Derivatives of [1,2,4] triazolo [4,3-a]khinoksalinona or their pharmaceutically acceptable salts, method of production thereof, pharmaceutical composition and method for inhibition of ampa receptors

 

(57) Abstract:

The proposed derivatives of [1,2,4]triazolo[4,3-a]khinoksalinona General formula (I) in which R1represents a straight or branched C1-6-alkyl, substituted COX or POX'X", where X' and X" independently are hydroxy or alkoxygroup, R6and R9represent hydrogen, R7is CF3and R8is imidazolyl, piperidino or morpholino, rings are optionally substituted by one or two substituents selected from phenyl and C1-6-alkyl, or their pharmaceutically acceptable salts. Compounds (I) possess antagonistic activity against AMPA and is suitable for the treatment of indications caused by hyperactivity of the excitatory neurotransmitters. Also proposed is a method of obtaining the compounds (I), pharmaceutical composition and method of inhibiting AMPA receptors. 4 C. and 4 h.p. f-crystals, 1 PL.

The present invention relates to therapeutically active heterocyclic compounds and method of production thereof, pharmaceutical compositions comprising these compounds, and in addition, the method of treatment using these compounds.

In chastnostyami readings, caused by hyperactivity of excitatory amino acids.

Various related compounds known from the prior art.

Thus, in the patent EP-A-0040401, among other things, describe the collection triazolinones-4-ones, substituted on the triazole ring, for example, alkyl, acyl or carbalkoxy group. These compounds are stated as having appropriate antihypertensive activity.

In U.S. patent N 5153196 revealed some receptor antagonists excitatory amino acids and methods of use thereof. These compounds, incidentally, correspond to thiazolinediones, with one Deputy, such as H, alkyl, aromatic or CF3in the triazole ring.

In addition, in published international application N WO 93/20077 disclosed condensed derivatives of khinoksalinona optionally substituted in the ring, triazole lower alkyl which may be substituted mono - or di (lower alkyl) amine.

L-glutamic acid, L-aspartic acid and a number of other closely related amino acids have the ability to activate the neurons of the Central nervous system (CNS). Biochemical, electrophysiological and pharmacological IO number of excitatory neurons in the mammalian CNS.

Effect of glutamic acid, mediating the transmission of nerve excitation, considered an important method for the treatment of neurological and psychiatric disorders. Thus, known antagonists of excitatory amino acids show a strong anxiolytic (Stephens et al., Psychopharmacology 90, 143-147, 1985), anticonvulsant properties (Croucher et al., Science 216, 899-901, 1982) and properties of muscle relaxant (Turski et al., Neurosci Lett. 53, 321-326, 1985).

It was assumed that the extracellular accumulation of excitatory amino acids, with subsequent excessive stimulation of neurons, may explain the degradation of nerve cells observed in neurological disorders such as amyotrophic lateral (side) sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, epilepsy and mental deficiency and insufficient physical activity that occurs after conditions of brain ischemia, anoxia and hypoglycemia or head trauma and spinal cord (McGeer et al. , Nature 263, 517-519, 1976; Simon et al., Science 226, 850-852, 1984; Wieloch, Science 230, 681-683, 1985; Faden et al., Science 244, 798-800, 1989, Turski et al., Nature 349, 414-418, 1991).

Other possible indications are psychosis, muscle rigidity, vomiting and analgesia.

Excitatory amino acids exert their d is s currently successfully divided into three groups on the basis of electrophysiological and neurochemical data: group 1 presents NMDA receptors (N-methyl-D-aspartate), group 2 presents AMPA-receptors and group 3 presents kainite-induced receptor. L-glutamic acid and L-aspartic acid, probably activate all of the above types of receptors of excitatory amino acids and possibly also other types of receptors.

The above classification of excitatory amino acid receptors on NMDA, AMPA and kainite-induced receptors originally based on the following electrophysiological and neurochemical data.

1) N-methyl-D-aspartic (NMDA) receptors exhibit high selectivity for NMDA excitation. Botanova acid, L-homocysteinemia acid, D-glutamic acid and TRANS-2,3-piperidinylcarbonyl acid (TRANS-2,3-PDA) have a strong influence on small agonistic activity of these receptors. Most potent and selective antagonists are D-isomers of 2-amino-5-phosphonocrotonate acids, for example, 2-amino-5-vostanovlenija acid and 3-[()-2-carboxy-piperazine-4-yl] -propyl-1-phosphonic acid (CPP), and D-isomers of long chain 2-iminodicarboxylic acids (e.g., D-2-aminoadenosine acid) and long-chain diaminocarbenes acids (for example, diaminopimelic acid) show a moderate antagonistic actively is e (J. Davies et al., J. Physiol. 297, 621-635, 1979) and it was shown that these responses are strongly inhibited by ions of Mg2+.

2) AMPA-receptors are selectively activated AMPA (2-amino-3-hydroxy-5-methyl-4-isoxazolidinone acid), other strong agonists, presents fiskalnoy acid and L-glutamic acid. Diethyl ester of glutamic acid (GDEE) is a selective, but very weak antagonist of this receptor. AMPA receptors are relatively insensitive to ions of Mg2+.

For a long time believed that the release of glutamate plays a major role in neuronal death in cerebral ischemia (Benveniste, N. Et al., J. Neurochem. 43, 1369-1374, 1984). It is well known that the influx of Ca2+caused by NMDA receptor, is an important mechanism in ischemic loss of nerve cells. The NMDA receptor, not connecting ionophor becomes impermeable to calcium. However, excitation via collaterals of Schaeffer is in the field not CA1 NMDA receptors, and this fact is important for the course of events in the postischemic period. Recent studies have shown that selective AMPA-antagonists have a neuroprotective effect in global ischemia in gerbils, even when they are giving a few hours later after Renai ischemia.

3) Kainat receptors. Answers excitation on kainic acid is relatively insensitive to antagonists of NMDA and GDEE and therefore suggested that kainic acid activates the third subclass of receptors acidic amino acids. Some licenzirovannye kainic acid derivatives are selective antagonists (O. Goldberg et al., Neurosci. Lett. 23, 187-191, 1981) and dipeptide 3-glutamylation also exhibits some selectivity for kainite-induced receptor. Ions of Ca2+but not Mg2+are a strong inhibitor of the binding of kainic acid.

The affinity of a substance for one or more different types of receptors for excitatory amino acids investigated in simple experiments on the binding. In essence, the method involves the incubation of individual ligand introduced with a radioactive label and a separate specific substances to explore the homogenate of the brain containing the receptor. Measurement of the filling of the receptor was carried out by determining the binding of the radioactive label from the homogenate and subtraction of nonspecific binding.

The binding of AMPA receptor was investigated using3H-AMPA as radioligand.

The effect of the analogues glutaminainpolvere of the phenomenon of spreading depression in the retina of the chicken. Such experiments allow to obtain information about the effectiveness (agonist/antagonist) of the test substances. They must be viewed in comparison with the results of studies linking, in which the received data only on the affinity of compounds to the receptor.

We have found that the compounds of the present invention have affinity with AMPA receptors and are antagonists, in accordance with this type of receptor, which makes them useful for the treatment of any of the numerous indications caused by hyperactivity of excitatory amino acids, destructive, mainly neurons, as observed in amyotrophic lateral sclerosis, trochaic of Hennington, Parkinson's disease, epilepsy, senile dementia or mental and motor dysfunctions revealed after conditions of brain ischemia, hypoxemia, hypoglycemia, and traumatic brain and spinal cord. Other possible indications are psychosis, muscle rigidity, vomiting, acute and chronic inflammatory disease and analgesia.

Compounds of the present invention represented by the General formula I.

< / BR>
in which R1represents POX'X" or right is B>1-6-alkoxy group, and

R6, R7, R8and R9independently represent hydrogen, C1-6-alkyl; halogen; NH2; NO2CN; CF3; SO2NY'Y"; COZ' in which Z' represents a NY'Y" or C1-6is alkyl, and Y' and Y" independently represent hydrogen or C1-6-alkyl; triazolyl; imidazolyl; piperidine; piperazinil; morpholino; thiomorpholine, rings are optionally substituted by one or more phenyl or C1-6-alkyl, and phenyl optionally substituted C1-6-alkoxy group, and their pharmaceutically acceptable salts.

The term "C1-6-alkyl", as used here, refers to a straight or branched saturated hydrocarbon chain having 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, tertbutyl, 3-pentyl, neopentyl or n-hexyl.

The term "C1-6-alkoxy", as used here, by itself or in combination, refers to a monovalent Deputy, including C1-6is an alkyl group linked through an ether oxygen having its free valence bond with the ether oxygen, e.g. methoxy, ethoxy, propoxy, isopropoxy, cyclopropylmethoxy, butoxy, pentox.

Those whom nThe implementation of the present invention R1represents C1-6-alkyl, substituted by a group COX' or POX'X".

In another preferred embodiment of the present invention R6, R7, R8and R9independently represent hydrogen, chlorine; NO2, NC; CF3; piperidino; morpholino; thiomorpholine; piperazinil; piperazinil substituted by methyl, phenyl or methoxyphenyl; triazolyl substituted by methyl; imidazolyl, disubstituted by methyl, ethyl, phenyl.

In another preferred embodiment of the present invention R6and R9represent hydrogen.

Preferred compounds of the present invention are: 1-(ethoxy-hydroxy-phosphorylmethyl)-8-(4-methyl-2-phenyl - 1H-imidazol-1-yl)-7-trifluoromethyl[2,4-1]triazolo[4,3-a] cinoxacin-4(5H)-he;

8-(4-methyl-2-phenyl-1H-imidazol-1-yl)-1-phosphonomethyl-7 - trifluoromethyl[1,2,4]triazolo[4,3-a]cinoxacin-4(5H)-he;

1-(ethoxy-hydroxy-phosphorylmethyl)-8-(2-ethyl-4 - methyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a] cinoxacin-4(5H)-he;

8-(2-ethyl-4-methyl-1H-imidazol-1-yl)-1 - phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a] cinoxacin-4(5H)-he;

8 morpholino-1-phosphonomethyl-7-trifluoromethyl [1,2,4]triazolo[4,3-a]cinoxacin-4(5H)-he;

8 morpholino-1-(1-phosphonoethyl)-7-[4,3-a]cinoxacin-4(5H)-he;

1-(2-ethoxycarbonylethyl)-8-morpholino-7-trifluoromethyl[1,2,4] triazolo [4,3-a]cinoxacin-4(5H)-he;

1-(2-carboxyethyl)-8-morpholino-7-trifluoromethyl[1,2,4] triazolo [4,3-a] cinoxacin-4(5H)-he;

1-(ethoxy-hydroxy-phosphorylmethyl)-8-(1H-imidazol-1-yl)- 7-trifluoromethyl[1,2,4]triazolo[4,3-a]cinoxacin-4(5H)-he;

8-(1H-imidazol-1-yl)-1-(phosphonomethyl)-7-trifluoromethyl [1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

1-(ethoxy-hydroxy-phosphorylmethyl)-8-(2-isopropyl-1H-imidazol-1-yl)-7 - trifluoromethyl[1,2,4]triazolo[4,3-a]cinoxacin-4(5H)-he;

8-(2-isopropyl-1H-imidazol-1-yl)-1-phosphonomethyl-7 - trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he.

Other preferred compounds of the present invention are:

8-(2,4-dimethyl-1H-imidazol-1-yl)-1-phosphonomethyl-7 - trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

7-cyano-8-(2,4-dimethyl-1H-imidazol-1-yl)-1-phosphonomethyl [1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

8-(2,4-dimethyl-1H-imidazol-1-yl)-7-nitro-1-phosphonomethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

7-cyano-8-(2-ethyl-4-methyl-1H-imidazol - 1-yl)-1-phosphonomethyl[1,2,4]triazolo[4,3-a]cinoxacin-4(5H)-he;

7-cyano-8-morpholino-1-phosphonomethyl[1,2,4] triazolo [4,3-a] cinoxacin-4(5H)-he;

8 morpholino-7-nitro-1-phosphonomethyl[1,2,4] triazolo[4,3-a] cinoxacin-4(5H)-he;

7-cyano who methyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

7-cyano-1-phosphonomethyl-8-piperidino[1,2,4] triazolo[4,3-a] cinoxacin-4(5H)-he;

1-phosphonomethyl-8-(piperazine-1-yl)-7 - trifluoromethyl[1,2,4]triazolo[4,3-a] cinoxacin-4(5H)-he;

7-cyano-1-phosphonomethyl-8-(piperazine-1-yl)[1,2,4]triazolo[4,3-a] cinoxacin-4(5H)-he;

8-(4-piperazine-1-yl)-1-phosphonomethyl-7 - trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

7-cyano-8-(4-phenylpiperazin-1-yl)-1-phosphonomethyl[1,2,4] triazolo [4,3-a] cinoxacin-4(5H)-he;

8-(4-(3-methoxyphenyl)piperazine-1-yl)-1-phosphonomethyl-7 - trifluoromethyl[1,2,4]triazolo[4,3-a]cinoxacin-4(5H)-he;

8-(4-(4-methoxyphenyl)piperazine-1-yl)-1-phosphonomethyl-7 - trifluoromethyl[1,2,4]triazolo[4,3-a]cinoxacin-4(5H)-he;

8-(2,4-dimethyl-1H-imidazol-1-yl)-1-phosphonoethyl-7 - trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

7-chloro-8-(2,4-dimethyl-1H-imidazol-1-yl)-1-phosphonomethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

8-(3,5-dimethyl-1,2,4-triazole-1-yl)-1-phosphonomethyl-7-trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

8-(4-methylpiperazin-1-yl)-1-phosphonomethyl-7-trifluoromethyl [1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

1-(2-carboxyethyl)-8-(2,4-dimethyl-1H - imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a] cinoxacin-4(5H)-he;

1-(2-carboxyethyl)-8-(2-ethyl-4-methyl-1H - imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a] cinoxacin-4(5H)-he;
the l)-8-(4-phenylpiperazin-1-yl)-7 - trifluoromethyl[1,2,4]triazolo[4,3-a)cinoxacin-4(5H)-he;

1-(2-carboxyethyl)-8-(2,4-dimethyl-1H-imidazol-1-yl)-7-nitro [1,2,4]triazolo[4,3-a]cinoxacin-4(5H)-he;

1-(2-carboxyethyl)-7-cyano-8-morpholino[1,2,4] triazolo[4,3-a] cinoxacin-4(5H)-he;

1-(2-carboxyethyl)-8-morpholino-7-nitro [1,2,4] triazolo[4,3-a] cinoxacin-4(5H)-he;

1-(2-carboxyethyl)-8-(4-methylpiperazin-1-yl)-7-trifluoromethyl [1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

1-(2-carboxyethyl)-7-chloro-8-(2,4-dimethyl-1H-imidazol-1-yl) [1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

1-(2-carboxyethyl)-8-(4-(4- methoxyphenyl)piperazine-1-yl)-7-trifluoromethyl[1,2,4]triazolo [4,3-a]cinoxacin-4(5H)-he;

1-(2-carboxyethyl)-8-piperidino-7-trifluoromethyl[1,2,4]triazolo [4,3-a]cinoxacin-4(5H)-he,

1-phosphonomethyl-8-(1H-1,2,4-triazole-1-yl)-7-trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

8-(4-methyl-1H-imidazol-1-yl)1-phosphonomethyl-7-trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

8-(2-methyl-1H-imidazol-1-yl)-1-phosphonomethyl-7 - trifluoromethyl[1,2,4]triazolo[4,3-a]cinoxacin-4(5H)-he;

8-(2-phenyl-1H-imidazol-1-yl)-1-phosphonomethyl-7-trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

7-cyano-8-(1H-imidazol-1-yl)-1-phosphonomethyl[1,2,4] triazolo[4,3-a] cinoxacin-4(5H)-he;

8-(1H-imidazol-1-yl)-1-(1-phosphonoethyl)- 7-trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

8-(2-ethyl-1H-imidazol-1-yl)-1-hostname is methyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

8-(1H-imidazol-1-yl)-7-nitro-1-phosphonomethyl[1,2,4] triazolo[4,3-a] cinoxacin-4(5H)-he;

8-(1H-imidazol-1-yl)-7-nitro-1-(1-phosphonoethyl)[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

8-(2-methyl-1H-imidazol-1-yl)-7-nitro-1-phosphonomethyl[1,2,4] triazolo [4,3-a]cinoxacin-4(5H)-he;

7-cyano-8-(2-methyl-1H-imidazol-1-yl)-1 - phosphonomethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

7-cyano-8-(2-phenyl-1H-imidazol-1-yl)-phosphonomethyl[1,2,4]triazolo [4,3-a] cinoxacin-4(5H)-he;

8-(4-phenyl-1H-imidazol-1-yl)-1-phosphonomethyl-7-trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

7-cyano-8-(2-isopropyl-1H-imidazol-1-yl)-1-phosphonomethyl [1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

7-cyano-8-(2-ethyl-1H-imidazol-1-yl)-1-phosphonomethyl[1,2,4] triazolo [4,3-a]cinoxacin-4(5H)-he;

7-cyano-8-(1H-imidazol-1-yl)-1-(1 - phosphonoethyl)[1,2,4] triazolo[4,3-a] cinoxacin-4(5H)-he;

7-(1H-imidazol-1-yl)-1-phosphonomethyl-8-trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

7-(2-methyl-1H-imidazol-1-yl)-1-phosphonomethyl-8-trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

8-cyano-7-(1H-imidazol-1-yl)-1-phosphonomethyl[1,2,4] triazolo[4,3-a] cinoxacin-4(5H)-he;

7-(1H-imidazol-1-yl)-8-nitro-1-phosphonomethyl[1,2,4] triazolo[4,3-a] cinoxacin-4(5H)-he;

1-phosphonomethyl-7-(1H-1,2,4-triazole-1-yl)-8-trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;
7-cyano-8-(2-n-propyl-1H-imidazol-1-yl)-1-phosphonomethyl[1,2,4] triazolo [4,3-a]cinoxacin-4(5H)-he;

7-cyano-8-(4-phenyl-1H-imidazol-1-yl)-1-phosphonomethyl[1,2,4] triazolo [4,3-a]cinoxacin-4(5H)-he;

7-cyano-1-phosphonomethyl-8-(1H-1,2,4-triazole-1-yl)[1,2,4] triazolo [4,3-a] cinoxacin-4(5H)-he;

7-nitro-1-phosphonomethyl-8-(1H-1,2,4-triazole-1-yl)[1,2,4] triazolo[4,3-a] cinoxacin-4(5H)-he;

7-chloro-8-(1H-imidazol-1-yl)-1-phosphonomethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he;

8-chloro-7-(1H-imidazol-1-yl)-1-phosphonomethyl[1,2,4] triazolo [4,3-a]cinoxacin-4(5H)-he.

These compounds of the present invention can be presented in different tautomeric forms. Therefore, the present invention includes all such tautomeric forms.

The following variant of implementation of the present invention is pharmaceutically acceptable salts, derivatives of [1,2,4]triazolo[4,3-a]khinoksalinona formula I. Such salts include salts derived from inorganic and organic acids, such as hydrochloric acid, Hydrobromic acid, acetic acid, sulfuric acid, nitric acid, oxalic acid, fumaric acid, tartaric acid and other Other salts include salts of alkali metals such as sodium or kliewer> In addition, in accordance with another objective of the present invention relates to a compound of General formula (I) or its pharmaceutically acceptable salt for use as a medicine, preferably for use as a drug for the treatment of indications associated with hyperactivity of the excitatory neurotransmitters, in particular, AMPA receptors.

The present invention relates also to a method for producing the above compounds. Presents the compounds of formula I get: a) the alkylation of compounds having the formula II:

(II)

in which R6, R7, R8and R9have the meanings given above, benzylalkonium with the formation of the compounds of formula III:

(III)

in which R6, R7, R8and R9have the meanings defined above, and halogenoalkanes connection with the formation of the compounds of formula IV:

(IV)

in which R6, R7, R8and R9have the meanings defined above, and Q is Br, Cl or I; the interaction of this compound with hydrazine to form compounds of formula V:

(V)

in which R6, R7, R8and R9have the meanings given above, and who meet the value as defined above for compounds of General formula I, in which X' and X" represents C1-6-alkoxy, with the formation of the compounds of formula VII:

(VII)

in which R1, R6, R7, R8and R9have the meanings defined above, followed by hydrogenolysis of this connection with the formation of the compounds of formula VIII:

(VIII)

in which R1, R6, R7, R8and R9have the meanings defined above, and subsequent thermal cyclization and simultaneous toxigenicity with the formation of the compounds of formula I, in which X' and X" independently are hydroxy or C1-6-alkoxy group; or

b) interaction of compounds having the formula IX:

(IX)

in which R6, R7, R8and R9have the meanings defined above, and Q represents Br, Cl or I, with a compound of General formula VI:

R1-COCl, (VI)

in which R1is set as shown above for compounds of General formula I, in which X' and X" represents C1-6-alkoxy group, with the formation of the compounds of formula XI:

(XI)

in which R1, R6, R7, R8and R9have the meanings defined above, and Q represents Br, Cl or I, and then doubt the I formula I, in which X' and X" independently are hydroxy or C1-6-alkoxy group; or

(C) substitution of compounds of formula XII:

(XII)

in which R6, R7, R8and R9have the meanings defined above, and Z represents a halogen or a C1-6-alkoxy group, a mono-, di - or trimetoksi-substituted benzylamino, with the formation of compounds of formula XIII:

(XIII)

in which R6, R7, R8and R9have the meanings defined above, and V' and V" independently represent hydrogen or methoxy group, and the interaction of this compound with heterocalixarenes with the formation of compounds of formula XIV:

(XIV)

in which R6, R7, R8and R9have the meanings defined above, and V' and V" independently represent hydrogen or methoxy group, and then either by hydrogenation, to the formation of an intermediate cyklinowanie N-hydroxy-compounds and subsequent deoksigenirovanii, or by cyclization of the hydrogenation with the formation of the compounds of formula XV:

(XV)

in which R6, R7, R8and R9have the meanings defined above, and V' and V" independently represent hydrogen or methoxy-group, followed by halogenoalkanes obtained connected what acylchlorides General formula VI, as shown above, and then cyclization with the formation of compounds of formula XVI:

(XVI)

in which R1, R6, R7, R8and R9have the meanings defined above, and V' and V" independently represent hydrogen or methoxy group, and hydrolysis with the formation of the compounds of formula I, in which X' and X" independently represent hydrogen or C1-6-alkoxy group, or

d) hydrolysis of compounds of formula I, in which X' and X" represents C1-6-alkoxy group, a water base with the formation of the compounds of formula I, in which X' represents a hydroxy group, and X represents C1-6-alkoxygroup, or

(e) the interaction of the compounds of formula I, in which X' represents a hydroxy group or a C1-6-alkoxy group, and X represents C1-6-alkoxygroup, gelatination with the formation of the compounds of formula I, in which X' and X" represent a hydroxy group.

Pharmaceutically acceptable salts can be obtained in accordance with standard techniques in the treatment of compounds of formula I corresponding acids or bases.

The source materials which are not here presented, are either known compounds (for example, from Mehedinti, either by analogy with known methods.

Pharmacological properties of the compounds of the present invention can be illustrated by determining their ability to displace radioactively labelled 2-amino-3-hydroxy-5-methyl-4-isoxazolidinone acid (AMPA) receptors of the AMPA type. Antagonistic properties of these compounds are shown by their ability to counteract fiskalnoy acid, stimulating spreading depression in the retina of the chicken.

Activity substitution compounds can be shown by determining the values of the IC50that reflects the concentration (μm) that causes 50% substitution is specifically associated 3H-AMPA.

This antagonism was measured by determining the values of the IC50reflecting the concentration at which receive the maximum 50% inhibition fiskalnoy acid, stimulating spreading depression in the retina of the chicken.

Binding3H-AMPA (Experiment 1)

500 ál ottange homogenate of cerebral cortical membranes of rats in Tris-HCl (30 mm), CaCl2(2.5 mm) and KSCN (100 mm) pH of 7.1 were incubated at 0oC for 30 min with 25 μl of3H-AMPA (final concentration 5 nm), ipsley (final concentration of 600 µm). The binding reaction was stopped by adding 5 ml ice-cold buffer followed by filtration through filters glass fiber Whatman GF/C and washing 2x5 ml ice-cold buffer. Bound peroxidase radioactive label was measured on a scintillation counter. IC50were determined using analysis of Hill and not less than four concentrations of the test compounds.

Spreading depression (Experiment 2)

Chicks (aged 3-10 days) were eviscerated, eyes, nucleosomal and cut along the Equatorial plane. After removal of the anterior chamber and the vitreous body, the rear chamber of each eye was placed in a small Petri dish containing physiological saline (P. S. S.) of the following composition (in mm): NaCl (100), KCl (6,0), CaCl2(1,0), MgSO4(1,0), NaHCO3(30), NaH2PO4(1,0), glucose (20).

The solution was saturated O2up to 100% and kept at a temperature of 26oC.

At first his eyes were incubated in normal P. S. S. within 15-30 min, and then transferred in P. S. S. containing kischlat (1 μg/ml). In this stimulating solution" S. D. S. began spontaneously, usually from the edge of the retina, and was easily observed with the naked eye. We measured the time required to run S. D. in each eye.

After the settlement of what was kopirovali within 15 minutes Then his eyes moved in the stimulation fluid containing the same concentration of the test compounds. Again we measured the time required to run S. D. in each eye. Then his eyes returned to normal P. S. S. and after 15 min again measured the time required to run S. D. in order to determine the degree of recovery after exposure to the respective drug.

The increase in time required to run S. D. , compared to control more than 30 was considered 100% inhibition of S. D. Therefore, the action of the medicinal product expressed as a percentage of the maximum response for a given dose. Experienced is regarded therefore as the concentration of test substance that causes the maximum 50% inhibition (IC50).

The experiment results obtained by testing some compounds of the present invention, shown in the following table 1.

The obtained pharmaceutical preparations comprising compounds of the present invention, it is possible to introduce people or animals orally, rectally or parenterally way.

Effective amounts of the active compounds or pharmaceutically acceptable salts thereof can op is operauser, in need of treatment.

Traditional eccipienti are pharmaceutically acceptable organic or inorganic substances, as carriers, which are suitable for parenteral use or through the intestines, which are neutral with respect to the active compounds.

Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyalkane castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, monoglycerides and diglycerides of fatty acids, PENTAERYTHRITE esters of fatty acids, hydroxymethylcellulose and polyvinylpyrrolidone.

If necessary, the pharmaceutical preparations can be sterilized and mixed with additional agents such as humectants, preservatives, stabilizers, wetting agents, emulsifiers, salts, influencing osmotic pressure, buffers and/or dyes and the like, which are in contact with the active compounds do not destroy them.

Injectable solutions or suspensions, preferably aqueous solutions of the active compounds dissolved in polyhydroxyalkane castor oil, especially suitable for CLASS="ptx2">

Tablets, coated tablets or capsules containing talc and/or a carrier or binder or the like, particularly suitable for oral administration. The carrier preferably is a lactose and/or corn starch and/or potato starch.

A syrup, elixir or the like can be used in cases when use or need to use a sweetened filling.

In General, the compounds of the present invention are prepared in the form of a unit dose comprising 0.5 to 1000 mg of active ingredient in a pharmaceutically acceptable carrier, or with him, per single dose.

In accordance with the present invention, when administered to patients, for example - people, as a drug, the dose of a compound according to the invention is 1-500 mg/day, for example about 50 to 100 mg, per dose.

Common tablet which can be manufactured by conventional tabletting technology, contains:

Core:

The active compound (as free compound or its salt) 100 mg

Colloidal silicon dioxide (Aerosil) 1.5 mg

Cellulose, microcryst (Avicel) - 70 mg

Modified all the
*Mywacett9-40T - approx. 0.9 mg

* The acylated monoglyceride used as plasticizer for shell film coating.

Free compounds of the present invention, which form salts of alkali metals or alkaline earth metals, can be used in a salt form. Such salts of alkali metals or alkaline earth metals are commonly formed by interaction of the compound with an equivalent amount or an excess of the chosen alkali metal or alkaline earth metal hydroxide, and often, respectively, by mixing in the presence of a neutral solvent, from which the salt can be precipitated or remove other in the traditional way, for example by evaporation. Introduction compounds of the present invention is often preferred in the form of a pharmaceutically acceptable water-soluble salt of an alkali metal or alkaline earth metal orally, rectally or parenterally in the form of a pharmaceutical preparation in which it is present together with a pharmaceutically acceptable liquid or solid carrier or diluent.

Compounds of the present invention, along the th single dose and in this form can be used in solid form, such as tablets or filled capsules, or in liquid form, e.g. as solutions, suspensions, emulsions, elixirs, or filled their capsules, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile solutions for injection parenteral use (including subcutaneous). Such pharmaceutical product and unit dosage forms may comprise conventional ingredients in conventional proportions, with an additional active compounds or their component parts, or without them, and such unit dosage forms may contain any suitable effective amount of the active ingredient, AMPA antagonistic assigned daily, within the fluctuations of the applied dose. Tablets containing 1-500 mg of the active ingredient, or more precisely 10-200 mg per pill, correspond to a suitable unit dosage form.

Due to the high level of antagonistic activity against AMPA, and low toxicity, which creates the most favorable therapeutic index, the compounds of the present invention it is possible to introduce the subject, the spine of the testimony, sensitive to changes in the status of the AMPA receptor, such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington disease, epilepsy; defects caused by ischemia, hypoxia, hypoglycemia, brain injury and spinal cord, psychosis, muscle rigidity, vomiting and analgesia, often preferably in the form of an alkali metal salt or alkaline earth metal, concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical preparation for oral or rectal, or parenteral (including subcutaneous) route, in an effective amount.

Suitable dosage ranges from 1-500 mg daily, preferably 10-200 mg daily, and especially 50 to 100 mg daily, depending on the accuracy of adherence introduction, forms of administration, indications, against which undertook the introduction of the subject, at the introduction, and the body weight of the subject, and the preference and experience of the physician or veterinarian engaged in the introduction.

This method of treatment can be described as treatment indications, due to or associated with hyperactivity of the excitatory neurotransmitters, particularly receptorbinding number of compounds of the present invention, opposing AMPA or pharmaceutically acceptable salts thereof.

In addition, the present invention relates to the use of compounds of the present invention for the manufacture of a medicinal product for the treatment of indications due to or associated with hyperactivity of the excitatory neurotransmitters, particularly AMPA receptors, we subject it to the needy.

Further, the present invention is more specifically explained with reference to the following examples.

Example 1

1-(Ethoxy-hydroxy-phosphorylmethyl)-8-(4-methyl-2 - phenyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a] cinoxacin-4(5H)-he

A. 1-Benzyloxy-3-chloro-6-(4-methyl-2 - phenyl-1H-imidazol-1-yl)-7-cryptometrics-2(1H)-he hydrochloride

A solution of 20% phosgene in toluene (18.2 ml, 35 mmol) was added dropwise to a stirred solution of 1-benzyloxy-6-(4-methyl-2 - phenyl-1H-imidazol-1-yl)-7-cryptometrics-2,3 (1H,4H)-dione (8.8 g, 17.5 mmol) in 100 ml of anhydrous N, N-dimethylformamide at 0oC. the Mixture was stirred at room temperature overnight, and the solid precipitate was separated by filtration and was washed with ether, receiving 8.0 g (84%) of the above compounds.

1H-NMR (DMSO-d6): to 2.42 (s, 3H), to 5.35 (s, 2H), 7,30-to 7.61 techinacally-2(1H)-he

A mixture of 1-benzyl-3-chloro-6-(4-methyl-2-phenyl-1H-imidazol-1 - yl)-7-cryptometrics-2(1H)-she hydrochloride (2.0 g, 3.6 mmole) and hydrated hydrazine (0,74 ml, 15 mmole) in 40 ml of dichloromethane was stirred at 0oC for 1 h and evaporated to dryness under vacuum. The residue is triturated with water, getting to 1.59 g (87%) of the above compounds. So pl. 127-130oC.

1H-NMR (DMSO-d6): of 2.21 (s, 1H), of 5.34 (s, 2H), 7,01 (s, 1H), 7,18 (s, 1H), 7,27 (s, 5H), 7,37 was 7.45 (m, 3H), of 7.48 (s, 1H), 7,51-of 7.60 (m, 2H).

c. 1-Benzyloxy-3-[2-[(diethoxyphosphoryl) acetyl] hydrazino] - 6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7 - cryptometrics-2(1H)-he

Solution (diethoxyphosphoryl)acetylchloride (0,67 g, 3.1 mmole) in 20 ml of anhydrous tetrahydrofuran was added dropwise to stirred solution of 1-benzyloxy-3-hydrazino-6-(4-methyl-2 - phenyl-1H-imidazol-1-(-yl)-7-cryptometrics-2(1H)-she (1.52 g, 3.0 mmole) and anhydrous triethylamine (of 0.43 ml, 3.1 mmole) in 50 ml of anhydrous tetrahydrofuran.

The mixture was stirred over night at room temperature and then evaporated to dryness under vacuum. The residue is triturated with water, obtaining 1.8 g (88%) of the above compounds. So pl. > 90oC with decomposition.

1H-NMR (DMSO-d6): 1,10-to 1.21 (m, 6H), of 2.20 (s, 3H), 2,99 (d, 2H), 4,01 (pattr, 4H), of 5.40 (s, 2H), what droxy - 6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-cryptometrics-2 (1H)-he

A suspension of 1-benzyloxy-3-[2-[(diethoxyphosphoryl)acetyl] hydrazino]-6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7 - cryptometrics-2(1H)-she (1.8 g, 2.6 mmole) and 50 mg of 5% palladium on coal in 50 ml of ethanol was first made at room temperature and atmospheric pressure for 9 hours, the Catalyst was separated by filtration, the filtrate is evaporated to dryness under vacuum and the final residue is triturated with ether, getting 1.51 g (97%) of the above compounds. So pl. > 177oC with decomposition.

1H-NMR (DMSO-d6): 1,10-1,22 (m, 6H), of 2.23 (s, 3H), 2,98 (d, 2H), 4.00 points (quintet, 4H), 7,12 (s, 1H), 7.18 in-7,30 (m, 5H), 7,31 (s, 1H), 7,92 (s, 1H), 10,24 (s, 2H), to 12.52 (br.s, 1H).

e. 1-(Ethoxy-hydroxy-phosphorylmethyl)-8-(4-methyl-2-phenyl - 1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a] cinoxacin-4(5H)-he

A solution of 3-[2-[(diethoxyphosphoryl)acetyl] hydrazino]-1 - hydroxy-6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethyl - cinoxacin-2(1H)-she (1.5 g, 2.5 mmole) and triphenylphosphine (1.3 g, 5 mmol) in 50 ml of glacial acetic acid was stirred overnight at 120oC.

The cooled mixture was filtered, and the separated product was washed with ether, receiving 0.64 g (48%) of the above compounds. So pl. 303-308oC.

1H-NMR (DMSO-d6): of 1.10 (t, 3H), of 2.25 (s, 3H), a 3.87 (quintet, 2H), 3,97 (d, 2H), 7,12 (s, 1H), 7,14 was 7.45 (m, 5H), 7,7[1,2,4]triazolo[4,3-a]cinoxacin - 4(5H)-he

Bromotrimethylsilane (1 ml, 7 mmol) was added dropwise to a stirred solution of 1-(ethoxy-hydroxy-phosphorylmethyl)-8-(4 - methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo [4,3-a]cinoxacin-4(5H)-she (500 mg, of 0.94 mmole) in 20 ml of anhydrous N,N-dimethylformamide.

The solution was stirred at room temperature overnight and evaporated to dryness under vacuum. The residue is triturated with 10 ml of water, and the solid precipitate was separated by filtration. After washing, a small amount of water and ethanol was obtained 0.45 g (95%) of net above-mentioned compounds. So pl. 321-325oC.

1H-NMR (DMSO-d6): 2,35 (s, 3H), 3,93 (d, 2H), 7,22-7,52 (m, 6H), 7,74 (s, 1H), 8,79 (s, 1H), and 12.4 (s, 1H).

Example 3

1-(Ethoxy-hydroxy-phosphorylmethyl)-8-(2-ethyl - 4 - methyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a] cinoxacin-4(5H)-he

The named compound was obtained from 1-benzyloxy-6-(2-ethyl-4 - methyl-1H-imidazol-1-yl)-7-cryptometrics-2,3 (1H,4H)-dione in a manner analogous to the method described in example 1, except that the end product (theoretically 10.8 mmole) were processed as follows. To the cooled solution was added 100 ml of dichloromethane and 100 ml of ether. The solid precipitate was separated by filtration and was extracted with boiling water (2 x 100 ml). This trevanian and dried, having 0,90 g (17%) of the above compounds.

1H-NMR (CF3COOD): to 1.38 (t, 3H), of 1.45 (t, 3H), of 2.51 (s, 3H), 2,72-3,10 (m, 2H), or 4.31 (quintet, 1H), 4,58 (dd, 2H (partially exchanged)), 7,22 (s, 1H), 8,32 (s, 1H), 9,00 (s, 1H).

Example 4

8-(2-Ethyl-4-methyl-1H-imidazol-1-yl)-1-phosphonomethyl-7 - trifluoromethyl[1,2,4]triazolo[4,3-a]cinoxacin-4(5H)-he

The named compound was obtained from 1-(ethoxy - hydroxypropylmethyl)-8-(2-ethyl-4-methyl-1H-imidazol-1-yl)-7 - trifluoromethyl[1,2,4.]triazolo[4,3-a]cinoxacin-4(5H)-she (870 mg, 1.8 mmole) in a manner analogous to the method described in example 2. Received: 710 mg (86%). So pl. > 300oC.

1H-NMR (DMSO-d6): of 1.10 (t, 3H), of 2.20 (s, 3H), 2,27-2,77 (m, 2H), 3,62-3,95 (m, 2H), 7,07 (s, 1H), a 7.85 (s, 1H), 8,55 (s, 1H); MS (FAB): m/e 457 (MH+).

(C17H16N6F3O4P 1/2H2O)

Calculation: C 43,48 H 3,68 N 18,06

Found: C 44,07 H 3,56 N 18,02

Example 5

8 Morpholino-1-phosphonomethyl-7-trifluoromethyl[1,2,4] triazolo [4,3-a]cinoxacin-4(5H)-he

a. 1-(Ethoxy-hydroxy-phosphorylmethyl)-8-morpholino-7-trifluoromethyl [1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he

The named compound was obtained from 1-benzyloxy-6-morpholino-7 - cryptometrics-2,3 (1H,4H)-dione in a manner analogous to the method described in example 1, except that the final product is ml dichloromethane and 50 ml of chloroform. The resulting solution was extracted with water (I ml) and the aqueous solution evaporated to dryness under reduced pressure by azeotropic distillation with 1-propanol to obtain the crude product which was used without further purification in the next stage.

b. 8 Morpholino-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo [4,3-a]cinoxacin-4(5H)-he

The named compound was obtained from crude 1-(ethoxy - hydroxy-phosphorylmethyl)-8-morpholino-7-trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-she in a manner analogous to the method described in example 2. So pl. > 300oC with decomposition (ethanol).

1H-NMR (DMSO-d6): 2,9-3,03 (m, 4H), 3,66-of 3.78 (m, 4H), 3,98 (d, 2H), 7,68 (s, 1H), 8,39 (s, 1H), 12,18 (s, 1H).

Example 6

8 Morpholino-1-(1-phosphonoethyl)-7-trifluoromethyl[1,2,4]triazolo [4,3-a]cinoxacin-4(5H)-he

A. 1-(1-(Ethoxy-hydroxy-phosphoryl)ethyl)-8-morpholino-7 - trifluoromethyl[1,2,4]-triazolo[4,3-a]cinoxacin-4(5H)-he

The named compound was obtained from 1-benzyloxy-6-morpholino-7-cryptometrics-2,3 (1H,4H)-dione in a manner analogous to the method described in example 5, except that 2-(diethoxyphosphoryl)propionate used instead of (diethoxyphosphoryl)acetylchloride. The resulting crude product was used Blo[4,3-a] cinoxacin-4(5H)-he

The named compound was obtained from the crude 1-(1-(atoxigenic-phosphoryl)ethyl)- 8-morpholino-7-trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-she in a manner analogous to the method described in example 2, except that the obtained product was purified by column chromatography. So pl. > 300oC with decomposition.

1H-NMR (DMSO-d6): 1,73 (dd, 3H), 2,87-to 3.02 (m, 4H), 3,68-of 3.78 (m, 4H), 4,11-to 4.38 (m, 1H), 7,68 (s, 1H), scored 8.38 (s, 1H), 12,18 (s, 1H).

Example 7

8-Piperidino-1-phosphonomethyl-7-trifluoromethyl [1,2,4]triazolo[4,3-a]cinoxacin-4(5H)-he

A. 1-(Ethoxy-hydroxy-phosphorylmethyl)-8-piperidino-7-trifluoromethyl [1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he

This named compound was obtained from 1-benzyloxy-6 - piperidino-7-cryptometrics-2,3 (1H, 4H)-dione in a manner analogous to the method described in example 3, except that the obtained crude product was used without further purification in the next stage.

b. 8-Piperidino-1-phosphonomethyl - 7-trifluoromethyl[1,2,4] triazolo[4,3-a] cinoxacin-4(5H)-he

This named connection received from crude 1-(toxigolocically)- 8-piperidino-7-trifluoromethyl [1,2,4]triazolo [4,3-a] cinoxacin-4(5H)-she in a manner analogous to the method described in example 2. 1-(2-Ethoxycarbonylethyl)-8-morpholino-7 - trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he

This named compound was obtained from 1-benzyloxy-6 - morpholino-7-cryptometrics-2,3(1H,4H)-dione and ethylsuccinate in a manner analogous to the method described in example 1, except that the final product is developed as follows. Received the cooled mixture was evaporated to dryness under vacuum and subjected to separation purification via flash chromatography successively with dichloromethane and ethyl acetate. Rubbing with ether allowed to obtain pure product. So pl. 204-210oC.

1H-NMR (DMSO-d6): to 1.22 (t, 3H), 2,88-3,00 (m, 4H), to 3.02 (t, 2H), 3,61-3,82 (m, 6H), 4,12 (g, 2H), 7,71 (s, 1H), to 7.99 (s, 1H), 12,2 (br.s, 1H).

Example 9

1-(2-Carboxyethyl)-8-morpholino-7-trifluoromethyl [1,2,4] triazolo[4,3-a] cinoxacin-4(5H)-he

A suspension of 1-(2-ethoxycarbonylethyl)-8-morpholino-7 - trifluoromethyl[1,2,4] triazolo[4,3-a] cinoxacin-4(5H)-she (365 mg, or 0.83 mmole) in 10 ml of 2 n potassium hydroxide was stirred at room temperature for 3 hours

Obtained, the resulting solution was filtered and the filtrate was acidified with 4 M hydrochloric acid to obtain a precipitate. The obtained product was separated by filtration, washed with water and dried to obtain the above-mentioned compounds. So pl. 170-176oC.

1
Stage A. 1-Benzyloxy-3-[2-[(diethoxyphosphoryl)acetyl] hydrazino]-6-(1H-imidazol-1-yl)-7-cryptometrics-2(1H)-he

Solution (diethoxyphosphoryl) acetylchloride (2.4 g, 11 mmol) in 20 ml of anhydrous tetrahydrofuran was added dropwise to a stirred solution of 1-benzyloxy-3-hydrazino-6-(1H-imidazol - 1-yl)-7-cryptometrics-2(1H)-she (4,16 g, 10 mmol) and anhydrous triethylamine (of 1.53 ml, 11 mmol) in 150 ml of anhydrous tetrahydrofuran.

The mixture was stirred for 2 h at room temperature and evaporated to dryness under vacuum. The residue is suspended in 100 ml of water and the pH brought about to 7.0, saturated aqueous sodium acid carbonate.

The crude product was separated by filtration and recrystallized from ethyl acetate/ether to obtain 4.7 g (79%) of the above compounds. So pl.: 159-161oC.

1H-NMR (DMSO-d6): of 1.23 (t, 6H), 3.04 from (d, 2H), 4,06 (quintet, 4H), of 5.39 (s, 2H), was 7.08 (s, 1H), 7,34-to 7.68 (m, 8H), 7,81 (s, 1H), 10,33 (br.s. 2H, exchangeable).

Stage b. 3-[2-[(Diethoxyphosphoryl)acetyl] hydrazino]-1-hydroxy-6-(1H - imidazol-1-yl)-7-cryptometrics-2(1H)-he

A suspension of 1-benzyloxy-3-[2-[(diethoxyphosphoryl)acetyl] hydrazino]-6-(1H-imidazol-1-yl)-7-cryptometrics-2(1H)- she (3,86 g, 6.5 mmol) and 500 mg of 10%within 3 hours The catalyst was removed by filtration and washed with small portions of ethanol. The combined filtrate and washings evaporated to dryness under vacuum, and the residue was ground into powder with ether, receiving 2,80 g (86%) of the above compounds.

1H-NMR (DMSO-d6): of 1.23 (t, 6H), 3,03 (d, 2H), 4,08 (pyatibrat. 4H), 7,07 (s, 1H), 7,40 (s, 1H), 7,41 (s, 1H), 7,83 (s, 1H), of 7.90 (s, 1H), 10,1-10,3 (2H), 12.5cm (very br.s., 1H).

Stage c. 1-(Ethoxy-hydroxy-phosphorylmethyl)-8-(1H-imidazol-1-yl)-7 - trifluoromethyl[1,2,4]triazolo[4,3-a]cinoxacin-4(5H)-he

A solution of 3-[2-[(diethoxyphosphoryl)acetyl] hydrazino]-1 - hydroxy-6-(1H-imidazol-1-yl)- 7-cryptometrics-2(1H)-she (2,52 g, 5 mmol) and triphenylphosphine (2,62 g, 10 mmol) in 100 ml of glacial acetic acid was stirred at 120oC for 23 hours To a cooled mixture was added 150 ml of ether.

The solid precipitate was separated by filtration and was washed with ether and acetone, getting 1,09 g (43%) of the above compounds. So pl. 324-328oC.

1H-NMR (DMSO-d6): of 1.10 (t, 3H), 1.91 a (s, 3H), 3,88 (quintet, 2H), of 4.05 (d, 2H), 7,21 (s, 1H), 7,50 (s, 1H), 7,82 (s, 1H), of 8.06 (s, 1H), and 8.50 (s, 1H), 12,49 (s, 1H).

Example 11

8-(1H-Imidazol-1-yl)-1-phosphonomethyl - 7-trifluoromethyl[1,2,4] triazolo [4,3-a]cinoxacin-4(5H)-he

Bromotrimethylsilane (2 ml, 14 mmole) was added dropwise to paramesh) in 20 ml of anhydrous N,N-dimethylformamide. The solution was stirred at room temperature for 3 days, was added 25 ml of water and evaporated to dryness under vacuum. The oily residue is triturated with a small amount of water, and the precipitate was separated by filtration and washed with small portions of cold water, ethanol and ether, receiving 210 mg of the above compound. So pl. 349-350oC.

1H-NMR (DMSO-d6): 3,98 (d, 2H), 7,20 (s, 1H), of 7.48 (s, 1H), 7,83 (s, 1H), with 8.05 (s, 1H), and 8.50 (s, 1H), and 12.4 (br.s, 1H).

(C14H10N6F3O4P 1.5 H2O)

Calculation: C 38,11; H 2,97; N 19,05.

Found: C 38,21; H 3,02; N 18,75.

Example 12

1-(Ethoxy-hydroxy-phosphorylmethyl)-8-(2 - isopropyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a] cinoxacin-4(5H)-he

Stage A. 1-Benzyloxy-3-chloro-6-(2-isopropyl-1H - imidazol-1-yl)-7-formatimaging.com-2(1H)-he

A solution of 20% phosgene in toluene (18 ml, 34.7 mmol) was added dropwise to a stirred solution of 1-benzyloxy-6-(2-isopropyl - 1H-imidazol-1-yl)-7-cryptometrics-2,3(1H,4H)-dione (5,04 g, 11.3 mmole) in 50 ml of anhydrous N, N-dimethylformamide at 0oC. the Mixture was stirred at 25oC overnight, and the solid precipitate was separated by filtration and was washed with ether, getting to 4.81 g (85%) of the above compound in vid (s, 1H), of 7.96 (s, 1H), to 8.62 (s, 1H).

Stage b. 1-Benzyloxy-3-hydrazino-6-(2-isopropyl-1H-imidazol-1 - yl)-7-cryptometrics-2(1H)-he

A mixture of 1-benzyloxy-3-chloro-6-(2-isopropyl-1H-imidazol-1-yl) -7-cryptometrics-2(1H)-he hydrochloride (4.8 g, 9.6 mmol) and hydroxide hydrazine (2.0 ml, 41 mmol) in 100 ml dichloromethane was stirred at 0oC for 2 hours the Mixture is evaporated to dryness under vacuum and the residue triturated with water, obtaining 4.1 g (93%) of the above compounds.

1H-NMR (DMSO-d6): of 1.10 (d, 6H), 2,42-to 2.65 (m, 1H), 5,32 (s, 2H), 6,91 (s, 1H), 7,07 (s, 1H), 7,28 (s, 1H), 7,37-7,47 (m, 3H), 7,50 (s, 1H), 7,52-of 7.60 (m, 2H).

Stage c. 1-Benzyloxy-3-[2-[(diethoxyphosphoryl)acetyl]hydrazino]-6-(2 - isopropyl-1H-imidazol-1-yl)-7-cryptometrics-2(1H)-he

Solution (diethoxyphosphoryl)acetylchloride (1,93 g, 9 mmol) in 25 ml of anhydrous tetrahydrofuran was added dropwise to a stirred solution of 1-benzyloxy-3-hydrazino-6-(2-isopropyl - 1H-imidazol-1-yl)-7-cryptometrics-2(1H)-she (4.0 g, 8.7 mmole) and anhydrous triethylamine (1.25 ml, 9 mmol) in 75 ml of anhydrous tetrahydrofuran.

The mixture was stirred over night at room temperature and evaporated to dryness. The residue was made in 500 ml of water and filtered. the pH of the filtrate was brought to 8.0 with saturated water is ract was obezvozhivani (anhydrous sodium sulfate), was filtered and evaporated to dryness under vacuum, obtaining 4.3 g (78%) of crude above-mentioned compounds.

1H-NMR (DMSO-d6): 1,25 (t, 12H), 2.63 in-2,77 (m, 1H), 3,03 (d, 2H), 4,07 (the Queen. , 4H), of 5.40 (s, 2H), 7,38-of 7.48 (m, 3H), 7,55-7,63 (m, 2H), 7,68 (s, 1H), 7,79 (s, 2H), 7,87 (s, 1H), 10,4 (br.s, 1H), 10,5 (br.s, 1H).

Stage d. 3-[2-[(Diethoxyphosphoryl)acetyl]hydrazino] -1-hydroxy-6-(2-isopropyl-1H-imidazol-1-yl)-7-trifluoromethyl - cinoxacin-2(1H)-he

A suspension of 1-benzyloxy-3-[2-[(diethoxyphosphoryl)acetyl] hydrazino]-6-(2-isopropyl-1H-imidazol-1-yl)-7-trifluoromethyl an cinoxacin-2(1H)-she (4.3 g, 6.6 mmole) and 100 mg of 5% palladium on coal in 100 ml of ethanol was hydrogenosomal within 2 hours the Catalyst was removed by filtration and washed with ethanol. The combined filtrate is evaporated to dryness under vacuum and the residue triturated with ether, obtaining 3.0 g (83%) of the above compounds. So pl. > 190oC with decomposition.

1H-NMR (DMSO-d6): 1,09 (two d, 6H), to 1.22 (t, 6H), 2,46-2,69 (m, 1H), to 3.02 (d, 2H), 4,05 (quintet, 4H), 6,94 (s, 1H), 7,15 (s, 1H), 7,38 (s, 1H), 7,94 (s, 1H).

Stage e. 1-(Ethoxy-hydroxy-phosphorylmethyl)-8-(2-isopropyl - 1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a] cinoxacin-4(5H)-he

A solution of 3-[2-[(diethoxyphosphoryl)acetyl] hydrazino]-1-hydroxy-6-(2-isopropyl-1H-imidazol-1-yl)-7 - cryptometrics-2(1H)-she (3.0 g, 5.5 mmol) and is cooled at room temperature and the solid precipitate was separated by filtration, was washed with ether, receiving 1.84 g of the above compound. So pl. 335-338oC.

1H-NMR (DMSO-d6): 1,68 (t, 3H), 1,82 (distorted t, 6H), 3,37 is 3.57 (m, 1H), to 4.62 (Quint. 2H), 4,78-5,00 (m, 2H), 7,88 (s, 2H), 8,69 (s, 1H), 9,35 (s, 1H).

Example 13

8-(2-Isopropyl-1H-imidazol-1-yl)-1-phosphonomethyl - 7-trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4(5H)-he

Bromotrimethylsilane (2.5 ml, 17.5 mmol) was added dropwise to stirred solution of 1-(ethoxy-hydroxy-phosphorylmethyl)-8- (2-isopropyl-1H-imidazol-1-yl)-7-trifluoromethyl [1,2,4]triazolo[4,3-a]cinoxacin-4(5H)-she (1.5 g, 2.7 mmole) in 10 ml of anhydrous N,N-dimethylformamide.

The solution was stirred at room temperature for 3 days and evaporated to dryness under vacuum. The oily residue is triturated with 20 ml of water, the resulting solid precipitate was separated by filtration and washed with water. The crude product was treated with 50 ml of 1M (pH of 7.4) buffer one-deputizing of califorina, the resulting potassium salt was filtered, then dissolved in 50 ml of water, decolorized with charcoal, filtered and finally, perioadele with concentrated hydrochloric acid. The obtained product was separated by filtration, washed with water and dried, obtaining 0,76 g (54%) of the above compounds. So pl. > 325oC.

1H-NMR (DMSO,2,4]triazolo[4,3-a]khinoksalinona General formula I

< / BR>
in which R1represents a straight or branched C1-6-alkyl, substituted COX' or POX' X', where X' and X" independently are hydroxy or C1-6-alkoxygroup;

R6and R9represent hydrogen;

R7is CF3;

R8is imidazolyl, piperidino or morpholino, rings are optionally substituted by one or two substituents selected from phenyl and C1-6-alkyl,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, in which R8means piperidino, morpholino or imidazolyl, optionally substituted stands, ethyl, phenyl or isopropyl.

3. Connection on p. 1 representing

1-(toxigolocically)-8-(4-methyl-2-phenyl-1H-imidazol-1-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]cinoxacin-4-(5H)-he;

8-(4-methyl-2-phenyl-1H-imidazol-1-yl)-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]cinoxacin-4-(5H)-he;

1-(toxigolocically)-8-(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]cinoxacin-4-(5H)-he;

8-(2-ethyl-4-methyl-1H-imidazol-1-yl)-1-phosphonomethyl-7-trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4-(5H)-he;

8 morpholino-1-phosphonomethyl-7-trifluoromethyl[1,2,4]Tr is n;

8-piperidino-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]cinoxacin-4-(5H)-he;

1-(2-ethoxycarbonylethyl)-8-morpholino-7-trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4-(5H)-he;

1-(2-carboxyethyl)-8-morpholino-7-trifluoromethyl[1,2,4] triazolo [4,3-a]cinoxacin-4-(5H)-he;

1-(toxigolocically)-8-(1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]cinoxacin-4-(5H)-he;

8-(1H-imidazol-1-yl)-1-phosphonomethyl-7-trifluoromethyl[1,2,4]triazolo[4,3-a] cinoxacin-4-(5H)-he;

1-(toxigolocically)-8-(2-isopropyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]cinoxacin-4-(5H)-he;

8-(2-isopropyl-1H-imidazol-1-yl)-1-phosphonomethyl-7-trifluoromethyl[1,2,4] triazolo[4,3-a]cinoxacin-4-(5H)-he.

4. The pharmaceutical composition is an antagonist of AMPA receptors, including the active ingredient, carrier or diluent, wherein the active component includes a connection PP.1 to 3, or its pharmaceutically acceptable salt in an effective amount.

5. The pharmaceutical composition under item 4 in the form of a dosage unit containing about 10 to 200 mg of active compound.

6. Connection PP.1 to 3, or pharmaceutically acceptable salt, which has antagonistic activity against that enter the connection PP.1 - 3 or its pharmaceutically acceptable salt in an effective amount.

8. The method of obtaining derivatives of [1,2,4] triazolo [4,3-a] khinoksalinona General formula I, characterized in p. 1, characterized in that exercise halogenoalkane the compounds of formula III

< / BR>
in which R6, R7, R8and R9have the meanings given in paragraph 1,

obtaining the compounds of formula IV

< / BR>
in which R6, R7, R8and R9have the meanings defined above;

Q represents Br, Cl, J,

and the interaction of this compound with hydrazine to form compounds of formula V

< / BR>
in which R6, R7, R8and R9have the meanings given above,

and the acylation of the compounds of formula V acylchlorides, the General formula VI

R1- COCl

in which R1represents a straight or branched C1- C6-alkyl, substituted COX1or POX1X", where X' and X" represent C1-6-alkoxy,

with the formation of the compounds of formula VII

< / BR>
in which R1, R6, R7, R8and R9have the meanings given above,

and hydrogenolysis of this connection with the formation of the compounds of formula VIII

< / BR>1-6-alkoxygroup,

and if necessary carry out the hydrolysis of the compounds of formula I, in which X' and X" represents C1-6-alkoxygroup, water base with the formation of the compounds of formula I, in which X' represents a hydroxy-group, and X represents C1-6-alkoxygroup, and/or the interaction of the compounds of formula I, in which X' is hydroxy or C1-6-alkoxygroup, and X represents C1-6-alkoxygroup, gelatination with the formation of the compounds of formula I, in which X' and X" represent a hydroxy-group.

 

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