[4-(heteroaryl)piperazine-1-yl]-(2,5-substituted phenyl)methanone derivatives as glycine-1 (glyt-1) carrier inhibitors for treating neurologic and psychoneurological diseases

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula I and to their pharmaceutically acceptable acid addition salts. The compounds of the present invention exhibit the properties of glycine carrier 1 (GlyT-1) inhibitors. In formula I , R1 represents -OR1', -SR1' or morpholinyl; R1' represents lower alkyl, halogen-substituted lower alkyl, or represents -(CH2)n-lower cycloalkyl; R2 represents -S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2 or CN; X1 represents CR3 or N; X2 represents CR3' or N; R3/R3' independently represent hydrogen, halogen, lower alkyl, CN, NO2, -S(O)2-phenyl, -S(O)2-lower alkyl, -S(O)2-pyridine-2, 3 or 4-yl, phenyl optionally substituted with one or two substitutes specified from the group consisting of NO2 or halogen, or represent halogen-substituted lower alkyl, or represent -C(O)-lower alkyl; n has a value of 0, 1 or 2. The invention also concerns a drug containing one or more compounds of the invention and pharmaceutically appropriate excipients.

EFFECT: preparation of the compounds exhibiting the properties of glycine carrier inhibitors.

20 cl, 1 tbl, 133 ex

 

The present invention relates to compounds of General formula

,

where

R1represents-OR1', -SR1'or is geterotsyklicescoe group;

R1'represents lower alkyl, lower alkyl substituted by halogen, or represents -(CH2)n-cycloalkyl;

R2represents-S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2or CN;

X1represents CR3or N;

X2represents CR3'or N;

R3/R3'independently of one another represent hydrogen, halogen, lower alkyl, CN, NO2, -S(O)2-phenyl, -S(O)2-lower alkyl, -S(O)2-pyridine-2 -, 3-or 4-yl, phenyl, possibly substituted by one or two substituents selected from the group consisting of NO2or halogen, or represents lower alkyl substituted by halogen, or represents-C(O)-lower alkyl;

n is 0, 1 or 2;

and their pharmaceutically acceptable salts accession acids.

The present invention relates to compounds of General formula I, to pharmaceutical compositions containing these compounds, and their use in the treatment of neurological and neuropsychiatric disorders. It has been unexpectedly found that compounds of General formula I ablauts is good inhibitors of the glycine vector 1 (GlyT-1) and that they have good selectivity for inhibitors of glycine vector 2 (GlyT-2).

Schizophrenia is a progressive and debilitating neurological disease characterized by episodic positive symptoms such as delusions, hallucinations, thought disorder and psychosis, and persistent negative symptoms such as blunted affect, impaired attention and social withdrawal, and cognitive impairment (Lewis D.A. and J.A. Lieberman, Neuron, 28: 325-33, 2000). For several decades, the study was focused on the hypothesis that dopaminergic hyperactivity disorder", which led to therapeutic interventions, including the blockade of the dopaminergic system (R.J. Vandenberg and Aubrey K.R., Exp. Opin. Ther. Targets, 5 (4): 507-518, 2001; Nakazato A. and S. Okuyama, et al., Exp. Opin. Ther. Patents, 10 (1): 75-98, 2000). This pharmacological approach is ill-suited to the treatment of negative and cognitive symptoms, which are the best indicators of functional outcome (Sharma T., Br. J. Psychiatry, 174 (suppl. 28): 44-51, 1999).

In the mid 1960's was proposed additional model of schizophrenia based on psychotomimetics action caused by blockade of glutamate system compounds such as phencyclidine (PCP) and related agents (ketamine), which are non-competitive antagonists of the NMDA receptor. Interestingly, in healthy volunteers PCP-induced psychotomimetic action includes positive and negatives is positive symptoms, as well as cognitive dysfunction and, thus, strongly resembles schizophrenia patients (Javitt D.C. et al., Biol. Psychiatry, 45: 668-679, 1999). In addition, transgenic mice expressing reduced levels of NMDAR1 subunit, show anomalies in behavior similar to those observed in pharmacologically induced models of schizophrenia, which confirms the model in which a decrease in the activity of the NMDA receptor leads to schizophrenic behavior (Mohn A.R. et al., Cell 98: 427-236, 1999).

Glutamic neurotransmission, in particular the activity of the NMDA receptor plays a key role in synaptic plasticity, learning and memory, namely NMDA receptors, apparently, serve as a differential switch for synchronization threshold synaptic plasticity and memory formation (Wiley N.Y.; Bliss T.V and G.L. Collingridge, Nature 361: 31-39, 1993). Transgenic mouse sverkhekspressiya NR2B-subunit of NMDA receptors, have shown an increased synaptic plasticity, better learning and better memory (Tang J.P. et al., Nature, 401: 63-69, 1999).

Thus, if the pathophysiology of schizophrenia involves a deficiency of glutamate, it can be expected that the increase in glutamate transmission, in particular through activation of the NMDA receptor, will be called as antipsychotic effects, and the effects of increasing cognitive function.

It is known that in the Central nervous system aminoxy the lot glycine has at least two important functions. By binding to the strychnine-sensitive glycine receptors, it acts as a brake amino acid, and acting as the main coagonist glutamate function of the receptor N-methyl-D-aspartate (NMDA), this amino acid also affects the excitatory activity. While glutamate released from synaptic endings depending on activity, glycine is present presumably at a more constant level and, apparently, modulating/controlling receptor to its response to glutamate.

One of the most effective ways to control synaptic concentrations of the neurotransmitter is to influence its reuptake at synapses. Vectors neurotransmitters act by removal of neurotransmitters from the extracellular space and can control their extracellular lifetime and thereby modulate the parameters of synaptic transmission (Gainetdinov R.R. et al., Trends in Pharm. Sci., 23 (8): 367-373, 2002).

Glycine vectors that belong to the sodium and Harizanova the family of vectors neurotransmitters play an important role in the termination of postsynaptic glycinergic impacts and the maintenance of low extracellular concentration of glycine by reuptake of glycine into the presynaptic nerve endings and in the nearby thin glial processes.

From the brain of mammals have been cloned two different gene glycine vectors (GlyT-1 and GlyT-2), which give rise to two vectors with approximately 50% homology of amino acid sequence. GlyT-1 is represented by four isoforms resulting from alternative splicing and alternative use of promoters (1A, 1b, 1C and 1d). Only two of these isoforms were found in the brain of rodents (GlyT-1A, GlyT-1b). GlyT-2 also shows a certain degree of heterogeneity. In the brain of rodents were identified two isoforms GlyT-2 (2A and 2b). It is known that GlyT-1 is localized in the CNS and in peripheral tissues, whereas GlyT-2 is specific to the CNS. GlyT-1 is predominantly glial distribution, and it is found not only in the areas corresponding to strichminuterie glycine receptors, but also outside these areas, where, as expected, he is involved in the modulation of the function of the NMDA receptor (Lopez-Corcuera In et al., Mol. Mem. Biol., 18: 13-20, 2001). Accordingly, one method of increasing the activity of the NMDA receptor consists in increasing the concentration of glycine in the local microenvironment of synaptic NMDA receptors by inhibiting carrier GlyT-1 (Bergereon R. et al., Proc. Natl. Acad. Sci. USA, 95: 15730-15734, 1998; Chen L. et al., J. Neurophysiol., 89 (2): 691-703, 2003).

Inhibitors of glycine vectors suitable for treating neurologist is mental and neuropsychiatric disorders. Most related illnesses are psychosis, schizophrenia (Armer RE and Miller DJ, Exp. Opin. Ther. Patents, 11 (4): 563-572, 2001), psychotic mood disorders such as major depressive disorder severe type, mood disorders associated with psychotic disorders such as acute manic syndrome or depression associated with bipolar disorders, and mood disorders associated with schizophrenia (Pralong ET et al., Prog. Neurobiol., 67: 173-202, 2002), autistic disorder (Carlsson M.L., J. Neural Trans. 105: 525-535, 1998), cognitive disorders such as dementia, including age-related dementia and senile dementia Alzheimers.com type, memory disorders in mammals, including humans, syndromes attention deficit, and pain (Armer R.E. and Miller D.J., Exp. Opin. Ther. Patents, 11 (4): 563-572, 2001).

Accordingly, the increased activation of NMDA receptors via inhibition of GlyT-1 can lead to agents that treat psychosis, schizophrenia, dementia and other diseases in which impaired cognitive processes, such as syndromes attention deficit or Alzheimer's disease.

The object of the present invention are the compounds of formula I per se, the use of compounds of the formula I and their pharmaceutically acceptable salts in the manufacture of medicaments for the treatment of diseases associated with activation of NMDA receptors pic what edstam inhibition of GlyT-1, receive them, the drugs based on the compounds according to the invention and their manufacture, as well as the use of compounds of formula I in the treatment or prevention of diseases such as psychoses, dysfunction in memory and learning, schizophrenia, dementia and other diseases in which impaired cognitive processes, such as syndromes attention deficit or Alzheimer's disease.

Preferred indications for the use of the compounds of the present invention is schizophrenia, a cognitive disorder, and Alzheimer's disease.

In addition, the invention includes all racemic mixtures, all corresponding enantiomers and/or optical isomers.

In the context of this description, the term "lower alkyl" means a saturated group with a normal or branched chain, containing from 1 to 7 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and the like. Preferred alkyl groups are groups with 1-4 carbon atoms.

In the context of this description, the term "cycloalkyl" means a saturated carbon ring, containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclopentyl or cycloheptyl.

The term "lower alkyl substituted by halogen"means a saturated group with a normal or branched chain, containing from 1 to 7 carbon atoms, such as the AK defined above, where one or more than one hydrogen atom substituted with halogen, for example-CF3, -CH2CF3, -CH2CF2CF3, -CH(CH3CF3- (CH3)2CF3or-CH(CF3)CH2CH3.

The term "halogen" means chlorine, iodine, fluorine and bromine.

The term "heteroseksualci" means a non-aromatic hydrocarbon radical, for example oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidine, pyrrolidine, piperidinyl, piperazinil, morpholinyl or thiomorpholine. Preferably morpholinyl.

The term "pharmaceutically acceptable salts join acid" includes salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, para-toluensulfonate acid and the like.

The present invention includes compounds of the following structures:

where the substituents are as described above.

Preferred compounds according to the present application are compounds of formula IA.

Especially preferred compounds of formula IA are with the organisations, in which R1is a OR1'and R1'represents lower alkyl, for example the following compounds:

[4-(5-benzazolyl-thiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon,

2-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazole-5-carbonitrile,

2-{4-[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoyl]-piperazine-1-yl}-thiazole-5-carbonitrile,

[4-(5-benzazolyl-thiazol-2-yl)-piperazine-1-yl]-[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-phenyl]-methanon,

[4-(5-benzazolyl-thiazol-2-yl)-piperazine-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanon,

{4-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-phenyl]-methanon,

(2-((R)-sec-butoxy)-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon,

(2-((S)-sec-butoxy)-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon or

(2 isopropoxy-5-methanesulfonyl-phenyl)-[4-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon.

Other preferred compounds of formula IA are compounds in which R1is a OR1'and R1'represents lower alkyl substituted by halogen, for example the following compounds:

2-{4-[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoyl]-piperazine-1-yl}-thiazole-5-to bontril,

{4-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,

[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-methyl-4-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon,

[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon,

[5-methanesulfonyl-2-(2,2,2-Cryptor-1,1-dimethyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon,

[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon,

[5-methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon,

[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-{4-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine-1-yl}-methanon,

[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-{4-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine-1-yl}-methanon,

[5-methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-{4-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine-1-yl}-methanon,

[5-econsultancy-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon,

[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon,

[5-methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(4-methyl-5-triptime the Il-thiazol-2-yl)-piperazine-1-yl]-methanon or

[5-methanesulfonyl-2-(2,2,3,3,3-pendaftar-propoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon.

Other preferred compounds of formula IA are compounds in which R1is a OR1'and R1'represents -(CH2)n-cycloalkyl, for example, the following connections:

2-[4-(2-cyclobutylmethyl-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazole-5-carbonitrile,

[4-(5-benzazolyl-thiazol-2-yl)-piperazine-1-yl]-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanon,

{4-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanon,

3-[4-(5-cyano-thiazol-2-yl)-piperazine-1-carbonyl]-4-cipointernet-N-methyl-benzosulfimide or

4 cyclopentyloxy-N-methyl-3-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-carbonyl]-benzosulfimide.

Other preferred compounds of formula IA are compounds in which R1represents SR1'for example, the following connection:

(2-isopropylphenyl-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon.

The compound of the formula IB where R1is a OR1'and R1represents lower alkyl, is

(2 isopropoxy-5-methanesulfonyl-phenyl)-[4-(3-phenyl-[1,2,4]thiadiazole-5-yl)-piperazine-1-yl]-methanon.

Soedinenieto IB, where R1is a OR1'and R1'represents (CH2)n-cycloalkyl, is

4 cyclopentyloxy-N-methyl-3-[4-(3-phenyl-[1,2,4]thiadiazole-5-yl)-piperazine-1-carbonyl]-benzosulfimide.

Compounds of formula IB where R1is a OR1'are, for example, the following connections:

(2 isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon,

(2 cyclopropylmethoxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon,

(2 isobutoxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon,

(5-methanesulfonyl-2-morpholine-4-yl-phenyl)-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon or

[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon.

These compounds of formula I and their pharmaceutically acceptable salts can be obtained in accordance with methods known in the art, for example in accordance with the techniques described below, which include

the interaction of the compounds of formula

with the compound of the formula

in the presence of an activating agent, such as TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetrameth uniterruptible),

with the formation of the compounds of formula

,

where X1and X2and the substituents R1and R2are as defined above,

and, if desired, the conversion of the compounds obtained into pharmaceutically acceptable salts accession acids.

The compounds of formula I can be obtained in accordance with one of the above methods and in accordance with the following schemes 1-7. The original substances either are commercially available or known from the chemical literature, or can be obtained in accordance with techniques well known in the art.

Compounds of General formula I can be obtained by reacting piperazine derivatives of the formula II with a suitable substituted acid of the formula III in the presence of activating agents such as TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylpropylenediamine), and bases, such as N-ethyldiethanolamine (Scheme 1).

Acid of the formula III can be obtained in different ways, shown in Schemes 2-5.

,

where X = halogen.

For example, the compounds of formula IIIa, where R1'represents lower alkyl, lower alkyl substituted by halogen, or -(CH2)n-cycloalkyl can be obtained at elevated temperatures by vzaimode istia halogen compounds of formula IV with an alcohol of formula R 1'OH, possibly in the presence of copper salts such as Cu(I)Br, and bases, such as triethylamine (Scheme 2).

Alternatively, the compounds of formula IIIa, where R1'represents lower alkyl, lower alkyl substituted by halogen, or -(CH2)n-cycloalkyl, can be obtained by interaction of hydroxycodone formula V with an alcohol of formula R1'OH, under the reaction conditions, Mitsunobu in the presence of a phosphine, such as triphenylphosphine or diphenyl-2-pyridyloxy, and dialkyldithiocarbamate, such as diethylazodicarboxylate (DEAD) or di-tert-utilisationbased, with the formation of intermediate compounds of formula VI and subsequent hydrolysis in the presence of aqueous base, such as potassium hydroxide, sodium hydroxide or lithium hydroxide (Scheme 3).

,

where X = halogen.

The compounds of formula IIIB, where R1'represents lower alkyl, lower alkyl substituted by halogen, or -(CH2)n-cycloalkyl can be obtained at elevated temperatures by reacting a halogen compound of the formula IV with a thiol of the formula R1'SH, possibly in the presence of a base such as cesium carbonate, potassium carbonate or sodium carbonate (Scheme 4).

where X = halogen.

The compounds of formula V, g is e R 1represents geterotsyklicescoe group containing an N atom, can be obtained at elevated temperatures by reacting a halogen compound of the formula IV with an amine of the formulapossibly in the presence of a base such as cesium carbonate, potassium carbonate or sodium carbonate (Scheme 5).

Halogen and hydroxylamine educt of the formula IV and V (shown in Schemes 2-5) are either commercially available or known from the chemical literature, or can be obtained using a number of techniques well known in the art.

hal = halogen

Y=H or a protective group (e.g. Boc)

Derivatives of piperazine of formula II can be obtained by heating piperazine with the corresponding halogen heterocyclic compound of the formula VII, possibly in the presence of palladianism catalyst (Scheme 6). Alternatively, the piperazine derivatives of the formula II can also be obtained by heating N-protected piperazine with the corresponding halogen heterocyclic compound of the formula VII, possibly in the presence of palladianism catalyst and subsequent removal of the protective group (Scheme 6). Typically, the protective group is a tert-butoxycarbonyl (Boc).

Halog nonamesandy heterocyclic compounds of formula VII are either commercially available, either known from the chemical literature, or can be obtained using a number of techniques well known in the art.

Y = protective group (e.g. Boc)

In the case when the heterocyclic compound of formula II is a derivative of thiazole, these compounds may be obtained by alternative, is shown in Scheme 7. Suitable substituted alpha-bromo-ketone, the compound of formula VIII, condense with Amida N-protected piperazine-1-thiocarbonic acid, a compound of formula IX. Then remove the protective group (e.g. Boc) with nitrogen and receive diazolidinyl piperazine, a compound of formula II.

In the case where the compounds of formula II contain reactive functional group (e.g. halide substituents, hydroxyl substituents, or carbonyl substituents) or latent reactive functional group (for example hidden carbonyl group or a masked hydroxyl group) in R3for the purpose of modification of the substituent R3can be added to the reaction either with compounds of the formula II, or with compounds of the formula I. Examples of such reactions include mutual transformations of functional groups (for example, changing the oxidation States in R3for example , when turning hidroxil the first Deputy in the carbonyl Deputy or thioester Deputy in sulfonovy Deputy), reactions of nucleophilic substitution (for example, in the case when R3there is a reactive halide Deputy), reaction mix, mediated ORGANOMETALLIC catalysts (for example the reaction of a combination of the Steele or Suzuki, in the case when R3there is a reactive halide Deputy), or of combination reaction, mediated stoichiometric reagents (such as Wittig reaction, in the case when R3there is a reactive carbonyl Deputy, or the exchange reaction of the halogen-metal with subsequent reaction with an electrophile, in the case when R3there is a reactive halide Deputy). Such reactions can be performed using a number of techniques well known in the art, and specific examples may be given by reference to the Examples given in this description below.

Isolation and purification of compounds

Isolation and purification of the compounds and intermediates described herein, can be performed, if desired, using any suitable methods of separation or purification, such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography, chromatography in a thick layer, preparative liquid chromatography low or you what the pressure will be about, or by combinations of these methods. Specific illustrations of suitable separation techniques, and selection can be given by reference to preparation examples and examples given in this description below. However, it can also be used, of course, other equivalent methods of separation or discharge. Racemic mixtures of chiral compounds of formula I can be separated using chiral ghvd (liquid chromatography high pressure).

Salts of compounds of formula I

The compounds of formula I may be the reason, for example, in cases where the remainder R1or R3/R3'contains a basic group, such as aliphatic or aromatic amine group. In such cases, the compounds of formula I can be converted into the corresponding salt accession acid.

This transformation is performed by processing at least a stoichiometric amount of a suitable acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, para-toluensulfonate acid, salicylic acid and the like. Usually the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and in the same solvent added acid. The temperature maintained within the range from 0°C to 50°C. the Obtained salt precipitates spontaneously or may be precipitated from a solution of the less polar solvent.

Salt accession of acids of the basic compounds of formula I can be converted into the corresponding free base by treating at least a stoichiometric equivalent of a suitable base, such as sodium hydroxide or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia and the like.

The compounds of formula I and their pharmaceutically acceptable salts accession possess useful pharmacological properties. Specifically, it was found that the compounds of the present invention are good inhibitors of the glycine vector I (GlyT-1).

These compounds have been investigated in accordance with the tests described in the present description below.

Solutions and substances

Complete DMEM: nutrient mixture F-12 (Gibco Life technologies), embryo the other calf serum (FBS) 5%, (Gibco life technologies), penicillin/streptomycin 1% (Gibco life technologies), hygromycin 0.6 mg/ml (Gibco life technologies), 1 mm glutamine (Gibco life technologies).

Buffer for capture (UB): 150 mm NaCl; 10 mm Hepes (N-2-hydroxyethylpiperazine-N'-2-econsultancy acid)-Tris, pH 7.4; 1 mm CaCl2; 2.5 mm KCl; 2.5 mm MgSO4; 10 mm (+)-D-glucose.

Cells Flp™-in-CHO (Invitrogen, Cat. No. R758-07), stable transfetsirovannyh mGlyT1b cDNA.

Analysis of inhibition capture glycine (mGlyT-1b)

On the first day of mammalian cells (Flp-in™-CHO), transfetsirovannyh mGlyT-1b cDNA, were seeded with a density of 40,000 cells/well in complete medium F-12 without hygromycin in 96-well culture plates. On the second day, the medium was aspirated and cells washed twice with a buffer for capture (UB). Then cells were incubated for 20 min at 22°With or without potential competing compounds (1), or with 10 mm non-radioactive glycine (2), or with the potential inhibitor in any concentration (3). In order to obtain data to calculate the concentration of inhibitor resulting in 50%increase inhibition (for example IR50concentration of competing compound providing 50%inhibition capture glycine)used a range of concentrations of potential inhibitors. Immediately after this was added a solution containing 60 nM [3H]-glycine (11-16 CI/mmol) and 25 μm non-radioactive glycine. The plates were incubated at AGCOM shaking, and the reaction was stopped by extraction of the mixture and washing (three times) cooled to 0°C UB. Cells were literally scintillation fluid was shaking for 3 hours, and the radioactivity of the cells was counted using a scintillation counter.

The preferred compounds show for GlyT-1 IR50(μm) in the range from 0,006-0,100, as shown in the table below.

Example No.IR50(µm)Example No.IR50(µm)Example No.IR50(µm)
40,061550,073790,067
100,082590,098800,046
140,083660,061810,044
160,06567 0,046840,076
190,043680,082930,075
290,017690,056990,021
300,023700,0571000,055
310,024710,0691010,026
390,070740,0311030,006
410,018770,100
420,046780,089

The compounds of formula I and pharmaceutically acceptable salts of compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. Data pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, it can also be done rectal administration, for example, in the form of suppositories, or parenteral administration, for example in the form of solutions for injection.

For the manufacture of pharmaceutical preparations of the compounds of formula I can be used together with pharmaceutically inert, inorganic or organic carriers. For example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules can be used lactose, corn starch or its derivatives, talc, stearic acid or its salts and the like. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. However, depending on the nature of the active substance in the case of soft gelatin capsules carriers usually are not required. Suitable carriers for the manufacture of solutions and syrups are, for example the EP, water, polyols, glycerine, vegetable oil, and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

Moreover, the pharmaceutical preparations can contain preservatives, soljubilizatory, stabilizing agents, moistening agents, emulsifiers, sweeteners, colorants, corrigentov, salts for regulating the osmotic pressure, buffer agents, masking agents or antioxidants. They can also contain other therapeutically useful substances.

Drugs, containing a compound of formula I or its pharmaceutically acceptable salt and a therapeutically inert carrier are also an object of the present invention, as the method of their production, which comprises bringing one or more than one compounds of formula I and/or pharmaceutically acceptable salts accession acids and, optionally, one or more than one other therapeutically useful substances to form Galanova drug together with one or more therapeutically inert carrier.

The most preferred indications in accordance with the present invention are those which include disorders of the Central nervous system, for example the treatment or prevention shiz is Freney, cognitive impairment and Alzheimer's disease.

Of course, the dosage can vary within wide limits and is generally in each case it should be selected in accordance with individual needs. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of the compounds of General formula I or the corresponding number of its pharmaceutically acceptable salts. The daily dose may be entered as a single dose or in the form of fractional doses, and, in addition, can also be exceeded when indicated.

The drug tablets (wet granulation)
ItemIngredientsmg tablet
5 mg25 mg100 mg500 mg
1.The compound of the formula I525100500
2.Lactose anhydrous DTG 12510530150
3.Sta-Rx 150066630
4.Microcrystalline cellulose303030150
5.Magnesium stearate1111
6.Only167167167831

The method of production

1. Substances 1, 2, 3 and 4 are mixed and granularit with purified water.

2. The granules are dried at 50°C.

3. The granules are passed through a suitable milling equipment.

4. Add substance 5, and stirred for three minutes; pressed on a suitable press.

Drug capsules
Item/td> Ingredientsmg tablet
5 mg25 mg100 mg500 mg
1.The compound of the formula I525100500
2.Lactose water159123148-
3.Corn starch25354070
4.Talc10151025
5.Magnesium stearate1225
6.Only 200200300600

The method of production

1. Substances 1, 2 and 3 are mixed in a suitable mixer for 30 minutes.

2. Add substances 4 and 5 and mix for 3 minutes.

3. Fill a suitable capsule.

The following examples illustrate the invention, but it is assumed that they do not limit its scope.

In the examples used the following abbreviations:

n-BOC-piperazine: tert-butyl 1-piperidinecarboxylate,

Oxone®: (monopersulfate potassium) 2KHSO5•KHSO4•K2SO4,

TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyleneglutaric.

Synthesis of intermediate compounds of formula III

Example A1

2 Isopropoxy-5-methanesulfonyl-benzoic acid

(a) 2-Chloro-5-methanesulfonyl-benzoic acid

To 99 mmol of 2-chloro-5-(methylthio)benzoic acid (purchased from Alcfrich) in 400 ml of methanol at 0°C was added 296 mmol Oxone®, and the mixture was allowed to mix at room temperature for 3.5 hours the Precipitate was filtered, and the filtrate was concentrated under reduced pressure. The residue was extracted 3 times with 400 ml of ethyl acetate, and the combined organic phases are washed twice with 300 ml of 1 N. HCl and 300 ml saturated aqueous NaCl and dried using MgSO4. In financial p is Tata evaporation under reduced pressure has been specified in the title compound, which was used in the next stage without additional purification.

(b) 2-Isopropoxy-5-methanesulfonyl-benzoic acid

A mixture of 2.13 mmol of 2-chloro-6-methanesulfonyl-benzoic acid, 0.64 mmol Cu(I)Br in 5 ml of triethylamine and 25 ml of isopropanol was heated to 120°C for 16 h in a hermetically sealed tube. Volatile components were removed under vacuum and the residue was transferred into 70 ml of 1 N. HCl. As a result of extraction with ethyl acetate, drying of the combined organic fractions and evaporation was obtained a residue, which was purified by obraniakowi preparative jhud with elution gradient acetonitrile/water. In the evaporation of the fractions containing the reaction product has been specified in the header connection. MS (mass/charge): 257,0 ([M-H]-, 100%).

Example A2

rat-5-Methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid

Was obtained in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1 (a)) and rat-1,1,1-Cryptor-propan-2-ol. The crude substance was purified by preparative Ehud obtaining specified in the title compounds as white solids. MS (mass/charge): 311,3 ([M-H]-, 100%).

Example A3

5-Methanesulfonyl-2-(2,2,2-Cryptor-ethoxy)-benzoic acid

Received analogues of the Sample A1 (b) from 2-chloro-6-methanesulfonyl-benzoic acid (Example A1 (a)) and 2,2,2-Cryptor-ethanol. The crude substance was purified by preparative Ehud obtaining specified in the title compounds as white solids. MS (mass/charge): 297,0 ([M-H]-, 100%).

Example A4

2 Cyclopentyloxy-5-methanesulfonyl-benzoic acid

Was obtained in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1 (a)) and Cyclopentanol. The crude substance was purified by flash chromatography to obtain specified in the title compound as a yellow solid. MS (mass/charge): 282,9 ([M-H]-, 100%).

Example A5

2 Cyclopropylmethoxy-5-methanesulfonyl-benzoic acid

Was obtained in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1 (a)) and cyclopropylmethanol. The crude substance was purified by flash chromatography to obtain specified in the title compounds as white solids. MS (mass/charge): 269,1 ([M-H]-, 100%).

Example A6

2 Cyclobutylmethyl-5-methanesulfonyl-benzoic acid

(a) 2-Cyclobutylmethyl-5-methanesulfonyl-benzoic acid methyl ester

The solution 6,51 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid methyl ester (WO 2002074774), 9,77 mmol of triphenylphosphine, 7,17 mmol of cyclobutylmethyl and 7,17 mm is eh di-tert-utilization.bacteria in 20 ml of THF (tetrahydrofuran) was stirred at 60°C for 2 hours. Then this reaction mixture was concentrated under vacuum and purified by column chromatography (SiO2) obtaining specified in the title compound as a pale yellow oil.

(b) 2-Temporalelement-5-methanesulfonyl-benzoic acid

To 6,51 mmol 2-cyclobutylmethyl-5-methanesulfonyl-benzoic acid methyl ester in 20 ml of tetrahydrofuran was added 40 mmol 2 N. aqueous NaOH solution, and this reaction mixture was stirred at 60°C for 2 hours. After this time the reaction mixture was acidified by adding concentrated HCl and was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue is triturated in diethyl ether to obtain specified in the title compound as a white solid (40% after two steps). MS (mass/charge): is 283.3 ([M-H]-, 100%).

Example A7

2 Cyclohexyloxy-5-methanesulfonyl-benzoic acid

Was obtained in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1 (a)) and cyclohexanol. The crude substance was purified by preparative Ehud obtaining specified in the title compounds as white solids. MS (mass/charge): 297,3 ([M-H]-, 100%).

P the emer A8

2 Isobutoxy-5-methanesulfonyl-benzoic acid

Was obtained in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1 (a)), and Isobutanol. The crude substance was purified by flash chromatography to obtain specified in the title compounds as white solids. MS (mass/charge): 271,1 ([M-H]-, 100%).

Example A9

2 CYCLOBUTANE-5-methanesulfonyl-benzoic acid

Was obtained in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1 (a)) and cyclobutanol. The crude substance was purified by preparative Ehud obtaining specified in the title compounds as white solids. MS (mass/charge): 269,3 ([M-H]-, 100%).

Example a10

Rat-2-Deut-Butoxy-5-methanesulfonyl-benzoic acid

Was obtained in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1 (a)) and rat-butane-2-ol. The crude substance was purified by preparative Ehud obtaining specified in the title compounds as white solids. MS (mass/charge): 271,4 ([M-H]-, 100%).

Example A11

2-(2,2-Dimethyl-propoxy)-5-methanesulfonyl-benzoic acid

Was obtained in analogy to Example A1 (b) from 2-chloro--methanesulfonyl-benzoic acid (Example A1 (a)) and 2,2-dimethyl-propane-1-ol. The crude substance was purified by preparative Ehud obtaining specified in the title compounds as white solids. MS (mass/charge): 285,1 ([M-H]-, 100%).

Example A12

2-tert-Butoxy-5-methanesulfonyl-benzoic acid

(a) 2-tert-Butoxy-5-methanesulfonyl-benzoic acid methyl ester

To a solution 2,17 mmol of methyl 5-(methanesulfonyl)-salicylate (WO 2002074774) in 5 ml of toluene was added 4,78 mmol N,N-dimethylformamide-di-tert-butylacetate, and this reaction mixture was stirred at 80°C for 1 hour. After this time the reaction mixture was concentrated under vacuum and purified by column chromatography to obtain specified in the title compounds as colorless oils. MS (mass/charge): 304,4 (M+NH4+, 100%).

(b) 2-tert-Butoxy-5-methanesulfonyl-benzoic acid

To 5,52 mmol 2-tert-butoxy-5-methanesulfonyl-benzoic acid methyl ester in 25 ml THF solution was added to 8.34 mmol monohydrate of lithium hydroxide in 25 ml of water, and this reaction mixture was stirred at room temperature for 4 hours. After this time the THF was removed under vacuum and the remaining aqueous solution was added 8 ml of 1 N. aqueous HCl, which resulted in precipitation of the compound. The precipitate was filtered and Promyshlennaya times with water to receive specified in the connection header (67%) as a white solid. MS (mass/charge): 289,9 (M+NH4+).

Example A13

5-Methanesulfonyl-2-morpholine-4-yl-benzoic acid

A mixture of 4.26 deaths mmol of 2-chloro-5-methanesulfonyl-benzoic acid (Example A1 (a)) in 8 ml of the research was heated at 110°C for 15 hours After evaporation of all volatiles the residue was acidified by adding 1 N. HCl and was extracted three times with ethyl acetate. The combined organic extracts were washed sequentially 1 N. HCl and saturated brine, dried over sodium sulfate and concentrated under vacuum to obtain specified in the title compound as a pale yellow amorphous solid (58%). MS (mass/charge): 284,1 ([M-H]-, 100%).

Example A14

5-Methanesulfonyl-2-(2,2,2-Cryptor-1,1-dimethyl-ethoxy)-benzoic acid

a) 2-Fluoro-5-methylsulfanyl-benzoic acid

Specified in the title compound was obtained in accordance with the method described in Journal of Organometallic Chemistry 1991, 419 (1-2), 1-8.

b) 2-Fluoro-5-methanesulfonyl-benzoic acid

To 2.68 mmol 2-fluoro-5-methanesulfonyl-benzoic acid in 5 ml of methanol at 0°C was added with 8.05 mmol Oxone®, and the mixture was allowed to mix at room temperature for 72 hours the Precipitate was filtered, and the filtrate was concentrated under reduced pressure. About who headed the remainder of the treated water and was extracted 3 times with 400 ml of dichloromethane. The combined organic phases were dried over sodium sulfate. In the evaporation at reduced pressure has been specified in the title compound as a white crystalline solid (yield 79%). MS (mass/charge): 217,2 (M-H+, 100%).

C) 5-Methanesulfonyl-2-(2,2,2-Cryptor-1,1-dimethyl-ethoxy)-benzoic acid

To a solution of 2.75 mmol 2-fluoro-5-methanesulfonyl-benzoic acid in 10 ml of N,N-dimethylacetamide was added 14.7 mmol 1,1,1-Cryptor-2-methyl-propane-2-ol and 8,29 mmol of cesium carbonate, and the mixture was stirred at 170°C for 72 hours. Then the reaction mixture was cooled to room temperature, acidified by adding formic acid and then concentrated under vacuum. The residue was purified by preparative Ehud obtaining specified in the title compound as light brown solid (yield 99%). MS (mass/charge): 325,3. ([M-H]-, 100%)

Example A15

5-Methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid

(a) rat-5-Methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid methyl ester

A mixture of 21.7 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid methyl ester (WO 2002074774), 32.5 mmol rat-Cryptor-methanesulfonic acid 2,2,2-Cryptor-1-methyl-ethyl ester [212556-43-9] and 43.4 mmol carbon is the potassium in 87 ml of DMF (N,N-dimethylformamide) was stirred at 80°C for 48 hours. After cooling to room temperature the mixture was concentrated under vacuum, resuspendable in the water and was stirred for 1 hour. By filtering the received specified in the header of the connection.

(b) 5-Methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid methyl ester

Specified in the title compound was obtained by dividing the rat-5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid methyl ester using chiral ghvd (Chiralcel OD; 15% ethanol/heptane; flow rate: 35 ml·min-1; 220 nm; retention time: 86 min.)

(C) 5-Methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid

Was obtained in analogy to Example A6 (b) from 5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid methyl ester. MS (mass/charge): 311,0 ([M-H]-, 100%).

Example A16

5-Methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid

(a) 5-Methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid methyl ester

Specified in the title compound was obtained by dividing the rat-5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid methyl ester (Example A15(a)) using chiral ghvd (Chiralcel OD; 15% ethanol/heptane, flow rate: 35 ml·min-1, 20 nm, retention time: 74 min).

(b) 5-Methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid

Was obtained in analogy to Example A6 (b) from 5-methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid methyl ester. MS (mass/charge): 311,0 ([M-H]-, 100%).

Example A17

Rat-5-Econsultancy-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid

(a) 5-Econsultancy-2-fluoro-benzoic acid ethyl ester

To a solution of 1.98 mol of sodium sulfite in 1 l of water was added in portions over 20 min 0,264 mol 5-chlorosulfonyl-2-fluoro-benzoic acid (CAS: 37098-75-2). This reaction mixture was stirred at room temperature for 2.5 hours, then was cooled to 0°C and acidified 230 ml of sulfuric acid (20%) to pH 2. The water evaporated, and the residue was transferred into a 200 ml DMF. Added 73 mmol of potassium carbonate and 86 mmol of itatani, and the reaction mixture was stirred at room temperature for 50 hours. The solvent was removed under vacuum. White solid was dissolved in 100 ml of water. The aqueous phase was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate. As the result of evaporation under reduced pressure and flash chromatography (SiO2, heptane/ethyl acetate 1/1) has been specified in the title compound as a colourless oil (yield 37%). MS (m is SSA/charge): 261,1 (M+N +, 100%).

(b) 5-Econsultancy-2-fluoro-benzoic acid

To the 10.8 mmol 5-econsultancy-2-fluoro-benzoic acid ethyl ester in 26 ml of tetrahydrofuran was added 26 ml of water and 16.1 mmol monohydrate of lithium hydroxide, and this reaction mixture was stirred at room temperature for 45 minutes. After this time the reaction mixture was acidified using 1 N. HCl, tetrahydrofuran evaporated, and the aqueous phase was twice extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated under vacuum to obtain specified in the title compound as a white solid (96%). MS (mass/charge): 232,1 ([M+, 100%).

(C) rat-5-Econsultancy-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid

Was obtained in analogy to Example A14 (C) from 5-econsultancy-2-fluoro-benzoic acid and rat-1,1,1-Cryptor-propan-2-ol. MS (mass/charge): 325,1 ([M-H]-, 100%).

Example A18

5-Econsultancy-2-isopropoxy-benzoic acid

Was obtained in analogy to Example A14 (C) from 5-econsultancy-2-fluoro-benzoic acid (Example A17 (b)) and isopropanol. MS (mass/charge): 271,1 ([M-H]-, 100%).

Example A19

Rat-5-Methanesulfonyl-2-(1-trifluoromethyl-propoxy)-benzoic acid

Was obtained in analogy to Example A14 (C) from 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14 (b)) and rat-1,1,1-Cryptor-butane-2-ol. MS (mass/charge): 325,0 ([M-H]-, 100%).

Example A20

2-((R)-sec-Butoxy)-5-methanesulfonyl-benzoic acid

Was obtained in analogy to Example A14 (C) from 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14 (b)) and (R)-butane-2-ol. MS (mass/charge): 271,1 ([M-H]-, 100%).

Example A21

2-((S)-sec-Butoxy)-5-methanesulfonyl-benzoic acid

Was obtained in analogy to Example A14 (C) from 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14 (b)) and (S)-butane-2-ol. MS (mass/charge): 271,1 ([M-H]-, 100%).

Example A22

2-Isopropylphenyl-5-methanesulfonyl-benzoic acid

To a solution 4,58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14 (b)) in 6 ml N,N-dimethylacetamide was added to 15.2 mol of cesium carbonate and 10.1 mmol 2-propandiol, and the mixture was stirred at 90°C for 3 h Then the reaction mixture was cooled to room temperature and acidified to pH 1 by adding hydrochloric acid, before it was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under vacuum to obtain specified in the connection header in the form with which ETLO yellow liquid, which was used in the next stage without further purification (yield 99%). EI-MS (mass spectrometry with ionization by electrons) (mass/charge): 274,1 (M+, 35%), 232,1 ([M-C3H6]+, 30%), 214,1 (M-C3H6-H2O)+, 100%).

Example A23

2-Ethylsulfanyl-5-methanesulfonyl-benzoic acid

To a solution 4,58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14(b)) in 6 ml N,N-dimethylformamide was added to 13.8 mol of cesium carbonate and a 9.25 mmol of ethanthiol, and the mixture was stirred at 90°C for 30 minutes and Then the reaction mixture was cooled to room temperature and acidified to pH 1 by adding hydrochloric acid, before it was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under vacuum to obtain specified in the title compound as a white solid, which was used in the next stage without further purification (yield 99%). MS (mass/charge): 259,0 ([M-H]-, 100%).

Example A24

5-Methanesulfonyl-2-(2,2,2-Cryptor-ethylsulfanyl)-benzoic acid

To a solution 4,58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14 (b)) in 6 ml N,N-dimethylformamide was added to 13.8 mol of cesium carbonate and 9,16 mmol 2,2,2-Cryptor-ethandiol, and this is Masi was stirred at 90°C for 30 minutes Then the reaction mixture was cooled to room temperature and acidified to pH 1 by adding hydrochloric acid, before it was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under vacuum to obtain specified in the title compound as a red-brown solid, which was used in the next stage without further purification (yield 99%). MS (mass/charge): 312,9 ([M-H]-, 100%).

Example A25

2-Isobutylphenyl-5-methanesulfonyl-benzoic acid

To a solution 4,58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14 (b)) in 6 ml N,N-dimethylformamide was added to 13.8 mol of cesium carbonate and 9.97 mmol 2-methyl-1-propanethiol, and the mixture was stirred at 90°C for 30 minutes and Then the reaction mixture was cooled to room temperature and acidified to pH 1 by adding hydrochloric acid, before it was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under vacuum to obtain specified in the title compound as a white solid, which was used in the next stage without further purification (yield 99%). MS (mass/charge): 287,0 ([M-H]-, 100%).

Example A26

5-Methanesulfonyl-2-methylsulfone the l-benzoic acid

To a solution 4,58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14 (b)) in 6 ml N,N-dimethylformamide was added to 13.8 mol of cesium carbonate and 10.0 mmol methanolate sodium, and the mixture was stirred at 90°C for 30 minutes and Then the reaction mixture was cooled to room temperature and acidified to pH 1 by adding hydrochloric acid, before it was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under vacuum to obtain specified in the title compounds as colorless oil, which was used in the next stage without further purification (yield 99%). MS (mass/charge): 244,9 ([M-H]-, 100%).

Example A27

5 2-Morpholine-4-yl-5-nitro-benzoic acid

To a solution of 12.2 mmol 2-fluoro-5-nitrobenzoic acid (CAS 7304-32-7; commercially available, for example, from Fluorochem) in 40 ml THF was added 18.2 mmol of the research, and the mixture was stirred at room temperature for 16 h the Volatile components were removed under vacuum, and the residue resuspendable in 25 ml of water and acidified to pH 4 by adding dropwise the aqueous HCl. The resulting mixture was stirred at room temperature for 30 min, and the obtained crystals were then collected by filtration and dried under vacuum at 50°C With the floor is the group specified in the title compound as yellow solid (yield 32%). MS (mass/charge): 251,0 ([M-H]-, 100%).

Example A28

5-Cyano-2-isopropoxy-benzoic acid

To 198 mmol of isopropanol was added to 19.8 mmol of sodium, and then the mixture was heated at 100°C until until dissolved the sodium (30 min). Then added 6,59 mmol 5-cyano-2-iodine-benzoic acid [CAS: 219841-92-6; WO 9901455] and of 1.32 mmol of copper bromide (I), and this reaction mixture was heated at 120°C for 2 h Then the reaction mixture was cooled to room temperature and concentrated under vacuum. The residue is suspended in 50 ml of 1 M aqueous HCl and was extracted 3x with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4and concentrated under vacuum. In the flash-chromatography on silica gel (eluent: heptane/ethyl acetate) has been specified in the title compound as a white solid (yield 55%). MS (mass/charge): to 204.1 ([M-H]-, 100%).

Example A29

2 Cyclopentyloxy-5-methylsulfanyl-benzoic acid

(a) 5-Chlorosulfonyl-2-hydroxy-benzoic acid

To 3,26 mole of chlorosulfonic acid at 0°C in small portions was added 652 mmol salicylic acid, and then the mixture was allowed to mix at room temperature for 1 h, then at 50°C for 1 h and finally at 70°C in t the value of 1 hour Then the mixture was added dropwise to 1000 ml of ice water with stirring, and the stirring continued for a further 30 minutes the Resulting white crystals were collected by filtration, washed three times with water and then dried under vacuum at 45°C for 16 h with obtaining specified in the connection header. MS (mass/charge): 236,8 ([{37Cl}M-N]-, 33%), 235,0 ([{37Cl}M-N]-, 100%).

(b) 2-Hydroxy-5-methylsulfanyl-benzoic acid

To 63 mmol 5-chlorosulfonyl-2-hydroxy-benzoic acid in 120 ml of dichloromethane at room temperature was added dropwise 317 mmol of methylamine (8 M solution in ethanol), and the mixture was allowed to mix at room temperature for 1 h Then the mixture was concentrated under vacuum. The residue is suspended in 1 M aqueous NaOH solution and was extracted twice with diethyl ether. The aqueous phase was acidified with 5 M aqueous HCl, saturated NaCl and was extracted 3 times with THF. The combined THF extracts were twice washed with a saturated aqueous solution of NaCl and dried Na2SO4. In the evaporation under vacuum has been specified in the header connection. MS (mass/charge): 249,0 (M+NH4+, 100%), 231,9 (M+H+, 63%).

(a) 2-Hydroxy-5-methylsulfanyl-benzoic acid methyl ester

To 77 mmol 2-hydroxy-5-metilsulfate the Il-benzoic acid in 300 ml of THF was added 85 mmol CDI (1,1'-carbonyldiimidazole), and this mixture was heated at 70°C for 1 h and Then was added 770 mmol of methanol, and the mixture was heated at 70°C for 16 hours Then the mixture was cooled to room temperature and concentrated under vacuum. The residue was chromatographically on silica gel (eluent: ethyl acetate/heptane/dichloromethane 45:45:10) to obtain specified in the connection header. MS (mass/charge): to 244.1 ([M-H]-, 100%).

(g) 2-Cyclopentyloxy-5-methylsulfanyl-benzoic acid methyl ester

To 2,85 mmol 2-hydroxy-5-methylsulfanyl-benzoic acid methyl ester, 3.14 mmol of Cyclopentanol and of 3.28 mmol of triphenylphosphine in 10 ml of THF was added 3.14 mmol di-tert-utilization.bacteria, and the mixture was stirred at room temperature for 2 hours Then the mixture was concentrated under vacuum. The residue was chromatographically on silica gel (eluent: ethyl acetate/heptane 2:3) to obtain specified in the title compounds as colorless oils. MS (mass/charge): 312,1 ([M-H]-, 100%).

(d) 2-Cyclopentyloxy-5-methylsulfanyl-benzoic acid

To 2.68 mmol 2-cyclopentyloxy-5-methylsulfanyl-benzoic acid methyl ester in 10 ml THF was added 20 mmol of 2 M aqueous NaOH, and the mixture was stirred at room temperature for 2 hours Then the mixture was twice extracted with diethyl ether the m The aqueous phase was acidified with 10% aqueous citric acid and was extracted 3 times with ethyl acetate. The combined organic phases were dried Na2SO4. In the evaporation under vacuum and subsequent trituration in diethyl ether has been specified in the title compound as a white solid. MS (mass/charge): 298,3 ([M-H]-, 100%).

Example A30

5-Methanesulfonyl-2-(2,2,3,3,3-pendaftar-propoxy)-benzoic acid

Was obtained in analogy to Example A14 (C) from 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14 (b)) and 2,2,3,3,3-pendaftar-1-propanol. MS (mass/charge): 346,9 ([M-H]-, 100%).

The synthesis of compounds of formula I according to the invention

Example 1

[4-(5-Bromo-thiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon

a) 1-(5-Bromo-thiazol-2-yl)-piperazine

A mixture of 2.06 mmol of 2,5-dibromothiazole, 6,17 mmol of piperazine and of 6.17 mmol of triethylamine in 6 ml of tetrahydrofuran in a hermetically sealed tube was heated at 160°C for 10 min using microwave radiation. The reaction mixture was concentrated, and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to obtain the specified title compound as a white crystalline solid (yield 94%). MS (mass/charge): 250,0 ({81Br}M+H+, 100%), 248,0 ({79Br}M+H+, 76%).

To a solution of 0.31 mmol 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) in 7 ml of tetrahydrofuran were added successively 0.46 mmol TBTU, 1,24 mmol of N-ethyldiethanolamine and 0.34 mmol 1-(5-bromo-thiazol-2-yl)-piperazine. This reaction mixture was stirred at room temperature for 16 h and then concentrated under vacuum. The result chromatography (SiO2, ethyl acetate/heptane) has been specified in the title compound as a white foam (yield 87%). MS (mass/charge): 490,3 ({81Br}M+H+, 100%), 488,3 ({79Br}M+H+, 84%).

Example 2

(2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(4-methyl-thiazol-2-yl)-piperazine-1-yl]-methanon

a) 2-Iodine-4-methyl-thiazole

To a solution of 21.7 mmol of Diisopropylamine in 50 ml of tetrahydrofuran was added dropwise to 19.7 mmol of chloride butylamine (2 M in tetrahydrofuran)and the mixture was stirred at room temperature overnight. Then added 10.1 mmol 4-methylthiazole, and stirring was continued for 1 hour at room temperature. At the end was added dropwise a solution of 25.7 mol of iodine in 50 ml of tetrahydrofuran, and stirring continued for a further 1 h Then the reaction mixture was suppressed by adding 20% aqueous sodium thiosulfate solution, and the mixture was extracted three times with ethyl acetate. The combined organic f the s was dried over sodium sulfate and concentrated under vacuum. The result chromatography (SiO2, diethyl ether/heptane) has been specified in the title compound as a brown solid (yield 83%). MS (mass/charge): 226,1 (M+N+, 100%).

b) 1-(4-Methyl-thiazol-2-yl)-piperazine

A mixture of 1.33 mmol 2-iodine-4-methyl-thiazole, 4.00 mmol of piperazine and 4.00 mmol of triethylamine in 4 ml of tetrahydrofuran in a hermetically sealed tube was heated at 160°C for 2 h using microwave radiation. This reaction mixture was concentrated, and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to obtain the specified title compound as a yellow oil (yield 65%). MS (mass/charge): 184,3 (M+N+, 100%).

C) (2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(4-methyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(4-methyl-thiazol-2-yl)-piperazine. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as an amorphous yellow solid (yield 87%). MS (mass/charge): 424,1 (M+H+], 100%).

Example 3

(2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-methyl-thiazol-2-yl)-piperazine-1-yl]-methanon

a) 2-Iodine-5-methyl-thiazole

Received by analogy with example 2 (a) and the 5-methylthiazole. The crude substance was purified by chromatography (SiO2, diethyl ether/heptane) to obtain the specified title compound as a brown oil (yield 69%). MS (mass/charge): 226,3 (M+N+, 100%).

b) 1-(5-Methyl-thiazol-2-yl)-piperazine

Received by analogy with example 2 (b) from 2-iodine-6-methyl-thiazole and piperazine. The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) to obtain the specified title compound as a yellow oil (yield 32%). MS (mass/charge): 184,3 (M+N+, 100%).

C) (2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-methyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-methyl-thiazol-2-yl)-piperazine. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a yellowish foam (yield 75%). MS (mass/charge): 424,3 (M+H+, 100%).

Example 4

[4-(5-Benzazolyl-thiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon

a) 4-(5-Bromo-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl methyl ether

A mixture of 24.7 mmol of 2,5-dibromothiazole, 49.4 mmol of tert-butyl 1-piperidinecarboxylate and to 74.1 mmol of triethylamine in 24 ml of tetrahydrofuran in a hermetically sealed PR the tag was heated at 160°C for 30 min using microwave radiation. This reaction mixture was concentrated, and the residue was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a white crystalline solid (yield 68%). MS (mass/charge): 350,2 ({81Br}M+H+, 100%), 348,2 ({79Br}M+H+, 98%).

b) 4-(5-Phenylsulfanyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl methyl ether

To a solution of 1.44 mmol of 4-(5-bromo-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 6 ml of tetrahydrofuran at -78°C was added dropwise a solution of 1.44 mmol n-utility (1.6 M in hexane), and the mixture was stirred at -78°C for 10 minutes Then added dropwise within 15 min the solution was 1.58 mmol of diphenyldisulfide in 1 ml of tetrahydrofuran, and then the reaction mixture was allowed to warm to room temperature. Then the reaction mixture was poured into saturated brine, and the mixture was extracted three times with a mixture of ethyl acetate/tetrahydrofuran (1:1). The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The result chromatography (SiO2, ethyl acetate/heptane) has been specified in the title compound as a yellow crystalline solid (yield 76%). MS (mass/charge): 378,3 (M+H+, 100%).

b) 4-(5-Benzazolyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl methyl ether

p> To a solution of 1.06 mmol of 4-(5-phenylsulfanyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 ml of dichloroethane was added to 2.65 mmol meta-chloroperbenzoic acid, and the mixture was stirred at room temperature for 16 hours Then the reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and then with water. The organic phase was dried over sodium sulfate and concentrated under vacuum to obtain specified in the title compound as a yellow crystalline solid (yield 77%). MS (mass/charge): 410,3 (M+H+, 100%).

g) 1-(5-Benzazolyl-thiazol-2-yl)-piperazine hydrochloride

To a solution of 0.73 mmol 4-(5-benzazolyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 ml of dioxane was added dropwise a solution to 7.32 mmol of hydrogen chloride (4 M in dioxane)and the mixture was stirred at 80°C for 2.5 h Then the reaction mixture was cooled to 0°C and diluted with diethyl ether. The resulting crystals were collected by filtration and washed with diethyl ether to obtain specified in the title compound as a pale brown crystalline solid (yield 81%). MS (mass/charge): 309,9 (M+H+, 100%).

d) [4-(5-Benzazolyl-thiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-benzazolyl-thiazol-2-yl)-piperazine hydrochloride. The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) to obtain the specified title compound as a white crystalline solid (yield 47%). MS (mass/charge): 550,2 (M+H+, 100%), 567,2 (M+NH4+, 100%).

Example 5

(2 Isopropoxy-5-methanesulfonyl-phenyl)-{4-[4-(2-nitro-phenyl)-thiazol-2-yl]-piperazine-1-yl}-metano

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[4-(2-nitro-phenyl)-thiazol-2-yl]-piperazine dihydrochloride. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellow crystalline solid (yield 61%). MS (mass/charge): 531,3 (M+N+, 100%).

Example 6

2-[4-(2-Isopropoxy-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazole-5-carbonitrile

a) 2-piperazine-1-yl-thiazole-5-carbonitrile

Received by analogy with example 2 (b) from 2-chloro-1,3-thiazole-5-carbonitrile and piperazine. The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) with receipt of the m specified in the title compound as a white crystalline solid (yield 86%). MS (mass/charge): 194,9 (M+N+, 100%).

b) 2-[4-(2-Isopropoxy-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazole-5-carbonitrile

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 2-piperazine-1-yl-thiazole-5-carbonitrile. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 69%). MS (mass/charge): 435,4 (M+N+, 100%).

Example 7

{4-[4-(2,4-Dichloro-phenyl)-thiazol-2-yl]-piperazine-1-yl}-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[4-(2,4-dichloro-phenyl)-thiazol-2-yl]-piperazine dihydrochloride. The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) (yield 17%). MS (mass/charge): 558,1 ({37Cl}M+H+, 19%), 555,9 ({37Cl35Cl}M+H+, 58%), 554,1 ({35Cl}M+H+, 100%).

Example 8

(2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-nitro-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 2 (b) from 2-bromo-5-nitrothiazole and piperazine. The crude substance was purified by chromatography (SiO2/sub> , methanol/dichloromethane) to obtain the specified title compound as a pale yellow crystalline solid (yield 50%). MS (mass/charge): 215,3 (M+N+, 100%).

b) (2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-nitro-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-nitro-thiazol-2-yl)-piperazine. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellow crystalline solid (yield 67%). MS (mass/charge): 455,4 (M+H+, 100%), 472.0 M. (M+NH4+, 100%).

Example 9

(2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(3-phenyl-[1,2,4]thiadiazole-5-yl)-5 piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 3-phenyl-5-piperazine derivatives-1,2,4-thiadiazole. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a white crystalline solid (yield 69%). MS (mass/charge): 487,3 (M+H+, 100%).

Example 10

2-{4-[5-Methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzo the]-piperazine-1-yl}-thiazole-5-carbonitrile

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A2) and 2-piperazine-1-yl-thiazole-5-carbonitrile (Example 6 (a)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 59%). MS (mass/charge): 489,1 (M+N+, 100%), 506,1 (M+NH4+, 78%).

Example 11

2-{4-[5-Methanesulfonyl-2-(2,2,2-Cryptor-ethoxy)-benzoyl]-piperazine-1-yl}-thiazole-5-carbonitrile

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-ethoxy)-benzoic acid (Example A3) and 2-piperazine-1-yl-thiazole-5-carbonitrile (Example 6 (a)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a pale brown crystalline solid (yield 57%). MS (mass/charge): 475,0 (M+H+, 100%), 492,3 (M+NH4+, 90%).

Example 12

2-[4-(2-Cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazole-5-carbonitrile

Received by analogy with example 1 (b) from 2-cyclopentyloxy-5-m is canalphones-benzoic acid (Example A4) and 2-piperazine-1-yl-thiazole-5-carbonitrile (Example 6 (a)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellowish crystalline solid (yield 64%). MS (mass/charge): 461,3 (M+H+, 100%).

Example 13

2-[4-(2-Cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazole-5-carbonitrile

Received by analogy with example 1 (b) from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example A5) and 2-piperazine-1-yl-thiazole-5-carbonitrile (Example 6 (a)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 75%). MS (mass/charge): 447,3 (M+H+, 100%).

Example 14

2-[4-(2-Cyclobutylmethyl-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazole-5-carbonitrile

Received by analogy with example 1 (b) from 2-temporalelement-5-methanesulfonyl-benzoic acid (Example A6) and 2-piperazine-1-yl-thiazole-5-carbonitrile (Example 6 (a)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the agolove compound as a white crystalline solid (yield 61%). MS (mass/charge): 461,3 (M+H+, 100%).

Example 15

2-[4-(2-Cyclohexyloxy-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazole-5-carbonitrile

Received by analogy with example 1 (b) from 2-cyclohexyloxy-5-methanesulfonyl-benzoic acid (Example A7) and 2-piperazine-1-yl-thiazole-5-carbonitrile (Example 6 (a)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 49%). MS (mass/charge): 475,4 (M+N+, 100%).

Example 16

2-[4-(2-Isobutoxy-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazole-5-carbonitrile

Received by analogy with example 1 (b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (Example A8) and 2-piperazine-1-yl-thiazole-5-carbonitrile (Example 6 (a)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 61%). MS (mass/charge): 449,4 (M+H+, 100%).

Example 17

2-[4-(2-Cyclobutene-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazole-5-carbonitrile

Received similar and with example 1 (b) from 2-cyclobutene-5-methanesulfonyl-benzoic acid (Example A9) and 2-piperazine-1-yl-thiazole-5-carbonitrile (Example 6 (a)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellowish crystalline solid (yield 54%). MS (mass/charge): 447,2 (M+H+, 100%).

Example 18

2-[4-(2-Deut-Butoxy-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazole-5-carbonitrile

Received by analogy with example 1 (b) from 2-Deut-butoxy-5-methanesulfonyl-benzoic acid (Example a10) and 2-piperazine-1-yl-thiazole-5-carbonitrile (Example 6 (a)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 34%). MS (mass/charge): 449,4 (M+H+, 100%).

Example 19

2-{4-[2-(2,2-Dimethyl-propoxy)-5-methanesulfonyl-benzoyl]-piperazine-1-yl}-thiazole-5-carbonitrile

Received by analogy with example 1 (b) from 2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoic acid (Example A11) 2-piperazine-1-yl-thiazole-5-carbonitrile (Example 6 (a)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in segaloviciene in the form of a white crystalline solid (yield 68%). MS (mass/charge): 463,3 (M+H+, 100%).

Example 20

2-[4-(2-tert-Butoxy-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazole-5-carbonitrile

Received by analogy with example 1 (b) from 2-tert-butoxy-5-methanesulfonyl-benzoic acid (Example A12) 2-piperazine-1-yl-thiazole-5-carbonitrile (Example 6 (a)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 52%). MS (mass/charge): 449,3 (M+N+, 50%), 466,4 (M+NH4+, 100%).

Example 21

(2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-methanesulfonyl-thiazol-2-yl)-piperazine-1-yl]-methanon

a) 4-(5-Methylsulfanyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl methyl ether

Received by analogy with example 4 (b) from 4-(5-bromo-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 4(a)), and dimethyl disulfide. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a yellow crystalline solid (yield 78%). MS (mass/charge): 316,3 (M+H+, 100%).

b) 4-(5-Methanesulfonyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl methyl ether

Received by analogy with PR is Merom 4 (C) from 4-(5-methylsulfanyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ether and meta-chloroperbenzoic acid. Specified in the title compound was obtained as a yellow crystalline solid (yield 86%). MS (mass/charge): 348,3 (M+N+, 100%).

C) 1-(5-Methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride

Received by analogy with example 4 (g) of 4-(5-methanesulfonyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ether and a solution of hydrogen chloride. The crude substance was purified by recrystallization from diethyl ether to obtain specified in the title compound as a pale brown crystalline solid (yield 99%). MS (mass/charge): 248,1 (M+N+, 100%).

g) (2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-methanesulfonyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride. The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) to obtain the specified title compound as a white crystalline solid (yield 43%). MS (mass/charge): 488,1 (M+N+, 100%), 505,0 (M+NH4+, 75%).

Example 22

[4-(5-Methanesulfonyl-thiazol-2-yl)-piperazine-1-yl]-[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon

Received the Academy of Sciences of the technology with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 29%). MS (mass/charge): 542,2 (M+N+, 100%), 559,2 (M+NH4+, 65%).

Example 23

(2 Cyclopropylmethoxy-5-methanesulfonyl-phenyl)-[4-(5-methanesulfonyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example A5) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellow crystalline solid (yield 36%). MS (mass/charge): 500,1 (M+N+, 100%), from 517.2 (M+NH4+, 69%).

Example 24

(2 Isobutoxy-5-methanesulfonyl-phenyl)-[4-(5-methanesulfonyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (Example A8) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21). The crude substance was purified by chromatography (SiO2+, 100%).

Example 25

Rat-(2-Deut-Butoxy-5-methanesulfonyl-phenyl)-[4-(5-methanesulfonyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from rat-2-Deut-butoxy-6-methanesulfonyl-benzoic acid (Example a10) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellowish crystalline solid (yield 44%). MS (mass/charge): 502,1 (M+N+, 99%), 519,3 (M+NH4+, 100%).

Example 26

[2-(2,2-Dimethyl-propoxy)-5-methanesulfonyl-phenyl]-[4-(5-methanesulfonyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoic acid (Example A11) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl who Fira has been specified in the title compound as a white crystalline solid (yield 36%). MS (mass/charge): 516,2 (M+H+, 100%).

Example 27

(2 Cyclohexyloxy-5-methanesulfonyl-phenyl)-[4-(5-methanesulfonyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-cyclohexyloxy-5-methanesulfonyl-benzoic acid (Example A7) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a light red crystalline solid (yield 38%). MS (mass/charge): consists 528.3 (M+H+, 100%).

Example 28

(2 Cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(5-methanesulfonyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example A4) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellowish crystalline solid (yield 38%). MS (mass/charge): 514,3 (M+N+, 100%).

Example 29

[4-(5-Benzazolyl-thiazol-2-yl)-piperazine-1-yl-[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-phenyl]-methanon

Received by analogy with example 1 (b) from 2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoic acid (Example A11) and 1-(5-benzazolyl-thiazol-2-yl)-piperazine hydrochloride (Example 4 (g)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 57%). MS (mass/charge): 578,2 (M+H+, 100%), 595,3 (M+NH4+, 92%).

Example 30

[4-(5-Benzazolyl-thiazol-2-yl)-piperazine-1-yl]-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanon

Received by analogy with example 1 (b) from 2-cipointernet-5-methanesulfonyl-benzoic acid (Example A4) and 1-(5-benzazolyl-thiazol-2-yl)-piperazine hydrochloride (Example 4 (g)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellowish crystalline solid (yield 57%). MS (mass/charge): 576,0 (M+N+, 100%), 593,3 (M+NH4+, 94%).

Example 31

[4-(5-Benzazolyl-thiazol-2-yl)-piperazine-1-yl]-(2-isobutoxy-5-meanswhen yl-phenyl)-methanon

Received the Academy of Sciences of the technology with example 1 (b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (Example A8) and 1-(5-benzazolyl-thiazol-2-yl)-piperazine hydrochloride (Example 4 (g)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellowish crystalline solid (yield 45%). MS (mass/charge): made 564.3 (M+H+, 100%), 581,3 (M+NH4+, 94%).

Example 32

[2-(2,2-Dimethyl-propoxy)-5-methanesulfonyl-phenyl]-[4-(5-econsultancy-thiazol-2-yl)-piperazine-1-yl]-methanon

a) 4-(5-Ethylsulfanyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl methyl ether

Received by analogy with example 4 (b) from 4-(5-bromo-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 4(a)) and diatinguished. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a white crystalline solid (yield 86%). MS (mass/charge): 330,3 (M+N+, 100%).

b) 4-(5-Econsultancy-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl methyl ether

Received by analogy with example 4 (C) from 4-(5-ethylsulfanyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ether and meta-chloroperbenzoic acid. Specified in the title compound was obtained as a yellow crystalline solid (yield 99%). MS (mass/charge): 362,3 (M+H+, 100%), 362,3 (M+NH4+, 70%).

C) 1-(5-Utans Lionel-thiazol-2-yl)-piperazine hydrochloride

Received by analogy with example 4 (g) of 4-(5-econsultancy-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ether and a solution of hydrogen chloride. The crude substance was purified by recrystallization from diethyl ether to obtain specified in the title compound as a pale brown crystalline solid (yield 86%). MS (mass/charge): 262,0 (M+N+, 100%).

g) [2-(2,2-Dimethyl-propoxy)-5-methanesulfonyl-phenyl]-[4-(5-econsultancy-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoic acid (Example A11) and 1-(5-econsultancy-thiazol-2-yl)-piperazine hydrochloride. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 63%). MS (mass/charge): 530,2 (M+H+, 64%), 547,2 (M+NH4+, 100%).

Example 33

[4-(5-Econsultancy-thiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-econsultancy-thiazol-2-yl)-piperazine hydrochloride (Example 32). N the purified substance was purified by chromatography (SiO 2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 71%). MS (mass/charge): 502,3 (M+N+, 100%), 519,3 (M+NH4+, 82%).

Example 34

[4-(4,5-Dimethyl-thiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon

a) 2-Iodine-4,5-dimethyl-thiazol

Received by analogy with example 2 (a) of 4,5-dimethylthiazole. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a pale brown crystalline solid (yield 66%). MS (mass/charge): 240,1 (M+N+, 100%).

b) 1-(4,5-Dimethyl-thiazol-2-yl)-piperazine

Received by analogy with example 2 (b) from 2-iodine-4,5-dimethyl-thiazole and piperazine. The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) to obtain the specified title compound as a yellow crystalline solid (yield 25%). MS (mass/charge): 198,3 (M+H+, 100%).

C) [4-(4,5-Dimethyl-thiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(4,5-dimethyl-thiazol-2-yl)-piperazine. Untreated westwoodside by chromatography (SiO 2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellowish crystalline solid (yield 65%). MS (mass/charge): 584,3 (M+H+, 100%), 601,4 (M+NH4+, 60%).

Example 35

(2 Cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(5-econsultancy-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example A4) and 1-(5-econsultancy-thiazol-2-yl)-piperazine hydrochloride (Example 32). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 77%). MS (mass/charge): consists 528.3 (M+H+, 35%), 545,4 (M+NH4+, 100%).

Example 36

[4-(5-Econsultancy-thiazol-2-yl)-piperazine-1-yl]-[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-(5-econsultancy-thiazol-2-yl)-piperazine hydrochloride (Example 32). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), the result of the subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 61%). MS (mass/charge): 556,3 (M+H+, 100%), 573,3 (M+NH4+, 55%).

Example 37

[4-(5-Econsultancy-thiazol-2-yl)-piperazine-1-yl]-[5-methanesulfonyl-2-(2,2,2-Cryptor-ethoxy)-phenyl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-ethoxy)-benzoic acid (Example A3) and 1-(5-econsultancy-thiazol-2-yl)-piperazine hydrochloride (Example 32). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 72%). MS (mass/charge): 542,2 (M+N+, 100%), 559,3 (M+NH4+, 60%).

Example 38

{4-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon

a) 4-(5-Butylsulfonyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl methyl ether

Received by analogy with example 4 (b) from 4-(5-bromo-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 4(a)) and dibutylthiourea. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain specified in the title compounds as colorless oil (yield 93%). MS (mass/charge): 358,3 (M+N+, 100%).

b) 4-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid t is et-butyl methyl ether

Received by analogy with example 4 (C) from 4-(5-butylsulfonyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ether and meta-chloroperbenzoic kislay. Specified in the title compound was obtained as a yellow crystalline solid (yield 82%). MS (mass/charge): 390,3 (M+H+, 100%), 407,3 (M+

NH4+, 80%).

C) 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride

Received by analogy with example 4 (g) of 4-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ether and a solution of hydrogen chloride. The crude substance was purified by recrystallization from diethyl ether to obtain specified in the title compound as a yellowish crystalline solid (yield 92%). MS (mass/charge): 290,0 (M+H+, 100%).

g) {4-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (o is d 54%). MS (mass/charge): us $ 530, 3 (M+N+, 35%), 547,5 (M+NH4+, 100%).

Example 39

{4-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 38). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 65%). MS (mass/charge): 584,3 (M+H+, 100%), 601,4 (M+NH4+, 60%).

Example 40

{4-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-[5-methanesulfonyl-2-(2,2,2-Cryptor-ethoxy)-phenyl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-ethoxy)-benzoic acid (Example A3) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 38). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 63%). MS (mass/charge): 570,4 (M+the +, 15%), 587,3 (M+NH4+, 100%).

Example 41

{4-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanon

Received by analogy with example 1 (b) from 2-cipointernet-5-methanesulfonyl-benzoic acid (Example A4) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 38). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 71%). MS (mass/charge): 556,3 (M+H+, 35%), 573,5 (M+NH4+, 100%).

Example 42

{4-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-phenyl]-methanon

Received by analogy with example 1 (b) from 2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoic acid (Example EN) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 38). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 69%). MS (mass/charge): 558,4 (M+N+, 20%), 575,4 (M+NH4+, 100%).

Example 43

{4-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-(5-methanesulfonyl-2-morpholine-4-yl-phenyl)-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-morpholine-4-yl-benzoic acid (Example A13) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 38). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a light red crystalline solid (yield 60%). MS (mass/charge): 557,2 (M+H+, 65%), 574,4 (M+NH4+, 100%).

Example 44

(2 Isopropoxy-5-methanesulfonyl-phenyl)-{4-[5-(propane-2-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-metano

a) 4-[5-(Propane-2-sulfonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl methyl ether

To a solution of 0.83 mmol of 4-(5-econsultancy-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 32(b)) in 3 ml of tetrahydrofuran at -78°C was added dropwise a solution of 1.08 mmol of bis(trimethylsilyl) potassium (0,91 M in tetrahydrofuran). After 3 min was added dropwise a solution of 1.24 mmol of iodomethane in 2 ml of tetrahydrofuran, and stirring was continued for 10 min at -78°C. Then the reaction mixture was left to warm to room temperature and was poured into a mixture of tetrahed furan/ethyl acetate (1:1). This mixture was washed with brine, and the organic phase was dried over sodium sulfate and concentrated under vacuum. The result chromatography (SiO2, ethyl acetate/heptane) has been specified in the title compound as a white crystalline solid (yield 30%). MS (mass/charge): 376,1 (M+H+, 100%).

b) 1-[5-(Propane-2-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride

Received by analogy with example 4 (g) of 4-[5-(propane-2-sulfonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ether and a solution of hydrogen chloride. The crude substance was purified by recrystallization from diethyl ether to obtain specified in the title compound as a white crystalline solid (yield 97%). MS (mass/charge): 276,4 (M+H+, 100%).

C) (2 Isopropoxy-5-methanesulfonyl-phenyl)-{4-[5-(propane-2-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-metano

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(propane-2-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 67%). MS (mass/dawn is): 516,3 (M+H +, 100%), 533,3 (M+NH4+, 85%).

Example 45

(2 Isopropoxy-5-methanesulfonyl-phenyl)-{4-[5-(pyridine-2-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-metano

a) 4-[5-(Pyridine-2-ylsulphonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl methyl ether

Received by analogy with example 4 (b) from 4-(5-bromo-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 4(a)) and 2,2'-dithiodipyridine. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a yellow crystalline solid (yield 94%). MS (mass/charge): 379,1 (M+N+, 100%).

b) 4-[5-(Pyridine-2-sulfonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl methyl ether

Received by analogy with example 4 (C) from 4-[5-(pyridine-2-ylsulphonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ether and meta-chloroperbenzoic acid. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a white crystalline solid (yield 54%). MS (mass/charge): 411,3 (M+N+, 100%).

C) 1-[5-(Pyridine-2-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride

Received by analogy with example 4 (g) of 4-[5-(pyridine-2-sulfonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl methyl ether and the solution of the hydrogen chloride. The crude substance was purified by recrystallization from diethyl ether to obtain specified in the title compound as a yellowish crystalline solid (yield 99%). MS (mass/charge): 311,0 [M+H+, 100%).

g) (2 Isopropoxy-5-methanesulfonyl-phenyl)-{4-[5-(pyridine-2-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-metano

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(pyridine-2-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 90%). MS (mass/charge): 551,2 (M+H+, 100%).

Example 46

(2 Isopropoxy-5-methanesulfonyl-phenyl)-{4-[5-(pyridine-3-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-metano

a) 4-[5-(Pyridine-3-ylsulphonyl)-thiazol-2-yl]-piperazin-1-carboxylic acid tert-butyl methyl ether

Received by analogy with example 4 (b) from 4-(5-bromo-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 4 (a)) and 3,3'-dithiodipyridine. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as an orange wt is a (yield 55%). MS (mass/charge): 379,1 (M+N+, 100%).

b) 4-[5-(Pyridine-3-sulfonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl methyl ether

Received by analogy with example 4 (C) from 4-[5-(pyridine-3-ylsulphonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ether and meta-chloroperbenzoic acid. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a white crystalline solid (yield 41%). MS (mass/charge): 411,1 (M+N+, 100%).

C) 1-[5-(Pyridine-3-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride

Received by analogy with example 4 (g) of 4-[5-(pyridine-3-sulfonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ether and a solution of hydrogen chloride. The crude substance was purified by recrystallization from diethyl ether to obtain specified in the title compound as a yellowish crystalline solid (yield 99%). MS (mass/charge): 311,0 [M+H+, 100%).

g) (2 Isopropoxy-5-methanesulfonyl-phenyl)-{4-[5-(pyridine-3-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-metano

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(pyridine-3-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride. The crude substance was purified way of the chromatography (SiO 2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellowish crystalline solid (yield 87%). MS (mass/charge): of 551.3 (M+H+, 100%).

Example 47

[5-Methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-{4-[5-(pyridine-2-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-metano

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[5-(pyridine-2-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 45 (C)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellowish crystalline solid (yield 68%). MS (mass/charge): 605,0 (M+N+, 100%).

Example 48

[5-Methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-{4-[5-(pyridine-3-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-metano

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-staxi)-benzoic acid (Example A2) and 1-[5-(pyridine-3-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 46). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of th is blowing trituration in diethyl ether has been specified in the title compound as a pale brown crystalline solid (yield 49%). MS (mass/charge): 605,2 (M+H+, 100%).

Example 49

(2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

a) 1-(4-Trifluoromethyl-thiazol-2-yl)-piperazin

To a solution of 6,89 mmol 1-piperazinecarboxamide in 10 ml of ethanol was added compared to 8.26 mmol of 3-bromo-1,1,1-triptorelin, and this mixture was heated at 70°C for 2 hours Then the mixture was concentrated under vacuum, and the residue resuspendable in dichloromethane. The insoluble substance was removed by filtration, and the filtrate was concentrated under vacuum. The result chromatography (SiO2, methanol/dichloromethane) has been specified in the title compound as a yellow crystalline solid (yield 41%). MS (mass/charge): 238,1 (M+N+, 100%).

b) (2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(4-trifluoromethyl-thiazol-2-yl)-piperazine. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in pentane has been specified in the title compound as a crystalline white solid (yield 55%). MS (mass/charge): 478,0 (M+H+, 100%).

Example 50

[5-Methanesulfonyl-2-(2,2,2-Cryptor-1-m is l-ethoxy)-phenyl]-[4-(4-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-(4-trifluoromethyl-thiazol-2-yl)-piperazine (Example 49 (a)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in pentane has been specified in the title compound as a crystalline white solid (yield 48%). MS (mass/charge): 531,8 (M+N+, 100%).

Example 51

(2 Cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example A4) and 1 -(4-trifluoromethyl-thiazol-2-yl)-piperazine (Example 49 (a)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in pentane has been specified in the title compound as a crystalline white solid (71%yield). MS (mass/charge): 504,0 (M+N+, 100%).

Example 52

(2 Isopropoxy-5-methanesulfonyl-phenyl)-{4-[5-(pyridine-4-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-metano

a) 4-[5-(Pyridine-4-ylsulphonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl methyl ether

Received by analogy with example 4 (b) from 4-(5-bromo-thiazol-2-the l)-piperazine-1-carboxylic acid tert-butyl ester (Example 4(a)) and 4,4'-dithiodipyridine. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a yellow oil (yield 79%). MS (mass/charge): 379,3 (M+H+, 100%).

b) 4-[5-(Pyridine-4-sulfonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl methyl ether

Received by analogy with example 4 (C) from 4-[5-(pyridine-4-ylsulphonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ether and meta-chloroperbenzoic acid. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a yellow crystalline solid (yield 37%). MS (mass/charge): 411,3 (M+N+, 100%).

C) 1-[5-(Pyridine-4-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride

Received by analogy with example 4 (g) of 4-[5-(pyridine-4-sulfonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ether and a solution of hydrogen chloride. The crude substance was purified by recrystallization from diethyl ether to obtain specified in the title compound as a pale yellow crystalline solid (yield 99%). MS (mass/charge): 311,0 (M+N+, 100%).

g) (2 Isopropoxy-5-methanesulfonyl-phenyl)-{4-[5-(pyridine-4-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-metano

Received by analogy with example 1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(pyridine-4-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a light red crystalline solid (yield 32%). MS (mass/charge): 551,2 (M+H+, 100%).

Example 53

[5-Methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-{4-[5-(pyridine-4-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-metano

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[5-(pyridine-4-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 52). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a pale yellow crystalline solid (yield 32%). MS (mass/charge): 551,2 (M+N+, 100%).

Example 54

(2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-methyl-4-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

a) 1-(5-Methyl-4-trifluoromethyl-thiazol-2-yl)-piperazine

Was obtained in analogy to example 49 (a) 1-piperazinecarboxamide and 3-bromo-1,1,1-Cryptor-2-butanone. The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) to obtain specified in the header with the unity in the form of a white crystalline solid (yield 25%). MS (mass/charge): 252,1 (M+N+, 100%).

b) (2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-methyl-4-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-methyl-4-trifluoromethyl-thiazol-2-yl)-piperazine. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a white crystalline solid (yield 60%). MS (mass/charge): 492,3 (M+H+, 100%).

Example 55

[5-Methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-methyl-4-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-(5-methyl-4-trifluoromethyl-thiazol-2-yl)-piperazine (Example 54 (a)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in pentane has been specified in the title compound as a white crystalline solid (yield 61%). MS (mass/charge): 546,3 (M+N+, 100%).

Example 56

(2 Isopropoxy-5-methanesulfonyl-phenyl)-{4-[4-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine-1-yl}-meth is non -

a) 1-[4-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine

Was obtained in analogy to example 49 (a) 1-piperazinecarboxamide and 1-bromo-4,4,4-Cryptor-butane-2-it. The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) to obtain the specified title compound as a brown oil (yield 24%). MS (mass/charge): 252,3 (M+N+, 100%).

b) (2 Isopropoxy-5-methanesulfonyl-phenyl)-{4-[4-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine-1-yl}-metano

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[4-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in pentane has been specified in the title compound as a white crystalline solid (yield 28%). MS (mass/charge): 492,1 (M+H+, 100%).

Example 57

[5-Methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-{4-[4-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine-1-yl}-metano

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[4-(2,2,2-triptorelin)-thiazol-2-yl]-piperazine (Example 56 (a)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), R is the result of subsequent trituration in pentane has been specified in the title compound as a white crystalline solid (yield 29%). MS (mass/charge): 546,3 (M+N+, 100%).

Example 58

(2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

a) 2-Benzazolyl-3-trifluoromethyl-ethylene oxide

To a solution of 25.4 mmol 3,3,3-Cryptor-1-(phenylsulfonyl)prop-1-ene in 80 ml of acetonitrile was added to 30.5 mmol peracetic acid (39% solution in acetic acid) and 101 mmol of potassium carbonate. This mixture was heated at 60°C for 4 h Then the reaction mixture was diluted with a mixture of ethyl acetate/tetrahydrofuran (1:1) and washed with brine. The organic phase was dried over sodium sulfate and concentrated under vacuum to obtain specified in the title compound as a pale yellow crystalline solid (yield 90%). EI-MS (mass/charge): 252,0 (M+, 15%), 125,1 (PhSO+, 100%), 77,2 (Ph+, 37%).

b) 4-(5-Trifluoromethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl methyl ether

To a solution of 17.5 mmol 2-benzazolyl-3-trifluoromethyl-ethylene oxide in 20 ml of N,N-dimethylformamide was added 15.9 mmol 4-thiocarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (obtained from tert-butyl 1-piperidinecarboxylate, 1,1'-thiocarbonyldiimidazole and ammonia according to the procedure described in J. Med. Chem. 1998, 41, 5037-5054). This mixture was heated at 90°C for 10 h and Then the reaction mixture was concentrated under vacuum, and the residue was purified PU is eat chromatography (SiO 2, ethyl acetate/heptane) to obtain the specified title compound as an orange crystalline solid (yield 26%). MS (mass/charge): 338,1 (M+H+, 100%).

C) 1-(5-Trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride

To a solution 3,59 mmol of 4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 20 ml of dioxane was added dropwise 53.8 mmol of a solution of hydrogen chloride (4 M in dioxane)and the mixture was stirred at 90°C for 4 h Then the reaction mixture was cooled to 0°C and diluted with diethyl ether. The resulting crystals were collected by filtration and washed with diethyl ether to obtain specified in the title compound as a yellowish crystalline solid (yield 99%). MS (mass/charge): 238,1 (M+N+, 100%).

g) (2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in pentane has been specified in the title compound as a white crystalline solid (yield 28%). MS (mass/charge: 478,3 (M+H +, 100%).

Example 59

[5-Methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in pentane has been specified in the title compound as a yellowish crystalline solid (yield 64%). MS (mass/charge): 532,0 (M+N+, 100%).

Example 60

(5-Methanesulfonyl-2-morpholine-4-yl-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-morpholine-4-yl-benzoic acid (Example A13) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in pentane has been specified in the title compound as a yellowish crystalline solid (yield 71%). MS (mass/charge): 505,3 (M+N+, 100%).

Example 61

(2 Cyclopropylmethoxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-Manon

Received by analogy with example 1 (b) from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example A5) and 1-(b-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in pentane has been specified in the title compound as a white crystalline solid (yield 22%). MS (mass/charge): 490,3 (M+H+, 100%).

Example 62

(2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon

a) 4-(5-Trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-carboxylic acid tert-butyl methyl ether

A mixture of 2.2 mmol of 2-bromo-5-trifluoromethyl-[1,3,4]thiadiazole (SA 37461-6-3; obtained according to DE 2533605), 2.3 mmol piperazine-1-carboxylic acid tert-butyl ether and 4.3 mmol of potassium carbonate in 10 ml of acetonitrile was subjected to reflux distilled for 4 hours. The reaction mixture was cooled, poured into water and was extracted 3 times with ethyl acetate. As a result of concentration and recrystallization of the crude substances from diethyl ether has been specified in the title compound as a colourless solid. MS (mass/charge): 397,2 ([M+CH3Soo]-, 100%).

b) 1-(5-Trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine triptorelin

0.83 mmol 4(5-Trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 ml of dichloromethane was treated with 6.6 mmol triperoxonane acid and was stirred for 2 hours at room temperature. This reaction mixture was concentrated to obtain specified in the title compound as a yellowish gum. MS (mass/charge): 239,1 (M+H+, 100%).

C) (2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1 -(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine trifenatate. The crude substance was purified by chromatography (SiO2, dichloromethane/methanol 99:1) to obtain the specified title compound as a colourless solid. MS (mass/charge): 479,2 (M+H+, 100%).

Example 63

(2 Cyclopropylmethoxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example A5) and 1 -(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine trifenatate (Example 62 (b)). The crude substance was purified by chromatography (SiO2, dichloromethane/methanol 98:2) to obtain the specified title compound as a colourless solid. MS (mass/charge): 491,2 (M+N+, 100%).

Example 64

(2 Isobutoxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-Manon

Received by analogy with example 1 (b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (Example A8) and 1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine trifenatate (Example 62 (b)). The crude substance was purified by chromatography (SiO2, dichloromethane/methanol 98:2) to obtain the specified title compound as a colourless solid. MS (mass/charge): 493,4 (M+H+, 100%).

Example 65

(5-Methanesulfonyl-2-morpholine-4-yl-phenyl)-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 6-methanesulfonyl-2-morpholine-4-yl-benzoic acid (Example A13) and 1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine trifenatate (Example 62 (b)). The crude substance was purified by chromatography (SiO2, dichloromethane/methanol 99:1) to obtain the specified title compound as a colourless solid, MS (mass/charge): 506,3 (M+N+, 100%).

Example 66

[5-Methanesulfonyl-2-(2,2,2-Cryptor-1,1-dimethyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-1,1-dimethyl-ethoxy)-benzoic acid (Example A14) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). Untreated prophetic the STV was purified by chromatography (ethyl acetate/heptane) to obtain specified in the title compounds as white solids (yield 52%). MS (mass/charge): 546,3 (M+H+, 100%). BP.=182-183°C.

Example 67

[5-Methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A15) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in pentane has been specified in the title compound as a yellowish crystalline solid (yield 52%). MS (mass/charge): 532,3 (M+N+, 100%).

Example 68

[5-Methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A16) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in pentane has been specified in the title compound as a yellowish crystalline solid (yield 57%). MS (mass/charge): 532,0 (M+N+, 100%).

Example 69

[5-Methanol is of IMT-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-{4-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine-1-yl}-metano

a) 4-(5-Hydroxymethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl methyl ether

To a solution of 179 mmol of 30% aqueous hydrogen peroxide in 60 ml of water was added 1 N. aqueous sodium hydroxide solution until the pH value was not equal to 9. Then the reaction mixture was cooled to 10°C., and added dropwise 163 mmol of acrolein. During this addition has introduced an additional quantity 1 N. aqueous sodium hydroxide solution to maintain the pH of the reaction mixture in the range of pH 8 to 9. The mixture was stirred for 30 min at 0°C, and then added to 40.8 mmol thiocarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (obtained from tert-butyl 1-piperidinecarboxylate, 1,1'-thiocarbonyldiimidazole and ammonia according to the procedure described in J. Med. Chem. 1998, 41, 5037-5054). To the resulting suspension was added 25 ml of ethanol, and this mixture was heated at 80°C for 30 minutes the resulting solution was diluted with a mixture of ethyl acetate/tetrahydrofuran (1:1), and this mixture was twice washed with brine. The organic phase was dried over sodium sulfate and concentrated under vacuum to obtain specified in the title compound as a yellow oil (yield 99%). MS (mass/charge): 300,3 (M+H+, 100%).

b) 4-(5-Formyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl methyl ether

To a solution of 40.0 mmol of 4-(5-hydroxymethyl-thiazol-2-yl)-piperazine-1-carboxylic to the slots tert-butyl ester in 300 ml of dichloromethane was added 289 mmol manganese oxide (IV), and this mixture was heated at the temperature of reflux distilled for 3 hours Then the mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a pale brown crystalline solid (yield 40%). MS (mass/charge): 298,3 (M+H+, 100%).

C) 4-[5-(2,2-Debtor-vinyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl methyl ether

To a solution of 6.73 mmol of triphenylphosphine in 13 ml of N,N-dimethylformamide was added was 6.73 mmol dibromodifluoromethane, and the mixture was stirred at room temperature for 1 h was Added to 3.36 mmol of 4-(5-formyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ether, and then the mixture was cooled to 0°C. was Added in small portions of 6.73 mmol of zinc dust, and the stirring was continued for 10 min at 0°C. Then the mixture was left to warm to room temperature and stirring continued for another 2 hours Then the reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a white crystalline solid (yield 19%). MS (mass/charge): 332,3 (M+N+, 10%), 276,0 ([M+2H-tBu]+, 100%).

g) 4-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-and the]-piperazine-1-carboxylic acid tert-butyl methyl ether

To a solution of 1.03 mmol 4-[5-(2,2-debtor-vinyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester in 7.5 DMSO and 0.3 ml of water was added to 7.18 mmol of potassium fluoride, and the mixture was heated at 120°C for 2 hours Then the mixture was diluted with ethyl acetate and washed successively with water and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a yellow crystalline solid (yield 90%). MS (mass/charge): 352,3 (M+N+, 100%).

d) 1-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine hydrochloride

To a solution of 0.91 mmol 4-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester in 30 ml of dioxane was added dropwise 18.2 mmol of a solution of hydrogen chloride (4 M in dioxane)and the mixture was stirred at 90°C for 90 minutes Then the reaction mixture was cooled to 0°C and diluted with diethyl ether. The resulting crystals were collected by filtration and washed with diethyl ether to obtain specified in the title compound as a pale brown crystalline solid (yield 73%). MS (mass/charge): 252,3 (M+H+, 100%).

(e) [5-Methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-{4-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazin-1-yl}-metano

Received by analogy with example 1 (b) from 5-metalsonic-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine hydrochloride. The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) to obtain the specified title compound as a white crystalline solid (yield 32%). MS (mass/charge): 546,3 (M+H+, 100%).

Example 70

[5-Methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-{4-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine-1-yl}-metano

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-((5)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A15) and 1-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine hydrochloride (Example 69 (e)). The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) to obtain the specified title compound as a white crystalline solid (yield 54%). MS (mass/charge): 546,3 (M+N+, 100%).

Example 71

[5-Methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-{4-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine-1-yl}-metano

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A16) and 1-[5-(2,2,2-Cryptor-ethyl)thiazol-2-yl]-piperazine hydrochloride (Example 69 (e)). The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) to obtain the specified title compound as a white crystalline solid (yield 41%). MS (mass/charge): 546,3 (M+N+, 100%).

Example 72

(2 Isopropoxy-5-methanesulfonyl-phenyl)-{4-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine-1-yl}-metano

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine hydrochloride (Example 69 (e)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a white crystalline solid (yield 36%). MS (mass/charge): 492,4 (M+H+, 100%).

Example 73

[5-Methanesulfonyl-2-(2,2,2-Cryptor-1,1-dimethyl-ethoxy)-phenyl]-{4-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine-1-yl}-metano

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-1,1-dimethyl-ethoxy)-benzoic acid (Example A14) and 1-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine hydrochloride (Example 69 (e)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a white crystalline solid (yield 27%). MS mass/charge): 560,3 (M+N +, 100%).

Example 74

[5-Econsultancy-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-econsultancy-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A17) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). The crude substance was purified by obraniakowi ghvd (acetonitrile/water), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellowish crystalline solid (yield 82%). MS (mass/charge): 546,4 (M+H+, 100%).

Example 75

(5-Econsultancy-2-isopropoxy-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-econsultancy-2-isopropoxy-benzoic acid (Example A18) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). The crude substance was purified by obraniakowi ghvd (acetonitrile/water), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellowish crystalline solid (yield 21%). MS (mass/charge): 492,1 (M+N+, 100%).

Example 76

[5-Methanesulfonyl-2-(1-trifluoromethyl-propoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperaz the n-1-yl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(1-trifluoromethyl-propoxy)-benzoic acid (Example A19) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). The crude substance was purified by obraniakowi ghvd (acetonitrile/water), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellowish crystalline solid (yield 11%). MS (mass/charge): 546,3 (M+H+, 100%).

Example 77

(2-((R)-sec-Butoxy)-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-((R)-sec-butoxy)-5-methanesulfonyl-benzoic acid (Example A20) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). The crude substance was purified by obraniakowi ghvd (acetonitrile/water), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellowish crystalline solid (yield 10%). MS (mass/charge): 492,4 (M+N+, 100%).

Example 78

(2-((S)-sec-Butoxy)-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-((S)-sec-butoxy)-5-methanesulfonyl-Benz is Inoi acid (Example 21) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). The crude substance was purified by obraniakowi ghvd (acetonitrile/water), as a result of subsequent trituration in diethyl ether has been specified in the title compound as a yellowish crystalline solid (yield 13%). MS (mass/charge): 492,4 (M+N+, 100%).

Example 79

(2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

(a) rat-(3,3,3-Cryptor-1-methyl-propylsulfonyl)-benzene

To a solution 54,9 mmol of 3-iodine-1,1,1-triptorelin in 50 ml of N,N-dimethylformamide was added to 49.9 mmol of thiophenol and 74.9 mmol of potassium carbonate. This mixture was treated with ultrasound at room temperature for 90 minutes Then the reaction mixture was diluted with diethyl ether and washed three times with water. The organic phase was dried over sodium sulfate and concentrated under vacuum to obtain specified in the title compounds as colorless oil (yield 79%). MS (mass/charge): 221,3 (M+, 15%).

b) rat-(4,4,4-Cryptor-butane-2-sulfonyl)-benzene

To a solution of 39.5 mmol rat-(3,3,3-Cryptor-1-methyl-propylsulfonyl)-benzene in 80 ml dichloromethane was added 178 mmol triperoxonane acid. Then added in small portions 148 mmol of urea peroxide, and then the mixture was heated at the temperature of reflux distilled for 4 hours Then the reaction mixture was diluted with dichloromethane and n is washed successively with water, 1 N. aqueous sodium hydroxide and again with water. Then the organic phase was dried over sodium sulfate and concentrated under vacuum to obtain specified in the title compounds as colorless oil (yield 80%). EI-MS (mass/charge): 252,1 (M+, 3%), 142,1 (PhSO2H+, 100%), to 91.1 (H3CCH=CHCF3+, 20%); 78,2 (PhH+, 74%), 77,2 (Ph+, 45%).

C) rat-(4,4,4-Cryptor-2-iodine-butane-2-sulfonyl)-benzene

To a solution of 28.5 mmol of Diisopropylamine in 18 ml of tetrahydrofuran at -78°C was added dropwise a solution of 28.5 mmol n-utility (1.6 M in hexane), and then this mixture was heated to room temperature. Then the resulting solution was added dropwise over 50 min to a solution of 19.0 mmol rat-(4,4,4-Cryptor-butane-2-sulfonyl)-benzene in 30 ml of tetrahydrofuran at -78°C, and stirring was continued for another 15 min at -78°C. At the end was added dropwise over 15 min a solution of 20.9 mol of iodine in 15 ml of tetrahydrofuran, and stirring was continued for another 15 min at -78°C and then the reaction mixture was allowed to warm to -20°C. the Reaction mixture was suppressed by adding 1 M hydrochloric acid and the mixture was extracted three times with ethyl acetate. The combined organic phase was washed sequentially with an aqueous solution of thiosulfate sodium and brine and then dried over sodium sulfate and concentrated under vacuum to obtain ukazannoj is in the title compound as a yellow oil (yield 87%). EI-MS (mass/charge): 377,9 (M+, 4%), 237,0 ([M-PhSO2]+, 40%), 142,0 (PhSO2H+, 100%), 125,1 (PhSO+, 93%), 78,2 (PhH+, 40%), 77,2 (Ph+, 31%).

g) ((E)-4,4,4-Cryptor-but-2-ene-2-sulfonyl)-benzene

To a solution of 14.0 mmol rat-(4,4,4-Cryptor-2-iodine-butane-2-sulfonyl)-benzene in 25 ml of tetrahydrofuran and 2.5 ml of water was added 42.1 mmol of triethylamine and 42.1 mmol of potassium carbonate. This mesh was heated at 70°C for 6 hours Then the reaction mixture was diluted with ethyl acetate and washed successively 1 N. hydrochloric acid and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a yellow oil (yield 72%). EI-MS (mass/charge): 250,1 (M+, 15%), 186,1 ([M-SO2+, 38%), 125,0 (PhSO+, 100%), 77,1 (Ph+, 38%).

d) rat-2-Benzazolyl-2-methyl-3-trifluoromethyl-ethylene oxide

To a solution of 15.2 mmol n-utility (1.6 M in hexane), dissolved in 20 ml of tetrahydrofuran at -78°C was added dropwise a solution of 15.2 mmol tert-butylhydroperoxide (5.5 M in nonane), and the mixture was stirred at -78°C for 10 min, then was warmed to -50°C. and again cooled to -78°C. Then was added dropwise a solution of 10.1 mmol ((E)-4,4,4-Cryptor-but-2-ene-2-sulfonyl)-benzene in 6 ml of tetrahydrofuran, and stirring continue and for another 30 min at -78°C, and then the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed successively 1 M hydrochloric acid and brine. Then the organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain specified in the title compounds as colorless oil (yield 49%). EI-MS (mass/charge): 251,1 ([M-CH3]+, 6%), 250,1 ([M-O]+, 20%), 126,1 (PhSOH+, 61%), 125,0 ([M-PhSO2]+, 100%), 78,2 (PhH+, 21%), 77,2 (Ph+, 44%), 43,3 (CH3SNSN3+, 73%).

e) 4-(4-Methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl methyl ether

The mixture to 4.92 mmol rat-2-benzazolyl-2-methyl-3-trifluoromethyl-ethylene oxide and 5.41 mmol 4-thiocarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (obtained from tert-butyl 1-piperidinecarboxylate, 1,1'-thiocarbonyldiimidazole and ammonia according to the procedure described in J. Med. Chem. 1998, 41, 5037-5054) in 15 ml of N,N-dimethylformamide was heated at 100°C for 4.5 h Then the reaction mixture was concentrated under vacuum, and the residue was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a yellow crystalline solid (yield 30%). MS (mass/charge): 352,3 (M+H+, 100%).

<> W) 1-(4-Methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride

To a solution of 1.45 mmol 4-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 ml of dioxane was added dropwise a solution to 21.8 mmol of hydrogen chloride (4 M in dioxane)and the mixture was stirred at 90°C for 2 h Then the reaction mixture was cooled to 0°C and diluted with diethyl ether. The resulting crystals were collected by filtration and washed with diethyl ether to obtain specified in the title compound as a white crystalline solid (yield 68%). MS (mass/charge): 252,3 (M+H+, 100%).

C) (2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(4-methyl-5-trifluoromethyl-20 thiazol-2-yl)-piperazine hydrochloride. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a white foam (yield 52%). MS (mass/charge): 492,0 (M+H+, 100%).

Example 80

25 [5-Methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-means lpanel-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A15) and 1-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 79 (W)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a white crystalline solid (yield 56%). MS (mass/charge): 546,0 (M+H+, 100%).

Example 81

[5-Methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A16) and 1-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 79 (W)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a white crystalline solid (yield 57%). MS (mass/charge): 546,0 (M+N+, 100%).

Example 82

1-{2-[4-(2-Isopropoxy-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazol-5-yl}-propane-1-he

a) 4-(Dimethylaminomethylene-thiocarbamoyl)-piperazine-1-carboxylic acid tert-butyl methyl ether

A mixture of 122 mmol N,N-dimethylformamide-dimethylacetal and 6,11 mmol 4-thiocarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (obtained from tert-butyl 1-piperidinecarboxylate, 1,1'-thiocarbonyldiimidazole and ammonia according to the procedure described in J. Med. Chem. 1998, 41, 5037-5054) was heated at 110°C for 3 h Then d is clonney the mixture was concentrated under vacuum, and the rest resuspendable in a mixture of ethyl acetate/tetrahydrofuran (1:1) and washed with brine. The organic phase was dried over sodium sulfate and concentrated under vacuum to obtain specified in the title compound as a pale yellow crystalline solid (yield 95%). MS (mass/charge): 301,4 (M+H+, 100%).

b) 4-(5-Propionyl the thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl methyl ether

To a solution of 0.83 mmol 4-(dimethylaminomethylene-thiocarbamoyl)-piperazine-1-carboxylic acid tert-butyl ester in 6 ml of ethanol was added to 2.50 mmol of triethylamine and 1.00 mmol of 1-bromo-2-butanone. This mixture was heated at 90°C for 16 hours Then the reaction mixture was concentrated under vacuum, and the residue was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a white crystalline solid (yield 72%). MS (mass/charge): to 326.1 (M+H+, 100%).

C) 1-(2-Piperazine-1-yl-thiazol-5-yl)-propane-1-she hydrochloride

To a solution of 0.58 mmol 4-(5-propionyl the thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 6 ml of dioxane was added dropwise a solution of 8,76 mmol of hydrogen chloride (4 M in dioxane)and the mixture was stirred at 90°C for 90 minutes Then the reaction mixture was cooled to 0°C and diluted with diethyl ether. The resulting crystals were collected p is the filtration and washed with diethyl ether to obtain specified in the title compound as a white crystalline solid (yield 99%). MS (mass/charge): 226,4 (M+N+, 100%).

g) 1-{2-[4-(2-Isopropoxy-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazol-5-yl}-propane-1-he

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(2-piperazine-1-yl-thiazol-5-yl)-propane-1-she hydrochloride. The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) to obtain the specified title compound as a pale brown crystalline solid (yield 24%), MS (mass/charge): 466,0 (M+H+, 100%).

Example 83

1-{2-[4-(2-Isopropoxy-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazol-5-yl}-2,2-dimethyl-propan-1-he

a) 4-[5-(2,2-Dimethyl-propionyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl methyl ether

Was obtained in analogy to example 82 (b) from 4-(dimethylaminomethylene-thiocarbamoyl)-piperazine-1-carboxylic acid tert-butyl ester (Example 82 (a)) and 1-bromo-pinacolin. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a white crystalline solid (yield 87%). MS (mass/charge): 354,3 (M+N+, 100%).

b) 2,2-Dimethyl-1-(2-piperazine-1-yl-thiazol-5-yl)-propane-1-she hydrochloride

Was obtained in analogy to example 82 (b) of 4-[5-(2,2-dimethyl-propionyl)-thiazol-2-yl]-piperazine-1-ka is oil acid tert-butyl ester. The crude substance was purified by recrystallization from diethyl ether to obtain specified in the title compound as a white crystalline solid (yield 93%). MS (mass/charge): 254,4 (M+N+, 100%).

C) 1-{2-[4-(2-Isopropoxy-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazol-5-yl}-2,2-dimethyl-propan-1-he

Received by analogy with example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 2,2-dimethyl-1-(2-piperazine-1-yl-thiazol-5-yl)-propane-1-she hydrochloride. The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) to obtain the specified title compound as a pale brown crystalline solid (yield 28%). MS (mass/charge): 494,1 (M+N+, 100%).

Example 84

(2-Isopropylphenyl-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-isopropylphenyl-5-methanesulfonyl-benzoic acid (Example A22) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane), as a result of subsequent trituration in pentane has been specified in the title compound as a white foam (yield 50%). MS (mass/charge): 494,4 (M+H+/sup> , 100%).

Example 85

(2-Ethylsulfanyl-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-ethylsulfanyl-5-methanesulfonyl-benzoic acid (Example A23) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a white foam (yield 41%). MS (mass/charge): 479,8 (M+N+, 100%).

Example 86

[5-Methanesulfonyl-2-(2,2,2-Cryptor-ethylsulfanyl)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,2-Cryptor-ethylsulfanyl)-benzoic acid (Example A24) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a pale yellow solid (yield 49%). MS (mass/charge): 534,0 (M+H+, 100%).

Example 87

(2-Isobutylphenyl-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-isobutylphenyl-5-methanesulfonyl-benzoic acid (PR which measures A25) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a pale yellow solid (yield 88%). MS (mass/charge): 508,3 (M+H+, 100%).

Example 88

(5-Methanesulfonyl-2-methylsulfanyl-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-methylsulfanyl-benzoic acid (Example A26) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as light brown solid (yield 18%). MS (mass/charge): 466,0 (M+N+, 100%).

Example 89

(2-Morpholine-4-yl-5-nitro-phenyl)-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) 2-morpholine-4-yl-5-nitro-benzoic acid (Example A27) and 1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine trifenatate (Example 62 (b)). The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) to obtain the specified title compound as a brown solid (yield 34%). MS (mass/charge): 473,4 (M+H+, 100%).

Example 90

(2-Isopropylphenyl-5-m is canalphones-phenyl)-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-isopropylphenyl-5-methanesulfonyl-benzoic acid (Example A22) and 1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine trifenatate (Example 62 (b)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain specified in the title compounds as white solids (yield 34%). MS (mass/charge): 495,0 (M+N+, 100%).

Example 91

(2-Isopropylphenyl-5-methanesulfonyl-phenyl)-[4-(3-phenyl-[1,2,4]thiadiazole-5-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 2-isopropylphenyl-5-methanesulfonyl-benzoic acid (Example A22) and 3-phenyl-5-piperazine derivatives-1,2,4-thiadiazole. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a yellowish solid (yield 83%). MS (mass/charge): 503,1 (M+H+, 100%).

Example 92

[5-Methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(3-phenyl-[1,2,4]thiadiazole-5-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A15) and 3-phenyl-5-piperazine derivatives-1,2,4-thiadiazole. The crude substance was purified by chromatography (SiO2utilized the t/heptane) to obtain the specified title compound as light brown solid (yield 60%). MS (mass/charge): to 541.3 (M+N+, 100%).

Example 93

[5-Methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (Example A15) and 1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine trifenatate (Example 62 (b)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a yellowish solid (yield 52%). MS (mass/charge): 533,0 (M+N+, 100%).

Example 94

4 Isopropoxy-3-[4-(3-phenyl-[1,2,4]thiadiazole-5-yl)-piperazine-1-carbonyl]-benzonitrile

Received by analogy with example 1 (b) from 5-cyano-2-isopropoxy-benzoic acid (Example A28) and 3-phenyl-5-piperazine derivatives-1,2,4-thiadiazole. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain specified in the title compounds as white solids (yield 74%). MS (mass/charge): of 434.1 (M+H+, 100%).

Example 95

4 Isopropoxy-3-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-carbonyl]-benzonitrile

Received by analogy with example 1 (b) from 5-cyano-2-isopropoxy-benzoic acid (Example A28) and 1-(5-triptime the l-[1,3,4]thiadiazole-2-yl)-piperazine trifenatate (Example 62 (b)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain specified in the title compounds as white solids (yield 80%). MS (mass/charge): 426,0 (M+N+, 100%).

Example 96

2-[4-(5-Cyano-2-isopropoxy-benzoyl)-piperazine-1-yl]-thiazole-5-carbonitrile

Received by analogy with example 1 (b) from 5-cyano-2-isopropoxy-benzoic acid (Example A28) and 2-piperazine-1-yl-thiazole-5-carbonitrile (Example 6 (a)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain specified in the title compounds as white solids (yield 70%). MS (mass/charge): 382,3 (M+H+, 100%).

Example 97

2-[4-(2-Morpholine-4-yl-5-nitro-benzoyl)-piperazine-1-yl]-thiazole-5-carbonitrile

Received by analogy with example 1 (b) 2-morpholine-4-yl-5-nitro-benzoic acid (Example A27) and 2-piperazine-1-yl-thiazole-5-carbonitrile (Example 6 (a)). The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) to obtain the specified title compound as yellow solid (yield 24%). MS (mass/charge): of 429.5 (M+N+, 100%).

Example 98

(2-Morpholine-4-yl-5-nitro-phenyl)-[4-(3-phenyl-[1,2,4]thiadiazole-5-yl)-piperazine-1-yl]-methanon

Received by analogy with the example of the m 1 (b) 2-morpholine-4-yl-5-nitro-benzoic acid (Example A27) and 3-phenyl-5-piperazine derivatives-1,2,4-thiadiazole. The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as yellow solid (yield 18%). MS (mass/charge): 481,0 (M+N+, 100%).

Example 99

3-[4-(5-Cyano-thiazol-2-yl)-piperazine-1-carbonyl]-4-cyclopentyloxy-N-methyl-benzosulfimide

Received by analogy with example 1 (b) from 2-cyclopentyloxy-5-methylsulfanyl-benzoic acid (Example A29) and 1 -(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58 (C)). The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) to obtain specified in the title compounds as white solids (yield 48%). MS (mass/charge): 476,3 (M+H+, 100%).

Example 100

4 Cyclopentyloxy-N-methyl-3-[4-(3-phenyl-[1,2,4]thiadiazole-5-yl)-piperazine-1-carbonyl]-benzosulfimide

Received by analogy with example 1 (b) from 2-cyclopentyloxy-5-methylsulfanyl-benzoic acid (Example A29) and 3-phenyl-5-piperazine derivatives-1,2,4-thiadiazole. The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) to obtain the specified title compound as a yellowish solid (yield 72%). MS (mass/charge): 528,5 (M+N+, 100%).

Example 101

4 Cyclopentyloxy-N-methyl-3-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-is)-piperazine-1-carbonyl]-benzosulfimide

Received by analogy with example 1 (b) from 2-cyclopentyloxy-5-methylsulfanyl-benzoic acid (Example A29) and 1-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine trifenatate (Example 62 (b)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain specified in the title compounds as white solids (yield 46%). MS (mass/charge): 520,3 (M+H+, 100%).

Example 102

[5-Methanesulfonyl-2-(2,2,3,3,3-pendaftar-propoxy)-phenyl]-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,3,3,3-pendaftar-propoxy)-benzoic acid (Example A30) and 1 -(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine trifenatate (Example 62 (b)). The crude substance was purified by chromatography (SiO2, methanol/dichloromethane) to obtain the specified title compound as a yellowish solid (yield 56%). MS (mass/charge): 569,3 (M+N+, 100%).

Example 103

[5-Methanesulfonyl-2-(2,2,3,3,3-pendaftar-propoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon

Received by analogy with example 1 (b) from 5-methanesulfonyl-2-(2,2,3,3,3-pendaftar-propoxy)-benzoic acid (Example A30) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochlor is Yes (Example 58 (C)). The crude substance was purified by chromatography (SiO2, ethyl acetate/heptane) to obtain the specified title compound as a brown solid (yield 68%). MS (mass/charge): 568,2 (M+N+, 100%).

1. Compounds of General formula

where R1represents-OR1', -SR1'or morpholinyl;
R1'represents lower alkyl, lower alkyl substituted by halogen, or represents -(CH2)nlowest cycloalkyl;
R2represents-S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2or CN;
X1represents CR3or N;
X2represents CR3'or N;
R3/R3'independently of one another represent hydrogen, halogen, lower alkyl, CN, NO2, -S(O)2-phenyl, -S(O)2-lower alkyl, -S(O)2-pyridine-2 -, 3-or 4-yl, phenyl, possibly substituted by one or two substituents selected from the group consisting of NO2or halogen, or represents lower alkyl substituted by halogen, or represents-C(O)-lower alkyl;
n is 0, 1 or 2;
and their pharmaceutically acceptable salts accession acids.

2. Compounds according to claim 1 of formula IA

where R1represents-OR1', -SR1'or morpholinyl;
R1'represents lower alkyl, lower alkyl substituted by halogen, or represents -(CH2)nlowest cycloalkyl;
R2represents-S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2or CN;
R3/R3'independently of one another represent hydrogen, halogen, lower alkyl, CN, NO2, -S(O)2-phenyl, -S(O)2-lower alkyl, -S(O)2-pyridine-2 -, 3-or 4-yl, phenyl, possibly substituted by one or two substituents selected from the group consisting of NO2or halogen, or represents lower alkyl substituted by halogen, or represents-C(O)-lower alkyl;
n is 0, 1 or 2;
and their pharmaceutically acceptable salts accession acids.

3. Compounds according to claim 1 of formula IB

where R1represents-OR1', -SR1'or morpholinyl;
R1'represents lower alkyl, lower alkyl substituted by halogen, or represents -(CH2)nlowest cycloalkyl;
R2represents-S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2or CN;
R3represents hydrogen, halogen, lower alkyl, CN, NO2, -S(O)2-phenyl, -S(O)2-lower alkyl, -S(O)2-pyridine-2 -, 3-or 4-yl, phenyl, possibly substituted by one or two substituents selected from the group consisting of NO2or halogen, or represents lower alkyl substituted by halogen, or represents-C(O)-lower alkyl;
n is 0, 1 or 2;
and their pharmaceutically acceptable salts accession acids.

4. Compounds according to claim 1 of formula IB

where R1represents-OR1', -SR1'or morpholinyl;
R1'represents lower alkyl, lower alkyl substituted by halogen, or represents -(CH2)nlowest cycloalkyl;
R2represents-S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2or CN;
R3represents hydrogen, halogen, lower alkyl, CN, NO2, -S(O)2-phenyl, -S(O)2-lower alkyl, -S(O)2-pyridine-2 -, 3-or 4-yl, phenyl, possibly substituted by one or two substituents selected from the group consisting of NO2or halogen, or represents lower alkyl substituted by halogen, or represents-C(O)-lower alkyl;
n is 0, 1 or 2;
and their pharmaceutically acceptable salts accession acids.

5. The compounds of formula IA according to claim 2, where R1is a OR1'and R1'represents lower alkyl.

6. The compounds of formula IA according to claim 5, which represent
[4-(5-benzazolyl-thiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methane is sulfonyl-phenyl)-methanon,
2-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazole-5-carbonitrile,
2-{4-[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoyl]-piperazine-1-yl}-thiazole-5-carbonitrile,
[4-(5-benzazolyl-thiazol-2-yl)-piperazine-1-yl]-[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-phenyl]-methanon,
[4-(5-benzazolyl-thiazol-2-yl)-piperazine-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanon,
{4-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-phenyl]-methanon,
(2-((R)-sec-butoxy)-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon,
(2-((S)-sec-butoxy)-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon or
(2 isopropoxy-5-methanesulfonyl-phenyl)-[4-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon.

7. The compounds of formula IA according to claim 2, where R1is a OR1'and R1'represents lower alkyl substituted by halogen.

8. The compounds of formula IA according to claim 7, which represent
2-{4-[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-benzoyl]-piperazine-1-yl}-thiazole-5-carbonitrile,
{4-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-methyl-4-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon,
[5 methanesulfonic is-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon,
[5-methanesulfonyl-2-(2,2,2-Cryptor-1,1-dimethyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon,
[5-methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon,
[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-{4-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine-1-yl}-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-{4-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine-1-yl}-methanon,
[5-methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-{4-[5-(2,2,2-Cryptor-ethyl)-thiazol-2-yl]-piperazine-1-yl}-methanon,
[5-econsultancy-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon,
[5-methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon or
[5-methanesulfonyl-2-(2,2,3,3,3-pendaftar-propoxy)-phenyl]-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon.

9. The compounds of formula IA according to claim 2, where R1is a OR1'and R1'represents -(CH2)nlowest cycloalkyl.

10. The compounds of formula IA according to claim 9, which represent
-[4-(2-cyclobutylmethyl-5-methanesulfonyl-benzoyl)-piperazine-1-yl]-thiazole-5-carbonitrile,
[4-(5-benzazolyl-thiazol-2-yl)-piperazine-1-yl]-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanon,
{4-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine-1-yl}-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanon,
3-[4-(5-cyano-thiazol-2-yl)-piperazine-1-carbonyl]-4-cyclopentyloxy-N-methyl-benzosulfimide or
4 cyclopentyloxy-N-methyl-3-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-carbonyl]-benzosulfimide.

11. The compounds of formula IA according to claim 2, where R1represents SR1'.

12. The compound of formula IA according to claim 11, which is a
(2-isopropylphenyl-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-yl]-methanon.

13. The compound of formula IB according to claim 3, where R1is a OR1'and R1'represents lower alkyl.

14. The compound of formula IB according to item 13, which represents a (2-isopropoxy-5-methanesulfonyl-phenyl)-[4-(3-phenyl-[1,2,4]thiadiazole-5-yl)-piperazine-1-yl]-methanon.

15. The compound of formula IB according to claim 3, where R1is a OR1'and R1'represents (CH2)nlowest cycloalkyl.

16. The compound of formula IB according to § 15, which is a
4 cyclopentyloxy-N-methyl-3-[4-(3-phenyl-[1,2,4]thiadiazole-5-yl)-piperazine-1-carbonyl]-benzosulfimide.

17. The compounds of formula IB according to claim 4, where R1is a OR1'.

18. The connection is of the formula IB according to 17, which are
(2 isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon,
(2 cyclopropylmethoxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon,
(2 isobutoxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon or
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon.

19. The compound according to claim 4, which is a
(5-methanesulfonyl-2-morpholine-4-yl-phenyl)-[4-(5-trifluoromethyl-[1,3,4]thiadiazole-2-yl)-piperazine-1-yl]-methanon.

20. Drug, possessing properties of inhibitors of glycine vector 1 (GlyT-1)containing one or more than one compound according to any one of claims 1 to 19 and a pharmaceutically suitable excipients.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where R1 is selected from group, including: phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, lower alkoxy group, halogen or lower halogenalkyl; naphtyl; tetrahydronaphtyl; C3-7cycloalkyl; -(CHR3)m-phenyl, where m stands for 1, 2, or 3; and phenyl is unsubstituted or mono-, di- or tri-substituted with lower alkoxy group, and where R3 is independently selected from hydrogen and lower alkyl; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur, and heteroaryl is mono-, di- or tri-substituted independently with lower alkoxy group; and R2 is selected from group including: n-butyl; phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, halogen or lower alkoxy group; heteroaryl, where term "heteroaryl" relates to aromatic 5-member ring, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; unsubstituted or mono-, di- or tri-substituted independently with lower alkoxy group; -C(O)-NR4R5; where R4 and R5 stand for lower alkyl or together with nitrogen atom, to which they are bound, form 5-member heterocycle, which can additionally contain heteroatom, selected from N or S, and to their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, able to inhibit DPP-IV.

13 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

EFFECT: obtaining compounds and a composition which can inhibit phosphatase cdc25, particularly phosphatase cdc25-C and can be particularly used for treating cancer.

12 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on CDK1 kinase. In formula I , R1 is hydrogen or R2-(X)n-; X is a lower alkylene or cyclic lower alkylene; R2 denotes ; where denotes phenyl; cycloalkyl containing 3-6 carbon atoms; 4-6-member heterocycloalkyl ring having 3-5 carbon atoms and 1-2 oxygen atoms; R5, R6 and R7 are independently selected from a group containing hydrogen or halide; R4 is hydrogen or -(O)k(CH2CH2O)y-R10; R19 is hydrogen; R20 is hydrogen or -C(O)-R11; R10 and R11 is a lower alkyl; n and k are equal to 0 or 1; y is an integer from 0 to 3.

EFFECT: obtaining a pharmaceutical composition with inhibitory effect on CDK1 kinase, containing one or more of the disclosed compounds.

15 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

FIELD: chemistry.

SUBSTANCE: formula (I) compounds, radicals of which are defined in the formula of invention, are described. A pharmaceutical composition containing formula (I) compounds is also described.

EFFECT: obtaining compounds which have inhibitory activity on protein kinase MEK1/2 and are meant for use as a therapeutically active substance which is useful for treating MEK1/2 mediated diseases.

13 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where R1 is selected from group, including: phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, lower alkoxy group, halogen or lower halogenalkyl; naphtyl; tetrahydronaphtyl; C3-7cycloalkyl; -(CHR3)m-phenyl, where m stands for 1, 2, or 3; and phenyl is unsubstituted or mono-, di- or tri-substituted with lower alkoxy group, and where R3 is independently selected from hydrogen and lower alkyl; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur, and heteroaryl is mono-, di- or tri-substituted independently with lower alkoxy group; and R2 is selected from group including: n-butyl; phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, halogen or lower alkoxy group; heteroaryl, where term "heteroaryl" relates to aromatic 5-member ring, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; unsubstituted or mono-, di- or tri-substituted independently with lower alkoxy group; -C(O)-NR4R5; where R4 and R5 stand for lower alkyl or together with nitrogen atom, to which they are bound, form 5-member heterocycle, which can additionally contain heteroatom, selected from N or S, and to their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, able to inhibit DPP-IV.

13 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel benzothiazinone derivatives of formula (I) and their use as antibacterial agents in infectious diseases caused by bacteria, especially mycobacterium tuberculosis (TB) and leprosy, in which R1 and R2 independently denote NO2, CN, CONR7R8, COOR9 CHO, halogen, SO2NR7R8, OCF3, trifluromethyl; R3 and R4 independently denote H or methyl; R5 and R6 independently denote a straight or branched aliphatic radical having 1-8 members in the chain, or R5 and R6 together denote a divalent radical -(CR92)m- or R5 and R6 together denote a divalent radical: R7, R8 and R9 independently denote H or a straight or branched aliphatic radical having 1-7 members in the chain, or phenyl.

EFFECT: design of an efficient method of obtaining benzothiazinone derivatives, a pharmaceutical composition having anti-mycobacterial activity.

12 cl, 6 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (XXI) where values of R1, Y, Ra and Rb are given in subparagraphs 1 and 2 of the formula of invention, as phosphatidylinositol-3-kinase inhibitors, a pharmaceutical composition based on said compounds and their use.

EFFECT: compounds can be used for treating and preventing diseases mediated by phosphatidylinositol-3-kinase.

5 cl, 5 tbl, 146 ex

FIELD: medicine.

SUBSTANCE: there is described thiomorpholine compound presented by formula (I) wherein the ring A represents benzene ring; the ring B represents benzene ring; R1 represents hydrogen atom, R2 represents C1-6-alkyl group; R3a and R3b are identical or different, each representing hydrogen atom or C1-6-alkyl group, and n represents an integer equal to 2, or its pharmaceutically acceptable salt. There is also described method for making the compound of formula (1), a pharmaceutical composition and application of the compound of formula (1) for making a medical product used for treatment and prevention of the disease chosen from inflammation, allergic diseases, pain, migraine, neuralgia, itch, cough, central nervous system diseases, alimentary organ diseases, nausea, vomiting and urological disorders.

EFFECT: compounds exhibits affinity to neurokinine-1 receptor.

6 cl, 4 tbl, 16 ex

Gsk-3 inhibitors // 2379300

FIELD: medicine.

SUBSTANCE: invention concerns GSK-3 inhibitors of general formula (I), method for making thereof and based pharmaceutical compositions which can be used in medicine: formula I, where R1 means an organic group containing at least 8 atoms, chosen of C or O, including aromatic ring of phenyl, naphthyl or methylene dioxypjenyl, which is not bound directly with N through -C(O)- or oxygen; Ra, Rb, Rz, R3, R4, R5 and R6 represent hydrogen.

EFFECT: production of new biologically active compounds for treatment of GSK-3 mediated diseases.

28 cl, 13 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzyloxy-derivatives of general formula (I) , where R1 is a halogen; R2 is a 5-member heteroaryl group containing 2 or 3 heteroatoms selected from a group consisting of N, O or S, which can be substituted with R3, where R3 is a lower alkyl or -C(O)R; R is -NR'R" or lower alkoxy; R'/R" independently represent H; as well as to their pharmaceutically acceptable salts. Formula I compounds inhibit monoamine oxidase B.

EFFECT: compounds can be used for preparing a medicinal agent.

5 cl, 15 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of aryl and heteroarylpiperidinecarboxylates, of formula (I): , where: type means integer numbers from 1 to 3, such that m+n is integer number from 2 to 5; p means integer number from 1 to 7; A means simple connection or is selected from one or several groups X, Y; X means -CH2-; Y means C2-alkynilene group; R1 means group R5, substituted with one or several groups R6 and/or R7; R2 means H, F, OH; R3 means H; R4 means H, C1-6-alkyl; R5 means group selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, chinolynyl, tetrahydrochinolinyl, isochinolinyl, tetrahydroisochinolinyl, indolyl, indolinyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzizoxazolyl, benzothiazolyl, benzithiazolyl, benzotriazolyl, benzoxadiazolyl, pyrrolopyridinyl; R6 means halogen, CN, C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, OH, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, or cycle selected from pyrrolidine and piperidine cycle, besides this cycle is unnecessarily substituted with C1-6-alkyl group; R7 means phenyl group, besides group or groups R7 may be substituted with one or several groups R6, identical or differing from each other, selected from halogen, C1-6-alkyl and C1-6-fluoroalkyl, C1-6-alkoxy, in the form of pharmaceutically acceptable base or acid-additive salt.

EFFECT: compounds are applicable as inhibitors of FAAH ferment.

10 cl, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives (indole-3-yl)heterocyclic compounds of formula 1: , where: A represents 5-member aromatic heterocyclic ring, where X1, X2 and X3 are independently selected from N, O, S, CR; R means H, (C1-4)alkyl; or R, when it is available in X2 or X3, may form 5-8-member ring together with R3; R1 means 5-8-member saturated carbocyclic ring, which unnecessarily contains heteroatom O; R2 means H; or R2 is connected to R7 with creation of 6-member ring, which unnecessarily contains heteroatom O, or where mentioned heteroatom is connected to position 7 of indole ring; R3 and R4 independently mean H, (C1-6)alkyl, which is unnecessarily substituted with OH, (C1-4)alkyloxy; or R3 together with R4 and N, with which they are connected, creates 4-8-member ring, which unnecessarily contains additional heteroatom, selected from O and S, and unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy or (C1-4)alkyloxy-(C1-4)alkyl; or R3 together with R5 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; or R3 together with R, when present in X2 or X3, creates 5-8-member ring; R5 means H; or R5 together with R3 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; R5' means H; R6 means one substituent selected from H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; R7 means H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; or R7 is connected to R2 with creation of 6-member ring, which unnecessarily contains additional heteroatom O, and where heteroatom is connected to position 7 of indole ring; or its pharmaceutically acceptable salt. Compounds of formula I display activity of agonists to cannabinoid receptor CB1.

EFFECT: possibility to use them for treatment of pains of various nature.

10 cl, 1 tbl, 42 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new chroman derivatives of formula I: , or to their pharmaceutically acceptable salts where m has a value of 0; p has a value of 2; q has a value of 2; Ar represents phenyl optionally substituted with halogen atom; R2 represents ; X represents -NR9-; n has a value of 2 or 3; each R3, R4, R5 and R6 independently represents hydrogen or C1-12alkyl; each R7 and R8 independently represents either hydrogen, or C1-12-alkyl, or R7 and R8 together with nitrogen whereto attached, can form 4-6-members ring, or one of R7 and R8 and one of R5 and R6 together with atoms whereto attached can form 4-6-members ring; and R9 represents hydrogen or C1-12-alkyl, or when R7 represents hydrogen or methyl, R9 together with R8 and atoms whereto attached can form 6-members ring.

EFFECT: preparation of chroman new derivatives and the pharmaceutical composition containing compounds of formula (I).

22 cl, 1 tbl, 5 ex

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