Substituted derivatives of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene, method for production thereof and drug having analgesic action

FIELD: organic chemistry.

SUBSTANCE: invention relates to substituted derivatives of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I in form of racemates, pure stereoisomers, particularly enantiomers or diastereomers in any ratio in mixture, in form of acids, or bases, or salts thereof, preferably physiologically acceptable salts, more preferably in form of hydrochlorides or solvates, in particular hydrates, wherein R1 and R2 are independently H, C3-C10-cycloalkyl, optionally substituted with O-alkylaryl, (C1-C12-alkyl)aryl, with the proviso, that at least one R1 and R2 is not H; R3 is H, SOR12 or COR13; R12 and R13 are independently C1-C10-alkyl, monocyclic 5-membered heterocyclic group having at least one heteroatom selected from sulfur atoms, optionally substituted with halogen; OR20, wherein R20 represents H, C1-C10-alkyl. Invention also relates to method for production of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I including a) compound of formula II interaction with methylenation agent, preferably with Ph3PCH3Br in presence of potassium tert-butylate in tetrahydrofuran (THF) to produce compound of formula III; d) compound of formula III interaction with ethylchloroximidoacetate of formula IV in presence of base, preferably of sodium hydrocarbonate or lithium hydroxide, preferably in organic solvent such as methanol, dichloromethane or TGF to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula V; c) compound of formula V interaction, directly or after previous saponification of functional group presenting in formula V (namely carboxylic acid ethyl ester) and optionally after activation of formed functional group (namely carboxylic acid) with amine of formula HNR1R2 wherein R1 and R2 are as defined above, to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula VI; d) protective group removing from compound of formula VI to produce compound of formula I, wherein R3 is H; and optionally e) converting of compound of formula I, wherein R3 is H, by treatment with acid chloride of formula R12SO2Cl to compound of formula I, wherein R3 is SO2R12 or converting by treatment with carboxylic acid chloride of formula R13COCl to compound of formula I, wherein R3 is COR13. Moreover disclosed is drug having analgesic action and containing at least one substituted 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula I.

EFFECT: new drug with analgesic action.

11 cl, 6 tbl

 

The present invention relates to substituted derivatives of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene, and method of production thereof, their use for obtaining medicines and containing these compounds medicines.

The treatment of chronic and nechanicky pain medicine attaches great importance. Currently, however, there remains an urgent need to develop effective methods of targeted, customized for the individual patient therapeutic treatment of chronic and nechanicky pain, involving among other things the successful and satisfactory for the patient's pain therapy. The urgency of this problem is found in numerous recently published scientific papers in the field of applied analgesics and fundamental studies of nociception.

Classical opioids, such as morphine, highly effective in the treatment of severe pain, including severe pain. However, their use is limited to such well-known side effects, such as respiratory depression, vomiting, taking sedatives, constipation and the development of tolerance. In addition, these opioids are ineffective when neuropathic or reappearance of pain, from notoryctidae mainly cancer patients.

Opioids are its analgesic action as a result of binding with the cell membrane receptors that belong to the family of so-called associated with G-protein receptors. Been recently information about the biochemical and pharmacological properties and characteristics of different subtypes of these receptors suggest that having specificity receptor of one or another subtype opioids have different compared to, for example, morphine profile action/spectrum of side effects. Simultaneously, the results of other pharmacological studies with a sufficiently high degree of probability indicate the existence of several subtypes of these opioid receptors (μ1that μ2that κ1that κ2that κ3that δ1and δ2).

Along with these receptors and other receptors and ion channels that play an important role in the occurrence of pain and conducting pain impulses, such as the so-called binding site batrachotoxin (VTH) (binding site 2) on the sodium channel or N-methyl-D-aspartate ion channel of the NMDA ion channel), through which the main interaction between synapses by regulating the exchange of calcium ions between n what erocita and his entourage.

One of the underlying the present invention tasks was to offer possessing analgesic activity of the compounds which would be suitable for pain therapy, and, under certain conditions, including for the treatment of chronic and neuropathic pain. In addition, such substances possibly not need to have any or at least may have manifested only in an insignificant degree of side-effects that usually accompany the use of opioids, such as morphine, and as an example which can be called nausea, vomiting, dependence, respiratory depression or constipation.

This task is solved by having the analgesic action of substituted derivatives of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene General formula (I)

not necessarily in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in the present form or in the form of their acids or their bases or in the form of their salts, especially physiologically compatible salts, or in the form of a solvate, especially hydrates, while

R1and R2independently of one another denote H, C1-18Alki is, With3-10cycloalkyl, (C1-12alkyl)-C3-10cycloalkyl, aryl, (C1-12alkyl)aryl, heterocyclyl, (C1-12alkyl)heterocyclyl or NH-C(=O)aryl, and at least one of the residues R1and R2does not denote H, or together denote -(CR4R5)m-(CR6R7)n-Y-(CR8R9)p-(CR10R11)q-where each of m, n, p and q equal to 0, 1, 2, 3, 4, or 5, provided that m+n≥1 and p+q≥1, or denote-CH2-CH2-C(aryl)=SN-SN2-,

R3denotes H, SO2R12or COR13,

R4, R5, R6, R7, R8, R9, R10and R11independently of one another denote H, C1-10alkyl, C3-8cycloalkyl, (C1-6alkyl)-C3-8cycloalkyl, aryl, (C1-6alkyl)aryl, heterocyclyl, (C1-6alkyl)heterocyclyl or C(=O)R14,

Y represents CR15R16, NR17or,

R12and R13independently of one another denote With1-10alkyl, C3-10cycloalkyl, (C1-6alkyl)-C3-10cycloalkyl, aryl, (C1-6alkyl)aryl, heterocyclyl, (C1-6alkyl)heterocyclyl or NR18R19,

R14denotes H, C1-10alkyl, C3-8cycloalkyl, (C1-6alkyl)-C3-8cycloalkyl, aryl, (C1-6alkyl)aryl, heterocyclyl, (C1-6alkyl)heterocyclyl or or20 ,

R15and R16independently of one another denote H, C1-10alkyl, C3-8cycloalkyl, (C1-6alkyl)-C3-8cycloalkyl, aryl, (C1-6alkyl)aryl, heterocyclyl, (C1-6alkyl)heterocyclyl or C(=O)R21,

R17denotes H, C1-10alkyl, C3-8cycloalkyl, (C1-6alkyl)-C3-8cycloalkyl, aryl, (C1-6alkyl)aryl, heterocyclyl, (C1-6alkyl)heterocyclyl or C(=O)R22,

R18and R19independently of one another denote H, C1-10alkyl, C3-8cycloalkyl, (C1-6alkyl)-C3-8cycloalkyl, aryl, (C1-6alkyl)aryl, heterocyclyl or (C1-6alkyl)heterocyclyl,

R20denotes H, C1-10alkyl, C3-8cycloalkyl, (C1-6alkyl)-C3-8cycloalkyl, aryl, (C1-6alkyl)aryl, heterocyclyl or (C1-6alkyl)heterocyclyl,

R21denotes H, C1-10alkyl, C3-8cycloalkyl, (C1-6alkyl)-C3-8cycloalkyl, aryl, (C1-6alkyl)aryl, heterocyclyl, (C1-6alkyl)heterocyclyl or or23,

R22denotes H, C1-10alkyl, C3-8cycloalkyl, (C1-6alkyl)-C3-8cycloalkyl, aryl, (C1-6alkyl)aryl, heterocyclyl, (C1-6alkyl)heterocyclyl or or24and

R23and R24independently of one another denote H, C1-10alkyl, C3-8cycloalkyl, (C1-6 alkyl)-C3-8cycloalkyl, aryl, (C1-6alkyl)aryl, heterocyclyl or (C1-6alkyl)heterocyclyl.

The above-described proposed in the invention compounds of General formula (I) have proven themselves as possessing analgesic activity of the compounds. These compounds can be contacted with the binding site WITH on the sodium channel, respectively, are NMDA antagonists with analgesic effect.

The terms "alkyl", "C1-18alkyl", "C1-12alkyl", "C1-10alkyl", "C1-8alkyl", "C1-6alkyl", "C1-4alkyl", "C1-3alkyl", "C1-2alkyl" in the context of the present invention refers to an acyclic saturated or unsaturated hydrocarbon residues, which may be branched or straight chain, and may be unsubstituted or one-deputizing or mnogosloinymi identical or different substituents and which contain (as in the case of1-18of alkyl of 1 to 18 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18), respectively (as in the case of1-12of alkyl of 1 to 12 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12), respectively (as in the case of1-10of alkyl of 1 to 10 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), respectively (as in the case of1-8of alkyl of 1 to 8 (i.e. 1, 2, 3, 4, 5, 6, 7 or 8), respectively (as in the case of1-6of alkyl of 1 to 6 (i.e. 1, 2, 3, 4, 5 or 6), respectively (ka is the case With 1-4of alkyl of 1 to 4 (i.e. 1, 2, 3 or 4), respectively (as in the case of1-3of alkyl of 1 to 3 (i.e. 1, 2 or 3), respectively (as in the case of1-2the alkyl), 1 or 2 C-atoms, i.e. With1-18-With1-12-With1-10-With1-8-With1-6-With1-4-With1-3-, respectively, With1-2-alkaline,2-18-With2-12-With2-10-With2-8-With2-6-With2-4-With2-3-, respectively, With2-alkeline and C2-18-With2-12-With2-10-With2-8-With2-6-With2-4-With2-3-, respectively, With2-alkyline group. This alkeneamine groups have at least one double and alkyline group is at least one triple carbon-carbon bond. Preferably the alkyl is selected from the group comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, ethynyl (vinyl), ethinyl, propinyl (-CH2CH=CH2, -CH=CH-CH3-C(=CH2)-CH3), PROPYNYL (-CH2With≡CH,- ≡CH3), butenyl, butynyl, pentenyl, pentenyl, hexenyl, hexenyl, octenyl and octenyl.

The term "C3-10cycloalkyl", respectively "C3-8cycloalkyl" (respectively "cycloalkyl") in the context of the present invention are indicated cyclic saturated or unsaturated what's hydrocarbon residues, which contain 3, 4, 5, 6, 7, 8, 9 or 10, respectively, 3, 4, 5, 6, 7 or 8 C-atoms, with each such residue may be unsubstituted or one-deputizing or mnogosloinym identical or different substituents, and optionally condensed with a benzene nucleus. In addition, such residues can also be a bi-, tri - or polycyclic ring system. As an example of cycloalkyl can be called cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and substituted and bicyclo[3.1.1]heptane-3-yl.

The term "aryl" in the context of the present invention refers to a residue which is selected from the group comprising phenyl, naphthyl, phenanthrene, anthracene and biphenyl, and which may be unsubstituted or mono - or multiply substituted by identical or different substituents. Preferably aryl is an unsubstituted or one-deputizing or multiply substituted by identical or different substituents phenyl, 1-naphthyl or 2-naphthyl.

The term "heterocyclyl" refers to a monocyclic or polycyclic organic residue in which at least one cycle contains 1 heteroatom or 2, 3, 4 or 5 identical or different heteroatoms selected/selected from the group comprising N, O and S and which is saturated or Nena is Ishenim and unsubstituted or one-deputizing or mnogosloinym identical or different substituents. Examples heterocyclyl residues in the context of the present invention are monocyclic five-, six - or semicolonies organic residues with 1 heteroatom or 2, 3, 4 or 5 identical or different heteroatoms, which/which are nitrogen, oxygen and/or sulphur and condensed with a benzene core counterparts. A special subgroup heterocyclyl residues form a "heteroaryl" remains, by which we mean those heterocyclyl groups in which at least one cycle containing one or more heteroatoms, is heteroaromatic. Each such heteroaryl residue may be unsubstituted or one-deputizing or mnogosloinym identical or different residues. As an example heterocyclyl residues in the context of the present invention can be called pyrrolidinyl, tetrahydrofuryl, 1,4-dioxane, piperidinyl, piperazinil first and foremost morpholinyl. Examples of heteroaryl residues are pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, isoxazolyl, thieno[2,3-d]pyrimidinyl, indolyl and pyridinyl, and their condensed with a benzene core counterparts. Each of these residues can be represented in unsubstituted or substituted.

The terms "(1-12alkyl)-C3-10cycloalkyl", "(sub> 1-6alkyl)-C3-10cycloalkyl", "(1-4alkyl)-C3-10cycloalkyl", "(1-3alkyl)-C3-10cycloalkyl", "(1-12alkyl)heterocyclyl", "(1-6alkyl)heterocyclyl", "(1-4alkyl)heterocyclyl", "(1-3alkyl)heterocyclyl", "(1-12alkyl)aryl", "(1-6alkyl)aryl", "(1-4alkyl)aryl and(C1-3alkyl)aryl" in the context of the present invention refers to groups in which cycloalkenyl, heterocyclyl, respectively aryl residue through With1-12-With1-6-With1-4-, respectively, With1-3is an alkyl group linked to a substituted their connection. As an especially preferred example of alkylcyclohexane" should be called cyclopropylmethyl the rest.

In the context of the present invention, the term "substituted"used in respect of "alkyl", "alkenyl", "alkenyl", "quinil" and "cycloalkyl"means, if this term is not otherwise defined in any other place of the present description, respectively, in the formula of the invention, single or multiple substitution of one or several hydrogen atoms, for example, atom (F, Cl, Br, I, group-CN, NH2, NH-alkyl, NH-aryl, NH-alkylaryl, NH-heterocyclyl, N(alkyl)2N(alkylaryl)2N-alkyl-N-aryl, a group of NO2HE, O-alkyl, S-alkyl, O-aryl, O-alkylaryl, O-alkyl-O-alkyl, S(=O)1-61-6alkylaryl, C(=O)-heterocyclyl, a group of CO2N, CO2-alkyl, CO2-alkylaryl, group C(=O)NH2With(=O)NH-alkyl, C(=O)NH, C(=O)NH-heterocyclyl, C(=O)N(alkyl)2With(=O)N(alkylaryl)2, cycloalkyl, aryl or heterocyclyl, under mnogosloinymi refers to the remnants of the remnants of that many times, for example two or three times substituted either on different or on the same atoms, for example three times substituted on the same C-atom, as in the case of CF3or-CH2CF3or on various provisions, as in the case of-CH(OH)-CH=CH-CHCl2. When multiple substitution, the substituents may be identical or different. The most preferred substituted alkyl according to the invention is CF3.

In the context of the present invention the term "substituted"used in respect to "aryl", "heterocyclyl"and "heteroaryl"means single or multiple, for example two, three or four times, substitution of one or more hydrogen atoms of the ring system is an acceptable substitute. If the values of such acceptable surrogates "aryl", "heterocyclyl" and "heteroaryl" is not specifically mentioned in any part of the present description, respectively, in the formula of the invention, such the substituents relative to the fast atom F, Cl, Br, I, group-CN, NH2, NH-alkyl, NH-aryl, NH-alkylaryl, NH-heterocyclyl, N(alkyl)2N(alkylaryl)2the group NO2, SH, S-alkyl, HE, O-alkyl, O-cycloalkyl, O-aryl, O-alkylaryl, O-heterocyclyl, Cho, C(=O)1-6alkyl, C(=O)aryl, C(=O)-C1-6alkylaryl, a group of CO2N, CO2-alkyl, CO2-alkylaryl, group C(=O)NH2With(=O)NH-alkyl, C(=O)NH, C(=O)NH-heterocyclyl, C(=O)N(alkyl)2the group SO2NH2, SO3H, CF3, CHF2CH2F, OCF3, OCHF2, OCH2F, SCF3, SCHF2, SCH2F, alkyl, cycloalkyl, aryl and/or heterocyclyl, and the substitution may be one or, under certain conditions on different atoms (and Deputy under certain conditions, in turn, can also be substituted). When multiple substitution of the substituents, in addition, may be identical or different. The most preferred substituents of "aryl" and "heterocyclyl are1-6alkyl, F, Cl, Br, I, CF3, O-alkyl, OCF3, phenyl, CN and/or NO2.

The expression "condensed with the benzene nucleus in the context of the present invention means that the benzene ring condensed with another cycle.

By "pharmaceutically acceptable salts", respectively "physiologically compatible salts" in the context of the present invention refers to such Sol is proposed in the invention compounds of General formula (I), their pharmaceutical use are physiologically compatible, especially when introduced into the body of a mammal and/or human, i.e. do not lead to any significant acute disturbances of physiological functions of a specific type. Such pharmaceutically acceptable (physiologically compatible salts can be formed, for example, with inorganic or organic acids or bases, if proposed in the invention compounds are acids, especially carboxylic acids.

Preferred pharmaceutically acceptable salts proposed in the invention compounds of General formula (I) are salts formed with hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, n-toluensulfonate acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid. If proposed in the invention compounds are acids, for example carboxylic acid, pharmaceutically acceptable salts can also be formed by interaction with bases such as sodium hydroxide, hydrocarb the NAT sodium or sodium carbonate. Such educated proposed in the invention compounds salts are, in particular, hydrochloride, hydrobromide, phosphates, carbonates, bicarbonate, formate, acetate, oxalate, succinate, tartratami, fumarate, citrates and glutaminate, sodium salt respectively. Equally preferred hydrates proposed in the invention compounds, which can be obtained, for example, by crystallization from aqueous solution.

Proposed in the invention the compounds of formula (I) have at least one asymmetric center may exist in the form of their racemates, in the form of pure enantiomers and/or (if there are multiple asymmetric centers) diastereomers or as mixtures of such enantiomers, diastereomers respectively, namely in the form of substances as such or in the form of physiologically compatible salts of these compounds. The ratio of stereoisomers in these mixtures can be any.

Preferred are those compounds of General structural formula (I), which are presented in the form of pure enantiomers.

Preferred among proposed in the invention compounds of General formula (I) are compounds which are characterized in that

R1and R2independently of one another denote H, C1-8alkyl, C3-8cycloalkyl, (C1-4alkyl)-C3-8silo lcil, aryl, (C1-6alkyl)aryl, heterocyclyl, (C1-4alkyl)heterocyclyl or NH-C(=O)aryl, and at least one of the residues R1and R2does not denote H, or together denote -(CR4R5)m-(CR6R7)n-Y-(CR8R9)p-(CR10R11)q-where m is 1, n is 0 or 1, R is 1 or 2, and q is 1 or 2, or-CH2-CH2-C(aryl)=SN-SN2-,

R3means SO2R12or COR13,

R4, R5, R6, R7, R8, R9, R10and R11independently of one another denote H, C1-8alkyl or C(=O)R14,

Y represents CR15R16or NR17,

R12stands With1-4alkyl, (C1-4alkyl)-C3-8cycloalkyl, aryl, (C1-4alkyl)aryl, heterocyclyl or NR18R19,

R13stands With1-6alkyl, C3-10cycloalkyl, aryl, (C1-4alkyl)aryl or heterocyclyl,

R14indicates OR20,

R15and R16independently of one another represent H, aryl or (C1-4alkyl)aryl,

R17denotes H, C3-8cycloalkyl, aryl, (C1-4alkyl)aryl, heterocyclyl or C(=O)R22,

R18and R19independently of one another denote H or C1-6alkyl,

R20stands With1-6alkyl,

R22denotes aryl, (C1-424and

R24stands With1-6alkyl or (C1-4alkyl)aryl.

Among this group of preferred compounds of formula (I) are particularly preferred subgroup is formed connections

R1stands With1-6alkyl, C3-8cycloalkyl, (C1-3alkyl)-C3-8cycloalkyl, aryl, (C1-3alkyl)aryl, heterocyclyl, (C1-3alkyl)heterocyclyl or NH-C(=O)aryl, a

R2denotes H, C1-4alkyl, (C1-3alkyl)aryl or (C1-3alkyl)heterocyclyl, with the most preferred are those compounds in which

R1denotes unsubstituted or substituted by an atom of F, Cl, Br, I, group-CN, N-alkyl-N-arylamino, N,N-dialkylamino, amidon, carboxylation, carboxybenzene methyl, ethyl, n-propyl, isopropyl, 2-methylpropyl, n-butyl, tert-butyl, n-pentyl, 3-methylbutyl or CH2- (CH3)=CH2above all methyl, ethyl, CH2- (CH3)=CH2CH(C(=O)och2CH=CH2)-CH2C(=O)O-tert-butyl, 2-cyanoethyl, CH2-CH2-NH-C(=O)CH3, 2-(N-ethyl-N-(3-were)amino)ethyl, 2-(N,N-dimethylamino)ethyl, 2-(C(=O)-NH-(β-naphthyl)ethyl, 1,2-(di(C(=O)O-tert-butyl)ethyl, 3-(N-methyl-N-phenylamino)propyl, 1-(C(=O)O-benzyl)-3-methylbutyl, 1-(C(=O)O-butyl)-3-methylbutyl, CH2CO2ethyl, CH2-CH2CO2ethyl, CH2-CH2-O-phenyl, With the 2-CH2-S-CH2-CH3or denotes an unsubstituted or substituted by an atom of F, Cl, Br, I, group-CN, alkyl, aryl, carboxylation, carboxybenzene, O-alkyl, O-benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.1.1]heptane-3-yl, especially 2-vinylcyclopropyl, 2-(O-benzyl)cyclopentyl, 2-(carboxyethyl)cyclohexyl, 7,7-dimethyl-2-methylbicyclo[3.1.1]heptane-3-yl, cyclopropylmethyl, 7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-ylmethyl, or denotes an unsubstituted or substituted by phenoxypropane, -CH2-P(=O)(O-ethyl)2phenyl, 1-naphthyl or 2-naphthyl, or represents CH2-aryl, CH2-CH2-aryl, CH2-CH2-CH2-aryl, CH2-CH2-CH2-CH2-aryl, CH(CH3)-aryl, CH(CH3)-CH2-aryl, CH2-CH(aryl)2CH(CO2-alkyl)-CH2-aryl, CH2-CH2-CH(aryl)2where aryl represents unsubstituted phenyl, 1-naphthyl or 2-naphthyl or substituted by an atom of F, Cl, Br, I, group-CN, -NO2, alkyl, a group of CF3, alkoxygroup, alkylenedioxy phenyl, especially benzyl, -CH2-naphthas-1-yl, 2-tormentil, 3-tormentil, 3-Chlorobenzyl, 3-methoxybenzyl, 2-ethoxybenzyl, 2,4-diferensial, 3,5-dichlorobenzyl, 3-fluoro-5-trifloromethyl, 3-fluoro-4-trifloromethyl, 2-chloro-6-tormentil, 2.5-dimethoxybenzyl, 2-PI is R-6-methylbenzyl, 3,4-dimethoxybenzyl, 3,4-dioxymethylene, CH(CH3)-phenyl, CH(CH3)-(4-CH3-phenyl), CH(CH3)-(4-nitrophenyl), CH(CH3)-(2,3-dioxyethylene), CH2-CH2-phenyl, CH2-CH2-(2-forfinal), CH2-CH2-(3-forfinal), CH2-CH2-(4-forfinal), CH2-CH2-(4-chlorophenyl), CH2-CH2-(3,4-dichlorophenyl), CH2-CH2-(3-methoxyphenyl), CH2-CH2-(2,5-acid), CH(CO2-tert-butyl)-CH2-phenyl, CH(CO2-methyl)-CH2-(4-chlorophenyl), CH2-CH(phenyl)2CH(CH3)-CH2-(4-chlorophenyl), CH2-CH2-CH(phenyl)2CH2-CH2-CH2-phenyl, or denotes an unsubstituted or substituted aryl, alkylaryl or carboxyethyl pyrrolidine or piperidine, primarily pyrrolidin-3-yl, N-(4-triptorelin)pyrrolidin-3-yl, N-(3-methoxybenzyl)pyrrolidin-3-yl, N-(CH2-(β-naphthyl)pyrrolidin-3-yl or N-(carboxyethyl)piperidine-4-yl, or represents unsubstituted or substituted alkyl, atom (F, Cl, Br, I, group-CN, aryl, alkylaryl (CH2)1-3-heterocyclyl where heterocyclyl is furanyl, benzofuranyl, 1,4-dioxane, benzo-1,4-dioxane, thienyl, pyridinyl, pyrrolidinyl, 1H-indolyl, imidazolyl, piperidinyl, tetrahydrofuranyl primarily denotes CH2-furan-2-yl, 5-metinfo the EN-2-yl, CH2-benzofuran-2-yl group

CH2-Tien-2-yl, CH2-pyridin-3-yl, CH2-pyridin-4-yl, CH2-CH2-pyridin-2-yl, CH2-CH2-(1H-indol-3-yl), CH2-CH2-pyrrolidin-1-yl, CH2-(N-2,6-dichlorobenzonitrile-3-yl), - CH2-CH2-(N-methylpyrrolidine-2-yl), -(CH2)3-imidazol-1-yl, CH2-(tetrahydrofuran-2-yl), groupCH(CO2methyl)-CH2-(1H-indol-3-yl) or NH-C(=O)-(4-diethylaminophenyl), and

R2denotes H, unsubstituted or substituted by an atom of F, Cl, Br, I, group-CN, methyl, ethyl or CH2- (CH3)=CH2above all methyl, ethyl, 2-cyanoethyl, CH2- (CH3)=CH2or denotes an unsubstituted or substituted by an atom of F, Cl, Br, I, group-CN, methoxy group, ethoxypropane benzyl or phenethyl, especially benzyl, 4-tormentil, 2-chloro-6-tormentil, 2.5-dimethoxybenzyl, phenethyl, or denotes CH2-furanyl, first of all SN2-furan-2-yl, CH2-benzofuranyl, first of all SN2-benzofuran-2-yl, CH2-pyridinyl, first of all SN2-pyridin-3-yl, CH2-tetrahydrofuranyl, first of all SN2-tetrahydrofuran-2-yl, CH2-CH2-pyridinyl, first of all SN2-CH2-pyridin-2-yl.

Another preferred group proposed in the image is the situation of the compounds of formula (I) are compounds which are characterized in that

R1and R2together denote the grouporwhere aryl represents phenyl or substituted by an atom of F, Cl, Br, I, phenyl, especially 4-forfinal,

R6denotes N or C1-4alkyl, especially methyl,

R10denotes H, C(=O)O-methyl, C(=O)O-ethyl, S(=O)O-n-propyl, C(=O)O-isopropyl, C(=O)O-n-butyl, C(=O)O-tert-butyl,

R15denotes N or CH2-aryl,

R16denotes H,

R17denotes H, C3-8cycloalkyl primarily cycloheptyl, aryl, especially unsubstituted or substituted stands, ethyl, n-propylene, isopropyl, n-bootrom, tert-bootrom, a group of CF3, atom (F, Cl, Br, I, group-CN, methoxy group, ethoxypropane, n-propoxyphene, isopropoxycarbonyl, n-butoxypropyl, tert-butoxypropyl phenyl or naphthyl, or represents ((CH2)1-3-alkyl)aryl or CH(CH3)aryl, where aryl represents unsubstituted or substituted alkyl group, CF3, atom (F, Cl, Br, I, group-CN, alkoxygroup phenyl or naphthyl, or represents unsubstituted or substituted alkyl group, CF3, atom (F, Cl, Br, I, group-CN, alkoxygroup pyridinyl, pyrazinyl or thieno[2,3-d]pyrimidinyl or denotes a C(=O)R22and

R22denotes phenyl, substituted alkoxygroup phenyl, O-methyl, O-ethyl, O-n-propyl, O-isopropyl, O-n-butyl, tert-butyl, O-benzyl, unsubstituted benzyl, substituted with F atom benzyl, an unsubstituted pyrazinyl or substituted by alkyl pyrazinyl, while among these compounds, particularly preferred compounds in which

R6denotes H or methyl,

R10denotes N or C(=O)O-ethyl,

R15denotes H or benzyl,

R16denotes H and

R17denotes H, cycloheptyl, phenyl, 2-were, 3-were, 2,4-dimetilfenil, 2-ethylphenyl, 3-trifluoromethyl, 4-forfinal, 4-chlorophenyl, 2-methoxyphenyl, 3,5-acid, 3-chloro-6-were, benzyl, CH2-(4-tert-butylphenyl), CH2-(β-naphthyl), CH(CH3)-phenyl, (CH2)3-phenyl, pyridin-2-yl, (4-trifluoromethyl)pyridine-2-yl, thieno[2,3-d]pyrimidine-4-yl, C(=O)-(4-methoxyphenyl), C(=O)benzyl, C(=O)-CH2-(3,4-differenl), C(=O)-(2-methylpyridin-5-yl), C(=O)O-tert-butyl or O-benzyl.

Preferred further those proposed in the invention compounds of General formula (I), in which

R3means SO2R12,

R12denotes methyl, ethyl, n-propyl, isopropyl, especially n-propyl, 7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-ylmethyl, phenyl or substituted stands, ethyl, n-propylene, isopropyl, n-bootrom, tert-bootrom, a group of CF3, F, Cl, Br, I, group-CN, NO2, a methoxy group, ethoxypropane, n-propoxyphene, isopropoxycarbonyl, n-butoxypropyl, tert-butoxypropan, group OCF3, CO2-stands phenyl, especially 4-were 3-triptoreline, 4-forfinal, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-trifloromethyl, 4-nitrophenyl, 2-CO2-were, 2,5-dichlorophenyl, 3-fluoro-6-were, 3-bromo-6-methoxyphenyl, 2-methyl-5-nitrophenyl, 2,4,6-trimetilfenil, benzyl or substituted stands, ethyl, n-propylene, isopropyl, n-bootrom, tert-bootrom, a group of CF3, atom (F, Cl, Br, I, group-CN, NO2, a methoxy group, ethoxypropane, n-propoxyphene, isopropoxycarbonyl, n-butoxypropyl, tert-butoxypropyl, group OCF3, benzyl, unsubstituted or substituted stands, ethyl, n-propylene, isopropyl, n-bootrom, tert-bootrom, a group of CF3, atom (F, Cl, Br, I, group-CN, NO2, a methoxy group, ethoxypropane, n-propoxyphene, isopropoxycarbonyl, n-butoxypropyl, tert-butoxypropyl furanyl or thienyl primarily Tien-2-yl, 5-chlortan-2-yl, or a group NR18R19and

R18and R19independently of one another denote H, methyl or ethyl.

Preferred are also those proposed in the invention compounds of General formula (I), in which

R3denotes COR13,

R13means nez is displaced or substituted O-stands, O-ethyl, group O-(CH2)2-Och3, O-benzyl, O-phenyl with unsubstituted or substituted by an atom of F, Cl, Br, I, group-CN-phenyl, O-C(=O)-stands, O-C(=O)-ethyl methyl, ethyl, C(=O)O-methyl, n-propyl, isopropyl, 2-methylpropyl, n-butyl, tert-butyl, n-pentyl or 3-methylbutyl, especially methyl, ethyl, n-propyl, n-butyl, tert-butyl, n-pentyl, CH2-O-CH2-CH2-Och3CH(CH3)-O-phenyl, CH2-CH2-C(=O)och3, (CH3)2-OC(=O)CH3CH2-O-benzyl, CH2-O-(3-chlorophenyl), CH2-CH2-CH2-O-phenyl, CH(OC(=O)methyl)CH3or denotes cyclopropyl, 2-vinylcyclopropyl, 1-substituted, unsubstituted, or substituted by an atom of F, Cl, Br, I, group-CN, phenyl, stands, ethyl, n-propylene, isopropyl, n-bootrom, tert-bootrom, a group of CF3, atom (F, Cl, Br, I, group-CN, NO2, a methoxy group, ethoxypropane, n-propoxyphene, isopropoxycarbonyl, n-butoxypropyl, tert-butoxypropyl, group OCF3, OCHF2The co2F, SCF3, SCHF2, SCH2F, SCH3CH2OS(=O) - phenyl, the group-N(CH3) phenyl or naphthyl, especially 4-forfinal, 2-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 4-phenylphenyl (4-biphenyl), 4-ethylphenyl, 4-CF3-phenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 4-tert-butyl, 3-OCF3-phenyl, 4-OCF3-phenyl, 4-SCF3-phenyl, 3-SCF2-phenyl, 2-CH2-OC(O)phenyl, 3-dimethylaminophenyl, 2,3-dichlorophenyl, 2,4-differenl, 3-chloro-4-forfinal, 3-chloro-2-forfinal, 4-CF3-3-forfinal, 3-CF3-6-forfinal, 4-bromo-3-were, 2-chloro-4-nitrophenyl, 2,3,4,5,6-pentafluorophenyl, 2,6-debtor-3-were, 2,3-debtor-4-were, 2-chloro-5-methyl-6-forfinal, 1-naphthyl, 2-naphthyl, or represents unsubstituted or substituted (C1-2alkyl)aryl, especially benzyl, phenethyl, CH(C2H5)-phenyl, CH(NH-SO2-(4-were))-CH2-phenyl, CH=CH-phenyl, CH=CH-(3-tryptophanyl), or denotes an unsubstituted or substituted alkyl furanyl, benzofuranyl, unsubstituted or substituted alkyl group, CF3, aryl, O-phenyl, chlorine, S-stands, S-ethyl thienyl, pyridinyl, pyrazolyl, benzodithiophene, isoxazolyl, especially 1,5-dimethylfuran-3-yl, 2-methyl-5-tert-butylfuran-3-yl, 3-chlortan-2-yl, 1-(4-chlorophenyl)-5-cryptomaterial-4-yl, 1-methyl-3-tert-butylphenol-5-yl grouppyridine-4-yl, 2-methylthiopyridine-3-yl, 2-ethylthiophen-3-yl, 2-phenoxypyridine-3-yl, 2-chloropyridin-3-yl, 5-methyl-3-(2,6-dichlorophenyl)isoxazol-4-yl, 5-methyl-3-(2-chloro-6-forfinal)isoxazol-4-yl.

Some of the most preferred amongst the invention compounds of formula (I) include the following:

methyl Efir-(1H-indol-3-yl)-2-{[8-(4-trifluromethanesulfonate)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-ka is bonyl]amino}propionic acid,

diethyl ether{4-[(8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl)amino]benzyl}phosphonic acid,

(4-cycloheptatrien-1-yl)-[8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

[8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-(4-phenylpiperazin-1-yl)methanon,

cyclopentolate 8-(2-chloro-4-nitrobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(4-naphthalene-2-iletileri-1-yl)-(8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl)methanon,

ventilated 8-dimethylsulphamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(1-phenylethyl)amide 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(3,4-dichlorophenyl)ethyl]amide 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

N'-[8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]hydrazide 4-diethylaminobenzoic acid,

(2-pyrrolidin-1-retil)amide 8-(3-chloro-4-therobertotronic)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ventilated 8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-dimethylaminoethyl)amide 8-benzazolyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[4-(3-phenylpropyl)piperazine-1-yl]-[8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

[3-(2-METI is piperidine-1-yl)propyl]amide 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(1H-indol-3-yl)ethyl]methylamide 8-(4-trifluromethanesulfonate)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-acetylamino)amide 8-(5-fluoro-2-methylbenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylpenicillin 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-dimethylaminoethyl)amide 8-(2-methyl-5-nitrobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-benzyloxyphenyl)amide 8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)amide 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(4-phenoxyphenyl)amide 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(1-n-triletal)amide 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

3-forbindelse 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

2-phenyl-1-{4-[8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]piperazine-1-yl}Etalon,

[1-(4-trifloromethyl)pyrrolidin-3-yl]amide 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-(4-o-tailpipes-1-yl)methanon,

benzyl(2-cyanoethyl)amide 8-(toluene-4-sulfonyl)-1-oxa-2,8-d is azaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-(4-thieno[2,3-d]pyrimidine-4-reparation-1-yl)methanon,

(benzo[1,3]dioxol-5-ylmethyl)amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(3-methyl-4-m-tailpipes-1-yl)-[8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

[4-(1-phenylethyl)piperazine-1-yl]-[8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

[4-(2,4-dimetilfenil)piperazine-1-yl]-[8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

cyclopentolate 8-(2-chloropyridin-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(4-naphthalene-2-iletileri-1-yl)-[8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

(pyridine-3-ylmethyl)amide 8-[3-phenyl-2-(toluene-4-sulfonylamino)propionyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-dimethylaminoethyl)amide 8-(5-fluoro-2-methylbenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(4-nitrobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

3-fluoro-5-triptoreline 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzhydrylamine 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-cyanoethyl)amide 8-[3-FeNi is-2-(toluene-4-sulfonylamino)propionyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester [(8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl)amino]acetic acid,

(2-cyanoethyl)amide 8-(3-dimethylaminobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[1-(naphthalene-2-ylcarbonyl)ethyl]amide 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(1-n-triletal)amide 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[4-(4-chlorophenyl)piperazine-1-yl]-(8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl)methanon,

(2-benzyloxyphenyl)amide 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-acetyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

2.5-differentiated 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(1-naphthalene-2-iletilenlerin-3-yl)amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

2-ethoxybenzene 8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(4-ethylbenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

1-allyl ester and 4-tert-butyl Efir-{[8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}succinic acid,

naphthalene-2-alamid 8-(4-trifloromethyl)-1-oxa-2,8-Diaz is Spiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 4-{[8-(2-phenylcyclopropanecarboxylic)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}piperidine-1-carboxylic acid,

ethyl ester of 4-{[8-(2,4-differentail)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}piperidine-1-carboxylic acid,

(2-dimethylaminoethyl)amide 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(4-chlorophenyl)ethyl]amide 8-dimethylsulphamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(5-methylfuran-2-ylmethyl)amide 8-(4-methoxybenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(4-chlorophenyl)ethyl]amide 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(1-methylpyrrolidine-2-yl)ethyl]amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 4-{[8-(4-bromobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}piperidine-1-carboxylic acid,

3,5-dichloraniline 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[1-(3-methoxybenzyl)pyrrolidin-3-yl]amide 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

dimethylamide 3-(4-naphthalene-2-iletileri-1-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-sulfonic acid,

ethyl ester of 3-{[8-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-elmersolver)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-CT is of IMT]amino}propionic acid,

(2-benzyloxyphenyl)amide 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

3,4-dimethoxybenzamide 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl)-[4-(3-phenylpropyl)piperazine-1-yl]metano,

dimethylamide 3-(4-thieno[2,3-d]pyrimidine-4-reparation-1-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-sulfonic acid,

[8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-[4-(3,5-acid)piperazine-1-yl]metano,

3-fluoro-4-triptoreline 8-dimethylsulphamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-benzyloxyphenyl)amide 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 4-[(8-butyryl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl)amino]piperidine-1-carboxylic acid,

(2-vinylcyclopropyl)amide 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-[4-(5-methylpyrazine-2-carbonyl)piperazine-1-yl]metano,

2,4-differentiated 8-dimethylsulphamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(3-forfinal)ethyl]amide 8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2.2-diphenylether)amide 8-(5-chlorothiophene-2-Sul is the IMT-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

dimethylamide 3-[4-(3-phenylpropyl)piperazine-1-carbonyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-sulfonic acid,

ethyl ester of 3-{[8-(3,5-differentail)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}propionic acid,

isobutyramide 8-(propane-1-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[4-(3-phenylpropyl)piperazine-1-yl]-[8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

[1-(2,3-dihydrobenzo[1,4]dioxin-5-yl)ethyl]amide 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

phenylamide 8 butyryl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclooctylamine 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-[2-(2-methoxyethoxy)acetyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

isobutyramide 8-(4-bromo-3-methylbenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[3-(methylpentylamino)propyl]amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl Efir-{[8-(2-methyl-5-nitrobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}piperidine-1-carboxylic acid,

[8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-[4-(4-forfinal)piperazine-1-yl]metano,

methylpyridin-3-ylmethylene 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-d is azaspiro[4.5]Dec-2-EN-3-carboxylic acid,

2-(3,4-differenl)-1-{4-[8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]piperazine-1-yl}Etalon,

cyclopropylmethyl 8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 3-{[8-(2-methyl-5-nitrobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}propionic acid,

(thiophene-2-ylmethyl)amide 8-[2-(3-chlorophenoxy)acetyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylpenicillin 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylpenicillin 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-cyanoethyl)pyridine-3-ylmethylene 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-cyanoethyl)-(tetrahydrofuran-2-ylmethyl)amide 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

methylpyridin-3-ylmethylene 8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-(pyridine-4-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl(2-methylallyl)amide 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(2-forfinal)ethyl]amide 8-(4-methoxybenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-to benovoy acid,

isobutyramide 8-(5-tert-butyl-2-methylfuran-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(3-phenylacrylate)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopropylmethyl 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopropylmethyl 8-(4-triftormetilfullerenov)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(5-methylfuran-2-ylmethyl)amide 8-(4-bromobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopropylmethyl 8-(3-fluoro-4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-ethylsulfanyl)amide 8-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-elmersolver)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(tetrahydrofuran-2-ylmethyl)amide 8-(2,4-differentail)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester {[8-(3-chlorothiophene-2-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}acetic acid,

methyl ester of 4-oxo-4-{3-[(thiophene-2-ylmethyl)carbarnoyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-yl}butyric acid,

benzylated 8-(2-ethylsulfanyl-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 3-{[8-(2-chlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}propionic acid,

cyclopropyl ilamed 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopropylmethyl 8-(4-phenoxybutyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-[4-(4-triptorelin-2-yl)piperazine-1-yl]metano,

cyclopropylmethyl 8-(2-chloro-5-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-benzyloxyphenyl)amide 8-(4-methoxybenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 4-{[8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}piperidine-1-carboxylic acid,

cyclopropylmethyl 8-(2-phenoxypropionyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(3-methoxyphenyl)ethyl]amide 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

isobutyramide 8-(2-methylsulfinylphenyl-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopentolate 8-(5-tert-butyl-2-methylfuran-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(4-chlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(naphthalene-1-ylmethyl)amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(4-forfinal)ethyl]amide 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid is,

(pyridine-4-ylmethyl)amide 8-(4-bromo-3-methylbenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-(4-methoxybenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

3-chlorobenzylamino 8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl)-(4-o-tailpipes-1-yl)methanon,

(8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl)-(4-pyridine-2-reparation-1-yl)methanon,

(thiophene-2-ylmethyl)amide 8-(4-triftormetilfullerenov)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

isobutyramide 8-(4-perbenzoic)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

methyl ester of 2-(3-isobutylamino-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-sulfonyl)benzoic acid,

tert-butyl ester 2-[(8-dimethylsulphamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl)amino]-3-phenylpropionic acid,

[1-(2,3-dihydrobenzo[1,4]dioxin-5-yl)ethyl]amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(4-bromobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(3-imidazol-1-ylpropyl)amide 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzyl ether of 4-[8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]piperazine-1-carboxylic acid,

dimethylamide 3-(4-cycloheptatrien-1-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-sulfonic acid,

tert-butyl ether 4-methyl-2-{[8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}pentanol acid,

(thiophene-2-ylmethyl)amide 8-(3-chloro-2-perbenzoic)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

tert-butyl ester 2-{[8-(4-methoxybenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}-4-methylpentanoic acid,

ethyl ester of 3-{[8-(6-chloro-2-fluoro-3-methylbenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}propionic acid,

benzylated 8-(2-phenoxypropionyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(5-fluoro-2-methylbenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-[4-(2-methoxyphenyl)piperidine-1-yl]metano,

(thiophene-2-ylmethyl)amide 8-(2-chlorobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopentolate 8-(2-phenoxypyridine-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-ethylsulfanyl)amide 8-(4-bromobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl Efir-[8-(5-chlorothiophene-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]piperidine-2-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(2-chlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopropylmethyl 8-(2,3-dichlorobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopropylmethyl 8-hexanoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopropylmethyl 8-(2,3-debtor-4-methylbenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2.5-dimethoxybenzyl)furan-2-ylmethylene 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-ethylsulfanyl)amide 8-dimethylsulphamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

3-methoxybenzylamine 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-benzyloxyphenyl)amide 8-dimethylsulphamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(4-chlorophenyl)-1-methylethyl]amide 8-(4-methoxybenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(3,4-dichlorophenyl)ethyl]amide 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-[2-(3-chlorophenoxy)acetyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-cyanoethyl)-(2-pyridin-2-retil)amide 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(4-chlorophenyl)-1-methylethyl]amide 8-(5-chartype the-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-benzyloxyphenyl)amide 8-(4-methoxybenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(2,6-debtor-3-methylbenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-(2-benzyloxyethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

phenylamide 8-(2,3-dichlorobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopentolate 8-(5-bromo-2-methoxybenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

2-(3-benzylcarbamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-yl)-1,1-dimethyl-2-oksietilnye ether acetic acid,

(2-ethylsulfanyl)amide 8-[3-(2-chloro-6-forfinal)-5-methylisoxazol-4-carbonyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[4-(3-phenylpropyl)piperazine-1-yl]-[8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

benzylated 8-[3-(2-chloro-6-forfinal)-5-methylisoxazol-4-carbonyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

isobutyramide 8-(naphthaleneboronic)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 1-[8-(5-tert-butyl-2-methylfuran-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]piperidine-2-carboxylic acid,

benzylated 8-(3-deformationeevent)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

phenylamide 8-(4-bromobenzoyl)-1-ACS is -2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-vinylcyclopropyl)amide 8-(4-methoxybenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(4-phenoxybutyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(3-chloro-4-perbenzoic)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-ethylsulfanyl)amide 8-(5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-[4-(3-phenylpropyl)piperazine-1-yl]metano,

(pyridine-4-ylmethyl)amide 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

2-(3-cyclopentanecarbonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-ene-8-carbonyl)benzyl ester of benzoic acid,

dimethylamide 3-[4-(4-tert-butylbenzyl)piperazine-1-carbonyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-sulfonic acid,

ethyl ester {[8-(2-ethoxybenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}acetic acid,

(2-benzyloxyphenyl)amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(naphthalene-1-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(3-phenylpropyl)amide 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)amide 8-(5-chloro shall iophen-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 1-[8-(4-tert-butylbenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]piperidine-2-carboxylic acid,

[2-(3-triptoreline)ethyl]amide 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-carbonyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[1-(naphthalene-2-ylcarbonyl)ethyl]amide 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-benzyloxyphenyl)amide 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

methyl ester of 3-(4-chlorophenyl)-2-{[8-(4-methoxybenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}propionic acid,

(2-benzyloxyphenyl)amide 8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-phenoxyethyl)amide 8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-(2-phenoxypyridine-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopropylmethyl 8-(naphthalene-2-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-(3-chloro-4-perbenzoic)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-cyanoethyl)amide 8-(2-phenylbutyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

2-FPO is benzylated 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(3-chlorobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(4-benzylpiperazine-1-yl)-[8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

benzylated 8-(3-chlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(4-benzylpiperidine-1-yl)-[8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

benzylated 8-(4-bromobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[1-(4-nitrophenyl)ethyl]amide 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

tert-butyl ether 4-methyl-2-{[8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}pentanol acid,

[4-(4-forfinal)-3,6-dihydro-2H-pyridine-1-yl]-(8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl)methanon,

[2-(ethyl-m-tolylamino)ethyl]amide 8-dimethylsulphamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-(2,5-dimethylfuran-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(4-cycloheptatrien-1-yl)-[8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

benzylated 8-(2-benzyloxyethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-benzyloxyphenyl)amide R,R-8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic sour is s,

and hydrochloride.

The present invention relates also to a method for its proposed derivatives of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene General formula (I). This method differs in that

(a) compound of formula (II)

which is commercially available or which can easily be obtained from piperidine-4-she and agent introduction of the BOC group, is subjected in the presence of potassium tert-butylate in THF interaction with agent methyltyrosine, preferably with a Ph3RSN3Br, to obtain the compounds of formula (III)

(b) is a compound of formula (III) is subjected in the presence of a base, preferably sodium hydrogen carbonate or lithium hydroxide, preferably in an organic solvent, primarily methanol, dichloromethane or THF, interaction with ethylchlorothioformate formula

with the formation of a derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene of the formula (V)

(C) this compound of formula (V), either directly or after prior saponification present in the compound of formula (V) functional group, which is the ethyl ester of carboxylic acid, and optionally after activation with resulting functional g is PI, which is a carboxylic acid, is subjected to the interaction with the amine of the formula HNR1R2in which R1and R2have the above values, to obtain the derived 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene of the formula (VI)

(g) compounds of formula (VI) remove the protective BOC-group to obtain the compounds of formula (I)in which R3denotes N

(d) if necessary, the compound of formula (I)in which R3denotes H, transform the processing of the acid chloride of the acid of formula R12SO2Cl in the compound of formula (I)in which R3means SO2R12where R12has the above values, or converted by treatment with a carboxylic acid chloride of the acid of formula R13COCl in the compound of formula (I)in which R3denotes COR13where R13has the above values.

The reaction for introducing the protective BOC-group (BOC represents a tert-butyloxycarbonyl) before stage (a), and the reaction for the formation of the Exo-methylene group at the stage of (a) and 1,3-dipolar cycloaddition at the stage (b) in the invention method is carried out similarly known from the literature recommendations according to WO 97/33887, p.78-82. Reactions to subsequent stages (C), (d) and optionally (d), allcauses in the amide formation based on spiropyran formula (V) its interaction with primary or secondary amine (stage (in)) (if necessary after prior removal of ethyl ether and optionally after activating the free functional group is a carboxylic acid, for example, dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole and triethylamine, respectively N-methylmorpholine and reagent Castro (BOP-reagent), for example, in DMF), remove the protective BOC-group of the amide of formula (VI) (stage (d)) and conducted, if necessary, in subsequent interactions with the anhydrides of the acids or anhydrides of sulfonic acids (stage (d)), carried out in accordance with well-known specialists of methods, for example in accordance with the methods described in "Peptide Chemistry", M.Bodansky, published by Springer-Verlag, 1993. The sequence carried out in accordance with the proposed invention by way of stages of the synthesis are summarized in the following reaction scheme.

Used in the implementation proposed in the invention method, compounds and reagents can be obtained if they are not commercially available products known in the art from the prior art methods.

Proposed in the invention derivatives of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene are toxicologically harmless and therefore suitable for use as a pharmaceutical action of the corresponding substances in medicinal products.

Accordingly another object of the present invention is a drug containing at least one substituted derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene of the above formula (I) in the form of its racemate, its pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in the present form or in the form of its acids or its bases or in the form of its salts, especially physiologically compatible salts, most preferably in his hydrochloride, or in the form of a solvate, especially hydrates.

Proposed in the invention medicines can be represented and used in the form of liquid dosage forms, for example in the form of injection solutions, drops or medicines, as well as semi-solid dosage forms such as granules, tablets, pills, patches, capsules, plasters or aerosols, and along at least one proposed in the invention a derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene of the formula (I) depending on the galenical form optionally also contain carriers, fillers, solvents, diluents, dyes and/or binder. The choice of excipients and used their number depend on the t, whether you're designing a drug for oral, oral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, transbukkalno, rectal or topical application, for example for application to infected areas of the skin, mucous membranes, or for introduction into the affected eye. For oral administration suitable, in particular, compositions in the form of tablets, pills, capsules, granules, drops, medicines and syrups, and for parenteral, local, and inhalation use suitable solutions, suspensions, easily recoverable dry compositions, as well as sprays. Proposed in the invention derivatives of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene in depot form, in dissolved form or embedded in a plaster, optionally with the addition of promote penetration through the skin of funds, also suitable for percutaneous introduction. Intended for oral or percutaneous injection dosage form can be a retard forms, which provide a slow release of the proposed invention derivatives of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene. Assigned to the patient an amount of the active substance varies depending on the weight of the patient, route of administration, indications for use and the severity of the disease. Usually p is at least one proposed in the invention is derived 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene of the formula (I) is introduced into the body in dosage, component from 2 to 500 mg/kg

Proposed in the invention derivatives of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene are preferably used for pain treatment, primarily for the treatment of chronic and neuropathic pain, but also in migraine, therefore, another object of the present invention is the use of at least one proposed therein derived 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene of the formula (I), including in the form of its racemates, enantiomers, diastereomers, primarily mixtures of its enantiomers or diastereomers or a single enantiomer or diastereoisomer, its bases and/or salts formed with physiologically compatible acids, primarily hydrochloride, to obtain a medicinal product intended for analgesic treatment, primarily for the treatment of neuropathic and/or chronic pain, and/or for the treatment and/or prevention of migraine.

The application of the proposed invention derivatives of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene General formula (I) also shows that, unexpectedly, it was found, and other painful conditions, especially for the treatment of urinary incontinence, itching, subjective perception of tinnitus and/or diarrhea. Accordingly another object of the present invention is the use of at least one offer is about it derived 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene of the formula (I), including in the form of its racemates, enantiomers, diastereomers, primarily mixtures of its enantiomers or diastereomers or a single enantiomer or diastereoisomer, its bases and/or salts formed with physiologically compatible acids, primarily hydrochloride, to obtain a medicinal product intended for the treatment and/or prevention of urinary incontinence, and/or itching, and/or subjective perception of tinnitus, and/or diarrhea.

Affinity presented in this description of the compounds in relation to the binding site WITH due to the possibility of their therapeutic applications and for other purposes, and therefore proposed in the invention substituted derivatives of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene General formula (I) in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in the present form or in the form of their acids or their bases or in the form of their salts, especially physiologically compatible salts, most preferably in the form of their hydrochloride, or in the form of a solvate, especially hydrates, can be used to obtain a medicinal product intended for anesthesia, primarily local anesthesia and/or for Leche is occurring and/or prevention of arrhythmia and/or vomiting and/or cardiovascular disease and/or cerebral ischemia and/or alcohol and/or drug dependence and/or drug addiction and/or inflammation and/or dizziness and/or as a nootropic (neurotropic) funds and/or muscle relaxant.

In addition, the affinity of the proposed invention compounds to NMDA receptor due to the possibility of their use for other purposes, because NMDA antagonists are known to possess among other things neuroprotective effect and therefore can be effectively used due to degeneration and damage to the nervous system diseases such as Parkinson's disease, Huntington's disease and other diseases. Proposed in the invention NMDA antagonists also shown for use in other diseases, which are epilepsy, glaucoma, osteoporosis, ototoxicity, reflected in the abuse of alcohol and/or drug withdrawal, stroke, and related cerebral ischemia, myocardial infarction, brain edema, hypoxia, anoxia, and can be used for anxiolysis and during anaesthesia. Accordingly another object of the present invention is the use of at least one proposed therein substituted derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene of the formula (I), including in the form of its racemates, enantiomers, diastereomers, primarily mixtures of its enantiomers or diastereomers or a single enantiomer or diastereoisomer, it founded the St and/or salts, formed with physiologically compatible acids, primarily hydrochloride, to obtain a medicinal product intended for the treatment/prevention of epilepsy, Parkinson's disease, Huntington's disease, glaucoma, ototoxicity, symptoms of withdrawal when alcohol and/or drug abuse, stroke, cerebral ischemia, myocardial infarction, cerebral edema, hypoxia, anoxia and/or for anxiolysis and/or anesthesia.

Proposed in the invention the compounds of formula (I) effectively communicate, in addition, α2Areceptor, respectively, proved as effective inhibitors capture/capture NT. Accordingly another object of the invention is the use of substituted derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene General formula (I) in the form of its racemate, its pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in the present form or in the form of its acids or its bases or in the form of its salts, especially physiologically compatible salts, most preferably in the form of his hydrochloride, or in the form of its the solvate, especially hydrates, for obtaining a medicinal product intended for the treatment and/or the prophylaxis of inflammatory and/or allergic reactions and/or gastritis and/or sores and/or depression and/or shock and/or narcolepsy and/or epilepsy and/or overweight and/or asthma and/or glaucoma and/or hyperkinetic syndrome, aspontaneity and/or bulimia and/or anorexia and/or catalepsy and/or for anxiolysis and/or to enhance vigilante and/or libido, for the treatment and/or prophylaxis of bipolar disorders and/or tides in the postmenopausal period and/or amyotrophic lateral sclerosis (als) and/or reflex sympathetic dystrophy (RSD) and/or spastic paralysis and/or tired leg syndrome and/or acquired nystagmus and/or multiple sclerosis and/or Parkinson's disease and/or Alzheimer's and/or Huntington's disease.

Another object of the invention is a method of treatment of a mammal or human in need of such treatment on the basis of important from a medical point of view of symptoms, which consists in the introduction to the patient a therapeutically effective dose proposed in the invention substituted derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene General formula (I), including in the form of its racemate, its pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in the present form or in the form its acids or its bases or in the form of its salts, especially physiologically compatible salts, most preferably in the form of his hydrochloride, or its solvate, preid the only hydrates, or proposed in the invention medicines. The invention relates primarily to the appropriate treatment of pain, especially neuropathic and/or chronic pain, and/or migraine and/or urinary incontinence and/or itching and/or subjective perception of tinnitus and/or diarrhoea and/or heart arrhythmia and/or vomiting and/or cardiovascular disease and/or cerebral ischemia and/or alcohol and/or drug dependence and/or drug addiction and/or inflammation and/or dizziness and/or inflammatory reactions and/or allergic reactions and/or gastritis and/or sores and/or depression and/or shock and/or narcolepsy and/or epilepsy and/or overweight and/or asthma and/or glaucoma and/or hyperkinetic syndrome and/or aspontaneity and/or bulimia and/or anorexia and/or catalepsy and/or for anxiolysis and/or to enhance vigilante and/or libido and/or for the prophylaxis of bipolar disorders and/or tides in the postmenopausal period and/or amyotrophic lateral sclerosis (als) and/or reflex sympathetic dystrophy (RSD) and/or spastic paralysis and/or tired leg syndrome and/or acquired nystagmus and/or multiple sclerosis and/or Parkinson's disease and/or Alzheimer's and/or Huntington's disease.

Below the present invention b is further illustrated in detail by examples, which, however, do not limit its scope.

Examples

Used chemicals and solvents were purchased from such offering them for sale manufacturers, as Acros, Geel; Avocado, Port of Heysham; Aldrich, Deisenhofen; Fluka, Seelze; Lancaster, Mullheim; Maybridge, Tintagel; Merck, Darmstadt; Sigma, Deisenhofen; TCI, Japan, or synthesized according to known prior art methods.

In the analysis of thin-layer chromatography (TLC) used a ready plates for TLC high resolution (DHWR) type silica gel 60 F 254 firms Emags, Darmstadt.

Each sample was analyzed using MC(ESI) and/or NMR spectroscopy. For mass spectrometric analysis (MS(ESI)used mass spectrometer LCQ Classic firm Finnegan. For1H-NMR analysis of the proposed invention compounds used operating at a resonance frequency of 300 MHz NMR spectrometer (DPX Advance (Bruker).

Getting proposed in the invention substituted derivatives of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene

tert-Butyl ether 4-methyleneimine-1-carboxylic acid

To a suspension of 5.34 g (15 mmol) of methyltriphenylphosphonium in 50 ml of diethyl ether with stirring and at 0°C (ice bath) was added 1.6 g (14 mmole) of potassium tert-butylate. After stirring for 15 min the suspension was slowly added a solution of 2.00 g (10 mmole) of 1-Boc-4-piperidone (Merck KGaA) in 15 ml of dietrologia. After that, the suspension was stirred for another 30 min at 0°C. After addition of 60 ml of 10%aqueous solution of NH4Cl the organic phase was separated, dried over magnesium sulfate and vacuum solvent was removed. After chromatography on silica gel (hexane/ethyl acetate in the ratio 5:1) received 1,71 g (89%) of tert-butyl methyl ether 4-methyleneimine-1-carboxylic acid as colorless liquid.

1H-NMR-spectrum (d6-DMSO/TMCEXT): δ=1,47 frequent./million (s, 9H, C(CH3)3); 2,16-2,19 frequent./million (m, 4H, CH2); 3,40-3,44 frequent./million (m, 4H, CH2); 4,74 (s, 2H, C=CH2).

8-tert-Butyl 3-ethyl ester 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene-3,8-dicarboxylic acid

To a mixture of 0.50 g (2.6 mmole) of tert-butyl methyl ether 4-methyleneimine-1-carboxylic acid and of 0.60 g (3.9 mmole) of ethyl ester of 2-chloro-2-hydroxylaminoxymes acid in 10 ml of dichloromethane at 0°C (ice bath) was slowly added to 0.55 ml (3.9 mmole) pre-fresh of triethylamine. Then the mixture was stirred for 12 h at RT and then at 0°was added 0,79 g (5.1 mmole) of ethyl ester of 2-chloro-2-hydroxylaminoxymes acid and 0.72 ml (5.1 mmole) of triethylamine and stirred for further 24 h After washing with 10%aqueous citric acid and saturated aqueous NaCl and drying of the organic phase (MgSO4and remove Rast is orites in vacuum received a yellow oil. As a result of his column chromatography on silica gel (hexane/diethyl ether in the ratio 4:1) received 320 mg (39%) 8-tert-butyl 3-ethyl ester 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene-3,8-dicarboxylic acid in the form of a slightly yellow coloured oil.

1H-NMR-spectrum (d6-DMSO/TMSEXT): δ=1,37 frequent./million (t, J=6.0 Hz, 3H, CH3); 1,46 frequent./million (s, 9H, C(CH3)3); 1,67-1,75 frequent./million (m, 2H, CH2); 1.85 to 1,92 frequent./million (m, 2H, CH2); 2,96 frequent./million (s, 2H, CH2); 3,39-3,49 frequent./million (m, 2H, CH2); 3,60-3,70 frequent./million (m, 2H, CH2); of 4.35 (q, J=6.0 Hz, 2H, CH2).

8-tert-Butyl ester 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene-3,8-dicarboxylic acid

A mixture of 320 mg (1 mmole) of tert-butyl 3-ethyl ester 4-methyleneimine-1-carboxylic acid in 2 ml of Meon and 70 mg (1.5 mmole) of the monohydrate of lithium hydroxide in 1.3 ml of N2About was stirred for 1.5 h at RT. After removal of the solvent mixture in vacuo the residue was dissolved in water and ethyl acetate and the separated phase, and the pH value of the aqueous phase was set to 4 using citric acid. The organic phase was dried (MgSO4) and the solvent was removed in vacuum. In this way received 280 mg (98%) of the free acid as a colorless solid.

1H-NMR-spectrum (d6-DMSO/TMSEXT): δ=1,47 frequent./million (s, 9H, C(CH3)3); 1,73-1,78 frequent./million (m, 2H, sub> 2); a 1.88-1.93 and frequent./million (m, 2H, CH2); 2,97 frequent./million (s, 2H, CH2); 3,39-3,48 frequent./million (m, 2H, CH2); the 3.65-3,74 frequent./million (m, 2H, CH2); a 9.35 (s, 1H, COOH).

General methodology for the interaction between 8-tert-butyl ester 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene-3,8-dicarboxylic acids and primary or secondary amines

A mixture of 1 equivalent of 8-tert-butyl ester 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene-3,8-dicarboxylic acid, 1 equivalent of the appropriate amine, 2.7 equivalent N-methylmorpholine and 1.8 equivalents of reagent Castro (BOP-reagent) in DMF was stirred for 12 h at RT. After removal of DMF in vacuo, the residue was mixed with N2O and ethyl acetate and separated phases. The organic phase is washed with H2O, 10%citric acid, saturated solution of Na2CO3and saturated NaCl solution, dried (MgSO4) and the solvent was removed in vacuum. After column chromatography (silica gel, diethyl ether/hexane in the ratio 10:1) received the corresponding reaction products of the combination.

In some cases, the reaction mix was performed using DCC (1 equivalent), 1-hydroxybenzotriazole (1 equivalent) and triethylamine (1 equivalent) in DMF at 0°C. After holding at 0°C for 1 h the reaction mixture was allowed to warm up to CT and was stirred for another 12 hours After that, the mixture was filtered and the filtrate was soap is delali between aqueous saturated solution of NaHCO 3and diethyl ether. The organic phase was washed with 10%citric acid, saturated solution of NaHCO3and saturated NaCl solution, dried (MgSO4) and the solvent was removed in vacuum. After column chromatography (silica gel, diethyl ether/hexane in the ratio 10:1) received the corresponding reaction products of the combination.

tert-Butyl ether 3-benzylcarbamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-ene-8-carboxylic acid

In accordance with the above-described General method (using reagent Castro) of 340 mg (1.2 mmole) of 8-tert-butyl ester 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene-3,8-dicarboxylic acid and 130 mg (1.2 mmole) of benzylamine received 250 mg (56%) of tert-butyl methyl ether 3-benzylcarbamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-ene-8-carboxylic acid as colorless solid.

1H-NMR-spectrum (d6-DMSO/TMSEXT): δ=1,46 frequent./million (s, 9H, C(CH3)3); and 1.63-1.70 to frequent./million (m, 2H, CH2); 1,79-1,89 frequent./million (m, 2H, CH2); 2,98 frequent./million (s, 2H, CH2); the 3.35-3.45 was frequent./million (m, 2H, CH2); 3,55-3,65 frequent./million (m, 2H, CH2); 4,51 frequent./million (d, J=6 Hz, 2H, N-CH2); 7,15-7,20 frequent./million (m, 1H, NH); 7,26-7,33 frequent./million (m, 5 H, aryl-H).

tert-Butyl ether R,R-3-(2-benzyloxycarbonylamino)-1-oxa-2,8-diazaspiro[4.5]Dec-2-ene-8-carboxylic acid

In accordance with the above-described General method (using DC) of 80 mg (2.8 mmole) of 8-tert-butyl ester 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene-3,8-dicarboxylic acid and 540 mg (2.8 mmole) of R,R-2-benzyloxycarbonylamino received 700 mg (55%) of tert-butyl methyl ether R,R-3-(2-benzyloxycarbonylamino)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-carboxylic acid as colorless solid.

1H-NMR-spectrum (d6-DMSO/TMSEXT): δ=1,46 frequent./million (s, 9H, C(CH3)3); 1,60-2,00 frequent./million (m, 9H, CH2); 2,15-2,30 frequent./million (m, 1H, CH2); 2,99 frequent./million (s, 2H, CH2); 3,40-3,50 frequent./million (m, 2H, CH2); 3,59-3,65 frequent./million (m, 2H, CH2); 3,80-3,90 frequent./million (m, 1H, CH); 4,25-4,35 frequent./million (m, 1H, CH); br4.61 frequent./million (m, 2H, O-CH2); 6,51-6,53 frequent./million (m, 1H, NH); 7,25-7,34 frequent./million (m, 5H, aryl-H).

A General method of removal of the BOC-group

The corresponding N-Boc-piperidine were mixed at RT with an excess of 4-molar solution of HCl in methanol and stirred (control by TLC). Upon completion of the reaction the solution was concentrated until the first signs of clouding, then mixed with diethyl ether and to complete the deposition was kept over night at 4°C. Precipitated precipitated solid was filtered off, washed with small portions of diethyl ether and dried in vacuum.

Hydrochloride benzylamine 1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid

In accordance with the above described technique of 250 mg (0.7 mmole) of tert-butyl methyl ether 3-benzylcarbamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-ene-8-carboxylic acid was obtained 130 mg (60%) of the hydrochloride of benzylamine 1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid as colorless solid.

1H-NMR with whom CTR (d 6-DMSO/TMSEXT): δ=1,92-2.06 to frequent./million (m, 4H, CH2); 3,10-3,18 frequent./million (m, 6N, CH2); or 4.31-4,40 frequent./million (m, 2H, CH2); 7,15-7,33 frequent./million (m, 5H, aryl-H); 8,99-9,13 frequent./million (m, 3H, NH).

Hydrochloride (2-benzyloxyphenyl)amide R,R-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid

In accordance with the above General method from 700 mg (2.5 mmole) of tert-butyl methyl ether R,R-3-(2-benzyloxycarbonylamino)-1-oxa-2,8-diazaspiro[4.5]Dec-2-ene-8-carboxylic acid obtained 490 mg (50%) of the hydrochloride (2-benzyloxyphenyl)amide R,R-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid as colorless solid.

1H-NMR-spectrum (d6-DMSO/TMSEXT): δ=1,50-1,75 frequent./million (m, 4H, CH2); 1,92-2,11 frequent./million (m, 6H, CH2); 3,06-3,20 frequent./million (m, 6H, CH2); 3,82-3,95 frequent./million (m, 1H, CH); 4,10-4,20 frequent./million (m, 1H, CH); 4,42-4,60 frequent./million (m, 2H, O-CH2); 7,20-7,34 frequent./million (m, 5H, aryl-H); of 8.47-8,54 frequent./million (m, 1H, NH); 9,05-9,15 frequent./million (m, 2H, NH).

General methodology for interaction between piperidine and halides of carboxylic or sulfonic acids

To a solution of the corresponding gelegenheid acid (1.5 equivalents), triethylamine (2 equivalents) and N,N-dimethyl-4-aminopyridine (DMAP, catalytic amount) in dichloromethane at 0°added the appropriate piperidine (1 equivalent). The mixture was allowed to warm up to the T and was stirred overnight. After hydrolysis of 10%aqueous solution of NH4Cl the organic phase was dried (MgSO4) and the solvent was removed in vacuum. After column chromatography on silica gel (mixture of ethyl acetate with hexane in different ratios) received target connection.

Benzylated 8-(2-benzyloxyethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid (example 219)

In accordance with the above-described General method 120 mg (0,42 mmole) of benzylamine 1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid (base, highlighted with aqueous NaOH) were subjected to interaction with 116 mg (0,63 mmole) of benzyloxyacetaldehyde to obtain 60 mg (34%) of benzylamine 8-(2-benzyloxyethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid. The resulting product was a colourless oil, which on long standing at room temperature slowly crystallizes.

1H-NMR-spectrum (d6-DMSO/TMSEXT): δ=1,55-1,69 frequent./million (m, 2H, CH2); a 1.75-1.85 to frequent./million (m, 2H, CH2); 2,92 frequent./million (s, 2H, CH2); 3,20-3,32 frequent./million (m, 1H, CH2); 3,35-3,48 frequent./million (m, 1H, CH2); 3,50-3,60 (m, 1H, CH2); 3,94-4,05 frequent./million (m, 1H, CH2); 6,95-7,05 frequent./million (m, 1H, NH); 7,15-7,35 frequent./million (m, 10H, aryl-H).

(2-Benzyloxyphenyl)amide R,R-8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid (example 220)

As described above metodike mg (1,24 mmole) (2-benzyloxyphenyl)amide R,R-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid (base, allocated using aqueous NaOH) were subjected to interaction with 410 mg (1,86 mmole) 5-chlorothiophene-2-sulphonylchloride to obtain 480 mg (72%) (2-benzyloxyphenyl)amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid. The resulting product was a colorless crystalline solid.

1H-NMR-spectrum (d6-DMSO/TMSEXT): δ=1,40-1.55V frequent./million (m, 1H, CH2)and 1.60-2.05 is frequent./million (m, 8H, CH2); 2,10-2,30 frequent./million (m, 1H, CH2); 2,93-3,05 frequent./million (m, 2H, CH2); 2,00 frequent./million (m, 2H, CH2); 3,41-3,55 frequent./million (m, 2H, CH2); 3.75 to 3,88 frequent./million (m, 1H, CH); 4,20-4,32 frequent./million (m, 1H, CH); 4,42-4,60 frequent./million (m, 2H, O-CH2); 6.42 per-6.48 in (d, 1H, aryl-H); 7,00 frequent./million (d, J=3 Hz, 1H, aryl-H); 7,22-7,40 frequent./million (m, 5H, aryl-H).

This method are presented in table 1 compounds, which in another embodiment can also be obtained by parallel synthesis in semiautomatic mode.

Pharmacological studies

Proposed in the invention substituted derivatives-oxa-2,8-diazaspiro[4.5]Dec-2-ene explored in the following pharmacological experiments.

Studies on the binding to the sodium channel

The interaction with the binding site 2 (inhibition of binding VTH)

The binding site 2 of the sodium channel is a so-called binding site batrachotoxin (VTH). As the ligand used α-benzoate[3H]-batrachotoxinin A20 (with a concentration of 10 nm in the mixture). These particles are ion channel (synaptosome) were isolated from cerebral cortex of rats according to the method described by Gray and Whittaker (E.G.Gray and V.P.Whittaker, J.Anat. 76, 1962, SS. 79-88 [in Russian]). Measure nonspecific binding is radioactivity, measured in the presence of veratridine. The mixture is incubated at 37°C for 120 min Experiments were carried out in accordance with the conditions described by Pauwels, Leysen and Laduron (P.J.Pauwels, J.E.Leysen and P.M.Laduron, Eur. J.Pharmacol. 124, 1986, SS. 291-298).

The analysis results obtained in the study proposed in the invention compounds in these experiments are shown below in table 2.

Table 2
Compound of example No.Expressed as % inhibition of binding WITH when the concentration of the test compound, equal to 10 microns
168
255
378
564
6 49
863
1169
1479
1588
1660
1853
1966
2069
2163
2360
2441
2684
2774

/tr>
Compound of example No.Expressed as % inhibition of binding WITH when the concentration of the test compound, equal to 10 microns
2852
3056
3180
3266
3367
3550
3770
3865
4047
4549
4771
4843
5087
5263
5347
5547
5745
6179
6249
6338
6491
6567
6780
6950
7154
7375
7447
7983
8044
8372
8458
8562
8742
8845
8981
9172
9265
9352
9672
9779
9856
9950
10243
10353
10662
10843

Compound of example No.Expressed as % inhibition of binding WITH when the concentration of the test compound, equal to 10 microns
11548
11972
12142
12454
12656
12770
13347
13585
13644
14060
14161
14453
14667
14940
15086
15256
15341
15548
15670
16075
16340
16452
16658
16869
16948
17059
17144
17260
17362
17676
17745
17955
18057
18150
18247
18368
84 73
18656
18877
18969
19175
19287
19366
19468
19585
19651

Compound of example No.Expressed as % inhibition of binding WITH when the concentration of the test compound, equal to 10 microns
19770
19967
20161
20553
20756
20874
20961
21062
21148
21258
21461
21664
21751
21879

Studies on the inhibition of reuptake of norepinephrine ()

To conduct these studies in vitro using freshly isolated from rat brain of synaptosome. In each case, use may produce so-called the P 2-the fraction that dissect in accordance with the recommendations described in Gray and Whittaker (E.G.Gray and V.P.Whittaker, J.Anat. 76, 1962, SS. 79-88 [in Russian]). To capture these vesicular particles are separated from the hypothalamus of the brain of male rats.

For conveyor has identified the following indicators:

capture:Km=0,32±of 0.11 μm (in each case N=4, i.e. the determined average values ± standard deviation of 4 independent series of experiments that were conducted in parallel in three replicates).

Detailed description of the method can be found in the literature (M.Ch.Frink, H.-H.Hennies, W.Englberger, M.Haurand and .Wilffert, Arzneim.-Forsch./Drug Res. 46 (III), 11, 1996, SS. 1029-1036).

The analysis results obtained in the study proposed in the invention compounds in these experiments are shown below in table 3.

Table 3
Compound of example No.Expressed as % inhibition of capture when the concentration of the test compound, equal to 10 microns
359
445
553
750
848
977
1141
1254
13 43
1470
1541
1864
2070
2161
2242
2349
2780
3048
3166
3243
3342
3752
3844
4247
4448
4559
4792
5050
5550
6461
6563
6759
6956
7393
7565
7842
7958
8060
8467
8968
9649
9783
9882
10143
102 48
10347
10449
10553

Compound of example No.Expressed as % inhibition of capture when the concentration of the test compound, equal to 10 microns
10647
10742
10842
10940
11045
11140
11245
11350
11442
11555
11660
11746
11846
11943
12040
12155
12241
12342
12449
12540
12667
12751
12845
12943
13061
13157
132 46
13348
13451
13556
13653
13749
13849
13951
14083
14161
14249
14347
14456
14546
14661
14950
15048
15345
15541
15660

Compound of example No.Expressed as % inhibition of capture when the concentration of the test compound, equal to 10 microns
16362
16480
16555
16653
16763
16879
16964
17043
17173
17241
173 60
17652
17747
17851
17949
18061
18151
18273
18367
18462
18545
18663
18744
18849
18945
19174
19241
19347
19465
19541
19640
19741
19852
19978
20043
20158
20358
20448
20546
20750
20852
20951
21042
21149
21255
21346
Compound of example No.Expressed as % inhibition of capture when the concentration of the test compound, equal to 10 microns
21445
21542
21640
21740
21844

Studies on the inhibition of serotonin reuptake (NT)

To conduct these studies in vitro using freshly isolated from rat brain of synaptosome. In each case use the so-called R2-the fraction that dissect in accordance with the recommendations described in Gray and Whittaker (E.G.Gray and V.P.Whittaker, J.Anat. 76, 1962, SS. 79-88 [in Russian]). To capture NT these vesicular particles are separated from the hypothalamus of the brain of male rats.

Detailed description of the method can be found in the literature (.Ch.Frink, H.-H.Hennies, W.Englberger, M.Haurand and .Wilffert, Arzneim.-Forsch./Drug Res. 46 (III), 11, 1996, SS. 1029-1036).

The analysis results obtained in the study proposed in the invention compounds in these experiments are shown below in table 4.

Table 4
Compound of example No.Expressed in % inhibition capture NT when the concentration of esteruelas connection equal to 10 microns
147
255
351
454
559
654
975
1040
1478
1555
1660
1746
1980
2440
2551
2665
2749
2843

Compound of example No.Expressed in % inhibition capture NT when the concentration of the test compound, equal to 10 microns
2942
3169
3357
3544
3770
3965
4045
4170
4341
4480
4640
484
4950
5057
5149
5260
5353
5443
5565
5652
5741
5855
5945
6065
6172
6273
6355
6461
6581
6640
6758
6852
6963
7054
7143
7242
7346
7443
7642
7741
8146
8242
8352
8468
8541
8646

Compound of example No.Expressed in % inhibition capture NT when the concentration of the test compound, equal to 10 microns
8740
8846
9048
9145
9251
9342
9457
9554
9944
10043
10146
10441
10956
13064
14441
14767
14847
15070
15241
15448
15641
15752
15842
15940
16050
16144
16240
16454
16541

Experience, by definition, interact with α2Areceptor

In this case, the tie is of the receptor is determined by the displacement of the labeled ligand. The experiment was carried out in accordance with the recommendations described in J.P. Devlin, "High throughput screening : the discovery of bioactive substances", published by Marcel Dekker, New York, 1997, SS. 275-453. In the experiment used a commercially available membrane containing αreceptor subtype 2A (human).

The analysis results obtained in the study proposed in the invention compounds in these experiments are shown below in table 5.

Table 5
Compound of example No.Expressed as % inhibition of binding to human α2Areceptor at a concentration of tested compounds is 1 µm
2131
2737
15133

Binding to the receptor binding site glycine at the NMDA receptor channel)

Studies to determine the affinity of the proposed in the invention compounds to the binding site glycine at the NMDA receptor channel were performed on homogenates of the membranes of brain cells (the homogenate of the cortex and the hippocampus of the brain of male rats of Wistar) (B.M.Baron, B.W.Siegel, B.L.Harrison, R.S.Gross, C.Hawes and .Towers, Journal of Pharmacology and Experimental Therapeutics, t, 1996, p.62).

With this purpose from svejeporublennogo of rat brain separates the cerebral cortex and the hippocampus, which is under ice cooling homogenized using a Potter homogenizer (firm Braun Melsungen, 10 strokes at 500 rpm) in Tris-acetate buffer with a concentration of 5 mmol/l and pH 7.4 (10 ml/g wet tissue), supplemented with sucrose at a concentration of 0.32 mol/l, and then centrifuged for 10 min at 1000 g and 4°C. Formed - the first supernatant was collected, and the residue is again homogenized under ice cooling using a Potter homogenizer (10 strokes at 500 rpm) in Tris-acetate buffer with a concentration of 5 mmol/l and with pH 7.4 (5 ml/g of the original weight of raw tissue), supplemented with sucrose at a concentration of 0.32 mol/l, and centrifuged for 10 min at 1000 g and 4°C. the Resulting supernatant was combined with that obtained with the first centrifugation, the supernatant liquid was centrifuged for 20 min at 17000 g and 4°C. Formed after centrifugation the supernatant was discarded and the membrane sediment was made in Tris-acetate buffer with a concentration of 5 mmol/l and pH 8.0 (20 ml/g the original weight of raw tissue) and homogenized with 10 strokes at 500 rpm

Then the homogenate cell membranes were incubated for 1 h at 4°S, and then centrifuged for 30 min at 50000 g and 4°C. the resulting centrifugation the supernatant was discarded, and the cell containing the membrane sediment was kept frozen with the standing for 24 h at -20° In sealed with paraffin film centrifuge tube. The next day containing cell membrane sediment was thawed, brought it in ice Tris-acetate buffer with a concentration of 5 mmol/l and pH 7.0 (10 mg/g initial weight of the raw fabric), supplemented with 0.1% saponin (weight/volume), homogenized with 10 strokes at 500 rpm and then centrifuged for 20 min at 50000 g and 4°C. the Resulting supernatant was discarded and the sediment portion of a small amount were made in Tris-acetate buffer with a concentration of 5 mmol/l and pH 7.0 (about 2 ml/g initial weight of the raw fabric) and again homogenized with 10 strokes at 500 rpm Then the homogenate cell membranes after determining the content of protein was diluted in Tris-acetate buffer with a concentration of 5 mmol/l and pH 7.0, bringing the concentration of the protein to 10 mg/ml, and to conduct experiments were stored in aliquot quantities in the frozen state.

For experiments on binding with the receptor aliquot of the sample was thawed, diluted in Tris-acetate buffer with a concentration of 5 mmol/l and pH 7.0 in the ratio of 1:10, then under ice cooling homogenized using a Potter homogenizer (10 strokes at 500 rpm) and centrifuged for 60 min at 55000 g and 4°C. the Resulting supernatant liquid decanter the Wali, and containing the cell membrane residue was diluted with ice Tris-acetate buffer with a concentration of 50 mmol/l and pH 7.0, bringing the protein concentration to 1 mg/ml, and then homogenized with 10 strokes at 500 rpm stirring with a magnetic stirrer in an ice bath maintained in a suspended condition. This homogenate cell membranes used in the experiments for the binding with the receptor.

In experiments on binding as the buffer used Tris-acetate buffer with a concentration of 50 mmol/l and pH 7.0, and as a radioactive ligand used (3H)-MDL 105.519 at a concentration of 1 nmol/l (Vmmap and others, 1996). The number of non-specific bound ligand was determined in the presence of glycine in a concentration of 1 mmol/L.

Other mixtures were added proposed in the invention compounds in various concentrations and determined the displacement of the radioactive ligand from its specific associated with the binding site glycine at the NMDA receptor channel condition. Mixtures were incubated for 120 min at 4°and then the homogenate cell membranes to determine the number of associated radioactive ligand was collected by filtering through Steklovolokno filter mats (type GF/B). Detained on Steklovolokno filters, radioactivity was measured after adding Scintilla the Torah with the help of counter β -particles.

The analysis results obtained in the study proposed in the invention compounds in these experiments are shown below in table 6.

Table 6
Compound of example No.Expressed as % inhibition of binding to binding site glycine at a concentration of tested compounds, equal to 10 microns
3437
3638
13736
17441
17591
19089
20259
20639

The pharmaceutical composition proposed in the invention of the medicinal product

1 g of the hydrochloride [1-(3-methoxybenzyl)pyrrolidin-3-yl]amide 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid (compound of example 64) was dissolved at room temperature in 1 liter of water for injection and then the addition of sodium chloride solution were transferred to isotonic.

1. Substituted derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene General formula (I)

in the form of its racemate, its pure stereoisomers, especially enantiomers or di is Stereolab, or as mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in free form or in the form of its bases or in the form of its salts, especially physiologically compatible salts, most preferably in the form of his hydrochloridw or in the form of a solvate, especially hydrates,

thus R1and R2independently of one another denote H, unsubstituted or substituted C1-18alkyl, C3-10cycloalkyl, (C1-12alkyl)- C3-10cycloalkyl, aryl, (C1-12alkyl)aryl, monocyclic or bicyclic condensed 5 - or 6-membered heterocyclyl containing at least one heteroatom selected from oxygen atoms, sulfur and/or nitrogen, monocyclic or bicyclic condensed 5 - or 6-membered (C1-12alkyl)heterocyclyl containing at least one heteroatom selected from oxygen atoms, sulfur and/or nitrogen, with at least one of the residues R1and R2different from N,

or together represent -(CR4R5)m-(CR6R7)n-Y-(CR8R9)p-(CR10R11)q-where each of m, n, p and q equal to 0, 1, 2, 3, 4, or 5, provided that m+n≥1 and p+q≥1,

where R4, R5, R6, R7, R8, R9, R10and R11independently from each other is oznachaet N

Y represents CR15R16, NR17,

where R15and R16denote N

R17represents C3-8cycloalkyl, aryl, (C1-6alkyl)aryl,

R3denotes H, SO2R12or COR13,

where R12and R13independently of one another denote an unsubstituted or substituted C1-10alkyl, aryl, monocyclic or bicyclic condensed 5 - or 6-membered heterocyclyl containing at least one heteroatom selected from oxygen atoms, sulfur and/or nitrogen, or NR18R19,

where R18and R19denote C1-10alkyl.

2. Substituted derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene according to claim 1, wherein R1and R2independently of one another denote H, C1-8alkyl, C3-8cycloalkyl, (C1-4alkyl)- C3-8cycloalkyl, aryl, (C1-4alkyl)aryl, monocyclic or bicyclic condensed 5 - or 6-membered heterocyclyl containing at least one heteroatom selected from oxygen atoms, sulfur and/or nitrogen, monocyclic or bicyclic condensed 5 - or 6-membered (C1-4alkyl)heterocyclyl containing at least one heteroatom selected from oxygen atoms, sulfur and/or nitrogen, with at least one of the residues R1and R2different Rel,

or together represent (CR4R5)m-(CR6R7)n-Y-(CR8R9)p-(CR10R11)q-where m is 1, n is 0 or 1, R is 1 or 2 and q is 1 or 2,

R3means SO2R12or COR13,

Y represents CR15R16or NR17,

R12represents C1-4alkyl, aryl, monocyclic or bicyclic condensed 5 - or 6-membered heterocyclyl containing at least one heteroatom selected from oxygen atoms, sulfur and/or nitrogen, or NR18R19,

R13represents C1-6alkyl, aryl, monocyclic or bicyclic condensed 5 - or 6-membered heterocyclyl containing at least one heteroatom selected from oxygen atoms, sulfur and/or nitrogen,

R17represents C3-8cycloalkyl, aryl, (C1-4alkyl)aryl,

R18Il19denote C1-6alkyl.

3. Substituted derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene according to claim 1 or 2, characterized in that

R1represents C1-6alkyl, C3-8cycloalkyl, (C1-3alkyl)-C3-8cycloalkyl, aryl, (C1-3alkyl)aryl, monocyclic or bicyclic condensed 5 - or 6-membered heterocyclyl containing at least one heteroatom selected from the atoms color is Yes, sulfur and/or nitrogen, monocyclic or bicyclic condensed 5 - or 6-membered (C1-3alkyl)heterocyclyl containing at least one heteroatom selected from oxygen atoms, sulfur and/or nitrogen, and

R2denotes H, C1-4alkyl, (C1-3alkyl)aryl or monocyclic or bicyclic condensed 5 - or 6-membered (C1-3alkyl)heterocyclyl containing at least one heteroatom selected from oxygen atoms, sulfur and/or nitrogen.

4. Substituted derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene according to claim 3, characterized in that

R1denotes unsubstituted or substituted by an atom of F, Cl, Br, I, group-CN, N-alkyl-N-arylamino, N,N-dialkylamino, amidon, carboxylation, carboxybenzene methyl, ethyl, n-propyl, isopropyl, 2-methylpropyl, n-butyl, tert-butyl, n-pentyl, 3-methylbutyl or CH2- (CH3)=CH2above all methyl, ethyl, CH2- (CH3)=CH2CH(C(=O)OCH2CH=CH2)-CH2C(=O)O-tert-butyl, 2-cyanoethyl, CH2-CH2-NH-C(=O)CH3, 2-(N-ethyl-N-(3-were)amino)ethyl, 2-(N,N-dimethylamino)ethyl, 2-(C(=O)-NH-(β-naphthyl)ethyl, 1,2-(di(C(=O)O-tert-butyl)ethyl, 3-(N-methyl-N-phenylamino)propyl, 1-(C(=O)O-benzyl)-3-methylbutyl, 1-(C(=O)O-butyl)-3-methylbutyl, CH2CO2ethyl, CH2-CH2CO2ethyl, CH2-CH2-Opener, CH2-CH2-S-CH2-The n 3or denotes an unsubstituted or substituted by an atom of F, Cl, Br, I, group-CN, alkyl, aryl, carboxylation, carboxybenzene, O-alkyl, O-benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.1.1]heptane-3-yl, especially 2-vinylcyclopropyl, 2-(O-benzyl)cyclopentyl, 2-(carboxyethyl)cyclohexyl, 7,7-dimethyl-2-methylbicyclo[3.1.1]heptane-3-yl, cyclopropylmethyl, 7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-ylmethyl, or denotes an unsubstituted or substituted by phenoxypropane, -CH2-P(=O)(Outila)2phenyl, 1-naphthyl or 2-naphthyl, or represents CH2-aryl, CH2-CH2-aryl, CH2-CH2-CH2-aryl, CH2-CH2-CH2-CH2-aryl, CH(CH3)aryl, CH(CH3)-CH2-aryl, CH2-CH(aryl)2CH(CO2alkyl)-CH2-aryl, CH2-CH2-CH(aryl)2where aryl represents unsubstituted phenyl, 1-naphthyl or 2-naphthyl or substituted by an atom of F, Cl, Br, I, group-CN, -NO2, alkyl, a group of CF3, alkoxygroup, alkylenedioxy phenyl, especially benzyl, -CH2-naphthas-1-yl, 2-tormentil, 3-tormentil, 3-Chlorobenzyl, 3-methoxybenzyl, 2-ethoxybenzyl, 2,4-diferensial, 3,5-dichlorobenzyl, 3-fluoro-5-trifloromethyl, 3-fluoro-4-trifloromethyl, 2-chloro-6-tormentil, 2.5-dimethoxybenzyl, 2-chloro-6-methylbenzyl, 3,4-dimethoxybenzyl, 3,4-dioxymethylene ensil, CH(CH3)-phenyl, CH(CH3)-(4-(CH3)-phenyl), CH(CH3)-(4-nitrophenyl), CH(CH3)-(2,3-dioxyethylene), CH2-CH2-phenyl, CH2-CH2-(2-forfinal), CH2-CH2-(3-forfinal), CH2-CH2-(4-forfinal), CH2-CH2-(4-chlorophenyl), CH2-CH2-(3,4-dichlorophenyl), CH2-CH2-(3-methoxyphenyl), CH2-CH2-(2,5-acid), CH(CO2-tert-butyl)-CH2-phenyl, CH(CO2-methyl)-CH2-(4-chlorophenyl), CH2-CH(phenyl)2CH(CH3)-CH2-(4-chlorophenyl), CH2-CH2-CH(phenyl)2CH2-CH2-CH2-phenyl, or denotes an unsubstituted or substituted aryl, alkylaryl or carboxyethyl pyrrolidine or piperidine, primarily pyrrolidin-3-yl, N-(4-triptorelin)pyrrolidin-3-yl, N-(3-methoxybenzyl)pyrrolidin-3-yl, N-(CH2-(β-naphthyl)pyrrolidin-3-yl or N-(carboxyethyl)piperidine-4-yl, or represents unsubstituted or substituted alkyl, atom (F, Cl, Br, I, group-CN, aryl, alkylaryl (CH2)1-3-heterocyclyl where heterocyclyl is furanyl, benzofuranyl, 1,4-dioxane, benzo-1,4-dioxane, thienyl, pyridinyl, pyrrolidinyl, 1H-indolyl, imidazolyl, piperidinyl, tetrahydrofuranyl primarily denotes CH2-furan-2-yl, 5-methylfuran-2-yl CH2-benzofuran-2-yl group

CH2-Tien-2-yl, CH2-pyridin-3-yl, CH2-pyridin-4-yl, CH2-CH2-pyridin-2-yl, CH2-CH2-(1H-indol-3-yl), - CH2-CH2-pyrrolidin-1-yl, CH2-(N-2,6-dichlorobenzonitrile-3-yl), - CH2-CH2-(N-methylpyrrolidine-2-yl), -(CH2)3-imidazol-1-yl, CH2-tetrahydrofuran-2-yl), a group

CH(CO2methyl)-CH2-(1H-indol-3-yl) or NH-C(=O)-(4-diethylaminophenyl), and

R2denotes H, unsubstituted or substituted by an atom of F, Cl, Br, I, group-CN, methyl, ethyl or CH2- (CH3)=CH2above all methyl, ethyl, 2-cyanoethyl, CH2- (CH3)=CH2or denotes an unsubstituted or substituted by an atom of F, Cl, Br, I, group-CN, methoxy group, ethoxypropane, benzyl or phenethyl, especially benzyl, 4-tormentil, 2-chloro-6-tormentil, 2.5-dimethoxybenzyl, phenethyl, or denotes CH2-furanyl, first of all SN2-benzofuran-2-yl, CH2-pyridinyl, first of all SN2-pyridin-3-yl, CH2-tetrahydrofuranyl, especially CH2-tetrahydrofuran-2-yl, CH2-CH2-pyridinyl, especially CH2-CH2-pyridin-2-yl.

5. Substituted derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene according to claim 1 or 2, characterized in that

R1and R2together denote a group

or

R6, R10, R15and R16denote N

R17stands With3-8cycloalkyl primarily cycloheptyl, aryl, especially unsubstituted or substituted stands, ethyl, n-propylene, isopropyl, n-bootrom, tert-bootrom, a group of CF3, atom (F, Cl, Br, I, group-CN, methoxy group, ethoxypropane, n-propoxyphene, isopropoxycarbonyl, n-butoxypropyl, tert-butoxypropyl, phenyl or naphthyl, or represents ((CH2)1-3-alkyl)aryl or CH(CH3)aryl, where aryl represents unsubstituted or substituted alkyl group, CF3, atom (F, Cl, Br, I, group-CN, alkoxygroup phenyl or naphthyl.

6. Substituted derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene according to claim 5, characterized in that

R6, R10, R15and R16denote N

R17means cycloheptyl, phenyl, 2-were, 3-were, 2,4-dimetilfenil, 2-ethylphenyl, 3-trifluoromethyl, 4-forfinal, 4-chlorophenyl, 2-methoxyphenyl, 3,5-acid, 3-chloro-6-were, benzyl, CH2-(4-tert-butylphenyl), CH2-(β-naphthyl), CH(CH3)-phenyl, (CH2)3-phenyl, C(=O)-(4-methoxyphenyl), C(=O)benzyl, C(=O)-CH2-(3,4-differenl), C(=O)O-tert-butyl or O-benzyl.

7. Substituted derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene according to claim 1 or 2, characterized in that h is about

R3means SO2R12,

R12denotes methyl, ethyl, n-propyl, isopropyl, especially n-propyl, 7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-ylmethyl, phenyl or substituted stands, ethyl, n-propylene, isopropyl, n-bootrom, tert-bootrom, a group of CF3, atom (F, Cl, Br, I, group-CN, NO2, a methoxy group, ethoxypropane, n-propoxyphene, isopropoxycarbonyl, n-butoxypropyl, tert-butoxypropyl, group OCF3, CO2the stands phenyl, especially 4-were 3-triptoreline, 4-forfinal, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-trifloromethyl, 4-nitrophenyl, 2-CO2were, 2,5-dichlorophenyl, 3-fluoro-6-were, 3-bromo-6-methoxyphenyl, 2-methyl-5-nitrophenyl, 2,4,6-trimetilfenil, or denotes benzyl or substituted stands, ethyl, n-propylene, isopropyl, n-bootrom, tert-bootrom, a group of CF3, atom (F, Cl, Br, I, group-CN, NO2, a methoxy group, ethoxypropane, n-propoxyphene, isopropoxycarbonyl, n-butoxypropyl, tert-butoxypropyl, group OCF3benzyl, unsubstituted or substituted stands, ethyl, n-propylene, isopropyl, n-bootrom, tert-bootrom, a group of CF3, atom (F, Cl, Br, I, group-CN, NO2, a methoxy group, ethoxypropane, n-propoxyphene, isopropoxycarbonyl, n-butoxypropyl, tert-butoxypropyl furanyl or thienyl, preid the entire Tien-2-yl, 5-chlortan-2-yl, or represents NR18R19and

R18and R19independently of one another denote methyl or ethyl.

8. Substituted derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene according to claim 1 or 2, characterized in that

R3denotes COR13and

R13denotes unsubstituted or substituted O-stands, O-ethyl, group O-(CH2)2-Och3, O-benzyl, O-phenyl with unsubstituted or

substituted atom (F, Cl, Br, I, group-CN, phenyl, O-C(=O)stands, O-C(=O) - ethyl, methyl, ethyl, n-propyl, isopropyl, 2-methylpropyl, n-butyl, tert-butyl, n-pentyl or 3-methylbutyl, especially methyl, ethyl, n-propyl, n-butyl, tert-butyl, n-pentyl, CH2-O-CH2-CH2-Och3CH(CH3)-O-phenyl, CH2-O-(3-chlorophenyl), CH2-CH2-CH2-O-phenyl, or unsubstituted or substituted atom (F, Cl, Br, I, group-CN, phenyl, stands, ethyl, n-propylene, isopropyl, n-bootrom, tert-bootrom, a group of CF3, atom (F, Cl, Br, I, group-CN, NO2, a methoxy group, ethoxypropane, n-propoxyphene, isopropoxycarbonyl, n-butoxypropyl, tert-butoxypropyl, group OCF3, OCHF2, OCH2F, SCF3, SCHF2, SCH2F, SCH3CH2OC(=O) - phenyl, the group-N(CH3) phenyl or naphthyl, especially 4-forfinal, 2-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 4-phenylphenyl (4-biphenyl), 4-terphenyl, 4-CF3-phenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 4-tert-butyl, 3-OCF3-phenyl, 4-OCF3-phenyl, 4-SCF3-phenyl, 3-SCF2-phenyl, 2-CH2-OC(=O)phenyl, 3-dimethylaminophenyl, 2,3-dichlorophenyl, 2,4-differenl, 3-chloro-4-forfinal, 3-chloro-2-forfinal, 4-CF3-3-forfinal, 3-CF3-6-forfinal, 4-bromo-3-were, 2-chloro-4-nitrophenyl, 2,3,4,5,6-pentafluorophenyl, 2,6-debtor-3-were, 2,3-debtor-4-were, 2-chloro-5-methyl-6-forfinal, 1-naphthyl, 2-naphthyl, or represents furanyl, benzofuranyl, thienyl, pyridinyl, pyrazolyl, benzodithiophene, isoxazolyl, especially 1,5-dimethylfuran-3-yl, 2-methyl-5-tert-butylfuran-3-yl, 3-chlortan-2-yl, 1-(4-chlorophenyl)-5-cryptomaterial-4-yl, 1-methyl-3-tert-butylphenol-5-yl group

pyridine-4-yl, 2-methylthiopyridine-3-yl, 2-ethylthiophen-3-yl, 2-phenoxypyridine-3-yl, 2-chloropyridin-3-yl, 5-methyl-3-(2,6-dichlorophenyl)isoxazol-4-yl, 5-methyl-3-(2-chloro-6-forfinal)isoxazol-4-yl.

9. Substituted derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene 1, characterized in that it is selected from the group including

methyl Efir-(1H-indol-3-yl)-2-{[8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}propionic acid,

diethyl ether {4-[(8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl)amino]benzyl}phosphonic acid,

(4-cyclog philpapers-1-yl)-[8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

[8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-(4-phenylpiperazin-1-yl)methanon,

cyclopentolate 8-(2-chloro-4-nitrobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(4-naphthalene-2-iletileri-1-yl)-(8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl)methanon,

ventilated 8-dimethylsulphamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(1-phenylethyl)amide 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(3,4-dichlorophenyl)ethyl]amide 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

N'-[8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]hydrazide 4-diethylaminobenzoic acid,

(2-pyrrolidin-1-retil)amide 8-(3-chloro-4-fluorescent-benzazolyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ventilated 8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-dimethylaminoethyl)amide 8-benzazolyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[4-(3-phenylpropyl)piperazine-1-yl]-[8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

[3-(2-methylpiperidin-1-yl)propyl]amide 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(1H-indol-3-yl)ethyl]methylamide 8-(4-t is aftermarketsolutions)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-acetylamino)amide 8-(5-fluoro-2-methylbenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylpenicillin 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-dimethylaminoethyl)amide 8-(2-methyl-5-nitrobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-benzyloxyphenyl)amide 8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)amide 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(4-phenoxyphenyl)amide 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(1-n-triletal)amide 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

3-forbindelse 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

2-phenyl-1-{4-[8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]piperazine-1-yl}Etalon,

[1-(4-trifloromethyl)pyrrolidin-3-yl]amide 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-(4-o-tailpipes-1-yl)methanon,

benzyl(2-cyanoethyl)amide 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[8-(2,5-is alimentacion)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-(4-thieno[2,3-d]pyrimidine-4-reparation-1-yl)methanon,

(benzo[1,3]dioxol-5-ylmethyl)amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(3-methyl-4-m-tailpipes-1-yl)-[8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

[4-(1-phenylethyl)piperazine-1-yl]-[8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

[4-(2,4-dimetilfenil)piperazine-1-yl]-[8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

cyclopentolate 8-(2-chloropyridin-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(4-naphthalene-2-iletileri-1-yl)-[8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

(pyridine-3-ylmethyl)amide 8-[3-phenyl-2-(toluene-4-sulfonylamino)propionyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-dimethylaminoethyl)amide 8-(5-fluoro-2-methylbenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(4-nitrobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

3-fluoro-5-triptoreline 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzhydrylamine 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-cyanoethyl)amide 8-[3-phenyl-2-(toluene-4-sulfonylamino)propionyl]-1-oxa-2,8-di is suspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester [(8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl)amino]acetic acid,

(2-cyanoethyl)amide 8-(3-dimethylaminobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[1-(naphthalene-2-ylcarbonyl)ethyl]amide 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(1-n-triletal)amide 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[4-(4-chlorophenyl)piperazine-1-yl]-(8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl)methanon,

(2-benzyloxyphenyl)amide 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-acetyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

2.5-differentiated 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(1-naphthalene-2-iletilenlerin-3-yl)amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

2-ethoxybenzene 8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(4-ethylbenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

1-allyl ester and 4-tert-butyl ester 2-{[8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}succinic acid,

naphthalene-2-alamid 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 4-{[8-(2-phenylcyclopropanecarboxylic)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}piperidine-1-carboxylic acid,

ethyl ester of 4-{[8-(2,4-differentail)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}piperidine-1-carboxylic acid,

(2-dimethylaminoethyl)amide 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(4-chlorophenyl)ethyl]amide 8-dimethylsulphamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(5-methylfuran-2-ylmethyl)amide 8-(4-methoxybenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(4-chlorophenyl)ethyl]amide 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(1-methylpyrrolidine-2-yl)ethyl]amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 4-{[8-(4-bromobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}piperidine-1-carboxylic acid,

3,5-dichloraniline-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[1-(3-methoxybenzyl)pyrrolidin-3-yl]amide 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

dimethylamide 3-(4-naphthalene-2-iletileri-1-Carbo who yl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-sulfonic acid,

ethyl ester of 3-{[8-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-elmersolver)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}propionic acid,

(2-benzyloxyphenyl)amide 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

3,4-dimethoxybenzamide 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl)-[4-(3-phenylpropyl)piperazine-1-yl]metano,

dimethylamide 3-(4-thieno[2,3-d]pyrimidine-4-reparation-1-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-sulfonic acid,

[8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-[4-(3,5-acid)piperazine-1-yl]metano,

3-fluoro-4-triptoreline 8-dimethylsulphamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-benzyloxyphenyl)amide 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 4-[(8-butyryl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl)amino]piperidine-1-carboxylic acid,

(2-vinylcyclopropyl)amide 8-(toluene-4-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-[4-(5-methylpyrazine-2-carbonyl)piperazine-1-yl]metano,

2,4-differentiated 8-dimethyls livemail-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(3-forfinal)ethyl]amide 8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2.2-diphenylether)amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

dimethylamide 3-[4-(3-phenylpropyl)piperazine-1-carbonyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-sulfonic acid,

ethyl ester of 3-{[8-(3,5-differentail)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}propionic acid,

isobutyramide 8-(propane-1-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[4-(3-phenylpropyl)piperazine-1-yl]-[8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

[1-(2,3-dihydrobenzo[1,4]dioxin-5-yl)ethyl]amide 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

phenylamide 8 butyryl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclooctylamine 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-[2-(2-methoxyethoxy)acetyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

isobutyramide 8-(4-bromo-3-methylbenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[3-(methylpentylamino)propyl]amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 4-{[8-(2-meth is l-5-nitrobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}piperidine-1-carboxylic acid,

[8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-[4-(4-forfinal)piperazine-1-yl]metano,

methylpyridin-3-ylmethylene 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

2-(3,4-differenl)-1-{4-[8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]piperazine-1-yl}Etalon,

cyclopropylmethyl 8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 3-{[8-(2-methyl-5-nitrobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}propionic acid,

(thiophene-2-ylmethyl)amide 8-[2-(3-chlorophenoxy)acetyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylpenicillin 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylpenicillin 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-cyanoethyl)pyridine-3-ylmethylene 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-cyanoethyl)-(tetrahydrofuran-2-ylmethyl)amide 8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

methylpyridin-3-ylmethylene 8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

of gasoline the amide 8-(pyridine-4-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl(2-methylallyl)amide 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(2-forfinal)ethyl]amide 8-(4-methoxybenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

isobutyramide 8-(5-tert-butyl-2-methylfuran-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(3-phenylacrylate)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopropylmethyl 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopropylmethyl 8-(4-triftormetilfullerenov)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(5-methylfuran-2-ylmethyl)amide 8-(4-bromobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopropylmethyl 8-(3-fluoro-4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-ethylsulfanyl)amide 8-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-elmersolver)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(tetrahydrofuran-2-ylmethyl)amide 8-(2,4-differentail)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester{[8-(3-chlorothiophene-2-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}acetic acid,

methyl ester of 4-oxo-4-{3-[(thiophene-2-ylmethyl)carbarnoyl]-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-yl}butyric acid,

benzylated 8-(2-ethylsulfanyl-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 3-{[8-(2-chlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}propionic acid,

cyclopropylmethyl 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopropylmethyl 8-(4-phenoxybutyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-[4-(4-triptorelin-2-yl)piperazine-1-yl]metano,

cyclopropylmethyl 8-(2-chloro-5-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-benzyloxyphenyl)amide 8-(4-methoxybenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 4-{[8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}piperidine-1-carboxylic acid,

cyclopropylmethyl 8-(2-phenoxypropionyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(3-methoxyphenyl)ethyl]amide 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

isobutyramide 8-(2-methylsulfinylphenyl-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopentolate 8-(5-tert-butyl-2-methylp the RAS-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(4-chlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(naphthalene-1-ylmethyl)amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(4-forfinal)ethyl]amide 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(pyridine-4-ylmethyl)amide 8-(4-bromo-3-methylbenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-(4-methoxybenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

3-chlorobenzylamino 8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl)-(4-o-tailpipes-1-yl)methanon,

(8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl)-(4-pyridine-2-reparation-1-yl)methanon,

(thiophene-2-ylmethyl)amide 8-(4-triftormetilfullerenov)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

isobutyramide 8-(4-perbenzoic)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

methyl ester of 2-(3-isobutylamino-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-sulfonyl)benzoic acid,

tert-butyl ester 2-[(8-dimethylsulphamoyl-1-oxa-8-diazaspiro[4.5]Dec-2-EN-3-carbonyl)amino]-3-phenylpropionic acid,

[1-(2,3-dihydrobenzo[1,4]dioxin-5-yl)ethyl]amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(4-bromobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(3-imidazol-1-ylpropyl)amide 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzyl ether of 4-[8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]piperazine-1-carboxylic acid,

dimethylamide 3-(4-cycloheptatrien-1-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-sulfonic acid,

tert-butyl ether 4-methyl-2-{[8-(thiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}pentanol acid,

(thiophene-2-ylmethyl)amide 8-(3-chloro-2-perbenzoic)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

tert-butyl ester 2-{[8-(4-methoxybenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}-4-methylpentanoic acid,

ethyl ester of 3-{[8-(6-chloro-2-fluoro-3-methylbenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}propionic acid,

benzylated 8-(2-phenoxypropionyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(5-fluoro-2-methylbenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-d is azaspiro[4.5]Dec-2-EN-3-yl]-[4-(2-methoxyphenyl)piperidine-1-yl]metano,

(thiophene-2-ylmethyl)amide 8-(2-chlorobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopentolate 8-(2-phenoxypyridine-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-ethylsulfanyl)amide 8-(4-bromobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl Efir-[8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]piperidine-2-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(2-chlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopropylmethyl 8-(2,3-dichlorobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopropylmethyl 8-hexanoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopropylmethyl 8-(2,3-debtor-4-methylbenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2.5-dimethoxybenzyl)-furan-2-ylmethylene 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-ethylsulfanyl)amide 8-dimethylsulphamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

3-methoxybenzylamine 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-benzyloxyphenyl)amide 8-dimethylsulphamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[-(4-chlorophenyl)-1-methylethyl]amide 8-(4-methoxybenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(3,4-dichlorophenyl)ethyl]amide 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-[2-(3-chlorophenoxy)acetyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-cyanoethyl)-(2-pyridin-2-retil)amide 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[2-(4-chlorophenyl)-1-methylethyl]amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-benzyloxyphenyl)amide 8-(4-methoxybenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(2,6-debtor-3-methylbenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-(2-benzyloxyethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

phenylamide 8-(2,3-dichlorobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopentolate 8-(5-bromo-2-methoxybenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

2-(3-benzylcarbamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-yl)-1,1-dimethyl-2-oksietilnye ether acetic acid,

(2-ethylsulfanyl)amide 8-[3-(2-chloro-6-forfinal)-5-methylisoxazol-4-carbonyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[4-(3-phenylpropyl)piperazine-1-yl]-[8-(4-trifloromethyl)-1-oxa-2,8-d is azaspiro[4.5]Dec-2-EN-3-yl]metano,

benzylated 8-[3-(2-chloro-6-forfinal)-5-methylisoxazol-4-carbonyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

isobutyramide 8-(naphthaleneboronic)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 1-[8-(5-tert-butyl-2-methylfuran-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]piperidine-2-carboxylic acid,

benzylated 8-(3-deformationeevent)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

phenylamide 8-(4-bromobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-vinylcyclopropyl)amide 8-(4-methoxybenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(4-phenoxybutyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(3-chloro-4-perbenzoic)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-ethylsulfanyl)amide 8-(5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]-[4-(3-phenylpropyl)piperazine-1-yl]metano,

(pyridine-4-ylmethyl)amide 8-(4-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

2-(3-cyclopentanecarbonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-ene-8-carbonyl)benzyl ester of benzoic KIS is the notes,

dimethylamide 3-[4-(4-tert-butylbenzyl)piperazine-1-carbonyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-8-sulfonic acid,

ethyl ester{[8-(2-ethoxybenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}acetic acid,

(2-benzyloxyphenyl)amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(naphthalene-1-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(3-phenylpropyl)amide 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)amide 8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

ethyl ester of 1-[8-(4-tert-butylbenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]piperidine-2-carboxylic acid,

[2-(3-triptoreline)ethyl]amide 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-carbonyl]-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[1-(naphthalene-2-ylcarbonyl)ethyl]amide 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-benzyloxyphenyl)amide 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

methyl ester of 3-(4-harfe who yl)-2-{[8-(4-methoxybenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}propionic acid,

(2-benzyloxyphenyl)amide 8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-phenoxyethyl)amide 8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-(2-phenoxypyridine-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

cyclopropylmethyl 8-(naphthalene-2-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-(3-chloro-4-perbenzoic)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-cyanoethyl)amide 8-(2-phenylbutyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

2-forbindelse 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(thiophene-2-ylmethyl)amide 8-(3-chlorobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(4-benzylpiperazine-1-yl)-[8-(2,5-dichlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

benzylated 8-(3-chlorobenzenesulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(4-benzylpiperidine-1-yl)-[8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

benzylated 8-(4-bromobenzoyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

[1-(4-nitrophenyl)ethyl]amide 8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]de the-2-EN-3-carboxylic acid,

tert-butyl ether 4-methyl-2-{[8-(3-trifloromethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carbonyl]amino}pentanol acid,

[4-(4-forfinal)-3,6-dihydro-2H-pyridine-1-yl]-(8-phenylmethanesulfonyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl)methanon,

[2-(ethyl-m-tolylamino)ethyl]amide 8-dimethylsulphamoyl-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

benzylated 8-(2,5-dimethylfuran-3-carbonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(4-cycloheptatrien-1-yl)-[8-(4-permentantly)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-yl]metano,

benzylated 8-(2-benzyloxyethyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

(2-benzyloxyphenyl)amide R,R-8-(5-chlorothiophene-2-sulfonyl)-1-oxa-2,8-diazaspiro[4.5]Dec-2-EN-3-carboxylic acid,

and hydrochloride.

10. The method of obtaining substituted derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene General formula (I)

in which R1, R2and R3have mentioned in one of claims 1 to 8 values, characterized in that

(a) compound of formula (II)

is subjected in the presence of potassium tert-butylate in THF interaction with agent methyltyrosine, preferably with a Ph3RSN3Br, to obtain compound f is rmula (III)

(b) a compound of the formula (III) is subjected in the presence of a base, preferably sodium hydrogen carbonate or lithium hydroxide, preferably in an organic solvent, primarily methanol, dichloromethane or THF, interaction with ethylchlorothioformate formula (IV)

with the formation of a derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene of the formula (V)

(C) a compound of the formula (V), either directly or after prior saponification present in the compound of formula (V) functional group, which is the ethyl ester of carboxylic acid, and optionally after activation with resulting functional group is a carboxylic acid, is subjected to the interaction with the amine of the formula HNR1R2in which R1and R2have mentioned in one of claims 1 to 8 values, to obtain the derived 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene of the formula (VI)

(g) from the compound of formula (VI) remove the protective BOC-group to obtain the compounds of formula (I)in which R3denotes N

(d) if necessary, the compound of formula (I)in which R3oznachaet N, turn the processing of the acid chloride of the acid of formula R12SO2Cl in the compound of formula (I)in which R3means SO2R12where R12is specified in one of claims 1 to 8 values, or converted by treatment with a carboxylic acid chloride of the acid of formula R13COCl in the compound of formula (I)in which R3denotes COR13where R13is specified in one of claims 1 to 8 values.

11. Drug with analgesic effect, containing at least one substituted derivative of 1-oxa-2,8-diazaspiro[4.5]Dec-2-ene General formula (I) according to claim 1 in the form of its racemate, its pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any of their ratio in the mixture, in free form or in the form of its bases or in the form of its salts, especially physiologically compatible salts, most preferably in the form of his hydrochloride, or the form of the solvate, especially hydrates.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

EFFECT: improved preparing method, valuable biochemical and medicinal properties.

10 cl, 6 tbl, 337 ex

The invention relates to new derivatives of oxazolidinones General formula (I) listed in the description, as well as their salt

FIELD: chemical-pharmaceutical industry, medicine, peptides.

SUBSTANCE: invention relates to preparing and using peptides of the formula (I) possessing analgesic activity: A-B-Tyr-Pro(D-Pro, dHPro, D-dHPro, DL-dHPro, Hyp)-C-X wherein A means -O, -Ala, -Asp, -Glu, -Phe, -Gly, -His, -He, -Lys, -Leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; B means 0, -Ala, -Asp, -Glu, -Phe, -Gly, -His, -He, -Lys, -leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; C means 0, -Ala, -Asp, -Glu, -Phe, -Gly, -His, -He, -Lys, -Leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; X means -OH, -OCH3, -NH2. Proposed peptides can be used for design of new medicinal preparations. Peptides possess the enhanced activity as compared with pentalgin, analgin and morphine and have no toxic properties.

EFFECT: improved and valuable medicinal properties of peptides.

5 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: method involves applying cannabinoid receptor agonists for treating for transitory relaxation of lower esophageal sphincter and states like gastroesophageal reflux disease, regurgitation, preventing reflux or insufficient mass increase caused by the relaxation.

EFFECT: enhanced effectiveness of treatment.

18 cl, 3 tbl

FIELD: pharmaceutical industry.

SUBSTANCE: rectal- and vaginal-administration suppositories contain 1,3-diethylbenzimidazolium triiodide as active principal, polyvinylpyrrolidone as solubilizer and stabilizer, and lipophilic base with specified proportions of components.

EFFECT: extended therapeutical activity and reduced occurrence of side effects.

4 cl, 2 ex

The invention relates to substituted derivatives of imidazolidine formula 1

where W denotes the R1-A-C(R13or

where the ring system may be substituted by 1, 2 or 3 identical or different substituents R13and where L denotes C(R13and ml and m2 independently of one another denote 0, 1, 2, 3 or 4, and the sum of m l + m2 is 3 or 4; Y represents a carbonyl group; A represents a direct bond or a bivalent residue of a phenylene, A denotes a divalent (C1-C6)-alkalinity balance, and (C1-C6)-alkilinity the residue is unsubstituted or substituted by one or more identical or different residues from the series (WITH1-C8)-alkyl and (C3-C10-cycloalkyl-(C1-C6)-alkyl, F denotes R10CO., HCO, or R8O-CH2; R is H or (C1-C8)-alkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl or, if necessary, substituted (C6-C14)-aryl, and all residues R are independently from each other may be the continuously or repeatedly substituted by fluorine, or the rest of the X-NH-C(=NH) -R20, X - N, R2- N or (C1-C8) -alkyl; R3- N, (C1-C10) -alkyl, which optionally can be substituted one or more times by fluorine, optionally substituted (C6-C14)-aryl, optionally substituted heteroaryl, (C6-C12-bicycloalkyl, R11NH, COOR21, CONHR4or CONHR15; R4- (C1-C10)-alkyl, which is unsubstituted or substituted once or many times, equal or different residues from the series hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C10)-alkyl)-aminocarbonyl, (C1-C8-alkoxycarbonyl, R5, R6-CO, R5denotes optionally substituted (C6-C14)-aryl, R6denotes the residue of a natural or unnatural amino acid, R8- N or (C1-C10)-alkyl, and R8independently from each other may be the same or different, R10hydroxy, (C1-C10)-alkoxy, (C1-C8-alkylsulphonyl hydroxy-(C1-C6)-alkoxy, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C10)-alkyl)-amino, or R8R8N-CO-(C1-C means R12a-O-CO-or R12a-S(OH)2, R12ameans (C1-C10)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C4)-alkyl, or R15, R13- N or (C1-C6)-alkyl, which may optionally be substituted one or more times by fluorine, R15means R16-(C1-C6)-alkyl, or R16; R16denotes a 6-membered to 24-membered bicyclic or tricyclic residue, R20denotes a direct bond or (C1-C6-alkylen; R21- N or (C1-C8)-alkyl, R30represents one of the residues R32(R)N-CO-N(R)-R31or R32(R)N-CS-N(R)-R31; R32-CO-N(R)-R31or R12AO-CO-N(R)-R31and R30cannot mean R32-CO-N(R)-R31,ifat the same time W denotes R1-A-C(R13), And denotes a direct bond and R1andR13- N, R31denotes the divalent residue of R33-R34-R35-R36and R36linked to the nitrogen atom in the ring of imidazolidine in formula 1, R32means (C1-C8)-alkyl, which, when neobloc substituted (C6-C14)-aryl, optionally substituted in the aryl (C6-C14)-aryl-(C1-C8)-alkyl or optionally substituted heteroaryl, R33denotes a direct bond, R34denotes a bivalent residue of a number (C1-C8-alkylene, optionally substituted (C6-C14)-Allen; R35denotes a direct bond or a bivalent residue (C1-C8)-alkylene; R36denotes a direct bond, e and h represent independently from each other 0 or 1; in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, process for the preparation of compounds I; pharmaceutical drug that has the ability to inhibit the adhesion and/or migration of leucocytes and/or VLA-4 receptor

The invention relates to 3-dibenzoylethylene-7-nitro-2-honokalani form (1) with analgesic activity

The invention relates to the use of derivatives tetrahydropyridine(or 4-hydroxypiperidine)butylation General formula (I) and their physiologically acceptable salts, when receiving therapeutic agents useful in therapy and veterinary medicine for the treatment of acute pain, neuropathic pain and nociceptive pain, alone or in combination with other analgesics, and in this case there is a synergy

The invention relates to medicine and can be used to treat a variety of rhinitis: allergic, polynosic, year-round
The invention relates to medicine, specifically to medicines, analgesic action

The invention relates to chemical-pharmacological industry and relates to an inhibitor of the expression of integrin, comprising as active ingredient a compound sulfonamida formula IaIbthat means, containing an inhibitor of the expression of integrin formula IaIbfor the treatment of arteriosclerosis, psoriasis, osteoporosis, angiogenesis, retinal angiogenesis, diabetic retinopathy, inflammatory diseases, and how to prevent, treat or alleviate disease associated with increased expression of integrin

The invention relates to pharmaceutical industry and relates to means for obtaining a medicinal product for the treatment of breast cancer and prostate cancer, which represents a quinoline derivative of General formula (I), furthermore, the invention relates to new compounds, pharmaceutical compositions and to methods for producing compounds of formula (I)

The invention relates to the field of chemistry and medicine, specifically to dopamine receptor ligands of formula (I), pharmaceutical compositions of such compounds and to the method of using such compounds for the effective treatment of patients suffering from dopaminezantac dysfunction of the Central or peripheral nervous system

FIELD: organic chemistry.

SUBSTANCE: invention relates to substituted derivatives of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I in form of racemates, pure stereoisomers, particularly enantiomers or diastereomers in any ratio in mixture, in form of acids, or bases, or salts thereof, preferably physiologically acceptable salts, more preferably in form of hydrochlorides or solvates, in particular hydrates, wherein R1 and R2 are independently H, C3-C10-cycloalkyl, optionally substituted with O-alkylaryl, (C1-C12-alkyl)aryl, with the proviso, that at least one R1 and R2 is not H; R3 is H, SOR12 or COR13; R12 and R13 are independently C1-C10-alkyl, monocyclic 5-membered heterocyclic group having at least one heteroatom selected from sulfur atoms, optionally substituted with halogen; OR20, wherein R20 represents H, C1-C10-alkyl. Invention also relates to method for production of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I including a) compound of formula II interaction with methylenation agent, preferably with Ph3PCH3Br in presence of potassium tert-butylate in tetrahydrofuran (THF) to produce compound of formula III; d) compound of formula III interaction with ethylchloroximidoacetate of formula IV in presence of base, preferably of sodium hydrocarbonate or lithium hydroxide, preferably in organic solvent such as methanol, dichloromethane or TGF to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula V; c) compound of formula V interaction, directly or after previous saponification of functional group presenting in formula V (namely carboxylic acid ethyl ester) and optionally after activation of formed functional group (namely carboxylic acid) with amine of formula HNR1R2 wherein R1 and R2 are as defined above, to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula VI; d) protective group removing from compound of formula VI to produce compound of formula I, wherein R3 is H; and optionally e) converting of compound of formula I, wherein R3 is H, by treatment with acid chloride of formula R12SO2Cl to compound of formula I, wherein R3 is SO2R12 or converting by treatment with carboxylic acid chloride of formula R13COCl to compound of formula I, wherein R3 is COR13. Moreover disclosed is drug having analgesic action and containing at least one substituted 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula I.

EFFECT: new drug with analgesic action.

11 cl, 6 tbl

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

SUBSTANCE: invention describes novel spiropyrazole compounds of the general formula (I): wherein W means hydrogen atom, (C1-C10)-alkyl, (C3-C7)-cycloalkyl, cyano-(C1-C10)-alkyl, -(C1-C4)-alkyl-COOV1 wherein V1 means hydrogen atom (H) or (C1-C6)-alkyl, -(C1-C5)-alkyl-C(=O)-W1 wherein W1 means amino-group, or -(C1-C5)-alkyl-NHS(=O)2-W1 wherein W1 means -(C1-C10)-alkyl; Q means phenyl; n mean a whole number 0 or 1; A, B and C mean hydrogen atom; Z means a simple bond, methylene or ethylene group; R1 means (C3-C12)-cycloalkyl substituted optionally with (C1-C10)-alkyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, indenyl, norbornyl, dibenzocycloheptyl, 9-acenaphthyl, phenyl substituted optionally with benzyloxy-group, biphenyl or (C1-C10)-alkyl substituted optionally with 1-3 substitutes chosen from phenyl, cyano-group, -COOV1 wherein V1 means (C1-C6)-alkyl and -(C1-C5)-alkyl-C(=O)-W1 wherein W1 means amino-, (C1-C4)-alkylamino- or di-(C1-C4)-alkylamino-group; R2 means (C1-C10)-alkyl, (C3-C7)-cycloalkyl or halogen atom. Also, invention to their pharmaceutically acceptable salts, solvates, pharmaceutical composition containing thereof, a method for treatment of pain and a method for modulation of pharmacological response of described ORL-1- or μ-receptors. Invention can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 3 tbl, 5 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes novel spiroazacyclic compounds of the general formula: wherein X means -CH2, -CH2O, -OCH2 or oxygen atom (O); Y represents O; Z means -CH or nitrogen atom (N); R1 means (C1-C6)-alkyl optionally substituted with morpholinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 2-oxoimidazolidinyl, imidazolidinyl, 2-oxooxazolidinyl, oxazalidinyl or (C3-C6)-cycloalkyl, (C2-C8)-alkyl ester or benzyl ester; m is chosen from group comprising 0 or 1; R4 means hydrogen atom or benzyl optionally substituted with halogen atom or (C1-C4)-alkyl; R5 means hydrogen atom or benzyl optionally substituted with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; R6 means hydrogen atom or benzyl optionally substituted with (C1-C4)-alkoxy-, cycloalkyl-(C1-C4-alkoxy)- or halogen-(C1-C4-alkoxy)-group; R2 and R3 mean hydrogen atom and at least two radicals among R4, R5 and R6 mean optionally substituted benzyl. Also, invention relates to a method for inhibition of activity of serotonin 5-HT2A receptors, a method for treatment of state mediated by serotonin 5-HT2A receptors, and using spiroazacyclic compounds proposed.

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

35 cl, 3 tbl, 2 dwg, 45 ex

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