Compounds of n-phenyl(pyperazinyl or homopyperazinyl)benzenesulphonamide or benzenesulphonylphenyl(pyperazine or homopyperazine), suitable for treatment of diseases responding to modulation of serotonin 5-НТ6 receptor

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of organic chemistry, namely to compounds of N-phenyl(pyperazinyl or homopyperazinyl)benzenesulphonamide or benzenesulphonylphenyl(pyperazine or homopyperazine), or to their physiologically acceptable acid addition salts, described by general formulas (I) and (I'), where X is a chemical bond or a group N-R4; R1 is hydrogen or methyl; R2 is hydrogen or methyl; R3 is hydrogen, C1-C3alkyl, fluorine, C1-C2alkoxy or fluorinated C1-C2alkoxy; R4 is hydrogen, C1-C4alkyl or C3-C4cycloalkyl-CH2-; R5 is hydrogen, fluorine, chlorine, C1-C2alkyl, C1-C2alkoxy or fluorinated C1-C2alkoxy; R6 is hydrogen and n is 1 or 2. The invention also relates to a pharmaceutical composition based on the compound of formula

or

.

EFFECT: novel compounds, modulating activity of the 5HT6 receptor are obtained.

35 cl, 2 tbl, 105 ex

 

The LEVEL of TECHNOLOGY

The present invention relates to compounds N-phenyl(piperazinil or homopiperazine)benzosulfimide or benzosulfimide(piperazine or homopiperazine), containing their pharmaceutical compositions and their use in therapy. The compounds possess valuable therapeutic properties and, in particular, can be used for the treatment of diseases that respond to modulation of the receptor 5-HT6serotonin.

Serotonin (5-hydroxytryptamine, 5-HT), monoamine neurotransmitter and hormone local actions, is formed by hydroxylation and decarboxylation of tryptophan. Its highest concentration is found in the cells of enterochromaffin the gastrointestinal tract, while the remainder is mainly in platelets and Central nervous system (CNS). 5-HT is involved in a wide array of physiological and pathophysiological pathways. At the periphery it reduces the number of smooth muscle and induces endothelium-dependent vasolidation. It is believed that in the Central nervous system it is associated with a large number of functions, including regulation of appetite, mood, anxiety, hallucinations, sleep, retching vomiting and pain perception.

Neurons that secrete 5-HT, called serotonergic. The function of 5-HT is based on its interaction with specific (with reconnaisance) neurons. To date, identified seven types of receptors 5-HT: 5-HT1(with subtypes 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1Eand 5-HT1F), 5-HT2(with subtypes 5-HT2A, 5-HT2Band 5-HT2C), 5-HT3, 5-HT4, 5-HT5(with subtypes 5-HT5Aand 5-HT5B), 5-HT6and 5-HT7. Most of these receptors are linked to G-proteins that affect the activity of either adenylate cyclase or phospholipase Cγ.

There is no doubt that the receptors 5-HT6person associated with adenylate cyclase. They are distributed in the limbic, veins and cortical areas of the brain and exhibit high affinity to brain.

It can be expected that modulation of the receptor 5-HT6with the help of suitable substances will positively affect certain disorders, including cognitive impairment, such as memory impairment, cognitively and ability to learn, in particular associated with Alzheimer's disease, senile cognitive impairment and mild cognitive impairment, attention deficit disorder with hyperactivity disorder, personality disorders, such as schizophrenia, in particular cognitive deficits related with schizophrenia, affective disorders such as depression, anxiety and obsessive-compulsive disorder, impaired mobility or movement disorders, such as over the ery Parkinson's and epilepsy, migraine, sleep disorders (including disturbances of circadian rhythm), eating disorders such as anorexia and bulimia, certain gastrointestinal disorders such as irritable bowel syndrome, diseases associated with neurodegeneration, such as stroke, spinal cord injury or head and traumatic brain injuries, such as hydrocephalus, a disease associated with harmful addiction, and obesity (see, for example, the publication of A. Meneses, Drug News Perspect 14(7) (2001) pp. 396-400 and quoted in her literature; J. Pharmacol. Sci. Vol. 101 (Suppl. 1), 2006, p. 124). In preclinical and clinical studies it was found that the receptor modulators of 5-HT6such as PRX-07034 (Epix Pharmaceuticals), are particularly suitable for the treatment of cognitive disorders, in particular associated with Alzheimer's disease or schizophrenia, or for the treatment of obesity (see, for example, information on the Internet on the website http://www.epixpharma.com/products/prx-07034.asp).

In patent documents WO 98/027081, WO 99/02502, WO 00/12623, WO 00/12073, US 2003/0069233, WO 02/08179, WO 02/92585, WO 2006/010629 describes some connection benzosulfonazole, which has antagonistic activity against receptor 5-HT6and proposed use of these compounds for the treatment of disorders which are susceptible to treatment with antagonists of the receptor 5-HT6such as some Central nervous system disorders, drug dependent is here, the syndrome of attention deficit hyperactivity disorder, obesity and diabetes type II. In patent documents WO 2004/080986 and WO 03/014097 described some compounds of diarylamino and proposed use of these compounds for the treatment of disorders which are susceptible to treatment with antagonists of the receptor 5-HT6,such as some Central nervous system disorders, drug addiction, attention deficit disorder with hyperactivity, obesity and diabetes type II. In the patent document WO 2008087123 available compounds with antagonistic activity against receptor 5-HT6to prevent relapse of drug addiction.

However, still there is a continuing need for the development of compounds with high affinity to the receptor 5-HT6and having a high selectivity for this receptor. In particular, the compounds should have low affinity to adrenergic receptors, such as α1-adrenergic receptor, histamine receptors, such as H1-a receptor, and dopamine receptors, such as the D2-a receptor, in order to eliminate or reduce significant adverse effects associated with modulation of these receptors, such as postural hypotension, reflex tachycardia, potentiation of hypotensive action is prazosin, terazosin, doxazosin and labetalola, or dizziness associated with blockade of α1-adrenergic receptor, weight gain, sedation, drowsiness, or potentiation of action of CNS depressants associated with the closure of H1-receptor, or extrapyramidal movement disorder, such as an upset tone, parkinsonism, akathisia, late dyskinesia or syndrome rabbit, or endocrine effects, such as increased prolactin (galactorrhea, gynecomastia, menstrual changes, sexual dysfunction in men) associated with the blockade of D2-receptor.

One object of the present invention is to develop compounds that have high affinity to the receptor 5-HT6. Another objective of the present invention is the development of compounds that selectively bind the receptor 5-HT6.

In addition, the connection must also have good pharmacological properties, such as high bioavailability and/or high metabolic stability.

The INVENTION

The present invention relates to N-phenyl(piperazinil or homopiperazine)benzosulfimide or benzosulfimide(piperazines or homopiperazine) of the formula (I) or (I')

where

X is a chemical bond and the and group N-R 4;

R1is hydrogen or stands;

R2is hydrogen or stands;

R3is hydrogen, C1-C3the alkyl (e.g., stands), fluorine, C1-C2alkoxy (e.g. methoxy) or fluorinated C1-C2alkoxy;

R4is hydrogen, C1-C4the alkyl (for example, stands, ethyl, n-propylene, isopropyl), C3-C4cycloalkyl or-CH2-C3-C4cycloalkyl (for example, cyclopropylmethyl);

R5is hydrogen, fluorine, chlorine, C1-C2the alkyl (e.g., stands), fluorinated C1-C2the alkyl, C1-C2alkoxy (e.g. methoxy) or fluorinated C1-C2alkoxy;

R6is hydrogen, fluorine or chlorine; and

n is 1 or 2,

and their physiologically acceptable salts accession acids and their N-oxides.

These compounds, i.e., N-phenyl(piperazinil or homopiperazine)benzosulfimide or benzensulfonamidelor or homopiperazine and their physiologically acceptable salts accession acids and their N-oxides, show, in a striking and unexpected degree, high affinity binding to the receptor 5-HT6and therefore they can be used as pharmaceuticals.

Therefore, in addition, the present invented the e refers to compounds of the formula (I) or (I') for use in therapy.

The present invention also relates to pharmaceutical compositions which include the compounds of formula (I) and (I') and, optionally, a physiologically acceptable carrier and/or excipient.

In particular, these compounds, i.e., N-phenyl(piperazinil or homopiperazine)benzosulfimide or benzosulfimide(piperazines or homopiperazine) and their physiologically acceptable salts accession acids and their N-oxides, are modulators of the receptor 5-HT6.

Therefore, in addition, the present invention relates to compounds of formula (I) or (I') for use for modulating receptor 5-HT6.

The present invention also relates to the use of compounds of formula (I) or (I') upon receipt of a drug to modulate receptor 5-HT6and appropriate methods of modulating receptor 5-HT6.

It is known that the receptor modulators of 5-HT6and, in particular, antagonists of the receptor 5-HT6apply for the treatment of several disorders.

Therefore, in addition, the present invention relates to compounds of formula (I) or (I') for use for the treatment of these disorders.

The present invention also relates to the use of compounds of formula (I) or (I') upon receipt of a medicinal product for treatment of the above disorders and according to the existing methods of treatment for these disorders.

A DETAILED DESCRIPTION of the INVENTION

Disorders and diseases that are susceptible to treatment with the compounds of formula (I) or (I') include, for example, disorders and diseases of the Central nervous system, in particular cognitive impairment, such as memory impairment, cognitively and ability to learn, in particular associated with Alzheimer's disease, senile cognitive impairment and mild cognitive impairment, attention deficit disorder with hyperactivity (ADHD), personality disorders, such as schizophrenia, in particular cognitive deficits related with schizophrenia, affective disorders such as depression, anxiety and obsessive-compulsive disorder, impaired mobility or movement disorders such as Parkinson's disease and epilepsy, migraine, sleep disorders (including disturbances of circadian rhythm), eating disorders such as anorexia and bulimia, certain gastrointestinal disorders such as irritable bowel syndrome, diseases associated with neurodegeneration, such as stroke, spinal cord injury or head and traumatic brain injuries, such as hydrocephalus, a disease associated with harmful addiction, and obesity.

The proposed compounds of formula (I) or (I') of this structure may exist in different spatial the locations, for example if they possess one or more centers of asymmetry, polyamidine rings or double bonds, or as different tautomers, the invention also relates to enantiomeric mixtures, in particular racemates, diastereomeric mixtures and tautomeric mixtures, but, preferably, corresponding to almost pure enantiomers (enantiomerically pure), diastereomers and tautomers of compounds of formula (I) or (I') and/or their salts and/or their N-oxides.

The invention also relates to physiologically acceptable salts of the compounds of formula (I) or (I'), in particular the salts of accession acid with physiologically acceptable acids. Examples of suitable physiologically acceptable organic and inorganic acids are hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, C1-C4-alkylsulfonate acid, such as methanesulfonate acid, aromatic sulfonic acid, such as benzolsulfonat acid and toluensulfonate acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid and benzoic acid. Other acid used is described in the publication Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 ff., Birkhauser Verlag, Basel and Stuttgart, 1966.

The invention also relates to N-oxide of the compounds of formula (I) or (I'), provided that these compounds contain a basic nitrogen atom such as nitrogen atom pieperazinove fragment.

Organic fragments, mentioned in the above definitions of the variables are, as the term halogen-collective terms for individual enumerations of the individual group members. The prefix Cn-Cmindicates in each case the possible number of carbon atoms in the group.

Used in the description of the present invention C1-C4alkyl is a linear or branched alkyl group having 1, 2, 3 or 4 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl (=2-butyl), 2-methylpropyl (=isobutyl) and 1,1-dimethylethyl (=tert-butyl).

Used in the description of the present invention fluorinated C1-C2alkyl is a linear alkyl group having 1 or 2 carbon atoms, in which at least one hydrogen atom, for example 1, 2, 3, 4 or 5 hydrogen atoms are substituted with fluorine. Examples of such groups include vermeil, deformity, trifluoromethyl, 2-foretel, 2,2-dottorati, 2,2,2-triptorelin, 1,1,2,2-tetraborate and 1,1,2,2,2-pentafluoroethyl.

Used in the description of the present invention C1-C2alkoxy is a linear alkyl group having 1 or 2 carbon ATO is a, which is connected with the rest of the molecule via an oxygen atom, i.e. methoxy, ethoxy.

Used in the description of the present invention fluorinated C1-C2alkoxy is defined above, CNS group in which at least one, e.g. 1, 2, 3, 4 or 5 hydrogen atoms substituted by fluorine atoms. Examples of such groups are formatosi, deformedarse, triptoreline, 2-floratone, 2,2-diflorasone, 2,2,2-triptoreline and 1,1,2,2-tetrafluoroethoxy.

Used in the description of the present invention C3-C4-cycloalkyl is a cycloaliphatic radical having from 3 to 4 carbon atoms, i.e. cyclopropyl and cyclobutyl.

From the point of view of the ability of compounds to modulate the receptor 5-HT6preferably, in order variables X, R1, R2, R3, R4, R5, R6and n have the following values, which, individually or in combination, represent particular embodiments of the compounds of formula (I) or (I').

X is a chemical bond or a group N-R4. The first preferred embodiment of the invention relates to compounds of formula I or I', to their pharmacologically acceptable salts and their N-oxides, where X is a group N-R4.

R1is hydrogen or stands. The second preferred variations is tons of carrying out the invention relates to compounds of formula I or I', to their pharmacologically acceptable salts and their N-oxides, where R1is hydrogen. Another variant embodiment of the invention relates to compounds of formula I or I', to their pharmacologically acceptable salts and their N-oxides, where R1is stands.

R2is hydrogen or stands. The third preferred embodiment of the invention relates to compounds of formula I or I', to their pharmacologically acceptable salts and their N-oxides, where R2is hydrogen.

Another variant embodiment of the invention relates to compounds of formula I or I', where R2is stands. If R2is stands, the carbon atom that bears R2creates a center of chirality. Therefore, a special variant embodiment of the invention relates to compounds of formula I or I', to their pharmacologically acceptable salts and their N-oxides, where R2is stands and where the carbon atom that bears R2has the S-configuration. Another particular variant embodiment of the invention relates to compounds of formula I or I', to their pharmacologically acceptable salts and their N-oxides, where R2is stands and where the carbon atom that bears R2has R-configuration.

Similarly, preferred are mixtures of compounds of the present invention, where a carbon at the m who is R2has the S-configuration or R-configuration, respectively. These mixtures can contain the same amount or different amounts of the compound I or the same amount or different amounts of compound I', respectively, which have the R-configuration relative to the fragment CH-R2and the compound I or I', which have the S-configuration relative to CH-R2.

The term "enantiomerically pure" means that the mixture contains the corresponding connection in enantiomeric excess, amounting to at least 80%, in particular at least 90% (ee).

R3is hydrogen, C1-C3the alkyl (e.g., stands), fluorine, C1-C2alkoxy (e.g. methoxy) or fluorinated C1-C2alkoxy.

Preference is given to compounds of the formula I or I', to their pharmacologically acceptable salts and their N-oxides, where R3is stands or methoxy, deformedarse or triptoreline, in particular, stands or methoxy, and most preferably, stands. The invention also relates to compounds of formula I or I', to their pharmacologically acceptable salts and their N-oxides, where R3is hydrogen or fluorine, in particular hydrogen.

R4is hydrogen, C1-C4the alkyl (for example, stands, ethyl, n-propylene, isopropyl), C3-C4 3-C4cycloalkyl-CH2(e.g., cyclopropylmethyl).

Preference is given to compounds of the formula I or I', to their pharmacologically acceptable salts and their N-oxides, where R4is hydrogen, stands, ethyl, n-propylene, isopropyl or cyclopropylmethyl. More preferred compounds of the present invention, where R4is hydrogen.

R5is hydrogen, fluorine, C1-C2the alkyl (e.g., stands), fluorinated C1-C2the alkyl, C1-C2alkoxy (e.g. methoxy) or fluorinated C1-C2alkoxy.

Preferably, R5selected from the group consisting of hydrogen, fluorine, methyl, trifloromethyl, methoxy, deformedarse, triptoreline, and more preferably from hydrogen, methoxy, deformedarse. Likewise, preference is given to compounds of the formula I or I', where R5is chlorine. In a specific preferred embodiment of the invention R5is hydrogen. In another specific preferred embodiment of the invention, R5selected from fluorine, methyl, trifloromethyl, methoxy, deformedarse, triptoreline, and more preferably from methyl, methoxy, deformedarse. Similarly, more preferred compounds of formula I or I', where R5what is fluorine. Similarly, more preferred compounds of formula I or I', where R5is chlorine.

R6is hydrogen, fluorine or chlorine, preferably hydrogen or fluorine. In a particularly preferred embodiment of the invention R6is hydrogen. In another particular embodiment of the invention R6is not hydrogen, in particular, is fluorine. If R6is not hydrogen, preferably, R6located a 5 - or 6-position of the benzene ring.

Preference is given to those compounds of formula I or I', to their pharmacologically acceptable salts and their N-oxides, where R3is stands or methoxy and R6is hydrogen, or R3is stands or methoxy and R6is fluorine, located a 5 - or 6-position of the benzene ring, or both R3and R6are hydrogen, or R3is hydrogen and R6is fluorine, located a 5 - or 6-position of the benzene ring.

According to a special variant of implementation of R5and R6are hydrogen, R3selected from the group consisting of C1-C2the alkyl (e.g. methyl) and C1-C2alkoxy (e.g. methoxy), and R4selected from the group consisting of hydrogen, C1-C4alkyl is (for example, methyl, ethyl, n-propyl, isopropyl) or cyclopropylmethyl.

n is 1 or 2, forming fragment piperazine or homopiperazine. Preference is given to n, is equal to 1, i.e. compounds having a piperazine fragment.

Particularly preferred variant implementation of the Ia of the invention relates to compounds of the formula I, to their pharmacologically acceptable salts and their N-oxides, where

R1is hydrogen;

R2is hydrogen;

R3is stands, methoxy, deformedarse or triptoreline, in particular the stands or methoxy; and

R4is hydrogen.

Additional particularly preferred variant implementation of the Ib of the invention relates to compounds of the formula I, to their pharmacologically acceptable salts and their N-oxides, where

R1is hydrogen;

R2is hydrogen;

R3is stands, methoxy, deformedarse or triptoreline, in particular the stands or methoxy; and

R4is stands.

Additional particularly preferred variant implementation of the Ic of the invention relates to compounds of the formula I, to their pharmacologically acceptable salts and their N-oxides, where

R1is stands;

R2is hydrogen;

R3is stands, methoxy, deformedarse or triptoreline, in particular the stands and the and methoxy; and

R4is hydrogen.

Additional particularly preferred variant implementation Id of the invention relates to compounds of the formula I, to their pharmacologically acceptable salts and their N-oxides, where

R1is stands;

R2is hydrogen;

R3is stands, methoxy, deformedarse or triptoreline, in particular the stands or methoxy; and

R4is stands.

Particularly preferred variant implementation of the Ie of the invention relates to compounds of the formula I, to their pharmacologically acceptable salts and their N-oxides, where

R1is hydrogen;

R2is hydrogen;

R3is hydrogen or fluorine, in particular hydrogen; and

R4is hydrogen.

Additional particularly preferred variant implementation If the invention relates to compounds of the formula I, to their pharmacologically acceptable salts and their N-oxides, where

R1is hydrogen;

R2is hydrogen;

R3is hydrogen or fluorine, in particular hydrogen; and

R4is stands.

Additional particularly preferred variant implementation of the Ig of the invention relates to compounds of the formula I, to their pharmacologically acceptable salts and their N-oxides, where

R1is stands;

R2is in what oredom;

R3is hydrogen or fluorine, in particular hydrogen; and

R4is hydrogen.

Additional particularly preferred variant implementation Ih invention relates to compounds of the formula I, to their pharmacologically acceptable salts and their N-oxides, where

R1is stands;

R2is hydrogen;

R3is hydrogen or fluorine, in particular hydrogen; and

R4is stands.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, preference is given to those in which the radicals R5and R6in the formula I are both hydrogen.

Similarly, among the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih are preferred to those in which the radical R5in the formula I is hydrogen and in which the radical R6in the formula I is fluorine, which is a 5 - or 6-position of the benzene ring.

Similarly, among the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih are preferred to those in which the radical R5in the formula I is methoxy and in which the radical R6in the formula I is hydrogen.

Similarly, among the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih are preferred to those in which the radical R5in the formula I is methoxy and in which the radical R 6in the formula I is fluorine, which is a 5 - or 6-position of the benzene ring.

Similarly, among the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih are preferred to those in which the radical R5in the formula I is deformedarse and in which the radical R6in the formula I is hydrogen.

Similarly, among the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih are preferred to those in which the radical R5in the formula I is deformedarse and in which the radical R6in the formula I is fluorine, which is a 5 - or 6-position of the benzene ring.

Similarly, among the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih are preferred to those in which the radical R5in the formula I is chlorine and in which the radical R6in the formula I is hydrogen.

Similarly, among the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih are preferred to those in which the radical R5in the formula I is fluorine and in which the radical R6in the formula I is hydrogen.

Similarly, among the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih are preferred to those in which the radical R5in the formula I is deformedarse and in which the radical R6in the formula I is hydrogen.

About obinna preferred implementation I a the invention relates to compounds of formula I', to their pharmacologically acceptable salts and their N-oxides, where

R1is hydrogen;

R2is hydrogen;

R3is stands, methoxy, deformedarse or triptoreline, in particular the stands or methoxy; and

R4is hydrogen.

Particularly preferred variant implementation I b of the invention relates to compounds of formula I', to their pharmacologically acceptable salts and their N-oxides, where

R1is hydrogen;

R2is stands;

R3is stands, methoxy, deformedarse or triptoreline, in particular the stands or methoxy; and

R4is hydrogen.

Particularly preferred variant implementation I c of the invention relates to compounds of formula I', to their pharmacologically acceptable salts and their N-oxides, where

R1is hydrogen;

R2is hydrogen;

R3is stands, methoxy, deformedarse or triptoreline, in particular the stands or methoxy; and

R4is stands.

Particularly preferred variant implementation of the I d of the invention relates to compounds of formula I', to their pharmacologically acceptable salts and their N-oxides, where

R1is hydrogen;

R2is stands;

R3is stands, methoxy, deformedarse or triptoreline, cha is the surrounding area of the stands or methoxy; and

R4is stands.

Particularly preferred variant implementation I e invention relates to compounds of formula I', to their pharmacologically acceptable salts and their N-oxides, where

R1is hydrogen;

R2is hydrogen;

R3is hydrogen or fluorine, in particular hydrogen; and

R4is hydrogen.

Particularly preferred variant implementation I f the invention relates to compounds of formula I', to their pharmacologically acceptable salts and their N-oxides, where

R1is hydrogen;

R2is stands;

R3is hydrogen or fluorine, in particular hydrogen; and

R4is hydrogen.

Particularly preferred variant implementation of I g of the invention relates to compounds of formula I', to their pharmacologically acceptable salts and their N-oxides, where

R1is hydrogen;

R2is hydrogen;

R3is hydrogen or fluorine, in particular hydrogen; and

R4is stands.

Particularly preferred variant implementation of the h I of the invention relates to compounds of formula I', to their pharmacologically acceptable salts and their N-oxides, where

R1is hydrogen;

R2is stands;

R3is hydrogen or fluorine, in particular odor the house; and

R4is stands.

Amongst the compounds of embodiments I a, I b, I c, I d, I e, I f, I g and I h are preferred to those in which the radicals R5and R6in the formula I' are both hydrogen.

Similarly, among the compounds of embodiments I a, I b, I c, I d, I e, I f, I g and I h are preferred to those in which the radical R5in the formula I is hydrogen and in which the radical R6in formula I' is fluorine, which is a 5 - or 6-position of the benzene ring.

Among the compounds of the formula I, in particular amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, particular preference is given to those in which OCHF2-radical is located on the benzene ring in the meta position relative to X. Among these compounds, particular preference is given to those compounds of the formula I, in which R5is hydrogen. Similarly, among these compounds, preference is given to compounds of the formula I, in which R5is not hydrogen, and in particular, it is chosen from fluorine, chlorine, methyl, trifloromethyl, methoxy, deformedarse, triptoreline and, more preferably, methyl, methoxy, deformedarse, and it is located in the para-position relative to X, or para-position relative to OCHF2-radical.

Similarly, among the compounds of the formula I, in private the tee amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, particular preference is given to those in which OCHF2-radical is located on the benzene ring in the ortho-position relative to X. Among these compounds, particular preference is given to those compounds of the formula I, in which R5is hydrogen. Similarly, among these compounds, preference is given to compounds of the formula I, in which R5is not hydrogen and, in particular, it is chosen from fluorine, chlorine, methyl, trifloromethyl, methoxy, deformedarse, triptoreline and, more preferably, methyl, methoxy, deformedarse, and it is located in the para-position relative to X, or in the para-position relative to OCHF2-radical.

Similarly, among the compounds of the formula I, in particular amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, particular preference is given to those in which OCHF2-radical is located on the benzene ring in the para-position relative to X. Among these compounds, particular preference is given to those compounds of the formula I, in which R5is hydrogen. Similarly, among these compounds, preference is given to compounds of the formula I, in which R5is not hydrogen and, in particular, it is chosen from fluorine, chlorine, methyl, trifloromethyl, methoxy, deformedarse, triptoreline and, more preferably, from IU the sludge, methoxy, deformedarse, and it is located in the meta-position relative to X.

Among the compounds of formula I', in particular amongst the compounds of embodiments I a, I b, I c, I d, I e, I f and I g, with particular preference given to those in which X is attached to the benzene ring in the α-position relative to the 1,3-dioxole rings. Among these compounds, particular preference is given to those compounds of formula I' in which R5is hydrogen.

Among the compounds of formula I', in particular amongst the compounds of embodiments I a, I b, I c, I d, I e, I f and I g, with particular preference given to those in which X is attached to the benzene ring in the β-position relative to the 1,3-dioxole rings. Among these compounds, particular preference is given to those compounds of formula I' in which R5is hydrogen.

Especially preferred embodiment of the invention relates to compounds of formula I or I', to their pharmacologically acceptable salts and their N-oxides, where

X is a chemical bond or a group N-R4;

R1is hydrogen or stands;

R2is hydrogen or stands, in particular hydrogen;

R3is hydrogen, C1-C2the alkyl, fluorine, C1-C2alkoxy or fluorinated C1-C2alkoxy, preferably hydrogen, stands, methoxy, diformate the C / triptoreline, in particular hydrogen, stands or methoxy;

R4is hydrogen, stands, ethyl, n-propylene, isopropyl or cyclopropylmethyl;

R5is hydrogen, fluorine, chlorine, stands, trifluoromethyl, methoxy, deformedarse, triptoreline, and more preferably, hydrogen, stands or methoxy;

R6is hydrogen or fluorine, which is a 5 - or 6-position of the benzene ring; and

n is 1 or 2.

Especially preferred embodiment of the invention relates to compounds of formula I or I', to their pharmacologically acceptable salts and their N-oxides, where

X is a chemical bond or a group N-R4;

R1is hydrogen or stands, preferably hydrogen;

R2is hydrogen;

R3is hydrogen, C1-C2the alkyl or C1-C2alkoxy, preferably hydrogen, stands or methoxy, in particular the stands or methoxy;

R4is hydrogen, stands, ethyl, n-propylene, isopropyl or cyclopropylmethyl, preferably hydrogen;

R5is hydrogen, chlorine, fluorine, deformedarse, stands or methoxy, preferably hydrogen, stands or methoxy, in particular hydrogen;

R6is hydrogen; and

n is 1 or 2, preferably 1.

Especially pre is respectful variant embodiment of the invention relates to compounds of formula I or I', to their pharmacologically acceptable salts and their N-oxides, where

X is a group N-R4;

R1is hydrogen;

R2is hydrogen;

R3is C1-C2the alkyl or C1-C2alkoxy, preferably the stands or methoxy;

R4is hydrogen;

R5is hydrogen;

R6is hydrogen; and

n is 1.

Especially preferred embodiment of the invention relates to compounds of formula I or I', to their pharmacologically acceptable salts and their N-oxides, where

X is a group N-R4;

R1is hydrogen;

R2is hydrogen;

R3is C1-C2the alkyl or C1-C2alkoxy, preferably the stands or methoxy;

R4is hydrogen;

R5is chlorine;

R6is hydrogen; and

n is 1.

Especially preferred embodiment of the invention relates to compounds of formula I or I', to their pharmacologically acceptable salts and their N-oxides, where

X is a group N-R4;

R1is hydrogen;

R2is hydrogen;

R3is C1-C2the alkyl or C1-C2alkoxy, preferably the stands or methoxy;

R4is hydrogen;

R5what is fluorine;

R6is hydrogen; and

n is 1.

Especially preferred embodiment of the invention relates to compounds of formula I or I', to their pharmacologically acceptable salts and their N-oxides, where

X is a group N-R4;

R1is hydrogen;

R2is hydrogen;

R3is C1-C2the alkyl or C1-C2alkoxy, preferably the stands or methoxy;

R4is hydrogen;

R5is deformedarse;

R6is hydrogen; and

n is 1.

Examples of compounds according to the present invention are the compounds of formula I, their pharmacologically acceptable salts and their N-oxides, where R6is hydrogen and the values of X, R1, R2, R3, R4and R5and R5and fragment OCHF2on the benzene ring are given in the following table A:

Table A
No.nR1R2R3XOCHF2* R5
1.1HHOCH3NHorthoH
2.1HHOCH3NHmetaH
3.1HHOCH3NHpairH
4.1HHOCH3NHorthoCH3(a pair of relatively NH)
5.1HHOCH3NHorthoCH3(a pair of relatively OCHF2)
6.1HHOCH3NHmetaOCH3(a pair of relatively NH)
7.1HHOCH3NHmetaOCH3(a pair of relatively OCHF2)
8.1HHOCH3NHmetaCH3(a pair of relatively NH)
9.1HHOCH3NHorthoCl (a pair of relatively NH)
10.1HHOCH3NHorthoCl (pair relation is sustained fashion OCHF 2)
11.1HHOCH3NHorthoF (a pair of relatively NH)
12.1HHOCH3NHorthoF (a pair of relatively OCHF2)

CH3
13.1HHOCH3NHmetaOCHF2(a pair of relatively NH)
14.1CH3HOCH3NHorthoH
15.1CH3HOCH3NH metaH
16.1CH3HOCH3NHpairH
17.1CH3HOCH3NHorthoCH3(a pair of relatively NH)
18.1CH3HOCH3NHorthoCH3(a pair of relatively OCHF2)
19.1CH3HOCH3NHmetaOCH3(a pair of relatively NH)
20.1CH3H OCH3NHmetaOCH3(a pair of relatively OCHF2)
21.1CH3HOCH3NHmetaCH3(a pair of relatively NH)
22.1CH3HOCH3NHorthoCl (a pair of relatively NH)
23.1CH3HOCH3NHorthoCl (a pair of relatively OCHF2)
24.1CH3HOCH3NHorthoF (a pair of relatively NH)
25.1HOCH3NHorthoF (a pair of relatively OCHF2)
26.1CH3HOCH3NHmetaOCHF2(a pair of relatively NH)
27.1HHOCH3NCH3orthoH
28.1HHOCH3NCH3metaH
29.1HHOCH3NCH3pairH
30.1 HHOCH3NCH3orthoCH3(pair relative to X)

31.1HHOCH3NCH3orthoCH3(a pair of relatively OCHF2)
32.1HHOCH3NCH3metaOCH3(pair relative to X)
33.1HHOCH3NCH3metaOCH3(a pair of relatively OCHF2)
34.1HHOCH3NCH3 metaCH3(pair relative to X)
35.1HHOCH3NCH3orthoCl (pair relative to X)
36.1HHOCH3NCH3orthoCl (a pair of relatively OCHF2)
37.1HHOCH3NCH3orthoF (pair relative to X)
38.1HHOCH3NCH3orthoF (a pair of relatively OCHF2)
39.1HH OCH3NCH3metaOCHF2(pair relative to X)
40.1CH3HOCH3NCH3orthoH
41.1CH3HOCH3NCH3metaH
42.1CH3HOCH3NCH3pairH
43.1CH3HOCH3NCH3orthoCH3(pair relative to X)
44.1CH3 HOCH3NCH3orthoCH3(a pair of relatively OCHF2)
45.1CH3HOCH3NCH3metaOCH3(pair relative to X)
46.1CH3HOCH3NCH3metaOCH3(a pair of relatively OCHF2)
47.1CH3HOCH3NCH3metaCH3(pair relative to X)

48.1CH3HOCH3NCH3Cl (pair relative to X)
49.1CH3HOCH3NCH3orthoCl (a pair of relatively OCHF2)
50.1CH3HOCH3NCH3orthoF (pair relative to X)
51.1CH3HOCH3NCH3orthoF (a pair of relatively OCHF2)
52.1CH3HOCH3NCH3metaOCHF2(pair relative to X)
53.1H HOCH3NCH2CH3orthoH
54.1HHOCH3NCH2CH3metaH
55.1HHOCH3NCH2CH3pairH
56.1HHOCH3NCH2CH3orthoCH3(pair relative to X)
57.1HHOCH3NCH2CH3orthoCH3(a pair of relatively OCHF2)
58.1 HHOCH3NCH2CH3metaOCH3(pair relative to X)
59.1HHOCH3NCH2CH3metaOCH3(a pair of relatively OCHF2)
60.1HHOCH3NCH2CH3metaCH3(pair relative to X)
61.1CH3HOCH3NCH2CH3orthoH
62.1CH3HOCH3NCH2CH3 metaH
63.1CH3HOCH3NCH2CH3pairH
64.1CH3HOCH3NCH2CH3orthoCH3(pair relative to X)
65.1CH3HOCH3NCH2CH3orthoCH3(a pair of relatively OCHF2)

66.1CH3HOCH3NCH2CH3metaOCH3(pair relative to X)
67. 1CH3HOCH3NCH2CH3metaOCH3(a pair of relatively OCHF2)
68.1CH3HOCH3NCH2CH3metaCH3(pair relative to X)
69.1HHOCH3N(CH2)2CH3orthoH
70.1HHOCH3N(CH2)2CH3metaH
71.1HHOCH3N(CH2)2CH3 pairH
72.1HHOCH3N(CH2)2CH3orthoCH3(pair relative to X)
73.1HHOCH3N(CH2)2CH3orthoCH3(a pair of relatively OCHF2)
74.1HHOCH3N(CH2)2CH3metaOCH3(pair relative to X)
75.1HHOCH3N(CH2)2CH3metaOCH3(a pair of relatively OCHF2)
76.1 HHOCH3N(CH2)2CH3metaCH3(pair relative to X)
77.1CH3HOCH3N(CH2)2CH3orthoH
78.1CH3HOCH3N(CH2)2CH3metaH
79.1CH3HOCH3N(CH2)2CH3pairH
80.1CH3HOCH3N(CH2)2CH3ortho CH3(pair relative to X)
81.1CH3HOCH3N(CH2)2CH3orthoCH3(a pair of relatively OCHF2)
82.1CH3HOCH3N(CH2)2CH3metaOCH3(pair relative to X)
83.1CH3HOCH3N(CH2)2CH3metaOCH3(a pair of relatively OCHF2)

84.1CH3HOCH3N(CH2)2CH3metaCH3(a couple of which have a relatively X)
85.1HHOCH3N(CH2-cyclopropylorthoH
86.1HHOCH3N(CH2-cyclopropylmetaH
87.1HHOCH3N(CH2-cyclopropylpairH
88.1HHOCH3N(CH2-cyclopropylorthoCH3(pair relative to X)
89.1HHOCH3N(CH2-cyclopropyl orthoCH3(a pair of relatively OCHF2)
90.1HHOCH3N(CH2-cyclopropylmetaOCH3(pair relative to X)
91.1HHOCH3N(CH2-cyclopropylmetaOCH3(a pair of relatively OCHF2)
92.1HHOCH3N(CH2-cyclopropylmetaCH3(pair relative to X)
93.1CH3HOCH3N(CH2-cyclopropylorthoH
94.1HOCH3N(CH2-cyclopropylmetaH
95.1CH3HOCH3N(CH2-cyclopropylpairH
96.1CH3HOCH3N(CH2-cyclopropylorthoCH3(pair relative to X)
97.1CH3HOCH3N(CH2-cyclopropylorthoCH3(a pair of relatively OCHF2)
98.1CH3HOCH3N(CH2-cyclopropylthe ETA OCH3(pair relative to X)
99.1CH3HOCH3N(CH2-cyclopropylmetaOCH3(a pair of relatively OCHF2)

100.1CH3HOCH3N(CH2-cyclopropylmetaCH3(pair relative to X)
101.1HHOCH3chemical bondorthoH
102.1HHOCH3chemical bondmetaH
103.1 HHOCH3chemical bondpairH
104.1HHOCH3chemical bondorthoCH3(pair relative to X)
105.1HHOCH3chemical bondorthoCH3(a pair of relatively OCHF2)
106.1HHOCH3chemical bondmetaOCH3(pair relative to X)
107.1HHOCH3chemical bondmetaOCH3 2)
108.1HHOCH3chemical bondmetaCH3(pair relative to X)
109.1CH3HOCH3chemical bondorthoH
110.1CH3HOCH3chemical bondmetaH
111.1CH3HOCH3chemical bondpairH
112.1CH3HOCH3chemical bond orthoCH3(pair relative to X)
113.1CH3HOCH3chemical bondorthoCH3(a pair of relatively OCHF2)
114.1CH3HOCH3chemical bondmetaOCH3(pair relative to X)
115.1CH3HOCH3chemical bondmetaOCH3(a pair of relatively OCHF2)

116.1CH3HOCH3chemical bondmetaCH3(pair relative to the nutrient X)
117.2HHOCH3NHorthoH
118.2HHOCH3NHmetaH
119.2HHOCH3NHpairH
120.2HHOCH3NHorthoCH3(a pair of relatively NH)
121.2HHOCH3NHorthoCH3(a pair of relatively OCHF2)
122.2HHOCH3NHmetaOCH3(a pair of relatively NH)
123.2HHOCH3NHmetaOCH3(a pair of relatively OCHF2)
124.2HHOCH3NHmetaCH3(a pair of relatively NH)
125.2HHOCH3NHorthoCl (a pair of relatively NH)
126.2HHOCH3NHorthoCl (protostele OCHF 2)
127.2HHOCH3NHorthoF (a pair of relatively NH)
128.2HHOCH3NHorthoF (a pair of relatively OCHF2)
129.2HHOCH3NHmetaOCHF2(a pair of relatively NH)
130.2CH3HOCH3NHorthoH
131.2CH3HOCH3NHmeta H
132.2CH3HOCH3NHpairH
133.2CH3HOCH3NHorthoCH3(a pair of relatively NH)

134.2CH3HOCH3NHorthoCH3(a pair of relatively OCHF2)
135.2CH3HOCH3NHmetaOCH3(a pair of relatively NH)
136.2CH3HOCH 3NHmetaOCH3(a pair of relatively OCHF2)
137.2CH3HOCH3NHmetaCH3(a pair of relatively NH)
138.2CH3HOCH3NHorthoCl (a pair of relatively NH)
139.2CH3HOCH3NHorthoCl (a pair of relatively OCHF2)
140.2CH3HOCH3NHorthoF (a pair of relatively NH)
141.2 CH3HOCH3NHorthoF (a pair of relatively OCHF2)
142.2CH3HOCH3NHmetaOCHF2(a pair of relatively NH)
143.2HHOCH3NCH3orthoH
144.2HHOCH3NCH3metaH
145.2HHOCH3NCH3pairH
146.2 HHOCH3NCH3orthoCH3(pair relative to X)
147.2HHOCH3NCH3orthoCH3(a pair of relatively OCHF2)
148.2HHOCH3NCH3metaOCH3(pair relative to X)
149.2HHOCH3NCH3metaOCH3(a pair of relatively OCHF2)
150.2HHOCH3NCH3metaCH3

151.2HHOCH3NCH3orthoCl (pair relative to X)
152.2HHOCH3NCH3orthoCl (a pair of relatively OCHF2)
153.2HHOCH3NCH3orthoF (pair relative to X)
154.2HHOCH3NCH3orthoF (a pair of relatively OCHF2)
155.2HHOCH3 NCH3metaOCHF2(pair relative to X)
156.2CH3HOCH3NCH3orthoH
157.2CH3HOCH3NCH3metaH
158.2CH3HOCH3NCH3pairH
159.2CH3HOCH3NCH3orthoCH3(pair relative to X)
160.2CH3 HOCH3NCH3orthoCH3(a pair of relatively OCHF2)
161.2CH3HOCH3NCH3metaOCH3(pair relative to X)
162.2CH3HOCH3NCH3metaOCH3(a pair of relatively OCHF2)
163.2CH3HOCH3NCH3metaCH3(pair relative to X)
164.2CH3HOCH3NCH3orthoCl (the Ara relative to X)
165.2CH3HOCH3NCH3orthoCl (a pair of relatively OCHF2)
166.2CH3HOCH3NCH3orthoF (pair relative to X)
167.2CH3HOCH3NCH3orthoF (a pair of relatively OCHF2)

168.2CH3HOCH3NCH3metaOCHF2(pair relative to X)
169.2H HOCH3NCH2CH3orthoH
170.2HHOCH3NCH2CH3metaH
171.2HHOCH3NCH2CH3pairH
172.2HHOCH3NCH2CH3orthoCH3(pair relative to X)
173.2HHOCH3NCH2CH3orthoCH3(a pair of relatively OCHF2)
174. 2HHOCH3NCH2CH3metaOCH3(pair relative to X)
175.2HHOCH3NCH2CH3metaOCH3(a pair of relatively OCHF2)
176.2HHOCH3NCH2CH3metaCH3(pair relative to X)
177.2CH3HOCH3NCH2CH3orthoH
178.2CH3HOCH3NCH2CH3 metaH
179.2CH3HOCH3NCH2CH3pairH
180.2CH3HOCH3NCH2CH3orthoCH3(pair relative to X)
181.2CH3HOCH3NCH2CH3orthoCH3(a pair of relatively OCHF2)
182.2CH3HOCH3NCH2CH3metaOCH3(pair relative to X)
183.2CH3 HOCH3NCH2CH3metaOCH3(a pair of relatively OCHF2)
184.2CH3HOCH3NCH2CH3metaCH3(pair relative to X)
185.2HHOCH3N(CH2)2CH3orthoH
186.2HHOCH3N(CH2)2CH3metaH

187.2HHOCH3N(CH2)2CH3pair H
188.2HHOCH3N(CH2)2CH3orthoCH3(pair relative to X)
189.2HHOCH3N(CH2)2CH3orthoCH3(a pair of relatively OCHF2)
190.2HHOCH3N(CH2)2CH3metaOCH3(pair relative to X)
191.2HHOCH3N(CH2)2CH3metaOCH3(a pair of relatively OCHF2)
192.2 HHOCH3N(CH2)2CH3metaCH3(pair relative to X)
193.2CH3HOCH3N(CH2)2CH3orthoH
194.2CH3HOCH3N(CH2)2CH3metaH
195.2CH3HOCH3N(CH2)2CH3pairH
196.2CH3HOCH3N(CH2)2CH3ortho CH3(pair relative to X)
197.2CH3HOCH3N(CH2)2CH3orthoCH3(a pair of relatively OCHF2)
198.2CH3HOCH3N(CH2)2CH3metaOCH3(pair relative to X)
199.2CH3HOCH3N(CH2)2CH3metaOCH3(a pair of relatively OCHF2)
200.2CH3HOCH3N(CH2)2CH3metaCH3(pair relative to X)
201. 2HHOCH3N(CH2-cyclopropylorthoH
202.2HHOCH3N(CH2-cyclopropylmetaH
203.2HHOCH3N(CH2-cyclopropylpairH
204.2HHOCH3N(CH2-cyclopropylorthoCH3(pair relative to X)

205.2HHOCH3N(CH2-cyclopropyl orthoCH3(a pair of relatively OCHF2)
206.2HHOCH3N(CH2-cyclopropylmetaOCH3(pair relative to X)
207.2HHOCH3N(CH2-cyclopropylmetaOCH3(a pair of relatively OCHF2)
208.2HHOCH3N(CH2-cyclopropylmetaCH3(pair relative to X)
209.2CH3HOCH3N(CH2-cyclopropylorthoH
210. 2CH3HOCH3N(CH2-cyclopropylmetaH
211.2CH3HOCH3N(CH2-cyclopropylpairH
212.2CH3HOCH3N(CH2-cyclopropylorthoCH3(pair relative to X)
213.2CH3HOCH3N(CH2-cyclopropylorthoCH3(a pair of relatively OCHF2)
214.2CH3HOCH3N(CH2-cycloprop the l metaOCH3(pair relative to X)
215.2CH3HOCH3N(CH2-cyclopropylmetaOCH3(a pair of relatively OCHF2)
216.2CH3HOCH3N(CH2-cyclopropylmetaCH3(pair relative to X)
217.2HHOCH3chemical bondorthoH
218.2HHOCH3chemical bondmetaH
219.2 HOCH3chemical bondpairH
220.2HHOCH3chemical bondorthoCH3(pair relative to X)

221.2HHOCH3chemical bondorthoCH3(a pair of relatively OCHF2)
222.2HHOCH3chemical bondmetaOCH3(pair relative to X)
223.2HHOCH3chemical bondOCH3(a pair of relatively OCHF2)
224.2HHOCH3chemical bondmetaCH3(pair relative to X)
225.2CH3HOCH3chemical bondorthoH
226.2CH3HOCH3chemical bondmetaH
227.2CH3HOCH3chemical bondpairH
228.2CH3H OCH3chemical bondorthoCH3(pair relative to X)
229.2CH3HOCH3chemical bondorthoCH3(a pair of relatively OCHF2)
230.2CH3HOCH3chemical bondmetaOCH3(pair relative to X)
231.2CH3HOCH3chemical bondmetaOCH3(a pair of relatively OCHF2)
232.2CH3HOCH3chemical bondmeta CH3(pair relative to X)
233.1HHOCHF2NHorthoH
234.1HHOCHF2NHmetaH
235.1HHOCHF2NHpairH
236.1HHOCHF2NHorthoCH3(a pair of relatively NH)
237.1HHOCHF2NHorthoCH3(a pair of relatively OCHF 2)

238.1HHOCHF2NHmetaOCH3(a pair of relatively NH)
239.1HHOCHF2NHmetaOCH3(a pair of relatively OCHF2)
240.1HHOCHF2NHmetaCH3(a pair of relatively NH)
241.1HHOCHF2NHorthoCl (a pair of relatively NH)
242.1HHOCHF2 NHorthoCl (a pair of relatively OCHF2)
243.1HHOCHF2NHorthoF (a pair of relatively NH)
244.1HHOCHF2NHorthoF (a pair of relatively OCHF2)
245.1HHOCHF2NHmetaOCHF2(a pair of relatively NH)
246.1CH3HOCHF2NHorthoH
247.1CH3H OCHF2NHmetaH
248.1CH3HOCHF2NHpairH
249.1CH3HOCHF2NHorthoCH3(a pair of relatively NH)
250.1CH3HOCHF2NHorthoCH3(a pair of relatively OCHF2)
251.1CH3HOCHF2NHmetaOCH3(a pair of relatively NH)
252.1 CH3HOCHF2NHmetaOCH3(a pair of relatively OCHF2)
253.1CH3HOCHF2NHmetaCH3(a pair of relatively NH)
254.1CH3HOCHF2NHorthoCl (a pair of relatively NH)

255.1CH3HOCHF2NHorthoCl (a pair of relatively OCHF2)
256.1CH3HOCHF2NHthe RTO F (a pair of relatively NH)
257.1CH3HOCHF2NHorthoF (a pair of relatively OCHF2)
258.1CH3HOCHF2NHmetaOCHF2(a pair of relatively NH)
259.1HHOCHF2NCH3orthoH
260.1HHOCHF2NCH3metaH
261.1HHOCHF2NCH3 pairH
262.1HHOCHF2NCH3orthoCH3(pair relative to X)
263.1HHOCHF2NCH3orthoCH3(a pair of relatively OCHF2)
264.1HHOCHF2NCH3metaOCH3(pair relative to X)
265.1HHOCHF2NCH3metaOCH3(a pair of relatively OCHF2)
266.1H HOCHF2NCH3metaCH3(pair relative to X)
267.1HHOCHF2NCH3orthoCl (pair relative to X)
268.1HHOCHF2NCH3orthoCl (a pair of relatively OCHF2)
269.1HHOCHF2NCH3orthoF (pair relative to X)
270.1HHOCHF2NCH3orthoF (a pair of relatively OCHF2)
271. 1HHOCHF2NCH3metaOCHF2(pair relative to X)

272.1CH3HOCHF2NCH3orthoH
273.1CH3HOCHF2NCH3metaH
274.1CH3HOCHF2NCH3pairH
275.1CH3HOCHF2NCH3ortho CH3(pair relative to X)
276.1CH3HOCHF2NCH3orthoCH3(a pair of relatively OCHF2)
277.1CH3HOCHF2NCH3metaOCH3(pair relative to X)
278.1CH3HOCHF2NCH3metaOCH3(a pair of relatively OCHF2)
279.1CH3HOCHF2NCH3metaCH3(pair relative to X)
280.1 CH3HOCHF2NCH3orthoCl (pair relative to X)
281.1CH3HOCHF2NCH3orthoCl (a pair of relatively OCHF2)
282.1CH3HOCHF2NCH3orthoF (pair relative to X)
283.1CH3HOCHF2NCH3orthoF (a pair of relatively OCHF2)
284.1CH3HOCHF2NCH3meta OCHF2(pair relative to X)
285.1HHOCHF2NCH2CH3orthoH
286.1HHOCHF2NCH2CH3metaH
287.1HHOCHF2NCH2CH3pairH
288.1HHOCHF2NCH2CH3orthoCH3(pair relative to X)
289.1HHOCHF2NCH2CH3 orthoCH3(a pair of relatively OCHF2)

1
290.1HHOCHF2NCH2CH3metaOCH3(pair relative to X)
291.1HHOCHF2NCH2CH3metaOCH3(a pair of relatively OCHF2)
292.1HHOCHF2NCH2CH3metaCH3(pair relative to X)
293.1CH3HOCHF2NCH2CH3orthoH
294.CH3HOCHF2NCH2CH3metaH
295.1CH3HOCHF2NCH2CH3pairH
296.1CH3HOCHF2NCH2CH3orthoCH3(pair relative to X)
297.1CH3HOCHF2NCH2CH3orthoCH3(a pair of relatively OCHF2)
298.1CH3HOCHF2NCH2CH3 metaOCH3(pair relative to X)
299.1CH3HOCHF2NCH2CH3metaOCH3(a pair of relatively OCHF2)
300.1CH3HOCHF2NCH2CH3metaCH3(pair relative to X)
301.1HHOCHF2N(CH2)2CH3orthoH
302.1HHOCHF2N(CH2)2CH3metaH
303.1H HOCHF2N(CH2)2CH3pairH
304.1HHOCHF2N(CH2)2CH3orthoCH3(pair relative to X)
305.1HHOCHF2N(CH2)2CH3orthoCH3(a pair of relatively OCHF2)
306.1HHOCHF2N(CH2)2CH3metaOCH3(pair relative to X)
307.1HHOCHF2N(CH2)2CH3meta OCH3(a pair of relatively OCHF2)

308.1HHOCHF2N(CH2)2CH3metaCH3(pair relative to X)
309.1CH3HOCHF2N(CH2)2CH3orthoH
310.1CH3HOCHF2N(CH2)2CH3metaH
311.1CH3HOCHF2N(CH2)2CH3pairH
312.1 CH3HOCHF2N(CH2)2CH3orthoCH3(pair relative to X)
313.1CH3HOCHF2N(CH2)2CH3orthoCH3(a pair of relatively OCHF2)
314.1CH3HOCHF2N(CH2)2CH3metaOCH3(pair relative to X)
315.1CH3HOCHF2N(CH2)2CH3metaOCH3(a pair of relatively OCHF2)
316.1CH3HOCHF 2N(CH2)2CH3metaCH3(pair relative to X)
317.1HHOCHF2N(CH2-cyclopropylorthoH
318.1HHOCHF2N(CH2-cyclopropylmetaH
319.1HHOCHF2N(CH2-cyclopropylpairH
320.1HHOCHF2N(CH2-cyclopropylorthoCH3(pair relative to X)
321.1 HHOCHF2N(CH2-cyclopropylorthoCH3(a pair of relatively OCHF2)
322.1HHOCHF2N(CH2-cyclopropylmetaOCH3(pair relative to X)
323.1HHOCHF2N(CH2-cyclopropylmetaOCH3(a pair of relatively OCHF2)
324.1HHOCHF2N(CH2-cyclopropylmetaCH3(pair relative to X)

325.1CH3H OCHF2N(CH2-cyclopropylorthoH
326.1CH3HOCHF2N(CH2-cyclopropylmetaH
327.1CH3HOCHF2N(CH2-cyclopropylpairH
328.1CH3HOCHF2N(CH2-cyclopropylorthoCH3(pair relative to X)
329.1CH3HOCHF2N(CH2-cyclopropylorthoCH3(a pair of relatively OCHF2)
330.1CH3HOCHF2N(CH2-cyclopropylmetaOCH3(pair relative to X)
331.1CH3HOCHF2N(CH2-cyclopropylmetaOCH3(a pair of relatively OCHF2)
332.1CH3HOCHF2N(CH2-cyclopropylmetaCH3(pair relative to X)
333.1HHOCHF2chemical bondorthoH
334.1HHOCHF2 chemical bondmetaH
335.1HHOCHF2chemical bondpairH
336.1HHOCHF2chemical bondorthoCH3(pair relative to X)
337.1HHOCHF2chemical bondorthoCH3(a pair of relatively OCHF2)
338.1HHOCHF2chemical bondmetaOCH3(pair relative to X)
339.1H HOCHF2chemical bondmetaOCH3(a pair of relatively OCHF2)
340.1HHOCHF2chemical bondmetaCH3(pair relative to X)

341.1CH3HOCHF2chemical bondorthoH
342.1CH3HOCHF2chemical bondmetaH
343.1CH3HOCHF2chemical bondpair H
344.1CH3HOCHF2chemical bondorthoCH3(pair relative to X)
345.1CH3HOCHF2chemical bondorthoCH3(a pair of relatively OCHF2)
346.1CH3HOCHF2chemical bondmetaOCH3(pair relative to X)
347.1CH3HOCHF2chemical bondmetaOCH3(a pair of relatively OCHF2)
348.1CH3 HOCHF2chemical bondmetaCH3(pair relative to X)
349.2HHOCHF2NHorthoH
350.2HHOCHF2NHmetaH
351.2HHOCHF2NHpairH
352.2HHOCHF2NHorthoCH3(a pair of relatively NH)
353.2HH OCHF2NHorthoCH3(a pair of relatively OCHF2)
354.2HHOCHF2NHmetaOCH3(a pair of relatively NH)
355.2HHOCHF2NHmetaOCH3(a pair of relatively OCHF2)
356.2HHOCHF2NHmetaCH3(a pair of relatively NH)
357.2HHOCHF2NHorthoCl (a pair of relatively NH)

358.2HHOCHF2NHorthoCl (a pair of relatively OCHF2)
359.2HHOCHF2NHorthoF (a pair of relatively NH)
360.2HHOCHF2NHorthoF (a pair of relatively OCHF2)
361.2HHOCHF2NHmetaOCHF2(a pair of relatively NH)
362.2CH3HOCHF2NHorthoH
363.2CH3HOCHF2NHmetaH
364.2CH3HOCHF2NHpairH
365.2CH3HOCHF2NHorthoCH3(a pair of relatively NH)
366.2CH3HOCHF2NHorthoCH3(a pair of relatively OCHF2)
367.2CH3HOCHF2NHmeta OCH3(a pair of relatively NH)
368.2CH3HOCHF2NHmetaOCH3(a pair of relatively OCHF2)
369.2CH3HOCHF2NHmetaCH3(a pair of relatively NH)
370.2CH3HOCHF2NHorthoCl (a pair of relatively NH)
371.2CH3HOCHF2NHorthoCl (a pair of relatively OCHF2)
372.2CH3H OCHF2NHorthoF (a pair of relatively NH)
373.2CH3HOCHF2NHorthoF (a pair of relatively OCHF2)
374.2CH3HOCHF2NHmetaOCHF2(a pair of relatively NH)

375.2HHOCHF2NCH3orthoH
376.2HHOCHF2NCH3metaH
377.2 HHOCHF2NCH3pairH
378.2HHOCHF2NCH3orthoCH3(pair relative to X)
379.2HHOCHF2NCH3orthoCH3(a pair of relatively OCHF2)
380.2HHOCHF2NCH3metaOCH3(pair relative to X)
381.2HHOCHF2NCH3metaOCH3(a pair of relatively OCHF2)
382.2HHOCHF2NCH3metaCH3(pair relative to X)
383.2HHOCHF2NCH3orthoCl (pair relative to X)
384.2HHOCHF2NCH3orthoCl (a pair of relatively OCHF2)
385.2HHOCHF2NCH3orthoF (pair relative to X)
386.2HHOCHF2NCH3 orthoF (a pair of relatively OCHF2)
387.2HHOCHF2NCH3metaOCHF2(pair relative to X)
388.2CH3HOCHF2NCH3orthoH
389.2CH3HOCHF2NCH3metaH
390.2CH3HOCHF2NCH3pairH
391.2CH3HOCHF2 NCH3orthoCH3(pair relative to X)
392.2CH3HOCHF2NCH3orthoCH3(a pair of relatively OCHF2)

NCH3 410.
393.2CH3HOCHF2NCH3metaOCH3(pair relative to X)
394.2CH3HOCHF2NCH3metaOCH3(a pair of relatively OCHF2)
395.2CH3HOCHF2NCH3metaCH3(steam is relatively X)
396.2CH3HOCHF2NCH3orthoCl (pair relative to X)
397.2CH3HOCHF2NCH3orthoCl (a pair of relatively OCHF2)
398.2CH3HOCHF2NCH3orthoF (pair relative to X)
399.2CH3HOCHF2NCH3orthoF (a pair of relatively OCHF2)
400.2CH3HOCHF2metaOCHF2(pair relative to X)
401.2HHOCHF2NCH2CH3orthoH
402.2HHOCHF2NCH2CH3metaH
403.2HHOCHF2NCH2CH3pairH
404.2HHOCHF2NCH2CH3orthoCH3(pair relative to X)
405.2HH OCHF2NCH2CH3orthoCH3(a pair of relatively OCHF2)
406.2HHOCHF2NCH2CH3metaOCH3(pair relative to X)
407.2HHOCHF2NCH2CH3metaOCH3(a pair of relatively OCHF2)
408.2HHOCHF2NCH2CH3metaCH3(pair relative to X)
409.2CH3HOCHF2NCH2CH3orthoH
2CH3HOCHF2NCH2CH3metaH

411.2CH3HOCHF2NCH2CH3pairH
412.2CH3HOCHF2NCH2CH3orthoCH3(pair relative to X)
413.2CH3HOCHF2NCH2CH3orthoCH3(a pair of relatively OCHF2)
414.2CH3H OCHF2NCH2CH3metaOCH3(pair relative to X)
415.2CH3HOCHF2NCH2CH3metaOCH3(a pair of relatively OCHF2)
416.2CH3HOCHF2NCH2CH3metaCH3(pair relative to X)
417.2HHOCHF2N(CH2)2CH3orthoH
418.2HHOCHF2N(CH2)2CH3metaH
419.2HHOCHF2N(CH2)2CH3pairH
420.2HHOCHF2N(CH2)2CH3orthoCH3(pair relative to X)
421.2HHOCHF2N(CH2)2CH3orthoCH3(a pair of relatively OCHF2)
422.2HHOCHF2N(CH2)2CH3metaOCH3(pair relative to X)
423.2HHOCHF2 N(CH2)2CH3metaOCH3(a pair of relatively OCHF2)
424.2HHOCHF2N(CH2)2CH3metaCH3(pair relative to X)
425.2CH3HOCHF2N(CH2)2CH3orthoH
426.2CH3HOCHF2N(CH2)2CH3metaH
427.2CH3HOCHF2N(CH2)2CH3pairH
428. 2CH3HOCHF2N(CH2)2CH3orthoCH3(pair relative to X)

429.2CH3HOCHF2N(CH2)2CH3orthoCH3(a pair of relatively OCHF2)
430.2CH3HOCHF2N(CH2)2CH3metaOCH3(pair relative to X)
431.2CH3HOCHF2N(CH2)2CH3metaOCH3(a pair of relatively OCHF2)
432.2 CH3HOCHF2N(CH2)2CH3metaCH3(pair relative to X)
433.2HHOCHF2N(CH2-cyclopropylorthoH
434.2HHOCHF2N(CH2-cyclopropylmetaH
435.2HHOCHF2N(CH2-cyclopropylpairH
436.2HHOCHF2N(CH2-cyclopropylorthoCH3(pair relative to X)
437.2HHOCHF2N(CH2-cyclopropylorthoCH3(a pair of relatively OCHF2)
438.2HHOCHF2N(CH2-cyclopropylmetaOCH3(pair relative to X)
439.2HHOCHF2N(CH2-cyclopropylmetaOCH3(a pair of relatively OCHF2)
440.2HHOCHF2N(CH2-cyclopropylmetaCH3(pair relative to X)
441.2CH3 HOCHF2N(CH2-cyclopropylorthoH
442.2CH3HOCHF2N(CH2-cyclopropylmetaH
443.2CH3HOCHF2N(CH2-cyclopropylpairH
444.2CH3HOCHF2N(CH2-cyclopropylorthoCH3(pair relative to X)

445.2CH3HOCHF2N(CH2-cyclopropylortho CH3(a pair of relatively OCHF2)
446.2CH3HOCHF2N(CH2-cyclopropylmetaOCH3(pair relative to X)
447.2CH3HOCHF2N(CH2-cyclopropylmetaOCH3(a pair of relatively OCHF2)
448.2CH3HOCHF2N(CH2-cyclopropylmetaCH3(pair relative to X)
449.2HHOCHF2chemical bondorthoH
450.2H HOCHF2chemical bondmetaH
451.2HHOCHF2chemical bondpairH
452.2HHOCHF2chemical bondorthoCH3(pair relative to X)
453.2HHOCHF2chemical bondorthoCH3(a pair of relatively OCHF2)
454.2HHOCHF2chemical bondmetaOCH3(pair relative to X)
455.2HHOCHF2chemical bondmetaOCH3(a pair of relatively OCHF2)
456.2HHOCHF2chemical bondmetaCH3(pair relative to X)
457.2CH3HOCHF2chemical bondorthoH
458.2CH3HOCHF2chemical bondmetaH
459.2CH3HOCHF2chemical bond pairH
460.2CH3HOCHF2chemical bondorthoCH3(pair relative to X)

461.2CH3HOCHF2chemical bondorthoCH3(a pair of relatively OCHF2)
462.2CH3HOCHF2chemical bondmetaOCH3(pair relative to X)
463.2CH3HOCHF2chemical bondmetaOCH3(a pair of relatively OCHF2)
464.2CH3HOCHF2chemical bondmetaCH3(pair relative to X)
465.1HHCH3NHorthoH
466.1HHCH3NHmetaH
467.1HHCH3NHpairH
468.1HHCH3NHorthoCH3(a pair of relatively NH)
469. 1HHCH3NHorthoCH3(a pair of relatively OCHF2)
470.1HHCH3NHmetaOCH3(a pair of relatively NH)
471.1HHCH3NHmetaOCH3(a pair of relatively OCHF2)
472.1HHCH3NHmetaCH3(a pair of relatively NH)
473.1HHCH3NHorthoCl (a pair of relatively NH)/td>
474.1HHCH3NHorthoCl (a pair of relatively OCHF2)
475.1HHCH3NHorthoF (a pair of relatively NH)
476.1HHCH3NHorthoF (a pair of relatively OCHF2)
477.1HHCH3NHmetaOCHF2(a pair of relatively NH)

478.1CH3HCH3 NHorthoH
479.1CH3HCH3NHmetaH
480.1CH3HCH3NHpairH
481.1CH3HCH3NHorthoCH3(a pair of relatively NH)
482.1CH3HCH3NHorthoCH3(a pair of relatively OCHF2)
483.1CH3HCH3 NHmetaOCH3(a pair of relatively NH)
484.1CH3HCH3NHmetaOCH3(a pair of relatively OCHF2)
485.1CH3HCH3NHmetaCH3(a pair of relatively NH)
486.1CH3HCH3NHorthoCl (a pair of relatively NH)
487.1CH3HCH3NHorthoCl (a pair of relatively OCHF2)
488.1CH3 HCH3NHorthoF (a pair of relatively NH)
489.1CH3HCH3NHorthoF (a pair of relatively OCHF2)
490.1CH3HCH3NHmetaOCHF2(a pair of relatively NH)
491.1HHCH3NCH3orthoH
492.1HHCH3NCH3metaH
493.1 HHCH3NCH3pairH
494.1HHCH3NCH3orthoCH3(pair relative to X)
495.1HHCH3NCH3orthoCH3(a pair of relatively OCHF2)

496.1HHCH3NCH3metaOCH3(pair relative to X)
497.1HHCH3NCH3meta OCH3(a pair of relatively OCHF2)
498.1HHCH3NCH3metaCH3(pair relative to X)
499.1HHCH3NCH3orthoCl (pair relative to X)
500.1HHCH3NCH3orthoCl (a pair of relatively OCHF2)
501.1HHCH3NCH3orthoF (pair relative to X)
502.1HHCH3 NCH3orthoF (a pair of relatively OCHF2)
503.1HHCH3NCH3metaOCHF2(pair relative to X)
504.1CH3HCH3NCH3orthoH
505.1CH3HCH3NCH3metaH
506.1CH3HCH3NCH3pairH
507.1CH3H CH3NCH3orthoCH3(pair relative to X)
508.1CH3HCH3NCH3orthoCH3(a pair of relatively OCHF2)
509.1CH3HCH3NCH3metaOCH3(pair relative to X)
510.1CH3HCH3NCH3metaOCH3(a pair of relatively OCHF2)
511.1CH3HCH3NCH3metaCH3(pair relative to X)
512.1CH3HCH3NCH3orthoCl (pair relative to X)

513.1CH3HCH3NCH3orthoCl (a pair of relatively OCHF2)
514.1CH3HCH3NCH3orthoF (pair relative to X)
515.1CH3HCH3NCH3orthoF (a pair of relatively OCHF2)
516.1CH3 CH3NCH3metaOCHF2(pair relative to X)
517.1HHCH3NCH2CH3orthoH
518.1HHCH3NCH2CH3metaH
519.1HHCH3NCH2CH3pairH
520.1HHCH3NCH2CH3orthoCH3(pair relative to X)
521.1HCH3NCH2CH3orthoCH3(a pair of relatively OCHF2)
522.1HHCH3NCH2CH3metaOCH3(pair relative to X)
523.1HHCH3NCH2CH3metaOCH3(a pair of relatively OCHF2)
524.1HHCH3NCH2CH3metaCH3(pair relative to X)
525.1CH3HCH3NCH2CH3 orthoH
526.1CH3HCH3NCH2CH3metaH
527.1CH3HCH3NCH2CH3pairH
528.1CH3HCH3NCH2CH3orthoCH3(pair relative to X)
529.1CH3HCH3NCH2CH3orthoCH3(a pair of relatively OCHF2)
530.1CH3H CH3NCH2CH3metaOCH3(pair relative to X)

531.1CH3HCH3NCH2CH3metaOCH3(a pair of relatively OCHF2)
532.1CH3HCH3NCH2CH3metaCH3(pair relative to X)
533.1HHCH3N(CH2)2CH3orthoH
534.1HHCH3N(CH2)2CH3meta H
535.1HHCH3N(CH2)2CH3pairH
536.1HHCH3N(CH2)2CH3orthoCH3(pair relative to X)
537.1HHCH3N(CH2)2CH3orthoCH3(a pair of relatively OCHF2)
538.1HHCH3N(CH2)2CH3metaOCH3(pair relative to X)
539.1HH CH3N(CH2)2CH3metaOCH3(a pair of relatively OCHF2)
540.1HHCH3N(CH2)2CH3metaCH3(pair relative to X)
541.1CH3HCH3N(CH2)2CH3orthoH
542.1CH3HCH3N(CH2)2CH3metaH
543.1CH3HCH3N(CH2)2CH3pairH
544.1CH3HCH3N(CH2)2CH3orthoCH3(pair relative to X)
545.1CH3HCH3N(CH2)2CH3orthoCH3(a pair of relatively OCHF2)
546.1CH3HCH3N(CH2)2CH3metaOCH3(pair relative to X)
547.1CH3HCH3N(CH2)2CH3metaOCH3(a pair of relatively OCHF2)
548.1CH3 HCH3N(CH2)2CH3metaCH3(pair relative to X)

549.1HHCH3N(CH2-cyclopropylorthoH
550.1HHCH3N(CH2-cyclopropylmetaH
551.1HHCH3N(CH2-cyclopropylpairH
552.1HHCH3N(CH2-cyclopropylortho CH3(pair relative to X)
553.1HHCH3N(CH2-cyclopropylorthoCH3(a pair of relatively OCHF2)
554.1HHCH3N(CH2-cyclopropylmetaOCH3(pair relative to X)
555.1HHCH3N(CH2-cyclopropylmetaOCH3(a pair of relatively OCHF2)
556.1HHCH3N(CH2-cyclopropylmetaCH3(pair relative to X)
557.1 CH3HCH3N(CH2-cyclopropylorthoH
558.1CH3HCH3N(CH2-cyclopropylmetaH
559.1CH3HCH3N(CH2-cyclopropylpairH
560.1CH3HCH3N(CH2-cyclopropylorthoCH3(pair relative to X)
561.1CH3HCH3N(CH2-cyclopropylorthoCH3 2)
562.1CH3HCH3N(CH2-cyclopropylmetaOCH3(pair relative to X)
563.1CH3HCH3N(CH2-cyclopropylmetaOCH3(a pair of relatively OCHF2)
564.1CH3HCH3N(CH2-cyclopropylmetaCH3(pair relative to X)

571.
565.1HHCH3chemical bondorthoH
566.1 HHCH3chemical bondmetaH
567.1HHCH3chemical bondpairH
568.1HHCH3chemical bondorthoCH3(pair relative to X)
569.1HHCH3chemical bondorthoCH3(a pair of relatively OCHF2)
570.1HHCH3chemical bondmetaOCH3(pair relative to X)
1HHCH3chemical bondmetaOCH3(a pair of relatively OCHF2)
572.1HHCH3chemical bondmetaCH3(pair relative to X)
573.1CH3HCH3chemical bondorthoH
574.1CH3HCH3chemical bondmetaH
575.1CH3HCH3chemical bond pairH
576.1CH3HCH3chemical bondorthoCH3(pair relative to X)
577.1CH3HCH3chemical bondorthoCH3(a pair of relatively OCHF2)
578.1CH3HCH3chemical bondmetaOCH3(pair relative to X)
579.1CH3HCH3chemical bondmetaOCH3(a pair of relatively OCHF2)
580.1 CH3HCH3chemical bondmetaCH3(pair relative to X)
581.2HHCH3NHorthoH

582.2HHCH3NHmetaH
583.2HHCH3NHpairH
584.2HHCH3NHorthoCH3(a pair of relatively NH)
585. 2HHCH3NHorthoCH3(a pair of relatively OCHF2)
586.2HHCH3NHmetaOCH3(a pair of relatively NH)
587.2HHCH3NHmetaOCH3(a pair of relatively OCHF2)
588.2HHCH3NHmetaCH3(a pair of relatively NH)
589.2HHCH3NHorthoCl (a pair of relatively NH)/td>
590.2HHCH3NHorthoCl (a pair of relatively OCHF2)
591.2HHCH3NHorthoF (a pair of relatively NH)
592.2HHCH3NHorthoF (a pair of relatively OCHF2)
593.2HHCH3NHmetaOCHF2(a pair of relatively NH)
594.2CH3HCH3NHortho H
595.2CH3HCH3NHmetaH
596.2CH3HCH3NHpairH
597.2CH3HCH3NHorthoCH3(a pair of relatively NH)
598.2CH3HCH3NHorthoCH3(a pair of relatively OCHF2)
599.2CH3HCH3NHmeta OCH3(a pair of relatively NH)

H 2
600.2CH3HCH3NHmetaOCH3(a pair of relatively OCHF2)
601.2CH3HCH3NHmetaCH3(a pair of relatively NH)
602.2CH3HCH3NHorthoCl (a pair of relatively NH)
603.2CH3HCH3NHorthoCl (a pair of relatively OCHF2)
604.2CH3CH3NHorthoF (a pair of relatively NH)
605.2CH3HCH3NHorthoF (a pair of relatively OCHF2)
606.2CH3HCH3NHmetaOCHF2(a pair of relatively NH)
607.2HHCH3NCH3orthoH
608.2HHCH3NCH3metaH
609.2H HCH3NCH3pairH
610.2HHCH3NCH3orthoCH3(pair relative to X)
611.2HHCH3NCH3orthoCH3(a pair of relatively OCHF2)
612.2HHCH3NCH3metaOCH3(pair relative to X)
613.2HHCH3NCH3metaOCH3(a pair of relatively OCHF2)
614.HHCH3NCH3metaCH3(pair relative to X)
615.2HHCH3NCH3orthoCl (pair relative to X)
616.2HHCH3NCH3orthoCl (a pair of relatively OCHF2)

2
617.2HHCH3NCH3orthoF (pair relative to X)
618.2HHCH3NCH3 orthoF (a pair of relatively OCHF2)
619.2HHCH3NCH3metaOCHF2(pair relative to X)
620.2CH3HCH3NCH3orthoH
621.2CH3HCH3NCH3metaH
622.2CH3HCH3NCH3pairH
623.2CH3HCH3orthoCH3(pair relative to X)
624.2CH3HCH3NCH3orthoCH3(a pair of relatively OCHF2)
625.2CH3HCH3NCH3metaOCH3(pair relative to X)
626.2CH3HCH3NCH3metaOCH3(a pair of relatively OCHF2)
627.2CH3HCH3NCH3metaCH3(pair relative to X)
628.CH3HCH3NCH3orthoCl (pair relative to X)
629.2CH3HCH3NCH3orthoCl (a pair of relatively OCHF2)
630.2CH3HCH3NCH3orthoF (pair relative to X)
631.2CH3HCH3NCH3orthoF (a pair of relatively OCHF2)
632.2CH3HCH3NCH3meta OCHF2(pair relative to X)
633.2HHCH3NCH2CH3orthoH
634.2HHCH3NCH2CH3metaH

635.2HHCH3NCH2CH3pairH
636.2HHCH3NCH2CH3orthoCH3(pair relative to X)
637.2HH CH3NCH2CH3orthoCH3(a pair of relatively OCHF2)
638.2HHCH3NCH2CH3metaOCH3(pair relative to X)
639.2HHCH3NCH2CH3metaOCH3(a pair of relatively OCHF2)
640.2HHCH3NCH2CH3metaCH3(pair relative to X)
641.2CH3HCH3NCH2CH3orthoH
642.2CH3HCH3NCH2CH3metaH
643.2CH3HCH3NCH2CH3pairH
644.2CH3HCH3NCH2CH3orthoCH3(pair relative to X)
645.2CH3HCH3NCH2CH3orthoCH3(a pair of relatively OCHF2)
646.2CH3HCH3NCH2CH metaOCH3(pair relative to X)
647.2CH3HCH3NCH2CH3metaOCH3(a pair of relatively OCHF2)
648.2CH3HCH3NCH2CH3metaCH3(pair relative to X)
649.2HHCH3N(CH2)2CH3orthoH
650.2HHCH3N(CH2)2CH3metaH
651.2 HHCH3N(CH2)2CH3pairH
652.2HHCH3N(CH2)2CH3orthoCH3(pair relative to X)

td align="center"> CH3
653.2HHCH3N(CH2)2CH3orthoCH3(a pair of relatively OCHF2)
654.2HHCH3N(CH2)2CH3metaOCH3(pair relative to X)
655.2HHCH3 N(CH2)2CH3metaOCH3(a pair of relatively OCHF2)
656.2HHCH3N(CH2)2CH3metaCH3(pair relative to X)
657.2CH3HCH3N(CH2)2CH3orthoH
658.2CH3HCH3N(CH2)2CH3metaH
659.2CH3HCH3N(CH2)2CH3pairH
660. 2CH3HCH3N(CH2)2CH3orthoCH3(pair relative to X)
661.2CH3HCH3N(CH2)2CH3orthoCH3(a pair of relatively OCHF2)
662.2CH3HCH3N(CH2)2CH3metaOCH3(pair relative to X)
663.2CH3HCH3N(CH2)2CH3metaOCH3(a pair of relatively OCHF2)
664.2CH3HN(CH2)2CH3metaCH3(pair relative to X)
665.2HHCH3N(CH2-cyclopropylorthoH
666.2HHCH3N(CH2-cyclopropylmetaH
667.2HHCH3N(CH2-cyclopropylpairH
668.2HHCH3N(CH2-cyclopropylorthoCH3(pair relative to X)
669.2 HHCH3N(CH2-cyclopropylorthoCH3(a pair of relatively OCHF2)

670.2HHCH3N(CH2-cyclopropylmetaOCH3(pair relative to X)
671.2HHCH3N(CH2-cyclopropylmetaOCH3(a pair of relatively OCHF2)
672.2HHCH3N(CH2-cyclopropylmetaCH3(pair relative to X)
673.2CH3HC 3N(CH2-cyclopropylorthoH
674.2CH3HCH3N(CH2-cyclopropylmetaH
675.2CH3HCH3N(CH2-cyclopropylpairH
676.2CH3HCH3N(CH2-cyclopropylorthoCH3(pair relative to X)
677.2CH3HCH3N(CH2-cyclopropylorthoCH3(a pair of relatively OCHF2)
678. 2CH3HCH3N(CH2-cyclopropylmetaOCH3(pair relative to X)
679.2CH3HCH3N(CH2-cyclopropylmetaOCH3(a pair of relatively OCHF2)
680.2CH3HCH3N(CH2-cyclopropylmetaCH3(pair relative to X)
681.2HHCH3chemical bondorthoH
682.2HHCH3metaH
683.2HHCH3chemical bondpairH
684.2HHCH3chemical bondorthoCH3(pair relative to X)
685.2HHCH3chemical bondorthoCH3(a pair of relatively OCHF2)

686.2HHCH3chemical bondmetaOCH3(pair relative to X)
687. 2HHCH3chemical bondmetaOCH3(a pair of relatively OCHF2)
688.2HHCH3chemical bondmetaCH3(pair relative to X)
689.2CH3HCH3chemical bondorthoH
690.2CH3HCH3chemical bondmetaH
691.2CH3HCH3chemical bondpair H
692.2CH3HCH3chemical bondorthoCH3(pair relative to X)
693.2CH3HCH3chemical bondorthoCH3(a pair of relatively OCHF2)
694.2CH3HCH3chemical bondmetaOCH3(pair relative to X)
695.2CH3HCH3chemical bondmetaOCH3(a pair of relatively OCHF2)
696.2CH3 HCH3chemical bondmetaCH3(pair relative to X)
697.1HHFNHorthoH
698.1HHFNHmetaH
699.1HHFNHpairH
700.1HHFNHorthoCH3(a pair of relatively NH)
701.1HHForthoCH3(a pair of relatively OCHF2)
702.1HHFNHmetaOCH3(a pair of relatively NH)

703.1HHFNHmetaOCH3(a pair of relatively OCHF2)
704.1HHFNHmetaCH3(a pair of relatively NH)
705.1HHFNHorthoCl (a pair of relatively NH)
706.1H HFNHorthoCl (a pair of relatively OCHF2)
707.1HHFNHorthoF (a pair of relatively NH)
708.1HHFNHorthoF (a pair of relatively OCHF2)
709.1HHFNHmetaOCHF2(a pair of relatively NH)
710.1CH3HFNHorthoH
711.1CH3H FNHmetaH
712.1CH3HFNHpairH
713.1CH3HFNHorthoCH3(a pair of relatively NH)
714.1CH3HFNHorthoCH3(a pair of relatively OCHF2)
715.1CH3HFNHmetaOCH3(a pair of relatively NH)
716.1CH3H FNHmetaOCH3(a pair of relatively OCHF2)
717.1CH3HFNHmetaCH3(a pair of relatively NH)
718.1CH3HFNHorthoCl (a pair of relatively NH)
719.1CH3HFNHorthoCl (a pair of relatively OCHF2)

720.1CH3HFNHorthoF (a pair of relatively NH)
721. 1CH3HFNHorthoF (a pair of relatively OCHF2)
722.1CH3HFNHmetaOCHF2(a pair of relatively NH)
723.1HHFNCH3orthoH
724.1HHFNCH3metaH
725.1HHFNCH3pairH
726.1H HFNCH3orthoCH3(pair relative to X)
727.1HHFNCH3orthoCH3(a pair of relatively OCHF2)
728.1HHFNCH3metaOCH3(pair relative to X)
729.1HHFNCH3metaOCH3(a pair of relatively OCHF2)
730.1HHFNCH3metaCH3(pair relative to X)
731. 1HHFNCH3orthoCl (pair relative to X)
732.1HHFNCH3orthoCl (a pair of relatively OCHF2)
733.1HHFNCH3orthoF (pair relative to X)
734.1HHFNCH3orthoF (a pair of relatively OCHF2)
735.1HHFNCH3metaOCHF2(pair relative to X)
736.1CH3HFNCH3orthoH
737.1CH3HFNCH3metaH

738.1CH3HFNCH3pairH
739.1CH3HFNCH3orthoCH3(pair relative to X)
740.1CH3HFNCH3orthoCH3 (a pair of relatively OCHF 2)
741.1CH3HFNCH3metaOCH3(pair relative to X)
742.1CH3HFNCH3metaOCH3(a pair of relatively OCHF2)
743.1CH3HFNCH3metaCH3(pair relative to X)
744.1CH3HFNCH3orthoCl (pair relative to X)
745.1CH3HFCH 3orthoCl (a pair of relatively OCHF2)
746.1CH3HFNCH3orthoF (pair relative to X)
747.1CH3HFNCH3orthoF (a pair of relatively OCHF2)
748.1CH3HFNCH3metaOCHF2(pair relative to X)
749.1HHFNCH2CH3orthoH
750.1HH FNCH2CH3metaH
751.1HHFNCH2CH3pairH
752.1HHFNCH2CH3orthoCH3(pair relative to X)
753.1HHFNCH2CH3orthoCH3(a pair of relatively OCHF2)
754.1HHFNCH2CH3metaOCH3(pair relative to X)

755. 1HHFNCH2CH3metaOCH3(a pair of relatively OCHF2)
756.1HHFNCH2CH3metaCH3(pair relative to X)
757.1CH3HFNCH2CH3orthoH
758.1CH3HFNCH2CH3metaH
759.1CH3HFNCH2CH3pairH
760.1CH3HFNCH2CH3orthoCH3(pair relative to X)
761.1CH3HFNCH2CH3orthoCH3(a pair of relatively OCHF2)
762.1CH3HFNCH2CH3metaOCH3(pair relative to X)
763.1CH3HFNCH2CH3metaOCH3(a pair of relatively OCHF2)
764.1CH3HF NCH2CH3metaCH3(pair relative to X)
765.1HHFN(CH2)2CH3orthoH
766.1HHFN(CH2)2CH3metaH
767.1HHFN(CH2)2CH3pairH
768.1HHFN(CH2)2CH3orthoCH3(pair relative to X)
769.1HH FN(CH2)2CH3orthoCH3(a pair of relatively OCHF2)
770.1HHFN(CH2)2CH3metaOCH3(pair relative to X)
771.1HHFN(CH2)2CH3metaOCH3(a pair of relatively OCHF2)
772.1HHFN(CH2)2CH3metaCH3(pair relative to X)

773.1CH3HFN(CH2)2CH3H
774.1CH3HFN(CH2)2CH3metaH
775.1CH3HFN(CH2)2CH3pairH
776.1CH3HFN(CH2)2CH3orthoCH3(pair relative to X)
777.1CH3HFN(CH2)2CH3orthoCH3(a pair of relatively OCHF2)
778.1CH3H FN(CH2)2CH3metaOCH3(pair relative to X)
779.1CH3HFN(CH2)2CH3metaOCH3(a pair of relatively OCHF2)
780.1CH3HFN(CH2)2CH3metaCH3(pair relative to X)
781.1HHFN(CH2-cyclopropylorthoH
782.1HHFN(CH2-cyclopropylmetaH
783. 1HHFN(CH2-cyclopropylpairH
784.1HHFN(CH2-cyclopropylorthoCH3(pair relative to X)
785.1HHFN(CH2-cyclopropylorthoCH3(a pair of relatively OCHF2)
786.1HHFN(CH2-cyclopropylmetaOCH3(pair relative to X)
787.1HHFN(CH2-cyclopropylmeta OCH3(a pair of relatively OCHF2)
788.1HHFN(CH2-cyclopropylmetaCH3(pair relative to X)
789.1CH3HFN(CH2-cyclopropylorthoH

790.1CH3HFN(CH2-cyclopropylmetaH
791.1CH3HFN(CH2-cyclopropylpairH
792.1CH3HN(CH2-cyclopropylorthoCH3(pair relative to X)
793.1CH3HFN(CH2-cyclopropylorthoCH3(a pair of relatively OCHF2)
794.1CH3HFN(CH2-cyclopropylmetaOCH3(pair relative to X)
795.1CH3HFN(CH2-cyclopropylmetaOCH3(a pair of relatively OCHF2)
796.1CH3HFN(CH2-cyclopropylmetaCH3 (pair relative to X)
797.1HHFchemical bondorthoH
798.1HHFchemical bondmetaH
799.1HHFchemical bondpairH
800.1HHFchemical bondorthoCH3(pair relative to X)
801.1HHFchemical bondorthoCH3 (a pair of relatively OCHF 2)
802.1HHFchemical bondmetaOCH3(pair relative to X)
803.1HHFchemical bondmetaOCH3(a pair of relatively OCHF2)
804.1HHFchemical bondmetaCH3(pair relative to X)
805.1CH3HFchemical bondorthoH

806.1CH3Hchemical bondmetaH
807.1CH3HFchemical bondpairH
808.1CH3HFchemical bondorthoCH3(pair relative to X)
809.1CH3HFchemical bondorthoCH3(a pair of relatively OCHF2)
810.1CH3HFchemical bondmetaOCH3(pair relative to X)
811.1 CH3HFchemical bondmetaOCH3(a pair of relatively OCHF2)
812.1CH3HFchemical bondmetaCH3(pair relative to X)
813.2HHFNHorthoH
814.2HHFNHmetaH
815.2HHFNHpairH
816.2H HFNHorthoCH3(a pair of relatively NH)
817.2HHFNHorthoCH3(a pair of relatively OCHF2)
818.2HHFNHmetaOCH3(a pair of relatively NH)
819.2HHFNHmetaOCH3(a pair of relatively OCHF2)
820.2HHFNHmetaCH3(a pair of relatively NH)
821.2HFNHorthoCl (a pair of relatively NH)
822.2HHFNHorthoCl (a pair of relatively OCHF2)

2
823.2HHFNHorthoF (a pair of relatively NH)
824.2HHFNHorthoF (a pair of relatively OCHF2)
825.2HHFNHmetaOCHF2(a pair of relatively NH)
826. 2CH3HFNHorthoH
827.2CH3HFNHmetaH
828.2CH3HFNHpairH
829.2CH3HFNHorthoCH3(a pair of relatively NH)
830.2CH3HFNHorthoCH3(a pair of relatively OCHF2)
831.2H 3HFNHmetaOCH3(a pair of relatively NH)
832.2CH3HFNHmetaOCH3(a pair of relatively OCHF2)
833.2CH3HFNHmetaCH3(a pair of relatively NH)
834.2CH3HFNHorthoCl (a pair of relatively NH)
835.2CH3HFNHorthoCl (a pair of relatively OCHF2)
836.CH3HFNHorthoF (a pair of relatively NH)
837.2CH3HFNHorthoF (a pair of relatively OCHF2)
838.2CH3HFNHmetaOCHF2(a pair of relatively NH)
839.2HHFNCH3orthoH
840.2HHFNCH3metaH

2HHFNCH3pairH
842.2HHFNCH3orthoCH3(pair relative to X)
843.2HHFNCH3orthoCH3(a pair of relatively OCHF2)
844.2HHFNCH3metaOCH3(pair relative to X)
845.2HHFNCH3metaOCH3(a pair of relatively OCHF 2)
846.2HHFNCH3metaCH3(pair relative to X)
847.2HHFNCH3orthoCl (pair relative to X)
848.2HHFNCH3orthoCl (a pair of relatively OCHF2)
849.2HHFNCH3orthoF (pair relative to X)
850.2HHFNCH3ortho F (a pair of relatively OCHF2)
851.2HHFNCH3metaOCHF2(pair relative to X)
852.2CH3HFNCH3orthoH
853.2CH3HFNCH3metaH
854.2CH3HFNCH3pairH
855.2CH3HFNCH3orthoCH 3(pair relative to X)
856.2CH3HFNCH3orthoCH3(a pair of relatively OCHF2)
857.2CH3HFNCH3metaOCH3(pair relative to X)

858.2CH3HFNCH3metaOCH3(a pair of relatively OCHF2)
859.2CH3HFNCH3metaCH3(pair relative to X)
860.2CH HFNHorthoCl (pair relative to X)
861.2CH3HFNHorthoCl (a pair of relatively OCHF2)
862.2CH3HFNHorthoF (pair relative to X)
863.2CH3HFNHorthoF (a pair of relatively OCHF2)
864.2CH3HFNHmetaOCHF2(pair relative to X)
865.2 HHFNCH2CH3orthoH
866.2HHFNCH2CH3metaH
867.2HHFNCH2CH3pairH
868.2HHFNCH2CH3orthoCH3(pair relative to X)
869.2HHFNCH2CH3orthoCH3(a pair of relatively OCHF2)
870. 2HHFNCH2CH3metaOCH3(pair relative to X)
871.2HHFNCH2CH3metaOCH3(a pair of relatively OCHF2)
872.2HHFNCH2CH3metaCH3(pair relative to X)
873.2CH3HFNCH2CH3orthoH
874.2CH3HFNCH2CH3metaH
875.2CH3HFNCH2CH3pairH

876.2CH3HFNCH2CH3orthoCH3(pair relative to X)
877.2CH3HFNCH2CH3orthoCH3(a pair of relatively OCHF2)
878.2CH3HFNCH2CH3metaOCH3(pair relative to X)
879.2CH3H FNCH2CH3metaOCH3(a pair of relatively OCHF2)
880.2CH3HFNCH2CH3metaCH3(pair relative to X)
881.2HHFN(CH2)2CH3orthoH
882.2HHFN(CH2)2CH3metaH
883.2HHFN(CH2)2CH3pairH
884.2 HHFN(CH2)2CH3orthoCH3(pair relative to X)
885.2HHFN(CH2)2CH3orthoCH3(a pair of relatively OCHF2)
886.2HHFN(CH2)2CH3metaOCH3(pair relative to X)
887.2HHFN(CH2)2CH3metaOCH3(a pair of relatively OCHF2)
888.2HHFN(CH2)2CH3 metaCH3(pair relative to X)
889.2CH3HFN(CH2)2CH3orthoH
890.2CH3HFN(CH2)2CH3metaH
891.2CH3HFN(CH2)2CH3pairH
892.2CH3HFN(CH2)2CH3orthoCH3(pair relative to X)
893.2CH3H FN(CH2)2CH3orthoCH3(a pair of relatively OCHF2)

894.2CH3HFN(CH2)2CH3metaOCH3(pair relative to X)
895.2CH3HFN(CH2)2CH3metaOCH3(a pair of relatively OCHF2)
896.2CH3HFN(CH2)2CH3metaCH3(pair relative to X)
897.2HHFN(CH2-cyclopropyl orthoH
898.2HHFN(CH2-cyclopropylmetaH
899.2HHFN(CH2-cyclopropylpairH
900.2HHFN(CH2-cyclopropylorthoCH3(pair relative to X)
901.2HHFN(CH2-cyclopropylorthoCH3(a pair of relatively OCHF2)
902.2HHFN(CH2)cyclopropyl MetaOCH3(pair relative to X)
903.2HHFN(CH2-cyclopropylmetaOCH3(a pair of relatively OCHF2)
904.2HHFN(CH2-cyclopropylmetaCH3(pair relative to X)
905.2CH3HFN(CH2-cyclopropylorthoH
906.2CH3HFN(CH2-cyclopropylmetaH
907.2CH3 HFN(CH2-cyclopropylpairH
908.2CH3HFN(CH2-cyclopropylorthoCH3(pair relative to X)
909.2CH3HFN(CH2-cyclopropylorthoCH3(a pair of relatively OCHF2)

910.2CH3HFN(CH2-cyclopropylmetaOCH3(pair relative to X)
911.2CH3HFN(CH2-cyclopropyl metaOCH3(a pair of relatively OCHF2)
912.2CH3HFN(CH2-cyclopropylmetaCH3(pair relative to X)
913.2HHFchemical bondorthoH
914.2HHFchemical bondmetaH
915.2HHFchemical bondpairH
916.2HHFchemical bond orthoCH3(pair relative to X)
917.2HHFchemical bondorthoCH3(a pair of relatively OCHF2)
918.2HHFchemical bondmetaOCH3(pair relative to X)
919.2HHFchemical bondmetaOCH3(a pair of relatively OCHF2)
920.2HHFchemical bondmetaCH3(pair relative to X)
921.2CH3 HFchemical bondorthoH
922.2CH3HFchemical bondmetaH
923.2CH3HFchemical bondpairH
924.2CH3HFchemical bondorthoCH3(pair relative to X)
925.2CH3HFchemical bondorthoCH3(a pair of relatively OCHF2)

926.2CH3HFchemical bondmetaOCH3(pair relative to X)
927.2CH3HFchemical bondmetaOCH3(a pair of relatively OCHF2)
928.2CH3HFchemical bondmetaCH3(pair relative to X)
* Position OCHF2regarding X

Examples of compounds according to the present invention are the compounds of formula I', to their pharmacologically acceptable salts and their N-oxides, in which R5and R6are hydrogen, and X, R1, R2, R3, R4and n and position X shown in the following table B:

Table B
nR1R2R3XThe position of X relative to diverticula
929.1HHOCH3NHortho
930.1HHOCH3NHmeta
931.1CH3HOCH3NHortho
932.1CH3HOCH3NHmeta
933.2HOCH3NHortho
934.2HHOCH3NHmeta

956.
935.2CH3HOCH3NHortho
936.2CH3HOCH3NHmeta
937.1HHOCH3NCH3ortho
938.1HHOCH3NCH3meta
939. 1CH3HOCH3NCH3ortho
940.1CH3HOCH3NCH3meta
941.2HHOCH3NCH3ortho
942.2HHOCH3NCH3meta
943.2CH3HOCH3NCH3ortho
944.2CH3HOCH3NCH3m is the
945.1HHOCH3NCH2CH3ortho
946.1HHOCH3NCH2CH3meta
947.1CH3HOCH3NCH2CH3ortho
948.1CH3HOCH3NCH2CH3meta
949.2HHOCH3NCH2CH3ortho
950.2HH OCH3NCH2CH3meta
951.2CH3HOCH3NCH2CH3ortho
952.2CH3HOCH3NCH2CH3meta
953.1HHOCH3NCH2CH2CH3ortho
954.1HHOCH3NCH2CH2CH3meta
955.1CH3HOCH3NCH2CH2CH3ortho
1CH3HOCH3NCH2CH2CH3meta
957.2HHOCH3NCH2CH2CH3ortho
958.2HHOCH3NCH2CH2CH3meta
959.2CH3HOCH3NCH2CH2CH3ortho
960.2CH3HOCH3NCH2CH2CH3meta
961.1H HOCH3Chemical bondmeta

962.1CH3HOCH3Chemical bondortho
963.1CH3HOCH3Chemical bondmeta
964.2HHOCH3Chemical bondortho
965.2HHOCH3Chemical bondmeta
966.2CH3HOCH3Chemical with the IDE ortho
967.2CH3HOCH3Chemical bondmeta
968.1HHOCHF2NCH3ortho
969.1HHOCHF2NCH3meta
970.1CH3HOCHF2NCH3ortho
971.1CH3HOCHF2NCH3meta
972.2HH OCHF2NCH3ortho
973.2HHOCHF2NCH3meta
974.2CH3HOCHF2NCH3ortho
975.2CH3HOCHF2NCH3meta
976.1HHOCHF2NCH2CH3ortho
977.1HHOCHF2NCH2CH3meta
978.1 CH3HOCHF2NCH2CH3ortho
979.1CH3HOCHF2NCH2CH3meta
980.2HHOCHF2NCH2CH3ortho
981.2HHOCHF2NCH2CH3meta
982.2CH3HOCHF2NCH2CH3ortho
983.2CH3HOCHF2NCH2CH3 meta
984.1HHOCHF2NCH2CH2CH3ortho
985.1HHOCHF2NCH2CH2CH3meta

td align="center"> H
986.1CH3HOCHF2NCH2CH2CH3ortho
987.1CH3HOCHF2NCH2CH2CH3meta
988.2HHOCHF2NCH2CH2CH3ortho
989.2HHOCHF2NCH2CH2CH3meta
990.2CH3HOCHF2NCH2CH2CH3ortho
991.2CH3HOCHF2NCH2CH2CH3meta
992.1HHOCHF2Chemical bondmeta
993.1CH3HOCHF2Chemical bondortho
994.1CH3OCHF2Chemical bondmeta
995.2HHOCHF2Chemical bondortho
996.2HHOCHF2Chemical bondmeta
997.2CH3HOCHF2Chemical bondortho
998.2CH3HOCHF2Chemical bondmeta
999.1HHCH3NCH3ortho
1000.1HHCH3NCH3meta
1001.1CH3HCH3NCH3ortho
1002.1CH3HCH3NCH3meta
1003.2HHCH3NCH3ortho
1004.2HHCH3NCH3meta
1005.2CH3HCH3NCH3 ortho
1006.2CH3HCH3NCH3meta
1007.1HHCH3NCH2CH3ortho
1008.1HHCH3NCH2CH3meta
1009.1CH3HCH3NCH2CH3ortho

meta
1010.1CH3HCH3NCH2CH3meta
1011.2 HHCH3NCH2CH3ortho
1012.2HHCH3NCH2CH3meta
1013.2CH3HCH3NCH2CH3ortho
1014.2CH3HCH3NCH2CH3meta
1015.1HHCH3NCH2CH2CH3ortho
1016.1HHCH3NCH2CH2CH3
1017.1CH3HCH3NCH2CH2CH3ortho
1018.1CH3HCH3NCH2CH2CH3meta
1019.2HHCH3NCH2CH2CH3ortho
1020.2HHCH3NCH2CH2CH3meta
1021.2CH3HCH3NCH2CH2CH3ortho
1022.2 CH3HCH3NCH2CH2CH3meta
1023.1HHCH3Chemical bondmeta
1024.1CH3HCH3Chemical bondortho
1025.1CH3HCH3Chemical bondmeta
1026.2HHCH3Chemical bondortho
1027.2HHCH3Chemical bond meta
1028.2CH3HCH3Chemical bondortho
1029.2CH3HCH3Chemical bondmeta
1030.1HHFNCH3ortho
1031.1HHFNCH3meta
1032.1CH3HFNCH3ortho
1033.1CH3HF NCH3meta

H
1034.2HHFNCH3ortho
1035.2HHFNCH3meta
1036.2CH3HFNCH3ortho
1037.2CH3HFNCH3meta
1038.1HHFNCH2CH3ortho
1039.1H HFNCH2CH3meta
1040.1CH3HFNCH2CH3ortho
1041.1CH3HFNCH2CH3meta
1042.2HHFNCH2CH3ortho
1043.2HHFNCH2CH3meta
1044.2CH3HFNCH2CH3ortho
1045. 2CH3HFNCH2CH3meta
1046.1HHFNCH2CH2CH3ortho
1047.1HHFNCH2CH2CH3meta
1048.1CH3HFNCH2CH2CH3ortho
1049.1CH3HFNCH2CH2CH3meta
1050.2HHFNCH2CH2CH 3ortho
1051.2HHFNCH2CH2CH3meta
1052.2CH3HFNCH2CH2CH3ortho
1053.2CH3HFNCH2CH2CH3meta
1054.1HHFChemical bondmeta
1055.1CH3HFChemical bondortho
1056.1CH3FChemical bondmeta
1057.2HHFChemical bondortho
1058.2HHFChemical bondmeta

1059.2CH3HFChemical bondortho
1060.2CH3HFChemical bondmeta

Table C:

Further examples are the compounds of formula I in which R6is hydrogen, n, R1, R3X and R5defined in the rows of table A, where R2is stands instead of hydrogen (compounds the Oia 1061 and 1988), and their physiologically acceptable salts accession acid or their N-oxides.

Table D:

Further examples are the compounds of formula I' in which R5and R6are hydrogen, n, R1, R3and X are defined in the rows of table B, where R2is stands instead of hydrogen (compounds 1989-2120), and their physiologically acceptable salts accession acid or their N-oxides.

The compounds I and I' according to the invention receive by analogy with methods known from the literature. An important approach for the synthesis of compounds according to the invention is the reaction of compound (II) 1-(piperazine-1-yl) or 1-(homopiperazin-1-yl), where R3is, for example, stands or methoxy, with chlorosulfonic acid and subsequent reaction of the intermediate compound of sulphonylchloride with a derivative of aniline IV, as shown in figure 1, or with a derivative of 2,2-debtorrent[1,3]dioxolane IVa, as shown in scheme 1a.

Scheme 1

Scheme 1a

In schemes 1 and 1a n, R2and R3defined above. Rais a protecting group for nitrogen, or stands. Suitable protective groups for the nitrogen described, for example, in the monograph by P. J. Kocienski "Protecting Groups", 2nded., Georg Thieme Verlag, Stuttgart 2000, pp. 186-237 and cited in the literature. Preferred examples of the protective group DL the nitrogen are for example, oxycarbonyl groups, such as C1-C6-alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl and Boc (tert-butoxycarbonyl), and other oxycarbonyl groups, such as benzyloxycarbonyl (Cbz), allyloxycarbonyl, 9-fluorenyl-methoxycarbonyl (Fmoc) 2-trimethylsilylethynyl (Teoc) or 2-propenyl (allyl). Especially preferred for the introduction of sulphonylchloride group is trifluoracetyl group as a protective group for the nitrogen of the piperazine or homopiperazine. X1is nucleophile substitutable leaving group, in particular a halogen atom, especially chlorine or bromine.

Sulfonic compounds of the present invention, where X is a chemical bond can be obtained according to schemes 2 and 3, any of the compounds VII (which can themselves be obtained from compounds of aniline VI, where the group of NH2turn in group X2which may be, for example, or iodine, or bromine, by reaction of Sandmeyer) in the reaction with thiophenols compound VIIIa and subsequent oxidation of the sulfide (scheme 2) using suitable oxidizing agents, such as oxen or percolate, or by reaction of compound VII with salt derived sulfinol acid VIIIb (usually sodium salt) without the need for subsequent oxidation steps (scheme 3; for example, Synlett, 2003, 361 Cacchi t al.).

In schemes 2 and 3 n, R2and R3defined above. Rais a protecting group for nitrogen, or stands.

Scheme 2

Scheme 3

The compounds of formula (IX) can be obtained using catalyzed by palladium reaction salt sulfinol acid VIIIb with compounds VII, where X2is bromine or iodine. A suitable palladium catalyst is Tris(dibenzylideneacetone)-dipalladium(0) (Pd2(dba)3). Sulfon (IX) are usually obtained in the presence of Xanthos, rigid bidentate ligand. The reaction is usually carried out in the presence of chloride n-tetrabutylammonium.

Sulfinate compound VIIIb or produced in industry, or may, for example, be derived from the corresponding sulphonylchloride in the reaction with sodium sulfite in alkaline conditions.

Compounds VIIa, where R3defined above, can also be obtained from the appropriate compounds of aniline in the reaction with a suitably protected bis(2-chloroethyl)amine, where Ramay, for example, be p-tolilsulfonil group.

Compounds of formula V and Va, where Rais a protecting group for nitrogen, in particular TRIFLUOROACETYL, C1-C6-alkoxycarbonyl group, such as methoxy ronil, etoxycarbonyl and Boc(tert-butoxycarbonyl), are new and therefore form part of the present invention.

The compounds of formula V, where Rais stands, correspond to compounds I, where R1is stands. The compounds of formula Va, where Rais stands, correspond to compounds I', where R1is stands.

The reactions depicted in schemes 1 and 1a, occurs when the reaction conditions which are generally accepted upon receipt arylsulfonamides compounds or complex arylsulfonic esters, respectively, and which are described, for example, in the monograph by J. March, Advanced Organic Chemistry, 3rdedition, John Wiley & Sons, New York, 1985, p. 444 and cited in the literature, publications, European J. Org. Chem. 2002 (13), pp. 2094-2108, Tetrahedron 2001, 57 (27) pp. 5885-5895, Bioorganic and Medicinal Chemistry Letters, 2000, 10(8), pp. 835-838 and Synthesis 2000 (1), pp. 103-108.

The reaction is usually carried out in an inert solvent, e.g. an ether, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether or tetrahydrofuran, in halogenougljovodonika, such as dichloromethane, aliphatic or cycloaliphatic hydrocarbon, such as pentane, hexane or cyclohexane, or an aromatic hydrocarbon, such as toluene, xylene, cumene and other similar solvents, or in mixtures of the above solvents. The reaction of compound III with compound IV or compound IV) is usually carried out in the presence of an auxiliary base. Suitable bases are inorganic bases such as sodium carbonate or potassium carbonate or sodium bicarbonate or potassium bicarbonate, or organic bases, such as trialkylamine, such as triethylamine, or pyridine compounds such as pyridine, lutidine, 4-dimethylaminopyridine and other similar compounds. The latter compound may simultaneously serve as solvents.

The auxiliary base is usually used at least in equimolar quantities with respect to the amine compound II.

The reaction of compound III with compound IV or IVa, respectively, gives compound V or Va, respectively, from which, if Rais a protecting group for nitrogen, remove the protection with obtaining compounds of General formula I or I', where R1is hydrogen. Removing protection from compounds V or Va, respectively, can be achieved using standard methods, for example using the methods described in the monograph by P. J. Kocienski "Protecting Groups", 2nded., Georg Thieme Verlag, Stuttgart 2000, pp. 186-237 and cited in the literature.

You can then use traditional methods of interaction of these compounds with meteorous reagent, such as methyliodide or dimethylsulfate, which results in the compounds of formula I or I', respectively, in which R1it is noted the. The reaction conditions required for this reaction, methylation, as described, for example, in the patent document WO 02/083652, publications Tetrahedron 2000, 56(38) pp. 7553-7560 and Synlett. 2000 (4), pp. 475-480.

Similarly, to obtain the compounds of formula I or I', respectively, in which R1is stands, may be subjected to known reactions reductive amination of the compound I or I' in which R1is hydrogen, with formaldehyde in the presence of a reducing agent. Suitable reductants are borhydride, such as sodium borohydride, cyanoborohydride sodium, triacetoxyborohydride sodium or branfireun. Reductive amination is usually carried out in an organic solvent, such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran or acetonitrile.

The reaction of the compound V or Va with an alkylating reagent gives compound of formula V' or V a, respectively, where n, Ra, R2and R3defined above. In the compound of formula V' or V a, respectively, hydrogen sulfonamide substituted C1-C4alkyl, C3-C4cycloalkyl or C3-C4cycloalkyl-CH2-.

Can be subjected to the reaction of compound V or Va with meteorous reagent, such as methyliodide or dimethylsulfate, obtaining the compounds of formula Vc or Vd, respectively, where n, Ra, R2and R3 defined above.

If Rain the formula Vc or Vd is a protecting group for nitrogen, with connection Vc or Vd, respectively, remove the protection with obtaining compounds of General formula I, where R1is hydrogen. To unprotect a connection Vc or Vd can be achieved by standard methods, for example methods described in the monograph by P. J. Kocienski "Protecting Groups", 2nded., Georg Thieme Verlag, Stuttgart 2000, pp. 186-237 and cited in the literature.

Compounds V and IX, where Rais stands, is best obtained by reaction of compounds V and IX, where Rais hydrogen, with formaldehyde in the above-described reducing conditions.

Compounds of General formula VI are essentially known, or they can be obtained by using method shown in scheme 4.

Scheme 4

Scheme 4 n, Ra, R2and R3defined above.

At stage i) of scheme 4, the compound X is subjected to nitration reaction under standard conditions obtaining in the compounds XI. The reaction conditions can be taken, for example, from the patent document US 6599904 or demonstration examples of this application.

At stage (ii) of scheme 4 protects the NH-group of compounds XI with either a description of the Noah above conventional protecting group for nitrogen, either by introducing a methyl group using meteorologi reagent, such as methyl bromide, methyliodide or dimethylsulfate. The introduction of protective groups for the nitrogen in compound XI can be achieved by standard methods, for example methods described in the monograph by P. J. Kocienski "Protecting Groups", 2nded., Georg Thieme Verlag, Stuttgart 2000, pp. 186-237 and cited in the literature. Similarly, methylation of compound XI carried out by standard methods of organic chemistry.

At stage iii) a nitro-group in compound XII to restore NH2the group receiving compound VI. The reaction conditions that are required for stage iii) correspond to the traditional conditions for the recovery of aromatic nitro groups, which are widely described in the literature (see, for example, the monograph by J. March, Advanced Organic Chemistry, 3rd ed., J. Wiley & Sons, New York, 1985, p. 1183 quoted in it literature). Recovery may be achieved, for example, by the reaction of nitro compounds XII with metal, such as iron, zinc or tin in acidic reaction conditions, i.e. using hydrogen at the time of selection, or using a complex hydride, such as alumalite lithium or sodium borohydride, preferably in the presence of transition metal compounds of Nickel or cobalt, such as NiCl2(P(phenyl)3)2or CoCl2(see the RUB publication Ono et al. Chem. Ind. (London), 1983 p.480), or using NaBH2S3(see publication Lalancette et al. Can. J. Chem. 49, 1971, p. 2990), it is possible to carry out these reactions recovery, depending on the given reagent, in essence, or in a solvent or diluent. Alternatively, the reduction of compound XII to compound VI can be carried out using hydrogen in the presence of a catalyst of a transition metal, for example, using hydrogen in the presence of catalysts based on platinum, palladium, Nickel, ruthenium or rhodium. The catalysts may contain a transition metal in elemental form or in the form of complex compounds of the salt or oxide of the transition metal, it is possible to modify the activity to use the traditional ligands, such as organic phosphine compounds such as triphenylphosphine, tricyclohexylphosphine or tri-n-butylphosphine or phosphites. The catalyst is usually used in amounts of 0.001 to 1 mol per mol of compound XII in the calculation of the metal catalyst. In a preferred embodiment, the restore is performed with the use of tin chloride(II) by analogy with the methods described in the publications Bioorganic and Medicinal Chemistry Letters, 2002, 12(15), pp. 1917-1919 and J. Med. Chem. 2002, 45(21), pp. 4679-4688. The reaction of the compound XII with tin chloride(II) is preferably carried out in an inert organic solvent, preferably alcohol, that is ω as methanol, ethanol, isopropanol or butanol.

Unless otherwise stated, the above reaction is usually carried out in a solvent at temperatures from room temperature to the boiling point of the used solvent. Alternatively, the activation energy, which is necessary for the implementation of the reaction can be summed up by the reaction mixture with microwave radiation, which is important, in particular, in the case of reactions catalyzed by transition metals (regarding the implementation of reactions using microwave radiation, see publication Tetrahedron 2001, 57, p. 9199 ff. p. 9225 ff., as well as the relatively common issues monograph "Microwaves in Organic Synthesis", Andre Loupy (Ed.), Wiley-VCH 2002.

Salt accession acid compounds I and I' get in the traditional way by mixing the free base with a corresponding acid, where appropriate in solution in an organic solvent, for example acetonitrile, a lower alcohol, such as methanol, ethanol or propanol, simple ether, such as diethyl ether, methyl tert-butyl ether or diisopropyl ether, a ketone, such as acetone or methyl ethyl ketone, complex ether, such as ethyl acetate, and their mixtures, and their mixtures with water.

Compounds of the present invention may be an agonist of the receptor 5-HT6including partial agonistic activity, or anti nistam receptor 5-HT 6including inverse agonistic activity.

Compounds of formulas I and I' according to the present invention, as well as their salts and their N-oxides, have surprisingly high affinity receptor 5-HT6. The high affinity of the compounds according to the invention receptor 5-HT6is reflected in the very low binding constant of the receptor in vitro (values of Ki(5-HT6)), components, typically less than 500, 100 or 50 nm (nmol/l), preferably less than 10 nm and in particular less than 5 nm. The displacement of3H-LSD may, for example, be used in studies on the binding of receptor to determine affinely binding to receptors 5-HT6.

In addition, the compounds of formulas I and I', as well as their salts and their N-oxides, are selective ligands of the receptor 5-HT6that, because of their low affinity for other receptors such as dopamine receptors, adrenergic receptors, muscarinic receptors, histamine receptors, opiate receptors, in particular dopamine D2α1-adrenergic and histamine H1receptors, produce less side effects than other, less selective 5-HT6the ligands.

For example, the selectivity of the compounds according to the present invention, the 5-HT6/D2, 5-HT61-adrene the logical or of 5-HT 6/H1then there are relations between the binding constant of the receptor Ki(D2)/Ki(5-HT6), Ki1-adrenergic)/Ki(5-HT6or Ki(H1)/Ki(5-HT6), are, as a rule, at least 25, preferably at least 50, even better at least 100.

The displacement of [3H]SCH23390 and [125I]spiperone can be used, for example, to conduct studies on the binding of the receptor in the case of D1D2and D4receptors.

In addition, the compounds of the present invention, due to their structural features, are characterized by a high propensity to penetrate into the brain compared with other known ligands of the receptor 5-HT6.

Due to their binding characteristics, the compounds of the present invention can be used for the treatment of diseases that respond to ligands of the receptor 5-HT6(or which are susceptible to treatment with a ligand of the receptor 5-HT6), i.e. they are effective for treating those medical disorders or diseases in which exerting influence (modulating) receptors 5-HT6leads to improvement in clinical symptoms or disease being treated. Examples of these diseases are disorders and diseases of the Central nervous force theme.

Under disorders or diseases of the Central nervous system include disorders that affect the spinal cord and, in particular, the brain. With regard to the invention, the term "disorder" refers to disorders and/or anomalies, which are generally regarded as pathological conditions or functions, and which can manifest itself in the form of specific signs, symptoms and/or dysfunctions. Despite the fact that the treatment according to the invention can be directed to individual disorders, i.e. anomalies or pathological conditions, however, can also be combined into a combination of several casuation related to each other anomalies, i.e. syndromes that can be treated in accordance with the invention.

Disorders that can be treated in accordance with the invention are, in particular, disorders, which are susceptible to modulation of the receptor 5-HT6. They include cognitive impairment, such as memory impairment, cognitively and ability to learn, in particular associated with Alzheimer's disease, senile cognitive impairment and mild cognitive impairment, attention deficit disorder with hyperactivity disorder, personality disorders, such as schizophrenia, in particular cognitive deficits associated with Shi is ophrenia, affective disorders, such as depression, anxiety and obsessive-compulsive disorder, impaired mobility or movement disorders such as Parkinson's disease and epilepsy, migraine, sleep disorders (including disturbances of circadian rhythm), eating disorders such as anorexia and bulimia, certain gastrointestinal disorders such as irritable bowel syndrome, diseases associated with neurodegeneration, such as stroke, spinal cord injury or head and traumatic brain injuries, such as hydrocephalus, a disease associated with harmful addiction, and obesity.

Diseases associated with harmful addiction include mental disorders and behavioural disorders caused by improper use of psychotropic substances, including certain medications, such as sedatives, anxiolytics, hypnotics or narcotics (hereinafter in this description of the application also known as drug dependence), as well as other diseases associated with harmful addiction such as addiction to gaming (gambling; disorders of control of impulses is not attributed to any other disorder). Examples of substances that are addictive are: opioids (e.g. morphine, heroin and codeine), cocaine; nicotine; alcohol; substance, to the which interact with a channel complex chloride gamma-aminobutanoic acid, sedatives, sleeping pills, and tranquilizers, such as benzodiazepines; LSD; cannabinoids; psychomotor stimulants, such as 3,4-methylendioxy-N-methylamphetamine (ecstasy), amphetamine and amphetaminetype substances, such as methylphenidate and other stimulants, including caffeine. Substances that cause addiction, which is particularly noteworthy are opioids, cocaine, amphetamine or amphetaminetype substances, hallucinogens, antagonists of the receptor N-methyl-D-aspartate, such as phencyclidine and related collidine, dextromethorphan, dextrorphan, Ibogaine, ketamin, tiletamine, cannabis, nicotine and alcohol. Other diseases associated with harmful addiction include addiction to gaming (gambling), including gambling addiction (compulsive attraction to gambling, gamblers), the dependence on computer and video games and the Internet.

With regard to the treatment of diseases associated with harmful addiction, particular preference is given to those compounds according to the present invention, which themselves do not have any psychotropic effects. This can be detected when tested on rats, in which, after the introduction of compounds that can be used in accordance with the invention, decreased uncontrolled ingestion of psychotropic substances the TV, for example, cocaine or alcohol.

According to another aspect of the present invention, the compounds according to the invention can be used for the treatment of disorders, the causes of which can, at least partially, be attributed to abnormal activity of the receptors 5-HT6.

According to another aspect of the present invention, the treatment is directed, in particular, on those disorders that can interfere with proper medical treatment, by linking receptors 5-HT6preferably with exogenous input binding partners (ligands).

Diseases that can be treated using compounds according to the invention, often characterized by a progressive development, that is, the above condition change over time; as a rule, the severity of the condition increases, and the condition can probably merge with each other, or other conditions can arise in addition to those that already exist.

Compounds of the present invention can be used to treat a large number of signs, symptoms and/or dysfunctions that are associated with disorders of the Central nervous system and, in particular, the above-mentioned conditions. These signs, symptoms and/or dysfunctions include, for example, a distorted perception of reality, lack adequate the th-esteem and ability to adhere to traditional norms of social conduct or life throws requirements changes in temperament, change drives, such as hunger, sleep, thirst and so on, and mood, impaired ability to observe and to unite, personality changes, in particular, emotional lability, hallucinations, disturbances of the functions of the ego, confusion, ambivalence, autism, depersonalization and false perceptions, delusions, speech, chanting, no synkinesia, gait with short step, curved position of the body and limbs, tremor, poor facial expression, monotonous speech, depression, apathy, slow involuntary actions and determination, low ability to associative thinking, anxiety, nervous excitement, stuttering, social phobia, panic disorder type withdrawal syndrome on a background of addiction, symptoms of megalomania, the state of excitation and confused thinking, restlessness, dyskinetic syndromes and tick disorder, for example horey of Huntington's disease and the syndrome of Gilles de La Tourette, the syndromes of vertigo such as peripheral positional, rotational and vibrational vertigo, melancholia, hysteria, hypochondria and other similar disorders.

In the sense of the invention, the treatment also includes preventive treatment (prophylaxis), in particular, in the form of relapse prevention or phase prevention, and treatment of acute or chronic symptoms, what the symptoms and/or dysfunctions. Treatment may be aimed symptomatically, for example in the form of suppression of symptoms. It can be done within a short period of time can be focused on medium-term or can be a long treatment, for example in the context of supportive therapy.

Compounds according to the invention can preferably be used for the treatment of diseases of the Central nervous system, more preferably, for the treatment of cognitive impairment and, in particular, for the treatment of cognitive impairment associated with schizophrenia or Alzheimer's disease.

According to another aspect of the invention, the compounds of the present invention are particularly suitable for the treatment of diseases associated with harmful addiction, caused, for example, misuse of psychotropic substances, such as medicines, drugs, nicotine or alcohol, including associated mental disorders and behavioral disorders. Similarly, the compounds of the present invention are particularly suitable for the treatment of diseases associated with harmful addiction, which is not caused by misuse of psychotropic substances, such as addiction to gaming (gambling), including gambling addiction (compulsive attraction to gambling, gamblers), dependence on computer and view the games and dependence on the Internet. In the case of diseases associated with harmful addiction, the compound of the present invention can be used for therapy while in a state of dependence, and to prevent recurrence of occurrence status of the dependency.

According to another aspect of the invention, the compounds of formulas (I) and (I)', their salts and their N-oxides are particularly suitable for the treatment of eating disorders such as obesity and related diseases, such as cardiovascular disease, digestive disorders, respiratory diseases, cancer or type 2 diabetes.

In the context of treatment application according to the invention described compounds involves the way. In this method, an effective amount of one or more joints, usually prepared in the form of a dosage form in accordance with the rules of the pharmaceutical and veterinary injected being treated individual, preferably a mammal, in particular human, productive animal or domestic animal. Do I need this treatment and in what form it should take depends on the individual case and is subject to medical evaluation (diagnosis), which takes into account the signs, symptoms and/or dysfunctions that are present, the risk of development of specific signs, symptoms and/or dysfunctions and other f ctory.

Typically, the treatment is carried out by daily single and repeated administration, when appropriate together or alternating with other active compounds or preparations containing the active compound, so that the exposed individual treatment was administered daily dose, which is preferably from about 0.1 to 1000 mg/kg body weight, in the case of oral administration, or from about 0.1 to 100 mg/kg of body weight, in the case of parenteral administration.

The invention also relates to the production of pharmaceutical compositions for the treatment of an individual, preferably a mammal, in particular human, productive animal or pet. Therefore, compounds of formula I or I', their salts and/or their N-oxides is usually administered in the form of pharmaceutical compositions that include pharmaceutically acceptable filler together with at least one compound according to the invention and, where appropriate, with other active compounds. These compositions can, for example, be administered orally, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal.

Examples of suitable pharmaceutical formulations are solid dosage forms such as powders, granules, tablets, in particular tablets, film-coated, tablets, sachet is, pills, tablets, sugar coating, capsules such as hard capsules and soft gelatin capsules, suppositories or vaginal dosage forms, semi-solid dosage forms such as ointments, creams, hydrogels, pastes or patches, and liquid dosage forms such as solutions, emulsions, particularly emulsions of the type oil-in-water, suspensions, such as lotions, injections and drugs for infusion and eye drops and ear drops. Implantable device for the release of drugs can also be used for injection of the inhibitors according to the invention. In addition, it is also possible use of liposomes or microspheres.

Upon receipt of the compositions of the compounds according to the invention optionally mixed or diluted with one or more fillers. Excipients can be solid, semi-solid or liquid materials that serve as foundations, media or medium for the active connection.

Suitable fillers are described in the relevant medical monographs. Additionally, the form may include pharmaceutically acceptable carriers or conventional auxiliary substances, such as substances that contribute to the slide; moisturizers, emulsifiers and suspiciouse means; preservatives; antioxidants; substances shall Rotel irritation; hepatoblastoma agents; excipients to form a coating; the stabilizers of emulsions; film formers; geleobrazovanie; reagents, masking the smell; substances corrective taste; resins; hydrocolloids; solvents; soljubilizatory; neutralizing reagent; accelerators diffusion; pigments; Quaternary ammonium compounds; degreasing and perejivayuschie reagents; bases for ointments, creams or oils, derivatives of silicon; substances that contribute to the distribution; stabilizers; sterilizing agent; fundamentals of suppositories; excipients for tablets, such as binders, fillers, substances promoting sliding, leavening agents or coatings; propellants; dehumidifiers; cloud emulsions; thickeners; waxes; plasticizers and light mineral oil. While the preparation of dosage forms based on professional approaches described, for example, in the encyclopedia Fiedler, H. P., Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4thedition, Aulendorf: ECV-Editio-Kantor-Verlag, 1996.

The following examples serve to explain the present invention without limiting its scope.

Compounds characterized or using proton NMR in d6-sulfoxide or d-chloroform on the instrument NMR at 400 MHz or 500 MHz (Bruker AVANCE), or using a Mac who spectrometry, usually registering using HPLC-MS with fast gradient on C18-material (mode ionization elektrorazpredelenie (ESI)), or by using the melting temperature.

The spectra of nuclear magnetic resonance (NMR) refer to chemical shifts (δ) expressed in parts per million (M. D.). The relative size of the shifts in the spectrum of1H-NMR corresponds to the number of hydrogen atoms for a particular functional type in the molecule. The nature of the shift, from the point of view of the multiplicity is indicated as singlet (s), broad singlet (S. lat.), doublet (d), broad doublet (D. W.), triplet (t), broad triplet (t Shir.), Quartet (square), quintet (Quint.) and multiplet (m).

I. the production of intermediate compounds V and IX

I. 1 intermediate compounds V

EXAMPLE of SYNTHESIS 1: N-(3-deformational)-4-methyl-3-[4-(2,2,2-TRIFLUOROACETYL)piperazine-1-yl]benzosulfimide

1.1 2,2,2-Cryptor-1-(4-o-tailpipes-1-yl)alanon

of 29.9 g of 2,2,2-triperoxonane aldehyde (104 mmol) was dissolved in 150 ml of dichloromethane, cooled to -20°C and added dropwise to 20 g of the chloride of 1-o-tailpipes-1,4-die (80 mmol) dissolved in 150 ml of dichloromethane. After stirring for 16 hours at room temperature was added 400 ml of ice water, the organic phase was separated, washed twice with water and adjust p to neutral values using 1% aqueous solution of sodium bicarbonate. The organic phase is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and the solvent evaporated to obtain a 21.5 g of product which was vykristallizovyvalas when cooled.

1.2 4-Methyl-3-[4-(2,2,2-TRIFLUOROACETYL)piperazine-1-yl]benzosulfimide chloride

To a solution of 2 g of 2,2,2-Cryptor-1-(4-o-tailpipes-1-yl)-ethanone (7,35 mmol) in 5 ml of dichloromethane at -5°C was slowly added to 19.7 g of chlorosulfonic acid (169 mmol). After stirring for 2 hours at -5°C. the reaction mixture was continued to stir for 16 hours and then slowly warmed to room temperature. After cooling to 0°C the reaction mixture was slowly added to a mixture of water/ice. The aqueous phase was extracted five times with dichloromethane, the combined organic phases are washed with aqueous sodium bicarbonate solution and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated to obtain 2.2 g of product as a white solid.

1.3 N-(3-Deformational)-4-methyl-3-[4-(2,2,2-TRIFLUOROACETYL)piperazine-1-yl]benzosulfimide

0,429 g 3-(deformedarse)aniline (2.7 mmol) was dissolved in 5 ml of pyridine. Was slowly added at room temperature, 1 g of 4-methyl-3-[4-(2,2,2-Triforce the l)piperazine-1-yl]benzosulfimide (2.7 mmol). After stirring for 16 hours at room temperature the reaction mixture is evaporated several times after addition of toluene. The residue was dissolved in dichloromethane and washed several times with 5% aqueous solution of ammonium chloride. The organic phase is then washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and the solvent evaporated. The crude product was purified by chromatography on silica gel using dichloromethane/methanol (0-5%) to give to 0.63 g of product.

To obtain the intermediate compounds V' or V a, respectively, that is, compounds of formula V or V', respectively, where sulfonamidnuyu hydrogen (R4= H) substituted with C1-C4of alkyl, C3-C4cycloalkyl or C3-C4cycloalkyl-CH2-(compound V or V', respectively, with R4= C1-C4alkyl, C3-C4cycloalkyl or C3-C4cycloalkyl-CH2-), where R4is, for example, methyl group, the corresponding trifluoracetyl group must be removed by the reaction in basic conditions, and then re-implemented protection with tert-BUTYLCARBAMATE carried out the reaction of this Boc-protected intermediate compound V with sodium hydride and an alkylating reagent, for example, in the case when R4the two who is the stands, with methyliodide. Then N-methylated derivative can be unsecured on pieperazinove or homopiperazine fragment in a standard acidic conditions to obtain the final products.

EXAMPLE of SYNTHESIS 2: N-(3-deformational)-4-methyl-3-[4-(2,2,2-TRIFLUOROACETYL)-[1,4]diazepan-1-yl]benzosulfimide

The connection can be obtained in the same manner as described in synthesis example 1, on the basis of output in industry 1-o-tolyl-[1,4]diazepan.

1.2 Obtaining intermediates IX

EXAMPLE of SYNTHESIS 3: 1-[5-(3-deformationsvetsaren)-2-were]-4-(toluene-4-sulfonyl)piperazine

3.1 1-(5-Iodine-2-were)-4-(toluene-4-sulfonyl)piperazine

becomes 9.97 g of N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (30.3 mmol) and of 5.03 g of potassium iodide (30.3 mmol) in 75 ml of cyclohexanol was stirred for 1 hour at 80°C. After addition of 7.7 g of sodium carbonate (72,7 mmol) and the 5.65 g of 5-iodine-2-methylaniline (or 24.2 mmol) stirring was continued for 8 hours at 160°C. the Mixture was filtered at room temperature, washed with dichloromethane and the filtrate evaporated to dryness. The residue was dissolved in dichloromethane, filtered and the solvent evaporated. The remaining residue was washed with n-heptane and the crystalline product was filtered, about ivali several times with n-heptane and dried in vacuum to obtain 10.7 g of product.

3.2 1-[5-(3-deformationsvetsaren)-2-were]-4-(toluene-4-sulfonyl)piperazine

0,521 g of 1-(5-iodine-2-were)-4-(toluene-4-sulfonyl)piperazine (1,14 mmol), 0,315 g 3-(deformedarse)benzosulfimide sodium (1.37 mmol), 0,558 g of cesium carbonate (1,713 mmol), was 0.026 g of Pd(dba)3(0,029 mmol), 0,033 g Xanthos (0,059 mmol) and 0,381 g of tetrabutylammonium chloride (1.37 mmol) was stirred for 8 hours in 10 ml of toluene. The reaction mixture was filtered and the solvent evaporated. The crude product was purified by chromatography on silica gel using toluene/methanol 20:1 (2.5% triethylamine), the fractions containing the product were combined and the solvents evaporated to obtain 0,386 g of the product.

II. The formation of compounds I

Example 1

N-(3-Deformational)-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

to 0.63 g of N-(3-deformational)-4-methyl-3-[4-(2,2,2-TRIFLUOROACETYL)piperazine-1-yl]benzosulfimide (1.28 mmol) was dissolved in 90 ml of methanol, was added 2,77 ml 6 N. aqueous sodium hydroxide solution (of 16.6 mmol) and the reaction mixture was stirred at 67°C for 10 minutes. Added 150 ml of water, the aqueous layer was extracted with ethyl acetate and the organic phase is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and the solvent is perivale. The residue was converted into cleaners containing hydrochloride salt by addition of HCl in diethyl ether. Evaporation to dryness and then dissolving the remaining white solid substance in water and lyophilization of the aqueous phase gave 0,535 g of the product.

ESI-MS: 398,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 10,45 (s, 1H), and 9.0 (broad, 2H), 7,3 was 7.45 (m, 3H), 7,25 (m, 1H), 7,15 (t, 1H), 6,95 (d, 1H), 6,9 (s, 1H), 6,85 (d, 1H), 3,25 (broad, 4H), of 3.0 (broad, 4H), of 2.25 (s, 3H).

Example 2

3-[1,4]Diazepan-1-yl-N-(3-deformational)-4-methylbenzenesulfonamide hydrochloride

The product was obtained in the same manner as described in example 1, by reaction of N-(3-deformational)-4-methyl-3-[4-(2,2,2-TRIFLUOROACETYL)-[1,4]diazepan-1-yl]benzosulfimide with aqueous sodium hydroxide solution.

ESI-MS: 412,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] at 10.5 (s, 1H), of 9.55 (s, broad, 2H), 7,45 (s, 1H), 7,0-7,4 (several m, 4H), to 7.0 (d, 1H), 6,95 (s, 1H), 6,8 (d, 1H), 4,0 (s, broad, 2H), and 3.2 (broad, 6H), 3.0 a (m, 2H, in), 2.25 (s, 3H).

Example 3

1-[5-(3-Deformationsvetsaren)-2-were]piperazine hydrochloride

Was mixed with 0.75 g of 4-hydroxybenzoic acid (7,06 mmol) and 2,485 ml 32% HBr in acetic acid (to 72.4 mmol) under stirring and the suspension was cooled to 0°C. was Added 0,379 g of 1-[5-(3-deformationsvetsaren)-2-were]-4-(toluene-4-sulfonyl)piperazine (0,706 mmol), rest is extended in 5 ml of acetic acid, and the reaction mixture was stirred for 16 hours. Added another 30 equivalents of HBr in acetic acid was stirred for 18 hours and the reaction mixture was slowly added to ice water. Adjust pH to neutral values by adding an aqueous solution of ammonia, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried over magnesium sulfate, filtered and the solvent evaporated. The crude product was purified by chromatography on silica gel using toluene/methanol 5:1 (2.5% triethylamine), the solvents evaporated and the residue was re-dissolved in a small amount of ethyl acetate. Hydrochloride besieged by adding 2 N. hydrochloric acid in diethyl ether to obtain 0,059 g of the product.

ESI-MS: 383,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,5 (s, broad, 2H), and 7.8 (d, 1H), and 7.7 (s, 1H), 7,65 (m, 1H), and 7.6 (d, 1H), 7.5 (m, 2H), 7,45 (d, 1H), and 7.4 (t, 1H), and 3.2 (broad, 4H), 3,1 (broad, 4H), 2,3 (s, 3H).

Connection examples 4-49 can be obtained as in the above-described syntheses.

Example 4

N-(2-Deformational)-N-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 412,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 6.9-7.5 (a few m, 9H), 3,5 (broad, 8H), 3,1 (s, 3H), of 2.75 (s, 3H).

Example 5

N-(2-Deform toxigenic)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 412,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 11.4 (broad, 1H), 9,9 (s, 1H), and 7.4 (s, 1H), 7,05-7,35 (several m, 6H), to 6.95 (t, 1H), 3.45 points (broad, 2H), and 3.2 (broad, 2H), 3,1 (broad, 4H), and 2.8 (s, 3H), 2,3 (s, 3H).

Example 6

N-(3-Deformedarse-4-were)-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 412,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.7 (broad, 3H), 7,45 (s, 1H), 7,38 (d, 1H), 7,32 (d, 1H), 7,15 (d, 1H), 7,05 (t, 1H), 6,95 (s, 1H), 6,9 (d, 1H), and 3.2 (broad, 4H), of 3.0 (broad, 4H), of 2.25 (s, 3H), of 2.05 (s, 3H).

Example 7

N-(4-Deformational)-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 398,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 10,35 (broad, 1H), of 9.55 (broad, 2H), 7,25 was 7.45 (several m, 3H), 7,15 (t, 1H), 7,15 (d, 2H), 7,05 (d, 2H), and 3.2 (broad, 4H), of 3.05 (broad, 4H), of 2.25 (s, 3H).

Example 8

N-(2,2-Debtorrent[1,3]dioxol-4-yl)-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 412,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.6 (broad, 1H), 7,25 was 7.45 (several m, 3H), 7,2 (d, 1H), and 7.1 (m, 1H), 6,9 (d, 1H), and 3.2 (broad, 4H), of 3.05 (broad, 4H), 2,3 (broad, 3H).

Example 9

N-Cyclopropylmethyl-N-(2-deformational)-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 452,2 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.55 (broad, 2H), 7,05-7,5 (several m, 7H), and 7.1 (t, 1H), 3,35 (m, 2H), and 3.2 (broad, 4H), of 3.05 (broad, 4H), 2,3 (broad, 3H), 0.75 in (m, 1H), 0,3 (m, 2H), be-0.05 (m, 2H).

Example 10

N-Cyclopropylmethyl-N-(3-deformational)-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 452,2 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.6 (broad, 2H), 6,8-7,55 (several m, 8H), 3,4 (m broad, 2H), and 3.2 (broad, 4H), of 3.05 (broad, 4H), 2,35 (broad, 3H), 0.75 in (m broad, 1H), 0,35 (m broad, 2H), 0,0 (m broad, 2H).

Example 11

N-(2-Deformational)-4-methyl-3-piperazine-1-yl-N-propylbenzenesulfonyl hydrochloride

ESI-MS: 440,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.55 (broad, 2H), and 7.4 (m, 2H), and 7.3 (d, 1H), 7,25 (d, 2H), and 7.1 (t, 1H), and 7.1 (m, 2H), 3,4 (m, 2H), and 3.2 (broad, 4H), of 3.05 (broad, 4H), 2,3 (s, 3H) and 1.3 (m, 2H), and 0.8 (t, 3H).

Example 12

N-(3-Deformational)-4-methyl-3-piperazine-1-yl-N-propylbenzenesulfonyl hydrochloride

ESI-MS: 440,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] and 9.4 (broad, 2H), and 7.4 (m, 2H), and 7.3 (t, 1H), 7,25 (d, 1H), 7,15 (d, 1H), 6,95 (s, 1H), 6,95 (d, 1H), 6,85 (s, 1H), 3.45 points (t, 2H), and 3.2 (broad, 4H), of 3.0 (broad, 4H), to 2.35 (s, 3H) and 1.3 (m, 2H), and 0.8 (t, 3H).

Example 13

N-(3-Deformational)-N-ethyl-4-methyl-3-piperazine-1-albenzaalbenza guy is rochloride

ESI-MS: 426,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] a 9.35 (broad, 2H), and 7.4 (m, 2H), 7,25 (m, 1H), 7,25 (d, 1H), 7,2 (d, 1H), 7,0 (s, 1H), 6,95 (d, 1H), 6,85 (s, 1H), 3,55 (m, 2H), and 3.2 (broad, 4H), of 3.0 (broad, 4H), to 2.35 (s, 3H), of 0.95 (t, 3H).

Example 14

N-(3-Deformational)-4,N-dimethyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 412,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,5 (broad, 2H), and 7.4 (m, 2H), and 7.3 (t, 1H), 7,2 (d, 1H), and 7.1 (d, 1H), 7,0 (d, 1H), 6,95 (s, 1H), 6,9 (s, 1H), 3,55 (m, 2H), and 3.2 (broad, 4H), 3,1 (s, 3H), 2.95 points (broad, 4H), to 2.35 (s, 3H).

Example 15

N-(2-Deformational)-N-ethyl-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 426,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.55 (broad, 2H), and 7.4 (m, 2H), 7,35 (d, 1H), 7,25 (m, 2H), 7,15 (t, 1H), 7,15 (d, 1H), and 7.1 (d, 1H), 3,5 (m, 2H), and 3.2 (broad, 4H), of 3.05 (broad, 4H), to 2.35 (s, 3H), of 0.95 (t, 3H).

Example 16

N-(2-Deformational)-N-methyl-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 412,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.7 (broad, 2H), and 7.4 (m, 2H), and 7.3 (d, 1H), 7,2 (m, 2H), and 7.1 (t, 1H), and 7.1 (m, 2H), and 3.2 (broad, 4H), of 3.05 (broad, 4H), 3,05 (s, 3H), 2,3 (s, 3H).

Example 17

N-(2-Deformational)-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 398,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,85 (s, 1H), and 9.1 (broad, 2H), 7.3 to 7.4 (m, 3H), 7,25 (d, 1H), 7,1-7,2 (m, 3H), 6,9 (t, 1H), 3,25 (broad, 4H), of 3.0 (broad, 4H), 2,3 (s, 3H).

Example 18

N-(3-Deformedarse-4-were)-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 428,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 7.3 (d, 1H), 7,2 (s, 1H), and 7.1 (d, 1H), 7,0 (d, 1H), 6,8-7,2 (t, 1H), 6,9 (s, 1H), 6,8 (d, 1H), and 3.8 (s, 3H), 2,8 (s, 8H, 2,1 (s, 3H).

Example 19

N-(4-Deformational)-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 414,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 10.25 (s, 1H), and 9.5 (broad, 2H), 7,35 (d, 1H), 7,25 (d, 1H), 7,15 (d, 2H), 7,15 (t, 1H), 7,05 (m, 3H), and 3.8 (s, 3H), and 3.2 (broad, 8H).

Example 20

3-[1,4]Diazepan-1-yl-N-(2-deformational)-4-methylbenzenesulfonamide hydrochloride

ESI-MS: 412,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.8 (s, 1H), and 9.4 (c broad, 2H), and 7.4 (s, 1H), 7,2-7,3 (m, 3H), 7,1-7,2 (m, 3H), 6,9 (t, 1H), 3,25 (m, 6H), 3.0 a (m, 2H), 2,3 (s, 3H), 2.0 (m, 2H).

Example 21

3-[1,4]Diazepan-1-yl-N-(3-deformedarse-4-were)-4-methylbenzenesulfonamide hydrochloride

ESI-MS: 426,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] at 10.3 (s, 1H), and 9.4 (c broad, 2H), and 7.4 (s, 1H), and 7.3 (m, 2H), 7,15 (d, 1H), 7,05 (t, 1H), 6,95 (m, 1H) 6,85 (m, 1H), 3,2-3,3 (m, 6H), 3.0 a (m, 2H), 2,3 (s, 3H), 2,1 (s, 3H), of 2.05 (m, 2H).

Example 22

N-(2-Deformedarse-4-were)-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 412,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.6 (broad, 3H), and 7.4 (s, 1H), and 7.3 (m, 2H), and 7.1 (d, 1H), 6,9-7,0 (m, 2H), 6,9 (t, 1H), and 3.2 (broad, 4H), of 3.05 (broad, 4H), 2,3 (s, 3H), of 2.25 (s, 3H).

Example 23

N-(2-Deformedarse-5-were)-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 412,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,4-9,9 (broad, 3H), and 7.4 (s, 1H), and 7.3 (m, 2H), and 7.1 (s, 1H), 6,9-7,0 (m, 2H), 6,85 (t, 1H), and 3.2 (broad, 4H), of 3.05 (broad, 4H), 2,3 (s, 3H), 2,2 (s, 3H).

Example 24

N-(3-Deformational)-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 414,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] at 10.5 (s, 1H), and 9.6 (c broad, 2H), and 7.4 (d, 1H), and 7.3 (s, 1H), 7,25 (m, 1H), 7,15 (t, 1H), and 7.1 (d, 1H), 7,0 (m, 1H), 6,95 (s, 1H), 6,8 (d, 1H), and 3.8 (s, 3H), 3,1-3,2 (broad, 8H).

Example 25

N-(3-Deformedarse-4-methoxyphenyl)-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 444,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 10.05 (s, 1H), and 9.3 (c broad, 2H), 7,35 (d, 1H), 7,25 (s, 1H), 6,8-7,1 (several m, 5H), 3,8 (s, 1H), and 3.7 (s, 3H), 3,2 (c broad, 4H), 3.15 in (c broad, 4H).

When is EP 26

N-(2-Deformational)-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 414,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.8 (s, 1H), 9,7 (c broad, 2H), 7,35 (d, 1H), and 7.3 (s, 1H), 7,25 (d, 1H), 7,1-7,2 (several m, 3H), 7,05 (d, 1H), 7,0 (t, 1H), and 3.8 (s, 3H), and 3.2 (broad, 8H).

Example 27

N-(2-Deformational)-4-methoxy-N-methyl-3-piperazine-1-albenzaalbenza hydrochloride

27.1 tert-Butyl 4-(5-(N-(2-(deformedarse)phenyl)sulfamoyl)-2-methoxyphenyl)piperazine-1-carboxylate

1 g of N-(2-(deformedarse)phenyl)-4-methoxy-3-(piperazine-1-yl)benzosulfimide (2,419 mmol) was dissolved in 15 ml of tetrahydrofuran. Added 0,674 ml of triethylamine (4,84 mmol) was then added 0,528 g of di-tert-BUTYLCARBAMATE (2,419 mmol) in 2 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 16 hours. After evaporation of the solvent the residue was dissolved in dichloromethane, washed with 5% aqueous citric acid solution. The organic phase is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and the solvent evaporated. The crude product containing about 25% bis-boc derivative was used without further purification in the next stage (1.2 g).

27.2 tert-Butyl 4-(5-(N-(2-(deformedarse)phenyl)methylsulfonyl)-methoxyphenyl)piperazine-1-carboxylate

0.15 g of tert-butyl 4-(5-(N-(2-(deformedarse)phenyl)-sulfamoyl)-2-methoxyphenyl)piperazine-1-carboxylate (0,219 mmol) was dissolved in 5 ml of dimethylformamide. Added 11.4 mg of sodium hydride (0,285 mmol, 60%) and the reaction mixture was stirred at 50°C for 20 minutes. Was added at room temperature 0,018 ml methyliodide (0,285 mmol). Stirring was continued for 16 hours at room temperature, then added another 0,018 ml methyliodide and was stirred for 16 hours. The solvent is evaporated, the residue was dissolved in dichloromethane and washed with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and the solvent evaporated. Purification via chromatography on silica gel (Redisep NP-cartridge) using cyclohexane/ethyl acetate (0-50%) to give 0.104 g g these compounds.

ESI-MS: 528,2 [M+H]+

27.3 N-(2-Deformational)-4-methoxy-N-methyl-3-piperazine-1-albenzaalbenza hydrochloride

in 0.104 g of tert-butyl 4-(5-(N-(2-(deformedarse)phenyl)methylsulfonyl)-2-methoxyphenyl)piperazine-1-carboxylate (0,197 mmol) was dissolved in 5 ml dichloromethane. Was added at room temperature 0,296 ml 2 N. aqueous solution of hydrochloric acid (0,591 mmol) and the reaction mixture was stirred for 16 hours and for 2 hours at 35°C. After addition of methanol stirring is continued during the 1 hour, then the solvents are evaporated and the residue several times together drove with diethyl ether to remove residual hydrochloric acid. The remaining solid was dissolved in water (pH 4), was extracted several times with dichloromethane and the aqueous layer was liofilizirovanny to obtain 0.08 g of the named compound.

ESI-MS: 428,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] and 9.3 (broad, 2H), 7,45 (m, 1H), and 7.4 (m, 1H), 7,25 (m, 2H), 7,2 (d, 1H), and 7.1 (d, 1H), and 7.1 (t, 1H), 7,0 (s, 1H), 3,9 (s, 3H), 3,2 (c broad, 4H), 3.15 in (c broad, 4H), 3,05 (s, 3H).

Connection examples 9, 10, 11, 12, 13, 14, 15, 16, 28, 29, 30, 31, 32, 33, 34, 36, 39 and 43 was obtained in the same manner as described in example 27, using as alkylating reagents or methyliodide, ethyliodide, propyl bromide, Isopropylamine or cyclopropylmethanol.

Example 28

N-(3-Deformedarse-4-methoxyphenyl)-4-methoxy-N-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 458,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,7 (c broad, 2H), 9,05 (c broad, 1H), 7,2 (m, 1H), 7,25 (m, 2H), 7,05 (t, 1H), 6,95 (m, 1H), 6,9 (s, 1H), 6,8 (s, 1H), 3,9 (s, 3H), 3,85 (s, 3H), and 3.2 (broad, 8H), was 3.05 (s, 3H).

Example 29

N-(3-Deformational)-N-ethyl-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 442,2 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,5 (c W is rocky, 2H), and 7.4 (m, 1H), 7,25 (m, 1H), 7,25 (m, 1H), 7,1-7,2 (several m, 2H), 6,9 (d, 1H), 6,8 (s, 2H), 3,85 (s, 3H), 3,5 (m, 2H), 3,2 (c broad, 4H), 3.15 in (c broad, 4H), and 0.9 (t, 3H).

Example 30

N-(3-Deformedarse-4-methoxyphenyl)-N-ethyl-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 472,2 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,3 (c broad, 2H), 7,25 (d, 1H), 7,1-7,2 (m, 2H), 7,0 (t, 1H), 6,95 (m, 1H), 6,9 (s, 1H), 6,8 (s, 1H), 3,9 (s, 3H), 3,85 (s, 3H), 3,5 (m, 2H), 3,2 (c broad, 4H), 3.15 in (c broad, 4H), of 0.95 (t, 3H).

Example 31

N-(2-Deformational)-N-ethyl-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 442,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,5 (s, broad, 2H), 7,45 (m, 1H), 7,35 (m, 1H), 7,2-7,3 (m, 2H), 7,2 (m, 1H), 7,15 (t, 1H), and 7.1 (d, 1H), 7,0 (s, 1H), 3,9 (s, 3H), 3,5 (m, 2H), 3,1-3,25 (c broad, 8H), of 0.95 (t, 3H).

Example 32

N-(3-Deformational)-4-methoxy-N-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 428,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,6 (c broad, 2H), and 9.0 (s, broad, 1H), and 7.4 (m, 1H), and 7.3 (t, 1H), 7,25 (m, 1H), 7,1-7,2 (m, 2H), 7,0 (d, 1H), 6,95 (s, 1H), 6,7 (s, 1H), 3,9 (s, 3H), 3,2 (c broad, 4H), 3,1 (c broad, 4H), 2,5 (m, 3H).

Example 33

N-(3-Deformedarse-4-methoxyphenyl)-4-methoxy-3-piperazine-1-yl-N-propylbenzenesulfonyl hydrochloride

ESI-MS: 486,2 [M+H]

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,3 (c broad, 2H), 7,25 (d, 1H), 7,15 (m, 2H), 7,0 (t, 1H), 6,95 (d, 1H), 6,85 (d, 1H), 6.75 in (s, 1H), 3,9 (s, 3H), and 3.8 (s, 3H), 3,4 (t, 2H), and 3.2 (broad, 4H), 3,1 (broad, 4H), 1.8 m (m, 2H), and 0.8 (t, 3H).

Example 34

N-(3-Deformational)-4-methoxy-3-piperazine-1-yl-N-propylbenzenesulfonyl hydrochloride

ESI-MS: 456,2 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.55 (c broad, 2H), and 7.4 (m, 1H), 7,25 (d, 2H), 7,15 (m, 2H), 6,95 (d, 1H), 6,85 (s, 1H), 6,8 (s, 1H), 3,85 (s, 3H), of 3.45 (t, 2H), and 3.2 (broad, 4H), 3,1 (broad, 4H), 1.8 m (m, 2H), 0.8 a (t, 3H).

Example 35

N-(3-Deformational)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 428,1 [M+H]+

1H-NMR (CDCl3, 400 Hz): δ [M. D.] was 7.45 (d, 1H), 7,2 (m, 2H), 6,8-7,0 (several m, 4H), of 6.45 (t, 1H), 3,9 (s, 3H), 3.0 a (s, 4H), and 2.6 (s, 4H), to 2.35 (s, 3H).

Example 36

N-(2-Deformational)-4-methoxy-3-piperazine-1-yl-N-propylbenzenesulfonyl hydrochloride

ESI-MS: 456,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,0 (broad, 2H), 7,45 (m, 1H), 7,35 (m, 1H), 6,9-7,3 (several m, 6H), at 3.9 (s, 3H), 3,4 (t, 2H), and 3.2 (broad, 4H), 3.15 in (broad, 4H), 1,3 (m, 2H), and 0.8 (t, 3H).

Example 37

N-(2-Deformational)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 428,1 [M+H]+

1H-NMR (DMSO-d , 400 Hz): δ [M. D.] 10,5 (c broad, 1H), and 9.7 (s, 1H), and 7.4 (d, 1H), and 7.3 (m, 2H), 7,05-7,2 (several m, 4H), to 6.95 (t, 1H), 3,85 (s, 3H), of 3.45 (m, 4H), 3,2 (m, 2H), 2.95 and (m, 2H), and 2.8 (d, 3H).

Example 38

N-(3-Deformedarse-4-methoxyphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 458,1 [M+H]+

1H-NMR (CDCl3, 400 Hz): δ [M. D.] 7,35 (m, 2H), 7,0 (m, 1H), 6,9 (s, 1H), 6,8 (m, 2H), 6,5 (t, 1H), 3,9 (s, 3H), and 3.8 (s, 3H), and 3.2 (broad, 4H), and 2.8 (broad, 4H), 2,5 (s, broad, 3H).

Example 39

N-(2-Deformational)-N-isopropyl-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 440,2 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,6 (c broad, 2H), 6,95-7,55 (several m, 8H), 4,3 (m, 1H), and 3.2 (broad, 4H), 3,1 (broad, 4H), 2,3 (s, 3H), and 1.0 (d, 3H), and 0.9 (d, 3H).

Example 40

N-(2,2-Debtorrent[1,3]dioxol-4-yl)-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 428,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 10.4 (s, 1H), and 9.6 (c broad, 2H), 7,35 (d, 1H), 7,25 (s, 1H), 7,2 (d, 1H), and 7.1 (m, 2H), 6,9 (d, 1H), 3,85 (s, 3H), and 3.2 (broad, 8H).

Example 41

N-(2-Deformational)-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 384,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] to 9.9 (s, 1H), 9,75 (c broad, 2H), and 7.4 (m, 2H), 7,25 (m, 2H), 7,1-7,2 (m, 4H), to 6.95 (t, 1H), 3,4 (broad, 4H), 315 (broad, 4H).

Example 42

N-(2-Deformational)-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 398,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 11.45 (c broad, 1H), 9,9 (c broad, 1H), 7,35-7,45 (m, 2H), 7,25 (m, 2H), 7,1-7,2 (m, 4H), to 7.0 (t, 1H), 3,0-3,9 (broad, 8H), to 2.75 (s, 3H).

Example 43

N-(2-Deformational)-N-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 398,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,5 (c broad, 2H), 7.5 (m, 1H), 7,45 (m, 1H), and 7.3 (m, 1H), 7,2 (m, 2H), and 7.1 (m, 3H), 7,05 (t, 1H), 3,4 (broad, 4H), and 3.2 (broad, 4H), 3,1 (s, 3H).

Example 44

N-(2-Deformational)-N-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 412,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 11.5 (broad, 1H), 7,55 (m, 1H), 7.5 (m, 1H), 7,45 (d, 1H), 7,25 (m, 2H), 7,05-7,2 (several m, 4H), 3,4 (broad, 8H), 3,1 (s, 3H), and 2.8 (s, 3H).

Example 45

1-[3-(3-Deformationsvetsaren)phenyl]piperazine hydrochloride

ESI-MS: 369,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,6 (c broad, 2H), a 7.85 (d, 1H), of 7.75 (s, 1H), and 7.7 (m, 1H), 7,45-7,55 (several m, 3H), and 7.4 (t, 1H), and 7.4 (d, 1H), and 7.3 (m, 1H), 3,5 (c broad, 4H), 3.15 in (c broad, 4H).

Example 46

1-[3-(3-Deformationsvetsaren)phenyl]-4-methylpiperazine hydrochloride

ESI-MS: 383,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] a 7.85 (d, 1H), and 7.8 (s, 1H), and 7.7 (m, 1H), 7,45-7,55 (several m, 3H), and 7.4 (d, 1H), and 7.4 (t, 1H), and 7.3 (d, 1H), 3,95 (d, 2H), 3,65 (d, 2H), 3,25 (m, 2H), 3.15 in (m, 2H), and 2.8 (d, 3H).

Example 47

1-[5-(3-Deformationsvetsaren)-2-methoxyphenyl]piperazine hydrochloride

ESI-MS: 399,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,5 (c broad, 2H), and 7.8 (d, 1H), and 7.7 (s, 1H), 7,65 (m, 2H), 7,45 (d, 1H), and 7.4 (t, 1H), and 7.4 (m, 1H), 7,2 (d, 1H), 3,85 (s, 3H), 3,25 (c broad, 4H), 3,2 (c broad, 4H).

Example 48

1-[5-(3-Deformationsvetsaren)-2-methoxyphenyl]-4-methylpiperazine hydrochloride

ESI-MS: 413,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 7.8 (d, 1H), of 7.75 (s, 1H), 7,65 (m, 2H), 7.5 (d, 1H), and 7.4 (t, 1H), and 7.4 (s, 1H), 7,2 (d, 1H), 3,85 (s, 3H), 3,55 (m, 2H), of 3.45 (m, 2H), 3,05-3,2 (m, 4H), and 2.8 (s, 3H).

Example 49

1-[5-(3-Deformedarse-4-methoxybenzenesulfonyl)-2-methoxyphenyl]piperazine hydrochloride

ESI-MS: 429,2 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.55 (c broad, 2H), a 7.85 (d, 1H), and 7.7 (s, 1H), and 7.6 (d, 1H), and 7.3 (m, 2H), 7,2 (t, 1H), 7,17 (d, 1H), 3,9 (s, 3H), 3,85 (s, 3H), 3,25 (c broad, 4H), 3,2 (c broad, 4H).

Example 50

N-(2-Deformedarse-5-were)-4-ethoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 442,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.7 (broad, 1H), and 9.0 (broad, 2H), 7,35 (d, 1H), 7,27 (s, 1H), and 7.1 (s, 1H), 7,05 (d, 1H), 6,95 (m, 2H), 6,85 (t, 1H), 4,1 (kV, 2H), and 3.2 (broad, 4H), 3.15 in (broad, 4H), 2,2 (s, 3H), of 1.35 (t, 3H).

Example 51

N-(3,4-Bis-deformational)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 494 [M+H]+

Example 52

N-(3,4-Bis-deformational)-4-methyl-3-piperazine-1-albenzaalbenza

ESI-MS: 464,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] to 10.6 (broad, 1H), and 9.6 (broad, 2H), 7,3 was 7.45 (m, 3H), 6,9-7,3 (several m, 5H), and 3.2 (broad, 4H), 3,05 (broad, 2H), 2,3.

Example 53

N-(5-Chloro-2-deformational)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 462 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] at 10.5 (broad, 1H), of 10.05 (broad, 1H), and 7.4 (d, 1H), 7,35 (s, 1H), 7,32 (s, 1H), 7.23 percent (d, 1H), 7,18 (d, 1H), and 7.1 (d, 1H), 7,0 (t, 1H), 3,85 (s, 3H), 3,5 (broad, 4H), and 3.2 (broad, 2H), and 3.0 (broad, 2H)that 2.8 (s, 3H).

Example 54

N-(2-Deformedarse-5-were)-4-ethyl-3-(4-methylpiperazin-1-yl)benzosulfimide

ESI-MS: 440,1 [M+H]+

Example 55

N-(5-Deformedarse-2-were)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 442,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 0,6 (broad, 1H), and 9.6 (broad, 1H), 7,35 (d, 1H), 7,05-7,25 (several m, 4H), 6,9 (d, 1H), 6,8 (s, 1H), 3,85 (s, 3H), 3,1-3,7 (broad, 8H), 3,4 (s, 3H), 2,0 (s, 3H).

Example 56

N-(5-Chloro-2-deformational)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 446,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 10,4 (very broad, 2H), of 7.48 (s, 1H), and 7.4 (m, 2H), 7,33 (s, 1H), 7.23 percent (d, 1H), 7,18 (d, 1H), 6,98 (t, 1H), 2.95 points to 3.7 (broad, 8H), 2,9 (s, 3H), 2,3 (s, 3H).

Example 57

N-(5-Chloro-2-deformational)-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 448,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 10.05 (s, 1H), and 9.1 (broad, 2H), and 7.4 (d, 1H), 7,32 (m, 2H), 7,22 (d, 1H), 7,17 (d, 1H), 7,10 (d, 1H), 7,0 (t, 1H), 3,85 (s, 3H), and 3.2 (broad, 4H), 3.15 in (broad, 4H).

Example 58

N-(5-Deformedarse-2-were)-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 412,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 7,2-7,4 (several m, 3H), 7,15 (d, 1H), and 7.1 (t, 1H), to 6.88 (d, 1H), PC 6.82 (s, 1H), 3,1 (broad, 4H), 2,9 (broad, 4H), 2,3 (s, 3H), of 1.95 (s, 3H).

Example 59

N-(5-Deformedarse-2-were)-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 428,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,65 and 9.8 (broad, 3H), and 7.3 (d, 1H), 7,2 (s, 1H), 7,18 (d, 1H), 7,12 (t, 1H), 7,1 (who, 1H) and 6.9 (d, 1H), 6.75 in (s, 1H), and 3.8 (s, 3H),3,15 (broad, 8H), of 1.95 (s, 3H).

Example 60

N-(3,4-Bis-deformational)-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 480,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 10,55 (s, 1H), and 9.5 (s, 2H), 7,43 (d, 1H), 7,25 (m, 2H), 6,9-to 7.15 (m, 5H), at 3.9 (s, 3H), and 3.2 (broad, 8H).

Example 61

N-(5-Chloro-2-deformational)-4-ethyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 446 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 10.25 (broad, 1H), of 9.55 (broad, 2H), and 7.5 (s, 1H), and 7.4 (m, 2H), and 7.3 (s, 1H), 7,25 (d, 1H), 7,2 (d, 1H), 7,0 (t, 1H), 3,25 (broad, 4H), of 3.05 (broad, 4H), and 2.7 (q, 2H), 1,2 (t, 3H).

Example 62

N-(2-Deformedarse-4-were)-4-ethyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 426,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,5 (broad, 2H), 7.3 to 7.4 (m, 3H), and 7.1 (d, 1H), 6,97 (d, 1H), 6,93 (s, 1H), 6,9 (t, 1H), and 3.2 (broad, 4H), of 3.0 (broad, 4H), 2,68 (kV, 2H, in), 2.25 (s, 3H), of 1.18 (t, 3H).

Example 63

N-(2-Deformedarse-5-were)-4-methyl-3-((R)-3-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: to 426.2 [M+H]+

1H-NMR (methanol-d4, 400 Hz): δ [M. D.] 7,3 was 7.45 (m, 4H), 6,9-7,05 (m, 2H), 6,4 (t, 1H), 2,7-3,7 (several m, 7H), and 2.4 (s, 3H), 2,3 (s, 3H), and 1.4 (d, 3H).

Example 64

N-(2-Deformedarse-5-methylp the Nile)-4-methyl-3-((S)-3-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: to 426.2 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,85 (s, 1H), 9,65 (broad, 1H), and 9.4 (broad, 1H), and 7.4 (s, 1H), 7,35 (s, 2H), and 7.1 (s, 1H), 6,95-7,0 (m, 2H), 7,0 (t, 1H), 3,4 (broad, 3H), 3,1 (m, 2H), 2.95 and (m, 1H), 2,8 (m, 1H), 2,3 (s, 3H), 2,22 (s, 3H) and 1.3 (d, 3H).

Example 65

N-(2-Deformedarse-5-were)-4-ethyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 426,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,85 (broad, 1H), and 9.6 (broad, 2H), 7,45 (s, 1H), and 7.4 (m, 2H), and 7.1 (s, 1H), 6,95-7,0 (m, 2H), 6,85 (t, 1H), up 3.22 (broad, 4H), to 3.02 (broad, 4H), 2,68 (kV, 2H), 2,2 (s, 3H) and 1.15 (t, 3H).

Example 66

N-(2,2-Debtorrent[1,3]dioxol-5-yl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 442,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] to 10.1 (broad, 1H), 7,33 (d, 1H), 7,28 (d, 1H), 7,08-to 7.15 (m, 2H), 7,05 (d, 1H), 6,8 (d, 1H), and 3.8 (s, 3H), 2,9 (broad, 4H), of 2.45 (broad, 4H), 2,2 (s, 3H).

Example 67

N-(2-Deformedarse-5-were)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

0,429 g of N-(2-(deformedarse)-5-were)-4-methoxy-3-(piperazine-1-yl)benzosulfimide (1,004 mmol) was dissolved in 5 ml dichloromethane. Added 0,086 ml of acetic acid (1,505 mmol) and 0,319 g triacetoxyborohydride sodium (a 3.01 mmol). After stirring for 10 minutes add the Yali 0,083 ml of an aqueous solution of formaldehyde (a 3.01 mmol) and the reaction mixture was stirred for 72 hours at room temperature. The solvents are evaporated and the residue was purified using preparative chromatography on silica gel (Super Flash cartridge (Interchim)), using as eluent a gradient of dichloromethane (+0.1% triethylamine) and methanol. The fractions containing the product were combined, the solvent evaporated and the product was transformed into cleaners containing hydrochloride salt by addition of hydrochloric acid in diethyl ether and then evaporated to dryness (yield 0,169 g).

ESI-MS: 442,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.6 (broad, 1H), and 7.3 (d, 1H), 7,2 (s, 1H), and 7.1 (s, 1H), 6,9-7,05 (several m, 3H), 6,8 (t, 1H), and 3.8 (s, 3H), 2,9 (broad, 4H), of 2.45 (broad, 4H), 2,2 (two s, 6H).

Example 68

N-(3-Deformational)-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 384,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] to 10.6 (s, 1H), 9,85 (broad, 1H), 9,45 (broad, 2H), and 7.4 (m, 2H), 7,2-7,35 (m, 3H), 7,2 (t, 1H), 7,0 (m, 1H), 6,95 (s, 1H), 6,85 (d, 1H), 3,15-the 3.65 (broad, 8H).

Example 69

N-(2-Deformedarse-4-forfinal)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 446,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 10,85 (broad, 1H), 9,75 (s, 1H), 7,2-7,35 (m, 3H), of 7.0 to 7.1 (m, 3H), 7,07 (t, 1H), 3,85 (s, 3H), 3,5 (m, 4H), 3,18 (m, 2H), to 3.02 (m, 2H), 2,85 (s, 3H).

Example 70

N-(2-Deformedarse-4-were)-4-methoxy-3-(4-methylpiperazin-1-yl)benzo is sulfonamide hydrochloride

ESI-MS: 442,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] and 11.2 (broad, 1H), and 9.6 (s, 1H), and 7.3 (m, 2H), 7,12 (d, 1H), 7,05 (d, 1H), 6,9-7,0 (several m, 2H), 6,92 (t, 1H), and 3.8 (s, 3H), of 3.45 (m, 4H), 3,17 (m, 2H), 3,05 (m, 2H), and 2.8 (s, 3H), of 2.25 (s, 3H).

Example 71

N-(5-Chloro-2-deformational)-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 432,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] at 10.3 (s, 1H), 9,75 (broad, 2H), 7,15-7,5 (several m, 6H), 7,05 (t, 1H), and 3.2 (broad, 4H), of 3.07 (broad, 4H), 2,3 (s, 3H).

Example 72

N-(2-Deformedarse-5-were)-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 428,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 463,93061H-NMR (DMSO-d6, 400 Hz): d [M. D.] of 9.7 (broad, 1H), and 9.6 (broad, 2H), 7,35 (d, 1H), and 7.3 (s, 1H), and 7.1 (s, 1H), 7,05 (d, 1H), 6,9-7,0 (m, 2H), 6,85 (t, 1H), and 3.8 (s, 3H), 3,1-of 3.25 (broad, 8H) 2,2 (s, 3H).

Example 73

N-(2-Deformedarse-4-were)-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 428,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 7.3 (d, 1H), 7,2 (s, 1H), 7,15 (d, 1H), 6,95 (d, 1H), 6,9 (d, 1H), 6,85 (t, 1H), and 3.8 (s, 3H), 2,8-2,95 (broad, 8H) 2,2 (s, 3H).

Example 74

N-(2-Deformedarse-4-forfinal)-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 416,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 7,15-7,35 (several m, 4H), and 7.1 (t, 1H), 6,8-to 6.95 (m, 2H), and 3.0 (broad, 4H), 2,85 (broad, 4H), 2,2 (s, 3H).

Example 75

N-(3-Deformedarse-4-were)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 426,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 11,35 (broad, 1H), 10,4 (s, 1H), and 7.4 (s, 1H), 7,35 (m, 2H), 7,15 (d, 1H), and 7.1 (t, 1H), 7,0 (s, 1H), 6,9 (m, 1H), 3,5 (broad, 2H), and 3.2 (broad, 2H), 3,1 (broad, 4H), and 2.8 (s, 3H), 2,3 (s, 3H)and 2.1 (s, 3H).

Example 76

N-(4-Deformedarse-3-methoxyphenyl)-4-methyl-3-piperazine-1-albenzaalbenza

ESI-MS: 428,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] and 9.4 (broad, 1H), and 7.4 (m, 1H), 7,37 (m, 2H), 7,03 (d, 1H), 6,9 (t, 1H), 6.87 in (s, 1H), 6,65 (d, 1H), and 3.7 (s, 3H), of 3.25 (broad, 4H), of 3.0 (broad, 4H), of 2.25 (s, 3H).

Example 77

N-(5-Deformedarse-2-methoxyphenyl)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide triptorelin

ESI-MS: 442,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.6 (s, 1H), 7,3 was 7.45 (m, 3H), 7,07 (d, 1H), 7,05 (t, 1H), 6,95 (m, 2H), 3,55 (s, 3H), 3,55 (broad, 2H), and 3.2 (broad, 4H), 2,9 (broad, 2H), 2,9 (s, 3H), 2,3 (s, 3H).

Example 78

N-(2-Deformedarse-5-methoxyphenyl)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide triptorelin

ESI-MS: 442,1 [M+H]+

1H-NMR (CDCl3, 400 Hz): δ [M. D.] 7.5 (d, 1H), 7,37 (s, 1H), 7,2 (d, 1H), 6,93 (m, 2H), and 6.6 (d, 1H), 6,2 (t, 1H), and 3.8 (s, 3H), to 3.67 (m, 2H), 3,2 (m, 2H), 3,1 (m, 2H), 3.0 a (m, 2H), 2,9 (s, 3H), 2,3 (s, 3H).

Example 79

N-(2-Deformedarse-4-forfinal)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide triptorelin

ESI-MS: 430,1 [M+H]+

1H-NMR (CDCl3, 400 Hz): δ [M. D.] 7,63 (m, 1H), 7,38 (m, 2H), 6,95 (m, 1H), 6,85 (s, 1H), 6,78 (d, 1H), 6,27 (t, 1H), 3,7 (m, 2H), 3,25 (m, 2H), 2.95 and is 3.2 (broad, 4H), 2,9 (s, 3H), 2,3 (s, 3H).

Example 80

N-(5-Deformedarse-2-methoxyphenyl)-4-methyl-3-piperazine-1-albenzaalbenza triptorelin

ESI-MS: 428,1 [M+H]+

1H-NMR (CDCl3, 400 Hz): δ [M. D.] of 9.8 (broad, 2H), 7,52 (d, 1H), 7,38 (s, 2H), and 7.1 (s, 1H), 6,8 (m, 1H), 6,7 (m, 1H), 6,45 (t, 1H), and 3.7 (s, 3H), 3,35 (broad, 4H), 3,1 (broad, 4H), 2,3 (s, 3H).

Example 81

N-(2-Deformedarse-5-methoxyphenyl)-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 428,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.7 (broad, 2H), 7,45 (s, 1H), 7,35 (m, 2H), 7,05 (d, 1H), 6,8 (d, 1H), 6,8 (t, 1H), 6,7 (d, 1H), the 3.65 (s, 3H), and 3.2 (broad, 4H), of 3.05 (broad, 4H), 2,3 (s, 3H).

Example 82

N-(2-Deformedarse-4-forfinal)-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 432,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 7,15-7,35 (several is about m, 3H), 6,9-7,05 (several m, 3H), 6,85-to 7.15 (t, 1H), and 3.8 (s, 3H), 3,05 (m, 4H), 3.0 a (m, 4H).

Example 83

N-(2,2-Debtorrent[1,3]dioxol-5-yl)-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 428,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] to 7.35 (d, 1H), 7,15 to 7.2 (m, 2H), 7,05 (s, 1H), 7,0 (d, 1H), 6,85 (d, 1H), and 3.8 (s, 3H), 2,85 to 3.0 (broad, 8H).

Example 84

N-(2,2-Debtorrent[1,3]dioxol-5-yl)-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 412,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 10.4 (s, 1H), 9,25 (broad, 2H), and 7.4 (s, 1H), 7,35 (m, 2H), 7,28 (d, 1H), 7,15 (m, 1H), to 6.88 (d, 1H), 3,25 (broad, 4H), of 3.05 (broad, 4H), 2,3 (s, 3H).

Example 85

N-(3-Deformedarse-4-methoxyphenyl)-4-methyl-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 428,2 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 8,8-10,4 (very broad, 3H), 7.3 to 7.4 (m, 3H), 7,03 (d, 1H), 6,95 (t, 1H), 6,85-7,0 (m, 2H, in), 3.75 (s, 3H), and 3.2 (broad, 4H), of 3.05 (broad, 4H), of 2.25 (s, 3H).

Example 86

N-(3-Deformedarse-4-methoxyphenyl)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 443,2 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 11,3 (very broad, 1H), 10,15 (s, 1H), and 7.4 (s, 1H), and 7.3 (m, 2H), 7,05 (d, 1H), 6,95 (m, 2H), 6,95 (t, 1H), and 3.7 (s, 3H), 3,05-3,5 (broad, 8H), and 2.8 (s, 3H), of 2.25 (s, 3H).

Example 87

N-(4-Deformedarse-3-were)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 427,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 10,3 (c broad, 1H), 7.3 to 7.4 (m, 3H), 7,15 (d, 1H), 7,0 (t, 1H), 6,95 (s, 1H), to 6.88 (m, 1H), 3,4 (broad, 4H), 3,1 (broad, 4H), and 2.8 (s, 3H), of 2.25 (s, 3H), 2,1 (s, 3H).

Example 88

N-(4-Deformational)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 413,2 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 10.25 (c broad, 1H), 7.3 to 7.4 (m, 3H), and 7.1 (DD, 2H), 7,05 (DD, 2H), 7,05 (t, 1H), 3,4 (broad, 4H), 3,1 (broad, 4H), to 2.75 (s, 3H), 2,3 (s, 3H).

Example 89

N-(3-Deformedarse-4-were)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 442,2 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 10,2 (c broad, 1H), and 7.4 (d, 1H), and 7.3 (s, 2H), 7,15 (d, 1H), was 7.08 (m, 1H), 7,03 (t, 1H), 6,95 (s, 1H), 6,9 (d, 1H), and 3.8 (s, 3H), 3.0 to 3.6V (broad, 8H), and 2.8 (s, 3H), 2,1 (s, 3H).

Example 90

N-(4-Deformedarse-3-methoxyphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide

ESI-MS: 458,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 7,42 (d, 1H), 7,27 (s, 1H), 7,05 (m, 2H), 6,9 (d, 1H), 6,9 (t, 1H), 6,7 (d, 1H), and 3.8 (s, 3H), and 3.7 (s, 3H), 3,1 (broad, 4H), 2,9 (broad, 4H), of 2.5 (s, 3H).

Example 91

N-(2-Deformedarse-4-were)-4-methyl--(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 427,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] to 11.3 (broad, 1H), 9,7 (c broad, 1H), and 7.4 (s, 1H), 7,25-7,35 (m, 2H), and 7.1 (d, 1H), 6,97 (d, 1H), 6,95 (s, 1H), 6,9 (t, 1H), 3.0 to 3.5 (broad, 8H), and 2.8 (s, 3H), 2,3 (s, 3H), of 2.25 (s, 3H).

Example 92

N-(2-Deformedarse-5-were)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 427,5 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] to 11.3 (broad, 1H), 9,8 (c broad, 1H), and 7.4 (s, 1H), 7,32 (s, 2H), and 7.1 (s, 1H), 7,0 (m, 2H), 6,85 (t, 1H), 6,9 (t, 1H), 3.0 to 3.5 (broad, 8H), and 2.8 (s, 3H), 2,3 (s, 3H), 2,2 (s, 3H).

Example 93

N-(4-Deformedarse-3-methoxyphenyl)-4-methoxy-3-piperazine-1-albenzaalbenza hydrochloride

ESI-MS: 444,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] and 8.4 (broad, 1H), 7,42 (m, 1H), 7,24 (s, 1H), 7,0-to 7.15 (m, 2H), 6,85-7,0 (m, 2H), 6,7 (m, 1H), and 3.8 (s, 3H), and 3.7 (s, 3H), of 3.0 (broad, 8H).

Example 94

N-(3-Deformational)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

ESI-MS: 412,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 10,5 (c broad, 1H), 7,2-7,4 (several m, 3H), 7,15 (t, 1H), 7,0 (d, 1H), 6,92 (s, 1H), PC 6.82 (d, 1H), 3.0 to 3.5 (broad, 8H), and 2.8 (s, 3H), of 2.25 (s, 3H).

Example 95

N-(4-Deformational)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide hydrochloride

/p>

ESI-MS: 428,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] to 11.3 (broad, 1H), 10,2 (s, 1H), 7,38 (d, 1H), and 7.3 (s, 1H), 7,15 (DD, 2H), 7,07 (m, 3H), and 7.1 (t, 1H), and 3.8 (s, 3H), 3,4 (broad, 4H), 3,1 (broad, 4H), and 2.8 (s, 3H).

Example 96

3-[1,4]Diazepan-1-yl-N-(3-deformational)-4-methylbenzenesulfonamide hydrochloride

ESI-MS: 412,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 10,53 (s, 1H), of 9.55 (s, 2H), 7,45 (s, 1H), 7,2-7,4 (m, 3H), 7,15 (t, 1H), 7,0 (d, 1H), 6,95 (s, 1H), 6,8 (d, 1H), 3,25 (broad, 6H), was 3.05 (m, 2H, in), 2.25 (s, 3H), 2.05 is (broad, 2H).

Example 97

3-[1,4]Diazepan-1-yl-N-(2-deformational)-4-methylbenzenesulfonamide hydrochloride

ESI-MS: 412,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] of 9.8 (s, 1H), and 9.4 (s, 2H), and 7.4 (s, 1H), 7,2-7,35 (m, 3H), 7,1-7,2 (m, 3H), 6,9 (t, 1H), 3,25 (broad, 6H), was 3.05 (m, 2H), 2,3 (s, 3H), 2.05 is (broad, 2H).

Example 98

3-[1,4]Diazepan-1-yl-N-(3-deformedarse-4-were)-4-methylbenzenesulfonamide hydrochloride

ESI-MS: 426,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] at 10.3 (s, 1H), 9,45 (s, 2H), and 7.4 (s, 1H), and 7.3 (s, 2H), 7,15 (d, 1H), 7,05 (t, 1H), 6,95 (s, 1H), 6.87 in (d, 1H), 3,25 (broad, 6H), was 3.05 (m, 2H), 2,3 (s, 3H), 2,1 (s, 3H), 2.05 is (broad, 2H).

Example 99

N-(3-Deformedarse-4-were)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)benzosulfimide hydrochloride

ESI-MS: 440,2 [M+H]+

Example 100

N-(2-Deformational)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)benzosulfimide hydrochloride

ESI-MS: 426,1 [M+H]+

1H-NMR (DMSO-d6, 400 Hz): δ [M. D.] 9,5-11,0 (very broad, 2H), and 7.4 (s, 1H), 7,2-7,35 (m, 3H), 7,1-7,2 (m, 3H), 6,93 (t, 1H), 3,4 (broad, 6H), was 3.05 (m, 2H), and 2.8 (s, 3H), 2,3 (s, 3H), of 2.15 (broad, 2H).

Example 101

N-(3-Deformational)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)benzosulfimide hydrochloride

ESI-MS: to 426.2 [M+H]+

Example 102

N-(5-Deformedarse-2-were)-4-deformedarse-3-piperazine-1-albenzaalbenza

Example 103

N-(5-Deformedarse-2-were)-4-deformedarse-N-methyl-3-piperazine-1-albenzaalbenza

Example 104

N-(5-Deformedarse-2-were)-4-fluoro-3-piperazine-1-albenzaalbenza

Example 105

N-(5-Deformedarse-2-were)-4-fluoro-N-methyl-3-piperazine-1-albenzaalbenza

III. Biological studies

The displacement of radio-connecting these cloned receptors

1. Preparation of membranes by treatment with ultrasound and differential centrifugation

Cells from stable clonal cell lines expressing sootvetstvujusjie (5-HT 6α1-adrenergic, dopamine D2or histamine H1receptors), washed with PBS (without Ca++, Mg++) and collected in PBS with 0.02% of EDTA. The cells were separated by centrifugation at 500 g for 10 minutes at 4°C, washed with PBS and centrifuged (500 g, 10 min at 4°C). To use the sediments were stored at -80°C. To obtain a membrane thawed sediment cells resuspendable in very cold sucrose buffer (0.25 M sucrose, 10 mm Hepes (pH of 7.4), 1 mm phenylmethylsulfonyl (PMSF) in DMSO, 5 µg/ml pepstatin-A, 3 mm EDTA, 0.025% bacitracin) and homogenized using an ultrasonic disintegrator Branson Sonifier W-250 (installed on the cage: timer 4; o 3; constant activation time: 2-3 cycles). The destruction of the cells was controlled by means of a microscope. The remaining intact cells were besieged by centrifugation at 1000 g for 10 minutes at 4°C. the Supernatant sucrose buffer and then centrifuged at 60000 g for 1 hour at 4°C (Beckman Ultrazentrifuge XL 80). Sediment resuspendable in 30 ml of very cold Tris buffer (20 mm Tris (pH of 7.4), 5 µg/ml pepstatin A, 0.1 mm PMSF, 3 mm EDTA) by unearth through serological pipette with a volume of 10 ml and centrifuged for 1 hour at 4°C for up to 60000 g. The final re-suspension was performed in a small volume of very cold Tris buffer (see above by punching through serological pipette and then ultrasonic treatment using ultrasonic disintegrator Branson Sonifier W-250 (installed on the cage: timer 1; output control 3; constant duty cycle: 1 cycle). Determined the protein concentration (set BCA Kit; Pierce) and aliquots were stored at -80°C or in liquid nitrogen for a long time.

2. Experiments on the binding of receptor

All experiments on receptor binding was carried out in a suitable buffer for analysis in a total volume of 200 μl in the presence of various concentrations of the test compounds (10-5M to 10-9M, a serial tenfold dilution, dual definition). The study was ended by filtering on tablets Packard Unifilter Plates (GF/C or GF/B) pre-soaked polyethylenimine (PEI of 0.1% or 0.3%) using the collector Mach III firm Tomtec to collect cells from the 96-well plate. After drying of the tablets for 2 hours at 55°C in a drying chamber, was added to scintillation cocktail (BetaPlate Scint; PerkinElmer). Radioactivity was measured by scintillation counter Microbeta Ttilux two hours after addition of scintillation mixture. Data obtained liquid scintillation measurement activity, were processed using an iterative nonlinear regression analysis using the statistical analysis system (SAS): a program similar to the program "LIGAND", as described in the publication Munson and Rodbard, Analytical Biochemistry, 107, 220-239 (1980).

a) the Study has been the project of the receptor 5-HT 6

HEK293 cells stably expressing the receptor h-5-HT6(NCBI Reference Sequence XM 001435), were cultured in RPMI1640 medium, supplemented with 25 mm HEPES, 10% fetal calf serum and 1 to 2 mm glutamine. The membrane preparation was performed as described in section 1. For these membranes was determined KDat 1.95 nm [3H]-LSD (lysergic acid diethylamide; Amersham, TRK1038) using experiments on saturation binding. The day of the test membranes were thawed, diluted with buffer to the study (50 mm Tris-HCl, 5 mm CaCl2, of 0.1% ascorbic acid, 10 μm of pargyline, pH of 7.4) to a concentration of 8 μg protein/research and homogenized by intensive mixing. For studies of inhibition of 1 nm of [3H]-lysergic acid diethylamide incubated in the presence of various concentrations of the test compound in the buffer for the study. Nonspecific binding was determined using 1 μm methiothepin. The binding reaction was carried out for 3.5 hours at room temperature. During incubation, the tablets were shaken on a plate shaker at 100 rpm and finished filtering on tablets Packard Unifilter GF/C (in 0.1% PEI), and then performed 2 cycles rinse with very cold 50 mm Tris-HCl, 5 mm CaCl2.

a) investigation of the binding of the dopamine D2receptor

HEK293 cells stably expressing adaminaby D 2receptor (NCBI Reference Sequence NM_000795), were cultured in RPMI1640 medium, supplemented with 25 mm HEPES, 10% fetal calf serum and 1 to 2 mm glutamine. The membrane preparation was performed as described in section 1. For these membranes was determined KDwhen 0,22 nm [125I]-ispiron (PerkinElmer Life Sciences, NEX284) using experiments on saturation binding. The day of the test membranes were thawed, diluted with buffer to the study (50 mm Tris-HCl, 120 mm NaCl, 5 mm MgCl2, 5 mm KCl, 1.5 mm CaCl2, a pH of 7.4) to a concentration of 15 μg protein/research and homogenized by intensive mixing. For inhibition studies, 0.01 nm [125I]-ispiron (PerkinElmer Life Sciences, NEX284) were incubated in the presence of various concentrations of the test compound in the buffer for the study. Nonspecific binding was determined using 1 μm haloperidol. The binding reaction was carried out for 1 hour at room temperature and stopped by filtration on tablets Packard Unifilter GF/C (in 0.1% PEI), then carried out 6 wash cycles with very cold 7% solution of polyethylene glycol.

b) investigation of the binding of α1-adrenergic receptor

CHO-K1cells stably expressing α1-adrenergic receptor (NCBI Reference Sequence NM_033303), were cultured in RPMI1640 medium, supplemented with 25 mm HEPES, 10% fetal calf savor is rigid and 1-2 mm glutamine. The membrane preparation was performed as described in section 1. For these membranes was determined KDwhen 0,12 nm [3H]-prazosin (PerkinElmer Life Sciences, NET823) using experiments on saturation binding. The day of the test membranes were thawed, diluted with buffer to the study (50 mm Tris-HCl, pH of 7.4) to a concentration of 4 μg protein/research and homogenized by intensive mixing. For studies of inhibition of 0.1 nm [3H]-prazosin (PerkinElmer Life Sciences, NET823) were incubated in the presence of various concentrations of the test compound in the buffer for the study. Nonspecific binding was determined using 1 μm fentolamina. The binding reaction was carried out for 1 hour at room temperature and stopped by filtration on tablets Packard Unifilter GF/C (in 0.1% PEI), then was carried out by 3 cycles of washing with very cold buffer for research.

c) investigation of the binding of histamine H1receptor

CHO-K1cells stably expressing the histamine H1receptor (Euroscreen-ES-390-C, NCBI Reference Sequence NM_000861), were cultured in RPMI1640 medium, supplemented with 25 mm HEPES, 10% fetal calf serum and 1 to 2 mm glutamine. The membrane preparation was performed as described in section 1. For these membranes was determined KDwhen 0,83 nm [3H]-pyrilamine (PerkinElmer Life Sciences, NET594) using the experimental is now by saturation binding. The day of the test membranes were thawed, diluted with buffer to the study (50 mm Na2HPO4, 50 mm KH2PO4, a pH of 7.4) to a concentration of 6 μg protein/research and homogenized by intensive mixing. For studies of inhibition of 1 nm of [3H]-pyrilamine (PerkinElmer Life Sciences, NET594) were incubated in the presence of various concentrations of the test compound in the buffer for the study. Nonspecific binding was determined using 1 μm of pyrilamine. The binding reaction was carried out for 50 minutes at room temperature and stopped by filtration on tablets Packard Unifilter GF/C (with 0.3% PEI), and then performed 2 cycles rinse with very cold buffer for research.

3. Data analysis

Data obtained liquid scintillation measurement activity, were processed using an iterative nonlinear regression analysis using the statistical analysis system (SAS): a program similar to the program "LIGAND", as described in the publication Munson and Rodbard, Anal. Biochem. 1980, 107, 220-239. The approximation was carried out in accordance with the formulas described in the publication Feldman, Anal. Biochem. 1972, 48, 317-338). The value of the IC50, nH and Kiwere expressed as geometric mean values. For test compounds with low affinity to the receptor when the highest concentration tested is Obedinenie inhibited less than 30% of specific radioligand binding, values of Kidetermined by the equation of Cheng-Prusoff (Biochem. Pharmacol. 1973, 22, 2099-2108) and was expressed as greater than (>)".

The results of the study of the binding of the receptor expressed in the form described above binding constant of receptor Ki(5-HT6), Ki(D2), Ki1-adrenergic) and Ki(H1), respectively, which are shown in table I.

In these tests, the compounds according to the invention show a very high affinity towards the receptor 5-HT6(Ki<500 nm or <100 nm or <50 nm or <20 nm and often <10 nm). In addition, these compounds selectively bind the receptor 5-HT6compared with affinato in relation to the receptors D2α1-adrenergic or H1. These compounds exhibit low affinity for receptors D2α1-adrenergic or H1(Ki>500 nm or >1000 nm and often >10000 nm).

Example 1: Ki(5-HT6)<10 nm

Example 5: Ki(5-HT6)<50 nm

Example 6: Ki(5-HT6)<50 nm

Example 7: Ki(5-HT6)<50 nm

Sample 8: Ki(5-HT6)<500 nm

Example 9: Ki(5-HT6)<500 nm

Example 10: Ki(5-HT6)<50 nm

Example 11: Ki(5-HT6)<500 nm

Example 12: Ki(5-HT6)<50 nm

Example 13: Ki(5-HT6)<50 nm

Example 14: Ki(5-HT6 )<100 nm

Example 15: Ki(5-HT6)<500 nm

Example 16: Ki(5-HT6)<500 nm

Example 17: Ki(5-HT6)<10 nm

Example 18: Ki(5-HT6)<10 nm

Example 24: Ki(5-HT6)<10 nm

Example 25: Ki(5-HT6)<10 nm

Example 26: Ki(5-HT6)<10 nm

Example 27: Ki(5-HT6)<50 nm

Example 28: Ki(5-HT6)<50 nm

Example 29: Ki(5-HT6)<10 nm

Example 30: Ki(5-HT6)<10 nm

Example 31: Ki(5-HT6)<50 nm

Example 32: Ki(5-HT6)<10 nm

Example 33: Ki(5-HT6)<10 nm

Example 34: Ki(5-HT6)<10 nm

Example 35: Ki(5-HT6)<10 nm

Example 36: Ki(5-HT6)<10 nm

Example 37: Ki(5-HT6)<10 nm

Example 38: Ki(5-HT6)<10 nm

Example 39: Ki(5-HT6)<500 nm

Example 40: Ki(5-HT6)<50 nm

Example 41: Ki(5-HT6)<10 nm

Example 42: Ki(5-HT6)<10 nm

Example 43: Ki(5-HT6)<500 nm

Example 45: Ki(5-HT6)<10 nm

Example 46: Ki(5-HT6)<10 nm

Example 47: Ki(5-HT6)<10 nm

Example 48: Ki(5-HT6)<10 nm

Example 49: Ki(5-HT6)<10 nm

Example 51: Ki(5-HT6)<10 nm

Example 52: Ki(5-HT6)<50 nm

Example 53: Ki(5-HT6)<10 nm

Example 54: Ki(5-HT6)<10 nm

i(5-HT6)<10 nm

Example 56: Ki(5-HT6)<50 nm

Example 57: Ki(5-HT6)<10 nm

Example 58: Ki(5-HT6)<10 nm

Example 59: Ki(5-HT6)<10 nm

Example 60: Ki(5-HT6)<10 nm

Example 61: Ki(5-HT6)<10 nm

Example 62: Ki(5-HT6)<10 nm

Example 63: Ki(5-HT6)<10 nm

Example 64: Ki(5-HT6)<10 nm

Example 65: Ki(5-HT6)<10 nm

Example 66: Ki(5-HT6)<10 nm

Example 67: Ki(5-HT6)<10 nm

Example 68: Ki(5-HT6)<10 nm

Example 69: Ki(5-HT6)<10 nm

Example 70: Ki(5-HT6)<10 nm

Example 71: Ki(5-HT6)<10 nm

Example 72: Ki(5-HT6)<10 nm

Example 73: Ki(5-HT6)<10 nm

Example 74: Ki(5-HT6)<50 nm

Example 75: Ki(5-HT6)<50 nm

Example 76: Ki(5-HT6)<50 nm

Example 77: Ki(5-HT6)<50 nm

Example 78: Ki(5-HT6)<50 nm

Example 79: Ki(5-HT6)<50 nm

Example 80: Ki(5-HT6)<50 nm

Example 81: Ki(5-HT6)<50 nm

Example 82: Ki(5-HT6)<10 nm

Example 83: Ki(5-HT6)<10 nm

Example 84: Ki(5-HT6)<50 nm

Example 85: Ki(5-HT6)<500 nm

Example 86: Ki(5-HT6)<500 nm

Example 87: Ki(5-HT6)<50 nm

Example 88: Ki(5-HT6 )<500 nm

Example 89: Ki(5-HT6)<10 nm

Example 90: Ki(5-HT6)<50 nm

Example 91: Ki(5-HT6)<50 nm

Example 92: Ki(5-HT6)<10 nm

Example 93: Ki(5-HT6)<10 nm

Example 94: Ki(5-HT6)<10 nm

Example 95: Ki(5-HT6)<10 nm

Example 96: Ki(5-HT6)<50 nm

Example 97: Ki(5-HT6)<10 nm

Example 98: Ki(5-HT6)<50 nm

Example 99: Ki(5-HT6)<500 nm

Example 100: Ki(5-HT6)<10 nm

Example 101: Ki(5-HT6)<10 nm

3. Determination of metabolic stability

The metabolic stability of compounds of the invention was determined using the following research by the determination of microsomal half-life. Subjects substances incubated at a concentration of 0.5 micron as follows:

0.5 µm test substance pre-incubated with liver microsomes of different species (0.25 mg protein/ml) in 0.05 M buffer of potassium phosphate pH 7.4 in titration microplate at 37°C for 5 minutes. The reaction is initiated by adding NADPH (restored nicotinamide-dinucleotides) (1 mg/ml). Selected aliquots of 0, 5, 10, 15, 20 and 30 minutes and the reaction stopped with a same volume of acetonitrile and cooled. The concentration of the remainder of the test compounds to determine whether n is a power of liquid chromatography / mass spectrometry. The values clearance calculated using a rate constant of elimination of the test compounds.

1. N-Phenyl(piperazinil or homopiperazine)benzosulfimide or benzosulfimide(piperazine or homopiperazine) of the formula (I) or (I')


where
X is a chemical bond or a group N-R4;
R1is hydrogen or stands;
R2is hydrogen or stands;
R3is hydrogen, C1-C3the alkyl, fluorine,1-C2alkoxy or fluorinated C1-C2alkoxy;
R4is hydrogen, C1-C4the alkyl or C3-C4cycloalkyl-CH2-;
R5is hydrogen, fluorine, chlorine, C1-C2the alkyl, C1-C2alkoxy or fluorinated C1-C2alkoxy;
R6is hydrogen and
n is 1 or 2,
or their physiologically acceptable salt accession acid.

2. Connection on p. 1, where R5is hydrogen, fluorine,1-C2the alkyl, C1-C2alkoxy or fluorinated C1-C2alkoxy.

3. Connection under item 1 or 2, where R1is hydrogen.

4. The compound according to any one of paragraphs.1 or 2, where R2is hydrogen.

5. The compound according to any one of the p. 1 or 2, where R2is stands.

6. The compound according to any one of paragraphs.1 or 2, where X is a group N-R4.

7. The compound according to any one of paragraphs.1 or 2, where n is 1.

8. The compound according to any one of paragraphs.1 or 2, where R3is stands or methoxy.

9. The compound according to any one of paragraphs.1 or 2, where R3is hydrogen or fluorine.

10. The compound according to any one of paragraphs.1 or 2, where R4is hydrogen, C1-C4the alkyl or cyclopropylmethyl.

11. Connection on p. 10, where R4is hydrogen.

12. The compound according to any one of paragraphs.1 or 2, where R5is hydrogen.

13. The compound according to any one of paragraphs.1 or 2, where R5is stands, methoxy or deformedarse.

14. The compound according to any one of paragraphs.1 or 2, where R5is chlorine or fluorine.

15. The compound according to any one of paragraphs.1 or 2, where R6is hydrogen.

16. The compound according to any one of paragraphs.1 or 2, where R5and R6are hydrogen, R3selected from the group consisting of C1-C2the alkyl and C1-C2alkoxy, and R4selected from the group consisting of hydrogen, C1-C4the alkyl and cyclopropylmethyl.

17. Connection on p. 1, where
X is a chemical bond or a group N-R4;
R1is hydrogen or stands;
R2one is by hydrogen;
R3is hydrogen, C1-C2the alkyl, C1-C2alkoxy;
R4is hydrogen, stands, ethyl, n-propylene, isopropyl or cyclopropylmethyl;
R5is hydrogen, stands or methoxy;
R6is hydrogen and
n is 1 or 2.

18. Connection on p. 17, where R3is stands.

19. Connection on p. 17 or 18, where R5is hydrogen.

20. Connection on p. 17, 18 or 19, where R4is hydrogen.

21. Connection on p. 17, 18 or 19, where R1is hydrogen.

22. Connection on p. 17, 18 or 19, where X is a group N-R4.

23. Connection on p. 17, 18 or 19, where n is 1.

24. The compound according to any one of paragraphs.1 or 2, where OCHF2-radical in formula I is located on the benzene ring in the ortho-position relative to X.

25. The compound according to any one of paragraphs.1 or 2, where OCHF2-radical in formula I is located on the benzene ring in the meta position relative to X.

26. The compound according to any one of paragraphs.1 or 2, where OCHF2-radical in formula I is located on the benzene ring in the para-position relative to X.

27. Connection on p. 1, selected from the group consisting of
N-(3-Deformational)-4-methyl-3-piperazine-1-albenzaalbenza;
3-[1,4]Diazepan-1-yl-N-(3-deformational)-4-methylbenzenesulfonamide;
1-[5-(3-Deformationsvetsaren)-2-meth is fenil]piperazine;
N-(2-Deformational)-N-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(2-Deformational)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(3-Deformedarse-4-were)-4-methyl-3-piperazine-1-albenzaalbenza;
N-(4-Deformational)-4-methyl-3-piperazine-1-albenzaalbenza;
N-(2,2-Debtorrent[1,3]dioxol-4-yl)-4-methyl-3-piperazine-1-albenzaalbenza;
N-Cyclopropylmethyl-N-(2-deformational)-4-methyl-3-piperazine-1-albenzaalbenza;
N-Cyclopropylmethyl-N-(3-deformational)-4-methyl-3-piperazine-eventlistenertype;
N-(2-Deformational)-4-methyl-3-piperazine-1-yl-N-propylbenzenesulfonyl;
N-(3-Deformational)-4-methyl-3-piperazine-1-yl-N-propylbenzenesulfonyl;
N-(3-Deformational)-N-ethyl-4-methyl-3-piperazine-1-albenzaalbenza;
N-(3-Deformational)-4,N-dimethyl-3-piperazine-1-albenzaalbenza;
N-(2-Deformational)-N-ethyl-4-methyl-3-piperazine-1-albenzaalbenza;
N-(2-Deformational)-N-methyl-4-methyl-3-piperazine-1-albenzaalbenza;
N-(2-Deformational)-4-methyl-3-piperazine-1-albenzaalbenza;
N-(3-Deformedarse-4-were)-4-methoxy-3-piperazine-1-albenzaalbenza;
N-(4-Deformational)-4-methoxy-3-piperazine-1-albenzaalbenza;
3-[1,4]Diazepan-1-yl-N-(2-deformational)-4-methylbenzenesulfonamide;
3-[1,4]Diazepan-1-yl-N-(3-what aftermatket-4-were)-4-methylbenzenesulfonamide;
N-(2-Deformedarse-4-were)-4-methyl-3-piperazine-1-albenzaalbenza;
N-(2-Deformedarse-5-were)-4-methyl-3-piperazine-1-albenzaalbenza;
N-(3-Deformational)-4-methoxy-3-piperazine-1-albenzaalbenza;
N-(3-Deformedarse-4-methoxyphenyl)-4-methoxy-3-piperazine-1-albenzaalbenza;
N-(2-Deformational)-4-methoxy-3-piperazine-1-albenzaalbenza;
N-(2-Deformational)-4-methoxy-N-methyl-3-piperazine-1-albenzaalbenza;
N-(3-Deformedarse-4-methoxyphenyl)-4-methoxy-N-methyl-3-piperazine-1-albenzaalbenza;
N-(3-Deformational)-N-ethyl-4-methoxy-3-piperazine-1-albenzaalbenza;
N-(3-Deformedarse-4-methoxyphenyl)-N-ethyl-4-methoxy-3-piperazine-1-albenzaalbenza;
N-(2-Deformational)-N-ethyl-4-methoxy-3-piperazine-1-albenzaalbenza;
N-(3-Deformational)-4-methoxy-N-methyl-3-piperazine-1-albenzaalbenza;
N-(3-Deformedarse-4-methoxyphenyl)-4-methoxy-3-piperazine-1-yl-N-propylbenzenesulfonyl;
N-(3-Deformational)-4-methoxy-3-piperazine-1-yl-N-propylbenzenesulfonyl;
N-(3-Deformational)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(2-Deformational)-4-methoxy-3-(4-methylpiperazin-1-yl)propylbenzenesulfonyl;
N-(3-Deformedarse-4-methoxyphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(2-Deformational)-N-isopr the MPI-4-methyl-3-piperazine-1-albenzaalbenza;
N-(2,2-Debtorrent[1,3]dioxol-4-yl)-4-methoxy-3-piperazine-1-albenzaalbenza;
N-(2-Deformational)-3-piperazine-1-albenzaalbenza;
N-(2-Deformational)-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(2-Deformational)-N-methyl-3-piperazine-1-albenzaalbenza;
N-(2-Deformational)-N-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide;
1-[3-(3-Deformationsvetsaren)phenyl]piperazine;
1-[3-(3-Deformationsvetsaren)phenyl]-4-methylpiperazine;
1-[5-(3-Deformationsvetsaren)-2-methoxyphenyl]piperazine;
1-[5-(3-Deformationsvetsaren)-2-methoxyphenyl]-4-methylpiperazine;
1-[5-(3-Deformedarse-4-methoxybenzenesulfonyl)-2-methoxyphenyl]piperazine;
N-(2-Deformedarse-5-were)-4-ethoxy-3-piperazine-1-albenzaalbenza;
N-(3,4-Bis-deformational)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(3,4-Bis-deformational)-4-methyl-3-piperazine-1-albenzaalbenza;
N-(5-Chloro-2-deformational)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(2-Deformedarse-5-were)-4-ethyl-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(5-Deformedarse-2-were)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(5-Chloro-2-deformational)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(5-Chloro-2-deformational)-4-methoxy-3-piperazine-albenzaalbenza;
N-(5-Deformedarse-2-were)-4-methyl-3-piperazine-1-albenzaalbenza;
N-(5-Deformedarse-2-were)-4-methoxy-3-piperazine-1-albenzaalbenza;
N-(3,4-Bis-deformational)-4-methoxy-3-piperazine-1-albenzaalbenza;
N-(5-Chloro-2-deformational)-4-ethyl-3-piperazine-1-albenzaalbenza;
N-(2-Deformedarse-4-were)-4-ethyl-3-piperazine-1-albenzaalbenza;
N-(2-Deformedarse-5-were)-4-methyl-3-((R)-3-methylpiperazin-1-yl)benzosulfimide;
N-(2-Deformedarse-5-were)-4-methyl-3-((S)-3-methylpiperazin-1-yl)benzosulfimide;
N-(2-Deformedarse-5-were)-4-ethyl-3-piperazine-1-albenzaalbenza;
N-(2,2-Debtorrent[1,3]dioxol-5-yl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(2-Deformedarse-5-were)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(3-Deformational)-3-piperazine-1-albenzaalbenza;
N-(2-Deformedarse-4-forfinal)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(2-Deformedarse-4-were)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(5-Chloro-2-deformational)-4-methyl-3-piperazine-1-albenzaalbenza;
N-(2-Deformedarse-5-were)-4-methoxy-3-piperazine-1-albenzaalbenza;
N-(2-Deformedarse-4-were)-4-methoxy-3-piperazine-1-albenzaalbenza;
N-(2-Deformedarse-4-forfinal)-4-methyl-3-piperazin-albenzaalbenza;
N-(3-Deformedarse-4-were)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(4-Deformedarse-3-methoxyphenyl)-4-methyl-3-piperazine-1-albenzaalbenza;
N-(5-Deformedarse-2-methoxyphenyl)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(2-Deformedarse-5-methoxyphenyl)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(2-Deformedarse-4-forfinal)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(5-Deformedarse-2-methoxyphenyl)-4-methyl-3-piperazine-1-albenzaalbenza;
N-(2-Deformedarse-5-methoxyphenyl)-4-methyl-3-piperazine-1-albenzaalbenza;
N-(2-Deformedarse-4-forfinal)-4-methoxy-3-piperazine-1-albenzaalbenza;
N-(2,2-Debtorrent[1,3]dioxol-5-yl)-4-methoxy-3-piperazine-1-albenzaalbenza;
N-(2,2-Debtorrent[1,3]dioxol-5-yl)-4-methyl-3-piperazine-1-albenzaalbenza;
N-(3-Deformedarse-4-methoxyphenyl)-4-methyl-3-piperazine-1-albenzaalbenza;
N-(3-Deformedarse-4-methoxyphenyl)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(4-Deformedarse-3-were)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(4-Deformational)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(3-Deformedarse-4-were)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(4-Deformedarse-3-methoxyphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(2-WPPT is ormaetxe-4-were)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(2-Deformedarse-5-were)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(4-Deformedarse-3-methoxyphenyl)-4-methoxy-3-piperazine-1-albenzaalbenza;
N-(3-Deformational)-4-methyl-3-(4-methylpiperazin-1-yl)benzosulfimide;
N-(4-Deformational)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide;
3-[1,4]Diazepan-1-yl-N-(3-deformational)-4-methylbenzenesulfonamide;
3-[1,4]Diazepan-1-yl-N-(2-deformational)-4-methylbenzenesulfonamide;
3-[1,4]Diazepan-1-yl-N-(3-deformedarse-4-were)-4-methylbenzenesulfonamide;
N-(3-Deformedarse-4-were)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)benzosulfimide;
N-(2-Deformational)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)benzosulfimide;
N-(3-Deformational)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)benzosulfimide;
N-(5-Deformedarse-2-were)-4-deformedarse-3-piperazine-1-albenzaalbenza;
N-(5-Deformedarse-2-were)-4-deformedarse-N-methyl-3-piperazine-1-albenzaalbenza;
N-(5-Deformedarse-2-were)-4-fluoro-3-piperazine-1-albenzaalbenza;
N-(5-Deformedarse-2-were)-4-fluoro-N-methyl-3-piperazine-1-albenzaalbenza,
and their physiologically-tolerated acid additive salts.

28. Connection on p. 27, which represents an
1-[5-(3-Deformationsvetsaren)-2-methoxyphenyl]piperazine
or fisiologicas and tolerable acid additive salt.

29. Connection on p. 27, which represents an
N-(2-Deformedarse-4-forfinal)-4-methoxy-3-(4-methylpiperazin-1-yl)benzosulfimide
or its physiologically tolerable acid additive salt.

30. Connection on p. 27, which represents an
N-(2-Deformedarse-5-were)-4-methoxy-3-piperazine-1-albenzaalbenza
or its physiologically tolerable acid additive salt.

31. Connection on p. 27, which represents an
N-(2-Deformedarse-4-were)-4-methoxy-3-piperazine-1-albenzaalbenza
or its physiologically tolerable acid additive salt.

32. Connection on p. 27, which represents an
N-(2-Deformedarse-4-forfinal)-4-methoxy-3-piperazine-1-albenzaalbenza
or its physiologically tolerable acid additive salt.

33. The compound according to any one of paragraphs.1 or 27 for use in therapy for the treatment of diseases that respond to modulation NT6the receptor.

34. Pharmaceutical composition for treating diseases that respond to modulation NT6receptor, comprising at least one compound according to any one of paragraphs.1-27 optionally together with at least one physiologically acceptable carrier or auxiliary substance.

35. The compound according to any one of paragraphs.1 or 27 for use in the treatment of disorders of wybrand the th of diseases of the Central nervous system, diseases associated with harmful addiction, or obesity.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives, possessing properties of inhibiting activity of receptor of kinase insertion domain (KDR), or their pharmaceutically acceptable salts. In formula (1): each of X and Y independently represent O, NR, where R represents H; Z represents CR', where R' represents H or halogen; V, U and T together represent or each of R1, R2, R3, R4 and R6 independently represent H, halogen, cyano, C1-10alkyl; R5 values are given in the invention formula; R7 represents C1-10alkyl.

EFFECT: invention also relates to method of treating angiogenesis-associated disorder such as cancer or age-related macular degeneration.

16 cl, 318 ex

FIELD: chemistry.

SUBSTANCE: compounds of formula (1) are described, where substitutes are as defined in the formula of invention. Methods of obtaining formula (1) compounds are described, when n equals 0. Described also is a fungicide composition based on formula (1) compounds and a phytopathogenic fungus control method which uses compounds in paragraph 1 or a composition based on the said compounds.

EFFECT: obtaining compounds with fungicide properties.

17 cl, 60 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: carboxylic acid compounds are presented by formula (I) where R1 represents (1) hydrogen atom, (2) C1-4alkyl; E represents -CO-; R2 represents (1) halogen atom, (2) C1-6 alkyl, (3) trihalogen methyl; R3 represents (1) halogen atom, (2) C1-6alkyl; R4 represents (1) hydrogen atom; R5 represents (1) C1-6alkyl; represents phenyl; G represents (1) C1-6alkylene; represents 9-12-merous bicyclic heterocycle containing heteroatoms, chosen of 1-4 nitrogen atoms, one or two oxygen atoms; m represents 0 or an integer 1 to 4, n represents 0 or an integer 1 to 4, and i represents 0 or an integer 1 to 11 where R2 can be identical or different provided m is equal to 2 or more, R3 can be identical or different provided n is equal to 2 or more, and R5 can be identical or different provided i is equal to 2 or more; both R12 and R13, independently represent (1) C1-4alkyl, (2) halogen atom, (3) hydroxyl or (4) hydrogen atom, or R12 and R13 together represent (1) oxo or (2) C2-5alkylene and where provided R12 and R13 simultaneously represent hydrogen atom, carboxylic acid compound presented by formula (I), represents a compound chosen from the group including the compounds (1) - (32), listed in cl.1 of the patent claim. Besides the invention concerns a pharmaceutical composition based in the compound of formula I and to application of the compound of formula I for making the pharmaceutical composition.

EFFECT: there are produced new carboxylic acid derivatives with antagonistic activity with respect to DP receptor.

14 cl, 74 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel soluble pharmaceutical salts formed from salt-forming active compound of the general formula (I) or (II) and sugar substitute that can be used in preparing medicinal agents useful in pain and enuresis treatment. Salt-forming active substance represents a salt-forming compound among 1-phenyl-3-dimethylaminopropane compounds of the general formula (I) wherein X means -OH, F, Cl, H or group -OCOR6; R1 represents (C1-C4)-alkyl group; R2 represents H or (C1-C4)-alkyl group; R3 represents H or (C1-C4)-alkyl group with a direct chain, or R2 and R3 form in common (C4-C7)-cycloalkyl group and if R5 means H then R4 represents group O-Z in meta-position wherein Z means H,(C1-C3)-alkyl, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl), -CONH-C6H4-(C1-C3-alkyl), -CO-C6H4-R7 wherein R7 represents -OCO-C1-C3-alkyl in ortho-position or group -CH2N(R8)2 in meta- or para-position and wherein R8 means (C1-C4)-alkyl or 4-morpholino-group, either R4 represents S-(C1-C3)-alkyl in meta-position, meta-Cl, meta-F, group -CR9R10R11 in meta-position wherein R9, R10 and R11 mean H or F, group -OH in ortho-position, O-(C2-C3)-alkyl in ortho-position, para-F or group -CR9R10R11 in para-position wherein R9, R10 and R11 mean H or F, or if R5 means Cl, F, group -OH or O-C1-C3-alkyl in para-position then R4 means Cl, F, group -OH or O-(C1-C3)-alkyl in meta-position, or R4 and R5 form in common group 3,4-OCH=CH- or OCH=CHO-; R6 means (C1-C3)-alkyl, or salt-forming active substance represents a salt-forming compound among 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula (II) wherein R1' represents H, -OH, Cl or F; R2' and R3' have similar or different values and represent H, (C1-C4)-alkyl, benzyl, -CF3, -OH, -OCH2-C6H5, O-(C1-C4)-alkyl, Cl or F under condition that at least one among radicals R2' either R3' means H; R4' represents H, -CH3, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl, -CO-NH-C6H4-(C1-C3)-alkyl, -CO-C6H4-R5', CO-(C1-C5)-alkyl), -CO-CHR6'-NHR7' or unsubstituted either substituted pyridyl, thienyl, thiazolyl or phenyl group; R5' represents -OC(O)-(C1-C3)-alkyl in ortho-position or -CH2N(R8')2 in meta- or para-position and wherein R8' means (C1-C4)-alkyl, or both radicals R8' in common with nitrogen atom (N) form 4-morpholino-group, and R6' and R7' have similar or different values and represent H or (C1-C6)-alkyl under condition that if both radicals R2' and R3' represent H then R4' doesn't mean -CH3 when R1' represents additionally H, -OH or Cl, either R4' doesn't mean H when R1' represents additionally -OH. Also, invention relates to a medicinal agent based on indicated salts.

EFFECT: valuable medicinal properties of salts and drug.

14 cl, 1 tbl, 8 ex

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

The invention relates to compounds of General formula I

including their optical isomers and mixtures of such isomers, where r1denotes hydrogen, C1-C6alkyl, C3-C6cycloalkyl or aryl, optionally substituted by 1-3 halogen atoms, R2and R3each independently of one another denote hydrogen or C1-C6alkyl, R4stands WITH1-C6alkyl or C3-C6quinil, R5, R6, R7and r8each denotes hydrogen and

,

r10denotes aryl, optionally substituted by 1-3 substituents selected from the group comprising halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl,1-WITH4haloalkoxy,1-C4alkoxy, C1-C4alkyl, C1-C6alkylthio,3-C6alkyloxy, nitro and C1-C6alkoxycarbonyl or optionally substituted heteroaryl representing aromatic kolicevo the t hydrogen, WITH1-C6alkyl or C3-C6quinil, R12denotes hydrogen or C1-C6alkyl, Z represents hydrogen,- CO-R16or-CO-COOR16and R16stands WITH1-C6alkyl, -CH2-CO - C1-C6alkyl or phenyl

FIELD: chemistry.

SUBSTANCE: in adamantane amino-derivatives of general formula (1), R=OH, R1=R2=R3=H, R4=C2H5, X=Cl, n=1 (I); R=Br, R1=R2=R3=H, R4=C2H5, X=Br, n=1 (II); R=OH, R1=R2=H, R3+R4=-CH2CH2CH2CH2-, X=Cl, n=1 (III); R=Br, R1=R2=H, R3+R4=-CH2CH2CH2CH2-, X=Br, n=1 (IV); R=OH, R1=R2=CH3, R3=R4=H, X=CI, n=1 (V); R=CH3, R1=-CH2OH, R2=R3=R4=H, X=Cl, n=1 (VI).

EFFECT: higher antiviral activity of derivatives towards influenza virus.

1 cl, 1 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention relates to novel compounds of formula or to its pharmaceutically acceptable salts, where n is 0 or 1; R1 represents H or F; R2 represents C1-4alkyl; R7 represents H or C1-4alkyl; and Z represents hydroxyl C1-6alkyl or C1-6alkoxycarbonyl, or 5- or 6-member heteroaromatic ring, which belongs to aromatic rings which have given number of atoms, of which at least one is N, O or S, the remaining being carbon atoms, and which also optionally has methyl substituting group. Invention also relates to pharmaceutical composition, to application of compounds, as well as to method of obtaining formula I compounds.

EFFECT: obtaining novel biologically active compounds, possessing activity of receptor 5-HT2A antagonists.

9 cl, 25 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 4-aminocyclohexanol of the general formula (I) being optionally as their physiologically acceptable salts and first of all physiologically compatible acids. In compound of the general formula (I) R1 and R2 mean independently of one another hydrogen atom (H) or (C1-C8)-alkyl that can be saturated or unsaturated but both R1 and R2 can't mean simultaneously H, or residues R1 and R form a ring in common and mean (CH2)3-6; R2 means unsubstituted phenyl or phenyl substituted with halogen atom that is added through saturated or unsaturated, branched or linear (C1-C4)-alkyl group; R4 means heteroaryl chosen from 5-membered heteroaryl wherein heteroatoms are chosen from nitrogen, oxygen or sulfur atoms and each of these atoms is condensed with benzene ring and means unsubstituted or monosubstituted (C1-C8)-alkyl; -CHR6R7, -CHR6-CH2R7, -CHR6-CH2-CH2R7, -CHR6-CH2-CH2-CH2R7 wherein R6 represents H; R7 represents phenyl that can be unsubstituted or mono- either multi-substituted with halogen atoms. Also, invention relates to a method for synthesis of compounds of the formula (I) and a medicinal agent based on thereof. Synthesized compounds can be sued for preparing a medicinal agent designated for treatment of pain being first of all acute, visceral, neuropathic or chronic pain, and to a medicinal agent designated for treatment of diseases mediated by function of ORL1-receptor, for example, such as fear state, epilepsy, cardiovascular diseases.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and drug.

10 cl, 1 tbl, 21 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to arylsulfonyl derivatives of the formula (I): , wherein Ar means naphthyl or phenyl substituted optionally with halogen atom or (C1-C6)-alkoxy-group; R1 means (C1-C6)-alkyl; R2 means hydrogen atom or (C1-C6)-alkyl, or their pharmaceutically acceptable salts or solvates. Proposed compounds show affinity to HT6 receptors. Also, the claim describes pharmaceutical compositions comprising indicated compounds, their using as therapeutic agents and a method for their preparing. Compounds can be useful in treatment of some disturbances in the central nervous system (CNS).

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

12 cl, 1 tbl, 12 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

The invention relates to omega-Amida N-arylsulfonamides formula I

and/or stereoisomeric forms of the compounds I and/or physiologically acceptable salts of the compounds I where R1means phenyl, phenyl, substituted once with halogen, the rest of the heterocycle of the following groups: morpholine, pyrrolidine; R2means N; R3means -(C1-C4)-alkyl-C(O)-N(R6)-R7where R6and R7together with the nitrogen to which they are bound, form a residue of formula IIa, IIe

moreover, in formula IIa, IIe q indicates an integer of zero or 1, Z denotes the carbon atom or a covalent bond, and R8means a hydrogen atom or halogen, or R3means -(C1-C4)-alkyl-C(O)-Y, where Y means the remainder of the formula IIC or IId

moreover, in formulas IIc and IId, R8means H or halogen, R9means H, or R3means -(C1-C4)-alkyl-C(O)-N(R9)-(CH2)about-N(R4)-R5and R9has the above values, means the integer 2 and R is substituted by-O-, And means covalent bond, B means -(CH2)m- where m is zero, X is-CH=CH-

FIELD: chemistry.

SUBSTANCE: present invention relates to fluorinated compounds of formula , where: D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more halogen atoms; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: halogen, C1-C10 alkyl; E denotes aryl which can be substituted with one or more fluoro-substitutes or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more fluoro-substitutes, and where Q denotes O; m denotes a number from 1 to 2; under the condition that: R3 is a fluoro-substitute, or group E includes a fluoro-substitute, or group Z includes a fluoro-substitute, with the condition that E does not denote 4-fluorophenyl or a compound of formula , where D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more of the following substitutes: chlorine, bromine, iodine; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: chlorine, bromine, iodine, C1-C10 alkyl; E denotes aryl which can be substituted with one or more chlorine, bromine or iodine atoms, and/or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more substitutes selected from chlorine, bromine, iodine or hydroxy, where Q denotes O, wherein when E denotes phenyl, E does not contain, as a substitute, iodine which is directly bonded to it at position 4; m denotes a number from 1 to 2; wherein at least one of Z, E and R3 includes iodine; under the condition that E does not denote 4-iodophenyl and under the condition that said compound is not a compound of formula (Ia), defined in the following table:

The invention also relates to a pharmaceutical composition based on the compound of formula (I) or (Ia), a diagnosis method, a method of treating said disorders, based on use of the compound of formula (I) or (Ia), and use of the compound of formula (I) or (Ia).

EFFECT: obtaining novel compounds useful in treating disorders in mammals, characterised by anomalous density of peripheral benzodiazepine receptors.

24 cl, 13 dwg, 9 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of the formula I

, where: m equals 0, 1 or 2, where if m=0, disappears such that an open ring or single bond forms, n equals 0, 1 or 2, wherein when n=0, disappears such that an open ring or single bond forms; m' and n' are independently equal to 0, 1 or 2; X denotes a carbon atom; Y denotes a carbon or sulphur atom; provided that m and n are not equal to 0 at the same time; denotes a single or double bond, if needed; --- absence of a bond or a single bond, if needed; R1 is selected from a group comprising CN, Hal, OAIk, OH, NRCN, C(CN)=C(OH)(OAlk), SR, NRR', (Alk)p-C(O)NRR', piperidine, wherein Alk is optionally substituted with Hal or OAlk, where p=0 or 1; R3, R4, R5 and R6 are identical or different and are independently selected from a group comprising H, OAIk, Alk, Hal, OH; R2 is selected from a group comprising H and O, and p'=0 or 1; R7 is selected from a group comprising H, O, OH, N-OH, N-aryl, N-OAlk, N-O-aryl, N-O-Alk-aryl, N-NR-CONRR', N-O-CO-Alk, or 2 R7, bonded with the same Y, together form lioksalan; wherein said Alk is optionally substituted with OAlk, -CO-(NR-Alk-CO)p'-OAlk, and p'=0 or 1; R and R', which are identical or different, are independently selected from a group comprising H, and Alk; or pharmaceutically acceptable salt or optical isomer or diastereomer thereof, except those compounds for which: R3, R4, R5, R6=H, R1=CN, denotes a single bond, and denotes -C(=N-(2,4,6-trimethylphenyl))-, -C(=N-(2,6- dimethylphenyl))-, -C(=N-(2,6-diethylphenyl))-, -C(=N(2-methylphenyl))-, -C(=N(2-ethylphenyl))-, -C(=N-(2-trifluoromethylphenyl))-, -C(=N-(2-isopropylphenyl))-, -C(=N-phenyl)-, -C(=N-(naphthyl)- or -C(=O)-, -CH2-, or R3, R5, R6=H, R4=OMe, R1=CN, denotes a single bond, and denotes -C(=O)-, or R3, R4, R5, R6=H, R1=NH2, denotes a single bond, and denotes -CH2- or -CH2-CH2-; or R3, R4, R5, R6=H, R,=NH2, denotes -CH2- or -CH2-CH2-, and denotes a single bond. The invention also relates to a cysteine protease based pharmaceutical composition based on compounds of formula I, use of the compound of formula I to prepare a drug for inhibiting cysteine protease, for treating and preventing cancer, as well as inflammatory diseases and others.

EFFECT: novel compounds which can be used in medicine are obtained and described.

38 cl, 43 ex, 2 tbl

The invention relates to new derivatives of 1-piperazine-1,2-dihydroindeno and their acid additive salts which are active in relation to dopamine receptors in the Central nervous system, in particular are potential antagonists of dopamine receptors D, medicinal products containing these derivatives as active ingredients, and to the use of these derivatives in the treatment of diseases of the Central nervous system

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine, in particular to a composition, the application of the composition and a method of treating abuse with substances, causing painful addiction in a subject. The composition contains a carbamoyl compound, or its pharmaceutically acceptable salt, or an ester as an active ingredient and the method includes the introduction of a therapeutically effective quantity of the carbamoyl compound, or its pharmaceutically acceptable salt, or the ester.

EFFECT: composition is used for the treatment of abuse with substances, causing painful addiction in a subject, as well as to an improvement of behaviour associated with the abuse.

14 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present group of inventions refers to medicine, namely to psychiatrics and addictology, and concerns treating psychoactive substance dependence, particularly alcohol and nicotine addiction. That is ensured by administering a therapeutic agent containing an activated potentiated form of antibodies against the brain-specific S-100 protein and an activated potentiated form of antibodies to a human cannabinoid receptor, more preferentially to the human cannabinoid receptor type I.

EFFECT: method provides suppressing both physical and mental alcohol and nicotine addiction.

11 cl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to immunology, and can be used for treating drug abuse, industrial and domestic poisonings, and in man-induced disasters, etc. The invention represents a synthetic immunogen for the protection against toxic action of narcotic and psychoactive substances. The immunogen is presented in the form of a conjugate of a macromolecular carrier specified in: natural or artificial protein, oligo- and polypeptide, carbohydrate, lipid or nucleotide, and haptene - a narcotic or psychotropic compound, and additionally contains poly(4-nitrophenyl)acrylate covalently bond to the conjugate within the range of ratios 2 to 7 moles of the conjugate per one mole of poly(4-nitrophenyl)acrylate with the ratio of haptene and the macromolecular carrier in the conjugate makes 2-17 moles of haptene per 1 mole of the carrier.

EFFECT: using this invention leads to eliciting a stable immune response for a long period of time and providing the body protection against toxic action of the narcotic and psychotropic substances by produced specific haptene antibodies.

3 cl, 4 tbl, 29 ex

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