JP2521999B2 - Azaspiro compound - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel azaspiro compound useful as a drug for improving cerebral function, particularly in senile dementia, Alzheimer's disease and the like.

Background Art With the advance of society, various compounds having a brain function improving action have been proposed. Among them, some technologies related to azaspiro compounds have been published.
(JP-A-60-36487, JP-A-61-167691) Problems to be Solved by the Invention Against the background of the social problems described above, drugs that act on the central nervous system, especially brain function improvement for senile dementia and Alzheimer's disease There is a strong demand for the emergence of medicines,
No satisfactory compound has been found yet.

Means for Solving the Problems The present inventors have made diligent efforts to search for a compound useful as a brain function-improving drug that acts on the central nervous system, especially on the acetylcholine receptor, and as a result, the formula (I) [In the formula, R ₁ and R ₂ are each hydrogen, a hydrocarbon residue which may have a substituent or an acyl group, and R ₃ is hydrogen or a hydrocarbon residue which may have a substituent. X ₁ and X ₂ are each an oxygen atom or a sulfur atom, Y is oxygen,
Sulfur or formula -N (R ₄₎ - (wherein, R ₄ is hydrogen or a lower alkyl group) a group represented by, m is 0 or 1, n
Represents 0 or 1. ] It was found that the azaspiro compound represented by the formula [4] or a salt thereof exhibits an excellent brain function improving action, and the present invention has been completed.

In the above formula (I), examples of the “hydrocarbon residue” of the “hydrocarbon residue which may have a substituent” represented by R ₁ , R ₂ and R ₃ include, for example, a chain, a ring and a saturated group. , Unsaturated and also hydrocarbon residues consisting of various combinations thereof. As the chain saturated hydrocarbon residue, for example, a linear or branched alkyl group having 1 to 6 carbon atoms (eg,
And methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl).

The chain unsaturated hydrocarbon residue may be a straight chain or branched chain.
Examples thereof include C _2-4 alkenyl (eg vinyl, aryl, 2-butenyl) and C _2-4 alkynyl (eg propargyl, 2-butynyl).

As the cyclic saturated hydrocarbon residue, a monocyclic cycloalkyl having 3 to 7 carbon atoms (eg, cyclobutyl, cyclopentyl,
Cyclohexyl), bridged cyclic saturated hydrocarbons having 8-14 carbon atoms (eg, bicyclo [3,2,1] oct-2-yl, bicyclo [3,2,1] nonan-2-yl), cyclic unsaturated Examples of the hydrocarbon residue include a phenyl group and a naphthyl group.

Substituents for these hydrocarbon residues include halogen atoms (eg, chloro, bromo, iodo), nitro, nitrile, hydroxy, C _1-4 alkoxy (eg, methyloxy,
Ethyloxy, propyloxy, butyloxy, isopropyloxy), C _1-4 alkylthio (eg, methylthio,
Ethylthio, propylthio, isopropylthio, butylthio), amino, mono- or di-C _1-4 alkyl-substituted amino (eg, methylamino, ethylamino, propylamino,
Dimethylamino, diethylamino), mono- or diaralkyl-substituted amino (eg, benzylamino, 2-hydroxyphenylmethylamino), mono- or di-pyridylcarbonyl-substituted amino (eg, 3-pyridylcarbonylamino), C _1-4 alkoxycarbonyl ( Eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl), hydroxycarbonyl, C _1-6
Alkylcarbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl), cycloC _3-6 alkylcarbonyl (eg, cyclopentylcarbonyl, cyclohexylcarbonyl), carbamoyl, mono- or di-C _1-4 alkyl-substituted carbamoyl (eg, methylcarbamoyl, Ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl), phenyl optionally having 1-4 substituents,
Phenoxy, benzoyl, phenoxycarbonyl, phenyl C _1-4 alkylcarbamoyl (eg, benzylcarbamoyl, phenethylcarbamoyl), phenylcarbamoyl [as a substituent in each phenyl group,
_1-4 alkyl group (eg, methyl, ethyl, propyl, butyl, isopropyl), halogen (eg, chloro, bromine,
Iodo), hydroxyl group, benzyloxy, amino, mono- or di-C _1-4 alkyl-substituted amino (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylethylamino), nitro, C _1-4 alkoxycarboxy (Eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl) and the like. ]
Is raised.

The number of substituents of these hydrocarbon residues is suitably about 1 to 3.

Examples of the acyl group represented by R ₁ and R ₂ include, for example,
Examples thereof include acyl carboxylate, acyl carbamate, acyl sulfonate, and substituted oxycarboxylate acyl, each of which may have a substituent. When the acyl group has a substituent, examples of the substituent include the groups exemplified as the above-mentioned substituents of the hydrocarbon group.

Examples of the acyl carboxylate include C _1-6 alkylcarbonyl such as acetyl, propionyl, butyryl, valeryl, hexanoyl, isobutyryl and isovaleryl (these are, for example, amino, 3-carbamoyl-1,4-dihydropyridin-1-yl, 3- It may be substituted with carbamoyl-1-pyridyl, phenoxy and the like, and specific examples of the C _1-6 alkylcarbonyl having a substituent include phenoxyacetyl, 4-aminobutyryl, aminomethylcarbonyl, 2- (3- Carbamoyl 1,4-dihydropyridin-1-yl) ethylcarbamoyl, 2- (3-
Examples thereof include carbamoylpyridin-1-yl) ethylcarbamoyl. ), C _3-8 cycloalkylcarbonyl such as cyclopentylcarbonyl and cyclohexylcarbonyl, C _3-8 cycloalkyl-C _1-6 alkylcarbonyl such as cyclopentylacetyl, acryloyl, crotonyl, 2-pentenoyl, 4-pentenoyl, 2-hexenoyl C _2-6 such as 3,3-hexenoyl and 2,4-hexadienoyl
Alkenyl or alkynylcarbonyl, benzoyl,
Arylcarbonyl such as naphthoyl, pyridylcarbonyl such as nicotinoyl, dihydropyridylcarbonyl [eg C _1-4 alkyl (methyl, ethyl, propyl,
Butyl), benzyl, methoxycarbonyl, 3-nitrophenyl, nitro, 2-trifluorophenyl and the like, and specific examples of dihydropyridylcarbonyl having these substituents include, for example, N—C _{1- 4-} alkyl-1,4-dihydropyridine-3-carbonyl (eg, N-methyl-1,4-dihydropyridine-3-carbonyl, N-ethyl-1,4-dihydropyridine-3-carbonyl, N-butyl-1,4 -Dihydropyridine-3-carbonyl), N-benzyl-1,4-dihydropyridine-3-
Carbonyl, 2,6-dimethyl-5-methoxycarbonyl-
4- (3-nitrophenyl) -1,4-dihydropyridin-3-ylcarbonyl, 2,6-dimethyl-5-nitro-4
-(2-trifluorophenyl-1,4-dihydropyridin-3-ylcarbonyl and the like.], Pyridinium carbonyl (nitrogen of pyridine ring is substituted with, for example, C _1-4 alkyl (eg, methyl, ethyl), benzyl) Examples thereof include C _1-4 alkylpyridinium-3-carbonyl (eg, methylpyridinium-3-carbonyl, ethylpyridinium-3-carbonyl, propylpyridinium-3-carbonyl), benzylpyridinium-3-carbonyl and the like. .) And so on.

Examples of the acyl carbamate include carbamoyl, mono- or di-substituted carbamoyl, and examples of the mono- or di-substituted carbamoyl include monocarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl and the like. Or J
C _1-4 alkylcarbamoyl, arylcarbamoyl, 3-
Examples include mono- or di-C _3-6 alkenyl or alkynyl carbamoyl such as butenyl carbamoyl, 4-pentenyl carbamoyl and diaryl carbamoyl, aromatic carbamoyl such as phenyl carbamoyl, naphthyl carbamoyl and diphenyl carbamoyl.

Examples of the acyl sulfonate include an inorganic sulfonyl group such as sodium sulfonyl, methylsulfonyl,
C _1-6 alkylsulfonyl such as ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc., C _2-6 alkenyl or alkynylsulfonyl such as allylsulfonyl, 2-methyl-2-propenesulfonyl, phenylsulfonyl, p-methylphenylsulfonyl, naphthalene Examples thereof include aromatic sulfonyls such as sulfonyl.

Examples of the substituted oxycarboxylic acid acyl include halogen (eg, chlorine, bromine, iodine), cyano, benzyloxy, phenoxy, di C _1-3 alkylamino (eg, dimethylamino, diethylamino, dipropylamino), C
_1-4 alkyloxy (eg, methyloxy, ethyloxy, butyloxy, t-butyloxy), C _1-3 alkylthio (eg, methylthio, ethylthio, propylthio), 4-
(3-Nitrophenyl) -2,6-dimethyl-3-methoxycarbonyl-1,4-dihydropyridin-5-ylcarbonylamino or C _1-6 alkyloxycarbonyl (methyl which may be substituted with dihydropyridylcarbonylamino) Oxycarbonyl, ethyloxycarbonyl, n
-Propyloxycarbonyl, i-propyloxycarbonyl, n-butyloxycarbonyl, sec-butyloxycarbonyl, tert-butyloxycarbonyl, n-hexyloxycarbonyl, 2-fluoroethyloxycarbonyl, 2
- chloroethyl oxycarbonyl, 2,2,2-trichloroethyl oxycarbonyl, and 3-methyl-1,4-dihydropyridin-1-yl-carbonyl amino methyloxy carbonyl), cyclopentyloxycarbonyl, C, such as cyclohexyloxycarbonyl _{3- 8} Cycloalkyloxycarbonyl (which may be substituted with halogen such as chlorine, bromine or iodine), cycloalkyl-alkyloxycarbonyl such as cyclopentylmethyloxycarbonyl, allyloxycarbonyl, crotyloxycarbonyl, 2-pentene C _2-7 alkenyl such as -1-oxycarbonyl or alkyloxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl,
Examples thereof include aromatic or araliphatic oxycarbonyl such as phenethyloxycarbonyl (eg, halogen such as chlorine, bromine and iodine, which may be substituted with nitro), quinuclidinyl and the like.

In the compound represented by the above formula (I), R ₁ is hydrogen, a C _1-6 alkyl group such as methyl, ethyl or propyl, a C _1-4 alkyloxycarbonyl such as methyloxycarbonyl or ethyloxycarbonyl, or benzyloxy. C6-C8 araliphatic oxycarbonyl such as carbonyl is preferable, and hydrogen, C _1-4 alkyl group and halogenated C _1-4 alkyloxycarbonyl group are particularly preferable. Y is preferably oxygen, and in that case, R ₂ is a hydrocarbon residue which may have a substituent, particularly methyl, ethyl, propyl, isopropyl,
C _1-6 alkyl such as butyl and alkyl halide such as chloromethyl are preferred. X ₁ and X ₂ are preferably oxygen. It is preferred that R ₃ is hydrogen. m is 0,
n is preferably 0.

When m is 1 in the general formula (I), R ₁ is preferably H or a hydrocarbon residue which may have a substituent.

When the compound (I) of the present invention is basic, it may form an acid addition salt, particularly a physiologically acceptable acid addition salt. Examples of such salts include inorganic acids (eg, Hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid) or organic acids (eg, acetic acid, propionic acid, fumaric acid, maleic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfone) Acid).

In the general formula (I), a compound in which m is 0 is represented by the formula (I
I) [Wherein X ₁ , X ₂ , n and R ₃ have the same meanings as described above, ▲ R ^′ ₁ ▼ has the same meaning as R ₁ above, or R ₁ is a functional group (hydroxyl group, carboxyl group or amino group) In the case of having a functional group protected by a protecting group, Z represents a leaving group. [III] NH ₂ —Y— ▲ R ^′ ₂ ▼ (III) [wherein Y is as defined above, ▲ R ^′ ₂ ▼ is as defined above R ₂ or R 3 _{When 2} has a functional group (hydroxyl group, carboxyl group or amino group), the functional group protected by a protecting group is shown. ] The product obtained by condensation with cyclization is cyclized and, if necessary, ▲ R ^′ ₁ ▼, ▲
R _^'2 ▼ itself or ▲ ^R' ₁ ▼, can be prepared by elimination of the protecting groups contained in ▲ R _^'2 ▼.

Examples of the leaving group represented by Z in the compound (II) include hydroxy, C _1-4 alkyloxy (eg, methyloxy, ethyloxy, propyloxy, butyloxy), halogen (eg, fluorine, chlorine, bromine, iodine). ), N-hydroxydiacyl imide esters (eg, N
-Hydroxysuccinimide ester, N-hydroxyphthalic acid imide ester, N-hydroxy-5-norbornene-2,3-dicarboximide ester), N-hydroxybenzotriazole ester, paranitrophenyl ester, phenyl ester, etc. Can be mentioned.

In the compounds represented by the formulas (II) and (III), when ▲ R ^' ₁ ▼ and ▲ R ^' ₂ ▼ have a functional group, the protecting group may be any commonly used protecting group known per se. Any of these may be used as the amino-protecting group such as a tert-butyloxycarbonyl group and a benzyloxycarbonyl group, and as the carboxyl-protecting group such as a benzyl, methyl, ethyl and tert-butyl ester. Examples of the protecting group include benzyl group, p-methoxybenzyl group, trityl group, acetyl group and the like.

A solvent is not always necessary in this condensation or cyclization reaction, but when used, it is usually a hydrocarbon solvent (eg,
Pentane, hexane, benzene, toluene), halogenated hydrocarbon solvents (eg, dichloromethane, chloroform,
Dichloroethane, carbon tetrachloride), ether solvents (eg,
It is preferable to use an organic solvent such as ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane), an amide solvent (eg, dimethylformamide, hexamethylphosphonotriamide), dimethyl sulfoxide, or the like. The compounding ratio is 1 mole of compound (II) to compound (III)
Is preferably 1 to 3 mol. The reaction is from -10 ℃
It can be performed at 200 ° C.

Further, a compound in which Z in formula (II) is hydroxy is converted into an acid anhydride by a method known per se, and then reacted with a compound represented by formula (III), and the obtained product is cyclized by a method known per se. It can also be manufactured.

As a method known per se for introducing the compound (II) in which Z is hydroxy into an acid anhydride, there is a method of directly heating, and as a dehydrating agent, phosphoryl chloride, an acid anhydride of a lower fatty acid (eg, acetic anhydride, trihydric anhydride). Fluoroacetic acid), haloformic acid ester (eg, chloroformic acid ethyl ester), imidazole derivative (eg, N, N′-carbodiimidazole, N-
Trifluoroacetyl imidazole, N-chloroacetyl imidazole), dicyclohexylcarbodiimide and the like can be used.

As an example, a method known per se for cyclizing a product obtained by reacting an acid anhydride of a compound (II) in which Z is hydroxy with a compound represented by the formula (III) may be used. Examples of the method include heating directly or in a solvent in the presence of a catalyst (eg, hydrogen chloride, hydrogen bromide, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid). The solvent used in these reactions may be any commonly used solvent, for example, chloroform, dichloroethane, benzene, toluene, acetonitrile,
Inert solvents such as dioxane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide are preferred. In addition, acid anhydrides of lower fatty acids (eg, acetic anhydride, trifluoroacetic anhydride) are also used, and in this case, if necessary, alkali metal salts of lower fatty acids (eg, sodium acetate, potassium acetate, sodium trifluoroacetate). Performed in the presence. The reaction is mainly carried out at 40 ° C to 200 ° C, but heating is not always necessary.

In the general formula (I), a compound in which m is 0 is represented by the formula (I
a) _{^{Wherein, ▲ R '2 ▼, R}} 3, X 1, X 2, Y and n are the same meaning as defined] a compound represented by, for example, formula _{^{(IV) ▲ R' 1 ▼}} -Z (IV) [ In the formula, ??? R ^' ₁ ▼, Z has the same meaning as described above, and the compound can also be produced by reacting with a compound represented by the above formula and removing the protecting group if necessary.

The solvent in this reaction may be any solvent commonly used in chemical reactions, for example, in an inert solvent such as water, chloroform, dichloroethane, benzene, toluene, acetonitrile, dioxane, tetrahydrofuran, dimethylformamide, for example, -10 ° C. ~ 12
It can be performed at 0 ° C. The use ratio of the raw material is preferably 1 to 3 mol of the compound (V) per 1 mol of the compound (Ia). Further, this reaction is carried out, if necessary, with organic bases such as pyridine, 4-dimethylaminopyridine, triethylamine, diisopropylamine, triethyleneamine and terramethylethylenediamine, and sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate. , Sodium hydroxide, potassium hydroxide, and other inorganic bases, sodium hydride, potassium hydride, n-butyllithium, and the like. The amount of the base used is preferably 1- to 3-fold the molar amount of the compound (Ia).

Further, the compound in which m is 0 in the general formula (I) is the compound (Ia) and the compound of the formula (V) ▲ R ^' ₁ ▼ -N = C = O (V) [wherein, ▲ R ^' ₁ ▼ is Is synonymous with. The compound can also be produced by subjecting it to a reaction with a compound represented by This reaction is usually carried out in the presence of a solvent, and as the solvent, halogenated aliphatic hydrocarbons (eg dichloromethane, chloroform), aromatic hydrocarbons (eg benzene, toluene, xylene), ethers (eg , Diethyl ether, dioxane, tetrahydrofuran), dimethylformamide and the like. The reaction temperature is usually room temperature to 60 ° C. The starting material compound is preferably used in an amount of 1 to 3 mol of the compound (V) per 1 mol of the compound (Ia). In addition, this reaction can be performed, for example, with trimethylamine, triethylamine,
It is preferably carried out in the presence of an organic base such as dimethylaminopyridine. The amount of the base used is preferably 1 to 3 times the molar amount of the compound (Ia).

In the general formula (I), a compound in which m is 0 is, for example, a compound represented by the formula: [In the formula, ▲ R ^' ₁ ▼, R ₃ , X ₁ , X ₂ , and n have the same meanings as described above, and R ₅ represents hydrogen or hydroxy. ] The compound represented by the formula: for example, ∑R ^′ ₂ ▼ -Z ′ (VI) [wherein, ∑R ^′ ₂ ▼ has the same meaning, and Z ′ represents halogen (eg, chlorine, bromine, iodine). ] The compound can also be produced by subjecting it to a reaction with a compound represented by the formula [1] and removing the protecting group if necessary. As the solvent used in this reaction, solvents such as alcohols (methanol, ethanol), halogenated hydrocarbons (dichloromethane, chloroform), ethers (tetrahydrofuran, dioxane), dimethylformamide, acetonitrile and the like can also be used. This reaction is optionally carried out, for example, with sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide,
It is carried out in the presence of sodium hydride, potassium hydroxide, n-butyllithium, etc., and the reaction temperature is usually -10 ° to 150 ° C.
° C. The use ratio of the raw material compound is preferably 1 to 3 mol of the compound (VI) per 1 mol of the compound (Ib).

In the general formula (I), the compound (I) in which m is 0 is represented by the formula [In the formula, ▲ R ^' ₁ ▼, R ₃ and n have the same meanings as defined above], for example, a compound represented by the formula (VII) ▲ R ^' ₂ ▼ -SZ '(VII) It can also be produced by subjecting a compound represented by the formula ^" _2, Z'has the same meaning as defined above" to the reaction and, if necessary, removing the protecting group. This reaction can be carried out in the same manner as the reaction between compound (Ib) and compound (VI).

General formula [Wherein R ₂ , X ₁ , X ₂ Y, and n have the same meanings as defined above, and ▲ R ^″ ₁ ▼ represents an optionally substituted lower alkyl of R ₁ defined above]. For example, the compound (I e) [In the formula, ▲ R ^″ ₁ ▼, R ₂ , R ₃ , X ₁ , X ₂ Y, n have the same meanings as above]
The compound represented by can be produced by a method known per se for producing an N-oxide. Examples of the oxidizer mentioned here include hydrogen peroxide, organic peroxides (eg, peracetic acid, metachloroperbenzoic acid) and the like. The use ratio of the oxidizing agent is preferably 1 to 3 times mol of the compound (I e). The reaction temperature is -10 to 60 ° C.

The compound of the general formula (II) (Z = hydroxy or lower (C _1-4 ) alkoxy) as a starting material is Helv.Chim.Act.
a., 49 , 1135 (1966), Arch.Pharm., 294 , 210 (1961), JA
m.Chem.Coc., 71, 384 (1950 ) or Belgian Patent 609,76
It is produced according to the method described in 6, or is produced by hydrolyzing it with an acid or an alkali. Hydrolysis can be carried out by a method known per se, for example, alkali metal hydroxide (eg, sodium hydroxide, lithium hydroxide, potassium hydroxide), alkali metal carbonate compound (eg, potassium carbonate,
Sodium carbonate, lithium carbonate) or mineral acids (eg,
It can be easily obtained by hydrolysis with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, iodic acid). Or the general formula (I
The compound of I) ▲ R _^'1 ▼ to, in a manner known per se, converted into the hydrogen, the resulting compound formula (VIII) [Wherein X ₁ , X ₂ , and n have the same meanings as described above, Z ″ represents hydroxy or (C _1-4 ) alkoxy] and compound (IV) or compound (V), by a method known per se. The compound (VIII) can be produced by subjecting the compound (VIII) to the general formula (II):
A method by catalytic hydrogen reduction in the case where R ^′ ₁ ▼ is a benzyl group and an oxidizing water decomposition in the case where R ^′ ₁ ▼ is an acyl group are effective. For the reaction of the compound (VIII) with the compound (VI) or the compound (V), any commonly used solvent may be used, such as water, chloroform, dichloroethane,
In an inert solvent such as benzene, toluene, acetonitrile, dioxane, tetrahydrofuran, or dimethylformamide, if necessary, for example, an organic base such as pyridine, 4-dimethylaminohyridine, triethylamine, diisopropylamine, triethylenediamine, or tetramethylethylenediamine, , For example, in the presence of an inorganic base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, n-butyllithium and the like.

With regard to the compound (II), a compound in which Z is a halogen, that is, an acid halide is a compound in which Z is hydroxy, that is, a carboxylic acid, can be prepared by a method known per se, for example, a halide agent (eg, phosphorus oxychloride, phosphorus oxybromide). , Phosphorus pentachloride, phosphorus pentabromide, phosphorus trichloride, phosphorus tribromide, thionyl chloride, thionyl bromide, sulfuryl chloride, oxalyl chloride, cyanuric chloride, boron tribromide, hydrogen iodide) Can be manufactured by.

The solvent used for halogenation may be any commonly used solvent, and is preferably an inert solvent such as chloroform, dichloromethane, dichloroethane, benzene, toluene.

With regard to the compound (II), Z is an N-hydroxydiacylimide ester, N-hydroxybenzotriazole ester, para-nitrophenol ester or phenol ester, and a compound in which Z is hydroxy, that is, a carboxylic acid can be prepared by a method known per se, for example, a carboxylic acid. Acid, N-
It can be produced in the presence of hydroxydiacylimide, N-hydroxybenzotriazole, para-nitrophenol or phenol using dicyclohexylcarbodiimide as a condensing agent.

The solvent for the above reaction may be any commonly used solvent, for example, chloroform, dichloromethane,
Inert solvents such as dichloroethane, benzene, toluene, N, N-dimethylformamide, tetrahydrofuran and dioxane are preferred.

The compound (I) of the present invention acts on the central nervous system of mammals, has a strong specific binding ability to muscarinic acetylcholine receptors, and has an anti-amnestic effect against various amnesic-inducing effects in mice. .

The compound (I) of the present invention has a very good separation between the action on the central nerves and the action on the peripheral nerves as compared with the above-mentioned known azaspiro derivatives and drugs currently marketed as acetylcholine antagonists, and anti-amnestic effects in mice. At doses that show effects (0.03 mg to 10 mg / body), there are no or very slight peripheral nerve effects such as convulsive effects, salivation effects, and diarrhea, and oral administration shows marked effects, so mammals including humans It is useful as a drug for improving brain function.

Examples of useful target disease names of the compound of the present invention include senile dementia, Alzheimer's disease, Huntington's ataxia, hyperkinesia, and mania, which can be used for prevention or treatment of these diseases.

The compound of the present invention can be orally or parenterally administered to mammals including human in various dosage forms such as tablets, granules, capsules, injections and suppositories. The dose varies depending on the type and symptom of the target disease, but in general, in adults, 0.1m per day for oral administration
It is from g to 500 mg, preferably from 1 mg to 50 mg.

Hereinafter, the present invention will be described more specifically with reference to Examples, Formulation Examples and Experimental Examples.

Example 1 2-Methoxy-8-methyl-2,8-diazaspiro [4,5]
Decane-1,3-dione hydrochloride (1-methyl-4-carboethoxypiperidine-4-
Yl) acetic acid ethyl ester 60g concentrated hydrochloric acid 400ml solution,
After stirring at 100 ° C for 24 hours, the solvent was distilled off under reduced pressure, and the residue was dried. 0.47 g of the obtained (1-methyl-4-carboxypiperidin-4-yl) acetic acid hydrochloride was dissolved in 10 ml of dimethylformamide, 0.45 g of dicyclohexylcarbodiimide was added to the solution, and the mixture was stirred at room temperature for 1 hour,
0.17 g of O-methylhydroxylamine hydrochloride and 0.28 ml of triethylamine were added, and the mixture was stirred at room temperature for 30 minutes. The precipitate was removed, the solvent was distilled off under reduced pressure, 8 ml of acetic anhydride and 420 mg of anhydrous sodium acetate were added to the remaining oily compound, and the mixture was heated to 100 ° C.
For 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, 30 ml of acetonitrile was added to the residue to remove insoluble matter, and then acetonitrile was removed under reduced pressure. 1N hydrochloric acid was added to the obtained residue.
3 ml and 20 ml of water were added and the insoluble material was filtered off. Recrystallization of the remaining solid from ethanol-acetic acid ethyl ester gave a melting point of 259
0.35 g of colorless crystals at ℃ was obtained.

Calculated elemental analysis _{C 10 H 17 ClN 2 O 3} : C 48.29 H 6.89 N 11.26 Found: C 48.18 H 6.90 N 10.97 Example 2 3-Methoxy-9-methyl-3,9-diazaspiro [5,5 ]
Undecane-2,4-dione / hydrochloride 1-methyl-4,4-dicarboxymethylpiperidine
A solution of 30 g of ethyl ester in 200 ml of concentrated hydrochloric acid was stirred at 100 ° C. for 24 hours, the solvent was distilled off under reduced pressure, and the residue was dried. Using the obtained 1-methyl-4,4-dicarboxymethylpiperidine hydrochloride (0.50 g), in the same manner as in Example 1,
0.23 g of colorless crystals having a melting point of 275-284 ° C. were obtained.

Elemental analysis value Calculated as C ₁₁ H ₁₉ ClN ₂ O ₃ : C 50.29 H 7.29 N 10.66 Experimental value: C 50.35 H 7.17 N 10.57 Example 3 8-benzyl-2-methoxy-2,8-diazaspiro [4,
5] Decane-1,3-dione hydrochloride (1-benzyl-4-carbethoxy-piperidine-
A solution of 60 g of 4-yl) acetic acid ethyl ester in 400 ml of concentrated hydrochloric acid was stirred at 100 ° C. for 24 hours, then the solvent was distilled off under reduced pressure and dried. Example 1 using the obtained (1-benzyl-4-carboxy-piperidin-4-yl) acetic acid hydrochloride (0.94 g)
Following the same procedure as for 0.28 g of colorless crystals with a melting point of 227-229 ° C.
I got

Calculated elemental analysis _{C 16 H 21 ClN 2 O 3} : C 59.17 H 6.52 N 8.62 Found: C 59.21 H 6.62 N 8.50 compounds shown in Table 1 in the same manner as in Example 4 Examples 1, 2, 3 was gotten.

Example 5 2-Hydroxy-8-methyl-2,8-diazaspiro [4,
5] decane-1,3-dione hydrochloride Example 4 Table 1 Compound No. 1 (2-benzyloxy-8-methyl-2,8-diazaspiro [4,5] decane-
6.4 g of 1,3-dione hydrochloride was added to methanol-water (1: 1, v /
v) It was dissolved in 50 ml and subjected to catalytic hydrogen reduction in the presence of a palladium catalyst for about 1 hour. The obtained solid was recrystallized from ethanol to give 4.3 kg of colorless crystals having a melting point of 284-286 ° C.

Calculated elemental analysis _{C 9 H 15 ClN 2 O 3} : C 46.06 H 6.44 N 11.94 Found: C 46.13 H 6.65 N 12.11 Example 6 2-ethyloxy-8-methyl-2,8-diazaspiro [4,5 ] Decane-1,3-dione-hydrochloride 2-hydroxy-8-methyl-2, obtained in Example 5
8-diazaspiro [4,5] decane-1,3-dione ・ hydrochloride
1.05 g was suspended in 45 ml of dimethylformamide. Oily 60% sodium hydride (0.36 g) was added thereto, and the mixture was stirred at room temperature for 1 hour, ethyl iodide (0.36 ml) was added, and the mixture was further stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, ethanol (20 ml) and 3.2N hydrogen chloride in dioxane (2 ml) were added to remove insolubles, and the solvent was removed under reduced pressure. The remaining solid was recrystallized from ethanol-ethyl acetate to obtain 0.6 g of colorless crystals having a melting point of 222-225 ° C.

Elemental analysis value Calculated value as C ₁₁ H ₁₉ ClN ₂ O ₃ : C 50.29 H 7.29 N 10.66 Experimental value: C 50.25 H 7.25 N 10.76 Example 7 The compounds shown in Table 2 were obtained in the same manner as in Example 6. .

Example 8 8-Benzyloxycarbonyl-2-methoxy-2,8-
Diazaspiro [4,5] decane-1,3-dione (1) (1-benzyl-4-carboxypiperidine-
4.56 g of 4-yl) acetic acid / hydrochloride was dissolved in 20 ml of water and subjected to catalytic hydrogen reduction for 8 hours at 80 ° C. under atmospheric pressure using palladium as a solvent. After the reaction was completed, the catalyst was removed, and sodium hydrogen carbonate was
3.6 g and benzyloxycarbonyl chloride 3 ml were added,
Stir overnight at room temperature. After the reaction, 40 ml of ethyl ether was added and stirred, the aqueous layer was adjusted to pH 3 with 1N hydrochloric acid, and the resulting oil was extracted with chloroform. The chloroform solution was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the remaining solid was recrystallized from ethyl ether to give colorless crystals having a melting point of 125-127 ° C. (1-benzyloxycarbonyl-4-carboxypiperidine-4- (Yl) acetic acid (3.8 g) was obtained.

Calculated elemental analysis _{C 16 H 19 NO 6: C} 59.81 H 5.96 N 4.36 Found: C 59.61 H 5.95 N 4.56 ( 2) (-4- 1- benzyloxycarbonyl-4-carboxy-yl) acetic acid 3.64g Dicyclohexylcarbodiimide in 30 ml of dimethylformamide
After adding 2.57 g and stirring at room temperature for 30 minutes, 0.95 g of O-methylhydroxylamine hydrochloride and 1.56 ml of triethylamine were added and stirred at room temperature for 30 minutes. The precipitate was removed and the solvent was removed under reduced pressure. 20 ml of acetic anhydride and 0.93 g of anhydrous sodium acetate were added to the remaining oily compound, and the mixture was stirred at 100 ° C. for 30 minutes. After the reaction was completed, the solvent was removed and the remaining oil was mixed with ethyl acetate 50
The mixture was dissolved in ml, washed successively with saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the remaining solid was recrystallized from ethyl ether-petroleum ether to give colorless crystals with a melting point of 98 ° C. 2.
1 g was obtained.

Elemental analysis value Calculated as C ₁₇ H ₂₀ N ₂ O ₅ : C 61.44 H 6.07 N 8.43 Experimental value: C 61.39 H 6.10 N 8.58 Example 9 2-methoxy-2,8-diazaspiro [4,5] decane-1 , 3
-Dione hydrochloride 8-benzyloxycarbonyl-obtained in Example 8-
2-Methoxy-2,8-diazaspiro [4,5] decane-1,3
-2.0 g of dione was dissolved in a mixed station of 30 ml of methanol and 10 ml of 1N hydrochloric acid, and catalytically reduced for 5 hours at room temperature and atmospheric pressure using palladium as a catalyst. After the reaction is completed, the catalyst is removed, the solvent is distilled off,
The remaining solid was recrystallized from ethanol-ethyl acetate to obtain 1.2 g of colorless crystals having a melting point of 265-273 ° C.

Elemental analysis value Calculated value as C ₉ H ₁₅ ClN ₂ O ₃ : C 46.06 H 6.44 N 11.94 Experimental value: C 45.91 H 6.46 N 12.03 This compound could also be synthesized by the following method.

3.24 g of 8-benzyl-2-methoxy-2,8-diazaspiro [4,5] decane-1,3-dione.hydrochloride obtained according to Example 3 was dissolved in 20 ml of water and used as a palladium catalyst at atmospheric pressure. Catalytic reduction was performed at 80 ° C for 5 hours. Thereafter, by the same operation as above, 2.1 g of a colorless crystal having a melting point of 265-273 ° C. was obtained.

Elemental analysis value Calculated as C ₉ H ₁₅ ClN ₂ O ₃ : C 46.06 H 6.44 N 11.94 Experimental value: C 46.12 H 6.51 N 11.78 Example 10 8- [3- (Ethyloxycarbonyl) propyl] -2
-Methoxy-2,8-diazaspiro [4,5] decane-1,3-
Dione hydrochloride salt 1.76 g of 2-methoxy-2,8-diazaspiro [4,5] decane-1,3-dione hydrochloride salt obtained in Example 9 was suspended in 50 ml of dimethylformamide. 0.66 g of oily 60% sodium hydrogen was added thereto, and the mixture was stirred at room temperature for 1 hour, and then 3-
Bromopropionic acid ethyl ester (1.07 ml) was added, and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, the precipitate was removed, the solvent was distilled off under reduced pressure, and silica gel column chromatography was performed as it was (developing solvent, chloroform: methanol: water = 14: 6: 1 (v / v)).
I went to After adding 3 ml of 3.2 N hydrogen chloride in dioxane to the solution containing the target substance, the solvent was distilled off, and the remaining solid was recrystallized from ethanol-acetic acid ethyl ester to give the melting point.
1.33 g of white crystals at 174 ° -176 ° C were obtained.

Elemental analysis value Calculated as C ₁₅ H ₂₅ ClN ₂ O ₅ : C 51.65 H 7.22 N 8.03 Experimental value: C 51.14 H 7.28 N 8.19 Example 11 The compounds shown in Table 3 were obtained in the same manner as in Example 10. .

Example 12 2-Methoxy-8-methylcarbamoyl-2,8-diazaspiro [4,5] decane-1,3-dione 2-methoxy-2,8-diazaspiro [4,5] decane-1,
To a solution of 3-dione / hydrochloride 1.5 g in 20 ml of water, 1 ml of triethylamine was added, and further 1 ml of methylisocyanate was added,
After stirring at room temperature for 30 minutes, water was distilled off under reduced pressure. It is directly subjected to silica gel column chromatography (developing solvent; chloroform-acetone-methanol = 10: 3: 2 (V / V)), and the solvent of the solution containing the target compound is distilled off under reduced pressure to give a colorless oily compound.
Obtained 1.4 g.

Calculated elemental analysis _{C 11 H 17 N 3 O 4} : C 51.76 H 6.71 N 16.46 Found: C 51.64 H 6.83 N 16.47 Example 13 8- tert-butyloxycarbonyl-2-methoxy-2,8
-Diazaspiro [4,5] decane-1,3-dione 2-methoxy-2,8-diazaspiro [4,5] decane-1,
To a solution of 1.5 g of 3-dione / hydrochloride in 100 ml of dimethylformamide, 1 ml of triethylamine was added, and further 2.05 ml of ditertiary butyl dicarbonate was added, followed by stirring at room temperature for 1 hour.
The solvent was distilled off under reduced pressure, and the remaining oil was diluted with dichloromethane 50
After adding ml, the mixture was washed with a 10% aqueous citric acid solution and then with water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the remaining solid was recrystallized with ethyl ether.
1.4 g of colorless crystals having a melting point of 117 ° were obtained.

Elemental analysis value Calculated as C ₁₄ H ₂₂ N ₂ O ₅ : C 56.36 H 7.43 N 9.39 Experimental value: C 56.57 H 7.39 N 9.55 Example 14 8-acetyl-2-methoxy-2,8-diazaspiro [4,
5] decane-1,3-dione 2-methoxy-2,8-diazaspiro [4,5] decane-1,
3-dione hydrochloride 2.35 g dimethylformamide 200 ml
2.8 ml of triethylamine was added to, and acetic acid chloride 0.8
ml was added, the mixture was stirred at room temperature for 30 minutes, and the solvent was evaporated under reduced pressure. 50 ml of dichloromethane was added to the remaining oily substance, and the mixture was washed with 1N hydrochloric acid and water in this order. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the remaining solid was recrystallized from ethanol-ethyl ether to obtain 1.2 g of colorless crystals having a melting point of 153-157 ° C.

Elemental analysis value Calculated as C ₁₁ H ₁₆ N ₂ O ₄ ; C 54.99 H 6.71 N 11.66 Experimental value; C 54,72 H 6.98 N 11.31 Example 15 The compounds shown in Table 4 were obtained in the same manner as in Example 14. Was given.

Example 16 8-Aminoacetyl-2-methoxy-2,8-diazaspiro [4,5] decane-1,3-dione hydrochloride (1) 2-Methoxy-2,8-diazaspiro [4,5] decane -1,3-dione hydrochloride 1.5 g dimethylformamide 1
Triethylamine (1 ml), tert-butylcarbonylglycine (1.23 g) and dicyclohexylcarbodiimide (1.44 g) were added to the 00 ml solution, and the mixture was stirred at 60 ° C. for 10 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the remaining oily substance was dissolved in 50 ml of dichloromethane, washed with 10% aqueous citric acid solution and water, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. I left. The remaining solid was recrystallized from ethyl acetate-ethyl ether to give colorless crystals with a melting point of 151 ° (8-
1.1 g of tert-butyloxycarbonylaminoacetyl-2-methoxy-2,8-diazaspiro [4,5] decane-1,3-dione) was obtained.

Elemental analysis value Calculated as C ₁₆ H ₂₅ N ₆ O ₃ ; C 54.07 H 7.09 N 11.82 Experimental value; C 54.19 H 7.21 N 11.79 (2) 8-tert-Butyloxycarbonylaminoacetyl-2-methoxy obtained above -2,8-diazaspiro [4,
5] To 1.0 g of decane-1,3-dione was added 5 ml of an ethanol solution of 6N hydrogen chloride, the mixture was allowed to stand at room temperature for 10 minutes, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-ethyl ether to give a melting point of 97. 0.8 g of colorless crystals at -102 ° C was obtained.

Elemental analysis value Calculated value as C ₁₁ H ₁₈ ClN ₃ O ₄ ; C 45.07 H 6.22 N 14.40 Experimental value; C 45.25 H 6.24 N 14.36 Example 17 8- (4-aminobutyryl) -2-methoxy-2,8-diazaspiro [4,5] decane-1,3-dione hydrochloride 2-methoxy-2,8-diazaspiro [4,5] decane-1,
To a solution of 1.5 g of 3-dione hydrochloride in 100 ml of dimethylformamide, 1 ml of triethylamine, 2.03 g of 4- (tert-butyloxycarbonylamino) butyric acid, 1.35 g of N-hydroxybenztriazole, and dicyclohexylcarbodiimide 2.
06 g were sequentially added, and the precipitate was removed after stirring at room temperature for 5 hours. The solvent was distilled off under reduced pressure, the remaining oily substance was dissolved in 50 ml of dichloromethane, and after washing with 10% aqueous citric acid solution and water,
After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the remaining oil was subjected to silica gel column chromatography (developing solvent, chloroform-acetone-methanol = 10: 3: 2).
Separated by (V / V). 20 ml of a 6N hydrogen chloride ethanol solvent was added to the obtained oily product, which was allowed to stand at room temperature for 10 minutes, and then the solvent was distilled off under reduced pressure. The obtained oily substance was separated by silica gel Garam chromatography (developing solvent, chloroform-methanol-water = 14: 6: 1) to obtain 1.2 g of an amorphous solid.

Elemental analysis value Calculated as C ₁₃ H ₂₂ ClN ₃ O ₄ ; C 48.83 H 6.93 N 13.14 Experimental value; C 48.91 H 6.82 N 13.13 Example 18 8-benzyloxycarbonyl-2-dimethylamino-
2,8-diazaspiro [4,5] decane-1,3-dione (1-benzyloxycarbonyl-4-carboxypiperidin-4-yl) acetic acid 1.28 g in dimethylformamide 10 ml solution, dicyclohexylcarbodiimide 0.82 g
In addition, after stirring at room temperature for 30 minutes, 0.61 ml of 1,1-dimethylhydrazine was added, and after stirring at room temperature for 30 minutes, the solvent was distilled off under reduced pressure. 10 ml of acetic anhydride and then 0.33 g of anhydrous sodium acetate were added to the remaining oily compound, and the mixture was stirred at 100 ° C. for 30 minutes, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate and washed with a saturated aqueous solution of sodium hydrocarbon, followed by water, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to leave an oily substance. This oily substance was separated by silica gel column chromatography (developing solvent, methanol-dichloromethane = 1: 19 (V / V)), and the solvent of the solution containing the target substance was distilled off to obtain 0.71 g of a colorless oily substance.

Elemental analysis value Calculated as C ₁₈ H ₂₃ N ₃ O ₄ ; C 62.59 H 6.71 N 12.17 Experimental value; C 62.32 H 6.82 N 12.06 Example 19 2-Dimethylamino-2,8-diazaspiro [4,5] decane- 1,3-dione.hydrochloride 8-benzyloxycarbonyl-2-obtained in Example 18
Dimethylamino-2,8-diazaspiro [4,5] decane-1,
Add 6N hydrochloric acid (20 ml) to 0.4 g of 3-dione, and add 3 at 100 ° C.
After stirring for an hour, the solvent was distilled off, and the remaining solid was recrystallized from ethanolic ethyl acetate to obtain 0.3 g of colorless crystals having a melting point of 257-260 ° C.

Elemental analysis C ₁₀ H ₁₈ ClN ₃ O ₂ Calculated; C 48.49 H 7.32 N 16.96 Found; C 48.50 H 7.53 N 16.66 Example 20 8-acetyl-2-methoxy-2,8-diazaspiro [4,
5] decane-1,3-dione 2-methoxy-2,8-diazaspiro [4,5] decane-1,
3-dione hydrochloride 2.35 g dimethylformamide 200 ml
To the above, 2.8 ml of triethylamine was added, and acetic anhydride 0.9
After adding 5 ml and stirring at room temperature for 12 hours, the solvent was distilled off under reduced pressure. 50 ml of dichloromethane was added to the remaining oily substance, and then 1
It was washed with normal hydrochloric acid and water in this order. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the remaining solid was recrystallized from ethanol-ethyl ether to give 1.1 g of the same compound as in Example 14 and colorless crystals having a melting point of 153-157 ° C. Obtained.

Elemental analysis value Calculated as C ₁₁ H ₁₆ N ₂ O ₄ ; C 54.99 H 6.71 N 11.66 Measured value; C 54.90 H 6.82 N 11.63 Example 21 2-methoxy-8-methyl-2,8-diazaspiro [4,5 ]
Decane-1,3-dione 8-oxide hydrochloride hydrochloride Synthesized according to Example 1. 2-Methoxy-8-methyl-2,8-diazaspiro [4,5] decane-1,3-dione
0.74 g of hydrochloride was suspended in 20 ml of chloroform. There 6
0.12 g of 0% oily sodium hydride was added, and the mixture was stirred at room temperature for 1 hour, then 1.86 g of chloromethaneperbenzoic acid and 40 m of chloroform were added.
The solution was added dropwise and further stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure, the remaining oily compound was separated by silica gel column chromatography (developing solvent, chloroform → methanol), the obtained oily compound was dissolved in 30 ml of methanol, and 2 ml of 2N hydrogen chloride in dioxane was added thereto. After
The solvent was evaporated under reduced pressure, leaving a solid. This was suspended in ethanol and collected by filtration to obtain 0.4 g of a colorless crystal having a melting point of 215 to 225 ° C (decomposition).

Calculated elemental analysis _{C 10 H 17 ClN 2 O 4} ; C 45.37 H 6.47 N 10.58 Found; C 45.10 H 6.55 N 10.36 Example 22 8- (2-bromoethoxy) -2-methoxy-2,8 -Diazaspiro [4,5] decane-1,3-dione 2-bromoethanol 0.81 ml and p-nitrophenyl chloroformate 2 g in ether 25 ml solution and pyridine 0.71 ml.
Was added dropwise under ice-cooling, the mixture was stirred overnight at room temperature, the precipitate was removed by filtration, the filtrate was washed successively with 1N hydrochloric acid and water, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.1 g of an oily substance.

1.9 g of 2-methoxy-2,8-diazaspiro [4,5] decane-1,3-dione.hydrochloride obtained in Example 9 was suspended in 16 ml of dimethylformamide. Sodium hydrogen there
0.43 g was added, and the mixture was stirred at 60 ° C for 30 minutes, then 2.1 g of the oil obtained above
Was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction, water 100m
l was added and stirred, and extracted with dichloromethane. After the dichloromethane solution was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the remaining oily substance was subjected to silica gel column chromatography (developing solvent, dichloromethane: ethyl acetate = 20: 1 (V /
V)). The solvent of the solution containing the target compound was distilled off under reduced pressure, and the remaining solid was recrystallized from ethyl ether to give a melting point of 134.
2.65 g of colorless crystals at ℃ were obtained. This compound was prepared in Example 15
Same as Table / Compound No. 5.

Elemental analysis value Calculated as C ₁₂ H ₁₇ BrN ₂ O ₄ ; C 41.28 H 4.91 N 8.02 Experimental value; C 41.51 H 4.95 N 7.98 Example 23 The compounds shown in Table 5 were obtained in the same manner as in Example 22. .

Example 24 2-Methoxy-8-nicotinoyl-2,8-diazaspiro [4,5] decane-1,3-dione 2-methoxy-2,8-diazaspiro [4,5] decane obtained in Example 9 A solution of 2.35 g of 1,3-dione hydrochloride and 1.8 g of nicotinoyl chloride hydrochloride in 20 ml of pyridine at 85 ° C.
After stirring for 1 hour at room temperature, it is cooled and saturated aqueous sodium hydrogen carbonate solution.
100 ml was added and extracted with dichloromethane. The dichloromethane solution was dried over anhydrous sodium sulfate, the solvent was distilled off, and the remaining solid was recrystallized from ethyl ether to give a melting point of 199-2.
2.35 g of colorless crystals at 01 ° C. were obtained.

Elemental analysis value Calculated as C ₁₅ H ₁₇ N ₃ O ₄ ; C 59.40 H 5.65 N 13.85 Experimental value; C 59.19 H 5.66 N 13.85 Example 25 2-methoxy-8- (1-methylpyridinium-3-carbonyl)- 2,8-diazaspiro [4,5] decane-1,3-
Dione iodide 2-methoxy-8-nicotinoyl-2,8-diazaspiro [4,5] decane-1,3-dione obtained in Example 24 0.75 g
2 ml of methyl iodide was added to 10 ml of methanol solution at 40 ℃.
It was stirred for 8 hours. The solvent was distilled off under reduced pressure, and the remaining solid was recrystallized from methanol to obtain 1 g of a yellow crystal having a melting point of 224-228 ° C.

Elemental analysis value Calculated as C ₁₆ H ₂₀ IN ₃ O ₄ ; C 43.16 H 4.53 N 9.44 Experimental value; C 42.99 H 4.52 N 9.54 Example 26 2-methoxy-8- (1-methyl-1,4-dihydropyridine- 3-Carbonyl) -2,8-diazaspiro [4,5] decane-1,3-dione 2-methoxy-8- (1-methylpyridinium-3-carbonyl) -2,8- obtained in Example 25 Diazaspiro [4,5] decane-1,3-dione iodide 0.89 g, sodium hydrosulfite 1.74 g and sodium carbonate 1.6
g of dichloromethane 30 ml-water 30 ml mixed solvent was added, and the mixture was vigorously stirred at room temperature for 20 minutes. After separating the dichloromethane layer, the aqueous layer was extracted with dichloromethane. The dichloromethane solutions were combined, washed with water, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.5 g of a yellow powder having a melting point of 46-62 ° C.

Elemental analysis value Calculated as C ₁₆ H ₂₁ N ₃ O ₄ ; C 60.18 H 6.63 N 13.16 Experimental value; C 59.92 H 6.54 N 12.99 Example 27 2-methoxy-8- (1-benzylpyridinium-3-carbonyl) -2,8-Diazaspiro [4,5] decane-1,3-
Dione bromide A yellow powder having a melting point of 130-149 ° C was obtained in the same manner as in Example 25.

Elemental analysis value Calculated as C ₂₂ H ₂₄ BrN ₃ O ₄ ; C 55.71 H 5.10 N 8.86 Experimental value; C 55.54 H 5.01 N 8.66 Example 28 2-methoxy-8- (1-benzyl-1,4-dihydropyridine- 3-Carbonyl) -2,8-diazaspiro [4,5]
Decane-1,3-dione 2-methoxy-8- (1-benzylpyridinium-3-carbonyl) -2,8-diazaspiro [4,5] decane-1,3-dione bromide obtained in Example 27 Example using
A yellow powder having a melting point of 27-73 ° C was obtained in the same manner as in 26.

Elemental analysis value Calculated as C ₂₂ H ₂₅ N ₃ O ₄ ; C 66.82 H 6.37 N 10.63 Experimental value; C 66.53 H 6.21 N 10.33 Example 29 3-carbamoyl-1- [2-[(1,3-dioxo- Two
-Methoxy-2,8-diazaspiro [4,5] decan-8-yl) carbonyl] ethyl] pyridinium bromide 2-Methoxy-2,8-diazaspiro [4,5] decane-1, obtained in Example 9 1.5 g of 3-dione hydrochloride was suspended in 30 ml of dimethylformamide. Sodium hydride (0.16 g) was added thereto, and the mixture was stirred at 55 ° C for 30 minutes, 3-bromopropionyl chloride (1.2 g) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction, 100 ml of water was added and extracted with dichloromethane. The dichloromethane solution was washed successively with 1N hydrochloric acid and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.92 g of a yellowish brown oily substance. A solution of 1.92 g of this oily substance and 0.7 g of nicotinamide in 10 ml of ethanol was heated under reflux for 12 hours. After the reaction, the solvent was distilled off under reduced pressure, and the remaining oily substance was diluted with water 50
ml and dichloromethane 50 ml were added, the aqueous layer was separated and washed with dichloromethane. Water was distilled off under reduced pressure, and the remaining solid was recrystallized from ethanol to obtain 1.4 g of colorless crystals having a melting point of 234-236 ° C.

Elemental analysis value Calculated as C ₁₈ H ₂₃ BrN ₄ O ₅ ; C 47.48 H 5.09 N 12.31 Experimental value; C 47.50 H 5.08 N 12.60 Example 30 3-carbamoyl-1- [2-[(1,3-dioxo- Two
-Methoxy-2,8-diazaspiro [4,5] decan-8-yl) carbonyl] ethyl] -1,4-dihydropyridine 3-carbamoyl-1- [2- obtained in Example 29
[(1,3-Dioxo-2-methoxy-2,8-diazaspiro [4,5] decan-8-yl) carbonyl] ethyl] pyridinium bromide was used in the same manner as in Example 26 to give the melting point.
A yellow powder at 64-80 ° C was obtained.

Calculated elemental analysis _{C 18 H 24 N 4 O 5} ; C 57.44 H 6.43 N 14.88 Found; C 57.24 H 6.28 N 14.59 Example 31 8- [1,4-dihydro-2,6-dimethyl-5- Methoxycarbonyl-4- (3-nitrophenyl) pyridine-3-
Carbonyl] -2-methoxy-2,8-diazaspiro [4,
5] decane-1,3-dione 0.21 g of 2-methoxy-2,8-diazaspiro [4,5] decane-1,3-dione.hydrochloride obtained in Example 9 and 1,4-sihydro-2 , 6-Dimethyl-5-methoxycarbonyl-4
-(3-Nitrophenyl) pyridine-3-carboxylic acid 0.
Dimethylformamide 7m of 3g and triethylamine 0.26ml
l To the solution, add 0.22 ml of diethyl cyanophosphate under ice cooling and
It was stirred for 0 minutes. After the reaction, 20 ml of water was added, the mixture was stirred at room temperature, and extracted with dichloromethane. The dichloromethane solution was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the oily substance left behind was subjected to silica gel column chromatography (developing solvent, ethyl acetate). The solvent of the solution containing the target substance was distilled off under reduced pressure, and the remaining solid was recrystallized from ethanol to give a melting point of 228-230.
0.31 g of yellow crystals at ℃ was obtained.

Elemental analysis value Calculated as C ₂₅ H ₂₈ N ₄ O ₈ ; C 58.59 H 5.51 N 10.93 Experimental value; C 58.54 H 5.53 N 10.93 Example 32 8- [1,4-dihydro-2,6-dimethyl-3- Nitro-4
-(2-Trifluoromethylphenyl) pyridine-5-
Carbonyl] -2-methoxy-2,8-diazaspiro [4,
5] decane-1,3-dione 1,4-dihydro-2,6-dimethyl-3-nitro-4-
Using (2-trifluoromethylphenyl) pyridine-5-carboxylic acid and in the same manner as in Example 31, melting point 261-263.
C. yellow crystals were obtained.

Elemental analysis value Calculated as C ₂₄ H ₂₅ F ₃ N ₄ O ₆ ; C 55.17 H 4.82 N 10.72 Experimental value; C 54.94 H 4.93 N 10.45 Example 33 1,4-dihydro-2,6-dimethyl-5- [ [2-[(1,3
-Dioxo-2-methoxy-2,8-diazaspiro [4,5]
Decan-8-yl) carbonyloxy] ethyl] aminocarbonyl] -2-methoxycarbonyl-4- (3-nitrophenylpyridine (1) 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4- (3-Nitrophenyl) pyridine-3
-Using 1 g of carboxylic acid and 0.2 g of 2-aminoethanol,
Analogous to Example 31, yellow powder with melting point 64-70 ° C, 1,4
0.85 g of -dihydro-2,6-dimethyl-5-[(2-hydroxyethyl) aminocarbonyl] -3-methoxycarbonyl-4- (3-nitrophenyl) pyridine was obtained.

Elemental analysis value Calculated as C ₁₈ H ₂₁ N ₃ O ₆ ; C 57.59 H 5.64 N 11.19 Experimental value; C 57.33 H 5.39 N 10.92 (2) 1,4-dihydro-2,6-dimethyl-5-[(2 −
Hydroxyethyl) aminocarbonyl] -3-methoxycarbonyl-4- (3-nitrophenyl) pyridine was used in the same manner as in Example 22 to obtain a yellow powder having a melting point of 107-113 ° C.

Elemental analysis value Calculated as C ₂₈ H ₃₃ N ₅ O ₁₀ ; C 56.09 H 5.55 N 11.68 Experimental value; C 55.97 H 5.41 N 11.44 Example 34 8-[(2-hydroxybenzoyl) aminomethyl]-
2-Methoxy-2,8-diazaspiro [4,5] decane-1,3
-Dione 2-methoxy-2,8-diazaspiro [4,5] decane-1,3-dione.hydrochloride 0.55 g, salicylamide 0.32 g, paraformaldehyde 0.11 g and triethylamine 2 ml ethanol obtained in Example 9. The 20 ml suspension was stirred at room temperature for 15 hours. After the reaction, the solvent was distilled off under reduced pressure and the remaining oil was subjected to silica gel column chromatography (developing solvent, ethyl acetate). The solvent of the solvent containing the target substance was distilled off under reduced pressure, and the remaining solid was recrystallized from ethyl ether to give a melting point of 96-99.
0.52 g of colorless crystals at 0 ° C. were obtained.

Elemental analysis value, calculated as C ₁₇ H ₂₁ N ₃ O ₅ ; C 58.78 H 6.09 N 12.10 experimental value; C 58.56 H 6.26 N 11.93 Example 35 8-[(3-pyridyl) carbonylaminomethyl] -2
-Methoxy-2,8-diazaspiro [4,5] decane-1,3-
Using dione nicotinamide, the melting point was the same as in Example 34.
A colorless powder at 112-119 ° C was obtained.

Elemental analysis value Calculated as C ₁₆ H ₂₀ N ₄ O ₄ ; C 57.82 H 6.07 N 16.86 Experimental value; C 57.59 H 6.08 N 16.61 Example 36 8-Methyl-2-methylamino-2,8-diazaspiro [4, 5] Decane-1,3-dione hydrochloride (1-methyl-4-carboxypiperidin-4-yl) acetic acid hydrochloride 1.9 g was dissolved in dimethylformamide 30 ml, and dicyclohexylcarbodiimide 1.82 was added to the solution.
Add g and stir for 1 hour, then add 0.43 ml of methylhydrazine and add 6
The mixture was stirred at 0 ° C for 24 hours. The precipitate was removed, the solvent was distilled off under reduced pressure, and the remaining oily compound was subjected to silica gel column chromatography (developing solvent, n-butanol: acetic acid: methanol: water = 1: 1: 1:
1 (V / V)). 1N hydrochloric acid in the solution containing the target substance
After adding 4 ml, the solvent was distilled off, and the remaining solid was recrystallized from ethanol to obtain 0.25 g of a colorless solid having a melting point of 235-260 ° C.

Elemental analysis value Calculated value for C ₁₀ H ₁₈ ClN ₃ O ₂ ; C 48.19 H 7.32 N 16.96 experimental value; C 47.95 H 7.47 N 16.83 Example 37 8-benzyl-2-benzyloxy-2,8-diazaspiro [4, 5] Decane-1,3-dione (1-benzyl-4-carboxypiperidin-4-yl) acetic acid hydrochloride (31.3 g) in dimethylformamide (200 ml) was mixed with dicyclohexylcarbodiimide (20.6 g) and stirred at room temperature for 1 hour. 16 g of amine hydrochloride and 14 ml of triethylamine were added, and the mixture was further stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. After adding 150 ml of acetic anhydride and 21 g of anhydrous sodium acetate to the mixture and stirring at 100 ° C for 1 hour,
The insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure. 200 ml of ethyl acetate was added thereto, and a saturated aqueous solution of sodium hydrogencarbonate was added until the aqueous layer became alkaline, the organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 100 ml of acetonitrile was added to the remaining oil, the insoluble matter was filtered off, the acetonitrile was distilled off, and the residue was recrystallized from acetonitrile-ethyl ether to give the melting point 146-152.
16.5 g of a colorless solid at 0 ° C was obtained.

Elemental analysis value Calculated as C ₂₂ H ₂₄ N ₂ O ₃ ; C 72.51 H 6.64 N 7.69 Experimental value; C 72.28 H 6.60 N 7.57 Example 38 2-Hydroxy-2,8-diazaspiro [4,5] decane-1 ,
3-dione hydrochloride 8-benzyl-2-benzyloxy-2,8-diazaspiro [4,5] decane-1,3-dione hydrochloride 16.0 g was dissolved in a mixed solvent of 100 ml of methanol and 50 ml of 1N hydrochloric acid. Using palladium as a catalyst, catalytic hydrogen reduction was carried out at 40 ° C for 12 hours at atmospheric pressure. After completion of the reaction, the catalyst was removed, the solvent was distilled off under reduced pressure, and the remaining solid was recrystallized from ethanol to obtain 8.9 g of a colorless solid having a melting point of 250-277 ° C.

Elemental analysis value Calculated as C ₈ H ₁₃ ClN ₂ O ₃ ; C 43.55 H 5.94 N 12.70 Experimental value; C 43.59 H 5.97 N 12.66 Example 39 8-tert-Butyloxycarbonyl-2-hydroxy-2,
8-diazaspiro [4,5] decane-1,3-dione 2-hydroxy-2,8-diazaspiro [4,5] decane-
1.35 g of 1,3-dione hydrochloride was dissolved in a mixed solvent of 50 ml of water and 50 ml of dioxane, and 14 ml of triethylamine and 2-
(Tertiary butyloxycarbonylthio) -4,6-dimethylpyrimidine (9.6 g) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the remaining oil was mixed with 100 ml of ethyl acetate.
It was dissolved in l and 100 ml of saturated aqueous sodium hydrogen carbonate solution was added. The aqueous layer is acidified with solid citric acid and extracted with 100 ml ethyl acetate. The organic layer was washed with 1N hydrochloric acid (50 ml) and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to leave an oil. This is diethyl ether-n-
Solidified from hexane and collected by filtration, melting point 151-1
There was obtained 9.6 g of a colorless solid at 54 ° C.

Elemental analysis value Calculated as C ₁₃ H ₂₀ N ₂ O ₅ ; C 54.92 H 7.09 N 9.85 Experimental value; C 54.90 H 7.17 N 9.67 Example 40 8-tert-Butyloxycarbonyl-2-cyanomethyloxy-2,8 -Diazaspiro [4,5] decane-1,3-dione 8-tert-butyloxycarbonyl-2-hydroxy-
88 mg of oily 60% sodium hydride was added to a solution of 2,6-diazaspiro [4,5] decane-1,3-dione 0.56 g in dimethylformamide 5 ml, and the mixture was stirred at room temperature for 1 hour. Chloroacetonitol (140 μm) was added thereto, the mixture was stirred at room temperature for 2 hours, ethyl acetate (30 ml) was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and 10% aqueous citric acid solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-diethyl ether to obtain 0.53 g of a colorless solid having a melting point of 138-139 ° C.

Elemental analysis value Calculated as C ₁₅ H ₂₁ N ₃ O ₅ ; C 55.72 H 6.55 N 13.00 Experimental value; C 55.60 H 6.56 N 12.98 Example 41 8-benzyloxycarbonyl-2-benzyloxycarbonyloxy-2,8- Diazaspiro [4,5] decane-1,
3-dione 2-hydroxy-2,8-diazaspiro [4,5] decane-
To a solution of 3.3 g of 1,3-dione / hydrochloride in 100 ml of water, 2.43 g of sodium hydrogen carbonate and 3.2 ml of benzyloxycarbonyl chloride.
Was added and stirred at room temperature for 3 hours, then ethyl acetate 100 ml
It was extracted with. After drying the organic layer over anhydrous magnesium sulfate,
The solvent was distilled off, and the remaining solid was recrystallized from diethyl ether-n-hexane to obtain 6.0 g of a colorless solid having a melting point of 114 ° C.

Elemental analysis value Calculated as C ₂₄ H ₂₄ N ₂ O ₇ ; C 63.71 H 5.35 N 6.19 Experimental value; C 63.72 H 5.37 N 6.21 Example 42 8-benzyloxycarbonyl-2-hydroxy-2,8
-Diazaspiro [4,5] decane-1,3-dione 8-benzyloxycarbonyl-2-benzyloxycarbonyloxy-2,8-diazaspiro [4,5] decane-
To a solution of 5.6 g of 1,3-dione in 50 ml of dichloromethane was added 1.9 ml of N, N-dimethyl-1,3-propanediamine, and the mixture was stirred overnight at room temperature, and then 50 ml of 1N hydrochloric acid was added. The organic layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the remaining solid was recrystallized from ethyl ether-n-hexane to give a melting point of 131.
3.8 g of a colorless solid at -132 ° C was obtained.

Elemental analysis value Calculated as C ₁₆ H ₁₈ N ₂ O ₅ ; C 60.37 H 5.70 N 8.80 Experimental value; C 60.42 H 5.79 N 8.65 Example 43 8-benzyloxycarbonyl-2-cyanomethyloxy-2,8-diazaspiro [4,5] decane-1,3-dione 8-benzyloxycarbonyl-2-hydroxy-2,
To a solution of 0.96 g of 8-diazaspiro [4,5] decane-1,3-dione in 5 ml of dimethylformamide was added 132 mg of oily 60% sodium hydride, and the mixture was stirred at room temperature for 1 hour. Chloroacetonitrile (210 μ) was added thereto, and the mixture was stirred at room temperature for 2 hours.
Thereafter, the same operation as in Example 40 gave 1.0 g of an amorphous solid.

Elemental analysis value Calculated as C ₁₈ H ₁₉ N ₃ O ₅ ; C 60.50 H 5.36 N 11.76 Experimental value; C 60.53 H 5.47 N 11.67 Example 44 2-Cyanomethyloxy-2,8-diazaspiro [4,5] decane -1,3-dione 8-benzyloxycarbonyl-2-cyanomethyloxy-2,8-diazaspiro [4,5] decane-1,3-dione
0.6 g was dissolved in a mixed solution of 10 ml of methanol and 10 ml of dimethylformamide and subjected to catalytic hydrogen reduction at room temperature and atmospheric pressure for 5 hours using palladium as a catalyst. After removing the catalyst and distilling off the solvent, the remaining solid was recrystallized from ethanol to obtain 0.38 g of a colorless solid having a melting point of 273-278 ° C.

Elemental analysis value Calculated as C ₁₀ H ₁₃ N ₃ O ₃ ; C 53.80 H 5.87 N 18.82 Experimental value; C 53.81 H 5.92 N 18.80 Example 45 8-tert-Butyloxycarbonyl-2- [2- (hydroxy) ethyloxy ] -2,8-Diazaspiro [4,5] decane-1,3-dione 8-tert-butyloxycarbonyl-2-hydroxy-
2,8-Diazaspiro [4,5] decane-1,3-dione 0.56g
Then, 210 μm of 2-bromoethanol was used to carry out the same operation as in Example 40 to obtain 0.40 g of a colorless solid having a melting point of 97-98 ° C.

Elemental analysis value Calculated as C ₁₅ H ₂₄ N ₂ O ₆ ; C 54.87 H 7.37 N 8.53 Experimental value; C 54.67 H 7.56 N 8.28 Example 46 2- [2- (hydroxy) ethyloxy] -2,8-diazaspiro [ 4,5] decane-1,3-dione hydrochloride 8-tert-butyloxycarbonyl-2- (2-hydroxy) ethyloxy-2,8-diazaspiro [4,5] decane-1,3-dione 0.72 g 2 ml of trifluoroacetic acid was added to and the mixture was allowed to stand at room temperature for 10 minutes. After adding 1 ml of ethanol solution to it, and further adding 1 ml of ethanol solution of 3.6 N hydrogen chloride,
The solvent was evaporated to dryness. Recrystallized from ethanol, melting point 11
0.57 g of a colorless solid having a temperature of 5-123 ° C. was obtained.

Elemental analysis value Calculated as C ₁₀ H ₁₇ ClN ₂ O ₄ ; C 45.37 H 6.47 N 10.58 Experimental value; C 45.67 H 6.21 N 10.41 Example 47 8-benzyloxycarbonyl-2-nitromethyloxy-2,8-diazaspiro [4,5] decane-1,3-dione 8-benzyloxycarbonyl-2-hydroxy-2,
Using 0.44 g of 8-diazaspiro [4,5] decane-1,3-dione and 140 μ of bromonitromethane, the same operation as in Example 40 was carried out to obtain 0.25 g of a colorless solid having a melting point of 137-139 ° C.

Elemental analysis value Calculated as C ₁₇ H ₁₉ N ₃ O ₇ ; C 54.11 H 5.08 N 11.13 Experimental value; C 54.24 H 5.13 N 11.22 Example 48 8-tert-Butyloxycarbonyl-2-methoxycarbonylmethyloxy-2, 8-Diazaspiro [4,5] decane-
1,3-dione 8-tert-butyloxycarbonyl-2-hydroxy-
An oily compound was obtained by the same procedure as in Example 40 using 0.56 g of 2,8-diazaspiro [4,5] decane-1,3-dione and 190 μm of methyl bromoacetate. This was separated by column chromatography (developing solvent dichloromethane) to obtain 0.67 g of a colorless oily compound.

Elemental analysis value Calculated as C ₁₆ H ₂₄ N ₂ O ₇ ; C 53.93 H 6.79 N 7.86 Experimental value; C 53.73 H 6.89 N 7.82 Example 49 2-Methoxycarbonylmethyloxy-2,8-diazaspiro [4,5] Decane-1,3-dione hydrochloride 8-tert-butyloxycarbonyl-2-methoxycarbonylmethyloxy-2,8-diazaspiro [4,5] decane-1,3-dione 0.5 g in trifluoroacetic acid 3 ml It was thawed and left at room temperature for 10 minutes. To this, 20 ml of methanol was added, 2 ml of a methanol solution of 1N hydrochloric acid was added, the solvent was distilled off under reduced pressure, and the remaining oil was crystallized from ether-methanol and collected by filtration to give 0.32 g of a colorless solid having a melting point of 174-178 ° C.
I got

Elemental analysis value Calculated as C ₁₁ H ₁₇ ClN ₂ O ₅ ; C 44.98 H 5.83 N 9.54 Experimental value; C 44.91 H 5.75 N 9.49 Example 50 8-benzyloxycarbonyl-2-methoxy-2,8-
Diazaspiro [4,5] decan-3-thion-1-one 8-benzyloxycarbonyl-2-obtained in Example 8
Methoxy-2,8-diazaspiro [4,5] decane-1,3-dione 2,9 g was added to a solution of Lawesson's reagent ([2,4-
2.38 g of bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide]),
After heating under reflux for 3 hours, the solvent was distilled off under reduced pressure, the remaining oil was dissolved in 50 ml of ethyl acetate and washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the remaining oil was subjected to silica gel column chromatography (developing solvent, methanol:
Dichloromethane = 1: 50 (V / V)) was applied to separate the pre- and post-effluent fractions. The solvent of the after-running fraction is distilled off,
The remaining solid was recrystallized from ethyl ether to give a melting point of 89-
2.1 g of a pale yellow solid at 90 ° C was obtained.

Elemental analysis value Calculated as C ₁₇ H ₂₀ N ₂ O ₄ S; C 58.60 H 5.79 N 8.04 Experimental value; C 58.48 H 5.84 N 7.97 Example 51 8-benzyloxycarbonyl-2-methoxy-2,8-
Diazaspiro [4,5] decane-1,3-dithione The pre-running fraction in the column chromatography of Example 50 was collected, the solvent was distilled off and the obtained crude crystals were recrystallized from ethyl ether to give a melting point of 127 ° C. 0.5 g of a yellow solid was obtained.

Elemental analysis value Calculated as C ₁₇ H ₂₀ N ₂ O ₃ S ₂ ; C 56.02 H 5.53 N 7.68 Experimental value; C 55.76 H 5.53 N 7.61 Example 52 2-Methoxy-2,8-diazaspiro [4,5] decane -3-
Thione-1-one hydrobromide 8-benzyloxycarbonyl-2 obtained from Example 50
0.5 g of -methoxy-2,8-diazaspiro [4,5] decan-3-thion-1-one was dissolved in 5 ml of a 25% solution of hydrogen bromide in acetic acid and left at room temperature for 20 minutes. There ethyl ether 10
0 ml was added, and the produced precipitate was collected by filtration and recrystallized from ethanol to obtain 0.4 g of a pale yellow solid having a melting point of 235-237 ° C.

Elemental analysis value Calculated as C ₉ H ₁₅ BrN ₂ O ₂ S; C 35.53 H 5.30 N 9.21 Experimental value; C 35.81 H 5.14 N 9.18 Example 53 2-Methoxy-2,8-diazaspiro [4,5] decane- 1,3
-Dithione hydrobromide 8-benzyloxycarbonyl-2 obtained from Example 51
-Methoxy-2,8-diazaspiro [4,5] decane-1,3-
Using 0.36 g of dithione and in the same manner as in Example 52, 0.3 g of a yellow solid having a melting point of 204 ° C. was obtained.

Elemental analysis value Calculated as C ₉ H ₁₅ BrN ₂ OS ₂ ; C 34.73 H 4.86 N 9.00 Experimental value; C 34.87 H 4.83 N 8.95 Formulation example 1 (1) 2-methoxy-2,8-diazaspiro [4,5] Decane-1,3-dione / hydrochloride 10g (2) Lactose 198g (3) Corn starch 50g (4) Magnesium stearate 2g (1), (2) and 20g corn starch were mixed, and from 15g corn starch Granulate with the paste made, add 15 g of corn starch and (4) and compress the mixture with a compression tablet machine to make 2000 tablets of 3 mm diameter containing (1) 5 mg per tablet. .

Formulation Example 2 (1) 2-methoxy-8-methyl-2,8-diazaspiro [4,5] decane-1,3-dione 20 g (2) Lactose 198 g (3) Corn starch 40 g (4) Magnesium stearate 2 g (1), (2) and 15 g of corn starch are mixed and granulated with a paste made from 15 g of corn starch, to which 10 g of corn starch and (4) are added, and the mixture is compressed with a compression tablet machine. , 2000 tablets with a diameter of 5 mm containing 10 mg (1) per tablet were produced.

[Experimental example]

1. Nootropic action The effect on carbon dioxide-induced amnesia The nootropic action of the compound (I) of the present invention was examined by a passive avoidance test. That is, a 5-week-old male mouse is first placed in a light room of a passive avoidance learning device consisting of 5 light and dark rooms. The mouse quickly moves to a dark room due to its habit. When moved, mice are given 0.5 milliamps of current from the darkroom floor for 3 seconds under unavoidable conditions. For several weeks, the mouse remembers the electric shock. The formation of this memory was impaired by the following types of manipulations, and the effect of the compound (I) of the present invention on this memory disorder was examined. That is, immediately after receiving an electric shock, the mouse was placed in the glass container 4 filled with carbon dioxide, and when the breathing was stopped, the mouse was taken out to recover the natural respiration by artificial respiration. This operation causes the mouse to forget that it received an electric shock.

Therefore, the next day, this memory recovery test was conducted. That is, the mouse was re-entered into the bright room of the passive avoidance learning device, and the time required to move to the dark room was measured. The mouse, who had forgotten that it had received an electric shock, moved to the dark room again in 10 to 20 seconds. On the other hand, the mice to which the compound (I) of the present invention was administered recovered the memory and did not try to move to the dark room, or even if they did, it took a long time to move. Therefore, as for the action of the test compound, the average value of the time during which the mice stayed in the bright room at the time of this test (8 mice per group) was used as a control group (a group to which only a 5% gum arabic suspension containing no test compound was administered). ). The results were expressed as a percentage change rate when the average value in the control group was 100 (Table 6). The test compound was a 5% gum arabic suspension and was orally (po) administered 30 minutes before the test.

2. General symptom (side effect) Using 4 mice per group, the mice were placed in a stainless steel observation cage of 13 × 18 × 25 cm, and the test compound was administered after acclimatization for about 1 hour. The symptoms (side effects) of the mice after administration of each compound were observed and recorded over time from 2 to 4 hours after administration. Diarrhea, salivation, and mydriasis as peripheral autonomic symptoms observed during administration of cholinergic drugs, and tremor, hypothermia, and sedation as effects on the central nervous system were observed, and the frequency and severity of symptoms were observed. Was used as an index.

The water-soluble compound was dissolved in physiological saline, and the insoluble compound was 100 mg / kg as a 5% gum arabic suspension intraperitoneally (i.
p.) was administered.

 The results are shown in Table 7. The scores are as follows.

: Remarkable: Medium +: Mild-: Not recognized 3. LD ₅₀ value and therapeutic index using mouse Using 10 mice per group, the dose (mg / kg, oral administration) (LD ₅₀ ) of the test drug required for the death of half was determined. The therapeutic index is LD ₅₀ / antiamnestic effect (minimum effective dose: ME
D) determined from. The results are shown in Table 8.

EFFECTS OF THE INVENTION The azaspiro compound (I) of the present invention and a salt thereof exhibit a strong nootropic action in a passive avoidance test in mice, and the action is stronger than known compounds such as RS-86. In particular, it is a safe nootropic drug with less general symptoms (side effects), less toxicity, and an extremely large therapeutic index compared to known compounds such as RS-86.

Examples of useful target disease names of the azaspiro compound (I) and salts thereof of the present invention include senile dementia (Alzheimer's dementia), cerebrovascular dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Creutzfeldt-Jakob's disease, Examples include Parkinson's disease and dementia based on cerebellar spinal degeneration, which can be used for prevention or treatment of these diseases.

Claims (3)

(57) [Claims] 1. A formula [In the formula, R ₁ and R ₂ are each hydrogen, a hydrocarbon residue which may have a substituent or an acyl group, and R ₃ is hydrogen or a hydrocarbon residue which may have a substituent. X ₁ and X ₂ are each an oxygen atom or a sulfur atom, Y is oxygen,
Sulfur or formula -N (R ₄₎ - (wherein, R ₄ is hydrogen or a lower alkyl group) a group represented by, m is 0 or 1, n
Represents 0 or 1. ] The azaspiro compound represented by these, or its salt. 2. A formula [Wherein X ₁ and X ₂ are each an oxygen atom or a sulfur atom, n is 0 or 1, R ₃ is hydrogen or a hydrocarbon residue which may have a substituent, ▲ R ^′ ₁ ▼ Is hydrogen, a hydrocarbon residue which may have a substituent (when the substituent is a functional group, the functional group is protected by a protecting group) or an acyl group, and Z is a leaving group. . A compound represented by the formula: NH ₂ —Y— ▲ R ^′ ₂ ▼ [wherein Y is oxygen, sulfur or the formula —N (R ₄ ) — (wherein R ₄ is hydrogen or a lower alkyl group). The group
▲ R _^'2 ▼ denotes hydrogen, (if the substituent is a functional group, that functional group is protected by a protecting group) and has optionally may hydrocarbon residue substituent or an acyl group. ] The product obtained by condensation with [] is cyclized and, if necessary, ▲ R ^′ ₁ ▼, ▲ R ^′ ₂ ▼ itself or ▲ R ^′ ₁ ▼, ▲
A formula characterized by elimination of a protecting group contained in R ^′ ₂ ▼ [In the formula, R ₁ and R ₂ each represent hydrogen, a hydrocarbon residue which may have a substituent or an acyl group, and other signals have the same meanings as described above. ] The manufacturing method of the azaspiro compound represented by these, or its salt. 3. A formula [In the formula, R ₁ and R ₂ are each hydrogen, a hydrocarbon residue which may have a substituent or an acyl group, and R ₃ is hydrogen or a hydrocarbon residue which may have a substituent. X ₁ and X ₂ are each an oxygen atom or a sulfur atom, Y is oxygen,
Sulfur or formula -N (R ₄₎ - (wherein, R ₄ is hydrogen or a lower alkyl group) a group represented by, m is 0 or 1, n
Represents 0 or 1. ] A brain function improving agent containing an azaspiro compound represented by the formula or a pharmaceutically acceptable salt thereof.