Derivative of cyclic amine and its salt

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new derivative of cyclic amine or its salts with the following formula (I): (where symbols stand for the following: A: 5-8-member cyclic amine, which may contain a double bond, a bridged structure and may contain substitutes R7-R11 in the ring, or -NH2, -NH(inferior alkyl), -N(inferior alkyl)2 or ) morpholin-1-yl; ring B: benzole, thiophene, furane, pyrrole, 5-7-member cycloalkane or 5-7-member cycloalkene; X1: a bond or inferior alkylene; X2: -(CR12R13)n-, -N(R14)-, -N(R14)CO-, -CON(R14)-, -CO-, -CH(OH)-, -N(R14)- (CR12R13)n-, (CR12R13)n-N(R14)-, -CON(R14)-(CR12R13)n-, -n(R14)CO-(CR12R13)n-, -(CR12R13)n-N(R14)CO-, -(CR12R13)n-CON(R14)-, -CO-(CR12R13)n- or -(CR12R13)n-CO-; Y1: -OH, -O-inferior alkyl, NH2 or -N3; R1 and R2: are identical or different and stand for a halogen atom, inferior alkyl or inferior alkylene-OH; R3-R6: are identical or different and stand for a hydrogen atom, a halogen atom, inferior alkyl, inferior alkenyl, inferior alkynyl, -O-inferior alkyl, -OH, -NH2, -NH(inferior alkyl), -N(inferior alkyl)2, -NH-CO- inferior alkyl, -N(inferior alkyl)-CO- inferior alkyl, -CN-, -NO2, -CF3, -O-inferior alkylene-OH, -inferior alkylene-OH, -inferior alkylene-halogen, -inferior alkylene-O-inferior alkyl, -CO-5-8-member cyclic amine, -COOH-inferior alkyl, -COO-inferior alkylene-aryl, pyridine, thiophene, -inferior alkylene-morpholine, aryl, which may contain a substitute: -O-inferior alkyl or -CF3; R7: hydrogen atom, inferior alkyl, -inferior alkylene-aryl or -inferior alkylene-pyridine: R7 is substitute on the nitrogen atom of the cyclic amine; R8-R14: are identical or different and stand for a hydrogen atom or inferior alkyl; n: is an integer, equal to 1, 2 or 3; where R5 and R6, R4 and R5 or R3 and R4 can form an inferior alkylene together, -O-inferior alkylene-O-, -O-inferior alkylene-, -inferior alkylene-O-, -C(R15)=C(R16)-O-, -O-C(R15)=C(R16)-, -C(R15)=C(R16)-C(R17)=C(R18)-; R3 and Y1 together can form -O-inferior alkylene-O- or -inferior alkylene-O-; R1 and Y1 together can form -inferior alkylene-O-; and Y1 and a branch on - X1-A together can form -O- or -O-inferior alkylene; R15-R18 stand for a hydrogen atom, under the condition that, 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol is not included in the group of compounds). The invention also pertains to a derivative of cyclic amine or its salts with formula (II), to a derivative of cyclic amine or its salts with formula (III), to pharmaceutical composition, as well as their use.

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on these compounds, with antagonist effect on NMDA receptors NMDA.

7 cl, 160 ex, 45 tbl

 

The technical field

The present invention relates to a derivative of the cyclic amine and its salts, which can be used as a medicine, primarily as antagonists of the NMDA receptor and the NMDA receptor antagonist containing as an active ingredient. Derived cyclic amine and its salt and the NMDA receptor antagonist containing as an active ingredient, according to the present invention can be used for the treatment and prevention of Alzheimer's disease, cerebral-vascular dementia, Parkinson's disease, ischemic apoplexy, pain, and so on.

The level of technology

Glutamic acid acts as a neurotransmitter of the Central nervous system of mammals and regulates the activity of neurocytol or neurotransmitter release by glutamate receptor that is present in synapses. At the present time on the basis of many physiological and biological studies of glutamate receptors are divided into "ion channel glutamate receptor and metabotropic glutamate receptor" (M. Hollmann and Heinemann, S., Annu. Rev. Neurosci., 17 (1994) 31-108). The NMDA receptor (N-methyl-D-asparagine) is a glutamate receptor-associated ion channel, which is particularly sensitive to the agonist NMDA (K. Moriyoshi et al., Nature, 354 (991) 31-37; Meguro, H. et al., Nature, 357 (1992) 70-74); and has a high permeability for Ca2+(During closing M. et al., J. Physiol., 424 (1990) 151-165). The NMDA receptor is expressed in a certain way in the Central nervous system (S. Ozawa et al., Prog. Neurobiol., 54 (1998) 581-618).

On the basis of numerous pharmacological and biological studies suggest that the NMDA receptor may be involved in neurological functions of higher order, such as, for example, the process of remembering and learning (Morris RG., et al., Nature, 319 (1986) 774-776; Tsien JZ. et al., Cell 87 (1996) 1327-1338). On the other hand, believe that acute or chronic overactive or underactive NMDA receptor may participate in various diseases of the nervous system, for example, ischemic stroke, hemorrhagic brain injury, traumatic brain injury, neurodegenerative diseases (such as Alzheimer's disease, cerebral-vascular dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, glaucoma, encephalopathy, AIDS, addiction, schizophrenia, depression, mania, disease associated with stress, epilepsy, pain (Beal MF., FASEB J. 6 (1992) 3338-3344; Heresco-Levy U. and Javitt DC, Euro. Neuropsychopharmacol., 8 (1998) 141-152; Hewitt DJ., Clin. J. Pain, 16 (2000) S73-79). Thus, drugs that can regulate the activity of the NMDA receptor, could be very effective in clinical application.

It was reported a large number of non-competitive antagonists of the NMDA receptor in the quality of medicines, is able to regulate the activity of the NMDA receptor, however, most of them still do not have clinical use because of side effects due to antagonism against the NMDA receptor, such as mental disorder, for example, hallucinations or confusion or dizziness. Some existing NMDA receptor antagonists, such as ketamine and dextromethorphan, have been clinically tested for the treatment of pain (K. Fisher et al., J Pain Manage Option., 20 (2000) 358-373), but the degree of security when treatment is small and their clinical use is limited (Eide PK., et al., Pain, 58 (1994) 347-354). Memantine is known as a noncompetitive antagonist of the NMDA receptor, which has relatively few side effects (Parsons CG., et al., Neuropharmacol., 38 (1999) 735-767); and recently it was reported that it can be effective in the treatment of Alzheimer's disease (Reisberg B., et al., N. Engl. J. Med., 348 (2003) 1333-1341). However, the degree of safety of memantine as medicines is still unsatisfactory and there is a need in the NMDA receptor antagonist with a higher degree of security (Ditzler K., Arzneimittelforschung, 41 (1991) 773-780; Maier C., et al., Pain 103 (2003) 277-283; Riederer P., et al., Lancet, 338 (1991) 1022-1023). It is expected that the establishment of such antagonist prescriptions the ora NMDA, with a higher degree of security can bring to a new clinical use of NMDA receptor antagonists.

In patent source 1 described pharmaceutical composition for the prevention and treatment of cerebral ischemia, which contains an adamantane derivative of the following formula or its pharmaceutically acceptable acid additive salt.

(where R1and R2are the same or different, each represents a hydrogen atom or a straight or branched alkyl group containing from 1 to 6 carbon atoms, or the like; R3and R4are the same or different, each represents a hydrogen atom or an alkyl group containing from 1 to 6 carbon atoms, or the like; R5represents a hydrogen atom or a straight or branched alkyl group containing from 1 to 6 carbon atoms; a more detailed description of the symbols in the formula, refer to the patent publication).

In patent source 1, the above memantine describes how investigational compound No. 1 (memantine is a compound of the formula where R1, R2and R3represent hydrogen atoms, and R4and R5represent a methyl group).

In patent source 2 describes the 1-aminoalkylsilanes with etousa formula, as a NMDA receptor antagonist.

(where R* represents -(CH2)n-(CR6R7)m-NR8R9; n+m = 0, 1, or 2; R1-R9independently selected from the group consisting of a hydrogen atom and C1-6lower alkyl group, and at least R1, R4and R5represent a lower alkyl group; a more detailed description of the symbols in the formula, refer to the patent publication).

In patent reference 3 describes a derived indana the following formula, which is a type of compound that contains indan ring and piperidine ring and which can be used as a treatment for allergies and asthma.

(where each R1and R2independently represents a C1-4alkyl group; R3represents a hydrogen atom, a C1-4alkyl group, a C1-4alkoxygroup or the like; and the ring A may have a Deputy; a more detailed description of the symbols in the formula, refer to the patent publication).

However, in the connection described in this source, the indan ring and piperidine ring are connected to each other via the double bond between them, and the connection structure differs from the structure of connections nastasemarian, where two rings are linked together via a single bond or a group of the lowest alkylene, and so on. In addition, the connection described in this source, can be used as a treatment for allergies and asthma, but it does not describe or imply antagonism connection in respect of the NMDA receptor and the possibility of using the compound as a treatment for Alzheimer's disease, cerebral-vascular dementia, Parkinson's disease, ischemic apoplexy, pain, and so on. As an intermediate compound to obtain the claimed compound in example 1, this source describes 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol following formula. However, it does not describe the use of intermediate compounds as a medicine.

In non-patent source 1 described compound of the following formula, which is a type of compound that contains indan ring and tetrahydronaphthalene ring, and can be used as an analgesic. However, the structure of this compound differs from the structure of the compounds of the present invention, described hereinafter, so that in the first saturated ring substituted phenyl group.

(where R is an atom in Dorada or methyl group; R' represents a methyl group; R" represents -(CH2)3N(CH3)2, -(CH2)3N(CH3)(CH2)2C6H5N-methylpiperidino group, -(CH2)2N(CH3)2; n is 0 or 1; a more detailed description of the symbols in the formula, refer to the patent publication).

Patent source 1: Japan patent No. 2821233,

Patent source 2: WO 99/01416,

Patent reference 3: JP-A 56-135472,

Non-patent source 1: Journal of Medicinal Chemistry, 1967, Vol. 10, No. 5, pp. 823-825.

Disclosure of invention

OBJECTIVES of the INVENTION

In connection with the growth in the number of elderly population is currently increasing the number of cases of Alzheimer's disease, cerebral-vascular dementia, ischemic stroke, and the like; and there is a great need in the field of medicines in creating the antagonist of the NMDA receptor, which could be effective for the treatment and prevention of such diseases as well as Parkinson's disease, pain and other diseases, and would have a high degree of security. The present invention is to obtain a new derivative of the cyclic amine and its salt, which has an excellent antagonistic activity against NMDA receptor and having a high degree of security, and receipt containing the th drug.

MEANS FOR solving the PROBLEM

The authors of the present invention have found that the new amine derivative and its salt [1], represented by the following formula (I), which is characterized by the fact that her Listeria structure associated with A 2-cycle or 3-cyclic condensed ring (for example, indan, tetralone, 4,5,6,7-tetrahydroxybenzophenone, 4,5,6,7-tetrahydroxybenzophenone, 7,8-dihydro-6H-indeno[4,5-b]furan, 2,3-dihydro-1H-cyclopent[a]naphthalene) in X1(for example, communication or lower alkylene), have excellent antagonistic activity against the NMDA receptor and a high degree of security, and developed the present invention. Specifically, the present invention relates to an amine derivative of the following formula (I) and salts thereof (hereinafter may be specified as "compound (I) of the present invention"). Further, the present invention also relates to the NMDA receptor antagonist containing a compound (I) or its salt of the present invention, in particular, the means for treatment or remedy for the prevention of Alzheimer's disease, cerebral-vascular dementia, ischemic stroke, pain, and so on. In the present invention compounds of the following sub-clause [2] are preferred, and compounds of the following sub-clause [3] are more preferred. is soedineniya subparagraph [4] are the most preferred.

[1] the Cyclic amine and its salt of the following formula (I):

(where the symbols have the following meanings:

A: 5-8-membered cyclic amine, optionally containing a double bond, optionally having a bridge structure and optionally containing substituent R7-R11in the ring, or-NH2, -NH(lower alkyl) or-N(lower alkyl)2;

Ring B: benzene, thiophene, furan, pyrrole, 5-7-membered cycloalkane or a 5-7 membered cycloalkene;

X1: communication, low alkylene or-L3-D-L4-;

L3and L4: the same or different and represent a link or lowest alkylen;

D: 5 - or 6-membered carbocycle or heterocycle, optionally containing a Deputy;

X2: -(CR12R13)n-, -N(R14)-, -N(R14)CO-, -CON(R14)-, -O-, -S-, -CO-, -CH(OH)-, -N(R14)-(CR12R13)n-, -(CR12R13)n-N(R14)-, -CON(R14)-(CR12R13)n-, -N(R14)CO-(CR12R13)n-, -(CR12R13)n-N(R14)CO-, -(CR12R13n-CON(R14)-, -CO-(CR12R13)n-, -(CR12R13)n-CO-, -O-(CR12R13)n-, -(CR12R13)n-O-, -S-(CR12R13)n - or -(CR12R13)n-S-;

Y1: -OH, -O-lower alkyl, -NH2or-N3;

R1and R2: the same or different and represent a halogen atom, lower alkyl or lower al the ilen-OH;

R3-R6: the same or different and represent a hydrogen atom, halogen atom, lower alkyl, lower alkenyl, lower quinil, -O-lower alkyl, -OH, -NH2, -NH(lower alkyl), -N(lower alkyl)2, -NH-CO-lower alkyl, -N(lower alkyl)-CO-lower alkyl, -NH-CO-O-lower alkyl, -N(lower alkyl)-CO-O-lower alkyl, -CN, -NO2, -CF3-the inferior alkylene-OH, -lower alkylene is a halogen atom, -O-lower alkylene-OH, -lower alkylene-O-lower alkyl, -CO-N(lower alkyl)2, -CO-NH-(lower alkyl), -O-CO-N(lower alkyl)2, -O-CO-NH-(lower alkyl), 5-8-membered cyclic amine, -CO-5-8-membered cyclic amine, -COOH, -COO-lower alkyl, -COO-lower alkylene-aryl, 5 - or 6-membered heterocycle, -a lower alkylene-5 - or 6-membered heterocycle, aryl, optionally containing a Deputy, or aryl, optionally containing lower alkylen-Deputy;

R7: a hydrogen atom, a lower alkyl, -lower alkylene-aryl or-lower alkylene-heteroaryl:

R7is a Deputy to the nitrogen atom of the cyclic amine;

R8-R14: the same or different and represent a hydrogen atom or lower alkyl;

n: an integer equal to 1, 2 or 3;

where R5and R6, R4and R5or R3and R4may together form a lower alkylene, -O-lower alkylene-O-, -O-lower alkylene-, -lower alkylene-O-, -S-lower alkylene-, -lower al the ilen-S-, -N(R19-the lowest alkylene-, -lower alkylene-N(R19)-, -C(R15)=C(R16)-O-, -O-C(R15)=C(R16)-, -C(R15)=C(R16)-C(R17)=C(R18)-, -S-C(R15)=C(R16)-, -C(R15)=C(R16)-S-, -N(R19)-C(R15)=C(R16)-, -C(R15)=C(R16)-N(R19)-, -N(R19)-C(R15)=N-, -N=C(R15)-N(R19)-, -N=C(R15)-C(R16)=C(R17)-, -C(R15)=C(R16)-C(R17)=N-, -C(R15)=N-C(R16)=C(R17)- or-C(R15)=C(R16)-N=C(R17)-; R3and Y1may together form-O-lower alkylene-O-, -lower alkylene-O - or-N(R19-the lowest alkylen-O-; R1and Y1may together form a lower alkylene-O-; and Y1and the branch is on-X1-A may together form-O - or-O-lower alkylene;

R15-R18: the same or different and represent a hydrogen atom, halogen atom or lower alkyl group;

R19: a hydrogen atom or a lower alkyl group;

provided that 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol excluded from the group of compounds).

[2] Derived cyclic amine and its salt of the following formula (II):

(where the symbols have the following meanings:

Ring A: 5-7-membered cyclic amine, optionally containing a double bond in the ring;

Ring B: benzene, thiophene, furan, pyrrole, 5-7-membered cloaken or a 5-7 membered cycloalkene;

X1: link or lowest alkylen;

X2: -(CR12R13)n-, -N(R14)-, -N(R14)CO-, -CON(R14)-, -O-, -S-, -CO-, -N(R14)-(CR12R13)n-, -(CR12R13)n-N(R14)-, -CON(R14)-(CR12R13)n-, -N(R14)CO-(CR12R13)n-, -(CR12R13)n-N(R14)CO-, -(CR12R13n-CON(R14)-, -CO-(CR12R13)n-, -(CR12R13)n-CO-, -O-(CR12R13)n-, -(CR12R13)n-O-, -S-(CR12R13)n - or -(CR12R13)n-S-;

Y1: -OH, -O-lower alkyl, -NH2or-N3;

R1and R2: the same or different and represent a halogen atom or lower alkyl;

R3-R6: the same or different and represent a hydrogen atom, halogen atom, lower alkyl, -O-lower alkyl, -OH, -CN or-CF3;

R7: a hydrogen atom, a lower alkyl, -lower alkylene-aryl or-lower alkylene-heteroaryl:

R8-R14: the same or different and represent a hydrogen atom or lower alkyl;

n: an integer equal to 1, 2 or 3;

provided that 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol excluded).

[3] the Cyclic amine and its salt of the following formula (III):

(where the symbols have the following meanings:

X1: link or lowest alkylen;

Y1: -OH, -O-lower alkyl, -NH2or-N3;/p>

R1and R2: the same or different and represent a halogen atom or lower alkyl;

R3-R6: the same or different and represent a hydrogen atom, halogen atom, lower alkyl, -O-lower alkyl, -OH, -CN or-CF3;

R7: a hydrogen atom, a lower alkyl, -lower alkylene-aryl or-lower alkylene-heteroaryl ;

R8-R11: the same or different and represent a hydrogen atom or lower alkyl;

provided that excluded 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol).

[4] the Compound and its salt according to [1], is selected from 2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 2,2,6-trimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 6-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 5-bromo-2,2-dimethyl-1-(1-methyl-piperidine-4-yl)indan-1-ol, 6-chloro-5-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 6-bromo-4-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 7-bromo-6-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 7-bromo-4-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 6-fluoro-7-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 4-fluoro-7-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 2,2-dimethyl-1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-ol, 4-fluoro-6-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 7-ethoxy-6-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 4-fluoro-6,7-dimmock and-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 5,6-debtor-7-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 6-cyano-4-fluoro-7-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 1-(2-amino-2-methylpropyl)-2,2,6-trimethylene-1-ol, 5-fluoro-7,7-dimethyl-8-(1-methyl-piperidine-4-Il)-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-8-ol, 4-(9-fluoro-5,5-dimethyl-2,3,5,6-tetrahydro-4aH-indeno[1,7-ef][1,4]doxepin-4a-yl-1-methylpiperidine, 1-[(6'-fluoro-7'-methoxy-2',2'-dimethyl-2',3',4,5-tetrahydro-3H-Spiro[furan-2,1'-inden]-5-yl)methyl]pyrrolidine.

The TECHNICAL RESULT

Compounds of the present invention have an antagonistic activity against the NMDA receptor and can be used for the treatment and prevention of Alzheimer's disease, cerebral-vascular dementia, Parkinson's disease, ischemic apoplexy, pain.

The BEST WAY of carrying out the INVENTION

The present invention is described specifically below.

If not stated otherwise, the term "lower"used in the definition of formulas herein, means a straight or branched carbon chain containing from 1 to 6 carbon atoms. Accordingly, the "lower alkyl" preferably represents a straight or branched C1-6alkyl group, including, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl. Of them, preferable are the two who are in the group, containing from 1 to 3 carbon atoms; and more preferred are methyl and ethyl.

"Lower alkylene" includes methylene, ethylene, propylene, butylene, and other branched groups of the lower alkylene. Preferred are groups of lower alkylene containing from 1 to 3 carbon atoms; more preferred are methylene and ethylene; and even more preferred is methylene.

"Halogen atom" includes fluorine atom, chlorine atom, bromine atom, iodine atom. Of them, preferred are a fluorine atom, a chlorine atom and a bromine atom.

The term "aryl" means from mono - to tri-cyclic aromatic hydrocarbon cyclic group containing from 6 to 14 carbon atoms. Preferably, the aryl includes phenyl, naphthyl, antril, tenantry. More preferred are phenyl and naphthyl. The term "lowest alkylen-aryl" specifically means, preferably benzyl or phenethyl.

The term "heteroaryl" means from mono - to tri-cyclic aromatic heterocyclic group containing from 6 to 14 carbon atoms. Preferably, heteroaryl represents a 5 - or 6-membered monocyclic aromatic heterocyclic group; more preferably, pyridyl, pyrimidyl, Persil, thienyl, furyl, oxazolyl, thiazolyl; even more preferably pyridyl. The term "lowest alkylen-heteroaryl concr the IDT means, preferably, picolyl.

The term "5 - or 6-membered carbocycle" means 5 - or 6-membered cycloalkane or cycloalkene, and benzene.

The term "5 - or 6-membered carbocycle" includes saturated ring, specifically such as pyrrolidine, piperidine, piperazine, morpholine, and the condensed ring, such as a tetrahydropyridine, furan, thiophene, pyrrole, pyridine, pyrazin, pyrimidine, oxazole, triazole.

The term "5-7-membered cycloalkyl" include cyclopentane, cyclohexane, Cycloheptane.

The term "5-7-membered cycloalkyl" includes cyclopenten, cyclohexen, cyclohepten.

The term "5-8-membered cyclic amine, optionally containing a double bond, optionally containing bridge structure and optionally containing substituent R7-R11in the ring"refers to an unsaturated or saturated 5-8 membered cyclic amine ring having a double bond in the ring, or bicillin preferably represents a saturated 5-7 membered cyclic amine ring, more preferably, pyrrolidine, piperidine, homopiperazine, morpholine, piperazine, even more preferably piperidine. Bicillin represents, preferably, Hinkley, 7-azabicyclo[2,2,1]heptane, 8-azabicyclo[3,2,1]octane, 9-azabicyclo[3,3,1]nonan, 3-azabicyclo[3,2,2]nonan.

Deputy "5 - or 6-membered carbocycle or 5 - or 6-membered GE is erotica, optionally containing a Deputy", and "aryl, optionally containing a substitute, include halogen atom, lower alkyl, lower alkenyl, -O-lower alkyl, -OH, -NH, -NH(lower alkyl), -N(lower alkyl)2, -NH-CO-(lower alkyl), -N(lower alkyl)-CO-(lower alkyl), -NHCO-(O-lower alkyl), -N(lower alkyl)-CO-(O-lower alkyl), -CN, -NO2, -CF3-the inferior alkylene-OH, -lower alkylene is a halogen atom, -O-lower alkylene-OH, -lower alkylene-O-lower alkyl, -CO-N(lower alkyl)2, -COOH, -CO-O-lower alkyl, which, however, is not limited to the present invention.

Compounds of the present invention include mixtures of various isomers such as tautomers and optical isomers, as well as separate of these isomers.

Compounds of the present invention may form an acid additive salt. Depending on the type of the substituent therein, the compounds can form salts with bases. Specifically, the salts include acid additive salts with inorganic acid such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid, phosphoric acid; organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic KIS the PTA, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, or acidic amino acid such as aspartic acid, glutamic acid; and salts with an inorganic base, such as sodium, potassium, magnesium, calcium, aluminum; organic base such as methylamine, ethylamine, ethanolamine; or with basic amino acid such as lysine, ornithine; and ammonium salts.

Further, the compounds of the present invention include hydrates, various pharmaceutically acceptable solvate and crystalline polymorphic substances.

Of course, the compounds of the present invention is not limited to the compounds described in the following examples, and include all compounds of the above formula (I) and their pharmaceutically acceptable salts.

In addition, the compounds of the present invention include prodrugs that are metabolized in living organisms c form compounds of the above formula (I) or their salts. Group to obtain prodrugs of the compounds of the present invention are described, for example, in Prog. Med., 5:2157-2161 (1985) and Development of Medicines (Hirokawa Publishing, 1990), Vol. 7, Molecular Planning, p. 163-198.

Ways to get

Taking advantage of the peculiarities of the structures associated with skeletal or his Deputy, the compounds according to the present invention can be obtained in accordance with various known methods of producing compounds. Depending on the type of functional group in the original compounds or intermediate compounds may be suitably protected, or, in other words, can be converted to a protected group, which can be easily converted into the functional group, and this may be technically efficient when it receives a connection. After implementing the method of the protective group may not necessarily be removed, and thus can be obtained the desired compound. The functional group includes, for example, hydroxyl group and carboxyl group. Their protective groups are described, for example, in Greene &Wuts' Protective Groups in Organic Synthesis, 2nd Ed. They can be appropriately used depending on the reaction conditions.

Typical methods of producing compounds of the present invention are described below.

The following diagrams 1-6 presents methods for obtaining cyclic ketones, which are the starting compounds for the compounds (I) of the present invention. Intanon (6), which can be a source connection for the compounds (I) of the present invention, can be obtained in accordance with the method shown in the following scheme 1. In particular, the aldehyde (1) is subjected to reaction knoevenagel specifically, the aldehyde (1) when heated is subjected to interaction with a derivative of malonic acid is you (2) in a solvent, such as pyridine, in the presence of a base, such as piperidine used as a catalyst; or it is subjected to reaction, Horner-Emmons specifically, the aldehyde (1) is subjected to interaction with the phosphonate (3) in a solvent such as THF, in the presence of a base, such as NaH, while cooling on ice or when heated. Then the derivative of cinnamic acid (4) is subjected to catalytic recovery, specifically, it is treated with a catalyst of palladium on coal (hereinafter indicated as Pd-C) in a solvent such as EtOH, THF or acetic acid, in an atmosphere of hydrogen or in the presence of a hydrogen source such as ammonium formate. When the connection has a Deputy, active Pd recovery, such as the group of bromine in R3-R6as the catalyst may be used a catalyst based on rhodium-carbon (hereinafter indicated as Rh-C). Then the derivative of propionic acid (5) is treated in the presence of acid, such as polyphosphoric acid, methanesulfonate acid (hereinafter indicated as MsOH), MsOH-P2O5, triftormetilfullerenov acid (hereinafter indicated as TfOH) or sulfuric acid, in an inert solvent (depending on the circumstances, the acid may also be used as solvent), at room temperature or by heating; or chlorine is the anhydride of compound (5) is treated by heating in the presence of a Lewis acid such as AlCl3in a solvent such as 1,2-dichloroethane or nitromethane, or in the absence of solvent and obtaining indanone (6). (R13represents a hydrogen atom or a lower alkyl group; each R14and R15represents a lower alkyl group; R16is any of R13or R14.)

(scheme 1)

The tetralone (10), which can be a source connection upon receipt of the compound (I) of the present invention, can be obtained in accordance with the method shown in the following scheme 2. The aldehyde (1) and the derived cyclopropane (7) is subjected to interaction in an inert solvent such as methylene chloride, in the presence of a catalyst based on a Lewis acid such as TiCl4while cooling or at room temperature and obtaining chloride (8), and catalytically restore in hydrogen atmosphere in the presence of a catalyst, such as Pd-C, in a solvent such as EtOH, THF or acetic acid, and obtaining derived butane acid (9). Then (9) is subjected to cyclization in a manner analogous to that described for the cyclization reaction, shown in scheme 1 with obtaining tetralone (10).

(scheme 2)

Cyclic ketone can also be obtained in accordance with sosososo, shown in scheme 3. Specifically, bromide (11) ciclitira by directional litrovaya with base, such as n-BuLi, lithium or N,N-diisopropylamide (hereinafter indicated as LDA) in an inert solvent, such as THF or diethyl ether, while cooling or at room temperature.

(scheme 3)

Ketones (15a) and (15b), which are the starting compounds for the compounds (I) of the present invention, where both R1and R2represent the group of lower alkyl, can be obtained in accordance with the method shown in the following scheme 4. In particular, when R1and R2represent the same group of lower alkyl, unsubstituted ketone (13) communicates with at least 2 equivalents of the lower alkylhalogenide or diallylsulfide, in the presence of a base, such as NaH, KN(TMS)2, t-BuOK or KOH and, optionally, the phase transfer catalyst such as ammonium salt, in a solvent such as THF, DMF or DMSO, under cooling or under heating. When R1and R2represent different lower alkyl groups, then LDA is used as the base, and ketone Paladino alkylate and obtaining the desired product. (X3represents a halogen atom.)

(scheme 4)

To the tone (15d), which is the original connection when obtaining the compound (I) of the present invention, where R1and R2both represent fluorine atoms, can be obtained in accordance with the method shown in the following scheme 5. In particular, the ketone (13) when heated is subjected to interaction with salt N-torpedine (18) in the presence of sulfuric acid and dimethylsulfate in a solvent such as MeCN, and obtaining ketone (15a). Compounds where one of R1or R2represents a lower alkyl group and the other represents a fluorine atom, can be obtained by fluorination monoalkylphenol connection (17) in a manner analogous indicated in figure 4, above.

(scheme 5)

As shown in scheme 6, the ketone (15f) can be obtained by cyclization of carboxylic acid derivative (19), in advance containing R1and R2that way cyclization similar specified in schemes 1-3. (R17represents a hydrogen atom or a bromine atom.)

(scheme 6)

Below describes how to obtain the compounds (I) of the present invention.

Of the compounds (I) according to the present invention, the compound (Ia), where Y1represents a hydroxyl group, can be obtained by the interaction of the derived cyclic what about the ketone (15) with a Grignard reagent or organolithium reagent (20), obtained from the corresponding halide, in a solvent such as THF, diethyl ether or methylene chloride, while cooling or at room temperature, as indicated in the following scheme 7. (In the diagram Z1represents a lithium atom or minihaloes.)

(scheme 7)

Of the compounds (I) according to the present invention, the compound (Ib), where Y1represents a hydroxyl group, and A represents N(R20)(R21), can be obtained by the interaction of the derived cyclic ketone (15) with a nucleophilic agent such as a Grignard reagent or organolithium reagent containing a hydroxyl group protected by appropriate protecting group, and then converting the protected hydroxyl group in the amino group, as shown in the following scheme 8. Specifically, a derivative of cyclic ketone is subjected to interaction with a Grignard reagent or organolithium reagent (21), which has a hydroxyl group protected by appropriate protecting group, such as group, tert-Bu(Me)2Si or benzyl group, in a solvent such as THF, diethyl ether or methylene chloride, at temperatures between -78°C and room temperature and obtaining the alcohol (22). When the protective group is a silyl group, then the product amrabat who live Bu 4NF, KF or CsF in a solvent such as THF or MeOH, under cooling or under heating; and when the protective group is a benzyl group, then the product is catalytically restore to remove the protective group c receiving despierta (23), and then treated with MsCl or TsCl in the presence of a base such as Et3N, in a solvent such as methylene chloride, obtaining connection sulfonyl (24), and then the connection is additionally subjected to interaction with the amine (25) in the presence of a base, such as (ISO-Pr)2EtN, Et3N or K2CO3in a solvent such as MeCN or THF, or creating excessive amount of amine (25), which itself serves as the basis for obtaining the amine (Ib). (Scheme G is a commonly used protective group for hydroxyl group, such as Me3Si, tert-Bu(Me)2Si, Bu3Si or benzyl; R20and R21the same or different, each represents a hydrogen atom or optionally substituted lower alkyl group; as for N(R20R21, R20and R21can be connected to each other to form 5-8-membered cyclic amine, optionally containing substituent R8-R11the ring has optional double bond, and optionally contains a bridge structure in the ring.)

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(scheme 8)

Of the compounds (I) according to the present invention, the compound (Ic), where X1-A represented by the following structural diagrams can be obtained by reduction of compound (27)obtained from the ketone (15) and amide (26)as shown in scheme 9. Specifically, the ketone (15) is subjected to interaction with amidon α-lithiate (26), obtained with LDA in a solvent such as THF or diethyl ether, at temperatures between -78°C and room temperature and obtaining (27), and the fragment with the amide bond in the resulting connection is established LiAlH4or BH3in a solvent such as THF, under cooling or under heating. (R22-R25each represents a hydrogen atom or optionally substituted lower alkyl group; and R22-R25can be connected to each other with the formation of the lower alkylene, optionally containing a heteroatom in its chain.)

(scheme 9)

Of the compounds (I) according to the present invention, the compound (Id), where Y1represents a hydroxyl group and X1-A represents a group of the following structural formulas can be obtained in accordance with the method shown in the following scheme 10. Specifically, the ketone (15) interacts with α-Letyat ether complex (28), obtained from appropriate estoodeeva of ester using LDA, at a temperature between -78°C and value of the room temperature and obtaining of ester (29), then treated regenerating agent such as LiAlH4, iBu2AlH or LiBH4in a solvent such as THF or MeOH, while cooling on ice or at room temperature and obtaining alcohol (30); then the same method shown above in scheme 8, a hydroxyl group in the resulting product is converted into the amino group and obtaining amine (Id). (R26and R27the same or different, each represents a hydrogen atom or a lower alkyl group; and R26and R27can be connected to each other with the formation of the lower alkylene, optionally containing a heteroatom in the chain.)

(scheme 10)

Of the compounds (I) according to the present invention, the compound (Ie), where Y1represents a hydroxyl group and X1-A represents a group of the following structural formulas can be obtained in accordance with the method shown in the following diagram 11. In particular, the ketone (15) is subjected to interaction with delicio-oxime (32)obtained from the oxime and n-BuLi, in a solvent such as THF or diethyl ether, at temperatures between -78°C and room temperature and obtaining the oxime (33); then subjected to interaction with P2O5 in a solvent such as chloroform or methylene chloride, while cooling, or subjected to interaction with sulfonylureas agent such as MsCl obtaining dihydroisoxazole (34). Then subjected to the interaction with the reagent alkylate (35) in the presence of BF3·Et2O CeCl or3in a solvent such as THF, methylene chloride or toluene, at temperatures between -78°C and room temperature and obtaining oxazolidine (36); and subjected to restore using LiAlH4in THF at room temperature, or restore the commonly used way catalytic reduction and obtaining amine (1e). (In the diagram, each R28and R29represents a lower alkyl group.)

(scheme 11)

Of the compounds (I) of the present invention the compound (If) or (Ig), where ring A is piperidine ring, ring B represents a benzene ring, Y1represents a hydroxyl group, X1is a bond and X2represents a methylene group, or the compound (Ih)in which the ring A is tetrahydropyridine ring, can be obtained by reduction of the corresponding compounds of pyridine, as shown in the following diagram 12. Specifically, benzylbromide (37) and acylpyrin (38) subject ot modestia in the presence of a base, such as LDA in a solvent such as THF or diethyl ether, while cooling or at room temperature and obtaining the compound (39); cyclist with base, such as LDA in a solvent such as THF or diethyl ether, while cooling or at room temperature, or cyclist when heated in the presence of a base such as Na2CO3c Pd catalyst such as Pd(OAc)2, ligand, such as tricyclohexylphosphine, and alcohol, such as n-hexanol, in a solvent such as DMF, and obtaining cyklinowanie connection (40); and restore the Rh-C in hydrogen atmosphere under normal pressure or increased pressure obtaining piperidine (If). The compound (40) can be subjected to interaction with alkylhalogenide in the solvent or in the absence of solvent at room temperature or when heated obtaining ammonium salts (41), and then treated regenerating agent such as NaBH4in a solvent such as MeOH, while cooling on ice or at room temperature, obtaining tetrahydropyridine (Ih). Further, the compound (Ih) can be treated in a hydrogen atmosphere in the presence of Pd-C in a solvent such as EtOH at room temperature; or the compound (41) can be subjected to direct reinstatement with platinum oxide in a solvent such as EtOH, in an atmosphere of hydrogen is ri normal pressure or increased pressure obtaining piperidine (Ig).

(scheme 12)

Of the compounds (I) of the present invention the compound (Ii), (Ij) or (Ik), where ring A is an unsubstituted piperidine ring or tetrahydropyridine ring, X1represents a methylene group, optionally substituted lower alkyl group, and Y1represents a hydroxyl group, can be obtained in accordance with the method shown in the following diagram 13. In particular, alkyl-substituted pyridine (42) metallinou using a base, such as n-BuLi or KN(ISO-Pr)2; then subjected to the interaction with the ketone (15) in a solvent such as THF, under cooling or at room temperature and obtaining pyridine (43); restore a variety of ways, for example, as shown in figure 12, c receiving piperidine (Ii) or (Ij) or tetrahydropyridine (Ik) (in the diagram, R17and R18the same or different, each represents a hydrogen atom or a lower alkyl group; and R17and R18can form the lowest alkylene, optionally containing a heteroatom in its chain).

(scheme 13)

Of the compounds (I) of the present invention the compound (Im), (In), (Io) or (Ip), where ring B is a benzene ring, X2represents-CO-, -CH(OH)-, -CH(Cl)- Il is-CH 2-, and Y1represents a hydroxyl group, can be obtained in accordance with the method shown in the following diagram 14. In particular, the ketone (45) and hydrazide (46) is subjected to interaction with heating in a solvent such as EtOH, I-D or acetic acid, optionally in the presence of a catalyst based acids, such as acetic acid or sulfuric acid, and obtaining hydrazide (47). Then spend interaction with PhI(OAc)2or Pb(OAc)4in an inert solvent, such as 1,2-dichloroethane, THF or toluene, at room temperature or when heated obtaining diketone (48), and then cyclist with base, such as tert-BuOK, NaOEt, DBU, KN(TMS)2or LDA in a solvent such as THF, 1,2-dichloroethane, toluene or EtOH, at a temperature between -78°C and high temperature and obtaining a cyclic ketone (Im). It restores the regenerating agent such as LiAlH4, NaBH4or (ISO-Bu)2AlH, in a solvent such as THF, MeOH or EtOH, at a temperature between -78°C and room temperature and obtaining alcohol (In). (In) can be galogenidov halogenation agent such as SOCl2in a solvent such as MeCN, while cooling or at room temperature and obtaining the halide (Io). The halide (Io) can be recovered in the acidic environment of the solvent acetic acid using Zn (powder) when heated, or catalytically restored in an atmosphere of hydrogen in the presence of a catalyst, such as Pd-C or Raney Ni, and obtaining the recovered product (Ip).

(Scheme 14)

Of the compounds (I) of the present invention the compound (Iq)-(Is), where Y1forms an oxygen-containing 5-7-membered ring together with R3or any of the R1or R2or branch on the-X'-A, can be obtained in accordance with the method shown in the following diagram 15. In particular, the diol (49), (50) or (51) is treated in the presence of concentrated sulfuric acid, hydrochloric acid or MsOH in a solvent such as MeOH, 1,4-dioxane or water, at room temperature or when heated obtaining the desired connection. (X4represents the lowest alkylene, -O-lower alkylene or-N(R30-the lowest alkylene; X5represents the lowest alkylene; Q represents a hydroxyl group containing-X1-A in-Q-OH.)

(scheme 15)

The compound (I) of the present invention can be subjected to conversion of substituents known to any person skilled in the art, to obtain the compounds containing the desired Deputy. Typical reactions of this transformation are described below.

Of the compounds (I) this is th invention the connection, where substituent R7the nitrogen atom of the ring A represents a hydrogen atom or a lower alkyl group, can be obtained by interaction of the compound (I) of the present invention, where R7represents a methyl group or benzyl group, with CHLOROFORMATES in the presence of a base such as Et3N, or in the absence of base, in a solvent such as toluene or methylene chloride, at room temperature or when heated obtaining carbamate, and then processed in the presence of a base, such as NaOH or KOH, in a solvent such as water or ethanol, when heated obtaining compounds, where R7represents a hydrogen atom. In the case when the reagent is 1-chloroethylphosphonic obtained carbamate can be heated in methanol for removal of the protective group. Connection, where R7represents a hydrogen atom, may be subjected to interaction with the aldehyde to recovery amination in a solvent such as methylene chloride or 1,2-dichloroethane, in the presence of acid, such as acetic acid, or based catalyst of the Lewis acid, using a reducing agent such as NaB(OAc)3H or NaB(CN)H3while cooling or at room temperature; or alkylated using alkylhalogenide in the presence of the basis of the Oia, such as the K2CO3in a solvent such as MeCN at room temperature or when heated obtaining compounds, where R7represents an alkyl group.

Of the compounds (I) according to the present invention is the compound where R3represents cyano and ring B is an aromatic ring, can be obtained by treating the corresponding compounds where R3represents a bromine atom, by using Zn(CN)2in the presence of a catalyst such as Pd(PPh3)4in a solvent such as DMF or N-methylpiperidin when heated.

Of the compounds (I) of the present invention the connection where any of R3-R6represents an optionally substituted aryl, lower alkenylphenol or lower alkylamino group, can be obtained by a Suzuki reaction or, in other words, the interaction of the corresponding compounds where any of R3-R6represents a bromine atom or an iodine atom, with arylboronic acid, alkenylboronic acid, alkenylboronic acid or their boronate esters in the presence of a catalyst such as Pd(PPh3)4, PdCl2(dppf) or Pd2(dba)3together with a base, such as K2CO3, Na2CO3, KOH, CsF or NaOEt, in a solvent such as DMF, N-methylpiperidin, DME or Tolu is l or mixtures of these solvents with water when heated.

Of the compounds (I) of the present invention compound, where X1represents a methylene group and A represents NH2can be obtained by reduction of the corresponding cyanhydrin with LiAlH4in a solvent such as THF. The original connection cyanohydrin can be obtained by interaction of the corresponding ketone with (TMS)CN in the presence of ZnI2in a solvent such as methylene chloride or 1,2-dichloroethane, when heated, or its interaction with KCN or NaCN in the acidic environment of acetic acid or sulphuric acid.

Of the compounds (I) of the present invention the compound where Y1is sidegroup, can be obtained by interaction of the compound (I), where Y1represents a hydroxyl group, with NaN3in the presence of acid, such as triperoxonane acid, in a solvent such as chloroform, or using as a solvent only acid under cooling or under heating. The connection can be restored in an atmosphere of hydrogen in the presence of Pd-C in a solvent such as EtOH or restored using a reducing agent, such as LiAlH4in a solvent such as THF, at heating and obtaining compounds, where Y1represents an amino group.

Of the compounds (I) of the present invention the connection, where the number of the TSO B represents an aromatic ring, and any one of R 3-R6is a nitro-group, can be obtained by nitration of the corresponding compounds where any of R3-R6represents a hydrogen atom under normal conditions of nitration, specifically, with fuming sulfuric acid in acetic anhydride under cooling or with concentrated nitric acid in a solvent of acetic acid under cooling or at room temperature, or with NO2BF4in a solvent such as sulfolan or THF, at low temperature or room temperature. The connection can be catalytically restored using Pd-C C obtain the corresponding aniline.

Of the compounds (I) of the present invention the compound where Y1represents a lower alkoxygroup can be obtained by treating the corresponding compounds where Y1represents a hydroxyl group, the solvent is a lower alcohol in the presence of an acid catalyst, such as camphorsulfonic acid under cooling or under heating.

The removal of the protective group can be achieved in the presence of an appropriate base in an appropriate solvent. Examples of bases are NaOH, KOH, NaOMe, NaOEt. Examples of the solvent are ethers, such as tetrahydrofuran, dioxane, diglyme; alcohols such as MeOH, EtOH, I-D; MeCN, water, and aspesi. Depending on the type of the reaction substrate and the reaction conditions, respectively, can be selected solvent. The reaction temperature may vary depending on the type of the initial compounds and the reaction conditions, typically in the range of temperature of cooling to the boiling temperature under reflux, preferably from about 0°C to about 100°C.

The removal of the protective group can also be carried out in the presence of a catalyst based on a metal such as Pd-C, Pd(OH)2or PtO2, in an appropriate solvent in an atmosphere of hydrogen, but may be carried out in the presence of an appropriate Lewis acid in an appropriate solvent. Examples of the Lewis acid are BCl3, BBr3, AlCl3and examples of the solvent are ethers, such as tetrahydrofuran, dioxane; esters such as ethyl acetate; alcohols such as MeOH, EtOH; MeCN; and mixtures thereof. Depending on the type of the reaction substrate and the reaction conditions, respectively, can be selected solvent. The reaction temperature may vary depending on the type of the source materials and the reaction conditions, typically in the range of temperature of cooling to the boiling temperature under reflux, preferably from about -80°C to about 30°C.

Thus obtained compound (I) present ademu the invention can be isolated as free compounds or in the form of their pharmaceutically acceptable salts. Salts of compounds (I) of the present invention can be obtained by treating the free base of the compounds (I) according to the present invention for commonly used salt.

The compound (I) of the present invention or their pharmaceutically acceptable salts can be isolated and purified in the form of their hydrates, solvate or crystalline polymorphic products. Isolation and purification can be achieved using commonly used chemical treatment, such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, chromatography.

Various isomers can be separated by appropriate selection of the parent compounds or their separation on the basis of the difference between the physical or chemical properties of the isomers. For example, optical isomers can lead to pure stereochemical isomers by selecting the appropriate starting compounds or racemic separation of racemic compounds (for example, converting then reduced to diastereoisomeric salts using commonly used optically active acid for optical separation).

Antagonistic activity of the compounds of the present invention in respect of the NMDA receptor is confirmed by the following methods research.

1. Study of the binding of MK-801

1) Obtaining the sample further machining work : the soft meninges rats

The SD rats aged 10 weeks were extracted in whole brain (30 goals, using Nippon SLC) and it removed the cerebellum. Part, containing the brain, was added of 0.32 M sucrose solution, cut in the mixer and homogenized using a homogenizer with TeflonTM. The obtained homogenate was centrifuged at 2800 rpm and 4°C for 15 minutes, and the supernatant re-centrifuged at 15000g and 4°C for 20 minutes. Cellular precipitate suspended in 50 mm Tris-HCL (pH 7.5)containing 0,08% Triton X-100, and left statically on ice for 30 minutes, then centrifuged at 15000g and 4°C for 20 minutes. Cellular precipitate suspended in added to 50 mm Tris-HCl (pH 7.5) and centrifuged at 15000g and 4°C for 20 minutes. Again to the precipitate was added 50 mm Tris-HCl (pH 7.5) and centrifuged similar to the above method. Sediment suspended in the added thereto 20 ml of 50 mm Tris-HCl (pH 7.5) and homogenized using a Teflon homogenizer™. The sample membrane was divided into small test tubes and kept in the freezer for deep freeze (-80°C). Before using the sample of double-membrane was washed five times by volume relative to the sample volume of 5 mm Tris-HCl (pH 7.5). The concentration was set at 1 mg protein/ml by adding thereto 5 mm Tris-HCl (pH 7.5) and using the Ali for the research.

2) the Study of [3H]MK-801 binding

To a solution of the compounds, dissolved in 1 μl of DMSO, was added 50 μl of the sample membrane rats (1 mg protein/ml). Then added 50 μl of a solution of the ligand (600 nm glutamate, 600 nm glycine, 8 nm [3H] MK-801 (Perkin-Elmer), thoroughly mixed, and spent interaction at room temperature for 45 minutes. Using a filter Uni Filter Plate GF/B 96 (Perkin-Elmer), pre-coated with 0.2% polyethylenimine, the sample membrane was collected and the filter was thoroughly washed in 5 mm Tris-HCl (pH 7.5). The filter was added 30 μl Microscinti 20 (Perkin-Elmer), and the radioactivity on the filter was measured with a scintillation counter for microplates (TopCount™, Beckman). On the basis of inhibition of MK-801 (final 1 mm), 100%, test case with only DMSO, concentration of the compound at 50% inhibition, calculated IC50. The binding affinity of [3H]MK-801 for sample membrane rats was obtained by research Scatchard and Kd=1.6 nm. The Ki value of the compound was calculated according to the calculation equation: Ki=IC50/(1+concentration radioligand (4 nm) in the study)/Kd (1.6 nm)).

As a result, the compounds of the present invention showed good affinity to the NMDA receptor. Table 1 below shows the values of Ki of affinity to the NMDA receptor of some typical compounds of the present invention.

Table 1
ConnectionKi(μm)ConnectionKi(μm)
Example 11,4Example 856,2
Example 60,88Example 911,1
Example 90,93Example 988,4
Example 150,86Example 1012,1
Example 281,0Example 1085,6
Example 320,44Example 1130,9
Example 341,8Example 1314,8
Example 361,9Example 1395,0
Example 440,93Example 1430,7
Example 534,1Example 1458,4

2. The study of intracellular calcium concentration using FLIPR (fluorescent imaging tablet count)

1) Getting neurocytol rats first generation

Anastasiosandy ether Wistar rats (Nippon SLC), pregnant for 19 days, were killed by blood loss from the cut in the chest. Dissect the abdominal cavity, animali the uterus and out of the separated germ. The brain was separated entirely, then, the brain was placed in a Neurobasal medium (Glu, Asp-free) (Gibco) and removed the brain membrane. The brain was centrifuged and suspended in cell dispersion solution (0.36 mg/ml papain, 150 U/ml Tnkase I, with 0.02% L-cysteine monohydrochloride monohydrate, is 0.02% bovine serum albumin, 0.5% of glucose, Ca2+Mg2+-free PBS) and treated at 37°C for 15 minutes. The resulting suspendu was centrifuged at 400g for 5 minutes and supernatant was removed by suction. The residue is suspended in the culture medium for neurocytol (Sumitomo Bakelite) and cell mass was removed by filtration. Counted the number of living cells and incubated on 96-well plate in the amount of 100,000 cell/well (Biocoat PDL96W black/clear, Nippon Becton Dickinson) at 37°C in 5% CO2.

2) the Study of intracellular calcium concentration using FLIPR (fluorescent imaging tablet count)

Culture neurocytol rats of the first generation (DIV7-9) was removed by suction and the cells were washed once analytical buffer solution (balanced salt solution, Henk (Ca2+, Mg2+-free), 20 mm Hepes-NaOH (pH of 7.4), 1 mm CaCl2). Added 100 μl of analytical buffer solution containing Fluo3 (Dojin Chemical) and incubated for 1 hour (37°C, 5% CO2). Cells were washed three times is 100 ál analytical buffer solution and then added to the control solution connection dissolved in 1 μl of DMSO, and 100 ál analytical buffer solution containing 2.5 μm (final concentration) of tetrodoxin, and incubated for 30 minutes (37°C, 5% CO2). The intensity of the fluorescent radiation is measured at intervals of 2 seconds. Ten seconds began dimension by adding 50 μl of a solution of the ligand (balanced salt solution, Henk (Ca2+, Mg2+-free)was added 20 mm Hepes-NaOH (pH of 7.4), 1 mm CaCl2, 9 μm NMDA, 30 μm glycine)containing the control solution of the compound dissolved in 0.5 μl DMSO, and measuring the intensity of fluorescent radiation system within 120 seconds from the start of measurement. The data measured for 120 seconds (60 in total) were averaged. On the basis of 10 μm MK-801 inhibition of 100%, test case only DMSO, concentration of the compound at 50% inhibition, calculated IC50.

As a result, the compounds of the present invention demonstrate good antagonistic activity against NMDA receptor.

Pharmaceutical composition containing as an active ingredient one or more compounds of the present invention and its pharmaceutically acceptable salts may be obtained, optionally together with carriers and fillers commonly used in the pharmaceutical industry, and other additives in the form of tablets, powders, INFI is nitesimally particles, granules, capsules, pills, solutions, injections, suppositories, ointments, lotions, and is administered to patients orally or neironalna.

Depending on the condition, body weight, age and sex of the patient, which enter the connection, for a person can be defined clinical dose of a compound of the present invention. It would typically ranges from 0.1 to 500 mg/adult/day for oral administration, and from 0.01 to 100 mg/adult/day for refererlog introduction, and may be entered at once all at once or a few times. The dose may vary under different conditions, and, depending on circumstances, may be less than the dose limit.

Solid composition for oral administration of the compounds of the present invention may be a tablet, a powder or granules. In solid compositions, one or more active substances can be mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate. In accordance with the conventional method, the composition may contain any other additives than the inert diluent, for example a lubricating substance, such as magnesium silicate, disintegrator, Taco is how the calcium the cellulose glycolate, a stabilizer such as lactose, solubilizer, or the dissolution accelerator, such as glutamic acid, aspartic acid. Tablets and pills may be coated with sugar or film, resistant to gastric juice, or enteric film.

Liquid composition for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup and elixir and contains the usual inert diluent, such as clean water, ethyl alcohol. The composition may contain any other additives than the inert diluent, for example, an auxiliary agent, such as a solubilizer, a dissolution accelerator, a wetting agent, suspendisse agent and sweetener, flavor, fragrance and preservative. Injection for refererlog injection include sterile solution is water-based or anhydrous solution, suspension and emulsion. The solvent for the aqueous solution and suspension include, for example, distilled water for injection and physiological saline. The diluent for anhydrous solution and suspension include, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, Polysorbate 80 (trade mark).

The composition may further contain any other additive, such as an additive for the project for isotonicity, preservative, wetting agent, emulsifier, dispersant, stabilizer, solubilizer, a dissolution accelerator. They can be sterilized by filtration through catching bacteria filter, or by adding germicide, or irradiation with light. Depending on circumstances, can be obtained sterile solid composition, and it is before the application can be dissolved in sterile water or a sterile solvent for injection and obtaining the desired liquid composition.

EXAMPLES

Compounds of the present invention is described with reference to the following examples. The source compounds for the compounds of the present invention include new connections, and obtaining them is illustrated in the reference examples below.

Reference example 1:

3-(3-Bromo-4-forfinal)propionic acid:

To a pyridine solution (250 ml) of 3-bromo-4-forventelige (20 g) and malonic acid (51 g) was added piperidine (1 ml) followed by heating under reflux for 3 hours. After completion of the reaction the solvent was evaporated under reduced pressure, adding water and neutralized by adding a solution of 1H. hydrochloric acid under stirring. Precipitated precipitated product was collected by filtration and obtained (2E)-3-(3-bromo-4-forfinal)acrylic acid was dissolved in THF (200 ml) with posledeistviem with 5% Rh-C (3 g) in a hydrogen atmosphere at room temperature for 12 hours. Nerastvorim product was removed by filtration and the solvent was evaporated under reduced pressure to obtain compound (15 g) of reference example 1.

In the reference example 2, the compound shown in table 2, obtained by the method similar to that described in reference example 1.

Reference example 3:

3-(2-Fluoro-5-were)propionic acid:

To a pyridine solution (50 ml) of 2-fluoro-5-methylbenzaldehyde (4,2 g) and malonic acid (16 g) was added piperidine (0.3 ml) followed by heating under reflux for 3 hours. After completion of the reaction the solvent was evaporated under reduced pressure, adding water and neutralized by adding a solution of 1H. hydrochloric acid under stirring. Precipitated precipitated product was collected by filtration and obtained (2E)-3-(2-fluoro-5-were)acrylic acid was dissolved in a mixed solvent (70 ml), THF and EtOH, and then was stirred with 10% Pd-C (0.5 g) in a hydrogen atmosphere at room temperature for 12 hours. Nerastvorim product was removed by filtration and the solvent was evaporated under reduced pressure to obtain compound (5.1 g) of reference example 3.

In the reference examples 4-7 compounds shown in table 2, obtained by the method similar to that described in reference example 3.

Referential example 8:

3-(4-Bromo-2-fluoro-5-were)propionic Ki the lot:

The compound (3.0 g) of reference example 3 was dissolved in a mixed solvent triperoxonane acid (15 ml) and concentrated sulfuric acid (3 ml) and gradually at room temperature was added N-bromosuccinimide (hereinafter indicated as NBS) (3.5 g), followed by stirring for 1 hour at the same temperature. The reaction solution was poured into ice water, then was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain compound (3.7 g) of reference example 8.

In the reference examples 9-12 compounds shown in table 2, obtained by the method similar to that described in reference example 8.

Reference example 13:

Methyl 3-(3,4,5-tryptophanyl)-2,2-dimethylpropionic:

To a solution of ISO-Pr2NH (25 ml) in THF (200 ml) at -20°C was added a solution of 1.6 M n-BuLi/hexane (100 ml), then stirred at this temperature for 30 minutes. Was cooled to -78°C, then added methyl 3-(3,4,5-tryptophanyl)propionate (24 g) and then was stirred for 1 hour. Then was added MeI (10 ml) and then was stirred for 1 hour. The reaction solution was heated to 0°C, then was added a saturated aqueous solution of ammonium chloride and then was extracted with diethyl ether, and then washed 1H. hydrochloric acid, saturated aqueous bicarbonate intothree is, water and saturated salt solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain methyl 3-(3,4,5-tryptophanyl)-2-methylpropionate.

Next to the LAD, who was likewise of ISO-Pr2NH (25 ml)was added at -78°C obtained above methyl 3-(3,4,5-tryptophanyl)-2-methylpropionate and stirred at the same temperature for 1 hour. Then was added MeI (10 ml) and was further stirred for 1 hour. The reaction solution was heated to 0°C, was added a saturated aqueous solution of ammonium chloride and was extracted with diethyl ether. Washed 1H. hydrochloric acid, saturated aqueous sodium bicarbonate, water and saturated saline, then was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain compound (21 g) of reference example 13.

Reference example 14:

6,7-Dichloride-1-he:

3-(3,4-Dichlorophenyl)propionic acid (500 mg) was stirred in TfOH (1.5 ml) in an argon atmosphere at 100°C within 24 hours. The reaction solution was poured into ice water, was extracted with diethyl ether, washed with water, saturated aqueous sodium hydrogen carbonate and saturated saline, then was dried over anhydrous sodium sulfate. Then the solvent was evaporated under decreased the pressure. The residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 5/1) to give 5,6-dichloride-1-she (115 mg) and the compound of reference example 14 (44 mg).

In the reference examples 15-22, compounds shown in table 2 and 3, obtained by the method similar to that described in reference example 14.

Reference example 23:

4-Bromo-6-fluoro-7-methoxy-1-indanone:

The compound (20 g) of reference example 9 was dissolved in TfOH (200 ml) and stirred in an argon atmosphere at 50°C for 2 hours. The reaction solution was poured into ice-cold water and with stirring and cooling on ice, neutralized with a saturated aqueous solution of ammonia. Precipitated precipitated product was collected by filtration, washed with water and dried under reduced pressure to obtain compound (13 g) of reference example 23 in the form of a brown solid.

In the reference examples 24-25 compounds shown in tables 2 and 3, obtained by the method similar to that described in reference example 14.

In the reference example 26 compound shown in table 3, was obtained from the compound obtained in reference example 13 and shown in table 2, in a way similar to that described in reference example 14.

Reference example 27:

6-Fluoro-2,2-dietlinde-1-he:

To a solution of 6-Florinda-1-it (388 mg) in THF (10 ml) in an argon atmosphere at room temperature until alali MeI (0,354 ml) and 55%NaH in oil (248 mg), followed by stirring at the same temperature for 30 minutes. To the reaction liquid was added a saturated aqueous solution of ammonium chloride, then was extracted with diethyl ether, washed with saturated saline, then was dried over anhydrous sodium sulfate. Next, the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 10/1) to obtain compound (241 mg) of reference example 27.

In the reference examples 28-55 compounds shown in tables 3-5 were obtained by the method similar to that described in reference example 27.

Reference example 56 and reference example 57:

7-Chloro-6-fluoro-2,2-dietlinde-1-he and 5-chloro-6-fluoro-2,2-dietlinde-1-he:

3-(3-Chloro-4-forfinal)propionic acid (9.8 g) was dissolved in TfOH (40 ml) and stirred in an argon atmosphere at 100°C within 24 hours. The reaction solution was poured into ice water, was extracted with diethyl ether and washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution. Then the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 10/1-3/1) to obtain a mixture (7.2 g) 5-chloro-6-Florinda-1-it 7-chloro-6-Florinda-1-it. Then the product was dissolved in THF (200 ml)was added MeI (6,1 ml) and with stirring at room temperature was slowly added a 55%n is th NaH in oil (4.3 g) for 30 minutes. After the termination of heat to the reaction solution was added saturated aqueous solution of ammonium chloride, then was extracted with diethyl ether and washed with saturated saline solution. The product was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 30/1-10) to obtain the compound (0.85 grams) of reference example 56 and the compound (5.9 g) of reference example 57.

In the reference examples 58-61 compounds shown in table 5, were obtained by the method similar to that described in referential examples 56 and 57.

Reference example 62:

4,6,7 there-Tribromo-2,2-dietlinde-1-he:

6-Bromo-2,2-dietlinde-1-he (600 mg) was dissolved in the mixed solution triperoxonane acid (5 ml) and concentrated sulfuric acid (4 ml) and at room temperature was added NBS (1,34 g), then stirred at the same temperature for 3 hours. The reaction solution was poured into ice water and neutralized with a saturated aqueous solution of ammonia. Precipitated precipitated product was collected by filtration to obtain compound (1.1 g) of reference example 62.

In the reference example 63 compound shown in table 5, were obtained by the method similar to that described in reference example 62.

Reference example 64:

6-Fluoro-7-methoxy-2,2-dimetyl the Dan-1-he:

To a solution of compound (15 g) of reference example 53 in EtOH (300 ml) was added ISO-Pr2NEt (8,9 ml) and 10% Pd-C (1 g) and stirred in a hydrogen atmosphere at room temperature for 1 hour. Nerastvorim product was removed by filtration, the solvent was evaporated under reduced pressure and to the residue was added water, then was extracted with diethyl ether and washed with saturated saline solution. The product was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain compound (1.1 g) of reference example 64.

In the reference examples 65 and 66 compounds shown in table 6, were obtained by the method similar to that described in reference example 64.

Reference example 67:

7-Fluoro-3,3-dimethylindoline-2,4(1H,3H)-dione:

To MsOH (100 ml) was added P2O5(10 g) and stirred at 80°C for 30 minutes. Was added 3-[(3-forfinal)amino]-2,2-dimethyl-3-oxopropionate acid (8 g) and was stirred at the same temperature for 2 hours. The reaction solution was cooled to room temperature, poured into ice water and added with stirring, a saturated aqueous solution of ammonia, making it so basic. Precipitated precipitated product was collected by filtration, washed with water and dried under reduced pressure to obtain compound (6 g) of reference example 67.

Reference when the EP 68:

Ethyl 4-(1-hydroxy-2,2,6-trimethyl-2,3-dihydro-1H-inden-1-yl)piperidine-1-carboxylate:

To toluene (50 ml) solution of desalted product (1.5 g) compound of example 6 was added Et3N (7 ml) and ethylchloride (4 ml), then stirred at 100°C for 2 hours. The reaction solution was subjected to separation of liquid-liquid using a mixture of ethyl acetate/water and the organic layer was washed with saturated saline, then was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 5/1) to obtain the compound (1.04 g) of reference example 68.

In the reference examples 69 and 70 of the compounds shown in table 6, were obtained by the method similar to that described in reference example 68. In the reference example 71 compound shown in table 6, were obtained by the method similar to that described in reference example 27. In the reference example 72 compound shown in table 7, obtained by the method similar to that described in reference example 68.

Reference example 73:

4-(2-Fluoro-5-methoxy)butane acid:

To 1,2-dichlorethane (50 ml) solution of TiCl4(of 2.06 ml) at room temperature was added 2-fluoro-5-methoxybenzaldehyde (2.5 g) and was stirred at the same temperature for 30 minutes. Was cooled to -78°C, Zutendaal 1 ethoxy-1-[(trimethylsilyl)oxy]cyclopropane (3,76 ml) and with stirring, they were heated to 0° C for 3.5 hours. The reaction solution was poured into ice water, extracted with chloroform, washed with saturated saline, then was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The resulting yellow oil was dissolved in ethanol (100 ml) was added 10% Pd-C (450 mg), followed by stirring in a hydrogen atmosphere at normal pressure for 2 hours. Nerastvorim product was removed by filtration using Celite, and the solvent was evaporated under reduced pressure to obtain a yellow oil. Then the product was dissolved in EtOH (50 ml) was added 1N. aqueous NaOH solution (17.5 ml) c, followed by stirring at room temperature for 4 days. The reaction solution was acidified with diluted hydrochloric acid, then was extracted with ethyl acetate and washed with saturated saline solution. Was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain compound (3,45 g) of reference example 73 as a brown solid.

In the reference example 74 a way similar to that described in reference example 23; in reference example 75 manner similar to that described in reference example 27; in reference example 76 by the method similar to that described in reference example 3; in reference example 77 in a manner similar to described is in reference example 14; in the reference example 78 by way similar to that described in reference example 27; in reference example 79 and by the way, is similar to that described in reference example 23; in reference example 80 by the method similar to that described in reference example 27; in reference example 81 manner similar to that described in reference example 117, obtained compounds are shown in table 7.

Reference example 82:

6-Bromo-2,2-dimethyl-7-methoxyindol-1-he:

To a solution of compound (989 mg) of reference example 81 and MeI (1,09 ml) in THF at room temperature was added 55%NaH in oil (760 mg) and stirred at 60°C for 3 hours. Was added a saturated aqueous solution of ammonium chloride, followed by separation of liquid-liquid using mixed solvent (3/1) ethyl acetate and THF. The organic layer was washed with saturated saline solution, dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent; hexane/ethyl acetate = 6/1) to obtain 6-bromo-2,2-dimethyl-7-hydroxyine-1-she (1.1 g). Then to a solution in DMF was added MeI (0,298 ml) and K2CO3(1,81 g) in that order and stirred at 60°C within 24 hours. After completion of the reaction was added water, followed by separation of liquid-liquid using ethyl acetate. The organic layer was washed of NASA the military saline, was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate = 9/ 1 to 4/1) to obtain compound (644 mg) of reference example 82 as a colorless powdery solid.

Reference example 83:

6-Fluoro-7-hydroxy-2,2-dietlinde-1-he:

To methylenechloride solution of the compound (8,10 g) of reference example 64 while cooling on ice gradually was added dropwise 1M solution of BBr3/methylene chloride (60 ml). Was stirred over night at room temperature was added a saturated aqueous solution of sodium bicarbonate, then extracted with methylene chloride. Was washed with saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain compound (7,86 g) of reference example 83 in the form of a brown solid.

Reference example 84:

7 Ethoxy-6-fluoro-2,2-dietlinde-1-he:

To a solution of the compound (4.0 g) of reference example 83 and K2CO3(8,54 g) in DMF was added at room temperature EtI (5.0 ml) and stirred overnight at the same temperature. To the reaction solution was added water, then was extracted with ethyl acetate and washed with water and saturated salt solution. Was dried over anhydrous sulfate is sodium and the solvent was evaporated under reduced pressure to obtain compound (4,47 g) of reference example 84 in the form of a brown oil.

In the reference example 83 manner similar to that described in reference example 3; in reference example 86 method similar to that described in reference example 96; in reference example 87 manner similar to that described in reference example 23 and then a method similar to that described in reference example 27; in reference example 88 manner similar to that described in reference example 3; in reference example 89 manner similar to that described in reference example 67; in reference example 90 manner similar to that described in reference example 27; in reference example 91 a way similar to that described in reference example 3 received connection shown in tables 7 and 8.

Reference example 92:

4-Fluoro-6-hydroxy-2,2,7-trimethylene-1-he:

By the way, is similar to that described in reference example 14 was obtained compound (442 mg) of reference example 92 and the compound (239 mg), 4-fluoro-6-hydroxy-2,2,5-trimethylene-1-she 4-fluoro-6-hydroxy-2,2-dietlinde-1-it, each in the form of a brown solid from the compound of reference example 91.

In the reference example 93 compound shown in table 8, was obtained from the compound of reference example 92 a way similar to that described in reference example 27.

Reference example 94:

1-(4-fluoro-2-hydroxyphenyl)-2-methylpropan-1-he:

A mixture of AlCl3(150 g) and NaCl (150 g) was melted at 160°C when s is remesiana. At the same temperature was added 3-forfinal 2-methylpropanoate (50 g), followed by stirring for 1 hour. The reaction liquid was cooled, then under cooling in an ice water was gradually added to decompose AlCl3. Then added concentrated hydrochloric acid, followed by heating and stirring for dissolving pulp. When the mass was suspended, it was cooled and was extracted with diethyl ether, washed with saturated saline, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain compound (49 g) of reference example 94 in the form of a brown oil.

Reference example 95:

1-(3,5-Dibromo-4-fluoro-2-hydroxyphenyl)-2-methylpropan-1-he:

To a mixed solution of the compound (49 g) of reference example 94 in triperoxonane acid (200 ml) and concentrated sulfuric acid (40 ml) at -10°C for 1 hour was added NBS (115 g). Then stirred at a temperature of from -10°C to 0°C for 1 hour and the reaction solution was poured into ice-cold water followed by extraction with diethyl ether. The organic layer was concentrated under reduced pressure, the residue was subjected to separation of liquid-liquid saturated aqueous solution of sodium bicarbonate and diethyl ether and the organic layer was washed several times with 5%is electroplated in an aqueous solution of sodium thiosulfate. Additionally washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain brown oil. After keeping it in this form, as it is observed partial crystallization. Zakristallizuetsya part was collected by filtration to obtain compound (91 g) of reference example 95 in the form of brown crystals.

Reference example 96:

N'-[1-(3,5-dibromo-4-fluoro-2-hydroxyphenyl)-2-methylpiperidin]-1-methylpiperidin-4-carbohydrazide acetate:

To ISO-D-th solution of the compound (34 g) of reference example 95 1-methylpiperidin-4-carbohydrazide (20 g) was added acetic acid (7.3 ml) followed by heating under reflux for 5 hours. After nerastvorim product precipitated, the reaction solution was cooled to room temperature and the product was collected by filtration and washed with ISO-D with obtaining compound (40 g) of reference example 96 in the form of a crystalline substance.

Reference example 97:

3,4-Debtor-5-methoxybenzaldehyde:

To a solution in diethyl ether, 5-bromo-1,2-debtor-3-methoxybenzene (497 mg) in an argon atmosphere at -70°C was added the solution was 1.58 M n-BuLi/hexane (1.4 ml) and was stirred at the same temperature for 1 hour. Was added DMF (0,259 ml), then was stirred for 30 minutes. PEFC the completion of the reaction was added water, then was extracted with diethyl ether, washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain compound (317 mg) of reference example 97.

In reference example 98, the compound in table 8 were obtained by the method similar to that described in reference example 84.

Reference example 99:

1-(2-Fluoro-6-methoxyphenyl)-2-methylpropan-1-ol:

To a solution of 3-fernicola (28 g) and N,N,N',N',N"-pentamethyldiethylenetriamine (48 ml) in THF in an argon atmosphere at -78°C was gradually added to the solution was 1.58 M n-BuLi/hexane (152 ml), then stirred at the same temperature for 1 hour. Gradually added Isobutyraldehyde (22 ml) and further stirred for 15 minutes. Was gradually heated to room temperature, then added water and was extracted with diisopropyl ether. Washed with water and saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain compound (47 g) of reference example 99 in the form of oil.

In the reference example 100 by the method similar to that described in reference example 27; in reference example 101 a way similar to that described in reference example 1, reference example 102 a way similar to that described in reference example 23; in reference example 103 method is m, similar to that described in reference example 27; in reference example 104 a way similar to that described in reference example 3 was obtained compounds are shown in table 9.

Reference example 105:

4-Bromo-5,5-debtor-7-methoxyindol-1-he:

The solution in the mixture triperoxonane acid/concentrated sulfuric acid (5/1) of the compound (4.4 g) of reference example 104 was cooled to 0°C and separately added is divided into 10 parts NBS (3.8 g), followed by stirring at 0°C for 1 hour. To the reaction solution was added water, then was extracted with ethyl acetate, washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 3-(2-bromo-3,4-debtor-5-methoxyphenyl)propionic acid as a crude product. Then was dissolved in TfOH (8,8 ml) and stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, then extracted with ethyl acetate, washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 4/1) to obtain compound (2,84 g) of reference example 105.

Reference example 106:

5,5-Debtor-7-methoxy-2,2-dietlinde-1-he:

It is astory compound (2.8 g) of reference example 105 and MeI (1.4 ml) in THF at room temperature was added 55%NaH in oil (978 mg), then was stirred at the same temperature for 1 hour. Was added a saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate, washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-bromo-5,5-debtor-7-methoxy-2,2-dietlinde-1-it is in the form of a crude product. Then the product was dissolved in EtOH was added 10% Pd-C and was stirred in hydrogen atmosphere (1 atmosphere) at room temperature for 20 hours. The insoluble substance was removed by filtration using Celite, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 9/1) to obtain compound (550 mg) of reference example 106 as a colorless oil.

Reference example 107:

5,6-Defterinden-1-ol:

To a solution of MeOH 5,6-defterinden-1-it (3,44 g) under cooling on ice, was added NaBH4(774 mg), followed by stirring at the same temperature for 1 hour. To the reaction solution, acetone was added, then the solvent was evaporated under reduced pressure and the residue was subjected to separation of liquid-liquid with saturated ammonium chloride and ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and dissolve the al was evaporated under reduced pressure to obtain compound (4,29 g) of reference example 107 in the form of oil.

Reference example 108:

5,6-Debtor-1-{[2-(trimethylsilyl)ethoxy]methoxy} indan:

To a solution of compound (4,29 g) of reference example 107 in DMF) while cooling on ice, was added 55%NaH in oil (1.31 g) and 1-(chloromethoxy)-2-(trimethylsilyl)ethane (5.0 g) and was stirred over night at room temperature. To the reaction solution was added ice water, extracted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 20/1) to obtain compound (4,25 g) of reference example 108 in the form of oil.

Reference example 110:

5,6-Debtor-7-hydroxymethyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}indan:

To a solution of compound (1,46 g) of reference example 107 in THF in an argon atmosphere at -78°C was added 1,58 M solution of n-BuLi/hexane (3.6 ml) and stirred at the same temperature for 1 hour. Was added DMF (0,49 ml) at the same temperature and slowly heated to room temperature, then subjected to separation of liquid-liquid saturated aqueous ammonium chloride and ethyl acetate and the organic layer was washed with saturated saline solution. The product was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the mod is to was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 4/1) to give 5,6-debtor-7-formyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}indane (1.31 g) as oil. To a solution of the product in MeOH when cooled on ice was added NaBH4(227 mg) and was stirred at the same temperature for 1 hour. To the reaction solution, acetone was added, then the solvent was evaporated under reduced pressure and the residue was subjected to separation of liquid-liquid saturated ammonium chloride and ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain compound (929 mg) of reference example 110 in the form of oil.

Reference example 111:

5,6-Debtor-7-methoxymethyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}indan:

To a solution of compound (929 mg) of reference example 110 and MeI (of 0.21 ml) in THF while cooling on ice, was added 55%NaH in oil (147 mg), then stirred overnight at room temperature. The reaction solution was subjected to separation of liquid-liquid saturated aqueous ammonium chloride and ethyl acetate and the organic layer was washed with saturated saline solution. The product was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 20/1) to obtain compound (905 mg) of reference example 111 in the form of oil.

Reference example 112:

5,6-Debtor-7-methox methylinden-1-ol:

To a solution of compound (899 mg) of reference example 111 in DMF) was added CsF (1,59 g), then stirred overnight while heating at 130°C. the Reaction solution was cooled to room temperature, was added ethyl acetate and stirred, and the insoluble substance was removed by filtration using Celite. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 2/1) to obtain compound (479 mg) of reference example 112 in the form of oil.

Reference example 113:

5,6-Debtor-7-ethoxymethylene-1-he:

The compound (479 mg) of reference example 112 N-methylmorpholin (393 mg) and Pr4N+RUO Li4-(V (79 mg) was added to the mixed 1/1 solvent consisting of MeCN and methylene chloride, then stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 2/1) to obtain compound (450 mg) of reference example 113 in the form of oil.

In the reference example 114 by way similar to that described in reference example 27; in reference example 115 manner similar to that described in reference example 8, but from the compound of reference example 71, was obtained compounds are shown in table 9.

Reference example 116:

1-(for-6-hydroxyphenyl)-2-methylpropan-1-he:

To a solution of 1M BBr3/methylene chloride (250 ml) in an argon atmosphere at -78°C was added a solution of compound (43 g) of reference example 99 in methylene chloride, was stirred for 1 hour at a temperature in the range from the specified temperature and -40°C, then slowly warmed up to 0°C. For the separation of liquid-liquid was added water, and the organic layer was washed with saturated saline solution. The product was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain compound (38 g) of reference example 116 in the form of oil.

Reference example 117:

1-(3-Bromo-6-fluoro-2-hydroxyphenyl)-2-methylpropan-1-he:

To a solution of tert-BuNH2(51 g) in toluene in an argon atmosphere at -30°C gradually dropwise added bromine (60 g). The product was stirred for 30 minutes at the same temperature, then was cooled to -78°C and slowly added methylenechloride solution of the compound (70 g) of reference example 116. The mixture then was stirred for 1 hour at the same temperature, then gradually heated to 0°C for 4 hours. To the reaction solution was added ice water, extracted with ethyl acetate, washed with water and saturated saline, then was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain compound (88 g) sylo the aqueous sample 117 in the form of oil.

Reference example 118:

N'-[1-(3-bromo-6-fluoro-2-hydroxyphenyl)-2-methylpiperidin]-Hinkley-3-carbohydrazide:

The mixture of the hydrochloride of the methyl Hinkley-3-carboxylate (1.0 g) and hydrazine monohydrate (3.0 ml) was stirred for 2 hours while heating at 100°C. In the heating process, the mixture was concentrated under reduced pressure and the residue was dissolved in ISO-D. Added the compound (2.7 g) of reference example 117 and acetic acid (0,596 ml), then was heated under reflux for 7 hours. After completion of the reaction the solvent was evaporated under reduced pressure and the residue was subjected to separation of liquid-liquid 0,5h. hydrochloric acid and diisopropyl ether. The aqueous layer was repeatedly washed with diisopropyl ether, and then was neutralized with sodium bicarbonate and was extracted three times with chloroform. Layer with chloroform, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain compound (710 mg) of reference example 118 in the form of a colorless amorphous substance.

Reference example 119:

1-(2-Fluoro-6-methoxyphenyl)-2-methylpropan-1-he:

To a solution of compound (47 g) of reference example 99 and Et3N (152 ml) in DMSO while cooling on ice was gradually added SO3·pyridine (139 g), then stirred overnight at room temperature. To the reaction RA is Toru was added water, was extracted with diisopropyl ether, washed with diluted hydrochloric acid, water and saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain compound (43 g) of reference example 119 in the form of oil.

Reference example 120:

6-Fluoro-7-methoxy-2,2-dimethyl-1-trimethylcyclohexylidene-1-carbonitrile:

To a solution of compound (485 mg) of reference example 64 and ZnI2(37 mg) in 1,2-dichloroethane at room temperature was added (TMS)CN (930 mg), then stirred at the same temperature for 2 hours. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, was extracted with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain compound (710 mg) of reference example 120.

Reference example 121:

Methyl (6-fluoro-1-hydroxy-7-methoxy-2,2-dimethyl-2,3-dihydro-1H-inden)acetate:

To a solution of ISO-Pr2NH (6.4 ml) in THF in an argon atmosphere at -78°C solution was added to 2.67 M n-BuLi/hexane (17 ml) and was stirred at the same temperature for 30 minutes. Added acetate (3.6 ml) and further stirred for 30 minutes. Then was added a solution of compound (1.9 g) of reference example 64 in THF and was stirred for 2 hours is. To the reaction solution was added ice water, extracted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain compound (2.8 g) of reference example 121.

Reference example 122:

6-Fluoro-1-(3-hydroxyethyl)-7-methoxy-2,2-dietlinde-1-ol:

To a suspension of LiAlH4(202 mg) in THF was added a solution of the compound (1.0 g) of reference example 121 in THF followed by heating c reflux at 80°C for 2.5 hours. The reaction solution was cooled, diluted with THF, was added water (0.8 ml) and 15%aqueous NaOH solution (0.2 ml) and stirred, nerastvorim product was removed by filtration using Celite. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 5/1-3/1) to give compound (366 mg) of reference example 122.

Reference example 123:

The oxime 1-(1-hydroxy-2,2,6-trimethyl-2,3-dihydro-1H-inden-1-yl)acetone:

To a solution of acetone oxime (3.94 g) in THF in an argon atmosphere at 0°C was added the solution was 1.58 M n-BuLi/hexane (86 ml), followed by stirring at the same temperature for 2 hours. Then added 2,2,6-trimethylene-1-he (7,83 g) and further stirred for 3 hours. To the reaction solution was added to yenny aqueous solution of ammonium chloride, were extracted with ethyl acetate and washed with water and saturated salt solution. The product was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain compound (12 g) of reference example 123.

Reference example 124:

2,2,3',6-Tetramethyl-2,3-dihydro-4'H-Spiro[inden-1,5'-isoxazol]:

To a solution of compound (12 g) of reference example 123 in chloroform under cooling on ice was gradually added P2O5(60 g) and was stirred at the same temperature for 2 hours. The reaction solution was poured into ice water, extracted with chloroform, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 10/1-4/1) to obtain compound (5.7 g) of reference example 124:

Reference example 125:

2,2,3',6-Tetramethyl-2,3-dihydro-4'H-Spiro[inden-1,5'-oxazolidin]:

To a solution of compound (1,15 g) of reference example 124 in methylene chloride in an argon atmosphere at -78°C was added BF3·Et2O (0,76 ml) and was stirred at the same temperature for 10 minutes. Then was added a solution of 0.98 M MeLi/diethyl ether (6,12 ml) followed by stirring at the same temperature for 2 hours. To the reaction solution was added saturated aqueous solution of bicarbonate into three and was extracted with chloroform. The product was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/ethyl acetate = 2/1) to obtain compound (421 mg) of reference example 125.

Reference example 126:

6-Fluoro-7-methoxy-2,2-dimethyl-1-(3-{[(tert-butyl)-dimethylsilane]oxy}propyl)indan-1-ol:

To a suspension of Mg (350 mg) in THF in an argon atmosphere was added dropwise (3 bromopropane)(tert-butyl)dimethylsilane (3,3 ml), followed by stirring overnight at room temperature. To the reaction mixture was added a solution of the compound (1.0 g) of reference example 64 in THF and then stirred under heating at 60°C for 1 hour. The reaction solution was cooled, was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 10/1) to obtain compound (865 mg) of reference example 126.

Reference example 127:

6-Fluoro-1-(3-hydroxypropyl)-7-methoxy-2,2-dietlinde-1-ol:

To a solution of compound (827 mg) of reference example 126 in THF was added 1M solution of n-Bu4NF/THF (4.4 ml), followed by stirring at room temperature for 2 hours. To the reaction is th solution was added water, were extracted with ethyl acetate, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 5/1-1/1) to obtain compound (384 mg) of reference example 127 in the form of oil.

Reference example 128:

6-Fluoro-7-methoxy-2,2-dimethyl-1-(pyridine-2-ylmethyl)indan-1-ol:

To a solution of ISO-Pr2NH (0,61 ml) in THF in an argon atmosphere at -78°C solution was added to 2.67 M n-BuLi/hexane, followed by stirring for 30 minutes at the same temperature. To the reaction mixture were added 2-picoline (0,43 ml), then heated to room temperature, followed by stirring for 30 minutes. To the reaction mixture was further added a solution of compound (460 mg) of reference example 64 in THF, followed by stirring at the same temperature for 2 hours. To the reaction solution was added ice water, extracted with ethyl acetate, washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 5/1) to obtain the compound (525 mg) of reference example 128 in the form of oil.

Reference example 129:

4-Fluoro-6,7-dihydroxy-2,2-dietlinde-1-he:

The solution is connected to the I (1.3 g) of reference example 90 in 1,2-dichloroethane when cooled on ice was added a solution of 1M BBr 3/methylene chloride (17 ml), followed by stirring at the same temperature for 1 hour. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, was extracted with chloroform, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 5/1 to 1/1) to obtain compound (735 mg) of reference example 129.

Reference example 130:

5-fluoro-7,7-dimethyl-6,7-dihydro-8H-indeno[4,5-d][1,3]-oxol-8-he:

To a solution of the compound (200 mg) of reference example 129 in DMF) was added KF (276 mg) and dibromomethane (0,074 ml), then stirred under heating at 100°C for 5 hours. The reaction solution was concentrated under reduced pressure, then subjected to separation of liquid-liquid ethyl acetate and saturated aqueous sodium bicarbonate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 5/1) to obtain the compound (40 mg) of reference example 130.

Reference example 131:

6-Fluoro-8,8-dimethyl-2,3,7,8-tetrahydro-9H-indeno[4,5-b][1,4]dioxin-9-he:

A solution of the compound (251 mg) of reference example 129, 1,2-dibromethane (0,11 ml) and K2CO3 (412 mg) in DMF was stirred while heating at 80°C for 4 hours. The reaction solution was concentrated under reduced pressure, then subjected to separation of liquid-liquid ethyl acetate and saturated aqueous sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 3/1) to obtain the compound (68 mg) of reference example 131.

In the reference example 132 connection in table 11 was obtained by the method similar to that described in reference example 129, but from the compound of reference example 71.

Reference example 133:

4-Fluoro-7-hydroxy-6-iodine-2,2-dietlinde-1-he:

Connection (4.26 deaths / g) of reference example 132 was dissolved in triperoxonane acid (169 ml) and concentrated sulfuric acid (35 ml) was added N-jodatime (5,18 g) at 0°C. the Reaction mixture was stirred at the same temperature for 1 hour, then added water and was extracted with ethyl acetate. The reaction mixture was washed with saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 10/1) to obtain compound (6,46 g) reference note the RA 133.

Reference example 134:

5-fluoro-7,7-dimethyl-2-(trimethylsilyl)-6,7-dihydro-8H-inden[5,4-b]furan-8-he:

To a solution of the compound (5.0 g) of reference example 133 in MeCN was added Et3N (43,5 ml), trimethylsilylacetamide (17.3 ml), PdCl2(PPh3)2(548 mg) and CuI (595 mg), then stirred at 50°C for 2 days. The reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate = 5/2) to obtain the compound (4.09 g) of reference example 134.

In the reference example 135 manner similar to that described in reference example 3; in reference example 136 by way similar to that described in reference example 23; in reference example 137 manner similar to that described in reference example 27 was obtained compounds are shown in table 11.

Reference example 138:

6-Fluoro-7-(2-hydroxyethoxy)-2,2-dietlinde-1-he:

A solution of the compound (500 mg) of reference example 83 2-bromoethanol (0,55 ml) and K2CO3(1.1 g) in DMF was stirred while heating at 80°C. After 6 hours and 8 hours was added 2-bromoethanol (0,55 ml), then stirred overnight while heating at the same temperature. To the reaction solution was added ice water, extracted with ethyl acetate and washed with water and saturated salt solution. The product was dried over anhydrous sodium sulfate, Rast is oritel was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent; n-hexane/ethyl acetate = 5/1) to obtain the compound (578 mg) of reference example 138 in the form of oil.

Reference example 139:

1-(3-Butene-1-yl)-6-fluoro-7-methoxy-2,2-dietlinde-1-ol:

To a suspension of Mg (350 mg) in THF in an argon atmosphere was added dropwise 4-bromo-1-butene (1.5 ml), then stirred overnight at room temperature. At room temperature was added a solution of the compound (1.0 g) of reference example 64 in THF and then stirred under heating at 60°C for 1 hour. To the reaction solution was added saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 10/1) to obtain compound (890 mg) of reference example 139.

Reference example 140:

6'-Fluoro-5-(iodomethyl)-7'-methoxy-2'2'-dimethyl-2',3',4,5-tetrahydro-3H-Spiro[furan-2,1'-inden]:

To a solution of iodine (1.7 g) and NaHCO3(1.5 g) in acetonitrile at room temperature gradually dropwise added to the solution of compound (888 mg) of reference example 139 in MeCN. The reaction mixture was stirred at the same temperature for 1 hour, then the reaction solution was added aqueous sodium thiosulfate solution was extracted with ethyl acetate, washed with saturated saline Rast is a PR and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 20/1) to obtain compound (985 mg) of reference example 140 in the form of oil.

Reference example 141:

2-(2-Hydroxyethyl)-6-methylinden-1-he:

A mixture of 3-(4-methylbenzyl)dihydrofuran-2(3H)-she (2.9 g) and TfOH (23 g) was stirred over night at 80°C. the Reaction mixture was allowed to cool to room temperature, then added water and was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 1/1) to obtain compound (1.4 g) of reference example 141.

Reference example 142:

2-(2-Hydroxyethyl)-2,6-dietlinde-1-he:

To a solution of compound (1,38 g) of reference example 141 in THF at room temperature was added 55%NaH in oil (696 mg), followed by stirring for 10 minutes. To the reaction mixture was added MeI (1,04 ml), then stirred at room temperature for 2 hours. To the reaction solution was added saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. The product was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a mixture connected to the I reference example 142 2-(2-methoxyethyl)-2,6-dietlinde-1-it. The product was dissolved in 1,2-dichloroethane and the solution was added 1M BBr3/dichloromethane (7.3 ml) and stirred at room temperature for 1 hour. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, was extracted with chloroform, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: n-hexane/ethyl acetate = 5/2) to obtain the compound (540 mg) of reference example 142 2-(2-bromacil)-2,6-dietlinde-1-it (1,25 d).

Reference example 143:

N'-[1-(3-butyl-6-fluoro-2-hydroxyphenyl)-2-methylpiperidin]-isonicotinohydrazide:

A suspension of compound (88 g) of reference example 117 and isonicotinohydrazide (55 g) in EtOH was heated under reflux for 6 hours. The solvent was evaporated, added water and diethyl ether, then stirred. Precipitated precipitated product was collected by filtration, washed with water and diethyl ether and dried under reduced pressure to obtain compound (92) reference example 143 in the form of a crystalline substance.

Referential example 144:

4-Bromo-7-fluoro-3-hydroxy-2,2-dimethyl-3-(pyridin-4-yl)indan-1-he:

To 1,2-dichlorethane solution of the compound (91 g) of reference example 143 at room temperature was added PhI(OAc)2(92 g), then stirred at the same pace is the atur within 2 hours. Was added a saturated aqueous solution of ammonium hydrogen carbonate and then stirred. Precipitated precipitated product was removed by filtration using Celite. The filtrate was subjected to separation of liquid-liquid, the organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was dissolved in 1,2-dichloroethane, then was added 1,8-diazabicyclo[5,4,0]undec-7-ene (7.2 ml), followed by stirring under heating at 60°C for 1 hour. The reaction suspension was cooled to room temperature, precipitated precipitated product was collected by filtration and washed with a small small amount of 1,2-dichloroethane to obtain compound (65 g) of reference example 144 in the form of a crystalline substance.

Example 1:

Monopolar 2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol:

To a solution (20 ml), 2,2-dietlinde-1-it (961 mg) in THF while cooling on ice, was added a solution of sodium chloride (1 methylpiperidin-4-yl)magnesium (2 equivalent) in THF, which was received separately from 4-chloro-1-methylpiperidine, Mg (2 equivalents) and EtBr (catalytic amount), then was stirred for 2 hours at a temperature in the range from the specified temperature to room temperature. To the reaction solution was added saturated aqueous solution of ammonium chloride and the aqueous layer was extracted with ethyl acetate, washed us is on saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/methanol/saturated aqueous ammonia = 10/1/0,1) to obtain a colorless crystalline substance (1,46 g). This substance was converted into its salt with 1 equivalent of fumaric acid and washed with diethyl ether to obtain the compound of example 1 in the form of a colorless crystalline substance.

In examples 2-5, the compounds shown in table 12 were obtained by the method similar to that described in example 1.

Example 6:

Monopolar 2,2,6-trimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol:

To a solution (100 ml) 2,2,6-trimethylene-1-she (8.0 g) in THF while cooling on ice, was added a solution of sodium chloride (1 methylpiperidin-4-yl)magnesium (2 equivalent) in THF, which was received separately from 4-chloro-1-methylpiperidine, Mg (2 equivalents) and EtBr (catalytic amount), then was stirred for 2 hours at a temperature within the specified temperature and room temperature. To the reaction solution was added saturated aqueous solution of ammonium chloride and the aqueous layer was extracted with ethyl acetate, washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: chlorine is of the form/methanol/saturated aqueous ammonia = 10/1/0,1) to obtain a colorless crystalline substance (9.2 grams). This substance was converted into its salt with 1 equivalent of fumaric acid and recrystallized from a mixture of ethanol/ethyl acetate to obtain the compound of example 6 in the form of a colorless crystalline substance.

In examples 7-12 compounds shown in table 13 and 14, obtained by the method similar to that described in example 6.

Example 13:

Monopolar 7-bromo-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol:

Connection (1,93 g) of example 48 was dissolved in a mixed solvent of THF (50 ml) and ethyl acetate (50 ml)was added ISO-PrNEt (0.68 ml) and then 10% PD-C (1 g) and in hydrogen atmosphere (normal pressure), the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethanol, the insoluble substance was removed by filtration and the solvent was evaporated under reduced pressure. The residue was subjected to separation of liquid-liquid saturated aqueous sodium bicarbonate and chloroform, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: chloroform/methanol/saturated aqueous ammonia = 20/1/0,1) obtaining a crystalline substance (735 mg). The resulting material was converted into its salt with one equivalent of fumaric acid and p is recrystallization from a mixture of EtOH/acetone to obtain the compound of example 13 in the form of a colorless crystalline substance.

In examples 14-16, the compounds shown in table 14 were obtained by the method similar to that described in example 6.

Example 17:

Monopolar 6-cyano-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol:

A solution of N-methylpyrrolidone (5 ml) was desalted product (500 mg) of the compound of example 14, Zn(CN)2(191 mg), Pd(PPh3)4(512 mg) and Ca(OH)2(121 mg) was stirred under heating at 100°C for 4 hours. The reaction solution was subjected to separation of liquid-liquid chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: chloroform/methanol/saturated aqueous ammonia = 10/1/0,1) obtaining a crystalline substance (330 mg). The resulting material was converted into its salt with one equivalent of fumaric acid and washed with diethyl ether to obtain the compound of example 17 as a colourless crystalline substance.

In the examples 18-62, the compounds shown in tables 15-23 received a manner similar to that described in example 6.

Example 63:

Monopolar 7-fluoro-3,3-dimethyl-4-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroquinolin-4-ol:

While cooling on ice is to (30 ml) solution of LiAlH 4(302 mg) in THF was added the compound (500 mg) of example 64, then was heated under reflux for 24 hours. The reaction solution was cooled with ice, was added Na2SO4·10H2O and Celite and stirred. Then the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/methanol/saturated aqueous ammonia = 10/1/0,1) to obtain amorphous substance (450 mg). The resulting material was converted into its salt with one equivalent of fumaric acid and washed with acetone to obtain the compound of example 63 in the form of a crystalline substance.

In the examples 64-70 compounds shown in table 23 and 24 were obtained by the method similar to that described in example 6.

In example 71 compound shown in table 24, were obtained by the method similar to that described in example 72 below.

Example 72:

Monopolar 2,2,6-trimethyl-1-(1-methylpyrrolidine-3-yl)indan-1-ol:

To a solution (20 ml) ISO-Pr2NH (0.7 ml) in THF at -10°C was added a solution of 1.6 M n-BuLi/hexane (3,16 ml), then stirred at the same temperature for 30 minutes. The reaction solution was cooled to -78°C was added N-organic (0,386 ml), then further stirred for 1 hour. Solution was added (5 ml) 2,2,6-three is yilinda-1-she (450 ml) in THF, followed by stirring for 30 minutes, and then was heated to -30°C. Then was added a saturated aqueous solution of ammonium chloride followed by extraction with diethyl ether. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (50 ml) and was added LiAlH4(950 mg), then was heated under reflux for 1 hour. To the reaction solution while cooling on ice was added Na2SO4·10H2O and Celite, followed by stirring. Then the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/methanol/saturated aqueous ammonia = 10/1/0,1) to obtain the substance in the form of oil (435 mg). This substance was converted into its salt with one equivalent of fumaric acid, and washed with ethyl acetate to obtain the compound of example 72 in the form of a colorless crystalline substance.

Example 73:

Monopolar 2,2,6-trimethyl-1-(piperidine-4-yl)indan-1-ol:

The compound (1.04 g) of reference example 68 was dissolved in a mixed solvent of MeOH (10 ml), EtOH (10 ml) and water (10 ml), was added KOH (15 g), then stirred at 80°C for 2 hours. The reaction solution was extracted with ethyl acetate, etc is mawali saturated salt solution, was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 5/1/0,1) to obtain amorphous substance (810 mg). This substance was converted into its salt with one equivalent of fumaric acid and washed with diethyl ether to obtain the compound of example 73 as a colorless crystalline substance.

In examples 74 and 75 of the compounds shown in table 25, were obtained by the method similar to that described in example 73.

In examples 76 and 77 of the compounds shown in table 25, were obtained by the method similar to that described in example 78 below.

Example 78:

Monopolar 2,2,6-trimethyl-1-(1-benzylpiperidine-4-yl)indan-1-ol:

To 1,2-dichlorethane solution (4 ml) was desalted product (200 mg) of the compound of example 73 and benzaldehyde (of) 0.157 ml) at room temperature was added acetic acid (of 0.44 ml) and then was stirred for 15 minutes. Then was added NaB(OAc)3H (817 mg) and was further stirred for 1 hour. To the reaction solution was added saturated aqueous solution of ammonia, then extracted with ethyl acetate and washed with saturated saline solution. Was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the residue was purified what cromatografia on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 20/1/0,1). This substance was converted into its salt with one equivalent of fumaric acid and washed with diethyl ether to obtain compound (178 mg) of example 78 in the form of a crystalline substance.

In example 79, the connection shown in table 26, were obtained by the method similar to that described in example 78.

Example 80:

Monopolar 4-(1-methoxy-2,2,6-trimethyl-2,3-dihydro-1H-inden-1-yl)-1-methylpiperidine:

To a solution of MeOH (5 ml) was desalted product (200 mg) of the compound of example 6 was added 10-camphorsulfonic acid (255 mg), then stirred at room temperature for 24 hours. The reaction liquid was subjected to separation of liquid-liquid saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 10/1/0,1), then converted into its salt with one equivalent of fumaric acid and recrystallized from a mixture of MeOH/diethyl ether to obtain compound (151 mg) of example 80 in the form of a colorless crystalline substance.

Example 81:

Monopolar [6-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)-2,3-dihydro-1H-inden-yl]amine:

To a solution of desalted product (to 2.29 g) compound of example 82 in MeOH was added 10%Pd-C (0.5 g) and stirred in hydrogen atmosphere (normal pressure) at room temperature for 20 hours. The insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, the residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 10/1/0,1), then converted into its salt with one equivalent of fumaric acid and washed with diethyl ether to obtain compound (1,81 g) of example 81 in the form of a colorless crystalline substance.

Example 82:

Monopolar 4-(1-azido-6-fluoro-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-1-methylpiperidine:

To a chloroform solution (15 ml) NaN3(1,36 g) under cooling on ice, chloroform was added a solution of triperoxonane acid (4,03 ml) and desalted product (2.4 g) compound of example 9, and then stirred at room temperature for 4 hours. To the reaction solution was added saturated aqueous solution of ammonia, then extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 5/1/0,1) to obtain the substances in the form of oil (2.48 in). This substance was converted into its salt with one equivalent of fumaric acid and washed with diethyl ether to obtain the compound of example 82 in the form of an amorphous substance.

In examples 83, 84 and 85 of the compounds shown in tables 26 and 27, was obtained by method similar to that described in examples 81, 82, and 6, respectively.

In example 86 in a manner analogous to the one described in example 73; and in example 87, in a way similar to that described in example 6, was obtained compounds are shown in table 27.

Example 88:

2,2-Dimethyl-1-(1-methylpiperidin-4-yl)-6-(piperidine-1-ylcarbonyl)indan-1-ol:

To a solution of desalted product (345 mg) of the compound of example 17 in MeOH was added 10%aqueous NaOH solution (17 ml), then stirred under heating at 60°C for 13 hours. After completion of the reaction product was neutralized 1H. hydrochloric acid to pH 5 to 6 and the solvent was evaporated under reduced pressure. Then the residue was dissolved in DMF and then added piperidine (0.6 ml), 1-hydroxybenzotriazole (164 mg), the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (232 mg), then stirred for 1 day. To the reaction solution to separate the liquid-liquid were added water and chloroform, the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated when s is low pressure, and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/methanol/saturated aqueous ammonia = 20/1/0,1-10/1/0,1) to obtain compound (12 mg) of example 88 in the form of a colorless amorphous substance.

Example 89:

Benzyl 3-hydroxy-2,2-dimethyl-3-(1-methylpiperidin-4-yl)indan-5-carboxylate:

To a solution of desalted product (600 mg) of the compound of example 17 in MeOH was added 10%aqueous NaOH solution (8,4 ml), then stirred at 70°C for 21 hours. The reaction solution was subjected to separation of liquid-liquid water and chloroform, the aqueous layer neutralize 1H. hydrochloric acid until a pH equal to or approximately equal to 6 or so, and the water was evaporated by heating under reduced pressure. The residue was dissolved in acetonitrile and cooled on ice was added benzyl alcohol (2.2 ml), N,N-dimethylpyridin-4-amine (258 mg) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (445 mg), then stirred at room temperature for 18 hours. The reaction solution was subjected to separation of liquid-liquid chloroform and water and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous Rast is the PR ammonia = 10/1/0,1) to obtain compound (8 mg) of example 89 in the form of a colorless amorphous substance.

In example 90 connection, shown in table 27 was obtained in a manner analogous to the one described in example 6.

In examples 91 and 100 of the compounds shown in table 28 and 29, was obtained in a manner analogous to the one described in example 6, but of a mixture of 4-fluoro-6-hydroxy-2,2,5-trimethylene-1-she 4-fluoro-6-hydroxy-2,2-dietlinde-1-she obtained in reference example 92.

In the examples 92-94, in a way similar to that described in example 6; and in example 95, by a method similar to that described in example 119, obtained compounds are shown in table 28.

Example 96:

Monopolar 7-ethyl-5-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol:

In MeOH in the presence of 10%Pd-C in hydrogen atmosphere at a pressure equal to one atmosphere at room temperature for 5 hours and stirred desalted product (27 mg) of the compound of example 116. The insoluble substance was removed by filtration using Celite. The solvent was evaporated under reduced pressure and the residue was converted into the fumarate with one equivalent of fumaric acid and then washed with diethyl ether to obtain compound (25 mg) of example 96 in the form of colorless powder.

In example 97 by the way, is similar to that described in example 6, but from the compound of reference example 82; and in examples 98, 99, 101 and 102 in a manner similar to that described in example 6, was obtained compounds are shown in TA the face 29 and 30.

Example 103:

5,7-Dibromo-6-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol:

To a suspension of compound (1.1 g) of example 153 in MeCN under cooling on ice gradually dropwise added SOCl2(0,89 ml). The reaction mixture was stirred at the same temperature for 1 hour, then the solvent was evaporated under reduced pressure at cooling water. The residue was dissolved in acetic acid was added Zn powder (0.8 g), then stirred under heating at 60°C for 2 hours. Zn was removed by filtration using Celite, acetic acid was evaporated under reduced pressure, and the residue was subjected to separation of liquid-liquid diluted aqueous solution of ammonia and chloroform. The chloroform layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 20/1/0,1) to obtain the compound (436 mg) of example 103 in the form of a colorless amorphous substance.

In the examples 104-106 manner similar to that described in example 6; in example 107 in a manner analogous to the one described in example 119; and in examples 108 and 109 in a manner analogous to the one described in example 6, was obtained compounds are shown in tables 30 and 31.

Example 110:

4-Fluoro-6-hydroxymethyl-7-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)is NDN-1-ol:

The solution is desalted product (207 mg) of the compound of example 113 in THF was cooled to -70°C and was added dropwise a solution of 1M ISO-Bu2AlH/toluene (3.1 ml), followed by stirring at -70°C for 1 hour. Then the reaction mixture was heated to room temperature and was further heated for 4 hours. To the reaction solution was added Na2SO4·10H2O and stirred, and then the insoluble substance was removed by filtration using Celite, and the solvent was evaporated under reduced pressure. The residue was dissolved in MeOH and cooled on ice was added NaBFLi (24 mg), then stirred at the same temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 10/1/0,1) to obtain compound (59 mg) of example 110 in the form of an amorphous substance.

Example 111:

4-Fluoro-7-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)-6-(morpholine-4-ylmethyl)indan-1-ol:

To a suspension of compound (30 mg) of example 112 in THF was added morpholine (0,07 ml) and ISO-Pr2NEt (0.01 ml), then stirred at room temperature for 7 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/feast upon the config aqueous ammonia = 10/1/0,1) to obtain compound (12 mg) of example 111 in the form of a colorless amorphous substance.

Example 112:

The hydrochloride of 6-chloromethyl-4-fluoro-7-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol:

A solution of compound (52 mg) of example 110 in MeCN was cooled to 0°C and then slowly added SOCl2(0.06 ml), followed by stirring for 1.5 hours. After completion of the reaction the solvent was evaporated under reduced pressure to obtain compound (61 mg) of example 112 in the form of an amorphous substance.

In example 113 in a manner analogous to the one described in example 119; in example 114 in a manner analogous to the one described in example 6; and in example 115 as a by-product of example 114 was obtained compounds are shown in table 32.

Example 116:

4-Fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)-7-vinyliden-1-fumarate:

To a toluene suspension (2 ml) of the compound (200 mg) of example 36 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (108 mg), Na2CO3(180 mg) and Pd(PPh3)4(58 mg) was added water (1 ml) and heated overnight c reflux. The reaction solution was subjected to separation of liquid-liquid chloroform and saturated aqueous sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 10/1/0,1), then the conversion is obyvali in his fumarate with one equivalent of fumaric acid and washed with diethyl ether to obtain the compound of example 116 in the form of colorless powder.

Example 117:

Fumarate 4-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)-7-phenylindol-1-ol:

To a suspension (1 ml) of the compound (102 mg) of example 36, PhB(OH)2(43 mg), Na2CO3(95 mg) and Pd(PPh3)4(35 mg) in toluene was added water (0.5 ml), then was heated under reflux for one day. The reaction solution was subjected to separation of liquid-liquid chloroform and saturated aqueous sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 10/1/0,1), then converted to the fumarate with one equivalent of fumaric acid and recrystallized from isopropanol to obtain compound (38 mg) of example 117 in the form of a colorless crystalline substance.

In example 118, compound, shown in table 23 were obtained by the method similar to that described in example 117.

Example 119:

Fumarate 7-cyano-4-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol:

A solution of compound (107 mg) of example 36, Zn(CN)2(47 mg), Pd(PPh3)4(69 mg) and Ca(OH)2(30 mg) in 1-methyl-2-pyrrolidinone was stirred under heating at 180°C for 8 hours. The reaction liquid was cooled and then subjected to razdelenieto-liquid chloroform and saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 10/1/0,1), then was converted to the fumarate with one equivalent of fumaric acid and washed when heated with MeCN to obtain compound (19 mg) of example 119 in the form of a colorless crystalline substance.

In the examples 120-122 manner similar to that described in example 117; in example 123 as a by-product in example 124; and in example 124 manner similar to that described in example 103, obtained compounds are shown in table 34.

Example 125:

Fumarate of 1-(aminomethyl)-4-fluoro-7-methoxy-2,2-dietlinde-1-ol:

A solution of the compound (700 mg) of reference example 120 in THF was added to the suspension in THF LiAlH4(175 mg), then stirred under heating at 60°C for 2 hours. The reaction solution was diluted with THF, was then added water (0.7 ml) and an aqueous solution of 15%sodium hydroxide (0,175 ml), followed by stirring. Then the insoluble substance was removed by filtration using Celite. The solvent was evaporated under reduced pressure, the residue was dissolved in THF and then added water (2 ml) and NaF (200 mg), followed by stirring overnight at room temperature. To reactionneuropathy was added a saturated aqueous solution of sodium bicarbonate, then was extracted with ethyl acetate, washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 20/1/0,1), then converted into its fumarate with one equivalent of fumaric acid and washed with ethyl acetate/MeCN with obtaining compound (72 mg) of example 125 in the form of a colorless crystalline substance.

Example 126:

Fumarate 4-fluoro-7-methoxy-2,2-dimethyl-1-(dimethylamino)indan-1-ol:

To a solution of desalted product (97 mg) of the compound of example 125 in THF was added formalin (0.4 ml) and formic acid (0.2 ml), then stirred under heating at 80°C for 7 hours. The reaction solution was subjected to separation of liquid-liquid with aqueous saturated solution of sodium bicarbonate and ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 20/1/0,1), then was converted into its fumarate with one equivalent of fumaric acid and washed with a mixture of ethyl acetate/acetone to obtain compound (72 mg) of example 126 in the form of colorless is a crystalline substance.

In the examples 127-130, compounds shown in tables 34 and 35, was obtained in a manner analogous to the one described in example 132, but from the compound of reference example 122.

Example 131:

Fumarate of 1-(2-amino-2-methylpropyl)-2,2,6-trimethylene-1-ol:

To a suspension in THF LiAlH4(186 mg) under cooling on ice, was added a solution of the compound (400 mg) of reference example 125 in THF and then stirred at room temperature for 1 hour. To the reaction solution was added Na2SO4·10H2O and stirred. Then the insoluble substance was removed by filtration using Celite, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 50/1/0,1 to 10/1/0,1), then converted to the fumarate with one equivalent of fumaric acid and recrystallized from a mixture of ethyl acetate/acetone to obtain compound (128 mg) of example 131 in the form of a colorless crystalline substance.

Example 132:

Fumarate 6-fluoro-7-methoxy-2,2-dimethyl-1-[3-(piperidine-1-yl)propyl]indan-1-ol:

To a solution of the compound (120 mg) of reference example 127 and ISO-Pr2NEt (0.4 ml) in THF at room temperature was added MsCl (0,11 ml), then stirred at the same temperature for 1 hour. The reaction solution was dried to solid state is ri reduced pressure, then the residue was dissolved in DMF. Added piperidine (0.25 ml), then stirred under heating at 80°C for 3 hours. The reaction solution was subjected to separation of liquid-liquid water and ethyl acetate and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 20/1/0,1) and then converted into its fumarate with one equivalent of fumaric acid to obtain compound (24 mg) of example 132 in the form of an amorphous substance.

In examples 133 and 134 of the compounds shown in tables 35 and 36, obtained by the method similar to that described in example 132.

Example 135:

Fumarate 6-fluoro-7-methoxy-2,2-dimethyl-1-[(1-methylpiperidin-2-yl)methyl]indan-1-ol:

A solution of the compound (355 mg) of reference example 128 and MeI (1 ml) in THF was heated under reflux for 1.5 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in ethanol, then added NaBH4(267 mg) c, followed by stirring at 60°C for 2 hours. The reaction solution was cooled, was added an aqueous solution of sodium bicarbonate, then extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent UE shall rivali under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 20/1/0,2). Then the obtained product was dissolved in EtOH, followed by stirring overnight in an atmosphere of hydrogen (one atmosphere) in the presence of 10%Pd-C at room temperature. The insoluble substance was removed by filtration using Celite, and the solvent was evaporated under reduced pressure to obtain the product. This substance was converted into the fumarate with one equivalent of fumaric acid to obtain compound (212 mg) of example 135 in the form of an amorphous substance.

Example 136:

6-Fluoro-7-methoxy-2,2-dimethyl-1-{5-[(dimethylamino)methyl]-2-thienyl}indan-1-ol fumarate:

To a solution of 2-(dimethylaminomethyl)thiophene (203 mg) in THF in an argon atmosphere at -78°C was added a 1.6 M solution of n-BuLi/hexane (0.9 ml), then stirred at the same temperature for 1 hour. Solution was added the compound (100 mg) of reference example 64 in THF, then further stirred for 1 hour. To the reaction solution was added water, then was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 20/1/0,1), and then was converted into its fumarate with one equivalent of fumaric acid to obtain compound (121 mg) of example 136 in the form of an amorphous substance.

In examples 137 and 138 of the compounds shown in table 36, obtained by the method similar to that described in example 6.

Example 139:

Fumarate 5-fluoro-7,7-dimethyl-8-(1-methylpiperidin-4-yl)-2,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-8-ol:

To a solution of desalted product (500 mg) of the compound of example 140 in MeOH, followed by stirring in an atmosphere of hydrogen (1 atmosphere) at room temperature for 5 hours was added 10% Pd-C. Insoluble substance was removed by filtration using Celite, and the solvent was evaporated under reduced pressure. This substance was converted into the fumarate with one equivalent of fumaric acid, and then were led out of THF with obtaining compound (536 mg) of example 139 in the form of a colorless crystalline substance.

Example 140:

Fumarate 5-fluoro-7,7-dimethyl-8-(1-methylpiperidin-4-yl)-7,8-dihydro-6H-indeno[4,5-b]furan-8-ol:

To a solution of the compound (2.0 g) of reference example 134 in THF solution was added (20 ml) of 0.7 M chloride (N-methylpiperidin-4-yl)magnesium in THF, then stirred at room temperature for 1 hour. Was added to the solution (24 ml), 1M (n-Bu)4NF in THF and stirred at room temperature for 1 hour. Was added a saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced d is the pressure and the obtained crude product was purified by recrystallization from ethyl acetate, were converted into the fumarate with one equivalent of fumaric acid and recrystallized from THF to obtain the compound of example 140 in the form of a colorless crystalline substance.

In examples 141 and 142 of the compounds shown in table 37, received a manner similar to that described in example 6.

Example 143:

Fumarate 4-(9-fluoro-5,5-dimethyl-2,3,5,6-tetrahydro-4aH-indeno[1,7-ef][1,4]doxepin-4a-yl-1-methylpiperidine:

To a solution of compound (910 mg) of example 142 in THF was added 3n hydrochloric acid (9 ml) and concentrated hydrochloric acid (2.3 ml), then stirred under heating at 60°C for 3 days. The reaction solution was neutralized with an aqueous solution of NaOH, then extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 20/1/0,1), then was converted to the fumarate with one equivalent of fumaric acid and recrystallized from acetone to obtain compound (320 mg) of example 143 in the form of a colorless crystalline substance.

Example 144:

Fumarate of 1-(6'-fluoro-7'-methoxy-2',2'-dimethyl-2',3',4,5-tetrahydro-3H-Spiro[furan-2,1'-inden]-5-yl)-N,N-dimethylethanamine:

To a solution of the compound (200 g) of reference example 140 in DMF was added 5%aqueous solution Me 2NH (1 ml), then stirred under heating at 80°C for 3 hours. The reaction solution was subjected to separation of liquid-liquid water and ethyl acetate and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 20/1/0,1) and were converted into the fumarate with one equivalent of fumaric acid to obtain compound (182 mg) of example 144 in the form of an amorphous substance.

In example 145 a way similar to that described in example 144; and in example 146 in a manner analogous to the one described in example 6, was obtained compounds are shown in table 38.

Example 147:

Fumarate of 1-methyl-4-(7-methyl-2,3,3a,4-tetrahydro-8bH-indeno[1,2-b]furan-8b-yl)piperidine:

To a solution of compound (1,59 g) of example 146 in THF was added 3n. aqueous HCl solution (15 ml) and was intensively stirred for 2 hours. To the reaction solution for alkalizing was added 1N. an aqueous solution of NaOH, then extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was converted to the fumarate with one equivalent of fumaric acid and recrystallized from a mixture of MeOH/diethyl ether with the teachings of the compound (1,41 g) of example 147 in the form of a colorless crystalline substance.

In example 148 connection, shown in table 38, received a manner similar to that described in reference example 149.

Reference example 149:

4,6-Dibromo-5-fluoro-3-hydroxy-2,2-dimethyl-3-(1-methylpiperidin-4-yl)indan-1-he:

A suspension of the compound (39 g) of reference example 96 and PhI(OAc)2(47 g) in 1,2-dichloroethane was stirred at 40°C for 3 hours. After it was confirmed that nitrogen was not fully completed, was added a saturated solution of sodium bicarbonate and an aqueous solution of 5%aqueous sodium thiosulfate, followed by stirring for separation of liquid-liquid. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. Then the residue was dissolved in THF and was added tert-BuOK (9.7 g) and stirred at 70°C for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and subjected to separation of liquid-liquid ethyl acetate and saturated salt solution. The organic layer was washed with saturated saline, then was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate (200 ml) and n-hexane (500 ml), followed by stirring. Then the insoluble substance was collected by filtration and washed with diethyl ether to obtain from the organisations (20 g) of reference example 149 in the form of a powder pale brown color.

In example 150 in a manner analogous to the one described in example 149; and in example 151 manner similar to that described in example 153, obtained compounds are shown in tables 38 and 39.

Example 152:

Fumarate CIS-7-bromo-4-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1,3-diol:

The compound (6.5 g) of example 11 was dissolved in 2n. hydrochloric acid solution (100 ml) followed by heating under reflux for 5 hours. While cooling on ice, the reaction mixture was neutralized by adding aqueous ammonia, followed by extraction with chloroform and drying over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure and the mixture of residue and TRANS-2,3-bis(benzoyloxy)succinic acid (6.3 g) was added isopropanol, and then stirred. The original TRANS-diol was deposited in the form of salt, and the precipitate was removed by filtration. The filtrate was concentrated under reduced pressure, subjected to the separation of liquid-liquid dilute aqueous ammonia and chloroform, layer with chloroform, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was converted into the fumarate with fumaric acid (1.4 g) and was led from acetone to obtain compound (4,25 g) of example 152 in the form of a colorless crystalline substance.

Example 153:

TRANS-5,7-dibromo-6-fluoro-2,2-dimethyl-1(1-methylpiperidin-4-yl)indan-1,3-diol:

Suspension in THF (200 ml) LiAlH4was cooled to -78°C with stirring for 15 minutes, was added dropwise a solution (50 ml) of the compound (20 g) of example 149 in THF. After addition the cooling bath was removed and the reaction liquid was heated to 0°C for 1 hour. When cooled on ice was added Na2SO4·10H2O, followed by stirring. Then the insoluble substance was removed by filtration using Celite. The filtrate is kept under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 20/1/0,1-5/1/0,1) to obtain compound (3.2 g) of example 153 in the form of an amorphous substance.

Example 154:

TRANS-7-bromo-4-fluoro-2,2-dimethyl-1-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)indan-1,3-diol:

To a solution of compound (1.04 g) of reference example 144 in THF was added MeI (0,52 ml), then was heated under reflux for 6 hours. The solvent was evaporated under reduced pressure to get iodide 4-(7-bromo-4-fluoro-1-hydroxy-2,2-dimethyl-3-oxo-2,3-dihydro-1H-inden-1-yl)-1-methylpyridine (1,46 g) as an amorphous substance. The product was dissolved in MeOH and -10°C was added NaBH4(545 mg), then stirred at the same temperature for 1 hour. The reaction solution was diluted with water and precipitated precipitated product was collected by filtration receipt the m compound (640 mg) of example 154 as a colourless crystalline substance.

Example 155:

CIS-7-bromo-4-fluoro-2,2-dimethyl-1-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)indan-1,3-diol:

To a methanol solution of iodide of 4-(7-bromo-4-fluoro-1-hydroxy-2,2-dimethyl-3-oxo-2,3-dihydro-1H-inden-1-yl)-1-methylpyridine (285 mg)obtained by the method similar to that described in reference example 154, and CeCl3(858 mg) was added a few drops of water, then stirred and -10°C was added NaBH4(132 mg) and was stirred for 3 hours. To the reaction solution was added water, then was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the compound of example 155 in the form of a colorless amorphous material (70 mg).

In example 156 connection, shown in table 40, obtained by the method similar to that described in example 153.

Example 157:

3-Hydroxy-2,2-dimethyl-3-(1-methylpiperidin-4-yl)indan-5-carboxylic acid:

Solution in EtOH compound (31 mg) of example 89 and 1,4-cyclohexadiene (0.6 ml) was stirred in argon atmosphere in the presence of 10%Pd-C at room temperature for 1 hour. After completion of the reaction to remove insoluble substances, the reaction mixture was filtered using Celite, and the solvent was evaporated under reduced pressure to obtain compound (24 mg) of example 157 in the form of colorless powder.

Example 158:

Fumar the t 7-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)-6-nitro-1,2,3,4-tetrahydronaphthalen-1-ol:

Solution in Ac2O (1.0 ml) of the compound (100 mg) of example 54 was cooled to 0°C and slowly added to the solution in Ac2O (1.0 ml) and fuming nitric acid (16 mg). The reaction mixture was stirred for 30 minutes, then was additionally added fuming nitric acid (30 mg), followed by stirring at the same temperature for 30 minutes. To the reaction solution was added ice water and stirred. Then the product was subjected to separation of liquid-liquid chloroform and saturated aqueous sodium bicarbonate and the organic layer was washed with saturated saline solution. The product was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain a mixture of 7-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)-6-nitro-1,2,3,4-tetrahydronaphthalen-1-ol and 7-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)-8-nitro-1,2,3,4-tetrahydronaphthalen-1-ol. This substance was converted into the fumarate with one equivalent of fumaric acid and recrystallized from EtOB obtaining compounds of example 158 in the form of a colorless crystalline substance.

Example 159:

7-Amino-6-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-ol, and

Example 160:

N-[5-hydroxy-2-methoxy-6,6-dimethyl-5-(1-methylpiperidin-4-yl)-5,6,7,8-tetrahydronaphthalen-1-yl]ndimethylacetamide:

10%Pd-C was added to the MCA is anomo solution of EtOH/ethyl acetate mixture (779 mg) 6-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)-7-nitro-1,2,3,4-tetrahydronaphthalen-1-ol and 6-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)-5-nitro-1,2,3,4-tetrahydronaphthalen-1-ol, obtained by nitration of the compound of example 55 in a manner analogous to the one described in example 158, and stirred in hydrogen atmosphere (1 atmosphere) at room temperature for 6 hours. After completion of the reaction, the insoluble substance was removed by filtration using Celite, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: chloroform/MeOH/saturated aqueous ammonia = 10/1/0,1) to obtain the compound (167 mg) of example 159 and compound (230 mg) of example 160 in the form of an amorphous substance (the formation of the compound of example 160 may be a result of residual acetic anhydride in the original connection).

In example 161 connection, shown in table 40, obtained by the method similar to that described in example 126, but from the compound of example 159.

The structural formula and physical-chemical characteristics of the compounds of the above reference examples and compounds of the above examples are presented in the following table 2-40. The compounds shown in tables 41-45, can be easily obtained by methods similar to those described in the above examples, or methods of production or in accordance with changes which are obvious to a person skilled in this field. Symbols used in the table have the following meanings.

Rf.reference example
Approx.example
STRUCTUREthe structural formula
DATAphysico-chemical data
SOLSol
Bnbenzyl group
Memethyl group
Etethyl group
NMRspectrum of nuclear magnetic resonance (TMS internal standard)
MSmass spectrum
FCfumaric acid

Table 2
Rf.STRUCTUREDATARf.STRUCTUREDATA
1FAB-MS

(m/z);

245, 247

[(M-1)+]
2FAB-MS

(m/z);

245, 247

[(M-1)+]
3FAB-MS

(m/z);

181

[(M-1)+]
4FAB-MS

(m/z);

181

[(M-1)+]
5FAB-MS

(m/z);

181

[(M-1)+]
61H-NMR

(CDCl3);

to 2.67(2H, t)

of 2.93(2H, t)
7FAB-MS

(m/z);

197

[(M-1)+]
8FAB-MS

(m/z);

259, 261

[(M-1)+]
9FAB-MS

(m/z);

275, 277

[(M-1)+]
101H-NMR

(CDCl3);

2,69(2H, t)

to 3.02(2H, t)
11FAB-MS

(m/z);

263, 265

[(M-1)+]
12FAB-MS

(m/z);

259, 261

[(M-1)+]
13EI-MS

(m/z);

246

[M+]
14FAB-MS

(m/z);

201

[(M+1)+]
15EI-MS

(m/z);

164

[M+]
16EI-MS

(m/z);

228, 230

[M+]

EI-MS

(m/z);

242, 244

[M+]
Table 3
Rf.STRUCTUREDATARf.STRUCTUREDATA
17EI-MS

(m/z);

164

[M+]
18EI-MS

(m/z);

228, 230

[M+]
19EI-MS

(m/z);

184

[M+]
20EI-MS

(m/z);

246, 248

[M+]
21EI-MS

(m/z);

306, 308,

310

[M+]
22EI-MS

(m/z);

242, 244

[M+]
23EI-MS

(m/z);

258, 260

[M+]
24EI-MS

(m/z);

242, 244

[M+]
2526EI-MS

(m/z);

214

[M+]
27EI-MS

(m/z);

178

[M+]
28EI-MS

(m/z);

238, 240

[M+]
29FAB-MS

(m/z);

195

[(M+1)+]
30FAB-MS

(m/z);

189

[(M+1)+]
31FAB-MS

(m/z);

175

[(M+1)+]
32EI-MS

(m/z);

228

[M+]

Table 4
Rf.STRUCTUREDATARf.STRUCTUREDATA
33FAB-MS

(m/z);

197

[(M+1)+]
34FAB-MS

(m/z);

229, 231

[(M+1)+]
35EI-MS

(m/z);

196

[M+]
36EI-MS

(m/z);

192

[M+]
371H-NMR

(CDCl3);

of 1.26(6H,c),

to 2.99(2H,c)
38EI-MS

(m/z);

256, 258

[M+]
39EI-MS

(m/z);

212

[M+]
40EI-MS

(m/z);

256, 258

[M+]
41EI-MS

(m/z);

196

[M+]
42EI-MS

(m/z);

196

[M+]
43FAB-MS

(m/z);

229, 231

[(M+1)+]
44EI-MS

(m/z);

212

[M+]
45EI-MS

(m/z);

192

[M+]
46EI-MS
/br> (m/z);

229, 231

[M+]
471H-NMR

(CDCl3);

1,25(6H,s),

2,96(2H,s)
48FAB-MS

(m/z);

335, 337,

339

[(M+1)+]

Table 5
Rf.STRUCTUREDATARf.STRUCTUREDATA
491H-NMR

(CDCl3);

of 1.27(6H,s),

2,89(2H,d)
50FAB-MS

(m/z);

271, 273

[(M+1)+]
51EI-MS

(m/z);

270, 272

[M+]
521H-NMR

(CDCl3);

1,25(6H,c),

of 2.44(3H,d),

2,90(2H,s)
53FAB-MS (m/z);

287, 289

[(M+1)+]
54EI-MS

(m/z);

180

[M+]
55 EI-MS

(m/z);

164

[M+]
56EI-MS

(m/z);

212

[M+]
57EI-MS

(m/z);

212

[M+]
58EI-MS

(m/z);

256, 258

[M+]
59EI-MS(m/z);

256, 258

[M+]
60EI-MS

(m/z);

192 [M+]
61EI-MS(m/z);

192 [M+]
62FAB-MS

(m/z);

397, 399

[(M+1)+]
63FAB-MS

(m/z);

331, 333,

335

[(M+1)+]
64EI-MS(m/z); 208 [M+]

Table 6
Rf.STRUCTUREDATARf.STRUCTUREDATA
65 EI-MS(m/z);

178 [M+]
661H-NMR

(CDCl3);

2,74-2,79

(2H, m)

3,10-3,15

(2H, m)
67FAB-MS

(m/z);

208

[(M+1)+]
68FAB-MS

(m/z);

332

[(M+1)+]
69FAB-MS

(m/z);

336

[(M+1)+]
70FAB-MS

(m/z);

332

[(M+1)+]
71EI-MS

(m/z);

208 [M+]

Table 7
Rf.STRUCTUREDATARf.STRUCTUREDATA
72FAB-MS

(m/z);

414,416

[(M+1)+]
73FAB-MS

(m/z); 211

[(M-1)+]
74 FAB-MS

(m/z);

195

[(M+1)+]
75FAB-MS

(m/z);

223

[(M+1)+]
76FAB-MS

(m/z);

201 [(M-1)+]
77EI-MS

(m/z);

184 [M+]
78El-MS(m/z);

212 [M+]
79EI-MS(m/z);

240, 242

[M+]
80FAB-MS

(m/z);

269, 271

[(M+1)+]
81FAB-

MS(m/z);

227, 229

[(M+1)+]
82ESI-MS

(m/z);

269, 271

[(M+1)+]
83FAB-MS

(m/z);

195

[(M+1)+]
84EI-MS

(m/z);

222 [M+]
85EI-MS

(m/z);

248 [M+]

tr>
Table 8
Rf.STRUCTUREDATARf.STRUCTUREDATA
86FAB-MS

(m/z);

400, 402

[(M+1)+]
87FAB-MS

(m/z);

259

[(M+1)+]
88ESI-MS

(m/z);

227

[(M-1)+]
89ESI-MS

(m/z);

211

[(M+1)+]
90FAB-MS

(m/z);

239

[(M+1)+]
91FAB-MS

(m/z);

197

[(M-1)+]
92FAB-MS

(m/z);

181

[(M+1)+]
93EI-MS

(m/z);

222 [M+]
94EI-MS

(m/z);

182 [M+]
95FAB-MS

(m/z);

337, 339,

341 [(M-1)+]
96FAB-MS

(m/z);

478, 480,

482 [(M+1)+]
97EI-MS

(m/z);

172 [M+]
98EI-MS(m/z);

236 [M+]
99EI-MS(m/z);

198 [M+]

Table 9
Rf.STRUCTUREDATARf.STRUCTUREDATA
100EI-MS

(m/z);

208 [M+]
1011H-NMR

(DMSO-d3);

of 3.75(3H, s)
102EI-MS

(m/z);

240, 242

[M+]
103FAB-MS

(m/z);

369, 371

[(M-1)+]
104FAB-MS

(m/z);

215

[(M-1)+]
105EI-MS

(m/z);

276, 278br>
[M+]
1061H-NMR

(CDCl3);

to 1.21(6H, s)
107EI-MS

(m/z);

170 [M+]
1081H-NMR

(CDCl3);

of 0.01(9H, s)
1101H-NMR

(CDCl3);

of 0.04(9H, s)
111FAB-MS

(m/z);

345

[(M+1)+]
112EI-MS

(m/z);

214 [M+]
113FAB-MS

(m/z);

213

[(M+1)+]
114EI-MS

(m/z);

240 [M+]
115EI-MS

(m/z);

286, 288

[M+]

Table 10
Rf.STRUCTUREDATARf.STRUCTUREDATA
116EI-MS

(m/z);

182 [M+]
117FAB-

MS(m/z);

261, 263

[(M-1)+]
118FAB-MS

(m/z);

412, 414

[(M+1)+]
119FAB-MS

(m/z);

197

[(M+1)+]
120ESI-MS

(m/z);

330

[(M+Na)+]
121ESI-MS

(m/z);

305

[(M+Na)+]
122ESI-MS

(m/z);

277

[(M+Na)+]
123FAB-MS

(m/z);

248

[(M+1)+]
124FAB-MS

(m/z);

230 [(M+1)+]
125FAB-MS

(m/z);

246 [(M+1)+]
126ESI-MS

(m/z);

405

[(M+Na)+]
127 ESI-MS

(m/z);

291

[(M+Na)+]
128FAB-MS

(m/z);

302

[(M+1)+]
129ESI-MS

(m/z);

209

[(M-1)+]
130ESI-MS

(m/z);

223

[(M+1)+]
131ESI-MS

(m/z);

237

[(M+1)+]

Table 11
Rf.STRUCTUREDATARf.STRUCTUREDATA
132ESI-MS

(m/z);

195

[(M+1)+]
133ESI-MS

(m/z);

319

[(M-1)+]
134ESI-MS

(m/z);

291

[(M+1)+]
135API-MS

(m/z);

217

[(M+1)+]
136ESI-MS

(m/z);

201

[(M+1)+]
137ESI-MS

(m/z);

229

[(M+1)+]
138ESI-MS

(m/z);

239

[(M+1)+]
139ESI-MS

(m/z);

287

[(M+Na)+]
140ESI-MS

(m/z);

413

(M+Na)+]
141ESI-MS

(m/z);

191

[(M+1)+]
142ESI-MS

(m/z);

227

[(M+Na)+]
143FAB-MS

(m/z);

380, 382

[(M+1)+]
144FAB-MS

(m/z);

350, 352

[(M+1)+]

Table 12
Etc.STRUCTURESOLDATA
11FAFAB-MS (m/z); 260 [M+1]

1H-NMR (DMSO-d3); 0,65-0,80 (1H, m), is 0.84 (3H, c), of 1.17 (3H, c), 1,45 is 1.70 (2H, m), 1.70 to 1.85 to 1H, m)2,00-2,10 (1H, m), 2,25-of 2.45 (2H, m), a 2.36 (3H, c), 2,50 (1H, d, J=16.2 Hz), 2,77 (1H, d, J=16.2 Hz), 2,92 (1H, userd, J=11.7 Hz), 3,14 (1H, userd, J=11.7 Hz), 4.72 in (OSiR.), 6,44 (2H, c), 7,07-7,20 (4H, m)
21FAFAB-MS (m/z); 290 [(M+1)+]
31FAFAB-MS (m/z); 290 [(M+1)+]
41FAFAB-MS (m/z); 290 [(M+1)+]
51FAFAB-MS (m/z); 274 [(M+1)+]
61FAFAB-MS (m/z); 274 [(M+1)+]

1H-NMR (DMSO-d3); 0,62-0,76 (1H, m), is 0.84 (3H, c), of 1.16 (3H, c), 1,46-to 1.59 (1H, m), 1,60 by 1.68 (1H, m), 1,71-of 1.81 (1H, m), 2,01-of 2.09 (1H, m), 2,28 (3H, c), of 2.33 (3H, c), 2,23-of 2.38 (2H, m), of 2.45 (1H, q, j 15.6 Hz), 2,73 (1H, d, J=15.6 Hz), 2,87 (1H, userd, J=11.7 Hz), 3,11 (1H, userd, J=11.7 Hz), 6,47 (2H, c), 6,97 (1H, d, J=8,3 Hz), 6,98 (1H, c), 7,01 (1H, d, J=8,3 Hz)

Table 13
Etc.STRUCTURESOLDATA
71FAFAB-MS (m/z); 274 [(M+1)+]
8 1FAFAB-MS (m/z); 288 [(M+1)+]
91FAFAB-MS (m/z); 278 [(M+1)+]

1H-NMR (DMSO-d3); 0,67-of 0.82 (1H, m)of 0.85 (3H, c), of 1.17 (3H, c), 1,44-to 1.59 (1H, m), of 1.65 (1H, userd, J=13,6 Hz), 1,74-of 1.85 (1H, m), 2,04 (1H, userd, J=13,6 Hz), 2.26 and is 2.43 (2H, m), a 2.36 (3H, c), 2,48 (1H, d, J=15.7 Hz), is 2.74 (1H, d, J=15.7 Hz), 2,92 (1H, userd, J=11.7 Hz), 3,14 (1H, userd, J=11.7 Hz), 6,46 (2H, c), of 6.90 (1H, DD, J=3.0 a, and 9.3 Hz), 6,93-7,01 (1H, m), to 7.15 (1H, DD, J=5,4, 8,3 Hz)
101FAFAB-MS (m/z); 278 [(M+1)+]

1H-NMR (DMSO-d3); 0,65-0,83 (1H, m)of 0.85 (3H, c), of 1.17 (3H, c), 1,45-to 1.60 (1H, m), 1,64 (1H, userd, J=13,6 Hz), 1,73-of 1.85 (1H, m), 2,04 (1H, userd, J=13,2 Hz), 2,28 is 2.46 (2H, m), is 2.37 (3H, c), of 2.51 (1H, d, J=16.1 Hz), 2,77 (1H, d, J=16.1 Hz), to 2.94 (1H, userd, J=11.7 Hz)and 3.15 (1H, userd, J=11.7 Hz), 5,01 (OSiR.), 6,46 (2H, c), 6,90-7,00 (2H, m), 7,12-7,20 (1H, m)
111FAFAB-MS (m/z); 278 [(M+1)+]

1H-NMR (DMSO-d3); of 0.64 to 0.80 (1H, m)of 0.87 (3H, c), of 1.20 (3H, c), 1,42 is 1.60 (1H, m), of 1.65 (1H, userd, J=13,7 Hz), 1,72-of 1.88 (1H, m), is 2.05 (1H, userd, J=13,7 Hz), 2.26 and is 2.46 (2H, m), a 2.36 (3H, c), 2,59 (1H, d, J=16.1 Hz), 2,72 (1H, d, J=16.1 Hz), with 2.93 (1H, userd, J=10,2 Hz), 3,14 (1H, userd, J=10,7 Hz), 4,82 (OSiR.), of 6.45 (2H, c), 6,94-7,06 (2H, m), 7.18 in-7,26 (1H, m)

Table 14
Etc.STRUCTURE SOLDATA
121FAFAB-MS (m/z);294 [(M+1)+]

1H-NMR (DMSO-d3); 0,65-0,83 (1H, m)of 0.85 (3H, c), of 1.17 (3H, c), 1,44 is 1.58 (1H, m), 1,64 (1H, userd, 13,2 Hz), 1,73-of 1.85 (1H, m), 2,04 (1H, userd, J=13,2 Hz), 2,29 is 2.44 (2H, m), is 2.37 (3H, c), of 2.51 (1H, d, J=16.1 Hz), 2,78 (1H, d, J=16.1 Hz), with 2.93 (1H, userd, J=11.2 Hz), 3,14 (1H, userd, J=11.2 Hz), 6,47 (2H, c), 7,14-of 7.23 (3H, m)
131FAFAB-MS (m/z)338, 340 [(M+1)+]

1H-NMR (DMSO-d3); 0,86 (3H, c)to 1.19 (3H, c), 1,26-of 1.44 (1H, m), 1,58-to 1.82 (3H, m), 1,88-2,02 (1H, m), 2,10-of 2.30 (2H, m), 2,33 (3H, c), 2,46 (1H, d, J=16.2 Hz), 2,80 (1H, d, J=16.2 Hz), 2,97 (1H, userd, J= 11.8 Hz), 3,05 (1H, userd, J=11.8 Hz), 3.45 points (OSiR.), br4.61 (1H, usher.), 6,50 (2H, c), to 7.09 (1H, t, J=7,6 Hz), 7,16 (1H, J=7,3 Hz), 7,34 (1H, d, J=7,8 Hz)
141FAFAB-MS (m/z)338, 340 [(M+1)+]
151FAFAB-MS (m/z)338, 340 [(M+1)+]

1H-NMR (DMSO-d3); 0,62-0,76 (1H, m), is 0.84 (3H, c), of 1.17 (3H, c), 1,38-and 1.54 (1H, m), 1.56 to its 1.68 (1H, m), 1.70 to to 1.82 (1H, m), 1,96-of 2.08 (1H, m), 2,17-is 2.37 (5H, m), 2,46 is 2.55 (1H, m), 2,78 (1H, d, J=16.2 Hz), 2,82-to 2.94 (1H, m), 3,02-3,14 (1H, m), of 6.49 (2H, c), 7,11 (1H, d, J=8,8 Hz), 7,30-7,38 (2H, m)
161FAFAB-MS (m/z); 328 [(M+1)+]

Table 15
Etc.STRUCTURESOLDATA
171FAFAB-MS (m/z)285 [(M+1)+]
181FAFAB-MS (m/z); 296(M+1)+]
191FAFAB-MS (m/z); 296(M+1)+]
201FAFAB-MS (m/z); 296(M+1)+]

1H-NMR (DMSO-d3); 0,65-0,83 (1H, m)of 0.87 (3H, c)to 1.19 (3H, c), 1,42-of 1.57 (1H, m), of 1.65 (1H, userd, J=13,2 Hz), 1,74 is 1.86 (1H, m), 2,03 (1H, userd, J=13,6 Hz), 2,28 is 2.44 (2H, m), a 2.36 (3H, c), 2,63 (1H, d, J=16.1 Hz), 2,75 (1H, d, J=16.1 Hz), with 2.93 (1H, userd, J=11.2 Hz), 3,13 (1H, userd, J=11.8 Hz), 6,46 (2H, c), 6,98 (1H, DD, J=4,4, 7,8 Hz), 7,15-of 7.25 (1H, m)
211FAFAB-MS (m/z); 296(M+1)+]
221FAFAB-MS (m/z); 296(M+1)+]

1H-NMR (DMSO-d3); of 0.90 (3H, c), 0,90-of 1.05 (1H, m)and 1.15 (3H, m), 1,44-of 1.62 (1H, m), 1,62 to 1.76 (1H, m), 1,78-of 1.94 (1H, m), 1,98-of 2.16 (1H, m), 2,30 is 2.46 (2H, m), is 2.40 (3H, c), of 2.56 (1H, d, J=16.1 Hz), 2,78 (1H, d, J=16.1 Hz), 2,99 (1H, userd, J=10,8 Hz), and 3.16 (1H, userd, J=10,8 Hz), 4,90 (OSiR.), 6,46 (2H, c), 6,80-6,94 (2H, m)

Table 16Etc.STRUCTURESOLDATA231FAFAB-MS(m/z); 296(M+1)+]241FAFAB-MS(m/z); 328, 330 [(M+1)+]251FAFAB-MS(m/z); 328, 330 [(M+1)+]261FAFAB-MS(m/z); 328, 330 [(M+1)+]

1H-NMR (DMSO-d3); 0,60-0,78 (1H, m)of 0.87 (3H, c), of 1.20 (3H, c), 1,40-of 1.55 (1H, m), and 1.63 (1H, userd, J=13,2 Hz), 1,75-of 1.85 (1H, m), 2,02 (1H, userd, J=13,6 Hz), 2,20-to 2.42 (2H, m), of 2.34 (3H, c), 2,60 (1H, d, J=16.6 Hz), of 2.81 (1H, d, J=16.6 Hz), 2,92 (1H, userd), of 3.12 (1H, userd), 5,02 (OSiR.), 6,48 (2H, c), 7,14 (1H, d, J=7.8 Hz), was 7.45 (1H, d, J=7,8 Hz)27-FAB-MS(m/z); 416, 418, 420 [(M+1)+]

Table 17
Etc.STRUCTURESOLDATA
281FAFAB-MS (m/z); 312 [(M+1)+]

1H-NMR (DMSO-d3); 0,66-0,83 (1H, m)of 0.85 (3H, m), and 1.7 (3H, m), 1,42 is 1.58 (1H, m)of 1.66 (1H, userd, J=13,2 Hz), 1,74 is 1.86 (1H, m), 2,03 (1H, userd, J=13,7 Hz), 2,29 at 2.45 (2H, m), is 2.37 (3H, c), of 2.51 (1H, d, J=16.1 Hz), 2,77 (1H, d, J=16.1 Hz), to 2.94 (1H, userd, J=11.8 Hz), and 3.16 (1H, userd, J=11.8 Hz), 6,47 (2H, c), 7,22 (1H, d, J=9.7 Hz), 7.23 percent (1H, d, J=7,3 Hz)
291FAFAB-MS (m/z); 312 [(M+1)+]
301FAFAB-MS (m/z); 312 [(M+1)+]

1H-NMR (DMSO-d3); 0,65-0,80 (1H, m)of 0.87 (3H, c)to 1.19 (3H, c), 1,44-of 1.56 (1H, m), of 1.65 (1H, userd, J=13,2 Hz), 1,76-to 1.87 (1H, m), 2,02 (1H, userd, J=13,2 Hz), 2,28 is 2.44 (2H, m), is 2.37 (3H, c), of 2.54 (1H, d, J=16.1 Hz), 2,72 (1H, d, J=16.1 Hz), to 2.94 (1H, userd, J=11.2 Hz), 3,14 (1H, userd, J=11.7 Hz), 6,46 (2H, c), 6,93 (1H, DD, J=2,4, 8,8 Hz), 7,22 (1H, DD, J=2,4, and 9.3 Hz)
311FAFAB-MS(m/z); 312 [(M+1)+]

1H-NMR (DMSO-d3); to 0.87 (3H, c), of 1.17 (3H, c), 1,18-1,32 (1H, m), 1.60-to around 1.74 (2H, m), 1,83 is 2.00 (2H, m), 2,20-2,31 (2H, m)to 2.35 (3H, c), a 2.45 (1H, d, J=15.6 Hz), 2,77 (1H, d, J=15.6 Hz), 2,97 (1H, userd, J=11.5 Hz), is 3.08 (1H, userd, J=11.5 Hz), 4,85 (OSiR.), of 6.49 (2H, c), 7,11-7,21 (2H, m)
321FAFAB-MS(m/z)356, 358(M+1)+]

1H-NMR (DMSO-d3); 0,65-of 0.79 (1H, m)0,86 (3H, c)to 1.19 (3H, c), 1,38-and 1.54 (1H, m), 1,6O-of 1.73 (1H, m), 1,73-of 1.85 (1H, m), 1,98-of 2.08 (1H, m), 2,25 is 2.43 (2H, m)to 2.35 (3H, c), of 2.56 (1H, d, J=16.2 Hz), 2,68 (1H, d, J=16,2 Hz), 2,92 (1H, userd, J=11.2 Hz), 3,13 (1H, userd, J=11.2 Hz), 6.48 in (2H, c),to 7.15 (1H, d, J=2.0 Hz), 7,34 (1H, DD, J=2.0 a, 8,8 Hz)

Table 18
Etc.STRUCTURESOLDATA
331FAFAB-MS(m/z)356, 358(M+1)+]
341FAFAB-MS(m/z)356, 358(M+1)+]

1H-NMR (DMSO-d3); 0,86 (3H, c), of 1.18 (3H, c), 1,25-1,45 (1H, m), 1.60-to of 1.85 (3H, m), 1,92-2,O4 (1H, m), 2,15-of 2.30 (2H, m), of 2.34 (3H, c), 2,43 (1H, d, J=15.7 Hz), 2,78 (1H, d, J=15.7 Hz), 2,99 (1H, userd, J=11.4 in Hz)of 3.07 (1H, userd, J=11,4 Hz), 4,78 (1H, usher.), of 6.49 (2H, c), 7,10-7,22 (2H, m)
351FAFAB-MS(m/z)356, 358(M+1)+]
361FAFAB-MS(m/z)356, 358(M+1)+]

1H-NMR (DMSO-d3); to 0.87 (3H, c), of 1.20 (3H, c), 1,21-of 1.36 (1H, m), 1,57-of 1.73 (2H, m), 1,73-of 1.84 (1H, m), 1,87 of 1.99 (1H, m), 2,07-of 2.21 (2H, m), 2,31 (3H, c), 2,52 (1H, d, J=16.1 Hz), 2,73 (1H, d, J=16.1 Hz), to 2.94 (1H, userd, J=11.2 Hz), 3,03 (1H, userd, J=11.2 Hz), 3,34 (OSiR.), rate 4.79 (1H, usher.), 6,51 (2H, c), of 7.00 (1H, t, J=8,3 Hz), 7,39 (1H, DD, J=8,8, 4,8 Hz)
371FAFAB-MS(m/z); 292 [(M+1)+]

1H-NMR (DMSO-d3); of 0.85 (3H, c), and 1.00-to 1.16 (1H, m)of 1.17 (3H, c), 1,46-to 1.67 (2H, m, 1,78-to 1.98 (2H, m), 2,31 (3H, d, J=2.4 Hz), of 2.38 (3H, c), 2,28-to 2.42 (3H, m), 2,73 (1H, d, J=15.7 Hz), 2,98 (1H, userd, J=11.2 Hz), 3,14 (1H, userd, J=11.2 Hz), 4,77 (OSiR.), 6,47 (2H, c), 6,86-6,98 (2H, m)
381FAFAB-MS(m/z); 292 [(M+1)+]

Table 19
Etc.STRUCTURESOLDATA
391FAFAB-MS(m/z); 292 [(M+1)+]
401FAFAB-MS(m/z); 292 [(M+1)+]
411FAFAB-MS(m/z); 292 [(M+1)+]
421FAFAB-MS(m/z)352, 354 [(M+1)+]
431FAFAB-MS(m/z); 320(M+1)+]
441FAFAB-MS(m/z); 308 [(M+1)+]

1H-NMR (DMSO-d3); to 0.92 (3H, c), 1,00-1,20 (1H, m)to 1.14 (3H, c), 1,57-1,72 (2H, m), 1,82-to 1.98 (2H, m), 2,25-of 2.36 (2H, m), is 2.37 (3H, c), 2,47 (1H, d, J=15.6 Hz), 2,68 (1H, d, J=15.6 Hz), 2,97 (1H, userd, J=11.7 Hz), 3,11 (1H, userd, J=11.7 Hz), 3,82 (3H, d, J=2.0 G is), 4,47 (1H, usher.), 6,48 (2H, c), 6,85 (1H, DD, J=8,3, 4,4 Hz),? 7.04 baby mortality (1H, DD, J=11,7, 8,3 Hz).

Table 20
Etc.STRUCTURESOLDATA
451FAFAB-MS(m/z); 314 [(M+1)+]

1H-NMR (DMSO-d3); from 0.84 to 1.00 (1H, m)to 0.89 (3H, c)and 1.15 (3H, c), 1,38-of 1.56 (1H, m), 1,6O-of 1.74 (1H, m), 1,76-1,90 (1H, m), 2,04 with 2.14 (1H, m), 2,18-of 2.38 (2H, m), 2,32 (3H, c), 2,53 (1H, d, J=16.1 Hz), 2,78 (1H, d, J=16,1 Hz), 2,90 (1H, userd, J=10.3 Hz), to 3.09 (1H, userd, J=10.3 Hz), 3,35 (OSiR.), to 5.03 (1H, usher.), of 6.49 (2H, c), 7,13 (1H, DD, J=9,3, 6,8 Hz)
461FAFAB-MS(m/z)374, 376(M+1)+]
47FAB-MS(m/z); 434, 436, 438 [(M+1)+]
481FAFAB-MS(m/z); 494, 496, 498, 500 [(M+1)+]
491FAFAB-MS(m/z); 430, 432, 434 [(M+1)+]
501FAFAB-MS(m/z)370, 372(M+1)+]

Table 21
Etc.STRUCTURESOLDATA
511FAFAB-MS(m/z)370, 372(M+1)+]
521FAFAB-MS(m/z)370, 372(M+1)+]
53-FAB-MS(m/z); 274 [(M+1)+]
541FAFAB-MS(m/z); 304 [(M+1)+]
551FAFAB-MS(m/z); 304 [(M+1)+]

60
Table 22
Etc.STRUCTURESOLDATA
561FAFAB-MS(m/z); 304 [(M+1)+]
571FAFAB-MS(m/z); 288 [(M+1)+]
581FAFAB-MS(m/z); 288 [(M+1)+]
591FAFAB-MS(m/z); 302 [(M+1)+]
1FAFAB-MS(m/z); 288 [(M+1)+]

Table 23
Etc.STRUCTURESOLDATA
611FAFAB-MS(m/z); 288 [(M+1)+]
621FAFAB-MS(m/z); 276 [(M+1)+]
631FAFAB-MS(m/z); 293 [(M+1)+]
641FAFAB-MS(m/z); 307 [(M+1)+]
651FAFAB-MS(m/z); 280 [(M+1)+]

Table 24
Etc.STRUCTURESOLDATA
661FAFAB-MS(m/z); 280 [(M+1)+]
671FAFAB-MS(m/z)264(M+1)+]
68img src="https://img.russianpatents.com/881/8813592-s.jpg" height="19" width="30" > 1FAFAB-MS(m/z)264(M+1)+]
691FAFAB-MS(m/z); 302 [(M+1)+]
701FAFAB-MS(m/z); 282 [(M+1)+]
711FAFAB-MS(m/z); 274 [(M+1)+]

td align="center">
Table 25
Etc.STRUCTURESOLDATA
721FAFAB-MS(m/z); 260 [(M+1)+]
731FAFAB-MS(m/z);260 [(M+1)+]
741FAFAB-MS(m/z)264(M+1)+]
751FAFAB-MS(m/z); 260 [(M+1)+]
761FAFAB-MS(m/z); 288 [(M+1)+]
771FAFAB-MS(m/z); 292 [(M+1)+]
781FAFAB-MS(m/z)350(M+1)+]

Table 26
Etc.STRUCTURESOLDATA
791FAFAB-MS(m/z)351(M+1)+]
801FAFAB-MS(m/z); 288 [(M+1)+]
811FAFAB-MS(m/z); 277 [(M+1)+]
821FAFAB-MS(m/z); 303 [(M+1)+]
831FAFAB-MS(m/z); 273 [(M+1)+]
841FAFAB-MS(m/z)299(M+1)+]

Table 27
Etc.STRUCTURESOLDATA
851HClFAB-MS(m/z); 308 [(M+1)+]

1H-NMR(DMSO-d3); of 0.95 (3H, c), of 1.16 (3H, c), 1,28-1,4 (1H, m), 1,68-of 2.16 (4H, m), 2,55-3,50 (N, m in), 3.75 (3H, c), at 6.84 (1H, DD, J=9,2, 4.0 Hz), 7,00 (1H, t, J=8.7 Hz), 10,11 (1H, user.)
860,5FAFAB-MS(m/z); 342, 344 [(M+1)+]

1H-NMR(DMSO-d3); to 0.87 (3H, c)to 1.21 (3H, c), 1,10-of 1.35 (1H, m), 1,50-1,70 (2H, m), 1,75-of 1.85 (1H, m), 2,00-2,10 (1H, m), 2,45-2,60 (3H, m), 2,73 (1H, d, J=16.4 Hz), to 3.02 (1H, userd, J=12,4 Hz), 3,11 (1H, userd, J=12,4 Hz), 3,34 (user.), 4,78 (1H, users), 6,32 (1H, c), of 7.00 (1H, t, J=8,4 Hz), 7,39 (1H, DD, J=4,8, and 8.4 Hz)
871FAFAB-MS(m/z)322(M+1)+]
88-FAB-MS(m/z); 371 [(M+1)+]
89-ESI-MS(m/z); 394(M+1)+]
901FAFAB-MS(m/z); 290 [(M+1)+]

Table 28
Etc.STRUCTURESOLDATA
911FAFAB-MS(m/z); 308 [(M+1)+]

1H-NMR(DMSO-d3); 0,58-0,72 (1H, m)0,86 (3H, c), of 1.17 (3H, c), 1,39-of 1.53 (1H, m), 1,57-to 1.67 (1H, m), 1,67-to 1.79 (1H, m), 1,96 e 2.06 (1H, m), 2.06 to to 2.35 (2H, m), and 2.26 (3H, c), 2,44 is 2.55 (1H), 2,63(1H, d, J=15.3 Hz), 2,82 (1H, userd, J=11,4 Hz), 3,03 (1H, userd, J=11,4 Hz), 3,74 (3H, c), 4,79 (1H, usher.), 6,50 (2H, c), to 6.58 (1H, d, J=2.1 Hz), 6,63 (1H, DD, J=2,1, to 10.8 Hz)
921FAFAB-MS(m/z); 312 [(M+1)+]

1H-NMR(DMSO-d3); to 0.88 (3H, c)to 1.19 (3H, c), of 1.12 to 1.31 (1H, m), was 1.58 to 1.76 (2H, m), 1,83 is 2.00 (2H, m), 2,18 of-2.32 (2H, m)to 2.35 (3H, c), to 2.55 (1H, d, J=16,9 Hz), 2,73 (1H, d, J=16,9 Hz), 2,98 (1H, userd, J=11,6 Hz)to 3.09 (1H, userd, J=11,6 Hz), 4,87 (OSiR.), of 6.49 (2H, c), 7,07 (1H, t, J=8,4 Hz), 7,22 (1H, DD, J=4,4, 8,4 Hz)
93-FAB-MS(m/z); 294 [(M+1)+]
941FAFAB-MS(m/z)368, 370(M+1)+]
951FAFAB-MS(m/z); 315 [(M+1)+]

Table 29
Etc.STRUCTURESOLDATA
961FAFAB-MS(m/z)306(M+1)+]

1H-NMR(DMSO-d3); to 0.87 (3H, c), 0,95-of 1.15 (1H, m)of 1.12 (3H, t, J=7,6 Hz)of 1.20 (3H, c), 1,40 by 1.68 (2H, m), 1.70 to was 1.94 (2H, m), 2,18-of 2.36 (2H, m), 2,33 (3H, c), 2,44-of 2.54 (1H), 2,58-of 2.72 (2H, m), 2,86-3,14 (3H, m)and 4.65 (1H, user.), 6,48 (2H, c)6,91 (1H, t, J=8,4 Hz), 7,05 (1H, DD, J=4,8, and 8.4 Hz)
97 1FAFAB-MS(m/z); 354, 356 [(M+1)+]
98I FAFAB-MS(m/z)322(M+1)+]

1H-NMR(DMSO-d3); of 0.93 (3H, c)to 1.14 (3H, c), 1,04-1,17 (1H, m)of 1.30 (3H, t, J=7.0 Hz), 1,64-to 1.77 (2H, m), 1,82-2,02 (2H, m), 2,39 (3H, c), 2,29-to 2.42 (2H, m), 2.49 USD (1H, d, J=15.7 Hz), 2,68 (1H, d, J=15.7 Hz), 3,01 (1H, userd, J=11,4 Hz)and 3.15 (1H, userd, J=11,4 Hz), 3,97 is 4.13 (2H, m), 4,42 (OSiR.), 6,47 (2H, c), at 6.84 (1H, DD, J=4,3, 8.0 Hz), 7,03 (1H, DD, J=8,0, 12.0 Hz)
991FAFAB-MS(m/z)358(M+1)+]
1001FAFAB-MS(m/z)322(M+1)+]

Table 30
Etc.STRUCTURESOLDATA
1011FAFAB-MS(m/z)338(M+1)+]

1H-NMR(DMSO-d3); of 0.93 (3H, c), of 1.05 to 1.19 (1H, m)and 1.15 (3H, c), 1,59-of 1.73 (2H, m), 1,83-of 1.95 (2H, m), 2,28 is 2.43 (2H, m), 2,38 (311, c), 2,49 (1H, d, J=15.7 Hz), 2,58 (1H, d, J=15.7 Hz), of 3.00 (1H, userd, J=11.8 Hz), 3,12 (1H, userd, J=l and 1.8 Hz), of 3.69 (3H, c), of 3.77 (3H, c), 6,47 (2H, c), is 6.78 (1H, d, J=10.0 Hz)
1021FAFAB-MS(m/z)322(M+1)sup> +]
103-FAB-MS(m/z); 434, 436, 438 [(M+1)+]
1041FAFAB-MS(m/z)336 [(M+1)+]
1051FAFAB-MS(m/z); 308 [(M+1)+]

1H-NMR(DMSO-d3); to 0.92 (3H, c), of 1.12 (3H, c), 1,06 of 1.28 (1H, m), 1,57-of 1.74 (2H, m), 1,82-to 1.98 (2H, m), 2,30 is 2.46 (2H, m), 2,41 (311, c), 2,5O(1H, d, J=16.1 Hz), to 2.67 (1H, d, J = 16.1 Hz), 3,03 (1H, userd, J=11,6 Hz)and 3.15 (1H, userd, J=11,6 Hz), 3,74 (3H, c), 6,48 (2H, c), to 6.57 (1H, DD, J=8,5, 1.8 Hz), of 6.66 (1H, DD, J=11,7, 1.8 Hz)
1061FAFAB-MS(m/z)368, 370(M+1)+]

Table 31
Etc.STRUCTURESOLDATA
1071FAFAB-MS(m/z); 315 [(M+1)+]
1081FAFAB-MS(m/z); 326 [(M+1)+]

1H-NMR(DMSO-d3); of 0.91 (3H, c), 1,01 is 1.16 (1H, m)of 1.13 (3H, s), 1,55-1,70 (2H, m), 1,82-of 1.97 (2H, m), 2,23-to 2.40 (2H, m), is 2.37 (3H, c), 2,48 (1H, d, J=15,8 Hz), 2,69 (1H, d, J=15,8 Hz), 2,97 (1H, userd, J=11,4 Hz), 3,11 (1H, userd, J=11,4 Hz), a 3.87 (3H, d, J= 1,8 Hz), 6.48 in (2H, c), 94 (1H, DD, J=6,5, and 9.6 Hz)
1090,5FAFAB-MS(m/z)340(M+1)+]

1H-NMR(DMSO-d3); 0,71-of 0.95 (1H, m)of 0.85 (3H, c), of 1.17 (3H, c), 1,34-1,49 (1H, m), 1,53-of 1.65 (1H, m), 1,68-1,89 (2H, m), 1,94 with 2.14 (2H, m), of 2.21 (3H, c), 2,38 is 2.55 (1H, m), 2,72-to 2.85 (2H, m), 2,9O-3,O1 (1H, m), 3.27 to (3H, c), 4,63 (1H, d, J=10.3 Hz), to 4.73 (1H, d, J=10.3 Hz), 4,82 (OSiR.), 6,47 (1H, c), 7,17 (1H, t, J=8,1 Hz)
110-FAB-MS(m/z)338(M+1)+]
111-FAB-MS(m/z)407(M+1)+]
112HClESI-MS(m/z)356(M+1)+]

/tr>
Table 32
Etc.STRUCTURESOLDATA
1131FAFAB-MS(m/z)333(M+1)+]

1H-NMR(DMSO-d3); 0,91-of 1.09 (1H, m)to 0.94 (3H, c), of 1.18 (3H, c), 1.56 to at 1.73 (2H, m), 1,87 is 2.01 (2H, m), 2,27-2,47 (2H, m), of 2.38 (3H, c), 2,65 (1H, d, J=and 17.2 Hz), was 2.76 (1H, d, J=and 17.2 Hz), 2,98 (1H, userd, J=11.7 Hz), 3,13 (1H, userd, J=11.7 Hz), 3,90 (3H, c), 6,48 (2H, c), to 7.64 (1H, d, J=7,8 Hz)
1141FAFAB-MS(m/z)386, 388(M+1)+]
1151FAFAB-MS(m/z)372, 374(M+1)+]
1161FAFAB-MS(m/z); 304 [(M+1)+]
1171FAFAB-MS(m/z); 354 [(M+1)+]

1H-NMR(DMSO-d3); to 0.94 (3H, c), and 1.00 (3H, c), 0,85 is 2.00 (7H, m)to 2.18 (3H, c), of 2.66 (1H, d, J=16.0 Hz), is 2.74 (1H, d, J=16.0 Hz), 2,65 is 2.75 (1H), 2,86 (1H, userd, J=11.2 Hz), 3,35 (OSiR.), the 4.65 (1H, usher.), 6,51 (2H, c), 6,98 (1H, DD, J=5,6, and 8.4 Hz), 7,07 (1H, t, J=8,4 Hz), 7,25 was 7.36 (3H, m), 7,40-to 7.50 (2H, m)

Table 33
Etc.STRUCTURESOLDATA
1181FAFAB-MS(m/z)384(M+1)+]
1191FAFAB-MS(m/z); 303 [(M+1)+]

1H-NMR(DMSO-d3); of 0.85 (3H, c), 0,70-1,00 (1H, m)to 1.21 (3H, c), 1,40-to 2.40 (6H, m)to 2.29 (3H, c), 2,58 (1H, d, J=16,8 Hz), 2,80 (1H, d, J=16,8 Hz), 2,84 (1H, userd, J=10,8 Hz), is 3.08 (1H, userd, J=10,8 Hz), 5,24 (1H, usher.), 6,50 (2H, c), 7,26 (1H, ushort, J=8,4 Hz), 7,72 (1H, users)
1201FAFAB-MS(m/z)422(M+1)+]
121 2FAFAB-MS(m/z); 355 [(M+1)+]

Table 24
Etc.STRUCTURESOLDATA
1221FAFAB-MS(m/z); 360 [(M+1)+]

1H-NMR(DMSO-d3); 0,80-of 1.35 (3H, m)of 1.06 (3H, c), of 1.13 (3H, c), 1,60-1,80 (3H, m), 1,90-2,10 (1H, m), 2,22 (3H, c), 2,65 (1H, d, J=16.4 Hz), 2,71 (1H, d, J=16.4 Hz), is 2.74 (1H, userd, J=10,8 Hz), 2,87 (1H, userd, J=10,8 Hz), 4,73 (1H, usher.), 6,51 (2H, c), 7,00-7,14 (2H, m), 7,31 (1H, d, J=4,8 Hz), 7,46 (1H, DD, J=2,8, 4,8 Hz), 7,55 (1H, d, J=2,8 Hz)
123HC1FAB-MS(m/z); 290 [(M+1)+]
124HC1FAB-MS(m/z)368, 370(M+1)+]
1251FAFAB-MS(m/z); 240 [(M+1)+]
1261FAFAB-MS(m/z); 268 [(M+1)+]
1271FAFAB-MS(m/z); 282 [(M+1)+]

Table 25
Etc.STRUCTURESOLDATA
1281FAFAB-MS(m/z); 310 [(M+1)+]
1291FAFA,B-MS(m/z); 308 [(M+1)+]
1301FAFAB-MS(m/z); 324 [(M+1)+]
1310,5FAFAB-MS(m/z); 248 [(M+1)+]

1H-NMR(DMSO-d3); of 0.85 (3H, c), of 0.95 (3H, c)to 1.14 (3H, c), of 1.23 (1H, c), 1,70 (1H, d, J=15.2 Hz), a 1.96 (1H, d, J=15.2 Hz), to 2.29 (3H, c), of 2.51 (1H, d, J=14,8 Hz), 2,56 (1H, d, J=14,8 Hz)and 3.31 (OSiR.), 6,37 (1H, c), to 6.95 (1H, d, J=7,6 Hz), 7,01 (1H, d, J=7,6 Hz), 7,29 (1H, c)
1321FAFAB-MS(m/z)336 [(M+1)+]
1331FAFAB-MS(m/z)322(M+1)+]

Table 36
Etc.STRUCTURESOLDATA
1341FAFAB-MS(m/z); 296(M+1)+]
135 1FAFAB-MS(m/z)322(M+1)+]
1361FAFAB-MS(m/z)350(M+1)+]
1371FAESI-MS(m/z)322(M+1)+]

1H-NMR(DMSO-d3); of 0.91 (3H, c), 0,86-a 1.01 (1H, m)to 1.14 (3H, c), 1,50-to 1.87 (3H, m), 2,01-2,11 (1H, m), 2,14 to 2.35 (2H, m), 2,32 (3H, c), 2,53 (1H, d, J=15.7 Hz), 2,60 (1H, d, J=15.7 Hz), 2,90 (1H, userd, J=11.5 Hz), 3,06 (1H, userd, J=11.5 Hz), 3.33 and (OSiR.), 5,97 (2H, q, j 9.9 Hz), of 6.49 (2H, c), of 6.73 (1H, d, J=8,4 Hz)
1381FAFAB-MS(m/z)336 [(M+1)+]

Table 37
Etc.STRUCTURESOLDATA
1391FAFAB-MS(m/z); 320(M+1)+]

1H-NMR(DMSO-d3); of 0.91 (3H, c), 0,96-1,17 (1H, m)of 1.12 (3H, c), 1,62-of 1.78 (2H, m), 1,82-of 1.92 (1H, m), I,97-2,07 (1H, m), 2,29 is 2.44 (2H, m), 2,39 (3H, c), of 2.54 (1H, d, J=16.1 Hz), 2,59 (1H, d, J= 16.1 Hz), 2,99 (1H, userd, J=11.3 Hz), is 3.08 (2H, t, J=8,3 Hz), 3,14 (1H, userd, J=11.3 Hz), 4,42-a 4.53 (2H, m), 6,45 (2H, c), 6,89 (1H, d, J=8,4 Hz)
1401FAFAB-MS(m/z); 318 [(M+1)+]

1H-NMR(DMSO-d3); 0,83 of 1.00 (1H, m)of 0.95 (3H, c, to 1.21 (3H, c), 1,57-to 1.79 (2H, m), 1,92-2,04 (1H, m), 2,17-of 2.28 (1H, m)to 2.35 (3H, c), 2,30 is 2.46 (2H, m), 2,70 (1H, d, J=15,9 Hz), 2,80 (1H, d, J=15,9 Hz), with 2.93 (1H, userd, J=11.5 Hz), 3,14 (1H, userd, J=11.5 Hz), 6,41 (2H, c), to 6.88 (1H, d, J=2.3 Hz), 7,28 (1H, d, J=8.5 Hz), of 7.96 (1H, d, J=2.3 Hz)
1411FAFAB-MS(m/z); 328 [(M+1)+]
142-ESI-MS(m/z)338(M+1)+]
1431FAFAB-MS(m/z); 320(M+1)+]

1H-NMR(DMSO-d3); to 0.97 (3H, c)to 1.19 (3H, c), 1,10-of 1.28 (1H, m), 1,49-of 1.62 (1H, m), 1,68-1,89 (2H, m), 1.93 and-2,05 (1H, m), 2,25 is 2.43 (2H, m), is 2.40 (3H, c), 2,46 (1H, d, 1=to 15.8 Hz), was 2.76 (1H, d, 1=to 15.8 Hz), 3,05 (1H, userd, J=and 11.8 Hz), 3,11 (1H, userd, J=11.8 Hz), 3,89-3,99 (2H, m), 4,06-4,16 (1H, m), 4,42-4,50 (1H, m), 6,51 (2H, c), PC 6.82 (1H, DD, J=4,1, 8.0 Hz), 7,06 (1H, DD, J=8.0 a, 11,1 Hz)
1441FAFAB-MS(m/z); 308 [(M+1)+]

Table 38
Etc.STRUCTURESOLDATA
1451FAFAB-MS(m/z)334(M+1)+]
146-ESI-MS(m/z); 304 [(+1) +]
1471FAFAB-MS(m/z); 286 [(M+1)+]

1H-NMR(DMSO-d3); of 0.56 to 0.69 (1H, m), 1,25 (3H, c), 1,45-and 1.54 (1H, m), 1,58 by 1.68 (1H, m), 1,75 is 1.86 (3H, m), 1.93 and-2,03 (1H, m), 2,28 (3H, c)to 2.35 (3H, c), 2,30 at 2.45 (2H, m), 2,70 (1H, d, J=15.7 Hz), and 2.83 (1H, d, J=15.7 Hz), 2,89 (1H, userd, J=11.8 Hz), 3,13 (1H, userd, J=11.8 Hz), 3,32 is 3.40 (1H, m), 3,76 (1H, q, J=8.1 Hz), 6,47 (2H, c), 7,01 (1H, c), 7,03 (1H, d, J=7.8 Hz), was 7.08 (1H, d, J=7,8 Hz)
148-FAB-MS(m/z)370, 372(M+1)+]
149-FAB-MS(m/z); 448, 450, 452 [(M+1)+]
150-FAB-MS(m/z)382, 384 [(M+1)+]

Table 39
Etc.STRUCTURESOLDATA
151-FAB-MS(m/z)372, 374(M+1)+]

1H-NMR(DMSO-d3); to 0.78 (3H, c), is 1.11 (3H, c), 1,18-1,25 (1H, m), 1.55V to 1.76 (5H, m)2,07 (3H, c), 2,02-of 2.16 (1H, m), 2,65 is 2.80 (2H, m), of 4.44 (1H, c), 4,50 (1H, d, J=5.3 Hz), to 5.56 (1H, d, J=5.3 Hz), of 6.99 (1H, t, J=8,5 Hz), 7,46 (1H, DD, J=4,6, 8,5 Hz)
152-FAB-MS(m/z; 372, 374(M+1)+]
153-FAB-MS(m/z); 450, 452, 454(M+1)+]
154-FAB-MS(m/z)370, 372(M+1)+]

1H-NMR(DMSO-d3); to 0.87 (3H, c), of 0.93 (3H, c), 1,50 by 1.68 (1H, m), 2,17 (3H, c), and 2.26-2,39 (3H, m), was 2.76-2.91 in (2H, m), 4,60 (1H, c), 4,71 (1H, d, J=4,8 Hz), 5,46 (1H, d, J=4,8 Hz), 5.40 to-5,52 (1H, usher.), 7,05 (1H, t, J=8,8 Hz), of 7.48 (1H, DD, J=4,4, 8,8 Hz)
155-EI-MS(m/z)369, 371 [(M+1)+]

Table 40
Etc.STRUCTURESOLDATA
156-ESI-MS(m/z); 384, 386(M+1)+]
157-FAB-MS(m/z); 304 [(M+1)+]
1581FAESI-MS(m/z); 349 [(M+1)+]
159-ESI-MS(m/z); 319 [(M+1)+]
160-FAB-MS(m/z); 361 [(M+1)+ ]
161-FAB-MS(m/z)347 [(M+1)+]

Table 41

Table 42

Table 43

Table 44

/tr>
Table 45

Industrial applicability

As described above, the compounds of the present invention have an antagonistic activity against NMDA receptor and can be used for the treatment and prevention of Alzheimer's disease, cerebral-vascular dementia, Parkinson's disease, ischemic apoplexy, pain, and so forth and have a great industrial applicability.

1. Derived cyclic amine or its salt of the following formula (I):

where the symbols have the following meanings:

A: 5-8-membered cyclic amine, optionally containing a double bond, optionally having a bridge structure and optionally containing substituents R7-R11in the ring, or-NH2, N H(lower alkyl), -N(lower alkyl)2or morpholine-1-yl;

ring: benzene, thiophene, furan, pyrrole, 5-7-membered cycloalkane or a 5-7 membered cycloalkene;

X1: link or lowest alkylen;

X2: -(CR12R13)n-, -N(R14)-, -N(R14)CO-, -CON(R14)-, -CO-, -CH(OH)-, -N(R14)-(CR12R13)n, -(CR12R13)n-N(R14)-, -CON(R14)-(CR12R13)n-, -N(R14)CO-(CR12R13)n-, -(CR12R13)n-N(R14)CO-, -(CR12R13n-CON(R14)-, -CO-(CR12R13)n - or -(CR12R13)n-CO-;

Y1: -OH, -O-lower alkyl, -NH2or-N3;

R1and R2: the same or different and represent a halogen atom, lower alkyl or lower alkylene-HE;

R3-R6: the same or different and represent a hydrogen atom, halogen atom, lower alkyl, lower alkenyl, lower quinil, -O-lower alkyl, -OH, -NH2-, -NH(lower alkyl), -N(lower alkyl)2, -NH-CO-lower alkyl, -N(lower alkyl)-CO-lower alkyl, -CN, -NO2, -CF3, -O-lower alkylene-OH, -lower alkylene-OH, -lower alkylene-halogen, -lower alkylene-O-lower alkyl, -CO-5-8-membered cyclic amine, -COOH, -COO-lower alkyl, -COO-lower alkylene-aryl, pyridine, thiophene, lowest alkylen-morpholine, aryl, optionally containing a Deputy: -O-lower alkyl or-CF2 ;

R7: a hydrogen atom, a lower alkyl, -lower alkylene-aryl or-lower alkylene-pyridine;

R7is a Deputy to the nitrogen atom of the cyclic amine;

R8-R14: the same or different and represent a hydrogen atom or lower alkyl;

n: an integer equal to 1, 2 or 3;

where R5and R6, R4and R5or R3and R4may together form a lower alkylene, -O-lower alkylene-O-, -O-lower alkylene-, -lower alkylene-O-, -C(R15)=C(R16)-O-, -O-C(R15)C(R16)-, -C(R15)=C(R16)-C(R17)=C(R18)-; R3and Y1may together form-O-lower alkylene-O - or-lower alkylene-O-; R1and Y1may together form a lower alkylene-O-; and Y1and the branch is on-X1-A may together form-O - or-O-lower alkylene;

R15-R18represent a hydrogen atom;

provided that 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol excluded from the group of compounds.

2. Derived cyclic amine or its salt of the following formula (II):

where conventions have the following meaning:

ring A: 5-7-membered cyclic amine, optionally containing a double bond in the ring;

ring: benzene, thiophene,furan, pyrrole, 5-7-membered cycloalkane or a 5-7 membered cycloalkene;

X1: link or lowest alkylen;

X2: -(CR12R13)n-, -N(R14)-, -N(R14)CO-, -CON(R14)-, -CO-, -N(R14)-(CR12R13)n-, -(CR12R13)n-N(R14)-, -CON(R14)-(CR12R13)n-, -N(R14)CO-(CR12R13)n-, -(CR12R13)n-N(R14)CO-, -(CR12R13n-CON(R14)-, -CO-(CR12R13)n - or -(CR12R13)n-CO-;

Y1: -OH, -O-lower alkyl, -NH2or-N3;

R1and R2: the same or different and represent a halogen atom or lower alkyl;

R3-R6: the same or different and represent a hydrogen atom, halogen atom, lower alkyl, -O-lower alkyl, -OH, -CN or-CF3;

R7: a hydrogen atom, a lower alkyl, -lower alkylene-aryl or-lower alkylene-pyridine;

R8-R14: the same or different and represent a hydrogen atom or lower alkyl;

n: an integer equal to 1, 2 or 3;

provided that 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol excluded from the group of compounds.

3. Derived cyclic amine or its salt of the following formula (III):

where the symbols have the following meanings:

X1: link or lowest Alki the Yong;

Y1: -OH, -O-lower alkyl, -NH2or-N3;

R1and R2: the same or different and represent a halogen atom or lower alkyl;

R3-R6; same or different and represent a hydrogen atom, halogen atom, lower alkyl, -O-lower alkyl, -OH, -CN or-CF3;

R7: a hydrogen atom, a lower alkyl, -lower alkylene-aryl or-lower alkylene-pyridine;

R8-R11: the same or different and represent a hydrogen atom or lower alkyl;

provided that 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol excluded from the group of compounds.

4. The compound or its salt according to claim 1, selected from 2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 2,2,6-trimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 6-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 5-bromo-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 6-chloro-5-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 6-bromo-4-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 7-bromo-6-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 7-bromo-4-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 6-fluoro-7-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 4-fluoro-7-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 2,2-dimethyl-1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-ol, 4-fluoro-6-methoxy-2,2-dimethyl-1-(1-m is typoberlin-4-yl)indan-1-ol, 7 ethoxy-6-fluoro-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 4-fluoro-6,7-dimethoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 5,6-debtor-7-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 6-cyano-4-fluoro-7-methoxy-2,2-dimethyl-1-(1-methylpiperidin-4-yl)indan-1-ol, 1-(2-amino-2-methylpropyl)-2,2,6-trimethylene-1-ol, 5-fluoro-7,7-dimethyl-8-(1-methylpiperidin-4-yl)-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-8-ol, 4-(9-fluoro-5,5-dimethyl-2,3,5,6-tetrahydro-an-indeno[1,7-ef] [1,4]doxepin-4A-yl-1-methylpiperidine, 1-[(6'-fluoro-7'-methoxy-2',2' -dimethyl-2',3',4,5-tetrahydro-3H-Spiro[furan-2,1'-inden]-5-yl)methyl]pyrrolidine, 7-bromo-2,2-dimethyl-(1-methylpiperidin-4-yl)indan-1-ol.

5. A pharmaceutical composition comprising a compound or its salt according to any one of claims 1 to 4, which is an antagonist of the NMDA receptor.

6. A pharmaceutical composition comprising a compound or its salt according to any one of claims 1 to 4, which is a treatment for dementia.

7. The use of a cyclic amine or its salt according to any one of claims 1 to 4 to obtain an antagonist of the NMDA receptor or for the treatment of dementia.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel quinuclidine derivatives and their using as pharmaceutical agents. Based on their pharmacological pattern proposed compounds can be useful in treatment of different diseases and disorders associated with cholinergic system of the central nervous system, peripheral nervous system, diseases and disorders associated with contraction of smooth muscle, endocrine diseases or disorders, diseases or disorders associated with neurodegeneration, diseases or disorders associated with inflammation, pain and abstinence syndrome caused by ceasing use of chemical substances.

EFFECT: valuable medicinal properties of compounds.

11 cl, 1 tbl, 46 ex

FIELD: organic chemistry, medicine, chemical technology.

SUBSTANCE: invention describes a method for synthesis of 1-hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane bromide represented by the formula: . Method involves interaction of 1-hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane with hydrobromic acid or its inorganic salt (for example, sodium bromide or potassium bromide) in water in the ionic exchange reaction. 1-Hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane bromide represents an immunotropic agent that shows versatile effect on human immune status and elicits antitumor, bacteriostatic and anti-aggregate effects. Invention proposes a method for synthesis of a novel synthetic low-molecular preparation possessing the expressed stimulating effect on the antitumor immunity system that is equal or exceeding by effectiveness effect of the modern domestic and foreign preparation - immunomodulators that represent natural high-molecular biologically active substances prepared by methods of genetic engineering.

EFFECT: improved method of synthesis, valuable medicinal and biological properties of substance.

1 cl, 6 tbl, 21 dwg, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds that represent quaternary ammonium salt of the formula (II): wherein R1 means group chosen from phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl; R2 means group chosen from (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, saturated or unsaturated (C3-C7)-cycloalkyl, saturated or unsaturated (C3-C7)-cycloalkylmethyl, phenyl, benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, pyridyl and pyridylmethyl; cyclic groups in R1 and R2 are optionally substituted with one, two or three substitutes chosen from halogen atom, linear or branched (C1-C8)-alkyl, hydroxy, linear or branched (C1-C8)-alkoxy wherein (C1-C8)-alkyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy or (C1-C8)-alkoxy groups, and (C1-C8)-alkoxy group is unsubstituted or substituted with one or more halogen atoms or hydroxy groups; p means 1 or 2, and carbamate group is joined at positions 2, 3 or 4 of azoniabobicyclic ring system; m means a whole number from 1 to 6; n means 0 or 1; A represents -CH2-, -CH=CH-, -C(O)-, -O-, -S- and -NMe-group; B represents hydrogen atom or group chosen from linear or branched (C1-C8)-alkyl, hydroxy, linear or branched (C1-C8)-alkoxy, cyano, nitro, -CH=CR'R'', -C(O)OR', -OC(O)R', (C3-C7)-cycloalkyl, phenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo[1.3]dioxolyl, 5-10-membered heteroaryl or heterocyclyl group wherein each R' and R'' represents independently hydrogen atom or linear or branched (C1-C8)-alkyl group, and wherein cyclic groups represented as B are substituted optionally with one, two or three substitutes chosen from halogen atom, hydroxy, linear or branched (C1-C8)-alkyl, -OR', -CONR'R'', -CN, and -COOR'; R' and R'' are given above and wherein (C1-C8)-alkyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy or (C1-C8)-alkoxy groups, and (C1-C8)-alkoxy groups are unsubstituted or substituted with one or more halogen atoms or hydroxy groups; X- represents a pharmaceutically acceptable anion of mono- or polyvalent acid, and involving all individual stereoisomers of compound of the formula (II) and their mixtures. Also, invention relates to a method for inhibition, pharmaceutical composition, combined product and their using in therapeutic treatment as antagonists of M3 muscarinic receptors. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 187 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 1-(2S,3S)-2-benzhyryl-N-(5-tert.-butyl-2-methoxybenzyl)quinuclidin-3-amine (further named in the claim as "compound of the formula (I)" ) and its pharmaceutically acceptable salts. Invention relates to an improved method of synthesis of citrate monohydrate salt of compound of the formula (Ia):

EFFECT: improved method of synthesis.

10 cl, 2 sch,

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to new compounds selected from 3(R)-(2-hedroxy-2,2-dithiene-2yl acetoxy)-1-(3-phenoxypropyl)-1-azoaniabicyclo[2,2,2]octane,X-, and 1-phenerhyl-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoaniabicyclo[2,2,2]octane,X-, wherein X- represents pharmaceutically acceptable anion of mono- or polyvalen acid having inhibiting activity in relates to muscarinic M3 receptors. Also disclosed are pharmaceutical compositions containing such compounds and method for treatment of respiratory diseases.

EFFECT: new quinuclidine analogs useful in treatment of respiratory diseases.

20 cl, 1 tbl, 184 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of carbamate of the formula (I): or to their pharmaceutically acceptable salts wherein R1 represents compounds of formulas: , , , ,

, , , or ; R3 means hydrogen, halogen atom or alkyl; R2 means benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophene-2-ylmethyl, thiophene-3-ylmethyl or alkyl; p = 1 or 2, and substitution in azabicyclic ring can be at position 2, 3 or 4. Compounds of the formula (I) and their salts possess inhibitory activity with respect to muscarinic M3 receptors and can be used in medicine.

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

25 cl, 1 tbl, 165 ex

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to an agent eliciting immunomodulating, antitumor, bacteriostatic and anti-aggregation properties and representing 1-hexadecyl-R-(-)-3-oxy-1-azoniabicyclo[2.2.2]octane bromide and a method for its synthesis. Method involves quartenization of R-(-)-azabicyclo[2.2.2]octane-3-ol with hexadecyl bromide at heating in organic solvent medium. Agent shows low toxicity, high effectiveness, it doesn't cause allergic effect and doesn't possess cumulative effect.

EFFECT: valuable medicinal properties of agent.

3 cl, 9 dwg, 6 tbl, 2 ex

FIELD: organic chemistry, pharmacology, pharmacy.

SUBSTANCE: invention relates to derivatives of quinuclidine of the general formula (I): wherein B means phenyl, pyrrolyl and other group; each among R1, R2 and R3 represents hydrogen, halogen atom, phenyl group and others; n means a whole number from 0 to 4; A represents the group chosen from -CH2-, -CH=CR9, -CR9R10 and others wherein R9 and R10 represent hydrogen atom or (C1-C8)-alkyl; m means a whole number from 0 to 8 under condition that if m = 0 then A doesn't mean -CH2-; p means a whole number from 1 to 2; R4 represents phenyl or 5-membered heteroaromatic cycle comprising oxygen or sulfur atom; R5 represents (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl and others; R6 represents hydrogen atom, hydroxy-group and others; X- represents a pharmaceutically acceptable anion of mono- or polyvalent acid. Compounds of the formula (I) possess the inhibitory activity with respect to M3-muscarinic receptors and can be used in medicine.

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

34 cl, 2 tbl, 104 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry.

SUBSTANCE: invention relates to quinuclidine compounds of the formula (I) , its salts or their hydrates wherein R1 represents hydroxyl group; W represents: (1) -CH2-CH2-; 2) -CH=CH-, or 3) -C≡C-; HAr represents 5-10-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom that in addition to the group -X-Ar can be substituted with 1-3 groups taken among: (1) halogen atom; (2) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl group substituted optionally with: (a) hydroxy-group; (b) (C1-C6)-alkoxycarbonyl; (c) (C1-C6)-alkanoyl optionally substituted with (C1-C6)-alkoxy-group; (d) hydroxylated (C3-C8)-cycloalkyl; (e) (C1-C6)-alkoxy-group; (f) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom, or (g) cyano-group; (3) (C1-C6)-alkoxy-group optionally substituted with: (a) hydroxy-group; (b) (C1-C6)-alkoxy-group optionally substituted with (C1-C6)-alkoxy-group; (c) halogen atom; (d) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (e) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (4) (C1-C6)-alkylthio-group optionally substituted with (C1-C6)-alkoxy-group or hydroxy-group; (5) 5-6-membered heterocyclyloxy-group comprising 1-2 oxygen atoms in heterocycle; (6) amino-group represented by the formula: -N(R3)R4 wherein R3 and R4 are similar or different and each represents hydrogen atom or group taken among: (a) (C1-C6)-alkyl group; (b) (C1-C6)-alkoxy-(C1-C6)-alkyl group; (c) carbonyl substituted with (C6-C14)-aryl; (d) (C6-C14)-arylsulfonyl or (e) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (7) (C3-C8)-cycloalkyl or cycloalkenyl hydrocarbon group optionally substituted with: (a) oxo-group or (b) hydroxy-group; (8) (C6-C14)-aromatic hydrocarbon ring optionally substituted with: (a) (C1-C4)-alkylene dioxy-group or (b) hydroxy-group; (9) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with: (a) cyano-group or (b) (C1-C6)-alkoxy-group; (10) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with one or some groups taken among: (a) hydroxy-group; (b) halogen atom; (c) cyano-group; (d) (C1-C6)-alkoxycarbonyl; (e) (C1-C6)-alkyl; (f) (C1-C6)-alkoxy-group that is optionally substituted with halogen atom or (C1-C6)-alkoxy-group; (g) (C1-C6)-alkanoyl; (h) (C1-C6)-alkoxy-(C1-C6)-alkyl; (i) oxo-group; (j) (C1-C4)-alkylenedioxy-group; (k) (C3-C8)-cycloalkylalkoxy-group or (C3-C8)-cycloalkenylalkoxy-group; (11) carbamoyl of the formula: -CO-N(R5)R6 wherein R5 and R6 can be similar or different and represent hydrogen atom, (C6-C14)-aryl wherein indicated aryl is optionally substituted with halogen atom, or (C3-C8)-cycloalkyl; or R5 and R6 form in common 3-6-membered ring; (12) carbonyl optionally substituted with (C1-C6)-alkoxy-group; X represents: (1) a simple bond; (2) (C1-C6)-alkylene chain; (3) (C1-C6)-alkenylene chain; (4) (C1-C6)-alkynylene chain; or (5) formula: -Q- wherein Q represents oxygen atom or sulfur atom; Ar represents: (1) (C6-C14)-aromatic hydrocarbon ring optionally substituted with one or some groups taken among: (a) halogen atom; (b) (C1-C4)-alkoxy-group or (c) (C1-C6)-alkylthio-group; or (2) 5-6-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom. Compounds of the formula (I) show inhibitory activity with respect to a squalene-synthesizing enzyme. Also, the invention relates to an inhibitor of squalene-synthesizing enzyme and the corresponding medicinal composition based on compound of the invention, a method for prophylaxis and treatment of disease wherein inhibition of squalene-synthesizing enzyme is effective. Also, invention proposes some methods for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable of medicinal and biochemical properties of com[pounds and composition.

25 cl, 10 tbl, 214 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: claimed invention relates to application of indazole derivatives of general formula (I) , in which: R stands for O; R3 stands for radical (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, said radicals being unsubstituted or substituted with one or several substitutes, given in item 1 of the formula; R4, R5, R6 and R7, independently on each other are selected from following radicals; hydrogen atom, halogen, CN, NO2, NH2, NHSO2R9, trifluoromethyl, trifluoromethoxygroup, (C1-C6)-alkyl, phenyl, phenyl-(C1-C6)-alkyl, pyridyl, possibly substituted with amino or hydroxygroup, thienyl, furanyl, morpholino, phenyl being unsubstituted or substituted with one or several substitutes, given in item 1 of the formula; R8, R9, R10, R11, independently on each other, stand for hydrogen atom, (C1-C6)-alkyl, phenyl possibly substituted with halogen; their racemates, enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts for obtaining medication, inhibiting phosphorylation of Tau-protein. Invention also relates to novel compounds of formula (I), particular indazole derivatives, their racemates, enantiomers, tautomers and pharmaceutically acceptable salts, pharmaceutical composition and based on them medication which inhibits Tau-protein phosphorylation, as well as to method of obtaining compounds of formula (I).

EFFECT: obtaining medication based on indazole derivatives, inhibiting Tau-protein phosphorylation.

9 cl, 118 ex, 3 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention claims ethers of substituted 1H-indol-3-carboxylic acid of the general formula 1 or their pharmaceutically acceptable salts. Compounds can be applied as active substance for pharmaceutical compositions and for application of these compositions in production of medicine for virus disease prevention and treatment, especially for diseases caused by infection hepatitis viruses (HCV, HBV) and influenza A viruses. In the general formula 1 R1 is aminogroup substitute selected out of hydrogen, optionally substituted inferior alkyl, optionally substituted C3-6cycloalkyl, optionally substituted aryl selected out of phenyl, naphthyl or 5-6 member heteroaryl containing 1-2 heteroatoms selected out of nitrogen, oxygen and sulfur, and possibly condensed with benzene ring of optionally substituted heterocyclyl, which can be optionally substituted 5-6-member heterocyclyl with 1-2 heteroatoms in heterocyclic ring selected out of nitrogen and oxygen; R2 is alkyl substitute selected out of hydrogen, optionally substituted hydroxyl group, optionally substituted mercapto group, optionally substituted arylsulfinyl group; optionally substituted amino group, optionally substituted 5-6-member heterocyclyl containing 1-2 heteroatoms selected out of nitrogen, oxygen and sulfur; R3 is hydrogen or optionally substituted inferior alkyl; R14 and R24 are independently substitutes of cyclic system, selected out of hydrogen or halogen atom, cyano group, trifluoromethyl, optionally substituted phenyl or optionally substituted heterocyclyl which is an optionally substituted 5-6-member heterocyclyl with 1-2 heteroatoms in heterocyclic ring, selected out of nitrogen, oxygen or sulfur, possibly condensed with benzene ring.

EFFECT: improved efficiency of compositions.

15 cl, 3 tbl, 1 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: present invention concerns application of new biologically active substances of the general formula of 1 either their racemates, or their optical isomers, or their pharmaceutically comprehensible salts and-or hydrates, and also to a pharmaceutical composition and its use at manufacturing of the medicinal preparations applied to treatment and-or preventive maintenance of diseases, caused by flu viruses. In compounds of the general formula 1, R1 are represented by the substituent to the amino group chosen from unessentially replaced C1-C6alkyl, unessentially replaced aryl or unessentially replaced 5-6 term azaheterocycl, R14 and R24 independently from each other represent the substituent to an amino group chosen from hydrogen, unessentially replaced C1-C6alkyl, unessentially replaced C3-C8cycloalkyl, or R14 and R24, together with atom of nitrogen to which they are bound, form through R14 and R24 unessentially replaced 5-6-term azaheterocycl with 1-3 heteroatoms in a ring and which can be monocyclic or condensed with a benzene ring, or aminoethanamidine; R2 is a substituent chosen from hydrogen, of unessentially replaced mercapto group, unessentially replaced amino group, unessentially replaced hydroxyl represents alkyn; R3 represents the lowest alkyl; R5 the substituent to the cyclic system chosen from hydrogen, atom of halogen, cyano group, unessentially replaced aryl or unessentially replaced 5-6-term heterocycl represents, the containing 1-2 heteroatoms chosen from nitrogen, oxygen or sulphur and which can be monocyclic or condensed with a benzene ring.

EFFECT: invention provides increase of efficiency of a composition and a method of treatment.

11 cl, 1 dwg, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compound of formula I: , where R1, R2 and R3 are equal or different and represent hydrogen, halogen, alkyl, aloxy, hydroxyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group, R4 represents hydrogen, alkyl or alkylaryl group; X represents CH2, oxygen atom and sulphur atom; n represents 2 or 3, and individual (R)- and (S)-enantiomers or the mixture of enantiomers and its pharmaceutically acceptable salts; where alkyl termine denotes straight and branched hydrocarbon chains, containing fro one to six atoms of carbon, optionally substituted by aryl, alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl groups, termine aryl denotes phenyl or naphtyl group, optionally substituted alkyloxy group, halogen or nitro group, termine halogen denotes fluorine, chlorine, bromine or iodine. The compounds have valuable pharmaceutical properties and perspectives for the treatment of cardiovascular disorder, such as hypertension and chronic heart failure. The method of production of individual (R)- and (S)-enantiomers or the mixture of enantiomers and pharmaceutically acceptable salts of the compound of formula I, pharmaceutical composition having inhibitor dophamine-β-hydrolaze potency, containing therapeutic effective volume of the compound of formula I, different variants of formula I compound application and intermediate compounds are described.

EFFECT: production of new compounds, imidazole derivatives having useful biological properties.

21 cl, 2 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzimidazol of the general formula I R1 designates phenyl group which unessentially contains up to three substitutors independently chosen of the group including F, Cl, Br, J, R4; R2 designates monocyclic or bicyclic 5-10-terms heteroaryl group which contains 1-2 heteroatoms, chosen of N, S and O; R3 designates H; R4 designatesC1-6alkyl; A designates C2-6 alkylene group; B designates group COOH, CONH2, CONHR5 or CONR5R5, in each case attached to atom of carbon of group A; R5 and R5 ' independently designate the residue chosen from group includingC1-6 alkyl where one C-atom can be replaced by O, and(C0-3 alkandiil-C3-7 cycloalkyl); and to their pharmaceutically acceptable salts, except for following compounds: 6 [[1-phenyl-2 (pyridine-4-il)-1H-benzimidazol-6-il] oxi] hexanic acid and 6 [[1-phenyl-2 (benzothien-2-il)-1H-benzimidazol-6-il] oxi] hexanic acid. The invention relates also to pharmaceuticals and to application of compounds of general formula I.

EFFECT: new biologically active compounds possess inhibiting effect on activation of microglia.

10 cl, 34 ex

FIELD: organic chemistry, medicine, pharmacy, chemical technology.

SUBSTANCE: invention relates to novel substituted esters of 1H-indol-3-carboxylic acids of the general formula (1): or their racemates, or their optical isomers, or their pharmaceutical acceptable salts and/or hydrates. Compounds can be used in treatment of such diseases as infectious hepatitis, human immunodeficiency, atypical pneumonia and avian influenza. In compound of the general formula (1) R1, R41 and R42 each represents independently of one another a substitute of amino group chosen from hydrogen atom, optionally linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and possibly an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 carbon atom in ring with one or some heteroatoms chosen from nitrogen oxygen or sulfur atoms; or R41 and R42 in common with nitrogen atom to which they are bound form 5-10-membered azaheterocycle or guanidyl through R41 and R42; R2 represents an alkyl substitute chosen from hydrogen atom, optionally substituted mercapto group, optionally substituted amino group, optionally substituted hydroxyl; R3 represents lower alkyl; R5 represents a substitute of cyclic system chosen from hydrogen atom, halogen atom, cyano group, optionally substituted aryl or optionally substituted and possibly an annelated heterocycle that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms. Also, invention relates to methods for treatment, drugs and pharmaceutical compositions using compounds of this invention.

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

22 cl, 3 tbl, 8 dwg, 6 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a compound of the formula (I): , wherein carbon atom designated as * is in (R)- or (S)-configuration; R1 represents (C1-C6)-alkyl; R2 represents hydrogen atom (H), (C1-C6)-alkyl or (C1-C6)-halogenalkyl; R3 represents H or halogen atom; R4 represents phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, isoxazolyl, pyrazolyl or pyrazinyl wherein R4 group is substituted optionally with 1-4 R14-substitutes; each among R5, R6 and R7 is chosen independently from the following group: H, halogen atom, -OR11, -CN, (C1-C4)-halogenalkyl or (C1-C6)-alkyl; or R5 and R6 taken in common can represent -O-C-(R12)2-O-; R8 represents H; R11 represents H or (C1-C4)-alkyl; R12 represents (C1-C4)-alkyl; R12 is chosen independently in each case from a substitute chosen from the following group: halogen atom, -OR11, -NR11R12, morpholinyl, (C1-C6)-alkyl and (C1-C4)-halogenalkyl, or its pharmaceutically acceptable salt or solvate. Also, invention describes a pharmaceutical composition used in blocking in reuptake of norepinephrine, dopamine and serotonin based on compounds of the formula (I). Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties, improved method of treatment.

39 cl, 2 tbl, 49 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to group of novel derivatives of 4,5-dihydro-1H-pyrazole and their stereoisomers that are strong antagonists of cannabinoid (CB1) receptors. These compounds are useful in treatment of some diseases associated with cannabinoid system disorders. Compounds have the general formula (I) wherein R represents phenyl or thienyl substituted with halogen atom, or R represents pyridyl; R1 represents phenyl that can be substituted with 1-2 substitutes chosen from halogen atom and trifluoromethyl group; R2 represents hydrogen atom; R3 represents hydrogen atom or branched or direct (C1-C4)-alkyl group; R4 represents branched or direct (C2-C4)-alkyl group that is substituted with hydroxy-, amino-, monoalkylamino-, dialkylamino-, methoxy-, acetoxy-, aminooxy-group or one fluorine atom, or R4 represents branched or direct (C1-C8)-alkoxy-group that can be substituted with amino-group, monoalkylamino-group or dialkylamino-group, or R4 represents (C4-C8)-nonaromatic heterocyclic or (C4-C8)-nonaromatic heterocycloalkyl-alkyl group that comprise 1-2 heteroatoms chosen from nitrogen (N) and oxygen (O) atom that can be substituted with (C1-C3)-alkyl group, or R4 represents hydroxy-group or imidazolylalkyl group or pyridylmethyl group; or if R represents hydrogen atom or methyl then R4 can represent group -NR6R7 wherein R6 represents hydrogen atom and R7 represents (C2-C4)-trifluoroalkyl; or R3 and R4 in common with nitrogen atom to which they are bound form saturated or unsaturated monocyclic or bicyclic heterocyclic group comprising 4-10 atoms in cycle that comprises 1-2 heteroatoms chosen from N and O, or group -SO2 wherein indicated group can be substituted with (C1-C4)-alkyl, hydroxy-group, hydroxyalkyl, pyridyl, amino-, monoalkylamino-, dialkylamino-group, monoalkylaminoalkyl, dialkylaminoalkyl or piperidyl group; R5 represents phenyl group substituted with 1-3 substitutes Y wherein Y represents halogen atom, trifluoromethyl group or (C1-C3)-alkyl, or R5 represents branched or direct (C1-C8)-alkyl. Also, invention relates to pharmaceutical compositions containing one or some these compounds as an active component.

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical compositions.

5 cl, 4 tbl, 92 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

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