NO301072B1 - Analogous Process for the Preparation of Therapeutically Active Triazolo-1,4-Diazepine Compounds - Google Patents

Description

The present invention relates to an analogue process for the production of therapeutically active triazolo-1,4-diazepine compounds and pharmaceutically acceptable salts thereof.

These and other features of the invention appear in the patent claim.

In recent years, a platelet activating factor (hereafter referred to as PAF) has attracted much attention and its relationship with various diseases has now been clarified. It is now assumed that PAF is not only involved in inflammation, but also in DIC, endotoxin shock, asthma, ulcers in the digestive tract, hepatitis and rejection reactions in connection with organ transplantation. In addition, attention has been directed towards PAF as a mediator in connection with allergic reactions.

Based on this, research has been carried out on compounds with anti-PAF activity. Among these compounds, e.g. a 1,4-diazepine compound with anti-PAF action e.g. has been proposed in Japanese Patent Application No. 63-33382.

A satisfactory anti-PAF agent particularly suitable for allergic reactions such as asthma has not yet been developed.

Accordingly, the investigations and studies have been continued with respect to 1,4-diazepine derivatives which have not only excellent PAF inhibitory activity but also activity over a longer period of time.

As a result, after thorough and long-term studies, it has been found that the above-mentioned purpose can be achieved with 1,4-diazepine derivatives indicated below or pharmaceutically acceptable salts thereof.

The present invention thus provides an analogous method for the preparation of therapeutically active triazolo-1,4-diazepine compounds of formula (I):

wherein R<1> and R<2> are the same or different and are a hydrogen atom or a lower alkyl group, R<3> is a halogen atom, R<4> is a hydrogen atom or a lower alkyl group, and X is (a) a group of the formula (b) a group of the formula in which R<5> is a hydrogen atom or a lower alkyl group, (c) a group of the formula in which R<6> is a lower alkyl group (d) a group of the formula

n is an integer 0 or 1, and

Y is

(1) a C3-C6 cycloalkyl group optionally substituted with C1-C8 alkyl or C1-C6 alkynyl, (2) a C3-C6 cycloalkyl C1-C8 alkyl group,

(3) a C 1 -C 8 alkynyl group,

(4) a group with the formula

in which R7 is

hydrogen or methyl and r is 0 or 1,

(5) a group of the formula NC-(CH2)p- wherein p is an integer from 1-6, (6) a group of the formula A-(CH2)q- wherein A is a group selected from a pyridyl-, pyranyl and a morpholino group and q is an integer from 0 to 6, (7) a C 1 -C 8 alkynyl group in which a phenyl group is attached to any of the carbon atoms, (8) a group of the formula (9) a group with the formula in which R<8> and R<9> are the same or different and are a hydrogen atom, a lower alkyl group, a pyridylmethyl group or a C3-C6 cycloalkyl group or R8 and R<9> can together with a nitrogen atom form morpholino, piperidyl or pyridyl, and B is a phenylene group or a lower alkylene group having from 1-3 carbon atoms, (10) a group of the formula (11) a group of the formula < (12) a group of the formula (13) a Cj-Cg alkyl group or C2- C6-alkenyl group, or

(14) a C3-C6 cycloalkyl C2-C6 alkenyl group,

(15) where s is 0, 1 or 2 (16) where t is 1 or 2 (17)

(±o) a thenyl-C1-C8-alkyl group which is optionally

substituted with halogen

(19) a phenyl-C2-C6-<a>lkenyl group,

(20) wherein R<10> is hydrogen or phenyl, R<11> is hydrogen or lower alkyl, or (21)

wherein G is C2-C6 alkenyl

or -J-(CH2)k- in which J is sulfur and k is 0, 1 or 2,

with the condition that when X is

(a)

or (b) Y is a group selected from (1) to (12), and when X is (d) Y is a group (13) and when n is 0, Y is an alkynyl group (3), and with the further condition that when

Y can't

be a group selected from (1) in which the cycloalkyl group is unsubstituted, (3), (4) in which r = 0 and (5), and pharmaceutically acceptable salts thereof, which are characterized in that

) a compound of formula (II)

wherein X is or

and

n is 1,

plus a compound of formula (III)

wherein R<1>, R<2>, R<3> and R<4> are as indicated above, is subjected to a condensation reaction to give the intended compound of formula (I<1>) wherein X, n, Y , R<1>, R<2>, R<3> and R<4> are as indicated above, or b) a carboxylic acid in which Y is as indicated above or its reactive acid derivative and a compound of formula

wherein R1, R<2>, R<3> and R<4> are as defined above, is subjected to a condensation reaction to give the

intended compound of formula (I'')

wherein Y, R<1>, R<2>, R3 and R<4> are as indicated above,

c) a compound of formula (VII)

in which Y and R<6> are as indicated above and Hal is a halogen atom, is reacted with a compound of formula (III) in which R<1>, R2, R<3> and R<4> are as indicated in the preceding, to give the intended compound of formula (I<1>'<1>)

wherein Y, R<6>, R<1>, R<2>, R<3> and R<4> are as indicated in the

preceding, or

d) a compound of formula (VIII)

wherein Y is as indicated above and Hal is a halogen atom, is reacted with a compound of formula (III)

wherein R<1>, R<2>, R3 and R<4> are as defined above, to

to give the intended compound of formula (I"")

in which Y, R<1>, R<2>, R3 and R<4> are as indicated above, and if desired, the obtained compounds are converted into pharmaceutically acceptable salts thereof.

In the formula according to the present invention, X is preferably (a) or (b). n is preferably 1 when X is (a) or (b).

Y is preferably one of (1) to (14), and more preferably (4), (3), (14) and (2). The most preferred examples of Y include cyclopropyl and HC=C-C(CH3)2~.

R1 is preferably hydrogen and R2 is methyl. Preferred compounds have the formula (I) where R 3 is chlorine, R 1 is hydrogen, R 4 is methyl, n is 1, and Y-X- and R 2 are defined by one of the following combinations:

The compounds that can be prepared by the invention or their salts can be used in a pharmaceutical preparation in a pharmacologically effective amount together with a pharmacologically tolerable carrier. A method of treating a disease against which anti-PAF activity is effective comprises administering a pharmacologically effective amount of the compound or a salt thereof as set forth above. The disease can be an allergic disease such as asthma.

The 1,4-diazepine compounds of general formula (I) have good and sustained PAF-inhibiting action together with high safety.

In the compounds (I) produced in accordance with the present invention, the lower alkyl group indicated for R1, R2, R4, R5, R6, R8, R9 and R11 is a straight-chain or branched alkyl group with from 1-6 carbon atoms and includes, f .ex. a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group (amyl group), isopentyl group, neo-pentyl group, tert-butyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3- dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group or the like. Of these, preferred groups include a methyl group, ethyl group, propyl group and isopropyl group, wherein the methyl group is most preferred.

The cycloalkyl group defined by Y is a cycloalkyl group with from 3-6 carbon atoms such as e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Of these, cyclopropyl, cyclobutyl and cyclopentyl are most preferred. Cycloalkyl may have a substituent such as methyl.

The cycloalkylalkyl group is a group derived from the above-mentioned cycloalkyl group. Typical examples include cyclopentylmethyl, cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl groups.

The cycloalkylalkenyl group is a group derived from the above-mentioned cycloalkylalkyl group. Typical and preferred groups include e.g. those with the following formulas:

The alkynyl group is a group with from 1-6 carbon atoms and with a triple bond in any position. Typical alkynyl groups include e.g. CH-C-CH2, CH-C-CH2-CH2, CH-C-CH2-CH2-CH2-, CH-C-CH2-CH2-CH2-CH2~,

CH3-OC-CH2-CH2, and CH3-OC-CH2. Of these are

CH-C-CH2-, CH»C-C<H>2-CH2-, CH»C-CH2-CH2-CH2- and CH»C-CH2-CH2-CH2-CH2- most preferred.

In the formula under definition (4) of Y, R<7> is most preferably a methyl group.

In the formula under definition (5) of Y, p is preferred from 1-4.

In the formula under definition (7) of Y, an alkynyl group comprises from 1-6 carbon atoms, in which a phenyl group is attached to any carbon atom, e.g. those groups having the following formulas: As described above, Y is a lower alkyl group, preferably a methyl or ethyl group when X is a group of the formula

The phenyl-C2-C6-alkenyl group preferably comprises the following two:

The group (20) indicated for Y preferably includes the following:

The group (21) specified for Y preferably includes the following:

In connection with the present invention, X is preferably a group represented by the formula (a) A more preferred group is the group with the formula Groups with the formula (d) or the formula (c) are preferably used

When n is 0, good results are obtained.

A first preferred group of compounds produced according to the invention are those with the following chemical structural formula:

in which R<1>, R2, R<3>, R<4> and Y respectively have the same meaning as indicated above where Y is most preferably a group of the formula in which R7 is hydrogen or methyl and r is 0 or 1, a group with the formula NC-(CH 2 )p where p is an integer from 1-6, or a C 1 -C 8 alkynyl group. Most preferably, R<4> is a methyl group. in which R<1>, R<2>, R<3>, R<4> and Y respectively have the same meanings as stated above, in which Y is most preferably a C3-C6-cycloalkyl-C1-C8-alkyl group, a C3-C6 cycloalkyl-C2-C6 alkenyl group, a group of the formula

or a group represented by the formula NC-(CH2)p where p is an integer from 1-6.

Another preferred group of compounds are those with the chemical structural formula (C)

wherein R1, R2, R3, R<4>, R<5> and Y respectively have the same meanings as indicated above wherein Y is most preferably a group of the formula wherein R<7> is as indicated above, a group of the formula NC -(CH2)p- where p is an integer from 1-6, or a C1-C6 alkynyl group. As regards R<1> and R<2> for the compound (I) produced according to the invention, R<1> is most preferably a hydrogen atom and R<2> is a lower alkyl group, especially a methyl group. This is more particularly shown by the following general formula in which Ra is a lower alkyl group, R<3> is a halogen atom, R<4> is a hydrogen atom or a lower alkyl group, X is (a) a group of the formula (b) a group of the formula wherein R<5> is a hydrogen atom or a lower alkyl group, (c) a group of the formula or (d) a group of the formula

wherein R<6> is a lower

alkyl group, Y is (1) a C 3 -C 6 cycloalkyl group, (2) a C 3 -C 6 cycloalkyl C 1 -C 8 alkyl group, (3) a C 1 -C 8 alkynyl group,

(4) a group with the formula

(wherein R7 is a hydrogen

atom or a methyl group),

(5) a group of the formula NC-(CH2)p-, (wherein p is an integer from 1-6), (6) a group of the formula A-(CH2)p-, (wherein A is a group selected from a pyridyl group, a pyranyl group and a

morpholino group and p is an integer from 0-6),

(7) an alkynyl group of from 1 to 6 carbon atoms, (wherein a phenyl group is attached to any of the carbon atoms), (8) a group of the formula (9) a group of the formula (wherein R<8> and R<9 > are the same or different and are a hydrogen atom, a lower alkyl group, a pyridylmethyl group or a cycloalkyl group or R<8> and R<9> together with a nitrogen atom can form morpholino, piperidyl or pyridyl, and B is a phenylene group or a lower alkylene group with from 1-3 carbon atoms), (10) a group of the formula (11) a group of the formula (12) a group of the formula

(13) a lower alkyl group, or

(14) a C3-C8 cycloalkyl-C2-C6 alkenyl group, with the proviso else that when X is is Y a group selected from (1) to (12), and when X is (c) Y is a group (13) and when n is 0, Y is an alkynyl group (3), and with the further condition that when X =

cannot Y be a group selected from (1) in which

the cycloalkyl group is unsubstituted, (3), (4) in which r = 0 and (5). In addition, Y includes (15) to (21) as indicated above.

In the above-mentioned general formula (D), Ra is a lower alkyl group with from 1-6 carbon atoms as indicated for R<1> and R<2> and is most preferably a methyl group.

The preferred compound in which Ra is a methyl group is represented by the following general formula (E)

wherein Y, R<3> and R<4> respectively have the same meanings as given above and Z is a group of the formula or a group of the formula

The most preferred halogen atom for R<3> is a chlorine atom.

R<4> is preferably an alkyl group and most preferably a methyl group.

Y is most preferably a group of the formula

wherein R<7> is hydrogen or methyl and r is 0 or 1, a group of the formula NC-(CH2)p-, where p is an integer from 1-6, a C3-C6 cycloalkyl group, a C3-C6 -cycloalkyl C 1 -C 8 alkyl group, a C 3 -C 6 cycloalkyl C 2 -C 6 alkenyl group, or a group of the formula When Z is a group of the formula, Y is preferably an alkynyl group such as e.g. CH-C-CH2-, CH-C-CH2-CH2• CH-C-CH2-CH2-CH2 or CH-C-CH2-CH2-CH2-CH2, a group of the formula wherein R<7> has the same meaning as indicated above, or a group of the formula NC-(CH2)p- (wherein p has the same meaning as indicated above). When Z is a group of the formula Y is most preferably a C3-C6-cycloalkyl-C1-C6-alkyl group, a C3-C6-cycloalkyl-C2-C6-alkenyl group or a group of the formula

These compounds (E) and especially the compounds in which the methyl group is introduced into the diazepine ring, unexpectedly exhibit better anti-PAF activity than known 1,4-diazepine compounds, which will be described below.

The pharmacologically tolerable salts which are produced in accordance with the present invention are commonly applicable harmless salts such as e.g. inorganic salts such as hydrochlorides, hydrobromides, sulphates, phosphates and the like, organic salts such as acetates, maleates, succinates, methanesulfonates and the like, and salts of amino acids such as arginine, aspartic acid, glutamic acid and the like.

The compounds produced in accordance with the present invention have asymmetric carbon in the molecule and the compounds can be in the form of a number of stereoisomers. The individual isomers and mixtures thereof are all within the scope of the present invention. The compound (D) stated above has e.g. an asymmetric carbon atom when Ra is methyl and therefore includes stereoisomers. The isomers can be obtained using commonly used methods. Moreover, some of the compounds can also form hydrates.

The compounds are prepared by means of usual procedures, typical methods being described in the following'.

Manufacturing example 1

Compounds of the general formula (I) in which X has

the formula (a)

or formula (b) is prepared according to the following reaction scheme

wherein X, n, Y, R<1>, R<2>, R3 and R4 respectively have the same meanings as stated above.

The compound of formula (II) and the compound of formula (III) are subjected to a condensation reaction to obtain the compound of general formula (I') which is one of the intended compounds.

The reaction is usually carried out under solvent-free conditions or in an inert solvent selected from chloroform, tetrahydrofuran, diethyl ether, acetone, benzene, toluene and dimethylformamide. The reaction temperature is usually from room temperature to 150°C, most preferably from 100-130°C.

In the above reaction, the compound with the general formula (II) is prepared, which is used as a starting compound, e.g. in accordance with the following reaction core:

in which Y, X and n respectively have the same meanings as stated above and Hal is a halogen atom. In the above reaction scheme, the compound of general formula (IV) is subjected to a condensation reaction with the halide of general formula (V) to obtain the compound of general formula (II).

The reaction should preferably be carried out in the presence of bases including amines such as triethylamine, pyridine and the like, alkali metal hydrides such as sodium hydride, potassium hydride and the like, and alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like.

The reaction can be carried out in the presence or absence of a solvent. Examples of suitable solvents include ethers such as tetrahydrofuran, dioxane and the like, halogen-based compounds such as methylene chloride, chloroform and the like, benzene compounds such as benzene, toluene, xylene and the like, and compounds such as dimethylformamide, dimethylsulfoxide and the like.

Manufacturing example 2

The compounds in which X has the formula

and n = 1, is prepared according to the following reaction scheme: or its reactive acid derivative

wherein Y, R<1>, R<2>, R3 and R<4> are as indicated above.

More particularly, a carboxylic acid of the general formula (VI) or its reactive derivative and the compound of the general formula (III) are subjected to a condensation reaction to give the compound of the general formula (I") which is one of the intended compounds.

This condensation reaction is carried out in the usual way. The reactive derivatives include: acid halides such as acid chlorides, acid bromides and the like, acid azides, N-hydroxy-benzotriazole, active esters such as N-hydroxysuccinimide, symmetrical acid anhydrides, acid anhydrides in a mixture with alkali metal carbonates, p-toluenesulfonic acid and the like. The reaction is carried out by heating under solvent-free conditions or in a solvent that does not participate in the reaction, e.g. benzene, toluene, xylene, tetrahydrofuran, chloroform, carbon tetrachloride, dimethylformamide or the like, to give e.g. a dehalogenation reaction. Better results are obtained when the reaction is carried out in the presence of inorganic salts such as sodium bicarbonate, potassium carbonate, sodium carbonate, caustic soda and the like or organic bases such as triethylamine, pyridine, pyrimidine, diethylaniline and the like.

When free carboxylic acids are used, better results are obtained for the reaction in the presence of a condensing agent such as dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole or the like.

Manufacturing example 3

Compounds in which X has the formula

and n = 1, is produced according to the following reaction core:

wherein Y, R<1>, R<2>, R<3>, R<4> and R<6> respectively have the same meaning as stated above and Hal is a halogen atom.

The halide compound of the general formula (VII) and the compound of the general formula (III) are reacted to obtain the compound (I'<1>') which is an intended compound. The reaction is a dehydrohalogenation reaction which is carried out in the usual way with heating and under solvent-free conditions or in an inert solvent such as e.g. is selected from benzene, toluene, xylene, tetrahydrofuran, chloroform, carbon tetrachloride and dimethylformamide. Better results are obtained when the reaction is carried out in the presence of inorganic salts such as sodium bicarbonate, potassium carbonate, sodium carbonate and caustic soda or organic bases such as triethylamine, pyridine, pyrimidine, diethylaniline and the like.

Manufacturing example 4

The following reaction scheme is used for the preparation of compounds with the general formula (I) in which n = 0 in which Y, R<1>, R<2>, R3 and R<4> respectively have the same meaning as stated above and Hal is a halogen atom. The halide compounds of the general formula (VIII) and the compounds of the general formula (III) are reacted to obtain the compound (I"") which is an intended compound.

The reaction is a dehydrohalogenation reaction which is carried out in the usual way with heating and under solvent-free conditions or in an inert solvent such as e.g. is selected from benzene, toluene, xylene, tetrahydrofuran, chloroform, carbon tetrachloride and dimethylformamide. Better results are obtained when the reaction is carried out in the presence of inorganic salts such as sodium bicarbonate, potassium carbonate, sodium carbonate and caustic soda or organic bases such as triethylamine, pyridine, pyrimidine, diethylaniline and the like.

The starting compound (III) used in the above-mentioned production examples 1-4 can e.g. produced according to the following procedure:

wherein R1, R2, R<3> and R<4> respectively have the same meanings as stated above. In the above reaction, the thioamine compound of the general formula (IX) is subjected to a hydrolysis reaction to obtain the compound of the general formula (III).

The reaction is carried out in the usual way in which the compound of the general formula (III) can be obtained by heating in the presence of e.g. sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium methoxide or the like. A solvent can be used in connection with the above reaction, e.g. an alcohol solvent such as methyl alcohol, ethyl alcohol, or the like, tetrahydrofuran, dimethoxyethane or an aqueous solvent.

When R<1> is a hydrogen atom, R<2> is a methyl group and R<4> is a methyl group in the above starting compound (III), the production process can be more particularly described as follows: in which the mark "<*>" is an asymmetric carbon atom and (XVIII) comprise the respective enantiomers.

The respective steps indicated above are briefly shown in the following.

(First step)

2-Bromopropionyl bromide of the formula (XI) is subjected to condensation reaction with the compound of the general formula (X) in a conventional manner to obtain the compound of the general formula (XII).

This reaction is carried out in a two-phase system (under Schotten-Bauimann conditions) by an organic solvent such as e.g. toluene, benzene, xylene and the like in the presence of either alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or the like or a base such as sodium hydrogen carbonate, potassium hydrogen carbonate or the like.

Alternatively, the reaction can be carried out in the presence of a base comprising an amine such as triethylamine, pyridine or the like, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or the like or an alkali metal hydride such as sodium hydride, potassium hydride or the like in an inert solvent such as e.g. dichloromethane, dichloroethane, tetrahydrofuran, toluene, benzene, xylene, dimethylformamide or the like.

(Second step)

In this step, ammonia gas is added to the compound of the general formula (XII) in the usual manner to obtain the compound (XIII). This reaction should preferably be carried out at low temperatures from e.g. 30-100°C. The reaction is carried out in solvent-free conditions or by using a suitable inert solvent selected from ethers such as tetrahydrofuran, dioxane and the like, ethyl acetate, chloroform, methanol, ethanol, pyridine and dichloroethane.

(Third step)

In this step, the compound of general formula (XII) is subjected to a dehydration reaction in the usual manner leading to ring formation to obtain the compound of general formula (XIV).

One of the procedures is specifically described. The compound is dissolved in a suitable inert solvent such as e.g. benzene, toluene, xylene, pyridine or the like, to which an equivalent of an acidic catalyst such as acetic acid, silica gel or the like is added. While removing the water formed during the reaction using a dehydrator or using a Dean Stark apparatus, the reaction system is heated.

(Fourth step)

In this step, phosphorus pentasulfide is added to the compound of general formula (XIV) to obtain the compound of general formula (XV). The reaction is carried out in a solvent such as pyridine, dimethoxyethane, diglyme, tetrahydrofuran, toluene, benzene, xylene or the like. The reagent may, apart from phosphorus pentasulfide, be Lauson's reagent, (2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphos-phetane-2,4-disulfide). In some cases, the reaction is carried out in the presence of a base such as sodium bicarbonate.

(Fifth step)

This step comprises the reaction in which acetohydrazide is reacted with the compound of general formula (XV) to give the cyclization reaction, thereby obtaining a compound of general formula (XVI). The reaction is carried out by heating acetohydrazide in an inert solvent such as e.g. dioxane, dimethoxyethane, diglyme or the like or under solvent-free conditions. Alternatively, the hydrazide hydrate is reacted in a solvent such as methanol or ethanol and the resulting hydrazide is reacted with ethyl orthoacetate to give the intended product. Alternatively, the hydrazide can be further reacted with acetyl chloride or acetic anhydride and the product obtained dehydrated to give the compound (XVI).

(Sixth step)

In this step, the compound of general formula (XVI) is hydrolyzed in the usual manner to obtain the compound of general formula (XVII). The reaction is carried out according to known procedures. The heating in the presence of potassium hydroxide, sodium hydroxide, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium methoxide or the like results e.g. in connection with the general formula (XVII). For this reaction, solvents can be used which include the alcohol solvent such as ethyl alcohol or methyl alcohol, tetrahydrofuran, dimethoxyethane or aqueous solvents.

A particular example of obtaining compounds of the general formula (XVII) by means of the above reaction series is shown in the introductory example given below in which R<3> is a chlorine atom.

The compound of the general formula (XVII) is a new compound and an important intermediate for obtaining the final compounds with good anti-PAF activity. More particularly, the final compounds prepared through the intermediate (ie the compounds of the general formula (I) in which R<1> is a hydrogen atom and R<2> is a methyl group) exhibit unexpectedly higher anti-PAF activity than known 1 ,4-diazepine compounds. Thus, the compounds of the general formula (III), in which R<1> is a hydrogen atom and R<2> is a lower alkyl group, especially a methyl group, are valuable as intermediates.

The intermediates have asymmetric carbon atoms and optical isomers are therefore present. According to the present invention, dl products can, if desired, be dissolved into optically active products.

The dissolution may be carried out in the step of the compound of the general formula (XIII) wherein an optical dissolving agent such as (+) or (-)-tartaric acid, ( + ) or (-)-camphoric acid,

(+) or (-)-dibenzoyltartaric acid, (+) or (-)-camphorsulfonic acid, (+) or (-)-mandelic acid or the like can be used for the solution. Alternatively, the dissolution can be carried out in the step with the compounds of general formula (III) or (XVII) using an optical dissolving agent such as dibenzoyl-D-tartaric acid or dibenzoyl-L-tartaric acid. Furthermore, resolution is possible in the step with the compounds of the general formula (XIII), (XVII) or (III) when using a column for resolution of optical isomers such as e.g. chiral polyamide silica gel HPLC (eluent: tetrahydrofuranhexane).

Other compounds than those described can be obtained in the same way by changing the respective starting materials.

The effects of the compounds produced according to the present invention are described more specifically by means of the following experimental example.

Experimental example

PAF receptor binding assay for human platelets

(Method)

Platelets are obtained from healthy men according to a commonly used method and suspended in a binding buffer to a concentration of 10<8> platelets/460 µl (10 mM phosphate buffer saline (pH 7.0), with 0.1% (wt/ volume) BSA and 0.9 nM CaCl2). Platelets (10<8>) in 460 µl of the buffer were added to polypropylene tubes and preincubated with the test compounds (20 µl), after mixing, for six minutes at 37°C. Then 20 µl of a binding buffer solution of <3>H-PAF (final <3>H-PAF concentration 0.6-1 nM) was added to the tubes which were incubated for six minutes. The binding reaction was stopped by the addition of 3 ml of an ice-cold wash solution (saline solution containing 0.1% (w/v) BSA). Platelets were isolated by vacuum filtration on glass filters (Whatman GF/C). After drying the glass filter, the radioactivity on the glass filter was measured in a scintillator with a liquid scintillation counter.

Percent inhibition is calculated according to the following equation and the value for IC is determined by interpolation from the figure.

Inhibition % =

Total binding: radioactivity of binding in the absence of cold

PAF or test compounds

Non-specific

binding: radioactivity of binding in the presence of IO"<5> M

PAF

These results are shown in table (1).

Non-specific

binding: radioactivity (dpm) after incubation with 10~<5>

M cold PAF

The results are shown in table 1.

The marking "<*>" indicates asymmetric carbon atoms and the markings "(+) and "(-)" indicate specific rotation.

As shown in Table 1, it is clear that these compounds prepared in accordance with the invention have anti-PAF activity. It has also been found that the compounds have a stronger and longer-acting anti-PAF activity and are safer than known compounds. The compounds produced according to the present invention thus have a great advantage. Accordingly, the compounds will be effective in the therapy and prophylaxis of all diseases mediated by PAF. Typical diseases in which the compounds are useful as a therapeutic and prophylactic agent include allergic diseases, asthma, thrombosis, cerebral apoplexy (cerebral hemorrhage, cerebral thrombosis), myocardial infarction (angina pec-toris), human disseminated intravascular coagulation syndrome (DIC), thrombophlebitis, glomerular hepatitis , anaphylactic shock, haemorrhagic shock and the like. The compounds prepared in accordance with the present invention are particularly useful as an anti-allergy agent and an anti-asthma agent.

When these compounds are administered as an anti-PAF agent, they can be administered orally in the form of tablets, powders, granules, capsules, syrups or the like. They can alternatively be administered parenterally in the form of suppositories, injections, externally or in the form of a drip. The compounds are preferably administered orally.

The dose may depend on the type of disease, the degree of symptoms and age. When the compounds are administered orally, doses from 0.001-10 mg/kg, preferably from 0.01-0.5 mg/kg will be advantageous.

For the preparation of doses that are used orally and parenterally, this can be carried out by using common pharmaceutically acceptable additives. For the preparation of injections or drips, pH modifiers, buffer solutions, stabilizers and solvents are added to the main substance if necessary. The mixture can, if necessary, be freeze-dried for the preparation of injections for subcutaneous, intramuscular, intravenous or drip administration.

EXAMPLES

In the following, typical examples of the compounds are given

produced in accordance with the present

5 invention.

It should be noted that the preparation of starting compounds or substances is described as sub-examples.

10 Example 1 6-(2-chlorophenyl-3-(1-cyano-1-methylethoxycarbonyl)-11-methyl-2,3,A,5-tetrahydro-8H-pyrido-[4',3':4,5 ]- thieno-[ 3, 2- f]-[ 1, 2, 4]- triazolo-[ 4, 3- a][ 1, 4]- diazepine

(1) Synthesis of 1-cyano-1-methylethylphenylcarbonate30 1.40 g (9 mmol) of phenylchloroformate was dropped into a pyridine solution (20 ml) of 0.85 g (10 mmol) of acetone cyanohydride under cooling on ice followed by stirring for 30 minutes. After completion of the reaction, the solvent was distilled off to obtain a residue which was dissolved in chloroform followed by washing with 1 N hydrochloric acid and a saturated aqueous sodium bicarbonate solution followed by drying with magnesium sulfate. The product obtained was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane = 1:49), thereby quantitatively obtaining the intended compound in the form of a colorless solid. (2) Synthesis of 6-(2-chlorophenyl)-3-(1-cyano-1-methylethoxycarbonyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3 ':4,5]-thieno-[3,2-f] [1,2,4]-triazolo-[4,3-a] [1,4]-diazepine

0.15 g of 1-cyano-1-methylethylphenyl carbonate and 0.15 g of 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4 ,5]-thieno-[3,2-f](1,2,5]-triazolo-[4,3-a][1,4]-diazepine was dissolved in chloroform to a uniform mixture after which the solvent was distilled off. The obtained mixture was stirred in a bath at a temperature of 120° C. for one hour. After cooling and purification by means of silica gel column chromatography (eluent: chloroform: methanol = 99:1), 0.18 g of the intended product obtained in the form of an amorphous substance.

• <1>H-NMR (90MHz, CDC13) 5

1.77(6H,s). 1.80 - 2.20 (2H.m). 2.68(3H,s), 3.10 -

3.60(2H,m). 4.22(lH.m). 4.50 - 4.88(2H,m), 5.60(1H,m).

7.35(4H,m)

• FABMS (M+H<+>) m/z:481

Example 2

6-( 2- chlorophenyl)- 3-( 3- cyanopropoxycarbonyl)- ll- methyl- 2, 3, 4, 5-tetrahydro- 8H- pyrido-[ 4', 3' :4', 5']- thieno- [ 3, 2- f ] [ 1, 2, 4]-triazolo-[ 4, 3- a][ 1, 4]- diazepine

(1) Synthesis of 3-cyanopropylphenyl carbonate 1.50 g of phenylchloroformate was dropped into a chloroform solution (20 ml) of 0.85 g of 4-hydroxybutyronitrile and 1.50 g of pyridine under cooling on ice followed by stirring for 30 minutes. After completion of the reaction, the reaction mixture is washed with a saturated aqueous sodium bicarbonate solution and dried with magnesium sulfate after which the solvent was distilled off followed by purification by silica gel column chromatography (eluent: ethyl acetate:n-hexane = 3:17), obtaining 1.20 g of the intended compound . (2) Synthesis of 6-(2-chlorophenyl)-3-(3-cyanopropoxycarbonyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3<1>:4, 5]-thieno-[3,2-f][1,2,4]-triazolo-[4,3-a][1,4]-diazepine

0.11 g of 1-cyanopropylphenyl carbonate and 0.13 g of 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3<*>:4,5 ]-thieno-[3,2-f][1,2,4]-triazolo-[4,3-a][1,4]-diazepine was dissolved in chloroform and the mixture was made homogeneous after which the solvent was distilled off . The resulting mixture was stirred at a bath temperature of 110°C for one hour. After cooling, purification by silica gel column chromatography (eluent: chloroform:methanol = 49:1) gave 0.10 g of the intended product.

<1>H-NMR (90MHz. CDC13) <5

1.41 - 1.80(m, 2H), 1.80 - 2.17(m, 2H). 2.22 - 2.52(m.2H).

2.60(p. 3H), 2.80 - 5.76(m. 6H), 4.20(t, J=7Hz, 2H), 7.30(m. 4H)

FABMS (M+H<+>) m/z.-481

Example 3

3-(3-butynyloxycarbonyl)-6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5]-thieno-[3 , 2- f] [ 1, 2, 4]-triazolo-[ 4, 3- a][ 1, 4]- diazepine

(1) Synthesis of 3-butynylphenyl carbonate

1.70 g of phenylchloroformate was dropped into a dichloromethane solution (20 ml) of 0.70 g of 3-butyn-1-ol and 1.50 g of pyridine while cooling on ice followed by stirring for 30 minutes.

After completion of the reaction, the reaction mixture was washed with a saturated aqueous sodium bicarbonate solution and dried with magnesium sulfate, after which the solvent was distilled off followed by purification by silica gel column chromatography (eluent: ethyl acetate:n-hexane = 1:49), whereby the intended compound was obtained in a quantitative yield in form of a colorless oil.

(2) Synthesis of 3-(3-butynyloxycarbonyl)-6-(2-chlorophenyl-propoxycarbonyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4, 5]-thieno-[3,2-f][1,2,4]-triazolo-[4,3-a][1,4]-diazepine

0.10 g of 3-butynylphenyl carbonate and 0.18 g of 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5]- thieno-[3,2-f][1,2,4]-triazolo-[4,3-a][1,4]-diazepine was dissolved in chloroform and the mixture was made homogeneous after which the solvent was distilled off. The resulting mixture was stirred at a temperature of 110°C for one hour. After cooling and purification by silica gel column chromatography (eluent: chloroform:methanol = 99:1), 0.17 g of the intended product was obtained.

• <1>H-NMR (90MHz. CDC13) 6

1.60 - 2.16 (m. 2H). 1-94 (p. 3H). 2.50(dt. J=2Hz. 7Hz. 2H).

2.66 (p. 3H). 2.86 - 5.74 (m. 6H). 4.17(t. J=7Hz. 2H). 7.29 (with 4H)

• MS m/z (Pos. Fab) :466(M+H)<+>

Example 4

6-( 2- Chlorophenyl)- 3-( 2- Cyanoethylaminocarbonyl)- 11- methyl-2, 3, 4, 5- tetrahydro- 8H- pyrido-[ 4', 3' :4, 5]- thieno-[ 3 , 2-f][ 1, 2, 4]- triazolo-[ 4, 3- a][ 1, 4]- diazepine

(1) Synthesis of N-(2-cyanoethyl)-carbamate 1.40 g of phenylchloroformate was dropped into a dichloroethane solution (20 ml) of 0.70 g of 3-aminopropionitrile and 1.20 g of triethylamine by cooling on ice followed by stirring for 30 minutes. After completion of the reaction, the reaction mixture was washed with a saturated aqueous sodium bicarbonate solution and dried with magnesium sulfate, after which the solvent was distilled off, followed by purification by silica gel column chromatography (eluent: ethyl acetate:n-hexane = 1:9), whereby 1.30 g of the intended compound was achieved. (2) Synthesis of 6-(2-chlorophenyl)-3-(2-cyanoethylaminocarbonyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5] -thieno-[3,2-f][1,2,4]-triazolo-[4,3-a][1,4]-diazepine

1Z

0.09 g of N-(2-cyanoethyl)-carbamate and 0.18 g of 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3' :4,5]-thieno-[3,2-f][1,2,4]-triazolo-[4,3-a][1,4]-diazepine was dissolved in chloroform and the mixture was homogenized after which solution - the agent was distilled off. The resulting mixture was stirred at 140°C for one hour. After cooling, purification by silica gel column chromatography (eluent: chloroform:methanol = 19:1) gave 0.12 g of the intended compound.

<1>H-NMR (90MHz, CDCl3) 8 ;

1.45 - 2.23(m, 2H), 2.60(t, J=7Hz, 2H), 2.64(s,3H), 2.80 -

5.69(m. 9H), 7.29(m, 4H)

MS m/z (Pos, Fab):466 (M+H)<+>

Example 5

6-(2-Chlorophenyl)-II-methyl-3-(2-propynyl)-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5]-thieno-[3 , 2-f][ 1, 2, 4]- triazolo-[ 4, 3-a][ 1, 4]- diazepine

30 mg of sodium hydride (60%) was added to a dimethylformamide solution (20 ml) of 0.12 g of 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[ 4',3':4,5]-thieno-[3,2-f] [1 1 2,4]-triazolo-[4,3-a] [1,4]-diazepine at room temperature followed by stirring at 60°C for one hour. 60 mg of 3-bromo-propyne was added at room temperature and the mixture was stirred at 60°C for one hour. After cooling, water was added to the reaction mixture which was then extracted with ethyl acetate and magnesium sulfate, followed by removal of the solvent and purification by silica gel column chromatography (eluent: chloroform:methanol = 98.5:1.5) to obtain 20 mg of the intended product.

'H-NMR (90MHz, CDC13) 6

1.52 - 2.12(m, 2H), 2.25(t, J=2Hz, 1H), 2.16 - 2.84(m,2H),

2.66(s. 3H), 3.45(d. J=2Hz,2H), 3.74(m. 2H), 3.90 - 4.40, 5.20 -

5.76(2m. 2H), 7.27(m. 2H)

• MS m/z: 407

Example 6

6-(2-chlorophenyl)-3-cinnamoyl-ll-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5]-thieno-[3,2-f ][ 1, 2, 4]- triazolo-[ 4, 3-a][ 1, 4]- diazepine

80 mg of cinnamoyl chloride was dissolved in 8 ml of N,N-dimethylformamide

to which 4 ml of an N,N-dimethylformamide solution of 120 mg of 6-(2-chlorophenyl)-3-cinnamoyl-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3': 4,5]-thieno-[3,2-f][1,2,4]-triazolo-[4,3-a][1,4]-diazepine and 160 mg of triethylamine were added dropwise,

followed by stirring the mixture. After removal of the solvent by distillation, a saturated aqueous sodium bicarbonate solution was added, followed by extraction with chloroform and drying with anhydrous magnesium sulfate. The solution was filtered off and, after removal of

the solvent by distillation, the residue was submitted

> silica gel column chromatography (eluent:

MeOH:CH2Cl2 = 1:99) to give 11 mg of the intended compound (yield 68%).

MS m/z (Pos. Fab): 500 (M+H)<+>

Example 7

6-(2-Chlorophenyl)-3-diethylphosphorus-II-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5]-thieno-[3,2-f ][ 1, 2, 4]- triazolo-[ 4, 3-a][ 1, 4]- diazepine

100 mg 6-(2-chlorophenyl-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3*:4,5]-thieno-[3,2-f] [1 ,2,4]-triazolo-[4,3-a] [1,4]-diazepine was dissolved in 5 ml of tetrahydrofuran and 1 ml of triethylamine to which 100 mg of diethylchlorophosphate was added, after which

the mixture was stirred at room temperature for one hour. The reaction solution was added to a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate and drying with anhydrous magnesium sulfate. The solvent was removed for concentration under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: CH 3 OH:CH 2 Cl 2 = 5:95) to give 100 mg of the intended compound (yield 72%).

MS(FAB)(M+H)<+> - 506

NMR (90MHz):

1.28(t, 6H, J=8.0), 1.44 - 2.20(m. 2H), 2.69(s. 3H), 3.70 - 4.60(m.9H), 5.33 - 5.72(m,lH), 7.12 - 7.48(m ,5H) Example 8 3-(3-butynyloxycarbonyl)-6-(2-chlorophenyl)-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5]- thieno-[ 3, 2- f ]-[1,2,41-triazolo-f 4,3-a1 Tl,41-diazeDin

To a solution of 57 mg of 3-(3-butynyloxycarbonyl)-6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5 ]-thieno-[3,2-f][1,2,4]-triazolo-[4,3-a][1,4]-diazepine dissolved in dimethylformamide (2 ml) was added 28 mg of sodium hydride (55 %) and 0.2 ml of methyl bromide, after which the solution was stirred at room temperature for one hour.

Water was added to the solution to stop the reaction and the solution was neutralized with acetic acid. The solvent was distilled off under reduced pressure and the residue was extracted with 10 ml of dichloromethylene and then with 20 ml of dichloromethylene. The solution was dried with magnesium sulfate and the solvent was removed, followed by purification by silica gel column chromatography (400 mesh, 10 g, eluent: methanol:dichloromethane = 1:99), obtaining 24 mg of the intended compound.

• NMR (90MHz. CDC13):

7.4(5H.Ar). 4.9(1H,d,J=18Hz, N-CH2[C-2]). .5(1H.d,J=18Hz,N-CH2[C-2]). 4.2(1H,m,CS-H), .1(2H,t.J=8Hz.0-CH2), 2.7(3H,s). 2.5(2H.dt,J=1, 7HzE-CH2),

.l(3H,d,J=7Hz CHCH3), 3.0 - 2.0(5H,m)

Example 9

6-( 2- chlorophenyl)- 8, 11- dimethyl- 3-( 3- cyanopropoxycarbonyl)-2, 3, 4, 5- tetrahydro- 8H- pyrido-[ 4', 3' :4, 5]- thieno- [ 3, 2- f]-[ 1, 2, 4]- triazolo-[ 4, 3- a][ 1, 4]- diazepine

To a solution of 62 mg of 6-(2-chlorophenyl)-3-(3-cyano-propoxycarbonyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4 ,5]-thieno-[3,2-f]-[1,2,4]-triazolo-[4,3-a][1,4]-diazepine dissolved in 2 ml of dimethylformamide, 34 mg of sodium hydride (55%) and 0.2 ml of methyl bromide, after which the mixture was stirred at room temperature for one hour. Water was added to the solution to quench the reaction and the solution was neutralized with acetic acid. The solvent was distilled off under reduced pressure and the residue obtained was extracted into 10 ml of dichloromethylene and then with 20 ml of dichloromethylene. The solution was dried with magnesium sulfate and the solvent was removed, followed by purification by silica gel column chromatography (400 mesh, 10 g, eluent: methanol:dichloromethane = 1:99), obtaining 21 mg of the intended compound.

• NMR (90MHz, CDCla):

7.4(5H.Ar). 4.9(1H,d.J=18Hz. N-CHa[C-2]). 4.5(lH.d.J=18Hz,N-CH2[C-2]). 4.2(lH.m.Cs-H). 4.1(2H,t,J=8Hz,0-CH2), 2.7(3H,s), 2.4(3H,d,J=7Hz),

2.l(3H,d,J=7Hz CHCHs), 3.0 - 2.0(6H.m)

Example 10

6-(2-chlorophenyl)-8,8-diethyl-3-(3-butynyloxycarbonyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5 ]- thieno-[ 3, 2- f]-[ 1, 2, 4]- triazolo-[ 4, 3- a][ 1, 4]- diazepine

CH 3— .^iK

\N

II _ S N -U/

NCCHaCHaCH2QC -N^jj Y \^CH2CH3

/<=>N CH aCH3

To a solution of 69 mg of 6-(2-chlorophenyl)-3-(3-butynyloxy-carbonyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4 ,5]-thieno-[3,2-f]-[1,2,4]-triazolo-[4,3-a][1,4]-diazepine dissolved in 2 ml of dimethylformamide at room temperature was added 10 mg sodium hydride (55%) and 0.03 ml methyl bromide followed by stirring at room temperature for two hours.

Thin layer chromatography showed the presence of the starting compound and two new products comprising a monoethyl product and a diethyl product. Accordingly, 10 mg of sodium hydride and 0.03 ml of ethyl bromide were further added and stirred for two hours, after which water was added to the solution to stop the reaction and the solution was then neutralized with acetic acid. The solvent was distilled off under reduced pressure and the residue obtained was extracted into 10 ml of dichloromethylene and then with 20 ml of dichloromethylene. The solution was dried with magnesium sulfate and the solvent was removed, followed by purification by silica gel column chromatography (400 mesh, 13 g, eluent: methanol:dichloromethane = 1:99), obtaining 41 mg of the intended compound.

NMR (90MHz, CDCl3):

7.4(5H,Ar), 4.9(1H,d,J=18Hz, N-CH2[C-2]), 4.5(lH.d.J=18Hz.N-CHs[C-2]), 4.1(2H,t.J = 8H2,0-CH2), 2.7(3H,s,CH3). 2.0 - 2.7(10H.n), 1.3(6H,t,J=7Hz,CH2CH3) Example 11 3-(3-butynyloxycarbonyl)-6-(2-chlorophenyl)-8,8-diethyl-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4 , 5] - thieno-[ 3, 2- f]-[ 1, 2, 4]- triazolo-[ 4, 3- a][ 1, 4]- diazepine

The general procedure of Example 9 was repeated using 65 mg of 3-(3-butynyloxycarbonyl)-6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4' ,3':4,5]-thieno-[3,2-f]-[1,2,4]-triazolo-[4,3-a][1,4]-diazepine as 23 mg of the intended compound was achieved.

NMR (90MHz. CDCls):

7.4(5H.Ar). 4.9(1H,d,J=18Hz, N-CH2[C-2]),

4.5(lH.d,J=18Hz,N-CH2[C-2]), 4.1(2H,t,J = 8H2.0-CH2),

2.7(3H,s.CH3), 2.0 - 2.7(8H.n,CH2CH3 and CHgCHs).

1. 3 ( 6H . t, J = 7Hz . CH2CH_3)

Example 12

6-(2-chlorophenyl)-3-(1-cyano-1-methylethoxycarbonyl)-7,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5 ]- thieno-[ 3, 2- f][ l, 2, 4]- triazolo-[ 4, 3- a][ 1, 4]- diazepine

0.24 g of sodium hydride (60%) was added to a solution of 1.12 g of the compound obtained in Example 1 in N,N-dimethylformamide (3 ml) while cooling on ice, after which the mixture was stirred for 13 minutes. Then 0.37 ml of methyl bromide was added to the solution which was stirred by cooling on ice for 30 minutes and then at room temperature for one hour. After completion of the reaction, water was added, followed by extraction with chloroform and drying with magnesium sulfate. The rest that remained

obtained after filtration and concentration was purified by silica gel column chromatography (eluent: chloroform:methanol = 99:1), obtaining 0.19 g of the intended compound.

• <1>H-NMR (90MHz. CDC13) 6 :

1.76 (p. 6H). 1.80 - 2.20(m,2H). 2.10(d,3H). 2.66(p.3H), 3.0 -

3.9(m,2H), 4.24(q,1H), 4.3 - 4.9(m,2H). 7.35 (m. 4H).

• FABMS[M+H<+>] m/z: 495

Examples 13-60

In the same manner as in the above example, the following compounds were prepared.

Example 13

6-(2-Chlorophenyl)-3-(1-cyano-1- methylethoxycarbonyl)- 8. 8. 11-trimethyl- 2. 3. 4. 5- tetrahydro- 8H- pyrido- T4'. 3' :4. 51- thieno-T3. 2- fl n. 2. 41- triazolo- r4. 3- a1 fl. 41- diazepine

• 'H-NMR (90MHz, CDC13) <5 :

1.8(p.6H), 2.8(p.3H), 3.1(p.3H), 3.0 - 3.9(m.4H). 3.8 (p. 3H). 4.4 - 4.9(m,2H), 7.4(m,4H) Example 14 6-(2-chlorophenyl)-3-(cyclopropylmethylaminocarbonyl)-11-methyl-2. 3. 4. 5-tetrahydro-8H-pyrido-f4'. 31:4. 5l- thieno- f3. 2- fl-fl.2.41-triazolo-U.l-al fl. 41- diazepine

• 1 H-NMR (90MHz. CDCI3) <5 :

0.04 - 0.32(ra,2H), 0.36 - 0.60(m.2H). 0.70 - 1.16 (m.lH).

1.52 - 2.17(m.2H), 2.66(s,3H). 2.84 - 5.85(m, 7H).

3.04(dd.J=6Hz,7Hz.2H). 7.32(m,4H)

• FABMS(M+H<+>) m/z:467

Example 15

6-(2-Chlorophenyl)-3-(1-ethynylcyclohexylaminocarbonyl)-11-methyl-2. 3. 4. 5-tetrahydro-8H-pyrido-U'.3':4.51-thieno-T3.2-f1-f1. 2. 41-triazolo-f4. 3- al Tl. 41- diazepine

- 1 H-NMR (90MHz, CDC13) «5 :

1.12 - 2.24(m, 12H). 2.37(p.lH). 2.80 - 5.76(m.7H),

7.29(m,4H)

• FABMS(M+H<+>) m/z:519

Example 16

6-(2-chlorophenyl)-3-(5-cyanopentylaminocarbonyl)-11-methyl-2. 3. 4. 5- tetrahydro-8H-pv rido- f41. 3' :4. 5l- thieno-f3.2-fl-fl.2.41-triazolo-f4.3-al Tl.41- diazepine

• 1 H-NMR (90MHz. CDC13) <5 :

1.28 - 2.16(m.8H). 2.32(t . J = 7Hz,2H) , 2.81 - 5.68(m.9H).

7.29(m.4H)

• FABMS(M+H<+>) m/z: 508

Example 17

6-(2-chlorophenyl)-3-(4-cyanophenylaminocarbonyl)-11-methyl-2. 3. 4. 5-tetrahydro-8H-pyrido-U'. 3' :4. 51- thieno- T3. 2- f1-f 1. 2. 41-triazolo- T4. 3- a1 f1.41-diazepine

1.55 - 2.18 (m.2H). 2.67 (p. 3H). 3.80 - 5.70 (m.6H).

7.32 (ra.4H). 7.47 (m. 4H). 8 . 40(br.s.1H)

• FABMS(M + H *) m/z: 514

Example 18

6-(2-chlorophenyl)-3-(3-cyanophenylaminocarbonyl)-11-methyl-2. 3. 4. 5-tetrahydro-8H-pyrido-f4'. 3' :4.5l-thieno-f3.2-f1-fl, 2. 41-triazolo-f4 . 3- al fl. 41- diazepine

• <1>H-NMR (90MHz, CDC13) 5 :

1.43 - 2.17(m,2H). 2.63(s,3H), 3.04 - 5.68(m.6H). 7.05 -

7.72(m.8H)

• FABMS(M+H<+>) m/z: 514

Example 19

6-(2-chlorophenyl)-3-(3-ethynylphenylaminocarbonyl)-11-methyl-2. 3. 4. 5-tetrahydro-8H-pyrido-U'. 3' :4. 5l-thieno-T3. 2- fl-Tl.2.41-triazolo-U.3-al W.41- diazepine

1.40 - 2.40 (m.2H). 2.66(p.3H), 3.01(p.1H). 3.05 -

5.08(m.6H). 6.64(br.s.1H), 6.88 - 7.48(m,8H)

• FABMS(M+H<+>) m/z: 513

Example 20

6-(2-chlorophenyl)-II-methyl-3-(morpholine-4-vi)-carbonyl-2.3.4.5-tetrahydro-8H-pyrido-f4'. 3' :4. 5l - thieno- f3. 2- f1 fl. 2. 41 - triazolo-T4.3-al ri.41-diazepine

• 'H-NMR (90MHz, CDC13) <5 :

1.32 - 2.44(m.2H), 2.66(s,3H), 2.92 - 5.80(m,6H),

3.21(t,J=6Hz,4H), 3.63(t.J=6Hz,4H), 7.29(m,4H)

• FABMS(M+H<+>) m/z: 483

Example 21

6-(2-chlorophenyl)-3-(1-e thynylcyclopentylaminocarbonyl)-11-methyl-2.3.4.5-tetrahydro-8H-pyrido- T41. 3' :4. 5l- thieno- f3. 2- f1-fl. 2. 41- triazolo- \ A . 3- al fl. 41- diazepine

• 'H-NMR (90MHz, CDC13) <5 :

1.40 - 2.44(m, 10H). 2.56(s,1H), 2.67(s,3H). 2.90 -

5.80(m,6H), 7.29(m,4H)

• FABMS(M+H<+>) m/z: 506

Example 22

6-(2-chlorophenyl)-3-(1.1-dimethyl-2-propynyloxycarbonyl)-11-methyl-2. 3. 4. 5- tetrahydro- 8H- pyrido- U'. 31:4. 5l-thieno-r3. 2- 1-ri,2.41-triazolo- \ 4.3- al fl. 41- diazepine

• <1>H-NMR(90 MHz, CDC13) 5 :

1.40 - 2.18(m, 2H). 1.68(p.6H), 2.53(p,lH), 2.67(p.3H),

2.90 - 5.76(m, 6H). 7.30 (m. 4H)

• FABMS (M+H<+>) m/z:480

Example 23

6-(2-Chlorophenyl)-11-methyl-3-(1-methyl-2-propynyloxycarbonyl)-2. 3. 4. 5-tetrahydro-8H-pyrido-f4'. 3' :4. 51- thieno- f3. 2- f1-Tl.2.41-triazolo-r 4.3-al fl.41- diazepine

• <1>H-NMR(90 MHz, CDC13) 6 :

1.38 - 2.32(m, 2H). 1.50(d,J=7Hz,3H), 2.45(d,J=2Hz,1H),

2.66(s.3H), 2.88 - 5.70(ra,6H), 5.34(dq,J=2Hz,7Hz.1H).

7.29(m,4H)

FABMS (M+H<+>) m/z:466

Example 24

6-(2-Chlorophenyl)-11-methyl-3-(1-methyl-3-butynyloxycarbonyl)-2,3,4,5-tetrahydro-8H-pyrido-f4'.3':4. 5l- thieno- f3. 2- f1 - Tl,2,41-triazo lo- r 4. 3- al \ 1 , 41- diazepine

■ 'H-NMR (90 MHz. CDC13) 6 :

1.30(d,J=7Hz,3H), 1.50 - 2.60(m,5H). 2.66(s,3H), 2.88 -

5.72(m,7H), 7.29(m,4H)

• FABMS (M+H<+>) m/z:480

Example 25

6-(2-Chlorophenyl)-11-methyl-3-(2-pentyloxycarbonyl)-2.3.4.5-tetrahydro-8H-pyrido-f4'.3':4 . 51- tieno- f3, 2- f1 fl. 2. 41-tri-azolo-f4. 3- al fl. 41- diazepine

1H-NMR (90 MHz, CDCl 3 ) «5 :

1.13(d.J = 7Hz,3H). 1.54 - 2.36(m.2H). 2.25(tq,J=2Hz, 7Hz .

2H). 2.67(s,3H), 2.84 - 5.76 (m,6H). 4.66(t.J=2Hz.2H).

7.30 (m, 4H)

• FABMS (M+H<+>) m/z:480

Example 26

6-(2-chlorophenyl)-II-methyl-3-(3-pentynyloxycarbonyl)-2.3.4.5-tetrahydro-8H-pyrido-f4'. 3' :4. 5l- thieno-f3. 2- fl fl. 2. 41-triazolo-f 4 . 3 - al fl. 41- diazepine

• 'H-NMR (90 MHz, CDC13) S :

1.50 - 2.20 (m.2H). 1.74(t.J=2Hz,3H). 2.42(m,2H),

2.66 (p. 3H). 2.90 - 5.70(m,6H), 4.11(t.J=7Hz,2H), 7.30(m.4H)

• FABMS (M+H<+>) m/z:480

Example 27

6-(2-chlorophenyl)-ll-methyl-3-(2.3.5.6-tetrahydropyran-4-yl)-oxycarbonyl-2.3.4.5-tetrahydro-8H-pyrido-f4 1 . 3 ' :4.51- thieno-T3. 2- f1 fl. 2. 41-triazolo-f4.3-al fl.41-diazepine

• 'H-NMR (90 MHz, CDC13) 5 :

1.40 - 2.12(m, 6H). 2.67(s,3H), 2.84 - 5.68(m.11H).

7.29(m.4H)

• FABMS (M+H<+>) m/z:498

Example 28

6-(2-chlorophenyl)-3-(5-hexynyloxycarbonyl)-11-methyl-2.3.4.5-tetrahydro-8H-pyrido-f41. 3' :4. 51- tieno- f3, 2- f1 fl. 2. 41-triazolo-T4. 3- a1 Tl.41 -diazeoin

• 1 H-NMR ( 90 MHz , CDC13) <5 :

1.20 - 2.32(m.6H), 1.94(t,J=2Hz,1H),

2.21(dt.J=2Hz,7Hz.2H), 2.66(s,3H). 2.84 - 5.76(m, 6H).

7.28(m.4H)

• FABMS (M+H<+>) m/z:494

Example 29

6-(2-chlorophenyl)-3-(3-cyanopropoxycarbonyl)-11-methyl-2.3.4.5-tetrahydro-8H-pyrido-f 4'. 3' :4. 51- thieno- f 3. 2 - f 1 Tl. 2. 41- triazolo- f4.3-al Tl. 41-diazepine

- 'H-NMR (90 MHz, CDCl3) 8 :

1.41 - 1.80(m.2H), 1.80 - 2.17(m.2H). 2.22 - 2.52(m, 2H).

2.66(s,3H), 2.86 - 5.76(m.6H), 4.20(t,t=7Hz,2H). 7.30 (m. 4H)

• FABMS (M+H<+>) m/z:481

Example 30

6-(2-chlorophenyl)-3-cyclohexyloxycarbonyl-11-methyl-2.3.4.5-tetrahydro-8H-pyrido-f4'. 3' :4. 5l- thieno-f3. 2- f1 fl. 2. 41-triazolo-f4. 3 - al fl. 41- diazepine

• <1>H-NMR(90 MHz, CDC13) 6 :

1.2 - 2.3(m, 12H). 2.7 (p. 3H). 3.0 - 4.0(m,2H). 4.0 -

4.8(m.1+1+2H), 5.4 - 5.8(m,1H), 7.4(m.4H)

• MS m/z (Pos. FAB):496

Example 31

6-(2-chlorophenyl)-3-cyclohexylethoxycarbonyl-11-methyl-2.3,4.5-tetrahydro-8H-pyrido-f4■. 3' :4. 5l-thieno-T3. 2- f1 fl. 2. 41-triazolo-T4.3-al Tl.41-diazepine

• 'H-NMR (90 MHz. CDC13) 6 :

0.6 - 2.7(m,17H), 2.7(s,3H), 3.0 - 4.0(m.2H), 4.0 -

4.4(m,1+2H), 4.4 - 4.8(m,2H), 5.4 - 5.8(ra,1H). 7.4(m,4H)

• MS m/z (Pos. FAB):538

Example 32

6-(2-Chlorophenyl)-3-cyclopropylmethoxycarbonyl-11-methyl-2.3.4.5-tetrahdro-fiH-pyrido-W. 3' :4. 5l - thieno- f3. 2- f1 - fl. 2. 41-triazolo-f4. 3- a1 fl. 41- diazepine

• 'H-NMR(90 MHz, CDC13) 6 :

0.2 - 2.0(m.7H). 2.7(s,3H), 3.0 - 4.0(m.2H), 3.8 -

4.0(d,2H), 4.4 - 4.8(m.l+2H). 5.4 - 5.8(m,lH), 7.4(m.4H)

• MS m/z (Pos. FAB):468

Example 33

6-(2-chlorophenyl)-3-cyclohexyloxycarbonyl-11-methyl-2.3.4.5-tetrahydro-8H-pyrido-f4'. 3' :4. 5l-thieno-T3. 2- f1 fl. 2. 41-triazolo-T4. 3- al Tl. 41- diazepine

• <1>H-NMR (90 MHz. CDCla) 0 :

0.8 - 2.2(m.l3H). 2.7 (p. 3H). 3.0 - 4.0(m.2H). 3.7 -

4.0(d.2H). 4.1 - 4.8(m.l+2H), 5.4 - 5.8(m.lH). 7.4(m.4H)

• MS m/z (Pos. FAB):510

Example 34

6-(2-chlorophenyl)-11-methyl-3-(4-pyridylcarbonyl)-2.3.4.5-tetrahydro-8H-pyrido-f4'. 3' :4. 51- thieno- T3. 2- f1 fl. 2. 41 - triazolo-T4.3-a 1 ri. 41- diazepine

• <1>H-NMR (90 MHz. CDC13) 5 :

1.4 - 2.5(m.2H). 2.67 (p. 3H). 3.1 - 3.75(m.2H). 3.9 -

5.8(m,4H). 7.0 - 7.7(m.6H). 8.4 - 8.8(m.2H)

• MS m/Z (Pos. FAB):475

Example 35

6-(2-Chlorophenyl)-3-cyclohexylmethylcarbonyl-11-methyl-2.3.4.5-tetrahydro-8H-pyrido-U'.3':4.51-thieno-f3. 2 - £1 Tbsp. 2. 41 - triazolo- ( 4. 3- al fl. 41- diazepine

• 'H-NMR(90 MHz, CDC13) 6 :

0.6 - 2.4(m, 13H). 2.16(d, J=6.5Hz, 2H), 2.67(s, 3H). 2.8 -

5.9(m.6H). 7.1 - 7.6(m,4H)

• MS m/z (Pos. Fab): 494 (M+H)<*>

Example 36

6-(2-chlorophenyl)-11-methyl-3-(3-pyridylcarbonyl)-2.3.4.5-tetrahydro-8H-pyrido-f4'. 3' :4. 51- thieno- T3. 2- f1 fl. 2. 41-triazolo-f4. 3- al fl. 41- diazepine

• <1>H-NMR(90 MHz, CDC13) 6 :

1.4 - 2.6(m,2H), 2.66(s,3H), 2.8 - 6.0(m,6H), 7.1 -

8.0(m.6H), 8.4 - 8.8(m,2H)

• MS m/z (Pos. FAB):475(M+H)<+>

Example 37

6- U'-(morpholin-4-yl-sulfonyl)-phenylaminocarbonyl1-6-(2-chlorophenyl)-11-methyl-2.3.4.5-tetrahydro-8H-pyrido-f4 1.31:4.5l-thieno - f3. 2- f1 fl. 2, 41-triazolo-f4. 3- al fl. 41- diazepine

• 'H-NMR(90 MHz, CDC13) 6 :

1.80 - 2.20(ra,4H), 2.63(s,3H), 2.80 - 3.08(m,4H). 3.24 -

3.90 (m. 9H). 4.60 - 4.90 (m.2H), 7.20 - 7.42 (m.4H). 7.45 -

7.68(m.4H), 7.75(brs.lH)

• MS: m/z 638

Example 38

3-f4'-(N-piperidinsulfonyl)-phenylaminocarbonyl! - 6-(2-chlorophenyl)-ll-methyl-2. 3. 4. 5- ter. rahYdro- 8H- pyrido- f4 ■ . 3' :4. 51 - thieno- f3. 2 - fl fl. 2. 41-triazolo-f4. 3- al fl. 4l- diazepine

• <1>H-NMR (90 MHz. CDC13) 6 :

1.10 - 2.30 (m, 10H). 2.64(p.3H). 2.75 - 3.10 (m.4H). 3.30 -

4.30 (m, 2H). 4.60 - 4.92(m,2H). 7.15 - 7.40 (m. 4H). 7.42 -

7.60(m,4H), 7.72(brs.lH)

• MS: m/z 636

Example 39

3-T4'-(sulfamoyl)-phenylaminocarbonyl1-6-(2-chlorophenyl)-11-methyl-2.3.4.5-tetrahydro-8H-pyrido-(4'.3':4.51-thieno-T3 .2- fl - f 1.2.41-triazolo-r 4.3-al Tl.41- diazepine

• 'H-NMR (90 MHz, CDC13) 5 :

1.40 - 2.20(m,4H), 2.62(s,3H), 3.60 - 4.40(m,2H). 5.10 -

5.50 (m.2H). 7,10 (p. 2H). 7.30 - 7.60 (m, 4H),

7.62(ABq,4H,J=9.0Hz), 8.95(s,lH)

• MS: m/z 568

Example 40

3-T4'-(N.N-diethylaminosulfonyl)-phenylaminocarbonyl-6-(2-chlorophenyl)-11-methyl-2. 3. 4. 5-tetrahydro-8H-pyrido-f 4 '. 3' -. 4. 51 - thieno- \ 3 . 2- f1 \ 1 . 2. 41-triazolo-f4. 3- al \ 1 . 41- diazepine

• ' H-NMR (90 MHz, CDC13) <5 :

1.10(t, 6h, J=7.2H). 1.70 - 2.30 (m, 4H). 2.62(p,3H).

3.16(q,4H,J=7.2Hz), 3.40 - 4.20(m,2H), 3.55 - 3.60(m.2H),

7.18 - 7.40(m,4H), 7.54(ABq,4H,J=9.0Hz), 7.70(s.lH)

■ MS: m/z 624

Example 41

3- T4'-( N-cyclohexylaminosulfonyl)- phenylaminocarbonyl-6- 12-chlorophenyl)- 11- methyl- 2. 3. 4. 5- tetrahydro- 8H- pyrido- T4'. 3':4.5l-thieno- \ 3 . 2- f1 \ 1 . 2. 41-triazolo-T4. 3- al fl.41-diazepine

• 'H-NMR(90 MHz, CDC13) 6 :

0.80 - 2.20(m,14H), 2.64(s,3H). 2.80 - 4.30 (m, 3H), 4.60 -

4.30(m,3H), 4.60 - 4.90(m,2H), 5.05(d,1H,J=7.2Hz), 7.20 -

7.40 (m. 4H). 7.56(ABq,4H.J=9.0Hz), 7.76(s.lH)

• MS: m/z 650

Example 42

3- T41 -(2''-pyridylmethylaminosulfonyl)-phenylaminocarbonyl-6-(2-chlorophenyl)-11-methyl-2,3,4.5-tetrahydro-8H-pyrido-T4'. 31:4. 51- thieno- f3. 2- f1 Tl. 2. 41- triazolo- T4. 3- al \ 1 . 41 -

• 'H-NMR (90 MHz, CDC13) 5 :

1.60 - 2.20(m,4H), 2.72(s,3H), 3.60 - 4.50(m.6H), 6.50 -

6.72(m,2H), 7.00 - 7.70(m,11H), 8.11 - 8.28(m.lH)

• MS m/z: 659

Example 43

3-[3-(N-piperidinesulfonyl)-propyloxycarbonyl 1-6-(2-chlorophenyl)-11-methyl-2.3.4.5-tetrahydro-8H-pyrido-f4'.3':4.51-thieno-f3. 2- f1 fl. 2. 41-triazolo-U. 3-al r1. 41- diazepine

'H-NMR (90 MHz, CDC13) 6 :

1.40 - 2.30 (m, 12H). 2.70(s,3H), 2.95(t,2H,J=7.2Hz),

3.10 - 3.40 (m.4H), 3.50 - 4.20 (m.2H). 4.22(t.2H.J=7.2Hz),

4.42 - 4.82(m.2H), 7.20 - 7.50(m.4H)

MS: m/z 603

Example 44

3- f4-( N- morpholinosulfonyl)- propyloxycarbonyl - 6-( 2- chlorophenyl) - 11- methyl- 2. 3. 4. 5- tetrahydro- 8H- pyrido- U1 . 3' :4. 51 - thieno- f3. 2 - f1 Tl. 2. 41- triazolo- f4. 3- all ride. 41- diazepine

• 'H-NMR (90 MHz. CDC13) S :

1.60 - 2.40 (m.6H). 2.70 (p. 3H). 2.98(t.2H.J=7.2Hz), 3.60 - .90(ra,4H). 2.80 - 4.40(m.2H), 4.22(t.2H.J=7.2Hz). 4.40 - .84(m,2H). 7.20 - 7.50 (m.4H)

• MS: m/z 605

Example 45

3-U'-(N-morpholinosulfonyl)-phenyloxycarbonyl-6-(2-chlorophenyl)-ll-methyl-2.3.4.5-tetrahydro-8H-pyrido-W. 3' :4. 5l-thieno- \ 3 . 2 - f 1 l" l. 2 . 41- triazolo- T4 . 3- al ri ■ 41 - diazepine

• 'H-NMR (90 MHz. CDCl3) 6 :

1.60 - 2.40 (m. 4H). 2.74 (p. 3H). 2.80 - 3.10(m.4H), 3.60 -

3.80(m,4H). 3.10 - 5.10 (m. 4H). 4.90 - 7.60 (m.8H)

• MS: m/z 639

Example 46

6-( 2- chlorophenyl)- 3-( 2- cyanoethylmethylamino)- carbonyl- 11- methyl-2.3.4.5- tetrahydro- 8H- pyrido- U1. 3' :4. 5l-thieno-T3. 2- f1-fl. 2. 41 - triazolo-f4. 3- al fl. 41 - diazepine

• 1 H-NMR (90 MHz. CDC13) <5 :

1.57 - 2.22(m.2H), 2.61(t.J=7Hz.2H), 2.67(s,3H),

2.94(p.3H). 3.00 - 5.80 (m. 6H). 3.43(t.J=7Hz.2H). 7.31 (m.4H)

• FABMS(M+H<+>) m/z: 480

Example 47

6-(2-Chlorophenyl)-3-(1-ethynyl-1-cyclohexyloxy-1-carbonyl-1-methyl-2.3.4.5-tetrahydro-8H-pyrido-f4'. 31:4. 51- thieno-\ 3 . 2- f1 - n . 2. 41- triazolo- f4. 3- al f 1. 41- diazepine

• 'H-NMR (90 MHz, CDC13) <5 :

1.63 - 2.30 (m.2H). 2.57(d.J=2Hz,1H). 2.65(s, 3H). 2.97 -

5.71(m, 6H). 6.35(d,J=2Hz,lH), 7.11 - 7.64(m,9H)

• FABMS(M+H<+>) m/z: 528

Example 49

6-(2-Chlorophenyl)-3-(2-cyanoethoxy)-carbonyl-11-methyl-2.3.4.5-tetrahydro-8H-pYrido-f4'. 3' :4. 51- thieno- \ 3 . 2- f1 fl. 2. 41- tri - azolo-T4.3-al \ 1,41-diazepine

• 'H-NMROO MHz, CDCI3) 5 :

1.40 - 2.34(m.2H). 2.66 (p. 3H). 2.70(t, J = 7Hz, 2H) . 2.79 -

5.76(m,6H). 4.28(h,J=7Hz,2H), 7.30(m.4H)

• FABMS(M+H<+>) m/z: 467

Example 50

6-(2-Chlorophenyl)-11-methyl-3-(2-propynyl)-aminocarbonyl-2,3,4,5-tetrahydro-8H-pyrido-U'. 3' :4. 5l - thieno- L3. 2- fl - fl.2.41-triazolo-f4.3-al M .41- diazepine

• <1>H-NMR (90 MHz. CDC13) 6 :

1.56 - 2.08(m,2H). 2.19(d.J=2Hz.1H), 2.65(s,3H). 2.96 -

5.70(dd,J=2Hz,7Hz.6H), 3.98(dd,J=2Hz,7Hz.2H),

4.83(t,J=7Hz.lH), 7.28(m.4H))

• FABMS(M+H<+>) m/z: 451

Example 51

3-(2-butynyloxycarbonyl)-6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-U'. 3' :4. 5l-thieno-T3. 2- f1 fl. 2.41 -triazolo- F4. 3- al fl. 41- diazepine

• 'H-NMRO0 MHz, CDCI3) 6 :

1.43 - 2.15(m,2H). 1.84(t,J=2Hz.3H), 2.66(s.3H). 2.80 -

5.74(m,6H), 4.64(q.J=2Hz.2H). 7.30 (m. 4H)

• FABMS(M+H<+>) m/z: 466

Example 52

6-(2-Chlorophenyl)-II-methyl-3-\2-(2-pyridyl)-ethylmethylamino-carbonyl-2.3.4.5-tetrahydro-8H-pyrido-f4',3':4.51-tisnn-T3.2 -fl fl.2.41-triazolo- \ A.3-al \ 1.41-diazepine

1.46 - 2.25(m.2H), 2.65(s,3H). 2.76 - 5.76(m, 6H).

2.92(t.J=7Hz,2H). 3.42 - 3.68(m,2H), 5.95 - 6.24(m,1H). 6.93 -

7.39(m.6H). 7.40 - 7.66(m,lH). 8.25 - 8.40 (m.lH)

• MS m/z: 517

Example 53

6-(2-chlorophenyl)-3-T2-(morpholin-4-yl)-ethylmethylaminocarbonyl-11-methyl-2. 3. 4. 5-tetrahydro-8H-pyrido-f4'. 3' -. 4. 51 - tieno-r3. 2- fl fl. 2. 41-triazolo-f4. 3- al fl. 41- diazepine

• 'H-NMR (90 MHz, CDCl3) 6 :

1.54 - 2.20 (m.2H). 2.30 - 258 (m, 6H). 2.67(p,3H), 2.88

5.80 (m. 6H). 3.17 - 3.42(m,2H), 3.55 - 3.74(m.4H), 5.03 -

5.19(m,lH), 7.30(m,4H)

• MS ra/z: 525

Example 54

6-(2-Chlorophenyl)-3- 4-(morpholine-4- vi -carbonyloxy)-2- hynthynyl -oxycarbonyl-11-methyl-2. 3. 4. 5-tetrahydro-8H-pyririo-f4', 3';4, 5l-thieno-f3. 2- f! etc. 2. 41-triazolo-f4. 3- al M . 41 - diazepine

• <1>H-NMR(90 MHz, CDC13) 8 :

1.55 - 2.28(m,2H). 2.66(s,3H), 2.87 - 5.75(m,6H), 3.34 -

3.54(m,4H), 3.54 - 3.72(m,4H), 4.75(s,4H), 7.30(s,4H)

• MS m/z: 594

Example 55

6-(2-Chlorophenyl)-11-methyl-3-[4-(pyridin-2-yl-methylamino-carboxyl)-2-butynoxycarbonyl]1-2.3. 4. 5- tetrahvdro- RH-pvrido- f4', 3' :4. 51- thieno- f3. 2- f1 fl. 2. 41-triazolo-f4. 3- al-f1.41-diaze<p>in

- 'H-NMR (90 MHz. CDC13) 8 :

1.6 - 2.2(m,2H), 2.70(s.3H), 3.00 - 5.75(m,6H),

4.46(d,J=5Hz,2H), 4.72(s.4H). 5.90 - 6.20(m,lH), 7.1 -

7.6(m,6H). 7.5 - 7.9(m,lH). 8.40 - 8.70 (m,lH)

• MS m/z: 615

Example 56

6-(2-chlorophenyl)-11-methyl-3-(4-pentynyloxycarbonyl)-2.3.4.s-tetrahydro-8H-pyrido-f4'. 3 ' :4 . 51- thieno-\ 3 . 2 - f 1 fl. 2. 41-tri-azolo-f4.3-al f l. 41- diazepine

• 'H-NMR (90 MHz. CDC13) to :

1.52 - 2.08(m, 4H). 1.92(t,J=2Hz.1H). 2.08 - 2.40 (m.2H),

2.66 (p. 3H). 2.84 - 5.72(m.6H). 4.17(t.J=7Hz.2H). 7.29(m.4H)

• MS ra/z: 479

Example 57

6-(2-chlorophenyl)-II-methyl-3-(2-propynyloxycarbonyl)-2.3.4.5-tetrahydro-8H-pyrido-f4'. 3' :4. 5l- thieno-f3. 2- fl fl. 2. 41-triazolo-f4. 3- al fl. 41- diazepine

• 'H-NMR(90 MHz, CDC13) 6 :

1.68 - 2.15(m.2H), 2.50(t.J=3Hz,1H), 2.62(s.3H). 2.85 -

5.79(m.6H). 4.65(d.J=3Hz,2H), 7.40(m.4H)

• MS m/z: 451

Example 58

6-(2-Chlorophenyl)-11-methyl-3-1 2-(pyridin-2-yl)-one oxocarbonyl1-2.3.4.5-tetrahydro-8H-pyrido-U1.3':4.51-thieno- f3. 2- f1 - fl. 2.41 - triazolo-U,3-al Tl.41- diazepine

• ' H-NMR (90 MHz, CDC13) <5 :

1.64 - 2.25(m,2H), 2.50 - 5.74(m.6H), 2.71(s,3H),

2.90(t.J=7Hz,2H), 3.91(t,J=7Hz,2H), 6.86 - 7.80(m.7H). 8.36 -

8.76(m,lH)

• MS m/z: 518

Example 59

6-(2-Chlorophenyl)-11-methyl-3-(tetrahydropyran-2-yl)-methoxycarbonyl)-2.3.4.5-tetrahydro-8H-pyrido-f4'. 3' :4. 5l- thieno-f3. 2- f1 fl. 2. 41-triazolo-f4. 3- al \ 1 ■ 41- diazepine

• 'H-NMR (90 MHz. CDCls) 5 :

1.12 - 2.32(m.8H), 2.66(s,3H). 2.92 - 5.72 (m.11H).

7.30 (m. 4H)

• MS m/z: 499

Example 60

6-(2-chlorophenyl)-11-methyl-3-\2-(morpholine-2-vi)-ethoxy-carbonyl-2,3,4,5-tetrahydro-8H-pyrido-\4<.3' : 4. 5l- thieno-f3.2-f1 T l. 2. 41- triazolo- T4. 3- al Tl. 41- diazepine

• 'H-NMR (90 MHz, CDC13) 5 :

1.54 - 2.24(m.2H), 2.36 - 2.64(m,6H). 2.68(p,3H). 3.04 -

5.84(m,6H). 3.52 - 3.80(m,4H), 4.24(t.J = 7Hz,2H), 7.39(m.4H)

• MS m/z: 526

Subexample 1

6- acetyl- 2-( 2- bromopropionylamino)- 3-( 2- chlorobenzoyl)- 4. 5. 6. 7-tetrahydrothieno-\ 2 . 3-cl-pyridine

13.3 g of toluene and 3.66 l of water were added to 600 g of 2-amino-3-(2-chlorobenzoyl)-6-acetyl-4,5,6,7-tetrahydrothieno-[2,3-c]- pyridine, to which 301 g of sodium bicarbonate was further added. While heating to 60°C, 301 ml of 2-bromopropionyl bromide was added dropwise to the solution. Furthermore, 170 g of sodium bicarbonate and 170 ml of 2-bromopropionyl bromide were added to complete the reaction. After cooling to room temperature, 500 g of sodium bicarbonate were added, after which the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate, followed by combin-

under reduced pressure and the resulting solid was washed with ether to give 800 g of the intended product.

• 'H-NMR (90 MHz, CDC13) <5 :

1.7 - 2.4(m.2H). 1.99(d, J=7.2Hz. 3H). 2.06 and 2.12 (each S, total 3H). 3.25 - 3.7(m,2H), 4.41(q.J=7.2Hz.1H). 4.4 - 4.8(m, 2H). 7.0 - 7.5(m.4H) Sub-example 2 6- acetyl- 2 -( 2- aminopropionylamino)- 3 -( 2- chlorobenzoyl)- 4. 5, 6. 7- tetrahydrothieno-\ 2,3-cl-pyridine

(method A)

841 g of 6-acetyl-2-(2-bromopropionylamino)-3-(2-chlorobenzoyl)-4,5,6,7-tetrahydrothieno-[2,3-c]-pyridine were dissolved in 0.72 l of dichloroethane and 1.08 1 of ethyl acetate to which ammonia gas was introduced at -10°C. The mixture was allowed to react in an autoclave at 100°C for one hour. After completion of the reaction, excess ammonia gas was removed and the reaction solution was poured into 3 N HCl while cooling on ice. After extraction with ethyl acetate, the aqueous phase was neutralized with a saturated aqueous sodium carbonate solution, followed by a further extraction with chloroform. The organic phase obtained was washed with a saturated aqueous salt solution, after which it was dried with anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure to give 636.8 g of the intended compound.

• <1>H-NMR(90 MHz, CDC13) 6 :

1.48(d. J=6.8Hz, 3H), 1.6 - 2.3(m.4H). 2.07 and 2.12 (respectively total 3H). 3.25 - 4.0(m.3H). 4.35 - 4.75(m,2H). 7.0 - 7.6(m,4H)

(method B)

10 g of 2-amino-3-(2-chlorobenzoyl)-6-acetyl-4,5,6,7-tetrahydro-thieno-[2,3-c]-pyridine were dissolved in 150 ml of chloroform at room temperature. 17 g of alanyl chloride hydrochloride was added little by little to the solution over a period of one hour with stirring and at room temperature. After the end of the reaction,

150 ml of water added to the mixture. Stirring was carried out for 30 minutes. The aqueous phase was removed. The chloroform phase was treated with 150 ml of water for extraction. The two aqueous phases were combined into one phase which was washed with chloroform.

The aqueous phase was neutralized with sodium bicarbonate and extracted with chloroform, and the obtained phase was distilled under reduced pressure to remove the solvent and to obtain 10.1 g of the intended compound as a yellow powder.

Subexample 3

8- acetyl- S-(2- chlorophenyl)- 3- methyl- 6.7.8.9-tetrahydr o- 1H. 3H-pyrido-T4'. 3' :4. 51- thieno- f3. 2- f1 ride. 41-diazepine-2-thion

636.8 g of 6-acetyl-2-(2-aminopropionylamino)-3-(2-chlorobenzoyl)-4,5,6,7-tetrahydrothieno-[2,3-c]-pyridine were dissolved in 2.3 1 toluene, 637 ml of pyridine and 94.3 ml of acetic acid and refluxed for 24 hours while water is removed from the reaction system. After removal of the reaction solution by distillation, benzene was added, whereupon the crystals were cooled and filtered to obtain 300 g of the intended compound.

• <1>H-NMR (90 MHz, CDC13) S :

1.3 - 2.6(m,2H), 1.76(d.J=6.8Hz,3H), 2.06 and 2.12(each S. total 3H), 2.8 - 4.1(m.2H), 3.87(q,J=6.8Hz,1H) , 4.1 -

5.1(m,2H), 7.1 - 7.5(m.4H). 9.0 - 9.5(bs,lH)

Subexample 4

3- methyl-5-f2-kl orphenyl)-8-thioac ethyl- 6■ 7. 8. 9- tetrahvdro- 1H. 3H-pyrido-f41. 3' :4, 5l-thieno-f3. 2- fl fl. 41-diazepine-2-thion

288 g 3-methyl-5-(2-chlorophenyl)-8-thioacetyl-6,7,8,9-tetrahydro-1H,3H-pyrido-[4',3':4,5]-thieno-[3 ,2-f][1,4]-diazepin-2-thione was dissolved in 3 L of dimethoxyethane to which 186 g of sodium bicarbonate and 364 g of phosphorus pentasulfide were added, followed by heating under reflux for three hours. The reaction solution was filtered through Celite, after which the solvent was distilled off under reduced pressure. Methanol and dichloromethane were added to the obtained residue in small amounts for adsorption on silica gel, followed by drying and purification by dry column chromatography (eluent: dichloromethane: methanol = 98:2), obtaining 300 g of the intended compound. Subexample 5 6-(2-chlorophenyl)-3-1ioacetyl-8.11-dimethyl-6.7.8. 9-tetrahydro-8H-pyrido-f4'. 3' :4. 5l - thieno- T3. 2- fl fl. 2. 41-triazolo-f4. 3-α1-[1,41-diazepine

4.81 g of 3-methyl-5-(2-chlorophenyl)-8-thioacetyl-6,7,8,9-tetrahydro-1H,3H-pyrido-[4',3':4,5]-thieno- [3,2-f][1,4]-diazepin-2-thione was dissolved in 70 ml of dioxane to which 660 g of acetohydrazide was added followed by heating at 100°C. After off-

cooling, the mixture was concentrated under reduced pressure and the obtained residue was purified by column chromatography (eluent: dichloromethane: methanol = 98:2), obtaining 750 g of the intended compound.

Subexample 6

6-( 2- chlorophenyl)- 8. ll- dimethyl- 2. 3. 4. 5- tetrahydro- 8H- pyrido-f41 . 3' :4. 51- thieno- f3. 2- f1 fl. 2. 41 - triazolo-f4. 3- a1 fl. 41 - diazepine

281 g 6-(2-chlorophenyl)-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5]-thieno-[3,2-f ] [1,2,4]-triazolo-[4,3-a]-[1,4]-diazepine was dissolved in one liter of methanol, to which 0.81 liter of 4 N sodium hydroxide was added followed by heating under reflux. After cooling, the reaction solution was salted out and extracted with chloroform, after which the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 95:5), obtaining 142 g of the intended compound.

• <1>H-NMR (90 MHz. CDC13) 6 :

1.1 - 2.3(m,3H), 2.10(d,J=6.8Hz,3H). 2.45 - 3.3(m.2H),

2.66 (p. 3H). 3.85 - 4.1(m.2H), 4.26(q.J=6.8Hz.1H). 7.1 -

7.6(m.4H)

MS m/z (Pos. Fab): 384(M+H)<*>

Subexample 7

(-) - 6-( 2- chlorophenyl)- 8. ll- dimethyl- 2. 3. 4. 5- tetrahydro- 8H-pyrido-f4■ .3' :4.51-thieno- f 3. 2 - f 1 fl . 2. 41-triazolo-f4. 3- a1-f1.41-diazepine

86 g ( + )-6-(2-chlorophenyl)-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3 1 :4,5]-thieno-[3 ,2-f] [1,2,4]-triazolo-[4,3-a]-[1,4]-diazepine and 45.86 g of dibenzoyl-D-tartrate were dissolved under heating in 980 ml of ethanol and 3 65 ml of water and allowed to stand at room temperature. The crystals obtained were collected by filtration and washed with ether, followed by liberation with an aqueous dilute sodium bicarbonate solution and extraction with dichloromethane twice. The organic phase obtained was washed with a saturated aqueous salt solution and dried with anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure to give 11.0 g of the intended compound.

The filtrate from which the tartrate was collected by filtration was further subjected to a similar procedure as above, obtaining 11.3 g of the intended compound.

[a] l6 -23.5° (C = 1, EtOH)

Subexample 8

( + )-6-(2-chlorophenyl)-8.11-dimethyl-2.3.4.5-tetrahdro-8H-pyrido-f41. 3' :4. 51- thieno- f3. 2-f1 fl.2.41-triazolo-U.3-a)-fl. 41- diazepine

In the same manner as in sub-example 7, dibenzoyl-L-tartaric acid was used to obtain the intended compound.

[α]^6 -17.56° (C = 0.02, EtOH)

Example 61

( + )- 6-( 2- chlorophenyl)- 3-( 1- cyano-1- methylethoxycarbonyl)- 8. 11-dimethyl-2.3.4.5-tetrahydro-8H-pyrido-f41 ■3' :4.51 -thieno -T3. 2- f1 fl.2.41-t riazolo- f4.3-al Tl. 41- diazepine

5 g (-)-6-(2-chlorophenyl)-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido-[4<1>,3':4,5]-thieno- [3,2-f][1,2,4]-triazolo-[4,3-a]-[1,4]-diazepine was dissolved in dichloromethane to which 5 g of 1-cyano-1-methylethylphenyl carbonate was added, followed by of reaction at 100°C for four hours while the solvent is removed by distillation. After completion of the reaction, the obtained residue was purified by column chromatography (eluent: chloroform:methanol = 99:1), obtaining 2.7 g of the intended compound.

'H-NMR (90 MHz. CDCl3) 6 :

1.76 (p. 6H). 1.80 - 2.20 (m.2H). 2.10(d.3H). 2.66(p,3H).

3.0 - 3.9(m.2H). 4.24(q.lH). 4.3 - 4.9(m.2H), 7.35(m.4H)

FABMS [M+H<+>] 481

[ cr ]<2>d +17.56° (C = 0.02. EtOH)

Example 62

( + )- 3-( 3- butynyloxycarbonyl)- 6-( 2- chlorophenyl)- 8. 11- dimethyl-2. 3. 4. 5-tetrahydro-8H-pyrido-U1. 31:4. 51 - thieno- f3 . 2- f 1 - fl. 2. 41 - triazolo-r4. 3- al f1. 41- diazepine

5 g (-)-6-(2-chlorophenyl)-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5]-thieno-[3 ,2-f] [1,2,4]-triazolo-[4,3-a]-[1,4]-diazepine was dissolved in dichloromethane to which 5 g of 3-butynylphenyl carbonate was added, and the mixture was allowed to react at 100° C for four hours while the solvent was distilled off. After completion of the reaction, the residue was purified by column chromatography (eluent: dichloromethane: methanol = 99:1), and 1.6 g of the intended compound was obtained.

• <1>H-NMR(90 MHz, CDC13) 5 :

7.4(5H,Ar). 4.9(1H.d,J=18Hz.N-CH2[C-2]), 4.5QH, d.

J=18Hz. N-CH2[C-2]), 4.2(1H.n,Cs-H), 4.1(2H,t, J=8Hz.0-CH2).

2.7(3H.s), 2.5(2H.dt.J=lHz.7Hz,E-CH2), 2.1(3H,d,J=7Hz,CHCHa),

3.0 - 2.0(5H.n)

[ a ]<2>£ +17.0° (Ol, CHCI3)

Other methods for preparing the compounds obtained in the previous examples are described in the following.

Subexample 9

1-(cyano-1-methylethoxy carbonyl)-4-hydroxypiperidine

50 g of 1-cyano-1-methylethylphenyl carbonate and 25 g of 4-hydroxypiperidine were heated at 130°C. After completion of the reaction, the obtained product was purified by silica gel column chromatography (eluent: hexane:ethyl acetate = 1:1 - 1:2 - 0:1, and 50.5 g of the intended compound was obtained.

• <1>H-NMR (90 MHz. CDC13) 6 :

1.26 - 2.10(m.5H). 1.80 (p. 6H). 2.96 - 3.35(m.2H). 3.60 -

4.15 (m.3H)

Subexample 10

1-(cyano-1-methylethoxycarbonyl)-4- piperidone

5.06 ml of dimethyl sulfoxide was gradually dropped, at -78°C, into a solution of 4.15 ml of oxalyl chloride in dichloromethane (50 ml), to which a dichloromethane solution of 5.05 g of 1-(1-cyano-1-methyl -ethoxycarbonyl)-4-hydroxypiperidine was added dropwise. After stirring at this temperature for one hour, 16.57 ml of triethylamine was added followed by stirring at room temperature for one hour. The reaction solution was filtered, washed with water and dried with anhydrous magnesium sulfate. The solvent was distilled off and the residue obtained. was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane = 1:9), obtaining 3.9 g of the intended compound.

• <l>H-NMR (90 MHz. CDC13) 6 :

1.80(S,6H), 2.48(t.J=7Hz,4H). 3.74(t.J=7Hz.4H) Subexample 11 2-amino-3-(2-chlorobenzoyl)-(1-cyano-1-methylethoxycarbonyl)-4. 5. 6. 7-tetrahydrothieno-\ 1 . 3-cl-pyridine

1.6 ml of triethylamine was added to a mixture of 3.9 g of the compound obtained in Sub-Example 10, 0.6 g of sulphur, 3.3 g of 2-chlorocyanoacetophenone and 20 ml of N,N-dimethylformamide at 40°C and the mixture was stirred at 60°C for three hours. After completion of the reaction, the solvent was evaporated to dryness and the residue was washed with ethyl acetate to give 5.0% of the intended compound.

• <1>H-NMR (90 MHz. CDC13) 6 :

1.60 - 1.95(m,2H), 1.75(s.6H). 3.40 (m. 2H). 4.32(m.2H). 7.10 - 7.50 (m, 6H) Sub-Example 12 2-(2-bromopropionylamino)-3-(2-chlorobenzoyl)-6-(1-cyano-1-methylethoxycarbonyl)-4.5.6.7-tetrahydrothieno-\2,3-cl-pyridine

4.6 g of 2-bromopropionyl bromide was added dropwise to a mixture of 5.0 g of the compound obtained in sub-example 11, 2.1 g of sodium carbonate, 50 ml of water and 200 ml of toluene at 60°C. After completion of the reaction, ethyl acetate was added and the aqueous phase was removed. The organic phase was washed with saturated aqueous salt solution and dried with anhydrous magnesium sulfate. The solvent was distilled off to give 6.0 g of the intended compound.

• 'H-NMR (90 MHz. CDC13) 6 :

1.76(s,6H), 1.88(m.2H), 2.00(d. J=7Hz. 3H), 3.24 -

3.60(m.2H), 4.20 - 4.68(m,2H). 4.62(q, J=7Hz. 1H), 7.00 -

7.50 (m.4H)

Subexample 13

2-(2-aminoprop ionylamino)- 3-( 2- chlorobenzoyl)- 6-( 1- cyano-l-methylethoxycarbonyl)- 5. 6. 7. 8- tetrahydrothieno-r2. 3- cl - pyri di n

6.0 g of the compound obtained in sub-example 12 was dissolved in 50 ml of ethyl acetate, to which ammonia was introduced at -20°C for two hours, followed by stirring in a sealed tube at 100°C for five hours. After the end of the reaction, the reaction product was extracted with 2 N hydrochloric acid and the obtained aqueous phase was neutralized with sodium bicarbonate which was then saturated with sodium chloride and extracted with chloroform. After drying with anhydrous magnesium sulfate, the solvent was distilled off and 0.7 g of the intended compound was obtained.

• <1>H-NMR(90 MHz, CDC13) 6 :

1.51(d. J=7Hz,3H), 1.50 - 2.04(m,2H), 1.78(s,6H). 3.28 - 3.60 (m.2H). 3.62 - 3.96(m,lH). 4.50(m.2H), 7.20 - 7.54(m,4H) Sub-Example 14 3-methyl-5-(2-chlorophenyl)-8-(1-cyano-1-methylethoxycarbonyl)-6. 7. 8. 9-tetrahydro-lH. 3H-pyrido-f4'. 3' :4. 5l- thieno- f2. 3- el-fl. 41-diazepine-2-thion

A mixture of 0.4 g of the compound obtained in Sub-Example 13, 0.7 g of phosphorus pentasulfide, 0.4 g of sodium bicarbonate and 40 ml of 1,2-dimethoxyethane was refluxed for two hours. After completion of the reaction, the solvent was distilled off, methanol was added and insoluble substances were removed by filtration and concentration. The residue was purified by silica gel column chromatography (eluent: chloroform:methanol = 99:1), obtaining 0.3 g of the intended compound.

• <l>H-NMR (90 MHz, CDC13) <5 :

1.50 - 2.0(m,2H). 1.76(s,6H), 1.92(d,J=7Hz,3H), 3.0 - 4.0(m,2H). 4.0 - 4.3(m,lH). 4.3 - 5.0(m.2H), 7.1 - 7.6(m,4H) Example 63 3-(1-cyano-1-methylethoxycarbonyl)-6-(2-chlorophenyl)-8.11-dimethyl-2. 3. 4. 5- tetrahydro- 8H- pyrido- U'.3■:4.51-thieno- f3. 2- fl Tl. 2. 41- triazolo- f4. 3- al fl.41-diazepine

0.3 g of the compound obtained in sub-example 14 and 0.3 g of acetohydrazide were dissolved in 20 ml of 1,4-dioxane and refluxed for three hours. After completion of the reaction, the solvent was distilled off and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol = 99:1), and 0.20 g of the intended compound was obtained.

• 1H-NMR (90 MHz, CDCls) 5 :

1.76(s,6H), 1.80 - 2.20(m,2H), 2.10(d,3H), 2.66(s.3H),

3.0 - 3.9(m,2H), 4.24(q.1H), 4.3 - 4.9(m,2H). 7.35 (m, 4H)

Subexample 15

N-(3-butynyloxycarbonyl)-4-hydroxypiperidine

10.0 g of 3-butynylphenyl carbonate and 5.8 g of 4-hydroxypiperidine were heated under solvent-free conditions at 100°C for 30 minutes. After completion of the reaction, silica gel column chromatograph (eluent: hexane-ethyl acetate = 1:1 - 1:2) was used for purification and 10.6 g of the intended compound was thus obtained.

• <l>H-NMR (90 MHz, CDC13) 5 :

1.16 - 2.1(m.5H), 1.98(t,J=2Hz,lH),

1.42(dt,J=2Hz,7Hz.2H), 2.9 - 3.5(m.2H). 3.6 - 4.1(m,3H),

4.15(t.J=7Hz, 2H)

Subexample 16

N-(3-butynyloxycarbonyl)-4-piperidone

25 ml of oxalyl chloride was added to 500 ml of dichloromethane, to which 41 ml of dimethylsulfoxide was added dropwise in a stream of nitrogen and at a temperature from -50 to -70°C. Then 10.3 g of N-(3-butynyloxycarbonyl)-4-hydroxypiperidine was dissolved in 50 ml of dichloromethane and the solution was added dropwise to the reaction mixture. Finally, 320 ml of trimethylamine was added dropwise to the reaction mixture and the temperature was then gradually increased to room temperature. The reaction solution was poured into a saturated aqueous salt solution, extracted three times with dichloromethane and dried with anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (eluent: hexane:ethyl acetate = 3:1), and 8.9 g of the intended compound was thereby obtained.

• 'H-NMR (90 MHZ, CDCla) 6 :

2.0(t,J=2Hz.lH), 2.3 - 2.8(m,6H), 3.76(t,J=7Hz,4H),

4.21(t,J=7Hz. 2H)

Subexample 17

2- amino- 3-( 2- chlorobenzoyl)- 6-( 3- butynyloxycarbonyl)- 4. 5. 6. 7-tetrahydrothieno-T2.3-cl-pyridine

7.4 g of N-(3-butynylphenylcarbonyl)-4-piperidone, 1.21 g of sulfur and 61.5 g of 2-chlorocyanoacetophenone were dissolved in 25 ml of dimethylformamide, to which 3.5 ml of triethylamine was further added followed by stirring at 60 °C for one hour. After completion of the reaction, silica gel column chromatography (eluent: dichloromethane: methanol = 99:1) was used for purification, obtaining 1.2 g of the intended compound.

• 'H-NMR (90 MHz. CDC13) 6 :

1.64 - 1.90 (m.2H). 1.96(t.J=2Hz.1H). 2.3 - 2.7(t,J=2Hz. 7 Hz. 2H), 3.4(t.J=7Hz.2H), 4.14(t.J=7Hz.2H). 4.3 - 4.5(m.2H). 7.0 - 7.5(m.6H) Subexample 18 2-(2-bromopropionylamino)-3-(2-chlorobenzoyl)-6-(3-butynyloxycarbonyl)-4.5.6.7-tetrahydrothieno-\2. 3-cl-pyridine

1.35 g of 2-amino-3-(2-chlorobenzoyl)-6-(3-butynyloxycarbonyl)-4,5,6,7-tetrahydrothieno-[2,3-c]-pyridine was dissolved in 20 ml of dioxane to which 0.33 g of pyridine was added followed by the dropwise addition at 0°C of 90 g of 2-bromopropionyl bromide. After completion of the reaction, the reaction mixture was poured into water, extracted with dichloromethane and dried with anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (eluent: dichloromethane:hexane = 1:1 - 1:0), whereby 1.19 g of the intended compound was obtained.

• <1>H-NMR(90 MHz, CDC13) 6 :

2.02(t.J=7Hz.3H), 1.7 - 2.2(m.3H). 3.5(dt,J=2Hz, 7Hz, 2H), 3.44(t,J=7Hz,2H), 4.16(t.J=7Hz. 2H). 4.4 - 4.8(m.3H). 7.0 - 7.5(m.5H) Sub-Example 19 2-(2-aminopropionylamino)-3-(2-chlorobenzoyl)-6-(3-butynyloxycarbonyl)-4.5.6.7-tetrahydrothieno-f 2.3-cl-pyridine

1.16 g of 2-(2-bromopropionylamino)-3-(2-chlorobenzoyl)-6-(3-butynyloxycarbonyl)-4,5,6,7-tetrahydrothieno-[2,3-c]-pyridine was dissolved in 36 ml of ethyl acetate and ammonia gas were introduced with cooling followed by heating in a sealed tube at 100°C. After completion of the reaction, the mixture was cooled and 50 ml of ethyl acetate was added. The mixture was washed with 1 N hydrochloric acid after which the aqueous phase was neutralized with an aqueous sodium carbonate solution and extracted with chloroform. The organic phase obtained was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue obtained was purified using silica gel column chromatography (eluent: dichloromethane) to obtain 0.36 g of the intended compound.

<l>H-NMR (90 MHz, CDC13) 6 :

1.5(t,J=7Hz.3H), 1.6 - 1.8(brs.2H). 1.8 - 2.1(m,3H),

2.52(dt.J=2Hz.7Hz,2H). 3.44(t.J=7Hz,2H), 3.76(q,J=7Hz,1H),

4.16(t,J=7Hz. 2H), 4.5 - 4.64(m.2H), 7.1 - 7.7(m.5H)

Subexample 20

3- methyl- 5-( 2- chlorophenyl)- 8-( 3- butynyloxycarbonyl)- 6. 7. 8. 9-tetrahydro- 1H. 3H-pyrido-f4'. 3' :4. 5l - thieno-f3.2-f1 Tl.41-diazepin-2-one

II S N—<°

CH^CCH,CH,0-C-N^ Y | f /~CH3

0.36 g of 2-(2-aminopropionylamino)-3-(2-chlorobenzoyl)-6-(3-butynyloxycarbonyl)-4,5,6,7-tetrahydrothieno-[2,3-c]-pyridine was dissolved in 10 ml of toluene and 0.8 ml of pyridine, to which 0.18 ml of acetic acid was added followed by treatment with reflux while removing formed water. After completion of the reaction, toluene was distilled off under reduced pressure and dichloromethane was added

to the distilled reaction solution followed by washing with water and drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified using silica gel column chromatography (eluent: dichloromethane: methanol = 100:0 - 97:3), obtaining 0.22 g of the intended compound.

• <1>H-NMR (90 MHz. CDC13) 8 :

1.76(d.J = 7Hz.3H) . 1.6 - 2.2(m.3H). 2. 5(dt,J = 2Hz,7Hz.2H), 2.9 - 4.0(m.2H). 3.86(q,J=7Hz.1H), 4.17(t.J=7Hz, 2H). 4.3 - 4.9(m,2H), 7.0 - 7.6(m.5H) Subexample 21 3-methyl-5-(2-chlorophenyl)-8-(3-butynyloxycarbonyl)-6.7.8.9-tetrahydro-1H. 3H- pyridine- r 41 . 3':4. 51 - thieno- f3. 2 - f1 fl. 41 - diazepine-2-thion

0.21 g 3-methyl-5-(2-chlorophenyl)-8-(3-butynyloxycarbonyl)-6,7,8,9-tetrahydro-1H,3H-pyrido-[4',3':4,5 ]-thieno-[3,2-f]-[1,4]-diazepin-2-one was dissolved in 10 ml of dimethoxyethane, to which 0.11 g of sodium bicarbonate and 0.22 g of phosphorus pentasulfide were added followed by heating at 80° C for three hours. After completion of the reaction, dichloromethane and methanol were added and the mixture was filtered, after which silica gel was added to the filtrate obtained and the solvent was evaporated to dryness. Silica gel column chromatography (eluent: dichloromethane: methanol = 99.1) was used for purification, obtaining 0.15 g of the intended compound.

• <1>H-NMR(90 MHz, CDC13) 6 :

1.12 - 2.00 (m, 2H). 1.73(d,J=7Hz.3H). 2.12(t,J=2Hz.1H).

2.40(dt,J=2Hz,7Hz,2H), 2.64 - 3.80(m.2H). 4.01(q,J=7Hz,1H),

4.02(t,J=7Hz. 2H). 4.10 - 4.76(m.2H), 7.28(m,2H)

Example 64

3-(S-butynyloxycarbonyl)-6-(2-chlorophenyl)-8.11-dimethyl-2.3.4.5-tetrahydro-8H-pyridine-f4'.3':4.5l-thieno-f3. 2- f1-fl.2.41-triazole o- f4. 3- a1 fl. 41- diazepine

0 T N

II /\/S^/N— <

CH = CCHaCH,0-C-N ]|_T VCH:J

100 mg of acetohydrazide was added to 150 mg of 3-methyl-5-(2-chlorophenyl)-8-(3-butynyloxycarbonyl)-6,7,8,9-tetrahydro-1H,3H-pyrido-[4<1>, 3':4,5]-thieno-[3,2-f][1,4]-diazepin-2-thione to which 2 ml of dioxane was further added followed by heating at 130°C for three hours while the solvent was distilled off. After completion of the reaction, the obtained residue was purified using silica gel column chromatography (eluent: dichloromethane:methanol = 98.2), obtaining 80 mg of the intended compound.

'H-NMR (90 MHz. CDCl3) 5 :

7.5(4H,Ar). 4.9(1H.d.J=18Hz.N-CH2[C-2:]),

4.5(1H,d.J=18Hz.N-CH2[C-2:]). 4.2(1H,m.C8-H).

4.1(2H.t.J=8HZ,0-CH2). 2.7(3H.s). 2.5(2H.dt,J=lHz.7Hz,

E-CH2), 2.1(3H, d.J=7Hz.CHCH), 3.0 - 2.0(5H.m)

Example 65

3-(2-tetrahydropyran-4-yl)-oxyethyl-oxycarbonyl-6-(2-chlorophenyl)-11-methyl-2.3. 4. 5-tetrahydro-8H-pyrido-f41. 3' :4. 51-tieno- T3. 2- f1- triazolo- Tl. 2. 41 U. 3- al Tl. 41- diazepine

<X>H-NMR (90MHz, CDCl3) 6:

1.30 - 2.40(m,6H), 2.68(s,3H), 2.80 - 5.70(m,15H), 7.20 - 7.54(m,4H) Example 66 6-(2-chlorophenyl)-3-cyclohexylethoxycarbonyl-11-methyl-2.3.4.5-tetrahydro-8H-pyrido-f4'. 3' :4. 5l- thieno- f3. 2- £1 - fl. 2. 41 \ A . 2 - al Tl. 41- diazepine

■""H-NMR (90MHz, CDCl3) 6:

0.6 - 2.3(m,15H), 2.7(s,3H), 3.0 - 4.0(m,2H), 4.0 - 4.4(m,l+2H), 4.4 - 4.8(m,2H), 5.4 - 5.8(m ,lH), 7.4(m,4H)

MS m/z (Pos. FAB): 524

Example 67

<1>H-NMR(90MHz, CDC13) 6:

1.20 - 2.32(m,6H), 1.94(t,J=2Hz,1H), 2.21(dt,J=2Hz,7Hz, 2H), 2.66(s,3H), 2.84 - 5.76(m,6H), 4.08 (t,J=7Hz,2H), 7.28(m,4H)

MS m/z (Pos. FAB): 495(M+H<+>)

Example 68

^■H-NMRt 90MHz, CDCl3) 6:

1.40 - 2.21(m,6H), 2.37(t,J=7Hz,2H), 2.67(s,3H), 2.92 - 5.80(m,6H), 4.11(t,J=7Hz,2H), 7.31(m ,4H)

MS m/z(POS. FAB): 494(M+H<+>)

Example 69

6-(2-Chlorophenyl)-3-(1-cyanoethoxy)-carbonyl-11-methyl-2.3.4.5-tetrahydro-8H-pyrido-f4'. 3' :4. 5l-thieno-T3. 2- f1 fl. 2. 41 - triazolo-f4.3-al fl.41-diaze<p>in

<1>H-NMR(90MHz, CDC13) 6:

1.70(t,J=7.0Hz,3H), 1.75(m,lH), 2.15(m,lH), 2.69(s,3H), 3.25(m,lH), 3.85(m,lH), 4.20(m ,1H), 4.53(m,1H), 4.85(m,1H), 5.43(m,1H), 5.65(m,1H), 7.23 - 7.65(m,4H)

• MS m/z (Pos. FAB): 467 (M<+>)

Example 70

6-(2-chlorophenyl)-3-cyclobutylcarbonyl-11-methyl-2.3.4.5-tetrahydro-8H-pyrido-f4 1 . 3' :4. 5l - thieno- T3. 2- fl Tl. 2. 41 - triazolo- f4. 3- al Tl. 41- diazepine

<1>H-NMR (90MHz, CDCl3) 6:

1.5 - 2.5(m,8H), 2.7(s,3H), 3.0 - 4.0(m,2H), 4.0 - 4.9(m, 1+1+2H), 5.4 - 5.8(m,lH), 7.4(m ,4H)

MS m/z (Pos. FAB): 468

Example 71

6-(2-chlorophenyl)-3-(2-methyl-2-cyanopropyloxy)-carbonyl-11-methyl-2.3.4.5-tetrahydro-8H-pyrido-f4'.3':4.5l-thieno -T3.2-f 1 Tl. 2. 41- triazolo- U. 3- al \ 1 . 41- diazepine

<1>H-NMR(90,MHz, CDC13) 6:

1.35(s,3H), 1.45(s,3H), 1.75(m,lH), 2.12(m,lH), 2.70(s,3H), 3.25(m,lH), 3.90(m.lH), 4.08 (s,2H), 4.22(m,1H), 4.55(m,lH), 4.56(m,lH), 5.62(m,lH), 7.30 - 7.45(m,4H)

MS m/z(Pos. FAB): 495(M<+>)

Example 72

6-(2-chlorophenyl)-II-methyl-3-(2-methylcyclohexyloxycarbonyl)-2. 3. 4. 5- tetrahYdro- 8H- pvrido- U' . 3' :4. 51- thieno- T3.2-f1 - ri. 2. 41-triazolo-T4. 3- al fl. 41- diazepine

6-(2-chlorophenyl)-11-methyl-3-(3-methylcyclohexyloxycarbonyl)-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5]-thieno-[3 ,2-f]-[1,2,4]-triazolo-[4,3-a][1,4]-diazepine 6-(2-chlorophenyl)-11-methyl-3-(4-methylcyclohexyloxycarbonyl)- 2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5]-thieno-[3,2-f]-[1,2,4]-triazolo-[4,3 -a][1,4]-diazepine

The above compounds all had the same NMR values as indicated below.

• <1>H-NMR(90MHz, CDC13,) 6 :

0.7 - 1.0(d,3H), 1.0 - 2.2(m,llH), 2.7(s,3H), 3.0 - 4.0(m,2H), 4.0 - 4.9(m,1+1+2H), 5.3 - 5.8 (m,lH), 7.4(m,4H)

• MS m/z (Pos. FAB): 510

Subexample 22

3-cyclopropylpropionic acid

100 ml of methanol, 100 ml of tetrahydrofuran and 2 g of 10% palladium carbon (containing 50% water) were added to 5.06 g of ethyl 3-cyclopropyl acrylate followed by a hydrogenation reaction overnight at normal temperature and normal pressure. The catalyst was removed by filtration and the solvent was distilled off. 20 ml of methanol, 20 ml of tetrahydrofuran, 10 ml of water and 7 g of sodium hydroxide were added to the residue and stirred at 8°C for 3.5 hours. The solvent was distilled off to which water was added, followed by washing with ethyl acetate. An aqueous hydrochloric acid solution was added to the obtained aqueous phase while cooling on ice to adjust the pH to 3, followed by extraction with chloroform under salting out conditions and drying with anhydrous magnesium sulfate. This was filtered and after removal of the solvent by distillation, the residue was subjected to silica gel column chromatography (eluent: dichloromethane) to give 1.8 g of the intended compound.

• <1>H-NMR(90MHz, CDCl3) 6:

0.65 - l.l(m,2H), 1.1 - 1.85(m,5H), 2.33(t, J=7.2Hz,2H), 8 . 9 (bs, 1H) Example 73 6-(2-chlorophenyl)-3-(3-cyclopropyl)-propionyl-11-methyl-2.3.4.5-tetrahydro-8H-pyrido-f4'. 3' :4. 5l-thieno-T3. 2nd row. 2. 41 - triazolo-T4.3-al\ 1.41-diazepine 50 mg 3-cyclopropylpropionic acid, 120 mg 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[ 4',3':4,5]-thieno-[3,2-f] [1, 2,4]-triazolo-[4,3-a] [1,4]-diazepine and 60 mg of 1-hydroxybenzotriazole monohydrate was dissolved in 8 ml of N,N-dimethylformamide, to which 80 mg of N,N'-dicyclohexylcarbodiimide was added while cooling on ice. After stirring for about 10 minutes, the mixture was further stirred overnight at 4°C.

The mixture was then stirred at room temperature for approximately one hour, after which the solvent was distilled off. A saturated aqueous sodium bicarbonate solution was added to the distilled product which was extracted with chloroform and dried with anhydrous magnesium sulfate. The solution was filtered and the solvent was distilled off, after which the residue was subjected to silica gel column chromatography (eluent: dichloromethane: methanol), obtaining the intended compound.

• <1>H-NMR(90MHz, CDCl3) , 6:

0.7 - 1.05(m,3H), 1.05 - 2.4(m,6H), 2.27(t, J=7Hz,2H), 2.67(s,3H), 2.8 - 5.9(m,6H), 7.1 - 7.55(m ,4H) Example 74 6-(2-chlorophenyl)-3-cinnamoyl-11-methyl-2.3.4.5-tetrahydro-8H-pyrido-T4'. 3' :4. 51 - thieno- T3. 2- fl n. 2. 4l - triazolo- T4 . 3a1 Q. 41 - diazepine

80 mg of cinnamoyl chloride were dissolved in 8 ml of N,N-dimethylformamide to which 4 ml of an N,N-dimethylformamide solution of 120 mg of 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H- pyrido-[4<*>,3':4,5]-thieno-[3,2-f] [1,2,4]-triazolo-[4,3-a] [1,4]-diazepine and 160 mg of triethylamine was added dropwise at -60°C followed by

stirring for 30 minutes. After removal of the solvent by distillation, a saturated aqueous sodium hydrogen

carbonate solution added followed by extraction with chloroform and drying with anhydrous magnesium sulfate. This was filtered off and the solvent was distilled off. The residue was subjected to silica gel column chromatography (eluent: methanol:dichloromethane = 1:99) to give 110 mg of the intended compound (yield 68

• ^-H-NMRfCDC^) 6:

1.2 - 2.6(m,2H), 2.48(s,3H), 2.8 - 5.9(m,6H), 6.74(t, J=15.1Hz,lH), 7.1 - 7.7(m,9H), 7.64(d, J=15.1Hz,1H)

• MS m/z (Pos. FAB): 500 (M+H)<+>

Example 75

6-(2-Chlorophenyl)-11-methyl-3-(2-methylcyclopropanecarbonyl)-2.3.4.5-tetrahydro-8H-pyrido-f4'.3':4.51-thieno-f3. 2- f1-fl.2.41-triazolo-f4.3-al fl.41-diazepine

50 mg 2-methylcyclopropanecarboxylic acid, 130 mg 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4<1>,3':4,5]-thieno- [3,2-f][1,2,4]-triazolo-[4,3-a][1,4]-diazepine and 70 mg of 1-hydroxybenzotriazole monohydrate were dissolved in 8 ml of N,N-dimethylformamide, to which 90 mg of N,N'-dicyclohexylcarbodiimide was added while cooling on ice followed by stirring for about ten minutes. Stirring was then continued at 4°C overnight and then at room temperature for one hour. After removal of the solvent by distillation, a saturated aqueous sodium bicarbonate solution was added followed by extraction with chloroform and drying with anhydrous magnesium sulfate. This was filtered off and the solvent was distilled off whereupon the residue obtained was subjected to silica gel column chromatography (eluent: dichloromethane:methanol = 99:1) to give 120 mg of the intended compound (yield 76%).

<1>H-NMR ( CDC13 ) 6:

0.4 - 0.72(m,lH), 0.72 - 1.0(m,1H), 1.26(s,3H), 1.4 - 2.4(m,2H), 2.68(s,3H), 2.9 - 5.9(m,6H), 7.1 - 7.7(m,4H)

• MS m/z (Pos. FAB): 452(M+H)<+>

Example 76

6-(2-Chlorophenyl)-11-methyl-3-phenylacetyl-2.3.4.5-tetrahydro-RH-pyrido-f4'. 3■ :4. 5l- thieno-f3. 2- f1 ride. 2. 4l-triazolo-f4. 3- al - fl.41-diazepine

120 mg 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5]-thieno-[3,2-f] [ 1,2,4]-triazolo-[4,3-a] [1,4]-diazepine and 160 ml of triethylamine were dissolved in 4 ml of N,N-dimethylformamide, and the mixture was added dropwise to 5 ml of a N, N-dimethylformamide solution by dissolving 60 mg of phenylacetic acid chloride at -60°C. After completion of the reaction, the solvent was distilled off from the reaction mixture to which a saturated aqueous sodium bicarbonate solution was added, followed by extraction with chloroform and drying with anhydrous magnesium sulfate. The magnesium sulfate was filtered off and the solvent was distilled off, after which the obtained residue was subjected to silica gel column chromatography (eluent: dichloromethane:methanol = 99:1) to give 110 mg of the intended compound (yield 69%).

• <1>H-NMR (CDC13) 6

1.0 - 2.6 (m,2H), 2.61 and 2.66 (each s, total 3H),

2.8 - 6.0 (m,6H), 3.69 and 3.77 (each s, total 2H), 6.8 - 7.7

(m, 9H)

MS m/z (Pos. FAB): 488 (M+H)<+>

Example 77

6-(2-chlorophenyl)-11-methyl-3-(3-methylcrotonoyl)-2.3.4.5-tetrahydro-8H-Dvrido-f4'. 3- :4. 5l-thieno-T3. 2- fl fl. 2. 41 - triazolo-T4. 3-al \ 1.41-diazepine

120 mg 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5]-thieno-[3,2-f] [ 1,2,4]-triazolo-[4,3a][1,4]-diazepine and 160 mg of triethylamine were dissolved in 4 ml of N,N-dimethylformamide which was added dropwise to 5 ml of an N,N-dimethylformamide solution prepared by dissolving 50 mg of 3-methylcrotonic acid chloride at -60°C. After completion of the reaction, the reaction solution was distilled off to which a saturated aqueous sodium bicarbonate solution was added followed by extraction with chloroform and drying with anhydrous magnesium sulfate which was then filtered off. The solvent was distilled off, after which the obtained residue was subjected to silica gel column chromatography (eluent: dichloromethane: methanol = 99:1) to give 130 mg of the intended compound.

<1>H-NMR(CDC13) 6:

1.0 - 2.5(m,8H), 2.70 (s,3H), 2.8 - 5.9(m,6H), 6.73(bs,lH), 7.1 - 7.6(m,4H)

• MS m/z (Pos. FAB): 452(M+H)<+>

Example 78

6-(2-Chlorophenyl)-11-methyl-3-(trans)-2-phenylcyclopropane-carbonyl-2.3.4.5-tetrahydro-8H-pyrido-f4'. 3' -. 4. 51 - thieno- T3. 2-f1 n .2.41 -triazolo-T4.3-al \ 1.41- diazepine

70 mg (trans)-2-phenyl-1-cyclopropanecarboxylic acid, 120 mg 6-(2-chlorophenyl)-1-methyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4 ,5]-thieno-[3,2-f][1,2,4]-triazolo-[4,3-a][1,4]-diazepine and 60 mg of 1-hydroxybenzotriazole monohydrate were dissolved in 12 ml of N,N -dimethylformamide, to which 80 mg of N,N'-dicyclohexylcarbodiimide was added while cooling on ice. After stirring for about ten minutes, the mixture was further stirred overnight at 4°C and then at room temperature for one hour. After removal of the solvent by distillation, a saturated aqueous sodium bicarbonate solution was added followed by extraction with chloroform and drying with anhydrous magnesium sulfate. The sulfate was removed by filtration and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (eluent: dichloromethane-methanol = 99:1) to give 160 mg of the intended compound.

• <1>H-NMR(CDC13) 6:

1.4 - 2.8(m,6H), 2.66(s,3H), 2.8 - 5.8(m,6H), 6.5 - 7.7(m,9H)

• MS m/z (Pos. FAB): 514(M+H)<+>

Example 79

6-(2-chlorophenyl)-11-methyl-3-(g-methylcinnamoyl)-2.3,4.5-tetrahydro-8H-pyrido-f4'.3':4.51-thieno-f3.2-fl fl.2.41-triazolo - U. 3- al Tl. 41- diazepine

• <1>H-NMR(CDC13) 6:

1.7 - 2.5(m,2H), 2.14(d, J=1.4Hz,3H), 2.72(s,3H), 2.8 - 5.9 (m,6H), 6.87(q,J=1.4Hz,1H), 7.0 - 7.7(m,9H) Example 80 6-(2-chlorophenyl)-11-methyl-3-(4-pyridylthio)-acetyl-2. 3. 4. 5-tetrahydro-8H-pyrido-f4■. 3' :4. 51- thieno- f3. 2- f1 Tl. 2. 41-triazolo-T4.3-al Tl.41-diazepine

• <1>H-NMR(CD30D-CDC13) 6:

1.4 - 2.6(m,2H), 2.68(s,3H), 2.8 - 5.9 (m,6H), 3.82(bs,2H), 7.05 - 7.6(m,6H), 8.1 - 8.6(m,2H)

• MS m/z (Pos. FAB): 521(M+H)<+>

Example 81

6-(2-Chlorophenyl)-11-methyl-3-(3-phenylpropionyl)-2,3,4,5-tetrahydro-8H-pyrido-f4'. 3' :4. 5l- thieno-f3.2-f1 n. 2. 41 - triazolo-U.3-al Tl.41-d iazepine

<1>H-NMR(CDC13) 6:

1.0 - 2.3(m,4H), 2.66(s,3H), 2.65 - 3.15(m,2H), 2.8 - 5.9(m,6H), 6.65 - 7.65(m,9H)

MS m/z (Pos. FAB): 502(M+H)<+>

Example 82

6-(2-chlorophenyl)-11-methyl-3-f3-f3-pyridyl-1-acryloyl-2.3.4,»;-tetrahydro-8H-pyrido-f4'. 3':4.5l-ti eno-f3. 2-fl Tl. 2. 41-triazolo-T4.3-al fl.41-diazepine

<1>H-NMR(CDC13) 6:

1.5 - 2.5(m,2H), 2.68(s,3H), 3.0 - 5.8(m,6H), 6.83(bd,J=15.5Hz,1H), 7.15 - 7.9(m,6H), 7.60(d, J=15.5Hz,1H), 8.3 - 8.5(m,lH), 8.64(bs,lH)

• MS m/z (Pos. FAB): 501(M+H)<+>

Example 83

6-(2-Chlorophenyl)-3-(3-cyclohexylpropionyl)-11-methyl-2.3. 4,5-tetrahydro-8H-pyrido-f4',3' :4,5l-thieno-T3,2-fl fl. 2. 41 - triazolo-T4.3-al T1.41-diazepine

<1>H-NMR(CDC13) 6:

0.6 - 2.5(m,15H), 2.28(bt,J=8Hz,2H), 2.66(s,3H), 2.8 - 5.9(m,6H), 7.1 - 7.6(m,4H)

MS m/z (Pos. FAB): 508 (M+H)<+>

Example 84

6-(2-chlorophenyl)-3-(4-fluorophenyl)-acetvl-ll-methyl-2.3.4.5-tetrahydro-BH-pyrido-f4'. 3' ; 4. 5l-thieno-T3. 2- f1 fl. 2. 41 - triazolo-T4.3-al T1.41-diazepine

• <1>H-NMR(CDC13) 6:

1.0 - 2.4(m,2H), 2.66(s,3H), 2.8 - 5.9(m,6H), 3.65(bs,2H), 6.65 - 7.6(m,8H) MS m/z (Pos. FAB): 506(M+H)<+> Subexample 23 Ethyl tetrahydropyran-A4,α-acetate 1.2 g (30 mmol) of sodium hydride was added to 100 ml of a dimethylformamide solution of 6.72 g (30 mmol) of diethylphosphonoethyl acetate while cooling on ice, the mixture was stirred in ten minutes. 2.5 g (25 mmol) of tetrahydro-4H-pyran-4-one was further added to the mixture while cooling on ice and the mixture was allowed to return to room temperature and it was stirred at 80°C for two hours. After completion of the reaction, ethyl acetate was added followed by washing with a saturated salt solution and drying with magnesium sulfate. This was concentrated under reduced pressure and the residue obtained was subjected to silica gel column chromatography (eluent: hexane:ethyl acetate = 9:1) with 4.2 g of the intended compound being obtained in the form of a pale yellow oily substance.

1.3(t,J=7,2Hz,3H), 2.0 - 2.3(m,2H), 3.0(bs,2H), 3.8 (t,J=5.4Hz,2H) , 4.0 - 4.3(m,2H), 4.1(q,J=7.2Hz,2H), 5.6(bs,1H)

Male example 24

Styl-4-tetrahydropyranyl acetate

0

II

O^-CH 2 -C-OC 2Hs

2.0 g of ethyltetrahydropyran-A<4,a->acetate was dissolved in 50 ml of netanol, to which 10% palladium-carbon was added followed by hydrogenation for three hours. After removal of the catalyst by filtration, the reaction mixture was concentrated under reduced pressure to give 1.6 g of the intended compound.

<1>H-NMR(CDC13) 6:

1.1 - 2.3(m,7H), 1.3(t,J=7,2Hz,3H), 3.2 -

3.6(td,J=12.6Hz,2.9Hz,2H), 3.8 - 4.3(m,2H), 4.1(q,J=7.2Hz,2H)

Male example 25

4-tetrahydropyranylacetic acid

20 ml of methanol, 10 ml of water and 1 g of sodium hydroxide were added to 0.9 g of ethyl 4-tetrahydropyranyl acetate and the mixture was stirred at 80°C for one hour. The solvent was removed by distillation and water was added. After washing with ethyl acetate, an aqueous hydrochloric acid solution was added to the obtained aqueous phase to pH = 3, followed by extraction with chloroform under salting out conditions and drying with anhydrous magnesium sulfate which was removed by filtration. The solvent was distilled off to obtain 0.87 g of an impure intended compound.

• <1>H-NMR(CDC13) 6:

1.0 - 2.4(m,5H), 2.28(bd,J=6.5Hz,2H), 3.37(td,J-11.5Hz,2.9Hz,2H), 3.7 - 4.1(m,2H), 7.85(bs,lH)

Example 85

6-(2-chlorophen<y>l)-11-meth<y>l-3-(tetrahydro<y>dro<y>ran-4-yl)-acet<y>l - 2.3.4.5-tetrahydro- 8H-pvrido-f4'.3':4.5l-thieno-T3.2-fl-fl. 2. 41-triazolo-T4. 3- al fl. 41- diazepine

<1>H-NMR(CD30D-CDC13) 6:

0.9 - 2.4(m,9H), 2.67(s,3H), 2.8 - 5.9 (m,10H), 7.1 - 7.5(m,4H)

MS m/z (Pos. FAB): 496(M+H)<+>

Subexample 2 6

Tetrahydropyran-A<4,a->acetic acid

10 ml of methanol, 10 ml of water and 1 g of sodium hydroxide were added to 0.8 g of ethyltetrahydopyran-A<4,a->acetate, the mixture was stirred at 80°C for two hours. After removal of the solvent by distillation, water was added to the mixture followed by washing with ethyl acetate. An aqueous hydrochloric acid solution was added to the aqueous phase to acidify it followed by extraction with chloroform under salting out conditions and drying with anhydrous magnesium sulfate which was filtered off. The solvent was distilled off, after which the obtained residue was subjected to silica gel column chromatography (eluent: dichloromethane), whereby 0.17 g of the intended compound was obtained (yield 25%).

• <1>H-NMR(CD3OD-CDCl3) 6:

2.34(bt, J=5.4Hz, 2H), 2.98(bt,J=5.4Hz,2H), 3.5 - 3.95(m,4H), 5.66(bs,lH), 8.45(bs,lH) Example 86 6- (2-Chlorophenyl)-11-methyl-3-(tetrahydropyran-A4' a-acety1-2.3.4.5-tetrahydro-8H-pyrido-f4'.3':4.5l-thieno-T3.2- fl- Tl. 2. 41- triazolo- T4. 3- al f1. 41- diazepine

• <1>H-NMR(CDC13) 6:

1.4 - 2.5(m,2H), 2.1 - 2.41(m,2H), 2.41 - 2.8(m,2H), 2.67(s,3H), 2.8 - 5.9 (m,6H), 3.45 - 3.9(m,4H ), 5.72(bs,lH), 7.15 - 7.5(m,6H)

MS m/z (Pos. FAB): 494(M+H)<+>

Example 87

6-(2-Chlorophenyl)-3-r(trans)-3-cyclopropylacryloyl-11-methyl-2.3.4.5-tetrahydro-8H-pyrido-\4>.3':4.5l-thie no-f3. 2- fl - Tl.2.41-triazolo-f 4.3-al fl.41- diazepine

<1>H-NMR(CDC13) 6:

0.4 - 1.15(m,4H), 1.2 - 2.6(m,3H), 2.66(s,3H), 2.8 - 6.0(m,6H), 6.13(d,J=21.6Hz,1H), 6.25( dd,J=21.6, 14.4Hz,lH), 7.1 - 7.5(m,4H)

• MS m/z (Pos. FAB): 464(M+H)<+>

Example 88

6-(2-Chlorophenyl)-3-(trans)-3-cyclopropionyl-acryloyl-8,11-dimethyl-2. 3. 4. 5- tet.T-ahyriro-8H-Dvrido- f4 1 .3' :4.51 - thieno- f3.2-fl ri.2.41-triazolo-f4.3-al Q.41-diazepine

(1) Preparation of ethyl (trans)-3-cyclopropyl acrylate

38.38 of ethyl diethylphosphonoacetate was dissolved in 300 ml of N,N-dimethylformamide, to which 6.85 g of 60% sodium hydride was added at 0°C, followed by stirring at room temperature for 30 minutes and dropwise addition of 10 g of cyclopropanealdehyde at 0°C. After stirring at room temperature for two hours, ice water was added, followed by extraction with ether, washing with water and drying with anhydrous magnesium sulfate which was then removed by filtration. A concentrated residue was subjected to silica gel column chromatography (eluent: ethyl acetate:hexane = 2:98), obtaining 11.18 g of the intended compound as a trans product (yield 60%).

• <1>H-NMR(CDC13) 6:

0.4 - 1.1(m, 4H), 1.26(t,J=7.2Hz, 3H), 1.3 - 1.8 (m,1H), 4.13(q,J=7.2Hz,2H), 5.82(d,J=15.5Hz ,1H), 6.37(dd,J=15.5Hz, 10.1Hz,1H)

(2) Preparation of (trans)-3-cyclopropylacrylic acid

100 ml of methanol, 50 ml of water and 6.4 g of sodium hydroxide were added to 11.18 g of ethyl (trans)-3-cyclopropyl acrylate obtained in the above method and the mixture was allowed to react at 80°C for 1.5 hours. After concentration, concentrated hydrochloric acid was added to acidify the mixture followed by extraction with chloroform, washing with saturated brine and drying with anhydrous magnesium sulfate which was then removed by filtration. The filtrate was concentrated to give 8.82 g of the intended compound (yield 99%).

<1>H-NMR(CDC13) 6:

0.3 - 1.2(m,4H), 1.2 - 1.9(m,1H), 5.83(d,J=15.1Hz,1H), 6.47(dd,J=15.1Hz, 6.5Hz,lH), 9.06(bs,lH ) (3) 6-(2-chlorophenyl)-3-[(trans)-3-cyclopropylacryloyl]-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3' :4,5] - thieno-[3,2-f] [1,2,4]-triazolo-[4,3-a] [1,4]-diazepine 90 mg (trans)-3-cyclopropylacrylic acid, 120 g 1-hydroxybenzotriazole monohydrate and 240 mg 6-(2-chlorophenyl)-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido-[4',3':4,5]-thieno-[ 3,2-f]-[1,2,4]-triazolo-[4,3-a][1,4]-diazepine was dissolved in 12 ml of N,N-dimethylformamide, to which 160 mg of 1,3-dicyclohexylcarbodiimide was added while cooling on ice followed by stirring at 4°C for nine hours and then at room temperature for one hour. After concentration, a saturated aqueous sodium bicarbonate solution was added followed by extraction with chloroform and drying with anhydrous magnesium sulfate which was then removed by filtration. The resulting filtrate was concentrated, and the residue was subjected to silica gel column chromatography! (eluent: solvent: dichloromethane = 1:99) to give 240 mg of the intended compound (yield 80%).

• 1H-NMR(CDC13, ) 6 :

0.4 - l.l(m,4H), 1.35 - 2.0(m,2H), 2.0 - 2.6(m,1H), 2.09(d,J=6.8Hz,3H), 2.65(s,3H), 2.8 - 4.1( m,2H), 4.1 - 5.3(m,2H), 4.26(q,J=6.8Hz,lH), 6.15(d,J=19.8Hz,1H), 6.31(dd,J=19.8Hz,15.1Hz, 1H), 7.1 - 7.55(m,4H)

MS m/z (Pos. FAB): 478(M+H)<+>

PATENT CLAIMS

Analogous process for the preparation of therapeutically active triazolo-1,4-diazepine compounds of formula (I):

wherein R<1> and R2 are the same or different and are a hydrogen atom or a lower alkyl group, R<3> is a halogen atom, R4 is a hydrogen atom or a lower alkyl group, and X is (a) a group of the formula (b) a group of the formula in which R<5> is a hydrogen atom or a lower alkyl group, (c) a group of the formula - in which R<6> is a lower alkyl group (d) a group of the formula

n is an integer 0 or 1, and

Y is

(1) a C3-C6 cycloalkyl group optionally substituted with C1-C8 alkyl or C1-C6 alkynyl,

(2) a C3-C6 cycloalkyl-C1-C6 alkyl group,

(3) a C 1 -C 6 alkynyl group,

(4) a group with the formula

in which R7 is

hydrogen or methyl and r is 0 or 1,

(5) a group of the formula NC-(CH2)p- wherein p is an integer from 1-6, (6) a group of the formula A-(CH2)q- wherein A is a group selected from a pyridyl-, pyranyl and a morpholino group and q is an integer from 0 to 6, (7) a C1-C6 alkynyl group in which a phenyl group is attached to any of the carbon atoms, (8) a group of the formula (9) a group of the formula in which R<8> and R<9> are the same or different and are a hydrogen atom, a lower alkyl group, a pyridylmethyl group or a C3-C6 cycloalkyl group or R<8> and R<9> can together with a nitrogen atom form morpholino, piperidyl or pyridyl, and B is a phenylene group or a lower alkylene group having from 1-3 carbon atoms, (10) a group of the formula (11) a group of the formula (12) a group of the formula (13) a C 1 -C 8 alkyl group or C2-C6 alkenyl group, or

(14) a C3-C6 cycloalkyl-C2-C6 alkenyl group,

(15) wherein s is 0, 1 or 2 (16) wherein t is 1 or 2 (17) (18) a phenyl-C-L-Cg-alkyl group which is optionally substituted with halogen (19) a phenyl-C2-C6- alkenyl group, (20) wherein R<10> is hydrogen or phenyl, R<11> is hydrogen or lower alkyl, or (21) wherein G is C2-C6 alkenyl or -J-(CH2)k- in which J is sulfur and k is 0, 1 or 2, with the proviso that when X is (a) when (b) Y is a group selected from (1) to (12), and when X is (d) is Y a group (13) and when n is 0, Y is an alkynyl group (3), and with the further condition that when

Y can't

be a group selected from (1) wherein the cycloalkyl group is unsubstituted, (3), (4) wherein r = 0 and (5), and pharmaceutically acceptable salts thereof,

characterized by that

a) a compound of formula (II)

wherein X is or

n is 1,

plus a compound of formula (III)

wherein R<1>, R<2>, R3 and R<4> are as indicated above, is subjected to a condensation reaction to give the intended compound of formula (I<1>) wherein X, n, Y, R< 1>, R2, R<3> and R<4> are as indicated above, or b) a carboxylic acid

wherein Y is as indicated above or

its reactive acid derivative and a compound of formula

(III)

wherein R1, R<2>, R3 and R<4> are as indicated above, is subjected to a condensation reaction to give the intended compound of formula (I<1>')

wherein Y, R<1>, R<2>, R3 and R<4> are as indicated above,

c) a compound of formula (VII)

in which Y and R<6> are as indicated above and Hal is a halogen atom, is reacted with a compound of formula (III) in which R<1>, R<2>, R3 and R<4> are as indicated in the preceding, to give the intended compound of formula (I<1>'')

wherein Y, R<6>, R<1>, R2, R3 and R<4> are as indicated in the

preceding, or

d) a compound of formula (VIII)

in which Y is as indicated above and Hal is a halogen atom, is reacted with a compound of formula (III) in which R<1>, R<2>, R<3> and R<4> are as indicated above, to give the intended compound of formula (I"")

in which Y, R<1>, R<2>, R3 and R<4> are as indicated above, and if desired, the obtained compounds are converted into pharmaceutically acceptable salts thereof.