Derivatives of 1,2-diphenylpyrrole, the pharmaceutical composition

 

(57) Abstract:

The compounds of formula (I) and (II), where R is hydrogen; R1is alkyl, amino or substituted amino; R2represents optionally substituted phenyl; R3represents hydrogen, halogen or optionally substituted alkyl; R4represents hydrogen, optionally substituted alkyl, aryl or aralkyl with analgesic, anti-inflammatory activity and ability to inhibit the production of leukotrienes, the ability to inhibit resorption (resorption) of bone and the ability to selectively inhibit the activity of MOR-2. Pharmaceutical composition based on them. They are relatively free from such effects, usually resulting from the introduction of compounds with these activities. 6 C. and 11 C.p. f-crystals, 13 PL.

The invention relates to a series of new derivatives of 1,2-diphenylpyrrole, which have valuable analgesic, anti-inflammatory, cough and antiallergic activity and ability to inhibit the production of leukotrienes and to inhibit resorption (resorption) of bone and relatively free from side effects, obienu these new compounds, compositions containing these compounds, and methods of obtaining these compounds.

Known widely used for clinical purposes nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of inflammatory diseases, such as pyrexia, pain and swelling. However, the harmful effects of these drugs, such as gastrointestinal and renal disorders, create problems for those patients who take medicine for a long time, as well as older patients. There are two metabolic pathways, beginning with arachidonic acids. They are the path leading to the production of prostaglandins (PG), and the path leading to the production of leukotrienes (LT).

It is believed that NSAIDs inhibit the action of PG cyclooxygenase (COX), which is a crucial step in the production of PG from arachidonic acid. Recently it was discovered that COX has two isozyme, called COX-1 and COX-2.

It was found that COX-1 is normally present in the stomach, intestines, kidneys and other tissues and is used for the production of PG, which is physiologically and COX-2 is induced by inflammatory cytokines and endotoxins, such as IL-1, TNF, etc., and is expressed, in particular, in the place in which the isozyme led to thoughts, what anti-inflammatory drugs, which, in particular, inhibit COX-2 without inhibiting COX-1, would be free from the side effects of traditional medicines, and could be a new type of anti-inflammatory agents.

On the other hand, it is known that inflammatory cytokines IL-1, TNF , IL-6 and IL-8 are produced in monocytes, macrophages and synovial cells in various inflammatory stimuli and affect a number of biological processes such as the production of PG, expression of cell adhesion molecules and the production of collagenase-protease activation of osteoclasts, pyrexia, producing Ostrovskogo protein and chemotactic activity of leukocytes.

They say that these cytokines are associated with the development of various diseases, such as chronic inflammatory diseases, including chronic rheumatoid arthritis. Therefore, drugs that inhibit the action of cytokines which are useful as anti-inflammatory agents of the new type.

Recent studies have shown that prostaglandins synthesized by osteoblasts under the influence of COX-2, activate osteoclasts and thereby visittime diseases, accompanied by resorption (destruction) of the bones or resulting from such resorption, such as osteoporosis, rheumatoid arthritis and osteoarthritis.

On the other hand, it was shown that a significant contribution to inflammation, allergies and ulceration of the stomach contribute leukotrienes.

So, I think that the synthesis inhibitors LT and PG are the more desirable of drugs for the treatment and prevention of inflammatory diseases.

To well-known derivatives of 1,2-diphenylpyrrole exhibiting analgesic and anti-inflammatory action, is the connection that is described in the German patent N 1938904 and having the following formula:

< / BR>
This compound is referred to hereinafter called "Compound A".

However, this connection is not very efficient and therefore desirable would be more effective connection.

These inventors discovered a series of new compounds with desired activity and does not exhibit the side effects of known compounds. In addition, it was unexpectedly found that the compounds possess the ability to inhibit the production of leukotrienes and to inhibit bone resorption, and both of these properties to them is thus, the present invention is the creation of several new compounds useful for the treatment, prevention and mitigation of pain and inflammation and inhibit the production of leukotrienes and resorption of bone.

Another, more specific object of the present invention is to provide such compounds, which are usually free or relatively less exposed to the manifestation of side effects in the form of gastro-intestinal disorders.

Other objectives and advantages of the present invention will be apparent from the following detailed description.

Compounds of the present invention are compounds of formula (I) and (II):

< / BR>
< / BR>
where

R represents a hydrogen atom, halogen atom or alkyl group having from 1 to 6 carbon atoms;

R1represents an alkyl group having from 1 to 6 carbon atoms, an amino group or a group of the formula-othera,

Rais alkanoyloxy group having from 1 to 25 carbon atoms, alkoxycarbonyl group having from 1 to 6 carbon atoms in the CNS part, aracelikarsaalyna group, in which kalkilya part is the same as defined below, alkanoyloxy the expansion from 1 to 6 carbon atoms in the CNS part, or (2-oxo-1,3-dioxolan-4-yl)methyl group, which is unsubstituted or substituted in position 5 dioxolane alkyl group having from 1 to 6 carbon atoms, or aryl group, as defined below;

R2represents a phenyl group which is unsubstituted or substituted by at least one Deputy, selected from the group consisting of substituents and substituents defined below;

R3represents a hydrogen atom, halogen atom or alkyl group which has from 1 to 6 carbon atoms and which is unsubstituted or substituted by at least one Deputy, selected from the group consisting of the substituents defined below;

R4represents a hydrogen atom, an alkyl group which has from 1 to 6 carbon atoms and which is unsubstituted or substituted by at least one Deputy, selected from the group consisting of the substituents defined below, cycloalkyl group having from 3 to 8 carbon atoms, aryl group as defined below, or aracelio group as defined below;

these aryl groups have from 6 to 14 ring carbon atoms in the carbocyclic ring and are the oil and deputies , defined below;

these kalkilya group and kalkilya part of these aracelikarsaalyna represent alkyl groups having from 1 to 6 carbon atoms and which is substituted by at least one aryl group, as defined above;

these substituents selected from the group consisting of hydroxy groups, halogen atoms, alkoxygroup having from 1 to 6 carbon atoms, and alkylthio having from 1 to 6 carbon atoms;

these substituents selected from the group consisting of alkyl groups which have from 1 to 6 carbon atoms and are unsubstituted or substituted by at least one Deputy, selected from the group consisting of the substituents defined above, alkanoyloxy having from 1 to 6 carbon atoms, mercaptopropyl, alkanoyloxy having from 1 to 6 carbon atoms, alkylsulfonyl groups having from 1 to 6 carbon atoms, cycloalkanes having from 3 to 8 carbon atoms, halogenlamp having from 1 to 6 carbon atoms, and alkylenedioxy, having from 1 to 6 carbon atoms; and their pharmaceutically acceptable salts.

In accordance with the present invention there is a method lgem the introduction of anti-inflammatory and analgesic compounds, selected from the group consisting of compounds of formulas (I) and (II) and their pharmaceutically acceptable salts.

In addition, in accordance with the present invention proposes a method of inhibiting resorption (resorption) of bone from suffering from it mammal (which can be a person), by introducing active compounds selected from the group consisting of compounds of formulas (I) and (II) and their pharmaceutically acceptable salts.

In accordance with the present invention there is a method of inhibiting the production of leukotrienes in a mammal (which can be a person), by introducing active compounds selected from the group consisting of compounds of formulas (I) and (II) and their pharmaceutically acceptable salts.

Detailed description of the invention

In the compounds of the present invention, when R represents a halogen atom, they can be an atom of fluorine, chlorine, bromine or iodine, of which are preferred fluorine atoms and chlorine, and most preferred is a fluorine atom.

When R represents an alkyl group having from 1 to 6 carbon atoms, it can be a group with an unbranched or branched chain, and its examples include local, isopentanol, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexoloy and isohexyl group. Of them, preferred are alkyl groups having from 1 to 4 carbon atoms, preferably methyl, ethyl, sawn, ISO-propyl, bucilina and isobutylene group and most preferably a methyl group.

In accordance with a preferred variant of the above groups and atoms R must represent a hydrogen atom, fluorine atom, chlorine atom or methyl group, of which the most preferred is a hydrogen atom.

When R1represents an alkyl group having from 1 to 6 carbon atoms, it can be a group with an unbranched or branched chain, and examples include methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert-boutelou, pentelow, isopentanol, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-boutelou, 2,3-dimethylbutyl, 2-ethylbutyl, hexoloy and isohexyl group. Of them, preferred are alkyl groups having from 1 to 4 carbon atoms, preferably methyl, ethyl, sawn, ISO-propyl, bucilina and isobutylene group and most preferably a methyl group.

When R1represents a group of formula-otherawhere Rais alkanoyloxy group, it is alkanolamines, which may be unbranched or branched group having from 1 to 25 carbon atoms, more preferably from 1 to 20 carbon atoms, more preferably from 1 to 6 carbon atoms, and most preferably from 1 to 4 carbon atoms. Examples of such alkanolamines include formylamino-, acetylamino-, propionamido, bucillamine, isobutylamino, paulolino, Valeriano, isovaleramide, hexanamine, leptanillinae, octanoylthio, nonboiling, decanoylamino, undecanoate, laurylamine, tridecanoate, myristoylation, palmitoylation, stearylamine, icotanoinee, docosanoate and placesonline.com, of which preferred are alkanolamines having from 1 detestable group of the formula-otherawhere Rais alkoxycarbonyl group having from 1 to 6 carbon atoms in the CNS part, it is alkoxycarbonylmethyl. CNS part can be a group with an unbranched or branched chain, having from 1 to 6 carbon atoms. Examples of such alkoxycarbonylmethyl include methoxycarbonylamino, ethoxycarbonylethyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonylamino, solutionline-, second -, butoxycarbonylamino-, tert-butoxycarbonylamino, ventilatsioonile, isobutylacetophenone, neopentecostalism-, 2-metallocarborane-, 1 ethylpropylamine-, 4-methylbenzyloxycarbonyl-, 3-methylbenzyloxycarbonyl-, 2-methylbenzyloxycarbonyl-, 1 etiopathological-, 3,3-dimethylbutylamino-, 2,2-dimethylbutylamino-, 1,1-dimethylbutylamino-, 1,2-dimethylbutylamino-, 1,3-dimethylbutylamino-, 2,3-dimethylbutylamino-, 2-metilbutanoilny, hexyloxyphenyl, and isohexadecane. Of them, preferred are alkoxycarbonylmethyl having from 1 to 4 carbon atoma-, isopropoxycarbonyl, butoxycarbonylamino, solutionline-, second -, butoxycarbonylamino - and tert-butoxycarbonylamino and most preferably methoxycarbonylamino or ethoxycarbonylmethoxy.

When R1represents a group of formula-otherawhere Rais aracelikarsaalyna group, aryl part is carbocyclic aromatic group, preferably having from 6 to 14 ring carbon atoms, more preferably from 6 to 10 ring carbon atoms and may be substituted or unsubstituted. In the case of a substituted group, the substituents preferably selected from the group consisting of substituents and substituents defined and described in the example above, there are no particular restrictions on the number of such substituents, in addition to the limitations imposed by the number of substitutable positions (5 in the case of a phenyl group and 7 in the case naftalina groups) and possibly by steric constraints. Examples of such aryl groups are given below, but preferred are unsubstituted groups, in particular phenyl group. Kalkilya group may contain from 1 to 3 such aryl groups, preferably one aryl is the number of example for R, but preferably a group having from 1 to 4 carbon atoms, preferably methyl, ethyl or through group and most preferably a methyl group. The most preferred aranceles group is a benzyl group. Specific examples of arachidonoylethanolamine, which can be represented by the symbol R1are benzyloxycarbonylamino-, 1 naphthalenemethylamine-, 2-naphthalenemethylamine-, o-, m - and p-chlorobenzenesulfonamide - and o-, m - and p-methylbenzyloxycarbonyl, of which the most preferred is benzyloxycarbonylamino.

When R1represents a group of formula-otherawhere Rais alkanoyloxy group, it has from 1 to 6 carbon atoms in alkanoyloxy part. Examples alkanoyl group are those alcoholnye groups which have from 1 to 6 carbon atoms and included in alkanolamines shown in the example above. Specific examples of alcoholcontaining include formyloxyethyl, acetoxymethyl, propionylthiocholine, butyrylcholine, isobutyrylacetate, pivaloyloxymethyl, galeriasemanacultural-, propionylthiocholine, butyrylcholine and pivaloyloxymethyl.

When R1represents a group of formula-otherawhere Rais alkoxycarbonylmethyl group having from 1 to 6 carbon atoms in the CNS part, CNS part can be a group with an unbranched or branched chain. Examples of such alkoxycarbonylmethyl include methoxycarbonylmethylene, ethoxycarbonylmethylene, propoxycarbazone, isopropoxycarbonyloxymethyl, butoxycarbonyloxyimino, msobuttoniconandcaption-, second -, butoxycarbonyloxyimino-, tert-butoxycarbonyloxyimino, pentyloxyphenylacetylene, isopentenyladenine, neopatrimonialism-, 2-methylmethanesulfonamide-, 1 ethylpropylamine-, 4-methylbenzyloxycarbonyl-, 3-methylbenzyloxycarbonyl-, 2-methylbenzyloxycarbonyl-, 1 methylendioxymethamphetamine-, 3,3-dimethylphenylethylamine-, 2,2-dimethylphenylethylamine-, 1,1-dimethylphenylethylamine-, 1,2-dimethylbutadiene is ybutalbitalacetaminophen2-, hexyloxybenzoyl and ethexiabowemilewel. Of them, preferred are alkoxycarbonylmethyl having from 1 to 4 carbon atoms in the CNS part, preferably methoxycarbonylmethylene, ethoxycarbonylmethylene, propoxycarbazone, isopropoxycarbonyloxymethyl, butoxycarbonyloxyimino, msobuttoniconandcaption-, second -, butoxycarbonyloxyimino - and tert-butoxycarbonyloxyimino and most preferably methoxycarbonylmethylene or ethoxycarbonylmethylene.

When R1represents a group of formula-otherawhere Rais (2-oxo-1,3-dioxolan-4-yl)methyl group, she is unsubstituted or substituted in position 5 dioxolane alkyl group having from 1 to 6 carbon atoms, or aryl group.

Examples of such alkyl groups include alkyl groups listed above as examples for R, preferably a methyl, ethyl or tert-boutelou group. Examples of such aryl groups include aryl groups listed below as examples for R4, predpochtitelnye-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-tert-butyl-2-oxo-1,3-dioxolan-4-yl)methyl and (5-phenyl-2-oxo-1,3-dioxolan-4-yl)methyl group.

In accordance with a preferred variant of the above groups and atoms, R1must represent a methyl group, an amino group or acetylamino, of which the most preferred are the amino group and acetylamino.

When R2represents a substituted phenyl group, it may have 1 to 5 substituents, preferably from 1 to 3 substituents, more preferably 1 or 2 substituent, and most preferably 1 substituent. If more than one substituent, they may be the same or different from each other. Substituents selected from the group consisting of substituents and substituents defined above and shown in the examples below, more preferably of deputies1and Vice 1defined and described in the examples below, and even more preferably from Vice1and Vice2defined and described in the examples below.

Substituents selected from the group consisting of the different atoms.

Deputies1selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, alkyl groups which have from 1 to 4 carbon atoms and are substituted by at least one Deputy, selected from the group consisting of substituents1, mercaptopropyl, alkanoyloxy having from 1 to 4 carbon atoms, halogenlamp having from 1 to 4 carbon atoms, and alkylenedioxy having from 1 to 4 carbon atoms.

Deputies2selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogenating groups having from 1 to 4 carbon atoms, mercaptopropyl, alkanoyloxy having from 1 to 4 carbon atoms, halogenlamp having from 1 to 4 carbon atoms, and alkylenedioxy having from 1 to 4 carbon atoms.

When Deputy or Deputy 1represents a halogen atom, they can be an atom of fluorine, chlorine, bromine or iodine, of which preferred are fluorine atoms, chlorine and bromine.

When Deputy or Deputy1is alkoxygroup having from 1 to 6 (or 4) carbon atoms, it can be unbranched or branched and her pentyloxy-, isopentylamine, neopentylene-, 2-methylbutoxy-, 1 ethylpropoxy-, 4-methylpentane-, 3-methylpentane-, 2-methylpentane-, 1 methylendioxy-, 3,3-dimethylbutene-, 2,2-Dimethylbutane-, 1,1-Dimethylbutane-, 1,2-Dimethylbutane-, 1,3-Dimethylbutane-, 2,3-Dimethylbutane-, 2-ethylbutane, hexyloxy and isohexadecane. Of them, preferred are alkoxygroup having from 1 to 4 carbon atoms, preferably methoxy, ethoxy-, propoxy-, isopropoxy, butoxy, isobutoxy-, second -, butoxy - and tert-butoxypropyl and most preferably methoxy and ethoxypropan.

When Deputy or Deputy1is allylthiourea having from 1 to 6 (or 4) carbon atoms, it can be unbranched or branched and examples include the methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylic-, second -, butylthio-, tert-butylthio, petitio, isopentyl, neopentyl-, 2-methylbutyl-, 1 ethylpropyl-, 4-methylphenylthio-, 3-methylphenylthio-, 2-methylphenylthio-, 1 methylphenylthio-, 3,3-dimethylbutyl-, 2,2-dimethylbutyryl-, 1,1-dimethylbutyl-, 1,2-dimethylbutyl-, 1,3-dimethylbutyl-, 2,3-dimethylbutyl-, 2-ethylbutyl-, hexylthio and isogenicity. Of them preferred the two is propylthio-, butylthio, isobutyric, verbality - and tert-butylthiourea and most preferably methylthio and atertiary.

When Deputy , Deputy1or Deputy 2represents an alkyl group having from 1 to 6 (or 4) carbon atoms, it can be unbranched or branched and examples include methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert-boutelou, pentelow, isopentanol, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutanol, hexoloy and isohexyl group. Of them, preferred are alkyl groups having from 1 to 4 carbon atoms, preferably methyl, ethyl, sawn, ISO-propyl, bucilina, isobutylene, second-bucilina and tert-bucilina group, and most preferably methyl and ethyl groups. Such groups may be unsubstituted or substituted by at least one of substituents (or1) defined and described in the examples you tomatillo, triptoreline, 2-foretelling, 2,2-deperately, 2,2,2-triptoreline, 2,2,2-trichlorethylene, 3-forproperty, 4-terbutaline, chlormethine, trichlorethylene, otmetilo and bromatology groups, which are preferred permetrina, deformational, triptoreline, 2-florachilena, 3-forproperty, 4-terbutalina, chlormethine, trichlorethylene and brometalia group and the most preferred permetrina, deformational and triptorelin group.

Generally, when Deputy , Deputy1or Deputy2represents a substituted alkyl group, there are no particular restrictions on the number of substituents, except by the number of substitutable positions or possibly by steric constraints. However, it is generally preferred from 1 to 3 such substituents.

When the Deputy represents alkanoyloxy, it can be unbranched or branched group having from 1 to 6 carbon atoms. Specific examples of alkanoyloxy include formyloxy-, acetoxy-, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, valeriote, isovalerianic and hexaniacinate, of which preferred are is alcoholcheap, it can be unbranched or branched group having from 1 to 6 (or 4) carbon atoms. Specific examples of alkanoyloxy include formally, acetylthio, propositio, butylthio, isobutyrate, pivaloate, valeriia, isovalerate and hexanitro, of which preferred are groups having from 1 to 4 carbon atoms, and more preferred acetylthio and propiertary.

When the Deputy is alkylsulfonyl group having from 1 to 6 carbon atoms, it can be unbranched or branched chain group and examples include methylsulfinyl, ethylsulfinyl, propylsulfonyl, isopropylacetanilide, butylsulfonyl, isobutylphenyl, second-butylsulfonyl, tert-butylsulfonyl, pentylaniline, isopentenyladenine, neopentylglycol, 2-methylbutyronitrile, 1-ethylpropylamine, 4-methylphenylsulfonyl, 3-methylphenylsulfonyl, 2-methylphenylsulfonyl, 1-methylphenylsulfonyl, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,2-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethylbutyl is sustained fashion are alkylsulfonyl group, having from 1 to 4 carbon atoms, preferably methylsulfinyl, ethylsulfinyl, propylsulfonyl, isopropylaniline, butylsulfonyl and isobutylphenyl group, and most preferably methylsulfinyl and ethylsulfinyl group.

When the Deputy represents cycloalkylation, it preferably has from 3 to 8 carbon atoms in one carbocyclic ring and its examples include cyclopropane, CYCLOBUTANE, cyclopentyloxy, cyclohexyloxy, cycloheptylamine and cyclooctylamine, of which preferred are cyclopentyloxy and cyclohexyloxy, and most preferred is cyclopentyloxy.

When Deputy , Deputy1or Deputy2is halogenlampe having from 1 to 6 (or 4) carbon atoms, it can be unbranched or branched group, and its examples include formatosi, deformedarse, triptoreline-, 2-floratone-, 2-chloroethoxy-, 2-bromoethoxy-, 2,2-diflorasone, 2,2,2-triptoreline-, 2,2,2-trichloroethane-, 3-forproperty-, 4-forbooks, chloromethoxy, trichlormethane, admetox and bromatology of which are predpochtite is timetake, 2 floratone-, 2-chloroethoxy-, 2-broadaxe, 3 forproperty-, 4-forbooks, hermetics-, 3-chloromethoxy and bromatology and most preferred formatosi, deformedarse and cryptometer.

When Deputy , Deputy1or Deputy2is alkylenedioxy having from 1 to 6 (or 4) carbon atoms, it can be unbranched or branched group, and its examples include methylenedioxy, Ethylenedioxy, trimethylenediamine, tetramethylbenzene, pentamethylbenzene, hexamethylendiamine and propyleneoxide, which are the preferred groups having from 1 to 4 carbon atoms, and more preferred methylendioxy and Ethylenedioxy.

Specific preferred examples of R2include phenyl group; phenyl groups having from 1 to 3 substituents selected from halogen atoms, C1-C4alkyl, C1-C4alkoxy, C1-C4alkylthio-, mercapto-, C1-C4alkanity and C1-C4alkylsulfonyl groups, such as 4-Fortunella, 4-chloraniline, 4-bratinella, p-tolila, 4-ethylvanillin, 4-metoksifenilny, 4-ethoxyphenyl, 4-methylthiophenyl, 4-et, 4-ethylsulfinyl, 3,4-differenly, 2,4-differenly, 3,4-dichloraniline, 2,4-dichloraniline, 3,4-dimethylaniline, 3,4-dimethoxyaniline, 3-chloro-4-Fortunella, 3-chloro-4-metoksifenilny, 3-fluoro-4-metoksifenilny, 3-methyl-4-metoksifenilny, 3,5-dichloro-4-metoksifenilny and 4-methoxy-3,5-dimethylaniline group; trifluoromethyl, deformedarse or triptoreline phenyl group such as 4-triftormetilfullerenov, 4-deformationally and 4-triphtalocyaninine group; and methylendioxy or ethylenedioxythiophene phenyl group, such as 3,4-methylenedioxyaniline and 3,4-ethylenedioxythiophene group.

In the compounds of formulas (I) and (II) R3represents a hydrogen atom, chlorine atom, alkyl group having from 1 to 6 carbon atoms, or an alkyl group having from 1 to 6 carbon atoms and substituted by at least one Deputy, selected from the group consisting of substituents , and preferably, at least one Deputy, selected from the group consisting of substituents1defined and described in the examples above, and more preferably by at least one halogen atom.

When R3represents the atom Gal is, having from 1 to 6 carbon atoms, it can be unbranched or branched chain group and examples include the methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert-boutelou, pentelow, isopentanol, neopentyl, 2-metabolising, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexoloy and isohexyl group. Of them, preferred are alkyl groups having from 1 to 4 carbon atoms, preferably methyl, ethyl, sawn, ISO-propyl, bucilina, isobutylene, second-bucilina and tert-bucilina group, and most preferably methyl and ethyl groups.

When R3represents a substituted alkyl group having from 1 to 6 carbon atoms, it can be unbranched or branched group, substituted by at least one Deputy, selected from the group consisting of substituents (or1) defined and described in the examples above, and in particular a halogen atom.

The examples and the minimum level of such halogenating groups include formeterol, deformational, triptorelin, 2-foretelling, 2,2-deperately, 2,2,2-triptoreline, 2,2,2-trichlorethylene, 3-forproperty, 4-terbutaline, chlormethine, trichlorethylene, otmetilo and bromatology groups, which are preferred permetrina, deformational, triptoreline, 2-florachilena, 3-forproperty, 4-terbutalina, yodmetilat, chlormethine, trichlorethylene, brometalia, 2-chloraniline and 3-chloropropylene group and the most preferred permetrina, deformational, triptoreline, 2-florachilena and 2-chloraniline group.

R3preferably represents a hydrogen atom; a halogen atom (such as fluorine atom, chlorine, bromine or iodine); methyl group, ethyl group, formeterol group, deformational group, 2-foretelling group or 2-chloraniline group.

In the compounds of formulas (I) and (II) R4represents a hydrogen atom, alkyl group having from 1 to 6 carbon atoms, alkyl group having from 1 to 6 carbon atoms and substituted by at least one of the substituents cycloalkyl group having from 3 to 8 carbon atoms, aryl group having 6 to 14 carbon atoms, aryl group, it is preferably, at least one of the substituents1defined and described in the examples above, or Vice3defined below and are included in the groups given as examples above in connection with substituents ), aracelio group (having from 1 to 6 carbon atoms in the alkyl part and from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms in the aryl part or aracelio group (having from 1 to 6 carbon atoms in the alkyl part and from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms in the aryl part), substituted by at least one of the substituents or substituents (preferably, at least one of the substituents1or Vice3).

Deputies3include alkyl groups having from 1 to 6 carbon atoms, alkyl groups having from 1 to 6 carbon atoms and substituted by at least one of the substituents , and cycloalkanes having from 3 to 8 carbon atoms, all of these groups represent groups that are defined and listed as examples above.

In particular, in accordance with the preferred option R4must represent a hydrogen atom, alking, at least one of the substituents selected from the group consisting of substituents 2,/ defined below and are included in the groups given as examples above in connection with the deputies , cycloalkyl group having 3 to 6 carbon atoms, aryl group which is unsubstituted or substituted by substituents2and Vice 4defined below and are included in the groups given as examples above in connection with the deputies , aracelio group, which is unsubstituted or substituted by at least one Deputy, selected from the group consisting of substituents 2and Vice4.

Deputies2include the hydroxy-group, halogen atoms and alkoxygroup having from 1 to 6 carbon atoms, all as defined and described in the examples above.

Deputies4include alkyl groups having from 1 to 6 carbon atoms and which is unsubstituted or substituted by at least one halogen atom, and cycloalkylcarbonyl having from 3 to 8 carbon atoms, all as defined and described in the examples above.

When R4represents alkyl groupline from 1 to 4 carbon atoms, and its examples include methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert-boutelou, pentelow, isopentanol, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexoloy and isohexyl group. Of them, preferred are alkyl groups having from 1 to 4 carbon atoms, preferably methyl, ethyl, sawn, ISO-propyl and bucilina group and most preferably a methyl group.

When R4represent a substituted alkyl group, it can be any of the alkyl groups mentioned as examples above, in particular methyl, ethyl, sawn, ISO-propyl, butilkoi, isobutylene, second-butilkoi, tert-butilkoi, Pintilei or hexylene group. Such groups are substituted by one or more substituents as defined and described in the examples above, in particular hydroxy-group, alkoxycarbonyl having from 1 to 4 carbon atoms, and atoms of halogeno the Roma restrictions imposed by the number of substitutable positions and possibly by steric constraints. However, generally preferred are 1-3 substituent. In the case of substituents other than halogen atoms, more preferred is one Deputy.

When R4is cycloalkyl group, this has from 3 to 8 carbon atoms, and its examples include cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo, cycloheptyl and cyclooctyl group, of which preferred are cyclopropyl, cyclobutyl, cyclopentolate and tsiklogeksilnogo group, and most preferred is cyclopropyl group.

When R4represents an aryl group, it is a carbocyclic aromatic group, preferably having from 6 to 10 ring carbon atoms, for example phenyl or naftalina (e.g., 1 - or 2-naftalina) group. This group may be substituted or unsubstituted and, if substituted, the substituents selected from the group consisting of substituents and substituents defined and presented as examples above.

When R4is aracelio group, she is an alkyl group (Kotor is happening from 1 to 4 carbon atoms and substituted preferably 1-3 (more preferably 1) aryl groups, which can be such as the groups defined and examples presented above. This kalkilya group can be substituted or unsubstituted in the aryl part and if it is substituted, the substituents selected from the group consisting of substituents and substituents defined and examples presented above. Specific examples of the unsubstituted groups include beilou, fenetylline, 3-phenylpropyl, 4-phenylbutyl, 1-netilmicin and 2-naphthylmethyl group.

When the above-mentioned aryl and kalkilya groups are substituted, there are no particular limitations regarding the number of such substituents, in addition to restrictions imposed by the number of substitutable positions (5 in the case of a phenyl group and 7 in the case naftalina groups) and possibly by steric constraints. Preferred examples of such substituents include halogen atoms such as fluorine atoms, chlorine, bromine and iodine; alkyl groups having from 1 to 6 carbon atoms, such as methyl, ethyl, sawn, ISO-propyl, bucilina, isobutylene, second-bucilina and tert-bucilina group; halogenoalkane group having from 1 to 6 carbon atoms, such as permetrina, deformational, triptoreline, charmet the-forproperty and 4-forproperty group; alkoxygroup having from 1 to 6 carbon atoms, such as methoxy, ethoxy-, propoxy-, isopropoxy, butoxy, isobutoxy-, second -, butoxy and tert-butoxypropyl; and cycloalkylcarbonyl having from 3 to 8 carbon atoms, such as cyclopropane, CYCLOBUTANE, cyclopentyloxy, cyclohexyloxy and cycloheptylamine.

Preferred examples of groups which may be represented by the symbol R4include a hydrogen atom; alkyl groups having from 1 to 4 carbon atoms, such as methyl, ethyl, ISO-propyl, bucilina and isobutylene group; di - or trichloranisole group having from 1 to 4 carbon atoms, such as permetrina, deformational, chlordiftormethane, predeformation, triptoreline, 2-florachilena and 2,2,2-triptorelin group; hydroxymethylene group; alkoxymethyl group having from 1 to 4 carbon atoms in the CNS part, such as methoxymethyl and ethoxymethylene group; cycloalkyl group, having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentolate and tsiklogeksilnogo group; phenyl group; mono - or differenly group, such as 4-Fortunella and 2,4-differenl is; tolylene group, such as p-tolila and on-tolila group; cyclopentyloxy(methoxy)phenyl group, such as 3-cyclopentyloxy-4-metoksifenilny group; triptoreline group, such as 4-triftormetilfullerenov group; benzyl group; a substituted benzyl group, such as 4-methoxyaniline and 3 cyclopentyloxy-4-methoxyaniline group; penicilina group; raftiline groups such as 1-naftalina and 2-naftalina group; and naphthylmethyl groups, such as 1-naphthylmethyl and 2-naphthylmethyl group.

Preferred classes of compounds of the present invention are those compounds of formula (I) and (II) and their salts, in which:

(A) R represents a hydrogen atom, halogen atom or alkyl group having from 1 to 4 carbon atoms.

(B) R1represents a methyl group, an amino group or acetylamino.

(C) R2represents a phenyl group or a phenyl group which is substituted by at least one Deputy, selected from the group consisting of substituents1and Vice1defined below,

deputies1selected from the group consisting of halogen atoms, alkoxygroup having from 1 . from the group consisting of alkyl groups having from 1 to 4 carbon atoms, alkyl groups which have from 1 to 4 carbon atoms and are substituted by at least one Deputy, selected from the group consisting of substituents1, mercaptopropyl, alkanoyloxy having from 1 to 4 carbon atoms, halogenlamp having from 1 to 4 carbon atoms, and alkylenedioxy having from 1 to 4 carbon atoms.

(D) R3represents a hydrogen atom, halogen atom, alkyl group having from 1 to 4 carbon atoms, or a substituted alkyl group having from 1 to 4 carbon atoms and substituted by at least one Deputy, selected from the group consisting of substituents1defined below;

deputies 1selected from the group consisting of halogen atoms, alkoxygroup having from 1 to 4 carbon atoms, and alkylthio having from 1 to 4 carbon atoms.

(E) R4represents a hydrogen atom, alkyl group having from 1 to 4 carbon atoms, a substituted alkyl group having from 1 to 4 carbon atoms and substituted by at least one Deputy, selected from the group consisting of the substituents defined above, the CEC is native atoms and is unsubstituted or substituted, at least one Deputy, selected from the group consisting of substituents1and Vice3defined below, aracelio group having from 1 to 4 carbon atoms in the alkyl part and containing at least one aryl group such as defined above;

deputies1selected from the group consisting of halogen atoms, alkoxygroup having from 1 to 4 carbon atoms, and alkylthio having from 1 to 4 carbon atoms; and

deputies3include alkyl groups having from 1 to 6 carbon atoms, alkyl groups having from 1 to 6 carbon atoms and substituted by at least one of the substituents , and cycloalkylcarbonyl having from 3 to 8 carbon atoms.

Particularly preferred compounds of the present invention are those compounds of formula (I) and their salts, in which R is as defined above in (A), R1such as defined above in (B), R2such as defined above in (C), R3such as defined above in (D), and R4such as defined above in (E).

More preferred classes of compounds of the present invention are those compounds of formula (I) and (I) and their salts, in which:

(F) R panograph or acetylamino.

(H) R2represents a phenyl group or a phenyl group which is substituted by at least one Deputy, selected from the group consisting of substituents1and Vice 2defined below, and more preferably 1-3 specified substituents;

deputies1selected from the group consisting of halogen atoms, alkoxygroup having from 1 to 4 carbon atoms, and alkylthio having from 1 to 4 carbon atoms; and

deputies2selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogenating groups having from 1 to 4 carbon atoms, mercaptopropyl, alkanoyloxy having from 1 to 4 carbon atoms, halogenlamp having from 1 to 4 carbon atoms, and alkylenedioxy having from 1 to 4 carbon atoms.

(I) R3represents a hydrogen atom, halogen atom, alkyl group having from 1 to 4 carbon atoms, or halogenation group having from 1 to 4 carbon atoms.

(J) R4represents a hydrogen atom, alkyl group having from 1 to 4 carbon atoms, a substituted alkyl group having from 1 to 4 carbon atoms and substituted by at least truppo, having 3 to 6 carbon atoms, aryl group which has from 6 to 10 ring carbon atoms and is unsubstituted or substituted by at least one Deputy, selected from the group consisting of substituents2and Vice4defined below, aracelio group having from 1 to 4 carbon atoms in the alkyl part and containing at least one aryl group such as defined above;

deputies2include the hydroxy-group, halogen atoms and alkoxygroup having from 1 to 6 carbon atoms; and

deputies4include alkyl groups having from 1 to 6 carbon atoms and which is unsubstituted or substituted by at least one halogen atoms, and cycloalkylcarbonyl having from 3 to 8 carbon atoms.

Particularly preferred compounds of the present invention are those compounds of formula (I) and (II) and their salts, in which R is as defined above in (F), R1such as defined above in (G), R2such as defined above in (H), R3such as defined above in (I), and R4such as defined above in (J).

The most preferred classes of compounds according to the present izaberete the preferred compounds of the present invention are those compounds of formula (I) and (II) and their salts, in which R is as defined above in (K), R1such as defined above in (G), R2such as defined above in (H), R3such as defined above in (I), and R4such as defined above in (J).

Compounds of the present invention may exist in the form of various stereoisomers (R and S isomers) depending on the presence of asymmetric carbon atoms. The present invention includes both the individual isomers and their mixtures, including racemic mixtures.

Under the influence of atmospheric compounds according to the present invention can consume water with its absorption or formation of hydrate. The present invention covers such hydrates. In addition, the compounds of the present invention can absorb some other solvents with the formation of a solvate, which also form part of the present invention.

Compounds of the present invention may form a salt. Examples of such salts include salts with alkali metal such as sodium, potassium or lithium; salts with alkaline earth metal such as barium or calcium; salts with another metal, such as magnesium or aluminum; ammonium salts; salts of organic bases, such as the other; and salts with basic amino acid such as lysine or arginine.

Specific examples of the compounds of the present invention are those compounds of formula (I) and (II), in which the substituting groups are those defined in one of tables 1 [formula (I)] and 2 [formula (II)]:

< / BR>
< / BR>
In these tables use the following abbreviations:

Ac - acetyl

Bu - butyl

Byr - butyryl

iByr - isobutyryl

Bz - benzyl

Et - ethyl

For - formal

Me - methyl

Ph - phenyl

Piv - pivaloyl

cPn - cyclopentyl

Pr - propyl

cPr - cyclopropyl

iPr is isopropyl

Prn - propionyl

iVal - isovaleryl

Val - valeryl

Of the above compounds, particularly preferred specific compounds are the following:

(1) 3-Methyl-2-(4-were)-1-(4-sulfamoylbenzoyl)propyl

(2) 4-Methyl-2-(4-were)-1-(4-sulfamoylbenzoyl)propyl

(3) 1-(4-Forfinal)-2-(4-sulfamoylbenzoyl)pyrrol

(4) 1-(4-Forfinal)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrol

(5) 5-fluoro-1-(4-forfinal)-2-(4-methylsulfinylphenyl)pyrrol

(6) 2-(4-Methoxyphenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol

(7) 1-(4-Methoxyphenyl)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrol

(8) 4-Ethyl-2-(4-labels-methylthiophenyl)-1-(4-sulfamoylbenzoyl)pyrrol

(11) 2-(4-Ethoxyphenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol

(12) 2-(4-Methoxy-3-were)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol

(13) 2-(3-Fluoro-4-methoxyphenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol

(14) 4-Methyl-2-phenyl-1-(4-sulfamoylbenzoyl)pyrrol

(15) 2-(3,4-Dimetilfenil)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol

(16) 2-(3-Chloro-4-methoxyphenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol

(17) 4-Methyl-1-(methylthiophenyl)-2-(4-sulfamoylbenzoyl)pyrrol

(18) 5-Chloro-1-(4-methoxyphenyl)-2-(4-sulfamoylbenzoyl)pyrrol

(19) 4-Methyl-1-(3,4-dimetilfenil)-2-(4-sulfamoylbenzoyl)pyrrol

(20) 5-Chloro-1-(4-ethoxyphenyl)-2-(4-sulfamoylbenzoyl)pyrrol

(21) 5-Chloro-1-(4-methylthiophenyl)-2-(4-sulfamoylbenzoyl)pyrrol

(22) 1-(4-Ethylthiophene)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrol

(23) 2-(3, 5dimethylphenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol

(24) 1-(4-Mercaptophenyl)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrol

(25) 1-(4-Acetylthiophene)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrol

(26) 1-(4-Acetylbenzenesulfonyl)-4-methyl-2-(4 - methoxyphenyl)pyrrol

(27) 1-(4-Acetylbenzenesulfonyl)-4-methyl-2-(3,4-dimetilfenil)pyrrole.

Of those, more preferred are the compounds:

NN(2), (6), (9), (10), (11), (12), (13), (15), (17), (26) and (27), and most preferred are the United way, well known in the field of production of compounds of this type, such as the following methods A-L.

The following methods A-E and K illustrate the formation of compounds of formula (I).

How A

He illustrates the formation of compounds of formula Ia, where R3represents a hydrogen atom, alkyl group or substituted alkyl group having at least one Deputy, selected from the group consisting of substituents .

In the above formulas R, R1, R2and R4such as defined above, and R3arepresents a hydrogen atom, alkyl group having from 1 to 6 carbon atoms, or a substituted alkyl group having from 1 to 6 carbon atoms and at least one Deputy, selected from the group consisting of the substituents defined and examples presented above.

Stage A1

At this stage, get aldimine formula (3) by a dehydration condensation of a benzaldehyde of the formula (1) with the aniline of formula (2) in an inert solvent.

The reaction is normally and preferably carried out in the presence of a solvent. There are no particular restrictions on the nature of the solvent, provided that it is not about the at least to a certain extent. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; alcohols, such as methanol, ethanol, propanol, isopropanol and butanol; and organic acids such as acetic and propionic acid. Of these solvents, preferred are alcohols.

The reaction may proceed in a wide range of temperatures and the precise reaction temperature is not required for the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and the used starting material or reagent. However, it is usually advisable to carry out the reaction at a temperature of from 5oC to 200oC, and more preferably from room temperature to 150oC. the Time required for the reaction can also be changed within wide limits depending on many factors, particularly the reaction temperature and the nature of Josiah, it is usually sufficient period of from 10 minutes to 20 hours, and more preferably from 1 to 15 hours.

The reaction may be carried out with removal of water generated during the reaction, but usually the reaction proceeds satisfactorily without such procedures.

Stage A2

At this stage receive anilinomethyl formula (4) by the addition of cyanide to aldimine formula (3) obtained as described in stage A1.

The reaction may be carried out by the interaction aldimine formula (3) with trimethylsilylcyanation (TMS-CN) in the presence of a Lewis acid such as aluminum chloride, tin chloride or zinc chloride.

The reaction is normally and preferably carried out in the presence of a solvent. There are no special restrictions regarding the nature of the solvent, provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane; and ethers, such as on the Ira.

The reaction may proceed in a wide range of temperatures and the precise reaction temperature is not required for the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and used starting materials or reagents. However, it is usually advisable to carry out the reaction at a temperature of from 5oC to 200oC, and more preferably from room temperature to 150oC. the Time required for the reaction can also be changed within wide limits depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 30 minutes to 100 hours, and more preferably from 1 to 30 hours.

Stage A3 and A4

At these stages receive the target compound of formula (Ia), a compound of the invention, by implementation of the interaction of anilinomethyl formula (4) obtained as described in stage 2, with , - unsaturated aldehyde or ketone of formula (5) to produce pyrrolidine formula (6), which is then dehydration and dehydrolinalool according to the modified method V. A. Tabah restrictions on the nature of the grounds and equally you can use any base, commonly used in reactions of this type. Examples of such bases include hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide; hydrides of alkali metals such as lithium hydride, sodium hydride and potassium hydride; amides of alkali metals such as lithium amide, sodium amide, potassium amide and bis(trimethylsilyl)amide and lithium; and alkoxides of alkali metals, such as ethoxide (ethylate) lithium methoxide (methylate) sodium, ethoxide sodium tert-piperonyl (tert-butyl) potassium. Of them, preferred are lithium amides.

The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent, provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; and alcohols, such as methanol, ethanol, propanol, isopropanol and butanol. In the kOhm range of temperatures and the precise reaction temperature is not essential for the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and the used starting material or reagent. However, it is usually advisable to carry out the reaction at a temperature of from -78oC to 100oC, and more preferably from -78oC to room temperature. The time required for the reaction can also be changed within wide limits depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 10 minutes to 30 hours, and more preferably from 1 to 20 hours.

Stage A4

At this stage, get the target compound of formula (Ia), a compound of the invention, by dehydration and dehydrozingerone the compounds of formula (6) obtained as described in stage 3.

This can be achieved by heating the residue obtained by removal of the solvent from the product of stage 3, or by heating the material obtained by extraction of the specified residue, washing with water and distillation of the solvent, at a temperature of not lower than 100oC in the presence or in the absence of a process is ritala, but when using solvent it is preferably inert and has a higher boiling point. Examples of suitable solvents include toluene, xylene, dimethylformamide, dimethylacetamide, dimethylsulfoxide, diglyme (dimethyl ether of diethylene glycol) and a simple diphenyl ether.

Method B (scheme of reactions is given at the end of the description).

This method is a modified method of obtaining the compounds of formula (Ia) in which R3represents a hydrogen atom, alkyl group having from 1 to 6 carbon atoms, or a substituted alkyl group having from 1 to 6 carbon atoms and at least one Deputy, selected from the group consisting of substituents alpha defined and examples presented above.

In the above formulas:

R, R1, R2, R3aand R4have the meanings defined above;

each of R5and R6represents an alkyl group having from 1 to 4 carbon atoms, or R5and R6together with the nitrogen atom to which they are attached, represent genericlink ring containing 5 or 6 ring atoms, of which one is indicated by a nitrogen atom, 0 or 1 is the ohms are carbon atoms;

R7represents a carboxy-protective group, and

Xarepresents a chlorine atom, bromine or iodine.

Used in this description, the term "carboxy-protective group" means a protective group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis.

Examples of such carboxy-protecting groups include:

alkyl groups having from 1 to 20 carbon atoms, more preferably from 1 to 6 carbon atoms, such as those cited as examples for R, and tertiary alkyl groups, are well known in the art, such as Reptilia, anjilina, Danilina, decile, Godzilla, redecilla, pentadactyla, octadecyl, Donatella and Casilina group, and most preferably methyl, ethyl and tert-bucilina group;

halogenated alkyl groups having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms in which the alkyl part is as defined and examples presented in connection with the above-mentioned alkyl groups, and the halogen atom is chlorine, fluorine, bromine or iodine, such as 2,2,2-trichlorethylene, 2-halogenation (for example, 2-chlorate clausilia group, having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentamine, tsiklogeksilnogo and cycloheptyl group;

kalkilya groups in which the alkyl part has from 1 to 3 carbon atoms and the aryl part is a carbocyclic aromatic group having from 6 to 14 carbon atoms which may be substituted or unsubstituted and, if substituted, has at least one of the substituents or substituents defined and examples presented above, although preferred are unsubstituted groups; examples of such Uralkalij groups include benzyl, fenetylline, 1-phenylethylene, 3-phenylpropanol, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-(1-naphthyl)-ethyl, 2-(2-naphthyl)ethyl, benzhydryl (i.e. diphenylmethyl), triphenylmethyl, bis(o-nitrophenyl)methyl, 9-antiloitering, 2,4,6-trimethylbenzyl, 4-brombenzene, 2-nitrobenzyl, 4-nitrobenzyl, 3-nitrobenzyl, 4-methoxybenzyl and piperonyl group;

alkeneamine group having from 2 to 6 carbon atoms, such as vinyl, allyl, 2-methylaniline, 1-protanilla, isopropylene, 1-bucinellina, 2-bucinellina, 3-bucinellina, 1-xenylla and 5-examilia group, of which are the preferred vinyl, allyl, 2-methylaniline, 1-protanilla, isopropylene and bucinellina group and the most preferred allyl and 2-methylaniline group;

substituted serialkiller groups in which the alkyl part is as defined and examples presented above, and the silyl group has up to 3 substituents, selected from alkyl groups having from 1 to 6 carbon atoms, and phenyl groups which are unsubstituted or have at least one Deputy, selected from substituents and substituents defined and examples presented above, for example, 2-trimethylsilylethynyl group;

aryl group having from 6 to 14 carbon atoms and optionally substituted by one or more of the substituents or substituents defined and examples presented above, for example, phenyl, - naftalina, - naftalina, indenolol and andrenaline group, preferably phenyl or indenolol group and more preferably a phenyl group; any of these aryl groups may be unsubstituted or substituted and, if it is substituted, preferably has at least one alkyl group having from 1 to 4 ug the dust;

fenceline group that may be unsubstituted or have at least one of the substituents or substituents defined and examples presented above, for example, the very Venizelou group or p-brompheniramine group; and

cyclic and acyclic terpinolene group, for example, geraniou, marilou, lunalilo, matchlock, manilow (in particular, m - and p-mantellinae), toyellow, marilou, pinarillo, Bardolino, notarile, nobinonly, norbornylene, mantenerlo, Campanile and norbornylene group.

Stage B1

At this stage receive 1,4-dioxooleana formula (9) by alkylation position raminosoa the compounds of formula (8) ventillation formula (7).

The reaction is normally and preferably carried out in the presence of a solvent. There are no special restrictions regarding the nature of the solvent, provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons, such, and dioxane. Of these preferred solvents are ethers.

This reaction can be carried out in the presence or absence of a base. Similarly, there are no special restrictions regarding the nature of the grounds and equally you can use any base commonly used in reactions of this type. Examples of such bases include pyridine, picoline, 4-(N, N-dimethylamino)pyridine, triethylamine, tributylamine, diisopropylethylamine and N-methylpiperidine.

The reaction may proceed in a wide range of temperatures and the precise reaction temperature is not critical to the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and the used starting material or reagent. However, it is usually advisable to carry out the reaction at a temperature of from -30oC to 200oC, and more preferably from 0oC to 100oC. the Time required for the reaction can be modified within wide limits depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually the first reaction, the reaction mixture is acidified with obtaining 1,4-dioxooleana formula (9).

Stage B2

At this stage, get the target compound of formula (Ia) of the present invention by dehydration condensation of 1,4-dioxooleana formula (9) obtained as described in stage B1, and aniline of formula (10) with shorting rings. The reaction can be performed under the same conditions as described in stage A1 of method A. However, it is preferable implementation of this stage by heating under reflux for 1 to 10 hours.

Stage B3

At this stage get complicated doxepin formula (12) by alkylation - complex atsoever formula (11) fenetylline formula (7).

The reaction is carried out in the presence of a base. There are no special restrictions regarding the nature of the grounds and equally you can use any base commonly used in reactions of this type. Examples of such bases include alkali metals such as lithium, sodium and potassium; hydrides of alkali metals such as lithium hydride, sodium hydride and potassium hydride; amides of alkali metals such as lithium amide, sodium amide and potassium amide; and alkoxides of alkali metals, such as ataxic lithium, sodium methoxide, ethoxide sodium tert-piperonyl potassium. From Westlaw in the presence of a solvent. There are no special restrictions regarding the nature of the solvent, provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides, such dimethylformamide and dimethylacetamide; alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol. Of them, preferred are ethers or alcohols.

The reaction may proceed in a wide range of temperatures and the precise reaction temperature is not critical to the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and the used starting material or reagent. However, it is usually advisable to carry out the reaction at a temperature of from 5oC to 200oC, and more preferably from room temperature to 150oC. the Time required for the reaction can also be changed in wide is impressive and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 10 minutes to 20 hours, and more preferably from 30 minutes to 15 hours.

Stage B4

At this stage, which is an alternative stage B1, receive 1,4-dioxooleana formula (9) by carrying out the decarboxylation of complex doxepina formula (12) obtained as described in stage B3, simultaneously with the hydrolysis. The hydrolysis reaction can be carried out using any acid or alkali, usually used in the chemistry of organic synthesis for reactions of this type.

Stage B5

This stage can be carried out, when R4in complex doxepine formula (12) represents a hydrogen atom. At this stage, get the connection formula (Ia-1) through the implementation of the interaction of complex doxepina formula (12) obtained as described in stage B3, with an aniline of formula (10). This reaction is essentially the same as described in stage B2, and can be implemented in a similar way.

Stage B6

At this stage, get the connection formula (Ia) of the present invention by hydrolysis of the ester portion of the compound of formula (Ia-1) obtained as epistolica can be carried out, as indicated above, traditional methods. The decarboxylation reaction can be carried out using acid or alkali or by heating, as is well known in the chemistry of organic synthesis (for example, metol, described in Yakugaku Zasshi, 93(5), 584-598 (1973)).

The method C

In this way we obtain a compound of formula (Ib) where R3represents a halogen atom, by halogenation of the corresponding compound where R3represents a hydrogen atom as shown in the following reaction scheme (reaction scheme given in the end of the description).

In the above formulas R, R1, R2and R4such as defined above, and R3brepresents a halogen atom such as fluorine atom, chlorine, bromine or iodine.

Stage C1

At this stage, get the target compound of formula (Ib) according to the present invention by halogenation of compounds of formula (Ia-2) of the present invention, which can be obtained, for example, as described in method A or method B. Examples of suitable halogenation agents include fluorinating agents, such as differed xenon; gloriouse agents, such as chlorine, sulfurylchloride or N-chlorosuccinimide; brainwashee agents, such as b methods described in "The Chemistry of Heterocyclic Compounds", volume 48, part 1, pages 348 - 395, published by John Wiley & Sons.

Method D

This method is a method of obtaining the compounds of formula (Ic-1), (Ic-2) or (Ic-3), where R3is halogenating group having from 1 to 6 carbon atoms (reaction scheme D is given at the end of the description).

In the above formulas:

R, R1, R2and R4have the meanings defined above;

R8represents a hydrogen atom or alkyl group having from 1 to 6 carbon atoms; and

Xbrepresents a halogen atom such as fluorine atom, chlorine, bromine or iodine.

Stage D1

At this stage receive acylpyrrole formula (13) by acylation of compounds of formula (Ia-2) of the present invention, which may be, or has received, for example, as described in method A or method B.

At this stage, can be obtained compound of the formula (13), where R8represents a hydrogen atom, through the implementation of the interaction of the reagent Vilsmaier, such as phosphorus oxychloride-dimethylforamide, oxybromide phosphorus-dimethylforamide or oxalicacid-dimethylforamide, with the compound of formula (Ia-2). The reaction is normally and preferably Khujand is provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane; amides, such as dimethylformamide.

The reaction may proceed and a wide range of temperatures and the precise reaction temperature is not critical to the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and used the source material and the reagent. However, it is usually advisable to carry out the reaction at a temperature of from -10oC to 150oC, and more preferably from 0oC to 100oC. the Time required for the reaction can also be changed within wide limits depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 15 minutes to 20 hours, and more preferably from 30 minutes to 10 hours.

Those compounds of formula (13), where R8progout be obtained by interaction of the acid anhydride or galodamadruga formula (R8aCO)2O or R8aCOXa(where Xasuch as defined above, and R8arepresents an alkyl group having from 1 to 6 carbon atoms, preferably from 1 to 3 carbon atoms) with the compound of the formula (Ia-2) in the presence of a Lewis acid (e.g. aluminum chloride, tin chloride or zinc chloride). The reaction is normally and preferably carried out in the presence of a solvent. There are no particular restrictions on the nature of the solvent, provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane; and carbon disulfide (carbon bisulfide).

The reaction may proceed in a wide range of temperatures and the precise reaction temperature is not critical to the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and used the source material and the reagent. Typically, however, is SUP>oC to 100oC. the Time required for the reaction can also be varied within wide limits depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 10 minutes to 20 hours, and more preferably from 30 minutes to 10 hours.

Stage D2

At this stage receive gidroksosoedinenii formula (14) by restoring the acyl group acylpyrrole formula (13), obtained as described in stage D1. The reaction can be carried out using a reducing agent (e.g. sodium borohydride, lithium borohydride, sociallyengaged, diisobutylaluminium or borane) or by catalytic reduction of the hydrogens. These reactions are well known in the field of chemistry and organic synthesis, and can be made well-known methods, such as described by J. Dale (J. Chem. Soc., (1961), 910) and by F. G. Bordwell et al. (J. Org. Chem., 33, 3385 (1968)), descriptions are included in this description by reference.

Stage D3

At this stage, get the target compound of formula (Ic-1), which is the connection nastoyka in stage D2. Suitable halogenation agents include fluorinating agents, such as diethylaminoacetate (DAST); gloriouse agents, such as thionyl chloride, trichloride phosphorus, pentachloride phosphorus oxychloride phosphorus or triphenylphosphine/carbon tetrachloride; brainwashee agents, such as Hydrobromic acid, thienylboronic, tribromide phosphorus or triphenylphosphine/tetrabromide carbon; and iadarola agents, such as iodomethane acid or triiodide phosphorus. These reactions are well known in the field of chemistry and organic synthesis, and can be made well-known methods, such as described by W. J. Middleton [J. Org. Chem., 40, 574 (1975)] and C. R. Noller & R. Dinsmore [Org. Synth., II, 358 (1943)], the descriptions of which are included in this description by reference.

Stage D4

At this stage, get the target compound of formula (Ic-2), which is the compound of the present invention, by heme-dihalogenoalkane carbonyl group acylpyrrole formula (13), obtained as described in stage D1, using a suitable halogenation agent. Suitable halogenation agents include fluorinating agents, such as tetraploid sulfur and DAST; gloriouse agents, such as pentachloride phosphorus and tio is ethylsilicate. These reactions are well known in the field of chemistry and organic synthesis, and can be made well-known methods, such as described by W. J. Middleton [J. Org. Chem., 40, 574 (1975)] and M. E. Jung et al. [J. Org. Chem., 43, 3698 (1978)], descriptions are included in this description by reference

Stage D5

At this stage, get a carboxylic acid of the formula (15) by oxidation of acylpyrrole formula (13), where R8represents a hydrogen atom, obtained as described in stage D1. Examples of suitable oxidizing agents which can be used at this stage include potassium permanganate, chromic acid, hydrogen peroxide, nitric acid, silver oxide (I) and silver oxide (II). These reactions are well known in the field of chemistry and organic synthesis, and can be made well-known methods, such as described by C. D. Hurd et al. [J. Am. Chem., Soc., 55, 1082 (1933)].

Stage D6

At this stage, get the target compound of formula (Ic-3), which is the compound of the present invention, by converting carboxypropyl carboxylic acid of the formula (15) obtained as described in stage D5, triptorelin group. This stage can be done using tetrafluoride is isanmaa).

He illustrates the formation of compounds of formula (Id-1), (Id-2), (Id-3) or (Id-4), where R4represents a substituted alkyl group, and R3represents a hydrogen atom or a halogen atom.

In the above formulas:

R, R1, R2, R3b, R7Xaand Xbhave the meanings defined above; R3crepresents a hydrogen atom or a halogen atom;

R9represents an alkyl group having from 1 to 6 carbon atoms;

R10represents a halogen atom or alkoxygroup having from 1 to 6 carbon atoms; and

Y represents cyano or a group of the formula-CO2R7where R7has the values defined above.

Stage E1

At this stage receive ventilatoare formula (17) by alkylation of cyanocobalamine formula (16) ventillation formula (7). This reaction is essentially the same as at stage B3 method B, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage E2

At this stage receive aminopyrrolo formula (18) through the implementation of the interaction of ventilatoare formula (17), obtained as described in stage E1, analina formalnye by K. M. H. Hilmy & E. B. Pedersen [Liebigs Ann. Chem. (1989), 1145-1146].

Stage E3

At this stage receive a derivative of pyrrole of the formula (19) by removing the amino groups from a derived aminopyrrolo formula (18), obtained as described in stage E2.

This can be achieved through the implementation of the interaction of Alternaria (for example, methylnitrite, amylnitrite, propylitic, butylnitrite, tert-butylnitrite or isoamylamine) with a derivative of aminopyrrolo formula (18). The reaction is normally and preferably carried out in the presence of a solvent. There are no special restrictions regarding the nature of the solvent, provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include aliphatic hydrocarbons, such as hexane or heptane; aromatic hydrocarbons such as benzene, toluene or xylene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane; and amides, such as dimethylformamide or dimethylacetamide. Of them, preferred are ethers.

The reaction may proceed in a wide range of topics the temperature of the reaction depends on factors such as the nature of the solvent and the used starting material or reagent. However, it is usually advisable to carry out the reaction at a temperature of from -10oC to 200oC, and more preferably from room temperature to 150oC. the Time required for the reaction can also be varied within wide limits depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 10 minutes to 20 hours, and more preferably from 30 minutes to 15 hours.

Stage E4

At this stage receive galagedera formula (20) by halogenation derived pyrrole of the formula (19), obtained as described in stage E3. This reaction is essentially the same as at stage C1 of method C, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage E5 and stage E6

At these stages receive ester of the formula (21) of the compounds of formula (19), obtained as described in stage E3, or (20), obtained as described in stage E4, where Y represents a cyano, by converting ceanography ), the corresponding alcohols and acids, such as chloromethane acid, sulfuric acid or p-toluensulfonate acid, by methods described R. Adams & A. F. Thal [Org. Synth., I, 270 (1941)].

Stage E7

At this stage, get a carboxylic acid of the formula (22) by hydrolysis of ester of the formula (21), obtained as described in stage E5 or E6. This reaction is essentially the same as at the stage B4 method B, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage E8

At this stage, get the target compound of formula (Id-2) of the present invention by converting carboxypropyl carboxylic acid of the formula (22), obtained as described in stage E7, triptorelin group. This reaction is essentially the same as at the stage D6 method D, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage E9 and stage E10

These stages together provide an alternative method for obtaining compounds of formula (Id-2) according to the present invention of a complex ester of the formula (21), obtained as described in stage E5 or E6. On stage E9 first secure carboxypropyl of ester f is Orbetello group using oxidative reactions pordesplorilo on stage E10. This method is described in detail by D. P. Matthews, J. P. Whitten & J. R. McCarthy [Tetrahedron Letters, 27(40), 4861-4864 (1986)], the link to which is included in this description for details.

Stage E11

At this stage, get the appropriate aldehyde of formula (24) by restoring the protected carboxypropyl of ester of the formula (21), obtained as described in stage E5 or E6. For example, this stage can be carried out using a reducing agent such as sociallyengaged, natroalunite, laetrilelamygdalin, diisobutylaluminium and so on , by methods described in detail in the work by L. I. Zakharkin & I. M. Khorlina [Tetrahedron Lett. , (1962), 619], the contents of which are included in this description for details.

Stage E12

At this stage, get the target compound of formula (Id-3) by heme-dihalogenoalkane aldehyde of formula (24), obtained as described in stage E11. This reaction is essentially the same as at stage D4 method D, and can be done in a similar way and using the same reagents and reaction conditions.

Stage E13

At this stage receive hydroxymethylene compound of formula (Id-1), which is the target compound of the present invention, by restoring protected about to carry out, using a reducing agent such as sociallyengaged, itibariyle or Isobutyraldehyde, methods, described in detail in the article by R. F. Nystrom et al. [J. Am. Chem. Soc., 71, 3245 (1945)], the contents of which are included in this description for details.

Stage E14

At this stage receive halogenmethyl connection or alkoxymethyl compound of formula (Id-4), which is the compound of the present invention, by halogenation or tarifitsirovana hydroxymethylene the compounds of formula (Id-1) obtained as described in stage E13. At this stage the reaction of halogenation can be performed the same way on stage D3 method D, and using the same reagents and reaction conditions.

The esterification reaction can be carried out by the interaction hydroxymethylene the compounds of formula (Id-1) alkylhalogenide.

The reaction is normally and preferably carried out in the presence of a solvent. There are no special restrictions regarding the nature of the solvent, provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents is s, such as benzene, toluene and xylene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; and amides, such as dimethylformamide or dimethylacetamide. Of them, preferred are ethers, and amides.

The reaction is carried out in the presence of a base. Also there are no special restrictions regarding the nature of the grounds and equally you can use any base commonly used in reactions of this type. Examples of such bases include hydrides of alkali metals such as lithium hydride, sodium hydride and potassium hydride; alkoxides of alkali metals such as sodium methoxide, ethoxide sodium tert-piperonyl potassium; and tertiary amines such as triethylamine, tributylamine, pyridine, picoline and 4-(N,N-dimethylamino)pyridine. Of them, preferred is sodium hydride or tert-piperonyl potassium.

The reaction may proceed in a wide range of temperatures and the precise reaction temperature is not essential for the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and the used starting material or reagent. However, it is usually prudent to carry out the reaction in temperament, may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 30 minutes to 48 hours, and more preferably from 1 hour to 24 hours.

Stage E15

At this stage oxidize the compound of formula (Id-1) to obtain the compounds of formula (24). This can be done by using an oxidant such as chromic acid, manganese dioxide or dimethyl sulfoxide, methods, described in detail by S. Bartel & F. Bohlmann [Tetrahedron Lett., (1985), 685].

The following methods F-J and L illustrate the formation of compounds of formula (II). Scheme F reactions are presented in the end of the description.

In the above formulas R, R1, R2, R3and R4have the meanings given above.

Reaction stage F1, stage 2, stage stage F3 and F4, essentially the same as the reaction stage A1 stage A2 stage A3 stage A4, respectively, and can be carried out using the same reagents and reaction conditions.

Method G

This method illustrates obtaining the compounds of formula (IIa-1), where R3prestoyou from 1 to 6 carbon atoms, and at least one Deputy, selected from the group consisting of the substituents defined and examples presented above. Scheme G reactions are given in the end of the description.

In the above formulas R, R1, R2, R3a, R4, R5, R6, R7and Xasuch as defined above.

Stage G1

At this stage receive 1,4-dioxooleana formula (33) by alkylation position raminosoa the compounds of formula (32) using penicillamine formula (31). This reaction is essentially the same as at stage B1 of method B, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage G2

At this stage, get the connection formula (IIa-1), which is the compound of the present invention, by condensation with dehydration of 1,4-dioxooleana formula (33), obtained as described in the G1 phase, and aniline derivative of the formula (25) with shorting rings. This reaction is essentially the same as at stage B2 of method B, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage G3

At this stage get complicated doxepin of fojnica formula (31). This reaction is essentially the same as at stage B3 method B, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage G4

At this stage receive 1,4-dioxooleana formula (33) by decarboxylation complex doxepina formula (35), obtained as described in stage G3, simultaneously with the hydrolysis. This reaction is essentially the same as at the stage B4 method B, and can be implemented in a similar way and using the same reagents and reaction conditions.

Method H

This method illustrates obtaining the compounds of formula (IIb), where R3represents a halogen atom. Scheme N reactions listed at the end of the description.

In the above formulas R, R1, R2, R3band R4have the meanings given above.

Stage H1

At this stage receive the derived nitropyrrole formula (36) by nitration of compounds of formula (IIa-2), which can be obtained as described in method G [a compound of the formula (IIa-1), where R3arepresents a hydrogen atom].

This stage is carried out using traditional nitrouse agent, such as nitric acid, fuming nitric acid is price 1, page 330 - 345, John Wiley & Sons.

Stage H2

At this stage receive aminopyrrolo formula (37) by nitrogroup reduction of nitropyrrole formula (36), obtained as described in stage H1. How to restore the nitro groups to amino groups is well known in the chemistry of organic synthesis and can be used any traditional method.

Stage H3

At this stage receive aminocholesterol formula (38) by halogenation of aminopyrrolo formula (37), obtained as described in stage H2. This reaction is essentially the same as at stage C1 of method C, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage H4

At this stage, get the target compound of formula (IIb) according to the present invention by removing the amino groups from aminocholesterol formula (38), obtained as described in stage H3. This reaction is essentially the same as in stage E3 method E, and can be implemented in a similar way and using the same reagents and reaction conditions.

Method 1

This method illustrates obtaining the compounds of formula (IIc-1), (IIc-2), (IIc-3) or (IIc-4), where R4pretesticular selected from the group consisting of substituents , and R3represents a hydrogen atom or a halogen atom. Scheme I, the reaction is given at the end of the description.

In the above formulas R, R1, R2, R3b, R3c, R7, R9, R10XaXband Y have the meanings defined above.

Stage I1

At this stage receive ventilatoare formula (40) by alkylation of cyanocobalamine formula (16) penacillamine formula (39). This reaction is essentially the same as at stage E1 of method E, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage I2

At this stage receive aminopyrrolo formula (41) through the implementation of the interaction of ventilatoare formula (40), obtained as described in stage I1, with an aniline derivative of the formula (25). This reaction is essentially the same as at stage E2 of method E, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage I3

At this stage receive aminoalkenes compound of formula (42) by halogenation of aminopyrrolo formula (41), obtained as described in stage I2. This reaction is essentially th reagents and reaction conditions.

Stage I4 and stage I5

At these stages are respectively a compound of formula (43) and the compound of formula (44) by removing the amino groups from aminopyrrolo (41) and aminoalkanoic the compounds of formula (42), respectively. This reaction is essentially the same as at the stage H4 method H, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage I6 and stage I7

At these stages receive ester of the formula (45) of those pyrrole derivative of formula (43) and (44), in which Y represents a cyano, by converting ceanography the protected carboxypropyl. This reaction is essentially the same as at the stage E5 method E, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage I8 and stage I9

At these stages receive triptoreline compound of formula (IIc-2), which is the target compound of the present invention, a complex ester of the formula (45), obtained as described in stage 16 or 17, through the carboxylic acid of formula (46). This reaction is essentially the same as at the stages of E7 and E8 way E, and can be implemented in a similar way and using the same texts triptoreline the compounds of formula (IIc-2) of a complex ester of the formula (45), obtained as described in stage 16 or 17, three(alkylthio)methyl compound of formula (47). This reaction is essentially the same as in the stages E9 and E10 method E, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage I12 and stage I13

At these stages receive dehalogenation compound of formula (IIc-3), which is the target compound of the present invention, a complex ester of the formula (45), obtained as described in stage 16 or 17, via the aldehyde of formula (48). This reaction is essentially the same as in the stages E11 and E12 method E, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage I14 and stage I15

At these stages receive the target compound of formula (IIc-4), which is the compound of the present invention, a complex ester of the formula (45), obtained as described in stage 16 or 17, through hydroxymethylene compound (formula IIc-1), which is also a compound of the present invention. This reaction is essentially the same as in the stages E13 and E14 of method E, and can be implemented in a similar way and using the same reagents and conditions re testwuide hydroxymethylene compounds of formula (Id-1) and (IIc-1), respectively, by converting hydroxymethylene group to the formyl group. The reaction in which hydroxymethylene group is converted into a formyl group, can be carried out using an oxidizing agent such as chromic acid, manganese dioxide or dimethyl sulfoxide, the methods described by S. Bartel & F. Bohlmann [Tetrahedron Lett., (1985), 685] .

Method J

This method is an alternative to G and provides the compounds of formula (IIa-3), where R3represents a hydrogen atom, alkyl group having from 1 to 6 carbon atoms, or a substituted alkyl group having from 1 to 6 carbon atoms, which is substituted by at least one Deputy, selected from the group consisting of the substituents defined above, and R4represents an alkyl group having from 1 to 6 carbon atoms, a substituted alkyl group having from 1 to 6 carbon atoms, which is substituted by at least one Deputy, selected from the group consisting of the substituents defined above or aracelio group. Scheme J reactions listed at the end of the description.

In the above formulas:

R, R1, R2, R3a, R7and Xahave the meanings defined above; and

R4arepresents an alkyl group having from 1 denna, at least one Deputy, selected from the group consisting of the substituents defined above, or aracelio group.

Stage J1

At this stage receive complex fluids penitsillanovoy acid of formula (50) by alkylation complex diapir of malonic acid of the formula (49) ventillation formula (31). This reaction is essentially the same as at stage B3 method B, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage J2

At this stage, get the connection formula (52) by alkylation complex diapir penitsillanovoy acid of formula (50), obtained as described in stage j-1, the halide of formula (51). This reaction is essentially the same as at stage B3 method B, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage J3

At this stage get complicated - ketoester formula (53) by hydrolysis of the compounds of formula (52), obtained as described in stage J2, followed by decarboxylation of the product. These reactions are essentially the same as in the stages B4 and B6 of method B, and can be implemented in a similar way and using the (54) by restoring the ketone and ester parts of the complex - keeeper formula (53), obtained as described in stage J3. This reaction is essentially the same as at the stage E13 method E, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage J5

At this stage receive ketoaldehyde formula (55) by oxidation of the two hydroxyl groups of diol of the formula (54), obtained as described in stage J4. This reaction can be performed well by known methods, using an oxidant (such as chromic acid, manganese dioxide or dimethyl sulfoxide), for example as described in the article by E. J. Corey, G. Schmidt et al. [Tetrahedron Lett., (1979), 399], to which reference is included in this description for details.

Stage J6

At this stage, get the connection formula (IIa-3), which is the compound of the present invention, by cyclization of ketoaldehyde formula (55), obtained as described in stage J5, and aniline derivative of the formula (25) in terms of a dehydration condensation. This reaction is essentially the same as at stage B2 of method B, and can be implemented in a similar way and using the same reagents and reaction conditions.

Method K

In this way we obtain a compound of formula (Ie-1) or (is th or alkanoyloxy, and R3represents a hydrogen atom, alkyl group having from 1 to 6 carbon atoms, or a substituted alkyl group having from 1 to 6 carbon atoms, which is substituted by at least one Deputy, selected from the group consisting of the substituents defined above. Scheme For the reactions given in the end of the description.

In the above formulas:

R, R1, R3a, R4and Xahave the meanings defined above; and R11is alkanoyloxy group having from 2 to 5 carbon atoms.

Stage K1

At this stage, get the connection formula (57) by a dehydration condensation of a benzaldehyde of formula (1) with aniline disulfide of the formula (56). This reaction is essentially the same as at stage A1 of method A, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage K2

At this stage, get the disulfide anilinomethyl formula (58) by the addition of cyanide to the compound of formula (57), obtained as described in stage K1. This reaction is essentially the same as at stage A2 of method A, and can be implemented in a similar way and using the same reapeter interaction of disulfide anilinomethyl formula (58), obtained as described in stage K2, with , - unsaturated aldehyde or ketone of formula (5) to obtain the disulfide pyrrolidine formula (59), which is then dehydration and dehydrolinalool. These reactions are essentially the same as in the stages A3 and A4 of A way, and can be implemented in a similar way and using the same reagents and reaction conditions.

Stage K5

At this stage, get the connection formula (Ie-1), which is the compound of the present invention, by the reduction of disulfide pyrrole of the formula (60), obtained as described in stage K4. This reaction can be performed well by known methods, using a reducing agent (such as sodium borohydride, lithium borohydride, sociallyengaged, diisobutylaluminium or borane), for example as described by J. J. D'amico [J. Org. Chem., 26, 3436 (1961)].

Stage K6

At this stage, get the connection formula (Ie-2), which is also a compound of the invention, by alkanolamine mercaptopropyl the compounds of formula (Ie-1), which is a compound of the invention and obtained as described in stage K5. This reaction can be performed by conventional methods using alkanolamine formula (61) or according G to obtain the compounds of formula (33). Scheme L reactions listed at the end of the description.

In the above formulas, Xa, R2, R3aand R4have the meanings given above.

Stage L1

At this stage receive bromacetyl formula (64) through the implementation of the interaction of unsaturated aldehyde of the formula (63) with gaseous bromovalerate and ethylene glycol. The reaction can be carried out by the method of Taylor et al. [J. Org. Chem., 48, 4852 - 4860 (1983)].

Stage L2

At this stage receive ketoacyl formula (68) through the implementation of the interaction of bromacetyl formula (64), obtained as described in the L1 stage, with metallic magnesium to obtain a Grignard reagent and then the interactions of the Grignard reagent to a nitrile of the formula (65), with allelochemical formula (66) or with amidol formula (67). The reaction can be carried out by the method Kruse et al. [Heterocycles, 26, 3141 - 3151 (1987)].

Stage L3

At this stage receive 1,4-dioxooleana formula (33) by hydrolysis acetaldol part of ketoacyl formula (68), obtained as described in stage L2. This stage can be accomplished in any conventional way hydrolysis using acid.

In accordance with an alternative ketoacyl formula (68) can be used for ecstasy alkyl group, having from 1 to 6 carbon atoms, can be used as a starting material compound in which alkylsulfonyl group (-SO2-alkyl) substituted by alkylthiophene (-S-alkyl). In all such cases, the reaction can be carried out as described above, and then allylthiourea can be oxidized well-known traditional ways in alkylsulfonyl group at any stage of the chain reactions.

For example, oxidation ancilliary in alkylsulfonyl group can be made by the interaction of alkylthiophene with 2 or more equivalents of the oxidising agent. There are no particular restrictions on the nature of the oxidants and equally you can use any oxidizing agent commonly used in reactions of this type. Examples of such oxidizing agents include percolate, such as peracetic acid, derbentina acid or m-chloroperbenzoic acid; hydrogen peroxide; and perhalogenated alkali metals, such as metapersonal sodium, metaperiodate sodium or metaperiodate potassium. Of them, preferred are percolate or hydrogen peroxide, in particular m-chlorbenzene acid.

The reaction is normally and preferably carried out in the presence of rest the AET harmful effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons, such as methylenchlorid, chloroform, carbon tetrachloride or dichloroethane; alcohols such as methanol, ethanol, propanol or butanol; esters such as ethyl acetate, propyl, butyl acetate or ethylpropane; carboxylic acids, such as acetic acid or propionic acid; water; or a mixture of any two or more of these solvents. Of them, preferred are halogenated hydrocarbons (particularly methylenechloride, chloroform, dichloroethane) or carboxylic acids (particularly acetic acid).

The reaction may proceed in a wide range of temperatures and the precise reaction temperature is not required for the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and used the source material and the reagent. However, it is usually prudent to carry out the reaction at a temperature of from -20oC to 150oC, and more preferably from 0oC to 100o is but the reaction temperature and the nature of the reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 10 minutes to 10 hours, and more preferably from 30 minutes to 5 hours.

In addition, all of the above reactions can be used a compound in which R2represent a phenyl group substituted by alkylthiol, with subsequent transformation into alkylsulfonyl group at any stage in the sequence of reactions as described above. The reaction can be performed, as described above, but with the amount of oxidant from 0.8 to 1.2 equivalents per equivalent of alkylthiophene.

Biological activity

Derivatives of 1,2-diphenylpyrrole and their pharmacologically acceptable salts according to the invention act as selective inhibitors of cyclooxygenase-2 and/or suppressing the production of inflammatory cytokines and is therefore useful for the prevention and therapy of diseases caused by cyclooxygenase-2 and/or inflammatory cytokines. In addition, they have the ability to inhibit the production of leukotrienes and to inhibit resorption (resorption) of bone. Therefore, these compounds can serve as analgesics, anti-inflammatory SMU invention can be used for the treatment or prevention of diseases, accompanied by bone resorption or resulting from such resorption, such as osteoporosis, rheumatoid arthritis and osteoarthritis. Analgesics, anti-inflammatories and/or antipyretics this type are effects not only in inflammatory diseases, such as pain, pyrexia and swelling, but also in chronic inflammatory diseases such as chronic rheumatoid arthritis and osteoarthritis, allergic inflammatory diseases, asthma, sepsis, psoriasis, various autoimmune diseases, systemic lupus erythematosus, juvenile diabetes, autoimmune intestinal diseases (such as ulcerative colitis, Crohn's disease), viral infections, tumors, and glomerulonephritis.

The biological activity of the compounds according to the present invention is illustrated by the following experiments.

Experiment 1

Inhibitory activity against cyclooxygenase-1 microsomes from sheep seminal vesicles (RSVM) and recombinant cyclooxygenase-2 (test in vitro)

To obtain microsomal cyclooxygenase-1 (COX-1) homogenized in a mixer seminal vesicles of sheep. To obtain microsomal cyclooxygenase-2 (COX-2) was introduced into COS cells, the vector Express. the ATEM traditional methods received microsome assay.

Enzymatic activity was determined as follows.

The mixture for the test contained 10 μl of microsomes COX-1 or COX-2 (5 - 15 μg), 2 μl of sample dissolved in dimethyl sulfoxide, 50 μl of 200 mm Tris (pH 7,6), 10 μl of 20 mm reduced glutathione, 10 μl of 10 mm epinephrine and 15.5 μl of distilled water. Then, after pre-incubation at 37oC for 15 minutes, to the mixture was added 2.5 μl of 10 mm arachidonic acid (dissolved in ethanol) (final volume of the mixture was 100 µl) and leaving the mixture to react at 37oC for 30 minutes. The final concentration of dimethyl sulfoxide and ethanol were respectively 2% and 2.5%. Then to the reaction mixture was added 15 μl of ice 0.2 M HCl to stop the reaction and cooled the mixture at 4oC for 5 minutes. Next, to the reaction mixture was added 15 μl of 0.2 M aqueous solution of sodium hydroxide to neutralize the pH. Using a commercially available ELISA kit (ELISA analysis) (Sautel) measured the amount of PGE2(prostaglandin E2) in the reaction mixture. The regression line defined by the factors inhibiting the formation of PGE2and concentree A represents 5-methyl-2-phenyl-1-(4-sulfamoylbenzoyl)pyrrole, which is disclosed in the above German patent N 1938904.

In this test, the compound of the present invention showed excellent inhibiting effects, election against cyclooxygenase-2.

Experiment 2

Inhibitory effect on the production of cytokines in peripheral monocytes (test in vitro)

(1) In healthy human volunteers took peripheral blood in the presence of heparin. After mixing it with an equal volume of phosphate-saline buffer solution (PBS, Nissui Pharmaceutical), the mixture was applied layers on Wednesday Ficoll Paque (Pharmacia) with the ratio of 2:1 and centrifuged at 520 x g at 25oC for 20 minutes. After centrifugation layer monocytes were removed and suspended in RPMI 1640 (Nissui Pharmaceutical) containing 10% fetal serum cows (FCS). Monocytes were washed once with the same medium, were placed in a plastic Petri dish, pre-treated human plasma and incubated for 2 hours in the presence of 5% CO2to get them to stick to the plate. After incubation, the Petri dish was washed twice with PBS solution to remove Aprilia cells. Then the plate was added to PBS containing 5% FCS and 0.2% EDTA (ethylenediaminetetraacetic acid), the EC cells suspended in RPMI 1640 at a concentration of 1.25 105cells/ml.

(2) Cultivation of human monocytes.

To 320 μl of cell suspension was added to 40 μl of a solution of the test compound and 40 μl of lipopolysaccharide (LPS; E. coli, 0,26:B6, Difco) with final concentration of 10 µg/ml Then the mixture was cultured for 20 hours in the presence of 5% CO2and after cultivation has removed the supernatant for analysis of IL-1 and TNF. The test compound was dissolved in dimethyl sulfoxide and diluted 100 times by FCS to achieve 10 times the final concentration (final concentration of dimethyl sulfoxide and FCS was 0.1% and 10% respectively).

(3) determining the amount of cytokines in supernatants environment

The number of IL-1 was measured using a kit (Cayman) ELISA after dilution supernatants environment in 15 or 30 times with ELISA buffer. Similarly, the number of TNF was measured using a kit (Genzyme) ELISA after dilution of the supernatant in 2 times.

The regression line defined by the coefficients of inhibition and concentrations of the test compounds was calculated IC50.

The results are presented in tables 4 and 5.

In this test, the compound of the present invention had excellent inhibitory action is on the pain caused by yeast inflammation in rats (method of Randall-Selitto) (test in vivo)

(1) Test connection

Compound suspended in 0.5% tragakant and is administered orally in an amount of 5 ml/kg Control group was injected only 0.5% tragakant as filler.

(2) Animals

This test used the rats Wistar-Imamichi (male, 5 weeks of age, body weight 80 - 100 g).

(3) test Method

The test was performed by the method of winter and Flataker [J. Pharmakol. Exp. Ther. , 150, 165 - 171 (1965)], which is a modification of the original method of Randall and Selitto [Arch. Int. Phatmacodyn. Ther., 111, 405 - 419 (1957)] . Rats were deprived of food for 16 hours before use. Caused inflammation by subcutaneous injection of 0.1 ml of a suspension of 20% brewer's yeast (Sigma) in the pad of the right hind legs of the animal. After 4.5 hours to the inflamed paw exerted pressure, growing at a constant rate, using Anaigesy Meter (trademark) (Ugo-Basile Co.). The pressure to which the animal responded squeak, measured and took him to the threshold of pain sensitivity (unit: g). Those rats in which the pain threshold was less than 200 grams (about 60 to 120 g), immediately administered orally compound and 0.5, 1 and 2 hours after administration was measured value of the threshold of pain sensitivity.

Pervonachalnogo group. If the groups subjected to treatment with drugs, is the pain threshold at least once, twice higher than the average of the control value at the same time, it was believed that this animal showed the effectiveness of the treatment. The degree of effectiveness of the drugs was assessed by the method of Blake [J. Pharm., 19, 367 - 373 (1967)]. The results are presented in table 6.

Experiment 4

Test the swelling caused by carrageenan (test in vivo)

Had the same compounds as in the test according to the method of Randall-Selitto in experiment 3. This test used the rats Wistar-Imamichi (males, age 6 weeks, body weight of 110 to 120 g).

Method of Vinter and others (Proc. Soc. Exp. Biol. Med., 111, 544 - 547 (1962)) slightly modified to perform this test [Sankyo Annual Reseatch Report, 39, 77 - 111 (1989]. Rats were deprived of food for 16 hours before use. By subcutaneous injection of 0.05 ml of 1% carrageenan (Viscarin 402) in the right hind paw of the animal caused inflammatory edema. 30 minutes before the injection of carrageenan was injected oral compound. Through Plethysmometr (trademark) was measured volume of the right hind paws just before the introduction of the test compound and with the 3 hour/volume of the right foot before injection) - 1]. To calculate the degree of inhibition (%) at each dose, which is presented in table 7.

Experiment 5

Test the pain caused by the burn test in vivo)

The test was performed according to the method of Iizuka and Tanaka [Jpn. J. Pharmacol., 70, 697 (1967)] . The test compound was administered as in experiment 3. Used rats male Wistar-Imamichi (age 4 - 5 weeks, body weight of approximately 100 g). Right rear paw of the animal under ether anesthesia was immersed for 6 seconds in hot water at 57oC to cause a burn. Two hours later burnt paw of the rat was irritated by immersion in hot water at 40oC for 5 seconds and the animal was returned to its cage.

Watched the behavior of the animal within 30 seconds. Raising burnt paws or licking it without contact with the metal cage was considered a reaction to the pain. Determined the reaction time for the pain as full-time reactions to pain during a 30-second observation period. Selecting only those animals that showed the right reaction to pain two hours after was caused by a burn, gave the animals the test compound by oral administration. After 1 and 2 hours after drug administration again measured breana relative to the control group.

The regression line determined by the degree of inhibition and the doses were calculated ID50.

The results are presented in table 8.

Experiment 6

Antipyretic effect caused by the yeast heat (test in vivo)

To perform this test a slightly modified method Rozhkovsky, etc. [J. Pharmacol. Exp. Ther., 179, 114 (1971)]. The test compound was administered as in experiment 3. In test were used rats male Wistar-Imamichi (age 6 weeks, body weight of about 120 g). Yeast (brewer's yeast, Sigma) suspended in physiological saline to a concentration of 25%, finely crushed in an agate mortar and were injected with subcutaneously in the back of the rats under ether anesthesia with a volume of 2 ml/rat. After injection of yeast rats were deprived of food. The next day (19 hours after injection of yeast) was inserted into the rectum approximately 5 cm thermistor thermometer catheter type (Japan Koden, MGA III) to measure the body temperature of the animal. Those animals which had been heat 1,5oC or more compared to normal animals, we selected and grouped so that the average temperature of heat of each group were approximately the same. Measured rectal temperature after 1 and 2 hours parmalee temperature of healthy animals. Using the average value in the moments after 1 and 2 hours after administration of the compound, calculate the degree of inhibition of heat in the group, which entered the compound, relative to the control group. The results are presented in table 9.

Experiment 7

Irritant effect on the mucous membrane of the stomach (test in vivo)

The experiments were conducted according to the method described by Jhan and Adrian [Arzneim. -Forsch. 19, 36 (1969)]. Rats male Wistar weight of about 120 g were deprived of food for 16 hours before the experiment. Drug was administered to rats orally, as described in experiment 3. After three and a half hours after injection, animals were killed under ether anesthesia, and the stomachs were placed in a 1% solution of formalin. Opened the stomach by cutting along the greater curvature and under the microscope (6,3 10) counted the number and length of lesions. Ulcerogenesis (expression) of each animal was assessed by Hitchens et al. [Pharmacologist, 9, 242 (1967)]. We determined the incidence as a proportion of rats with 4 or more ulcers of longer than 0.5 mm and morbidity and the dose was calculated by the method of probit (unit probability) analysis UD50(dose giving a 50% incidence). The results are presented in table 10.

Experiment 8

Test inhibi the ode Kitamura and others [Bone, 14, 829 - 837 (1993)]. Tibial and femoral bone extracted from mice of ICR age 18 - 20 days, crushed scissors and was stirred for 30 seconds in 10 ml of culture medium (D-MEM containing 10% FCS). Cell suspension was defended by 2 minutes and the resulting supernatant was centrifuged at 800 rpm for 3 minutes to obtain a precipitate of refractionary bone cells, including osteoclasts and preosteoblast. The precipitate, re-suspended in the medium, were incubated in the presence of 5 to 10-8M rPTH (1-34) at 37oC for 6 days in an incubator with 5% CO2. After incubation, the cells were collected using trypsin-EDTA, washed with medium twice, brought to a density of 5 to 10 cells/ml and were sown in 200 µl/well on 96 durable Board on which each of the holes contained a slice of ivory (diameter 6 mm, thickness 0.15 mm). Slices were incubated in the presence of the tested compounds dissolved in dimethyl sulfoxide at 37oC for 2 days in an incubator with 5% CO2. Scraped off the cells were treated sections with hematoxylin acid for 10 minutes to paint the formed pits and washed them with water. Were counted under an optical microscope, the number of dimples and expressed inhibitory activity connection is astasia invention showed excellent inhibition of bone resorption.

Experiment 9

The effects on depression of bones in rats with removed ovaries (test in vivo)

Rats-female Spraque Dawley bought at the age of eight weeks, and subjected them oophorectomy at the age of 9 weeks. After surgery animals daily was administered orally with the test compound suspended in 0.5% tragakant, when the volume of 2 ml/kg for 2 weeks. The next day after the last injection the animals were killed and extracted bilateral femur to measure bone mineral density using x-ray analyzer minerals bones. For comparison, rats, allegedly operated (Sham) and undergone oophorectomy (OVX), gave only 0.5% tragakant and produced the same dimensions, and that in the group exposed to treatment. The results were expressed as averages S. E. M. (standard deviation). In this experiment, the compounds of the present invention showed excellent inhibition of the reduction of bone mineral density from OVX.

Experiment 10

Inhibitory effect on the production of LTB4from peripheral human monocytes (test in vitro)

(1) isolation of peripheral human monocytes

The selection is in

Cultivation of the cells was carried out as described in experiment 2-(2).

(3) Measurement of the content of LTB4in the environment of the culture of monocytes.

The supernatant of the nutrient medium after incubation were analyzed by ELISA (Cayman). The regression line determined on the basis of the degrees of inhibition and dose was calculated by the method of least squares values IC50. The results are presented in table 11.

As you can see from the above experiments, the compounds of the present invention have excellent analgesic, anti-inflammatory and antipyretic (cough) activities, and reduce bone resorption. Therefore, they can be used for the treatment of humans and animals.

Derivatives of 1,2-diphenylpyrrole of the present invention can be introduced in any conventional form, for example, in the form of tablets, capsules, granules, powders or syrups, or parenterally by injection or in the form of suppositories, ointments, etc., These dosage forms can be obtained by mixing the compounds of the present invention with conventional additives, such as conventional fillers, binders, loosening substances, lubricants is obreteniyu change depending on the state, age and body weight of the patient, and the method of administration, the type of disease and other factors, but the compounds of the present invention can be entered with a daily dose of from 0.01 to 50 mg/kg body weight, preferably from 0.1 to 10 mg/kg for adults in a single dose or in separate doses.

Further, the formation of compounds of the present invention is illustrated in the following non-limiting examples.

Example 1

1-(4-Methoxyphenyl)-2-(4-methylsulfinylphenyl)pyrrole (Compound N 1-33)

1(i) 4-Methoxy-N-(4-methylsulfonylbenzoyl)aniline

In 15 ml of ethanol was dissolved in 1.00 g (5.4 mmol) of 4-methylsulfonylbenzoyl and 0.67 g (5.4 mmol) of 4-methoxyaniline and the solution was heated under reflux for 1 hour. At the end of this time the reaction solution was cooled to room temperature and the crystals precipitated precipitates were collected by filtration and washed with ethanol, resulting in 1.48 g (yield 95%) indicated in the title compounds as yellow prismatic crystals. Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques :

to 8.57 (1H, singlet);

8,11 - 8,01 (4H, multiplet);

7,33 - 7,26 (2H, multiplet);

6,99 - 6,93 (2H, multiplet);

of 3.85 (3H, singlet);

of tetrahydrofuran added 1.48 g (5.1 mmol) of 4-methoxy-N-(4-methylsulfonylbenzoyl)aniline [received so as described above in stage (i)] and to the resulting suspension were added to 0.80 ml (6.0 mmol) of 95% of trimethyl seleccionada and 0,85 g (6.0 mmol) of zinc chloride at 0oC with stirring. Then let the temperature of the reaction mixture to return to room temperature and stirred the mixture overnight. At the end of this time was added water and the mixture was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous sodium sulfate, after which it was concentrated by evaporation under reduced pressure and precipitated precipitated crystals were collected by filtration, receiving a result of 1.05 g (yield 65%) indicated in the title compound as a yellowish powder. Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) memorial plaques:

of 8.04 (1H, doublet, J = 8 Hz);

to 7.84 (2H, doublet, J = 8 Hz);

a-3.84 (4H, singlet);

of 6.45 (1H, doublet, J = 10 Hz);

6,10 (1H, doublet, J = 10 Hz);

to 3.67 (3H, singlet);

of 3.25 (3H, singlet).

1(iii) 1-(4-Methoxyphenyl)-2-(4-methylsulfinylphenyl)pyrrol

In 15 ml of anhydrous tetrahydrofuran added to 1.00 g (3.2 mmol) - (4-methoxyaniline) -- (4-methylsulfinylphenyl)acetonitrile [obtained as described above in stage (ii)] and to the resulting suspension to the Lil)lithium amide in tetrahydrofuran at a temperature of from -60oC to -65oC with stirring. The mixture was stirred at the same temperature for 1 hour, after which the temperature of the mixture was allowed to return to room temperature and stirred the mixture for another 1.5 hours. At the end of this time the reaction solution was added saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous sodium sulfate. Then removed under reduced pressure, the solvent and the residue was heated at 200oC for 1 hour. Then he was transferred to the chromatographic column with silica gel and was suirable mixture of hexane and methylene chloride (1:9 by volume) to obtain 0.32 g (yield 31%) specified in the procurement connection in the form of a pale yellow powder, melting at 148 - 149oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,74 (2H, doublet, J = 8 Hz);

7,27 (2H, doublet, J = 8 Hz);

7,13 - 7,07 (2H, multiplet);

6,95 - 6,85 (3H, multiplet);

6,58 - to 6.57 (1H, multiplet);

6,39 - 6,36 (1H, multiplet);

of 3.84 (3H, singlet);

totaling 3.04 (3H, singlet).

Example 2

1-(4-Chlorophenyl)-2-(4-methylsulfinylphenyl)pyrrole (Compound 1-35 N)

Following a similar procedure to that described in three stadien, got mentioned in the title compound as a pale yellow powder, melting at 184 - 188oC. the Yield of compound (pale yellow prismatic crystals) in the first stage was 94%, in the second stage (white powder) - 93% at the third stage - 42%.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

for 7.78 (2H, doublet, J = 8 Hz);

7,37 - 7,26 (4H, multiplet);

7,13 - to 7.09 (2H, multiplet);

6,97 (1H, singlet);

6,58 - to 6.57 (1H, multiplet);

6.42 per - to 6.39 (1H, multiplet);

3,05 (3H, singlet).

Example 3

1-(4-Triptoreline)-2-(4-methylsulfinylphenyl)pyrrole (Compound N 1-45)

Following a similar procedure to that described in the three stages of examples 1(i) 1(ii) 1(iii), but using as starting material 4-triptorelin instead of 4-methoxyaniline got mentioned in the title compound as a white powder, melting at 187 - 190oC. the Yield of compound (pale yellow prismatic crystals) in the first stage was 64%, in the second stage (white powder) is 95% and the third stage is 57%.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,80 (2H, doublet, J = 8 Hz);

to 7.64 (2H, doublet, J = 8 Hz);

7,28 (4H, doublet, J = 10 Hz);

7,02 (1H, single is SS="ptx2">

Example 4

1-(4-Trifloromethyl)-2-(4-methylsulfinylphenyl)pyrrole (Compound 1-46 N)

Following a similar procedure to that described in the three stages of examples 1(i) 1(ii) 1(iii), but using as starting material 4-triphtalocyaninine instead of 4-methoxyaniline got mentioned in the title compound as a white powder, melting at 150 - 152oC. the Yield of compound (pale yellow prismatic crystals) in the first stage was 59%, in the second stage (white powder) - 97% and at the third stage - 52%.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

for 7.78 (2H, doublet, J = 8 Hz);

7,29 - to 7.18 (6H, multiplet);

6,98 (1H, singlet);

6,59 return of 6.58 (1H, multiplet);

to 6.43 - 6,41 (1H, multiplet);

3,05 (3H, singlet).

Example 5

1-(3-Chloro-4-forfinal)-2-(4-methylsulfinylphenyl)pyrrole (Compound N 1-39)

Following a similar procedure to that described in the three stage of examples 1(i) 1(ii) 1(iii), but using as starting material 3-chloro-4-foronline instead of 4-methoxyaniline got mentioned in the title compound as a pale yellow powder, melting at 146 - 149oC. the Yield of compound (white powder) in the first stage was 93%, Cl3) memorial plaques:

7,80 (2H, doublet, J = 8 Hz);

7,33 - 6,95 (6H, multiplet);

to 6.57 (1H, doublet, J = 2 Hz);

6,41 - to 6.39 (1H, multiplet);

3,05 (3H, singlet).

Example 6

1-(3,4-Differenl)-2-(4-methylsulphonyl)pyrrole (Compound N 1-51)

Following a similar procedure to that described in the three stages of examples 1(i) 1(ii) 1(iii), but using as starting material 3,4-diferencia instead of 4-methoxyaniline got mentioned in the title compound as a pale yellow powder, melting at 137 - 139oC. the Yield of compound (pale yellow prismatic crystals) in the first stage was 66%, in the second stage (white powder) is 92% and the third stage is 46%.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,80 (2H, doublet, J = 8 Hz);

7,28 (2H, doublet, J = 8 Hz);

7,22 - 6,87 (6H, multiplet);

6,58 - 6,56 (1H, multiplet);

6.42 per - to 6.39 (1H, multiplet);

a 3.06 (3H, singlet).

Example 7

1-(2,4-Differenl)-2-(4-methylsulfinylphenyl)pyrrole (Compound N 1-53)

Following a similar procedure to that described in the three stages of examples 1(i) 1(ii) 1(iii), but using as starting material 2,4-diferencia instead of 4-methoxyaniline got mentioned in the title compounds is Talal 79%, in the second stage (white powder) - 97% and at the third stage - 10%.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

to 7.77 (2H, doublet, J = 8 Hz);

7,30 - 2,19 (3H, multiplet);

6,95 - 6,89 (3H, multiplet);

6,60 - 6,59 (1H, multiplet);

of 6.45 - 6.42 per (1H, multiplet);

totaling 3.04 (3H, singlet).

Example 8

1-(3,4-Dimetilfenil)-2-(4-methylsulfinylphenyl)pyrrole (Compound 1-55 N)

Following a similar procedure to that described in the three stages of examples 1(i) 1(ii) 1(iii), but using as starting material 3,4-dimethylaniline instead of 4-methoxyaniline got mentioned in the title compound as a white powder, melting at 134 - 137oC. connection Output (yellow prismatic crystals) in the first stage was 95%, in the second stage (white powder) - 96% and at the third stage - 23%

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,74 (2H, doublet, J = 8 Hz);

7,29 (2H, doublet, J = 8 Hz);

7,10 - PC 6.82 (4H, multiplet);

6,57 - 6,55 (1H, multiplet);

6,38 - 6,36 (1H, multiplet);

3,03 (3H, singlet);

to 2.29 (3H, singlet);

Example 9

1-(4-Were)-2-(4-methylsulfinylphenyl)pyrrole (Compound N 1-37)

Following a similar procedure to that described in the three stages of note is Lucile specified in the title compound as a pale yellow powder, melting at 112 - 114oC. the Yield of compound (white powder) in the first stage was 97%, in the second stage (white powder) was 98% and the third stage is 19%.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) / memorial plaques:

7,74 (2H, doublet, J = 8 Hz);

7,28 (2H, doublet, J = 9 Hz);

7,16 (2H, doublet, J = 8 Hz);

7,05 (2H, doublet, J = 8 Hz);

6,97 (1H, multiplet);

6,57 - 6,56 (1H, multiplet);

6,39 - 6,37 (1H, multiplet);

3,03 (3H, singlet);

2,39 (3H, singlet);

Example 10

1-(3,4-Dichlorophenyl)-2-(4-methylsulfinylphenyl)pyrrole (Compound N 1-57)

Following a similar procedure to that described in the three stages of examples 1(i) 1(ii) 1(iii), but using as starting material 3,4-dichloraniline instead of 4-methoxyaniline got mentioned in the title compound as a white powder, melting at 139 - 142oC. the Yield of compound (white powder) in the first stage was 91%, in the second stage (white powder) 93% and at the third stage - 41%.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,83 (2H, doublet, J = 8 Hz);

7,43 - 7,26 (4H, multiplet);

of 6.96 - 6,91 (4H, multiplet);

6,58 - to 6.57 (1H, multiplet);

to 6.43 - 6,41 (1H, multiplet);

a 3.06 (3H, singlet).

Example 11

1-(3,4-IU is automatically written in the three stages of examples 1(i), 1(ii) 1(iii), but using as starting material 3,4-methylenedioxyaniline instead of 4-methoxyaniline got mentioned in the title compound as a pale yellow powder, melting at 172 - 175oC. the Yield of compound (pale yellow powder) in the first stage was 95%, in the second stage (grey powder) - 91% and in the third stage of 29%.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

to 7.77 (2H, doublet, J = 9 Hz);

7,31 (2H, doublet, J = 9 Hz);

6,93 (3H, singlet);

is 6.78 (1H, doublet, J = 8 Hz);

of 6.66 (2H, doublet, J = 8 Hz);

6,55 (1H, singlet);

6,37 to 6.35 (1H, multiplet);

6,03 (2H, singlet);

3,05 (3H, singlet);

Example 12

1-(4-Methoxyphenyl)-4-methyl-2-(4-methylsulfinylphenyl)pyrrole (Compound 1-34 N)

Following a similar procedure to that described in example 1(iii), but using methacrolein instead of acrolein got mentioned in the title compound as a pale yellow powder (yield 21%), melting at 154 - 160oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,72 (2H, doublet, J = 8 Hz);

of 7.25 (2H, doublet, J = 8 Hz);

to 7.09 - 7.03 is (2H, multiplet);

6,89 - 6,84 (2H, multiplet);

of 6.73 (1H, singlet);

6,41 (1H, doublet, J = 2 Hz);

a 3.83 (3H, sing the rol (Compound N 2-62)

13(i) N-(4-formanilide)-4-sulfanilamide

Following a similar procedure to that described in example 1(i), but using as starting materials 4-forventelige and 4-sulfamerazine got mentioned in the title compound as a white powder (yield 63%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated acetone) memorial plaques:

8,64 (1H, singlet);

8,12 - 8,03 (2H, multiplet);

to 7.93 (2H, doublet, J = 9 Hz);

7,40 - 7,28 (4H, multiplet);

to 6.57 (2H, singlet).

13(ii) - (4-forfinal) -- (4-sulfamerazine)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material N-(4-formanilide)-4-sulfamerazine [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as a white powder (yield 95%)

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) memorial plaques:

of 7.75 (2H, doublet, J = 9 Hz);

7,66 - of 7.55 (2H, multiplet);

7,20 - 7,10 (2H, multiplet);

for 6.81 (2H, doublet, J = 9 Hz);

of 6.71 (1H, doublet, J = 8 Hz);

6.35mm (2H, singlet);

5,61 (1H, doublet, J = 8 Hz).

13(iii) 2-(4-forfinal)-1-(4-sulfamoylbenzoyl)pyrrol
o
C.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,88 (2H, doublet, J = 9 Hz);

7,26 (2H, doublet, J = 9 Hz);

7,14? 7.04 baby mortality (2H, multiplet);

7,00 - 6,90 (3H, multiplet);

6,95 - 6,87 (2H, multiplet);

to 4.87 (2H, singlet).

Mass spectrum (EI) m/z 316 [M+].

Example 14

2-(4-forfinal)-3-methyl-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-64)

Following a similar procedure to that described in example 13(iii), but using crotonic aldehyde instead of acrolein got mentioned in the title compound as a white powder (yield 19%), melting at 187 - 188oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,81 (2H, doublet, J = 9 Hz);

to 7.15 (2H, doublet, J = 9 Hz);

7,10 - to 6.95 (2H, multiplet);

make 6.90 (2H, doublet, J = 3 Hz);

of 6.29 (2H, doublet, J = 3 Hz);

4,78 (2H, singlet);

and 2.14 (3H, singlet).

Mass spectrum (EI) m/z: 330 [M+].

Example 15

2-(4-Forfinal)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-63)

Sleep got mentioned in the title compound as a pale yellow powder (yield 24%), melting at 168 - 170oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

the 7.85 (2H, doublet, J = 9 Hz);

7,21 (2H, doublet, J = 9 Hz);

7,12 - 7,03 (2H, multiplet);

7,00 - 6,89 (2H, multiplet);

6,74 (1H, singlet);

6,27 (1H, singlet);

4,82 (2H, singlet);

to 2.18 (3H, singlet).

Mass spectrum (EI) m/z: 330 [M+].

Example 16

2-(4-Were)-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-87)

16(i) N-(4-Methylbenzylidene)-4-sulfanilamide

Following a similar procedure to that described in example 1(i), but using as starting materials 4-methylbenzaldehyde and 4-sulfamerazine has been specified in the procurement compound as a white powder (yield 91%). Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) memorial plaques:

at 8.60 (1H, singlet);

of 7.90 - 7,81 (4H, multiplet);

7,42 - to 7.32 (4H, multiplet);

is 2.40 (3H, singlet).

16(ii) - (4-Were) -- (4-sulfamoyl)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material N-(4-methylbenzylidene)-4-sulfamerazine the treatment in the form of a white powder (yield 94%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) memorial plaques:

of 7.70 (2H, doublet, J = 9 Hz);

of 7.48 (2H, doublet, J = 9 Hz);

7,26 (2H, doublet, J = 9 Hz);

of 6.68 (1H, doublet, J = 8 Hz);

at 6.84 (2H, doublet, J = 9 Hz);

6,72 (2H, singlet);

5,67 (1H, doublet, J = 8 Hz);

of 2.38 (3H, singlet).

16(iii) 2-(4-Were)-1-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - (4-were) -- (4-sulfamerazine)acetonitrile [obtained as described above in stage (ii)] and acrolein has been specified in the procurement compound as a brown powder (yield 13%), melting at 183 - 184oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3, memorial plaques:

7,87 (2H, doublet, J = 9 Hz);

7,28 (2H, doublet, J = 9 Hz);

7,09 - 6,98 (4H, multiplet);

of 6.96 - 6,93 (1H, multiplet);

6,44 - 6,38 (2H, multiplet);

to 4.81 (2H, singlet);

of 2.33 (3H, singlet).

Mass spectrum (EI) m/z: 313(M+H)+].

Example 17

3-Methyl-2-(4-were)-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-88)

Following a similar procedure to that described in example 16(iii), but using crotonic aldehyde instead acrolect NMR (270 MHz, CDCl3, memorial plaques:

7,79 (2H, doublet, J = 9 Hz);

7,16 (2H, doublet, J = 9 Hz);

to 7.09 (2H, doublet, J = 9 Hz);

6,97 (2H, doublet, J = 9 Hz);

6,89 (1H, doublet, J = 3 Hz);

6,28 (1H, doublet, J = 3 Hz);

a 4.83 (2H, singlet);

of 2.34 (3H, singlet);

of 2.15 (3H, singlet).

Mass spectrum (EI) m/z: 326 [M+].

Example 18

4-Methyl-2-(4-were)-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-89)

Following a similar procedure to that described in example 16(iii), but using as starting material methacrolein instead of acrolein got mentioned in the title compound as a pale brown powder (yield 5%), melting at 175 - 176oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

to 7.84 (2H, doublet, J = 9 Hz);

of 7.23 (2H, doublet, J = 9 Hz);

7,08 - 6,97 (4H, multiplet);

of 6.73 (1H, doublet, J = 2 Hz);

6,27 (1H, doublet, J = 2 Hz);

rate 4.79 (2H, singlet);

2,32 (2H, singlet);

to 2.18 (2H, singlet).

Example 19

1-(4-Forfinal)-2-(4-sulfamoylbenzoyl)pyrrole (Compound N 1-73)

19(i) 4-Fluoro-N-(4-sulfamoylbenzoyl)aniline

Following a similar procedure to that described in example 1(i), but using as starting materials 4-sulfamoylbenzoic and 4-foranyone, the floor of the cluster magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) memorial plaques:

a total of 8.74 (1H, singlet);

8,11 (2H, doublet, J = 8 Hz);

of 7.96 (2H, doublet, J = 8 Hz);

to 7.50 (2H, singlet);

7,43 - of 7.25 (4H, multiplet).

19(ii) - (4-Foronline) -- (4-sulfamoylbenzoyl)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting materials 4-fluoro-N-(4-sulfamoylbenzoyl)aniline [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as a slightly yellow powder (yield 83%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) memorial plaques:

to 7.93 (2H, doublet, J = 8 Hz);

7,76 (2H, doublet, J = 8 Hz);

was 7.45 (2H, singlet);

7,05 (2H, triplet, J = 9 Hz);

6.73 x - 6,85 (3H, multiplet);

6,12 (1H, doublet, J = 10 Hz).

Mass spectrum (EI) m/z: 279 [M+].

19(iii) 1-(4-forfinal)-2-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - (4-foronline) -- (4-sulfamoylbenzoyl)acetonitrile [obtained as described above in stage (ii)] and acrolein got mentioned in the title compound as a white porosa (yield 48%dimethyl sulfoxide) memorial plaques:

to 7.67 (2H, doublet. J = 8 Hz);

7,32 - 7,22 (8H, multiplet);

7,14 (1H, triplet, J = 2 Hz);

6,59 (1H, doublet of doublets, J = 4 and 2 Hz);

6,36 (1H, triplet, J = 3 Hz).

Mass spectrum (EI) m/z: 316 [M+]

Example 20

1-(4-forfinal)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrole (Compound 1-74 N)

Following a similar procedure to that described in example 19(ii), but using methacrolein instead of acrolein got mentioned in the title compound as a white powder (yield 62%), melting at 126 - 127oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,87 (2H, doublet, J = 9 Hz);

7,39 - 7,17 (6H, multiplet);

6,87 (1H, singlet);

6,53 (1H, singlet);

is 4.93 (2H, singlet);

2,31 (3H, singlet).

Mass spectrum (EI) m/z: 330 [M+]

Example 21

2-(4-Forfinal)-3-methyl-1-(4-methylsulfinylphenyl)pyrrole (Compound N 2-8)

21(i) N-(4-formanilide)-4-methylthioinosine

Following a similar procedure to that described in example 1(i), but using as starting materials 4-forventelige and 4-methylthioinosine got mentioned in the title compound as pale yellow needle-like crystals (yield 87%).

Spectrum of nuclear magnetic resonance (270 MHz, CDClEt);

2,52 (3H, singlet).

21(ii) - (4-Forfinal) -- (4-methylthioinosine)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material N-(4-formanilide)-4-methylthioinosine [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as a pale yellow powder (yield 96%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3memorial plaques:

7,63 - rate of 7.54 (2H, multiplet);

7,27 (2H, doublet, J = 9 Hz);

7,21 for 7.12 (2H, multiplet);

of 6.73 (2H, doublet, J = 9 Hz);

of 5.40 (1H, doublet, J = 9 Hz);

4,01 (1H, doublet, J = 9 Hz);

of 2.45 (3H, singlet).

21(iii) 2-(4-Forfinal)-3-methyl-1-(4-methylsulfinylphenyl)pyrrol

A solution of 2.00 g (7.3 mmol) - (4-forfinal) -- (4-methylthioinosine)acetonitrile [obtained as described above in stage (ii)] in 15 ml of tetrahydrofuran was cooled to -78oC under a stream of nitrogen and the resulting solution was added to 0.67 ml (8.1 mmol) crotonic aldehyde. To the mixture was added dropwise 8,10 ml (8.1 mmol) of 1.0 M solution of bis(trimethylsilyl) amide lithium and the resulting mixture was stirred at -78oC, after which the mixture was stirred overnight, allowing the temperature of the mixture naturally povyshayutsya the mixture was washed with a saturated aqueous solution of ammonium chloride, water and saturated aqueous sodium chloride, in that order. The organic layer was separated and dried over anhydrous magnesium sulfate, and then solvent was removed by distillation under reduced pressure. The obtained residue was dissolved in 20 ml of dichloroethane and the resulting solution was added in several portions under ice cooling 3,98 g (16.2 mmol) of 70% m-chloroperbenzoic acid. Then the mixture was stirred with ice cooling for 30 minutes. At the end of this time the reaction mixture was diluted with methylene chloride and then washed with 10% (weight/volume) aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium bicarbonate (twice each) in that order. After that, the organic layer was separated and dried over anhydrous magnesium sulfate. Then solvent was removed by distillation under reduced pressure. The residue was heated at 150oC for 2 hours, after which it was transferred to the chromatographic column with silica gel and was suirable, using as eluent a mixture of hexane and ethyl acetate (2: 1 by volume), the result obtained 0.36 g (yield 15%) specified in the title compound as a white powder, melting at 157 - 158oC.

Range of the poison is 10 - to 6.95 (4H, multiplet);

6,91 (1H, doublet, J = 3 Hz);

6,30 (1H, doublet, J = 3 Hz);

a 3.06 (3H, singlet);

and 2.14 (3H, singlet).

Mass spectrum (EI) m/z: 329 [M+].

Example 22

2-(4-Forfinal)-1-(4-methylsulfinylphenyl)pyrrole (Compound N 2-3)

Following a similar procedure to that described in example 21(iii), but using acrolein instead of crotonic aldehyde, has been specified in the title compound as a white powder (yield 7%), melting at 195 - 196oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

of 7.90 (2H, doublet, J = 9 Hz);

7,31 (2H, doublet, J = 9 Hz);

7,13 - 7,05 (2H, multiplet);

7,01 - 6,92 (3H, multiplet);

6,46 - 6,40 (2H, multiplet);

is 3.08 (3H, singlet).

Mass spectrum (EI) m/z: 315 [M+].

Example 23

2-(4-Forfinal)-4-methyl-1-(4-methylsulfinylphenyl)pyrrole (Compound N 2-11)

Following a similar procedure to that described in example 21(iii), but using methacrolein instead of crotonic aldehyde, has been specified in the title compound as a white powder (yield 36%), melting at 151 - 154oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,87 (2H, doublet, J = 9 Hz);

7,26 (2H, doublet, J = 9 G);

is 3.08 (3H, singlet);

to 2.18 (3H, singlet).

Mass spectrum (EI) m/z: 329 [M+].

Example 24

3-Ethyl-2-(4-forfinal)-1-(4-methylsulfinylphenyl)pyrrole (Compound N 2-9)

Following a similar procedure to that described in example 21(iii), but using 2-pentenal instead of crotonic aldehyde, has been specified in the title compound as a white powder (yield 15%), melting at 107 - 108oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

of 7.82 (2H, doublet, J = 9 Hz);

7,21 - 6,93 (7H, multiplet);

6,36 (1H, doublet, J = 3 Hz);

3,05 (3H, singlet);

of 2.50 (2H, Quartet, J = 8 Hz);

to 1.19 (3H, triplet, J = 8 Hz);

Mass spectrum (EI) m/z: 343 [M+].

Example 25

2-(4-Forfinal)-1-(4-methylsulfinylphenyl)-3-profileerror (Compound N 2-10)

Following a similar procedure to that described in example 21(iii), but using 2-hexenal instead of crotonic aldehyde, has been specified in the title compound as white prismatic crystals (yield 20%), melting at 116 - 117oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

of 7.82 (2H, doublet, J = 9 Hz);

7,19 (2H, doublet, J = 9 Hz);

7,06 - 6,92 (5H, multiplet);

6,33 (1H, doublet, J = 3 Hz);Mass spectrum (EI) m/z: 357 [M+].

Example 26

2-(4-Chlorophenyl)-1-(4-methylsulfinylphenyl)pyrrole (Compound N 2-23)

26(i) N-(4-Chlorobenzylidene)-4-methylthioinosine

Following a similar procedure to that described in example 1(i), but using as starting materials 4-chlorobenzaldehyde and 4-methylthioinosine got mentioned in the title compound as pale yellow needle-like crystals (yield 94%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

8,43 (1H, singlet);

7,83 (2H, doublet, J = 9 Hz);

was 7.45 (2H, doublet, J = 9 Hz);

7,30 (2H, doublet, J = 9 Hz);

to 7.18 (2H, doublet, J = 9 Hz);

of 2.51 (3H, singlet).

26(ii) - (4-Chlorophenyl) -- (4-methylthioinosine)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material N-(4-chlorobenzylidene)-4-methylthioinosine [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as a pale yellow powder (yield 84%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

at 7.55 (2H, doublet, J = 9 Hz);

7,44 (2H, doublet, J = 9 Hz);

7,27 (2H, doublet, J = 9 Hz);

6,72 (2H, doublet, J = 9 Hz);

of 5.40 (1H, doublet, J = 9 Hz);

as 4.02 (1H, is the procedure similar to that described in example 21(iii), but using as starting materials - (4-chlorphenyl) -- (4-methylthioinosine)acetonitrile [obtained as described above in stage (ii)] and acrolein got mentioned in the title compound in the form of a powder orange (yield 32%), melting at 203 - 205oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

to $ 7.91 (2H, doublet, J = 9 Hz);

to 7.32 (2H, doublet, J = 9 Hz);

of 7.23 (2H, doublet, J = 9 Hz);

7,05 (2H, doublet, J = 9 Hz);

7,00 - 6,97 (1H, multiplet);

6,48 - of 6.45 (1H, multiplet);

6,44 - 6,40 (1H, multiplet);

to 3.09 (3H, singlet).

Mass spectrum (EI) m/z: 331 [M+].

Example 27

2-(4-Chlorophenyl)-3-methyl-1-(4-methylsulfinylphenyl)pyrrole (Compound N 2-24)

Following a similar procedure to that described in example 26(iii), but using crotonic aldehyde instead of acrolein got mentioned in the title compound as a pale yellow powder (yield 21%), melting at 173 - 174oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

to 7.84 (2H, doublet, J = 9 Hz);

7,27 (2H, doublet, J = 9 Hz);

7,21 (2H, doublet, J = 9 Hz);

7,01 (2H, doublet, J = 9 Hz);

6,92 (2H, doublet, J = 3 Hz);

6,30 (1H, doublet,28

2-(4-Methoxyphenyl)-1-(4-methylsulfinylphenyl)pyrrole (Compound N 2-20)

(28(i) N-(4-Methoxybenzylidene)-4-methylthioinosine

Following a similar procedure to that described in example 1(i), but using as starting materials 4-methoxybenzaldehyde and 4-methylthionine got mentioned in the title compound as yellow powder (yield 100%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

8,39 (1H, singlet);

to 7.84 (2H, doublet, J = 9 Hz);

7,29 (2H, doublet, J = 9 Hz);

7,16 (2H, doublet, J = 9 Hz);

6,98 (2H, doublet, J = 9 Hz);

3,88 (3H, singlet);

of 2.51 (3H, singlet).

28(ii) - (4-Methoxyphenyl) -- (4-methylthioinosine)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material N-(4-methoxybenzylidene)-4-methylthioinosine [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as a pale brown powder (yield 92%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,47 (2H, doublet, J = 9 Hz);

7,27 (2H, doublet, J = 9 Hz);

6,97 (2H, doublet, J = 9 Hz);

of 6.73 (2H, doublet, J = 9 Hz);

of 5.34 (1H, doublet, J = 9 Hz);

of 3.97 (1H, doubleanal)pyrrol

Following a similar procedure to that described in example 21(iii), but using as starting materials - (4-methoxyphenyl) -- (4-methylthioinosine)acetonitrile [obtained as described above in stage (ii)] and acrolein got mentioned in the title compound as a white powder (yield 9%), melting at 183 - 184oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,88 (2H, doublet, J = 9 Hz);

to 7.32 (2H, doublet, J = 9 Hz);

7,05 (2H, doublet, J = 9 Hz);

7,98 - to 7.93 (1H, multiplet);

to 6.80 (2H, doublet, J = 9 Hz);

to 6.43 - 6,37 (1H, multiplet);

of 3.80 (3H, singlet);

is 3.08 (3H, singlet).

Mass spectrum (EI) m/z: 327 [M+].

Example 29

2-(4-Were)-1-(4-methylsulfinylphenyl)pyrrole (Compound N 2-25)

28(i) N-(4-Methylbenzylidene)-4-methylthioinosine

Following a similar procedure to that described in example 1(i), but using as starting materials 4-methylbenzaldehyde and 4-methylthioinosine got mentioned in the title compound as yellow powder (yield 96%).

Mass spectrum (EI) m/z: 241 [M+].

29(ii) - (4-Were) --/ (4 methylthioinosine)acetonitrile

Following a similar procedure to that described in example 1(ii), but with isana higher in stage (i)] and trimethylsilylacetamide, got mentioned in the title compound as a pale yellow powder (yield 73%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,47 (2H, doublet, J = 9 Hz);

7,27 (2H, doublet, J = 9 Hz);

of 6.73 (2H, doublet, J = 9 Hz);

are 5.36 (1H, doublet, J = 8 Hz);

to 3.99 (1H, doublet, J = 8 Hz).

of 2.44 (3H, singlet);

is 2.40 (3H, singlet).

29(iii) 2-(4-Were)-1-(4-methylsulfinylphenyl)pyrrol

Following a similar procedure to that described in example 21(iii), but using as starting materials - (4-were) -- (4-methylthioinosine)acetonitrile [obtained as described above in stage (ii)] and acrolein got mentioned in the title compound as a yellow powder (yield 16%), melting at 186 - 187oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,88 (2H, doublet, J = 9 Hz);

to 7.32 (2H, doublet, J = 9 Hz);

7,10 - 6,94 (5H, multiplet);

6,45 - to 6.39 (2H, multiplet);

is 3.08 (3H, singlet);

of 2.33 (3H, singlet).

Mass spectrum (EI) m/z: 311 [M+].

Example 30

2-(4-Methoxyphenyl)-3-methyl-1-(4-methylsulfinylphenyl)pyrrole (Compound N 2-21)

30(i) - (4-Methoxyphenyl) -- (4-methylsulfonylamino)acetonitrile

In 160 ml of dichloroethane was dissolved 6,41 g (20,3 obtained solution was added in several portions under ice cooling 12,23 g (49,8 mmol) of 70% m-chloroperbenzoic acid. Then the mixture was stirred for 30 minutes, after which it was diluted with methylene chloride and washed once with 10% (weight/volume) aqueous sodium thiosulfate solution and once with saturated aqueous sodium hydrogen carbonate solution in this order, and then repeated it to wash in the specified order. The organic layer was separated and dried over anhydrous magnesium sulfate and then solvent was removed by distillation under reduced pressure. The obtained residue was transferred to a chromatographic column with silica gel and was suirable a mixture of ethyl acetate and hexane (1:2 by volume) to obtain the 3.65 g specified in the title compounds as a pale yellow powder (yield 51%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,83 (2H, doublet, J = 9 Hz);

to 7.50 (2H, doublet, J = 9 Hz);

of 6.99 (2H, doublet, J = 9 Hz);

6,83 (2H, doublet, J = 9 Hz);

5,43 (1H, doublet, J = 8 Hz);

4,56 (1H, doublet, J = 8 Hz);

of 3.85 (3H, singlet);

3,03 (3H, singlet).

30(ii) 2-(4-Methoxyphenyl)-1-methyl-1-(4-methylsulfinylphenyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - (4-methoxyphenyl) -- (4-methylsulfonylamino)acetonitrile [obtained as described to enter the ETA (yield 40%), melting at 131 - 132oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,81 (2H, doublet, J = 9 Hz);

7,21 (2H, doublet, J = 9 Hz);

7,01 (2H, doublet, J = 9 Hz);

6,89 (1H, doublet, J = 3 Hz);

at 6.84 (1H, doublet, J = 3 Hz);

of 6.29 (1H, doublet, J = 3 Hz);

3,81 (3H, singlet);

3,05 (3H, singlet);

and 2.14 (3H, singlet).

Mass spectrum (EI) m/z: 341 [M+].

Example 31

3-Methyl-2-(4-were)-1-(4-methylsulfinylphenyl)pyrrole (Compound N 2-26)

31(i) - (4-Were) -- (4-methylsulfonylamino)acetonitrile

Following a similar procedure to that described in example 30(i), but using as starting materials - (4-were) -- (4-methylthioinosine)acetonitrile [obtained as described in example 29(ii)] and m-chloroperbenzoic acid, has been specified in the title compound as a white powder (yield 93%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,83 (2H, doublet, J = 9 Hz);

7,47 (2H, doublet, J = 9 Hz);

7,30 (2H, doublet, J = 9 Hz);

at 6.84 (2H, doublet, J = 9 Hz);

the 5.45 (1H, doublet, J = 8 Hz);

4,55 (1H, doublet, J = 8 Hz);

3,03 (3H, singlet);

to 2.41 (3H, singlet).

31(ii) 3-Methyl-2-(4-were)-1-(4-methylsulfinylphenyl)pyrrol

Following proced the Nile) -- (4-methylsulfonylamino)acetonitrile [received so as described above in stage (i)] and crotonic aldehyde, has been specified in the title compound as a pale brown powder (yield 46%), melting at 158 - 160oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,81 (2H, doublet, J = 9 Hz);

7,21 (2H, doublet, J = 9 Hz);

7,10 (2H, doublet, J = 9 Hz);

6,97 (2H, doublet, J = 9 Hz);

make 6.90 (1H, doublet, J = 3 Hz);

of 6.29 (1H, doublet, J = 3 Hz);

3,05 (3H, singlet);

of 2.35 (3H, singlet);

of 2.15 (3H, singlet).

Mass spectrum (FAB) m/z: 326(M+H)+].

"FAB" means "Fast Atom Bombardment" (fast atom bombardment).

Example 32

2-(4-Deformational)-3-methyl-1-(4-methylsulfinylphenyl)pyrrole (Compound N 2-37)

32(i) - (4-Deformational) -- (4-methylthioinosine)acetonitrile

Following a similar procedure to that described in example 1(i) but using as starting materials 4-deformationally and 4-methylthioinosine received N-(4-deportationselites)-4-methylthioinosine with the release of 91%. Then interacted with each other the specified aniline derivative and trimethylsilylacetamide, in the same way as described in example 1(II), and the result has been specified in the header of the connection with the to 7.61 (2H, doublet, J = 9 Hz);

7,27 (2H, doublet, J = 9 Hz);

7,22 (2H, doublet, J = 9 Hz);

of 6.73 (2H, doublet, J = 9 Hz);

6,56 (1H, pats, J = 73 Hz);

5,41 (1H, doublet, J = 9 Hz);

4,01 (1H, doublet, J = 9 Hz);

of 2.45 (3H, singlet).

32(ii) - (4-Deformational) -- (4-methylsulfonylamino)acetonitrile

Following a similar procedure to that described in example 30(i), but using as starting materials - (4-deformational) -- (4-methylthioinosine)acetonitrile [obtained as described above in stage (i)] and m-chloroperbenzoic got mentioned in the title compound as a pale yellow powder (yield 89%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

to 7.84 (2H, doublet, J = 9 Hz);

to 7.61 (2H, doublet, J = 9 Hz);

of 7.25 (2H, doublet, J = 9 Hz);

at 6.84 (2H, doublet, J = 9 Hz);

to 6.57 (1H, triplet, J = 9 Hz);

the 5.51 (1H, doublet, J = 8 Hz);

4,60 (1H, doublet, J = 8 Hz);

3,03 (3H, singlet).

32(iii) 2-(4-Deformational)-3-methyl-1-(4-methylsulfinylphenyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - (4-deformational) -- (4-methylsulfonylamino)acetonitrile [obtained as described above in stage (ii)] and Croton is - 99oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,83 (2H, doublet, J = 9 Hz);

7,21 (2H, doublet, J = 9 Hz);

7,12 - 7,02 (4H, multiplet);

6,91 (1H, doublet, J = 3 Hz);

is 6.54 (1H, triplet, J = 74 Hz);

6,30 (1H, doublet, J = 3 Hz);

a 3.06 (3H, singlet);

of 2.15 (3H, singlet).

Mass spectrum (EI) m/z: 377 [M+].

Example 33

1-(4-Forfinal)-2-(4-methylsulfinylphenyl)pyrrole (Compound N 1-3)

33(i) - (4-Foronline) -- (4-methylthiophenyl)acetonitrile

Following a similar procedure to that described in example 1(i), but using as starting materials 4-methylthiazolidine and 4-foranyone, received 4-fluoro-N-(4-methylthiazolidine)aniline with a yield of 89%. Then interacted with each other the specified aniline derivative and trimethylsilylacetamide, in the same way as described in example 1(ii), and the result was indicated in the title compound as a slightly yellow powder (yield 47%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

to 7.50 (2H, doublet, J = 9 Hz);

7,31 (2H, doublet, J = 9 Hz);

6,98 (2H, triplet, J = 9 Hz);

of 6.73 (2H, doublet of doublets, J = 9 and 4 Hz);

5,33 (1H, doublet, J = 9 Hz);

to 3.92 (1H, doublet, J = 9 Hz);

of 2.51 (3H, singlet).

emer 21(iii), but using as starting materials - (4-foronline) -- (4-methylthiophenyl)acetonitrile [obtained as described above in stage (i)] and acrolein got mentioned in the title compound as a yellow powder (yield 7%), melting at 145 - 147oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

to 7.77 (2H, doublet, J = 9 Hz);

7,27 (2H, doublet, J = 9 Hz);

7,18? 7.04 baby mortality (4H, multiplet);

of 6.96 (1H, doublet of doublets, J = 3 and 2 Hz);

to 6.58 (1H, doublet of doublets, J = 4 and 2 Hz);

6,40 (1H, doublet of doublets, J = 4 and 3 Hz);

totaling 3.04 (3H, singlet).

Mass spectrum (EI) m/z: 315 [M+].

Example 34

1-(4-Forfinal)-4-methyl-2-(4-methylsulfinylphenyl)pyrrole (Compound 1-15 N)

Following a similar procedure to that described in example 33(ii), but using methacrolein instead of acrolein got mentioned in the title compound as a white powder (yield 4%), melting at 127 - 130oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

of 7.75 (2H, doublet, J = 9 Hz);

from 7.24 (2H, doublet, J = 9 Hz);

7,15 - 7,03 (4H, multiplet);

6,74 (1H, doublet, J = 2 Hz);

6.42 per (1H, doublet, J = 2 Hz);

totaling 3.04 (3H, singlet);

to 2.18 (3H, singlet).

Mass spectrum (EI) m/z: 329 [M+}.aqueous tetrahydrofuran was dissolved 0.32 g (1.0 mmol) 1-(4-forfinal)-2-(4-methylsulfinylphenyl)pyrrole (obtained, as described in example 33) and to the resulting solution were added under ice cooling 0.18 g (1.0 mmol) of N-bromosuccinimide. Then the mixture was stirred under ice cooling for 1 hour. At the end of this time, to the mixture was added water and the resulting mixture was extracted with methylene chloride. The organic extract was dried over anhydrous magnesium sulfate and then solvent was removed by distillation under reduced pressure. The obtained residue was transferred to a chromatographic column with silica gel and was suirable a mixture of ethyl acetate and hexane (1: 3 by volume), resulting in 0.28 g specified in the title compound as a white powder (yield 70%), melting at 174 - 176oC).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,73 (2H, doublet, J = 9 Hz);

7.23 percent - to 7.09 (6H, multiplet);

to 6.57 (1H, doublet, J = 4 Hz);

6,44 (1H, doublet, J = 4 Hz);

to 3.02 (3H, singlet).

Mass spectrum (EI) m/z: 393 [M+].

Example 36

5-Bromo-1-(4-forfinal)-4-methyl-2-(4-methylsulfinylphenyl)pyrrole (Compound 1-18 N)

Following a similar procedure to that described in example 35, but using as starting material 1-(4-forfinal)-4-methyl-2-(4-methylsulfinylphenyl)pyrrole (obtained (30% yield), melting at 158 - 159oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCK3) memorial plaques:

7,71 (2H, doublet, J = 9 Hz);

7,19 - 7,11 (6H, multiplet);

of 6.49 (1H, singlet);

to 3.02 (3H, singlet);

of 2.15 (2H, singlet).

Mass spectrum (EI) m/z: 407 [M+].

Example 37

5-Chloro-1-(4-forfinal)-4-methyl-2-(4-methylsulfinylphenyl)pyrrole (compound 1-17 N)

Following a similar procedure to that described in example 35, but using N-chlorosuccinimide instead of N-bromosuccinimide got mentioned in the title compound as a white powder (yield 58%), melting at 151 - 154oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,71 (2H, doublet, J = 9 Hz);

7,20 - 7,05 (6H, multiplet);

6,44 (1H, singlet);

to 3.02 (3H, singlet).

Mass spectrum (EI) m/z: 363 [M+].

Example 38

5-Chloro-1-(4-forfinal)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrole (Compound 1-75 N)

1-(4-forfinal)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrole (obtained as described in example 20) was chlorinated as described in example 37, with the receipt specified in the title compounds as white prismatic crystals (yield 67%), melting at 119 - 120oC.

Range nuclear magnet is multiplet);

6,55 (1H, singlet);

of 2.10 (3H, singlet).

Mass spectrum (EI) m/z: 364 [M+].

Example 39

5-Chloro-1-(4-forfinal)-2-(4-methylsulfinylphenyl)pyrrol (Compound 1-75 N)

1-(4-forfinal)-2-(4-methylsulfinylphenyl)pyrrole (obtained as described in example 33) was chlorinated as described in example 37, with the receipt specified in the title compound as a white powder (yield 86%), melting at 180 - 182oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,73 (2H, doublet, J = 9 Hz);

7.23 percent - to 7.09 (6H, multiplet);

is 6.54 (1H, doublet, J = 4 Hz);

6,32 (1H, doublet, J = 4 Hz);

to 3.02 (3H, singlet).

Mass spectrum (EI) m/z: 349 [M+].

Example 40

1-(4-Forfinal)-5-iodine-2-(4-methylsulfinylphenyl)pyrrole (Compound 1-7 N)

Following a similar procedure to that described in example 35, but using N-iodosuccinimide instead of N-bromosuccinimide got mentioned in the title compound as a yellow powder (yield 51%), melting at 174 - 176oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,73 (2H, doublet, J = 9 Hz);

7,22 for 7.12 (6H, multiplet);

6,63 (1H, doublet, J = 4 Hz)

6,59 (1H, doublet, J = 4 Hz)

to 3.02 (3H, singlet).

Massena N 1-4)

In 10 ml of acetonitrile in a reactor made of polyethylene was dissolved 0,90 g (2.7 mmol) of 1-(4-forfinal)-2-(4-methylsulfinylphenyl)pyrrole (obtained as described in example 33) and to the resulting solution were added at 0oC with stirring and 0.46 g (2.7 mmol) of diferida xenon. Then the temperature of the reaction mixture was allowed to return to room temperature and stirred the mixture at room temperature for 20 hours. At the end of this time, to the mixture was added 20 ml of a saturated aqueous solution of sodium carbonate and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium carbonate and then with water, after which it was dried over anhydrous magnesium sulfate. Then solvent was removed by distillation under reduced pressure. The obtained residue was transferred to a chromatographic column with silica gel and was suirable with a mixture of hexane and ethyl acetate (3:1 by volume), resulting in 0.32g specified in the title compounds as white prismatic crystals (yield 34%), melting at 140 - 141oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,74 (2H, doublet, J = 9 Hz);

7,26 - to 7.15 (6H, multiplet);

6,41 (1H, doublet of doublets, J = 6 and 4 Hz);

5,76 Fluoro-1-(4-forfinal)-4-methyl-2-(4-methylsulfinylphenyl)pyrrole (Compound 1-16 N)

Following a similar procedure to that described in example 41, but using 1-(4-forfinal)-4-methyl-2-(4-methylsulfinylphenyl)pyrrole (obtained as described in example 34), have been specified in the title compound as a white powder (yield 10%), melting at 109 - 110oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,71 (2H, doublet, J = 9 Hz);

7,19 - 7,10 (6H, multiplet);

6,30 (1H, doublet, J = 6 Hz);

to 3.02 (3H, singlet);

of 2.08 (3H, singlet).

Mass spectrum (EI) m/z: 347 [M+].

Example 43

1-(4-Forfinal)-5-methyl-2-(4-methylsulfinylphenyl)pyrrole (Compound N 1-8)

43(i) Methyl 2-(4-methylthiophenyl)acetoacetate

In 40 ml of 2-methyl-2-propanol was dissolved 2.28 g (19,7 mmol) methylacetoacetate and to the resulting solution were added under nitrogen of 2.21 g (19,7 mmol) of tert-butoxide potassium. Then the mixture was stirred at room temperature for 1 hour, then added to it dropwise a solution 4,82 g (19,7 mmol) of 4-methylthiophenethylamine in 30 ml of benzene. The resulting mixture was stirred at 60oC for 3 hours and then cooled. Then it was poured into ice water and was extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of the nom pressure. The obtained residue was transferred to a chromatographic column with silica gel and was suirable a mixture of ethyl acetate and hexane (1:4 by volume) to obtain 4.42 g (yield 80%) indicated in the title compound as slightly yellow powder.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,89 (2H, doublet, J = 9 Hz);

7,27 (2H, doublet, J = 9 Hz);

to 4.23 (1H, doublet of doublets, J = 8 and 6 Hz);

of 3.78 (3H, singlet);

of 3.69 (1H, doublet of doublets, J = 18 and 8 Hz);

of 3.48 (1H, doublet of doublets, J = 18 and 6 Hz);

of 2.53 (3H, singlet);

of 2.44 (3H, singlet).

43(ii) Methyl 2-(4-methylsulfinylphenyl)acetoacetate

In 150 ml of methylene chloride was dissolved 4.42 g (15.8 mmol) of methyl 2-(4-methylthiophenyl)acetoacetate [obtained as described above in stage (i)] and to the resulting solution was added with ice cooling to 7.77 g (to 31.5 mmol) of 70% m-chlorbenzoyl acid. Then the mixture was stirred at room temperature for 1 hour. Was added to a mixture of 30 ml of 10% (weight/volume) aqueous solution of sodium thiosulfate and after intensive stirring was divided into a liquid phase. The organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride in that order, p is the situation. The residue was transferred to a chromatographic column with silica gel and was suirable a mixture of ethyl acetate and hexane (1:1 by volume) to obtain the 3.65 g (yield 74%) indicated in the title compound as slightly yellow powder.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

is 8.16 (2H, doublet, J = 9 Hz);

8,07 (2H, doublet, J = 9 Hz);

4.26 deaths (1H, doublet of doublets, J = 8 and 6 Hz);

of 3.80 (3H, singlet);

of 3.75 (1H, doublet of doublets, J = 19 and 8 Hz);

to 3.52 (1H, doublet of doublets, J = 19 and 6 Hz);

to 3.09 (3H, singlet);

the 2.46 (3H, singlet).

43(iii) 1-(4-Forfinal)-4-methoxycarbonyl-5-methyl-2-(4 - methylsulfinylphenyl)pyrrol

In 100 ml of acetic acid was dissolved 3.00 g (9.6 mmol) of methyl 2-(4-methylsulfinylphenyl)acetoacetate [obtained as described above in stage (ii)] and to the resulting solution was added 0.97 g (8,7 mmol) 4-foranyone. The resulting mixture was heated under reflux for 5 hours. At the end of this time the solvent was removed by distillation under reduced pressure, was added to the residue saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. UD silica gel and was suirable a mixture of ethyl acetate and hexane (1:2 by volume) to obtain 3,10 g specified in the title compound as a powder (yield 92%), melting at 154 - 155oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,73 (2H, doublet, J = 9 Hz);

7,21 for 7.12 (6H, multiplet);

6,94 (1H, singlet);

a 3.87 (3H, singlet);

to 3.02 (3H, singlet);

to 2.41 (3H, singlet).

Mass spectrum (EI) m/z: 387 [M+].

43(iv) 1-(4-Forfinal)-5-methyl-2-(4-methylsulfinylphenyl)pyrrol

In 20 ml of ethanol is added to 1.00 g (2.6 mmol) of 1-(4-forfinal)-4-methoxycarbonyl-5-methyl-2-(4 - methylsulfinylphenyl)pyrrole [obtained as described above in stage (iii)] and the resulting suspension was added 2.5 ml of 20% (weight/volume) aqueous solution of potassium hydroxide. Then the mixture was heated under reflux for 15 hours. At the end of this time the mixture was cooled and added to her diethyl ether. Then the mixture which was separated liquid phase. To the aqueous layer was added for acidification 3 N. aqueous solution chloroethanol acid and then was extracted with him ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure, resulting in 0,92 g of carboxylic acid, which is the hydrolysis product is and if 200oC for 30 minutes. At the end of this time the reaction mixture was poured into ice water and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was transferred to a chromatographic column with silica gel was suirable a mixture of ethyl acetate and hexane (1:4 by volume) to obtain 0.55 g (yield 65%) indicated in the title compound as a white powder, melting at 110 - 112oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

to 7.68 (2H, doublet, J = 9 Hz);

7,20 - was 7.08 (6H, multiplet);

6,51 (1H, doublet, J = 4 Hz);

6,13 (1H, doublet, J = 4 Hz);

a 3.01 (3H, singlet);

to 2.13 (3H, singlet).

Mass spectrum (EI) m/z: 329 [M+].

Example 44

5-Trifluoromethyl-1-(4-forfinal)-2-(4-methylsulfinylphenyl)pyrrole (Compound 1-14 N)

44(i) of Ethyl 4,4,4-Cryptor-2-(4-methylthiophenyl)acetoacetate

Following a similar procedure to that described in example 43(i), but using ethyl 4,4,4-triftoratsetata instead of methylacetoacetate got mentioned in the title compound as a yellowish powder (in the/BR> 7,28 (2H, doublet, J = 9 Hz);

of 4.54 (1H, doublet of doublets, J = 10 and 5 Hz);

4.26 deaths (2H, Quartet, J = 7 Hz);

of 3.84 (1H, doublet of doublets, J = 18 and 10 Hz);

3,68 (1H, doublet of doublets, J = 18 and 5 Hz);

of 2.53 (3H, singlet);

of 1.29 (3H, triplet, J = 7 Hz).

44(ii) 5,5,5-Cryptor-1-(4-methylthiophenyl)pentane-1,4-dione

In 15 ml of dimethylformamide was dissolved 1,65 g (4.7 mmol) of ethyl 4,4,4-Cryptor-2-(4-methylthiophenyl)acetoacetate [obtained as described above in stage (i)] and to the resulting solution was added 85 ml (4.7 mmol) of water and 0.20 g (4.7 mmol) of lithium chloride. Then the mixture was stirred at 140oC for 1 h, then poured it into ice water and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous magnesium sulfate, and then solvent was removed by distillation under reduced pressure. The obtained residue was transferred to a chromatographic column with silica gel and was suirable mixture of hexane and ethyl acetate (3: 1 by volume) to obtain 0.26 g (yield 20%) specified in the connection header in the form of a yellowish powder.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,89 (2H, doublet, J = 9 Hz);

7,28 (2H, doublet, J = 9 Hz);

to 3.38 (2H, triplet, J = 6 Hz);

3,14 (2H, triplet, J = 6 G is Oh, that described in example 43(iii), but using as starting materials 5,5,5-Cryptor-1-(4-methylthiophenyl)pentane-1,4-dione [obtained as described above in stage (ii)] and 4-foranyone got mentioned in the title compound as a pale brown oily substance (yield 42%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

of 7.25 (8H, multiplet);

6,76 (1H, doublet, J = 4 Hz);

6,36 (1H, doublet, J = 4 Hz);

of 2.44 (3H, singlet).

44(iv) 5-Trifluoromethyl-1-(4-forfinal)-2-(4-methylsulfinylphenyl)pyrrol

5-Tryptophanyl-1-(4-forfinal)-2-(4-methylsulfinylphenyl)pyrrole [obtained as described above in stage (iii)] was oxidized in the same manner as described in example 43(ii) obtaining specified in the title compound as a white powder (yield 69%), melting at 136 - 139oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,87 (2H, doublet. J = 9 Hz);

7,30 - 7,22 (4H, multiplet);

7,15 - 7,06 (2H, multiplet);

for 6.81 (1H, doublet. J = 4 Hz);

of 6.52 (1H, doublet. J = 4 Hz);

3,03 (3H, singlet).

Mass spectrum (EI) m/z: 383 [M+].

Example 45

1-(4-Forfinal)-4,5-dimethyl-2-(4-methylsulfinylphenyl)pyrrole (Compound 1-20 N)

45(i) Methyl 2-methyl-2-(4-(4-methylsulfinylphenyl)acetoacetate [received so as described in example 43(ii)] and to the resulting solution was added with ice cooling under nitrogen 92 mg (2.3 mmol) of sodium hydride [60% (weight/weight) dispersion in mineral oil]. The mixture was stirred 10 minutes, then added with ice cooling to 1.1 ml (2.5 mmol) under the conditions and the resulting mixture was stirred for 2 hours. At the end of this time, to the mixture was added water and was extracted with a mixture of ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was transferred to a chromatographic column with silica gel and was suirable a mixture of ethyl acetate and hexane (2:3 by volume) to obtain 0.54 g (yield 80%) indicated in the title compound as a yellowish powder.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

to 8.14 (2H, doublet, J = 9 Hz);

of 8.06 (2H, doublet, J = 9 Hz);

of 3.77 (3H, singlet);

of 3.69 (1H, doublet, J = 18 Hz);

to 3.58 (1H, doublet, J = 18 Hz);

is 3.08 (3H, singlet);

of 2.35 (3H, singlet);

to 1.60 (3H, singlet).

45(ii) 1-(4-Forfinal)-4,5-dimethyl-2-(4-methylsulfinylphenyl)pyrrol

Was carried out as described in example 44(ii), hydrolysis and Decarie (i)] with 3-methyl-1-(4-methylsulfinylphenyl)pentane-1,4-dione. Then interacted this dinonogo connection and 4-foronline as described in example 43(iii), and the result was indicated in the title compound as a yellow powder (yield 11%), melting at 159 - 162oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

to 7.67 (2H, doublet, J = 9 Hz);

7,18 - to 7.09 (6H, multiplet);

6,41 (1H, singlet);

a 3.01 (3H, singlet);

a 2.12 (3H, singlet);

2,04 (3H, singlet).

Mass spectrum (FAB) 344(M+H)+].

Example 46

1-(4-Forfinal)-4-hydroxymethyl-2-(4-methylsulfinylphenyl)pyrrole (Compound 1-61 N)

46(i) Methyl 2-(4-methylthiophenyl)acetoacetate

In 150 ml of anhydrous tetrahydrofuran was dissolved 5,70 g (57.6 mmol) of medicinehat.ca and to the resulting solution were added under ice cooling 7,10 g (63.3 mmol) of tert-butoxide potassium, after which the mixture was stirred for 30 minutes. At the end of this time the mixture was slowly added dropwise under ice cooling a solution of 14,11 g (57.6 mmol) of 4-methylthiophenethylamine in 50 ml of tetrahydrofuran. The mixture was stirred under ice cooling for 2 hours, after which was added a saturated aqueous solution of ammonium chloride and ethyl acetate. Was filtered, the insoluble material is m sulfate mania and then solvent was removed by distillation under reduced pressure. The residue was transferred to a chromatographic column with silica gel and was suirable a mixture of ethyl acetate and hexane (1:2 by volume) to obtain 3.11 g (yield 21%) indicated in the title compound as a yellowish powder.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) / memorial plaques:

7,87 (2H, doublet, J = 9 Hz);

7,27 (2H, doublet, J = 9 Hz);

of 4.16 (1H, doublet, J = 7 and 6 Hz);

a 3.83 (3H, singlet);

3,74 (1H, doublet, J = 18 and 7 Hz);

of 3.53 (1H, doublet, J = 18 and 6 Hz);

of 2.54 (3H, singlet).

46(ii) 5-Amino-1-(4-forfinal)-4-methoxycarbonyl-2-(4-methylsulfinylphenyl)pyrrol

In 150 ml of methylene chloride was dissolved 3.11 g (to 11.8 mmol) of methyl 2-(4-methylthiophenyl)cyanoacetate [obtained as described above in stage (i)] and to the resulting solution were added under ice cooling of 5.83 g (23.6 mmol) of 70% m-chloroperbenzoic acid. The resulting mixture was stirred at room temperature for 1 hour. At the end of this time, to the mixture was added 50 ml of 10% (weight/volume) aqueous solution of sodium thiosulfate and the mixture was intensively which, then separated into a liquid phase. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride in that order, after Zolochiv the result of 3.15 g of methyl 2-(4-methylsulfinylphenyl)cyanoacetate in the form of a pale brown powder.

The obtained powder (3.15 g) was dissolved in 100 ml of ethanol and to the solution was added 1,58 g (of 14.2 mmol) 4-foronline and 12 drops of concentrated aqueous solution chloroethanol acid. Then the mixture was heated under reflux for 3 days. At the end of this time the reaction mixture was concentrated by evaporation under reduced pressure, to the residue were added methylene chloride and then was filtered, the insoluble materials. The filtrate was concentrated by evaporation under reduced pressure and the residue was transferred to a chromatographic column with silica gel and was suirable a mixture of ethyl acetate and hexane (1:1 by volume), received in the result of 2.10 g (yield 46%) indicated in the title compound as a white powder.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

to 7.68 (2H, doublet, J = 9 Hz);

7,26 - 7,11 (6H, multiplet);

6,76 (1H, singlet);

further 5.15 (2H, broad singlet);

of 3.85 (3H, singlet);

a 3.01 (3H, singlet).

46(iii) 1-(4-Forfinal)-4-methoxycarbonyl-2-(4-methylsulfinylphenyl)pyrrol

In 50 ml of anhydrous tetrahydrofuran was dissolved 2.00 g (5.2 mmol) of 5-amino-1-(4-forfinal)-4-methoxycarbonyl-2-(4 - methylsulfinylphenyl)pyrrole [obtained as described above in stage (ii)] shall eat the mixture was stirred at room temperature for 30 minutes, after which it was heated under reflux for 2 hours. Solvent was removed by distillation under reduced pressure and the residue was transferred to a chromatographic column with silica gel and was suirable a mixture of ethyl acetate and hexane (2:3 by volume), received in the result of 1.30 g (yield 68%) indicated in the title compound as a yellow powder, melting at 144 - 146oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

of 7.95 (2H, doublet, J = 9 Hz);

7,56 (1H, doublet, J = 2 Hz);

7,27 (1H, doublet, J = 9 Hz);

7,21 - 7,06 (4H, multiplet);

of 6.96 (1H, doublet, J = 2 Hz);

a 3.87 (3H, singlet);

3,05 (3H, singlet).

Mass spectrum (EI) m/z: 373 [M+].

46(iv) 1-(4-Forfinal)-4-hydroxymethyl-2-(4-methylsulfinylphenyl)pyrrol

In 25 ml of diethyl ether is added 0.15 g (4.00 mmol) of sociallyengaged and the suspension heated under reflux in a nitrogen atmosphere, was added dropwise a solution of 0.98 years (2.6 mmol) of 1-(4-forfinal)-4-methoxycarbonyl-2-(4-methylsulfinylphenyl)pyrrole [obtained as described above in stage (iii)] in 20 ml of methylene chloride. The mixture was stirred at reflux for 1 hour, after which it was added 0.15 ml of water, 0.15 ml of 15% (mass is room temperature for 3 minutes. At the end of this time the mixture dehydrational by adding anhydrous magnesium sulfate and filtered through an auxiliary filtering material Celite (trade mark). From the filtrate solvent was removed by distillation under reduced pressure. The residue was transferred to a chromatographic column with silica gel and was suirable a mixture of ethyl acetate and hexane (2: 1 obhama) receiving 0,69 g (yield 76%) indicated in the title compound as a white powder, melting at 88 - 90oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

to 7.77 (2H, doublet, J = 9 Hz);

7,26 (2H, doublet, J = 9 Hz);

7,28 - 7,05 (4H, multiplet);

6,97 (1H, doublet, J = 2 Hz);

6,60 (1H, doublet, J = 2 Hz);

the 4.65 (2H, doublet, J = 5 Hz);

totaling 3.04 (3H, singlet).

Example 47

1-(4-Forfinal)-4-hydroxymethyl-5-methyl-2-(4-methylsulfinylphenyl) pyrrole (Compound 1-62 N)

1-(4-Forfinal)-4-methoxycarbonyl-5-methyl-2-(4-methylsulfinylphenyl) pyrrole [obtained as described in example 43(iii)] was recovered as described in example 46(iv), obtaining specified in the title compound as a yellow powder (yield 84%), melting at 140 - 142oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl);

a 3.01 (3H, singlet);

to 2.13 (3H, singlet).

Mass spectrum (FAB) m/z: 360(M+H)+].

Example 48

5-Deformity-1-(4-forfinal)-2-(4-methylsulfinylphenyl)pyrrole (Compound 1-13 N)

48(i) 1-(4-Forfinal)-5-formyl-2-(4-methylsulfinylphenyl)pyrrol

In 30 ml of dimethylformamide was dissolved 1,67 g (5.3 mmol) of 1-(4-forfinal)-2-(4-methylsulfinylphenyl)pyrrole [obtained as described in example 33] , to the resulting solution was added to 0.50 ml (5.3 mmol) of phosphorus oxychloride and the mixture was stirred at 60oC for 2 hours. At the end of this time the reaction mixture was gradually introduced into water with ice and brought the pH of the mixture to a value of 8 to 9 by adding sodium carbonate. Then the mixture was extracted with ethyl acetate. The organic extract was washed with water and then dried over anhydrous sodium sulfate and solvent was removed by distillation under reduced pressure. The residue was transferred to a chromatographic column with silica gel and was suirable with a mixture of hexane and ethyl acetate (5:1 by volume) with the receipt of 0.90 g (yield 50%) specified in the title compound as a white powder, melting at 135 - 137oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

of 9.55 (1H, singlet);

7,80 (2H, dget).

48(ii) 5-Deformity-1-(4-forfinal)-2-(4-methylsulfinylphenyl)pyrrol

In 3 ml of anhydrous diglyme (dimethyl ether of diethylene glycol) was dissolved 0.50 g (1.5 mmol) 1-(4-forfinal)-5-formyl-2-(4-methylsulfinylphenyl)pyrrole [obtained as described above in stage (i)] and to the resulting solution was added 0.17 ml (2.9 mmol) of diethylaminoacetate. Then the mixture was stirred at 100oC for 6 hours. At the end of this time the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic extract was washed with water and then dried over anhydrous sodium sulfate and solvent was removed by distillation under reduced pressure. The obtained residue was transferred to a chromatographic column with silica gel and was suirable with a mixture of hexane and ethyl acetate (7:3 by volume) to obtain 0.12 g (yield 23%) indicated in the title compound as a yellowish powder, melting at 111 - 112oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,76 (2H, doublet, J = 9 Hz);

7,27 - 7,21 (5H, multiplet);

7,15 - was 7.08 (2H, multiplet);

of 6.71 - 6,69 (1H, multiplet);

6,56 - is 6.54 (1H, multiplet);

6.42 per (1H, triplet, J = 54 Hz);

3,03 (3H, singlet).

Mass spectrum (EI) m/z: 365 [M+
In 30 ml of methylene chloride was dissolved 0,58 g (1.7 mmol) of 1-(4-forfinal)-4-hydroxymethyl-2-(4-methylsulfinylphenyl)pyrrole [obtained as described in example 46] and to the resulting solution was added to 2.40 g of manganese dioxide. The mixture was stirred at room temperature for 3 hours. At the end of this time the reaction mixture was filtered through an auxiliary filtering material Celite (trade mark) and the filtrate was concentrated by evaporation under reduced pressure. The obtained residue was transferred to a chromatographic column with silica gel and was suirable a mixture of ethyl acetate and hexane (2:3 by volume) to obtain 0.52 g (yield 90%) indicated in the title compound as a white powder, melting at 169 - 171oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

of 9.89 (1H, singlet);

of 7.82 (2H, doublet, J = 9 Hz);

7,56 (1H, doublet, J = 2 Hz);

7,29 (2H, doublet, J = 9 Hz);

7,22 - was 7.08 (4H, multiplet);

of 6.99 (1H, doublet, J = 2 Hz);

a 3.06 (3H, singlet).

49(ii) 1-(4-forfinal)-4-deformity-2-(4-methylsulfinylphenyl)pyrrol

Following a similar procedure to that described in example 48(ii), but using as starting material 1-(4-forfinal)-4-formyl-2-(4-methylsulfone the title compound as a white powder (yield 16%), melting at 98 - 100oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,80 (2H, doublet, J = 9 Hz);

7,28 (2H, doublet, J = 9 Hz);

7,18? 7.04 baby mortality (5H, multiplet);

6,74 (1H, triplet, J = 57 Hz);

6,69 (1H, singlet);

3,05 (3H, singlet).

Example 50

1-(4-Forfinal)-4-deformity-5-methyl-2-(4-methylsulfinylphenyl)pyrrole (Compound 1-30 N)

50(i) 1-(4-Forfinal)-4-formyl-5-methyl-2-(4-methylsulfinylphenyl)pyrrol

Following a similar procedure to that described in example 49(ii), but using as starting material 1-(4-forfinal)-4-hydroxymethyl-5-methyl-2-(4-methylsulfinylphenyl)pyrrole (obtained as described in example 47) and manganese dioxide has been specified in the title compound as a white powder (yield 98%), melting at 167 - 169oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

9,99 (1H, singlet);

of 7.75 (2H, doublet, J = 9 Hz);

7,24 - 7,16 (6H, multiplet);

6,94 (1H, singlet);

3,03 (3H, singlet);

to 2.42 (3H, singlet).

Mass spectrum (FAB) m/z: 358(M+H)+].

50(ii) 1-(4-Forfinal)-4-deformity-5-methyl-2-(4-methylsulfinylphenyl)pyrrol

Following a similar procedure to that described in example 48(ii) Ola [received so as described above in stage i)] and diethylaminoacetate got mentioned in the title compound as a white powder (yield 70%), melting at 136 - 138oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,72 (2H, doublet, J = 9 Hz);

7,22 - was 7.08 (6H, multiplet);

of 6.73 (1H, triplet, J = 56 Hz);

of 6.66 (1H, singlet);

to 3.02 (3H, singlet);

to 2.18 (3H, singlet).

Mass spectrum (EI) m/z: 379 [M+].

Example 51

2-(4-Forfinal)-4-phenyl-1-(sulfamoyl)pyrrole (Compound N 2-69)

51(i) 3-(4-Perbenzoic)-2-phenylpropionaldehyde

In 50 ml of toluene was dissolved 45% (weight/volume) solution of phenylacetaldehyde in diethylphthalate containing 25,00 g (94 mmol) of phenylacetaldehyde, and to the resulting solution was added of 7.96 g (94 mmol) of piperidine. Then the mixture was heated under reflux with removal of released water until the termination of its discharge (about 1 hour). At the end of this time the solvent was removed by distillation under reduced pressure and the obtained 31,78 g of a mixture of piperidinedione and diethylphthalate as a red oily substance.

In 70 ml of anhydrous tetrahydrofuran was dissolved 4.68 g of the mixture of piperidinedione and diethylphthalate and to perphenazine and the mixture was stirred at room temperature for 3 hours. At the end of this time the reaction mixture was added 30 ml of 1 N. aqueous solution chloroethanol acid and the mixture was stirred at room temperature for another 1 hour. Then it was extracted with diethyl ether. The organic extract was washed with water and dried over anhydrous sodium sulfate. Solvent was removed by distillation under reduced pressure and the residue was transferred to a chromatographic column with silica gel and was suirable with a mixture of hexane and ethyl acetate (95: 5 by volume) to obtain 0.50 g specified in the title compound as yellowish oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

9,80 (1H, singlet);

8,03 - 7,98 (2H, multiplet);

7,42 - of 7.25 (5H, multiplet);

7,16 - 7,10 (2H, multiplet);

Mass spectrum (FAB) m/z: 257(M+H)+].

51(ii) 2-(4-forfinal)-4-phenyl-1-(4-sulfamoylbenzoyl)pyrrol

In 20 ml of acetic acid was dissolved 0.32 g (1.25 mmol) of 3-(4-perbenzoic)-2-phenylpropionaldehyde [obtained as described above in stage (i)] and 0.26 g (1.5 mmol) 4-sulfamerazine and the mixture was heated under reflux for 4 hours. Solvent was removed by distillation under reduced pressure and to the residue was added water, then the mixture extraly the solvent by distillation under reduced pressure and the residue was transferred to a chromatographic column with silica gel and was suirable with a mixture of hexane and ethyl acetate (3:2 by volume) to obtain 0.35 g (yield 60%) specified in the connection header in the form of a yellowish powder, melting at 192 - 194oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

to $ 7.91 (2H, doublet, J = 9 Hz);

7,58 (2H, doublet, J = 7 Hz);

7,39 - 7,22 (6H, multiplet);

7,18 for 7.12 (2H, multiplet);

of 6.99 (2H, triplet, J = 9 Hz);

of 6.73 (1H, doublet, J = 2 Hz);

4,84 (2H, singlet).

Mass spectrum (EI) m/z: 392 [M+].

Example 52

2-(4-Methoxyphenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-74)

52(i) N-(4-Methoxybenzylidene)-4-sulfanilamide

Following a similar procedure to that described in example 1(i), but using as starting materials 4-methoxybenzaldehyde and 4-sulfamerazine got mentioned in the title compound as a pale yellow powder (yield 95%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

8,35 (1H, singlet);

7,94 (2H, doublet, J = 9 Hz);

7,86 (2H, doublet, J = 9 Hz);

of 7.23 (2H, doublet, J = 9 Hz);

7,00 (2H, doublet, J = 9 Hz);

5,98 (2H, singlet);

are 3.90 (3H, singlet).

52(ii) - (4-Methoxyphenyl) -- (4-sulfamerazine)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material N-(4-methoxybenzylidene)-4-sulfamerazine [the rule of law in the form of a pale yellow powder (yield 98%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

7,74 (2H, doublet, J = 9 Hz);

7,51 (2H, doublet, J = 9 Hz);

6,97 (2H, doublet, J = 9 Hz);

PC 6.82 (2H, doublet, J = 9 Hz);

6,60 (1H, doublet, J = 8 Hz);

6,41 (2H, singlet);

5,54 (1H, doublet, J = 8 Hz);

of 3.84 (3H, singlet).

52(iii) 2-(4-Methoxyphenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - (4-methoxyphenyl) -- (4-sulfamerazine)acetonitrile [obtained as described above in stage (ii)] and methacrolein got mentioned in the title compound as a pale brown powder (yield 6%), melting at 163 - 166oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

to 7.84 (2H, doublet, J = 9 Hz);

of 7.23 (2H, doublet, J = 9 Hz);

7,03 (2H, doublet, J = 9 Hz);

6,79 (2H, doublet, J = 9 Hz);

of 6.73 (1H, singlet);

6,23 (1H, singlet);

4,78 (2H, singlet);

with 3.79 (3H, singlet);

to 2.18 (3H, singlet).

Mass spectrum (EI) m/z: 342 [M+].

Example 53

1-(3,4-Acid)-2-(4-methylsulfinylphenyl)pyrrole (Compound N 1-59)

Following a similar procedure to that described in three is-methoxyaniline, got mentioned in the title compound as a white powder, melting at 123 - 126oC. the Yield of compound (yellow powder) in the first stage was 96% in the second stage (brown prismatic crystals) 48% and in the third stage - 15%.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

of 7.75 (2H, doublet, J = 7 Hz);

7,30 (2H, doublet, J = 7 Hz);

6,98 (1H, multiplet);

at 6.84 (1H, doublet, J = 8 Hz);

6,74 - 6,70 (2H, multiplet);

to 6.57 (1H, multiplet);

6,39 - 6,37 (1H, multiplet);

to 3.92 (3H, singlet);

3,74 (3H, singlet);

3,03 (3H, singlet).

Mass spectrum (EI) m/z: 357 [M+].

Example 54

1-(3-Fluoro-4-methoxyphenyl)-2-(4-methylsulfinylphenyl)pyrrole (Compound N 1-47)

Following a similar procedure to that described in the three stages of examples 1(i) 1(ii) 1(iii), but using as starting material 3-fluoro-4-methoxyaniline instead of 4-methoxyaniline got mentioned in the title compound as a pale yellow powder, melting at 116 - 118oC. the Yield of compound (pale yellow powder) in the first stage was 94%, in the second stage (white powder) 87% and in the third stage is 16%.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques


6,39 - 6,37 (1H, multiplet);

to 3.92 (3H, singlet);

3,05 (3H, singlet).

Mass spectrum (EI) m/z: 345 [M+].

Example 55

1-Phenyl-2-(4-methylsulfinylphenyl)pyrrole (Compound N 1-1)

Following a similar procedure to that described in the three stages of examples 1(i) 1(ii) 1(iii), but using as starting material aniline instead of 4-methoxyaniline got mentioned in the title compound as white prismatic crystals, melting at 140 - 142oC. the Yield of compound (pale yellow powder) in the first stage was 76%, in the second stage (pale yellow powder) - 95% and at the third stage is 16%.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,74 (2H, doublet, J = 8 Hz);

7,40 - 7,33 (3H, multiplet);

7,27 (2H, doublet, J = 8 Hz);

7,18 - 7,15 (H, multiplet);

7,00 (1H, multiplet);

6,59 return of 6.58 (1H, multiplet);

6,41 - to 6.39 (1H, multiplet);

3,03 (3H, singlet).

Example 56

4-Methyl-1-(3,4-dimetilfenil)-2-(4-methylsulfinylphenyl)pyrrole (Compound N 1-56)

Following a similar procedure to that described in example 8, but using the third stage of methacrolein instead of acrolein got mentioned in the title compound as a pale yellow p>
) memorial plaques

7,72 (2H, doublet, J = 9 Hz);

7,27 - 7,24 (2H, multiplet);

7,08 - 7,05 (1H, multiplet);

of 6.96 (1H, singlet);

6,83 - 6,79 (1H, multiplet);

6,74 (1H, singlet);

6,41 (H, singlet);

3,03 (3H, singlet);

of 2.27 (3H, singlet);

of 2.23 (3H, singlet);

to 2.18 (3H, singlet).

Mass spectrum (EI) m/z: 339 [M+].

Example 57

1-(4-Were)-2-(4-sulfamoylbenzoyl)pyrrole (Compound N 1-99)

57(i) N-(4-Sulfamoylbenzoyl)-4-methylaniline

Following a similar procedure to that described in example 1(i), but using as starting materials 4-sulfamoylbenzoic and 4-methylaniline, got mentioned in the title compound as a yellow powder (yield 82%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

8,56 (1H, singlet);

8,01 (4H, singlet);

7,27 for 7.12 (6H, multiplet);

of 2.38 (3H, singlet);

57(ii) - (4-Methylaniline) -- (4-sulfamoylbenzoyl)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material N-(4-sulfamoylbenzoyl)-4-methylaniline [obtained as described above in stage (i)] and trimethylsilylacetamide received specified in zerolabstation dimethyl sulfoxide) M. D.

to 7.99 (2H, doublet, J = 8 Hz);

of 7.75 (2H, doublet, J = 8 Hz);

7,03 (2H, doublet, J = 8 Hz);

6,89 (2H, singlet);

6,69 (2H, doublet, J = 8 Hz);

5,70 - of 5.55 (2H, multiplet);

of 2.25 (3H, singlet).

57(iii) 1-(4-Were)-2-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - (4-methylaniline) -- (4-sulfamoylbenzoyl)acetonitrile [obtained as described above in stage (ii)] and acrolein got mentioned in the title compound as a pale brown powder (yield 28%), melting at 131 - 134oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,73 (2H, doublet, J = 8 Hz);

from 7.24 (2H, doublet, J = 8 Hz);

7,16 (2H, doublet, J = 8 Hz);

? 7.04 baby mortality (2H, doublet, J = 8 Hz);

of 6.96 (1H, triplet, J = 2 Hz);

6,55 (1H, doublet of doublets, J = 3 and 2 Hz);

6,38 (1H, triplet, J = 3 Hz);

4,74 (2H, singlet);

of 2.38 (3H, singlet).

Mass spectrum (EI) m/z: 312 [M6+].

Example 58

4-Methyl-1-(4-were)-2-(4-sulfamoylbenzoyl)pyrrole (Compound 1-100 N)

Following a similar procedure to that described in example 57(iii), but using methacrolein instead of acrolein got mentioned in the title compound as a yellow on the Sabbath.
) memorial plaques

7,71 (2H, doublet, J = 8 Hz);

7,21 (2H, doublet, J = 8 Hz);

7,14 (2H, doublet, J = 8 Hz);

7,01 (2H, doublet, J = 8 Hz);

to 6.39 (1H, singlet);

4,71 (2H, singlet);

is 2.37 (3H, singlet);

to 2.18 (3H, singlet).

Mass spectrum (EI) m/z: 326 [M+].

Example 59

1-(4-Chlorophenyl)-2-(4-sulfamoylbenzoyl)pyrrole (Compound 1-96 N)

59(i) 4-Chloro-N-(4-sulfamoylbenzoyl)aniline

Following a similar procedure to that described in example 1(i), but using as starting materials 4-sulfamoylbenzoic and 4-Chloroaniline, got mentioned in the title compound as a pale yellow powder (yield 72%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

charged 8.52 (1H, singlet);

8,02 (4H, singlet);

7,38 (2H, doublet, J = 9 Hz);

then 7.20 (2H, doublet, J = 9 Hz);

6,87 (2H, singlet).

59(ii) - (4-Chloroanilino) -- (4-sulfamoylbenzoyl)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material 4-chloro-N-(4-sulfamoylbenzoyl)aniline [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as a white powder (yield 93%).

Range nuclear

7,74 (2H, doublet, J = 8 Hz);

7,14 (2H, doublet, J = 9 Hz);

for 7.12 (2H, singlet);

6,74 (2H, doublet, J = 9 Hz);

of 6.52 (1H, doublet, J = 9 Hz);

5,69 (1H, doublet, J = 9 Hz);

59(iii) 1-(4-Chlorophenyl)-2-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - (4-chloroanilino) -- (4-sulfamoylbenzoyl)acetonitrile [obtained as described above in stage (ii)] and acrolein got mentioned in the title compound as a pale yellow powder (yield 38%), melting at 179 - 181oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

to 7.77 (2H, doublet, J = 9 Hz);

7,34 (2H, doublet, J = 9 Hz);

of 7.23 (2H, doublet, J = 9 Hz);

7,10 (2H, doublet, J = 9 Hz);

of 6.96 (1H, triplet, J = 2 Hz);

6,56 (1H, doublet of doublets, J = 3 and 2 Hz);

6,40 (1H, triplet, J = 3 Hz);

4,78 (2H, singlet).

Mass spectrum (EI) m/z: 332 [M+].

Example 60

1-(4-Chlorophenyl)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrole (Compound 1-97 N)

Following a similar procedure to that described in example 59(iii), but using methacrolein instead of acrolein got mentioned in the title compound as a pale yellow powder (yield 53%), melting at 171 - 173o/BR> 7,31 (2H, doublet, J = 8 Hz);

7,21 (2H, doublet, J = 8 Hz);

7,06 (2H, doublet, J = 8 Hz);

6,74 (1H, singlet);

6,41 (1H, singlet);

4,80 (2H, singlet);

to 2.18 (3H, singlet);

Mass spectrum (EI) m/z: 346 [M+].

Example 61

1-(4-Methoxyphenyl)-2-(4-sulfamoylbenzoyl)pyrrole (Compound 1-85 N)

61(i) 4-Methoxy-N-(4-sulfamoylbenzoyl)aniline

Following a similar procedure to that described in example 1(i), but using as starting materials 4-sulfamoylbenzoic and 4-methoxyaniline got mentioned in the title compound as a pale yellow powder (yield 72%)

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

a total of 8.74 (1H, singlet);

of 8.09 (2H, doublet, J = 8 Hz);

of 7.95 (2H, doublet, J = 8 Hz);

of 7.48 (2H, singlet);

7,37 (2H, doublet, J = 9 Hz);

7,01 (2H, doublet, J = 9 Hz);

of 3.80 (3H, singlet);

61(ii) - (4-Methoxyaniline) -- (4-sulfamoylbenzoyl)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting materials 4-methoxy-N-(4-sulfamoylbenzoyl)aniline [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as a white powder is J = 8 Hz);

7,76 (2H, doublet, J = 8 Hz);

the 7.43 (2H, singlet);

to 6.80 (4H, multiplet);

6,40 (1H, doublet, J = 10 Hz);

6,03 (1H, doublet, J = 10 Hz);

to 3.67 (3H, singlet).

61(iii) 1-(4-Methoxyphenyl)-2-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - (4-methoxyaniline) -- (4-sulfamoylbenzoyl)acetonitrile [obtained as described above in stage (ii)] and acrolein got mentioned in the title compound as a yellow powder (yield 9%), melting at 112 - 114oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,78 - to 7.68 (2H, multiplet);

7,26 - 6,85 (7H, multiplet);

6,53 - 6,51 (1H, multiplet);

6,37 to 6.35 (1H, multiplet);

5,07 (2H, singlet);

3,81 (3H, singlet).

Mass spectrum (EI) m/z: 328 [M+].

Example 62

1-(4-Methoxyphenyl)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrole (Compound N 1-86)

Following a similar procedure to that described in example 61(iii), but using methacrolein instead of acrolein got mentioned in the title compound as a pale yellow powder (yield 35%), melting at 63 - 64oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDClyears, J = 9 Hz);

6,72 (1H, singlet);

6,38 (1H, singlet);

5,04 (2H, singlet);

of 3.80 (3H, singlet);

to 2.18 (3H, singlet).

Mass spectrum (EI) m/z: 342 [M+].

Example 63

4-Butyl-1-(4-methoxyphenyl)-2-(4-sulfamoylbenzoyl)pyrrole (Compound 1-87 N)

Following a similar procedure to that described in example 61(iii), but using 2-butylamine instead of acrolein got mentioned in the title compound as a pale yellow powder (yield 85%), melting at 115 - 117oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

of 7.69 (2H, doublet, J = 8 Hz);

7,26 - 7,19 (2H, multiplet);

7,08 - 7,05 (2H, multiplet);

6,88 - 6,87 (2H, multiplet);

6,72 (1H, singlet);

6,41 - 6,40 (1H, multiplet);

4,89 (2H, singlet);

is 3.82 (3H, singlet);

of 2.53 (3H, triplet, J = 8 Hz);

1,68 - of 1.57 (2H, multiplet);

1,49 - of 1.36 (2H, multiplet);

of 0.95 (3H, triplet, J = 7 Hz);

Mass spectrum (EI) m/z: 384 [M+].

Example 64

1-Ethyl-2-(4-methoxyphenyl)-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-75)

64(i) 1-(N,N-Diisopropylamino)-1-butene

In 30 ml of benzene was dissolved and 6.25 ml (or 69.3 mmol) Butyraldehyde and 19,44 ml (139 mmol) of Diisopropylamine and the mixture was heated under reflux with removal bideleux and under reduced pressure and the residue was distilled at atmospheric pressure. Collecting fractions of distillate having a boiling point of from 140 to 160oC, got 6,95 g specified in the title compounds as a pale yellow oily substance (yield 65%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

5,94 (1H, doublet, J = 14 Hz);

of 4.05 (1H, doublet of triplets, J = 14 and 7 Hz);

3,50 - to 3.34 (2H, multiplet);

2,01 - of 1.88 (2H, multiplet);

of 1.03 (6H, doublet, J = 7 Hz);

of 0.91 (3H, triplet, J = 7 Hz);

64(ii) 2-(4-Methoxyphenacyl)Butyraldehyde

In 10 ml of benzene was dissolved in 1.00 g (6.4 mmol) of 1-(N,N-diisopropylamino)-1-butene [obtained as described above in stage (i)] and to the resulting solution was added dropwise with stirring and with ice cooling and 0.98 g (4.3 mmol) of 4-methoxybenzylamine. The reaction mixture was stirred under ice cooling for 15 minutes and then at room temperature for 48 hours. At the end of this time, to the mixture was added 9 ml of 1 N. aqueous solution chloroethanol acid and the mixture was stirred for 15 minutes. Then it was neutralized by adding concentrated aqueous ammonia solution and extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous magnesium sulfate, and then solvent was removed by whom and with a mixture of hexane and ethyl acetate (4:1 by volume) with the receipt of 0.47 g (yield 49%) indicated in the title compounds as a pale yellow oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

9,83 (1H, singlet);

of 7.96 (2H, doublet, J = 9 Hz);

6,94 (2H, doublet, J = 9 Hz);

3,88 (3H, singlet);

3,49 - to 3.33 (1H, multiplet);

3,09 - of 2.93 (1H, multiplet);

1,92 - 1,74 (1H, multiplet);

1,70 - and 1.54 (1H, multiplet);

a 1.01 (3H, triplet, J = 7 Hz);

64(iii) 4-Ethyl-2-(4-medociprin)-1-(4-sulfamoylbenzoyl)pyrrol

In 5 ml of acetic acid was dissolved 0,47 g (2.1 mmol) of 2-(4-methoxyphenacyl)Butyraldehyde [obtained as described above in stage (ii)] and 0.44 g (2.5 mmol) of 4-sulfamerazine and the resulting solution was heated under reflux for 2 hours. At the end of this time the mixture was cooled to room temperature, was added concentrated aqueous ammonia to bring the pH to a value of 8.0 and extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was transferred to a chromatographic column with silica gel and was suirable with a mixture of hexane and ethyl acetate (3:2 by volume) with the receipt of 0.57 g (yield 76%) indicated in the title compounds as a pale yellow powder, melting at 154 - 156oC.

Range I have);

? 7.04 baby mortality (2H, doublet, J = 9 Hz);

6,79 (2H, doublet, J = 9 Hz);

6,74 (1H, singlet);

6,27 (1H, singlet);

4,78 (2H, singlet);

with 3.79 (3H, singlet);

to 2.57 (2H, Quartet, J = 8 Hz);

of 1.26 (3H, triplet, J = 8 Hz).

Example 65

2-(4-Chlorophenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-85)

65(i) 1-(N,N-Diisobutylamine)-1-propene

Following a similar procedure to that described in example 64(i), but using as starting materials Propionaldehyde and diisobutylamine got mentioned in the title compound as a colorless oily substance (yield 29%), boiling at 63 - 66oC/10 mm RT.article.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

of 5.89 (1H, doublet, J = 14 Hz);

3,92 - with 3.79 (1H, multiplet);

of 2.66 (2H, doublet, J = 7 Hz);

1,92 - of 1.74 (2H, multiplet);

and 1.54 (3H, doublet, J = 7 Hz);

0,80 (12H, doublet, J = 7 Hz);

65(ii) 2-(4-Chlorophenacyl)Propionaldehyde

Following a similar procedure to that described in example 64(ii), but using as starting materials 1-(N,N-diisobutylamine)-1-propene [obtained as described above in stage (i)] and 4-chlorpheniramine got mentioned in the title compound as a pale brown oily substance (you is R> a 7.92 (2H, doublet, J = 9 Hz);

was 7.45 (2H, doublet, J = 9 Hz);

3,47 (1H, doublet of doublets, J = 18 and 7 Hz);

3,22 totaling 3.04 (1H, multiplet);

2,95 (1H, doublet of doublets, J = 18 and 7 Hz);

of 1.25 (3H, doublet, J = 7 Hz);

65(iii) 2-(4-Chlorophenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 64(iii), but using as starting materials 2-(4-chlorophenacyl)Propionaldehyde [obtained as described above in stage (ii)] and 4-sulfamerazine got mentioned in the title compound as a pale brown powder (yield 35%), melting at 196 - 198oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

the 7.85 (2H, doublet, J = 9 Hz);

of 7.36 (2H, doublet, J = 9 Hz);

7,22 (2H, doublet, J = 9 Hz);

7,03 (2H, doublet, J = 9 Hz);

to 6.75 (1H, singlet);

6,30 (1H, singlet);

4,80 (2H, singlet);

2,17 (3H, singlet).

Mass spectrum (EI) m/z: 342 [M+].

Example 66

4-Methyl-2-(4-methylthiophenyl)-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-82)

66(i) N-(4-Methylthiazolidine)-4-sulfanilamide

Following a similar procedure to that described in example 1(i), but using as starting materials 4-methylthiazolidine and 4-sulfamerazine, recip is on resonance (270 MHz, hexadeuterated dimethyl sulfoxide) / memorial plaques

8,46 (1H, singlet).

of 7.90 (2H, doublet, J = 9 Hz);

to 7.84 (2H, doublet, J = 8 Hz);

7,33 (2H, doublet, J = 9 Hz);

7,27 (2H, doublet, J = 8 Hz);

to 7.15 (2H, broad singlet);

to 2.55 (3H, singlet).

66(ii) - (4-Methylthiophenyl) -- (4-sulfamerazine)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material N-(4-methylthiazolidine)-4-sulfamerazine [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as a yellow powder (yield 100%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

7,66 (2H, doublet, J = 9 Hz);

7,52 (2H, doublet, J = 8 Hz);

7,31 (2H, doublet, J = 8 Hz);

7,25 - 7,13 (1H, multiplet);

make 6.90 (2H, broad singlet);

6,86 (2H, doublet, J = 9 Hz);

of 5.89 - of 5.83 (1H, multiplet);

of 2.50 (3H, singlet).

66(iii) 4-Methyl-2-(4-methylthiophenyl)-1-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - (4-methylthiophenyl) -- (4-sulfamerazine)acetonitrile [obtained as opisaniya crystals (yield 31%), melting at 172 - 173oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

the 7.85 (2H, doublet, J = 9 Hz);

from 7.24 (2H, doublet, J = 9 Hz);

for 7.12 (2H, doublet, J = 9 Hz);

7,02 (2H, doublet, J = 8 Hz);

6,74 (1H, doublet, J = 2 Hz);

of 6.29 (1H, doublet, J = 2 Hz);

4,82 (2H, broad singlet);

2,47 (3H, singlet).

Mass spectrum (EI) m/z: 358 [M+]

Example 67

2-(4-Ethoxyphenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-78)

67(i) N-(4-Ethoxybenzylidene)-4-sulfanilamide

Following a similar procedure to that described in example 1(i), but using as starting materials 4-ethoxybenzaldehyde and 4-sulfamerazine got mentioned in the title compound as a pale yellow powder (yield 76%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

scored 8.38 (1H, singlet);

7,88 (2H, doublet, J = 9 Hz);

the 7.85 (2H, doublet, J = 9 Hz);

from 7.24 (2H, doublet, J = 9 Hz);

6,98 (2H, doublet, J = 9 Hz);

of 4.12 (2H, Quartet, J = 7 Hz);

of 1.45 (3H, triplet, J = 7 Hz).

(67(ii) - (4-Ethoxyphenyl) -- (4-sulfamerazine)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as the source is of silenceand, got mentioned in the title compound as a slightly yellow powder (yield 88%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

the 7.65 (2H, doublet, J = 8 Hz);

of 7.48 (2H, doublet, J = 8 Hz);

7,20 - 7,03 (1H, multiplet);

6,99 - to 6.80 (6H, multiplet);

5,88 - USD 5.76 (1H, multiplet);

Android 4.04 (2H, Quartet, J = 7 Hz);

to 1.38 (3H, triplet, J = 7 Hz).

67(iii) 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - (4-ethoxyphenyl) -- (4-sulfamerazine)acetonitrile [obtained as described above in stage (ii)] and methacrolein got mentioned in the title compound as a brown powder (yield 3%) melting at 135 - 139oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,83 (2H, doublet, J = 9 Hz);

7,22 (2H, doublet, J = 9 Hz);

7,02 (2H, doublet, J = 9 Hz);

6,77 (2H, doublet, J = 9 Hz);

6,72 (1H, broad singlet);

6,23 (1H, doublet, J = 2 Hz);

rate 4.79 (2H, broad singlet);

a 4.03 (2H, Quartet, J = 7 Hz);

2,17 (3H, singlet);

of 1.41 (3H, triplet, J = 7 Hz).

Mass spectrum (EI) m/z: 356 [M+].

Example 68

Following a similar procedure to that described in example 1(i), but using as starting materials 4-propoxybenzaldehyde and 4-sulfamerazine got mentioned in the title compound as a pale yellow powder (yield 84%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

scored 8.38 (1H, singlet);

a 7.92 (2H, doublet, J = 9 Hz);

the 7.85 (2H, doublet, J = 9 Hz);

of 7.23 (2H, doublet, J = 8 Hz);

of 6.99 (2H, doublet, J = 8 Hz);

for 6.81 (2H, broad singlet);

to 4.01 (2H, triplet, J = 6 Hz);

1,91 - of 1.78 (2H, multiplet);

of 1.07 (3H, triplet, J = 7 Hz).

68(ii) - (4-Propoxyphenyl) -- (4-sulfamerazine)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material N-(4-propoxybenzene)-4-sulfamerazine [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as a pale yellow powder (yield 80%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

to 7.68 (2H, doublet, J = 9 Hz);

7,51 (2H, doublet, J = 8 Hz);

7,20 - 7,14 (1H, broad doublet, J = 8 Hz);

6,98 (2H, doublet, J = 9 Hz)plet, J = 6 Hz);

1,87 - of 1.74 (2H, multiplet);

the 1.04 (3H, triplet, J = 7 Hz).

68(iii) 4-Methyl-2-(4-propoxyphenyl)-1-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - (4-propoxyphenyl) -- (4-sulfamerazine)acetonitrile [obtained as described above in stage (ii)] and methacrolein got mentioned in the title compound as a pale brown powder (yield 5%), melting at 142 - 145oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,83 (2H, doublet, J = 9 Hz);

of 7.23 (2H, doublet, J = 9 Hz);

7,02 (2H, doublet, J = 9 Hz);

is 6.78 (2H, doublet, J = 9 Hz);

6,72 (1H, doublet, J = 2 Hz);

6,23 (1H, doublet, J = 2 Hz);

5,86 (2H, broad singlet);

are 3.90 (2H, triplet, J = 7 Hz);

1,89 - of 1.84 (2H, multiplet);

of 1.03 (3H, triplet, J = 7 Hz);

Mass spectrum (EI) m/z: 370 [M+].

Example 69

4-Methyl-2-(4-methoxy-3-were)-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-109)

69(i) N-(4-Methoxy-3-methylbenzylidene)-4-sulfanilamide

Following a similar procedure to that described in example 1(i), but using as starting materials 4-methoxy-3-methylbenzaldehyde and 4-sulfamerazine, the floor is on resonance (270 MHz, CDCl3) memorial plaques

cent to 8.85 and 8,31 (total: 1H, each singlet);

to 7.93 (1H, doublet, J = 8 Hz);

to 7.77 - the 7.65 (2H, multiplet);

7,26 - of 7.23 (2H, multiplet);

6,91 - 6,86 (1H, multiplet);

of 6.71 - to 6.88 (1H, multiplet);

4,77 and 4,14 (total: 1H, each singlet);

to 3.92 (3H, singlet);

2,28 and of 2.21 (General: 3H, each singlet).

69(ii)- - (4-Methoxy-3-were) -- (4-sulfamerazine)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material N-(4-methoxy-3-methylbenzylidene)-4-sulfamerazine [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as a white powder (yield 63%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

a 7.62 (2H, doublet, J= 8 Hz);

7,39 - 7,34 (2H, multiplet);

7,26 (1H, doublet, J = 9 Hz);

? 7.04 baby mortality - 7,02 (3H, multiplet);

make 6.90 (2H, doublet, J = 8 Hz);

5,97 (1H, doublet, J = 9 Hz);

of 3.96 (2H, triplet, J = 6 Hz);

3,81 (3H, singlet);

of 3.33 (3H, singlet).

69(iii) 4-Methyl-2-(4-methoxy-3-were)-1-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as source the stage (ii)] and methacrolein, got mentioned in the title compound as a pale yellow powder (yield 39%), melting at 149 - 151oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

of 7.82 (2H, doublet. J = 9 Hz);

7,26 - 7,20 (2H, multiplet);

6,99 (1, singlet);

for 6.81 - of 6.65 (3H, multiplet);

6,21 (1H, singlet);

the 4.90 (2H, singlet);

with 3.79 (3H, singlet);

2,17 (3H, singlet);

and 2.14 (3H, singlet).

Mass spectrum (EI) m/z: 332 [M+].

Example 70

2-(3,4-Dichlorophenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-124)

70(i) N-(3,4-Dichlorobenzamide)-4-sulfanilamide

Following a similar procedure to that described in example 1(i), but using as starting material 3,4-dichlorobenzaldehyde and 4-sulfamerazine got mentioned in the title compound as a white powder (yield 52%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

8,49 (1H, singlet).

of 8.09 (1H, doublet, J = 2 Hz);

7,94 (1H, doublet, J = 9 Hz);

of 7.82 (1H, doublet of doublets, J = 2 and 8 Hz);

7,63 (1H, doublet, J = 8 Hz);

7,30 (2H, doublet, J = 9 Hz);

7,10 (2H, broad singlet).

70(ii) - (3,4-Dichlorophenyl) -- (4-sulfamerazine)acetonitrile
rials N-(3,4-dichlorobenzamide)-4-sulfamerazine [received so as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as a white powder (yield 91%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

7,76 (1H, doublet, J = 2 Hz);

of 7.70 (2H, doublet, J = 9 Hz);

of 7.60 (1H, doublet, J = 8 Hz);

7,53 (1H, doublet of doublets, J = 2 and 8 Hz);

from 7.24 (1H, broad doublet, J = 9 Hz);

at 6.84 (2H, broad singlet);

6,83 (2H, doublet, J = 9 Hz);

of 5.92 (1H, broad doublet, J = 9 Hz).

70(iii) 2-(3,4-Dichlorophenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - (3,4-dichlorophenyl) -- (4-sulfamerazine)acetonitrile [obtained as described above in stage (ii)] and methacrolein got mentioned in the title compound as a pale brown powder (yield 33%), melting at 136 - 138oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,89 (2H, doublet, J = 9 Hz);

7,30 (1H, doublet, J = 3 Hz);

7,29 (1H, doublet, J = 9 Hz);

from 7.24 (2H, doublet, J = 9 Hz);

6,79 (1H, doublet of doublets, J = 2 and 9 Hz);

6,76 (1H, doublet, J = 2 Hz);

6,34 (1H, doublet, J = 2 Hz);

a 4.83 (2H, broad singlet);
who)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-106)

71(i) N-(3-Fluoro-4-methoxybenzylidene)-4-sulfanilamide

Following a similar procedure to that described in example 1(i), but using as starting materials 3-fluoro-4-methoxybenzaldehyde and 4-sulfamerazine got mentioned in the title compound as yellow powder (yield 57%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

to 8.40 (1H, singlet);

a 7.92 (2H, doublet, J = 9 Hz);

7,74 (1H, doublet of doublets, J = 2 and 8 Hz);

a 7.62 (1H, doublet, J = 9 Hz);

of 7.25 (2H, doublet, J = 9 Hz);

for 7.12 (1H, doublet, J = 8 Hz);

7,02 (2H, broad singlet);

of 3.97 (3H, singlet).

71(ii) - (3-Fluoro-4-methoxyphenyl) -- (4-sulfamerazine)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as the starting material N-(3-fluoro-4-methoxybenzylidene)-4-sulfamerazine [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as yellow powder (yield 98%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

of 7.69 (2H, doublet, J = 9 Hz);

7,37 - 7,33 (2H, multiplet);

7,13 - 7,05 (1H, Shir is 1H, multiplet);

3,91 (3H, singlet).

71(iii) 2-(3-Fluoro-4-medociprin)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - (3-fluoro-4-methoxyphenyl) -- (4-sulfamerazine)acetonitrile [obtained as written above in stage (ii)] and methacrolein got mentioned in the title compound as a white powder (yield 28%), melting at 170 - 173oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,86 (2H, doublet, J = 9 Hz);

of 7.23 (2H, doublet, J = 9 Hz);

6,90 - for 6.81 (3H, multiplet);

6,79 (1H, doublet, J = 2 Hz);

6,74 (1H, doublet, J = 2 Hz);

4,82 (2H, broad singlet);

a 3.87 (3H, singlet);

2,17 (3H, singlet).

Mass spectrum (EI) m/z: 360 [M+].

Example 72

2-(2,4-Differenl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-115)

72(i) N-(2,4-Differenziale)-4-sulfanilamide

Following a similar procedure to that described in example 1(i), but using as starting material 2,4-diferentialglea and 4-sulfamerazine got mentioned in the title compound as a pale yellow powder (yield 52%).

Range nuclear magnet,97 (2H, doublet of doublets, J = 2 and 7 Hz);

7,28 (2H, doublet of doublets, J = 2 and 7 Hz);

7,05 - 6,98 (1H, multiplet);

6,95 - 6,87 (1H, multiplet);

4,88 (2H, broad singlet).

72(ii) - (2,4-Differenl) -- (4-sulfamerazine)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material N-(2,4-differenziale)-4-sulfamerazine [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as a pale yellow powder (yield 88%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

7,76 (2H, doublet, J = 9 Hz);

7,71 - the 7.65 (1H, multiplet);

7,05 - 6,92 (2H, multiplet);

PC 6.82 (2H, doublet, J = 9 Hz);

6,79 (1H, multiplet);

6,37 (2H, broad singlet);

5,73 (1H, doublet, J = 9 Hz).

72(iii) 2-(2,4-Differenl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - (2,4-differenl) -- (4-sulfamerazine)acetonitrile [obtained as described above in stage (ii)] and methacrolein got mentioned in the title compound as pale brown Poo
) memorial plaques

to 7.84 (2H, doublet, J = 9 Hz);

then 7.20 (2H, doublet, J = 9 Hz);

7,21 - 7,13 (1H, multiplet);

6,87 is 6.67 (2H, multiplet);

to 6.80 (1H, broad singlet);

of 6.31 (1H, broad singlet);

is 4.85 (2H, broad singlet);

are 2.19 (3H, singlet).

Mass spectrum (EI) m/z: 348 [M+].

Example 73

2-(4-Methoxyphenyl)-3-methyl-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-76)

Following a similar procedure to that described in example 52(iii), but using crotonic aldehyde instead of methacrolein got mentioned in the title compound as a brown amorphous powder (yield 21%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,79 (2H, doublet, J = 9 Hz);

7,16 (2H, doublet, J = 9 Hz);

7,01 (2H, doublet, J = 9 Hz);

to 6.88 (1H, doublet, J = 3 Hz);

6,83 (2H, doublet, J = 9 Hz);

6,28 (1H, doublet, J = 3 Hz);

a 4.86 (2H, singlet);

of 3.80 (3H, singlet);

and 2.14 (3H, singlet).

Mass spectrum (EI) m/z: 342 [M+].

Example 74

2-(3,4-Differenl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-112)

74(i) N-(3,4-Differenziale)-4-sulfanilamide

Following a similar procedure to that described in example 1(i), but using as starting material 3,4-diferent 67%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

to 8.40 (1H, singlet);

of 7.96 (2H, doublet of doublets, J = 7 and 2 Hz);

7,89 - 7,81 (1H, multiplet);

to 7.67 to 7.62 (1H, multiplet);

7,37 - 7,24 (1H, multiplet);

of 7.25 (2H, doublet of doublets, J= 7 and 2 Hz);

of 6.71 (2H, broad singlet).

74(ii) - (3,4-Differenl) -- (4-sulfamerazine)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material N-(3,4-differenziale)-4-sulfamerazine [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as yellow powder (yield 92%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

7,76 (2H, doublet, J = 9 Hz);

7,52 - 7,24 (3H, multiplet);

6,82 - 6,79 (3H, multiplet);

6,28 (2H, broad singlet);

5,64 (1H, doublet, J = 8 Hz).

74(iii) 2-(3,4-Differenl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - (3,4-differenl) -- (4-sulfamerazine)acetonitrile [obtained as opisowych 51%), melting at 177 - 179oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,88 (2H, doublet of doublets, J = 2 and 7 Hz);

of 7.23 (2H, doublet of doublets, J = 2 and 7 Hz);

7,08 - 6,89 (2H, multiplet);

for 6.81 - 6,76 (1H, multiplet);

6,74 (1H, doublet, J = 2 Hz);

of 6.29 (1H, doublet, J = 2 Hz);

at 4.99 (2H, broad singlet);

2,17 (3H, singlet).

Mass spectrum (EI) m/z: 348 [M+].

Example 75

1-(2,4-Differenl)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrole (Compound 1-122 N)

75(i) 2,4-Debtor-N-(4-sulfamoylbenzoyl)aniline

Following a similar procedure to that described in example 1(i), but using as starting materials 4-sulfamoylbenzoic and 2,4-diferencia got mentioned in the title compound as a white powder (yield 47%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) / memorial plaques

8,79 (1H, singlet);

to 8.12 (2H, doublet, J = 8 Hz);

of 7.97 (2H, doublet, J = 8 Hz);

7,58 - 7,34 (4H, multiplet);

7,21 - 7,13 (1H, multiplet).

75(ii) - (2,4-Diptiranjan) -- (4-sulfamoylbenzoyl)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material 2,4-ditto the Chile specified in the title compound as a white powder (yield 100%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

to $ 7.91 (2H, doublet, J = 8 Hz);

7,76 (2H, doublet, J = 8 Hz);

7,44 (2H, singlet);

7,25 - 7,17 (1H, multiplet);

6,97 - 6,94 (2H, multiplet);

of 6.73 (1H, doublet, J = 10 Hz);

of 6.17 (1H, doublet, J = 10 Hz).

75(iii) 1-(2,4-Differenl)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - (2,4-diptiranjan) -- (4-sulfamoylbenzoyl)acetonitrile [obtained as described above in stage (ii)] and methacrolein got mentioned in the title compound as a white powder (yield 63%), melting at 140 - 141oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

of 7.75 (2H, doublet, J = 8 Hz);

of 7.23 - 7,16 (3H, multiplet);

6,94 - to 6.88 (2H, multiplet);

6,69 (1H, singlet);

to 6.43 (1H, singlet);

at 4.99 (2H, singlet);

of 2.20 (3H, singlet).

Mass spectrum (EI) m/z: 348 [M+].

Example 76

2-(4-Methoxyphenyl)-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-73)

Following a similar procedure to that described in example 52(iii), but using acrolein instead of methacrolein, got specified the Range of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,92 - to 7.84 (2H, multiplet);

7,39 - of 7.23 (2H, multiplet);

7,11? 7.04 baby mortality (2H, multiplet);

6,95 - 6,93 (1H, multiplet);

6,82 - of 6.78 (2H, multiplet);

to 6.39 (2H, multiplet);

4,84 (2H, singlet);

of 3.80 (3H, singlet).

Mass spectrum (EI) m/z: 342 [M+].

Example 77

4-Methyl-2-phenyl-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-60)

77(i) N-Benzylidene-4-sulfanilamide

Following a similar procedure to that described in example 1(i), but using as starting materials benzaldehyde and 4-sulfamerazine got mentioned in the title compound as a pale yellow powder (yield 91%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

to 8.45 (1H, singlet);

7,97 - of 7.90 (2H, multiplet);

of 7.95 (2H, doublet, J = 9 Hz);

EUR 7.57 - 7,47 (3H, multiplet);

of 7.25 (2H, doublet. J = 9 Hz);

6,74 (2H, broad singlet).

77(ii) - Phenyl -- (4-sulfamerazine)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting materials N-benzylidene-4-sulfamerazine [obtained as described above in stage (i)] and trimethylsilylacetamide, has been specified for the MHz, hexadeuterated dimethyl sulfoxide) M. D.

for 7.78 (2H, doublet, J = 9 Hz);

of 7.64 - to 7.61 (2H, multiplet);

7,55 - 7,47 (3H, multiplet);

6,85 (2H, doublet, J = 9 Hz);

of 6.52 (1H, broad doublet, J = 8 Hz);

6,24 (2H, broad singlet);

to 5.66 (1H, broad doublet, J = 8 Hz);

77(iii) 4-Methyl-2-phenyl-1-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials - phenyl -- (4-sulfamerazine)acetonitrile [obtained as described above in stage (ii)] and methacrolein got mentioned in the title compound as a pale yellow powder (yield 47%), melting at 165 - 168oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

to 7.84 (2H, doublet of doublets, J = 2 and 7 Hz);

of 7.23 (2H, doublet of doublets, J = 2 and 7 Hz);

7,28 - 7,20 (3H, multiplet);

7,12 - to 7.09 (2H, multiplet);

to 6.75 (1H, doublet, J = 2 Hz);

of 6.31 (1H, doublet, J = 2 Hz);

4,88 (2H, broad singlet);

to 2.18 (3H, singlet).

Mass spectrum (EI) m/z: 312 [M+].

Example 78

4-Methyl-2-(3,4-dimetilfenil)-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-118)

78(i) N-(3,4-Dimethylbenzylidene)-4-sulfanilamide

Following a similar procedure to that obisanya, got mentioned in the title compound as a pale yellow powder (yield 45%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

at 8.36 (1H, singlet);

a 7.92 (2H, doublet, J = 9 Hz);

of 7.69 (1H, doublet, J = 2 Hz);

to 7.59 (1H, doublet of doublets, J = 1 and 7 Hz);

7,26 - was 7.08 (1H, multiplet);

7,22 (2H, doublet, J = 9 Hz);

6,46 (2H, broad singlet);

of 2.34 (3H, singlet).

78(ii) - (3,4-Dimetilfenil) -- (4-sulfamerazine)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material N-(3,4-dimethylbenzylidene)-4-sulfamerazine [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as yellow powder (yield 91%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

7,72 (2H, doublet, J = 9 Hz);

7,34 (1H, singlet);

7,30 (1H, doublet, J = 8 Hz);

then 7.20 (1H, doublet, J = 8 Hz);

PC 6.82 (2H, doublet, J = 9 Hz);

6,74 - 6,70 (1H, broad multiplet);

6,56 (2H, broad multiplet);

5,54 (1H, broad doublet. J = 8 Hz);

of 2.30 (3H, singlet);

to 2.29 (3H, singlet).

78(iii) 4-Methyl-2-(3,4-dimethypentane as source materials (3,4-dimetilfenil) -- (4-sulfamerazine)acetonitrile [obtained as described above in stage (ii)] and methacrolein got mentioned in the title compound as a brownish amorphous powder (yield 69%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,83 (2H, doublet, J = 9 Hz);

7,22 (2H, doublet, J = 9 Hz);

6,98 - to 6.95 (2H, multiplet);

to 6.75 (1H, multiplet);

6,72 (1H, broad multiplet);

of 6.25 (1H, doublet, J = 7 Hz);

4,84 (2H, broad singlet);

of 2.23 (3H, singlet);

are 2.19 (3H, singlet);

2,17 (3H, singlet).

Mass spectrum (EI) m/z: 340 [M+].

Example 79

2-(3-Chloro-4-methoxyphenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-100)

79(i) N-(3-Chloro-4-methoxybenzylidene)-4-sulfanilamide

Following a similar procedure to that described in example 1(i), but using as starting materials 3-chloro-4-methoxybenzaldehyde and 4-sulfamerazine got mentioned in the title compound as a pale yellow powder (yield 72%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

of 8.37 (1H, singlet);

of 8.00 (1H, doublet, J = 2 Hz);

to 7.93 (1H, doublet, J = 9 Hz);

to 7.77 (1H, doublet doublet the singlet).

79(ii) - (3-Chloro-4-methoxyphenyl) -- (4-sulfamerazine)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material N-(3-chloro-4-methoxybenzylidene)-4-sulfamoyl [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as yellow powder (yield 64%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

7,76 - 7,46 (4H, multiplet);

7,02 (1H, doublet, J = 9 Hz);

to 6.80 (2H, doublet, J = 9 Hz);

of 6.71 return of 6.58 (1H, broad multiplet);

6,44 - 6,27 (2H, broad multiplet);

to 5.57 (1H, broad doublet, J = 8 Hz);

of 3.94 (3H, singlet).

79(iii) 2-(3-Chloro-4-methoxyphenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(III), but using as starting materials - (3-chloro-4-methoxyphenyl) -- (4-sulfamerazine)acetonitrile [obtained as described above in stage (ii)] and methacrolein got mentioned in the title compound as yellow powder (yield 37%), melting at 160 - 163oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

9 Hz);

is 6.78 (1H, doublet, J = 9 Hz);

of 6.73 (1H, broad multiplet);

of 6.25 (1H, doublet, J = 2 Hz);

a 4.83 (2H, broad singlet);

3,88 (3H, singlet);

2,17 (3H, singlet).

Mass spectrum (EI) m/z: 376 [M+].

Example 80

2-(4-Methoxyphenyl)-4-methyl-1-(4-methylsulfinylphenyl)pyrrole (Compound N 2-22)

Following a similar procedure to that described in example 28(iii), but using methacrolein instead of acrolein got mentioned in the title compound as a white powder (yield 36%, melting at 159 - 161oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

the 7.85 (2H, doublet, J = 9 Hz);

7,27 (2H, doublet, J = 9 Hz);

7,03 (2H, doublet, J = 9 Hz);

6,79 (2H, doublet, J = 9 Hz);

6,74 (1H, singlet);

6,24 (1H, singlet);

of 3.80 (3H, singlet);

of 3.07 (3H, singlet);

to 2.18 (3H, singlet).

Mass spectrum (FAB) m/z: 341 [M+].

Example 81

4-(3-Cyclopentyloxy-4-methoxybenzyl)-2-(4-methoxyphenyl)-1- (4-sulfamoylbenzoyl)pyrrole (Compound N 2-150)

81(i) of Diethyl - (4-methoxyphenacyl)malonate

In 60 ml of anhydrous tetrahydrofuran was dissolved 3.50 g (to 21.8 mmol) of diethylmalonate and to the resulting solution were added under ice cooling 2.70 g (24,0 mmol) of tert-butoxide potassium. A mixture of AC is the solution of 5.00 g (to 21.8 mmol) of 4-methoxybenzylamine in 40 ml of anhydrous tetrahydrofuran. The mixture was stirred under ice cooling for 1 hour and then was added a saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous magnesium sulfate, and then solvent was removed by distillation under reduced pressure. The residue was transferred to a chromatographic column with silica gel and was suirable a mixture of ethyl acetate and hexane (1:4 by volume) to obtain 4,87 g specified in the title compound as yellowish oily substance (yield 73%). Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

of 7.97 (2H, doublet, J = 9 Hz);

6,94 (2H, doublet, J = 9 Hz);

of 4.25 (4H, Quartet of doublets, J = 7 and 2 Hz);

Android 4.04 (1H, triplet, J = 7 Hz);

3,88 (3H, singlet);

to 3.58 (2H, doublet, J = 7 Hz);

of 1.29 (6H, triplet, J = 7 Hz).

81(ii) Diethyl -(3-cyclopentyloxy-4-methoxybenzyl)--(4-methoxyphenacyl)malonate

To 50 ml of anhydrous tetrahydrofuran was added to 0.29 g (7.1 mmol) of sodium hydride (60% dispersion in mineral oil) and the resulting mixture was stirred for 10 minutes. At the end of this time the mixture was slowly added dropwise under ice cooling a solution of 2.00 g (6.5 mol) of diethyl - (4-methoxyphenacyl)malonate [received, the Lyali to the mixture solution 1,72 g (7.1 mol) of 3-cyclopentyloxy-4-methoxybenzylamine in 20 ml of anhydrous tetrahydrofuran and 0.97 g (6.5 mmol) of sodium iodide and the resulting mixture was heated under reflux for 2 hours. At the end of this time the mixture was cooled to room temperature, then acidified by adding 3 n solution chloroethanol acid and was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous magnesium sulfate, and then solvent was removed by distillation under reduced pressure. The residue was transferred to a chromatographic column with silica gel and was suirable a mixture of ethyl acetate and hexane (1:4 by volume) with the receipt of 2.45 g specified in the title compounds as a pale yellow oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

to $ 7.91 (2H, doublet, J = 9 Hz);

6,91 (2H, doublet, J = 9 Hz);

of 6.68 (1H, doublet, J = 8 Hz);

of 6.45 (1H, doublet of doublets, J = 8 and 2 Hz);

6,36 1H, doublet, J = 2 Hz);

or 4.31 - 4,22 (1H, multiplet);

4,24 (4H, Quartet, J = 7 Hz);

3,86 (3H, singlet);

of 3.77 (3H, singlet);

to 3.49 (3H, singlet);

3,44 (3H, singlet);

1,72 - of 1.45 (8H, multiplet);

of 1.27 (6H, triplet, J = 7 Hz).

81(iii) Ethyl - (3-cyclopentyloxy-4-methoxybenzyl) -- (4-methoxyphenyl)acetate

In 50 ml of benzene was dissolved 2,43 g (4.7 mmol) of diethyl - (3-cyclopentyloxy-4-methoxybenzyl) -- (4-methoxyphenacyl)malonate [obtained as described above in Alia in ethanol. The mixture was stirred 30 minutes, then was removed from the reaction mixture, the ethanol by distillation under reduced pressure. The remaining reaction solution was heated under reflux for 14 hours and then cooled the reaction mixture to room temperature. Next, the mixture was acidified by adding 3 N. aqueous solution chloroethanol acid and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous magnesium sulfate, and then solvent was removed by distillation under reduced pressure. The residue was transferred to a chromatographic column with silica gel and was suirable a mixture of ethyl acetate and hexane (1:4 by volume) to give 1.68 g specified in the title compound as yellowish crystals (yield 81%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

a 7.92 (2H, doublet, J = 9 Hz);

make 6.90 (2H, doublet, J = 9 Hz);

is 6.78 (1H, doublet, J = 8 Hz);

6,74 is 6.67 (2H, multiplet);

4,76 - of 4.67 (1H, multiplet);

of 4.12 (2H, Quartet, J = 7 Hz);

3,86 (3H, singlet);

is 3.82 (3H, singlet);

3,39 - up 3.22 (2H, multiplet);

3,07 of 2.92 (2H, multiplet);

2,83 - of 2.72 (1H, multiplet);

1,97 - of 1.53 (8H, multiplet);

to 1.19 (3H, triplet, J = 7 Hz).

81(iv) 4-(the new ether was dissolved 200 mg (0.46 mmol) ethyl - (3 cyclopentyloxy-4-methoxybenzyl) -- (4-methoxyphenacyl)acetate [obtained as described above in stage (iii)] and to the resulting solution was added with ice cooling to 20 mg (of 0.68 mmol) sociallyengaged. The mixture was stirred for 1 hour under ice cooling. At the end of this time was added to the mixture, 30 μl of water, 30 μl of 15% (wt/vol) aqueous sodium hydroxide solution and 80 μl of water in this order and the resulting mixture was stirred at room temperature for 10 minutes. For the dehydration of the reaction mixture were added thereto anhydrous magnesium sulfate, after which the mixture was filtered using an auxiliary filtering material Celite (trademark). Then the filtrate was concentrated by evaporation under reduced pressure to obtain 140 mg of the residue.

All this residue was dissolved in 20 ml of methylene chloride and the resulting solution was added 1.70 g (4,59 mmol) of pyridinium dichromate, after which the mixture was stirred at room temperature overnight. Filtered the reaction mixture through the auxiliary filtering material Celite (trade mark) and the filtrate was concentrated by evaporation under reduced pressure to obtain a residue. The obtained residue was transferred to chromatogr the nogo -(3-cyclopentyloxy-4-methoxybenzyl)--(4-methoxyphenacyl)of acetaldehyde in the form of a pale brown oily substance. All of this product was dissolved in 3 ml of acetic acid and the resulting solution was added 26 mg (0.15 mmol) 4-sulfamerazine. The mixture was heated under reflux for 1 hour, and then deleted the acetic acid by distillation under reduced pressure. To the residue was added water and the mixture was neutralized with a saturated aqueous solution of sodium bicarbonate. Then the mixture was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous magnesium sulfate, and then solvent was removed by distillation under reduced pressure. Resulting balance was transferred to the chromatographic column with silica gel and was suirable a mixture of ethyl acetate and hexane (1: 2 by volume) to obtain 20 mg indicated in the title compound as a yellow powder (yield 9%), melting at 81 - 84oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

of 7.82 (2H, doublet, J = 9 Hz);

then 7.20 (2H, doublet, J = 9 Hz);

7,02 (2H, doublet, J = 9 Hz);

6,87 - 6,72 (5H, multiplet);

6,63 (1H, broad singlet);

6,24 (1H, doublet, J = 2 Hz);

4,84 (2H, broad singlet);

4,80 - 4,70 (1H, multiplet);

a 3.83 (3H, singlet);

of 3.80 (2H, singlet);

of 3.78 (3H, singlet);

1,95 - of 1.53 (8H, multiplet).


To a solution 6,46 g (50 mmol) of Diisopropylamine, 39 g of molecular sieves 4 and 10 mg of 2,6-di-tert-butyl-4-METHYLPHENOL in 50 ml of tetrahydrofuran was added under a stream of nitrogen 4,36 g (75 mmol) of propionic aldehyde and the mixture was left to stand for 3 hours. At the end of this time, to the mixture was added 5.73 g (25 mmol) of 4'-methoxy-2-braziliera and the mixture was left overnight to stand at room temperature. Then the reaction mixture was filtered and to the filtrate was added 55 ml of 1 N. aqueous solution chloroethanol acid to separate it into a liquid phase. The aqueous layer was separated and was extracted twice with ethyl acetate. The organic extracts were combined and washed with water and saturated aqueous sodium chloride, in that order. The resulting solution was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. Resulting balance was transferred to the chromatographic column with silica gel and was suirable with a mixture of hexane and ethyl acetate (2: 1 by volume) and as a result got 2,82 g (yield 26%) indicated in the title compounds as a pale yellow oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

9,80 (1H, singlet);

of 7.96 (2H,7 - 3,03 (1H, multiplet);

of 2.97 (1H, doublet of doublets, J = 6 and 17 Hz);

of 1.23 (3H, doublet, J = 7 Hz).

82(ii) 1-(4-Acetylbenzenesulfonyl)-2-(4-methoxyphenyl)-4-methylpyrrole

The solution 2,82 g (12.8 mmol) of 3-(4-methoxybenzoyl)-2-methylpropionamidine [obtained as described above in stage (i)] and is 2.74 g (12.8 mmol) of 4-acetylaminofluorene in 30 ml of acetic acid was heated under reflux for 3 hours, and then deleted the acetic acid by distillation under reduced pressure. The residue was dissolved in chloroform and the resulting solution was added to its separation into a liquid phase saturated aqueous solution of sodium bicarbonate. The organic extract was washed with water and saturated aqueous sodium chloride in that order and dried over anhydrous magnesium sulfate, and then concentrated by evaporation under reduced pressure. Resulting balance was transferred to the chromatographic column with silica gel and was suirable with a mixture of hexane and ethyl acetate (2: 3 by volume). Then it was recrystallized from ethanol to obtain 0,79 g (yield 16%) indicated in the title compound as a white powder, melting at 215 - 217oC.

Range nuclear R> from 7.24 (2H, doublet, J = 9 Hz);

7,03 (2H, doublet, J = 9 Hz);

6,79 (2H, doublet, J = 9 Hz);

of 6.73 (1H, singlet);

6,23 (1H, singlet);

of 3.80 (3H, singlet);

2,17 (3H, singlet);

of 2.09 (3H, singlet).

Mass spectrum (FAB) m/z: 384 [M+]

Example 83

1-(4-Acetylbenzenesulfonyl)-2-(3,4-dimetilfenil)-4-methylpyrrole (Compound N 2-149)

82(i) Ethylenically 3-bromo-2-methylpropionamidine

Into the flask was loaded 16,03 ml (0.12 mol) of tetralin and to it was added dropwise under ice cooling 24,27 ml (0.47 mol) of bromine. Obtained in this gazoobraznye bromovalerate was Rublyovo through a tube in 55,21 ml (0,99 mol) of ethylene glycol under ice cooling. 4 hours to the mixture was added dropwise 25 ml (0.30 mol) of methacrolein and then stirred at room temperature for 1 hour. Next, the reaction mixture was extracted twice with pentane and the organic extract washed with 5% aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, in that order. Then it was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was distilled under reduced pressure to get 29,81 g (51% yield) specified in the connection header in vinovo resonance (270 MHz, CDCl3) memorial plaques

a 4.83 (1H, doublet, J = 5 Hz);

4,03 - a-3.84 (4H, multiplet);

of 3.53 (1H, doublet of doublets, J = 5 and 10 Hz);

3,37 (1H, doublet of doublets, J = 5 and 10 Hz);

2,18 is 2.01 (1H, multiplet);

a 1.11 (3H, doublet, J = 7 Hz).

83(ii) Ethylenically 3-(3,4-dimethylbenzoyl)-2-methylpropionamidine

To a suspension of 1.66 g (68,1 mmol) of magnesium in 5 ml of anhydrous tetrahydrofuran was added under a stream of nitrogen to 0.29 ml (3.4 mmol) of 1,2-dibromethane. To the mixture was added dropwise under ice cooling 9,96 g (51,1 mmol) ethylenically 3-bromo-2-methylpropionamidine [obtained as described above in stage (i)], after which the mixture was stirred for 1 hour. Then to the mixture was added dropwise a solution to 6.58 g (34,1 mmol) of N-methoxy-N-methyl-3,4-dimethylbenzamide in 30 ml of tetrahydrofuran and the resulting mixture was stirred under ice cooling for 1 hour. Next, to the mixture was added saturated aqueous solution of ammonium chloride and the resulting mixture was extracted twice with ethyl acetate. The organic extracts were combined and washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. Resulting balance was transferred to khromatograficheskoe is related to the title compound as a colorless oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

of 7.75 (1H, singlet);

7,71 (1H, doublet, J = 8 Hz);

then 7.20 (1H, doublet, J = 8 Hz);

4,82 (1H, doublet, J = 4 Hz);

4,01 - a 3.83 (4H, multiplet);

3,18 (1H, doublet of doublets, J = 5 and 16 Hz);

was 2.76 (1H, doublet of doublets, J = 9, 16 Hz);

2,62 - 2,47 (1H, multiplet);

2,31 (6H, singlet);

of 1.02 (3H, doublet, J = 7 Hz).

83(iii) 1-(4-Acetylbenzenesulfonyl)-2-(3,4-dimetilfenil)-4 - methylpyrrole

In a mixture of 52 ml (52 mmol) of 1 N. aqueous solution chloroethanol acid and 16 ml of tetrahydrofuran was dissolved 3,26 g (of 13.1 mmol) ethylenically 3-(3,4-dimethylbenzoyl)-2-methylpropionamidine [obtained as described above in stage (ii)] and of 2.81 g (of 13.1 mmol) of 4-acetylaminofluorene and the mixture was heated at 70oC for 1 hour. By the end of that time gave the mixture to stand to cool. Then the mixture was extracted three times with ethyl acetate. The organic extracts were combined and washed with saturated aqueous sodium chloride. The resulting solution was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. Resulting balance was transferred to the chromatographic column with silica gel and was suirable with a mixture of hexane and et is agolove connection in the form of a white powder, melting at 192 - 193oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

of 7.95 (2H, doublet, J = 9 Hz);

8,05 - to 7.93 (1H, broad singlet);

of 7.25 (2H, doublet, J = 9 Hz);

6,98 (1H, doublet, J = 8 Hz);

6,93 (1H, singlet);

6,76 (1H, doublet, J = 8 Hz);

6,74 (1H, singlet);

of 6.26 (1H, singlet);

of 2.23 (3H, singlet);

2,17 (6H, singlet);

of 2.08 (3H, singlet).

Mass spectrum (EI) m/z: 382 [M+].

Example 84

4-Methyl-1-(4-methylthiophenyl)-2-(4-sulfamoylbenzoyl)pyrrole (Compound N 1-164)

84(i) 4-Methylthio-N-(4-sulfamoylbenzoyl)aniline

Following a similar procedure to that described in example 1(i), but using as starting materials 4-sulfamoylbenzoic and 4-methylthioinosine got mentioned in the title compound as a yellow powder (yield 95%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

8,76 (1H, singlet);

8,10 (2H, doublet, J = 8 Hz);

of 7.95 (2H, doublet, J = 8 Hz);

to 7.50 (2H, singlet);

7,33 (4H, multiplet);

of 2.50 (3H, singlet).

84(ii) -(4-Methylthioinosine)--(4-sulfamoylbenzoyl)acetonitrile

Following a similar procedure to that described in example 1(ii) but using the in phase (i)] and trimethylsilylacetamide, got mentioned in the title compound as a yellow powder (yield 100%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

a 7.92 (2H, doublet, J = 8 Hz);

of 7.75 (2H, doublet, J = 8 Hz);

was 7.45 (2H, singlet);

to 7.18 (2H, doublet, J = 9 Hz);

6,92 - of 6.78 (3H, multiplet);

x 6.15 (1H, doublet, J = 9 Hz);

of 2.38 (3H, singlet).

84(ii) 4-Methyl-1-(4-methylthiophenyl)-2-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials/ (4 methylthioinosine)--(4-sulfamoylbenzoyl)acetonitrile [obtained as described above in stage (ii)] and methacrolein got mentioned in the title compound as yellow powder (yield 33%), melting at 194 - 196oC.

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

rate of 7.54 (2H, doublet, J = 8 Hz);

7,29 - 7,20 (6H, multiplet);

7,10 (2H, doublet, J = 9 Hz);

to 6.88 (1H, singlet);

6,41 (1H, multiplet);

2,48 (3H, singlet);

of 2.10(3H, singlet).

Mass spectrum (EI) m/z: 358 [M+].

Example 85

1-(4-Ethylthiophene)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrole (Compound N 1-165)

85(i) 4-Atilt what whether as starting materials 4-sulfamoylbenzoic and 4-ethylthiourea, got mentioned in the title compound as a yellow powder (yield 56%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

8,76(1H, singlet);

8,10 (2H, doublet, J = 8 Hz);

of 7.95 (2H, doublet, J = 8 Hz);

to 7.50 (2H, singlet);

7,40 - 7,30 (4H, multiplet);

a 3.01 (2H, Quartet, J = 7 Hz);

1,27 - 1,22 (3H, multiplet).

85(ii) -(4-Achiltibuie)--(4-sulfamoylbenzoyl)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting materials 4-ethylthio-N-(4-sulfamoylbenzoyl)aniline [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as a yellow powder (yield 100%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

to $ 7.91 (2H, doublet, J = 8 Hz);

rate of 7.54 (2H, doublet, J = 8 Hz);

7,44 (2H, singlet);

of 7.23 (2H, doublet, J = 8 Hz);

6,93 (1H, doublet, J = 9 Hz);

to 6.80 (2H, doublet, J = 8 Hz);

6,14 (1H, doublet, J = 9 Hz);

and 2.79 (2H, Quartet, J = 7 Hz);

to 1.14 (3H, triplet, J = 7 Hz).

85(iii) 1-(4-Ethylthiophene)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in PR the sludge [received so as described above in stage (ii)] and methacrolein got mentioned in the title compound as yellow powder (yield 69%), melting at 139 - 141oC.

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

the 7.65 (2H, doublet, J = 8 Hz);

7,34 - 7,31 (4H, multiplet);

7,21 (2H, doublet, J = 9 Hz);

7,10 (2H, doublet, J = 8 Hz);

make 6.90 (1H, singlet);

6.42 per - 6,41 (1H, multiplet);

to 2.99 (2H, Quartet, J = 7 Hz);

of 2.10 (3H, singlet);

to 1.24 (3H, triplet, J = 7 Hz).

Mass spectrum (EI) m/z: 372 [M+].

Example 86

4-Methyl-1-(3,4-dimetilfenil)-2-(4-sulfamoylbenzoyl)pyrrole (Compound N 1-160)

86(i) 3,4-Dimethyl-N-(4-sulfamoylbenzoyl)aniline

Following a similar procedure to that described in example 1(i), but using as starting materials 4-sulfamoylbenzoic and 3,4-dimethylaniline, got mentioned in the title compound as a yellow powder (yield 60%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

to 8.94 (2H, doublet, J = 8 Hz)

8,72 (1H, singlet);

7,94 (2H, doublet, J = 8 Hz)

of 7.48 (2H, singlet);

7,21 - 7,06 (3H, multiplet);

of 2.27 (3H, singlet);

of 2.24 (3H, singlet).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

to $ 7.91 (2H, doublet, J = 8 Hz);

7,53 (2H, doublet, J = 8 Hz);

7,44 (2H, singlet);

6,93 (1H, doublet, J = 8 Hz);

of 6.66 (1H, multiplet);

6,57 - of 6.49 (1H, multiplet);

6,07 (1H, doublet, J = 10 Hz);

and 2.14 (3H, singlet);

of 2.10 (3H, singlet).

86(iii) 4-Methyl-1-(3,4-dimetilfenil)-2-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials -(3,4-dimethylaniline)--(4-sulfamoylbenzoyl)acetonitrile [obtained as described above in stage (ii)] and methacrolein got mentioned in the title compound as yellow powder (yield 43%), melting at 118 - 120oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

of 7.82 (2H, doublet, J = 8 Hz);

7,19 (2H, doublet, J = 8 Hz);

7,05 (1H, doublet, J = 8 Hz);

6,97 (1H, singlet);

6,79 (1H, doublet, J = 8 Hz);

of 6.73 (1H, C).

Mass spectrum (EI) m/z: 340 [M+].

Example 87

4-Methyl-2-(3, 5dimethylphenyl)-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-147)

87(i) N-(3,5-Dimethylbenzylidene)-4-sulfanilamide

Following a similar procedure to that described in example 1(i), but using as starting material 3,5-dimethylbenzaldehyde and 4-sulfamerazine got mentioned in the title compound as a pale yellow powder (yield 59%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

8,55 (1H, singlet);

the 7.85 (2H, doublet, J = 8 Hz);

EUR 7.57 (2H, singlet);

7,37 (4H, doublet, J = 8 Hz);

7,22 (1H, singlet);

of 2.35 (6H, singlet).

87(ii) -(3, 5dimethylphenyl)--(4-sulfamerazine)acetonitrile

Following a similar procedure to that described in example 1(ii), but using as starting material N-(3,5-dimethylbenzylidene-4-sulfamerazine [obtained as described above in stage (i)] and trimethylsilylacetamide got mentioned in the title compound as a pale yellow powder (yield 90%).

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

to 7.61 (2H, doublet, J = 8 Hz);

7,29 (1H

of 2.30(6H, singlet).

87(iii) 4-Methyl-2-(3, 5dimethylphenyl)-1-(4-sulfamoylbenzoyl)pyrrol

Following a similar procedure to that described in example 1(iii), but using as starting materials -(3, 5dimethylphenyl)--(4-sulfamerazine)acetonitrile [obtained as described above in stage (ii)] and methacrolein got mentioned in the title compound as brown powder (yield 28%), melting at 163 - 166oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,83 (2H, doublet, J = 9 Hz);

of 7.23 (2H, doublet, J = 9 Hz);

6,85 (1H, singlet);

of 6.73 (3H, singlet);

6,27 (1H, doublet, J = 2 Hz);

is 4.85 (2H, singlet);

of 2.21 (6H, singlet);

2,17 (3H, singlet).

Mass spectrum (EI) m/z: 340 [M+].

Example 88

3-Methyl-2-(4-methylthiophenyl)-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-83)

Following a similar procedure to that described in example 66(iii), but using crotonic aldehyde instead of methacrolein got mentioned in the title compound as a pale yellow powder (yield 24%), melting at 132 - 134oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,81 (2H, doublet, J = 9 Hz);

to 7.18 (2H, doublet, J =;

4,78 (2H, singlet);

2,48 (3H, singlet).

of 2.15 (3H, singlet).

Mass spectrum (EI) m/z: 358 [M+].

Example 89

1-(4-Methoxyphenyl)-5-methyl-2-(4-sulfamoylbenzoyl)pyrrole (Compound N 1-88)

Following a similar procedure to that described in example 61(iii), but using methyl vinyl ketone are instead of acrolein got mentioned in the title compound as a pale yellow powder (yield 39%), melting at 196 - 197oC.

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

7,56 (2H, doublet, J = 7 Hz);

7,22 (2H, singlet);

7,16 - 7,13 (4H, multiplet);

of 6.99 (2H, doublet, J = 7 Hz);

6,46 - 6,44 (1H, multiplet);

6,07 (1H, multiplet);

of 3.33 (3H, singlet);

2,03 (3H, singlet).

Mass spectrum (EI) m/z: 342 [M+].

Example 90

5-Methyl-1-(4-methylthiophenyl)-2-(4-sulfamoylbenzoyl)pyrrole (Compound N 1-95)

Following a similar procedure to that described in example 84(iii), but using methyl vinyl ketone are instead of methacrolein got mentioned in the title compound as a yellow powder (yield 65%), melting at 139 - 141oC.

Spectrum of nuclear magnetic resonance (270 MHz, hexadecacarbonyl timetrouble, J = 3 Hz);

of 2.50 (3H, singlet);

2,07 (3H, singlet).

Mass spectrum (EI) m/z: 358.

Example 91

1-(4-Chlorophenyl)-5-methyl-2-(4-sulfamoylbenzoyl)pyrrole (Compound 1-98 N)

Following a similar procedure to that described in example 59(iii), but using methyl vinyl ketone are instead of acrolein got mentioned in the title compound as a pale yellow powder (yield 44%), melting at 152 - 154oC.

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

to 7.61 (2H, doublet, J = 8 Hz);

7,53 (2H, doublet, J = 8 Hz);

7,28 - 7,20 (4H, multiplet);

to 7.15 (2H, doublet, J = 8 Hz);

of 6.49 (1H, doublet, J = 3 Hz);

6,12 (1H, doublet, J = 3 Hz);

of 2.08 (3H, singlet).

Mass spectrum (EI) m/z: 346 [M+].

Example 92

1-(4-Methylthiophenyl)-2-(4-sulfamoylbenzoyl)pyrrole (Compound 1-93 N)

Following a similar procedure to that described in example 84(iii), but using acrolein instead of methacrolein got mentioned in the title compound as a pale yellow powder (yield 15%), melting at 159 - 161oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

of 7.75 (2H, doublet, J = 9 Hz);

7,26 - 7,21 (4H, multiplet);

7,10 Hz);

4,82 (2H, singlet);

of 2.50 (3H, singlet).

Mass spectrum (Ei) m/z: 344 [M+].

Example 93

1-(2,4-Dichlorophenyl)-2-(4-sulfamoylbenzoyl)pyrrole (Compound N 1-127)

Following a similar procedure to that described in the three stages of examples 19(i) 19(ii) 19(iii), but using as starting material 2,4-dichloraniline instead of 4-foranyone got mentioned in the title compound as a white powder, melting at 147 - 149oC. the Total output connections on all three stages was 15%.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,79 (2H, doublet, J = 9 Hz);

7,42 and 7.36 (2H, multiplet);

7,26 - of 7.23 (2H, multiplet);

of 6.96 - of 6.90 (2H, multiplet);

of 6.50 (1H, doublet of doublets, J = 3 and 1 Hz);

6,40 (1H, triplet, J = 3 Hz);

to 4.87 (2H, singlet).

Mass spectrum (EI) m/z: 366 [M+].

Example 94

1-(4-Ethoxyphenyl)-2-(4-sulfamoylbenzoyl)pyrrole (Compound N 1-89)

Following a similar procedure to that described in the three stages of examples 19(i) 19(ii) 19(iii), but using as starting material 4-edocengine instead of 4-foranyone got mentioned in the title compound as a white powder, melting at 126 - 128oC. Total yield compounds the initial sulfoxide) M. D.

the 7.65 (2H, doublet, J = 8 Hz);

7,30 - 7,22 (4H, multiplet);

7,14 - 7,06 (3H, multiplet);

of 6.96 (2H, doublet, J = 9 Hz);

6,56 (1H, doublet of doublets, J = 3 and 1 Hz);

6,32 (1H, triplet, J = 3 Hz);

Android 4.04 (2H, Quartet, J = 7 Hz);

of 1.33(3H, triplet, J = 7 Hz).

Example 95

4-Methyl-2-(4-methylsulfinylphenyl)-1-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-151)

In 50 ml of chloroform was dissolved 0.35 g (1.0 mmol) of 4-methyl-2-(4-methylthiophenyl)-1-(4-sulfamoylbenzoyl)pyrrole [obtained as described in example 66] and to the resulting solution was added in several portions under ice cooling 0.27 g (1.1 mmol) of 70% m-chloroperbenzoic acid, after which the mixture was stirred for 1 hour under ice cooling. Diluted the reaction mixture with chloroform and washed it 10% (weight/volume) aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium bicarbonate twice each in the order listed. Then the organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. Resulting balance was transferred to the chromatographic column with silica gel and was suirable mixture of methylene chloride and methanol (95: 5 by volume) to obtain a 0.23 g (yield 63%) powder pale orange color ptx2">

7,88 (2H, doublet, J = 9 Hz);

7,52 (2H, doublet, J = 8 Hz);

7,26 (2H, doublet, J = 3 Hz);

of 7.25 (2H, doublet, J = 3 Hz);

6,79 (1H, singlet);

to 6.39 (1H, doublet, J = 2 Hz);

the 4.90 (2H, singlet);

to 2.74 (3H, singlet);

2,22 (3H, singlet).

Mass spectrum (EI) m/z: 374 [M+].

Example 96

4-Methyl-1-(4-methylsulfinylphenyl)-2-(4-sulfamoylbenzoyl)pyrrole (Compound N 2-153)

4-Methyl-1-(4-methylthiophenyl)-2-(4-sulfamoylbenzoyl)pyrrole (obtained as described in example 84) was oxidized in the same manner as described in example 95, and the result was indicated in the title compound as a white powder (yield 84%), melting at 249 - 251oC.

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

7,73 - 7,66 (4H, multiplet);

7,37 - 7,31 (4H, multiplet);

of 7.23 (2H, doublet, J = 8 Hz);

7,00 (1H, multiplet);

6,46 (1H, multiplet);

2,78 (3H, singlet);

a 2.12 (3H, singlet).

Mass spectrum (EI) m/z: 374 [M+].

Example 97

5-Chloro-1-(4-methoxyphenyl)-2-(4-sulfamoylbenzoyl)pyrrole (Compound N 1-147)

1-(4-Methoxyphenyl)-2-(4-sulfamoylbenzoyl)pyrrole (obtained as described in example 61) was chlorinated in the same manner as described in example 37, and as a result p is>. Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

of 7.69 (2H, doublet, J = 8 Hz);

7,17 (2H, doublet, J = 8 Hz);

7,11 (2H, doublet, J = 9 Hz);

6,92 (2H, doublet, J = 9 Hz);

of 6.50 (1H, doublet, J = 4 Hz);

of 6.29 (1H, doublet, J = 4 Hz);

4,82 (2H, singlet);

of 3.85 (3H, singlet).

Mass spectrum (EI) m/z: 362 [M+].

Example 98

5-Bromo-1-(4-methoxyphenyl)-2-(4-sulfamoylbenzoyl)pyrrole (Compound N 1-148)

1-(4-Methoxyphenyl)-2-(4-sulfamoylbenzoyl)pyrrole (obtained as described in example 61) bromisovali in the same manner as described in example 35, and the result was indicated in the title compound as a pale yellow powder (yield 76%), melting at 121 - 123oC.

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

a 7.62 (2H, doublet, J = 8 Hz);

7,28 - 7,17 (6H, multiplet);

7,02 (2H, doublet, J = 9 Hz);

6,63 (1H, doublet, J = 4 Hz);

6,48 (1H, doublet, J = 4 Hz);

of 3.80 (3H, singlet).

Mass spectrum (EI) m/z 406 [M+].

Example 99

5-Chloro-1-(4-methoxyphenyl)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrole (Compound N 1-149)

1-(4-Methoxyphenyl)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrole (obtained as described in example 62) was chlorinated in the same abramoski (yield 80%), melting at 155 - 156oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

to 7.67 (2H, doublet, J = 9 Hz);

7,16 - 7,06 (4H, multiplet);

make 6.90 (2H, doublet, J = 9 Hz);

6,40 (1H, singlet);

4,94 (2H, singlet);

of 3.84 (3H, singlet);

and 2.14 (3H, singlet).

Mass spectrum (EI) m/z: 376 [M+].

Example 100

5-Chloro-1-(4-ethoxyphenyl)-2-(4-sulfamoylbenzoyl)pyrrole (Compound N 1-151)

1-(4-Ethoxyphenyl)-2-(4-sulfamoylbenzoyl)pyrrole (obtained as described in example 94) was chlorinated in the same manner as described in example 37, and the result was indicated in the title compound as a white powder (yield 93%), melting at 124 - 125oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

of 7.70 (2H, doublet, J = 9 Hz);

7,11 - 7,07 (4H, multiplet);

make 6.90 (2H, doublet, J = 9 Hz);

of 6.50 (1H, doublet, J = 4 Hz);

of 6.29 (1H, doublet, J = 4 Hz);

of 4.75 (2H, singlet);

4,06 (2H, Quartet, J = 7 Hz);

of 1.45 (3H, triplet, J = 7 Hz);

Mass spectrum (EI) m/z: 376 [M+].

Example 101

5-Chloro-1-(4-methylthiophenyl)-2-(4-sulfamoylbenzoyl)pyrrole (Compound 1-152 N)

1-(4-Methylthiophenyl)-2-(4-sulfamoylbenzoyl)pyrrole (obtained as described in example 92) was chlorinated in the same on the a (yield 68%), melting at 141 - 142oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,71 (2H, doublet, J = 9 Hz);

7,26 - 7,07 (6H, multiplet);

of 6.50 (1H, doublet, J = 4 Hz);

of 6.31 (1H, doublet, J = 4 Hz);

4,78 (2H, singlet);

2,52 (3H, singlet);

Mass spectrum (EI) m/z: 378 [M+].

Example 102

5-Chloro-1-(2,4-dichlorophenyl)-2-(4-sulfamoylbenzoyl)pyrrole (Compound N 1-155)

1-(2,4-Dichlorophenyl)-2-(4-sulfamoylbenzoyl)pyrrole (obtained as described in example 93) was chlorinated in the same manner as described in example 37, and the result was indicated in the title compound as a white powder (yield 73%), melting at 186 - 187oC.

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.

7,78 - to 7.67 (4H, multiplet);

7,32 - of 7.25 (5H, multiplet);

6,63 (1H, doublet, J = 4 Hz);

6,48 (1H, doublet, J = 4 Hz);

Mass spectrum (EI) m/z: 400 [M+].

Examples 103-111

Repeating a similar procedure to that described in example 19, steps (i) and (ii), but using as starting materials 4-sulfamoylbenzoic and different types of anilines, and as a result received appropriate - aniline --(4-sulfamoylbenzoyl)acetonitrile, the uly:

< / BR>
where

R2has different values, shown in table 12. In tables 12 and 13 used the same abbreviations and symbols for the replacement of groups, as in tables 1 and 2, and the abbreviation "so square" means "melting point".

Examples 112-128

Repeating a similar procedure to that described in example 13, steps (i) and (ii), but using as starting materials 4-sulfamerazine and various types of benzaldehyde, and as a result received - phenyl --/ (4 sulfamerazine)acetonitrile, which then carried out the reaction as described in example 15, to obtain the compounds having the following formula:

< / BR>
where

R2has different values, shown in table 13.

Example 129

1-(4-Mercaptophenyl)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrole (Compound 1-156)

129(i) Bis(4-AMINOPHENYL)disulfide

In 100 ml methylenechloride was dissolved 7,42 g (40 mmol) of 4-acetamidophenol and to the resulting solution was added 40 ml (40 mmol) of 10% (weight/volume) aqueous solution of potassium bicarbonate. Then to the mixture was slowly added dropwise 3,20 g (20 mmol) of bromine with stirring and ice cooling. The mixture was stirred at room temperature for 15 minutes and the this product was dissolved in 100 ml of ethanol and to the resulting solution was added 50 ml of concentrated aqueous chloroethanol acid. The mixture was stirred at 80oC for 6 hours. At the end of this time the reaction solution was concentrated by evaporation under reduced pressure and the residue was dissolved in 200 ml of water. Brought the pH of the mixture to a value equal to at least 9, by adding 1 to N. (weight/volume) aqueous solution of sodium hydroxide. The obtained yellow precipitate was collected by filtration and washed with water, resulting in 3,92 (yield 39%) indicated in the title compound as a yellow powder, melting at 75 - 77oC.

Mass spectrum (EI) m/z: 248 [M+]

129(ii) Bis[4-(4-sulfamoylbenzoyl)phenyl]disulfide

Following a similar procedure to that described in example 1(i), but using as the starting material bis(4-AMINOPHENYL)disulfide [obtained as described above in stage (i)] and 4-sulfamoylbenzoic got mentioned in the title compound as yellow powder (yield 58%), melting at 200 - 230oC.

129(iii) Bis [4-(- cyano-4-sulfamoylbenzoyl)phenyl]disulfide

Following a similar procedure to that described in example 1(ii), but using as starting material bis[4-(4-sulfamoylbenzoyl)phenyl] disulfide [received logo amorphous powder (yield 92%)

Spectrum of nuclear magnetic resonance (400 MHz, hexadeuterated dimethyl sulfoxide) M. D.

7,95 - to $ 7.91 (2H, multiplet);

of 7.75 (2H, doublet, J = 8 Hz);

was 7.45 (2H, singlet);

7,31 (2H, doublet, J = 8 Hz);

7,19 (1H, doublet, J = 9 Hz);

6,82 - 6,79 (H, multiplet);

to 6.19 (1H, doublet, J = 9 Hz).

Mass spectrum (FAB) m/z: 636 [M+].

129(iv) Bis{4-[4-methyl-2-(4-sulfamoylbenzoyl)pyrrol-1-yl]-phenyl}disulfide

Following a similar procedure to that described in example 1(iii), but using as starting material bis [4-(- cyano-4-sulfamoylbenzoyl)phenyl] disulfide [obtained as described above in stage (iii)] and methacrolein got mentioned in the title compound as a pale yellow powder (yield 42%), melting at 251 - 255oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,73 (4H, doublet, J = 9 Hz);

7,46 (4H, doublet, J = 9 Hz);

to 7.18 (4H, doublet, J = 9 Hz);

7,10 (4H, doublet, J = 9 Hz);

to 6.75 (2H, singlet);

6,46 (4H, singlet);

6.35mm (2H, singlet);

of 2.16 (6H, singlet).

Mass spectrum (FAB m/z: 686 [M+].

129(v) 1-(4-Mercaptophenyl)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrol

In a mixture of 40 ml of tetrahydrofuran and 10 ml of methanol was dissolved in 1.00 g (1.5 IMO the v)] and to the resulting solution was added 55 mg (1.5 mmol) of sodium borohydride. Then the mixture was stirred at room temperature for 15 minutes, after which was added 5% (weight/volume) aqueous solution of sulfuric acid for acidification of the mixture, and then 25 ml of water. The resulting mixture was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure and the obtained 1.07 g (yield 100%) specified in the title compounds as a pale yellow amorphous powder.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

7,74 (2H, doublet, J = 9 Hz);

from 7.24 (2H, doublet, J = 9 Hz);

7,21 (2H, doublet, J = 9 Hz);

6,98 (2H, doublet, J = 9 Hz);

of 6.73 (1H, singlet);

6,40 (1H, singlet);

was 4.76 (2H, singlet);

3,50 (1H, singlet);

2,17 (3H, singlet).

Mass spectrum (EI) m/z: 344 [M+].

Example 130

1-(4-Acetylthiophene)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrole (Compound 1-157)

In 15 ml of tetrahydrofuran was dissolved 0,90 g (2.6 mmol) of 1-(4-mercaptophenyl)-4-methyl-2-(4-sulfamoylbenzoyl)pyrrole (obtained as described in example 129 and to the resulting solution was added with 0.27 ml (2.9 mmol) of acetic anhydride. Then to the mixture was added of 0.53 ml (6.5 mmol) of pyridine, after which its paramashiva eigendom pressure and to the residue was added a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous magnesium sulfate, after which it was concentrated by evaporation under reduced pressure. Resulting balance was transferred to the chromatographic column with silica gel and was suirable with a mixture of hexane and ethyl acetate (3: 2 by volume) with the receipt of 0.44 g (yield 43%) indicated in the title compound as a white powder, melting at 149 - 152oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques

of 7.75 (2H, doublet, J = 9 Hz);

7,38 (2H, doublet, J = 9 Hz);

7,22 (2H, doublet, J = 9 Hz);

7,16 (2H, doublet, J = 9 Hz);

to 6.80 (1H, singlet);

6,41 (1H, singlet);

4,78 (2H, singlet);

of 2.44 (3H, singlet);

to 2.18 (3H, singlet).

Mass spectrum (FAB) m/z: 386 [M+].

Preparative form 1. The drug in powder form

5 g of 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrole (compound of example 67), 895 g of lactose and 100 g of corn starch are mixed and pulverized using a vibration mill for 30 minutes to obtain the desired final form of the drug in powder form.

Preparative form 2. The drug in capsule form

5 g of 2-(3,4-dimethylphenyl is and magnesium are mixed and pulverized using a vibration mill for 30 minutes. Gelatin capsules are then filled with the mixture to obtain the desired finished product in the form of capsules. The drug is in the form of capsules containing 5 mg of active compound per capsule.

Preparative form 3. The drug in pill form

5 g of 1-(4-acetylbenzenesulfonyl)-4-(3,4-dimetilfenil)-4 - methylpyrrole (the compound of example 83), 90 g of lactose, 20 g of corn starch and 1 g of magnesium stearate are mixed and pulverized using a vibration mill for 30 minutes. Then using tabletiruemogo device prepared tablets.

1. Derivatives of 1,2-diphenylpyrrole General formula (I) and (II)

< / BR>
< / BR>
where R represents a hydrogen atom;

R1represents an alkyl group having from 1 to 6 carbon atoms, an amino group or a group of the formula - otherawhere Rais alkanoyloxy group having from 1 to 25 carbon atoms;

R2represents a phenyl group which is unsubstituted or substituted by at least one of the substituents and/or substituents defined below;

R3represents a hydrogen atom, halogen atom or alkyl group which has from 1 to 6 carbon atoms and which is illegal is no hydrogen atom, alkyl group which has from 1 to 6 carbon atoms and which is unsubstituted or substituted by at least one of the substituents defined below, aryl group as defined below, or aracelio group as defined below;

these aryl groups have from 6 to 14 ring carbon atoms in the carbocyclic ring and is unsubstituted or substituted by at least one of the substituents and/or substituents defined below;

these kalkilya groups represent alkyl groups which have from 1 to 6 uglerodnych atoms and are substituted by at least one aryl group, as defined above;

these substituents selected from hydroxy groups, halogen atoms, alkoxygroup having from 1 to 6 carbon atoms, and alkylthio having from 1 to 6 carbon atoms;

these substituents selected from alkyl groups which have from 1 to 6 carbon atoms and are unsubstituted or substituted by at least one of the substituents defined above, mercaptopropyl, alkanoyloxy having from 1 to 6 carbon atoms, alkylsulfonyl groups having from 1 to 6 carbon atoms, cycloalkanes having from 3 to 8 who to 6 carbon atoms,

and their pharmaceutically acceptable salts.

2. Connection on p. 1, in which R1represents a methyl group, an amino group or an acetylamino group.

3. Connection under item 1 or 2, in which R1represents an amino group or an acetylamino group.

4. The compound according to any one of paragraphs.1 to 3, in which R2represents a phenyl group or a phenyl group which is substituted by at least one of the substituents1and/or Deputy1defined below; substituents1selected from halogen atoms, alkoxygroup having from 1 to 4 carbon atoms, and alkylthio having from 1 to 4 carbon atoms, and the substituents1selected from alkyl groups having from 1 to 4 carbon atoms, alkyl groups which have from 1 to 4 carbon atoms and which are substituted by at least one of the substituents1, mercaptopropyl, alkanoyloxy having from 1 to 4 carbon atoms, halogenlamp having from 1 to 4 carbon atoms, and alkylenedioxy having from 1 to 4 carbon atoms.

5. The compound according to any one of paragraphs.1 to 3, in which R2represents a phenyl group or a phenyl group which is substituted by at least one of C the gene, alkoxygroup having from 1 to 4 carbon atoms, and alkylthio having from 1 to 4 carbon atoms, and the substituents2selected from alkyl groups having from 1 to 4 carbon atoms, halogenating groups having from 1 to 4 carbon atoms, mercaptopropyl, alkanoyloxy having from 1 to 4 carbon atoms, halogenlamp having from 1 to 4 carbon atoms, and alkylenedioxy having from 1 to 4 carbon atoms.

6. The compound according to any one of paragraphs.1 to 5, in which R3represents a hydrogen atom, halogen atom, alkyl group having from 1 to 4 carbon atoms, or a substituted alkyl group having from 1 to 4 carbon atoms and substituted by at least one of the substituents1defined below; substituents 1selected from halogen atoms, alkoxygroup having from 1 to 4 carbon atoms, and alkylthio having from 1 to 4 carbon atoms.

7. The compound according to any one of paragraphs.1 to 5, in which R3represents a hydrogen atom, halogen atom, alkyl group having from 1 to 4 carbon atoms, or halogenation group having from 1 to 4 carbon atoms.

8. The compound according to any one of paragraphs.1 to 7, in which R4represents a hydrogen atom, ALK is Dom and substituted by at least one of the substituents defined above, aryl group which has from 6 to 10 ring carbon atoms and is unsubstituted or substituted by at least one of the substituents1and/or Deputy3defined below, aracelio group having from 1 to 4 carbon atoms in the alkyl part and containing at least one aryl group such as defined above; Vice1selected from halogen atoms, alkoxygroup having from 1 to 4 carbon atoms, and alkylthio having from 1 to 4 carbon atoms; the substituents3include cycloalkylcarbonyl having from 3 to 8 carbon atoms.

9. The compound according to any one of paragraphs.1 to 7, in which R4represents a hydrogen atom, alkyl group having from 1 to 4 carbon atoms, a substituted alkyl group having from 1 to 4 carbon atoms and substituted by at least one of the substituents2defined below, aryl group which has from 6 to 10 ring carbon atoms and is unsubstituted or substituted by at least one of the substituents 2and/or Deputy4defined below, aracelio group having from 1 to 4 carbon atoms in the alkyl part and containing at least one the group having from 1 to 6 carbon atoms, and the substituents4include cycloalkylcarbonyl having from 3 to 8 carbon atoms.

10. Connection on p. 1, in which R represents a hydrogen atom; R1represents a methyl group, an amino group or an acetylamino group; R2represents a phenyl group or a phenyl group which is substituted by at least one of the substituents1and Vice1defined below; R3represents a hydrogen atom, halogen atom, alkyl group having from 1 to 4 carbon atoms, or a substituted alkyl group having from 1 to 4 carbon atoms and substituted by at least one of the substituents1defined below; R4represents a hydrogen atom, alkyl group having from 1 to 4 carbon atoms, a substituted alkyl group having from 1 to 4 carbon atoms and substituted by at least one of the substituents defined above, aryl group which has from 6 to 10 ring carbon atoms and is unsubstituted or substituted by at least one of the substituents1and/or Deputy3defined below, aracelio group having from 1 to 4 carbon atoms in the alkyl part and sotiriadou is exigrep, having from 1 to 4 carbon atoms, and alkylthio having from 1 to 4 carbon atoms, the substituents1selected from alkyl groups having from 1 to 4 carbon atoms, alkyl groups which have from 1 to 4 carbon atoms and are substituted by at least one of the substituents1, halogenlamp, mercaptopropyl, alkanoyloxy having from 1 to 4 carbon atoms, and alkylenedioxy having from 1 to 4 carbon atoms, and the substituents3include cycloalkane group having from 3 to 8 carbon atoms.

11. Connection on p. 1, in which R represents a hydrogen atom, R1represents an amino group or an acetylamino group; R2represents a phenyl group or a phenyl group which is substituted by at least one of the substituents1and/or Deputy 2defined below; R3represents a hydrogen atom, halogen atom, alkyl group having from 1 to 4 carbon atoms, or halogenation group having from 1 to 4 carbon atoms; R4represents a hydrogen atom, alkyl group having from 1 to 4 carbon atoms, a substituted alkyl group having from 1 to 4 carbon atoms and substituted by at least one Deputy who is unsubstituted or substituted by at least one of the substituents2and/or Deputy4defined below, aracelio group having from 1 to 4 carbon atoms in the alkyl part and containing at least one aryl group as defined above; Vice1selected from halogen atoms, alkoxygroup having from 1 to 4 carbon atoms, and alkylthio having from 1 to 4 carbon atoms; the substituents2include the hydroxy-group, halogen atoms and alkoxygroup having from 1 to 6 carbon atoms; the substituents2selected from alkyl groups having from 1 to 4 carbon atoms, mercaptopropyl, halogenating groups having from 1 to 4 carbon atoms, halogenlamp having from 1 to 4 carbon atoms, alkylenedioxy having from 1 to 4 carbon atoms, and alkanoyloxy having from 1 to 4 carbon atoms, and the substituents4include cycloalkane group having from 3 to 8 carbon atoms.

12. Connection on p. 1, representing the following:

4-methyl-2-(4-were)-1-(4-sulfamoylbenzoyl)pyrrol,

2-(4-methoxyphenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol,

2-(4-chlorophenyl)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol,

4-methyl-2-(4-methylthiophenyl)-1-(4-unfamilier)pyrrol,

2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfame what-methyl-1-(4-sulfamoylbenzoyl)pyrrol,

2-(3,4-dimetilfenil)-4-methyl-1-(4-sulfamoylbenzoyl)pyrrol,

4-methyl-1-(4-methylthiophenyl)-2-(4-sulfamoylbenzoyl)pyrrol,

1-(4-acetylbenzenesulfonyl)-4-methyl-2-(4-methoxyphenylazo and

1-(4-acetylbenzenesulfonyl)-4-methyl-2-(3,4-dimetilfenil)pyrrole.

13. Derivatives of 1,2-diphenylpyrrole General formula (I) or (II) or its pharmaceutically acceptable salt according to any one of paragraphs.1 - 12 with anti-inflammatory and analgesic activity.

14. Derivatives of 1,2-diphenylpyrrole General formula (I) or (II) or its pharmaceutically acceptable salt according to any one of paragraphs.1 - 12, with the ability to inhibit resorption (resorption) of bone.

15. Derivatives of 1,2-diphenylpyrrole General formula (I) or (II) or its pharmaceutically acceptable salt according to any one of paragraphs.1 - 12, with the ability to inhibit the production of leukotrienes.

16. Derivatives of 1,2-diphenylpyrrole General formula (I) or (II) or its pharmaceutically acceptable salt according to any one of paragraphs.1 - 12, with the ability to selectively inhibit the activity of MOR-2.

17. Pharmaceutical composition comprising an active compound, a pharmaceutically acceptable carrier or diluent, characterized in that cachectl according to any one of paragraphs.1 - 12.

 

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The invention relates to medicine, specifically to pharmacology
The invention relates to pharmaceutical industry and relates to the creation of new dosage forms in the form of ointments with photosensitizers that may be used in medical practice, in particular when conducting photodynamic therapy

The invention relates to the field of medicine and relates to a pharmaceutical composition having anticonvulsive and analgesic activity

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The invention relates to medicine, in particular to rheumatology, and for the treatment of arthritis

FIELD: medicine.

SUBSTANCE: method involves introducing 0.1-0.3 ml of photosensitizing gel preliminarily activated with laser radiation, after having removed neovascular membrane. The photosensitizing gel is based on a viscoelastic of hyaluronic acid containing khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-2% by mass. The photosensitizing gel is in vitro activated with laser radiation having wavelength of 661-666 nm during 3-10 min with total radiation dose being equal to 100-600 J/cm2. The gel is introduced immediately after being activated. To compress the retina, vitreous cavity is filled with perfluororganic compound or air to be further substituted with silicon oil. The operation is ended with placing sutures on sclerotomy and conjunctiva areas. Compounds like chealon, viscoate or hyatulon are used as viscoelastic based on hyaluronic acid. Perfluormetylcyclohexylperidin, perfluortributylamine or perfluorpolyester or like are used as the perfluororganic compound for filling vitreous cavity.

EFFECT: excluded recurrences of surgically removed neovascular membrane and development of proliferative retinopathy and retina detachment; retained vision function.

3 cl, 5 dwg

FIELD: medicine.

SUBSTANCE: method involves making incision in conjunctiva and Tenon's capsule of 3-4 mm in size in choroid hemangioma projection to sclera 3-4 mm far from limb. Tunnel is built between sclera and Tenon's capsule to extrasclerally introduce flexible polymer magnetolaser implant through the tunnel to the place, the choroid hemangioma is localized, after performing transscleral diaphanoscopic adjustment of choroid hemangioma localization and size, under visual control using guidance beam. The implant has permanent ring-shaped magnet in the center of which a short focus scattering lens of laser radiator is fixed. The lens is connected to light guide in soft flexible envelope. The permanent implant magnet is axially magnetized and produces permanent magnetic field of 2-3 mTesla units intensity. It is arranged with its north pole turned towards the choroid hemangioma so that extrascleral implant laser radiator disposition. The other end of the implant is sutured to sclera 5-6 mm far from the limb with two interrupted sutures through prefabricated openings. The implant is covered with conjunctiva and relaxation sutures are placed over it. Light guide outlet is attached to temple using any known method. 0.1-1% khlorin solution is injected in intravenous bolus dose of 0.8-1.1 mg/kg as photosensitizer and visual control of choroid hemangioma cells fluorescence and fluorescent diagnosis methods are applied. After saturating choroid hemangioma with the photosensitizer to maximum level, transscleral choroid hemangioma laser radiation treatment is carried out via laser light guide and implant lens using divergent laser radiation at wavelength of 661-666 nm with total radiation dose being equal to 30-120 J/cm2. The flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, samarium-iron-nitrogen or neodymium-iron-boron system material. The photosensitizer is repeatedly intravenously introduced at the same dose in 2-3 days after the first laser radiation treatment. Visual intraocular neoplasm cells fluorescence control is carried out using fluorescent diagnosis techniques. Maximum level of saturation with the photosensitizer being achieved in the intraocular neoplasm, repeated laser irradiation of the choroid hemangioma is carried out with radiation dose of 30-60 J/cm2.

EFFECT: enhanced effectiveness of treatment.

4 cl

FIELD: medicine.

SUBSTANCE: method involves creating tunnel between sclera and Tenon's capsule in intraocular neoplasm projection. Intraocular neoplasm localization and size is adjusted by applying transscleral diaphanoscopic examination method. 0.1-0.3 ml of photosensitizing gel based on viscoelastic of hyaluronic acid, selected from group containing chealon, viscoate or hyatulon, is transsclerally introduced into intraocular neoplasm structure using special purpose needle in dosed manner. The photosensitizing gel contains khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-1% by mass. Flexible polymer magnetolaser implant is extrasclerally introduced into the built tunnel in intraocular neoplasm projection zone under visual control using guidance beam. The implant has permanent ring-shaped magnet axially magnetized and producing permanent magnetic field of 3-4 mTesla units intensity, in the center of which a short focus scattering lens of laser radiator is fixed. The lens is connected to light guide in soft flexible envelope. The implant is arranged with its north pole turned towards the intraocular neoplasm so that implant laser radiator lens is extrasclerally arranged in intraocular neoplasm projection zone. The implant light guide is sutured to sclera 5-6 mm far from the limb with single interrupted suture. The implant is covered with conjunctiva and relaxation sutures are placed over it. Light guide outlet is attached to temple using any known method. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, transscleral intraocular neoplasm laser radiation treatment is carried out via laser light guide and implant lens using divergent laser radiation at wavelength of 661-666 nm. The treatment course being over, the flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, neodymium-iron-boron or samarium-iron-nitrogen. 0.1-1% khlorin solution as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is additionally intravenously introduced in 2-3 days at a dose of 0.8-1.1 mg/kg and repeated laser irradiation of the intraocular neoplasm is carried out with radiation dose of 30-45 J/cm2 15-20 min later during 30-90 s.

EFFECT: complete destruction of neoplasm; excluded its further growth.

4 cl

FIELD: medicine.

SUBSTANCE: method involves applying transscleral diaphanoscopic examination method for adjusting intraocular neoplasm localization and size. Rectangular scleral pocket is built 2/3 times as large as sclera thickness which base is turned from the limb. Several electrodes manufactured from a metal of platinum group are introduced into intraocular neoplasm structure via the built scleral pocket. Next to it, intraocular neoplasm electrochemical destruction is carried out in changing electrodes polarity with current intensity of 100 mA during 1-10 min, and the electrodes are removed. Superficial scleral flap is returned to its place and fixed with interrupted sutures. 0.1-2% aqueous solution of khlorin as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is intravenously introduced at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, transpupillary laser radiation of 661-666 nm large wavelength is applied at a dose of 30-120 J/cm2. the operation is ended with placing sutures on conjunctiva. Platinum, iridium or rhodium are used as the metals of platinum group. The number of electrodes is equal to 4-8. 0.1-1% khlorin solution, selected from group containing photolon, radachlorine or photoditazine, is additionally repeatedly intravenously introduced in 2-3 days at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, repeated laser irradiation of the intraocular neoplasm is carried out with radiation dose of 30-45 J/cm2.

EFFECT: complete destruction of neoplasm; excluded tumor recurrence; reduced risk of tumor cells dissemination.

3 cl, 3 dwg

FIELD: medicine.

SUBSTANCE: method involves intravenously administering 0.1-1% aqueous solution of khlorin, selected from group containing photolon, radachlorine or photoditazine at a dose of 0.2-0.5 mg/kg or 0.2-1% aqueous solution of porphyrin like photogem at a dose of 0.2-1 mg/kg. Laser irradiation of blood is carried out 5-15 min later after beginning photosensitizer injection into cubital vein of one arm via laser light guide set in advance in the cubital vein of the other arm during 10-40 min at wavelength of 661-666 nm and power of 20-50 mW one session per day during 3-10 days with the aqueous solution of khlorin used as the photosensitizer, or laser irradiation of blood with wavelength equal to 630-633 nm during 10-45 min with power of 20-50 mW one session per day with the aqueous solution of porphyrin used as the photosensitizer. Repeated intravenous administration of photosensitizer is carried out 1-3 months later combined with repeated laser irradiation of blood.

EFFECT: reduced risk of tumor cells dissemination and metastasis development.

2 cl

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacology, pharmacy.

SUBSTANCE: invention relates to a medicinal agent used for prophylaxis and treatment of diseases and disorders associated with dysfunction of benzodiazepine receptors. This medicinal agent comprises compound of the formula (I)

. Compound of the formula (I) elicits high cardioprotective, neurotrophic, renoprotective activity and enhanced bioavailability.

EFFECT: valuable medicinal properties of compounds.

5 cl, 1 tbl, 1 ex

FIELD: medicine, cardiology.

SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.

EFFECT: higher efficiency of therapy.

3 ex

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