Phenyl-piperazine methanone derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula

, where R1 is a

or or or group, R2 is morpholine or OR' or N(R")2; R' is a lower alkyl, a lower alkyl substituted with a halogen, or -(CH2)n-cycloalkyl; R" is a lower alkyl; R is NO2 or SO2R'; R4 is hydrogen, hydroxy, halogen, NO2, lower alkoxy, SO2R' or C(O)OR"; R5/R6/R7 denote hydrogen, halogen, lower alkyl; X'/X1 denote CH or N, provided that X1 /X1' are not CH at the same time; X2 is O or S; n equals 0 or 1, and to their pharmaceutically active acid-addition salts. The invention also relates to a drug.

EFFECT: obtaining novel biologically active compounds which are active as glycine transporter 1 inhibitors.

11 cl, 24 ex, 1 tbl

 

The present invention relates to compounds of General formula

where

R1represents a group

oror

or;

R2represents the non-aromatic heterocycle or represents OR' or N(R")2;

R' represents lower alkyl, lower alkyl substituted by halogen, or

-(CH2)n-cycloalkyl;

R" represents lower alkyl;

R3represents NO2CN or SO2R';

R4represents hydrogen, hydroxy, halogen, NO2, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, SO2R' or C(O)OR";

R5/R6/R7represent hydrogen, halogen, lower alkyl or lower alkyl substituted by halogen;

X1/X1'represent CH or N, provided that X1/X1'they are CH;

X2represents O, S, NH or N(lower alkyl);

n represents 0, 1 or 2;

and to pharmaceutically active acid additive salts.

The present invention relates to compounds of General formula I, a process for the production of these compounds, to pharmaceutical compositions containing them and to their use for Leche is the research Institute of neurological and neuropsychiatric diseases.

It has been unexpectedly found that compounds of General formula 1 are good inhibitors of the carrier glycine 1 (GlyT-1) and that they have a high selectivity to inhibitors vector glycine 2 (GlyT-2).

The present invention includes the following compounds of formula IA, IB, IB and Iك:

The compound of the formula

where

R2represents the non-aromatic heterocycle or represents OR' or N(R")2;

R' represents lower alkyl, lower alkyl substituted by halogen, or

-(CH2)n-cycloalkyl;

R" represents lower alkyl;

R3represents NO2CN or SO2R';

R4represents hydrogen, hydroxy, halogen, NO2, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, SO2R' or C(O)OR";

X1represents CH or N;

X2represents O, S, NH or N(lower alkyl);

n represents 0, 1 or 2;

and pharmaceutically active acid additive salt.

The compound of the formula

where

R2represents the non-aromatic heterocycle or represents OR' or N(R")2;

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

R" represents particularly the lower alkyl;

R3represents NO2CN or SO2R';

R5represents hydrogen, halogen, lower alkyl or lower alkyl substituted by halogen;

X1represents CH or N;

X2represents O, S, NH or N(lower alkyl);

n represents 0, 1 or 2;

and pharmaceutically active acid additive salt.

The compound of the formula

where

R2represents the non-aromatic heterocycle or represents OR' or N(R")2;

R' represents lower alkyl, lower alkyl substituted by halogen, or

-(CH2)n-cycloalkyl;

R" represents lower alkyl;

R3represents NO2CN or SO2R';

R6represents hydrogen, halogen, lower alkyl or lower alkyl substituted by halogen;

X1/X1'represent CH or N, provided that X1/X1'they are CH;

n represents 0, 1 or 2;

and pharmaceutically active acid additive salt.

The compound of the formula

where

R2represents the non-aromatic heterocycle or represents OR' or N(R")2;

R' represents lower alkyl, lower alkyl substituted by halogen, or

-(CH2)n

R" represents lower alkyl;

R3represents NO2CN or SO2R';

R7represents hydrogen, halogen, lower alkyl or lower alkyl substituted by halogen;

X1represents CH or N;

X2represents O, S, NH or N(lower alkyl);

n represents 0, 1 or 2;

and pharmaceutically active acid additive salt.

It has been unexpectedly found that compounds of General formula I are good inhibitors of the carrier glycine 1 (GlyT-1) and that they have a high selectivity to inhibitors vector glycine 2 (GlyT-2).

Schizophrenia is a progressive and destructive neurological disease characterized by periodic positive symptoms such as delusions, hallucinations, mental disorders and psychosis, and persistent negative symptoms such as blunted affect, impaired attention and social withdrawal, and cognitive impairments (Lewis DA and Lieberman JA, Neuron, 2000, 28: 325-33). For decades, research has focused on the hypothesis that dopaminergic hyperactivity disorder", which has led to therapeutic treatment, including the blockade of the dopaminergic system (Vandenberg RJ and Aubrey KR., Exp.Opin. Ther. Targets, 2001, 5(4): 507-518; Nakazato A and Okuyama S, et al., 2000, Exp.Opin. Ther. Patents, 10(1): 75-98). This pharmacologic the RCM approach is poorly consistent with the negative and cognitive symptoms, which are the best indicators of functional outcome (Sharma So, Br.J. Psychiatry, 1999, 174 (suppl. 28): 44-51).

The complementary model of schizophrenia proposed in the mid-1960's, was based on psychotomimetics action caused by the blockade of the glutamate system connections similar to phencyclidine (PCP) and related agents (ketamine), which are non-competitive antagonists of the NMDA receptor. Interestingly, in healthy volunteers PCP-induced psychotomimetic action unites both positive and negative symptoms and cognitive dysfunction, thus strongly resembling schizophrenia patients (Javitt DC, et al., 1999, Biol. Psychiatry, 45: 668-679 and Ref. here). In addition, transgenic mice expressing reduced levels of NMDAR1 subunit, show behavioral abnormalities similar to those observed in pharmacologically induced models of schizophrenia, confirming the model in which reduced activity of the NMDA receptor leads to behavior that is similar to schizophrenia (Mohn AR, et al., 1999, Cell 98: 427-236).

Glutamic neurotransmission, in particular the activity of the NMDA receptor plays a pivotal role in synaptic plasticity, learning and memory, as it is believed that NMDA receptors serve as differential switch for synchronization limit synaptic plasticine and and memory formation (Hebb DO, 1949 The organization of behavior, Wiley, NY, Bliss TV and Collingridge GL, 1993, Nature, 361: 31-39). Transgenic mouse sverkhekspressiya NMDA NR2B subunit, show increased synaptic plasticity and significant capacity for learning and memory (Tang JP, et al., 1999, Nature: 401: 63-69).

Thus, if the pathophysiology of schizophrenia includes the lack of glutamate, it is possible to predict that increased glutamate transmission, in particular by activation of the NMDA receptor will cause as antipsychotic effects, and the effects of increasing cognitive function.

It is known that the amino acid glycine, which performs at least two important functions in the CNS. Acts as an inhibitory amino acid, binding is sensitive to strychnine glycine receptors, and also affects the excitatory activity, acting as the primary coagonist with glutamate for the function of the receptor N-methyl-O-aspartate (NMDA). When glutamate is released from synaptic endings dependent on the activity method, glycine, surely there on a more permanent level, and it is believed that modulates/controls the receptor to its response to glutamate.

One of the most effective ways to control synaptic neurotransmitter concentrations is to affect their re-uptake at the synapse. The vectors of the neurotransmitter, removing neurotransmitters from the extracellular what blasty, can control their extracellular lifetime and, therefore, modulate the magnitude of synaptic transmission (Gainetdinov RR et al, 2002, Trends in Pharm. Sci., 23(8): 367-373).

Vectors glycine, which are part of sodium chloride and a family of vectors of the neurotransmitter, plays an important role in completing the postsynaptic glycinergic action and the maintenance of low extracellular concentration of glycine in the course of re-absorption of glycine into the presynaptic nerve endings accurate and surrounding glial processes.

Two different gene vectors glycine were cloned (GlyT-1 and GlyT-2) of the mammalian brain, they give rise to two vectors with the homology of the amino acid sequence of ~50%. GlyT-1 is present in four isoforms, resulting from alternative splicing and alternative uses of the promoter (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. Two GlyT-2 isoforms (2A and 2b) were identified in the brain of rodents. It is known that GlyT-1 is located in the Central nervous system and peripheral tissues, whereas GlyT-2 is typical of the Central nervous system. GlyT-1 has a predominantly glial distribution and is found not only in areas relevant sensitive to strychnine glycine receptors, but t is the train outside of these areas, where, as is involved in the modulation of the function of the NMDA receptor (Lopez-Corcuera In et al., 2001, Mol. Mem. Biol., 18: 13-20). Thus, one method of increasing the activity of the NMDA receptor is to increase the concentration of glycine in the local microenvironment of synaptic NMDA receptors during inhibition carrier GlyT-1 (Bergereon R. Et al., 1998, Proc. Natl. Acad. Sci. USA, 95: 15730-15734; Chen L et al., 2003, J. Neurophysiol., 89 (2): 691-703).

Inhibitors vectors glycine suitable for treatment of neurological and neuropsychiatric diseases. Most implied painful conditions is a psychosis, schizophrenia (Armer RE and Miller DJ, 2001, Exp. Opin. Ther. Patents, 11 (4): 563-572), psychotic mood disorders such as severe major depressive disorder, 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., 2002, Prog. Neurobiol., 67: 173-202), autistic disease (Carlsson ML, 1998, J. Neural Transm. 105: 525-535), cognitive disorders such as dementia, including age-related dementia and senile dementia type Alzheimer's disease, memory disorders in mammals, including humans, a syndrome of attention deficit and pain (Armer RE and Miller DJ, 2001, Exp. Opin. Ther. Patents, 11 (4): 563-572).

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

Objects of the present invention are the compounds of formula I as such, the use of compounds of the formula I and their farmacevtichesky acceptable salts for the manufacture of medicaments for the treatment of diseases related to activation of NMDA receptors via inhibition of GlyT-1, their manufacture, medicaments based on a compound according to this invention, and their manufacture, as well as the use of compounds of formula I for the treatment or prevention of illnesses 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.

The preferred readings of using compounds of the present invention are schizophrenia, a cognitive disorder, and Alzheimer's disease.

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

Used herein, the term "lower alkyl" means a saturated unbranched or branched group containing from 1 to 7 carbon atoms, for example methyl, ethyl, propyl, ISO-propyl, n-butyl, ISO-butyl, 2-BU the sludge, tert-butyl and the like, Preferred alkyl groups are groups with 1-4 carbon atoms.

Used herein, the term "lower alkoxy" means a saturated unbranched or branched group containing from 1 to 7 carbon atoms, as defined above, and which is attached via an oxygen atom.

Used herein, the term "cycloalkyl" means a saturated carbon ring, containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclopentyl or cyclohexyl.

Used herein, the term "the non-aromatic heterocycle" means a five - or six-membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of O, N or S. Preferred rings are 1-pyrrolidine, 1-piperidine, 1-piperazine or 1-morpholine.

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

Used herein, the term "lower alkyl substituted by halogen" denotes an alkyl group as defined above where at least one hydrogen atom substituted with halogen, for example CF3, CHF2CH2F, CH2CF3etc.

The term "pharmaceutically acceptable acid additive salts" includes salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, is Umarova acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, p-toluensulfonate acid, etc.

The most preferred compounds of formula I are compounds of formula IA and IB.

Preferred compounds of formula IA are as follows:

[4-(6-chloro-benzothiazol-2-yl)-piperazine-1-yl]-(2-morpholine-4-yl-5-nitro-phenyl)-methanon,

[4-(6-chloro-benzothiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon,

(4-benzoxazol-2-yl-piperazine-1-yl)-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanon,

(4-benzoxazol-2-yl-piperazine-1-yl)-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanon,

(2 isopropoxy-5-methanesulfonyl-phenyl)-[4-(6-methoxy-benzothiazol-2-yl)-piperazine-1-yl]-methanon,

(2 isopropoxy-5-methanesulfonyl-phenyl)-[4-(6-nitro-benzothiazol-2-yl)-piperazine-1-yl]-methanon,

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

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

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

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

[4-(6-ethoxy-benzothiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon,

[4-(6-chloro-benzothiazol-2-yl)piperazine-1-yl]-(2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-methanon or

[4-(6-chloro-benzothiazol-2-yl)-piperazine-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon.

Preferred compounds of formula IB are

(2 isobutoxy-5-methanesulfonyl-phenyl)-(4-(quinoline-2-yl-piperazine-1-yl)-methanon,

[4-(6-chloro-quinoline-2-yl)-piperazine-1-yl]-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanon,

(2 isobutoxy-5-methanesulfonyl-phenyl)-(4-cinoxacin-2-yl-piperazine-1-yl)-methanon,

(2 isopropoxy-5-methanesulfonyl-phenyl)-(4-cinoxacin-2-yl-piperazine-1-yl)-methanon,

(2 cyclopentyloxy-5-methanesulfonyl-phenyl)-(4-cinoxacin-2-yl-piperazine-1-yl)-methanon,

(2 isobutoxy-5-methanesulfonyl-phenyl)-(4-quinoline-3-yl-piperazine-1-yl)-methanon or

(2 cyclopentyloxy-5-methanesulfonyl-phenyl)-(4-quinoline-3-yl-piperazine-1-yl)-methanon.

The preferred compound of formula IB is

(2 isobutoxy-5-methanesulfonyl-phenyl)-[4-(2-methyl-benzothiazol-5-yl)-piperazine-1-yl]-methanon.

Preferred compounds of formula Iك represent

(4-benzo[d]isothiazol-3-yl-piperazine-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon,

(4-benzo[d]isothiazol-3-yl-piperazine-1-yl)-(2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-methanon or

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

These compounds of formula I and their pharmaceutically PR is acceptable salts can be obtained is known from the prior art methods, for example, the methods described below, in which

a) compound of the formula

subjected to interaction with the compound of the formula

in the presence of an activating agent, such as TBTU,

obtaining the compounds of formula

where the substituents are as defined above, or

b) the compound of the formula

subjected to interaction with the compound of the formula

in the presence of a base such as potassium carbonate, or adding a catalyst that is similar to the Cu(I)I

obtaining the compounds of formula

where the substituents R1, R2and R3are as defined above, and X represents a halogen, or

C) the compound of the formula

subjected to interaction with the compound of the formula

obtaining the compounds of formula

where the substituents R1and R3are as defined above, and R' represents lower alkyl, lower alkyl substituted by halogen, or -(CH2)n- cycloalkyl, and X represents a halogen, or

g) the compound of the formula

subjected to interaction with the compound of the formula

when the reaction conditions, Mitsunobu

obtaining the compounds of formula

where the substituents R1and R3are as defined above, and R' represents lower alkyl, lower alkyl substituted by halogen, or -(CH2)n- cycloalkyl, and

if desired, transfer the compounds obtained into pharmaceutically acceptable acid additive salt.

The compounds of formula I can be obtained according to the options of the methods a), b), C) or d) and in the following schemes 1, 2, 3 and 4. All source materials are either commercially available, described in the literature, or they can be well-known from prior art methods.

The following abbreviation is used:

TBTU = (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylpropylenediamine)

Scheme 1

Obtaining compounds of formula II and I:

where R1, R2and R3are as described above, R12represents hydrogen or a protective group such as tert-butyloxycarbonyl or benzyloxycarbonyl, and X represents a halogen, mesilate or triplet.

When X is an activated leaving group (for example, in ortho-position to the nitrogen atom), connect four is uly X get heating the compound of formula VIII in the presence of the compounds of formula IX and a base such as potassium carbonate or sodium, in a suitable solvent, such as alcohol, acetone or acetonitrile.

When X is non-activated leaving group, compound X get known reactions combination catalyzed by Pd or Cu, between the compounds of formulas VIII and IX (see example S.L.Buchwald EA., Org. Lett. 4, 581 (2002) or J.F.Hartwig ea., JOC 67, 6479 (2002)).

When R12is a protective group, removing the protective group known from the prior art methods provides compounds of formula II. Then the compound of formula II is treated with a compound of formula III in the presence of TBTU and a base, such as N-ethyldiethanolamine, obtaining the compounds of formula I.

Scheme 2

Obtaining compounds of formula III:

where R2and R3are as described above, and Gal means halogen.

The compounds of formula III can be obtained in the usual way. If H-R2is a non-aromatic heterocycle such as morpholine, the reaction is carried out at room temperature for approximately 2 hours.

If R2is OR', where R' represents lower alkyl, lower alkyl substituted by halogen, or -(CH2)n-cycloalkyl, the reaction is carried out with the appropriate alcohol of formula V Rea is tion with a mixture of compounds of formula XI and Cu(I)Br in triethylamine.

Scheme 3

Obtaining compounds of the formula I:

where R1, R2and R3are as described above and X represents halogen.

X can be replaced with R2the usual way in the presence of a base, such as triethylamine, or adding a catalyst that is similar to the Cu(I)Br.

Scheme 4

Obtaining compounds of the formula I2:

where R', R1and R3are as described above and X represents halogen.

Acid additive salts of basic compounds of formula I can be converted into the corresponding free base when processing at least a stoichiometric equivalent of a suitable base, such as sodium hydroxide or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, etc.

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

Compounds investigated under test, below.

Solutions and materials

Complete DMEM: nutrient mixture F-12 (Gibco life technologies), fetal calf serum (FBS) and 5% (Gibco life technologies), penicillin/streptomycin 1% (Gibco life technologies), hygromycin 0.6 mg/is l (Gibco life technologies), the 1 mm glutamine (Gibco life technologies).

Buffer absorption (BP): 150 mm NaCl, 10 mm Hepes-Tris, pH of 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 cDNA mGlyT1b.

Analysis of the inhibition of the absorption of glycine (mGlyT-1b)

On the first day of mammalian cells (Flp-in™-CHO), transfetsirovannyh mGlyT-1b cDNA, were sown at a density of 40,000 cells/well in complete medium F-12 without hygromycin on 96-well culture plates. On the second day, the medium was aspirated and cells washed twice with buffer absorption (BP). Then cells were incubated for 20 minutes at 22°C (i) in the absence of a potential competitor, (ii) with 10 mm non-radioactive glycine, (iii) with some potential concentration of inhibitor. Used a range of concentrations of the potential inhibitor, to generate data for calculating the concentration of inhibitor causing 50% effect (e.g., IR50concentrations of competitor, inhibiting the uptake of glycine by 50%). Then directly added to the solution containing 60 nm (11-16 CI/mmol) [3H]-glycine and 25 μm non-radioactive glycine. The plates were incubated at weak shaking and the reaction was stopped by aspiration of the mixture and washing (three times) with ice PSU. Cells were subjected to lysis with scintillation fluid was shaken for 3 hours and radioactives the cells were counted, using scintillation counter.

The preferred compounds show IR50(μm) when GlyT-1<0.5 in.

Example No.IR50(µm)Example No.IR50(µm)
1.1 formula IA0,2711,15 formula IA0,339
1.2 formula IA0,3981.17 formula IB0,440
1.4 formula IA0,0971,23 formula IB0,167
1.5 formula IA0,1441.24 formula IB0,287
1.8 formula IA0,1741,25 formula IB0,067
1.9 formula IA0,2061,27 formula IB0,082
1,11 formula IA0,1481,28 formula IB 0,149
1,12 formula IA0,3751,29 formula Iك0,500
1,13 formula IA0,1581.31 formula Iك0,467
1,14 formula IA0,2181,33 formula Iك0,055
1,19 formula IB0,0781,39 formula IA0,230
1.22 formula IB0,3991,40 formula IA0,039

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. The 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, can be effective rectal administration, for example in the form of suppositories, or parenterally, for example in the form of solutions for injection.

The compounds of formula I can be processed with pharmaceutical the Ki inert, inorganic or organic carriers for pharmaceutical drugs. Lactose, corn starch or its derivatives, talc, stearic acid or its salts etc can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules. 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 for soft gelatin capsules carriers usually are not required. Suitable carriers for the receiving of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils, etc. 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, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for regulating the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

Drugs, containing a compound of formula 1 or its pharmaceutically acceptable salt and a therapeutically inert wear the spruce, also are the subject of the present invention, as the method of their manufacture, in which one or more compounds of formula 1 and/or pharmaceutically acceptable acid additive salts and, if required, one or more other therapeutically valuable substances turn into herbal dosage form together with one or more therapeutically inert carrier.

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

The dosage may vary within wide limits and, of course, must be chosen according to individual requirements in each particular case. 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 dosage can be entered as a single dose or divided doses, and, in addition, the upper limit can be exceeded when it is established that it is necessary.

Manufacturing of tablets (wet granulation)
PointsComponentsmg tablet
5 mg25 mg100 mg500 mg
1The compound of formula IA or IB525100500
2Anhydrous lactose DTG12510530150
3Sta-Rx 150066630
4Microcrystalline cellulose303030150
5Magnesium stearate1111
167167167831

The procedure of production

1. Mix 1, 2, 3 and 4 and granularit with purified water.

2. Dry the granules at 50°C.

3. Pass the granules through a suitable milling equipment.

4. Add 5 and stirred for three minutes; pressed under the appropriate pressure.

Manufacturing capsules
PointsComponentsmg/capsule
5 mg25 mg100 mg500 mg
1The compound of formula IA or IB525100500
2Water lactose159123148-
3Corn starch 25354070
4Talc10151025
5Magnesium stearate1225
Only200200300600

The procedure of production

1. Mix 1, 2 and 3 in a suitable mixer for 30 minutes.

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

3. Fill a suitable capsule.

The following examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius.

All source materials are either commercially available, described in the literature (see, SA room), or you can get them well-known from prior art methods.

Example 1.1

Obtain [4-(6-chloro-benzothiazol-2-yl)-piperazine-1-yl]-(2-morpholine-4-yl-5-nitro-phenyl)-methanone

a) 6-Chloro-2-piperazine-1-yl-benzothiazole

A mixture of 10 mmol of 2,6-dichlorobenzothiazole, 12.3 mmol of piperazine and 20 mmol of potassium carbonate in 50 ml of acetonitrile was heated under reflux for 3 hours. The reaction mixture was concentrated and treated with 25 ml water. Extraction with ethyl acetate, drying over magnesium sulfate and evaporation of the solvent gave specified in the title compound as a colourless solid. MS (m/e): 254,7 (MH+).

b) [4-(6-Chloro-benzothiazol-2-yl)-piperazine-1-yl]-(2-morpholine-4-yl-5-nitro-phenyl)-methanon

To a solution of 0.25 mmol of 2-morpholine-4-yl-5-nitro-benzoic acid (example 2.1) in 0.7 ml of dimethylformamide was sequentially added 0.26 mmol TBTU, 1.6 mmol of N-ethyldiethanolamine and 0.25 mmol of 6-chloro-2-piperazine-1-yl-benzothiazole. The reaction mixture was then stirred at room temperature for two hours, concentrated in vacuo and treated with 5 ml of water. The solid was filtered and recrystallized from methanol to obtain specified in the title compound as a yellow solid. MS (m/e): 488,1 (M+H+).

Example 1.2

Obtain [4-(6-chloro-benzothiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone

Was obtained in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) and 6-chloro-2-piperaz the n-1-yl-benzothiazole. The crude material was purified by chromatography (SiO2CH2Cl2/Meon = 95/5) to obtain the specified title compound as a yellowish solid. MS (m/e): 552,3 (M+CH3COOH+).

Example 1.3

Receive (4-benzoxazol-2-yl-piperazine-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone

a) Tert-butyl ether 4-benzoxazol-2-yl-piperazine-1-carboxylic acid

A mixture of 52.5 mmol of 2-chlorobenzoxazole, 53.6 mmol tert-butyl ether piperazine-1-carboxylic acid and 63 mmol of potassium carbonate in 60 ml of acetonitrile was heated under reflux for 16 hours. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated to obtain specified in the title compounds as a pale orange solid. MS (m/e): 304,2 (M+H+).

b) Hydrochloride of 2-piperazine-1-yl-benzoxazole

the 10.8 mmol tert-butyl ester 4-benzoxazol-2-yl-piperazine-1-carboxylic acid was treated with 30 ml of dioxane saturated with gaseous hydrochloric acid. The heterogeneous mixture was stirred at room temperature for 1 hour before evaporating the solvent. Got mentioned in the title compound as a colourless solid. MS (m/e): 2041 (M+H +).

in) (4-Benzoxazol-2-yl-piperazine-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon

Was obtained in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) hydrochloride and 2-piperazine-1-yl-benzoxazole. The crude material is triturated with diethyl ether to obtain specified in the title compound as a colourless solid. MS (m/e): 444,1 (M+H+).

Example 1.4

Receive (4-benzoxazol-2-yl-piperazine-1-yl)-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanone

Was obtained in analogy to example 1.1 b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (example 2.3) hydrochloride and 2-piperazine-1-yl-benzoxazole. The crude material was purified by chromatography (SiO2, ethyl acetate) to obtain the specified title compound as a colourless solid. MS (m/e): 470,1 (M+N+).

Example 1.5

Receive (4-benzoxazol-2-yl-piperazine-1-yl)-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone

Was obtained in analogy to example 1.1 b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) hydrochloride and 2-piperazine-1-yl-benzoxazole. The crude material was purified by chromatography (SiO2, ethyl acetate) to obtain the specified reception in the e connection in the form of a pale yellow solid. MS (m/e): 458,1 (M+H+).

Example 1.6

Receive (2 cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(5-econsultancy-benzoxazol-2-yl)-piperazine-1-yl]-methanone

a) 5-Econsultancy-benzoxazol-2-thiol

100 mmol of 1-amino-5-ethylsulfonyl-2-hydroxybenzoyl was dissolved in 200 ml of ethanol and 150 ml of carbon disulfide. Added 120 mmol of potassium hydroxide and the mixture was heated under reflux overnight. The solvent is evaporated, the residue was treated with 1 M hydrochloric acid, was extracted with ethyl acetate and dried. Evaporation gave the crude product, which was recrystallized from ethyl acetate to obtain specified in the title compound as a yellowish solid. MS (m/e): 242,4 (M-N).

b) 2-Chloro-5-econsultancy-benzoxazol

8 mmol of 5-econsultancy-benzoxazol-2-thiol was dissolved in 10 ml of thionyl chloride. Added 1 drop of N,N-dimethylformamide and the reaction mixture was kept at 65°C for 45 minutes. Evaporation of the solvent gave specified in the title compound as a brownish solid. MS (m/e): 262,9 (M+NH4+).

C) Tert-butyl ester 4-(5-econsultancy-benzoxazol-2-yl)-piperazine-1-carboxylic acid

A mixture of 8.1 mmol of 2-chloro-5-econsultancy-benzoxazole, 8.3 mmol tert-butyl ether p is perazin-1-carboxylic acid and 9.8 mmol of potassium carbonate in 20 ml of acetonitrile was heated under reflux for 16 hours. The reaction mixture was cooled, concentrated in vacuo and treated with 50 ml water. Extraction with ethyl acetate and recrystallization from a concentrated solution of ethyl acetate gave specified in the title compound as a brownish solid. MS (m/e): 454,4 (M+CH3Soo).

g) of the Hydrochloride of 5-econsultancy-2-piperazine-1-yl-benzoxazole

the 10.8 mmol tert-butyl ester 4-(5-econsultancy-benzoxazol-2-yl)-piperazine-1-carboxylic acid was treated with 256 ml of dioxane saturated with gaseous hydrochloric acid. The heterogeneous mixture was stirred overnight at room temperature. Evaporation of the solvent gave specified in the title compound as a colourless solid. MS (m/e): usd296.4 (M+H+).

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

Was obtained in analogy to example 1.1 b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (example 2.3), and hydrochloride of 5-econsultancy-2-piperazine-1-yl-benzoxazole. The crude material was purified by chromatography (SiO2, ethyl acetate) to obtain the specified title compound as a colourless solid. MS (m/e): 562,3 (M+H+).

Example 1.7

Obtain [4-(5-econsultancy-benzoxazol-2-yl)-piperazine-1-the l]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone

Was obtained in analogy to example 1.1 b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) hydrochloride and 5-econsultancy-2-piperazine-1-yl-benzoxazole. The crude material was purified by chromatography (SiO2, ethyl acetate) to obtain the specified title compound as a colourless solid. MS (m/e): 550,2 (M+N+).

Example 1.8

Receive (2 isopropoxy-5-methanesulfonyl-phenyl)-[4-(6-methoxy-benzothiazol-2-yl)-piperazine-1-yl]-methanone

a) 6-Methoxy-2-piperazine-1-yl-benzothiazole

A mixture of 1.50 mmol 2-chloro-6-methoxybenzothiazole (SA=[2605-14-3]), 4,51 mmol of piperazine and 4.51 mmol of triethylamine in 5 ml of tetrahydrofuran in a closed vessel was heated at 160°C for 5 minutes under 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 solid. MS (m/e): 250,3 (M+H+).

b) (2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(6-methoxy-benzothiazol-2-yl)-piperazine-1-yl]-methanon

Was obtained in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) and 6-methoxy-2-piperazine-1-yl-benzothiazole in tetrahydrofuran. Raw mater what al was purified by chromatography (SiO 2, heptane/ethyl acetate) to obtain the specified title compound as a white foam. MS (m/e): 490,3 (M+H+).

Example 1.9

Receive (2 isopropoxy-5-methanesulfonyl-phenyl)-[4-(6-nitro-benzothiazol-2-yl)-piperazine-1-yl]-methanone

a) 6-Nitro-2-piperazine-1-yl-benzothiazole

A mixture of 1.40 mmol of 2-chloro-6-nitrobenzothiazole (SA=[2407-11-6]), 4,19 mmol of piperazine and 4.19 mmol of triethylamine in 5 ml of tetrahydrofuran in a closed vessel was heated at 160°C for 10 minutes under 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 yellow solid. MS (m/e): 264,9 (M+H+).

b) (2 Isopropoxy-5-methanesulfonyl-phenyl)-[4-(6-nitro-benzothiazol-2-yl)-piperazine-1-yl]-methanon

Was obtained in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) and 6-nitro-2-piperazine-1-yl-benzothiazole in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate) and then the resulting residue is triturated in ether to obtain specified in the title compound as a yellow solid. MS (m/e): 505,3 (M+H+).

Example 1.10

Obtaining methyl ester (2-[4-(2-isopropoxy-5-methanol who were radioactive-benzoyl)-piperazine-1-yl]-benzothiazole-4-carboxylic acid

Was obtained in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) and methyl ester hydrochloride 2-piperazine-1-yl-benzothiazole-4-carboxylic acid in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate) and then the resulting residue is triturated in ether to obtain specified in the title compounds as white solids. MS (m/e): 518,5 (M+N+).

Example 1.11

Receive (2 isopropoxy-5-methanesulfonyl-phenyl)-[4-(4-methoxy-benzothiazol-2-yl)-piperazine-1-yl]-methanone

Was obtained in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2), and hydrochloride of 4-methoxy-2-piperazine-1-yl-benzothiazole in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate) and then the resulting residue is triturated in ether to obtain specified in the title compounds as white solids. MS (m/e): 490,5 (M+H+).

Example 1.12

Receive (2 isopropoxy-5-methanesulfonyl-phenyl)-[4-(4-nitro-benzothiazol-2-yl)-piperazine-1-yl]-methanone

Was obtained in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2), and hydrochloride of 4-nitro-2-piperazine-1-yl-benzothiazole in t is traditionale. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate) and then the resulting residue is triturated in ether to obtain specified in the title compounds as white solids. MS (m/e): 505,3 (M+N+).

Example 1.13

Obtain [4-(4-hydroxy-benzothiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone

Was obtained in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) hydrochloride and 2-piperazine-1-yl-benzothiazol-4-ol in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate) and then the resulting residue is triturated in ether to obtain specified in the title compounds as white solids. MS (m/e): 476,0 (M+N+).

Example 1.14

Obtain [4-(5-chloro-benzothiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone

a) 5-Chloro-2-piperazine-1-yl-benzothiazole

A mixture of 0.49 mmol of 2,5-dichlorobenzothiazole (SA=[2941-48-2]), 1,47 mmol of piperazine and 1.47 mmol of triethylamine in 5 ml of tetrahydrofuran in a closed vessel was heated at 160°C for 5 minutes under microwave radiation. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to obtain specified in the header is the connection in the form of a white solid. MS (m/e): 254,1 ({35Cl}M+H+), 256,2 ({37Cl}M+H+).

b) [4-(5-Chloro-benzothiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon

Was obtained in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) and 5-chloro-2-piperazine-1-yl-benzothiazole in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate) and then the resulting residue is triturated in ether to obtain specified in the title compounds as white solids. MS (m/e): 494,3

({35Cl}M+N+), 496,2 ({37Cl}M+N+).

Example 1.15

Obtain [4-(6-ethoxy-benzothiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone

a) 6-Ethoxy-2-piperazine-1-yl-benzothiazole

A mixture of 1.36 mmol 2-chloro-6-ethoxy-benzothiazole (SA=[79071-17-3]), 3.00 mmol of piperazine and 3.00 mmol of triethylamine in 5 ml of tetrahydrofuran in a closed vessel was heated at 160°C for 5 minutes under 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 solid. MS (m/e): 264,3 (M+H+).

b) [4-(6-Ethoxy-benzothiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-m is the Thanon

Was obtained in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) and 6-Ethoxy-2-piperazine-1-yl-benzothiazole in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate) and then the resulting residue is triturated in ether to obtain specified in the title compounds as white solids. MS (m/e): 504,1 (M+N+).

Example 1.16

Receive (2 isopropoxy-5-methanesulfonyl-phenyl)-[4-(2-methyl-benzothiazol-5-yl)-piperazine-1-yl]-methanone

a) Tert-butyl ester 4-(2-methyl-benzothiazol-5-yl)-piperazine-1-carboxylic acid

To a mixture of 1.3 mmol of 5-bromo-2-methylbenzothiazole, 1.4 mmol piperazine-1-carboxylic acid, 2.0 mmol of potassium hydroxide, 0.01 mmol of bis(tri-tert-butylphosphine)palladium and 0.01 mmol of cetyltrimethylammonium bromide in 1 ml of toluene was added 1 drop of water. The reaction mixture was heated overnight in an argon atmosphere at 90°C. the Addition of water and extraction with ethyl acetate gave a brownish oil, which was purified by chromatography (SiO2, cyclohexane/ethyl acetate 7:3) to obtain the specified title compound as a yellowish solid. MS (m/e): 334,4 (M+H+).

b) Hydrochloride of 2-methyl-5-piperazine-1-yl-benzothiazole

Received by analogy the AI by example 1.6 g) of tert-butyl ester 4-(2-methyl-benzothiazol-5-yl)-piperazine-1-carboxylic acid and dioxane, saturated with gaseous hydrochloric acid. MS (m/e): 234,1 (M+N+).

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

Was obtained in analogy to example 1.1 b) of the hydrochloride of 2-methyl-5-piperazine-1-yl-benzothiazole and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Rubbing in diethyl ether gave specified in the title compound as a yellowish solid. MS (m/e): 474,1 (M+H+).

Example 1.17

Receive (2 isobutoxy-5-methanesulfonyl-phenyl)-[4-(2-methyl-benzothiazol-5-yl)-piperazine-1-yl]-methanone

Was obtained in analogy to example 1.1 b) of the hydrochloride of 2-methyl-5-piperazine-1-yl-benzothiazole and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as a brownish solid. MS (m/e): 488,4 (M+H+).

Example 1.18

Receive (2 isopropoxy-5-methanesulfonyl-phenyl)-(4-(quinoline-2-yl-piperazine-1-yl)-methanone

a) Tert-butyl ether 4-quinoline-2-yl-piperazine-1-carboxylic acid

A mixture of 6.1 mmol 2-chlorhydrin, 6.7 mmol tert-butyl ether piperazine-1-carboxylic acid and 12.2 mmol of potassium carbonate in 15 ml of acetonitrile was heated with about the feats of the fridge all night. The reaction mixture was concentrated, added water and the compound was extracted with ethyl acetate. Chromatography (SiO2, cyclohexane/ethyl acetate, 9/1) gave specified in the title compound as a colourless solid. MS (m/e): 314,3 (M+H+).

b) Hydrochloride of 2-piperazine-1-yl-quinoline

Was obtained in analogy to example 1.6 g), from tert-butyl ether 4-quinoline-2-yl-piperazine-1-carboxylic acid and dioxane saturated with gaseous hydrochloric acid. MS (m/e): 214,4 (M+H+).

C) (2 Isopropoxy-5-methanesulfonyl-phenyl)-(4-(quinoline-2-yl-piperazine-1-yl)-methanon

Was obtained in analogy to example 1.1 b) of the hydrochloride of 2-piperazine-1-yl-quinoline and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Rubbing in diethyl ether gave specified in the title compound as yellowish foam. MS (m/e): 454,4 (M+N+).

Example 1.19

Receive (2 isobutoxy-5-methanesulfonyl-phenyl)-(4-(quinoline-2-yl-piperazine-1-yl)-methanone

Was obtained in analogy to example 1.1 b) of the hydrochloride of 2-piperazine-1-yl-quinoline and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as a yellowish solid. MS (m/): 468,4 (M+H +).

Example 1.20

Obtain [4-(6-chloro-quinoline-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone

a) Tert-butyl ester 4-(6-chloro-quinoline-2-yl)-piperazine-1-carboxylic acid

Received by analogy with example 1.18 a) of 2,6-dichlorohydrin and tert-butyl methyl ether piperazine-1-carboxylic acid. Crystallization from methanol gave specified in the title compound as a colourless solid. MS (m/e): 348,5 (M+N+).

b) Hydrochloride of 6-chloro-2-piperazine-1-yl-quinoline

Was obtained in analogy to example 1.6 g) of tert-butyl ester 4-(6-chloro-quinoline-2-yl)-piperazine-1-carboxylic acid and dioxane saturated with gaseous hydrochloric acid. MS (m/e): 248,1 (M+H+).

C) [4-(6-Chloro-quinoline-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon

Was obtained in analogy to example 1.1 b) of the hydrochloride of 6-chloro-2-piperazine-1-yl-quinoline and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as yellowish foam. MS (m/e): 488,1 (M+H+).

Example 1.21

Obtain [4-(6-chloro-quinoline-2-yl)-piperazine-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone

Come and by analogy with example 1.1 (b) of the hydrochloride of 6-chloro-2-piperazine-1-yl-quinoline and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as a colourless solid. MS (m/e): 503,1 (M+H+).

Example 1.22

Obtain [4-(6-chloro-quinoline-2-yl)-piperazine-1-yl]-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanone

Was obtained in analogy to example 1.1 b) of the hydrochloride of 6-chloro-2-piperazine-1-yl-quinoline and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (example 2.3) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as a colourless solid. MS (m/e): 515,1 (M+H+).

Example 1.23

Receive (2 isobutoxy-5-methanesulfonyl-phenyl)-(4-cinoxacin-2-yl-piperazine-1-yl)-methanone

a) Tert-butyl ether 4-cinoxacin-2-yl-piperazine-1-carboxylic acid

A mixture of 9.1 mmol 2-chlorphenoxamine, 10.0 mmol tert-butyl ether piperazine-1-carboxylic acid, of 22.8 mmol of potassium carbonate and 2.1 mmol of potassium iodide in 20 ml of toluene was heated under reflux overnight. The reaction mixture was cooled, poured into water and was extracted 3 times with ethyl acetate. The organic phase was dried, evaporated, and indicated in the title compound crystallized from methanol. Yellowish solid. MS (m/e): 315,0 (M+H+).

b) Hydrochloride of 2-piperazine-1-yl-cinoxacin

Was obtained in analogy to example 1.6 g), from tert-butyl ether 4-cinoxacin-2-yl-piperazine-1-carboxylic acid and dioxane saturated with gaseous hydrochloric acid. MS (m/e): 215,4 (M+N+).

C) (2 Isobutoxy-5-methanesulfonyl-phenyl)-(4-cinoxacin-2-yl-piperazine-1-yl)-methanon

Was obtained in analogy to example 1.1 b) of the hydrochloride of 2-piperazine-1-yl-finokalia and 2 isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as yellowish foam. MS (m/e): 527,3 (M+CH3Soo).

Example 1.24

Receive (2 isopropoxy-5-methanesulfonyl-phenyl)-(4-cinoxacin-2-yl-piperazine-1-yl)-methanone

Was obtained in analogy to example 1.1 b) of the hydrochloride of 2-piperazine-1-yl-finokalia and 2 isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as yellowish foam. MS (m/e): 455,5 (M+H+).

Example 1.25

Receive (2 cyclopentyloxy-5-methanesulfonyl-phenyl)-(4-cinoxacin-2-yl-piperazine-1-yl)-methanone

Was obtained in analogy to example 1.1 b) of the hydrochloride of 2-piperazine-1-yl-finokalia and 2 cyclopentyloxy-5-methanesulfonyl-benzoic acid (example is 2.3) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as yellowish foam. MS (m/e): 481,5 (M+H+).

Example 1.26

Receive (2 isopropoxy-5-methanesulfonyl-phenyl)-(4-quinoline-3-yl-piperazine-1-yl)-methanone

a) Tert-butyl ether 4-quinoline-3-yl-piperazine-1-carboxylic acid

Received by analogy with example 1.18 a) from 3-brainline and tert-butyl methyl ether piperazine-1-carboxylic acid. Chromatography (SiO2, cyclohexane/ethyl acetate, 1/1) after crystallization from diethyl ether/cyclohexane gave specified in the title compound as a colourless solid. MS (m/e): 314,2 (M+H+).

b) Hydrochloride of 3-piperazine-1-yl-quinoline

Was obtained in analogy to example 1.6 g), from tert-butyl ether 4-quinoline-3-yl-piperazine-1-carboxylic acid and dioxane saturated with gaseous hydrochloric acid. Yellow solid. MS (m/e): 214,4 (M+H+).

C) (2 Isopropoxy-5-methanesulfonyl-phenyl)-(4-quinoline-3-yl-piperazine-1-yl)-methanon

Was obtained in analogy to example 1.1 b) of the hydrochloride of 3-piperazine-1-yl-quinoline and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as a colourless is received. MS (m/e): 454,5 (M+N+).

Example 1.27

Receive (2 isobutoxy-5-methanesulfonyl-phenyl)-(4-quinoline-3-yl-piperazine-1-yl)-methanone

Was obtained in analogy to example 1.1 b) of the hydrochloride of 3-piperazine-1-yl-quinoline and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as a colourless solid. MS (m/e): 468,3 (M+N+).

Example 1.28

Receive (2 cyclopentyloxy-5-methanesulfonyl-phenyl)-(4-quinoline-3-yl-piperazine-1-yl)-methanone

Was obtained in analogy to example 1.1 b) of the hydrochloride of 3-piperazine-1-yl-quinoline and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (example 2.3) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as a colourless solid. MS (m/e): 480,3 (M+H+).

Example 1.29

Receive (4-benzo[d]isothiazol-3-yl-piperazine-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone

Was obtained in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2), and hydrochloride of 3-piperazine-1-yl-benzo[d]isothiazole (SA=87691-88-1) in dimethylformamide. The crude material was purified by HPLC (Bond XDB, reversed phase, water/acetonitrile) with what rucenim specified in the title compound as a white foam. MS (m/e): 460,3 (M+H+).

Example 1.30

Receive (4-benzo[d]isothiazol-3-yl-piperazine-1-yl)-(2-diethylamino-5-methanesulfonyl-phenyl)-methanone

Was obtained in analogy to example 1.1 b) from 2-diethylamino-5-methanesulfonyl-benzoic acid (example 2.5), and hydrochloride of 3-piperazine-1-yl-benzo[d]isothiazole (SA=87691-88-1) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as a colourless solid. MS (m/e): 473,4 (M+H+; 100%).

Example 1.31

Receive (4-benzo[d]isothiazol-3-yl-piperazine-1-yl)-(2-morpholine-4-yl-5-nitro-phenyl)-methanone

Was obtained in analogy to example 1.1 b) from 2-morpholine-4-yl-5-nitro-benzoic acid (example 2.1) and hydrochloride 3-piperazine-1-yl-benzo[d]isothiazole (SA=87691-88-1) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as a colourless solid. MS (m/e): 454,2 (M+H+; 100%).

Example 1.32

Receive (4-benzo[d]isothiazol-3-yl-piperazine-1-yl)-(2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-methanone

Was obtained in analogy to example 1.1 b) from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (example 2.6), and hydrochloride of 3-piperazine-1-yl-benzo[d]isothiazole (SA=87691-88-1) in acetonitrile. Chromatography (SiO2, ethyl acetate) giving the La is indicated in the title compound as a colourless solid. MS (m/e): 472,1 (M+H+; 100%).

Example 1.33

Receive (4-benzo[d]isothiazol-3-yl-piperazine-1-yl)-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanone

Was obtained in analogy to example 1.1 b) from 5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (example 2.7), and hydrochloride of 3-piperazine-1-yl-benzo[d]isothiazole (SA=87691-88-1) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as a colourless solid. MS (m/e): 514,1 (M+H+; 37%).

Example 1.34

Obtain [4-(6-chloro-quinoline-2-yl)-piperazine-1-yl]-(2-diethylamino-5-methanesulfonyl-phenyl)-methanone

Was obtained in analogy to example 1.1 b) of the hydrochloride of 6-chloro-2-piperazine-1-yl-quinoline (example b) and 2-diethylamino-5-methanesulfonyl-benzoic acid (example 2.5) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as a colourless solid. MS (m/e): 501,4 (M+H+; 100%).

Example 1.35

Obtain [4-(6-chloro-quinoline-2-yl)-piperazine-1-yl]-(2-morpholine-4-yl-5-nitro-phenyl)-methanone

Was obtained in analogy to example 1.1 b) of the hydrochloride of 6-chloro-2-piperazine-1-yl-quinoline (example b) and 2-morpholine-4-yl-5-nitro-benzoic acid (example 2.1) in acetonitrile. Chromatography (SiO2e is ylacetic) gave specified in the title compound as a colourless solid. MS (m/e): RUB 482.2 (M+H+; 100%).

Example 1.36

Obtain [4-(6-chloro-quinoline-2-yl)-piperazine-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanone

Was obtained in analogy to example 1.1 b) of the hydrochloride of 6-chloro-2-piperazine-1-yl-quinoline (example b) and 5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (example 2.7) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as a colourless solid. MS (m/e): USD 542.3 (M+H+; 100%).

Example 1.37

Obtain [4-(6-chloro-quinoline-2-yl)-piperazine-1-yl]-(2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-methanone

Was obtained in analogy to example 1.1 b) of the hydrochloride of 6-chloro-2-piperazine-1-yl-quinoline (example b) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (example 2.6) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as a colourless solid. MS (m/e): 500,3 (M+H+; 100%).

Example 1.38

Obtain [4-(6-chloro-benzothiazol-2-yl)-piperazine-1-yl]-(2-diethylamino-5-methanesulfonyl-phenyl)-methanone

Was obtained in analogy to example 1.1 b) from 5-chloro-2-piperazine-1-yl-benzothiazole (example a) and 2-diethylamino-5-methanesulfonyl-benzoic acid (example 2.5) in acetonitrile. X is omatography (SiO 2, ethyl acetate) gave specified in the title compound as a colourless solid. MS (m/e): are 507, 5 (M+N+; 100%).

Example 1.39

Obtain [4-(6-chloro-benzothiazol-2-yl)-piperazine-1-yl]-(2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-methanone

Was obtained in analogy to example 1.1 b) from 5-chloro-2-piperazine-1-yl-benzothiazole (example a) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (example 2.6) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as a colourless solid. MS (m/e): 506,3 (M+H+; 100%).

Example 1.40

Obtain [4-(6-chloro-benzothiazol-2-yl)-piperazine-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanone

Was obtained in analogy to example 1.1 b) from 5-chloro-2-piperazine-1-yl-benzothiazole (example a) and 5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoic acid (example 2.7) in acetonitrile. Chromatography (SiO2, ethyl acetate) gave specified in the title compound as a colourless solid. MS (m/e): 548,2 (M+H+; 100%).

Example 2.1

Getting 2-morpholine-4-yl-5-nitro-benzoic acid

To a solution of 2-fluoro-5-nitrobenzoic acid (a 4.86 g, to 26.2 mmol) in dioxane (50 ml) was added morpholine (11.5 ml). The mixture was stirred pikantnoi temperature for 2 hours. The solvent was removed in vacuum. The residue was dissolved in water and the mixture was acidified using 2 N. HCl. The solid was filtered, washed with water and dried to obtain specified in the title compound (6.2 g, 93%) as a yellow solid. MS (m/e): 251,2 (M-H; 100%).

Example 2.2 Obtaining 2-isopropoxy-5-methanesulfonyl-benzoic acid

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

To 99 mmol of 2-chloro-5-(methylthio)benzoic acid in 400 ml of methanol at 0°C was added 296 mmol Oxone® and the mixture was stirred 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 were washed 2 times with 300 ml of 1 N. HCl and 300 ml saturated aqueous NaCl and dried with MgSO4. Evaporation under reduced pressure gave specified in the header of the connection.

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

A mixture of 2.13 mmol of 2-chloro-5-methanesulfonyl-benzoic acid, 0.64 mmol Cu(I)Br in 5 ml NEt3and 25 ml of isopropanol was heated to 120°C for 16 hours in a closed vessel. Volatile components were removed in vacuum and the residue was placed in 70 ml of 1 N. HCl. Extraction with ethyl acetate, drying of the combined organic fractions and evaporation gave the OST is OK which was purified using reverse-phase preparative HPLC, elwira gradient acetonitrile/water. Evaporation of the product fractions gave specified in the header connection. MS (m/e): 257,0 (MN-; 100%).

Example 2.3 Obtaining 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid

Received by analogy with example 2.2 (b) from 2-chloro-5-methanesulfonyl-benzoic acid and Cyclopentanol. MS (m/e): 282,9 (MH-; 100%).

Example 2.4 Obtaining 2-isobutoxy-5-methanesulfonyl-benzoic acid

Received by analogy with example 2.2 (b) from 2-chloro-5-methanesulfonyl-benzoic acid and Isobutanol. MS (m/e): 271,1 (MN-; 100%).

1. Compounds of General formula

where R1represents a group
oror
or;
or R2represents a morpholine or represents OR' or N(R")2;
R' represents lower alkyl, lower alkyl substituted by halogen, or -(CH2)n-cycloalkyl;
R" represents lower alkyl;
R3represents NO2or SO2R';
R4represents hydrogen, hydroxy, halogen, NO2, lower alkoxy, SO2R' or C(O)OR";
R5/R6/R represent hydrogen, halogen, lower alkyl;
X1/Xl'represent CH or N, provided that X1/X1'they are CH;
X2represents O or S;
n represents 0 or 1;
and pharmaceutically active acid additive salt.

2. The compound of formula IA according to claim 1, where R1is a group And,

where R2represents a morpholine or represents OR' or N(R")2;
R' represents lower alkyl, lower alkyl substituted by halogen, or -(CH2)n-cycloalkyl;
R" represents lower alkyl;
R3represents NO2or SO2R';
R4represents hydrogen, hydroxy, halogen, NO2, lower alkoxy, SO2R' or C(O)OR";
X1represents CH or N;
X2represents O or S;
n represents 0 or 1;
and pharmaceutically active acid additive salt.

3. The compound of formula IB according to claim 1, where R1is a group B,

where R2represents maronil or represents OR' or N(R")2;
R' represents lower alkyl, lower alkyl substituted by halogen, or -(CH2)n-cycloalkyl;
R" represents lower alkyl;
R3represents the t of a NO 2or SO2R';
R5represents hydrogen, halogen, lower alkyl;
X1represents CH or N;
X2represents O or S;
n represents 0 or 1;
and pharmaceutically active acid additive salt.

4. The compound of formula IB according to claim 1, where R1is a group,

where R2represents a morpholine or represents OR' or N(R")2;
R' represents lower alkyl, lower alkyl substituted by halogen, or -(CH2)n-cycloalkyl;
R" represents lower alkyl;
R3represents NO2or SO2R';
R6represents hydrogen, halogen, lower alkyl;
X1/X1'represent CH or N, provided that X1/X1'they are CH;
n represents 0 or 1;
and pharmaceutically active acid additive salt.

5. The compound of formula Iك according to claim 1, where R1is a group G,

where R2represents a morpholine or represents OR' or N(R")2;
R' represents lower alkyl, lower alkyl substituted by halogen, or -(CH2)n-cycloalkyl;
R" represents lower alkyl;
R3represents NO2or SO2R';
R7before the hat is hydrogen, halogen, lower alkyl;
X1represents CH or N;
X2represents O or S;
n represents 0 or 1;
and pharmaceutically active acid additive salt.

6. The compounds of formula IA according to claim 2, which represent
[4-(6-chloro-benzothiazol-2-yl)-piperazine-1-yl]-(2-morpholine-4-yl-5-nitro-phenyl)-methanon,
[4-(6-chloro-benzothiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon,
(4-benzoxazol-2-yl-piperazine-1-yl)-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanon,
(4-benzoxazol-2-yl-piperazine-1-yl)-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanon,
(2 isopropoxy-5-methanesulfonyl-phenyl)-[4-(6-methoxy-benzothiazol-2-yl)-piperazine-1-yl]-methanon,
(2 isopropoxy-5-methanesulfonyl-phenyl)-[4-(6-nitro-benzothiazol-2-yl)-piperazine-1-yl]-methanon,
(2 isopropoxy-5-methanesulfonyl-phenyl)-[4-(4-methoxy-benzothiazol-2-yl)-piperazine-1-yl]-methanon,
(2 isopropoxy-5-methanesulfonyl-phenyl)-[4-(4-nitro-benzothiazol-2-yl)-piperazine-1-yl]-methanon,
[4-(4-hydroxy-benzothiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon,
[4-(5-chloro-benzothiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon,
[4-(6-ethoxy-benzothiazol-2-yl)-piperazine-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon,
[4-(6-chloro-benzothiazol-2-yl)-piperazine-1-yl]-(2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-Manon or
[4-(6-chloro-benzothiazol-2-yl)-piperazine-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon.

7. The compounds of formula IB according to claim 3, one of which is a
(2 isobutoxy-5-methanesulfonyl-phenyl)-[4-(2-methyl-benzothiazol-5-yl)-piperazine-1-yl]-methanon.

8. The compounds of formula IB according to claim 4, which represent
(2 isobutoxy-5-methanesulfonyl-phenyl)-(4-(quinoline-2-yl-piperazine-1-yl)-methanon,
[4-(6-chloro-quinoline-2-yl)-piperazine-1-yl]-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanon,
(2 isobutoxy-5-methanesulfonyl-phenyl)-(4-cinoxacin-2-yl-piperazine-1-yl)-methanon,
(2 isopropoxy-5-methanesulfonyl-phenyl)-(4-cinoxacin-2-yl-piperazine-1-yl)-methanon,
(2 cyclopentyloxy-5-methanesulfonyl-phenyl)-(4-cinoxacin-2-yl-piperazine-1-yl)-methanon,
(2 isobutoxy-5-methanesulfonyl-phenyl)-(4-quinoline-3-yl-piperazine-1-yl)-methanon or
(2 cyclopentyloxy-5-methanesulfonyl-phenyl)-(4-quinoline-3-yl-piperazine-1-yl)-methanon.

9. The compounds of formula Iك according to claim 5, which represent
(4-benzo[d]isothiazol-3-yl-piperazine-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon,
(4-benzo[d]isothiazol-3-yl-piperazine-1-yl)-(2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-methanon or
(4-benzo[d]isothiazol-3-yl-piperazine-1-yl)-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon.

10. Drug, possess activity as inhibitors is of erteschik glycine 1, containing one or more compounds according to any one of claims 1 to 9, and pharmaceutically acceptable excipients.

11. The medication of claim 10 for the treatment of Alzheimer's disease.



 

Same patents:

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; medicine.

SUBSTANCE: invention relates to 3-phenylpropionic acid derivatives of formula (I) as ligand of peroxisome proliferator-activated gamma-receptor (PPARγ), to their pharmaceutically acceptable salts, as well as to their application, treatment method and based on them pharmaceutical composition. Compounds can be applied for treatment and prevention of diseases mediated by peroxisome proliferator-activated gamma-receptor (PPARγ), for instance type 2 diabetes, insulin-resistance, metabolic syndrome, complications resulting from or connected with diabetes, cardio-vascular dysfunctions, atherosclerosis, obesity, cognition disturbances and lipid metabolism derangements. In general formula (I): W represents COOH or -COO-C1 - C4-alkyl group; Y represents NH; Z represents S or O; X represents O; R1 - R8 each independently represents hydrogen atom or halogen atom; A represents mono-, bi- or tri-cyclic 5-13-member heteroaryl with 1 or 2 heteroatoms selected from N, S or O, aryl, selected from phenyl and naphtyl, or -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, where heteroaryl is optionally substituted with 1-3 substituents, independently selected from group, consisting of C1-C4-alkyl, CN, phenyl halogen and phenyl, optionally substituted with 1-3 substituents, independently selected from C1-C4alkoxy, halogen and ethylenedioxy-group; and n represents integer number from 0 to 3 including; and their pharmaceutically acceptable salts.

EFFECT: increased efficiency of composition and treatment method.

20 cl, 14 dwg, 10 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of formula (I) and its pharmaceutically acceptable salts and esters. Compounds of the present invention are characterised with properties of DGAT-1 inhibitor. In general formula (I) , Q represents O, S or NR5; A represents a linker chosen from where p is equal to 1 or 2, and , where m is equal to 0, and n is equal to 1, 2, 3 or 4, or m is equal to 1, while n is equal to 1, 2 or 3, where specified linker is optionally substituted with one or two groups R8; R1 and R2 are independently chosen from hydrogen, haloid; R3 is chosen from hydrogen, (C1-C6)alkyl optionally substituted with hydroxyl and phenyl optionally substituted with haloid; R4 is chosen from hydrogen, nitro and (C1-C6)alkyl; or R3 and R4 together with carbon atoms whereto attached, can form benzene ring optionally substituted with 1-2 substitutes. The invention also concerns compounds of formula (Ia) and (Ib) with structural formulas presented in the patent claim, and also to a pharmaceutical composition, a medical product, to application of compounds for making a medical product and compound process.

EFFECT: new compounds possess useful biological activity.

19 cl, 2 tbl, 7 dwg, 215 ex

FIELD: chemistry.

SUBSTANCE: invention concerns benzothiazole derivatives of general formula (I) and their pharmaceutically acceptable salts as adenosine receptor ligands and based medicinal product. Compounds can be applied in treatment and prevention of diseases mediated by A2A adenosine receptors, such as Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease. In the general formula (I) , R1 is C5-C6-cycloalkyl substituted by CF3 group, lower alkyl, -(CH2)nOH or -(CH2)n-O- lower alkyl, or is 1-bicyclo[2,2,1]hept-2-yl, 1-(7-oxa-bicyclo[2,2,1]hept-2-yl, 1-(5-exo-hydroxybicyclo[2,2,1]hept-2-exo-yl, 1-(5-exo-hydroxybicyclo[2,2,1]hepto-2-endo-yl, or is 1-adamantane-1-yl; R2 is lower alkyl; or R1 and R2 together with N atom form 8-oxa-3-aza-bicyclo[3,2,1]octane group, n is 0 or 1.

EFFECT: improved efficiency of treatment.

9 cl, 2 dwg, 15 ex

FIELD: chemistry.

SUBSTANCE: invention concerns benzothiazole derivatives of general formula (1) and their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands with high affinity to A2A adenosine receptor, and based medicine. Compounds can be applied in treatment and prevention of diseases mediated by A2A adenosine receptors, such as Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease. In general formula (I) , R is C5-C6-cycloalkyl non-substituted or substituted by hydroxy group, or is ethyl or isobutyl, or is tetrahydropyrane-4-yl or -(CH2)n-tetrahydrofurane-2 or 3-yl or is 5-hydroxybicyclo[2,2,1]hept-2-yl; X is CH or N; n is 0 or 1.

EFFECT: enhanced efficiency of composition and treatment method.

12 cl, 2 dwg, 14 ex

FIELD: chemistry.

SUBSTANCE: this invention refers to new compounds of formula (Ia) and to their pharmaceutically acceptable salts. Compounds of this invention are characterised by CB1 receptor antagonist properties. In formula (Ia) , R1 means phenyl independently mono-, di- or tri-substituted with haloid, (lower)alkoxy, (lower)alkyl, halogenated (lower)alkoxy or di(lower)alkylamino; R2 means phenyl, independently mono-, di- or tri-substituted with haloid, halogenated (lower)alkyl, nitro or cyano; R3 means hydrogen, nitro, amino, -NHSO2-R3a or -NHCO-R3b; R3a means (lower)alkyl, di(lower)alkylamino, benzyl, phenyl or phenyl monosubstituted with (lower)alkyl; R3b means benzyl or phenyl monosubstituted with (lower)alkyl.

EFFECT: application of compounds thereof as therapeutically active substance with CB1 receptor agonist properties and to relevant pharmaceutical composition.

18 cl, 1 dwg, 5 tbl, 70 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula II as neuropeptide FF receptor antagonist, their pharmaceutically acceptable acid-additive salts, medication based on them, as well as their application. Compounds can be applied for treatment and prevention of diseases mediated by activity of neuropeptide FF receptor, such as pain, hyperalgesia, enuresis, for elimination of syndromes arising in case of alcohol, psychotropic and nicotine addiction, for regulation of insulin release, digestion, memory functions, blood pressure or electrolytic and energy exchange. In general formula II , A together with thiazole ring forms 4,5,6,7-tetrahydrobenzothiazole, 5,6,7,8-tetrahydro-4H-cycloheptathiazole, 5,6-dihydro-4H-cyclopentathiazole fragments; R1 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tret-butyl, 1,1-dimethylpropyl or phenyl; R2-R6 each represents hydrogen or methyl.

EFFECT: obtaining solutions, which ca be used for treatment and prevention of diseases, mediated by activity of neuropeptide FF receptor.

6 cl, 4 tbl, 106 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole. Method involves the following successive steps: (i) interaction of bromine with 4-acetamidocyclohexanone an aqueous solution to yield 2-bromo-4-acetamidocyclohexanone; (ii) addition of thiourea to yield 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole; (iii) addition of hydrobromic acid an aqueous solution to yield 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole without isolation of 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole synthesized at stage (ii); (iv) isolation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole and if necessary separation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole isolated at stage (iv) for R-(+)- and S-(-)-enantiomers, and isolation of R-(+)- and/or S-(-)-enantiomer. 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole is used for synthesis of pramipexole. Also, invention relates to a method for synthesis of pramipexole by synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole by using the method said and its conversion to pramipexole and if necessary by separation of pramipexole for its R-(+)- and S-(-)-enantiomers and isolation of R-(+)- and/or S-(-)-enantiomer.

EFFECT: improved method of synthesis.

15 cl, 1 sch, 3 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds that possess affinity for adenosine A2A-receptors and represent compounds of the general formula: wherein R1 and R2 represent independently hydrogen atom, lower alkyl, tetrahydropyrane-2,3- or 4-yl, -(CH2)n-O-lower alkyl, -C(O)-lower alkyl, -(CH2)n-C(O)-lower alkyl, -(CH2)n-C(O)-NR'R'', -(CH2)n-phenyl substituted optionally with lower alkyl, lower alkoxy-group or -(CH2)n-pyridinyl, -(CH2)n-tetrahydropyrane-2,3- or 4-yl, -C(O)-piperidine-1-yl; or R1 and R2 in common with nitrogen atom (N) to which they are added form the ring 2-oxa-5-azabicyclo[2,2,1]hept-5-yl; R3 represents lower alkoxy-group, phenyl substituted optionally with halogen atom, -(CH2)n-halogen or -(CH2)n-N(R')-(CH2)n+1-O-lower alkyl, or represents pyridinyl substituted optionally with lower alkyl, halogen atom or morpholinyl; n means 1 or 2; R'/R'' represent independently of one another hydrogen atom or lower alkyl, and their pharmaceutically acceptable acid-additive salt. Except for, invention relates to a medicinal agent showing affinity to adenosine A2A-receptors containing one or some compounds by any claims 1-11, and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of compounds and agents.

13 cl, 38 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing a substituted alkylamine derivative from the 2-aminothiophenol compound with high industrial yield that can be used as an intermediate compound used in medicine or in agriculture. Invention proposes a method for preparing substituted alkylamine derivative represented by the following general formula (3): wherein X mean halogen atom, alkyl group, alkoxy-group, cyano-group or nitro-group; n means a whole number from 1 to 4; each R1 and R2 means independently hydrogen atom of phenyl-substituted, or unsubstituted alkyl group that can in common form 5- or 6-membered cycle, or its additive acid salt. Method involves addition of 2-aminothiophenol derivative salt represented by the following formula (1): wherein X and n have abovementioned values to acid to provide pH value 6 or less and to convert salt to free 2-aminothiophenol derivative of the general formula (1) followed by addition of 2-aminothiophenol derivative with amino-N-carboxyanhydride to the reaction represented by the following general formula (2): wherein each R1 and R2 have abovementioned values. Invention provides the development of a method for unimpeded preparing 1-(2-benzothiazolyl)-alkylamine derivative, i. e. substituted alkylamine derivative from the 2-aminothiophenol derivative with the satisfactory industrial yield and without pollution of the environment.

EFFECT: improved preparing method, valuable properties of compound.

8 cl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein A means benzene ring optionally substituted with one or more the following groups: -OR2 wherein R2 mean linear or branched (C1-C5)-alkyl; X means -CH=, -CH2-, -N= or -NH-radical; Y means radical -CH2, oxygen or sulfur atom or group -NR7 wherein R7 means hydrogen atom or linear or branched (C1-C5)-alkyl; R1 means hydrogen atom, linear or branched (C1-C5)-alkyl, and to pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition showing anti-diabetic activity. The pharmaceutical composition comprises compound of the general formula (I) as an active component and an inert excipient. Invention provides bicyclic derivatives of guanidine eliciting anti-diabetic activity.

EFFECT: valuable medicinal properties of compounds and composition.

8 cl, 2 tbl, 4 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing a substituted alkylamine derivative from the 2-aminothiophenol compound with high industrial yield that can be used as an intermediate compound used in medicine or in agriculture. Invention proposes a method for preparing substituted alkylamine derivative represented by the following general formula (3): wherein X mean halogen atom, alkyl group, alkoxy-group, cyano-group or nitro-group; n means a whole number from 1 to 4; each R1 and R2 means independently hydrogen atom of phenyl-substituted, or unsubstituted alkyl group that can in common form 5- or 6-membered cycle, or its additive acid salt. Method involves addition of 2-aminothiophenol derivative salt represented by the following formula (1): wherein X and n have abovementioned values to acid to provide pH value 6 or less and to convert salt to free 2-aminothiophenol derivative of the general formula (1) followed by addition of 2-aminothiophenol derivative with amino-N-carboxyanhydride to the reaction represented by the following general formula (2): wherein each R1 and R2 have abovementioned values. Invention provides the development of a method for unimpeded preparing 1-(2-benzothiazolyl)-alkylamine derivative, i. e. substituted alkylamine derivative from the 2-aminothiophenol derivative with the satisfactory industrial yield and without pollution of the environment.

EFFECT: improved preparing method, valuable properties of compound.

8 cl, 13 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing amido acid ester that is useful as an intermediate substance in synthesis of agrochemical preparation. Invention relates to amido acid ester represented by compound of the general formula (7): wherein A represents substituted or free lower alkylene group, and so on; R1 represents substituted or free lower alkyl group, and so on; R3 represents hydrogen atom or lower alkyl group. Method for preparing amido acid ester involves interaction of amino acid represented by compound of the general formula (1): in presence of water with halogenated carboxylic acid ester represented by compound of the general formula (2): wherein X represents halogen atom with formation of amide represented by compound of the formula (3): Then amide compound interacts with halogenated carboxylic acid ester represented by compound of the general formula (4): wherein R2 represents substituted or free lower alkyl group, and so on; X represents halogen atom with preparing carboxylic acid mixed anhydride represented by compound of the general formula (5): Then carboxylic acid mixed anhydride interacts with amine compound represented by compound of the general formula (6): A, R1 and R3 have the same values as given above; Het represents substituted of free heterocyclic group. Invention provides reducing economic indices of the process.

EFFECT: improved preparing method.

9 cl, 2 ex

The invention relates to new derivatives of asola General formula I, where R1and R2the same or different, each represents hydrogen, cycloalkyl and so forth, or R1and R2forming (a) a condensed ring, (b) or (C), which may be optionally substituted substituted lower alkyl, amino group and the like; R3, R6, R7, R8the same or different, each represents a hydrogen atom, and so on; R4represents a cyano, tetrazolyl, -COOR9and so on; R5represents a hydrogen atom or lower alkyl; D represents optionally substituted lower alkylene; X and Z are the same or different, each represents oxygen or sulfur, Y is-N= or-CH=; A is-B is-O-, -S-B-, -B-S - or-In-; represents the lowest alkylene or lower albaniles; n = 2

The invention relates to a method for producing derivatives of General formula (I), which allows to improve the yield of these products

The invention relates to the field exitlinks acids, in particular to the intermediate compounds - derivatives of 1-oxo-3H-phthalazine-1-acetic acid of General formula

< / BR>
(A) where R1-C1-C6-alkyl, and the method of obtaining derivatives complex alilovic esters of 4-oxo-3H-phthalazine-1-acetic acid of General formula

< / BR>
(I) where R1-C1-C6-alkyl, R2and R3may be the same or different and represent a hydrogen atom, chlorine or trifluoromethyl, which are inhibitors oldselected

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexafluoroisopropanol-substituted ether derivatives of formula (I) to their pharmaceutically acceptable salts and to esters which are capable of bonding with LXR-alpha and/or LXR-beta, as well as to pharmaceutical compositions based on said compounds. In formula (I) R1 is hydrogen, lower alkyl or halogen, one of groups R2 and R3 is hydrogen, lower alkyl or halogen, and the second of groups R2 and R3 is -O-CHR4-(CH2)m-(CHR5)n-R6. Values of R4, R5, R6 m and n are given in the formula of invention.

EFFECT: novel compounds have useful biological properties.

22 cl, 4 dwg, 102 ex

The invention relates to new chemical compounds derived from anthra[2,1-d]isothiazol-3,6,11-trione General formula I, where a is the lowest alkylene, R1and R2(independent) - lower alkyl, or R1and R2together with the nitrogen atom form a six-membered saturated, a heterocycle, which may optionally contain a heteroatom such as oxygen atom, and their pharmaceutically acceptable salts

The invention relates to a method for producing 2-alkylbenzoates, which includes the interaction bisimide formula 2 in water or water-containing organic liquid bisulfite or allocating the bisulfite agent with the formation of salts of the Rebellion and the transformation of the salt Riot in alkaline conditions in the 2-alkyl-BIT
Up!