Spirocyclic azaindole derivatives

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel spirocyclic azaindole derivatives of formula I: , where: one of A stands for N, and the other ones stand for CR7-10; W stands for NR4; X stands for O, S; R1 and R2, independently on each other stand for H; C1-5-alkyl each time saturated, branched or unbranched, non-substituted or monosubstituted with -OC1-6alkyl; phenyl, thienyl, morpholinyl, benzothiophenyl or benzodioxilyl, each time non-substituted or monosubstituted with F, C1-6alkyl; or 5-membered heteroaryl, containing three nitrogen atoms as heteroatoms, substituted with C1-3alkyl; bound with C1-3-alkyl group phenyl non-substituted or monosubstituted with F or C1-6alkyl; R4 stands for H; R5 stands for H; R6 stands for H; R7, R8, R9 and R10 stand for H or CP3; in form of siastereomers, mixtures of diastereomers or separate diastereomer; bases and/or salts of physiologically compatible acids. Compounds are suitable for treatment of a number of diseases, for instance, pain, stress, depressions, etc. Described is method of their obtaining.

EFFECT: compounds are suitable for treatment of a number of diseases, for instance, pain, stress, depressions.

11 cl; 1 tbl; 34 ex

 

The present invention relates to substituted spirocycles azaindole derivative, method of receipt, and medicines containing these compounds and to the use of substituted spiritlessly azaindole derivatives to obtain drugs.

Treatment of chronic and nechanicky pains for medicine is of great importance. Worldwide there is a need for well-functioning pain therapy. The urgent need for action to meet patients and targeted treatment of chronic and nechanicky pain States, and must be taken into account successful and satisfactory treatment of pain patients, documented in a large number of scientific papers that have appeared recently in the field of applied analgesics or fundamental studies of nociception.

Classical µ-opioids, such as morphine, in the treatment of strong and severe pain are well established and for pain therapy are of great importance, if along with the µ-opioid receptor is also affected by other opioid receptors, in particular the ORL-1 receptor, as pure μ-opioids also have undesirable side effects, such as constipation and respiratory depression, and can lead to addiction. Opioid prescriptions is ora δ, κ and ORL-1 are also involved in pain sensitivity (Opioids: Introduction, cc.127-150, Further Opioid Receptors, 455-476, in: Analgesics - From Chemistry and Pharmacology to Clinical Application, Wiley VCH, 2002).

In addition, ORL1-receptor else involved in the regulation of other physiological and pathophysiological processes. Here among other things include learning and memory formation (Manabe et al., Nature, 394, 1997, S.577-581), the ability to hear (Nishi et al., EMBO J. 16, 1997, S.1858-1864), as well as numerous other processes. In a review article Calo et al. (Br. J. Pharmacol., 129, 2000, 1261-1283) provides an overview of the indications or biological processes, for which the ORL1-receptor has a value or could have with high probability. In particular, mentioned: analgesia, stimulation and regulation of food intake, the effect on µ-agonists, such as morphine, treatment of the symptoms of the syndrome, decreased narcotic potential of opioids, anxiolysis, modulation of motor activity, memory disorders, epilepsy; modulation of neurotransmitter distribution, in particular glutamate, serotonin and dopamine, and together with this neurodegenerative disease; the impact of the cardiovascular system, the emergence of an erection, diuresis, antinutrient, electrolyte balance, arterial blood pressure, a disease associated with water retention, gastro-intestinal motility (diarrhoea), relaxing effects on the respiratory tract, moonis Skatertny reflex (urinary incontinence). Next is discussed the use of agonists and antagonists as anoretics, analgesics (also with a joint reception with opioids) or nootropics.

In the prior art (WO 04043967) known similar in structure to the compounds that have affinity for the ORL-1-receptor and to the µ-opioid receptor. However, in these compounds the aromatic heterocycle is an indole ring, in which one carbon atom may not be substituted by a nitrogen atom.

The present invention was to make available to other drugs which affect the system opioid receptor and thereby suitable for pharmaceuticals, particularly for the treatment of various related diseases, respectively, for use in directly related indications.

Therefore, an object of the invention are substituted spirocycles isoindoline derivatives of General formula I,

in which

A represents N or CR7-10moreover , And at least once and at most twice means N

W means NR4,

X is NR17, O or S,

R1and R2independently from each other signify H, C1-5-alkyl, each time a saturated or unsaturated, branched or unbranched, monogame the military, or politeley or unsubstituted; C3-8-cycloalkyl, every time monosubstituted or politeley or unsubstituted; or bound C1-3the alkyl aryl, C3-8-cycloalkyl or heteroaryl, every time monosubstituted or politeley or unsubstituted;

or the remains of R1and R2together mean CH2CH2OCH2CH2CH2CH2NR11CH2CH2or (CH2)3-6,

and R11means N; C1-5-alkyl, each time a saturated or unsaturated, branched or unbranched, monosubstituted, or politeley or unsubstituted; C3-8-cycloalkyl, every time monosubstituted or politeley or unsubstituted; aryl or heteroaryl, every time monosubstituted or politeley or unsubstituted; or bound C1-3the alkyl aryl, C3-8-cycloalkyl or heteroaryl, every time monosubstituted or politeley or unsubstituted; C(O)phenyl, C(O)heteroaryl, S(O)1-5-alkyl, each time a substituted or unsubstituted;

R3means C1-8-alkyl, each time a saturated or unsaturated, branched or unbranched, monosubstituted, or politeley or unsubstituted; C3-8-cycloalkyl, every time monosubstituted or politeley or unsubstituted; aryl or heteroaryl, every time unsubstituted, remorselessly, or politeley; associated C1-3is an alkyl group, aryl, heteroaryl or3-8-cycloalkyl, every time unsubstituted, or monosubstituted or politeley;

R4means N; C1-5-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or politeley; aryl or heteroaryl, every time a substituted or unsubstituted; associated C1-3is an alkyl group, aryl, heteroaryl or cycloalkyl, every time monosubstituted or politeley or unsubstituted; COR12; SO2R12,

and R12means N; C1-5-alkyl, each time a saturated or unsaturated, branched or unbranched, monosubstituted, or politeley or unsubstituted; C3-8-cycloalkyl, every time a saturated or unsaturated, monosubstituted, or politeley or unsubstituted; aryl or heteroaryl, every time monosubstituted or politeley or unsubstituted; or associated With1-3the alkyl aryl, C3-8-cycloalkyl or heteroaryl, every time monosubstituted or politeley or unsubstituted; OR13; NR14R15;

R5means =O; N; COOR13, CONR13, OR13; C1-5-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or politeley; 3-8-cycloalkyl, saturated or unsaturated, unsubstituted, or monosubstituted or politeley; aryl or heteroaryl, unsubstituted, or monosubstituted or politeley; or bound C1-3the alkyl aryl, C3-8-cycloalkyl or heteroaryl, unsubstituted, or monosubstituted or politeley;

R6means H, F, Cl, NO2, CF3, OR13, SR13, SO2R13, SO2OR13, CN, COOR13, NR14R15; C1-5-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or politeley; C3-8-cycloalkyl, saturated or unsaturated, unsubstituted, or monosubstituted or politeley; aryl or heteroaryl, unsubstituted, or monosubstituted or politeley; or bound C1-3the alkyl aryl, C3-8-cycloalkyl or heteroaryl, unsubstituted, or monosubstituted or politeley;

or R5and R6together imply (CH2)n with n = 2, 3, 4, 5 or 6, with individual hydrogen atoms can also be substituted by F, Cl, Br, I, NO2, CF3, OR13CN or C1-5-alkyl;

R7, R8, R9and R10independently from each other mean

H, F, Cl, Br, I, NO2, CF3, OR13, SR13, SO2R13, SO2OR13, CN, COOR13, NR14R15; C1-5 -alkyl, C3-8-cycloalkyl, unsubstituted, or monosubstituted or politeley; aryl or heteroaryl, unsubstituted, or monosubstituted or politeley; or associated With1-3the alkyl aryl, C3-8-cycloalkyl or heteroaryl, unsubstituted, or monosubstituted or politeley;

and R13means N; C1-5-alkyl, each time a saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or politeley; C3-8-cycloalkyl, every time a saturated or unsaturated, unsubstituted, or monosubstituted or politeley; aryl or heteroaryl, unsubstituted, or monosubstituted or politeley; or associated With1-3the alkyl aryl, C3-8-cycloalkyl or heteroaryl, unsubstituted, or monosubstituted or politeley;

R14and R15independently of one another denote H; C1-5-alkyl, each time a saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or politeley; or (C3-8-cycloalkyl, every time a saturated or unsaturated, unsubstituted, or monosubstituted or politeley; aryl or heteroaryl, unsubstituted, or monosubstituted or politeley; or bound C1-3the alkyl aryl, C3-8-cycloalkyl or heteroaryl, unsubstituted, or monosubstituted, Il is politeley;

or R14and R15together form CH2CH2OCH2CH2CH2CH2NR16CH2CH2or (CH2)3-6,

and R16means H, C1-5-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or politeley;

R17means N; C1-8-alkyl, saturated or unsaturated, branched or unbranched; COR12or SO2R12;

in the form of the racemate; of the enantiomers, of the diastereomers, mixtures of enantiomers or diastereomers or of an individual enantiomer or diastereoisomer; the bases and/or salts of physiologically compatible acids.

Compounds according to the invention show good binding to the µ-opioid receptor and the ORL-1-receptor.

The concepts of "C1-8-alkyl, C1-3-alkyl" and "C1-5-alkyl" in the sense of this invention comprise acyclic saturated or unsaturated hydrocarbon residues, which may be branched or straight-chain and unsubstituted or mono - or polyamidine, with from 1 to 8 or 1 to 3 C-atoms or 1-5 C-atoms, i.e. C1-8-alcalali,2-8alkenyl and C2-8-alkinyl or1-3-alcalali,2-3alkenyl and C2-3-alkinyl or C1-5-alcalali,2-5alkenyl and C2-5-alkinyl. At the same time, alkenyl have at least one C-C double bond and alkinyl at least one C-C triple bond. Mainly alkyl selected from the group which includes methyl, ethyl, n-propyl, 2-propyl, n-butyl, ISO-butyl, sec-butyl, tert-butyl, n-pentyl, out-of pentyl, neo-pentyl, n-hexyl, 2-hexyl, n-heptyl, n-octyl, 1,1,3,3-TETRAMETHYLBUTYL; ethylenic (vinyl), ethinyl, propinyl (-CH2CH=CH2, -CH=CH-CH3-C(=CH2)-CH3), PROPYNYL (-CH-C≡CH, -C≡C-CH3), butenyl, butynyl, pentenyl, pentenyl, hexenyl, hexenyl, heptenyl, heptenyl, octenyl and octenyl. Particularly advantageous methyl, ethyl, n-propyl, n-butyl, sec-butyl, ISO-butyl.

The expression "cycloalkyl" or "C3-8-cycloalkyl" means, for the purposes of this invention, cyclic hydrocarbons with 3, 4, 5, 6, 7 or 8 carbon atoms, and the hydrocarbon can be saturated or unsaturated (but not aromatic), unsubstituted or mono - or polyamideimide. As cycloalkyl, the term also includes saturated or unsaturated (but not aromatic) cycloalkyl, in which one or two carbon atom by a heteroatom S, N or O. the Preferred3-8-cycloalkyl from the group that contains cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctanol and tetrahydropyranyl, dioxane, dioxolane, morpholine is, piperidinyl, piperazinil, pyrazolinone and pyrrolidinyl. Particularly preferred cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The expression "aryl" means in the sense of this invention, aromatic hydrocarbons, in particular family and nattily. Akrilovye residues may also be condensed with other saturated, (partially) unsaturated or aromatic cyclic systems, so arrowy the remainder forms an aromatic cyclic system at most 20 C-atoms. Each of these6-20-arolovich residues can be unsubstituted or monosubstituted or polyamidine, and arrowie substituents may be the same or different and can be in any and possible position of the aryl. Preferably aryl is selected from the group containing phenyl, 1-naphthyl, 2-naphthyl, and each may be unsubstituted or mono - or polyamideimide. Particularly preferred phenyl residue.

The expression "heteroaryl" means a 5-, 6 - or 7-membered cyclic aromatic residue, which contains at least 1, optionally also 2, 3, 4 or 5 heteroatoms, where the heteroatoms are identical or different and the heterocycle may be unsubstituted or mono - or polyamidine; in the case of substitution of the heterocycle, the substituents may be the same or different and nd the change in and any possible position heteroaryl. The heterocycle can also be part of a bicyclic or polycyclic system in conjunction with up to 20 ring members. Preferred heteroatoms are nitrogen, oxygen and sulfur. Is preferred when heteroallyl residue selected from the group which contains pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothiazyl, benzothiadiazoles, benzothiazolyl, benzotriazolyl, benzodioxolyl, benzodioxane, phthalazine, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazoles, purinol, indolizinyl, chinoline, ethenolysis, hintline, carbazolyl, phenazines, phenothiazines, triazolyl or oxadiazolyl, and the binding to compounds of the General structure I can be any possible ring member of heteroanalogues balance. Preferred pyridyl, furyl, thienyl, indolyl, benzothiazyl, pyrrolyl, triazolyl and isoxazolyl, particularly preferably pyridyl, thienyl, sensational and triazolyl.

The expression "bound C1-3the alkyl aryl or heteroaryl" for the purposes of this invention means that C1-3-alkyl and aryl or heteroaryl have some higher values and arrowy or heteroallyl the remainder tied With1-3-alkyl group to the compound of General structure I. Especially predpochtite the flaxes in the sense of the invention, the benzyl and phenetyl.

In connection with "alkyl" or "cycloalkyl" the term "substituted" in the sense of the invention understand the substitution of the hydrogen of residue by F, Cl, Br, I, -CN, NH2, NH-C1-6-alkyl, NH-C1-6-alkyl-HE, N(C1-6-alkyl)2, N(C1-6-alkyl-OH)2, NO2, SH, S-C1-6-alkyl, S-benzyl, OCF3O-C1-6-alkyl, HE, O-C1-6-alkyl-HE, =O, C1-6-alkyl, benzyl, O-benzyl, O-phenyl, C(=O)1-6-alkyl, CO2H, CO2-C1-6-alkyl, and under polyamidine residues should be understood by those residues that are different or the same atoms are substituted several times, for example twice or three times, for example three times on the same C-atom, as in the case of CF3or-CH2CF3or in different places, as in the case of-CH(OH)-CH=CH-CHCl2. Multiple substitution can occur with the same or different substituent. Preferably, for the purposes of the present invention "monosubstituted or politeley" in connection with alkyl means replacement with SOON3The co3HE COOC2H5, F or Cl.

As for the "aryl" and "heteroaryl"in the sense of this invention under the "mono - or polyamidine" understand mono - or poly-, for example, twice, three times or four times, substitution of one or more hydrogen atoms of the cyclic system by F, Cl, Br, I, CN, NH2, NH-C1-6of alkyl, NH-C1-6-alkyl-HE, N(C1-6-alkyl), N(C1-6-alkyl-OH)2, NO2, SH, S-C1-6-alkyl, HE, O-C1-6-alkyl, O-C1-6-alkyl-HE, C(=O)1-6-alkyl,;CO2N, CO2-C1-6-alkyl, CF3, OCF3C1-6-alkyl; one or optionally different atoms (and Deputy if necessary on its part may be substituted). Multiple substitution happens with the same or different substituent. For "aryl" and "heteroaryl"while the preferred substituents are F, -Cl, -CF3, -O-CH3HE, methyl, ethyl, n-propyl, nitro, tert-butyl,and-CN. Especially preferred is-F and-Cl.

Under the notion of a salt formed with a physiologically compatible acid, in the sense of the invention understand salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, especially when used in humans and/or mammals. Preferred is the hydrochloride, citrate, polycitra and methansulfonate. Especially preferred methansulfonate. Examples of physiologically compatible acids are: hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonate acid is one formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, malic acid, maleic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-λ6-benzo[d]isothiazol-3-one (some saccharine acid), monomethylmercury acid, 5-oxo-Proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3 - or 4 - aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, α-lipanova acid, acetylglycine, hippuric acid, phosphoric acid and/or aspartic acid. Preferred citric acid, methanesulfonate acid and hydrochloric acid. Especially preferred methansulfonate acid.

Under the concept (CH2)3-6or (CH2)4-5it should be understood-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2and CH2-CH2-CH2-CH2-CH2-CH2- or-CH2-CH2-CH2-CH2- and-CH2-CH2-CH2-CH2-CH2-.

Preferred compounds of General formula I,

in which the residues A, W, X and R1-17have the above values,

and

above1-8-alkali,1-5-alkali,1-3-alkali or C1-3-alkylene or3-8-cycloalkyl OST the TCI every time can be mono - or polyamideimide with F, Cl, Br, I, CN, NH2, NH-C1-6-alkyl, NH-C1-6-alkyl-HE, N(C1-6-alkyl)2N(C1-6-alkyl-OH)2, NO2, SH, S-C1-6-alkyl, HE, O-C1-6-alkyl, O-C1-6-alkyl-HE, C(=O)1-6-alkyl, CO2H, CO2-C1-6-alkyl, CF3, OCF3C1-6-alkyl,

above akrilovye or heteroaryl remains each time can be mono - or polyamideimide with F, Cl, Br, I, CN, NH2, NH-C1-6-alkyl, NH-C1-6-alkyl-HE, N(C1-6-alkyl)2N(C1-6-alkyl-OH)2, NO2, SH, S-C1-6-alkyl, HE, O-C1-6-alkyl, O-C1-6-alkyl-HE, C(=O)1-6-alkyl, CO2H, CO2-C1-6-alkyl, CF3, OCF3With1-6-alkyl,;or phenoxy,

in the form of the racemate; of the enantiomers, of the diastereomers, mixtures of enantiomers or diastereomers or of an individual enantiomer or diastereoisomer; the bases and/or salts of physiologically compatible acids.

Further described as the preferred residues and groups respectively, the substituents in the compounds according to the invention can be combined with the widest meaning of other residues, as well as with the preferred values of other residues and groups respectively deputies.

My favorite form of exercise spirocycles of asand is selected derivatives according to the invention relates, that

R1and R2independently of one another denote H; C1-5-alkyl, saturated or unsaturated, branched or unbranched, monosubstituted, or politeley or unsubstituted;

or the remains of R1and R2together form a cycle and mean CH2CH2Och2CH2CH2CH2NR11CH2CH2or (CH2)3-6,

and R11means N; C1-5-alkyl, saturated or unsaturated, branched or unbranched, monosubstituted, or politeley or unsubstituted.

Especially preferred spirocycles isoindoline derivatives, in which R1and R2independently from each other mean of CH3or N, and R1and R2do not simultaneously denote H,

or R1and R2mean (CH2)3.

Very particularly preferred spirocycles isoindoline derivatives, in which R1and R2mean CH3

Further preferred spirocycles isoindoline derivatives, in which

R3means ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclopentyl, cyclohexyl, phenyl, benzyl, naphthyl, anthracene, thiophenyl, benzothiophene, furyl, benzofuranyl, benzodioxolyl, indolyl, indanyl, benzodioxane, pyrrolyl, pyridyl, pyrimidyl or pyrazinyl, each time not alseny, or monosubstituted or politeley; linked saturated, unbranched1-3is an alkyl group With5- or6-cycloalkyl, phenyl, naphthyl, anthracene, thiophenyl, benzothiophene, pyridyl, furyl, benzofuranyl, benzodioxolyl, indolyl, indanyl, benzodioxane, pyrrolyl, pyrimidyl, triazolyl or pyrazinyl, every time unsubstituted, or monosubstituted or politeley;

in particular

R3means propyl, butyl, pentyl, hexyl, phenyl, furyl, thiophenyl, naphthyl, benzyl, benzofuranyl, indolyl, indanyl, benzodioxane, benzodioxolyl, pyridyl, pyrimidyl, pyrazinyl, triazolyl or benzothiophene, every time unsubstituted, or monosubstituted or politeley; linked saturated, unbranched C1-3is an alkyl group, phenyl, furyl or thiophenyl, every time unsubstituted, or monosubstituted or politeley.

Especially preferred spirocycles isoindoline derivatives, in which R3means propyl, butyl, pentyl, hexyl, phenyl, phenethyl, thiophenyl, pyridyl, triazolyl, benzothiophene or benzyl, each time a substituted or unsubstituted, particularly preferably propyl, 3-methoxypropyl, butyl, pentyl, hexyl, phenyl, 3-were 3-forfinal, benzo[1,3]-dioxole, thienyl, benzothiophene, 4-Chlorobenzyl, benzyl, 3-Chlorobenzyl, 4-methylbenzyl, 2-Chlorobenzyl, 4-Forbes is l, 3-methylbenzyl, 2-methylbenzyl, 3-tormentil, 2-tormentil, 1-methyl-1,2,4-triazolyl or phenethyl.

Very particularly preferred spirocycles isoindoline derivatives, in which R3means butyl, ethyl, 3-methoxypropyl, benzothiophene, phenyl, 3-were 3-forfinal, benzo[1,3]-dioxole, benzyl, 1-methyl-1,2,4-triazolyl, thienyl or phenethyl.

R4predominantly means N.

In addition, the preferred spirocycles isoindoline derivatives, in which R5means H, C1-5-alkyl, branched or unbranched, unsubstituted or monosubstituted or polyamidine, or COOR13.

Especially preferred spirocycles isoindoline derivatives, in which R5means of CH3CH2OH, COOH or SOON3.

Very particularly preferred spirocycles isoindoline derivatives, in which R5means N.

Preferred also spirocycles isoindoline derivatives, in which R6means H, C1-5is alkyl, aryl or connected With1-3-alkyl aryl group.

Especially preferred spirocycles isoindoline derivatives, in which R6means H, CH3, phenyl or benzyl.

Very particularly preferred spirocycles isoindoline derivatives, in which R6means N.

From the above it is also preferred spirocycles isoindoline derivatives, in which R7, R8, R9and R10independently of one another denote H; methyl, ethyl, propyl, butyl; pyridyl, O-benzyl, F, Cl, Br, I, CF3HE co3, NH2, COOH, SOON3, NHCH3or N(CH3)2or NO2.

Especially preferred spirocycles isoindoline derivatives, in which R7, R8, R9and R10independently from each other denote H, F, HE, CH3, Cl, co3, Br or NO2.

Very particularly preferred spirocycles isoindoline derivatives, in which R7, R8, R9and R10mean N.

Preferred are also substituted isoindoline derivatives of General formula I, in which one means N and the rest of the remains And take the value of CR7-9or CR8-10or CR7and CR9-10or CR7-8and CR10.

Especially preferred compounds of General formulas Ia and Ib:

in which X, W, and the remains of R1-R10that in the widest definition is provided, and which is designated as the preferred definitions can take are described values.

Very particularly preferred substituted azaindole derived from the group

(1) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-Indo is)]

(2) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; methanesulfonate

(3) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)]

(4) 4-(dimethylamino)-4-thiophene-2-yl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; methanesulfonate

(5) 4-(dimethylamino)-4-thiophene-2-yl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)]

(6) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (4:3)

(7) 4-(methylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)

(8) 4-(methylamino)-4-thiophene-2-yl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (4:3)

(9) 4-(dimethylamino)-4-benzo[1,3-dioxol]-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (1:1)

(10) 4-(dimethylamino)-4-(benzothiophen-2-yl)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)

(12) 4-(dimethylamino)-4-(3-forfinal)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (4:3)

(13) 4-(dimethylamino)-4-(3-were)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)

(14) 4-(dimethylamino)-4-(buta-1-yl)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (1:1)

(15) 4-(dimethylamino)-4-phenylethyl-Spiro[cyclohexane-1,8'-(3-t is iformity-5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)

(17) 4-(dimethylamino)-4-ethyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (2:3)

(18) 4-(dimethylamino)-4-phenylethyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (2:3)

(19) 4-benzyl-4-morpholino-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)

(20) 4-(dimethylamino)-4-(3-methoxypropyl)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)

(21) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)

(22) 4-(dimethylamino)-4-thiophene-2-yl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)

(23) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)], citrate (1:1)

(24) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)], citrate (1:1)

(25) 4-butyl-4-(dimethylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)

(26) 4-butyl-4-(dimethylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (1:1)

(27) 4-benzyl-4-morpholino-Spiro[cyclohexane-1,8'-(3-trifluoromethyl-5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)

(28) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(3-trifluoromethyl-5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (1:1)

(29) 4-(azetidin-1-yl)-4-phenyl-Spiro[CEC shall Alexan-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (1:1)

(30) 4-butyl-4-(pyrrolidin-1-yl)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (2:1)

(31) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-thiopyrano[3,4-b]-7-Aza-indole)], citrate (1:1)

(32) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-thiopyrano[3,4-b]-5-Aza-indole)], citrate (1:1)

(33) 4-(1-methyl-1H-1,2,4-triazole-5-yl)-4-(methylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (1:1)

(34) 4-(1-methyl-1H-1,2,4-triazole-5-yl)-4-(methylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (1:1)

in the form of the racemate; of the enantiomers, of the diastereomers, mixtures of enantiomers or diastereomers or of an individual enantiomer or diastereoisomer; the bases and/or salts of physiologically compatible acids.

The substances according to the invention are, for example, is associated with various diseases relevant µ-opioid receptor, so they are suitable as a pharmaceutical active substance in the medicinal product. Therefore, another object of the invention is a medicinal product containing at least one spirocyclohexane azaindole derivative according to the invention and optionally suitable additives and/or auxiliary substances and/or optionally other active ingredients.

Drug is the means according to the invention along with, at least one spirocycles azaindole derivative according to the invention contain, optionally, suitable additives and/or excipients, such as carriers, fillers, solvents, diluents, dyes and/or binders, and can be used as liquid dosage forms in the form of injection solutions, drops or syrups, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters/spray plasters or aerosols. The choice of auxiliary substances etc. and they are used depend on whether the drug is used orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccal, rectally or topically, for example to the skin, mucous membranes or eyes. For oral administration suitable preparations in the form of tablets, pills, capsules, granules, drops, juices and syrups, for parenteral, local, and inhalation use suitable solutions, suspensions, easily recoverable dry preparations and sprays. Spirocycles azaindole derivatives according to the invention are suitable percutaneous compositions for use in the preparation of prolonged action, in dissolved form or in a plaster, when necessary, is Timoti with the addition means, promote penetration through the skin. Applied oral or dermal formulation can release slowly spirocycles azaindole derivatives according to the invention. Spirocycles azaindole derivatives according to the invention can also be used in parenteral forms of prolonged action, such as, for example, the implant or implant pumps. In principle to medicines according to the invention may be added other ingredients which are known to the person skilled in the technical field.

The number of entered patients of the active substance varies depending on the weight of the patient, route of administration, the indication and the severity of the disease. Usually used from 0,00005 to 50 mg/kg, preferably from 0.01 to 5 mg/kg of at least one spirocycles azaindole derivative according to the invention.

For all the above forms of medicines according to the invention is particularly preferred, if the medicinal product, together with at least one spirocycles isoindoline derivative contains one additional active substance, in particular opioid, mainly a strong opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane.

In p edocfile form of the medicinal product contained spirocyclohexane azaindole derivative according to the invention is in the form of a pure diastereoisomer and/or enantiomer, in the form of the racemate or in the form of requiredno or equimolar mixture of the diastereomers and/or enantiomers.

ORL-1 receptor and mu-opioid receptor in particular were identified in pain sensitivity. Accordingly spirocycles azaindole derivatives according to the invention can be applied to obtain drugs for the treatment of pain, in particular acute, neuropathic, chronic pain or inflammatory pain.

Therefore, another object of the invention is the use of spirocycles azaindole derivative according to the invention for obtaining a medicinal product for the treatment of pain, in particular acute, inner, neuropathic or chronic pain.

Another object of the invention is the use of spirocycles azaindole derivative according to the invention for obtaining a medicinal product for the treatment of States of fear, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, catalepsy, General cognitive dysfunctions, disorders of learning and memory (as nootrop), withdrawal symptoms, abuse and/or dependence of alcohol and/or drug and/or medication, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, Mihr is no, deafness, lack of bowel motility, impaired food intake, anorexia, obesity, locomotor disorders, diarrhoea, cachexia, urinary incontinence or as a muscle relaxant, anticonvulsive or anaesthetic or for co-admission for treatment with an opioid analgesic or with an anaesthetic, for diuresis or antinatriuretic, anxiolysis, for modulation of motor activity, for modulation of the distribution of neurotransmitters and treatment related neurodegenerative diseases, for the treatment of withdrawal symptoms and/or to reduce the narcotic potential of opioids.

In one of the above applications it may be preferable, if applicable spirocyclohexane azaindole derivative is in the form of a pure diastereoisomer and/or enantiomer, racemate or requiredno or equimolar mixture of the diastereomers and/or enantiomers.

Another object of the invention is a method of treatment, especially when one of the above indications, nonhuman mammal or human, to whom or which it is necessary to treat pain, in particular chronic pain, by introducing a therapeutically effective dose spirocycles azaindole derivative according to the invention or of a medicinal product according to the invention.

Another object of the invention which is a method of receiving according to the invention spirocycles azaindole derivative, as shown in the following description and examples.

In stage 1 compounds of the above General formula a in which X denotes a halogen residue or an ester of sulfonic acid, particularly preferably iodine, bromine or triftorbyenzola, the value of indole synthesis according to Larose subjected to interaction with alkynes of General formula II in the reaction medium, mostly selected from the group consisting of methanol, ethyl acetate, ethanol, isopropanol, n-butanol, dioxane, chloroform, dichloromethane, pyridine, dimethyl sulfoxide, toluene, tetrahydrofuran, dimethylformamide, acetonitrile, diethyl ether, water and corresponding mixtures, particularly preferably selected from the group consisting of of dimethylformamide, ethyl acetate, tetrahydrofuran, water and corresponding mixtures, mainly adding at least one palladium catalyst, predominantly selected from the group consisting of palladium dichloride(II), [PdCl2], acetate bis(triphenylphosphine)-palladium(II) [Pd(PPh3)2(OAc)2], chloride bis(triphenylphosphine)-palladium(II) [PdCl2(PPh3)2], palladium(II) acetate [Pd(OAc)2; Ac = acetate], chloride, bis(acetonitrile)-palladium(II) [(CH3CN2)PdCl2], chloride bis(benzonitrile)-palladium(II) [(PhCN)2PdCl2/sub> ] and tetrakis(triphenylphosphine)palladium [(PPh3)4Pd], particularly preferably selected from the group consisting of Pd(PPh3)2(OAc)2, (PPh3)4Pd and PdCl2(PPh3)2optionally in the presence of at least one phosphine, mainly one phosphine selected from the group consisting of triphenylphosphine, tri-(tert-butyl)-phosphine, triphenylarsine and tri-(ortho-toluyl)-phosphine, particularly preferably in the presence of triphenylphosphine, optionally with the addition of at least one inorganic salt, preferably with the addition of lithium chloride or tetrabutylammonium chloride, optionally with the addition of at least one inorganic bases, mostly selected from the group consisting of potassium carbonate, sodium carbonate, potassium acetate, sodium bicarbonate and cesium carbonate, and/or adding at least one organic base selected from the group consisting of triethylamine, Diisopropylamine, diisopropylethylamine and [1,4]-diazabicyclo-[2.2.2]octane at temperatures mainly from -70°C to 300°C., particularly preferably from -70°C to 150°C, to obtain the compounds of General formula III.

Compounds of General formula And are commercially available or known from the literature. For example, the syntheses obtain compounds of the General formula As described in the examples.

In stage 2 of the compounds of General formula III is subjected to interaction in the reaction medium, mostly selected from the group consisting of methanol, ethyl acetate, ethanol, isopropanol, n-butanol, dioxane, chloroform, dichloromethane, pyridine, dimethyl sulfoxide, toluene, tetrahydrofuran, dimethylformamide, acetonitrile, diethyl ether, water and corresponding mixtures, particularly preferably selected from the group consisting of acetonitrile, tetrahydrofuran, methanol, ethanol, ethyl acetate, pyridine, water and corresponding mixtures, in the presence of a fluoride selected from the group consisting of fluoride, Tetra-n-butylamine, hydrofluoric acid (HF, HF-pyridine), potassium fluoride and/or sodium fluoride, cesium fluoride, or in the presence of organic or inorganic acids, mainly HCl, acetic acid, triperoxonane acid, nortryptaline, at temperatures mainly from -70°C to 300°C., particularly preferably from -70°C to 150°C, to obtain the compounds of General formula IV.

To obtain spiritlessly compounds of General formula VIII ketones of General formula VII is subjected to interaction with heteroaromatic General formula IV with the addition of at least one organic acid or its complex trimethylsilyl ether, primarily selected from the group consisting the th of complex trimethylsilyl ether triftormetilfullerenov acid, triftormetilfullerenov acid, methanesulfonic acid, triperoxonane acid, acetic acid, phosphoric acid, p-toluensulfonate acid or one inorganic acid selected from the group consisting of nortryptaline, chloride, indium(III), titanium tetrachloride, aluminum chloride(III), or by adding at least one salt of a transition metal, mainly with the addition of at least one transition metal triflate (triftorbyenzola transition metal), particularly preferably with the addition of at least one triftoratsetata transition metal selected from the group consisting of triftoratsetata scandium(III), ytterbium triftoratsetata(III) and triftoratsetata India(III), in a suitable solvent or mixture of solvents, such as, for example, dichloromethane, dichloroethane, chloroform, acetonitrile, diethyl ether or nitroethane, at temperatures from 0 to 150°C., if necessary with the use of microwaves.

The synthesis of cyclohexanone derivatives with the General formula VII are known from the literature (WO 04043967, WO 0290317, US 4065573, Lednicer et al., J. Med. Chem., 23, 1980, 424-430).

Examples

The following examples serve for a detailed explanation of the invention but do not restrict the General inventive idea.

The outputs of the compounds obtained are not of optimizirovan the mi.

All temperatures are immutable.

Reduction

days.days
DHMdichloromethane
DMFN,N-dimethylformamide
A simple etherdiethyl ether
EtOAcethyl ester of acetic acid
H2Owater
Meonmethanol
NEt3the triethylamine
CTroom temperature
TBAFfluoride tetrabutylammonium
THFtetrahydrofuran
TMEDAN,N,N',N'-tetramethylethylenediamine
Approx.example

Microwave: Biotage Initiator, 2.45 GHz.

Ketone elementary links

General elementary links

8-Dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile:

Variations is t 1: 8-dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile

To a mixture of 4N hydrochloric acid (50 ml) and methanol (30 ml) was added under ice cooling to 40-percent. aqueous solution of dimethylamine (116 ml of 0.92 mol), cyclohexane-1,4-dione-monoethylether (30 g, 0,192 mol) and potassium cyanide (30 g, 0.46 mol). The mixture was stirred 74 h at room temperature and then, after addition of water (80 ml) was extracted with diethyl ether (4×100 ml). After concentration the residue resuspendable in dichloromethane (200 ml) and dried with magnesium sulfate overnight. The organic phase was concentrated and ketal received in the form of a white solid with a melting point of at 86-88°C with a yield of 97% (40 g).

Option 2: 8-dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile

To a mixture of 4N hydrochloric acid (50 ml) and methanol (30 ml) under ice cooling was added 40%. aqueous solution of dimethylamine (116 ml of 0.92 mol), cyclohexane-1,4-dione-monoethylether (30.0 g, 0,192 mol) and potassium cyanide (300 g, 0.46 mol). The mixture was stirred 72 h at room temperature and then, after addition of water (80 ml) was extracted with simple ether (4×100 ml). After concentrating the solution, the residue resuspendable in dichloromethane (200 ml) and magnesium sulfate during the night was dried. The organic phase was concentrated and got ketal in the form of a white solid.

Output: 38,9 g (96%).

Melting point: 86-88°C.

1H-NMR (DMSO-d6): 1.57 (2H, m); 1.72 (2H; m); 1.85 (2, m); 1.99 (2H, m); 2.25 (6H, s); 3.87 (4H, m).

13C-NMR (DMSO-d6): 30.02; 31.32; at 60.66; 63.77; 106.31; 118.40.

8-Methylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile

To a mixture of 4N hydrochloric acid (12.5 ml) and methanol (7.5 ml) was added under ice cooling to 40%aqueous solution of methylamine (29.0 ml, 0.23 mol), cyclohexane-1,4-dione-monoethylether (7.50 g, 0,048 mol) and potassium cyanide (7.50 g). The mixture was stirred for 7 days. at room temperature. After adding water (20 ml) were extracted by a simple ether (4×25 ml). After concentrating the solution, the residue resuspendable in dichloromethane (50 ml) and dried with MgSO4throughout the night. The organic phase was concentrated and got ketal in the form of oil, which was crystallinewas.

Output: 7,05 g (80%).

1H-NMR (DMSO-d6): 1.54 (2H, m); 1.71 (4H, m); 1.95 (2H, m); 2.30 (3H, d); 2.72 (1H, q); 3.86 (4H, s).

Elementary link Ket-1

Dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]Dec-8-yl)amine hydrochloride

To 1,82 M chloride solution vinylmania in THF (109 ml, 0,198 mol) under argon and cooled with ice for 15 min was added 8-dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile (21 g, 0.1 mol)dissolved in THF (210 ml), and then stirred 16 h at room temperature. For processing of the reaction mixture under ice cooling was added a saturated solution of ammonium chloride (150 ml) and was extracted with diethyl ether (3×100 ml). The organic phase in tracheal with water (100 ml) and saturated NaCl solution (100 ml) and concentrated. Remained yellow oil (25,2 g). The original product was dissolved in ethylmethylketone (280 ml) and cooled with ice was mixed with ClSiMe3(18.8 ml, 0.15 mol). After the duration of the reaction in 6 hours you can dedicate dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]Dec-8-yl)amine hydrochloride with a yield of 35 percent (10.5 g) as a white solid.

4-Dimethylamino-4-phenylcyclohexanone (Ket-1)

Dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]Dec-8-yl)amine hydrochloride (10.5 g, of 35.2 mmol) was dissolved in 7,5N hydrochloric acid (36 ml) and stirred for 96 h at room temperature. After over hydrolysis, the reaction mixture was extracted with diethyl ether (2×50 ml). The aqueous phase while cooling with ice podslushivaet using 5N sodium liquor was extracted with dichloromethane (3×50 ml) and concentrated. Thus, 4-dimethylamino-4-phenylcyclohexanone (Ket-1) may be allocated in the form of a yellow solid with a melting point in 104-108°C with a yield of 97% (7,4 g).

Elementary link Ket-2

Dimethyl-(8-thiophene-2-yl-1,4-dioxaspiro[4.5]Dec-8-yl)amine hydrochloride

2-Idioten (22.9 g, 109 mmol) was dissolved under argon in THF (80 ml) and for 30 min at 0°C was mixed with 2M chloride Isopropylamine (35,7 ml, 72 mmol) in THF. After the duration of the reaction 1 h at 3-5°C was added 8-dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile (10 g, or 47.6 mmol)dissolved in tetrahydrofuran (20 ml), and 20 h p is remedial at room temperature. The processing composition was carried out by adding a saturated solution of NH4Cl (85 ml) and extraction with diethyl ether (3×100 ml). The organic phase was shaken with water (50 ml) and saturated NaCl solution (50 ml) and concentrated. You could get a dark brown oil (21,3 g). The original product was dissolved in ethylmethylketone (140 ml) and mixed with ClSiMe3(9.1 ml, and 71.4 mmol). After the duration of the response at 6 h were isolated dimethyl-(8-thiophene-2-yl-1,4-dioxaspiro[4.5]Dec-8-yl)amine hydrochloride as a white crystalline compound with a yield of 60% (a total of 8.74 g).

4-Dimethylamino-4-thiophene-2-illlogical (Ket-2)

Dimethyl-(8-thiophene-2-yl-1,4-dioxaspiro[4.5]Dec-8-yl)amine hydrochloride (8,68 g, 28,6 h over hydrolysis, the reaction mixture was extracted with diethyl ether (2×50 ml). The aqueous phase was podslushivaet under ice cooling by means of 5N sodium liquor was extracted with dichloromethane (3×50 ml) and concentrated. Ket-2 were received, therefore, in the form of a yellow solid with a melting point of at 108-110°C with a yield of 89% (5,66 g).

Elementary link Ket-3

Complex of dimethyl ester of 4-cyano-4-phenylheptanoic acid

Phenylacetonitrile (11.7 g, 0.1 mol) and methyl acrylate (47 ml, 0.5 mol) were placed in tert-butanol (60 ml) and heated to boiling. Then the heating source was removed. Dissolved in tert-butanol (23 ml) and Triton B (Oh Ben is ultimatemenu, 40%. in methanol, 15.2 ml) was added dropwise slowly at first, then quickly. After addition of the composition was heated for 4 h in a flask with reflux condenser. Over night the reaction mixture was cooled to room temperature. For processing the composition was mixed with toluene (100 ml) and water (70 ml). The organic phase was separated and washed with water (1×70 ml) and saturated sodium chloride solution (1×50 ml). After drying with Na2SO4 the solvent because of the strong gas person to distil in the hood. Purification was carried out by distillation in the tube with ball extension at a pressure of 7.8×10-2 mbar and a temperature of 235°C. the Target complex dimethyl 4-cyano-4-phenylheptanoic acid can be highlighted with access to 21,45 g (72%) as a colourless viscous flow of the substance.

Methyl ester of 5-cyano-2-oxo-5-phenylcyclohexanecarboxylic acid

Complex of dimethyl ester of 4-cyano-4-phenylheptanoic acid (accounted for 14.45 g, 0.05 mol) was dissolved in dry tetrahydrofuran (350 ml). Then added in portions of tert-butyl sodium (9.6 g, 0.1 mol). With this addition the reaction mixture turned orange. After that, the composition was heated 5 h in a flask with reflux condenser. During boiling formed a viscous suspension beige color. Over night the reaction mixture was cooled to room temperature. When cooled, LDA is to the reaction mixture was slowly added dropwise 2,5N acetic acid (170 ml). Then the composition was mixed with toluene (100 ml). The organic phase was separated and washed with a saturated solution of sodium bicarbonate (3×70 ml), water (3×50 ml) and a solution of sodium chloride (1×70 ml). After drying with Na2SO4the solvent in the rotary evaporator apparatus chased off and the residue was recrystallized from methanol. The target product can be highlighted with the release of 10.7 g (83%) as a yellow solid with a melting point of at 75-80°C.

4-Cyano-4-phenylcyclohexanone

Methyl ester of 5-cyano-2-oxo-5-phenylcyclohexanecarboxylic acid (7,71 g, 0.03 mol) was dissolved in 10%. H2SO4and conc. acetic acid (240 ml). The reaction mixture was stirred 24 h at 100°C. Over the course of the reaction is observed with DC. For processing the composition with ice cooling was diluted with water (400 ml) and was extracted with ethyl acetate (3×100 ml). Then the organic phase is thoroughly washed with water (6×100 ml), saturated sodium hydrogen carbonate solution (10×100 ml) and saturated sodium chloride solution (1×100 ml). After drying with Na2SO4the solvent drove in a rotary evaporation apparatus. The target product can be highlighted with access to 5,46 g (92%) with a melting point of at 106-107°C.

8-Cyano-8-phenyl-1,4-dioxaspiro[4.5]Decan

4-Cyano-4-phenylcyclohexanone (5,97 g, 30 mmol) resuspendable in Tolu is Le (200 ml) and was mixed with ethylene glycol (4 ml, 71,6 mmol). After adding p-toluensulfonate acid (86 mg, 0.5 mmol) composition was heated to boiling in the water separator. The reaction was observed using DC chromatography. After 20 h in DC the original product is no longer detected. After cooling, the toluene solution was shaken with water (5×30 ml) and saturated aqueous NaC (3×20 ml) and dried over Na2SO4. After removal of the solvent in a rotary evaporation apparatus was the target ketal with yield 6.8 g (94%) as a white solid with a melting point of at 108-110°C.

8-Phenyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid

(Schneider, Woldemar; Krombholz, Gottfried; ARPMAS; Arch. Pharm. (Weinheim Ger.); 313; 6; 1980; 487-498)

8-Cyano-8-phenyl-1,4-dioxaspiro[4.5]decane (a 4.86 g, 20 mmol) was dissolved in ethylene glycol (40 ml)was mixed with NaOH (4 g, 100 mmol) and then in the flask with reflux condenser was heated to boiling. The reaction was observed with DC. After 20 h the nitrile was no longer detected. For processing the composition was mixed with ice (approx. 100 g)was layered simple ether (40 ml) and acidified by slowly adding policecontributing HCl (50 ml). The aqueous phase was extracted with simple ether (3×30 ml). The combined organic extracts were washed with saturated solution of NH4C- (2×30 ml), dried over Na2SO4and in a rotary evaporation apparatus was drained. By precrystallizer the obtained solid from toluene allocated target carboxylic acid in the form of a crystalline solid with a melting point in 134-139°C with a yield of 3.1 g (59%).

8-Isocyanato-8-phenyl-1,4-dioxaspiro[4.5]Decan

8-Phenyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (3 g, 11.5 mmol) were placed in anisole (30 ml). The resulting suspension in a bath of ice and salt was cooled to a temperature of 0°C and was mixed with triethylamine (2.25 ml, 16 mmol). Formed light solution, which was stirred for further 15 min at 0°C. Then the mixture for 5 min was mixed with azide diphenyl ether phosphoric acid (2.5 ml, 11.5 mmol). The reaction mixture was stirred 20 min at 0°C for another 20 min drove to CT and then was heated in an oil bath for 2 h to 100°C (bath temperature). For processing the anisole drove in a vacuum oil pump. Chromatographic purification was performed on silica gel with toluene. The target product was obtained as crystalline solid with a melting point of at 38-41°C to yield 2.7 g (91%).

Methyl-(8-phenyl-1,4-dioxaspiro[4.5]Dec-8-yl)Amin

LiAlH4(535 mg, 14,08 mmol) suspended under exclusion of humidity in dry THF (4 ml). 8-Isocyanato-8-phenyl-1,4-dioxaspiro[4.5]decane (to 2.29 g, 8,8 mmol, dissolved in 40 ml of dry THF) was added dropwise within 20 minutes After complete addition the reaction mixture for 4 h was heated in a flask under reflux to boiling. After cooling, the reaction mixture while cooling with ice was mixed at first, Ostara is but with aqueous THF (1 ml H 2O in 3 ml), then with 1.7 ml of 15%. sodium liquor and finally with 5 ml of H2O. the Composition was stirred 20 min and then filtered through silica gel. Obtained after repeated washing the filter cake with ethyl acetate solvent mixture was concentrated in a rotary evaporator apparatus to dryness. The target product was obtained with the yield 2.1 g (97%) as a viscous oil.

4-Methylamino-4-phenylcyclohexanone (Ket-3)

(Decision Upjohn Lednicer, US 4065573 A1, 1977)

Methyl-(8-phenyl-1,4-dioxaspiro[4.5]Dec-8-yl)amine (2.1 g, 8.4 mmol) was poured with a mixture of conc. HCl (15 ml) and water (8 ml) and stirred for 5 days at RT. For processing the reaction mixture was diluted with water (20 ml) and was extracted with simple ether (3×30 ml). The ether phase is averted. The aqueous phase was then podslushivaet using 2N NaOH and was extracted with dichloromethane (3×30 ml). Thus obtained organic phase was dried with Na2SO4and then concentrated in a rotary evaporator apparatus. The ketone Ket-3 can be obtained by chromatographic purification on silica gel with ethyl acetate/ethanol (4:1) to yield 1.38 g (81%) in the form of a solid substance with a melting point of at 32-38°C.

Elementary link Ket-4: 2-(chloromethyl)thiophene

Thiophene (50 g) was mixed with a solution of conc. HCl (25 ml) and the mixture was cooled to 0-5°C. Under constant HCl-gas stream was now added dropwise an aqueous solution formalize the IDA (54,8 ml, 40%) during the period of time in 4 h at 0-15°C. the Reaction mixture was stirred for 10 min at RT and then was mixed with ethyl acetate (500 ml). The organic phase was extracted with a saturated solution of NaHCO3(3×250 ml) and water (1×250 ml) and dried over Na2SO4. Distillation under vacuum at 100°C-110°C (oil bath temperature) gave (60°C temperature top) of the target product (8 mm Hg).

Yield: 24 g (30%), colorless oil.

2-(Thiophene-2-yl)acetonitrile

A solution of 2-(chloromethyl)thiophene (22 g) in DHM (60 ml) was mixed with a mixture of water (90 ml) and NaCN (12.2 g). The reaction mixture at 35-40°C for 18 h was heated under reflux. The mixture was cooled to CT and phase DHM separated. Were extracted using DHM (2×100 ml) and the combined organic phases were washed with saturated solution of NaCl and dried over Na2SO4. The solvents were removed under reduced pressure and the residue at 140-150°C (oil bath temperature) person to distil (temperature top: 115-120°C). Subsequent chromatographic purification (SiO2with 5% EtOAc/n-hexane) gave the desired product.

Yield: 9.2 grams (45%), light brown oil.

Ethyl 3-bromopropionate

A solution of ethyl acrylate (200 g) in a simple ether (400 ml) was cooled to 0-5°C. In a separate reaction vessel over a period of time of 3 h was added dropwise bromine (278 ml) tetraline (213 ml) and spin-off HB-gas is directed to the solution of the acrylate.

The reaction mixture was stirred for 12 hours a Simple ether was removed under reduced pressure and the residue at 70°C person to distil (9 mm Hg).

Output: 360 g (99%), colorless oil.

Ethyl 5-cyano-2-oxo-5-(thiophene-2-yl)cyclohexanecarboxylate

A solution of 2-(thiophene-2-yl)acetonitrile (10 g) in toluene (300 ml) was mixed with ethyl-3-bromopropionate cases (33.8 g) and the mixture was cooled to -10°C. NaNH2(27 g) was added in portions over a period of time of 1 h (the temperature was kept below 0°C). The reaction mixture was heated to CT and within 1 h was heated under reflux (111°C). Then the mixture was cooled to 0-5°C. and was mixed with Asón/water (50 ml/100 ml). Toluene phase was separated and the aqueous phase was extracted with toluene (3×200 ml). The combined organic extracts were washed with 5% solution of Na2CO3(1×150 ml) and water (1×00 ml) and dried over Na2SO4.

The solvent was removed under reduced pressure.

Yield: 12 g (55%), dark brown oil.

4-Cyano-4-(thiophene-2-yl)cyclohexanone

Ethyl 5-cyano-2-oxo-5-(thiophene-2-yl)cyclohexanecarboxylate (12 g) in acetic acid (120 ml) was mixed with conc. HCl (60 ml). The reaction mixture for 3 h was heated in a flask under reflux (110°C-120°C). The mixture was cooled to 0°C and a solution of 2N NaOH (200 ml), neutralized (pH 7). The aqueous phase was extracted with ethyl acetate (3×150 ml). Obyedinenie the e organic phase was washed with water (1×300 ml) and a saturated solution of NaHCO 3(1×300 ml) and dried over Na2SO4. The solvents were removed under reduced pressure and the residue was purified by column chromatography (SiO2, 15% EtOAc/n-hexane).

Yield: 37 g (43%), light yellow solid.

8-Cyano-8-(thiophene-2-yl)-1,4-dioxaspiro[4.5]Decan

A solution of 4-cyano-4-(thiophene-2-yl)cyclohexanone (15 g) in benzene (120 ml) was mixed with ethylene glycol (remaining 9.08 g) and p-toluensulfonate acid (0,0139 g) and the reaction mixture for 4 h at 110°C (instrumentation Dean-Stark) was boiled under reflux in a water separator. The reaction mixture was cooled to CT and the organic phase is washed with aqueous sodium bicarbonate solution (1×150 ml), water (1×150 ml) and saturated NaCl solution (1×150 ml). After drying over Na2SO4the solvents were removed under reduced pressure.

Yield: 16.5 g (90%), light yellow solid.

8-(Thiophene-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxylic acid

8-Cyano-8-(thiophene-2-yl)-1,4-dioxaspiro[4.5]decane (20 g) in ethylene glycol (240 ml) was mixed with KOH (22,48 g) and the reaction mixture is boiled under reflux for 16 h at 140-150°C. the Mixture was cooled to CT and then at 0-5°C was simple layered with ether (500 ml). Was added ice water (250 ml) and HCl (30 ml) and the pH of the aqueous phase adjusted to pH~2. The organic phase was separated, washed with water (1×300 ml) and saturated NaCl solution (1×300 ml) and dried on the Na 2SO4. The solvent was removed under reduced pressure.

Yield: 20.5 g (95%), yellow solid.

8-Isocyanato-8-(thiophene-2-yl)-1,4-dioxaspiro[4.5]Decan

To a solution of 8-(thiophene-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (26 g) in toluene (221 ml) was added TEA (14.1 ml) and DPPA (32,38 g) and the reaction mixture was heated for 30 min to 60-70°C. Then the toluene was removed under reduced pressure and the residue was purified by column chromatography (raw SiO2, 1. current: 10% EtOAc/n-hexane, 2. current: 10% EtOAc/hexane).

Yield: 14 g (54%), light green oil.

N-methyl-8-(thiophene-2-yl)-1,4-dioxaspiro[4.5]Decan-8-amine

8-Isocyanato-8-(thiophene-2-yl)-1,4-dioxaspiro[4.5]decane (4 g) was dissolved in dry THF (140 ml) and the solution was cooled to 0-10°C. LAH (4 g) was added in portions over a period of time of 30 min and the reaction mixture for a further 30 min was heated to 60°C. the Mixture was cooled to 0-10°C. and was mixed with a saturated solution of ammonium chloride (100 ml). Now, the mixture was filtered through celite and washed with ethyl acetate (3×150 ml). After removal of the solvents the crude product resuspendable in ethyl acetate (200 ml) and was stirred for 3 min at 0-10°C. an ethyl acetate phase was separated, the aqueous phase was podslushivaet a saturated solution of NaOH (pH~10-14) and was extracted with ethyl acetate (3×200 ml). The combined organic phase was dried over Na2SO4. The solvent UD is ranged under reduced pressure.

Yield: 7.5 g (56%), colorless solid.

4-Methylamino-4-thiophene-2-hallowicked (Ket-4)

N-methyl-8-(thiophene-2-yl)-1,4-dioxaspiro[4.5]Decan-8-amine (2 g, 7.9 mmol) was mixed with a mixture of conc. HCl (15 ml) and water (8 ml) and 5 days was stirred at RT. For processing the reaction mixture was diluted with water (30 ml) and was extracted with simple ether. The ether phase is averted. Then the aqueous phase was podslushivaet using 2N NaOH and was extracted with dichloromethane (3×30 ml). Thus obtained organic phase was dried by Na2SO4and then concentrated in a rotary evaporator apparatus. The residue was purified by column chromatography [silica gel 60 (50 g); 500 ml of ethyl acetate/ethanol (5:1)] and Ket-4 was obtained with the yield 1.4 g (85%) in the form of a solid substance with a melting point of at 72-74°C.

Elementary link Ket-5

(8-Benzo[1,3]dioxol-5-yl-1,4-dioxa-Spiro[4.5]Dec-8-yl)-dimethyl-amine hydrochloride

To a solution of 8-dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile (5,25 g, 25 mmol) in abs. THF (75 ml) under argon and cooled with ice for 15 min was added dropwise a solution of bromide 1M 3,4-(methylendioxy)vinylmania in toluene/THF (1:1) (62.5 ml, 62.5 mmol) at 5-10°C. and then at RT was stirred 20 hours For processing of the reaction mixture under ice cooling was added a 20%solution of ammonium chloride (20 ml) and water (25 ml) and the mixture was extracted with simple ether (3×50 m is). The organic phase is washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuum. Remained colorless oil (of 11.26 g)which was dissolved in ethylmethylketone (35 ml) and cooled with ice was mixed with trimethylchlorosilane and 4.75 ml, 37.5 mmol). Was stirred in an open flask 5 h at RT. In the sediment precipitated colorless solid, which was aspirated and air-dried.

Yield: 2.7 g (32%).

1H-NMR (DMSO-d6): 1.71 (2H, t); 1.72 (2H; d); 2.09 (2H, t); 2.43 (6H, s); 2.84 (2H, d); 3.82 (4H, m); 6.11 (2H, s); 7.07 (1H, d); 7.15 (1H, d); 7.32 (1H, s); 10.74 (1H, bs).

4-Benzo[1,3]dioxol-5-yl-4-dimethylamino-cyclohexanone (Ket-5)

(8-Benzo[1,3]dioxol-5-yl-1,4-dioxa-Spiro[4.5]Dec-8-yl)-dimethyl-amine hydrochloride (2.70 g, to $ 7.91 mmol) was mixed with 6N hydrochloric acid (10 ml) and stirred at RT over night. After over hydrolysis, the reaction mixture was extracted with simple ether (2×20 ml), aqueous solution with ice cooling was podslushivaet using 5N sodium liquor, the reaction mixture was extracted with dichloromethane (3×50 ml), the organic phase was dried over sodium sulfate and concentrated in vacuum.

Output (Ket-5): 1,99 g (96%), colorless crystals.

Melting point: 122-124°C.

1H-NMR (DMSO-d6): 2.01 (6H, s); 2.10 (4H, m); 2.43 (6H, m); 6.01 (2H, s); 6.88 (2H, m); 7.02 (1H, s).

13C-NMR (DMSO-d6): 32.39; at 36.68; 38.88; at 58.82; 100.76; 107.12; 107.67; 120.46; 131.34; 145.69; 147.03; 210.27.

Elementary link Ket-6

2-Iodine-benzo[b]thiophene

In a 500 ml three-neck flask was placed under argon atmosphere utility 1.6 m in hexane (112,5 ml, 180 mmol) and abs. simple ether (70 ml) and cooled in an ice bath to 0°C. Then benzothiophen (20,1 g, 150 mmol), dissolved in abs. simple ether (40 ml), and under ice cooling for 30 minutes was added dropwise and stirred for 2.5 h in an ice bath. The reaction composition was standing over night in the refrigerator. In a 500 ml three-neck flask under argon atmosphere was placed iodine (75,0 g) and abs. simple ether (50 ml) and was added dropwise a solution of compounds of lithium under ice cooling. The composition was slowly heated to room temperature, hydrolysable water, washed with sodium thiosulfate solution and the organic phase was dried over sodium sulfate. Then the reaction solution was concentrated in vacuo and purified using flash chromatography with cyclohexane.

Output: 24,1 g (62%), semi-solid, light-brown crystals.

1H-NMR (DMSO-d6): 7.32 (2H, m); 7.75 (1H, s); 7.81 (1H, m); 7.93 (1H, m).

(8-Benzo[b]thiophene-2-yl-1,4-dioxa-Spiro[4.5]Dec-8-yl)-dimethyl-amine hydrochloride

IB 100 ml three-neck flask were placed Mg (238 mg) in abs. simple ether (2 ml) under argon, there was slowly added dropwise 2-iodine-benzo[b]thiophene (of 2.51 g, 9.6 mmol) in abs. simple ether (8 ml). After adding abs. simple ether (10 ml) composition 5 hours boiling the or in the flask with reflux condenser. The reaction solution was cooled in an ice bath and 10°C was added dropwise 8-dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile (1,03 g, 4.9 mmol) in THF (10 ml). The composition was stirred at room temperature overnight, the reaction mixture was mixed under cooling with ice with a solution of NH4Cl (5 ml) and water (7 ml) and was extracted with simple ether (3×30 ml). Organic. phase washed with water (30 ml) and then saturated NaCl solution (20 ml), dried over Na2SO4and concentrated in vacuum.

Output: 1,99 g (66%).

The original product was dissolved in ethylmethylketone (19 ml), while cooling with ice mixed with trimethylchlorosilane (1,63 ml, 12.8 mmol) and stirred at room temperature for 5 hours the Resulting precipitate was aspirated and dried in vacuum.

Yield: 600 mg (35%).

1H-NMR (DMSO-d6): 1.46 (2H, m); 1.79 (2H, m); 2.37 (2H, m); 2.63 (6H, s); 2.75 (2H, m); 7.47 (2H, m); 7.91 (1H, s); 7.95 (1H, m); 8 06 (1H, m); 11.40 (1H, s).

13C-NMR (DMSO-d6): 30.43; 31.13; 37.84; 63.88; 66.42; 105.84; 122.48; 124.55; 124.89; 125.71; 128.99; 135.00; 138 91; 139 58.

4-Benzo[b]thiophene-2-yl-4-dimethylamino-cyclohexanone (Ket-6)

(8-Benzo[b]thiophene-2-yl-1,4-dioxa-Spiro[4.5]Dec-8-yl)-dimethyl-amine hydrochloride (0,60 g, 1.7 mmol) was dissolved in water (0.8 ml), was mixed with concentrated hydrochloric acid (1,04 ml, 151 mmol) and stirred 3 days. at room temperature. After over hydrolysis, the reaction mixture was extracted with diatrofi the ether (2×25 ml) and the aqueous phase was podslushivaet using 5N sodium lye, was extracted with dichloromethane (3×25 ml), dried over sodium sulfate and concentrated in vacuum.

Output (Ket-6): 0,44 g (95%).

1H-NMR (DMSO-d6): 2.19 (10H, m); 2.52 (4H, m); 7.35 (3H, m); 7.84 (1H, m); 7.91 (1H, m).

13C-NMR (DMSO-d6): 33.74; 36.51; 38.05; 58.60; 121.87; 121.94; 123.35; 124.02; 124.16; 138.19; 139.17; 144.28; 209.50.

Elementary link Ket-7

Option 1: [8(3-fluoro-phenyl)-1,4-dioxaspiro[4.5]Dec-8-yl]-dimethyl-amine hydrochloride

To a solution of 8-dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile (19,8 g, 94 mmol) in THF (100 ml) under argon and cooled with ice was added during 15 min bromide solution 0.5m 3-performane in THF (3,750 ml, 375 mmol) and then stirred 16 h at room temperature. For processing of the reaction mixture under ice cooling was added a saturated solution of ammonium chloride (150 ml) and water (60 ml) and was extracted with diethyl ether (3×100 ml). The organic phase was shaken with water (50 ml) and saturated NaCl solution (50 ml) and concentrated. Remained brown oil (26.5 g), which in addition to connecting phenyl 4 contained more ketal 2. The original product was dissolved in ethylmethylketone (156 ml) and cooled with ice was mixed with ClSiMe3(of 17.8 ml, 141 mmol). After the duration of the reaction in 6 hours you can dedicate hydrochloride with a yield of 55% (16.3 g) as a white solid with a melting point in 275-278°C.

Option 2: [8-(3-fluoro-phenyl)-1,4-dioxa-sleep is about[4.5]Dec-8-yl]-dimethyl-amine hydrochloride

A solution of 1-bromo-3-fervently (of 5.00 g, 28.6 mmol) in abs. simple ether (15 ml) was added dropwise to a suspension of magnesium (694 mg, 28.6 mmol) in abs. simple ether (10 ml) so that a simple ether was boiled. After the final addition was stirred 10 min at RT, then the magnesium was completely dissolved. The reaction solution was cooled in an ice bath and 10°C was added dropwise 8-dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile (3.00 g, and 14.3 mmol) in abs. THF (30 ml). The composition was stirred at room temperature overnight, the reaction mixture while cooling with ice was mixed with 20%solution of NH4Cl (20 ml) and water (30 ml) and was extracted with simple ether (3×50 ml). Organic. phase washed with water (50 ml) and then saturated NaCl solution (50 ml), dried over Na2SO4and concentrated in vacuum.

The original product was dissolved in ethylmethylketone (25 ml), while cooling with ice mixed with ClSiMe3(3.2 ml, 25 mmol) and stirred at room temperature for 5 hours the precipitate was filtered and dried in vacuum.

Yield: 2.8 g (62%).

1H-NMR (DMSO-d6): 1.91 (8H, m); 2.54 (6H, s); 3.91 (4H, d); 7.37 (1H, m); 7.61 (3H, m).

Option 1: 4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexanone (Ket-7)

[8-(3-Fluoro-phenyl)-1,4-dioxa-Spiro[4.5]Dec-8-yl]-dimethyl-amine hydrochloride (7.2 g, 22,75 mmol) was dissolved in water (9.6 ml), was mixed with concentrated with what Laney acid (14 ml, 455 mmol) and 4 days. was stirred at room temperature. After over hydrolysis, the reaction mixture was extracted with diethyl ether (2×50 ml), the aqueous phase while cooling with ice podslushivaet using 5N sodium liquor, and the product precipitated. The ketone Ket-7 may be allocated in the form of a yellow solid with a melting point of at 83-88°C and 50% (6,05 g).

Option 2: 4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexanone (Ket-7)

[8-(3-Fluoro-phenyl)-1,4-dioxa-Spiro[4.5]Dec-8-yl]-dimethyl-amine hydrochloride (2,80 g, 8,86 mmol) was dissolved in water (3,7 ml)was mixed with concentrated hydrochloric acid (5.5 ml) and stirred at RT 4 days. After over hydrolysis, the reaction mixture was extracted with simple ether (2×10 ml), aqueous solution with ice cooling was podslushivaet using 5N sodium liquor, the reaction mixture was extracted with dichloromethane (3×50 ml), the organic phase was dried over sodium sulfate and concentrated in vacuum. The original product was purified by flash chromatography with CHCl3/Meon (20:1).

Output (Ket-7): 676 mg (32%), colorless solid.

Melting point: 62-67°C.

1H-NMR (DMSO-d6): 2.02 (6H, s); 2.12 (5H, m); 2.45 (3H, m); 7.24 (3H, m); 7.43 (1H, m).

Elementary link Ket-8

Dimethyl-(8-m-tolyl-1,4-dioxa-Spiro[4.5]Dec-8-yl)-amine hydrochloride

In a 500 ml three-neck flask were placed 8-dimethylamino-1,4-dioxa-Spiro[4.5]Dec the n-8-carbonitrile (8,4 g, 40 mmol) in abs. THF (150 ml) under argon and cooled with ice. At 0°C for 15 min was added dropwise bromide m-talismania, 1M solution in THF (100 ml, 100 mmol). The reaction composition is then stirred 16 h at room temperature.

The composition when cooled with ice was mixed with a solution of ammonium chloride (20%, 37 ml) and water (50 ml) and simple ether (3×50 ml) was extracted.

The organic phase is washed with water (50 ml) and saturated NaCl solution, dried over sodium sulfate and concentrated in vacuum. The yield of the crude product was 11,25 g (brown oil).

The original product was dissolved in ethylmethylketone (60 ml) and at 0°C was mixed with trimethylchlorosilane (7,6 ml, 60 mmol). After 5 h of stirring at room temperature, precipitated in the sediment residue was pumped out and re-washed with a small amount of cold ethylmethylketone.

Output: 5,64 g (45%), white solid.

Melting point: 230-234°C.

1H-NMR (DMSO-d6): 1.19 (2H, t); 1.67 (2H; d); 2.13 (2H, t); 2.44 (9H, m); 2.89 (2H, d); 3.87 (4H, m); 7.43 (4H, m); at 10.82 (1H, bs).

4-Dimethylamino-4-m-tolyl-cyclohexanone (Ket-8)

Dimethyl-(8-m-tolyl-1,4-dioxa-Spiro[4.5]Dec-8-yl)-amine hydrochloride (2.76 g, 10 mmol) was dissolved in water (4,2 ml)was mixed with concentrated hydrochloric acid (6,15 ml) and 76 h was stirred at RT.

The solution was extracted with simple ether (2×25 ml), the ether phase is averted. To aqueous solution is about drops) was added 5N NaOH, while he was not alkaline. Then was extracted with dichloromethane (3×25 ml), the organic phase is again washed with water (25 ml), dried over Na2SO4and concentrated.

Output Ket-8: 1,69 g (73%), yellow oil.

1H-NMR (DMSO-d6): 2.05 (10H, m); 2.35 (3H, s); 2.52 (2H, m); 2.62 (2H, m); 7.12 (1H, m); 7.23 (3H, m).

Elementary link Ket-9

Option 1: (8-butyl-1,4-dioxa-Spiro[4.5]Dec-8-yl)-dimethyl-amine hydrochloride

8-Dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile (10.5 g, 50 mmol) were placed in THF (150 ml) under ice cooling and argon. Within 15 min was added dropwise chloride 2M butylamine in THF (62.5 ml, 125 mmol) and stirred 16 h at RT.

The composition when cooled with ice was mixed with 20%solution of ammonium chloride (37 ml) and water (50 ml) and was extracted with simple ether (3×50 ml). Organic. phase washed with water (1×50 ml) and saturated sodium chloride solution (1×50 ml), the organic phase was dried with Na2SO4and concentrated in vacuum. The original product (2,05 g) was dissolved in ethylmethylketone (75 ml), while cooling with ice mixed with ClSiMe3(9,5 ml, 75 mmol) and 6 h and stirred at RT. Fell into the residue white residue was pumped out and dried in vacuum.

Yield: 3.1 g (22%).

1H-NMR (DMSO-d6): 0.91 (3H, t); 1.31 (4H, m); 1.56 (2H, m); 1.75 (8H, m); 2.64 (6H, s); 3.87 (4H, s); 9.87 (1H, s).

Option 1: 4-butyl-4-dimethylamino-cyclohexanone (Ket-9)

8-Butyl-1,4-dioxa-Spiro[4.5]the EC-8-yl)-dimethyl-amine hydrochloride (3,10 g, 11.1 mmol) were placed in H2O (4,7 ml) and conc. HCl (7 ml) and 24 h was stirred at RT. The composition was extracted with simple ether (1×15 ml), the aqueous phase while cooling with ice podslushivaet using 5N NaOH and was extracted with dichloromethane (3×20 ml). Organic. phase was dried over Na2SO4and concentrated in vacuum.

Output: 1,96 g (89%), oil.

1H-NMR (DMSO-d6): 0.88 (3H, t); 1.23 (4H, m); 1.40 (2H, m); 1.68 (2H, m); 1.91 (2H, m); 2.31 (2H, m); 2.22 (6H, s); 2.42 (2H, m).

13C-NMR (DMSO-d6): 13.91; 23.21; 26.06; 29.53; 31.07; 37.04; 38.88; 55.36; 210.37.

Option 2: (8-butyl-1,4-dioxa-Spiro[4.5]Dec-8-yl)-dimethyl-amine hydrochloride

To a solution of 8-dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile (38,3 g of 0.182 mol) in abs. tetrahydrofuran (420 ml) under cooling with a mixture of ice and salt was slowly added under argon a solution of chloride 2M n-butylamine in THF (228 ml, 0,456 mol). The temperature of the reaction should not exceed 10°C. Then stirred 16 h at room temperature. Formed a brown transparent solution. For processing the reaction mixture was added dropwise while cooling with ice (0 to 10°C) saturated solution of ammonium chloride (150 ml). This formed a white solid, which was dissolved by adding water (about 250 ml). The reaction mixture was extracted with diethyl ether (4×100 ml). The organic phase is washed with water (100 ml) and neymann the m NaCl solution (100 ml), was dried and concentrated. Remained yellow oil (44,5 g), which also target butyl compounds contained also the original product nitrile. The original product was dissolved in ethylmethylketone (275 ml), while cooling with ice mixed with ClSiMe3(32 ml, 0,245 mol) and stirred in an open flask at room temperature. The hydrochloride was separated by repeated filtration with an interval of 2 hours After the duration of the reaction in the 6-8 hours it was possible to select (8-butyl-1,4-dioxa-Spiro[4.5]Dec-8-yl)-dimethyl-amine hydrochloride with a yield of 82% (41.8 g) as a white solid.

Option 2: 4-butyl-4-dimethylamino-cyclohexanone (Ket-9)

(8-Butyl-1,4-dioxa-Spiro[4.5]Dec-8-yl)-dimethyl-amine hydrochloride (41.8 g, 0.15 mmol) was dissolved with water (78 ml) and while stirring and cooling with ice was mixed with 37%. hydrochloric acid (100 ml, 1.2 mol). Transparent reaction solution was stirred for 7 days at room temperature. After over hydrolysis, the reaction mixture was extracted with diethyl ether (2×70 ml). The organic extracts were taken. The aqueous phase while cooling with ice podslushivaet through 5N sodium liquor (approximately 250 ml) and strongly stirred. The solution was extracted with diethyl ether (3×100 ml). The combined organic extracts were washed with water (2×70 ml), dried and concentrated. 4-Butyl-4-dimethylamino-cyclohexanone (et-9) was isolated as a light brown oil with a yield of 96% (28.4 g). The output of ketone - in the terms used in the first stage, ketal - amounted to 75%.

Elementary link Ket-10

Dimethyl-(8-phenethyl-1,4-dioxa-Spiro[4.5]Dec-8-yl)amine hydrochloride

To a solution of 8-dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile (39 g, 186 mmol) in THF (300 ml) was added under argon and with ice cooling for 15 min a solution of 1M chloride 2-phenylethylamine in THF (550 ml, 550 mmol) and then stirred 16 h at room temperature. For processing of the reaction mixture under ice cooling was added a saturated solution of ammonium chloride (295 ml) and water (120 ml) and was extracted with diethyl ether (3×150 ml). The organic phase is washed with water (100 ml) and saturated NaCl solution (100 ml) and then concentrated. Remained brown oil (60,4 g). The original product was dissolved in ethylmethylketone (310 ml) and cooled with ice was mixed with ClSiMe3(35,6 ml, 282 mmol). After 16 h at RT the resulting solid was aspirated and washed with ethylmethylketone.

Yield: 50 g (83%).

Melting point: 275-278°C.

Dimethylamino-4-fenetylline (Ket-10)

Dimethyl-(8-phenethyl-1,4-dioxa-Spiro[4.5]Dec-8-yl)amine hydrochloride (50 g, 154 mmol) was dissolved in water (60 ml)was mixed with concentrated hydrochloric acid (97,2 ml, and 3.16 mol) and 4 days. was stirred at room temperature. After over hydrolysis, the reaction mixture was extracted with di is tilov ether (2×100 ml) and the aqueous phase while cooling with ice podslushivaet using 5N sodium lye, and in the sediment precipitated solid, which was aspirated, washed with H2O (3×20 ml) and then dried.

Output Ket-10: 25,3 g (67%), yellow solid.

Melting point: 60°C.

Elementary link Ket-12

This is an elementary level received at the specified reaction conditions instead of the desired target product. It is obvious that (8-ethyl-1,4-dioxa-Spiro[4.5]Dec-8-yl)-dimethyl-amine hydrochloride purposefully can be obtained from the bromide of ateline and 8-dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile.

(8-Ethyl-1,4-dioxa-Spiro[4.5]Dec-8-yl)-dimethyl-amine hydrochloride

A mixture of ethylbromide (30.0 g, 0.3 mol) and 3-bromopyridin (16.0 g, 0.1 mol) was dropwise applied to magnesium powder (10.0 g) in diethyl ether (50 ml). After you have completed the formation of the Grignard reagent, gray solution at 0°C for 15 min was mixed with 8-dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile (10.5 g, or 47.6 mmol) in THF (80 ml) and the reaction solution was stirred over night at RT. Then the reaction solution while cooling with ice was mixed with 20%solution of ammonium chloride (50 ml) and water (50 ml). The reaction solution was diluted with diethyl ether (100 ml), organic. phase was separated and the aq. phase 2× were extracted using EtaO (100 ml). United organic. the phases were washed with water (50 ml) and NaCl solution (50 ml), dried over Na2SO4, fil is listed and the solvent was removed in vacuum. The remainder resuspendable in 2-butanone (200 ml) and at 0°C was mixed with Me3SiCl (10 ml). The reaction solution 5 h was mixed with humidity and loose precipitated solid substance was sucked out.

Yield: 6.8 g (64%)of light brown solid.

1H-NMR (DMSO-d6): 0.94 (3H, t); 1.51-1.60 (2H, m); 1.77-1.86 (8H, m); 2.64 (6H, 2 s); 3.83-3.89 (4H, m).

4-Dimethylamino-4-ethyl-cyclohexanone (Ket-12)

(8-Ethyl-1,4-dioxa-Spiro[4.5]Dec-8-yl)-dimethyl-amine hydrochloride in (6.67 g, was 0.026 mmol) was dissolved in 6N HCl (40 ml) and stirred at room temperature overnight. The reaction mixture was twice extracted with diethyl ether (100 ml). Then, with ice cooling was podslushivaet using 5N NaOH and again three times were extracted with Et20 (100 ml). United organic. the phases were dried over NaSO4was filtered and the solvent was removed in vacuum.

Output: 4,16 g (92%), brown oil.

1H-NMR (DMSO-d6): 0.81 (3H, t); 1.43-1.50 (2H, q); 1.67-1.89 (2H, m); 1.83-1.89 (2H, m); 1.99-2.06 (2H, m); 2.22 (6H, 2 s); 2.39-2.43 (4H, m).

13C-NMR (DMSO-d6): 8.71; 21.99; 30.41; 36.17; at 37.07; at 38.66; 55.53; 210.57.

Elementary link Ket-13

4-(8-Benzyl-1,4-dioxaspiro[4.5]Dec-8-yl)morpholine

In a heated flask was heated solution of the research (958 mg, of 0.96 ml, 11 mmol), 1,4-dioxaspiro[4.5]Dec-8-he (1.56 g, 10 mmol) and 1,2,3-triazole (829 mg, 12 mmol) in toluene (10 ml) for 6 h was boiled in a water separator under reflux. Then the solution for the argon was added dropwise to a 2M solution of chloride benzylamine in tetrahydrofuran (20 ml, 40 mmol) in such a way that the internal temperature remained below 24°C. the Mixture was stirred 2 h at room temperature and then upon cooling, ice water was added dropwise to a 20% solution of ammonium chloride (25 ml). The organic phase was separated and the aqueous phase was extracted with diethyl ether (3×20 ml). The combined organic phases were washed with 2N sodium liquor (40 ml) and water (40 ml), dried with sodium sulfate and concentrated in vacuum. The original product (4 g) was purified by flash chromatography (400 g, 20×7.5 cm) with ethyl acetate/cyclohexane (1:3).

Output: 2,87 g (90%), white crystals.

Melting point: 97-101°C.

1H-NMR (CDCl3): 1.35-1.52 (m, 4H); 1.72-1.96 (m, 4H); 2.61-2.66 (m, 4H); 2.67 (s, 2H); 3.68-3.75 (m, 4H); 3.78-3.92 (m, 4H); 7.08-7.34 (m, 5H).

4-Benzyl-4-morpholine-4-illlogical (Ket-13)

To a solution of 4-(8-benzyl-1,4-dioxaspiro[4.5]Dec-8-yl)research (1,00 g and 3.15 mmol) in acetone (5 ml) was added 6M hydrochloric acid (5 ml). After 24 h the reaction solution was mixed with an additional 6M hydrochloric acid (2.5 ml), stirred for 3 days. at room temperature, then was podlachian (pH~9) with 25% potassium carbonate solution and was extracted with diethyl ether (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated in vacuum.

Output: 753 mg (87%), white solid (Ket-13).

Melting point: 124-127°is.

1H-NMR (CDCl3): 1.47-1.72 (m, 2H); 1.98-2.14 (m, 4H); 2.48-2.68 (m, 2H); 2.70-2.77 (m, 2H); 2.78 (s, 4H); 3.72-3.81 (s, 4H); 7.12-7.36 (m, 5H).

Elementary link Ket-14

1-Chloro-3-methoxy-propane

(Letsinger; Schnizer; J. Org. Chem.; 16; 1951; 704, 706)

3-Methoxypropan-1-ol (47,1 g, 50 ml, 0,523 mol) was dissolved in pyridine (41,3 g of 42.6 ml, 0,523 mol), cooled to 10°C and at 10-30°C under strong stirring dropwise was mixed with thionyl chloride (93,3 g, 56,9 ml, 0,784 mol). In the sediment precipitated solid residue, then the mixture was stirred 3 h at 65°C.

The composition was poured into a mixture of ice (130 g) and conc. HCl (26 ml). The aqueous solution was extracted with simple ether (2×20 ml) and the combined organic phases were washed with a solution of K2CO3. Adding a drying agent K2CO3showed a strong leg, so the solution was left to settle overnight.

The drying agent was filtered and the organic phase is washed with a solution of K2CO3until an alkaline reaction. The organic phase was separated, washed with water and dried over K2CO3was filtered and person to distil at normal pressure.

Boiling point: 113°C.

Output: 41,2 g (72%), colorless liquid.

1H-NMR (DMSO-d6): 1.93 (2H, m); 3.23 (3H, s); 3.44 (2H, t); 3.66 (2H, t).

[8-(3-Methoxy-propyl)-1,4-dioxa-Spiro[4.5]Dec-8-yl]-dimethyl-amine

Magnesium (10.0 g, 92 mmol) and (I2in the abs. diethyl ether (30 ml) boatmasters argon and when temporary heat was mixed dropwise with a solution of 1-chloro-3-methoxy-propane (10.0 g, 92 mmol) in abs. simple ether (15 ml). Then the composition boiling under reflux was stirred 60 min, after that magnesium was not completely dissolved.

Under ice cooling was added dropwise a solution of 8-dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile (9,68 g, 46 mmol) in abs. THF (30 ml). In the sediment fell viscous residue, for better mixing was added 100 ml of abs. THF. The mixture was stirred at room temperature for 24 hours

The composition when cooled with ice was mixed with 20%solution of NH4Cl (100 ml) and water (120 ml), the organic phase was separated and the aqueous phase was extracted with simple ether (3×120 ml).

The combined organic phases were washed with saturated NaCl solution (120 ml) and water (120 ml), dried over Na2SO4and concentrated in vacuum. Crude yield was 10.8 g of brown oil.

of 9.8 g of the crude product was purified using flash chromatography with CHCl3/Meon

Output: 8,11 g (75%), yellow oil.

1H-NMR (DMSO-d6): 1.44 (8H. m); 1.62 (4H, m); 2.25 (6H, s); 3.21 (3H, s); 3.31 (2H, m); 3.82 (4H, s).

13C-NMR (DMSO-d6): 23.99; 26.52; 28.87; 29.88; 36.97; 55.24; 57.67; 63.40; 72.62; 108.07.

4-Dimethylamino-4-(3-methoxy-propyl)-cyclohexanone (Ket-14)

[8-(3-Methoxy-propyl)-1,4-dioxa-Spiro[4.5]Dec-8-yl]-dimethyl-amine (8,11 g of 31.5 mmol) was dissolved in water (12 ml)under ice cooling, the mixture is Vali with conc. HCl (19,5 ml) and 3 days. was stirred at room temperature. The reaction mixture was washed with a simple ether (2×75 ml). Then the solution was podslushivaet using 5N NaOH and was extracted with dichloromethane (3×75 ml). The combined organic phases were washed with water (75 ml), dried over Na2SO4was filtered and the solvent was removed in vacuum.

Output: 6,03 g (90%), yellow oil.

1H-NMR (DMSO-d6): 1.44 (4H, m); 1.68 (2H; m); 1.88 (2H, m); 2.00 (1H, m); 2.05 (1H, m); 2.20 (6H, s); 2.41 (2H, m); 3.22 (3H, s); 3.28 (2H, m).

13C-NMR (DMSO-d6): 24.01; 26.34; 30.88; 36.15; 37.06; 55.26; 57.70; 72.55; 210.39.

Elementary link Ket-15

8-Azetidin-1-yl-1,4-dioxaspiro[4.5]decane-8-carbonitrile

To a mixture of 4N hydrochloric acid (8.1 ml), methanol (4.9 ml) and azetidine (8.5 g, 10 ml, 149 mmol) was applied while cooling with ice first, 1,4-dioxaspiro[4.5]decane-8-he (4,84 g, 31 mmol) and then potassium cyanide (4,85 g of 74.4 mmol) in water (15 ml). The mixture was stirred 5 days. at room temperature, then mixed with water (50 ml) and was extracted with diethyl ether (3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated in vacuum.

Output: 6,77 g (98%), oil.

1H-NMR (DMSO-d6): 1.45-1.63 (m, 4H); 1.67-1.82 (m, 4H); 1.99 (q, 2H, J=7.1 Hz); 3.21 (t, 4H, J=7.1 Hz); 3.86 (s, 4H).

1-(8-Phenyl-1,4-dioxaspiro[4.5]Dec-8-yl)azetidin

2M solution of chloride vinylmania in tetrahydrofuran (12 ml, 24 mmol) under argon and cooled with ice what about the drops were mixed with the solution just obtained nitrile (2.20 g, 9.9 mmol) in anhydrous tetrahydrofuran (25 ml) and then stirred at room temperature overnight. After adding a saturated solution of ammonium chloride (5 ml) and water (5 ml), the phases were separated and the aqueous was extracted with diethyl ether (3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated in vacuum. The original product was purified by flash chromatography (100 g, 20×4.0 cm) with ethyl acetate/cyclohexane (1:1).

Yield: 670 mg (25%), colorless oil.

1H-NMR (DMSO-d6): 1.27-1.40 (m, 2H); 1.55-2.00 (m, 8H); 2.86 (t, 4H, J=6.8 Hz); 3.76-3.89 (m, 4H); 7.24-7.45 (m, 5H).

4-Azetidin-1-yl-4-phenylcyclohexanone (Ket-15)

The solution just obtained acetal (370 mg, 1.3 mmol) in acetone (30 ml) was mixed with 6N hydrochloric acid (2 ml) and during the night was stirred at room temperature. By adding 5N sodium liquor was set to pH 10 and the aqueous phase was extracted with dichloromethane (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated in vacuum.

Output: 274 mg (92%), white solid (Ket-15).

Melting point: not determined.

1H-NMR (DMSO-d6): 1.67 (td, 2H, J=13.8, 6.9 Hz); 1.95-2.13 (m, 4H); 2.20-2.33 (m, 2H); 2.40-2.47 (m, 1H); 2.52-2.57 (m, 1H); 2.94 (t, 4H, J=6.9 Hz); 7.28-7.47 (m, 5H).

Elementary link Ket-16

1-(8-Pyrrolidin-1-yl-1,4-dioxaspiro[4.5]Dec-8-yl)-1H-[1,2,3]triazole

To a solution of 1,4 dioxaspiro[4.5]d is the Kahn-8-it (3,9 g, 25 mmol) in toluene (40 ml) was applied pyrrolidin (1,95 g to 2.29 ml, 27.5 mmol), 1,2,3-triazole (2,07 g, 30 mmol) and molecular sieve 4 Å (7,14 g). The mixture was stirred 7 h at 90°C. Then a solution decantation and immediately subjected to further interaction.

1-(8-Butyl-1,4-dioxaspiro[4.5]Dec-8-yl)pyrrolidin

To a 2M solution of chloride of n-butylamine (25 ml, 50 mmol) in tetrahydrofuran under ice cooling and argon was added dropwise to the reaction solution just derived triazole (approx. 6,9 g, 25 mmol) in toluene (38 ml). The reaction mixture was stirred over night at room temperature and then was poured into a saturated solution of ammonium chloride (60 ml). The phases were separated and the aqueous was extracted with diethyl ether (3×70 ml). The combined organic phases were dried with sodium sulfate, concentrated in vacuum and the residue (12 g) was purified by flash chromatography (400 g, 20×7.6 cm) with ethyl acetate/methanol (9,1).

Output: 2.70 g (40% in two stages), brown oil.

1H-NMR (DMSO-d6): 0.87 (t, 3H, J=7.1 Hz); 1.12-1.29 (m, 4H); 1.30-1.45 (m, 4H); 1.46-1.60 (m, 4H); 1.61-1.75 (m, 6N); 1.93 (t, 1H, J=7.1 Hz); 2.36 (t, 1H, J=7.0 Hz), 2.58 (br s, 2H), 3.83 (s, 4H).

4-Butyl-4-pyrrolidin-1-yl-cyclohexanone (Ket-16)

The solution just obtained acetal (2.70 g, 10.1 mmol) in acetone (100 ml) was mixed with water (10.0 ml) and 37% hydrochloric acid (14,0 ml) and was stirred over night at room temperature. Satem mixture was slowly added dropwise 4M sodium lye, when pH is not reached 10. The mixture was extracted with diethyl ether (4×40 ml), the combined organic phases were dried with sodium sulfate and concentrated in vacuum. The original product (2.6 g) was purified by flash chromatography (260 g, 30×5.6 cm) with ethyl acetate/methanol (9,1).

Yield: 1.06 g (47%), brown oil (Ket-16).

1H-NMR (DMSO-d6): to 0.88 (t, 3H, J=6.7 Hz); 1.14-1.34 (m, 4H); 1.40-1.50 (m, 2H); 1.62-1.88 (m, 8H); 2.04 (dt, 2H, J=15.0, 3.9 Hz); 2.42 (ddd, 2H, J=6.3, 11.8, 15.5 Hz); 2.63 (t, 4H, J=6.0 Hz).

Elementary link Ket-17

Methyl-[8-(2-methyl-2H-[1,2,4]triazole-3-yl)-1,4-dioxa-Spiro[4.5]Dec-8-yl]-amine

Under argon atmosphere was placed utility (2.5m in hexane, and 9.2 ml, 23,0 mmol) and was cooled to -78°C. 1-Methyl-1,2,4-triazole (1,30 ml, 23 mmol) was dissolved in abs. tetrahydrofuran (60,0 ml) and added dropwise with ice cooling at -78°C. Then, at this temperature, was stirred 10 min. To this solution was rapidly added dropwise 8-methylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile (2,12 g to 10.8 mmol) in abs. tetrahydrofuran (15 ml) in a bath of coolant mixture at -78°C. After addition, the reaction solution of 1 h was stirred in a bath of cooling the mixture and then slowly heated to 0°C. At room temperature the reaction mixture was stirred over night. Then hydrolytically at 0°C. water (10 ml), the aqueous phase was extracted with chloroform (3×50 ml), the organic phase is washed with water (50 ml) and neymann the m NaCl solution (50 ml), dried over Na2SO4and concentrated in vacuum.

The product was purified using flash chromatography with chloroform/methanol (15:1).

Output: 1,93 g (71%).

1H-NMR (DMSO-d6): 1.54 (2H, m); 1.72 (2H, m); 1.91 (5H, m); 2.10 (2H, m); 3.84 (4H, m); 4.01 (3H, s); 7.74 (1H, s).

4-Methylamino-4-(2-methyl-2H-[1,2,4]triazole-3-yl)-cyclohexanone (Ket-17)

Methyl-[8-(2-methyl-2H-[1,2,4]triazole-3-yl)-1,4-dioxaspiro[4.5]Dec-8-yl]-amine (4,2 g, 16,646 mmol) at room temperature was mixed with 5%. sulfuric acid (330 ml) and 3 days. was stirred at room temperature. The reaction composition was mixed with simple ether (120 ml). The phases were separated. The aqueous phase was podslushivaet using 5N NaOH and was extracted with dichloromethane (4×50 ml). The organic phase was dried over sodium sulfate and concentrated in vacuum to dryness. The product was obtained as a colorless crystalline solid with a yield of 83% (2,89 g 13,862 mmol).

Indole elementary links

Synthesis of elementary links

Syntheses of iodopyridine known from the literature and presented by autometallography relevant protected by pivaloyl of aminopyridines in the three-step sequence: J.A.Turner, J.Org. Chem. 1983, 48, 3401; L.Estel, F.Marsais, G.Quéguiner, J.Org. Chem. 1988, 53, 2740; J. Malm, W. Rehn, A.-B.Hörnfeldt, S.Gronowitz, J.Het. Chem. 1994, 31, 11.

Synthesis of 4-(triethylsilyl)but-3-in-1-ol is described in the literary sources is the framework and is similar to the following guidelines: ..Bishop, I.F.Cottrell, D.Hands Synthesis, 1997, 1315; .Cheng, D.R.Lieberman, R.D.Larsen, R.A.Reamer, T.R.Verhoeven, P.J.Reider Tet. Lett., 1994, 6981.

Astrobiology obtained by heterointerface the finish line (Larock) with palladium as a mediator, triethylsilyl protected precursors known from literary sources: F.Ujjainwalla, D.Warner Tet. Lett., 1998, 5355.

General elementary links

Triethyl(4-(triethylsilyl)but-3-enyloxy)silane

3-buten-1-ol (34,99 g, 0.50 mol) was dissolved in THF (1,2 I) under nitrogen and cooled to -30°C. To this solution was added dropwise within 15 min n-BuLi (640 ml of 1.02 mol, 1.6 m solution in n-hexane) in such a way that the temperature did not exceed -20°C. After 1 h at -20°C was added dropwise a solution of triethylchlorosilane (171,4 ml of 1.02 mol) in THF (300 ml) for 30 minutes the Bath of cooling the mixture was removed and the reaction solution was stirred for 15 h at RT. While cooling in an ice bath, the reaction mixture was rapidly cooled aqueous solution of Na2CO3(1%) and were extracted with hexane (2×500 ml). The combined organic phases were washed with saturated NaCl solution (300 ml) and dried over MgSO4. After filtering the drying agent, the solvent was removed in a rotary evaporator apparatus and the residue was purified by distillation (p=0.05 mbar, the temperature of top = 115-110°C) and received triethyl(4-(triethylsilyl)but-3-enyloxy)silane (88.9 g, 60%).

4-(Triethylsilyl)but-3-in-1-ol

Triethyl(4-(treat lilil)but-3-enyloxy)silane (32,99 g, 110,66 mmol) was dissolved in Meon (336 ml)was mixed with 2N HCl (62 ml) and the mixture of 4 h was stirred at RT. Then to the solution was added hexane (250 ml) and H2O (200 ml) and the aqueous phase was extracted with hexane (3×100 ml). The combined organic phases were washed by H2O (100 ml) and then saturated NaCl solution (50 ml) and dried over MgSO4. After filtering the drying agent, the solvent was removed in a rotary evaporator apparatus. Column chromatography of the residue (hexane/simple ether = 4:1, then a simple ether) gave 4-(triethylsilyl)but-3-in-1-ol (19.6 g, 96%) as a colourless oil.

Elementary link Ind-1

N-(pyridine-2-yl)pivalate

Under nitrogen resuspendable 2-aminopyridine (25,00 g, 265,6 mmol) in DHM (425 ml) and mixed with the NEt3(46,00 ml, 332 mmol) the Solution was cooled to -5°C., dropwise mixed with a solution of trimethylacetylchloride (35,95 ml, 292,20 mmol) in DHM (50 ml) and was stirred an additional 15 min at -5°C. Then the mixture was stirred 2 h at RT. The suspension was washed with H2O (200 ml), then diluted aqueous NaHCO3and the organic phase was dried over MgSO4. After filtration of the drying agent and removal of the solvent in a rotary evaporator apparatus residue (48,30 g) was recrystallized from hexane (100 ml) at boiling. Received N-(pyridin-2-yl)pivalate (42,80 g, 91%) as colorless crystals.

N-(3-yodellin-2-Revlimid

N-(pyridine-2-yl)pivalate (of 14.25 g, 80 mmol) and TMEDA (29,80 ml, 200 mmol) was dissolved in THF (400 ml) under nitrogen at -75°C dropwise was mixed with n-BuLi (125 ml, 200 mmol; 1.6 m solution in n-hexane). The mixture was stirred 15 min at -75°C., then 2 h at -10°C. After the secondary cooling to -75°C. was added dropwise a solution of iodine (50,76 g, 200 mmol) in THF (200 ml) and the reaction mixture was stirred for 2 h was Heated to 0°C and rapidly cooled saturated aqueous sodium thiosulfate. The aqueous phase was extracted with DHM (2×150 ml) and the combined organic phase was dried over MgSO4. After filtration of the drying agent and removal of the solvent in a rotary evaporator apparatus residue was purified by column chromatography (simple ether: cyclohexane = 3:1) thus obtained N-(3-yodellin-2-yl)pivalate (14,80 g, 61%).

3-Yodellin-2-amine

N-(3-yodellin-2-yl)pivalate (13,80 g, 45,36 mmol) resuspendable in H2SO4(24 wt.%, 394 ml) and the mixture was stirred 60 min in a flask with reflux condenser. After cooling to CT was neutralized with 4N NaOH and solid NaHCO3, the aqueous phase was extracted through DHM (3×200 ml) and the combined organic phase was dried over MgSO4. After filtration the solvent was removed in a rotary evaporator apparatus. Received 3-yodellin-2-amine (9,70 g, 97%) as a solid substance of Krumovo the color.

2-(2-(Triethylsilyl)-1H-pyrrolo[2,3-b]pyridine-3-yl)ethanol

Under nitrogen, a mixture of 3-yodellin-2-amine (0,46 g of 2.09 mmol), 4-(triethylsilyl)but-3-in-1-ol (0,58 g, 3.14 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane (0.083 g, 0,105 mmol), lithium chloride (0,086 g of 2.09 mmol) and sodium carbonate (0,44 g, 4,18 mmol) in DMF (21 ml) was stirred 15 h at 100°C. the Reaction mixture was cooled to CT, was mixed with EtOAc/simple ether (1:1) and was submitted in the H2O. Biphasic suspension was filtered through the filter earth. After separation of the phases the aqueous phase was extracted with EtOAc (2x). The organic phases were combined and washed by H2O and saturated NaCl solution and dried over MgSO4. After filtering the drying agent, the solvent was removed in a rotary evaporator apparatus. Column chromatography of the residue (n-hexane/EtOAc = 2:1, then n-hexane/EtOAc = 1:1) gave 2-(2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine-3-yl)ethanol (0,46 g, 80%).

2-(1H-pyrrolo[2,3-b]pyridine-3-yl)ethanol (Ind-1)

2-(2-(Triethylsilyl)-1H-pyrrolo[2,3-b]pyridine-3-yl)ethanol (1,00 g, 3.62 mmol) was stirred with TBAF (10,86 ml, 10,86 mmol; 1M solution in THF) 6 h at 50°C and then 10 h at RT. The solvent was removed in a rotary evaporator apparatus and the residue was purified column chromatography (DHM/Meon = 9:1, then 1:1). Received 2-(1H-pyrrolo[2,3-b]pyridine-3-yl)ethanol (0,46 g, 79%) as a white solid.

Elements is ary link Ind-2

2-(1H-pyrrolo[2,3-C]pyridine-3-yl)ethanol (Ind-2)

2-(2-(Triethylsilyl)-1H-pyrrolo[2,3-C]pyridine-3-yl)ethanol (1,99 g of 7.24 mmol) was dissolved in THF (17 ml) and at 0°C was mixed with TBAF (of 7.96 ml, of 7.96 mmol; 1M solution in THF). The mixture was stirred for 1 h at 0°C and then heated up to CT. Followed secondary add TBAF (of 7.96 ml, of 7.96 mmol, 1M solution in THF) and H2O (5 drops). After 2 days. at RT was added 20 ml of H2O and the aqueous phase was extracted through DHM (3×60 ml). The organic phases were combined and washed with saturated solution of NaCl (2×20 ml) and dried over MgSO4. After filtering the drying agent, the solvent was removed in a rotary evaporator apparatus and the residue was purified column chromatography (DHM/Meon = 4:1). Received 2-(1H-pyrrolo[2,3-C]pyridine-3-yl)ethanol (0,60 g, 51%) as a colourless oil, which eventually hardened.

Elementary link Ind-3

N-(5-(trifloromethyl)pyridine-2-yl)pivalate

Under nitrogen resuspendable 5-(trifloromethyl)pyridine-2-amine (15 g, of 92.5 mmol) in DHM (190 ml) and mixed with the Net3(16 ml, 115, 7mm mmol). The solution was cooled to -5°C., dropwise mixed with a solution of trimethylacetylchloride (12.5 ml, to 101.8 mmol) in DHM (65 ml) and was stirred an additional 15 min in an ice bath. Then the mixture was stirred 2 h at RT. The suspension was washed by H2O (150 ml), then diluted aqueous NaHCO3and the organic phase is dried over MgSO 4. After filtration of the drying agent and removal of the solvent in a rotary evaporator apparatus residue was crystallizable. Received N-(5-(trifluoromethyl)pyridin-2-yl)pivalate (20,8 g, 91).

N-(3-iodide-5-(trifluoromethyl)pyridin-2-yl)pivalate

N-(5-(trifluoromethyl)pyridin-2-yl)pivalate (22 g, 89,4 mmol) and TMEDA (33.3 ml, 223,4 mmol) was dissolved in THF (400 ml) under nitrogen at -75°C dropwise was mixed with n-BuLi (139,6 ml, 223,4 mmol; 1.6 m solution in n-hexane). A mixture of 2 hours and stirred at -75°C. while Maintaining the temperature was added dropwise a solution of iodine (56.7 g, 223,4 mmol) in THF (280 ml) and the reaction mixture was stirred for 2 h was Heated to 0°C and rapidly cooled saturated aqueous sodium thiosulfate. The aqueous phase was extracted through DHM (2×150 ml) and the combined organic phase was dried over MgSO4. After filtration of the drying agent and removal of the solvent in a rotary evaporator apparatus residue was purified by column chromatography (simple ether/cyclohexane = 1:1) and thus obtained N-(3-iodide-5-(trifluoromethyl)pyridin-2-yl)pivalate (13 g, 39.1 per cent).

3-Iodine-5-(trifluoromethyl)pyridin-2-amine

N-(3-iodine-5-(trifluoromethyl)pyridin-2-yl)pivalate (16,8 g, 45,1 mmol) resuspendable in H2SO4(24 wt.%, 392 ml) and the mixture was stirred 60 min in a flask with reflux condenser. After cooling to CT was neutralized with 4N NaOH and the solid is th NaHCO 3, the aqueous phase was extracted through DHM (3×200 ml) and the combined organic phase was dried over MgSO4After filtration the solvent was removed in a rotary evaporator apparatus. Received 3-iodide-5-(trifluoromethyl)pyridin-2-amine (13 g, 100%) as a cream solid color.

2-(2-(Triethylsilyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-yl)ethanol

Under nitrogen was stirred mixture of 3-iodine-5-(trifluoromethyl)pyridin-2-amine (13 g, 45,1 mmol), 4-(triethylsilyl)but-3-in-1-ol (12.4 g, + 67.7 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane (1.78 g, and 2.26 mmol), lithium chloride (1.86 g, 45,1 mmol) and sodium carbonate (9,54 g of 90.3 mmol) in DMF (460 ml) 15 h at 100°C. the Reaction mixture was cooled to CT, was mixed with 2 L EtOAc/simple ether (1:1) and was applied in 2 L H2O. Biphasic suspension was filtered through the filter earth. After separation of the phases the aqueous phase was extracted with EtOAc (2×1 L). The organic phases were combined and washed by H2O and saturated NaCl solution and dried over MgSO4. After filtering the drying agent, the solvent was removed in a rotary evaporator apparatus. Column chromatography of the residue (simple tert-butyl methyl ether/n-hexane = 2:3). Then the obtained mixed fraction resuspendable 4× every once in 20 ml of dichloromethane and was aspirated from the white crystalline solids is. The first 3 fractional residue was combined 2-(2-(triethylsilyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-yl)ethanol (3.8 g, 24.4 percent).

2-(5-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-yl)ethanol (Ind-3)

2-(2-(Triethylsilyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-yl)ethanol (3.8 g, 11.0 mmol) was stirred with TBAF (33,1 ml, up 33.1 mmol; 1M solution in THF) 6 h at 50°C and then 10 h at RT. The solvent was removed in a rotary evaporator apparatus. Received 2-(5-(trifloromethyl)-1H-pyrrolo[2,3-b]pyridine-3-yl)ethanol (2.4 g, 94.5%of).

Elementary link Ind-4

S-2-(1H-pyrrolo[2,3-b]pyridine-3-yl)ethyl attentioin

Under protective gas dissolved triphenylphosphine (of 3.56 g, 13,57 mmol) in absolute THF (20 ml). Bright solution was cooled to -5°C. With stirring was added dropwise dissolved in THF (20 ml) aminobutiramida-azodicarboxylate (2,75 g of 13.6 mmol) for 15 minutes in the sediment dropped the white balance. The suspension was stirred 30 min at -5°C. After that for 30 minutes was added dropwise a mixture of Ind-1 (1100 mg of 6.78 mmol) and teoksessa acid (965 μl, 13,57 mmol)dissolved in THF (20 ml). The reaction was slightly exothermic. The temperature was then kept for one hour at -5°C. With slow warming to room temperature the slurry solution became transparent. After 18 h of stirring at 23°C drove THF to a considerable extent. The mixture of substances (8.5 g, brown oil) Rabaul is whether with ethyl acetate (30 ml) and was extracted with 1N hydrochloric acid (1×10 ml, 3×5 ml). To the combined aqueous phase was carefully added to a saturated solution of sodium bicarbonate (25 ml). The mixture was extracted with dichloromethane (3×10 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent is kept in vacuum. S-2-(1H-pyrrolo[2,3-b]pyridine-3-yl)ethyl attentioin was obtained as an almost white solid (1.12 g, 75%).

2-(1H-pyrrolo[2,3-b]pyridine-3-yl)ethanthiol hydrochloride (Ind-4)

Under argon was cooled methanol (20 ml) to below 0°C. and Then slowly added dropwise acetylchloride (3 ml, 42 mmol). The reaction was exothermic. During the addition the temperature was kept below 15°C. the Reaction mixture was stirred 1 h at room temperature. S-2-(1H-pyrrolo[2,3-b]pyridine-3-yl)ethyl atantic (600 mg, 2,724 mmol) was dissolved in methanol/dichloromethane 1:1 (10 ml) and then was added dropwise within 10 minutes the Reaction mixture was stirred 18 h at 23°C. the Solvent drove away. The orange residue suspended in cyclohexane (5 ml), was filtered and washed with cyclohexane (3×1 ml). Ind-4 beige, probably, was obtained as hydrochloride (578 mg, 99%, melting point 138-150°C).

Elementary link Ind-5

S-2-(1H-pyrrolo[3,2-C]pyridine-3-yl)ethyl attentioin

Under protective gas dissolved triphenylphosphine (3,83 g, 14.6 mmol) in absolute THF (20 ml). Bright solution was cooled to -5°C. While stirring in t is an increase of 15 min was added dropwise dissolved in THF (20 ml) aminobutiramida-azodicarboxylate (2,18 g, 10,78 mmol). When this precipitate fell out white balance. The suspension was stirred 30 min at -5°C. After that for 30 minutes was added dropwise a mixture of Ind-2 (1700 mg, 5,38 mmol, purity approx. 51% (g/g)) and teoksessa acid (765 μl, of 10.75 mmol)dissolved in THF (20 ml). The reaction was slightly exothermic. The temperature was then another hour and kept at -5°C. With slow warming to room temperature the slurry was bright solution. After 65 h of mixing at 23°C drove THF in a considerable amount. The mixture of substances (7,3 g, brown oil) was diluted with ethyl acetate (30 ml) and was extracted with 1N hydrochloric acid (1×10 ml, 3×5 ml). To the combined aqueous phase was carefully added to a saturated solution of sodium bicarbonate (60 ml). The mixture was extracted with dichloromethane (3×10 ml). The combined organic phases were dried over sodium sulfate. After filtering, the solvent is kept in vacuum. S-2-(1H-pyrrolo[3,2-C]pyridine-3-yl)ethyl attentioin was obtained as a brown oil (1,05 g, 82%).

2-(1H-pyrrolo[3,2-C]pyridine-3-yl)ethanthiol hydrochloride (Ind-5)

Under argon was cooled methanol (30 ml) to below 0°C. and Then slowly added dropwise acetylchloride (3 ml, 42 mmol). The reaction was exothermic. During the addition the temperature was kept below 15°C. the Reaction mixture was stirred 1 h at room .S-2-(1H-pyrrolo[3,2-C]pyridine-3-yl)ethyl atantic (1,05 g, 4.77 mmol) was dissolved in methanol (10 ml) and then for 10 min was added dropwise. The reaction mixture was stirred 18 h at 23°C. the Solvent drove away. The orange residue suspended in diethyl ether (10 ml), was filtered and washed with diethyl ether (3×1 ml). Ind-5 beige color obtained, probably as hydrochloride (975 mg, 95%, melting point 182-195°C).

Examples

Example 1

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], 1 diastereoisomer

The ketone Ket-1 (0,13 g of 0.62 mmol) were placed together with Ind-1 (0.10 g, of 0.62 mmol) in dichloromethane Ultraschall (4 ml). A microwave vessel was closed with septum and flushed with nitrogen. Then carried out quickly add trimethylsilyltrifluoromethane (of 0.47 ml, 2,47 mmol). The mixture was heated for 2×20 min at 120°C in the microwave. Then the reaction mixture was mixed with 2N NaOH and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x). The combined organic extracts were washed with water and dried over MgSO4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. The obtained solid (0.71 g) was mixed with methanol (7 ml) and the mixture was stirred for 2 h at room temperature. The solid was sucked out, repeatedly washed with a small amount of methanol and visas the Wali.

Output (Approx. 1): 0.17 g (78%), solid cream color.

1H-NMR (600 MHz, D6-DMSO) δ frequent. per million: 1.65-2.8 (m, 16H), 3.17 (s, 1H), 3.96 (m, 2H), 6.93-6.8 (m, 1H), 7.40-7.70 (bm, 4H), 7.76 (d, 1H), 8.06 (d, 1H), 11.40 (s, 1H).

Example 2

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; methanesulfonate, a mixture of diastereomers

The ketone Ket-1 (0,13 g of 0.62 mmol) were placed together with Ind-1 (0.10 g, of 0.62 mmol) in dichloromethane (4 ml, ultrashot). A microwave vessel was closed with septum and flushed with nitrogen. Then carried out quickly add trimethylsilyltrifluoromethane (0,26 ml of 1.36 mmol). The mixture was heated for 2×10 min at 90°C in the microwave. Then again added trimethylsilyltrifluoromethane (0,26 ml of 1.36 mmol) and the mixture is 1×10 min, then 1×20 min at 120°C. in a microwave heated.

The reaction mixture is finally mixed with 2N NaOH and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x). The combined organic extracts were washed with water and dried over MgSO4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. The obtained solid was mixed with methanol (7 ml) and the mixture was stirred for 2 h at room temperature. The solid was aspirated, washed with a small amount of methanol, dried (0.14 g, 63%). For USAID is of methansulfonate solid (0.14 g, 0,39 mmol) was smokepole in dichloromethane (2 ml) and mixed with methanesulfonic acid (0,028 ml). Now to light the solution was added over 1 min acetone (0.5 ml) and dropwise a simple ether, until he got to stir the mixture. Was stirred 30 min at room temperature. Then the precipitate with the exclusion of air was aspirated portions were washed with simple ether, and dried under high vacuum at 50°C. Yield (Approx. 2): 0.16 g (90%), a mixture of diastereomers (CA. 6:1).

Example 3

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)], a mixture of diastereomers

The ketone Ket-1 (0,13 g of 0.62 mmol) were placed together with Ind-2 (0.10 g, of 0.62 mmol) in ultrashort dichloromethane (4 ml). A microwave vessel was closed with septum and flushed with nitrogen. Then carried out quickly add trimethylsilyltrifluoromethane (of 0.47 ml, 2,47 mmol) in a Mixture of 40 min at 120°C was heated in the microwave. Then the reaction mixture was mixed with 2N NaOH and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x). The combined organic extracts were washed with water and dried over MgSO4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. The obtained solid was mixed with methanol (7 ml) and the mixture was stirred for 48 h at room temperature. the solid substance was sucked out, re-washed with a small amount of methanol and dried.

Output (Approx. 3): 0.06 g (28%), solid cream color (mixture of diastereomers: approx. 5:1).

1H-NMR (600 MHz, D6-DMSO) δ frequent. per million: diastereoisomer 1: 1.63 (t, 2H), 2.13 (bd, 2H), 2.16 (t, 2H), 2.27 (s, 6H), 2.11 (bd, 2H), 2.77 (m, 2H), 3.98 (m, 2H), 7.26 (d, 1H), 7.37 (d, 1H), 7.5 (m, 1H), 7.56 (t, 2H), 7.63 (m, 2H), 8.12 (d, 1H), 8.76 (s,, 1H), 11.33 (bs, 1H), additional peaks, diastereoisomer 2: 1.74-1.80 (bt, 4H), 2.06 (s, 6H), 3.91 (m, 2H), 7.43-7.48 (m, 1H), 8,19 (d, 1H), 8.84 (s, 1H), 11.8 (bs, 1H).

Example 4

4-(Dimethylamino)-4-thiophene-2-yl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; methanesulfonate, 1 diastereoisomer

The ketone Ket-2 (0,13 g of 0.62 mmol) and 2-(1H-pyrrolo[2,3-b]pyridine-3-yl)ethanol Ind-1 (0.10 g, of 0.62 mmol) were placed under nitrogen in dichloromethane (4 ml, ultrashot). Then carried out quickly add trimethylsilyltrifluoromethane (of 0.48 ml, 2,47 mmol). A mixture of 5 days was stirred at room temperature. After adding tetrahydrofuran and the mixture was podslushivaet using 1M aqueous solution of Na2CO3(pH 11) and was stirred 20 min at room temperature. The organic phase was separated and the aqueous phase was extracted with tetrahydrofuran (2x). The combined organic phases were washed with saturated NaCl solution and dried over MgSO4. After filtering the drying agent, the solvent was removed in a rotary evaporator apparatus. The obtained solid substance is mixed with methanol (3 ml) and 18 h was stirred at room temperature. The solid was aspirated, washed with a small amount of methanol and dried in a vacuum oil pump at 50°C (0.09 g, 43%). For the deposition of methansulfonate solid (0.07 g, 0,19 mmol) was smokepole in dichloromethane (2 ml) and at room temperature was mixed with methanesulfonic acid (0,014 ml). Suspension after 5 min was mixed with simple ether (10 ml). After 30 min of stirring at room temperature, the solid was sucked out with the exclusion of air, washed by a simple ether and at 50°C in a vacuum oil pump was dried.

Output (Approx. 4): 0.07 g (79%).

1H-NMR (600 MHz, D6-DMSO) δ frequent. per million: 1.87-1.98 (m, 4H), 2.26-2.35 (m, 5H), 2.59-2.65 (m, 8H), 2.71 (t, 2H), 3.97 (t, 2H), 6.98-7.04 (m, 1H), 7.32 (t, 1H), 7.55 (d, 1H), 7.83 (d, 1H), 7.92 (d, 1H), 8.11 (d, 1H), 9.55 (bs, 1H), 11.60 (s, 1H).

Example 5

4-(Dimethylamino)-4-thiophene-2-yl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)], 1 diastereoisomer

The ketone Ket-2 (0,13 g of 0.62 mmol) and Ind-2 (0.10 g, of 0.62 mmol) were placed under nitrogen in dichloromethane (4 ml, ultrashot). Then carried out quickly add trimethylsilyltrifluoromethane (of 0.48 ml, 2,47 mmol). The mixture was stirred for 6 days at room temperature. After adding tetrahydrofuran and the mixture was podslushivaet using 1M aqueous solution of Na2CO3(pH 11) and was stirred 20 min at room temperature. The organic phase was separated and the aqueous phase was extracted with ethyl is the first ether acetic acid (2). The combined organic phases were washed with saturated NaCl solution and dried over MgSO4. After filtering the drying agent, the solvent was removed in a rotary evaporator apparatus. Purification of column chromatography of the residue (dichloromethane:methanol = 19:1) gave Approx. 5 (0.05 g, 22%).

1H-NMR (600 MHz, D6-DMSO) δ frequent. per million: 1.84 (bt, 2H), 2.01 (bd, 2H), 2.29 (bt, 2H), 2.5 (s, 6H maplestory DMSO), 2.60 (bd, 2H), 2.85 (t, 2H), 4.01 (t, 2H), 7.30-7.34 (m, 1H), 7.48-7.53 (m, 1H), 7.63 (d, 1H), 7.86-7.91 (m, 1H), 8.29 (d, 1H), 9.09 (s, 1H), 12.37 (bs, 1H).

Example 6

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (4:3), 1 diastereoisomer

Ket-1 (0.27 g, of 1.23 mmol) were placed together with Ind-1 (0.20 g, of 1.23 mmol) in dichloromethane (4 ml, ultrashot). A microwave vessel was closed with septum and flushed with nitrogen. Then carried out quickly add trimethylsilyltrifluoromethane (1.1 ml, 4.9 mmol). The mixture was heated for 40 min at 120°C in the microwave. The reaction mixture is finally mixed with a 1M solution of Na2CO3(pH 11) and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x). The combined organic extracts were washed with water and dried over MgSO4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. The obtained solid was mixed with methanol (7 ml) and the mixture p is remedial for 2 h at room temperature. The solid was aspirated, washed with a small amount of methanol, dried (0,257 g, 57%).

For the deposition of citrate solid (0.1 g, 0.27 mmol) was smokepole in hot ethanol (6 ml) and mixed with a hot solution of citric acid (0,053 g) in ethanol (1.4 ml). The solution was stirred 3 days at room temperature. Then the precipitate was aspirated portions were washed simple with ether, and dried in high vacuum at 60°C.

Output (Approx. 6): 0,109 g (71%).

1H-NMR (600 MHz, D6-DMSO) δ frequent. per million: 1.68-1.89 (m, 4H), 2.1-2.3 (m, 8H), 2.50-2.58 (q, 3H), 2.68 (m, 4H), 3.96 (m, 2H), 6.93-6.99 (m, 1H), 7.43-7.64 (m, 5H), 7.75 (d, 1H), 8.06 (d, 1H), 11.40 (s, 1H).

Example 7

4-(Methylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), 1 diastereoisomer

The ketone Ket-3 (0.125 g, of 0.62 mmol) were placed together with Ind-1 (0.10 g, of 0.62 mmol) in dichloromethane (4 ml, ultrashot). A microwave vessel was closed with septum and flushed with nitrogen. Then carried out quickly add trimethylsilyltrifluoromethane (of 0.48 ml, 2.5 mmol). The mixture was heated 30 min at 120°C in the microwave. The reaction mixture is finally mixed with a solution of 2N NaOH and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x). The combined organic extracts were washed with water and dried over MgSO4. After filtration of the drying agent the solvent in which alali in a rotary evaporation apparatus. Purification of column chromatography of the residue (dichloromethane:methanol = 4:1) gave 4-(methylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)] (0.06 g, 28%). For the deposition of citrate was smokepole 4-(methylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)] (0,053 g, 0.15 mmol) in hot ethanol (4 ml) and mixed with a hot solution of citric acid (to 0.032 g) in ethanol (1 ml). The solution was stirred 3 h at room temperature. Then the precipitate was aspirated portions were washed simple with ether, and dried in high vacuum at 60°C.

Output (Approx. 7): 0.07 g (85%).

1H-NMR (600 MHz, D6-DMSO) δ frequent. per million: 1.76-1.83 (bt, 2H), 1.87-1.93 (bd, 2H), 2.08 (s, 3H), 2.16-2.25 (bt, 2H), 2.47 (d, 2H). 2.54 (d, 2H), 2.55-2.60 (m, 2H), 2.70 (bt, 2H), 3.98 (bt, 2H), 6.95-6.99 (m, 1H), 7.49 (t, 1H), 7.56 (t, 2H), 7.66 (d, 2H), 7.77 (d, 1H), 8.08 (d, 1H), 11.46 (s, 1H), Breites Signal at 8.5-12.0.

Example 8

4-(Methylamino)-4-thiophene-2-yl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (4:3), 1 diastereoisomer

The ketone Ket-4 (0,13 g of 0.62 mmol) were placed together c Ind-1 (0.10 g, of 0.62 mmol) under nitrogen in dichloromethane (4 ml, ultrashot). Then carried out quickly add trimethylsilyltrifluoromethane (of 0.48 ml, 2.5 mmol). The mixture was stirred for 15 days at room temperature. After adding tetrahydrofuran and the mixture was podslushivaet using a 1M solution of Na2CO3and was stirred 20 min. The organic phase OTDELA and the aqueous phase was extracted with tetrahydrofuran (2x). The combined organic extracts were washed with saturated NaCl solution and dried over MgSO4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. The obtained solid was mixed with methanol (5 ml) and the mixture was stirred for 18 h at room temperature. The solid was aspirated, washed with a small amount of methanol, dried in a vacuum oil pump (amount of 0.118 g, 54%). For the deposition of citrate was smokepole solid (0,112 g, 0.32 mmol) in hot ethanol (4 ml) and mixed with a hot solution of citric acid (of 0.066 g) in ethanol (1.5 ml). The solution was stirred 3 h at room temperature. Then the precipitate was aspirated portions were washed simple with ether, and dried in high vacuum at 60°C.

Output (Approx. 8): 0,117 g (68%).

1H-NMR (600 MHz, D6-DMSO) δ frequent. per million: 1.86-1.99 (m, 4H), 2.14 (s, 3H), 2.18 (bd, 2H), 2.31 (bd, 2H), 2.47 (d, 1.4H), 2.54 (d, 1.4H), 2.69 (t, 2H), 3.95 (t, 2H), 6.96-6.99 (m, 1H), 7.16 (m, 1H), 7.30 (m, 1H), 7.66 (d, 1H), 7.77 (d, 1H), 8.09 (d, 1H), 11.51 (s, 1H), Shir. the signal at 8.0-12.0.

Example 9

4-(Dimethylamino)-4-benzo[1,3-dioxol]-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), 1 diastereoisomer

The ketone Ket-5 (0.16 g, of 0.62 mmol) were placed together with Ind-1 (0.10 g, of 0.62 mmol) under nitrogen at ultrashort dichloromethane (4 ml). Then carried out quickly add trimethylsilyl formeasurement (of 0.48 ml, 2.5 mmol). The mixture was stirred for 15 days at room temperature. After adding tetrahydrofuran and the mixture was podslushivaet using a 1M solution of Na2CO3and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with tetrahydrofuran (2x). The combined organic extracts were washed with saturated NaCl solution and dried over MgSO4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. The obtained solid was mixed with methanol (5 ml) and the mixture for 2 h and was stirred at room temperature. The solid was aspirated, washed with a small amount of methanol and dried in a vacuum oil pump at 50°C (0,052 g, 21%).

For the deposition of citrate solid (0,047 g, 0.11 mmol) was smokepole in hot ethanol (4 ml) and mixed with a hot solution of citric acid (0,024 g) in ethanol (1 ml). A solution of 3 h was stirred at room temperature. Then the precipitate was aspirated portions were washed simple with ether, and dried in high vacuum at 60°C.

Output (Approx. 9): 0,061 g (88%).

1H-NMR (600 MHz, D6-DMSO) δ frequent. per million: 1.7-1.78 (t, 2H), 1.83-1.90 (d, 2H), 2.09-2.17 (m, 2H), 2,32-2.41 (m, 6H), 2.53 (d, 2H), 2.58 (d, 2H), 2.68 (t, 4H), 3.96 (t, 2H), 6.13 (s, 2H), 6.95-6.99 (m, 1H), 7.05-7.10 (m, 1H), 7.10-7.17 (m, 1H), 7.25 (m, 1H), 7.76 (d, 1H), 8.08 (d, 1H), 11.42 (bs, 1H).

Example 10

4-(Dimethylamino)-4-(benzothiophen-2-yl)-Spiro[cyclohex the EN-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), 1 diastereoisomer

The ketone Ket-6 (0.17 g, of 0.62 mmol) were placed together with Ind-1 (0.10 g, of 0.62 mmol) under nitrogen in dichloromethane (4 ml, ultrashot). Then carried out quickly add trimethylsilyltrifluoromethane (of 0.48 ml, 2.5 mmol). The mixture was stirred for 7 days at room temperature. After adding tetrahydrofuran and the mixture was podslushivaet using a 1M solution of Na2CO3and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x). The combined organic extracts were washed with saturated NaCl solution and dried over MgSO4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. The obtained solid was mixed with methanol (5 ml) and the mixture was stirred for 2 h at room temperature. The solid was aspirated, washed with a small amount of methanol and dried in a vacuum oil pump at 50°C (0,158 g, 61%).

For the deposition of citrate solid (0,154 g and 0.37 mmol) was smokepole in hot ethanol (4 ml) and mixed with a hot solution of citric acid (0,071 g) in ethanol (2.5 ml). A solution of 3 h was stirred at room temperature. Then the precipitate was aspirated portions were washed simple with ether, and dried in high vacuum at 60°C.

Output (Approx. 10): rate of 0.193 g (85%).

1H-NMR (600 MHz, D6-DMSO) δ frequent. the and million: 1.89-2.03 (m, 4H), 2.19-2.28 (m, 2H), 2.39 (bs, 6H), 2.56-2.62 (m, 3H), 2.65-2.71 (m, 5H); 3.96 (m, 2H), 6.94-6.98 (m, 1H), 7.38-7.46 (m, 2H), 7.63 (bs, 1H), 7.76 (d, 1H), 7.93 (d, 1H), 8.02 (d, 1H), 8.05 (d, 1H), 11.43 (bs, 1H).

Example 12

4-(Dimethylamino)-4-(3-forfinal)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (4:3), 1 diastereoisomer

The ketone Ket-7 (0,145 g of 0.62 mmol) were placed together with Ind-1 (0.10 g, of 0.62 mmol) under nitrogen at ultrashort dichloromethane (4 ml). Then carried out quickly add trimethylsilyltrifluoromethane (of 0.48 ml, 2.5 mmol). A mixture of 7 days was stirred at room temperature. After adding dichloromethane and the mixture was podslushivaet 1M solution of Na2CO3and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x). The combined organic extracts were washed with saturated NaCl solution and dried over MgSO4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. The obtained solid was mixed with methanol (5 ml) and the mixture was stirred for 2 h at room temperature. The solid was aspirated, washed with a small amount of methanol and dried in a vacuum oil pump at 50°C (0,054 g, 23%).

For the deposition of citrate solid (0,054 g, 0.14 mmol) was smokepole in hot ethanol (3 ml) and mixed with a hot solution of citric acid (or 0.027 g) in ethanol (1 ml). A solution of 3 h per Merivale at room temperature. Then the precipitate was aspirated portions were washed simple with ether, and dried in high vacuum at 60°C.

Output (Approx. 12): 0,048 g (59%).

1H-NMR (600 MHz, D6-DMSO) δ frequent. per million: 1.69 (bt, 2H), 1.85 (bd, 2H), 2.09 (bt, 2H), 2.20 (bs, 6H), 2.51-2.55 (d, 1.5H), 2.56-2.62 (d, 1.5H), 2.63 (m, 2H), 2.67 (t, 2H), 3.95 (t, 2H), 6.94-6.97 (m, 1H), 7.25-7.31 (m, 1H), 7.35-7.42 (m, 2H), 7.52-7.58 (m, 1H), 7.76 (d, 1H), 8.07 (d, 1H), 11.37 (s, 1H).

Example 13

4-(Dimethylamino)-4-(3-were)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), 1 diastereoisomer

The ketone Ket-8 (0,142 g of 0.62 mmol) were placed together with Ind-1 (0.10 g, of 0.62 mmol) under nitrogen at ultrashort dichloromethane (4 ml). Then carried out quickly add trimethylsilyltrifluoromethane (of 0.48 ml, 2.5 mmol). A mixture of 7 days was stirred at room temperature. After adding dichloromethane and the mixture was podslushivaet using a 1M solution of Na2CO3and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x). The combined organic extracts were washed with saturated NaCl solution and dried over MgSO4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. The obtained solid was mixed with methanol (5 ml) and the mixture was stirred for 2 h at room temperature. The solid was aspirated, washed with a small amount of methanol and dried under vacuum mA is Lenogo pump at 50°C (0,117 g, 50%).

For the deposition of citrate solid (0,112 g, 0.30 mmol) was smokepole in hot ethanol (4 ml) and mixed with a hot solution of citric acid (0,057 g) in ethanol (2 ml). A solution of 3 h was stirred at room temperature. Then the precipitate was aspirated portions were washed simple with ether, and dried in high vacuum at 60°C.

Output (Approx. 13): amount of 0.118 g (70%).

1H-NMR (600 MHz, D6-DMSO) δ frequent. per million: 1.73 (m, 2H), 2.15 (m, 2H), 2.3 (bs, 6H), 2.43 (s, 3H), 2.56-2.58 (m, 3H), 2.67-2.69 (m, 4H), 3.96 (m, 2H), 6.95-6.97 (m, 1H), 7.32 (bm, 1), 7.42-7.44 (m, 3H), 7.77 (d, 1H), 8.07 (d, 1H), 11.41 (s, 1H).

Example 14

4-(Dimethylamino)-4-(buta-1-yl)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (1:1), 1 diastereoisomer

The ketone Ket-9 (0.3 g, 0.185 mmol) were placed together with Ind-1 (0.10 g, of 0.62 mmol) under nitrogen at ultrashort dichloromethane (4 ml). Then carried out quickly add trimethylsilyltrifluoromethane (of 0.48 ml, 2.5 mmol). The mixture was stirred for 5 days at room temperature. After adding dichloromethane and the mixture was podslushivaet with a solution of 1M Na2CO3and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x). The combined organic extracts were washed with saturated NaCl solution and dried over MgSO4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. Purification of column chromatography is raffia balance (dichloromethane:methanol = 4:1) gave 4-(dimethylamino)-4-(buta-1-yl)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)] (0,026 g, 12%).

For the deposition of citrate solid (0.02 g, 0.06 mmol) was smokepole in hot ethanol (2 ml) and mixed with a hot solution of citric acid (0,012 g) in ethanol (1 ml). A solution of 3 h at room temperature and was stirred. Then the precipitate was aspirated portions were washed simple with ether, and dried in high vacuum at 60°C.

Output (Approx. 14): 0,021 g (67%).

Example 15

4-(Dimethylamino)-4-phenylethyl-Spiro[cyclohexane-1,8'-(3-trifluoromethyl-5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), 1 diastereoisomer

The ketone Ket-10 (0,319 g of 1.30 mmol) were placed together c Ind-3 (0.3 g, of 1.30 mmol) in ultrashort dichloromethane (3.4 ml). A microwave vessel was closed with septum and flushed with nitrogen. Then carried out quickly add trimethylsilyltrifluoromethane (1,01 ml, 5.2 mmol). The composition was heated for 10 min at 120°C in the microwave. Then the reaction mixture was mixed with 1M aqueous solution of Na2CO3and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x). The combined organic extracts were washed with water and saturated NaCl solution and dried over MgSO4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. The obtained foamy solid was purified by column chromatography (silica gel 60 KG, dichloromethane:methanol 9:1). Produces and 4-(dimethylamino)-4-phenylethyl-Spiro[cyclohexane-1,8'-(3-trifluoromethyl-5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)] (0.14 g, 23,5%).

For the deposition of citrate solid (0,140 g, 0,306 mmol) was dissolved in hot ethanol (2 ml) and was mixed with citric acid (0,058 g) and diethyl ether (10 ml). The solution was stirred at room temperature. The solid was aspirated and dried under high vacuum at 60°C.

Output (Approx. 15): 0,173 g (87%).

Example 17

4-(Dimethylamino)-4-ethyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (2:3), a mixture of diastereomers

Ket-12 (0.25 g, 1.48 mmol) were placed together with Ind-1 (0.24 g, 1.48 mmol) in ultrashort dichloromethane (3.3 ml). A microwave vessel was closed with septum and flushed with nitrogen. Then carried out quickly add trimethylsilyltrifluoromethane (1,14 ml of 5.92 mmol). The composition was heated at 120°C for 20 min in the microwave. Then the reaction mixture was mixed with 1M aqueous solution of Na2CO3and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x). The combined organic extracts were washed with water and us. NaCl and dried over MgSO4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. The obtained solid was mixed with methanol (5 ml) and the mixture for 2 h and was stirred at room temperature. The solid was sucked out, repeatedly washed with small amount of methanol and dried under high vacuum at 50°C. Got a solid cream color (0.07 g, 15.1 per cent).

Solid (0.07 g, 0.22 mmol) was smokepole in hot ethanol (2 ml) and mixed with a hot solution of citric acid (0,043 g) in ethanol (1 ml). The solution was stirred 3 h at room temperature. Light the solution was concentrated to dryness and dried under high vacuum at 60°C.

Output (Approx. 17): 0.083 g (62%).

Example 18

4-(Dimethylamino)-4-phenylethyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (2:3), 1 diastereoisomer

Ket-10 (0,227 g, 0,925 mmol) were placed together with Ind-1 (0.15 g, 0,925 mmol) in ultrashort dichloromethane (3.6 ml). A microwave vessel was closed with septum and flushed with nitrogen. Then carried out quickly add trimethylsilyltrifluoromethane (0,715 ml, 3,70 mmol). The composition was stirred 10 days. by CT. Due to incomplete interaction and the mixture was heated for 2× 15 min at 120°C in the microwave. Then the reaction mixture was mixed with 1M aqueous solution of Na2CO3and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x). The combined organic extracts were washed with water and dried over MgSO4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. The obtained solid was mixed with methanol (7 ml) and the mixture was stirred for 1 h at to the room temperature. The solid was sucked out, repeatedly washed with a small amount of methanol and dried. Got a solid cream color (0.15 g, 41.4 per cent).

Solid (0,144 g and 0.37 mmol) was smokepole in hot ethanol (3 ml) and mixed with a hot solution of citric acid (0,071 g) in ethanol (2 ml). A solution of 3 h at room temperature and was stirred. Then the precipitate was aspirated, washed with a small amount of ethanol and 2 simple with ether, and dried in high vacuum at 60°C.

Output (Approx. 18): 0,184 g (73%).

1H-NMR (600 MHz, D6-DMSO) δ frequent. per million: 1.74-1.83 (m, 2H), 1.90-1.96 (m, 2H), 2.02-2.10 (m, 4H), 2.22-2.30 (m, 2H), 2.52-2.58 (d, 3H), 2.58-2.65 (d, 3H), 2.65-2.75 (m, 5H), 2.79 (bs, 5H), 3.94 (t, 2H), 6.99-7.04 (m, 1H), 7.18-7.32 (m. 2H), 7.34-7.43 (m, 3H), 7.82 (d, 1H), 8.14 (d, 1H), 11.70 (s, 1H).

Example 19

4-Benzyl-4-morpholino-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), 1 diastereoisomer

Ket-13 (0,252 g, 0,925 mmol) were placed together with Ind-1 (0.15 g, 0,925 mmol) in ultrashort dichloromethane (3.6 ml). A microwave vessel was closed with septum and flushed with nitrogen. Then carried out quickly add trimethylsilyltrifluoromethane (0,715 ml, 3,70 mmol). The composition was stirred 10 days. by CT. Then the reaction mixture was mixed with 1M aqueous solution of Na2CO3and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x). United organic the ski extracts were washed with water and dried over MgSO 4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. The obtained solid was mixed with methanol (7 ml) and the mixture was stirred 2 h at room temperature. The solid was sucked out, repeatedly washed with a small amount of methanol and dried under high vacuum at 50°C (0,248 g, 64.2 per cent, solid cream color).

Solid (0,234 g of 0.56 mmol) was smokepole in hot ethanol (5 ml) and mixed with a hot solution of citric acid (to 0.108 g) in ethanol (3 ml). Solution during the night was stirred at room temperature. Then the precipitate was aspirated, washed with a small amount of ethanol and 2 simple with ether, and dried in high vacuum at 60°C.

Output (Approx. 19): 0,280 g (82%).

1H-NMR (600 MHz, D6-DMSO) δ frequent. per million: 1.35-1.55 (bs, 2H), 1.87 (bm, 4H), 2.20 (m, 2H), 2.62-2.74 (m, 10H), 3.13 (bm, 2H), 3.58 (bm, 4H), 3.92 (m, 2H), 7.00 (m, 1H), 7.17 (m, 1H), 7.32 (m, 1H), 7.46 (d, 1H), 7.80 (d, 1H), 8.16 (d, 1H), 11.66 (s, 1H).

Example 20

4-(Dimethylamino)-4-(3-methoxypropyl)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), 1 diastereoisomer

Ket-14 (0,197 g, 0,925 mmol) were placed together with Ind-1 (0.15 g, 0,925 mmol) in ultrashort dichloromethane (3.6 ml). A microwave vessel was closed with septum and flushed with nitrogen. Then carried out quickly add trimethylsilyltrifluoromethane (0,715 ml, 3,70 mmol). Costituzionali 13 days. by CT. The composition was heated for 2× 15 min at 120°C in the microwave. Then the reaction mixture was mixed with 1M aqueous solution of Na2CO3and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x). The combined organic extracts were washed with water and dried over MgSO4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. The resulting oil was purified by column chromatography (silica gel 60 KG, dichloromethane:methanol 4:1) (0.1 g, 30.2 percent, solid cream color).

For the deposition of citrate solid (0,095 g, 0.27 mmol) suspended in hot ethanol (2 ml) and mixed with a hot solution of citric acid (0,051 g) in ethanol (2 ml). The solution was stirred over night at room temperature. Then the precipitate was aspirated, washed with a small amount of ethanol and 2 simple with ether, and dried in high vacuum at 60°C.

Output (Approx. 20): 0,111 g (76%).

Example 21

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), 1 diastereoisomer

The ketone Ket-1 (247 mg, 1.1 mmol) was dissolved together with Ind-1 (184 mg, 1.1 mmol) in dichloromethane (20 ml). Then was carried out by adding triftormetilfullerenov acid (363 mg, 0,215 ml, 2,42 mmol), and the composition was painted in a dark color. Was stirred 20 h at RT. For lane is processing the reaction mixture was mixed with 1N NaOH (8 ml) and was stirred 10 min. The color changed from dark red to light brown. In the sludge precipitated colorless solid. Solid (126 mg) was aspirated and washed with dichloromethane (5 ml). The phases of the filtrate were separated. The aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were dried with sodium sulfate, filtered and concentrated in vacuum. Got a light brown solid (491 mg). The original product was mixed with ethyl acetate (10 ml), the precipitate precipitated colorless solid, which was aspirated (119 mg) and washed with ethyl acetate (10 ml). Both solids were identical and got together (245 mg, 62%) with a melting point in 266-274°C.

Solid (215 mg, 0.59 mmol) was heated in ethanol (70 ml) to a boil. To turbid solution was added citric acid (274 mg, 1,43 mmol), dissolved in hot ethanol (5 ml). The solution was bright. After 20 hours stirring at RT precipitated precipitated colorless residue was aspirated and washed with ethanol (10 ml).

Approx. 21, therefore, was obtained with the yield of 88% (288 mg).

1H-NMR (400 MHz, CD3OD) δ frequent. per million: 1.01 (t, J=7.01 Hz, 1.5H), 1.53-1.78 (m, 2H), 1.78-1.93 (m, 2H), 2.00-2.41 (m, 8H), 2.42-2.61 (m, 5H), 2.61-2.82 (m, 3H), 3.40 (d, J=6.83 Hz, 1H), 3.85-4.02 (m, 2H), 6.87-7.02 (m, 1H), 7.41-7.58 (m, 3H), 7.58-7.69 (m, 2H), 7.73 (d, J=7.74 Hz, 1H), 8.03 (d, J=4.57 Hz, 1H), 11.40 (s, 1H).

13C-NMR (101 MHz, CD3OD) δ frequent. per million: 18.5, 21.6, 26.2, 31.1 37.4, 44.0, 56.0, 59.0, 70.8, 71.3, 104.3, 114.9, 118.6, 125.5, 128.6, 128.8, 129.1, 138.7, 141.8, 148.5, 171.1, 176.4.

Example 22

4-(Dimethylamino)-4-thiophene-2-yl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), 1 diastereoisomer

The ketone Ket-2 (268 mg, 1.2 mmol) was dissolved together with astrobiolog Ind-1 (195 mg, 1.2 mmol) in 1,2-dichloroethane (20 ml). Then was carried out by adding triftormetilfullerenov acid (397 mg, 0,235 ml of 2.64 mmol), and the composition was painted in a dark purple color. All together was stirred for 40 h at RT. For processing the reaction mixture with 1N NaOH (8 ml) was adjusted to pH 11, and 15 min were mixed. The color changed to light brown and in the sediment dropped a light brown solid. Solid (140 mg) was aspirated and washed with methanol (15 ml). When this product is bleached. The phases of the filtrate were separated. The aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were dried with sodium sulfate, filtered and concentrated in vacuum. Solid brown residue was stirred with methanol (10 ml) for 10 min, then was aspirated (58 mg) and washed with methanol (10 ml). Both solids were identical and the joint (198 mg, 45%).

Solid (123 mg, 0.33 mmol) was heated in ethanol (90 ml) to a boil. To turbid solution was applied citric acid (152 mg, of 0.79 mmol), dissolved in hot ethanol (5 ml). The solution was St. tlim. He was advanced boiling for 5 min, then cooled to room temperature and concentrated in vacuo to approx. half of its volume. Then the solution was stirred 20 h at room temperature, and the precipitate was becoming colorless residue. It was aspirated and washed with ethanol (10 ml). Approx. 22 was isolated with a yield of 54% (100 mg) with a melting point in 278-283°C.

1H-NMR (400 MHz, CD3OD) δ frequent. per million: 1.75-1.99 (m, 4H), 2.03-2.36 (m, 8H), 2.36-2.78 (m, 8H), 3.85-4.05 (m, 2H), 6.91-7.04 (m, 1H), 7.16-7.34 (m, 2H), 7.63-7.73 (m, 1H), 7.73-7.84 (m, 1H), 8.04-8.15 (m, 1H), 11.51 (s, 1H).

Example 23

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)], citrate (1:1), non-polar diastereoisomer

Example 24

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)], citrate (1:1), polar diastereoisomer

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)] (non-polar and polar diastereoisomer)

The ketone Ket-1 (267 mg, of 1.23 mmol) and 5-attrition (Ind-2) (200 mg, of 1.23 mmol) was dissolved in abs. 1,2-dichloroethane (40 ml), was mixed with triftormetilfullerenov acid (0,12 ml, 204 mg of 1.36 mmol) and 16 h was stirred at room temperature. In the reaction flask was deposited light oil. Re-added triftormetilfullerenov acid (0,12 ml, 204 mg of 1.36 mmol) and 5 h was heated in a flask with reflux condenser. The composition at room what the temperature was mixed with water (30 ml) and 1N sodium lye (10 ml) and was stirred 30 min. The phases were separated. The aqueous phase was extracted with 1,2-dichloroethane (3×30 ml). The organic phases were combined, dried with sodium sulfate and concentrated. The rest was a solid beige color (455 mg), which was separated by chromatography [silica gel 60 (120 g); ethyl acetate/methanol 4:1 (500 ml), ethyl acetate/methanol 1:1 (500 ml), methanol (300 ml)]. 4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)] (non-polar diastereoisomer) was isolated as a colourless solid with a yield of 30% (133 mg). Polar diastereoisomer was contaminated (158 mg, 35%).

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)], citrate (1:1), non-polar diastereoisomer (Approx. 23)

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)] (non-polar diastereoisomer) (120 mg, of 0.332 mmol) was dissolved at 60°C. in ethanol (15 ml) and was mixed with ethanol solution (2 ml) of citric acid (140 mg, 0.73 mmol). After 22 h was added diethyl ether (20 ml). After 30 min was separated colourless solid by filtration and washed with ethanol/ethyl acetate 1:1 (3 ml) and diethyl ether (2 ml). Approx. 23 was obtained with the yield of 56% (102 mg) with a melting point in 273-277°C.

1H-NMR (300 MHz, DMSO-d6) δ frequent. per million: 1.80-2.04 (m, 2H), 2.18-2.4 (m, 4H), 2.48 (s, 6H), 2.57 (dd, 4H), 2.79 (t, 2H), 3.91 (t, 2H), 7.15-7.3 (m, 6H), 8.24 (d, 1H), 8.94 (s, 1H),12.17 (s, 1H).

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)], citrate (1:1), polar diastereoisomer (Approx. 24)

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)] (polar diastereoisomer contaminated) (140 mg, 0.38 mmol) was dissolved in ethanol (7 ml) and was mixed with citric acid (163 mg, 0.85 mmol), dissolved in ethanol (2 ml). The hour had begun deposition. After 2 h by filtering the separated colourless solid (103 mg) and washed with ethanol (2×2 ml) and diethyl ether (2 ml). The filtrate was mixed with diethyl ether (10 ml), the precipitate was separated and washed with diethyl ether (2×2 ml) (38 mg). Two fractions of solids were combined and mixed with sodium lye and trichloromethane (107 mg). The obtained solid in ethanol (30 ml) was mixed with citric acid (124 mg, of 0.65 mmol)dissolved in ethanol (3 ml). After 20 min, the separated solid was washed with ethanol (2×3 ml) and diethyl ether (2×2 ml) (59 mg). The filtrate was mixed with diethyl ether (30 ml) and 16 h was stirred at room temperature. By filtering and washing with diethyl ether (2×2 ml) was allocated colorless solid.

Output (Approx. 24): 0,040 g (25%), melting point in 122-127°C.

1H-NMR (300 MHz, DMSO-d6) δ frequent. per million: 1.63 (t, 2H), 1.92 (d, 2H), 2.13-2.27 (m, 2H), 2.36 (s, 6H), 2.57 (dd, 4H), 2.68-2.83 (m, 4H), 3.99 (t, 2H), 7.32 (d, 1H), 7.49-7.63 (m, 3H), 7.66-7.73 (m, 2H), 8.15 (d, 1H), 8.83 (s, 1H), 11.50 (s, 1H).

Example 25

4-Butyl-4-(dimethylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), non-polar diastereoisomer

Example 26

4-Butyl-4-(dimethylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), polar diastereoisomer

4-Butyl-4-(dimethylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)] (non-polar and polar diastereoisomer)

The ketone Ket-9 (462 mg, 2.34 mmol) together with astrobiolog Ind-1 (380 mg, 2.34 mmol) was dissolved in 1,2-dichloroethane (40 ml). Then was carried out by adding triftormetilfullerenov acid (773 mg, 0,457 ml of 5.15 mmol), and the composition was bleached. All together was stirred 4 days. by CT. For processing the reaction mixture was mixed with water (10 ml)with 1N NaOH (10 ml) was adjusted to pH 11, and 15 min were mixed. Then the phases were separated. The aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic extracts were dried with sodium sulfate, filtered and vacuum concentrated. The brown oil residue was mixed with methanol (10 ml), and precipitated precipitated colorless solid, which was aspirated and washed with methanol (10 ml). It was a 4-butyl-4-(dimethylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)] (depolar the initial diastereoisomer) (39 mg, 5%, slightly polluted). The mother liquor was concentrated and separated using chromatography [silica gel 60 (50 g); ethyl acetate (1200 ml), ethyl acetate/methanol 4:1 (500 ml), 1:1 (500 ml)]. Received a yellow solid (239 mg), which is 30 min heavily mixed with chloroform (25 ml), 1N NaOH (5 ml) and water (10 ml). Then the phases were separated. The aqueous phase was extracted with chloroform (2×10 ml). The combined organic extracts were dried with sodium sulfate, filtered and vacuum concentrated. Yellow semi-solid residue (230 mg, 30%) was a polar diastereoisomer, which contained approx. 24% of the non-polar product. The separation was going to happen over the formation of citrate.

4-Butyl-4-(dimethylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), non-polar diastereoisomer (Approx. 25)

4-Butyl-4-(dimethylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)] (non-polar diastereoisomer) (27 mg, 0.08 mmol) was dissolved in ethanol (20 ml) by heating and mixed with citric acid (37 mg, 0,192 mmol), dissolved in hot ethanol (5 ml). After 20 h stirring at RT the bright solution was almost completely concentrated and mixed with diethyl ether (5 ml). In the sediment began to fall colourless solid, which was aspirated.

Output (Approx. 25): 38 mg (88%).

The point is and melting: 86-92°C.

4-Butyl-4-(dimethylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), polar diastereoisomer (Approx. 26)

4-Butyl-4-(dimethylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)] (non-polar diastereoisomer) (contaminated non-polar diastereoisomer, 230 mg, 0.67 mmol) was dissolved in ethanol (20 ml) by heating and mixed with citric acid (310 mg, of 1.62 mmol), dissolved in hot ethanol (5 ml). After one hour of stirring at RT the bright solution was concentrated to CA. a third of its volume and was mixed with diethyl ether (10 ml). In the sediment began to fall colourless solid, which was aspirated.

Output (Approx. 26): 91 mg (25%).

Melting point: 95-103°C.

Example 27

4-Benzyl-4-morpholino-Spiro[cyclohexane-1,8'-(3-trifluoromethyl-5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), 1 diastereoisomer

Ket-13 (0,593 g, 2,17 mmol) were placed together c Ind-3 (0.5 g, 2,17 mmol) in ultrashort dichloromethane (11 ml). A microwave vessel was closed with septum and flushed with nitrogen. Then carried out quickly add trimethylsilyltrifluoromethane (1,68 ml, 8.69 mmol). The composition was heated for 10 min at 120°C in the microwave. Then the reaction mixture was mixed with 1M aqueous solution of Na2CO3and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with what dichloromethane (3x). The combined organic extracts were washed with water and saturated NaCl solution and dried over MgSO4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. The obtained foamy solid was purified by column chromatography (silica gel 60 KG; dichloromethane:ester acetic acid 9:1). Received 4-benzyl-4-morpholino-Spiro[sikorksy-1,8'-(3-trifluoromethyl-5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)] (0.12 g, 8,2%) as a cream solid color.

Solid (0,120 g, 0.25 mmol) was dissolved in hot ethanol (15 ml) and was mixed with citric acid (0,051 g) and diethyl ether (10 ml). The solution was stirred over night at room temperature. The solvent was removed in a rotary evaporator apparatus. The residue was led by using n-hexane/ethanol (10 ml; of 9.5:0.5 to). The solid was aspirated and dried under high vacuum at 60°C.

Output (Approx. 27): 0,173 g (100%).

Example 28

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(3-trifluoromethyl-5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), 1 diastereoisomer

Ket-1 (0,283 g of 1.30 mmol) were placed together with Ind-3 (0.3 g, of 1.30 mmol) in ultrashort dichloromethane (3.4 ml). A microwave vessel was closed with septum and flushed with nitrogen. Then carried out quickly add trimethylsilyltrifluoromethane (1,01 ml, 5.2 mm is eh). The composition was heated for 10 min at 120°C in the microwave. Then the reaction mixture was mixed with 1M aqueous solution of Na2CO3and was stirred 20 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x). The combined organic extracts were washed with water and saturated NaCl solution and dried over MgSO4. After filtration of the drying agent the solvent was removed in a rotary evaporator apparatus. The obtained foamy solid was purified by column chromatography (silica gel 60 KG, dichloromethane:methanol 9:1) (0,116 g, 20.7 per cent). For the deposition of citrate solid (0,100 g, 0.23 mmol) was dissolved in hot ethanol (2 ml) and was mixed with citric acid (0,058 g) and diethyl ether (45 ml). Was stirred at room temperature for 1. The solid was aspirated and 5 h was dried in high vacuum at 60°C.

Output (Approx. 28): to 0.108 g (75%).

Example 29

4-(Azetidin-1-yl)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (1:1), 1 diastereoisomer

The ketone Ket-15 (275 mg, 1.2 mmol) was dissolved together with astrobiolog Ind-1 (195 mg, 1.2 mmol) in dichloromethane (30 ml). Then was carried out by adding triftormetilfullerenov acid (397 mg, 0,235 ml of 2.64 mmol), and the composition was painted in a dark color. Was stirred 20 h at RT. For processing the reaction mixture was mixed with 1N NaOH (10 ml) and water (10 ml) and 10 min paramesh the Wali. The color changed from dark red to light brown. The phases of the filtrate were separated. The aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were dried with sodium sulfate, filtered and concentrated in vacuum. Received a yellow solid, which was stirred 10 min with dichloromethane (5 ml), then was aspirated and washed with dichloromethane (5 ml) (116 mg, 26%, diastereoisomers pure, melting point: 269-274°C).

Solid (101 mg, 0.27 mmol) was heated in ethanol (60 ml) to a boil. To turbid solution was added citric acid (125 mg, of 0.65 mmol), dissolved in hot ethanol (5 ml). The solution was transparent. After 20 h stirring at RT the solution was concentrated to approx. 3 ml and was mixed with diethyl ether (5 ml) prior to crystallization. Precipitated precipitated colorless residue was aspirated and washed with diethyl ether (5 ml).

Output (Approx. 29): 80 mg (53%).

Melting point: 208-212°C.

1H-NMR (300 MHz, DMSO-d6) δ frequent. in mn: 1.50-1.81 (m, 2H), 1.81-2.04 (m, 4H), 2.04-2.25 (m, 2H), 2.30-2.50 (m, 2H), 2.56 (dd, J=26.01, 15.16 Hz, 4H), 2.64-2.77 (m, 2H), 3.47-3.77 (m, 4H), 3.97 (t, J=5.08 Hz, 2H), 6.89-7.07 (m, 1H), 7.46-7.89 (m, 6H), 8.00-8.16 (m, 1H), 11.44 (s, 1H).

13C-NMR (101 MHz, DMSO-d6) δ frequent. per million: 15.3, 21.6, 24.2, 30.6, 44.0, 47.6, 59.0, 62.8, 71.1, 71.3, 104.2, 114.9, 118.6, 125.5, 128.5, 128.9, 132.3, 138.8, 141.8, 148.5, 171.1, 176.5.

Example 30

4-Butyl-4-(pyrrolidin-1-yl)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro the-pyrano[3,4-b]-7-Aza-indole)]; citrate (2:1), 1 diastereoisomer

The ketone Ket-16 (268 mg, 1.2 mmol) and 7-attrition (Ind-1, 195 mg, 1.2 mmol) was dissolved in abs. 1,2-dichloroethane (40 ml) and mixed with triftormetilfullerenov acid (0,117 ml, 198 mg of 1.32 mmol) and stirred 3 days. at room temperature. 7 h was heated up to 80°C (bath temperature), then added triftormetilfullerenov acid (0,117 ml, 198 mg of 1.32 mmol) and 8 h was stirred at 80°C. the Mixture was stirred for another 5 days at room temperature. The composition was mixed with water (15 ml) and 1N sodium lye (5 ml) and was stirred 15 min. The phases were separated. The aqueous phase was extracted with 1,2-dichloroethane (2×20 ml). The organic phases were combined, dried with sodium sulfate and concentrated. The rest was a solid beige color (424 mg), which resuspendable in ethyl acetate/methanol 4:1 (3 ml). When this precipitate began to fall colorless solid. Added ethyl acetate (5 ml) and a solid substance was separated by filtration. Received 4-butyl-4-(pyrrolidin-1-yl)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)] (diastereoisomer net output in 12% (52 mg) with a melting point in 246-250°C.

The filtrate was concentrated and separated using chromatography [silica gel 60 (50 g); ethyl acetate/methanol 4:1 (500 ml), methanol (200 ml)] and thus provided additional product (107 mg, 24%).

Solid (91 is g, 0,247 mmol) at 30°C was dissolved in ethanol (7 ml) and was mixed with ethanolic citric acid (105 mg, 0,545 mmol, 3 ml). After 2 h, the solution was mixed with simple ethyl ether (50 ml) and stirred 2 days. at room temperature. Thus was formed a light brown precipitate, which was separated by filtration (50 mg). The filtrate was concentrated, resuspendable in ethanol (1 ml)was mixed with diethyl ether (20 ml) and was stirred 30 min. In the sediment precipitated colorless solid, which was filtered and washed with diethyl ether (2×2 ml) (50 mg). Both solids were identical.

Output (Approx. 30): 0,100 g (54%).

1H-NMR (300 MHz, DMSO-d6) δ frequent. per million: 1.02 (t, 3H), 1.25-1.53 (m, 5H), 1.63-1.75 (m, 2H), 1.79-2.08 (m, 15H), 2.58-2.74 (m, 6H), 3.93 (t, 2H), 6.99-7.07 (m, 1H), 7.79-7.86 (m, 1H), 8.13-8.18 (m, 1H).

Example 31

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-thiopyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), 1 diastereoisomer

Ind-4 (258 mg, 1.2 mmol) under argon was dissolved together with the ketone Ket-1 (261 mg, 1.2 mmol) in abs. 1,2-dichloroethane (24 ml) and mixed with triftormetilfullerenov acid (of 0.44 ml, 4,96 mmol). The composition was stirred 1 h at 150°C in the microwave. For processing the reaction solution was mixed with a saturated solution of sodium bicarbonate (10 ml). The mixture was stirred for a further 15 minutes After separation of the phases the aqueous phase was extracted with dichlo is methane (3×10 ml). The combined organic extracts were dried over Na2SO4and then concentrated. The crude product (346 mg, yellow foam) was purified column chromatography [silica gel 60 (20 g); cyclohexane/ethyl acetate 4:1 (500 ml), cyclohexane/ethyl acetate 1:1 (1000 ml)].

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-thiopyrano[3,4-b]-7-Aza-indole)] was obtained in the form of a solid beige color (87 mg, 19%, TPL: 246-253°C, diastereoisomers clean). From the aqueous phase during the night to precipitate additional product. The solid was filtered and washed with water (3×0.5 ml) and methanol (2×0.5 ml) (51 mg, 11% solid beige color, melting point 262-267°C).

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-thiopyrano[3,4-b]-7-Aza-indole)] (135 mg, 0,358 mmol, diastereoisomers pure) was dissolved in dichloromethane (6 ml) and mixed with citric acid (78 mg, 0,406 mmol), dissolved in ethyl acetate (12 ml). While adding acid to the residue to precipitate. Then the mixture was stirred 17 h at 23°C, then filtered and the precipitate washed with ethyl acetate (3×0.5 ml).

Output (Approx. 31): 188 mg (92%), white solid.

Melting point: 130-136°C.

1H-NMR (400 MHz, CD3OD) δ frequent. per million: 2.01-2.15 (m, 4H), 2.52-2.71 (m, 7H), 2.71-2.90 (m, 5H), 2.90-3.05 (m, 6H), 7.02 (dd, J=7.79, 4.86 Hz, 1H), 7.59-7.72 (m, 3H), 7.74-7.81 (m, 2H), 7.81-7.88 (m, 1H), 8.08 (d, J=4.40 Hz, 1H).

133OD) δ frequent. per million: 24.4, 25.2, 28.4, 34.9, 38.4, 44.7, 45.4, 70.5, 74.2, 110.0, 116.4, 121.9, 127.9, 130.7, 130.8, 130.9, 131.5, 138.8, 143.1, 148.6, 174.7, 179.0.

Example 32

4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-thiopyrano[3,4-b]-5-Aza-indole)], citrate (1:1), 1 diastereoisomer

Ind-5 (430 mg, 2.0 mmol) under argon was dissolved together with the ketone Ket-1 (435 mg, 2.0 mmol) in abs. 1,2-dichloroethane (25 ml) and mixed with triftormetilfullerenov acid (of 0.533 ml, 6.0 mmol). The composition was stirred 1 h at 150°C in the microwave. For processing the reaction solution was mixed with 1N-sodium hydroxide solution (20 ml). The mixture was stirred an additional 15 minutes After separation of the phases the aqueous phase was extracted with dichloromethane (3×20 ml). The combined organic extracts were dried over Na2SO4and then concentrated. The crude product (715 mg, brown solid) was purified column chromatography [silica gel 60 (30 g); cyclohexane/ethyl acetate 4:1 (500 ml), cyclohexane/ethyl acetate 2:1 (600 ml), ethyl acetate/methanol 100:1 (1000 ml), ethyl acetate/methanol 5:1 (600 ml)]. 4-(Dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-thiopyrano[3,4-b]-5-Aza-indole)] was obtained as an almost white solid (320 mg, 42%, TPL: 163-168°C, diastereoisomers net).

Solid (233 mg, 0,617 mmol) was dissolved in hot isopropanol (10 ml) and was mixed with citric acid (130 mg, 0,677 mmol), restoren the th in hot isopropanol (10 ml). During the addition of acid precipitated sludge. Then the mixture was stirred 2 h at 5°C, then filtered and the precipitate was washed with isopropanol (2×0.5 ml) and acetone (3×0.5 ml).

Output (Approx. 32): 350 mg (97%), white solid.

Melting point: 132-140°C.

1H-NMR (400 MHz, DMSO-d6) δ frequent. per million: 1.04 (d, J=5.87 Hz, 1.5H), 1.82-2.03 (m, 4H), 2.16-2.39 (m, 7H), 2.49-2.70 (m, 5H), 2.75-2.91 (m, 2H), 2.91-3.14 (m, 4H), 3.68-3.86 (m, 0.25H), 7.24-7.44 (m, 1H), 7.44-7.84 (m, 5H), 8.07-8.27 (m, 1H), 8.74-8.94 (m, 1H), 11.47 (s, broad, 1H).

13C-NMR (101 MHz, DMSO-d6) δ frequent. per million: 23.3, 23.5, 25.4, 27.4, 33.4, 37.5, 44.0, 44.6, 62.0. 65.3, 71.5, 107.1, 109.8, 123.8, 126.6, 127.5, 128.6, 128.7, 131.9, 136.7, 138.1, 139.3, 140.4, 171.3, 176.5.

Example 33

4-(1-Methyl-1H-1,2,4-triazole-5-yl)-4-(methylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (1:1), polar diastereoisomer

Example 34

4-(1-Methyl-1H-1,2,4-triazole-5-yl)-4-(methylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (1:1), non-polar diastereoisomer

4-(1-Methyl-1H-1,2,4-triazole-5-yl)-4-(methylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)] (non-polar and polar diastereoisomer)

The ketone Ket-17 (250 mg, 1.2 mmol) and 7-attrition (Ind-1,195 mg, 1.2 mmol) was dissolved in abs. 1,2-dichloroethane (30 ml) under argon was mixed with methanesulfonic acid (0,467 ml, 692 mg, 7.2 mmol). After 17 h the composition of 7 h was stirred at a temperature bath at 90°C and 15 hours at 75°C. the Reaction mixture was mixed with 1N sodium y the beginning (15 ml) and water (10 ml) and was stirred 15 min. The phases were separated. The aqueous phase was extracted with 1,2-dichloroethane (2×20 ml). The organic phases were combined, dried with sodium sulfate and concentrated. The rest was a solid beige color, which resuspendable in ethyl acetate (5 ml). When this started to precipitate a colorless solid, which was separated by filtration and washed with ethyl acetate (2 ml).

Received 4-(1-methyl-1H-1,2,4-triazole-5-yl)-4-(methylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)] in a mixture of diastereoisomers (130 mg). The filtrate was concentrated and separated using chromatography [silica gel 60 (30 g); ethyl acetate/methanol 6:1 (700 ml)] (220 mg, colorless solid, a mixture of diastereoisomers).

Both factions have chromatographically [silica gel 60 (20 g); chloroform/methanol 30:1 (500 ml)] and was assigned 4-(1-methyl-1H-1,2,4-triazole-5-yl)-4-(methylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)] (non-polar diastereoisomer) with access to 40% (164 mg) as a colourless solid with a melting point in 282-287°C. the Polar diastereoisomer was obtained with the yield of 11% (48 mg) with a melting point in 285-289°C.

4-(1-Methyl-1H-1,2,4-triazole-5-yl)-4-(methylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (1:1), polar diastereoisomer (Approx. 33)

4-(1-Methyl-1H-1,2,4-triazole-5-yl)-4-(methylamino)-Spiro[clohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)] (polar diastereoisomer) (48 mg, 0,136 mmol) was dissolved by heating in ethanol (20 ml) and was mixed with citric acid (58 mg, 0.3 mmol)dissolved in ethanol (2 ml). After 3 days of stirring at room temperature a clear solution was almost entirely concentrated and the residue was mixed with diethyl ether (5 ml) prior to crystallization.

Output (Approx. 33): 71 mg (96%), colorless solid.

Melting point: 90-93°C.

1H-NMR (300 MHz, DMSO-d6) δ frequent. per million: 1.72-1.92 (m, 2H), 1.92-2.02 (m, 2H), 2.04 (s, 3H), 2.07-2.19 (m, 4H), 2.56-2.83 (m, 10H), 3.91 (t, J=5.17 Hz, 2H), 4.10 (s, 3H), 6.94-7.09 (m, 1H), 7.78 (s, 1 H), 7.79-7.86 (m, 1H), 8.10-8.22 (m, 1 H), 11.35 (s, 1H).

13C-NMR (101 MHz, DMSO-d6) δ frequent. per million: 21.7, 27.0, 28.9, 29.0, 37.2, 42.8, 55.4, 59.1, 70.7, 72.3, 104.1, 115.0, 118.7, 125.7, 139.8, 141.8, 148.2, 148.9, 158.1, 171.2, 174.7.

4-(1-Methyl-1H-1,2,4-triazole-5-yl)-4-(methylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], non-polar diastereoisomer (Approx. 34)

4-(1-Methyl-1H-1,2,4-triazole-5-yl)-4-(methylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)] (non-polar diastereoisomer) (149 mg, 0,423 mmol) was dissolved in ethanol (20 ml) and was mixed with citric acid (179 mg, of 0.93 mmol)dissolved in ethanol (2 ml). After 3 days. mixing at room temperature, it was possible to suck citrate 8K/9K in the form of a colorless solid.

Output (Approx. 34): 74 mg (91%).

Melting point: 192-193°C.

1H-NMR (300 MHz, DMSO-d6) δ frequent. per million: 1.80-2.10 (m, 6H), 2.11 (s, 3H), 2.52-2.77 (m, 8H), 3.95 (t, J=5.27 Hz, 2H), 4.08 (s, 3H), 6.93-7.04 (m, 1H), 7.73-7.83 (m, 1H), 7.99 (s, 1H), 8.06-8.16 (m, 1H), 11.41 (s, 1H).

13C-NMR (101 MHz, DMSO-d6) δ frequent. per million: 21.7, 27.7, 29.0, 31.2, 38.0, 38.9, 43.4, 57.0, 59.0, 71.2, 71.8, 104.1, 114.9, 118.6, 125.5, 139.2, 141.8, 148.5, 149.3, 152.4, 171.2, 175.7.

Research on the effectiveness of the connection according to the invention

Measurement of binding ORL1

Cyclohexane derivatives of the General formula I were investigated in the analysis of the binding3H-nociceptin/orphanin FQ with membranes of recombinant CHO-ORL1 cells. This test system was carried out according to the method presented by Ardati et al. (Mol. Pharmacol., 51, 1997, cc.816-824). Concentration3H-nociceptin/orphanin FQ in these experiments was 0.5 nm. Analyses of binding were carried out with 20 μg of membrane protein in 200 µl of composition 50 mm Hepes, pH of 7.4, 10 mm MgCl2and 1 mm EDTA. Binding to the ORL1-receptor was determined using 1 mg of WGA-SPA Beads (Amersham-Pharmacia, Freiburg) by one-hour incubation composition by CT and subsequent measurement in a Trilux scintillation counter (Wallac, Finland). Affinity are listed in table 1 as nanomolar Kivalue or % inhibition at C=1 ám.

Measurement of the µ-link

The affinity of the receptor for the human μ-opiate receptor was determined in a homogeneous composition in microtiter plates. To do this, incubated with the diluted series of relevant verifiable connections receptory membrane preparation (15-40 μg of protein per 250 μl of incubation composition) Cho-K1 cells, which Express the human μ-opiate receptor (RB-HOM receptor membrane preparation firm NEN, Zaventem, Belgium) in the presence of 1 nmol/l of the radioactive ligand [3H]-naloxone (NET719, firm NEN, Zaventem, Belgium)and 1 mg of WGA-SPA Beads (Wheat germ agglutinin SPA Beads company Amersham/Pharmacia, Freiburg, Germany) in a total volume of 250 μl for 90 minutes at room temperature. As the incubation buffer used 50 mmol/l Tris-HCl supplemented from 0.05 wt.% of sodium azide and with 0.06 wt.% albumin bovine serum. To determine nonspecific binding was further added 25 μmol/l of naloxone. After ninety-minutes long incubation period microtiter tablets was separated by centrifugation and within 20 minutes at 1000 g and the radioactivity was measured in a B-counter (Microbeta-Trilux, the company PerkinElmer Wallac, Freiburg, Germany). Determined the percentage displacement of the radioactive ligand from its binding to the human μ-opiate receptor at a concentration of reference substance in 1 µmol/l and indicated as the percentage inhibition (% inhibition) of the specific binding. Partly on the basis of the percentage displacement, due to the different concentrations of the control compounds of General formula I IC50expected inhibiting concentration that caused a 50% displacement of the radioactive Li gang is and. By recalculation using the proportion of Chen-Prusoff (Cheng-Prusoff) received Ki values for test compounds.

Check analgesia in the test "OTDELENIE tail (Tail-Flick) in mice

Mice every time one was placed in a cell for testing and tail were subjected to focusing thermal radiation electric lamp (Tail-flick-Typ 50/08/1. bc, Labtec, Dr. Hess). The light intensity was set so that the time from switching on the lamp to flash otdergivanija tail (pain latency) naturgas treatment of mice was 3 to 5 seconds. Before the introduction of solutions containing the compound according to the invention, or the appropriate standard solutions mouse for five minutes twice subjected to a preliminary test, and the average value of these measurements was calculated as the average pre-test.

Solutions of compounds of General formula I according to the invention, as well as standard solutions were then introduced intravenously. The pain measurement was made every 10, 20, 40 and 60 minutes after intravenous injection. Analgesic effect was defined as an increase in pain latency (% of the maximum possible antinociceptive effect) according to the following formula:

[(T1-T0)/(T2-T0)]×100

At the same time T0represents the latent period is before the introduction, time T1a latent period after application of the combination of active substances and the time T2- maximum exposure (12 seconds).

Check analgesia in the test "OTDELENIE tail (Tail-Flick) on rats

Analgesic activity of the tested compounds were investigated focal beam through a test "otdergivanija tail (Tail-flick) on rats according to the method D of the Amur river and Smith (D'amour and Smith) (J.Pharm. Exp. Ther. 72, 74 79 (1941)). Used female rats Sprague Dawley with a mass between 134 189, Animals are individually placed in a special cage for testing and tail were subjected to focusing thermal radiation lamp (Tail-flick Tour 50/08/1 .bc extension, Labtec, Dr. Hess). The light intensity was set so that the time from switching on the lamp to flash otdergivanija tail (pain latency) naturgas treatment of animals was 2.5-5 seconds. Before taking the tested compounds animals twice pre-tested within 30 minutes and the average value of these measurements was calculated as the average pre-test. The pain measurement was performed at 20, 40 and 60 min after the intravenous dose. Analgesic effect was defined as an increase in pain latency (% MPE) according to the following formula:

[(T1-T0)/(T2-T0)]×100

While T0the stand is made by a latent period before and T 1the latent period after administration of the substance, T2is the maximum shutter speed (12 sec).

To determine the dose dependence was applied the appropriate test compound in 3-5 logarithmically increasing doses, every time consisted limit and the maximum effective dose, and the values of the ED50were determined using regression analysis. The calculation of the ED50was carried out at the maximum steps, 20 minutes after intravenous injection of the substance.

The following table represents the approximate connection in the form of reason without the guidance of some of the diastereoisomer in question; in cases in which the approximate connection was presented as salt or dedicated polar and non-polar diastereoisomer, it can be taken from the corresponding description of the synthesis.

Some Ki-values are given in the following table. Ki-values were not determined for all compounds. For example, we studied two compounds in the test "otdergivanija" tail-flick).

ExampleStructure (if necessary, without counterion and denote diastereoisomer)ORL1-receptor, Ki-value [µm]µ-opioid receptor, Ki-value [µm]Tail-flick
10.01470.0123
20.00530.0044Rat, i.v. ED50: 15 ág/kg
30.01970.0147
40.00600.0118Mouse, i.v. 72% MPE at 464 mg/kg
50.18000.3033
60.02370.0250
72.39500.6367
0.06570.0483
90.15330.0773
100.0567
120.06830.0317
130.28000.0817
14
150.0380
17 0.08700.0010
180.66330.0014
192.9067
200.0835
210.02800.0190
220.01670.0337
230.00230.0019
24
250.0006
260.0061
27
282.63670.6375
29
30
31
32
33
34

Parenteral solution spirocycles derivative according to the invention

3 g of one of spirocycles azaindole derivatives according to the invention, in this case, Example 1, at room temperature, was dissolved in 1 l of water for injection purposes and then by addition of anhydrous glucose for injection purposes adjusted to isotonic conditions.

1. Spirocycles isoindoline derivatives of General formula I

which one And N means, and other means of CR7-10,
W means NR4,
X is O or S,
R1and R2independently of one another denote H; C1-5-alkyl, each time a saturated, branched or unbranched,
or the remains of R1and R2together mean CH2CH2Och2CH2or (CH2)3-6,
R3means C1-8-alkyl, each time a saturated, branched or unbranched, nezam the seal or monosubstituted-OC 1-6-alkyl; phenyl, thienyl, morpholinyl, benzothiophene or benzodioxolyl, every time unsubstituted or monosubstituted F or C1-6-alkyl; or a 5-membered heteroaryl containing three nitrogen atom as heteroatoms, substituted C1-3by alkyl; associated With1-3is an alkyl group, phenyl, unsubstituted or monosubstituted F or C1-6by alkyl;
R4means N;
R5means N;
R6means N;
R7, R8, R9and R10mean N or CF3;
in the form of the diastereomers, mixtures of diastereomers or a single diastereoisomer; the bases and/or salts of physiologically compatible acids.

2. Spirocycles azaindole derivative according to claim 1, in which R1and R2mean CH3.

3. Spirocycles azaindole derivative according to claim 1 or 2, in which R3means propyl, butyl, pentyl, hexyl, phenyl, thiophenyl, benzyl, benzodioxolyl or benzothiophene, every time unsubstituted or monosubstituted F, C1-6by alkyl; associated unbranched saturated With1-3-alkyl phenyl group.

4. Spirocycles azaindole derivative according to claim 3 in which R3means butyl, ethyl, 3-methoxypropyl, benzothiophene, phenyl, 3-were 3-forfinal, benzo[1,3]-dioxole, benzyl, 1-methyl-1,2,4-triazolyl, thienyl or phenethyl.

5. Spirocycles azaindole the e derivative according to claim 1 or 2, in which R7, R8, R9and R10mean N.

6. Compounds according to claim 1 or 2, in which the General formula I takes the value of one of General formulas Ia or Ib

and group X and W, as well as the remains of R1-R10have the meanings given in claims 1 to 5.

7. Spirocycles azaindole derivative according to claim 1, selected from the group
(1) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]
(2) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; methanesulfonate
(3) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano [3,4-b]-5-Aza-indole)]
(4) 4-(dimethylamino)-4-thiophene-2-yl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; methanesulfonate
(5) 4-(dimethylamino)-4-thiophene-2-yl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)]
(6) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (4:3)
(7) 4-(methylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)
(8) 4-(methylamino)-4-thiophene-2-yl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (4:3)
(9) 4-(dimethylamino)-4-benzo[1,3-dioxol]-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)
(10) 4-(dimethylamino)-4-(benzothiophen the-2-yl)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)
(12) 4-(dimethylamino)-4-(3-forfinal)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (4:3)
(13) 4-(dimethylamino)-4-(3-were)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)
(14) 4-(dimethylamino)-4-(buta-1-yl)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (1:1)
(15) 4-(dimethylamino)-4-phenylethyl-Spiro[cyclohexane-1,8'-(3-trifluoromethyl-5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)
(17) 4-(dimethylamino)-4-ethyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (2:3)
(18) 4-(dimethylamino)-4-phenylethyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (2:3)
(19) 4-benzyl-4-morpholino-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)
(20) 4-(dimethylamino)-4-(3-methoxypropyl)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)
(21) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)
(22) 4-(dimethylamino)-4-thiophene-2-yl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)
(23) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)], citrate (1:1), non-polar diastereoisomer,
(24) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-5-Aza-indole)], citrate (1:1), the polar diastereomer is,
(25) 4-butyl-4-(dimethylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), non-polar diastereoisomer,
(26) 4-butyl-4-(dimethylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1), polar diastereoisomer,
(27) 4-benzyl-4-morpholino-Spiro[cyclohexane-1,8'-(3-trifluoromethyl-5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)
(28) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(3-trifluoromethyl-5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)
(29) 4-(azetidin-1-yl)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (1:1)
(30) 4-butyl-4-(pyrrolidin-1-yl)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)]; citrate (2:1)
(31) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-thiopyrano[3,4-b]-7-Aza-indole)]; citrate (1:1)
(32) 4-(dimethylamino)-4-phenyl-Spiro[cyclohexane-1,6'-(5,6,8,9-tetrahydro-thiopyrano[3,4-b]-5-Aza-indole)], citrate (1:1)
(33) 4-(1-methyl-1H-1,2,4-triazole-5-yl)-4-(methylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (1:1), polar diastereoisomer,
(34) 4-(1-methyl-1H-1,2,4-triazole-5-yl)-4-(methylamino)-Spiro[cyclohexane-1,8'-(5,6,8,9-tetrahydro-pyrano[3,4-b]-7-Aza-indole)], citrate (1:1), non-polar diastereoisomer,
in the form of the diastereomers, mixtures of diastereomers or a single diastereoisomer; the bases and/or salts of physiologically compatible acids.

8. With the persons receiving spiritlessly isoindoline derivatives of General formula I according to claim 1, where X is Oh, wherein compounds of General formula III is subjected to conversion in the reaction medium in the presence of a fluoride selected from the group consisting of fluoride, Tetra-n-butylamine, hydrofluoric acid (HF, HF-pyridine), potassium fluoride and/or sodium fluoride, cesium fluoride or in the presence of organic or inorganic acids, mainly HCl, acetic acid, triperoxonane acid, nortryptaline, at temperatures mainly from -70 to 300°C To produce compounds of General formula IV

which then adding at least one organic acid or its complex trimethylsilyl ether one or inorganic acid or by adding at least one salt of a transition metal is subjected to interaction with ketones of General formula VII

in a suitable solvent or mixture of solvents such as dichloromethane, dichloroethane, chloroform, acetonitrile, diethyl ether or nitroethane, at temperatures from 0 to 150°C., if necessary with the use of microwaves.

9. Drug for treatment of pain, containing at least one spirocyclohexane azaindole derivative according to claim 1, optionally in the form of pure diastereomers in any mixing ratio; in the form of its bases or in the form of his physical is logically compatible salts; and optionally containing suitable additives and/or auxiliary substances.

10. Use one spirocycles azaindole derivative according to claim 1 optionally in form of its diastereomers in any mixing ratio; in the form of its bases or in the form of its physiologically compatible salts; to obtain drugs for the treatment of pain, in particular acute, neuropathic or chronic pain.

11. Use one spirocycles azaindole derivative according to claim 1 for obtaining a medicinal product for the treatment of States of fear, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, catalepsy, General cognitive dysfunctions, disorders of learning and memory (as nootrop), withdrawal symptoms, abuse and/or dependence of alcohol and/or drug and/or medication, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraine, deafness, lack of bowel motility, impaired food intake, anorexia, obesity, locomotor disorders, diarrhoea, cachexia, urinary incontinence or as a muscle relaxant, anticonvulsive or anaesthetic or for co-admission for treatment with an opioid analgesic or with an anaesthetic, plagiarize or antinatriuretic, anxiolysis, for modulation of motor activity, for modulation of the distribution of neurotransmitters and treatment related neurodegenerative diseases, for the treatment of withdrawal symptoms and/or to reduce the narcotic potential of opioids.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new substituted tertahydro-4H-tieno-pyrrolo[3,2- c] pyridines of general formula 1, their geometric isomers or a mixture whereof and their pharmaceutically acceptable salts. In the general formula 1 Th represents an annulated tien cycle; W represents an single bond (in this case R3 is immediately bonded to the pyrrole cycle nitrogen atom), methylene, 1,2-ethane, 1,2-ethylene, 1,2-acetylene, 1,3-propane or 1,3-allyl bridge, non-obligatorily substituted by a hydroxy group; R1 and R2 represent hydrogen, C1-C4alkyl, a halogen or -CH2OH; R3 represents hydrogen, non-obligatorily substituted phenyl, non-obligatorily substituted by azaheteroaryl; R4 represents C1- C4alkyl, CO2C2H5 or CO2C(CH3)3; R5, R6, R7 (independent of each other) represent hydrogen or C1- C4alkyl or R5 and R6 together form an ethylene bridge while R7 represents hydrogen or R5 and R7 together form an ethylene bridge while R6 represents a hydrogen atom, they representing substituted tetrahydro-4H-tieno-pyrrolo [3,2-c] pyridines pf general formula 1, their geometric isomers, a mixture of such geometric isomers, their pharmaceutically acceptable salts as per any of Items 1-5.

EFFECT: obtainment of compounds representing ligands with receptor activity with regard to alpha-oadrenoreceptors, dopamine receptors, histamine receptors and serotonin receptors which compounds may be used during prevention and treatment of central nervous system diseases and for study of peculiarities of physiologically active substances possession biological activity with regard to the said receptors.

11 cl, 3 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, specifically to 4-substituted-3-(1-alkyl-2-chloro-1H-indol-3-yl)furan-2,5-diones of general formula I , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R3=phenyl, naphthyl, 2-phenyl-1-ethenyl, thienyl, furyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, synthesis method thereof and use as compounds capable of photochemical generation of stable fluorophores of formula II, which can be used, for instance in information storage systems, particularly as photosensitive components of material for three-dimensional recording and storage of information. The invention also relates to novel 4,5-substituted-6-alkyl-1H-furo[3,4-c]carbazole-1,3(6H)diones of general formula II , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R4=H, R5=phenyl, R4, R5=benzo, naphtho, thieno, furo, pyrrolo, benzothieno, benzofuro, indolo, method for synthesis of said compounds and use as fluorophores.

EFFECT: obtaining novel compounds and possibility of using said compounds as fluorophores.

14 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention refers to novel compounds with affinity to MC4 receptors, of the general formula (I): , where A is -CH2- or -C(O)-; R1 is (C1-C8)alkyl; R2 is (C1-C8)alkyl; R3 is radical of the formula -(CH2)s-R'3; R'3 is 5-6-member heterocycloalkyl containing one or two nitrogen atoms and possibly one oxygen atom possibly substituted with (C1-C6)alkyl or benzyl; or radical of the formula -NW3W'3; W3 is hydrogen atom or (C1-C8)alkyl; W'3 is radical of the formula -(CH2)s'-Z3; Z3 is hydrogen atom, (C1-C8)alkyl; s and s' are independently an integer within 0 to 6; B is 5-6-member monocyclic unsaturated, aromatic or non-aromatic radical which can be condensed with 5-6-member unsaturated, aromatic or non-aromatic radical forming bicyclic condensed system, and B is possibly containing one or more equal or different heteroatoms selected out of O, S and N, and possibly substituted with one or more equal or different radicals selected out of halogen atom, nitro group, cyano group, oxy group, -XB-YB and phenyl possibly substituted with one substitute selected out of halogen atom and (C1-C6)alkyl; XB is a covalent bond, -O-, -S-, -C(O)-, -C(O)-O-; YB is (C1-C6)alkyl; or pharmaceutically acceptable salt of claimed compounds.

EFFECT: improved obtainment and application efficiency of compounds for production of drug for treatment of diseases related to MC4 receptor activation.

20 cl, 4 dwg, 2 tbl, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , where R1 is C1-C7-alkyl; R2 is C1-C7-alkyl, C1-C7-haloalkyl, C3-C8-cycloalkyl; R3 is -NRaRb; possibly substituted phenyl, thiophenyl, furanyl, where the substitutes are selected from a group consisting of halogen, C1-C7-alkoxy, C1-C7-alkylsulphonyl and -C(O)O-C1-C7-alkyl; R4 is hydrogen or C1-C7-alkyl; R5 is hydrogen, halogen, C1-C7-alkyl, phenyl; or R5 together with R4 can form a ring selected from a group consisting of C5-C7-cycloalkyl, tetrahydrofuranyl, piperidine, tetrahydropyran, phenyl or pyridinyl, which can possibly be substituted with -C(O)O-C1-C7-alkyl; Ra and Rb together with the nitrogen atom to which they are bonded form piperidine; and to pharmaceutically acceptable salts thereof. The invention also relates to a medicinal agent based on the said compounds which has GABA-B receptor allosteric enhancement effect.

EFFECT: obtaining novel compounds and a medicinal agent based on the said compounds, which can be used in medicine for treating central nervous system disorders.

13 cl, 42 ex

FIELD: pharmacology.

SUBSTANCE: present invention relates to antagonists of serotonin 5-HT5 receptors with general formula 1 and their pharmaceutically acceptable salts and/or hydrates, particularly to substituted 3-sulphonyl-[1,2,3]triazolo[1,5-a]quinazolines and 3-sulphonyl-thieno[2,3-e][1,2,3]triazolo [1,5-a]pyrimidines, as active compounds for pharmaceutical compositions and medicinal agents, and methods of producing said compounds. In general formula 1 , Ar is a phenyl which is unsubstituted or substituted with halogen or at least one lower alkyl; R1 is a hydrogen atom or optionally substituted amine group, or optionally substituted 5-6 member azaheterocyclyl, bonded by a nitrogen atom to a carbon atom of a triazolopyrimidine ring with 1-2 heteroatoms selected from nitrogen, oxygen or sulphur, and optionally annulated with a benzene ring; where the substitutes are selected from hydrogen, optionally substituted C1-C5alkyl, optionally substituted C3-C8cycloalkyl, alkoxy group, acyl, saturated or unsaturated optionally annulated 5-7 member heterocyclyl, where heteroatoms are selected from nitrogen, oxygen or sulphur, optionally substituted phenyl; R2 and R3 together with carbon atoms to which they are bonded form an optionally substituted benzene or thiophene ring, where substitutes are selected from C1-C5alkyl or halogen atom.

EFFECT: invention also relates to pharmaceutical compositions and medicinal agents, a method of treating or preventing development of CNS diseases mediated by action of serotonin 5-HT5 receptors, for example Alzheimer's disease.

20 cl, 6 dwg, 4 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes a compound of the general formula (I) or (II) wherein R1 represents hydrogen atom; R2 is taken among the group consisting of aryl and heteroaryl; R3 is taken among the group consisting of halogen atom, nitro-, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl, trifluoromethoxy-group, -NH2, -NH-(C1-C6)-alkyl and -N-(C1-C6)-alkyl)2; b is a whole number from 0 to 4; R4 is taken independently among the group consisting of halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxycarbonyl, phenyl (wherein phenyl group can be substituted optionally with one-three substitutes taken independently among RD), phenylsulfonyl, heteroaryl (wherein heteroaryl can be substituted optionally with one-three substitutes taken independently among RD), heterocycloalkyl, -NH2, -NHRA, -N-(RA)2,

wherein each RD is taken independently among halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C4)-alkyl, (C1-C4)-alkylthio, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyl, trifluoromethyl, trifluoromethoxy-group, -NH2. -NHRA, -N-(RA)2, -C(O)N(RA)2, -SO2N(RA)2, acetylamino-, nitro-, cyano-group, formyl, (C1-C6)-alkylsulfonyl, carboxy-(C1-C6)-alkyl and aralkyl; c = 0; a means a whole number from 0 to 1; Y is taken among the group consisting of a residue -(C1-C)-alkyl, -C(O)-, -(C2-C6)-alkenyl)-carbonyl, -carbonyl-(C1-C6)-alkyl)-, -C(S)-, -C(O)NH-(C1-C6)_alkyl), -C(O)-(C3-C7)-cycloalkyl)- and (C3-C7)-cycloalkyl)-C(O)-; represents phenyl;

is taken among the group consisting of phenyl, heteroaryl and cycloalkyl under condition that when R1 represents hydrogen atom, R3 represents hydrogen atom, b = 0, c = 1, Y represents -CH2-, represents phenyl and represents phenyl then R2 is not trimethoxyphenyl, and its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition designated for inhibition of activity of phosphodiesterase comprising a pharmaceutically acceptable vehicle and compound by cl. 1, method for preparing pharmaceutical composition, methods for treatment of sexual dysfunction by using compound by cl. 1 or pharmaceutical composition, method for increasing the concentration of cGMP in penis tissue and method for treatment of state when inhibition of activity of phosphodiesterase shows the favorable effect. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 7 tbl, 98 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new anellated carbamoyl azaheterocycles of the general formula (1)

or (2) possessing the inhibitory effect on protein kinase activity, a focused library comprising these compounds, and pharmaceutical composition based on thereof. In the general formula (1) or (2) R1 represents hydrogen atom or optionally substituted (C1-C6)-alkyl; R2 and R3 represent independently of one another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; R4 represents optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; A and B in common with carbon and nitrogen atoms joined to the form an optionally substituted and optionally condensed azaheterocycle; D and F in common with carbon atoms joined form an optionally substituted and optionally condensed phenyl or aryl, optionally substituted and optionally condensed azaheterocycle. K and L in common with carbon and nitrogen atoms joined to them form an optionally substituted azaheterocycle. Also, invention related to methods for preparing compounds of the general formulae (1) or (2).

EFFECT: improved preparing methods.

10 cl, 2 sch, 25 tbl, 7 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of pyridothienodiazepine. Invention describes derivatives of pyridothienodiazepine of the general formula (I):

as a racemate or in form of enantiomers or diastereomers, or their mixture wherein R1 represents hydrogen atom or radical of the formula: R'1-NH-C(Y)- wherein R' represents phenyl radical optionally substituted with one or more similar or different substitutes taken among lower alkyl, lower alkoxy-group, lower alkylthio-group, lower alkoxycarbonyl, lower alkylsulfonyl, halogen atom, trifluoromethyl, trifluoromethyloxy-group, hydroxy-, nitro-, cyano-group, phenyl, phenoxy-group, cycloalkyl or heterocycloalkyl; R2 represents lower alkyl, trifluoromethyl or phenyl radical optionally substituted with one or more similar or different substitutes taken among hydroxy-group, halogen atom, lower alkyl or lower alkoxy-group; X and Y represent independently oxygen (O) or sulfur (S) atom; R3a represents hydrogen atom, lower alkyl, hydroxy-group or radical of the formula -OC(O)R'3a wherein R'3a represents alkyl radical comprising from 1 to 10 carbon atoms optionally substituted with radical of the formula: NR''3aR'''3a wherein NR''3a and R'''3a represent independently hydrogen atom, lower alkyl, phenyl, lower phenylalkyl, alkylcarbonyl or alkoxycarbonyl; R3b represents hydrogen atom or lower alkyl radical; R4 represents radical of the formula: -(CH2)n-CHR'4R''4 wherein n represents a whole number 0, 1, 2, 3, 4, 5 or 6; R'4 and R''4 represent independently hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkylalkyl, phenyl, pyridyl, phenylcarbonyl or adamantyl wherein indicated radicals are substituted optionally with one or more similar or different substitutes taken among hydroxy-group, halogen atom, trifluoromethyl, lower alkyl or lower alkoxy-group; A----B represents -C=N- or -C-N(R5)- wherein R5 represents hydrogen atom, amino-radical, lower alkylamino-group, di-(lower alkyl)-amino-group, cycloalkyl, heterocycloalkyl, guanidyl optionally substituted with nitro- or cyano-group, phenyl optionally substituted with one or more similar or different substitutes taken among alkyl or alkoxyalkyl wherein indicated alkyl or alkoxyalkyl are substituted optionally with oxy- or amino-group; indolyl or radical of the formula: -NH-C(O)-(CH2)c-NH-C(O)(CH2)d-NH2; p represents a whole number 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; c and d represent independently a whole number 0, 1, 2 or 3; or salts of these compounds. Also, invention describes methods for preparing compounds of the general formula (I), pharmaceutical composition based on compounds of the general formula (I) eliciting activity to inhibit binding somatostatin-14 and an intermediate compound of the formula (2) given in the invention description. Invention provides preparing new compounds eliciting useful biological properties.

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

17 cl, 70 ex

FIELD: chemistry.

SUBSTANCE: compounds, which have formula I , in which A, B, R1, R1a, R2, R3, R4, R5 R6, R7 and R8 have values given in description and are inhibitors of receptor tyrosinkinases, useful in treatment of diseases, mediated by class 3 and class 5 receptor tyrosinkinases. It has been also discovered that specific compounds of the claimed invention are Pim-1 inhibitors. Also claimed is method of obtaining formula I compound.

EFFECT: increase of compound efficiency.

27 cl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, specifically to 4-substituted-3-(1-alkyl-2-chloro-1H-indol-3-yl)furan-2,5-diones of general formula I , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R3=phenyl, naphthyl, 2-phenyl-1-ethenyl, thienyl, furyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, synthesis method thereof and use as compounds capable of photochemical generation of stable fluorophores of formula II, which can be used, for instance in information storage systems, particularly as photosensitive components of material for three-dimensional recording and storage of information. The invention also relates to novel 4,5-substituted-6-alkyl-1H-furo[3,4-c]carbazole-1,3(6H)diones of general formula II , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R4=H, R5=phenyl, R4, R5=benzo, naphtho, thieno, furo, pyrrolo, benzothieno, benzofuro, indolo, method for synthesis of said compounds and use as fluorophores.

EFFECT: obtaining novel compounds and possibility of using said compounds as fluorophores.

14 cl, 2 tbl, 8 ex

FIELD: medicine; pharmacology.

SUBSTANCE: new annelated asaheterocycles include pyrimidine fragment of general formula I in the form of free bases or pharmaceutically acceptable salts. Compounds of this invention possess properties of PI3 kinase inhibitors. In general formula I X represents oxygen atom or sulphur atom; Z represents oxygen atom, R1 represents hydrogen atom or optionally substituted C1-C6alkyl, or Z represents nitrogen atom together with bound carbon atom forming through Z and R1 optionally substituted annelated imidazoline cycle; R2 represents optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, possibly annelated with 5-6-term heterocyclyl containing heteroatoms chosen from oxygen and nitrogen, optionally substituted 5-6-term heterocyclyl containing heteroatoms chosen from nitrogen, oxygen and/or sulphur, possibly annelated with phenyl ring. Invention also concerns method of production of compounds, pharmaceutical compositions and medical products.

EFFECT: effective application for preparation of medical products for oncologic therapy.

14 cl, 3 dwg, 1 tbl, 4 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel polycyclic compounds of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7, cycle A, cycles B, X, Y and Z have values given in the invention claims and in description of the claim, and to their pharmaceutically acceptable salts also. Proposed compound possess an antitumor activity and can be used in treatment of oncological diseases. Also, invention relates to a pharmaceutical composition based on these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

23 cl, 1 tbl, 57 ex

FIELD: organic synthesis.

SUBSTANCE: invention relates to synthesis of camptotecin analogues from 2'-amino-5'-hydroxypropiophnone corresponding to AB ring portion of camptotecin structure and tricyclic ketone converted into CDE ring portion in camptotecin structure. Preparation of 2'-amino-5'-hydroxypropiophnone comprises following steps: (1) preparing compound (b) by mixing compound (a), benzylation agent, and a base followed by stirring mixture obtained in solvent on heating under reflux; (2) preparing compound (c) by dropwise adding Grignard reagent to compound (b) under an inert gas atmosphere; (3) preparing compound (d) by mixing compound (c) with an oxidant and stirring resulting mixture; and (4) preparing compound (e) via catalytic reduction of compound (d) (see scheme 1 below). Intermediate compounds (c') and (d') are described. Also described is a method for preparing tricyclic ketone to provide efficient complete synthesis of camptotecin serving as starting compound for irinotecan hydrochloride and a various types of camptotecin derivatives as well as for stable preparation of camptotecin and its derivatives. Scheme 1: .

EFFECT: expanded synthetic possibilities in camptotecin derivatives series.

5 cl, 17 tbl, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry of heterocyclic compounds, biology, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of the general formula (1): or (2): or their pharmaceutically acceptable salts, N-oxides or hydrate possessing physiologically active properties, in particular, eliciting ability to induce apoptosis in tumor cells causing their death. In the general formula (1) or (2) X represents sulfur or oxygen atom; Y represents sulfur atom, group -SO, group -SO2, group -NH or group -NR6; R1 represents aryl, substituted aryl, heteroaryl; R2 and R5 represent hydrogen atom, alkyl, allyl, substituted benzyl, group -CH2-C(O)R3, group -CH2-C(O)NR3R4 wherein R3, R4 and R6 represent inert substitute. Also, invention relates to new combinatory libraries for search compound-leaders and candidates for medicinal compounds preparing by screening the combinatory libraries.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new substance eliciting an antiviral and antibacterial activity that is based on derivatives of 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and their 10-aza-analogues. This substance comprises derivative of indicated group of the general formula: A1*M: wherein X is taken among the group: oxygen atom (O), NH, N-alkyl; R1 is taken among the group: hydrogen atom (H), OH, chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, NH-Ar, N-(alkyl)2, SH, S-alkyl; R2 is taken among the group: unsubstituted or substituted phenyl, naphthyl, thienyl; R3 is taken among the group: hydrogen atom (H), chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, S-dihydroxypyrimidinyl; M is absent or taken among the group: cation Na, K, Li, ammonium or any other pharmacologically acceptable cation; or complex of pharmacologically acceptable cation (see above) with anion of one of derivatives of A1 (variants R1-R3 are given above). Invention provides preparing new compounds eliciting an antiviral and antibacterial activity.

EFFECT: valuable medicinal properties of substance.

17 cl, 7 tbl, 16 ex

The invention relates to a method for producing a condensed polycyclic alkaloids of General formula I, including new, including phase cyclization of azometynoylid General formula II, where a is optionally substituted aryl, Z is oxygen, n = 1, Y is optionally substituted aryl, W and X together with the nitrogen atoms and the carbon to which they are attached, form a saturated or unsaturated nitrogen-containing heterocyclic group, possibly substituted and possibly condensed with aryl, carbocyclic or heterocyclic group

The invention relates to novel condensed pyrrolo (2,3-C)carbazole-6-Onam represented by the General formulas (I) and (II)

Therapeutic agents // 2468025

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula:

,

which is atypical antipsychotic drug, and which is used for treatment of schizophrenia, bipolar disorder and anxiety in patients.

EFFECT: obtaining antipsychotic drug, used for treatment of schizophrenia, bipolar disorder and anxiety in patients.

5 cl, 1 tbl, 1 ex

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