Derived imidazolidine, the pharmaceutical composition, its preparation and methods of deriving imidazolidine

 

(57) Abstract:

The invention relates to new imidazolidine formula I, their pharmaceutically acceptable additive salts and stereochemical isomeric forms, where each dashed line independently represents an optional bond; -a-b - represents a radical of the formula-X-C=CH (a-1), -CH=CH-X- (a-2) or-CH=CH-CH=CH- (a-3); X represents O, S or NR1; R1represents N or C1-C6- alkyl; represents a radical of the formula = 0 (b-1); HE (b-2) or = N-IT (b-3); and L represents hydrogen, C1-C4- allyloxycarbonyl, C1-C6-alkyl or C1-C6-alkyl, substituted C1-C4-allyloxycarbonyl, aryl, aryloxy or a radical of formula (C), where D is Z represents-S-CH=CH -, and aryl represents phenyl or phenyl, substituted by halo, hydroxy or C1-C4- alkyloxy. Describes compositions comprising these compounds, methods of making the compounds and use of these compounds for the treatment of allergic diseases. 4 C. and 10 C.p. f-crystals.

WO 92/22551 and WO 92/22553 describe imidazolidine having antiallergic activity. In EP-0339978 describes (benzo or pyrido)cyclohepta-heterocyclic compounds that are useful is by benzo[5,6]cycloheptatriene, which have anti-inflammatory activity.

Compounds according to the present invention differ structurally from the cited known in the art compounds by the fact that the Central 7-membered ring always contains a nitrogen atom condensed imidazole ring is substituted carbonyl, hydroxy or hydroxyimino group. Their favorable anti-allergic activity is proved by the absence of their sedative properties at therapeutic doses.

The present invention relates to new imidazolidine formula:

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their pharmaceutically acceptable additive salts and stereochemical isomeric forms, in which

each dashed line independently represents an optional bond;

-A-B - represents a radical of the formula

-X-CH=CH- /a-1/,

-CH=CH-X- /a-2/, or

-CH=CH-CH=CH- /a-3/;

X represents O, S, or NP1;

R1represents hydrogen or /1-6/C alkyl;

...Y represents a radical of the formula

=O /b-1/,

-OH /b-2/, or

=N-IT /b-3/, and

L represents a hydrogen /1-4/alkylsulphonyl, /1-4/allyloxycarbonyl, phenylcarbinol, /1-6/With alkyl or /1-6/alkyl substituted With /1-4/C-allyloxycarbonyl, hydroxycarbonyl is, S-CH2-CH2-CH2-, -CH=CH-CH=CH-, or-CH2-CH2-CH2-CH2- and

aryl represents phenyl or phenyl substituted by halogen, hydroxy or /1-4/With alkyloxy group.

In the sense, as the terms are used in the previous definitions, halogen denotes fluorine, chlorine, bromine or iodine; /1-4/With alkyl refers to saturated hydrocarbon radicals with a straight or branched chain, having from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl; /1-6/With alkyl is /1-4/With alkyl radicals defined here above, and their higher homologues, having from 5 to 6 carbon atoms, such as, for example, pentyl and hexyl.

The term pharmaceutically acceptable salt additive used here above, denotes a non-toxic therapeutically active additive form salts that can form the compounds of formula (I). The compounds of formula I having basic properties, can be transformed into the corresponding therapeutically active, non-toxic acid-additive form salts by treatment of the free base form with a suitable amount of an appropriate acid, following conventional techniques. P the lot and similar; or organic acids, such as, for example, acetic, propanoic, hydroxyestra, 2-hydroxypropanoic, 2-oxopropanoic, ethane DIACID, preventiva acid, Balandina acid, /Z/-2-Buendia acid, /E/-2-Buendia acid, 2-hydroxybutanoic acid, 2,3-dihydroxybutanedioate acid, 2-hydroxy-1,2,3-propantriol acid, methanesulfonate, econsultancy, benzolsulfonat, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2 - hydroxybenzoic acid and similar acids.

The compounds of formula (I) exhibiting acid properties, can be transformed in a similar way with the use of suitable bases into the corresponding therapeutically active, non-toxic form of additive salts of the bases. Examples of such forms of additive salts of the bases are, for example, sodium, potassium, calcium salts, and also salts with pharmaceutically acceptable amines such as ammonia, alkylamines followed, benzathine, N-methyl-D-glucamine, geranamine, amino acids, e.g. arginine, lysine. The term pharmaceutically acceptable salt additive also includes a solvate, which can form compounds of the formula I, for example hydrates, alcoholemia various isomeric, as well as conformational forms which may have compound of the formula /I/. If not mentioned, or not mentioned, the chemical designation of compounds, is meant a mixture of all possible stereochemical and conformationally isomeric forms, and these mixtures containing all diastereomers, enantiomers and/or conformers of the main molecular structure. Have in mind that the scope of the present invention covers all stereochemical isomeric forms of the compounds of the formula /I/, as in pure form or in mixture with each other.

Some compounds of the present invention may exist in different tautomeric forms, and mean that all such tautomeric forms are included within the scope of the present invention.

Interesting compounds are the compounds of formula I having the formula:

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More interesting compounds are the compounds of formula I in which a represents a radical of the formula =O /b-1/.

Another interesting group of compounds are compounds of the formula I in which a represents a radical of the formula-IT /b-2/.

The next group of interesting compounds are the compounds of formula I in which RA is the more specific formula

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More preferred are those of the preferred compounds in which A-B represents the radical of the formula-CH=CH-X- /a-2/.

Further preferred compounds are those preferred compounds in which X represents /1-4/With alkylamino.

Even more preferred compounds are those of the above preferred compounds in which L is /1-6/With alkyl.

The most preferred compound is 7,10-dihydro-7 - methyl-10-(1-methyl-4-piperidinylidene)imidazo[1,2-a]pyrrolo[3,2-d]- azepin-6/5H/he, its pharmaceutically acceptable salt additive and stereochemical isomeric form.

The compounds of formula I in which a represents a radical of the formula =O /b-1/, and these compounds are represented by the formula /I-a/, can be obtained by reaction of the intermediate compounds of formula (II) in the presence of acid, for example, triftormetilfullerenov acid and similar.

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The compounds of formula I in which a represents a radical of the formula-IT /b-2/, these compounds are represented by formula I-b/ can be obtained through reaction of compounds of the formula /I-a/ in the presence of a reducing reagent, for example, boron is BR>
The compounds of formula I in which a represents a radical of the formula = N-OH /b-3/, in other words compounds represented by the formula /I-s/, can be obtained by the reaction of compounds of the formula /I-a/ with hydroxylamine or a salt, for example, chlorhidrate his salt, in an inert towards the reaction solvent, for example, pyridine and similar.

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The compounds of formula I in which L represents /1-6/With alkyl or /1-6/From alkyl, substituted /1-4/allyloxycarbonyl, hydroxycarbonyl, aryl, aryloxy or a radical of the formula /s/, the compounds represented by the formula /I-d/, and L - group LIcan be obtained by N-alkylation of compounds of formula I, in which

L represents hydrogen, the compounds represented by the formula /I-s/, with a reagent of formula LI-W /III/

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In the formula (III and forth in the description of W is an appropriate leaving group, such as, for example, halogen, e.g. chlorine, bromine and similar; or sulfonyloxy group, such as, for example, methanesulfonate, 4-methylbenzenesulfonate and similar.

This reaction of N-alkylation may conveniently be carried out in an inert towards the reaction solvent, such as, for example, aromatic uglily mixture of such solvents. The addition of an appropriate base, such as, for example, carbonates, bicarbonates, alcoholate, hydrides, amides, hydroxides or oxides of alkali or alkaline earth metals, or organic bases, such as, for example, amine, can be used to collect acid, which is liberated during the reaction. In some cases, suitable is the addition of the iodide salt, preferably the alkali metal iodide. Several elevated temperatures and mixing can enhance the reaction rate. Alternatively, the specified N-alkylation may be carried out using known in the art, the conditions of the reactions catalyzed transfer phases.

The compound of the formula /I-d/ can be obtained through reaction of addition of the compounds of formula /I-s/ to the corresponding alkene of the formula /IV/, in which L2 represents a hydrogen /1-4/allyloxycarbonyl, hydroxycarbonyl, aryl, aryloxy or a radical of the formula /s/, in a reaction-inert solvent, e.g. methanol and the like.

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The compounds of formula /I-s/ can be obtained using dibenzylamine compounds of the formula

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following known in the art procedures, such as catalytic guy who presents to the formula /I-e-I/, can be obtained through hydrolysis of the intermediate compound of the formula /V/ in the presence of acid, for example, Hydrobromic acid, triperoxonane acid and similar.

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In some cases, the reaction of the intermediate compound of the formula /V/ in the presence of acid can give the compounds of formula

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The compounds of formula (I) can further be transformed into each other using a known technique procedures of transformation of functional groups.

For example, the compounds of formula I in which L represents /1-4/allyloxyphenyl/1-6/With alkyl, may be transformed into compounds of formula I in which L represents hydroxyphenyl/1-6/With alkyl, after treatment with acid, such as Hydrobromic acid, itestosterone acid or Lewis acid, e.g. boron TRIFLUORIDE, trichloride aluminum and similar.

Pure stereochemical isomeric forms of the compounds of formula I can be obtained by applying known in the art procedures. Diastereoisomer can be separated using physical methods such as selective crystallization and chromatography techniques, e.g. counter current distribution, liquid chromatography and similar. Enantia, for example, by selective crystallization of other diastereomeric salts with chiral acids. In particular, the enantiomers can be separated using column chromatography using a chiral stationary phase such as derivational appropriately cellulose, for example, three(dimethylcarbamoyl)cellulose (Chiralcel Of Dand similar chiral stationary phases. Pure stereochemical isomeric forms may also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that the reaction proceeds in a stereospecific.

Intermediate compounds of formula (II) can be obtained through reaction of the intermediate compounds of formula /VI/ reagent formula /VII/ in the presence of a base, e.g. sodium hydride, in a reaction-inert solvent, e.g. N,N-dimethylformamide and similar.

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Intermediate compounds of formula /VI/, in which the piperidine is connected with a substituted methyl group, a double bond, and these intermediate compounds represented by formula /VI-a/ can be obtained through dehydration of the intermediate compounds of formula /VIII/, for example, by the reactions is m acid, for example, acetic anhydride.

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Intermediate compounds of formula /VIII/ can be obtained by the reaction of intermediate compounds of formula IX/ with a reagent of the formula /X/ in the presence of utility and a suitable base, for example, N-(1-methylethyl)-2-propanamine, in a reaction-inert solvent, e.g. tetrahydrofuran, using known in the art procedures.

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Intermediate compounds of formula /VIII/ can also be obtained through reaction of the intermediate compounds of formula /XI/ with a reagent of formula /XII/ in the presence of utility using known in the art techniques.

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Intermediate compounds of the formula /V/ can be obtained by the reaction of compounds of formula I-a/, where L is /1-6/With alkyl, the compounds represented by formula (I-a-2/, /1-4/alkylchlorosilanes in the presence of a suitable base, such as N,N-diethylethanamine in a reaction-inert solvent, such as methylbenzene, and similar.

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The compounds of formula (I), and intermediate compounds of the formula /V/, their pharmaceutically acceptable salts and stereospecific isomeric form their possess useful pharmacological properties. In particular, they are what tatami tests obtained in a series of demonstration experiments.

Antihistamine activity can be demonstrated by testing to protect rats from induced compound 48/80 lethality (Arch. Int. Pharmacodyn Jher., 234, 164-176, 1978); test-induced histamine lethality in Guinea pigs (Arch. Int. Pharmacodyn Jher., 251, 39-51, 1981); and extensive anti-allergic activity can be demonstrated in the test of passive cutaneous anaphylaxis in rats (Drug Dev. Res. , 5, 137-145, 1985). (For some compounds this test was modified by replacing compound 48/80 allergens Ascaris) and test Allergy Askaris on dogs (Arch. Int. Pharmacodyn Jher. 251, 39-51, 1981 and Res., 8, 95-102, 1986).

Compounds of the present invention show a wide range of antiallergic profile, as evidenced by the results obtained using a variety of procedures, tests, referred to here above.

Further, these compounds have an inhibitory effect on the migration of eosinophils, the latter are anti-inflammatory cells in allergic reactions.

Important valuable as these compounds is their lack or absence of sedative properties at levels of terapeutiche the mi and antiallergic compounds. Nnegative properties of the present compounds can be demonstrated, for example, the results obtained in the study of the cycle of falling asleep and awakening in rats (Psychopharmacology 97, 436-442, (1989)).

Another property of these compounds of interest, is their rapid onset of action and a favorable duration of their action. The latter characteristic may be given the opportunity to assign the connection to receive once a day.

Due to its anti-allergic properties of the compounds of formula I and intermediate compounds of the formula /V/, additive salt and stereochemical isomeric forms are very useful in the treatment of a wide spectrum of allergic diseases such as allergic rhinitis, allergic conjunctivitis, chronic urticaria, allergic asthma and similar.

Because of their useful antiallergic properties of the compounds which are the subject of consideration, can be transformed into various pharmaceutical forms for the purposes of the assignment. To obtain the antiallergic compositions of this invention, an effective amount of a specific compound in the form of a base or an acid additive salt BEM, which may have a wide variety of forms depending on the desired destination for the form of the drug. These pharmaceutical compositions are presented preferably in the form of dosage units, preferably suitable for oral, rectal, intradermal destination or for parenteral injection. For example, upon receipt of the compositions in oral dosage forms may be used any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols, and similar, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, agents, binders, dezintegriruetsja agents, and similar in the case of powders, pills, capsules and tablets. Because of their ease and simplicity when taking tablets and capsules represent the most prominent form of oral single doses, and in this case clearly apply solid pharmaceutical carriers. For parenteral compositions, the carrier typically includes sterile water, at least a large part, although may include other ingredients, for example in order to facilitate solubility. Injectable solutions, for example, mogumogu also be prepared injectable suspension, in which case you can apply the appropriate liquid carriers, suspendresume agents and similar. In the compositions suitable for injection through the skin, the carrier optionally comprises an agent that enhances the penetration and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor quantities /supplements/ does not have significant adverse effects on the skin. These supplements can facilitate the application towards the skin and/or may be useful to obtain the desired compositions. These compositions can be assigned to receive a variety of methods, for example, in the form of transdermal patches, spots or in the form of ointment. Additive salts of the discussed compounds due to their high solubility in water compared with the appropriate form of the base, are obviously more suitable in the preparation of aqueous compositions.

The above-mentioned pharmaceutical compositions are especially advantageous to formulate in the form of single doses or dosage units for ease and uniformity of dosage. Form of unit doses or dosage units used in this description and in the claims, predopredelenie amount of the active ingredient, calculated to produce the desired therapeutic effect in combination with the required pharmaceutical carrier. Examples of such forms of single doses are tablets (including tablets with marks or notches or coated tablets), capsules, pills, powders packaging, wafers, injectable solutions or suspensions, dosing, a teaspoon, a tablespoon, and similar, and segregated multiple forms.

The present invention relates also to a method of treating warm-blooded animals suffering from these allergic diseases, by assigning to receive the specified warm-blooded animals of an effective anti-allergic amount of a compound of formula (I), the form of its pharmaceutically acceptable salts or its stereochemical isomeric form.

The present invention relates also to compounds of formula (I), the form of their pharmaceutically acceptable salts and stereochemical isomeric forms for their use as medicaments. In particular, the present invention relates to the discussed compounds for use as medicaments for the treatment of warm-blooded animals suffering from allergic diseases.

Abegg body weight, and more preferably from about 0.01 mg/kg to 0.5 mg/kg body weight.

The following examples are intended to illustrate but not to limit the present invention in all its aspects.

Experimental part

A. Obtaining intermediates

Example 1

a) a Mixture of magnesium shavings /0.34 mol/ and brometane /0.1 g/ tetrahydrofuran /180 ml/ stirred in nitrogen atmosphere. Was added dropwise 4-chloro-1-methylpiperidin /0.34 mol, and the mixture was brought to the temperature of reflux distilled and the mixture is stirred and heated under reflux for 2 hours. The mixture was cooled to 0oC. was Added dropwise 3-furancarboxaldehyde /0.26 mol, dissolved in tetrahydrofuran, at a temperature of less than 20oC. the Mixture was brought to room temperature for 1 hour. The mixture was decomposed with a solution of ice and ammonium chloride and was extracted with 4-methyl-2-pentanone. The organic layer was dried (magnesium sulfate), filtered and evaporated. The residue was purified using column chromatography on silica gel (eluent: methylene chloride /mixture of methanol and ammonia 95/5). Pure fractions were collected and evaporated, giving of 38.7 g /76%/ product. Sample /1.2 g/ turned into (Z)-2-mutendi the 50,3oC (ex.1).

b) a Mixture of the free base of intermediate compounds /I/ /0,19 mol/ and manganese dioxide /370 g/ trichlormethane /1200 ml/ stirred and heated under reflux for 18 hours. The mixture was filtered, rinsed with trichloromethane and evaporated. The residue was purified on a glass filter on silica gel (eluent : methylene chloride) mixture of methanol and ammonia 95/5). Pure fractions were collected and evaporated, yielding 24 g /65%/ product. Sample /1.5 g/ turned into salt (E)-2-botanically (fumaric acid) (1:1) in ethanol, giving 1.1 g /E/-2-butenedioate (3-furanyl)(1-methyl-4-piperidinyl)methanol (1:1); so pl. 145,9oC (split timing. 2).

Example 2

a) a Mixture of sodium methylate /1.1 mol/ methanol /700 ml/ stirred in nitrogen atmosphere at room temperature. Dropwise added 1-methyl-2-pyrroleacetic /1.1 mol/ over a period of 15 minutes. Then dropwise over a 15 minute period was added 1-methyl-4-piperidinol /1 mol, and the mixture is brought to the temperature of reflux distilled. The mixture is stirred and heated under conditions of reflux distilled for 3 hours and evaporated. The residue was destroyed ice water and was extracted with dichloromethane. The organic layer was dried (Coultre through silica gel (eluent: methylene chloride/mixture (methanol/ammonia) 97/3). Pure fractions were collected and evaporated. The residue was turned into salt /E/-2-butandiol acid (1:1) in ethanol, giving 4,78 g (E)-2-butenedioate 1-methyl--(1-methyl-4-piperidinylidene)-1H-pyrrole-2-acetonitrile (1: 1); so pl. 165,5oC (ex. 3).

b) a Mixture of the free base of intermediate compounds /3/ /0.97 mol/ 2-propanol /1200 ml/ stirred and heated to 40oC. Portions over a 15 minute period was added sodium borohydride /1.94 mol, and the reaction mixture was heated to the temperature of reflux distilled. The mixture is stirred and heated under conditions of reflux distilled within 18 hours. The mixture was cooled, poured into ice water and was extracted 2,2'-oxybisethanol. The separated organic layer was dried (magnesium sulfate), filtered, and the solvent was evaporated, yielding 196 g /93%/ crude residue. Sample /5 g/ purified on silica gel on a glass filter /eluent: methylene chloride /methanol/ammonia/97: 3/. Pure fractions were collected and the solvent was evaporated. The residue was dissolved in ethanol and was turned to salt (E)-2-butandiol acid /1:1/. The precipitate was filtered off and precrystallization from ethanol. The crystals were filtered off and dried, giving 2,45 g /29,7%/ (E)-2 - butenedioate ()-1-methyl--(1-methyl-1H-pyrrol-2R> -(1-methyl-1H-pyrrol-2-yl)-1-(phenylmethyl)-4 - piperidinecarbonitrile; so pl. 105,5oC (intermediate 25).

(C) a Mixture of sodium hydroxide /1.6 mol/ and chloride of benzyltriethylammonium /0.04 mol/ dimethylsulfoxide /340 ml/ mixed with a mechanical stirrer. Was added to the free base of intermediate compounds /4/ /0.88 mol, dissolved in dimethyl sulfoxide /180 ml/, and within 6 hours barotiwala air /temperature rose to 55oC/. The mixture was poured into water /2700/ ml and was extracted with 4-methyl-2-pentanone. The organic layer was washed twice with water, dried (magnesium sulfate), filtered and evaporated. The residue was converted, giving 83 g /46%/ product. Sample /1 g/ turned into salt (E)-2-butandiol acid (1:1) in ethanol, giving 0,89 g (E)-2 - butenedioate (1-methyl-4-piperidinyl)(1-methyl-1H-pyrrol-2-yl)methanone (1:1), so pl. 186,2oC (ex.5).

Likewise happened:

(E)-2-butenedioate (1-methyl-1H-pyrrol-2-yl)[1-(phenylmethyl)-4-piperidinyl] methanone (1:1); so pl. USD 183.0oC (ex.26).

d) a Mixture of the free base of intermediate compounds /5/ /0.4 mol/ triperoxonane acid /1500 ml/ and N,N-dimethylformamide /0.1 ml/ stirred and heated in conditions delegirovali with methylene chloride. The organic layer was dried (magnesium sulfate), filtered and evaporated. The residue was converted, giving 46 g /56%/ product. Sample /1.5 g/ turned into salt {Z)-2 - butandiol acid (1:1) in 2-propanone and precrystallization from 2-propanone, yielding 1.52 g (Z)-2-butenedioate (1-methyl-4-piperidinyl) (1-methyl-1H-pyrrol-3-yl)methanone (1:1); so pl. 150,9oC (ex.6).

Likewise happened:

(1-methyl-1H-3-pyrrolidinyl) [1-(phenylmethyl)-4 - piperidinyl]metano; so pl. 145,3oC (intermediate compound 27).

Example 3

A mixture of N-(1-methylethyl)-2-propanamine /5,23 mol/ tetrahydrofuran /600 ml/ mixed under nitrogen atmosphere and cooled to -78oC. Portions at -78oC was added a 2.5 M solution of utility in hexane /0,215 mol. The mixture was brought to -40oC and stirred at this temperature for 15 minutes, 1-(Diethoxylate)imidazole /0.22 mol, dissolved in tetrahydrofuran, was added dropwise at -78oC, and the mixture is stirred at -78oC for 1 hour. Dropwise at -78oC was added to the free base of intermediate compounds /6/ /0.2 mol, dissolved in tetrahydrofuran, and the mixture is stirred at -78oC for 1 hour. The mixture was brought to room is up acetic acid /200 ml/, and the mixture is stirred at room temperature for 30 minutes. The mixture was podslushivaet potassium carbonate and evaporated. The residue was taken in water and extracted with dichloromethane. The organic layer was dried (magnesium sulfate), filtered and evaporated. The residue is crystallized from acetonitrile, yielding 46 g /84%/ (+)--(1H-imidazol-2-yl)-1-methyl--(1-methyl-1H-pyrrol-3-yl)-4-piperidinemethanol; so pl. 171,4oC (ex. Conn. 7).

Likewise happened:

(a)--3-furanyl--1H-imidazol-2-yl-1-methyl-4 - piperidinemethanol; so pl. 189,7oC (intermediate Conn. 8);

()--1H-imidazol-2-yl-1-methyl--3-thienyl-4 - piperidinemethanol; so pl. 173,4oC (intermediate Conn. 9);

()--1H-imidazol-2-yl-1-methyl--phenyl-4 - piperidinemethanol; so pl. RUR 219.4oC (intermediate compound 10); and

()--1H-imidazol-2-yl--(1-methyl-1H-pyrrol-3-yl)-1- (phenylmethyl)-4-piperidinemethanol (intermediate Conn. 28).

Example 4

Triperoxonane acid /700 ml/ mixed at room temperature. Portions were added intermediate connection /7/ /of) 0.157 mol, and the mixture was brought to boiling and the mixture is stirred and heated under conditions of reflux distilled for 30 minutes. The mixture was cooled, was partially evaporated (3/4), resulted in the MCA which was filtrovala and evaporated. The residue was purified using column chromatography on silica gel (eluent: a mixture of methylene chloride/methanol:ammonia) 95/5). Pure fractions were collected and evaporated. The residue was kristalizovyvatsja twice from acetonitrile, yielding 23 g /57%/ 4-[1H-imidazol-2-yl-(1-methyl-1H-pyrrol-3-yl)-methylene]-1 - methylpiperidine; so pl. 154,8oC (intermediate 11).

Likewise happened:

4-[3-furanyl(1H-imidazol-2-yl)methylene] -1-methylpiperidin, so pl. of 147.2oC (intermediate compound 12);

4-[1H-imidazol-2-yl-(3-thienyl)methylene] -1-methylpiperidin; so pl. 174,8oC (intermediate compound 13);

4-[1H-imidazol-2-infermation)-1-methylpiperidin; so pl. amount of 203.9oC (intermediate compound 14); and

4-[1H-imidazol-2-yl(1-methyl-1H-pyrrol-3-yl)methylene]-1- (phenylmethyl)piperidine; so pl. 188,2oC (intermediate compound 29).

Example 5

A mixture of sodium hydride 60% /0.045 mol in N,N-dimethylformamide /300 ml stirred at room temperature under nitrogen atmosphere. Was added dropwise intermediate connection /II/ /0.03 mol/ dissolved in N,N-dimethylformamide, and the mixture is stirred at room temperature for 1 hour. Upon cooling, was added dropwise methylchloride /0.045 mol, dissolved in N,N-DIMET is carbonate sodium and extracted with dichloromethane. The organic layer was dried (magnesium sulfate), filtered and evaporated. The residue was purified on a glass filter using silica gel (eluent: methylene chloride: (mixture of methanol/ammonia) 96:4). Pure fractions were collected and evaporated, yielding 7.9 g /80%/ product. Sample /1.5 g/ turned into salt (E)-butandiol acid (2:3) in ethanol, giving, 1.51 g (E)-2-butenedioate 2-[(1-methyl-4 - piperidinylidene) (1-methyl-1H-pyrrol-3-yl)methyl]-1H-imidazole-1 - acetate (2:3), so pl. 159,1oC (intermediate compound 15).

Likewise happened:

methyl 2-[3-furanyl(1-methyl-4-piperidinylidene)methyl]-1H - imidazole-1-acetate (intermediate compound 16);

methyl 2-[(1-methyl-4-piperidinylidene)-3-thienylmethyl]-1H - imidazole-1-acetate (intermediate compound 17);

methyl 2-[(1-methyl-4-piperidinylidene)phenylmethyl]-1H-imidazole-1-acetate; so pl. 105,7oC (intermediate compound 18); and

methyl 2-[(1-methyl-1H-pyrrol-3-yl) [1-(phenylmethyl)-4 - piperidinylidene] methyl]-1H-imidazole-1-acetate (intermediate compound 24).

Example 6

A mixture of compound /I/ /to 0.011 mol and N,N-diethylethanamine /0,033 mol/ methylbenzene (100 ml) was stirred and heated under reflux. When reflux was added dropwise was acylhydrolase, was poured into a mixture of water and potassium carbonate and separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate), filtered and evaporated. The reaction was started again with the rest, the same quantities of ethylchloride, N,N-diethylethanamine and methylbenzol using the same procedure. The residue was purified on a glass filter on silica gel (eluent: a mixture of methylene chloride/ethanol 97:3). Pure fractions were collected and evaporated, yielding 4.5 g /95%/ ethyl 4-/6-[(etoxycarbonyl) oxy] -10H-imidazol[1,2-a] thieno[3,2-d] -azepin-10-ilidene] -1-piperidinecarboxylate (intermediate compound 19).

Likewise happened:

ethyl 4-[6-[(etoxycarbonyl)oxy] -11N-imidazo/2,1 - b/[3]benzazepin-11-ilidene] -1-piperidinecarboxylate; so pl. 149,9oC (ex. 20); and ethyl 4-[6-[(etoxycarbonyl)oxy]-7,10-dihydro-7 - methylimidazo[1,2-a]-pyrrolo[3,2-d] azepin-10-ilidene] -1 - piperidinecarboxylate; so pl. 128,9oC (intermediate compound 23).

Example 7

a) N,N-dimethylformamide /200 ml/ mixed at room temperature in a nitrogen atmosphere, and the portions was added a dispersion of sodium hydride 50% in mineral oil /0,113 mol. Portions were added 2-phenylmethyl-1H-imidazole /0,075 M0,113 mol, dissolved in N, N-dimethylformamide, and the mixture is stirred at room temperature for 30 minutes. The mixture was poured into sodium bicarbonate solution and was extracted with dichloromethane. The organic layer was dried (magnesium sulfate), filtered and evaporated. The residue was purified on a glass filter on silica gel (eluent:methylene chloride/methanol 95:5). Pure fractions were collected and evaporated, yielding 16 g /93%/ product. Sample /1 g/ crystallized from 2,2'-oxybisethane/acetonitrile, giving of 0.58 g of methyl 2-(phenylmethyl)-1H-imidazole-1-acetate; so pl. 70,8oC (intermediate compound 21). A mixture of intermediate substance /21/ /0,017 mol/ triftoratsetata /25 ml/ mixed at 140oC during the night. The mixture was cooled, poured into a mixture of potassium carbonate solution and ice water and was extracted with a mixture of dichloromethane and ethanol. The organic layer was dried (magnesium sulfate), filtered and evaporated, yielding 1.5 g /45%/ product. This faction was turned into a salt of (E)-2-butandiol acid (2:1) in ethanol and precrystallization from ethanol, giving 1,76 g /40,4%/ (E)-2-butenedioate 11N-imidazo[2,1-b] [3]benzazepin-6- (5H)-he (2:1); so pl. 166,3oC (intermediate compound 22).

C. the Receiving end is a lot /75 ml/ mixed at 105oC for 6 hours. The mixture was cooled, poured into a mixture of ice/potassium carbonate solution and extracted with dichloromethane. The organic layer was dried (magnesium sulfate), filtered and evaporated. The residue was purified on a glass filter on silica gel (eluent: methylene chloride (methanol/ammonia) 95/5). Pure fractions were collected and evaporated. The residue is stirred in a mixture of methylene chloride/water/barium carbonate. The precipitate was filtered off; the filtrate was separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate), filtered and evaporated. The residue is crystallized from acetonitrile, yielding 5.2 g /58%/ 10-(1-methyl-4-piperidinylidene)-10H-imidazo[1,2-a] thieno[3,2-d] azepin - 6(5H)-it; so pl. 153,3oC is connected. 1).

Likewise happened:

(E) -2-butenedioate 11-(1-methyl-4-piperidinylidene)-5H - imidazo[2,1-d][3] benzazepin-6(11H)-she (2:3); so pl. 208,0oC /connection 2/;

(E)-2-butenedioate 7,10-dihydro-7-methyl-10-(1-methyl-4 - piperidinylidene)imidazo[1,2-a] pyrrolo[3,2-d] azepin-6(5H)-she (2: 3); so pl. 229,1oC (compound 3);

(Z)-2-butenedioate 10-(1-methyl-4-piperidinylidene)-10H - furo[3,2-d]-imidazo[1,2-a]azepin-6(5H)-it /1:2/ (compound 4); and

7,10-dihydro-7-methyl-10-[1-(phenylmethyl)-4 - the organisations /22/ /0,037 mol/ methanol /150 ml/ gerasoulis at room temperature (atmospheric pressure) using palladium on charcoal, the palladium content of 10% /2 g/ as a catalyst. After uptake of hydrogen (0.7 equivalent), the catalyst was filtered, and the filtrate was evaporated. The residue was purified on silica gel on a glass filter /eluent:methylene chloride/methanol/ methanol/ammonia) 90/5/5 by changing the ratio to 90/0/10). Two fractions were collected and their solvent was evaporated. Both fractions were dissolved in ethanol and was turned to salt (E)-2-butandiol acid (1:1). Precipitation was filtered off and dried, giving 5.3g /36%/ (E)-2 - butenedioate 7,10-dihydro-10-(4-piperidinylidene)-imidazo[1,2-a] pyrrolo[3,2-a] azepin-6(5H)-she (1:1) (compound 23) and 5.1 g /35%/ (E)-2-butenedioate 7,10-dihydro-10-(4-piperidinyl)imidazo [1,2-a] pyrrolo[3,2-d]azepin-6(5H)-she (1:1), so pl. 243,5oC (compound 24).

Example 9

a) a Mixture of intermediate compounds /20/ /0.014 mol/ 48% solution of Hydrobromic acid in water /80 ml/ stirred and heated under conditions of reflux distilled for 2 hours. The mixture was evaporated. The residue was boiled in ethanol, yielding 6 g /97%/ dihydrobromide 10-(4-piperidinylidene)-11N-imidazo [2,1-d][3]benzazepin-6-(5H)-she (compound 5).

Likewise happened:

(E)-2-butenedioate 10-(4-piperidinylidene)-10H-imidazo [1,2-a]thieno-[3,2-d] azepin-6(5H)-she (1:1) (compound 6 which was characterised in terms reflux distilled within 18 hours. The mixture was evaporated, the residue was poured into a mixture of ice/water/potassium carbonate and extracted with dichloromethane. The organic layer was dried (magnesium sulfate), filtered and evaporated. The residue was purified on a glass filter on silica gel (eluent:methylene chloride/ethanol 96/4). Pure fractions were collected and evaporated. The residue is crystallized from a mixture of acetonitrile and 2,2-oxybisethane, giving 5.3g /75%/ ethyl 4-(5,6,7,10-tetrahydro-7-methyl-6-accomidate-[1,2-a] pyrrolo [3,2-d] azepin-10-ilidene)-1-piperidinecarboxylate; so pl. 146,6oC (compound 26).

Example 10

A mixture of monochlorohydrin 6-(2-chloroethyl)-7-methyl-5H-thiazolo [3,2-a]pyrimidine-5-it /0,013 mol/ free base compounds /5/ /0.01 mol/ sodium carbonate /0,024 mol/ or potassium iodide /10 mg/ 4-methyl-2-pentanone /200 ml/ stirred and heated under conditions of reflux distilled within 36 hours. The mixture was cooled and evaporated. The residue was taken in a mixture of methylene chloride and water, and the mixture was divided. The aqueous layer was extracted with dichloromethane. The organic layer was dried (magnesium sulfate), filtered and evaporated. The residue was purified on a glass filter using silica gel (eluent: methylene chloride/ methanol/ammonia) 97/3). Pure fractions were collected and evaporated. Estherville]-5H-imidazo-[2,1-d][3]benzazepin-6(5H)-it; so pl. 221,6oC (compound 7).

Likewise happened:

hemihydrate (E)-2-butenedioate(1:1) 11-[1-[3-(4-pertenece) propyl]-4-piperidinylidene]-11N-imidazo[2,1-b][3]-benzazepin - 6(5H)-it; so pl. 201,8 thousand cub.oC (compound 8);

hemihydrate (E)-2-butenedioate 11-[1-[2-(4-methoxyphenyl) ethyl]-4-piperidinylidene] -11N-imidazo[2,1-b] [3] benzazepin-6(5H)-she (1:1); so pl. 157,9oC (compound 9);

hemihydrate (E)-2-butenedioate 10-[1-[2-(4-methoxyphenyl) ethyl]-4-piperidinylidene] -10H-imidazo[1,2-a] thieno[3,2-d] azepin-6(5H)-she (1: 1), so pl. 174,9oC (compound 10);

hemihydrate (E)-2-butenedioate 10-[1-[3-(4-pertenece) propyl]-4-piperidinylidene] -10H-imidazo[1,2-a] thieno[3,2-d] azepin-6(5H)-she (1:1), so pl. 177, 9mmoC (compound 11);

10-[1-[2-(7-methyl-5-oxo-5H-thiazolo[3,2-a] pyrimidine-6-yl) ethyl]-4-piperidinylidene]-10H-imidazo[1,2-a]thieno[3,2-d] azepin-6(5H)-he] compound 12); and

7,10-dihydro-7-methyl-10-[1-[2-(7-methyl-5-oxo-5H-thiazolo [3,2-a]pyrimidine-6-yl)ethyl] -4-piperidinylidene]imidazo[1,2-a] pyrrolo[3,2-d]azepin-6(5H)-he; so pl. 248,2oC (compound 25).

Example 11

Methyl 2-propenoate /0.012 mol/ added dropwise with stirring to a mixture of compound /5/ /0.01 mol/ methanol /100 ml at room temperature, and the mixture was mixed at room temperature was dragirovaniya dichloromethane. The organic layer was dried (magnesium sulfate), filtered and evaporated. The residue was turned into salt cyclohexanesulfamic acid /1:2/ 2-propanone, yielding 1,32 g /18%/ cyclohexylsulfamate hemihydrate methyl 4-(5,6-dihydro-6-oxo-11N-imidazo[2,1-b] [3] benzazepin-11-ilidene)-1 - piperidineacetate (1:2) (compound 13).

Likewise happened:

methyl 4-(5,6-dihydro-6-oxo-10H-imidazo[1,2-a]thieno [3,2-d]azepin-10-ilidene)-1-piperidinophenyl; so pl. 123,7oC (compound 14).

Example 12

A mixture of compound /10/ /to 0.007 mol/ 48% solution of Hydrobromic acid in water /100 ml were mixed and heated under conditions of reflux distilled for 1 hour. The mixture was evaporated, the residue was taken in water, podslushivaet potassium carbonate and was extracted with dichloromethane. The organic layer was dried, filtered and evaporated. The residue was purified using column chromatography on silica gel (eluent: methylene chloride/ methanol/ammonia) to 95:5). Pure fractions were collected and evaporated. The residue was turned into a salt of (E)-2-butandiol acid (1: 1) in ethanol. The precipitate was filtered off and dried, giving 1,17 g /32%/ (E)- 2-butenedioate 10-[1-[2-(4-hydroxyphenyl)ethyl/-4 - piperidinylidene/-10H-imidazo[1,2-a] thieno[3,2-d] azepin-6(5H)-she (1: 1)piperidinylidene]-11N-imidazo[2,1-b][3]-benzazepin-6(5H)-she (1:1), so pl. 227,9oC (compound 16).

Example 13

A mixture of compound /I/ /0,025 mol/ methanol /100 ml were mixed and cooled. Portions over a 15 minute period was added sodium borohydride /0.05 mol/ and the mixture is stirred at room temperature for 1 hour. The mixture was evaporated at a temperature of less than 40oC.

The residue was taken in water and extracted with dichloromethane. The organic layer was boiled in acetonitrile, yielding 7.5 g /100%/ ()-6,10-dihydro-10-(1-methyl-4-piperidinylidene)-5H-imidazo[1,2-a] thieno[3,2-d]-azepin-6-ol; so pl. 230,3oC (compound 17).

Likewise happened:

()-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H - imidazo[2,1-b] -[3] -benzazepin-6-ol; so pl. 138,0oC (compound 18); and

ethanolate ()-5,6,7,10-tetrahydro-7-methyl-10-(1-methyl-4 - piperidinylidene)imidazo[1,2-a] pyrrolo[3,2-d]azepin-6-ol (1:1). (E)-2-butenedioate (1:1); so pl. 191,4oC (compound 19).

Example 14

A mixture of compound /I/ /0.01 mol/ and monohydrochloride hydroxylamine /0.02 mol/ pyridine /20 ml/ stirred and heated under conditions of reflux distilled for 1 hour. The mixture was evaporated, the residue was taken in water, podslushivaet potassium carbonate and was extracted with dichloromethane. The organic layer of 3 g /96%/ (E+Z)-10-(1 - methyl-4-piperidinylidene)-10H-imidazo[1,2-a] thieno[3,2-d] - azepin-6(5H)-he-oxime; so pl. 187,5oC (compound 20).

Likewise happened:

7,10-dihydro-7-methyl-10-(1-methyl-4-piperidinylidene) imidazo[1,2-a] -pyrrolo[3,2-d]azepin-6(5H) -, oxime; so pl. 206,9oC (compound 21).

C. Examples of songs

The following forms of drugs or preparative forms illustrate, as examples, a typical pharmaceutical composition in the form of single doses suitable for systemic or topical purpose of warm-blooded animals in accordance with the present invention.

"Active ingredient" /A. I./ used throughout these examples relates to a compound of formula I or the compound of the formula /V/ to pharmaceutically acceptable acid additive salt or a stereochemical isomeric form.

Example 15: Oral drops

500 g of A. I. was dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol at about 60 - 80oC. After cooling to 30 - 40oC was added 35 l of polyethylene glycol, and the mixture is mixed well. Then was added a solution of 1750 g of sodium saccharin in 2.5 l of purified water, and with stirring was added 2.5 l of cocoa flavoring substance and polyethylene glycol as needed to objpackage containers.

Example 16: Oral solution

9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate was dissolved in 4 l of purified water. In 3 l of this solution were dissolved first 10 g of 2,3-dihydroxybutanedioate acid, and then 20 g of A. I. the Latter solution is combined with the rest of the first solution, and the mixture is added to 12 l 1,2,3-propanetriol and 3 l of 70% solution of sorbitol. 40 g Matricaria dissolved in 0.5 l of water, and add 2 ml of raspberry and 2 ml of gooseberry family essences. The latter solution is combined with the first, water is added in an amount necessary up to a volume of 20 liters, giving oral solution containing 5 mg A. I. teaspoon /5 ml/. The resulting solution is filled in suitable containers.

Example 17: Capsules

20 A. I., 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of magnesium stearate vigorously mixed together. The resulting mixture is subsequently filled into 1000 suitable hardened gelatin capsules, each containing 20 mg A. I.

Example 18: Tablets, film-coated

Obtain core tablets

A mixture of 100 g A. I., 570 g lactose and 200 g starch mixes well and thereafter humidified solution is camping damp powder sifted, dried and screened again. Then added 100 g microcrystalline cellulose (Avicel) and 15 g hydrogenated vegetable oil (Sarotex). All is well mixed and pressed into tablets, giving 10.000 tablets, each containing 10 mg of active ingredient.

Floor

To a solution of 10 g methyl cellulose (Metozel 60 HG) in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose (Ethocel 22 PJC) in 150 ml of dichloromethane. Then added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The last solution is added to the first, and then added 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrolidone and 30 ml of concentrated dye suspension (Opaspray K-1-2109), and all homogenized. Core tablets are coated thus obtained mixture in a device for coating.

D. Pharmacological example

Example 19

It was found that the values U50/mg/kg/ test "Protect rats from death induced by compound 48/80/", equal to or below 0.16 for compounds 1, 3, 4, 6, 10, 11, 12, 15, 22, 23, 25 and 26 and for matemticas acceptable additive salt or a stereochemical isomeric form,

in which each of the dashed lines independently represents an optional bond;

-A-B - represents a radical of the formula-X-C=CH- (a-1), -CH=CH-X- (a-2) or-CH=CH-CH=CH- (a-3);

X represents O, S or NR1, R1represents H or C1- C6-alkyl;

represents a radical of the formula =O (b-1); -OH (b-2) or =N-OH (b-3);

L represents hydrogen, C1- C4-allyloxycarbonyl, C1- C6-alkyl or C1- C6-alkyl, substituted C1- C4-allyloxycarbonyl, aryl, aryloxy or a radical of formula (c)

< / BR>
where D is Z represents-S-CH=CH -, and aryl represents phenyl or phenyl, substituted by halo, hydroxy or C1- C4-alkyloxy.

2. Connection on p. 1 having the formula

< / BR>
3. Connection on p. 2, in which A-B represents the radical of the formula-CH= CH-X- (a-2).

4. Connection on p. 3, which is 7,10-dihydro-7-methyl-10-(1-methyl-4-piperidinylidene)imidazo[1,2-a] pyrrolo[3,2-d] azepin-6(5H)-he, its pharmaceutically acceptable additive salt or a stereochemical isomeric form.

5. Pharmaceutical composition having anti-allergic activity, comprising an active substance and a pharmaceutically acceptable carrier, characterized in that as 6. A method of obtaining a pharmaceutical composition having anti-allergic activity, characterized in that an effective amount of the compounds under item 1 is mixed with a pharmaceutically acceptable carrier.

7. Derived imidazolidine under item 1, with anti-allergic properties.

8. The method of deriving imidazolidine stated in paragraph 1, characterized in that an intermediate compound of formula II in which L and A-B have the meanings given in paragraph 1, is treated with acid to obtain the compounds of formula I-a

< / BR>
9. The method of deriving imidazolidine under item 1, characterized in that the compound of formula I-a, where L and A-B have the above meanings, is subjected to reaction in the presence of a reducing reagent in a reaction-inert solvent to obtain compounds of formula I-b

< / BR>
10. The method of deriving imidazolidine under item 1, characterized in that the compound of formula I-a is subjected to reaction with hydroxylamine or its salt in a reaction-inert solvent to obtain compounds of formula I-c

< / BR>
11. The method of deriving imidazolidine under item 1, characterized in that the compound of formula I-e where A-B and Y have the above znachenie-alkyl or C1- C6-alkyl, substituted C1- C4-allyloxycarbonyl, hydroxycarbonyl, aryl, aryloxy or a radical of formula (c);

W represents a reactive leaving group.

in a reaction-inert solvent to obtain compounds of formula I-d

< / BR>
12. The method of deriving imidazolidine under item 1, characterized in that the compound of formula I-e is subjected to reaction with an alkene of the formula IV in which L2represents hydrogen, C1- C4-allyloxycarbonyl, hydroxycarbonyl, aryl, aryloxy or a radical of formula (c), in a reaction-inert solvent to obtain compounds of formula I-d

< / BR>
13. The method of deriving imidazolidine under item 1, characterized in that an intermediate compound of formula V is subjected to hydrolysis to obtain the compounds of formula I-e-I

< / BR>
14. The method of deriving imidazolidine under item 1, characterized in that the compound of formula I-f dibenzyline, receiving the compound of formula I-e

< / BR>
and, if necessary, make the compounds of formula I with each other using known in the art of transformation reactions of functional groups, and further, if necessary, make the compounds of formula I in teobert turn salt into the free base or acid, respectively, by treatment with alkali or acid and/or get their stereochemical isomeric form.

 

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