HUT72610A - Process for producing cyclic amide derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

The compounds of the present invention are represented by the general formula (I). Wherein R1 is a substituted or unsubstituted group derived from a cyclic amif, n is 0-10, an integer, Z is (ex) or (b) wherein R2 is an optionally substituted aryl or heterocyclic group, m is 0-2, integer, q is 02, the number R 3 is hydrogen or lower alkyl, R 4 is heterocyclic, p is 1-6, integer, provided that the cyclic amide is quinazolinone or quinazoline dione, then R2 and R4 are other than aryl or substituted aryl. The compounds can be used to prevent and cure diseases caused by deficiencies in central choline functions.

Description

m is 0-2, integer,

S \ -A, q is 02, integer

R ³ is hydrogen or lower alkyl,

R ⁴ represents a heterocyclic group, p is 1-6, integers, with the proviso that when the cyclic amide quinazolinone or quinazoline-dion, R ² and R ⁴ are other than aryl or substituted aryl group.

The compounds are useful in the prophylaxis and treatment of diseases resulting from deficiencies of central choline function.

Bzr / ₃ 5 _x

MY PUBLISHING EXAMPLE ''

Representative:

DANUBIA PATENT AND TRADEMARK OFFICE

1995 AUG 16th

CYCLIC PROCEDURE FOR DERIVATIVES AND THEIR CONSTITUENTS

MEDICINAL PRODUCTS © - _ '. ©

EISAI Co., Ltd., Tunkyo-ku, Tokyo, Japan

inventors:

SUGIMOTO Hachiro, Ushiku-shi, Ibaraki, Japan YONAGA Masahiro, Tsukuba-shi, Ibaraki, Japanese KARIBE Norio, Kitasouma-gun, Ibaraki, Japan

IIMURA Youichi, Tsukuba-shi, Ibaraki, Japan

NAGATO Satoshi, Tsukuba-shi, Ibaraki, Japan

SASAKI Atsushi, Tsukuba-shi, Ibaraki, Japan

YAMANISHI Yoshiharu, Ryugasaki-shi, Ibaraki, Japan OGURA Hiroo, Bethesda, Midland, United States KOSASA Takashi, Tsukuba-shi, Ibaraki, Japan UCHIKOSHI Kumi, Tsuchiura-shi, Ibaraki, Japan YAMATSU Kiyomi, Kamakura , Japan

Date of filing: 08/8/1995

Priority: 06/15/1990 (157,134/90) Japan

82377-4962-GI ····

The present invention relates to novel cyclic amine derivatives and to pharmaceutical compositions containing them.

The growing population of the elderly urgently requires the development of medication for the treatment of old-fashioned mental illnesses such as Alzheimer's disease.

There have been attempts to cure old-fashioned mental illness, but no effective drug has yet been developed.

Various studies are ongoing to find a therapeutic agent for these diseases. In particular, research on acetylcholine precursors and acetylcholinesterase inhibitors is proposed, as Alzheimer's disease is associated with cerebral cholinergic hypofunction and is currently being investigated. Typical anticholinergic esterase inhibitors include physostigmine and tetrahydroaminoacridine. However, they have the disadvantage that their effects are not sufficient and have unpleasant side effects. Thus, there are currently no suitable therapeutic agents.

Long-term, intensive experiments have been conducted with various compounds to develop a drug that provides a very safe and long-lasting effect.

It has now been found that the object of the invention is achieved by the compounds of formula (I).

In particular, it has been found that compounds of formula I have potentially highly selective antiacetylcholinesterase activity, increase acetylcholine levels in the brain, and are effective in memory impairment.

- In 3 treatment models, they last longer and are safer than the physostigmine commonly used in this field. The compounds of the invention are thus very valuable.

The compounds of the present invention have been found to be inhibitors of acetylcholinesterase and are effective in the treatment and prevention of various diseases resulting from deficiencies of central choline function, i.e., the absence of acetylcholine as an in vivo neurotransmitter.

Typically, such diseases are mental illnesses such as Alzheimer's senile mental illness. Also included are Huntington's Chorea, Pick's Disease and Late Movement Disorder.

The invention therefore relates to the preparation of novel amine derivatives and their pharmacologically acceptable salts which are useful as medicaments, in particular for the treatment and prevention of diseases of the central nervous system. The invention further relates to a process for the preparation of pharmaceutical compositions containing these novel amine derivatives.

The cyclic amine derivatives of the present invention are represented by formula (I). In the formula

R ¹ is (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (1) , (m), (n), (o), (p), (q) or (r),

U is hydrogen, halogen, lower alkyl, lower alkoxy or nitro, * ·. ·· ···

...... ··; · · ,, · is 1, n is 0-10, integer,

Z is a group of formula (ex) or (B) wherein

R ² is phenyl, naphthyl, mono- or dihalophenyl, 1,3-dioxolan-2-yl or pyridyl, m is an integer from 0 to 2, q is an integer from 0 to 2,

R ³ is hydrogen or lower alkyl,

R ⁴ is furyl or thienyl, p is 0-2, integer, provided that when the cyclic amide is quinazolinone or quinazolinedione, R ² and R ⁴ are not aryl or substituted.

When Z is a group of formula (<<), R ² is preferably phenyl, pyridyl or 1,3-dioxan-2-yl, n is 1 or 2, m is 1 or 2 and R 1 is group derived from one of the cyclic amides:

- 1,2,3,4-tetrahydroquinazoline-2,4-dione,

- 1,2,3,4-tetrahydroquinazolin-2-one,

- 1,2,3,4-tetrahydropyrido [3,2-d] pyrimidine-2,4-dione,

- 1,2,3,4-tetrahydropteridine-2,4-dione,

- 1,2,3,4-tetrahydropyrido [3,2-d] pyrimidin-2-one.

Preferably, R is substituted by ^one lower alkyl or lower alkoxy.

When Z is a group of the formula B, R ³ is preferably lower alkyl.

The most preferred of the compounds of formula I is the following:

- 3- {2- [1- (1,3-dioxolan-2-ylmethyl) -4-piperidyl] ethyl} -

5-methoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione.

The present invention also relates to the preparation of a pharmaceutical composition comprising a compound of formula (I) containing a pharmacologically effective amount of the active ingredient in a pharmacologically acceptable carrier. These pharmaceutical compositions are useful in the treatment and prevention of diseases resulting from deficiencies of central choline function.

Examples of compounds of formula (I) include the piperidine derivatives of formula (I ^1), wherein ^R1 is as defined above,

X is ~ (CH 2) n ',

R ² 'is - (CH2) iti ^-A - wherein m is 0-2, is an integer, A is the same as R ² report.

Examples of monovalent groups derived from cyclic amide derivatives in the definition of compounds of Formula I include, but are not limited to, 1,2,3,4-tetrahydroquinazolin-2-one, 1,2,3,4-tetrahydroquinazoline-2,4 -dione, 4-benzylpyrrolidin-2-one, 4-benzylpyrrolidin-2,4-dione, 1,2,3,4-tetrahydropteridin-2-one, 1,2,3,4 -tetrahydropteridine-2,4-dione, 1,2,3,4-tetrahydropyrido [3,2-d] pyrimidin-2-one, 1,2,3,4-tetrahydropyrido [3,2-d] pyrimidine -2,4-dione, 8H-4,5,6,7-tetrahydroazepino [2,3-b] thiophen-7-one,

10-methyl-1H-2,3,4,5-tetrahydroazepino [2,3-b] indol-2-one, 1-methylene-3-oxoisoindoline, 7-methylene-pyrrolidino [3,4- b] pi · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · - - Razin-5-on-, 4Η-1,3-dimethylpyrazolo [5,4-c] [ 2] benzazepine-9-η, 7-hydroxy-7-methylpyrrolidino [3,4-b] pyrazin-5-one, 2Η-3,4-dihydropyrido [2,3-e] -m-oxazine-2 -one, 2Η-3,4-dihydro [2,3-e] -m-oxazine-2-thione, 5Η-6,7,8,9-tetrahydro [3,2-b] azepine-6- οπ-, 9Η-5,6,7,8-tetrahydro [2,3-b] azepin-8-one and

2-benzoxazolinone group. Cyclic amides are understood to mean monocyclic or fused heterocyclic compounds. Preferred fused heterocyclic compounds are benzene, thiophene, indole, pyrazine or pyrazole fused heterocyclic compounds. The benzene ring may be substituted with one or two halogen atoms, preferably fluorine, chlorine or bromine, one to three lower C 1-6 lower alkoxy groups, preferably methoxy, lower C 1-6 alkyl groups or nitro groups.

In the above definitions, lower alkyl means straight or branched C 1 -C 6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, (amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl -, 2-methyl-pentyl, 3-methyl-pentyl, 1,1-dimethyl-butyl, 1,2-dimethyl-butyl, 2,2-dimethyl-butyl, 1,3-dimethyl-butyl- , 2,3-dimethyl-butyl, 3,3-dimethyl-butyl, 1-ethyl-butyl, 2-ethyl-butyl, 1,1,2-trimethyl-propyl, 1,2,2-trimethyl- propyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Of these, methyl, ethyl, propyl and isopropyl are preferred, with methyl and ethyl being particularly preferred.

The term "lower alkoxy" refers to C 1-6 alkoxy groups derived from the above lower alkyl groups. The most preferred alkoxy groups are methoxy, ethoxy and n-propoxy.

In the formula (I), when Z is a group of the formula (CX), n is 0-3, preferably 1 or 2, in particular

2. When Z is a group of formula (β), n is

3-7, preferably 4-6, particularly preferably 5.

Of the groups represented by the formula (a) to (s) as substituents R ^1, groups (a), (b), (c), (d), (g), (h) and (i) are preferred, especially preferred groups (a), (b) and (d).

The R ² substituent may be pyridyl, such as 2-pyridyl, 3-pyridyl or 4-pyridyl, phenyl, mono- or dihalophenyl or 1,3-dioxolan-2-yl. Of these, pyridyl and 1,3-dioxolan-2-yl are particularly preferred.

m and p are preferably 1 or 2, particularly preferably 2.

Particularly important compounds of formula I are those wherein R ¹ is a group of formula (a), (b) or (d), n is 1 or 2, Z is a group of formula (β), R ² is phenyl, pyridyl or 1,3-dioxolan-2-yl, m is 1 or 2, and the benzene ring in (a), (b) and (d) may be optionally substituted with methoxy.

Compounds of formula (I) may be prepared by analogous methods known in the art. These methods are briefly described below.

The production process

When R ^{1 in} formula (I) is derived from tetrahydroquinazolinedione, aza-tetrahydrobenzazepinone, benzylpiperidininone or benzoylpiperidinone, the compounds may be prepared as shown in Scheme A. In the formulas, n is 1-6, R ² is as defined above, Hal is halogen.

That is, 9-aza-1-benzazepin-2-one of formula (II) is conventionally condensed with a compound of formula (III) in the presence of, for example, sodium hydride, in a solvent such as dimethylformamide to give the product of formula (IV).

When R ^{1 is} different from the group derived from 9-aza-1-benzazepin-2-one, the 9-aza-1-benzazepin-2-one is replaced by tetrahydroquinazolinedione, benzylpiperidinone or benzoylpiperidinone and condensed in (III). to give the desired compound.

Production Process B

When R ^{1 in} formula (I) is derived from tetrahydroquinazolinedione, the compounds can be prepared as shown in Scheme B. In the formulas, U, 1, n and R ² are as defined above.

That is, a diester of formula (V) is reacted, with or without heating, with a piperidine derivative of formula (VI) to give the desired quinazoline derivative of formula (VII), with or without heating.

Preparation C

When R ^{1 in the} formula (I) is derived from tetrahydroquinazolinedione, tetrahydropteridinedione or tetrahydropyridinopyrimidinedione, the compounds may be prepared as shown in Scheme C. In the formulas, U, 1, n and R ² are as defined above.

That is, the N-acyl derivative of a compound of formula VIII is condensed in a solvent such as tetrahydrofuran with an amine of formula VI and the condensate is further reacted with 1,1-carbonyldiimidazole to give the desired compound of formula X.

Production Method D

When R ^{1 in} formula (I) is derived from substituted or unsubstituted tetrahydroquinazolinone or tetrahydropteridine, the compounds may be prepared as shown in Scheme G. In the formulas, U, 1, n and R ² are as defined above.

That is, an aminobenzaldehyde derivative (XXI) and an amine (VI) are condensed in a solvent such as methanol and the condensate is reduced with sodium borohydride to give a compound (XXII) in a solvent such as tetrahydrofuran Reaction with 1,1-carbonyldiimidazole gives the desired compound of formula XXIII.

This production process

If, in formula (I), RI is for you · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ··· · w *

- a group derived from 10 tertiary or unsubstituted tetrahydrobenzoxazin-2-one or 2-benzoxazolinone, the compounds can also be prepared as shown in Scheme J. In the formulas, U, 1, n and R ² are as defined above and R ³ is a protecting group such as benzyl, methoxymethyl or methoxyethoxymethyl.

That is, an amine of formula (XXVII) is condensed with a carboxylic acid of formula (XXVIII) to give the amide dehydrogenase of formula (XXIV), which is deprotected to afford a compound of formula (XXX) which is lithium aluminum hydride in a solvent such as tetrahydrofuran reduction to give the amine XXXI which can be reacted with 1,1-carbonyldiimidazole in a solvent, tetrahydrofuran or acetonitrile to give the desired compound XXXII.

The compounds of the formula I according to the invention and their acid addition salts are useful in the treatment of various mental disorders of the elderly, in particular Alzheimer's disease.

The following pharmacological tests were carried out to test the utility of the compounds of formula I according to the invention and their acid addition salts.

Experimental Example 1

In vitro acetylcholinesterase inhibitory activity

The esterase activity was determined by the method of Ellman et al., Ellman, G.L., Courtney, K.D., Andres, V., and Featherston, R.

M. Biochem. Pharmacol. 7, 88-95 (1961)] using a mouse brain homogenate as the source of acetylcholinesterase. Acetylthiocoline, the sample and DTNB were added to the mouse brain homogenate as substrate, and the mixture was incubated. To determine acetylcholine ester activity, the yellow product formed by reaction of thiocholine produced with DTNB was determined by the change in absorbance at 412 nm.

The acetylcholinesterase inhibitor activity of the sample was expressed as 50% inhibitor concentration (IC50).

The results are summarized in Table 1.

Table 1

Compound (formula number) AChE inhibitory activity IC ₅₀ (nmol) Compound (formula number) AChE inhibitory activity IC50 (nmol) 9 8.38 60 5.6x10 ⁴ 10 31.8 61 0.79 11 99.6 62 10.4 12 1.82 64 9.11 13 20.3 65 3.4x10 ⁴ 14 23.8 66 288.1 20 69.1 68 219.6 23 3.92 71 137.3 27 45.5 74 27.7 75 20.8

From the above pharmacological experimental data it can be seen that the piperidine derivatives of the present invention have excellent acetylcholinesterase inhibitory activity.

The structure of the cyclic amide derivatives according to the invention is completely different from the known acetylcholinesterase inhibitors, has excellent acetylcholine esterase inhibitory activity, the difference between the desired effect and the opposite effect is long, the compounds are quite long they are stable and have a high water solubility, which is advantageous for formulation, are well utilized in vivo, are essentially inactive and have a high rate of migration into the brain.

The invention thus also relates to pharmaceutical compositions containing as active ingredient a compound of formula (I) or a pharmacologically acceptable salt thereof, which are useful in the treatment of various mental disorders and cerebral vascular disorders.

The compounds of the present invention are useful in the treatment of senile dementia, in particular of Alzheimer's disease, stroke, atherosclerosis and extrinsic headaches, inattention, speech disorder, impaired will, emotional disturbances, inability to cure, palsy, , or to improve. They are advantageously used in the treatment of Alzheimer's disease, Huntington's chorea, Pick's disease and late motion disorder.

The compounds of the invention may be administered orally or parenterally for the treatment of said diseases. It is usually administered parenterally, for example by intravenous, subcutaneous or intramuscular injection, or it can be administered as a suppository or sublingual tablet. The dose of the compounds is not limited as it depends on the symptoms, the age, sex, weight and sensitivity of the subject being treated.

- 13 ges, the mode of treatment, the duration and frequency of administration, the nature, composition and form of the composition administered and the properties of the active ingredient. The daily dose is usually from 0.1 to 300 mg, preferably from 1 to 100 mg, one to four times daily.

The pharmaceutical compositions of the present invention may be formulated for injection, suppository, sublingual tablet, tablet or capsule by conventional means.

The injection may also optionally be treated with a pH adjusting agent, a buffer, a suspending agent, a solubilizer, a stabilizer, an isotonizing agent, and a preservative, and may be prepared by intravenous, subcutaneous or intramuscular injection. If desired, it can be freeze-dried by the usual method.

Suitable suspending agents include methylcellulose, Polysorbate 80, hydroxyethylcellulose, acacia, tragacanth powder, sodium carboxymethylcellulose and polyoxyethylene sorbitan monolaurate.

Suitable solubilizers are polyoxyethylene-hardened castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol and ethyl esters of castor oil fatty acids.

Sodium sulfite, sodium metasulfite and ethers may be used as stabilizers. Suitable preservatives include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol and chlorcresol.

The invention is illustrated by the following examples, which are not intended to be limiting.

Example 1

5- [2- (1-Benzyl-4-piperidinyl) -ethyl-5H-6,7,8,9-tetrahydro-pyridyl] -3,2-blazepin-6-one dihydrochloride (8). compound

Sodium hydride (0.73 g) was washed with n-hexane and suspended in 1 ml of Ν, Ν-dimethylformamide (DMF). The suspension was stirred under ice-cooling and a solution of 0.989 g of 5H-6,7,8,9-tetrahydropyrid [3,2-o] azepin-6-one in 15 ml of DMF was added dropwise. The mixture was stirred at 60 C for twenty minutes ^this was added piperidine hydrochloride 2.51 g of l-benzyl-4- (2-chloroethyl) under ice-cooling. The mixture was stirred for two and a half hours while maintaining the temperature at 60 ° C. The solvent was evaporated and water was added. The mixture is extracted with methylene chloride, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent is evaporated. The resulting oily product was purified by silica gel column chromatography. The product was converted to the hydrochloride salt by conventional means to give the title product as a colorless amorphous material (2.09 g).

Melting point: amorphous Formula: 023 ^ 9 ^ 0 ^ 01

NMR (CDCl ₃ ) δ:

1.21 - 2, 04 (9H, m), 2.26 (4H, bs), 2.82 (4H, bd) 3.44 (2H, s), 3.81 (2H, bt), 7.08 - 7.45 (7H, m), 8.30 (1H, dd, J = 1.3Hz, 4.6Hz)

MS: M ^{@ +} = 363 (DI-EI).

Example 2

3- [2- (1-Benzyl-4-piperidyl) ethyl] -2H-3,4-dihydro-6-methylpyrido [2,3-a] m-oxazine-2-thione hydrochloride / Compound (9)

Excess Schiff's base obtained by refluxing 0.50 g of 3-hydroxy-6-methyl-2-pyridine carboxaldehyde and 1.00 g of 1-benzyl- [4- (2-aminoethyl)] piperidine in methanol an amount of sodium borohydride was added. After stirring at room temperature for 30 minutes, the reaction mixture was poured into 0.2N aqueous sodium hydroxide solution. Etil-a • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ·

Extract with a mixture of 16 acetate and diethyl ether, wash with saturated sodium chloride solution, dry over anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, and dissolve the residue in 30 mL of acetonitrile. To the solution was added 2.00 g of 1,1'-thiocarbonyldiimidazole and reacted at 70 ° C for thirty minutes. The liquid reaction mixture was poured into 0.2 N aqueous sodium hydroxide solution. Extract with ethyl acetate / diethyl ether, wash with saturated sodium chloride solution, dry over anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride: methanol = 97: 3, v / v). The resulting blue oil was converted to the hydrochloride salt and treated with Norit SX-3 to give 0.40 g (26%) of the title product as light yellow crystals.

138-139 ° C (dec.) Formula: C22H27N3OS · HCl

NMR (CDCl ₃ ) δ:

1.16 ~ 2.10 (9H, m), 2.49 (3H, s), 2.64-2.97 (2H, m), 3.47 (2H, s), 3.96 (2H, t), 4.49 (2H,

s), 6.95 ~ 7.40 (7H, m)

MS: (M + 1 *) = 382

Example 3

3-42- [4- (1-Benzyl) -piperidyl-ethyl} -piperazinor [2,3-d] -pyrimidine-2,4-dione fumarate (10) g of 3-aminopyrazine-2-carboxylic acid and 6 7 g of 1,1'-carbonyldiimidazole are suspended in 200 ml of acetonitrile and refluxed for six hours. The green• ·

- 17 inert materials were filtered off and the residue was cooled to room temperature. The acylimidazole derivative (3.5 g) was obtained as yellow needle crystals by filtration.

1.5 g of the acylimidazole compound and 1.4 g of 2- [4- (1-benzyl) piperidyl] ethylamine are dissolved in 15 ml of tetrahydrofuran and the solution is stirred at room temperature overnight. The tetrahydrofuran was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: methylene chloride: methanol = 9: 1) to obtain 1.9 g of the amide derivative.

1.9 g of the amide derivative and 2.2 g of 1,1'-carbodiimidazole are dissolved in a mixture of 50 ml of acetonitrile and 50 ml of tetrahydrofuran and the solution is refluxed for twenty-six hours. The solvent was evaporated under reduced pressure and water was added to the residue. Extract with methylene chloride, dry over anhydrous magnesium sulfate, and purify by silica gel column chromatography (eluent: methylene chloride: methanol = 10: 1) to obtain 1.5 g of the amide derivative. The product is converted to the fumarate by conventional means to give a powder product.

Melting point: 223-226 ° C

Formula: C20H23N5O2 Ό4Η4Ο4

NMR (CDCl 3) δ:

1.08 ~ 2.20 (9H, m), 2.76-3.08 (2H, m), 3.52 (2 H, s), 3, 80 ~ 4.24 (2 H, m), 6.32 (1H, br s), 6.92 - 7.32 (5H, m), 8.52 (2 H, s)

366

MS: (M + 1 *)

Example 4

1- (2- (4-yl-Benzyl) -piperidyl 1-ethyl-D-2H-hydroxy-v-methyl-piperazinor [2,3-c] pyrrolidin-2-one (11)

A mixture of 4.8 g of 2,3-pyrazine dicarboxylic anhydride, 7 g of 2- [4- (1-benzyl) piperidyl] ethylamine and 70 ml of toluene is refluxed for 2 hours. The reaction mixture was cooled to room temperature and the resulting 10 g of N- {2- [4- (1-benzyl) piperidyl] ethyl} -2-pyrazinecarboxamide-3-carboxylic acid was filtered off.

The resulting amidocarboxylic acid derivative (1.76 g) was heated in acetic anhydride (25 ml) at 70 ° C for 30 minutes. The volatile components were evaporated under reduced pressure and the residue azeotroped with toluene and used without purification.

The crude product obtained is dissolved in 20 ml of tetrahydrofuran and 2 ml of a 3M solution of methyl magnesium bromide in ether are added dropwise over 2 minutes at room temperature. After stirring at room temperature for thirty minutes, aqueous ammonium chloride solution was added. Extract with methylene chloride, dry over anhydrous magnesium sulfate, and purify by silica gel column chromatography (eluent: methylene chloride: methanol = 9: 1) to obtain 0.15 g of the desired product.

Melting point: amorphous

C21H26N4O2

NMR (CDCl ₃ ) δ:

1.00 - 2.24 (12H, m), 2.72 - 3.20 (2H, m), 3.40 -

3.72 (4H, m), 7.16 - 7.40 (5H, m), 8.52 - 8.68 (2H, dd) • · · · · · ··· · · · • * ·· ·· · «· · ··

- 19 MS: (M + 1 ⁺ ) = 367

Example 5

1- [2- [4- (1-Benzyl) piperidyl] ethyl] -7-methylene-piperazino [2,3-c] pyrrolidin-2-one fumarate (12)

Dissolve 0.1 g of 1- (2- [4- (1-benzyl) -piperidyl] ethyl) -7-hydroxy-7-methylpiperazino [2,3-c] pyrrolidin-2-one in 3 ml of acetic anhydride, and the solution was refluxed for three and a half hours, the volatiles were evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: methylene chloride: methanol = 9: 1) to give 0.06 g of product, m.p. which is converted to the fumarate by a conventional method.

Melting point: amorphous

C211H24N4O * 0411404

NMR (CDCl ₃ ) δ:

1.04 - 2.20 (9H, m), 2.68 - 3.04 (2H, m), 3.48 (2H, s), 3.76 - 4.04 (2H, t), 5.04 - 5.12 (1H, d), 5.72-5.80 (1H, d), 7.12 - 7.40 (5H, m), 8.64 ~ 8.80 (2H, dd)

MS: (M + ^1F ) = 349

Example 6

1- [2- (4- (1-Benzyl) piperidyl] ethyl] -4-benzoylpyrrolidin-2-one hydrochloride

Step 1: 1- [2- (4- (1-Benzyl) -piperidyl-ethyl) -pyrrolidin-2-one-4-carboxylic acid (13a) g Itaconic acid and 20 g of 4- (2-amino-ethyl) ) -1-Benzylpiperidine is heated at 150-160 ° C for two and a quarter hours., · · · · · · · · · · · · · · · · · · · · · · · · The reaction mixture is extracted with water and the aqueous phase is washed with ro-ethylene chloride, distilled under reduced pressure and azeotroped with toluene to give 27 g of crude carboxylic acid.

Step 2: 1- <2- [4- (1-Benzyl) -piperidyl-ethyl] -benzoyl-pyrrolidin-2-one hydrochloride / Compound 13

4.3 g of the crude carboxylic acid obtained in Step 1 are dissolved in 80 ml of methylene chloride and 5 ml of thionyl chloride are added dropwise over 5 minutes at room temperature. The mixture was stirred for an additional 10 minutes at room temperature and then the volatiles were evaporated under reduced pressure.

The residue was dissolved in methylene chloride (79 mL) and benzene (12 mL) was added under ice-cooling. 5.5 g of aluminum chloride are then added over 5 minutes. The mixture was stirred at room temperature overnight, then poured onto ice, basified with sodium hydroxide, extracted with methylene chloride, dried over anhydrous magnesium sulfate. The methylene chloride was evaporated under reduced pressure and the resulting crude product (6 g) was purified by silica gel column chromatography (eluent: methylene chloride: methanol = 9: 1) to give 1 g of the free base which was converted to the hydrochloride salt by conventional procedure. The product of formula Ia is obtained in the form of a hygroscopic amorphous material. Melting point: amorphous Formula: C25H30N2O2 * HCl

NMR (CDCl ₃ ) δ:

1.00 ~ 4.28 (20H, m), 7.04 ~ 6.68 (8H, m), 7.72 ~

8.00 (2H, m)

MS: (Μ + 1Ί

391

- 21 • · · · · · · ♦ ·· * · ·······················•

Example 7

1- (2- [1- (Benzyl) piperidyl) ethyl] -1,4-benzylpyrrolidin-2-one hydrochloride Compound (14)

0.58 g of 1- {2 - [(1-benzyl) piperidyl] ethyl} -4-benzoylpyrrolidin-2-one is dissolved in 10 ml of methanol and 60 mg of sodium borohydride are added at room temperature. The mixture was stirred for 10 minutes. The methanol was evaporated under reduced pressure and water was added to the residue. Extract with methylene chloride, dry over anhydrous magnesium sulfate, evaporate the methylene chloride under reduced pressure, and purify by silica gel column chromatography (eluent: methylene chloride: methanol = 9: 1) to obtain 0.41 g of the alcohol. in the form of a viscous oil which is a mixture of the two isomers and which is used without further separation in the reaction.

0.41 g of the alcohol derivative obtained above is dissolved in 5 ml of pyridine and 0.22 mg of p-toluene chlorothionoformate is added at room temperature. The mixture was stirred for three hours and then water was added. Extract with ethyl acetate, dry over anhydrous magnesium sulfate, evaporate the ethyl acetate under reduced pressure, and purify by silica gel column chromatography (eluent: methylene chloride: methanol = 95: 5) to give 0.4 g of a thiocarbonate oil. form.

0.39 g of the ticarbonate derivative prepared above are dissolved in 9 ml of toluene and 0.5 ml of tributyltin hydride and a catalytic amount of 2,2'-azobisobutyronitrile are added. The mixture was heated at 70-80 ° C for eight hours. The toluene was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: methylene chloride: methanol = 9: 1) to give 0.12 g of the free base, which was converted to the hydrochloride salt by conventional means. . Melting point: amorphous Molecular formula: C25H32 ^N ° 2 'HC1

NMR (CDCl ₃ ) δ:

1.16 - 3.48 (20H, m), 3.52 (2H, s), 7.00 - 7.40 (10H, m)

MS: M + - 376 (FD)

Example 8

3- <2- [1- (1,3-Dioxolan-2-ylmethyl) -4-piperidin-1-yl] -S-methoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione hydrochloride / Compound 15

1.8 g of 1- (2-amino-6-methoxyphenylcarbonyl) imidazole and 2.14 g of 1- (1,3-dixolan-2-ylmethyl) -4- (2-aminoethyl) Piperidine was dissolved in 150 ml of tetrahydrofuran and stirred at room temperature for two hours. The solvent was evaporated and the residue was dissolved in THF (100 mL). To the solution was added 3.7 g of N, N'-carbonyldiimidazole and refluxed overnight. The solvent was evaporated and methylene chloride was added to the residue. Wash with water and dry over anhydrous magnesium sulfate. After filtration, the solvent was evaporated and the oily product obtained was purified by silica gel column chromatography. This gave a white crystalline product which was converted to the hydrochloride salt by conventional means to give 1.6 g of the desired product as an amorphous material.

···· * ♦ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ·

- 23 Formula: C 20 H 27 ^N 3 ° 5 ' ^HCl

NMR (CDCl 3) δ:

1.20 - 2.20 (9H, m), 2.60 (2 H, d); 2.98 (2 H, d); 3.69 - 4.20 (6H, m), 3.97 (3H, s); 5.03 (1H, m), 6.56 - 6.74 (2 H, m), 7.50 (1H, dd)

MS: (Μ + Γ) »390

Example 9

3- (2- (1- (1,3-Dioxolan-2-ylmethyl) -4-piperidyl) ethyl · -1,2,3,4-tetrahydroquinazolin-2-one hydrochloride (16) Dissolve 1.04 g of 1- (1,3-dioxolan-2-ylmethyl) -4- (2-aminoethyl) piperidine in 1 ml of methanol and add 1.47 g of

2-amino-5-methoxybenzaldehyde in 30 ml of methanol. The mixture was stirred at room temperature for 30 minutes and then cooled in ice. The reaction mixture was quenched by the addition of sodium borohydride in small portions. The solvent was evaporated and water was added to the residue. Extract with ethyl acetate, dry over anhydrous magnesium sulfate, evaporate the solvent, and dissolve the resulting oil in 30 mL of tetrahydrofuran. To the solution was added 2.42 g

N, N'-carbonyldiimidazole and reflux for two and a half hours. The solvent was evaporated and the resulting oily material was purified by silica gel column chromatography. The product was converted to the hydrochloride salt by conventional means to give 0.19 g of the desired product as a light yellow amorphous material.

Melting point: amorphous Molecular formula: C2o ^H 29 ^N 3 ^o 5 ' ^Hc ^ ·· * ··· · * ·

4 ·

2.4

NMR (CDCl ₃ ) δ:

1/20 - 1.38 (3H, m), 1.52 - 1.54 (2H, bq), 1.71 (2H, bd), 2.04 (2H, t, J = 9.2Hz), 2.54 (2H, d, J = 4.6Hz), 2.97 (2H, bd), 3.44 (2H, t, J = 7.4Hz), 3.66 (3H, s), 3.80 - 3.84 (2H, m), 3.92 - 3.95 (2H, m), 4.99 (1H, t, J = 4.6Hz), 6.57 (1H, d, J = 3.2Hz), 6.62 (1H, d, J = 8.4Hz) 6.70 (1H, q, J = 3.2Hz, 8.4Hz) (M + 1 ⁺ ) = 376

Example 10

3- (2-Γ1- (1,3-dioxolan-2-ylmethyl) -4-ethyl-piperidil1 · -

-1,2,3,4-Tetrahydroquinazoline-2,4-dione hydrochloride (17) Dissolve 0.83 g of 1- (1,3-dioxolan-2-ylmethyl) -4- (2- aminoethyl) piperidine and 0.93 g of 1- (2-amino-5-methoxyphenylcarbonyl) imidazole is added. The mixture was stirred, N, N'-carbonyldiimidazole (1.26 g) was added and the mixture was refluxed for ninety hours. The solvent was evaporated and the resulting oily material was purified by silica gel column chromatography. The product was converted to the hydrochloride salt by conventional means to give 0.30 g of the desired product as a pale yellow amorphous material.

Melting point: amorphous Formula: C20 ^h 27 ⁿ 3 ° 5 ' ^hc

NMR (CDCl ₃ ) δ:

1.36 (3H, bs) 1.59 - 1.64 (2H, m), 1.76 (2H, bd) 2.05 (2 H, bt) 2 | , 53 (2H, d, J = 4.6Hz), 2.98 (2 H, bd), 3.80 ~ 3, 83 (2H, m), 3.83 (3H, s),

·· ···· · ·· · · 9 · · · · · · · · · · · · · · · · · · · · · ···

- 25 3.91 - 3.93 (2, m), 4.08 (2H, bt), 4.98 (1H, t, ^J - 4.6Hz), 7.04 (1H, d, J - 8 , 8Hz), 7.18 (1H, q,

J - 2.8Hz, 8.8Hz), 7.49 (1H, d, J - 2.8Hz), 11.05 (1H, bs)

MS: (M + H +)> 390

11-34. example

The products listed below are shown in Figures 1-10. is prepared as described in Example 3b.

Compound 18 (Example 11)

Melting point: amorphous

^C 27 ^H 33 ^N 3 ° ' ^HCl

NMR (CDCl ₃ ) δ:

1.2 - '2.1 (9H, m), 2.31 (4H, bs), 2.78 (4H, bd), 3.41 (2 H, s), 3.67 (3H, s), 3.90 (2H, bt), 7.02 7.46 (9H, m) MS: M * = »415 (FD)

Compound 19 (Example 12)

Melting point: amorphous

^C 22 ^H 28 ^N 2 ^OS 'HCl

NMR (CDCl 3 ·) δ:

1.18 - 2.01 (9H, m), 2.26 - 2.30 (4H, m), 2.68 2.88 (4H, m), 3.41 (2H, s), 3.67 (2H, bt), 6.79 (1H, d, J = 5.7Hz), 7.00 (1H, d, J = 5.7Hz), 7.18 (5H, s)

MS: M + = 368 (FD) (20) (Example 13)

Melting point: amorphous

Total formula: C23H2gN3O'2HCl ···· «

··· · ··· • · ··· · · *

- - ··· ···· t * ··

MS: (Μ + Γ) - 364 (FAB)

NMR (CDCl 3):

1.20 ~ 1, 86 (9H , m) , 2 .24 - 2.29 (4H, m), 2.59 2.81 (4H, m) , 3 43 (2 H t s) t 4.05 (2 H, bt), , 7.01 (1H, dd, J = 4th 9, 1 5Hz), 7.20 (5H, s); 7.46 (1H, dd, J = 8 Hz, 1 5Hz), 8.29 (1H, dd, j =: 1.8Hz , 4 »9 Hz)

Compound 21 (Example 14)

Melting point: amorphous

^C 27 ^H 32 ^N 4 ° C ^HCl

NMR (CDCl ₃ ) δ:

1.24 - 2.04 (11H, m), 2.18 (3H, s), 2.83 (2H, bd), 3.37 - 3.48 (4H, m), 3.64 (3H, s), 6.96 7.36 (8H, m), 7.62 (1H, dd, J = 2.8Hz, 5.5Hz)

MS: (Μ + Γ) = 429 (FAB) Compound 23 (Example 15)

Melting point: amorphous

C21H25N2O3 * HCl

NMR (CDCl3) δ:

1.28 - 2.04 (9H, m), 2.85 (2H, bd), 2.45 (2H, s),

- 2.50 (2H, t, J = 7.3Hz), 4.49 (2H, s), 7.02 -

7.32 (7H, m), 8.24 (1H, dd, J = 2.1Hz, 4.1Hz)

MS: (Μ + Γ) = 352 (FAB)

27 '(27).

example) ♦ ··· * · *:; ··· s * ·· * * ··· · * ·· * * · · · · · · · · · ·

Melting point: amorphous

Molecular formula: C23H26 ^N ° 2 ^'HC ^ ·

NMR (CDCl 3) δ:

bd), (2H,

1.18

3.47 (2H, s),

2.11 (9 H, m), 2.85

3.76 (2 H, t, J ”7.3Hz), 4.78 (1H, d, J = 2.3Hz) 5.14 (1H, d. J = 2.3Hz), 7.24 (5H, s), 7.38 - 7.81 (4H, m)

(FAB)

MS: (Μ + Γ) = 347 (Example 17)

Melting point: 176.2-176.8 ° C

C21H24N2O2-0411404

NMR (CDCl 3) δ:

1:31 - 1.36 (3H, m), 1.69 - 1.76 (4H, m), 1.95 (2 H, bt), 2.88 (2H, bd), 3.49 (2H r S) _z 3.85 (2H, t, J = 7, 4Hz), 6.95 (1H, d, J = 7 j 6Hz) , 7.10 - 7.31 (8H, m)

MS: (Μ + Γ) = 337 (FAB) (58) (Example 18)

Melting point: 261-263 ° C (dec.)

Formula: C21H25N3O2-HCl

NMR (CDCl ₃ ) δ:

1.16 - 2.26 (7H, m), 2.48 (3H, s), 2.76 - 3.05 (2H, m), 3.32 (2H, d), 3.54 (2H, s), 4.48 (2H, s), 6.92-7.34 (7H, m)

MS: M + = 351 (FD) Compound 60 (Example ¹⁹ )

Melting point: 250-252 ° C (dec.)

Formula: C20H23N3O2-HCl

NMR (CDCl ₃ ) ¢:

1.60 - 2.40 (6H, m ) 2.48 (3H, s), 2.84 - 3.12 (2 H, m), 3.52 (2H, s) , 4, 04 - 4.32 (1H, m), 4.41 (2 H, s), 6.88-7, 16 (2 H, m), 7.25 (5H, bs)

MS: M '- 337 (FD) Compound 61 (Example ²⁰ )

Melting point: 210-213 ° C (dec.)

C22 ^H 27 ^N 3 ° 2 ' ^HC ^ ·

NMR (CDCl ₃ ) δ:

1.16-2.15 (9H _Z m), 2.48 (3H, s), 2.70-2.96 (2H, m), 3.45 (2H, s), 3.47 (2H, t), 4.44 (2H, s), 6.80-7.40 (7H, m)

MS: M + 1 * = 366 (FAB) (62) (Example 21)

Melting point: 183-184 ° C (dec.)

C 21 H 26 ^N 4 ° 2 · 3/2 ^C 4 H 4 ^O 4

NMR (CDCl 3) δ:

1.08 - 2.20 (9H, m), 2.49 (3H, s), 2.64 - 2.96 (2H, m), 3.44 (2H, s), 3.50 (2H, t), 4.47 (2H, s), 6.88-7.30 (4H, m), 8.44 (2H, d)

MS: M '+ 1 = 367 (FAB) (63) (Example 22)

Melting point: 111 ° C

Formula: C19H27N3O4

NMR (CDCl ₃ )

1.27-1.80 (7H, m), 2.08 (2H, t), 2.53 (3H, s),

2.57 (2H, d), 2.99 (2H _z d) _z 3.55 (2 H, t) _z 3.80 4.04 (4H, m), 4.51 (2 H, s); 5.00 (1H, t) _z 7.06 (1H, d), 7.24 (1H, d)

MS: M '+ 1 = · 362 (FAB) Compound 64 (Example ²³ )

Melting point: 70 ° C: C 22 H 25 N 3 O 3 · HCl

NMR (CDCl ₃ ) δ:

1.24 - 1.40 ( 3H, m) , 1.62 - 1.84 (4H, m), 1.88 - 2.05 (2H, t), 2.70 (3H, s), 2.87 (2H, d), 3.48 (2 H, s), 4.09 (2 H, t), 7.20 - Ί, 3 16 (5H, m) , 7.48 (1H, d), 7.53 (1H, d) MS: M + 1 = 380 (FAB)

(Example 24) Compound 65

Melting point: 233-235 ° C

C23H26N2O2 * HCl

NMR (CDCl ₃ ) δ:

1.44

-2.28 (6 H, m), 2.60

- 3.08 (4H, m),

3.32 4.24 (6H, m), 7.12 - 7.72 (8H, m), 7.76 8.00 (2H,

m)

MS: (Μ + Γ) = 363 (FAB) Compound 66 (Example 25)

Melting point: 158-160 ° C (born).

Formula: ^C 13 ^H 26 ^N 4 ° 3 ' ^C 4 ^H 4 ^O 4

NMR (CDCl ₃ ) δ:

1.78 (2H,

m),

t),

1.20

8.20

~ 1, 40 (3H, m), 1.47 ~ 1, 60 (2H, m), 1.65 (2 H, m), 2.00 - 2.13 (2 H, br t), 2.53 - 2, d); 2.93 - 3.03 (2 H, d); 3.40 - 3.50 (2H, 3.80 - 4.00 (4H, m), < 1.41 (2H, s) , 4.98 (1H 6.80 - 6.87 (1H, dd) 7.31 - 7.37 ( _1HZ m), - θ, 27 (1H, m), 9.08 (1H, s)

MS: (MtI *) = 347 (FAB) · · (67) (Example 26)

M.p. 262-263 ° C (bor.): 013 ^ 4 ^ 04 · 2HCl

NMR (CDCl 3) δ:

1.30 - 1.45 (2 H, m) , 1.50 - 1.85 (5H, m), 00.00 - 2.15 (2H, br t); 2, 52 ~ 2.60 (2 H, d); 2 _; 95 - 3.05 (2 H, br d), 3.80 - 4.15 (6H, m), 5.01 (1H, t), 7.20 ~ 7.27 (1H, m) , 8.42 - 8.47 UH, m), 8.70- 8.75 (1H, m) , 10, 96 (1H, br s)

MS: (M + 1 *) = 361 (FAB) (68) (Example 27)

Melting point: 166-168 ° C

Formula for C19H24N4O6 · ΗΟ1

NMR (CDCl 3) δ:

1.25 - 1.4 5 (2H, m), 1.50-1.80 (5H, m), 2.00 - 2.13 (2 H, br t), 2.53 - 2.60 (2H, d), 2.95 - 3.05 (2 H, br d) , 3.80 - 4.15 (6H, m), 5.00 UH, t); 7.34 (1H, t), 8, 50-8.55 (1H, dd), δ , 55 - 8.60 (1H, dd) 10.43 (1H, br s)

MS: (M + 1 *) = 405 (FAB) Compound 69 (Example 28)

Melting point: 235-238 ° C (dec.)

Formula: C21H22F2N4O2 * 2HCl

NMR (CDCl ₃ / CD ₃ OD) δ:

1.08 - 2.24 (9H, m), 2.64 3.04 (2 H, m), 3.48 (2H, s), 3.92 - 4.24 (2 H, m), 6.52 - 7.00 (3H, m), 7.12-7.40 (1H, dd), 8.32 - 8.52 (1H, dd) 8.56 - 8.72 (1H, dd) (M + V) = 401 (FAB)

- 3 'ί - (70) compound (Example 29) Melting point: 245-247 C. ^e Calc'd: C23H26N4O2'HCl (dec.)

NMR (CDCl) o:

1.08 - 2.24 (9H, m), 2.76 - 3.28 (4H, m), 3.80 - 4.20 (2H, m), 6.04 - 6.64 (2H, m) , 7.00 - 7.40 (6H, m), 8.24 - 8.48 (1H, dd), 8.56 - 8.76 (1H, dd)

MS: (M + 1 *) = 391 (FAB) (71) ( ^{Example 30} * ⁾

Melting point: 182-184 ° C

C20H23N5O2 * 0411404

NMR (CDCl-) δ:

1.08 - 2.28 (9H, m), 2.64 - 3.00 (2H, m), 3.44 (2H, s), 3.84 ~ 4.20 (2H, m), 7, 00 - 7.36 (3H, m), 8.24 - 8.80 (4H, m)

MS (M * + l) = 366 (FAB) (72) A compound of formula f · P ® ^{31 see} a)

Melting point: 220 ° C (dec.)

Formula: C21H23FN4O2 · 2HCl

NMR (CDCl ₃ ) δ:

1.04 - 2.24 (9H, m), 2.68 - 3.04 (2H, m), 3.44 (2H, s), 3.88-4.24 (2 H, m), 6.76- 7.36 (5H, m), 8.28 ~ 8.48 (1H, dd) 8.60 ~ 8.76 (1H, m) MS: (M + 1 *) = 383 (FAB) Compound (73) t (Example 32) Melting point: 220-222 ° C (dec ·) C21H24N4O2 • 2HC1

• «

- 32 NMR (CDCl3) δ:

1.00 - 2.20 (9H, m), 2.60 - 3.00 (2H, m), 3.44 (2H, s), 3.88 - 4.20 (2 H, m), 7, 08 to 7.36 (6H, m), 8.28 - 8.48 (1H, dd) 8.60 - 8.76 (1H, dd)

MS: (M + 1 *) &lt; 36 &gt; (FAB) (74). Compound (Example ³³ )

Melting point: amorphous

Formula: C27H34N2O3 · HCl

NMR (CDCl ₃ ) δ:

1.04 ~ 2.20 (12H, m), 2.56 - 3.00 (4H, m), 3.12 -

3.80 (6H, m), 3.88 - 4.32 (3H, m), 6.72 - 7.72 (9H, m)

MS: (M + = 434 (FD) 75). Compound (Example ³⁴ )

Melting point: amorphous

C27H34N2O3-HCl

NMR / CDCl,) He:

1.00 -2.40 (12H, m), . 2.48-3 04 (4H, m), 3.08 - 4.28 (9H, m), 6.80 - 7.00 (2H, d); 7.08 - 7.36 (5H, m), 7.72-7.96 (2H, d) MS: M * = 434 (FD)

• ·

PREPARATION

Γ (N-Benzyl-N-methyl) -5-aminophenyl-6-methoxy-2H-3,4-dihydro-1,3-benzoxazin-2-one fumarate / Compound 81 is dissolved in 1 ml of methanol. 62 g of 1-benzyl-1-methyl-1,5-diaminopentane and stirred at room temperature. 0.98 mL of 5-methoxysalicylaldehyde was added and the mixture was stirred for 20 minutes. The reaction mixture was cooled on ice and sodium borohydride was added in small portions until the reaction mixture turned pale yellow. After stirring for an additional 30 minutes at room temperature, the solvent was evaporated. The residue was saturated with aqueous sodium bicarbonate and ethylΒ · ···· ···· · · · *

Β · · · · ·

Β · «« · ♦ ♦ ♦ ♦ ♦

acetate was added and the mixture was stirred well. The organic phase was separated. The physical phase was extracted with ethyl acetate. The organic layer and the extract were combined and washed with brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was dissolved in tetrahydrofuran (30 mL). N, N-carbonyldiimidazole (1.91 g) was added and the solution was refluxed for 3 hours. The solvent was evaporated and the oily residue was purified by silica gel column chromatography to give 1.44 g of a colorless oil, which was dissolved in methanol. 0.45 g of fumaric acid dissolved in methanol was added. The solvent was evaporated to give the title product as a colorless amorphous material (1.89 g).

Melting point: amorphous

^C 22 ^H 28 ^N 2 ° 3 ' ^C 4 ^H 4 ° 4

NMR (δ, CDCl 3)

1.33-1.41 (2H, m), 1.52-1.70 (4H, m),

2.18 (3H, s), 2.36 (2H, t, J = 7.4 Hz),

3.45 (2H, t, J = 7.6 Hz), 3.47 (2H, s), 3.78 (3H, s), 4.41 (2H, s), 6.59 (1H, d) , J = 2.8 Hz), 6.80 (1H, dd, J = 2.8 Hz, 8.8 Hz),

6.96 (1H, d, J = 8.8 Hz), 7.21 ~ 7.30 (5H, m)

MS: M ⁺ = 369 (FAB) (M + 1 ⁺ )

The following compound was prepared according to the reference example:

Compound 87 (Example 35)

Melting point: amorphous

(C20H24ClN3O3 * 04) 1404

NMR (δ, CDCl 3) 1.05 (3H, t, J = 7.2 Hz), 1.39 (2 H, the edge S Uvintet), 1.56 (2H, Wide quintet) 1.72 (2H, $ Tá] p £ quintet) 2.44 (2H, t,

J = 7.2 Hz), 2.51 (2H, q, J = 7.2 Hz),

3.64 (2 H, s) , 4.06 (2H, t, , J = 7.6 Hz), 6.15 (1H, d. J = 3.4 Hz), 6.29 (1H, dd, J = 2 , 0 H z, 3.4 Hz), 7.05 (1H, d, J = 8.8 Hz), 7.35 (1H, dd , J = 0.8 Hz, 2.0 Hz), 7.54 (1H, dd , J = 2.4 Hz, 8.8 Hz), 8.10 (1H, d. J = 2.4 Hz)

MS: M ⁺ = 390 (FAB) (M + 1 ⁺ ) · · ·

Claims (6)

Claims A process for the preparation of cyclic amine derivatives of the formula I and their pharmacologically acceptable salts, wherein R ¹ is (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (1) , (m), (n), (o), (p), (q) or (r), U is hydrogen, halogen, lower alkyl, lower alkoxy or nitro, 1 is 1, n is 0 to 10, integer, Z is a group of formula (o () or (β) wherein R ² is phenyl, naphthyl, mono- or dihalo-phenyl, 1,3-dioxolan-2-yl or pyridyl group, m is 0-2, integers, q is 0-2, integers, R ³ is hydrogen or lower alkyl, R ⁴ is furyl or thienyl, p is 0-2, integer provided that when R ^{1 is a} quinazolinone or quinazolinedione, R ² and R ⁴ are other than aryl or substituted aryl, • * · - 37 ~ (a) condensing a benzazepinone of formula (II) with a compound of formula (III), or b) ^this 9Y ^(v) a N-acyl derivative or diester of formula (VIII) is condensed with an amine of formula (VI), or c) condensing a benzaldehyde derivative of formula XXI with an amine of formula VI and then cyclizing the resulting product; or d) condensing an amine of formula (XXVII) with an acid of formula (XXVIII), reducing the resulting product and cyclizing and, if desired, converting the resulting compound of formula (I) into a pharmacologically acceptable salt. Process for the preparation of the cyclic amine derivatives of the formula I and their pharmacologically acceptable salts according to claim 1, wherein Z is a group of the formula (ex), characterized in that the appropriate starting materials are used. A process for the preparation of a cyclic amide derivative of the formula (I) and its pharmacologically acceptable salts according to claim 1, wherein Z is a group of the formula (O), R ² is a phenyl, pyridyl or 1,3-dioxolan-2-yl group. , n is 1 or 2 and m is 1 or 2, characterized in that the appropriate starting materials are used. The process for the preparation of the cyclic amide derivatives of the formula (I) and their pharmacologically acceptable salts according to claim 1, wherein Z is (δ () general). R ² is phenyl, pyridyl, or a group of the formula: 1,3-dioxolan-2-yl, n is 1 or 2, m is 1 or 2, and R ¹ is 1,2,3,4-tetrahydroquinazoline-2,4-dione, 1,2,3 , 4-Tetrahydroquinazolin-2-one, 1,2,3,4-tetrahydropyrido [3,2-d] pyrimidine-2,4-dione, 1,2,3,4-tetrahydropteridine-2,4-dione or 1,2,3,4-tetrahydropyrido [3,2-d] pyrimidinone, characterized in that the appropriate starting materials are used. A process for the preparation of a cyclic amide derivative of the formula (I) and its pharmacologically acceptable salts according to claim 4, wherein R ^{1 is} lower alkyl or lower alkoxy substituted with appropriate starting materials. The process for the preparation of the cyclic amide derivatives and their pharmacologically acceptable salts of the formula (I) according to claim 4, wherein R ^{1 is a} methoxy substituted group, characterized in that the appropriate starting materials are used.