MXPA00000558A - 5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1h)-one derivatives - Google Patents

Abstract

Novel 5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivatives represented by general formula (I) wherein Het represents oxadiazolyl;R1 represents H, lower alkyl, lower cycloalkyl, lower alkenyl, lower alkoxy, optionally substituted aryl, optionally substituted heteroaryl, etc.;and R2 represents H, lower alkyl, lower cycloalkyl, optionally substituted aryl, etc. Because of having high affinities selectively with benzodiazepine receptors, these compounds are useful as benzodiazepine receptor agonists, in particular, inverse agonists thereof, for example, brain activators and remedies for memory disorders associating senile dementia, Alzheimer's disease, etc.

Description

DERIVATIVES OF THE 3- OXADIAZOLIL - 1,6-NAFTIRIDIN- 2 (1H) -0NA SUBSTITUTED IN POSITION 5 Field of the Invention The present invention relates to novel 3-oxadiazolyl-1,6-naphyridin-2 (1 H) - or na derivatives, substituted at the 5-position, or a pharmaceutical acid addition salt thereof. acceptable, of them, which is useful as a medicine; and to the use of them as medicines; and additional intermediates to prepare them.

BACKGROUND ART The compounds of Benzo iazepine (BZP), such as diazepam, which is a representative compound, have antianxiety activity and because of this have been developed as anxiolytic drugs, but also have anticonvulsant, sedative and hypnotic activities and for this reason these drugs have been used in many clinical fields, such as (1) anxiolytic drugs, (2) sedatives (hypnotics), (3) muscle relaxants, and (4) antiepileptic drugs. The BZP compounds have mainly pharmacological activities such as (1) activity of REF .: 32328 acclimation, (2) hypnotic activity, (3) central muscle relaxant activity, (4) activity at n t i co n v u I s i v a. It is understood that these activities are not presented by independent mechanisms, separately, but are induced by mechanisms closely related to each other. From the last years of the 1970's, with the progress of the pharmacological investigation of the BZP compounds, two bases have been found to clarify the mechanism of the activities presented by them; one is the phenomenon of increasing the agonistic neurotransmitter mechanism of α-aminobutyric acid (GABAergico), of the central nervous system, by the BZP drugs; and the other is the finding of the specific binding site of the BZP (BZP receptor) and the test of a mechanism of the functional connection between the brain receptor of the BZP and the GABA receptor. As a result of this research, it has almost been established that the GABAergic neurotransmitter mechanism participates in the pharmacological activities of the BZP compounds. The administration of BZP compounds induces side effects such as ataxia, hypnosis, muscular relaxation, or the reduction in the capacity of knowledge or reflex movement and additional formation of drug resistance and dependence, and hence there are many problems to be resolved in the BZP compounds. Studies have been carried out on non-BZP compounds, which have a structure different from that of the BZP compounds, but which have functions in the activation mechanisms. Those compounds that include non-BZP compounds are the so-called benzodiazepine receptor agonist drugs. As compounds that are not BZP compounds, for example, compounds having the chemical formulas (A), (B) and (C) are known, as shown below. The compounds having the formulas (A) and (B) are described in the Journal of Medicinal Chem istry, vol. 34, p. 2060 (1991).

(A) (B) where Ra is a hydrogen atom, Rb-Rd are a methyl group, etc., and Re is a methoxy group, etc. The compounds of the formula (C) are described in document E P-A 2-0588500.

(C) where Het is an oxadazolyl group, R1 is a benzyl group, etc., and R2 is a methoxy group, etc. However, with the progress in the investigations, a certain compound has been found, among the non-BZP compounds, which has a high selective affinity, similar to that of the benzodiazepine receptor (BZP), but which has activities completely reverse [Braestrup, C. et al., Ne u ro pha rm acó I. , 22, pgs. 1451-1457 (1983)]. When these compounds are admired, they present pharmacological activities such as: activity of increase of ulsions, activity to induce anxiety, muscular hypertonia. Therefore, the old BZP compounds, which until now have been used as anxiolytic drugs, are defined as agonists, and the compounds that have these inverse activities are defined as inverse agonists. Since these inverse agonists were found, intensive studies have been conducted on the correlation between the mode of modification (binding) and the pharmacological activities of the compounds to which they bind (which exhibit affinity) to the BZP receptor. According to these studies, it has been found that the BZP receptor is present between the GABA receptor (a depressive neurotransmitter) and a chloride ion channel, and is a molecular unit to form a complex. The GABA receptor includes a GABAA receptor, of the ion channel type; and a GABAB receptor, of the type controlling the metabolism, and the GABAA receptor forms a complex with a BZP receptor and the Cl ion channel. The compounds that are going to bind to the BZP receptor are now classified as agonist (which subsequently it was further classified as a full agonist and partial agonist), inverse agonist (which subsequently was further classified as a full reverse agonist and partial reverse agonist) and antagonist. The agonist binds selectively to the BZP compounds and, therefore, acts increasing the coupling of the GABA receptor and the Cl ion channel, and increasing the flow of the Cl ion towards the cells, due to the increase of the frequency of apertu ration of the Cl ion channel; and then stimulates cellular activities due to the decrease in negative electric charge (increases cell stimulation). It is said that the antagonist does not change the coupling function thereof, but inhibits the binding of the agonist, or the inverse agonist, to the BZP receptor. There are many methods for verifying the mode of binding of the compounds to the receptor of the b e n z od ia ze p i n a, and one of the known methods is the TBPS binding assay. As mentioned above, the GABAA receptor forms a complex ion on a receptor for a compound of the BZP and the Cl ion channel, and it is known that a receptor for a neurosteroid compound is present on the membrane of the GABAA receptor, and that A recognition site of the TBPS link (t-butylbicyclophosphonate thionate is located around the Cl ion. The GABA function for the nervous system is modified and controlled by controlling the opening of the Cl ion channel and the transmission of the Cl ion to the cells, within the receptor's complex molecule GABAA, under complicated mutual effects. By checking many drugs that act directly or indirectly on the function of the GABAA receptor complex, it is known that there is a good inverse correlation between the test data of the TBSP binding and the test data of the uptake of Cl ions in the cells. For example, uptake of the Cl ion in the cells is decreased by the GABAA receptor agonists (eg, Mucimol), by the agonists of the neurosteroid receptor, diazepam, which is the representative agonist of the benzodiazepine receptor, or the clonazepam, which is a partial agonist; and increased by the inverse agonist of the benzodiazepine receptor [eg, DMCM (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate] and a partial inverse agonist [eg, FG7142 (N-methyl -ß-carbolin-3-carboxamide)] Therefore, the TBPS binding assay is useful to clarify the function of the GABAA receptor by in vitro biochemical screening of drugs that act via the allosteric binding site of the drugs of the be n zod ia ze pina, the GABAA receptor complex, etc., and the mechanisms of drug action.

Most of the old BZP drugs, such as the compounds of formulas (A), (B) and (C), have agonistic properties. On the contrary, some compounds having inverse agonistic properties are known, for example, the compounds of the following formulas (D) and (E) (DMCM and FG7142): ÍD) (E) DMCM PG7142 The DMCM and FG7142 are described in Colin R. Gardner, Drugs of the Future, vol. 14, pgs. 51-67 (1987). In addition, much research has also been conducted on the correlation between the mode of receptor binding of be n zo d i az e p a n a and the pharmacological activities of the compounds. As mentioned above, BZP agonists have been used as anxiolytic drugs, curing agents for hypnotic disorders (sleep-inducing drugs) or antiepileptic drugs, but it is known that, in addition to these activities, They also have amnestic activity in animals, including humans. Therefore, it is expected that the inverse agonists of the BZP have activities inverse to the amnesia-inducing activity, that is to say, an activity at nt i - a m nés i ca, activity p s i coa n to I e t i ca. In addition, it is known that the activity of acetylcholine, which has an important relationship with cognitive function, is reduced with the BZP agonists and is increased with the inverse agonists of the BZP, and from this it is expected that the inverse agonists of the BZP present an activity of reinforcement of the cognitive function. Therefore, it has been expected that inverse agonists of BZP may be useful as medical drugs and as medicines for the treatment of dysmenia, in senile dementia, in cerebrovascular dementia and in Alzheimer's dementia. There is no report related to the compounds of the present invention, which have the formula (I), which are described later and which have a high selective affinity for the be nzod ia ze pinay receptor that act in particular as inverse agonists of the BZP.

Description of the invention This invention provides a novel derivative of 3 -oxa d i at zo I i I-1, 6-n a f t i r i d i n-2 (1 H) -or n a, substituted at the 5-position, having the following formula (I); or a pharmaceutically acceptable acid addition salt thereof, which has a high selective affinity for a be n z or d i a ze p i n a receptor, and the use thereof as a medicament. where H e t is a group or x a d i a z or I i lo; R1 is a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, a trifluoromethyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkoxy lower alkyl group, a lower hydroxyalkyl group, an a substituted or unsubstituted aryl group, or a substituted or unsubstituted, substituted or substituted group; and R 2 is a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, a lower cycloalkylmethyl group, a lower alkenyl group, a group with a lower alkyl, a lower alkynyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted radical group. This invention also provides novel derivatives of 1,6-naphthyridin-2 (1 H) -one, of the following formula (I ') / which are useful as intermediates for preparing the 3-or xa d-a derivatives zo I i I - 1, 6 - n ftiridin - 2 (1 H) - on a, substituted at position 5, of the formula (I) mentioned above, useful as medicaments. where R is a cyano group, a carbamoyl group, a carboxyl group, a lower alkoxycarbonyl group, or a substituted or unsubstituted, substituted or unsubstituted; and R 2 is a lower alkyl group, a lower cycloalkyl group, a lower alkenyl group, a C 1 to I or lower I group, a lower alkynyl group, a substituted or unsubstituted aryl group, or a hetero group. substituted or unsubstituted, with the proviso that R2 is not a methyl group, or a pyridyl group.

During intensive studies of non-benzodiazepine compounds, which have affinity with an internal receptor for benzodiazepine, the inventors have found that the derivatives of 3-oxadiazolyl-1, 6-naphthyridin-2 (lH) -one, substituted at position 5, of the formula (I) mentioned above, have a high selective affinity with a benzodiazepine receptor (BZP) and, therefore, are useful as agonistic drugs of the benzodiazepine receptor and that these compounds, in addition, include a compound having a agonistic activity of the BZP and a compound having a reverse agonistic activity of the BZP, which depend on the classes of combinations of the substituents R1 and R2. Among the compounds of this invention, the preferred compounds are the compounds of the formula (I), wherein R1 is a C1-C3 alkyl group, a C3-C4 cycloalkyl group, or a C2-C3 alkenyl group; and R 2 is a hydrogen atom, a C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted, substituted or substituted moiety group. The most preferred compounds are the compounds of the formula (I) wherein R 1 is a C 1 -C 3 alkyl group or a C-C4 cycloalkyl group; and wherein R 2 is a hydrogen atom, a C 1 -C 3 alkyl group, a C 3 -C 4 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted heteroaromatic group. Additional preferred compounds are the following compounds. 3- (5-eti! -l, 2,4-oxadiazol-3-yl) -5- (2-methylcyclo-propyl) -l, 6-naphthyridin-2 (lH) -one; 3- (5-methyl-l, 2,4-oxadiazol-3-yl) -5- (2-methylphenyl) -l, 6-naphthyridin-2 (lH) -one; 3- (5-methyl-l, 2,4-oxadiazol-3-yl) -5- (3-methoxyphenyl) -l, 6-naphthyridin-2 (lH) -one; 3- (5-methyl-l, 2,4-oxadiazol-3-H) -5- (4-methoxyphenyl) -l, 6-naphthyridin-2 (lH) -one; 3- (5-ethyl-l, 2,4-oxadiazol-3-y) -5- (2-thienyl) -l, 6-naphthyridin-2 (lH) -one; 3- (5-methyl-l, 2,4-oxadiazol-3-yl) -5- (4-pyridyl) -l, 6-naphthyridin-2 (lH) -one; 3- (3-ethyl-l # 2,4-oxadiazol-5-yl) -5-metM-l, 6-naphthyridin-2 (lH) -one; 3- (3-ethyl-l, 2,4-oxadiazol-5-yl) -5- (3-fluorophenyl) -l, 6-naphthyridin-2 (lH) -one; 3- (3-methyl-l, 2,4-oxadiazol-5-yl) -5- (3-methylphenii) -1,6-naphthyridin-2 (lH) -one; 3- (3-methyl-l, 2,4-oxadiazol-5-yl) -5- (3-methoxyphenyl) -l, 6-naphthyridin-2 (lH) -one; 3- (3-ethyl-l, 2,4-oxadiazol-5-yl) -5- (4-methoxyphenyl) -l, 6-naphthyridin-2 (lH) -one; 3- (3-ethyl-l, 2,4-oxadiazol-5-yl) -5- (4-pyridyl) -l, 6-n a f t i r i d i n-2 (1 H) - or n a; and 3- (3-cyclopropyl-l, 2,4-oxadiazol-5-yl) -5- (3-thienyl) -l, 6-naphthyridin-2 (1 H) -one; The pharmaceutically acceptable acid addition salts of the compounds of the formula (I) include the addition salts of inorganic acids, such as the hydrochloride, idrobromide, hydroiodide, sulfate, phosphate; and the addition salts of organic acids, such as oxalate, maleate, fumarate, malonate, lactate, malate citrate, tartrate, benzoate, m e tths, or thioate or tosylate. In the specification, the terms "lower alkyl group" and the chemical group "lower alkyl" mean a straight or branched chain alkyl group having from 1 to 6 carbon atoms, for example, the methyl, ethyl, propyl, isopropyl groups , butyl, isobutyl, tert-butyl, pentyl and hexyl. The term "lower cycloalkyl group" means a cycloalkyl group having from 3 to 6 carbon atoms, for example, cyclopropyl groups, cyclobutyl, cyclopentyl and cyclohexyl, wherein the ring may be substituted by a C1-C3 alkyl group or a halogen atom. The terms "lower alkenyl group" and "lower alkynyl group" have a straight or branched chain having from 2 to 6 carbon atoms and include, for example, allyl, 1-propenyl, propargyl and 2-methyl-1-ethynyl groups . The term "lower cycloalkenyl group" means a cycloalkyl group having from 5 to 6 carbon atoms, for example, the cyclohexenyl group. The terms "lower alkoxy group" and "lower alkoxy" domain mean a straight-chain or branched-chain alkoxy group having from 1 to 6 carbon atoms and include, for example, methoxy, ethoxy, propoxy, isopropyloxy, butyloxy , isobutyloxy, tert-butyloxy, pentyloxy, and hexxy I oxy. The terms "aryl group" and chemical domain of "aryl" means a phenyl group or a naphthyl group and the ring thereof may optionally have 1 to 3 substituents which are selected from a halogen atom, a C1-C3 alkyl group, a trifluoromethyl group, a hydroxyl group, a alkoxyl group C1-C3, a group t r if I u rom ethoxy, a cyano group and an amino group, and a nitro group. The term "heteroaromatic group" means a 5- or 6-membered heterocyclic aromatic group, containing the same or different heterans, from 1 to 2, which are selected from a nitrogen atom, an atom oxygen and a sulfur atom, and includes, for example, the furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl and pyrimidinyl groups, wherein these heteroaromatic groups may, optionally, have from 1 to 3 substituents which are selected from a halogen atom, a C i -C 3 alkyl group, a hydroxyl group, a C 1 -C 3 alkoxy group and an amino group. In the "substituted or unsubstituted benzyloxycarbonyl group", the substituent is selected from a C1-C3 alkyl group, a C1-C3 alkoxy group, a cyano group and a nitro group. The term "halogen atom" means a fluorine, chlorine, bromine or iodine atom. The compounds of this invention can be prepared by processes 1 to 4, as mentioned below.

(Process i) In the compound of the formula (la) where R1 and R2 are the same as defined above, or of the formula (Ib): where R1 and R2 are the same as defined above; when R1 is a group other than a lower alkoxy group, the compound can be prepared by subjecting a compound of the formula (II): (II) where R1 'is the same as R1, different from a lower alkoxy group, R e s as defined above; or of the formula (III): where R1 'is the same as R1, different from a lower alkoxy group, and R2 is as defined above, in an intramolecular cyclization reaction. The cyclization reaction can be carried out in the presence of a dehydrating agent, but generally it can be carried out by heating the compound in a suitable solvent, which does not affect the reaction. The solvent includes aromatic hydrocarbons (e.g., benzene, toluene, xylene), ethers (e.g., tetrahydrofuran, dioxane), N, N-d i m e t i I f or r m a m i d a. These solvents can be used alone or in combination of two or more thereof. The temperature of the reaction may vary depending on the types of starting materials, etc., but it is generally in the range of 50 to 150 ° C, preferably 80 to 120 ° C.

(Process 2) In the compound of the formula (la), when R 1 is a lower alkoxy group, the compounds can be prepared by subjecting a compound of the formula (IV): where R1 is a lower alkoxy group, Ph means a phenyl group and R2 is the same as defined above, to an intramolecular cyclization reaction, in a manner similar to that described, for example, in Synthesis, p. 843 (1986).

The cyclization reaction is generally carried out by heating the initial compound in a suitable solvent. The solvent includes the aromatic hydrocarbons (e.g., benzene, toluene, xylene), ethers (e.g., tetrahydrofuran, dioxane). The temperature of the reaction may vary depending on the types of starting materials, etc., but it is generally in the range of 50 to 150 ° C, preferably 80 to 120 ° C.

(Process 3) In the compound of the formula (Ib), when R1 is a lower alkoxy group, the compound can be prepared by reacting a compound of the formula (V): where R1"is a lower alkoxy group, and R2 is same as defined above, with a hydroxylamine, in a manner similar to that described in, for example, Journal of Heterocyclic Chemistry, vol.18, page 1197 (1981) The reaction is generally carried out in a suitable solvent.The solvent includes alcohols (eg, methanol, ethanol), water.The temperature of the reaction may vary depending on the types of starting materials, etc., but is generally found in the interval from 50 to 90 ° C.

(Process 4) The compound of the formula (le): where R1 and R2 are the same as defined above, it can be prepared by subjecting a compound of the formula (VI): where R1 and R2 are the same as defined above, to an intramolecular cyclization reaction. The cyclization reaction can be carried out in the presence of a dehydrating agent, but it can be carried out generally by heating the compound in a suitable solvent, which does not affect the reaction. The solvent includes the aromatic hydrocarbons (e.g., benzene, toluene, xylene), ethers (e.g., tetrahydrofuran, dioxane), N, - d i m et i If or m a m id a. These solvents can be used alone or in a combination of two or more of them. The temperature of the reaction may vary depending on the types of starting materials, etc., but it is generally in the range of 50 to 150 ° C, preferably 80 to 120 ° C. The cyclization reaction can also be carried out in a manner similar to that described in document E P-A 2-0588500, in a suitable solvent, which does not affect the reaction, in the presence of a trivalent phosphorus compound (e.g., triphenylphosphine) and an ester of dialkylazodicarboxylic acid. The temperature of the reaction may vary depending on the types of the starting materials, etc., but it is generally in the range of 0 to 110 ° C, preferably 0 to 60 ° C. The compounds (I) of this invention, prepared by processes 1 to 4, mentioned above, can be isolated and purified by conventional methods such as chromatography, recrystallization, or reprecipitation. The compounds (I) of this invention can be obtained in the form of a free base or an acid addition salt thereof, depending, for example, on the types of starting materials that were selected for use.; of the reaction conditions and procedures. The acid addition salt can be converted to a free base by treating it with a conventional base, such as an alkali metal carbonate and an alkali metal hydroxide. In addition, the free base can be converted to an acid addition salt by treating it with a type of various acids, in the usual manner. The processes for preparing the initial compounds are explained below. The compounds of formulas (II) to (VI), used in Processes 1 to 4 mentioned above, are novel compounds and can be prepared by a process as shown in the following Reaction Scheme 1.

Reaction Scheme 1 II) where it is the same as R, except a lower alkoxy group; and R2 is the same as defined above. The compound (1) is reacted with hydroxylamine in the usual manner to give the compound (2), and this compound is reacted with a reactive compound derived on the carboxylic group of a carboxylic acid of the formula: R ^ COOH ( where R1 'is as defined above), in the presence of a base, to give the compound of the formula (II). The compound of the formula (III), used in Process 1, mentioned above, can be prepared by a process as shown in the following Reaction Scheme 2.

Reaction Scheme 2 (3) (4) (III) where R1 'is the same as R1, except a lower alkoxy group; and R2 is the same as defined above. The compound (3), or a derivative reagent, in the carboxyl group thereof, is reacted with a type of various amidoximes (4), under the reaction conditions for a conventional amidation to give the compound of the formula (III) . The compound of the formula (IV), used in Process 2, mentioned above, can be prepared by a process as shown in the following Reaction Scheme 3.

Reaction Scheme 3 (5) (6) (7) (8) (9) (10) (U) (IV) where R1"is a lower alkoxyl group, R 'is a lower alkyl group or a substituted or unsubstituted benzyl group, Ph means a phenyl group and R2 is the same as defined above.The compound (5) is reduced with an agent reducing agent such as sodium borohydride, tertiary butyl boron hydride, lithium aluminum hydride, in a suitable solvent, to give the compound (6), and then the compound is oxidized with activated manganese dioxide, in the appropriate solvent, to give the compound (7). The compound (7) is reacted with hydroxylamine under the conditions for the conventional oxime formation reaction, to give the compound (8), and then, the compound is reacted with inimidated N-c I orosu, in a similar manner. which is described, for example, in the Journal of Organic Chemistry, vol. 45, p. 3916 (1980), to give the compound (9). Compound (9) is reacted with sodium azide in a suitable solvent, similarly to that described, for example, in Synthesis, p. 102 (1979), to give the compound (10), and then, the compound is reacted with a compound of the formula: XCOR1"(where X is a halogen atom and R1" is a lower alkoxy group), in a suitable solvent, similar to that described in, for example, Synthesis, p. 843 (1986), to give the compound (11); and this compound is subsequently reacted with t r i f e n i i f osf a n a to give the compound of the formula (IV). The compound of the formula (V), used in Process 3, mentioned above, can Prepare by a process as shown in the following Reaction Scheme 4. Reaction Scheme 4 (3) (12) (V) where R1"is a lower alkoxy group and R2 is the same as defined above The compound (3), or a reactive derivative in the carboxyl group, thereof, is reacted with an alkali metal thiocyanate, in a suitable solvent , to give the compound (12), and then the compound is subjected to alcoholics to give the compound (V). The compound of the formula (VI), used in Process 4, mentioned above, can be prepared by a process as described above. mentioned in the following Reaction Scheme.

Reaction Scheme 5 < 3) (13) (VI) where R1 and R2 are the same as defined above. The compound (3), or a reagent derived at the carboxyl group thereof, is reacted with a hydrazine (13), of the formula: R * CONHNH 2 (where R 1 is the same as defined above), by a reaction conventional amidation, to give the compound of the formula (IV). The compound (VI) can also be prepared by a two-step reaction, that is, by reacting the compound (3), or a reagent derivative at the carboxyl group thereof, with the hydrazine, by a conventional amidation reaction, followed by the reaction of the resulting product with a derivative reagent, in the carboxyl group of a carboxylic acid of the formula: R! COOH (R1 is the same as defined above).

A process for the preparation of the intermediate compound of the formula is explained below The compounds of the formula (I '), wherein R is a cyano group or a carboxyl group, i.e., the compound (1) and the compound (3), such as, are used in Reaction Scheme 1 and in the Reaction Scheme 2, can be prepared in a manner similar to that described, for example, in the Journal of Heterocyclic Chemistry, vol. 27, p. 2085 (1990); or in Journal of Medicinal Chemistry, vol. 35, p. 4858 (1992), as shown in the following Reaction Scheme 6.

Reaction Scheme 6 (14) (15) (16) (17) (1) (3) (5) wherein X is a lower dialkylamino group, a cyclic amino group, a hydroxyl group, a halogen atom, or a lower alkoxy group, R 'is a lower alkyl group or a substituted or unsubstituted benzyl group, and R is same as defined above. In the above reaction scheme, the compound (16) can be prepared by reacting the compound (14) with d i m e t i I to keta I of N, N-dimethylformamide or an ester of the orthoformic acid, in a suitable solvent, in a manner similar to that described, for example, in H ete rocy c le s, vol. 29, p. 1517 (1989), or in Journal of Heterocycic Chemistry, vol. 27, p. 511 (1990), to give the compound (15), followed by the reaction thereof with c i a n or ceta m i d a, in the presence of a suitable base. The compound (16), prepared in this way, is subsequently reacted with dimethyl I aceta I of N, -dimeti I formamide in a suitable solvent, to give the compound (17), and then this compound is reacted with ammonia or an ammonium salt, in a suitable solvent, to give the compound (1). The compound (1), obtained in this way, is hydrolyzed with an acid or an alkali, by a conventional method, to give the compound (3). In addition, the compounds of the formula (I '), where R is, for example, a lower alkoxycarbonyl group or a substituted or unsubstituted benzyloxycarbonyl group, the compounds (5) can be prepared by the esterification of the compound (1) or the compound (3), by a conventional method.

Pharmacological Experiments The pharmacological properties of the compounds (I) of the present invention are manifested by The following experiments with representative compounds.

Experiment 1 Test of the Union of the Recipient of the Benzodiazepine The benzodiazepine receptor binding assay was carried out according to the method described in Life Science vol. 20, p. 2101 (1977). A crude fraction of the synaptosome membrane, prepared from the brains of Wistar rats (age: 7 to 8 weeks), was suspended in 15 mM Tris-HCl buffer (pH 7.4), containing 118 mM sodium chloride, potassium chloride 4.8 mM, 1.28 mM calcium chloride and 1.2 mM magnesium sulfate, at a concentration of 1 g (wet weight) of brain per 20 mL of the buffer, to give a source of membrane receptors. [3 H] -diazepam was used as a radioactively labeled ligand. A test compound (a known amount), rj3H] -diazepam (final concentration: 1.5 nM), the membrane receptor and buffer mentioned above, were added to a test tube (final volume: 1 mL). The reaction was initiated by adding the membrane receptor. The test tube was incubated at 0 ° C for 20 minutes, and the reaction mixture was terminated by rapid filtration through a Whatman GF / B glass fiber filter, attached to a cell cultivator (manufactured by Brandell). Immediately, the radioactively labeled ligand-receptor complex of the membrane was washed three times with 50 mM Tris-HCl buffer (pH 7.7, per 5 mL), cooled with ice. The radioactivity in the filter was measured by means of a counter of liquid, to determine the. amount of [3H] -diazepam bound to the membrane receptor (total binding).

Separately, the same procedure was repeated, except that 1 μM diazepam was added, and, therefore, the amount of [3 H] -diazepam bound to the membrane receptor (non-specific binding) was measured in a similar manner. This non-specific binding was subtracted from the total binding to give the specific binding. Based on the specific binding that was obtained in this way, the inhibition activity (IC50) of the test compound was determined by a probability unit method. The results are shown in the following Tables 1 to 4.

Table 1 TEST OF THE UNION OF THE RECEIVER OF THE BENZODIAZEPINE Table 2 Table 3 Table 4 Experiment 2 TBPS binding assay (Method) The binding assay of TBPS (t-butylbicyclophosphonate thionate) and the preparation of the membrane sample were performed in a manner similar to the Biggio method, G., et al. [cf. European Journal of Pharmacology, vol. 161, pgs. 173-180 (1989)]. The membrane sample was prepared from the cerebral cortex of the Wistar rats (age: 7 to 8 weeks), by the following procedure. That is, the volume of an ice-cooled buffer (50 mM Tris-citrate buffer, containing 100 mM sodium chloride, pH 7.4) was added to the cerebral cortex 50 times and the mixture was homogenized at a temperature of 0 to 4 ° C, then centrifuged at 20,000 g for 20 minutes. The buttons thus obtained were subjected once to h o m and g e n e i z ation in a buffer and to centrifugation by the same procedure mentioned above, and then kept in a freezing state at -80 ° C for more than 20 hours. On the day of the test, the frozen buttons were thawed and then subjected to the homogenization-centrifugation procedure twice, as described previously. The buttons obtained in this way were suspended in a buffer, at a concentration of 1 g (wet weight) per 25 mL of buffer, to give a membrane sample to be used in the binding assay. The binding assay was performed by the following procedure, using, as a radioactively labeled ligand, [35 S] TBPS (final concentration: 0.4 nM), and as a non-radiolabelled ligand, Picrotoxin (final concentration: 100 μM) in the presence of GABA ( final concentration: 1 μM).

A test compound (a known amount), Gand labeled with r 35ss] membrane sample, GABA and a buffer, were added to a test tube (final volume: 1 mL). The reaction was initiated by the addition of the membrane sample (200 μL). The test tube was incubated at 25 ° C for 90 minutes, and the reaction was terminated by filtration through Whatman GF / B glass fiber (which was previously immersed in 0.01% polyethyleneimine, for one day) attached to a cell cultivator. (manufactured by Brandell), and, consequently, the ligand-labeled membrane-bound complex was recovered in the filter. Immediately, the marked ligand complex The recovered bound membrane was washed with a 50 mM Tris-HCl buffer, cooled with ice (pH 7.7, for every 5 L), three times. Subsequently, the filter was removed in a liquid scintillation vial and then a liquid scintillation cocktail (ACS-II, manufactured by Amersham, USA, 10 mL) and allowed to stand for a fixed period of time. Subsequently, the radioactivity in the filter was measured by a liquid flash counter (type 2000CA, manufactured by Paccard, USA) to determine the total amount of binding. Separately, the same procedure was repeated in the presence of Picrotoxin, to determine the total amount of binding. The amount of non-specific binding was subtracted from the total binding amount, to give the specific binding amount. The binding activity of the test compound was calculated by the rate of variation, i.e., the rate of the specific binding amount of the test compound with respect to the amount of specific binding in the control (using a solvent) (Evaluation criteria) Value +% means that it exhibits inverse agonist properties; Value -% means that it exhibits agonist properties and 0% means that it exhibits agonist properties. The results are shown in Table 5 and Table 6. Table 5 TBPS binding test Table 6 Experiment 3 Evidence of increased activity on induced seizure with pe n t i I in te ra zo I. It is known that inverse agonists of the benzodiazepine receptor increase the seizure induced by the p e n t i I n t t a zo I [cf. Progress in Neuro-P s and c h o p h a r m a co I o g y and Biological Psychiatry, vol. 12, p. 951 (1988)]. Some compounds of the present invention were evaluated for the activities of the increment of convulsion induced by pentylenetetrazole. A test compound (the compounds described in the working examples) was administered orally to male ddY mice (weight: 22-25 g, five mice / group) in an amount of 5 -100 mg / kg. Fifteen minutes later, pentylenetetrazole was injected subcutaneously (70 mg / kg, which does not induce tonic seizure by the comatose alone) into the mice and, immediately, the mice were observed as to the appearance of the tonic seizure in the back leg for 30 minutes. The effects were evaluated by the number of mice among five mice, in which effects of the increase of the seizures The results are shown in Table 7. Table 7 As shown in the above results, the application compounds of the present invention showed high selective affinity for the benzodiazepine receptor and hence they are useful as medicaments for acting on the receptor of the b e p z d ia ze p a n. Although some of the compounds of this invention also have agonistic properties, the compounds of this invention are particularly useful as inverse agonists. Compounds which have inverse agonistic properties are expected to be used in clinical fields completely different from those of agonists, for example, as medicinal drugs or as drugs, or as drugs for the treatment of senile dementia, or eimer's disease.

PHARMACEUTICAL USE OF THE COMPOUNDS OF THIS COMPARISON The compounds of this invention can be administered either orally, orally, or orally, when they are used as a medicament to act on the recipient of the drug. benzodiazepine, but preferably orally. The dose of the compounds varies according to the route of administration, the conditions and ages of the patients, or the types of treatment (eg, prophylaxis or treatment), and the like, but is generally in the range of 0.01 to 10 mg / kg / day, preferably in the range of 0.02 to 5 mg / kg / day. The present compounds can be administered in the form of a conventional pharmaceutical preparation, mixed with a conventional pharmaceutically acceptable carrier or diluent. The pharmaceutically acceptable carrier or diluent may be any which are used in this field and which do not react with the present compound, for example, lactose, glucose, mannitol, dextran, starch, white sugar, magnesium aluminate metasilicate, silicate. synthetic aluminum, crystalline cellulose, sodium carboxymethylcellulose, calcium carbomethylcellulose, hydroxypropylmethylcellulose, ion exchange resins, methyl cellulose, gelatin, gum arabic, hydroxypropylcellulose, hydroxypropylcellulose substituted with lower groups, hydroxypropylmethylcellulose , polyvinylpyrrolidone, polyvinyl alcohol, light silicic anhydride, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, sorbitan ester fatty acid, sodium lauryl sulfate, glycerin, fatty acid glyceryl ester, purified lanolin, giicerogelatine, polysorbate, macrogol, vegetable oil, wax, liquid paraffin, white petrolatum, nonionic surfactant, propylene glycol, water, and the like. The pharmaceutical preparations are tablets, capsules, granules, powders, syrups, suspensions, suppositories, gels, injectable preparations, and the like. These preparations can be prepared by conventional methods. When a liquid preparation is prepared, it may be previously in the form of a solid preparation, which is dissolved or suspended in water or in a solvent, at the time of its use. In addition, the tablets or granules can be coated by a conventional method, and the injectable preparations which are prepared by dissolving the compound (I), of the present invention, or an acid addition salt thereof, in distilled water, for injection, or a physiological saline solution, but, if necessary, it can be dissolved in an isotonic solution; and, in addition, a compound for adjusting the pH, a buffer or a condom can be added thereto. These pharmaceutical preparations can contain the present compound in an amount of more than 0.0136, by weight, pre-Benzyl BH 0.05 to 10% by weight, and may contain other pharmacologically active ingredients.

BEST MODALITY FOR CARRYING OUT THE INVENTION The compounds of this invention are illustrated by the following examples. The symbols in the tables mean the following: Me: methyl; Et: ethyl; n-Pr: n-propyl; i-Pr: isopropyl; c-Pr: c i c I o p r o p i i o; n-Bu: n-butyl; t-Bu: tert-butyl; Ph: phenyl. The position of the substituents is indicated in this way, for example, 3-Me-Ph, means 3-m e t i I f e n i I o.

Example 1 Preparation of 3- (5-cyclopropyl-l, 2,4-oxadiazol-3-yl) -5-methyl-l, 6-naphthyridin-2 (lH) -one: (1) To a solution of hydroxylamine hydrochloride (4.17 g), in water (50 mL), sodium carbonate (3.18 g) was added, with stirring, with cooling with ice. To the solution were added subsequently, ethanol (200 mL) and 1,2-dihydro-5-m and i-2-oxo-1,6-naphthyridine-3-carbonitriio (3.70 g), and the mixture was subjected to reflux for 2 hours. After removing the solvent by distillation, under reduced pressure, water was added to the residue, and the crystals precipitates were separated by means of filtration. The product was washed with water, isopropanol, diisopropyl ether, in this order; and dried to give 1,2-dihydro-5-methyl-2-oxo-l, 6-naphthyridin-3-amidoxime (4.2 g). This compound was used in the next reaction, without being purified. (2) To a suspension of the amidoxime mentioned above (1.09 g), sodium carbonate (0.83 g) and methyl ethyl ketone (200 mL), cyclopropanecarbonyl chloride (0.57 g) was added, with stirring under ice cooling, and The mixture was stirred at room temperature overnight. After removing the solvent by means of distillation, under reduced pressure, water was added to the residue and the precipitated crystals were separated by filtration, washed with water, isopropanol and ether di pso p or p, in that order, and then they dried. To the resulting crystals was added dimethylfor ida (DMF) (50 mL), and the mixture was stirred at 130 ° C for 5 hours. After removing the solvent by distillation under reduced pressure, isopropanol was added to the residue and the crystals were separated by filtration. The resulting crystals were reactivated from ethanol chloroform, to give the title compound (0.65 g), as colorless crystals. P. F. 259-260 ° C.

Examples 2 to 85 In the same manner as described in Example 1, the corresponding starting materials were reacted to give the compounds of Examples 2 to 85, as shown in Tables 8 to 12.

Table 8 Table 9 Table 10 Table 11 Table 12 EXAMPLE 86 Preparation of 3 - (5-met i I-1, 2, 4-oxa dia zol-3-yl) -5- (3-methoxyphenyl) -l, 6-naphthyrdin-2 (lH) -one: To a solution of acetic acid (0.90 g), in DMF (100 mL), N, N-ca r bo or 1 diimi dazo I (2.43 g) was added and the mixture was stirred at 70 ° C for 3 hours. hours. To the solution was added l, 2-dihydro-5- (3-methoxyphenyl) -2-oxo-l, 6-naphthyridin-3-amidoxime (3.10 g), prepared in the same manner as described in Example 1 ( 1), and the mixture was stirred at 70 ° C for 2 hours, and subsequently at 130 ° C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure, and water was added to the residue; the precipitated crystals were separated by filtration and washed with water, isopropanol and diisopropyl ether, in this order, and then dried. The resulting crystals were subjected to column chromatography on silica gel and eluted with chloroform-methanol (50: 1). The resulting crystals will be r e a mixture c I o r of o r m o-eta not I, to give the title compound (2.22 g) as colorless crystals. P.F. 286-288 ° C. Hydrochloride of the title compound, P.F. 281-282 ° C (recrystallized from ethanol).

Examples 87 to 172 In the same manner as described in Example 86, the corresponding starting materials were reacted to give the compounds of Examples 87 to 172, as shown in Tables 13 to 17.

Table 13 Table 14 Table 15 Table 16 Table 17 Example 1 Preparation of 3 - (3 - eti I - 1, 2, 4 - oxa diazo I - 5 - i I) - 5- (2-thienyl) -l, 6-naphthyridin-2 (lH) -one : To a solution of 1,2-dihydro-5- (2-thienyl) -2-oxo-l, 6-naphthyridine-3-carboxylic acid (3.81 g) in DMF (50 mL), N was added. - rboni I diimida zo I (3.41 g) and the mixture was stirred at 70 ° C for 4 hours. To the solution was added amidoxime propionate ca (1.85 g), and the mixture was stirred at 70 ° C for 1 hour, and subsequently at 130 ° C for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure and water was added to the residue; and the precipitated crystals were separated by filtration and washed with water, isopropanol and diethyl ether in this order, and then dried. The resulting crystals were subjected to column chromatography on silica gel and eluted with chloroform-methanol (50: 1). The resulting crystals are re c r i sta t i n g from c r o o r m o - e t a n o I, to give the title compound (2.60 g), as colorless crystals. P.F. 265-268 ° C.

Example 174 to 307 In the same manner as described in Example 173, the corresponding starting materials were reacted to give the compounds of Examples 174 to 307, as shown in Tables 18 to 24.

Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Example 308 Preparation of 3- (5-eti I-1, 3, 4-oxa di azo I-2-i I) -5- (2-thienyl) -l, 6-naphthridin-2 (lH) - ona: (1) A solution of 1,2-dihydro-5- (2-1 ien i I) - 2-oxo-l, 6-naphthyridine-3-carboxylic acid (1.36 g) and N, N '- carboni I diii dazo I (1.22 g), in DMF (50 mL), was stirred at 70 ° C for 4 hours. To the solution was added propionyl hydrazide (0.53 g), and the mixture was stirred at 70 ° C for 2 hours. The reaction mixture was concentrated to dryness, under reduced pressure, and isopropanol was added to the residue; and the precipitated crystals were separated by filtration. The product was washed with isopropanol and diisopropyl ether, in this order, and dried to give 1,2-dihydro-N'-propionyl-5- (2-thienyl) -2-oxo-l, 6 - naphthridin-3 - ca r bo hydrazide (1.21 g), as yellow crystals. This compound was used in the next reaction without being purified. (2) To a suspension of the hydrocarbon obtained above (1.09 g), trifluoride (1.57 g) and triethylamine (1.06 g), in tetrahydrofuran (THF) (50 mL), dropwise addition of diethyl ether (1.04 g) was added, with cooling with ice. The mixture was stirred at 70 ° C for 4 hours. After cooling, water was added to the mixture, and then it was concentrated under reduced pressure, and isopropanol was added to the residue. The precipitated crystals were separated by filtration and dried. The resulting crystals were subjected to column chromatography on silica gel and eluted with a chloroform-methanol mixture (50: 1). The crystals were reacted with ethanol to give the title compound (0.21 g) as colorless crystals. P.F. > 300 ° C.

Examples 309 to 368 In the same manner as described in Example 308, the corresponding starting materials were reacted to give the compounds of Examples 309 to 368, which are shown in Tables 25 to 27.

Table 25 Table 26 Table 27 Example 369 Preparation of 1, 2 - d i h id ro - 5 - m e ti i - 2 - oxo - i, 6 n a f t i r i d i n - 3 - c a r b o n i t r i I o: (1) A mixture of acetic acid (41 L), dimet, and ceta I of formed N, N-dimeti I (106.2 mL) and THF (200 L) was stirred at room temperature. during 3 hours. After removing the solvent by distillation, under reduced pressure, the residue was added dropwise to a solution which was prepared by dissolving metallic sodium (13.8 g) in ethanol (600 mL) and adding, thereto, cyanoacetamide (33.6 g); and the mixture was refluxed for 1 hour. The reaction mixture was cooled with ice, and the precipitated crystals were separated by filtration. The crystals were dissolved in water (1 liter) and then acidified weakly with 3N hydrochloric acid. The precipitated crystals were separated by filtration and recrystallized from DMF-methanol, to give 5-acetyl-6-methyl-1,2-dihydro-2-oxb-3-pyridinecarbo-nitrile (60 g), as colorless crystals. . P.F. 230 ° C. (2) A solution of the above-obtained carbonitrile (30 g), dried the N, N-dimethylformamide (25 mL) and DMF (150 mL), was stirred at room temperature overnight. The precipitated crystals were separated by filtration, washed with methanol and then dried. The crystals obtained in this way, and ammonium acetate (21.9 g), were added to DMF (300 mL), and the mixture was stirred at 130 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue; and the resulting crystals were separated by filtration and r e c r i s ta ted from DMF, to give the title compound (Compound No. 1) (25 g) as colorless crystals. P.F. 278 ° C. In the same way as described in the Example 369, the corresponding starting materials were reacted to give compounds Nos. 2 to 43, as shown in Tables 28 to 29.

Table 28 Table 29 EXAMPLE 370 Preparation of 1,2-dihydrogen-5 - (2-ti eni I) -2-oxo-l, 6-naphthyridine-3-carboxylic acid: A mixture of 1,2-dihydroxycarboxylic acid (2 - 1 ieni I) - 2 -oxo - 1, 6-naph tir id in - 3 -ca r bon itri I o (10.0 g), ethanol (300 mL) and NaOH ION (300 mL) was refluxed overnight. After cooling, the reaction mixture was neutralized with acetic acid, and the precipitated crystals were separated by filtration, washed with water, isopropanol and ether d i i s or p r o p i i co, in this order; and then dried to give the title compound (Compound No. 44) (10.5 g), as pale yellow crystals. P.F. 278 ° C. In the same manner as described in Example 370, the corresponding starting materials were reacted to give Compounds Nos. 45 to 86, as shown in Tables 30 to 31.

Table 30 Table 31 Preparation, 1 Capsules: 3- (5-methyI-1, 2,4-oxadiazoi-3-yl) -5- (3-methoxyphenyl) -1,6-na f t i r i d i n-2 (1 H) -or n at 5 g Corn starch 57 g Lactose 10 g Crystalline cellulose 25 g H i d ox i p r o p i I cellulose 2 g Lightweight silicon anhydride 0.5 Magnesium stearate 0.5 According to a method with ention, the components mentioned above are mixed and kneaded in 1000 capsules, to give a preparation in capsules (each of 100 mg).

Preparation 2 Tablets: 3- (5-methyl-l, 2,4-oxadiazol-3-yl) -5- (3-methoxyphenyl) -l, 6-naphthyridin-2 (lH) -one 5 g Corn starch 20 g Lactose 30 g H i d r o x i p r o p i I cellulose 5 g H i d rox i p ro p i I cellulose with s u s t i t? and low molecular weight IO g According to a conventional method, the aforementioned components are mixed and kneaded and then light silicon anhydride and magnesium stearate are added; and the mixture is tableted to give tablets containing 5 mg of the active ingredient in each tablet.

Preparation 3 Dust 3- (5-methyl-l, 2,4-oxadiazol-3-yl) -5- (3-methoxy phenyl) -l, 6-naphthyridin-2 (lH) -one 5 g Corn starch 173 g Lactose 300 g H i d r ox i p ro p i l cellulose 20 g According to a conventional method, the aforementioned components are mixed and kneaded, pulverized and then light silicic anhydride (in sufficient quantity) is added to give 50-trituration.

INDUSTRIAL APPLICATION The compounds of this invention have a high selective affinity for the benzodiazepine receptor. Although some of the compounds of this invention has agonistic properties, the compounds of this invention are particularly useful as inverse agonists. Compounds which have inverse agonistic properties are expected to be used in clinical fields completely different from those of agonistic compounds, for example, as psychoactive drugs or as drugs for the treatment of dysmengia in senile dementia or in Alzheimer's disease. It is noted that, in relation to this date, the best method known to the applicant to carry out the aforementioned invention is the conventional one for the manufacture of the objects or substances to which it refers.

Claims (8)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property.

1. A derivative of 3-oxadiazolyl-l, 6-naphthyridin-2 (lH) -one, substituted at the 5-position, characterized in that it has the following formula (I): where Het is an oxygen radical group, R 1 is a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, a trifluoromethyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, an alkoxy group lower-lower alkyl, a lower hydroxyalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaromatic group; and Rz is a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, a c i c i or a I q u i i m or i I or lower group, a lower aikenyl group, a lower cycloalkenyl group, an alkynyl group lower, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaromatic group; or a pharmaceutically acceptable acid addition salt thereof.

2. The derivative of 3-oxa dia zo ii 1-16,6-naphthyridin-2 (1H) -one, substituted at the 5-position, in accordance with the rei indication 1, characterized in that R1 is a C1-C3 alkyl group, a C3-C4 cycloalkyl group, or a C2-3 alkenyl group; and R 2 is a hydrogen atom, a C 1 -C 4 alkyl group / a C 3 -C 6 cycloalkyl group / a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaromatic group, or an acid addition, pharmaceutically acceptable salt of the same.

3. The 3-oxadiazolyl-l, 6-naphthyridin-2 (lH) -one derivative substituted in the 5-position, according to claim 1, characterized in that R1 is a C?-C3 alkyl group or a C3 cycloalkyl group -C4; and wherein R 2 is a hydrogen atom, a C 1 -C 3 alkyl group, a C 3 -C 4 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted heteroaromatic group; or a pharmaceutically acceptable acid addition salt thereof.

4. The 3-oxadiazolyl-1,6-naphthyridin-2 (lH) -one derivative substituted in the 5-position, characterized in that it is selected from the following compounds or an acid-addition, pharmaceutically acceptable salt thereof: - (5-etii-l, 2,4-oxadiazol-3-yl) -5- (2-methylcyclo-propyl) -l, 6-naphthyridin-2 (lH) -one; 3- (5-methyl-l, 2,4-oxadiazol-3-yl) -5- (2-methylphenyl) -l, 6-naphthyridin-2 (lH) -one; 3- (5-methyl-l, 2,4-oxadiazo! -3-yl) -5- (4-methoxyphenii) -1,6-naphthyridin-2 (lH) -one; 3- (5-etii-l, 2,4-oxadiazol-3-yl) -5- (2-tlenyl) -l, 6-naphthyridin-2 (lH) -one; 3- (5-methyl-l, 2,4-oxadiazol-3-yl) -5- (4-pyridyl) -l, 6-naphthyridin-2 (lH) -one; 3- (3-ethyl-l, 2,4-oxadiazoi-5-yl) -5-methyl-l, 6-naphthyridin-2 (lH) -one; 3- (3-ethyl-l, 2,4-oxadiazol-5-yl) -5- (3-phlorophenyl) -l, 6-naphthyridin-2 (lH) -one; 3- (3-metit-l, 2,4-oxadiazol-5-yl) -5- (3-methylphenyl) -l, 6-naphthyridin-2 (lH) -one; 3- (3-methyl-l, 2,4-oxadiazol-5-yl) -5- (3-methoxyphenyl) -l, 6-naphthyridin-2 (lH) -one; 3- (3-etit-l, 2,4-oxadiazol-5-yl) -5- (4-methoxyphenyl) -l, 6-naphthyridin-2 (lH) -one; 3- (3-ethyl-l, 2,4-oxadiazol-5-yl) -5- (4-pyridyl) -l, 6-na f t i r i d i n-2 (1 H) -o na; and 3- (3-cyclopropyl-l, 2,4-oxadiazol-5-yl) -5- (3-thienyl) -l, 6-naphthyridin-2 (lH) -one.

5. The compound 3 - (5-m eti I-1, 2, 4-oxadiazo I-3- i 1) -5- (3 -me tox if eni I) - 1, 6 - n af tiridin - 2 (1 H) - onao a far acidic acid addition salt acceptable thereof.

6. A pharmaceutical composition, for acting on the benzodiazepine receptor, characterized in that it comprises the compound, according to any of claims 1 to 5, mixed with a pharmaceutically acceptable carrier or diluent.

7. A medicine for acting on the bezodiazepine receptor, characterized in that it comprises, as an active ingredient, the compound according to any of claims 1 to 5.

8. A derivative of l, 6-naphthyridin-2 (lH) -one, characterized in that it is of the formula (I '): where R is a cyano group, a carbamoyl group, a carboxyl group, a lower alkoxycarbonyl group, or a substituted or unsubstituted benzyl group; and R2 is a lower cycloalkyl group, a lower alkenyl group, a lower cycloalkenyl group, a lower alkynyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaromatic group, provided that R2 is not a group pyridyl. SUMMARY OF THE INVENTION A derivative of 3-oxadiazolyl-1, 6-naphthyridin-2 (lH) -one, substituted at the 5-position, of the formula (I): where Het is an oxadiazolyl group; R1 is H, a lower alkyl group, a lower cycloalkyl group, a trifluoromethyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkoxy group at I or lower, a lower hydroxyquinic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaromatic group; and R2 is H, a lower alkyl group, a lower cycloalkyl group, a lower cycloalkyl ethyl group, a lower alkenyl group, a lower cycloalkenyl group, a lower alkynyl group, a substituted or unsubstituted aryl group, or a substituted heteroaromatic group or not replaced; or a pharmaceutically acceptable acid addition salt thereof, which has high selective affinity for the benzodiazepine receptor and which is useful particularly as a benzodiazepine inverse agonist, for example, as a psychoactive medication or a medicament for the treatment of dysmnesia in senile dementia or in Alzheimer's disease.