixture is poured into molds of suitable size and by cooling is transferred to the solid state.

Liquid preparations include solutions, suspensions and emulsions. As examples, intended for parenteral injection of aqueous solutions which may contain propylene glycol. As the liquid preparation may also be called a solution designed for vnutripuzarno and, which may be in the form of a mixture with a pharmaceutically acceptable carrier, such as, for example, inert compressed gas.

In the scope of the invention also include solid preparations, which immediately before the application can be translated in liquid form intended for oral or parenteral application. Such liquid forms include solutions, suspensions and emulsions.

The proposed connection can also be applicirovti transdermal. The transdermal compositions can be in the form of a cream, lotion, aerosol, and/or emulsion. They can be included in a transdermal preparations matrix type or depo-type. Such drugs are well known.

Preferably proposed connection give oral.

The proposed pharmaceutical composition is preferably present in the form of a dosage unit. Such dosage unit contains the appropriate amount of the active substance, i.e. the quantity required to achieve the desired actions.

Dosage units contain about 0.1-1000 mg, preferably approximately 1-300 mg of active substance. The appropriate dose can be determined by comparing the activity proposed connection with activelle)-5H - benzo[5,6]cyclohepta[1,2-b]pyridine, described in U.S. patent No. 4 282 233.

Necessary in each specific case, the dose depends on the requirements of the patient and the severity of the disease. Typically, the number appliciruemah compound and its pharmaceutically acceptable salts and frequency of their application are determined by the physician taking into account such factors as age, condition and height of the patient, and the severity of the treated symptoms. In case of oral application, it is recommended to apply the proposed connection from 10-1500 mg/day, preferably 10-1000 mg/day. This number is divided into two to four doses in order to achieve attenuation of symptoms. If the proposed connection apply these doses, they are non-toxic.

The following examples illustrate how to obtain the new compounds of the formula (I).

Example 1. 8-chloro-6,11-dihydro-11-[1-(4-pyridinylmethyl)-4-piperidinylidene]-5H - benzo[5,6]cyclohepta[1,2-b]pyridine

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In a nitrogen atmosphere to a mixture of 527 mg (3,22 mmol) of the hydrochloride of 4-picolyl chloride in 20 ml of dry tetrahydrofuran type of 0.90 ml (to 6.43 mmol) of triethylamine at room temperature. The reaction mixture was cooled to 0oC, then add 1.0 g (3,22 mmol) of 4-(8-chloro-5,6-dihydro-11H-benzo-[5,their nights. Then add 528 mg (3,22 mmol) of the hydrochloride of 4-picolyl chloride and 450 µl (3,22 mmol) of triethylamine. After 4.5 h the reaction mixture was poured into a 1.0 N aqueous sodium hydroxide and extracted three times with ethyl acetate. The combined organic phases are washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue is subjected to flash chromatography using as eluent saturated with ammonia 4% methanol in methylene chloride. Get 322 g of target compound vitreous consistency. MC (fast atom bombardment) m/z: 402 (M++1).

Example 2. N-oxide of 8-chloro-6,11-dihydro-11-[1-(4-pyridinylmethyl)-4-piperidinylidene]-5H - benzo[5,6]cyclohepta[1,2-b]pyridine

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In a nitrogen atmosphere to a mixture of 104 mg (0,835 mmol) of N-oxide 4-pyridylcarbinol and 335 μl (2,40 mmol) of triethylamine in 7 ml of dry methylene chloride add 93 μl (1.2 mmol) of acid chloride of methansulfonate at 0oC. After 1 h, add 250 mg (0,808 mmol) of 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridine-11-ilidene)piperidine. The reaction mixture was stirred at room temperature for 1 h, after which it was heated under reflux overnight. Then pour it in 1.0 N aqueous sodium hydroxide and Tania, filtered and concentrated in vacuum. The residue is subjected to flash chromatography using as eluent saturated with ammonia 5% methanol in methylene chloride. Obtain 73 mg of the target compound vitreous consistency. MC (fast atom bombardment) m/z 418 (M++1).

Example 3. A. N-oxide ()-8-chloro-6,11-dihydro-11-[4-(4-pyridinylmethyl)-1 - piperazinil]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine

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In a nitrogen atmosphere to a mixture of 1,204 g (9,63 mmol) of N-oxide 4-pyridylcarbinol and 2.7 ml (to 19.4 mmol) of triethylamine in 90 ml of dry methylene chloride added dropwise within 10 min 742 μl (9,59 mmol) of acid chloride of methansulfonate at 0oC. After 20 min successively added 833 mg (9,60 mmol) of methyl lithium and a 3.01 g (a 9.60 mmol) of 8-chloro-6,11-dihydro-11-(4-piperazinil)-5H-benzo[5,6] cyclohepta[1,2-b] pyridine, after which the reaction mixture is heated under reflux in a period of 4.75 hours Then the reaction mixture is poured into a 1.0 N aqueous sodium hydroxide and three times extracted with methylene chloride. The combined organic phases are washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue is purified by flash chromatography using as eluent saturated with ammonia and 10% methanol in chlorine is>B. N-oxide (+)-8-chloro-6,11-dihydro-11-[4-pyridinylmethyl)-1-piperazinil] -5H - benzo[5,6] cyclohepta[1,2-b] pyridine N-oxide (-)-8-chloro-6,11-dihydro-11-[4-(4-pyridinylmethyl)-1-piperazinil] -5H-benzo[5,6] cyclohepta[1,2-b] pyridine

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Stage B1. In an argon atmosphere to a mixture of 213 mg (1.70 mmol) of N-oxide 4-pyridylcarbinol and 563 mg (1.70 mmol) tetrabromide carbon in 14 ml of dry methylene chloride is added in one step 446 mg (1.70 mmol) of triphenylphosphine at room temperature. After 45 min successively added 313 mg (0,997 mmol) of (+)-8-chloro-6,11-dihydro-11-(4-piperazinil)-5H-benzo[5,6] cyclohepta[1,2-b] pyridine and 237 ml (1.78 mmol) of triethylamine. The reaction mixture was stirred at room temperature overnight, after which she served in methylene chloride and successively washed with 0.5 N aqueous sodium bicarbonate and brine. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuum. The residue is purified by flash chromatography using as eluent saturated with ammonia 5% methanol in methylene chloride. Obtain 305 mg of the N-oxide of (+)-8-chloro-6,11-dihydro-11-[4-(4-pyridinylmethyl)-1-piperazinil] -5H - benzo[5,6] cyclohepta[1,2-b]pyridine vitreous consistency. MC (Cl) m/z 421 (M++1). []2D6= +44,5.
++1). []2D6= -44,0.

Example 4. 1-ocis-[(4-(5H-dibenzo[a,d]cyclohepten-5-ilidene)-1-piperidinyl] methyl]pyridine

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In a nitrogen atmosphere to a mixture of 203 mg (1.6 mmol) of N-oxide 4-pyridylcarbinol and 650 ál (of 4.66 mmol) of triethylamine in 10 ml of dry methylene chloride add 180 μl (1.8 mmol) of acid chloride of methansulfonate at 0oC. After 1 h, add 504 mg (1.8 mmol) of 4-(5H-dibenzo[a,b]cyclohepten-5-ilidene)-1-piperidine and the reaction mixture stirred at room temperature is the major organic phases are washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue is purified by flash chromatographie using as eluent saturated with ammonia 3% methanol in ethylene chloride and recrystallization from a mixture of methylene chloride and easy isopropyl ether. Obtain 103 mg of the target compound as a white solid. MS (fast atom bombardment m/z 381 (M++1).

Example 5. 1-oxide 4-[[4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-or - den)-1-piperidinyl]methyl]pyridine

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In a nitrogen atmosphere to a mixture of 452 mg (3.61 mmol) of N-oxide 4-pyridylcarbinol and 1.53 ml (11 mmol) of triethylamine in 30 ml of dry methylene chloride add 835 μl (about 10.8 mmol) of acid chloride of methansulfonate at 0oC. the Reaction mixture is allowed to slowly warm to room temperature. After 3 hours, add 1.0 g (of 3.64 mmol) of 4-(5H-dibenzo[a,b]cyclohepten-5-ilidene)-1-piperidine and the reaction mixture stirred at room temperature overnight. Then it is served in 1.0 N aqueous sodium hydroxide and three times extracted with methylene chloride. The combined organic phases are washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue is purified by flash chromatography with PR is th connection vitreous consistency. MS (Cl) m/e (M++1).

Example 6. N-ocis-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-4-(4 - pyridinylmethyl)piperazine

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In a nitrogen atmosphere to a mixture of 190 mg (of 1.52 mmol) of N-oxide 4-pyridylcarbinol and 600 μl (or 4.31 mmol) of triethylamine and 15 ml of dry methylene chloride add 335 μl (4,33 mmol) of acid chloride of methansulfonate at -15oC. the Reaction mixture is allowed to slowly warm to room temperature. After 3 hours add 410 mg (1,47 mmol) 1-(10,11-dihydro-5H-dibenzo-[a,b]cyclohepten-5 - yl)piperazine and the reaction mixture stirred at room temperature overnight. Through further 18,3 h, the reaction mixture was poured into a 1.0 N aqueous sodium hydroxide and three times extracted with methylene chloride. The combined organic phases are washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue is purified by flash chromatography using as an eluent of 4% methanol in methylene chloride and purified product is torn into powder with the addition of pentane. Obtain 49 mg of the target compound as a white solid. MS (fast atom bombardment m/z 386 (M++1).

Example 7. N-ocis-chloro-6,11-dihydro-3-methyl-11-[1-(4-pyridinylmethyl)-4 - piperidinylidene]-5H-is La and 331 mg (1.0 mmol) chetyrehpostovye carbon in 8 ml of methylene chloride add 262 mg (1.0 mmol) of triphenylphosphine. The reaction mixture was stirred for 30 min, and then successively add 0,139 ml (1.0 mmol) of triethylamine, 324 (1.0 mmol) 3-methyl-8-chloro-6,11-dihydro-11-(4-piperidyl-den)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine. The reaction mixture was stirred overnight, then diluted with 0.1 N sodium hydroxide and extracted two times with methylene chloride. The organic phase is washed with brine and dried over sodium sulfate. After filtration and removal of solvent to obtain a solid, which is subjected to chromatography on silica gel using as eluent 10% methanol in methylene chloride. Get 195 mg (45% dearie) of target compound as a brown solid. MS (fast atom bombardment) m/z 432 (M++1).

Example 8. N'-oxide of 8-chloro-5,11-dihydro-11-[1-(4-pyridinylmethyl)-4-piperidinylidene][1] benzocaine[4,3-b]pyridine

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In a nitrogen atmosphere to a mixture of 0.95 mg (to 7.61 mmol) of N-oxide 4-pyridylcarbinol and 2.52 mg (to 7.61 mmol) tetrabromide carbon in 65 ml of dichloromethane added 2.0 g (to 7.61 mmol) of triphenylphosphine. The reaction mixture was stirred at room temperature for 45 min, after which successively added 1.40 g (4,48 mmol) of 8-chloro-5,11-dihydro-11-(4-piperidinylidene)[1]b the temperature for 16 h, then add an additional amount of dichloromethane, washed with a saturated solution of bicarbonate sodium and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuum. The resulting oil is dissolved in dichloromethane and subjected to chromatography on silica gel using as eluent 10% methanol in dichloromethane. The appropriate fractions are collected and concentrated under reduced pressure. Obtain 0.28 g (15% of theory) of the target compound as a foamy solid substance with a melting point of 102 105oC. MS (EI) m/e 404 (M+-16).

Example 9. N'-oxide of 8-chloro-5,11-dihydro-11[4-(4-pyridinylmethyl)-1-piperazin - Nile][1]benzocaine[4,3-b]pyridine

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In a nitrogen atmosphere to a mixture of 1.35 g (10.77 mmol) of N-oxide 4-pyridylcarbinol and 3.57 g (10,77 mmol) tetrabromide carbon in 50 ml of dichloromethane add 2,82 g (10,77 mmol) of triphenylphosphine. The reaction mixture was stirred at room temperature for 45 min, and then added 2.0 g (6,33 mmol) of 8-chloro-5,11-dihydro-11-(1-piperazinil) [1] benzocaine [4, 3-d] pyridine and 1.50 ml of 1.09 g (10,77 mmol) of triethylamine. The reaction mixture was stirred at room temperature for 17 h, then add 50 ml of saturated rest ml. The combined organic phases are washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuum. The resulting oil is dissolved in dichloromethane and subjected to chromatography on silica gel using as eluent 7% methanol in dichloromethane. The appropriate fractions are collected and concentrated under reduced pressure. The obtained yellow solid was dissolved in ethanol and added 1.1 equivalent of crimson acid. Add a simple diethyl ether to precipitate the maleate, which is filtered, washed with simple diethyl ether and dried in high vacuum. Get 1,02 g (73% of theory) of the target compound as a white solid with a melting point of 179 181oC. MC (fast atom bombardment) m/z 423 (M++1).

Example 10. N'-oxide of 8-chloro-5,11-dihydro-11-[1-(4-pyridinylmethyl)-1-piperidinylidene] [1] benzothieno [4,3-b] pyridine

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The mixture 943 mg (7,53 mmol) of N-oxide 4-pyridylcarbinol and 3.95 g (16,1 mmol) of triphenylphosphine in 25 ml tetrachloride carbon is heated under reflux for 3.5 h in nitrogen atmosphere, and then add 5 ml of acetonitrile and the reaction mixture heated under reflux for 5 minutes Then the reaction ). The resulting residue is subjected to flash chromatography using as element 10 methanol in methylene chloride. Get 432 mg N-oxide 4-chloromethylpyridine as a black resin.

Suspension 246 mg (0,748 mmol) of N-oxide of 8-chloro-5,11-dihydro-11-(4-piperidinylidene) [1] benzothieno [4, 3-b] pyridine, of 0.11 ml (0.79, which mmol) of triethylamine and 226 mg (1, 57 mmol) of N-oxide of 4-chloromethylpyridine in 10 ml of acetonitrile was stirred at room temperature for 20 h, then additionally stirred at 40oC for 20 h Obtained by condensation in vacuum, the residue is subjected to purification flash chromatographia. The resulting product is torn into powder with the simple addition of a mixture of diethyl ether and hexanol in the ratio of 1:1. Thus obtain 148 mg of the target compound as a solid substance with a melting point 131, 5mm output reached 125.5oC (decomp. ). MC (fast atom bombardment m/z 436 (M++1).

Example 11. N'-oxide of 8-chloro-5,11-dihydro-11-[4-(4-pyridinylmethyl)-1-piperazinil] [1] benzothieno [4, 3-b] pyridine

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To a solution of 0.96 g mg (to 7.67 mmol) of N-oxide 4-pyridylcarbinol and 2.55 g (of 7.69 mmol) tetrabromide carbon in 18 ml of methylene chloride add 2,02 g (7.7 mmol) of triphenylphosphine in 15 of the 25oC. After RA is ing for 20 min at 10 15oC successively added a solution of 1.01 g (totaling 3.04 mmol) of 8-chloro-5,11-dihydro-11-(1-piperazinil)-[1] benzothieno [4, 3-b] pyridine in 5 ml of methylene chloride and a solution of 1.07 ml (7.1 mmol) of triethylamine in 1 ml of methylene chloride at 7 9,5oC. the Reaction mixture is heated to room temperature and stir for 24 h, after which it served on ice, stirred with methylene chloride, filtered over kieselguhr and share. The aqueous layer was extracted three times with methylene chloride and the organic phase collected. After triple washing with water and a single washing with brine and drying over sodium sulfate concentrated in vacuo. Obtain 3.8 g of crude product which is subjected to flash chromatography using as eluent a mixture of methylene chloride, methanol and acetic acid in the ratio of 90: 9:0,125. Get br135.8 mg of target compound, which according to thin-layer chromatography has high purity. This substance combines with another substance obtained from similar experiments. The combined substance is subjected to a triple flash chromatography using as eluent the first and second phases of a mixture of methylene chloride, methanol and ammonium hydroxide in the 90:10:0,125. Get the target compound as a solid substance with a melting point of 122 126,5oC (decomp.) MS (fast atom bombardment) m/z 439 (M++1).

Example 12. N'-oxide 10 [1-(4-pyridinylmethyl)-4-piperidinylidene]-10H-[1] benzopyrano [3, 2-b] pyridine

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To a solution of 381 mg N-oxide 4-pyridylcarbinol and 1,02 g tetrabromide carbon in 25 ml of methylene chloride add 811 mg of triphenylphosphine. The resulting solution was stirred for 1 h, after which successively added 480 mg of 10-[4-piperidinylidene]-10H-[1]benzopyrano[3,2-b]pyridine and 431 μl of triethylamine. The reaction mixture was stirred for 90 min, after which it was diluted with 150 ml of methylene chloride, successively washed with 0.5 M aqueous potassium carbonate solution and brine and then dried over sodium sulfate. In the filtration and removal of solvent to obtain the crude product, which was subjected to chromatography on silica gel using as eluent saturated with ammonia 3% methanol in methylene chloride. While getting 465 mg of the target compound. MC (EI) m/e 371 (M+).

Example 13. N'-oxide 1-(9H-fluoren-9-yl)-4-(4-pyridinylmethyl)piperazine

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To a solution of 423 mg N-oxide 4-pyridylcarbonyl and 1.1 g chetyrehmatchevaya add 500 mg of 1-(9H-fluoren-9-yl)-piperazine and 471 mg of triethylamine, then the reaction mixture is stirred for 3.5 hours the Reaction mixture was successively washed with 0.5 M aqueous sodium bicarbonate and brine and then dried over sodium sulfate. In the filtration and removal of solvent to obtain the crude product, which was subjected to chromatography on silica gel using as eluent saturated with ammonia 5% methanol in methylene chloride. Thus obtain 378 mg of the target compound as a white solid with melting point 192-194oC. MC (fast atom bombardment) m/z 378 (M++1).

Example 14. Repeat example 7 with the difference that instead of 3-methyl-8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6] cyclohepta[1,2-b] pyridine is used is specified in the column table. 3 Amin. You get listed in column 2 of the table. 3 target products.

Example 15. Repeat example 7 with the difference that instead of N-hydroxy 4-pyridylcarbinol used are listed in the column of the table. 4 carbinole. Thus obtain the target compounds are summarized in column 2 of the table. 4.

The following examples illustrate possible pharmaceutical preparations which contain the proposed compounds as the active substance (see tab. 5 and 6).

who built the mixture was transferred into pellets by mixing with ingredient N3. If necessary get wet pellets are passed through a coarse sieve, for example the size of the holes 0,63 see the Wet pellets are dried, if necessary, sieved and then mixed with the ingredient N4 for 10-15 minutes After adding the ingredient N5 the mixture is stirred for 1-3 minutes, then on a suitable tablet press machine to produce tablets of the desired size and weight.

Preparation of (capsules PL. 6). Ingredients N1,N2 and N3 are mixed in a suitable mixer for 10-15 minutes, then add the ingredient N4 and the resulting mixture is stirred for 1-3 minutes the resulting mixture is filled into suitable two-component capsules of hard gelatin on a suitable machine.

1. Derivatives of bis-benzo - or benzodiazepipnrapaaraten, piperidylidene and piperazine of General formula I

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where Z/CH2-Ywhere Y is CH2-, oxygen or sulfur, group or Association;

L nitrogen or group

X is nitrogen or the group-CH=

T nitrogen or carbon

R1hydrogen or lower alkyl;

R2hydrogen or halogen;

the presence or absence of communication.

2. Pharmaceutical composition having the antagonist properties, activating the CSO began in an effective amount and a pharmaceutically acceptable carrier, characterized in that the quality of the derived benzotiazolokhinolina it contains derivatives of bis-benzo - or benzodiazepipnrapaaraten, piperidylidene and piperazine of General formula I on p. 1.

 

Same patents:

The invention relates to new 2-imidazolin-2-yl)thieno - foroperational compounds, to intermediates used to obtain these compounds, and the way of dealing with these compounds with unwanted annual and perennial plants, namely 6-(2-imidazolin-2-yl)thieno - and furo[2,3-b] and 5-(2-imidazolin-2-yl)thieno - and furo[3,2-b]the pyridine compounds and the corresponding 2,3-dihydrothieno and 2,3-dihydropyrimidine with structural formulas (Ia) and (Ib):

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whererepresents a single or double bond; R1represents a C1-C4alkyl; R2represents a C1-C4alkyl or C3-C6cycloalkyl; R1and R2together with the carbon atom to which they are joined, can form WITH3-C6cycloalkyl, optionally substituted stands; And represents СООR3CHO, CH2OH, COCH2HE, CONHCH2CH2OH, CONHOH or

R3hydrogen, C1-C12alkyl, which can be broken od is alkoxy, halogen, hydroxyl, C3-C6cycloalkyl, benzyloxy, fullam, phenyl, furfuryl, galopera, lower alkylphenyl, lower alkoxyphenyl, nitrophenyl, carboxyla, lower alkoxycarbonyl, cyano, C1-C4alkylthio or three (lower) alkylammonium; C3-C6alkenyl, optionally substituted by one of the following groups:1-C3alkoxy, phenyl, halogen or two WITH1-C3alkoxygroup or two halogen groups; C3-C6cyclooctyl, optionally substituted by one or two1-C3alkyl groups; C3-C10quinil, optionally substituted by phenyl, halogen or CH2IT; or the cation of an alkali metal or alkaline-earth metal (CA, BA) manganese, copper, iron, ammonium, or organic ammonium; RWITHand RDrepresent N or CH3; Represents N; COR4or SO2R5provided that when a represents a COR4or SO2R5and is a СOOR3the radical R3cannot be hydrogen or a salt-forming cation; R4represents a C1-C11alkyl, chloromethyl or phenyl, optionally substituted A5 alkyl or phenyl, optionally substituted one metalno, chloro - or nitro-group; W represents 0 or S; X represents 0, S or whenis a single bond, the group S 0; Y and Y', Z and Z' represent hydrogen, halogen, C1-C6alkyl, C1-C4hydroxy (lower) alkyl, C1-C6alkoxy, C1-C6acyloxy, benzoyloxy, optionally substituted by one or two1-C4alkyl, C1-C4alkoxygroup or halogen; C1-C4alkylthio, phenoxy,1-C4haloalkyl,1-C4haloalkoxy, nitro, cyano, C1-C4alkylamino,1-C4dialkylamino,1-C4alkylsulfonyl or phenyl, optionally substituted by one or more1-C4the alkyl, C1-C4alkoxy, halogen, or any combination of these two groups, where Y and Z are the same provided that Y and Z represent hydrogen, halogen, alkyl or alkoxy, and when Y and Y' or Z and Z' are the same group they are hydrogen or alkyl; and taken together, Y and Z form a ring in which YZ has the structural formula -(CH2)n- where n являе/www.fips.ru/fullimg/rupat2/19962/004.dwl/2058313-8t.gif" ALIGN="ABSMIDDLE">-=where L, M, Q, and R7each represent hydrogen, halogen, nitro, C1-C4lower alkyl, C1-C4lower alkoxy, methoxy, phenyl, phenoxy, provided that only one of the radicals L, M, Q or R7may have a value different from hydrogen, halogen, C1-C4the alkyl or C1-C4alkoxy; or a pyridine-N-oxides, when W represents oxygen or sulfur and a is COOR3; and when R1and R2not the same, the optical isomers of these compounds, except for the case when R3represents a salt-forming cation, their salts kislotoustoichivam

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to new chemical compound, particularly to a 10-methoxy-5-methyl-6-(1', 1'-dioxido-2' -meta-chlorvinyls-3'-hydroxy-4' -methoxy-benzo[b] thiophene-7-yl)-5H-3,4,6,7-tetrahydro[4,3,2-Q]-[3]benzazocine formula

(I) with an antidepressant

The invention relates to new derivatives of benzopyran that have protivogipertenzin activity and can be used in the treatment and prevention of cardiovascular diseases

The invention relates to compounds of the formula I

(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

-A1= AND2- A3= AND4- bivalent radical having the formula

-CH=CH-CH=CH- (a-1)

-N=CH-CH=CH- (a-2)

-CH=CH-CH=N (a-5) or

-N=CH-N=CH- (and-6),

n=1 or 2

IN - NR4or CH2< / BR>
R4is hydrogen or C1-C6alkyl

L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula

-Alk - R5(b-1),

-Alk - Y - R6(b - 2),

-Alk - Z1- C(=X) - Z2- R7(b-3), or

-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)

Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;

R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast
R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

Y is O or NH;

Z1or Z2each independently NH or a direct link X-O

each Аlk independently - C1-C6alcander

The invention relates to new derivatives of dihydropyridines including substituted piperidinyloxy group

The invention relates to new derivatives of pyridine and their salts, to a method for their herbicide composition containing a specified derivative as an effective ingredient, and to a method of controlling weeds

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to the production of new proizvodnyh of thiazolidine that are used in pharmaceutical compositions

The invention relates to a series of racemic and optically active derivatives of pyrido[1,2-a] pyrazine, which are used as antidepressants and anxiolytics, as well as intermediates of these derivatives

The invention relates to imidazolium and pyridium derived phenylsilane 1,4-dihydropyridines, to the way they are received and containing pharmaceutical compositions
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